Cryoablation

Number: 0100

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Scope of Policy

This Clinical Policy Bulletin addresses cryoablation.

  1. Medical Necessity

    Aetna considers cryoablation medically necessary for the following:

    1. Adrenal gland metastases (up to 4-cm in size)
    2. Cervical intraepithelial neoplasia
    3. Cryoablation of the prostate for prostate cancer as a primary therapy alternative to surgery or irradiation in individuals with localized disease (T1 or T2 [organ confined] or T3 [locally advanced]) or as salvage therapy for recurrent cancer following failure of radiation therapy
    4. Cryoablation of a renal mass for either confirmed or suspected renal cell carcinoma, up to 4-cm in size, when any of the following criteria is met:

      1. Persons who are considered high-risk surgical candidates; or
      2. Persons with renal insufficiency, as defined by a glomerular filtration rate of less than or equal to 60 ml/min/m2; or
      3. Persons with a solitary kidney
    5. Cryoablation (e.g., cryoballoon) for the treatment of atrial fibrillation, with evidence of a localized site(s) of origin when the tachycardia is drug-resistant or the member is drug- intolerant or does not desire long-term drug therapy (e.g., pulmonary vein isolation procedures)
    6. Desmoid tumor (aggressive fibromatosis)
    7. Esophageal dysplasia
    8. Fibro-adipose vascular anomaly (FAVA) lesions
    9. Low-risk superficial basal cell carcinoma, and squamous cell carcinoma in situ (Bowen disease), where surgery or radiation is contraindicated or impractical
    10. Malignant endobronchial obstruction
    11. Metastatic hemangiopericytoma to the lung if member is not a surgical candidate; and has less than 5 small metastases that are each less than 3 cm in diameter
    12. Osteoid osteoma when treatment with salicylates or non-steroidal anti-inflammatory drug has failed
    13. Painful bone metastases (with size of less than or equal to 2 cm) from any cancer/malignancy
    14. Painful vascular tumors (epithelioid hemangiomas)
    15. Palliation of symptomatic spinal metastases refractory to radiation therapy
    16. Peri-renal liposarcoma for debulking to relieve pain
    17. Pulmonary metastatic lesions if member is not a surgical candidate, and has 6 or less lesions that are each less than 4 cm in diameter
    18. Retinal dialysis
    19. Sacral chordomas that are less than 10 cm in size
    20. Soft tissue sarcoma of the extremities or the trunk in symptomatic persons with disseminated metastases.
  2. Experimental and Investigational

    Aetna considers interventions experimental and investigational because the effectiveness of these approaches has not been established:

    1. Cryoablation of the prostate for members with benign prostatic hypertrophy
    2. Cryoablation of breast carcinoma and fibroadenoma
    3. Cryoablation for the following (not an all-incusive list): 

      1. Abdominal wall arterio-venous malformation
      2. Abdominal wall endometriosis (endometrioma)
      3. Allergic and non-allergic rhinitis (e.g., by means of the ClariFix device)
      4. Barrett's esophagus without dysplasia
      5. Benign prostatic hypertrophy
      6. Bone and soft tissue tumors
      7. Breast carcinoma and fibroadenoma
      8. Cancer pain
      9. Chronic headache
      10. Colon cancer (other than hepatic metastases)
      11. Cutaneous sporotrichosis in pregnant women
      12. Drooling
      13. Endometrial cancer
      14. Esophageal cancer
      15. Facet joint pain
      16. Hookworm-related cutaneous infection
      17. Idiopathic ventricular tachycardia (VT)
      18. Intercostal nerves for post-operative analgesia after placement of left ventricular assist device / video-assisted thoracoscopic surgery
      19. Knee pain
      20. Leiomyosarcoma
      21. Lipoma
      22. Metastatic hepatocellular carcinoma
      23. Morton's neuroma
      24. Neuroendocrine tumors (other than hepatic metastases)
      25. Neuroma
      26. Non-small cell lung cancer (other than malignant endobronchial obstruction)
      27. Pancreatic cancer
      28. Pathologic compression fracture due to multiple myeloma
      29. Peripheral nerve damage in the lower extremity
      30. Plantar fibroma
      31. Pleural lesions
      32. Post-infarction VT
      33. Premature ejaculation
      34. Reduction of pain or opioid consumption after total knee arthroplasty
      35. Residual facial arterio-venous malformations
      36. Retinopathy of prematurity
      37. Retroperitoneal soft-tissue sarcoma
      38. Sacroiliac joint pain
      39. Spinal giant cell tumors
      40. Talc granuloma pain
      41. Tuberous sclerosis-associated renal angiomyolipoma
      42. Venous malformations.
    4. Spray cryotherapy for the treatment of subglottic stenosis and cervical tracheal stenosis because of insufficient evidence
    5. Endoluminal cryoablation for the treatment of symptomatic varicose veins because of insufficient evidence.
  3. Related Policies


Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes covered if selection criteria are met:

Cryoablation of adrenal gland, epithelioid hemangiomas, desmoid tumor cryoablation, spinal metastases cryoablation - no specific code
0441T Ablation, percutaneous, cryoablation, includes imaging guidance, lower extremity distal/peripheral nerve
20982 Ablation therapy for reduction or eradication of 1 or more bone tumors (eg, metastasis) including adjacent soft tissue when involved by tumor extension, percutaneous, including imaging guidance when performed; radiofrequency
20983 Ablation therapy for reduction or eradication of 1 or more bone tumors (eg, metastasis) including adjacent soft tissue when involved by tumor extension, percutaneous, including imaging guidance when performed; cryoablation
31641 Bronchoscopy (rigid or flexible); with destruction of tumor or relief of stenosis by any method other than excision (e.g., laser therapy, cryotherapy)
32994 Ablation therapy for reduction or eradication of 1 or more pulmonary tumor(s) including pleura or chest wall when involved by tumor extension, percutaneous, including imaging guidance when performed, unilateral; cryoablation
33254 Operative tissue ablation and reconstruction of atria, limited (eg, modified maze procedure)
33256 Operative tissue ablation and reconstruction of atria, extensive (eg, maze procedure); with cardiopulmonary bypass
+ 33257 Operative tissue ablation and reconstruction of atria, performed at the time of other cardiac procedure(s), limited (eg, modified maze procedure) (List separately in addition to code for primary procedure)
+ 33259 Operative tissue ablation and reconstruction of atria, performed at the time of other cardiac procedure(s), extensive (eg, maze procedure), with cardiopulmonary bypass (List separately in addition to code for primary procedure)
43229 Esophagoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide wire passage, when performed) [not covered for cryoablation of Barrett's esophagus or malignant neoplasm of esophagus]
43270 Esophagogastroduodenoscopy, flexible, transoral; with ablation of tumor(s), polyp(s), or other lesion(s) (includes pre- and post-dilation and guide wire passage, when performed) [not covered for cryoablation of Barrett's esophagus or malignant neoplasm of esophagus]
50250 Ablation, open, 1 or more renal mass lesion(s), cryosurgical, including intraoperative ultrasound guidance and monitoring, if performed
50593 Ablation, renal tumor(s), unilateral, percutaneous, cryotherapy
55873 Cryosurgical ablation of the prostate (includes ultrasonic guidance for interstitial cryosurgical probe placement)
57511 Cautery of cervix; cryocautery, initial or repeat
64600 Destruction by neurolytic agent, trigeminal nerve; supraorbital, infraorbital, mental, or inferior alveolar branch [cryoablation of chronic headaches]
67101 Repair of retinal detachment, including drainage of subretinal fluid when performed; cryotherapy
67107 Repair of retinal detachment; scleral buckling (such as lamellar scleral dissection, imbrication or encircling procedure), including, when performed, implant, cryotherapy, photocoagulation, and drainage of subretinal fluid
67108 Repair of retinal detachment; with vitrectomy, any method, including, when performed, air or gas tamponade, focal endolaser photocoagulation, cryotherapy, drainage of subretinal fluid, scleral buckling, and/or removal of lens by same technique
+93657 Additional linear or focal intracardiac catheter ablation of the left or right atrium for treatment of atrial fibrillation remaining after completion of pulmonary vein isolation (List separately in addition to code for primary procedure)

CPT codes not covered for indications listed in the CPB:

Cryoablation, Cryoablation with ClariFix device, spray cryotherapy, knee pain and venous malformation cryoablation - no specific code:

0581T Ablation, malignant breast tumor(s), percutaneous, cryotherapy, including imaging guidance when performed, unilateral
19105 Ablation, cryosurgical, of fibroadenoma, including ultrasound guidance, each fibroadenoma
32998 Ablation therapy for reduction or eradication of 1 or more pulmonary tumor(s) including pleura or chest wall when involved by tumor extension, percutaneous, radiofrequency, unilateral [cryoablation for nonobstructive non-small cell lung cancer]

Other CPT codes related to the CPB:

17000 - 17286 Destruction, benign or premalignant lesions, or malignant lesions, any method
47371 Laparoscopy, surgical, ablation of one or more liver tumor(s); cryosurgical
47381 Ablation, open, of one or more liver tumor(s); cryosurgical
58353 Endometrial ablation, thermal, without hysteroscopic guidance
58356 Endometrial cryoablation with ultrasonic guidance, including endometrial curettage, when performed
58563 Hysteroscopy, surgical; with endometrial ablation (e.g., endometrial resection, electrosurgical ablation, thermoablation)
77013 Computed tomography guidance for, and monitoring of, parenchymal tissue ablation
77022 Magnetic resonance guidance for, and monitoring of, parenchymal tissue ablation

HCPCS codes not covered for indications listed in the CPB:

C9771 Nasal/sinus endoscopy, cryoablation nasal tissue(s) and/or nerve(s), unilateral or bilateral

Other HCPCS codes related to the CPB:

C1886 Catheter; extravascular tissue ablation, any modality (insertble)
C2618 Probe/needle, cryoablation

ICD-10 codes covered if selection criteria are met:

C34.00 - C34.92 Malignant neoplasm of bronchus and lung [malignant endobronchial obstruction]
C41.4 Malignant neoplasm of pelvic bones, sacrum and coccyx
C44.01
C44.111 - C44.119
C44.211 - C44.219
C44.310 - C44.319
C44.41
C44.510 - C44.519
C44.611 - C44.619
C44.711 - C44.719
C44.81
C44.91
Basal cell carcinoma [covered for low risk, superficial basal cell carcinoma where surgery or radiation is contraindicated or impractical]
C49.10 - C49.6 Malignant neoplasm of connective and other soft tissue [soft tissue sarcoma of extremities and trunk in symptomatic persons with disseminated metastases] [not covered for leiomyosarcoma]
C61 Malignant neoplasm of prostate
C64.1 - C64.9 Malignant neoplasm of kidney, except renal pelvis [renal cell carcinoma - see criteria] [peri-renal liposarcoma]
C65.1 – C65.9 Malignant neoplasm of renal pelvis
C72.0 Malignant neoplasm of spinal cord
C78.00 - C78.02 Secondary malignant neoplasm of lung
C79.49 Secondary malignant neoplasm of other parts of nervous system
C79.51 Secondary malignant neoplasm of bone
C79.70 - C79.72 Secondary malignant neoplasm of adrenal gland
C79.82 Secondary malignant neoplasm of genital organs [prostate]
D02.20 - D02.22 Carcinoma in situ of bronchus and lung
D04.0 - D04.9 Carcinoma in situ of skin [covered for squamous cell - Bowen's disease where surgery or radiation is contraindicated or impractical]
D06.0 - D06.9 Carcinoma in situ of cervix uteri [cervical intraepithelial neoplasia III (CIN III)]
D07.5 Carcinoma in situ of prostate
D16.0 - D16.9 Benign neoplasm of bone and articular cartilage [when treatment with salicylates or non-steroidal anti-inflammatory drug has failed]
D18.00-D18.09 Hemangioma
D41.10 – D41.12 Neoplasm of uncertain behavior of renal pelvis
D48.1 Neoplasm of uncertain behavior of connective and other soft tissue [extra-abdominal desmoid tumor] [metastatic hemangiopericytoma]
D49.2 Neoplasm of unspecified nature of bone, soft tissue, and skin [extra-abdominal desmoid tumor]
H33.041 – H33.049 Retinal detachment with retinal dialysis
I48.0 - I48.2, I48.91 Atrial fibrillation
K22.710 - K22.719 Barrett's esophagus with dysplasia
N28.89 Other specified disorders of kidney and ureter [Renal mass]
N87.0 - N87.1 Mild and moderate dysplasia of cervix (cervical intraepithelial neoplasia I and II [CIN Iand CIN II])
Q27.31 Arteriovenous malformation of vessel of upper limb [fibro-adipose vascular anomaly (FAVA) lesions] [not covered for residual facial arterio-venous malformations]
Q27.32 Arteriovenous malformation of vessel of lower limb [fibro-adipose vascular anomaly (FAVA) lesions] [not covered for residual facial arterio-venous malformations]
Q27.8 Other specified congenital malformations of peripheral vascular system [fibro-adipose vascular anomaly (FAVA) lesions] [not covered for residual facial arterio-venous malformations]

ICD-10 codes not covered for indications listed in the CPB:

B42.89 Other forms of sporotrichosis [in pregnancy]
B76.0 - B76.9 Hookworm diseases
C15.3 - C15.9 Malignant neoplasm of esophagus
C18.0 - C20 Malignant neoplasm colon
C22.0 Liver cell carcinoma
C48.0 Malignant neoplasm of retroperitoneum [retroperitoneal soft-tissue sarcoma]
C49.0
C49.8 - C49.9
Malignant neoplasm of connective and other soft tissue [leiomyosarcoma, lipoma/neuroma]
C50.011 - C50.929 Malignant neoplasm of breast
C53.0 - C54.9 Malignant neoplasm endometrium
C7A.00 - C7B.8 Malignant neuroendocrine tumors
C78.2 Secondary malignant neoplasm of pleura
C79.00 - C79.02 Secondary malignant neoplasm of kidney and renal pelvis
C79.81 Secondary malignant neoplasm of breast
D05.00 - D05.92 Carcinoma in situ of breast
D17.0 - D17.9 Lipoma
D21.0 - D21.9 Other benign neoplasm of connective and other soft tissue [plantar fibroma] [neuroma] [bone and soft tissue tumors]
D24.1 - D24.9 Benign neoplasm of breast
D33.3 Benign neoplasm of cranial nerves [acoustic neuroma]
F52.4 Premature ejaculation
G44.021 - G44.029 Chronic cluster headache
G44.221 - G44.229 Chronic tension-type headache
G56.00 - G57.93 Mononeuropathies
G89.3 Neoplasm related pain (acute) (chronic) [Pain after total knee arthroplasty]
G89.18 Other acute postprocedural pain
H35.101 - H35.179 Retinopathy of prematurity
I47.0 - I47.9 Paroxysmal tachycardia [post-infarction, idiopathic]
I80.00 - I80.3 Phlebitis and thrombophlebitis of superficial and deep vessels of lower extremities
I82.401 - I82.4Z9 Acute embolism and thrombosis of deep veins of lower extremity
I82.501 - I82.5Z9 Chronic embolism and thrombosis of deep veins of lower extremity
I82.811 - I82.819 Embolism and thrombosis of superficial veins of lower extremity
I83.001 - I83.029 Varicose veins of lower extremities with ulcer
I83.10 - I83.12 Varicose veins of lower extremities with inflammation
I83.201 - I83.229 Varicose veins of lower extremities with ulcer and inflammation
I83.811 - I83.899 Varicose veins of lower extremities with other complications
I87.001 - I87.099 Postphlebitic syndrome
I87.2 Venous insufficiency (chronic) (peripheral)
J30.0 - J30.9 Vasomotor and allergic rhinitis
J31.0 - J31.2 Chronic rhinitis, nasopharyngitis and pharyngitis
J38.6 Stenosis of larynx
J39.8 Other specified diseases of upper respiratory tract [tracheal stenosis]
K11.7 Disturbances of salivary secretion[drooling]
K22.10 - K22.11 Ulcer of esophagus
L92.0 - L92.9 Granulomatous disorders of skin and subcutaneous tissue [talc granuloma pain]
M25.561 - M25.569 Pain in knee
M45.0 - M54.9 Dorsopathies [facet or sacroiliac joint pain]
M72.2 Plantar fascial fibromatosis [plantar fibroma]
M84.50xA - M84.58xS Pathological fracture in neoplastic disease [pathologic compression fracture due to multiple myeloma]
N40.0 - N40.3 Enlarged prostate
O99.711 –O99.719 Diseases of the skin and subcutaneous tissue complicating pregnancy [sporotrichosis]
Q27.30, Q27.33– Q27.39 Arteriovenous malformation (peripheral) [except vessel of upper and lower limb]
Q27.4 Congenital phlebectasia
Q27.9 Congenital malformation of peripheral vascular system, unspecified
Q31.1 Congenital subglottic stenosis
Q32.1 Other congenital malformations of trachea [tracheal stenosis]
Q85.00 - Q85.09 Neurofibromatosis [multiple neuroma]
S84.00xA - S84.92xS Injury of nerves at lower leg level
T87.30 - T87.34 Neuroma of amputation stump
Z96.651 - Z96.659 Presence of artificial knee joint [Pain after total knee arthroplasty]

Background

Prostate Cancer

Cryosurgical ablation is an established method of treating localized prostate cancer.  In 1996, the American Urological Association revised their policy statement regarding cryosurgical ablation of the prostate to state that they believe that cryosurgical treatment of the prostate should be accepted as one of the methods of management of adenocarcinoma of the prostate.  They indicated that because the long-term curative efficacy of this treatment modality has not been established, when used, appropriate disclosure of facts regarding all other treatments for prostate cancer should be made to the patient.

Endobronchial Obstruction

Cryosurgical ablation has been shown to be an effective method for palliation of symptoms from malignant endobronchial obstruction.  The National Institute for Clinical Excellence (NICE, 2005) assessed cryotherapy for malignant endobronchial obstruction, and concluded that "[c]urrent evidence on the safety and efficacy of cryotherapy for malignant endobronchial obstruction appears adequate to support the use of the procedure provided that the normal arrangements are in place for consent, audit and clinical governance."  The assessment noted that the main aim of the procedure is palliation of symptoms such as cough, dyspnea and hemoptysis.  In 1 case series of 521 patients, 86 % had improvement in one or more symptoms and quality of life scores were significantly improved.  Dyspnea improved in 59 % of patients.  In 2 further studies, dyspnea improved in 71 % and 81 % of patients.  The assessment also noted that cryotherapy does not provide immediate relief of bronchial obstruction and is therefore not suitable for the emergency treatment of acute respiratory distress.

Renal Cancer

Cryotherapy may be used as an alternative to nephrectomy for renal carcinoma in persons who are not surgical candidates.  Incidental detection of solid renal masses during abdominal imaging is increasing in older patients.  Although these masses often are malignant histologically, many are indolent clinically.  A therapeutic option for patients who are poor surgical candidates is cryoablation, in which cryoprobes are inserted percutaneously into the mass, creating an "ice ball" that destroys the tumor.  According to the peer-reviewed medical literature, cryotherapy for ablation of renal cell carcinoma is a promising alternative for persons who are not candidates for total or partial nephrectomy.  Although it is potentially an attractive addition to available nephron-sparing surgical techniques, refinement of MR image guidance and percutaneous techniques for introducing cryogenic probes into the kidneys and other deep abdominal organs must be developed, and long-term data on the effectiveness of cryoablation of renal cell carcinoma are limited.

Cestari et al (2004) reported their experience with laparoscopic renal cryoablation in select cases of small renal neoplasms (n = 37).  They concluded that laparoscopic renal cryoablation for small renal masses appears to be a safe, reproducible, minimally invasive technique.  Medium term follow-up is encouraging, although further studies and prolonged follow-up are needed to access properly the role of this surgical technique.  This is in agreement with the findings of Johnson et al (2004) as well as Moon et al (2004).  Johnson and associates stated that ablation technologies (cryoablation and radiofrequency ablation) appear to have a low complication profile when used to treat small renal tumors.  The majority of complications are minor and require observation only.  Further study and follow-up are needed to determine their long-term effectiveness.  Moon and colleagues concluded that longer follow-up is required to fully define the role of laparoscopic cryoablation for the treatment of small renal tumors.

Desai et al (2005) compared peri-operative and short-term outcomes of laparoscopic partial nephrectomy versus laparoscopic cryoablation in patients with peripheral small renal tumors and concluded that, "[a]lthough the technical simplicity, decreased blood loss, and somewhat lower complication rate are attractive features of renal cryotherapy, this must be balanced against the current lack of long-term follow-up data that are needed to confirm the oncologic adequacy of this developmental procedure."  These findings are consistent with a review by Aron and Gill (2005) on renal tumor ablation methods that stated, "Although the initial outcomes of cryoablation and radiofrequency ablation are encouraging, long-term studies are necessary to confirm their lasting efficacy.  The optimal modality for tumor targeting, monitoring therapy, and follow-up remains to be determined."

Kaouk et al (2006) examined the experimental and clinical evolution of cryotherapy for small renal masses.  The authors stated that the major criticism of this and other ablative techniques is the associated lack of histological confirmation of complete tumor ablation.  They noted that long-term, diligently performed clinical trials that provide detailed, meticulous, sequential 5-year radiological and histological data are needed to confirm lasting effectiveness.  Furthermore, these data must be compared with those related to partial nephrectomy, which remains the reference standard.

Littrup and colleagues (2007) evaluated the results of initial and current techniques for percutaneous renal cryotherapy, including long-term imaging outcomes.  Computed tomography (CT)-guided percutaneous cryotherapy was performed on 49 masses in 48 out-patients and procedure comfort noted for each.  These 49 masses included 36 primary renal cell carcinomas (RCCs), 3 oncocytomas, 1 angiomyolipoma, 6 renal inflammatory lesions, 2 benign parenchymal changes, and 1 colon cancer metastasis.  All complications were graded according to standardized criteria.  Patients received only local anesthesia and moderate sedation during the procedure and were discharged with minimal discomfort within 4 to 6 hours.  All cryotherapy zones were well defined by CT during ablation as hypodense ice with an average diameter of 5.3 cm, covering an average tumor size of 3.3 cm.  Average ablation zone diameters showed significant reduction over time (p < 0.001), becoming significantly less than the original tumor size by 12 months (p < 0.05).  Major and minor complications were seen in 3 (6 %) and 11 (22 %) procedures, respectively.  At a mean follow-up of 1.6 years (range of 1 week to 3.8 years) for primary RCC patients, 4 failures (11.1 %) by imaging criteria were noted, but 1 proved to be inflammatory tissue at re-biopsy (estimated neoplastic failure rate = 3/36 [8.3 %]).  The authors concluded that percutaneous renal cryotherapy is a well-tolerated out-patient procedure that allows safe, CT monitoring of ice formation beyond visible tumor margins.  With appropriate cryoprobe placements, a low failure rate appears less dependent on tumor size or location.  Ablation volume involution was greater than 80 % after 6 months.

Atwell et al (2008) determined technical feasibility, safety and short-term outcomes following percutaneous renal cryoablation.  These investigators performed a retrospective review of 115 renal tumors in 110 elderly patients (mean age 72 years) treated with percutaneous cryoablation.  For most patients, cryoablation was recommended instead of surgery because of substantial medical co-morbidities or prior contralateral nephrectomy.  Mean tumor size was 3.3 cm (range of 1.5 to 7.3 cm), including 29 tumors 4.0 cm or larger and 21 tumors in the anterior kidney.  Of 90 renal mass biopsies performed, 52 (58 %) showed renal cell carcinoma.  All patients were admitted to the hospital following cryoablation and most (87 %) were discharged home the next day (range of 1 to 12 days).  There were 7 major complications associated with the 113 cryoablation procedures (6 %),  including pulmonary embolism, urosepsis, and large hematomas. Technical success (defined as extension of the ice ball beyond tumor margins and no post-ablation contrast enhancement of tumor parenchyma) was achieved in 112 of the 115 (97 %) treated tumors and 3 residual tumors were seen on 3-month follow-up imaging.  There has been no local progression in 80 tumors (100 % treatment success) followed 3 months or longer (mean of 13.3 months). Commenting on this study, Brett (2008) stated that cryoablation is a technically feasible approach for patients with incidentally discovered renal masses who are not good surgical candidates. Brett observed however, that follow-up was relatively brief, and the complication rate was not trivial. Brett noted that because many small renal tumors in older patients progress slowly or not at all, simple observation without intervention is another reasonable option.

Hinshaw and colleagues (2008) compared the outcome, complications, and charges of percutaneous renal cryoablation and laparoscopic cryoablation of solid renal masses.  A total of 30 percutaneous renal cryoablations (mean tumor size of 2.1 cm) in 30 patients (mean age of 67.0 years) and 60 laparoscopic renal cryoablations (mean tumor size of 2.5 cm) in 46 patients (mean age of 67.4 years) were compared.  The size of the tumor, procedural complications, hospital charges, length of hospital stay, and tumor follow-up parameters were recorded.  Monitoring after ablation was performed every 3 months using contrast-enhanced MRI or CT.  Both percutaneous cryoablation and laparoscopic cryoablation of solid renal masses had a high technical success rate (30/30 [100 %] and 59/60 [98.3 %]).  There was no significant difference in the rate of residual disease (3/30 [10 %] and 4/60 [6.7 %], p = 0.68), and the secondary effectiveness rate is 100 % for both groups to date.  One renal mass treated using laparoscopic cryoablation had a local recurrence, but none of the masses treated using percutaneous cryoablation had a recurrence.  The disease-specific survival is 100 % in both groups with no significant difference in the mean follow-up time (14.5 versus 14.6 months, p = 1.0) or major complication rate (0/30 [0 %] versus 3/60 [5.0 %], p = 0.55).  For the treatment of solid renal masses, percutaneous cryoablation was associated with 40 % lower hospital charges (mean of $14,175 versus $23,618, p < 0.00001) and a shorter hospital stay (mean +/- SD, 1.1 +/- 0.3 versus 2.4 +/- 2.1 days; p < 0.0001) than laparoscopic cryoablation.  The authors concluded that although certain tumors require laparoscopic intervention because of the location or size of the tumor, percutaneous renal cryoablation is safe and effective and is associated with lower charges when used for the treatment of small renal tumors.

Finley et al (2008) reviewed their 4-year experience with percutaneous cryoablation and laparoscopy for treating small renal masses.  An in-depth analysis was performed concerning demographics, hospital course and short-term outcome with respect to percutaneous versus laparoscopic cryoablation.  A total of 37 patients underwent treatment for 43 renal masses.  Of the 37 patients 19 underwent laparoscopic cryoablation (24 tumors) and 18 underwent percutaneous cryoablation (19 tumors) using computerized tomography fluoroscopy.  For percutaneous cryoablation a saline instillation was used in 58 % of cases to move non-renal vital structures away from the targeted renal mass.  There were 5 cases of hemorrhage requiring transfusion, all of which were associated with the use of multiple cryoprobes.  The transfusion rate in the percutaneous and laparoscopic cryoablation groups was 11.1 % and 27.8 %, respectively.  Operative time was significantly longer in the laparoscopic cryoablation group compared to the percutaneous cryoablation group at 147 minutes (range of 89 to 209) versus 250.2 (range of 151 to 360) minutes, respectively.  The overall complication rate (including transfusion) was lower in the percutaneous cryoablation group compared to the laparoscopic cryoablation group (4 of 18 [22.2 %] versus 8 of 20 [40 %], respectively).  Hospital stay was significantly shorter in the percutaneous versus laparoscopic cryoablation group at 1.3 versus 3.1 days, p < 0.0001, respectively.  Narcotic use in the percutaneous cryoablation group was more than half that used by the laparoscopic cryoablation group (5.1 versus 17.8 mg, p = 0.03, respectively).  Among patients with biopsy proven renal cell carcinoma during a median follow-up of 11.4 and 13.4 months in the percutaneous and laparoscopic cryoablation groups, cancer specific survival was 100 % and 100 %, respectively, and the treatment failure rate was 5.3 % and 4.2 %, respectively.  The authors concluded that percutaneous cryoablation is an efficient, minimally morbid method for the treatment of small renal masses and it appears to be superior to the laparoscopic approach.  Short-term follow-up has shown no difference in tumor recurrence or need for re-treatment.  Of note, hemorrhage was solely associated with the use of multiple probes.

Weight et al (2008) stated that follow-up after radiofrequency ablation and cryotherapy for small renal lesions lacks pathological analysis.  The definition of successful tumor ablation has been the absence of contrast enhancement on post-treatment magnetic resonance imaging or computerized tomography.  These researchers hypothesized that adding post-ablation kidney biopsy would help confirm treatment success.  From April 2002 to March 2006, a total of 109 renal lesions in 88 patients were ablated with percutaneous radiofrequency ablation and from September 1997 to January 2006 a total of 192 lesions in 176 patients were treated with laparoscopic cryoablation.  Patients were followed with radiographic imaging and post-ablation biopsy at 6 months.  Radiographic success at 6 months was 85 % (62 cases) and 90 % (125) for radiofrequency ablation and cryoablation, respectively.  At 6 months 134 lesions (45 %) were biopsied and success in the radiofrequency ablation cohort decreased to 64.8 % (24 cases), while cryoablation success remained high at 93.8 % (91).  Six of 13 patients (46.2 %) with a 6-month positive biopsy after radiofrequency ablation demonstrated no enhancement on post-treatment magnetic resonance imaging or computerized tomography.  In patients treated with cryoablation all positive biopsies revealed post-treatment enhancement on imaging just before biopsy.  The authors recommend post-radiofrequency ablation follow-up biopsy due to the significant risk of residual renal cell cancer without radiographic evidence, although to their knowledge the clinical significance of these viable cells remains to be determined.  In contrast, radiographic images of renal lesions treated with cryotherapy appeared to correlate adequately with corresponding histopathological findings in our series.

The National Comprehensive Cancer Network's clinical practice guideline for kidney cancer (2008) stated that patients in satisfactory medical condition should undergo surgical excision of stage I through III tumors.  However, a small set of elderly or infirm patients with small tumors may be offered surveillance alone or energy ablative techniques, such as radiofrequency ablation or cryoablation.

An assessment by the National Institute for Health and Clinical Excellence (NICE, 2007) concluded: "Current evidence suggests that cryotherapy for renal cancer ablates tumour tissue and that its safety is adequate.  However, the evidence about its effect on long-term local control and survival is not yet adequate to support the use of this procedure without special arrangements for consent and for audit or research."  The NICE assessment noted that its specialist advisors commented that, because only a small number of patients have been treated with this procedure, long-term efficacy has yet to be established.  The specialist advisors to NICE also noted that the lack of histological data makes it difficult to determine whether total ablation of tumors has been achieved.

There is little evidence for use of cryoablation for large renal masses; larger tumors are more likely to be metastatic.  The NICE guidance on “Percutaneous cryotherapy for renal cancer” (2011) found that the maximum renal tumor size for which cryotherapy is recommended is approximately 4 cm (small, stage I tumors).

Breast Fibroadenomas

Cryoablation has been proposed as an alternative method for management of breast fibroadenomas.  A fibroadenoma is a benign solid lump of breast tissue, which is thought to result from an increased sensitivity to estrogen.  Fibroadenomas are very common and it is not unusual to have more than one.  They are mostly found in young women but can occur in women of any age.  Most fibroadenomas do not enlarge after diagnosis.  Some get smaller and some eventually disappear over time.  Fibroadenomas are usually managed conservatively, with periodic ultrasound evaluation.  Women who are very anxious about the presence of a tumor or who have enlarging masses are often referred for excisional biopsy.  The excised material can be submitted to pathology to confirm the benign diagnosis.

While the use of cryoablation for the treatment of breast fibroadenoma has gained in popularity, there is insufficient published literature to demonstrate the efficacy of this procedure.  Kaufman et al (2002, 2004) reported on the outcomes of cryoablation in 57 patients with breast fibroadenomas.  This study was limited to 12-month follow-up from a single investigator group, and did not include a direct comparison to surgical excision.  Kaufman et al (2005) reported outcomes for cryoablation in 37 treated fibroadenomas with a longer follow-up period of 2.6 years on average.  Of the original 84 % palpable fibroadenomas prior to treatment, 16 % remained palpable to the patient.  Of those fibroadenomas that were initially less than or equal to 2.0 cm in size, 6 % remained palpable.  A median volume reduction of 99 % was observed with ultrasound.  Although this procedure may offer a less invasive method of treating breast fibroadenomas, long-term data on the clinical effectiveness of this procedure versus surgical excision are needed.  Studies of cryoablation of breast carcinomas have been limited to preliminary evaluation studies.  There are no studies directly comparing the effectiveness of cryoablation to surgical incision in treatment of breast carcinomas.  Although cryoablation is less invasive than surgical incision, a key disadvantage of cryoablation is the lack of a tissue sample to examine histologically to ensure adequate surgical margins and complete removal of tumor.

Edwards et al (2004) provided a retrospective summary from a nationwide group of the early experience of cryoablation for the percutaneous treatment of breast fibroadenomas.  The authors concluded that an early community experience with office-based cryoablation of breast fibroadenomas is encouraging and comparable to the initial experience of high-volume tertiary centers.  More follow-up is necessary to determine long-term results and residual mammographic changes.

In a review of ablative approaches and breast cancer, Agnese and Burak (2005) stated that, "[a]blative therapies, including laser ablation, focused ultrasound, microwave ablation, radiofrequency ablation, and cryoablation, have been described.  All of these techniques have shown promise in the treatment of small cancers of the breast; however, additional research is needed to determine the efficacy of these techniques when they are used as the sole therapy and to determine the long-term local recurrence rates and survival associated with these treatment strategies."

An assessment on cryoablation for the treatment of breast fibroadenomas by the California Technology Assessment Forum (CTAF, 2006) concluded that this technology does not meet CTAF's criteria.  The assessment expressed concerns about the limitations in studies with long-term follow-up, and the lack of studies directly comparing cryoablation with other methods of management of breast fibroadenomas.  The CTAF assessment documents serious methodological problems with these studies.  The CTAF assessment states: "The largest series [Nurko et al, 2005] reported on 444 lesions, but follow-up was incomplete with fewer than 20 % of lesions evaluated at 12 months.  None of the case-series document the systematic use of any validated instrument to establish patient satisfaction, adverse events or to evaluate any other outcomes.  Follow-up was grossly inadequate to report intermediate length follow-up."

Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia, and is present in approximately 35 % of patients presenting for mitral valve surgery and in 1 to 6 % of adult patients undergoing other forms of cardiac surgery.  If left untreated, atrial fibrillation is associated with increased morbidity, and, in some subgroups, increased mortality.  Thus, concomitant management of the arrhythmia is indicated in most cardiac surgery patients with pre-existing AF.  Although the cut-and-sew Cox-maze III procedure is extremely effective, the advent of ablative energy sources such as radiofrequency and cryoablation has simplified the surgical treatment of atrial AF during concomitant cardiac procedures (Gillinov and Saltman, 2007).

A number of studies have examined the efficacy of cryoablation for atrial fibrillation. Doll and associates (2003) described their early experience in treatment of patients with chronic or paroxysmal AF with a tool for left atrial cryoablation.  A total of 28 patients underwent left atrial cryoablation with the Surgifrost CryoCath.  Patients underwent cryotherapy as an isolated procedure (n = 1), in combination with mitral valve surgery (n = 13), or with other surgical procedures (n = 14).  In all patients contiguous lesion lines to the orifices of the pulmonary veins (PVs) connected to the mitral annulus and the atriotomy were created.  Surgery was performed through a conventional sternotomy in 8 patients (29 %) and a right lateral mini-thoracotomy using video-assistance in 20 patients (71 %).  Post-operatively sinus rhythm (SR) was restored in 27 patients (96 %).  At discharge 82 % (23/28) of patients were in SR and 18 % (5/28) were in AF.  Four patients (14 %) required pace-maker implantation.  There was no in-hospital mortality.  At 6-month follow-up (19/28 patients) all were alive and 74 % were in stable SR, New York Heart Association functional class was 1.2 +/- 0.4.  The authors concluded that left atrial cryoablation with the Surgifrost argon cryocatheter is effective for the treatment of AF.  This new device is technically easy to handle, it can be applied through a median sternotomy or lateral mini-thoracotomy.  They stated that long-term follow-up is necessary to evaluate further rhythm outcome.

In a feasibility study, Hoyt and colleagues (2005) reported the findings of PV isolation (PVI) with cryoablation in 31 patients with paroxysmal AF.  Event monitors were used to measure the AF episode burden.  Serial spiral CT scans were obtained to monitor PV stenosis pre- and post-cryoablation.  Cryoablation was immediately successful for PVI in 29 of 31 patients (94 %), with 5.9 +/- 1.2 months of follow-up.  Additional radiofrequency ablation (RFA) was performed for AF recurrences in 7 patients.  The remaining 22 patients with a single cryoablation procedure demonstrated a time-dependent, long-term reduction in the frequency of AF episodes.  At 6-month follow-up, 18 of 22 of cryo-treated only patients (82 %) were free of symptomatic AF episodes, and anti-arrhythmic drugs (AADs) were discontinued in 12 of 22 patients.  Serial spiral CT scans demonstrated no change in the cryo-treated PV ostial diameter.  The authors concluded that PV cryoablation was effective to control paroxysmal AF in most patients.  Early recurrences of AF post-cryoablation were common, though tended to resolve within 6 months post-ablation, consistent with a process of reverse atrial remodeling.  Cryoablation of the PVs did not cause PV stenosis or other serious adverse events.

Gaita and co-workers (2005) examined the role of PVI alone versus left atrial linear lesions in the treatment of permanent AF in patients with left atrial dilatation and valvular disease.  The primary end point was to assess the persistence of SR off AADs at 2-year follow-up and to correlate clinical outcome with surgical results validated with electro-anatomical mapping (EAM).  A total of 105 patients with permanent AF undergoing valve surgery were assigned to 3 different groups: in groups "U" and "7," left atrial linear cryoablation was performed, whereas in group "PV" patients, anatomical cryoisolation of pulmonary veins only was performed.  In groups U and 7, SR was achieved in 57 % of patients, whereas it was achieved in 20 % of PV patients during 2-year follow-up.  In the first 51 patients, the ablation schemes were validated with EAM.  The EAM showed that the U lesion was never obtained: in 59 % of these patients, a complete 7 lesion was achieved instead; in the 7 group, a complete 7 lesion was present in 65 % of patients, whereas a complete PVI was obtained in 71 % of patients.  Considering patients in whom a complete 7 lesion was demonstrated with the EAM, SR without AADs was achieved in 86 % of patients, whereas only 25 % of patients with complete PVI were in SR without AADs.  The authors concluded that in patients with permanent AF, left atrial dilatation and valvular heart disease linear lesions in the posterior region of the left atrium are more effective than PVI alone.  With cryoablation, the surgical intent is fulfilled in only approximately 65 % of the cases.

Mack et al (2005) reported their findings of using argon-based endocardial cryoablation for the treatment of AF in patients undergoing concomitant cardiac procedures.  A total of 63 patients with AF who were undergoing concomitant cardiac procedures had the same left atrial endocardial lesion set using a flexible argon-based cryoablative device.  Mean age was 65.1 +/- 1.3 years.  Sixty-two percent had permanent AF, whereas 38 % had paroxysmal AF.  Mean duration of AF was 30.5 +/- 4.8 months.  Mean left atrial diameter was 5.5 +/- 0.1 cm.  Mean ejection fraction was 45 +/- 1.4 %.  All endocardial lesions were performed for 1 minute once tissue temperature reached -40 degrees C.  Follow-up echocardiograms were obtained to determine freedom from AF. Kaplan-Meier analysis demonstrated an 88.5 % freedom from AF rate at 12 months.  Ablation time was 16.8 +/- 0.6 minutes.  There were no in-hospital deaths and no strokes.  Twelve patients (19 %) required post-operative permanent pace-maker placement.  The authors concluded that cryoablation using this flexible argon-based device for the treatment of AF during concomitant cardiac procedures was safe and effective, with 88.5 % of patients free from AF at 12 months.

Neuwirth et al (2007) evaluated effectiveness of surgical cryoMAZE ablation for chronic AF in patients undergoing mitral valve surgical intervention.  A total of 47 patients (31 females), aged 67.3 +/- 7.3 years who underwent surgical intervention for severe mitral regurgitation were studied.  Mitral valvuloplasty was performed in 21 patients, and mitral valve replacement in 26 patients.  Combined procedure was employed in 35 patients; simultaneous aorto-coronary bypass was performed in 16 patients, tricuspid valvuloplasty (TVP) in 5 patients, and aortic valve replacement (AVR) in 5 patients.  The mean follow-up time was 19 +/- 10 months.  After 6 or 12 months, 36 or 32 patients were seen and 23 (64 %) or 22 (69 %) of them were in stable SR, respectively.  In the subset of 24 patients with simultaneous intervention on a different valve (TVP or AVR), after 6 or 12 months, 14 (74 %) or 15 (83 %) patients had stable SR, respectively.  In the follow-up period, 2 patients underwent successful catheter ablation for type I atrial flutter or for a residual left atrial atypical flutter.  The authors concluded that cryoMAZE ablation for chronic AF performed during the mitral valve surgical intervention resulted in a long-term stable SR in a high proportion of patients, particularly in patients with simultaneous intervention on two or three different valves.

Blomström-Lundqvist et al (2007) examined the effectiveness of epicardial left atrial (LA) cryoablation in eliminating AF in patients undergoing mitral valve surgery (MVS).  These researchers hypothesized that MVS combined with LA cryoablation is superior to MVS alone.  A total of 69 patients with permanent AF, included at four centers, underwent MVS with or without epicardial LA cryoablation.  The primary endpoint was regained SR.  Risk factors for failed AF cryoablation were elucidated.  Sixty-five out of 69 patients reached the primary endpoint.  At 6- and 12-month follow-up, 73.3 % of patients who underwent cryoablation had regained SR at both follow-ups, compared with 45.7 % and 42.9 % of patients, respectively, who underwent MVS alone (group differences, at 6-month p = 0.024, at 12-month p = 0.013).  The in-hospital complication rate was 11.4 % in the MVS group and 26.5 % in the cryoablation group (p = 0.110).  Risk factors for failed elimination of AF by cryoablation were duration of permanent AF (p = 0.012) and presence of coronary artery disease (p = 0.047), according to multiple logistic regression analysis.  The authors concluded that this prospective randomized study showed that combining MVS with epicardial LA cryoablation is significantly better in eliminating pre-operative permanent AF than MVS alone.

The National Institute for Clinical Excellence (2005) concluded that current evidence on the safety and effectiveness of cryoablation for AF in association with other cardiac surgery appears adequate.

The American College of Cardiology and the American Heart Association clinical guidelines addressing management of AF (Wann 2011) offered a Class I recommendation based on Level A data for catheter ablation in patients with symptomatic paroxysmal AF who have failed treatment with an anti-arrhythmic drug. This recommendation does not distinguish between radiofrequency or cryoballoon ablation. A Heart Rhythm Society consensus statement on the management of AF similarly gave a class I recommendation for catheter-based ablation for the treatment of drug refractory recurrent symptomatic paroxysmal AF based on studies comparing ablation to standard drug therapy that consistently reported that ablation resulted in a significant improvement in rhythm control. The consensus statement included a review of the randomized STOP-AF trial comparing cryoballoon ablation with the standard of drug therapy. Similar to studies of radiofrequency ablation, the results of the STOP-AF trial indicate that cryoballoon ablation results in a significant improvement in rhythm control. 

Skin Cancer

Guidelines on basal cell skin cancer from the National Comprehensive Cancer Network (NCCN, 2009) provide a limited role of cryotherapy in the treatment of skin cancers.  The NCCN guidelines state that, in patients with low-risk, superficial basal cell skin cancer or low-risk squamous cell carcinoma in situ (Bowen's disease), vigorous cryotherapy may be considered where surgery or radiation is contraindicated or impractical, even though the cure rate may be lower.  The British Association of Dermatologists' guidelines for the management of basal cell carcinoma (Telfer et al, 2008) stated that cryosurgery is a good treatment for low-risk basal cell carcinoma.

Other Indications

Guidelines from the National Comprehensive Cancer Network (NCCN, 2009) on soft tissue sarcoma have included cryoablation as an option for symptomatic persons with disseminated metastatic soft tissue sarcoma of the trunk and extremities.

There is a lack of evidence regarding the use of cryoablation for the treatment of plantar fibroma.  In the absence of peer-reviewed data, the use of cryoablation is not recommended for this condition.

Birkenmaier and colleagues (2007) stated that facet joint pain is an important aspect of degenerative lumbar spine disease, and radiofrequency medial branch neurotomy remains an established therapy, while cryodenervation has still been poorly examined.  In a prospective clinical case series, these researchers examined the effects of medial branch cryodenervation in the treatment of lumbar facet joint pain.  Patient selection was based on medical history, physical examination and positive medial branch blocks.  Percutaneous medial branch cryodenervation was performed using a Lloyd Neurostat 2000.  Target parameters were LBP (by means of visual analog scale [VAS], limitation of activity (McNab) and overall satisfaction.  A total fo 50 patients were recruited, and 46 completed the study.  The follow-up time was 1 year.  At 6 weeks, 33 patients (72 %) were pain-free or had major improvement of LBP; 13 (28 %) had no or little improvement.  Including failures, mean LBP decreased significantly from 7.7 pre-operatively to 3.2 at 6 weeks, 3.3 at 3 months, 3.0 at 6 months and 4.2 at 12 months (p < 0.0001).  Limitation of the activities of daily living improved parallel to reduced pain.  The authors cited
  1. other sources of LBP,
  2. false-positive diagnostic blocks, and
  3. inadequate technique as possible explanations for cryodenervation failure in some of the study subjects.

Kujak and colleagues (2010) described their early experiences with using percutaneous cryoablation for local control of extra-abdominal desmoid (EAD) tumors in patients whose tumors had failed to respond to standard therapy.  A total of 5 patients (2 males and 3 females) were included in this study.  Three of these patients had been referred for cryoablation for local tumor control, and 2 had been referred for palliation of inoperable tumors.  The age range of the patients at the time of cryoablation was 9 to 41 years.  Treated EAD tumors were located in the neck, shoulders and trunk and ranged in size from 3.0 cm to 10.0 cm.  Medical records were reviewed for short-term and long-term follow-up, and patients were contacted for additional follow-up.  Patients were asked to rate their pain as absent, mild, moderate or severe, and to compare it with their levels before cryoablation, describing it as improved, unchanged or worsened.  Radiology records were reviewed to follow the size of the EAD tumors before and after cryotherapy.  For the 3 patients referred for local control of EAD tumors, complete tumor coverage with the ablation zones was achieved.  Two of these patients, with masses 3.0 cm and 4.9 cm in diameter, reported complete absence of pain at both short-term and long-term follow-up at 13 months and 49 months.  Their tumors had completely resolved on long-term imaging follow-up at 19 months and 43 months.  The third patient, with a 6.1 cm mass, reported improved mild pain at 6 months, and imaging showed a moderate decrease of tumor size.  For the 2 patients referred for palliative therapy, initial partial pain relief was felt 2 weeks after the procedure.  At long-term (58 months) follow-up of 1 patient with a 9.1 cm mass, the tumor was still present although reduced in size, and local pain had returned to its former moderate level.  In the other patient who underwent only partial treatment of a 10.0 cm mass, at long-term follow-up (36 months) the mass had enlarged and pain had returned to the pre-treatment, moderate level.  The authors concluded that cryoablation appears to be an effective alternative treatment for local control of small and moderately sized EAD tumors, but it is likely of limited use in patients with larger tumors that have untreatable regions due to involvement of vital structures.  They stated that continued research evaluating cryoablation for the treatment of EAD tumors is needed.

In a multi-center, retrospective, cohort study, Greenwald et al (2010) evaluated the safety and effectiveness of cryotherapy in esophageal carcinoma.  Subjects with esophageal carcinoma in whom conventional therapy failed and those who refused or were ineligible for conventional therapy were included in this study; and they received cryotherapy with follow-up biopsies.  Treatment was complete when tumor eradication was confirmed by biopsy or when treatment was halted because of tumor progression, patient preference, or co-morbid condition.  Main outcome measures were complete eradication of luminal cancer and adverse events.  A total of 79 subjects (median age of 76 years, 81 % male, 94 % with adenocarcinoma) were treated.  Tumor stage included T1-60, T2-16, and T3/4-3.  Mean tumor length was 4.0 cm (range of 1 to 15 cm).  Previous treatment including endoscopic resection, photodynamic therapy, esophagectomy, chemotherapy, and radiation therapy failed in 53 subjects (67 %).  Only 49 patients completed treatment.  Complete response of intraluminal disease was seen in 31 of 49 subjects (61.2 %), including 18 of 24 (75 %) with mucosal cancer.  Mean (standard deviation) length of follow-up after treatment was 10.6 (8.4) months overall and 11.5 (2.8) months for T1 disease.  No serious adverse events were reported.  Benign stricture developed in 10 (13 %), with esophageal narrowing from previous endoscopic resection, radiotherapy, or photodynamic therapy noted in 9 of 10 subjects.  The authors concluded that spray cryotherapy is safe and well-tolerated for esophageal cancer.  They noted that short-term results suggested that it is effective in those who could not receive conventional treatment, especially for those with mucosal cancer.  Limitations of this study included its retrospective study design, short-term follow-up, and that only 49 of the 79 subjects (62 %) completed treatment, which could have skewed the findings of this study.

Timmermans et al (2010) reported the feasibility and safety of catheter-based cryoablation for the treatment of post-infarction and idiopathic ventricular tachycardia (VT).  Catheter-based cryoablation was performed in 17 patients (15 men, 58 +/- 18 years).  Ventricular tachycardia occurred after a prior myocardial infarction in 10 and was idiopathic in 7 patients.  Cryoablation was performed with a 10-F, 6.5-mm tipped catheter.  The ablation site was selected using entrainment mapping techniques for post-infarction VT.  The site of the earliest activation time with optimal pace mapping was used for ablation of idiopathic VT.  All targeted VTs (12 post-infarction and 7 idiopathic) were acute successfully ablated after a median number of 2 applications of 5 mins with an average temperature of -82 +/- 4 degrees C.  Mean procedure and fluoroscopy times were 204 +/- 52 and 52 +/- 20 mins for post-infarction VT and 203 +/- 24 and 38 +/- 15 mins for idiopathic VT.  No cryocatheter or cryoenergy complications were observed.  After a follow-up of 6 months, 4 of the 10 patients with post-infarction VT had a recurrence.  In 1 of the 7 patients with idiopathic VT the index arrhythmia recurred.  The authors concluded that in this small patient population, catheter-based cryoablation of VT was safe and effective.  They stated that future studies are needed to evaluate the effect of cryothermy in a larger group of patients, especially those with post-infarction VT.

Yamauchi and colleagues (2012) evaluated the mid-term results of percutaneous cryoablation for medically inoperable stage I non-small cell lung cancer.  Between January 2004 and June 2010, a total of 160 patients underwent computer tomography-guided percutaneous cryoablation for lung tumors at the authors’ institution.  Of these patients, histologically proven stage I lung cancer patients with more than 1 year of follow-up, were retrospectively reviewed.  All of these patients were considered to be medically inoperable with Charlson co-morbidity index of 3 or greater.  Follow-up was based primarily on computed tomography.  There were 22 patients with 34 tumors who underwent 25 sessions of cryoablation treatment.  Complications were pneumothoraces in 7 treatments (28 %, chest tube required in 1 treatment), and pleural effusions in 8 treatments (31 %).  The observation period ranged from 12 to 68 months, average 29 +/- 19 months, median 23 months.  Local tumor progression was observed in 1 tumor (3 %).  Mean local tumor progression-free interval was 69 +/- 2 months.  One patient died of lung cancer progression at 68 months.  Two patients died of acute exacerbations of idiopathic pulmonary fibrosis which were not considered to be directly associated with cryoablation, at 12 and 18 months, respectively.  The overall 2- and 3-year survivals were 88 % and 88 %, respectively.  Mean overall survival was 62 +/- 4 months.  Median overall survival was 68 months.  The disease-free 2- and 3-year survivals were 78 % and 67 %, respectively.  Mean disease-free survival was 46 +/- 6 months.  Pulmonary function tests were done in 16 patients (18 treatments) before and after cryoablation.  Percentage of predicted vital capacity, and percentage of predicted forced expiratory volume in 1 second, did not differ significantly before and after cryoablation (93 +/- 23 versus 90 +/- 21, and 70 +/- 11 versus 70 +/- 12, respectively).  The authors concluded that although further accumulation of data is necessary regarding efficacy, cryoablation may be a feasible option in medically inoperable stage I lung cancer patients.

In a report by the American Academy of Ophthalmology, Simpson and associates (2012) evaluated the role of cryotherapy in the current treatment of retinopathy of prematurity (ROP).  Literature searches of PubMed and the Cochrane Library were conducted on December 2, 2009, for articles published after 1984.  The searches included all languages and retrieved 187 relevant citations; 13 articles were deemed relevant to the assessment question and were rated according to the strength of evidence.  Four articles reported results from 2 large multi-center randomized clinical trials, and the remaining 9 articles reported results of 3 small randomized trials that directly compared cryotherapy and laser.  Neither of the multi-center randomized clinical trials was a direct comparison of cryotherapy with laser.  These studies were used to evaluate the comparative trials based on treatment criteria, study populations, and clinical results.  Higher percentages of poor structural and functional outcomes generally were seen in eyes treated with cryotherapy compared with eyes undergoing laser treatment.  Higher rates of systemic complications and myopia also were identified after treatment with cryotherapy.  No clinical studies are available to support treatment with cryotherapy for type 1 ROP as defined by the Early Treatment for ROP [ETROP] Study, especially given practical factors such as the need to treat posteriorly in younger patients who may be more susceptible to systemic complications from treatment The authors concluded that despite a relative paucity of level I evidence directly comparing cryotherapy and laser treatment for threshold ROP, the literature suggests that neonatal facilities should gain access to laser technology and laser-trained ophthalmic staff to achieve better outcomes for treatment of the disease.  Advantages of laser photocoagulation, including easier administration, lower rates of complications, and efficacy that is at least equivalent to cryotherapy, reduce the necessity for further study and make further randomized clinical trials comparing these 2 treatment methods unlikely.  Any future trials are likely to sue a pharmacologic approach such as bevacizumab alone or bevacizumab either in combination with or in comparison with laser as the preferred method for ablative therapy.

Martin-Hirsch et al (2010) stated that cervical intraepithelial neoplasia (CIN) is the most common pre-malignant lesion.  Atypical squamous changes occur in the transformation zone of the cervix with mild, moderate or severe changes described by their depth (CIN 1, 2 or 3).  Cervical intraepithelial neoplasia is treated by local ablation or lower morbidity excision techniques.  Choice of treatment depends on the grade and extent of the disease.  Ina Cochrane review, these investigators evaluated the effectiveness and safety of alternative surgical treatments for CIN.  They searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE and EMBASE (up to April 2009).  They also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies.  Randomized controlled trials (RCTs) of alternative surgical treatments in women with CIN were selected for analysis.  Two review authors independently abstracted data and assessed risks of bias.  Risk ratios that compared residual disease after the follow-up examination and adverse events in women who received laser ablation, laser conisation, large loop excision of the transformation zone (LLETZ), knife conisation, or cryotherapy were pooled in random-effects model meta-analyses.  A total of 29 trials were included; 7 surgical techniques were tested in various comparisons.  No significant differences in treatment failures were demonstrated in terms of persistent disease after treatment. L arge loop excision of the transformation zone appeared to provide the most reliable specimens for histology with the least morbidity.  Morbidity was lower than with laser conisation, although the trials did not provide data for every outcome measure.  There were not enough data to assess the effect on morbidity when compared with laser ablation.  The authors concluded that the evidence suggested that there is no obvious superior surgical technique for treating CIN in terms of treatment failures or operative morbidity.

Lewis et al (2011) noted that in low-resource settings, cryotherapy can be cost-effective, affordable, and a first-line treatment for CIN of any grade.  These investigators reported the acceptability, safety and effectiveness of cryotherapy for women with CIN in Western Kenya.  Visual inspection with acetic acid (VIA)-positive women and those suspected of having cervical cancer based on an initial evaluation at a primary health facility were referred to the district hospital for colposcopy and additional evaluation using visual inspection with Lugol's iodine (VILI) and/or visual inspection with acetic acid and magnification (VIAM).  Cryotherapy was offered immediately to women diagnosed with appropriate CIN lesions based on colposcopy or after waiting for a confirmatory cervical biopsy and a follow-up visit occurred 1 year later.  A total of 91 women (aged 30 to 39 years) had CIN appropriate for cryotherapy.  Approximately 36 % (24/67) were due for their 1 year follow-up visit and 20 of 24 (83.3 %) attended.  Complete data were available for 18 of 20 (90 %) and 13 (72.2 %) had no sign of CIN.  No serious adverse events were reported 1 to 3 months after cryotherapy.  All respondents reported that the treatment experience was acceptable.  The authors concluded that cryotherapy was acceptable, safe and effective.

Sauvaget et al (2013) provided an updated and comprehensive estimate of the efficacy of cryotherapy for CIN.  A literature search identified original studies (RCTs and clinical reports).  Studies reporting cure rates, acceptability, and safety of cryotherapy were included in the analysis.  Number of persistent or recurrent lesions at follow-up, adverse events, and complications were recorded.  Quality of the methodology was also assessed.  Meta-analyses were performed according to CIN thresholds, geographic region, study year, setting, study design, presence of endocervical involvement, freezing method, duration of follow-up, and status of the cryotherapy provider.  A total of 146 articles were retrieved; 77 papers -- equivalent to 28,827 cases of treated CIN -- were included in the meta-analysis.  Cryotherapy achieved cure rates of 94.0 % (CIN1), 92.0 % (CIN2), and 85.0 % (CIN3).  Use of the double-freeze method and absence of endocervical involvement significantly increased cure rates.  Minimal complications were reported as adverse effects.  The authors concluded that cryotherapy is an effective, safe, and acceptable treatment for CIN.  It has been shown to be successful in low-resource settings, enabling availability and accessibility of early detection services.

In a multi-center RCT, Klem et al (2009) compared cryo-stripping of the great saphenous vein (GSV) with conventional stripping.  The study randomized 494 patients with symptomatic (CEAP) clinical severity class 2 to 4 to cryo-stripping (n = 249) or conventional stripping (n = 245).  The primary outcome was residual GSV 6 months after surgery measured by venous duplex ultrasound imaging.  Secondary outcomes were quality of life, operation time, and post-operative neural damage.  Duration of follow-up was 6 months.  Quality of life was measured at 6 and 26 weeks post-operatively with the Aberdeen Varicose Vein Questionnaire (AVVQ) and Medical Outcomes Study Short-Form 36 (SF-36) Health Survey.  The 2 groups were well-matched at baseline.  The percentage of patients with residual GSV at 6 months (primary outcome) was 44 % (102 of 230) in the cryo-stripping group and 15 % (33 of 215) in the conventional group (difference 29 %; 95 % confidence interval [CI]: 21 % to 37 %, p < 0.001).  Median operation time was significantly shorter in the cryo-stripping group (30 minutes) compared with the conventional group (39 minutes).  Neural damage was 12 % in both groups, and thus not significantly different.  Scores on the subdomains of the SF-36 showed no significant change between the groups.  The AVVQ after conventional stripping was 8.0, which was a better result than the 11.7 result after cryo-stripping (difference of 2.6 points; 95 % CI: 1.0 to 4.2; p = 0.001, repeated measurements analysis of variance with adjustment for baseline scores).  The authors concluded that cryo-stripping accounts for numerous procedural failures and hence residual GSV in patients.  The AVVQ showed small but significantly better results for patients after a conventional stripping.  Thus, cryo-stripping has no benefits over conventional stripping.

Krummel et al (2014) stated that renal angiomyolipomas (AMLs) are frequent in tuberous sclerosis and are responsible for a significant proportion of the morbidity in adulthood, mainly from bleeding complications, which are correlated to the size of the AMLs.  These researchers described the case of a 19-year old female with multiple bilateral renal AMLs.  The renal AMLs measured up to 6-cm in size.  She was first treated with a low-dose of the mammalian target of rapamycin (mTOR) inhibitor sirolimus (up to 3 mg/day over a 12-month period) and following significant AML size reduction, percutaneous cryoablation was performed.  No side-effects of either treatment were reported.  At 12 months post-cryoablation, no recurrence of the AML was noted.  The authors concluded that this was the first report of this treatment strategy and the case study revealed that combining a low-dose of an mTOR inhibitor with percutaneous cryoablation to treat small tumors mitigates the side-effects while providing a good clinical outcome.  They stated that this therapeutic approach is a novel tool for the clinician involved in the management of patients with tuberous sclerosis.

Song et al (2014) examined the safety and effectiveness of palliative bypass surgery combined with cryoablation to treat patients with advanced pancreatic cancer and compared them with those of palliative bypass surgery alone.  Medical records of 118 patients with advanced pancreatic cancer who received palliative bypass surgery combined with cryoablation (the combination treatment group) or bypass surgery alone (the bypass surgery group) from June 30, 2008 to December 31, 2010 were retrospectively reviewed.  Their baseline and post-operative parameters were collected and compared.  In both groups, abdominal distension and pain was significantly improved after treatment.  Pre-operative jaundice was more common in the bypass surgery group.  Backache was more frequent in the combination treatment group, which were both relieved.  Pre-operative serum bilirubin level was higher in the bypass surgery group that was decreased significantly after treatment.  However, significant reductions in tumor size as well as serum carbohydrate antigen 19-9 (CA19-9) level were only found in the combination treatment group.  There was no significant difference in the incidence of post-operative complications and prognosis between the 2 groups.  The authors concluded that cryoablation can reduce the tumor size and relieve the patients' symptoms and signs such as abdominal discomfort and backache, although it could not improve the patients' prognosis significantly.

In a preliminary study, Cornelis et al (2014) reported the short-term local control of percutaneous image-guided cryoablation of localized symptomatic abdominal scar endometrioma.  A total of 4 consecutive patients (mean age of 34.5 years) with a total of 10 lesions were included, with mean pre-operative pain of 7 (range of 5 to 9) on the VAS.  Cryoablation was performed in a single session under general anesthesia.  Post-operative superficial edema disappeared within 2 weeks for all patients.  No severe complications (greater than grade 2 according to the common terminology criteria for adverse events [CTCAE] classification) were reported.  Mean post-operative pain was 1.7 at 6 months (range of 0 to 5) and magnetic resonance imaging demonstrated a significant volume decrease for all patients (range of 72.2 to 100 %; p = 0.028).  The authors concluded that percutaneous cryoablation showed promising local control in patients with symptomatic abdominal wall endometriosis.  These preliminary findings need to be validated by well-designed studies.

Bone and Soft Tissue Tumors

Iguchi et al (2016) noted that a single-center, prospective study is being conducted to evaluate the safety of the cryoablation for patients with pathologically diagnosed painful bone and soft tissue tumors.  Enrollment of 10 patients is planned over the 3-year recruitment period.  Patients have related local pain after receiving medications or external radiation therapies will be included in this study.  Percutaneous cryoablation will be performed under imaging guidance, and a temperature sensor will be used during treatment as necessary.  The primary end-point is prevalence of severe adverse events (AEs) within 4 weeks after therapy.  The secondary end-point is effectiveness 4 weeks after the procedure.

Drooling

Buethe and colleagues (2016) evaluated the imaging, histologic changes and safety of CT-guided cryoablation of the parotid glands in a porcine model.  Unilateral CT-guided parotid gland cryoablation was performed in 5 juvenile miniature pigs.  The ablated parotid glands underwent 2 cycles of 10-minute freeze and 5-minute thaw using three 17-G cryoprobes.  The animals were monitored daily for complications including pain, frost-bite, infection, and sialocele or fistula formation.  Follow-up CT was performed at 6 weeks post-cryoablation.  Pathologic evaluation was performed on 2 of the ablated parotid glands.  All cryoablations in 5 right parotid glands, with 3 sites in each gland, were technically successful.  No symptoms suggestive of facial nerve damage were observed during 6-week follow-up.  One pig developed an infected sialocele, which was treated with percutaneous drainage and oral antibiotic therapy.  No CT evidence of sialocele or other abnormality was identified at the 6-week follow-up in all pigs.  Histologic evaluation was performed on 2 of the parotid gland specimens, 1 with the treated sialocele, and 1 of the remaining pigs without sialocele.  Both glands demonstrated post-procedural intra-glandular lymph nodes and reactive changes without evidence of sialocele or abscess on histopathology.  The authors concluded that cryoablation of parotid glands was technically feasible in a porcine model.  Only 1 pig developed sialocele, which was successfully treated.  They stated that further research is needed to determine the potential use of salivary gland cryoablation to treat patients with drooling.

Premature Ejaculation

David Prologo et al (2013) evaluated the feasibility, safety, and effectiveness of image-guided cryoablation for the of premature ejaculation (PE).  Prospective institutional review board approval was obtained, and 24 subjects with PE were enrolled.  All patients underwent unilateral percutaneous CT-guided cryoablation of the dorsal penile nerve (DPN).  Post-procedural intravaginal ejaculatory latency times (IELTs) and PE Profile (PEP) results served as outcome variables.  In addition, subjects were asked whether they would have the procedure done again based on their experience at the 180- and 360-day marks.  The technical success rate was 100 %.  Baseline average IELT was 54.7 seconds ± 7.8 (n = 24), which increased to a maximum of 256 seconds ± 104 (n = 11; p = 0.241) by day 7 and decreased to 182.5 seconds ± 87.8 (n = 6; p = 0.0342) by day 90.  The mean IELT remained at 182.5 seconds ± 27.6 at day 180 (n = 23; p < 0.0001) and decreased to 140.9 seconds ± 83.6 by 1 year (n = 22; p < 0.001); PEP scores improved overall, IELTs significantly improved at 180 and 360 days, and 83 % of subjects reported that they would undergo the procedure again if given the same opportunity.  There were no procedure-related complications.  The authors concluded that CT-guided percutaneous unilateral cryoablation of the DPN is a feasible, safe, single-day out-patient procedure for the treatment of symptomatic PE.  These preliminary findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Treatment of male sexual dysfunction” (Cunningham and Khera, 2016) does not mention cryoablation as a therapeutic option.

Residual Facial Arterio-Venous Malformations

Woolen and Gemmete (2016) reported the findings of 4 patients (mean age of 22 years; range of 17 to 26) with facial arterio-venous malformations (AVMs) who underwent arterial ethanol and N-butyl cyanoacrylate embolization followed by percutaneous cryoablation of residual inaccessible AVMs.  After the procedure, minor complications classified as type B according to the Society of Interventional Radiology (SIR) classification system occurred in 75 % (3/4) of patients; 1 patient achieved 90 % obliteration of AVM, and 3 patients had complete obliteration of AVM at 1-year follow-up.  The authors concluded that the findings of this study showed that percutaneous cryoablation may be a viable therapeutic option for residual facial AVMs after ethanol and glue embolization.  These preliminary findings need to be validated by well-designed studies.

Retroperitoneal Soft-Tissue Sarcoma

Fan and colleagues (2016) evaluated the pain-alleviating effect of CT-guided percutaneous cryoablation for recurrent retroperitoneal soft-tissue sarcomas (RPSs).  Data from 19 men and 20 women (median age of 50.3 years) with recurrent malignant RPS who underwent percutaneous cryoablation were reviewed retrospectively.  A total of 50 tumors were treated by cryoablation, including a single tumor in 29 patients, 2 tumors in 9, and 3 tumors in 1; AEs and analgesic outcomes were compared as a function of tumor size (less than 10 cm and greater than or equal to 10 cm).  Efficacy was assessed based on modified Response Evaluation Criteria In Solid Tumors and progression-free survival (PFS).  Grade 1/2 AEs included fever (n = 17), emesis (n = 7), frost-bite (n = 5), and local pain (n = 4).  The median follow-up period and PFS were 18.5 months (range of 12 to 42) and 13.4 months ± 6.2, respectively.  At the end of follow-up, 13 patients had died and 26 were living.  The mean severe local pain scores on pre-treatment day 1 and post-treatment days 1, 5, 10, 15, 20, and 25 were 7.49, 7.40, 6.51, 5.81, 5.35, 5.04, and 5.44, respectively, and significant differences versus pre-treatment (p < 0.001) were reported for post-treatment days 5 to 25.  Immediate relief occurred more frequently in the small-tumor group (4 of 7; 57.1 %; p = 0.018), whereas delayed relief occurred more frequently in the large-tumor group (17 of 22; 77.3 %; p = 0.030).  The authors concluded that minimally invasive percutaneous cryoablation improved local pain and is a feasible treatment for recurrent RPSs.  These preliminary findings need to be validated by well-designed studies.

Spinal Giant Cell Tumors

Schwimer and co-workers (1981) reported 4 cases of giant cell tumor (GCT) of the cervico-thoracic spine.  Patients were women aged 17 to 20 years.  These investigators noted that treatment consisted of surgical extirpation and radiation therapy; however, carefully monitored cryotherapy of this lesion may be a feasible new therapeutic method.  The author stated that due to their relatively inaccessible location, spinal GCT (SGCT) will be difficult to treat adequately, and can be expected to recur and cause neurologic compromise in a significant proportion of cases.

Althausen and colleagues (2002) stated that sacral GCTs are rare primary bone tumors.  Recent reports have demonstrated diminished GCT recurrence with cryosurgery by using a "direct pour" technique with liquid nitrogen.  Although successful in decreasing tumor recurrence, this technique was accompanied by a 4 to 8 % rate of skin necrosis and high rates of pathologic fracture.  These researchers described resection and a novel, controlled method of argon-based cryotherapy (followed by a unique pelvic reconstruction) for a large, sacral GCT.  A 29-year old woman presented with complaints of right foot-drop and decreased sensation of the right buttock, posterior thigh, posterior calf, and lateral aspect of the right foot.  Radiographic evaluation revealed a mass in the right sacrum; histologic examination of CT-guided biopsy revealed a GCT.  A combined anterior abdominal and posterior sacral approach was performed, the tumor was resected, and the margin of the cavity was treated with controlled argon-based cryotherapy.  The combination of thermocouples, electromyographic monitoring, and rapid freeze-thaw cycles allowed a controlled ablation of the tumor margin while ensuring that surrounding structures, such as the rectal wall, sacral nerves, and gluteal muscles, were not damaged.  Posterior spinal fusion L4 to sacrum, posterior spinal instrumentation L4 to pelvis, and allograft reconstruction of the right sacrum were performed.  The patient recovered well without skin necrosis or pathologic fracture.  Urinary and fecal continence were preserved.  At the 20-month follow-up the patient had no evidence of local tumor recurrence and was fully ambulatory without a brace or narcotic medication.  The  authors concluded that a novel multi-modality approach, consisting of resection, controlled cryosurgery, and a unique lumbo-pelvic reconstruction, was safe and successful in managing a challenging proximal sacral GCT; 20 months after surgery the patient had excellent bowel and bladder control, no tumor recurrence, and functional ambulation without a brace or pain.  This was a single-case study with a multi-modality approach.

Luksanapruksa and associates (2016) noted that SGCT remain challenging tumors to treat.  Although advancements in surgical techniques and adjuvant therapies have provided new options for treatment, evidence-based algorithms are lacking.  These investigators reviewed the peer-reviewed literature that addresses current therapeutic options and management of SGCT to produce an evidence-based treatment algorithm.  They performed a systematic review.  Articles published between January 1, 1970 and March 31, 2015 were selected from PubMed and Embase searches using keywords "giant cell tumor" and "spine" and "treatment".  Relevant articles were selected by the authors and reviewed.  A total of 515 studies were identified, of which 81 studies were included.  Complete surgical resections of SCGT resulted in the lowest recurrence rates.  However, morbidity of en bloc resections is high and in some cases, surgery is not possible.  Intralesional resection can be coupled with adjuvant therapies, but evidence-based algorithms for use of adjuvants remain elusive.  Several recent advancements in adjuvant therapy may hold promise for decreasing SGCT recurrence, specifically stereotactic radiotherapy, selective arterial embolization, and medical therapy using denosumab and interferon.  The authors concluded that complete surgical resection of SGCT should be the goal when possible, particularly if neurologic impairment is present; denosumab holds promise as an adjuvant and perhaps stand-alone therapy for SGCT.  According to these researchers, the best level of evidence regarding the use of cryotherapy as an intra-operative adjuvant modality for intralesional resections was III.

Domovitov and colleagues (2016) stated that there is no consensus regarding the appropriate treatment of sacral GCT.  There are 3 main management problems:
  1. tumor control,
  2. neurological loss, and
  3. pelvic instability. 

These researchers examined oncological, neurological, and structural outcomes of sacral GCT after intralesional excision and local intra-operative adjunctive treatment. They retrospectively reviewed the records of 24 patients with sacral GCT who underwent conservative surgery (intralesional resection/curettage) at Memorial Sloan Kettering Cancer Center from 1973 through 2012.  They analyzed patient demographic data, tumor characteristics, and operative techniques, and examined possible correlations with post-operative functional outcomes, complications, recurrence, and mortality.  There were 7 local recurrences (30 %) and 3 distant recurrences (13 %); 3 of 24 patients (12.5 %) had significant neurological loss after treatment -- specifically, severe bowel and/or bladder dysfunction, but all regained function within 1 to 4 years.  Larger tumor size (greater than 320 cm3) was associated with greater post-operative neurological loss.  Radiation therapy and pre-operative embolization were associated with prolonged disease-free survival (DFS).  There were no local recurrences among the 11 patients who were treated with both modalities.  Based on radiographic and clinical assessment, spino-pelvic stability was present in 23 of 24 patients at final follow-up.  The authors concluded that high local and distant recurrence rates associated with sacral GCT suggested the need for careful local and systemic follow-up in managing these patients.  Intra-operative preservation of sacral roots was associated with better pain relief, improvement in ambulatory function, and retention of bowel/bladder function in most patients.  Fusion and instrumentation of the sacroiliac joint successfully achieved spino-pelvic stability in cases deemed clinically unstable.  They stated that despite improvement in the management of sacral GCT over 35 years, a need for novel therapies remains.  The strategy of combining radiotherapy and embolization merits further study.  Cryosurgery is one of the keywords described in this study.

Furthermore, an UpToDate review on “Giant cell tumor of bone” (Thomas and Desai, 2016) stated that “Local adjuvants -- In an attempt to decrease local recurrence rates after intralesional curettage, various surgical adjuvant therapies have been tried.  Examples include the use of bone cement (polymethylmethacrylate, PMMA), aqueous zinc chloride, phenol, cryotherapy with or without cement, argon beam coagulation, and the use of a high-speed burr to remove peritumoral bone.  There are no randomized trials to support benefit of a local adjuvant over curettage alone.  In contemporary retrospective series of patients treated with intralesional curettage with a local adjuvant, local recurrence rates are 13 to 22 %, which compare favorably with those seen following wide local excision.  However, a large series suggested no benefit from the use of local adjuvants, provided there is adequate surgical tumor removal.  There are also no trials comparing outcomes with different adjuvant approaches.  However, bone cement has emerged as the preferred adjuvant agent.  Filling the cavity with bone cement allows immediate weight bearing, and the heat induced during the setting of the cement is thought to kill any remaining tumor cells, thus decreasing the risk of a local recurrence.  Furthermore, the radiologic features of a cement-filled cavity are ideal to permit early identification of local recurrences”.

Bony Metastases from Renal Cell Carcinoma

European Society for Medical Oncology (ESMO)’s clinical practice guidelines on “Renal cell carcinoma” (Escudier et al, 2016) recommended radiotherapy for the management of symptomatic bone lesions.

Coupal and colleagues (2017) stated that metastases to the bone are common in cancer patients, and it has been estimated that up to 50 % of patients with pelvic bone metastases will not achieve adequate pain control with medications alone.  This has resulted in a paradigm shift over recent years towards the development of minimally invasive image-guided therapeutic options for palliation of bony metastases.  Despite these advents, large metastatic lesions are still often considered to be "hopeless cases" that would garner little to no benefit from image-guided intervention.  In a retrospective analysis, these investigators evaluated the safety and effectiveness of a novel approach -- combined percutaneous cryoablation and cementoplasty -- for palliation of such large metastases to the pelvis.  This study was conducted from January 2013 to December 2016, where consecutive patients referred for pain management of large pelvic bone metastases underwent combination percutaneous cryoablation and cementoplasty.  This study took place at a tertiary care center after patients were referred following formal review from a multi-disciplinary conference, which was comprised of interventional radiologists, pain management and palliative care physicians, radiation and medical oncologists, and when available, anesthesiologists.  A total of 48 patients (36 men and 12 women) with a mean cohort age of 77.5 years (range of 52 to 89 years) were referred from the multi-disciplinary conference for palliation of pelvic bone metastases.  The inclusion criteria included patients with metastases greater or equal to 5.0 cm and significant pain refractory to conventional pain management regimens.  All of the patients were deemed not to be surgical candidates.  Mean pain scores were collected at numerous time-points along with procedural technical success rates and complication rates.  Combination cryoablation and cementoplasty was performed on 48 consecutively referred patients with a 100 % technical success rate and no immediate complications.  The pain levels demonstrated a significant decrease (p < 0.001) following intervention, with mean pain scores of 7.9 (range of 5 to 10) and 1.2 (range of 0 to 7) throughout the week prior to intervention and at 24 hours post-intervention, respectively.  The post-intervention pain scores remained stable at 1 to 9 weeks follow-up (mean of 4.1 weeks); 3 patents (6.3 %) reported no change in pain following the intervention; however, no patients reported worsened pain.  The authors concluded that combination cryoablation and cementoplasty is a novel and effective treatment option for palliation of large pelvic bone metastases.  Marked improvements in pain, as well as mobility and quality of life (QOL), were often attainable.

The drawbacks of this study included its retrospective nature, which limited the acquisition of ancillary data for all of the patients, such as: pre- and post-procedural opiate requirements, improvement in mobility, and formal QOL measures.  These investigators noted that while they had numerous qualitative measures demonstrating profound improvements in mobility and QOL, prospective studies are needed in the future literature.  Another drawback of this study was the length of follow-up (mean of 4.1 weeks), which was restricted in many cases given the life expectancy of the study cohort.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Kidney cancer” (Version 1.2018) has no recommendation for cryoablation of metastases.  The guidelines recommends cryosurgery for localized renal lesions.

Chronic Headache

UpToDate reviews on “Overview of chronic daily headache” (Garza and Schwedt, 2017a), “Headache in children: Approach to evaluation and general management strategies” (Bonthius et al, 2017), and “New daily persistent headache” (Garza and Schwedt, 2017b) do not mention cryoablation as a therapeutic option

Hookworm-Related Cutaneous Infection

UpToDate reviews on “Hookworm infection” (Weller and Leder, 2017a) and “Hookworm-related cutaneous larva migrans” (Weller and Leder, 2017b) do not mention cryotherapy as a therapeutic option.

Peripheral Nerve Damage in the Lower Extremity

Chen et al (2004) evaluated the effectiveness of axonal repair technique for treatment of peripheral nerve injury clinically.  In 1998, the authors applied axonal repair technique to treat peripheral nerve injuries in 12 patients with 13 nerves.  It consisted of 4 steps, i.e.,
  1. stumps of the nerve being soaked in a modified Collins fluid,
  2. frozen,
  3. trimmed, and
  4. coated with glue, making the injured nerve repaired at the axonal level. 

Patients were followed-up for an average of 13 months.  Results showed that in 4 cases of 1st-stage contralateral C7 transfer, regenerating axons reached to the sternoclavicular joint or axilla at 4 to 7 months, offering the timing for performing the 2nd-stage contralateral C7 transfer.  In 5 cases of accessory nerve transferred to the suprascapular nerve, the abduction of the shoulder was 40 degree on average.  In the other 3 patients with 4 different nerves repaired, results were also satisfactory.  The authors concluded that this technique was promising in the treatment of peripheral nerve injury.

Allergic and Non-Allergic Rhinitis (e.g., by Means of the ClariFix Device)

Hwang et al (2017) reported the first series of patients treated for chronic rhinitis using a novel device designed for office-based cryosurgical ablation of the posterior nasal nerve (PNN).  A total of 27 patients with chronic rhinorrhea and/or nasal congestion for greater than 3 months were recruited (allergic or non-allergic rhinitis), with minimum rhinorrhea and/or congestion sub-scores of 2 as part of the Total Nasal Symptom Score [TNSS]).  Under local anesthesia, a hand-held cryotherapy device (the ClariFix device) was applied endoscopically to the posterior middle meatus and was used to freeze the PNN region bilaterally.  Patients were followed-up after 7, 30, 90, 180, and 365 days to assess TNSS.  The procedure was successfully completed in 100 % of patients, with no complications; 74 % reported no or mild discomfort by the 1st post-procedure day.  TNSS was reduced significantly at 30 days (mean ± standard deviation: 6.2 ± 0.5 at baseline, 2.6 ± 0.3 at 30 days, n = 27, p < 0.001), with continued reduction at 90 (2.7 ± 0.4, n = 24, p < 0.001), 180 (2.3 ± 0.5, n = 21, p < 0.001), and 365 days (1.9 ± 0.3, n = 15, p < 0.001).  Both rhinorrhea and congestion sub-scores decreased significantly at 30, 90, 180, and 365 days compared to baseline (p < 0.001).  Allergic and non-allergic sub-cohorts both appeared to benefit from treatment.  The authors concluded that office-based cryotherapy of the PNN region was safe and well-tolerated; symptom scores were significantly decreased by 7 days post-procedure and remained lower at 30, 90, 180, and 365 days.  Moreover, these researchers stated that in addition to following the current cohort for an extended period of time, larger cohort studies for both allergic rhinitis and non-allergic rhinitis will be conducted, to fully evaluate the ClariFix device and procedure for these patient subsets.

The authors stated that the drawbacks of this study included the small sample size (n = 27) and loss to follow‐up during the extended period (6patients were lost to follow‐up at 180 days, and 12 patients could not be reached at 365 days).  Medication use was not systematically tracked in this study but will be tracked in future studies.

Paprocka-Zjawiona and colleagues (2018) noted that pharmacotherapy of both allergic and non-allergic rhinitis is not always effective.  These investigators examined the effectiveness of treatment of patients with allergic and non-allergic vasomotor rhinitis using cryoablation.  The study involved 60 patients, including 28 women and 32 men, aged 17 to 76 years (average of 39) with rhinitis.  All participants were assigned into 2 groups: Group I -- 18 patients with chronic allergic rhinitis; and Group II -- 42 patients with chronic non-allergic vasomotor rhinitis.  The research methodology included: anamnesis, otolaryngologic examination, rhino-manometer test, performed before and 3 months after the cryoablation of nasal turbinates , which was performed under local anesthesia, with a xylocaine solution using the Cryo-S device.  Following cryoablation, both groups exhibited statistically significant improvements in the subjective assessment of symptoms of nasal obstruction and in the mean rhino-manometry of air flows through the nasal passages during inspiration and exhalation.  The authors concluded that cryoablation was not the 1st-line treatment for the treatment of allergic and non-allergic vasomotor rhinitis, it did not remove the causes of the disease.  However, they stated that this approach may be an effective method of treatment for some patients and a supplement to existing treatment.

Kompelli and associates (2018) stated that chronic rhinitis impacts 60 million Americans and is associated with significant costs for patients.  Although medical treatments are 1st-line, some patients require surgical intervention such as vidian or posterior nasal neurectomy.  Previous reviews have examined the role of surgical management in chronic rhinitis, but none has investigated a long-standing treatment with recent interest: cryotherapy.  These investigators evaluated the safety, efficacy, and durability of treatment response of cryotherapy in treating chronic rhinitis.  They carried out a systematic literature review to identify studies that investigated the utility of cryotherapy in chronic rhinitis.  Only studies with the primary objective of assessing the efficacy of cryotherapy on chronic rhinitis were included.  Patients were classified as allergic rhinitis, non-allergic rhinitis (vasomotor rhinitis), or mixed rhinitis using the original author's criteria.  Data were extracted regarding reported complications, treatment efficacy, and length of follow-up.  A total of 110 abstracts were identified, of which 15 were included in this review.  Epistaxis and nasal obstruction were commonly reported complications; no serious AEs were reported.  For obstructive symptoms, "reduced" symptoms were reported in 63.4 % to 100 % of patients.  In regard to rhinorrhea, reports of reduced symptoms were experienced from 77 % to 100 % of patients; 7 studies used only patient-reported improvements without stratifying results based on symptom type; general improvements ranged from 67 % to 100 %; 9 studies noted symptom improvement in non-allergic cohorts ranging from 67 % to 97.5 % of patients; 4 studies noted improvement in allergic cohorts ranging from 63.4 % to 80 % of patients; 2 studies noted improvement in patients with mixed pictures ranging from 92.5 % to 100 %.  The authors concluded that a although cryotherapy appeared safe and effective, heterogeneous past investigations with low-quality evidence made strong, evidence-based recommendations difficult to make.  These researchers stated that further study with validated metrics and controlled populations is needed and should be encouraged.

Furthermore, UpToDate reviews on “Clinical presentation, diagnosis, and treatment of nasal obstruction” (Bhattacharyya, 2018), “Chronic rhinosinusitis: Management” (Hamilos, 2018), and “Chronic nonallergic rhinitis” (Lieberman , 2018) do not mention cryoablation as a therapeutic option.

In a prospective, single-arm study, Chang and associates (2020) examined safety and efficacy of cryoablation of the PNN for treatment of chronic rhinitis.  This trial included 98 adult patients at 6 U.S. centers with chronic allergic and non-allergic rhinitis.  Cryoablation of the PNN was carried out in-office under local anesthesia using the Clarifix device.  Patients discontinued use of intra-nasal ipratropium 3 days before treatment and throughout the study period.  Reflective TNSS (rTNSS) was measured at pre-treatment baseline and post-treatment at 1 month, 3 months, 6 months, and 9 months.  The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was completed at pre-treatment and 3 months post-treatment; AEs and post-procedure medication usage were recorded.  A total of 98 procedures (100 %) were successfully completed.  rTNSS significantly improved over pre-treatment baseline (6.1 ± 1.9) at 1 month (2.9 ± 1.9, p < 0.001), 3 months (3.0 ± 2.3, p < 0.001), 6 months (3.0 ± 2.1, p < 0.001), and 9 months (3.0 ± 2.4, p < 0.001) post-procedure.  Nasal congestion and rhinorrhea sub-scores improved significantly at all time-points (p < 0.001).  Both allergic and non-allergic rhinitis sub-cohorts showed improvement (p < 0.001), with a comparable degree of improvement between groups.  RQLQ significantly improved over pre-treatment baseline (3.0 ± 1.0) at 3 months (1.5 ± 1.0, p < 0.001), and all RQLQ subdomains demonstrated improvement.  Of 54 patients using intra-nasal medication at baseline, 19 (35.2 %) were able to discontinue use; 29 AEs were reported, including headache, epistaxis, and sinusitis.  The authors concluded that the findings of this study suggested that cryoablation was a safe, effective, and feasible therapeutic option for medically refractory allergic and non-allergic rhinitis.

The authors stated that this study had several drawbacks.  Foremost, this study lacked a control treatment arm.  Also, the study was not blinded for either the provider or the patient, which may have introduced bias from both parties when reporting outcomes.  Future RCTs, perhaps incorporating a sham treatment arm, would be helpful to further validate the efficacy of PNN cryoablation.  Furthermore, the inclusion criteria required that patients had failed 4 weeks of intra-nasal corticosteroids (INCS) but did not explicitly require treatment failure with ipratropium or other non-steroidal medications.  Although many patients had tried other forms of medication in addition to INCS, these researchers acknowledged the possibility that some included study patients may still have benefited from other classes of intra-nasal medications as an alternative to cryosurgical treatment.  Additionally, although there was significant improvement in QOL outcomes by RQLQ at 90 days, RQLQ scores were not tracked beyond this time-point; therefore, limiting the ability to determine if RQLQ improvements remained durable in parallel with the improved rTNSS scores noted beyond 90 days.  Although it may be reasonable to assume that disease‐specific QOL correlated with rhinitis symptom metrics, and thus would remain improved at later time-points, future studies would benefit from tracking long‐term QOL outcomes in addition to long‐term symptom outcomes.  These researchers also acknowledged that 3 patients were excluded during the study period from subsequent outcome analysis upon resumption of ipratropium use.  Although excluded from the statistical analyses to avoid confounding effects of ipratropium use, these patients may have represented additional treatment failures.

Cancer Pain

In a systematic review, Ferrer-Mileo and colleagues (2018) evaluated the current scientific evidence on the use of cryoablation to control cancer pain.  These researchers carried out a systematic search of the Scopus, PubMed, and Cochrane databases.  All articles published before December 31, 2015, whose title or abstract specified cancer pain control as the end-point were selected.  Articles without abstracts and all non-systematic reviews were excluded.  A total of 22 articles were included: 1 RCT, 2 non-RCTs, 1 ambispective study, 9 retrospective studies, 2 non-specified cohort studies, 3 case series, and 4 case reports.  A total of 496 patients with 580 lesions were treated.  Lung cancer was the most common primary tumor; 82.8 % of the metastases were bone metastases, with or without soft tissue involvement.  Cryoablation decreased mean pain scores by 62.5 % at 24 hours post-cryoablation, by 70 % at 3 months, and by 80.9 % at 6 months.  Cryoablation was associated with a 44.2 % improvement in quality of life (QOL) after 4 weeks and a 59.6 % improvement at 8 weeks.  The need for opioids decreased by 75 % at 24 hours and by 61.7 % at 3 months.  Cryoablation in combination with radiotherapy, vertebroplasty, or bisphosphonates appeared to be better than cryoablation alone.  Complications were highly variable among the studies, but no fatal complications were reported.  The authors concluded that cryoablation was effective in controlling cancer pain without relevant side effects; however, they stated that more studies are needed to confirm these findings.

Cutaneous Sporotrichosis in Pregnant Women

Fichman and colleagues (2018) noted that pregnant women with sporotrichosis should not receive systemic anti-fungal therapy except in severe cases when amphotericin B is recommended.  Thermotherapy is the most reported treatment described in this group of patients.  It entails weeks of daily self-application of heat to the lesions, requires that the patient faithfully apply it, and it could cause skin burns.  Cryosurgery is a useful therapeutic tool for many cutaneous infectious diseases, safe for pregnant women, but not well-evaluated for sporotrichosis treatment in this group.  In a retrospective study, these investigators reviewed the clinical records of 4 pregnant patients diagnosed with cutaneous sporotrichosis and treated with cryosurgery.  Treatments were performed monthly up to clinical cure.  Molecular identification of the Sporothrix species was performed in 2 cases using T3B PCR fingerprinting assays.  All patients were in the 2nd trimester of pregnancy and their age ranged from 18 to 34 years.  With regard to clinical presentation, 2 patients had lympho-cutaneous and 2 had the fixed form; S. brasiliensis was identified in 2 cases as the causative agent.  Cryosurgery was well-tolerated and the number of sessions ranged from 1 to 3.  All the patients reached a complete clinical cure.  The authors concluded that these findings suggested that cryosurgery is a safe and well-tolerated; it is a promising alternative in the treatment of cutaneous sporotrichosis in pregnant women.  Moreover, these researchers stated that further studies with a larger number of patients are needed to confirm efficacy of cryosurgery for sporotrichosis in pregnant patients.

Fibro-Adipose Vascular Anomaly (FAVA) Lesion

Shaikh and colleagues (2016) noted that fibro-adipose vascular anomaly (FAVA) is a complex vascular malformation that typically presents with persistent pain, discomfort, contracture and other disabling symptoms.  There are no minimally invasive treatment options to effectively control these symptoms.  Image-guided percutaneous cryoablation, which has been used to control pain in people with cancer, could be used for similar indications in FAVA.  In a retrospective cohort study, these researchers examined the role of image-guided percutaneous cryoablation for control of symptoms in FAVA lesions.  A total of 20 children and young adults with FAVA who underwent percutaneous cryoablation at 26 sites, from September 2013 to August 2015 were included in this analysis.  The outcome was based on the brief pain inventory scoring (BPI), concurrent symptoms, clinical response and patient satisfaction.  After cryoablation, there was significant improvement in pain, which dropped by 3 points (pain now) to 3.7 points (pain in the last 24 hours).  Most patients indicated that pain interfered less in their everyday social life.  Concurrent symptoms like swelling, physical limitations and skin hyperesthesia also improved.  Clinical response was greatest at 2 to 5 months follow-up after cryoablation, with acceptable patient satisfaction thereafter.  Technical response was 100 %; there were no major complications.  The authors concluded that image-guided percutaneous cryoablation was a safe and effective option for treatment of symptomatic FAVA lesions.  This was a small (n = 20) retrospective study with short-term follow-up (2 to 5 months); its findings need to be validated by well-designed studies.

Metastatic Hepatocellular Carcinoma

Gosalia and colleagues (2017) stated that stated that hepato-cellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths worldwide.  Treatment of HCC has rapidly evolved with interventional radiology.  Percutaneous ethanol injection (PEI), RFA, microwave ablation (MWA), cryoablation, and trans-arterial chemo-embolization (TACE) are the major modalities utilized to control growth of HCC lesions.  Cryoablation has been less utilized as more advanced ablative techniques have emerged, but still plays a role in select patients.  The technique requires laparoscopy with direct application of a cryoprobe, with either liquid nitrogen or argon gas placed on the HCC lesion.  Freezing induces irreversible damage to the tissue.  Typically, 2 to 3 cycles are performed in a single session, and intra-operative ultrasound (US) is used to monitor tumor destruction in real time.  Cryoablation can be used as monotherapy or as part of a multi-modal therapeutic approach.  There are no RCTs evaluating the effectiveness of cryoablation compared to other ablative modalities, although retrospective trials and case-series studies have evaluated the efficacy of cryoablation.  One large series of patients receiving cryotherapy demonstrated a 39.8 % 5-year survival rate, and among the subset of patients with lesions less than 5 cm, survival was 55.4 %.  The main disadvantage of cryoablation is that it is most often performed laparoscopically and may cause morbidity in patients with advanced cirrhosis.  Complication rates have been reported to be upwards of 50 % and include coagulopathy, cardiac arrhythmia, and liver fracture.  However, percutaneous application of cryoablation may mitigate these risks.  The authors stated that cryoablation may have a role in special situations, such as treatment of residual disease at resection margins, but is rarely considered as a 1st-line therapy in the treatment of HCC.

Furthermore, an UpToDate review on “Nonsurgical local treatment strategies for colorectal cancer liver metastases” (Venook, 2018) states that “There is insufficient evidence to conclude that cryotherapy is of any benefit in patients with liver metastases from various primary sites.  Because of the availability of newer and safer modalities, cryotherapy is rarely used in this setting”.

Osteoid Osteoma

In a prospective, phase-I clinical trial, Miyazaki and colleagues (2018) evaluated the safety of percutaneous cryoablation for osteoid osteoma (OO).  A total of 9 patients with OO (mean tumor size of 5.9 mm; tibia, n = 5; femur, n = 2; lumbar spine, n = 2) were enrolled and treated with percutaneous cryoablation.  The primary end-point was the evaluation of the treatment safety as determined using step-by-step registration.  The secondary end-points were the incidence and grade of AEs by CTCAE version 4.0, and the short-term efficacy of this treatment.  Based on a decrease in the numerical rating scale (NRS) score, efficacy was classified as significantly effective (SE greater than or equal to 5 or reached 0 to 2), moderately effective (ME 2 to 4), or not effective (NE less than 2 or increase).  Cryoablation was completed in all patients; major AEs (greater than or equal to grade 3) related to the procedure were not observed; minor AEs (less than or equal to grade2) were observed in 22 to 67 %.  The mean NRS score was 7 before treatment, 0.6 at 4-week, 0.1 at 6-month, and 0 at 1-year post-treatment.  All procedures were classified as SE.  The authors concluded that percutaneous cryoablation is a safe treatment for OO.  Moreover, they stated that future phase-II clinical trials with large patient cohorts are needed.

Reduction of Pain or Opioid Consumption after Total Knee Arthroplasty

Tedesco et al (2018) stated there is increased interest in non-pharmacological treatments to reduce pain after total knee arthroplasty (TKA).  However, little consensus supports the effectiveness of these interventions.  These investigators systematically reviewed and meta-analyzed evidence of non-pharmacological interventions for post-operative pain management after TKA.  Database searches of Medline (PubMed), Embase (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Web of Science (ISI database), Physiotherapy Evidence (PEDRO) database, and ClinicalTrials.gov for the period between January 1946 and April 2016 were performed.  Randomized clinical trials comparing non-pharmacological interventions with other interventions in combination with standard care were included.  Two reviewers independently extracted the data from selected articles using a standardized form and assessed the risk of bias.  A random-effects model was used for the analyses.   Of 5,509 studies, 39 randomized clinical trials were included in the meta-analysis (2,391 patients).  The most commonly performed interventions included continuous passive motion (CPM), pre-operative exercise, cryotherapy, electrotherapy, and acupuncture.  Moderate-certainty evidence showed that electrotherapy reduced the use of opioids (mean difference [MD], -3.50; 95 % CI: -5.90 to -1.10 morphine equivalents in mg/kg/ 48 hours; p = 0.004; I2 = 17 %) and that acupuncture delayed opioid use (MD, 46.17; 95 % CI: 20.84 to 71.50 mins to the first patient-controlled analgesia; p < 0.001; I2 = 19 %).  There was low-certainty evidence that acupuncture improved pain (MD, -1.14; 95 % CI: -1.90 to -0.38 on a VAS at 2 days; p = 0.003; I2 = 0 %).  Very low-certainty evidence showed that cryotherapy was associated with a reduction in opioid consumption (MD, -0.13; 95 % CI: -0.26 to -0.01 morphine equivalents in mg/kg/48 hours; p = 0.03; I2 = 86 %) and in pain improvement (MD, -0.51; 95 % CI: -1.00 to -0.02 on the VAS; p < 0.05; I2 = 62 %).  Low-certainty or very low-certainty evidence showed that CPM and pre-operative exercise had no pain improvement and reduction in opioid consumption: for CPM, the MDs were -0.05 (95 % CI: -0.35 to 0.25) on the VAS (p = 0.74; I2 = 52 %) and 6.58 (95 % CI: -6.33 to 19.49) opioid consumption at 1 and 2 weeks (p = 0.32, I2 = 87 %), and for pre-operative exercise, the MD was -0.14 (95 % CI: -1.11 to 0.84) on the Western Ontario and McMaster Universities Arthritis Index Scale (p = 0.78, I2 = 65 %).  The authors concluded that in this meta-analysis, electrotherapy and acupuncture after TKA were associated with reduced and delayed opioid consumption.

Neuroendocrine Tumor

Quraishi et al (2012) noted that metastatic involvement of the sacrum is rare and there is a paucity of studies which deal with the management of these tumors since most papers refer to primary sacral tumors.  These investigators reviewed the available literature in the management of sacral metastatic tumors as reflected in the current literature.  They carried out a systematic review of the English language literature for relevant articles published over the last 11 years (1999 to 2010).  The PubMed electronic database and reference lists of key articles were searched to identify relevant studies using the terms "sacral metastases" and "metastatic sacral tumours".  Studies involving primary sacral tumors only were excluded.  For the assessment of the level of evidence quality, the CEBM (Oxford Centre of Evidence Based Medicine) grading system was utilized.  The initial search revealed 479 articles.  After screening, 16 articles identified meeting the inclusion criteria (1 prospective cohort study on radiosurgery [level II]; 2 case series [level III]; 4 retrospective case series [level IV] and 9 case reports [level IV]).  The authors concluded that the mainstay of management for sacral metastatic tumors is palliation.  Pre-operative angio-embolization was shown to be of value in cases of highly vascularized tumors.  Radiotherapy was used as the primary treatment in cases of inoperable tumors without spinal instability where pain relief and neurological improvement were attainable.  Minimal invasive procedures such as sacroplasties were shown to offer immediate pain relief and improvement with ambulation, whereas more aggressive surgery, involving decompression and sacral reconstruction, was utilized mainly for the treatment of local advanced tumors that compromised the stability of the spine or threatened neurological status.  Adjuvant cryosurgery and radiosurgery have demonstrated promising results (if no neurological compromise or instability) with local disease control.

Lee et al (2013) stated that multiple therapeutic options have been introduced for the treatment of sacral tumoral bone pain.  These options include pre-operative sacral embolization, percutaneous cryoablation, alcohol ablation, and sacroplasty.  The authors showed that in the correct clinical scenario, a combination of the 4 procedures performed as a 2-stage process could effectively treat tumoral bone pain refractory to medical therapy. Moreover, these researchers stated that further studies are needed to examine the effectiveness of this approach in carefully selected patients with extensive sacral tumoral disease.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Neuroendocrine and adrenal tumors” (Version 1.2019) states that "Cytoreductive surgery or ablative therapies suvh as radiofrequency ablation (RFA) or cryoablation may be considered if near-complete treatment oftumor burden can be acheived (category 2B)".

Colon Cancer

Onik et al (1991) noted that cryosurgery has been proposed in the past as a possible treatment for unresectable hepatic tumors.  Its advantage lies in the fact that it is a very focal treatment sacrificing less normal tissue than surgical resection, allowing treatment of multiple lobes.  Because cryosurgery does not affect large vessels, tumors in difficult locations, such as adjacent to the inferior vena cava (IVC), can be treated.  With the use of intra-operative ultrasound (US) to place the cryoprobes and monitor the freezing process, 18 patients with unresectable metastatic colon carcinoma confined to the liver were treated.  Of the 18 patients treated, 4 (22 %) were in complete remission (CR) as determined by computed tomography (CT) scans and carcino-embryonic antigen (CEA) levels, with a mean follow-up of 28.8 months; 4 patients (22 %) were not adequately treated at the time of cryosurgery.  The number of lesions frozen in each patient ranged from 1 to 12, with a mean of 6 lesions; 14 patients had bi-lobar disease; 3 patients had previous right lobectomies with recurrences in their remaining left lobes prior to cryosurgery, and 1 patient had uni-lobar disease.  Mean survival of the 14 cases with recurrence was 21.4 months, with 2 of the 14 still alive.  The authors concluded that US-guided hepatic cryosurgery appeared to be an effective treatment for metastatic colon carcinoma to the liver that was unresectable (including patients with bi-lobar and multiple lesions).  These researchers stated that these preliminary results indicated that the procedure warrants further study.

de Baere et al (2015) examined the feasibility, safety and local tumor control of cryoablation for treatment of pulmonary metastases.  This Health Insurance Portability and Accountability Act (HIPAA) compliant, institution review board (IRB)-approved, prospective, single-arm, multi-center study included 40 patients with 60 lung metastases treated during 48 cryoablation sessions, with currently a minimum of 12 months of follow-up.  Patients were enrolled according to the following key inclusion criteria: 1 to 5 metastases from extra-pulmonary cancers, with a maximal diameter of 3.5 cm.  Local tumor control, disease-specific survival (DSS) and overall survival (OS) rates were estimated using the Kaplan-Meier method.  Complications and changes in physical function and quality of life (QOL) were also evaluated using Karnofsky performance scale, Eastern Cooperative Oncology Group performance status (ECOG – PS) classification, and Short Form-12 health survey.  Patients were 62.6 ± 13.3 years old (26 to 83).  The most common primary cancers were colon (40 %), kidney (23 %), and sarcomas (8 %).  Mean size of metastases was 1.4 ± 0.7 cm (0.3 to 3.4), and metastases were bilateral in 20 % of patients.  Cryoablation was performed under general anesthesia (67 %) or conscious sedation (33 %).  Local tumor control rates were 56 of 58 (96.6 %) and 49 of 52 (94.2 %) at 6 and 12 months, respectively.  Patient's QOL was unchanged over the follow-up period; 1-year OS rate was 97.5 %.  The rate of pneumothorax requiring chest tube insertion was 18.8 %.  There were 3 Common Terminology Criteria for Adverse Events grade-3 procedural complications during the immediate follow-up period (pneumothorax requiring pleurodesis, non-cardiac chest pain, and thrombosis of an arterio-venous fistula), with no grade 4 or 5 complications.  The authors concluded that cryoablation was a safe and effective treatment for pulmonary metastases with preserved quality of life following intervention.

A Cochrane review of cryoablation for liver metastases (Bala et al, 2013) concluded that "there is insufficient evidence to conclude if in patients with liver metastases from various primary sites cryotherapy brings any significant benefit in terms of survival or recurrence compared with conventional surgery".

Adrenal Gland Metastases from Renal Cell Carcinoma

Beland and Mayo-Smith (2009) noted that adrenal tumors represent a diverse group of neoplasms that include multiple etiologies, each with a different prognosis, malignant potential, and recommended treatment.  Percutaneous techniques to treat adrenal neoplasms have been described including RFA, cryoablation, and chemical ablation.

Venkatesan and colleagues (2010) stated that adrenal tumors comprise a broad spectrum of benign and malignant neoplasms and include functional adrenal adenomas, pheochromocytomas, primary adrenocortical carcinoma, and adrenal metastases.  Percutaneous ablative approaches that have been described and used in the treatment of adrenal tumors include percutaneous chemical ablation, cryoablation, MWA, and RFA.

In a retrospective review, Welch and colleagues (2011) examined the safety, technical success, complications, and hemodynamic changes associated with the adrenal cryoablation procedure.  This study was approved by the IRB, with waiver of informed consent, and was compliant with the HIPAA.  Adult patients with adrenal metastasis who were treated with adrenal cryoablation between May 2005 and October 2009 were eligible for this review.  A total of 12 patients (undergoing 13 procedures) with single adrenal tumors were included in the analysis.  For statistical analysis, hemodynamic data were averaged for the patient undergoing the procedure twice.  Technical success, safety, and local control were analyzed according to standard criteria.  Hemodynamic changes during the procedure were analyzed and compared with data from an unmatched cohort of patients who underwent kidney (not in the upper pole) cryoablation (Wilcoxon rank sum test).  A further sub-analysis of hemodynamic changes was carried out on the basis of whether pre-procedural alpha- or beta-adrenergic blockade was used.  With adrenal cryoablation, local control was achieved following treatment in 11 (92 %; 95 % CI: 65.1 % to 99.6 %) of 12 tumors; 1 patient with known adrenal insufficiency underwent conservative ablation and developed ipsilateral adrenal recurrence, which was re-treated; 5 patients developed hypertensive crisis during the final, active thaw phase of the cryoablation procedure, and 1 patient developed hypertensive crisis in the immediate post-ablation period.  Patients undergoing adrenal cryoablation experienced a significant increase in systolic blood pressure (SBP; p = 0.005), pulse pressure (p = 0.02), and mean arterial pressure (p = 0.01) when compared with the cohort of kidney cryoablation patients.  Adrenal cryoablation patients who were not pre-medicated with an alpha-blocker (n = 5) had a higher level of SBP increase during the cryoablation procedure when compared with their counterparts who were pre-medicated (n = 7) (p = 0.034).  The authors concluded that adrenal cryoablation was technically feasible with a high rate of local control.  Patients pre-medicated with the alpha-blocker phenoxybenzamine appeared to have a reduced risk of hypertensive crisis.

Ierardi and associates (2020) noted that while surgery represents the gold standard for the treatment of adrenal primary malignant tumors, metastatic involvement of the adrenal glands is generally approached conservatively; however, surgery for local control has been controversial, and several reports have described the utility of surgical removal in terms of prolonged survival in selected patients.  Different techniques, including chemical ablation, cryoablation, laser induced thermal therapy (LITT), MWA, and RFA are employed in percutaneous image-guided ablation for primary and metastatic malignancies of the adrenal glands, in case of patients with multiple co-morbidities or who refuse surgery.  Technical success, clinical success and safety were analyzed and discussed in this systematic review.  For cryoablation, the response rate in terms of complete/partial ablation after the 1st ablation was high (90.3 % to 92 %); moreover, patients with residual disease were all successfully re-treated in subsequent sessions.  Tumor size was found a significant determinant for local disease control; histology of the primary malignancy and co-existence of tumor elsewhere were correlated with prognosis.  These researchers stated that although a consensus has not been achieved yet on a threshold tumor size, better results have been reported for adrenal masses smaller than 5 cm.  Other investigators reported a lower threshold, i.e., 4 cm or even 3 cm for lesions successfully treated with a single ablative session, or to prevent local tumor progression.  These procedures were found to be feasible and safe, with hypertensive crisis representing the most common complication.  The authors concluded that although there is lack of evidence in the literature concerning outcomes compared with surgery, percutaneous ablation may represent a useful therapeutic option for controlling unresectable adrenal metastases, offering patients opportunities for improved survival.

Barrett Esophagus-Associated Neoplasia

Hamade and associates (2019) noted that cryotherapy has been used as salvage therapy; however, its efficacy as 1st-ine treatment in patients with Barrett's esophagus (BE)-associated neoplasia has not been well studied.  In a systematic review, these researchers examined the efficacy of cryotherapy as the primary treatment of BE.  They carried out an electronic data-base search (PubMed, Embase, Cochrane, and Google Scholar) to identify studies with cryotherapy as the initial primary modality of ablation in patients with BE-associated neoplasia.  Studies that included patients with other prior forms of therapy were excluded.  The primary outcomes were the pooled rates of complete eradication of intestinal metaplasia (CE-IM) and CE of neoplasia (CE-N); secondary outcomes were recurrence rates of neoplasia and intestinal metaplasia (IM) and AEs.  The statistical software OpenMetaAnalyst was used for analysis with pooled estimates reported as proportions (%) with 95 % CI with heterogeneity (I2) among studies.  The search revealed 6 eligible studies with a total of 282 patients (91.5 % men, average age of 65.3 years) with 459 person-years of follow-up; 69.35 % [95 % CI: 52.1 % to 86.5 %)] of patients achieved CE-IM and 97.9 % (95 % CI: 95.5 % to 100 %) had CE-N; 7.3 % of patients had persistent dysplasia with 4 % progressing to cancer.  The recurrence rate of neoplasia was 10.4 and that of IM was 19.1 per 100 patient-years of follow-up.  The overall rate of stricture formation was 4.9 %.  There were scarce data on the use of cryotherapy as the primary modality for the treatment of BE dysplasia.  The authors concluded that the published data demonstrated efficacy rates of 69 % and 98 % for complete eradication of metaplasia and neoplasia, respectively.  Moreover, these researchers stated that these findings need to be examined in prospective, comparative trials with other forms of therapy.

Westerveld and colleagues (2020) stated that balloon cryoablation (BC) is a novel procedure for endoscopic ablation of Barrett esophagus (BE)-associated neoplasia.  In a systematic review and meta-analysis, these investigators examined the feasibility, safety and effectiveness of BC for treatment of BE-associated neoplasia.  Several data-bases were searched for relevant articles (PubMed, Web of Science, Google Scholar, Embase) as well as abstracts of recent gastroenterology meetings.  Data extraction was carried out by 2 investigators using standardized forms, including age, gender, length of BE segment, prior treatments, procedural time and number ablation sessions, technical feasibility, AEs, and eradication rates of intestinal metaplasia (CE-IM) and dysplasia (CE-D) at follow-up.  Quality of the studies was assessed using a modified Newcastle Ottawa Scale.  A total of 7 studies met inclusion criteria for a total of 548 ablation sessions in 272 patients.  The most common histopathology reported prior to BC was high-grade dysplasia (n = 131), followed by low-grade dysplasia (n = 75), and intramucosal adenocarcinoma (n = 52).  The pooled rate for technical feasibility was 95.8 % (95 % CI: 93.6 to 97.5 %; I2 = 13.2 %; p = 0.3).  Pooled rates of CE-IM and CE-D were 85.8 % (95 % CI: 77.8 to 92.2 %, I2 = 55.5 %; p = 0.04) and 93.8 % (95 % CI: 85.5 to 98.7 %, I2 = 74.2 %; p = 0.001), respectively.  The overall AE rate was 12.5 % (34 out of 272 patients), of which stricture formation was the most common (5.8 %), followed by mucosal laceration (0.7 %), perforation (0.4 %), and bleeding (0.4 %).  All AEs were successfully managed endoscopically.  The authors concluded that the findings of this meta-analysis suggested that BC is a safe and effective ablative technique for treatment of BE-associated neoplasia; future prospective comparative trials are needed to corroborate these initial findings.

Guidelines on esophageal cancer from the National Comprehensive Cancer Network (NCCN, 2020) recommend consideration of cryoablation for residual or recurrent esophageal dysplasia. "Endoscopic cryoablation has been reported to be safe and well-tolerated in patients with Barrett esophagus and early stage esophageal cancers."   

Painful Vascular Tumors (Epithelioid Hemangioma)

Koch and colleagues (2018) stated that benign bone tumors consist of a wide variety of neoplasms that do not metastasize but can still cause local complications.  Historical management of these tumors has included surgical treatment for lesion resection and possible mechanical stabilization.  Initial percutaneous ablation techniques were described for osteoid osteoma management.  The successful experience from these resulted in further percutaneous image-guided techniques being attempted, and in other benign bone tumor types.  These investigators presented the most common benign bone tumors and described the available results for the percutaneous treatment of these lesions.  These researchers noted that vertebral hemangiomas (VH) are benign vascular lesions involving the spine with an incidence of 10 to 12 %, usually found in young adults, with a slight female predilection.  Most VH are latent and do not require specific treatment; only 1 % of VH become symptomatic.  Pain and aggressiveness, by its extension into the spinal canal or to the paravertebral space, are indications of a symptomatic VH.  Many tumor ablation techniques have been described including cryoablation, embolization, ethanol treatment, radiosurgery, radiotherapy, and vertebroplasty.

Bone Metastases from Prostate Cancer

Coupal et al (2017) stated that metastases to the bone are common in cancer patients, and it has been estimated that up to 50 % of patients with pelvic bone metastases will not achieve adequate pain control with medications alone.  This has led to a paradigm shift over recent years towards the use and development of minimally invasive image-guided therapeutic options for palliation of bony metastases.  Despite these developments, large metastatic lesions are still often considered to be "hopeless cases" that would garner little to no benefit from image-guided intervention.  This study was the 1st large series study to describe the novel use of combination percutaneous cryoablation and cementoplasty for palliation of such large metastases to the pelvis.  In a retrospective analysis, these researchers examined the safety and efficacy of image-guided percutaneous cryoablation and cementoplasty for palliation of large pelvic bone metastases.  This trial was approved by the authors’ institutional review board (IRB), and was conducted from January 2013 to December 2016, where consecutive patients referred for pain management of large pelvic bone metastases underwent combination percutaneous cryoablation and cementoplasty.  It took place at a tertiary care center after patients were referred following formal review from a multi-disciplinary conference, which was comprised of interventional radiologists, pain management and palliative care physicians, radiation and medical oncologists, and when available, anesthesiologists.  A total of 48 patients (36 men and 12 women) with a mean cohort age of 77.5 years (range of 52 to 89 years) were referred from the multi-disciplinary conference for palliation of pelvic bone metastases.  The inclusion criteria included patients with metastases greater or equal to 5.0 cm and significant pain refractory to conventional pain management regimens.  All of the patients were deemed not to be surgical candidates.  Mean pain scores were collected at numerous time-points along with procedural technical success rates and complication rates.  Combination cryoablation and cementoplasty was performed on 48 consecutively referred patients with a 100 % technical success rate and no immediate complications.  The pain levels demonstrated a significant decrease (p < 0.001) following intervention, with mean pain scores of 7.9 (range of 5 to 10) and 1.2 (range of 0 to 7) throughout the week prior to intervention and at 24 hours post-intervention, respectively.  The post-intervention pain scores remained stable at 1 to 9 weeks follow-up (mean of 4.1 weeks); 3 patents (6.3 %) reported no change in pain following the intervention; however, no patients reported worsened pain.  The authors concluded that combination cryoablation and cementoplasty is a novel and efficacious therapeutic option for palliation of large pelvic bone metastases.  Marked improvements in pain, as well as mobility and quality of life (QOL), were often attainable.  The authors stated that the drawbacks of this study included its retrospective nature and the length of follow-up, which was often restricted given the life expectancy of this patient cohort.  These findings were also confounded by the combined use of cryoablation and cementoplasty.

Furthermore, an UpToDate review on “Bone metastases in advanced prostate cancer: Management” (Sartor and DiBiase, 2020) does not mention cryoablation as a therapeutic option.

Desmoid Tumors of the Extremities and the Trunk

Gomez et al (2014) stated that ablation techniques are widely used for solid malignant tumors in adults.  There is no large series assessing the effectiveness of local ablative therapies in the treatment of malignant or aggressive benign lesions in children.  These investigators reviewed the existing evidence on the techniques and results of ablation for pediatric solid malignant or aggressive benign tumors.  They searched Medline for papers published between 1995 and 2012 that reported outcomes of radiofrequency (RF), microwave and cryoablation, interstitial laser therapy, irreversible electroporation and percutaneous ethanol injection for patients younger than 18 years old.  Data collection included factors related to the patient, tumor biology, ablation technique and cancer-specific endpoints.  Additional series of predominantly adults including data on patients younger than 18 years old were also identified.  These researchers identified 28 patients treated by ablation in 29 regions: 5 patients undergoing ablation for liver lesions, 9 patients for lung metastases, 11 patients for bone and/or soft tissue and 4 patients for kidney or pancreas.  The ablation was performed to treat primary tumors, local recurrences and metastases.  The histology of the tumors was osteosarcoma in 6 patients, Wilms tumor in 3, rhabdomyosarcoma in 3, hepatoblastoma in 3, desmoid tumor in 3, adrenocortical carcinoma in 2, and a single case each of leiomyosarcoma, Ewing sarcoma, paraganglioma, solid-pseudopapillary neoplasm, sacrococcygeal teratoma, hepatic adenoma, juxtaglomerular cell tumor and plantar fibromatosis; 18 of the patients (64 %) experienced a complication, but only 6 (21 %) of these needed treatment other than supportive care.  The authors concluded that although ablative techniques are feasible and promising treatments for certain pediatric tumors, large, prospective, multi-center studies are needed to establish their efficacies.

Schmitz et al (2016) stated that extra-abdominal desmoid (EAD) tumors pose a therapeutic challenge because they often recur locally and behave aggressively.  Accepted management options include surgery, radiation, chemotherapy, and observation.  These researchers examined the safety and efficacy of percutaneous cryoablation for the treatment of EAD tumors.  They carried out a retrospective search of their cryoablation data-base to identify patients with EAD tumors treated with percutaneous cryoablation between June 15, 2004 and June 15, 2014.  During this 10-year time period, these researchers treated 18 patients with 26 discrete tumors during 31 treatment sessions.  After cryoablation, contrast-enhanced (CE) MRI or CT was performed.  Any enhancing soft tissue was considered viable EAD tumor and was measured in 3 planes.  Of the 26 EAD tumors treated, follow-up imaging with IV contrast material was available for 23 tumors.  The mean imaging follow-up was 16.2 ± 20.0 (standard deviation [SD]) months.  All 31 sessions were technically successful procedures.  No residual viable EAD tumor was observed in 9 of 23 tumors (39.1 %).  Some degree of volume reduction was evident in 22 of 23 tumors (95.7 %).  Progressive disease was observed in 1 of the 23 tumors (4.3 %).  Of the cases with residual or progressive disease, the recurrence occurred at the margin of the treated tumor in all cases.  No major complications were observed, and none of the complications was more severe than Clavien-Dindo grade-I.  The authors concluded that percutaneous cryoablation was a safe, effective, and repeatable treatment for achieving local control of EAD tumors.  Moreover, these researchers stated that a prospective study of cryoablation is needed to define the role of cryoablation in the overall treatment of EAD tumors.  The drawback of this study included its retrospective nature, small sample size (n = 18 subjects), variable follow-up, and the fact that 24 of the 26 tumors had received prior therapies that had failed.

Colangeli et al (2018) stated that cryotherapy, also called cryoablation (CA), is a technique that provides a local treatment to various pathological conditions.  In musculo-skeletal tumors management, CA is accepted and validated as a treatment in palliative cures for metastatic patients.  Recently, CA has been proposed also as an alternative to RF ablation (RFA) in osteoid osteoma and other benign tumor treatment with promising results.  Cryotherapy with argon ice-balls as local adjuvant in open surgery is a tool that can provide enlargement of surgical margins if used properly; however, there is still inadequate evidence supporting use of CA as local adjuvant in musculo-skeletal open surgery as the series cited above were very small and there was no comparative RCT between local adjuvant therapies including CA.  In a retrospective, case-series study, a total of 183 patients were treated with CA from 2000 and 2018 in the Musculoskeletal Tumors Surgery Unit of Careggi (Florence) and the University 2nd Clinic of Pisa.  In this study group, 38 patients (26.6 %) were affected by bone metastasis, 16 patients (11.1 %) by aneurismal bone cysts or angiomas, 22 patients (15.4 %) by low-grade malignant musculo-skeletal tumors, 2 patients (1.4 %) by fibromatosis, 63 patients (44.1 %) by benign musculo-skeletal tumors (principally giant cell tumors-GCT) and 2 patients (1.4 %) by osteosarcomas.  In 125 cases (87.4 %), CA has been used as an adjuvant therapy, in 12 cases (8.4 %) as a percutaneous ablation therapy and in 6 cases (4.2 %) as adjuvant to remove tumoral lesions “en bloc” or as a “poor technique” for its sterilizing effect on previously resected bones.  Mean follow-up was 10 years; 23 patients (16 %) were classified as “alive with disease (AWD)” due to local recurrence or tumor progression (14 metastases, 5 low-grade malignant bone tumors, 4 GCTs); 8 patients died due to the disease (6 metastases, 2 osteosarcomas), while 1 died from leukemia; 111 patients (78 %) were classified as “continues disease free (CDF)”.  All patients reported decrease in pain-related symptoms after surgery and all surgeons reported better control of blood loss; 3 cases (2 %) of local skin necrosis or wound dehiscence were reported.  No local recurrences were reported after fibromatosis ablation.  The authors concluded that these findings confirmed that CA could be considered as a safe and effective technique to treat various conditions as adjuvant and palliative therapy.  In particular, in open surgery, cryotherapy as an adjuvant treatment could lead to very low rates of recurrence in locally aggressive tumors like GCTs.  Moreover, these researchers stated that these results could be generalized but a better understanding about indications and outcomes can be reached studying CA in specific populations with comparation to other adjuvant techniques.

Redifer Tremblay et al (2019) noted that desmoid tumors are rare locally invasive, benign neoplasms that develop along aponeurotic structures.  Current treatment is complicated by associated morbidity and high recurrence rates.  In a retrospective, single-institution review, these investigators identified 23 patients (age of 16 to 77 years) with EAD tumors who received CT-guided percutaneous CA as either a 1st-line (61 %) or salvage (39 %) treatment in 30 sessions between 2014 and 2018.  Median maximal lesion diameter was 69 mm (range of 11 to 209).  Intent was curative in 52 % and palliative in 48 %; CE cross-sectional imaging was obtained before and after treatment in addition to routine clinical follow-up.  Technical success was achieved in all patients.  The median follow-up was 15.4 months (3.5 to 43.4).  Symptomatic improvement was demonstrated in 89 % of patients.  At 12 months, the average change in viable volume was  -80 % (range of -100 % to  + 10 %) and response by modified response evaluation criteria in solid tumors (mRECIST) was CR 36 %, PR 36 %, and SD 28 % .  No rapid post-ablation growth or track seeding was observed; 4 patients underwent repeat CA for either residual or recurrent disease; 2 patients sustained a major procedural complication consisting of significant neuropraxia.  The authors concluded that CA for desmoid tumors demonstrated a high degree of symptom improvement and local tumor control on early follow-up imaging with relatively low morbidity.  Moreover, these researchers stated that while early recurrence rates were favorable, additional long‐term follow‐up studies are needed to ascertain whether disease control rates compare favorably with current standards of care in this very persistent disease.

The authors stated that this study had several drawbacks as a small (n = 23), retrospective series with variable follow‐up times.  It was important to highlight that the current patient cohort was heterogenous and comprised of several distinct patient groups that should be considered somewhat separately.  A key distinction was between the subset in which a complete A0 ablation with an intent to cure can be performed safely and the subset in which it could not, usually due to pre‐existing proximity to or invasion of critical structures, most often nerves, which would carry unacceptable morbidity if injured.  In these cases, only partial ablation was performed with the intent to debulk the tumor mass for palliative symptom control, which inherently biased the collective imaging response of the cohort.  Notably, this series did not include any patients with intra-abdominal desmoid lesions, which are typically are more aggressive, more difficult to treat with ablation, and more prone to recurrence.

de Bruyns et al (2020) noted that due to the rarity and varied natural history of desmoid-type fibromatosis, evidence-based treatment standards for this disease remain lacking.  These researchers evaluated outcomes in patients with desmoid-type fibromatosis managed at a Canadian institution over the past 20 years.  Records of 227 patients with desmoid-type fibromatosis referred from 1990 to 2013 were retrospectively reviewed to examine management strategies including active surveillance, surgery, radiation therapy, CA, and systemic therapy, including tamoxifen and chemotherapy; 32 % of cases were men, median age of 40 years, median tumor size of 5.4 cm.  Initial treatments were surgery (79 %), tamoxifen (13 %), radiation therapy (5.0 %), chemotherapy (1.8 %) and CA (1.2 %).  Active surveillance was used upfront in 26 % of cases, most after 2005.  At a median follow-up of 77 months, 1 patient died of disease, 13 died of unrelated causes and the remainder were alive with no evidence of disease (56 %), stable/responding disease (33 %) or progressive disease (4 %).  The recurrence rate was 25 % after upfront surgery.  Response rates and disease control rates were 40 % and 76 % for active surveillance; 68 % and 96 % for radiation therapy; 31 % and 67 % for tamoxifen; and 53 % and 80 % for chemotherapy.  On univariable analysis, factors associated with a higher recurrence after initial surgery were young age (p = 0.012), male gender (p = 0.012) and extremity location (p = 0.005).  On multivariable analysis, only young age was significantly associated with recurrence risk (p = 0.010).  The authors concluded that active surveillance was associated with spontaneous regression and long-term disease control consistent with other studies.  Primary radiation therapy appeared to provide a similar response and disease control compared with systemic treatments and may be a viable option for patients who are not candidates for surgery or active surveillance.

Saltiel et al (2020) stated that CA has gained popularity in the treatment of benign and malignant musculo-skeletal tumors.  While EAD tumors are not malignant, they remain challenging to treat because of their high local recurrence rate.  These researchers reviewed all EAD tumors treated with CA at their institution between November 2012 and March 2020.  A total of 14 procedures were carried out on 9 females and 1 male (mean age of 33 ± 18 years) as either 1st-line (n = 4) or salvage therapy (n = 6) with curative intent (n = 8) or tumor debulking (n = 2).  Mean tumor size was 63.6 cm3 (range of 3.4 to 169 cm3); CE-MRI was carried out before treatment and at 3-, 6-, and 12-month follow-up.  Treatment outcome was based on the change in enhanced tumor volume (ET-V).  For curatively treated patients, the mean ET-V change was -97 ± 7 %, -44 ± 143 %, and +103 ± 312 % at 3, 6, and 12 months, respectively.  For debulking patients, the mean ET-V change was -98 ± 4 %, +149 ± 364 %, and +192 ± 353 % at 3, 6, and 12 months, respectively.  During a mean follow-up of 53.7 months (range of 12 to 83 months), 1 grade-III and 1 grade-IV complication were observed.  The authors found CA to be safe and well-tolerated in patients with EAD.  Moreover, these researchers stated that prospective studies with long-term follow-up are required to clarify the safety and efficacy of CA and to further establish its place in the treatment of EAD tumors.

The authors stated that the drawbacks of this study were related to the inherent bias of retrospective studies.  Furthermore, these investigators included only a small number of patients (n = 10).  Other drawbacks were the heterogeneity of the guidance modality (percutaneous versus open surgery) and the presence of concurrent additional treatments (e.g., chemotherapy or isolated limb perfusion); thus, the statistical analyses may be of limited value.

Furthermore, an UpToDate review on “Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy” (Ravi et al, 2020) does not mention cryoablation as a therapeutic option.

Pathologic Compression Fracture Due to Multiple Myeloma

Smith (2012) stated that treatments for painful osseous metastases may not only diminish pain, but also may improve quality of life (QOL) and independence/mobility, and reduce skeletal morbidity, potential pathologic fractures, spinal cord compression, and other "skeletal-related events".  Treatment strategies for painful osseous metastases include: Systemic analgesics, intrathecal analgesics, glucocorticoids, radiation (external beam radiation, radiopharmaceuticals), ablative techniques [radiofrequency ablation (RFA) and cryoablation], bisphosphonates, chemotherapeutic agents, inhibitors of RANKL-RANK interaction (e.g., denosumab), hormonal therapies, interventional techniques (e.g., kyphoplasty), and surgical approaches.  The mechanisms underlying the development of bone metastases remain incompletely understood.  A greater understanding of the pathophysiology of painful osseous metastases may lead to improved and more selective targeted analgesic therapy.  Furthermore, potential future therapeutic approaches to painful osseous metastases may revolutionize approaches to analgesia for this condition, leading to optimal outcomes with maximal pain relief and minimal adverse effects.

Desmoid Tumor (Aggressive Fibromatosis)

National Comprehensive Cancer Network’s clinical practice guideline on “Soft tissue sarcoma” (Version 2.2021) states that “For patients presenting with disseminated disease …the guideline have included ablation procedures (e.g., radiofrequency ablation [RFS] or cryotherapy) or SBRT as options for symptomatic patients”.

Fibro-Adipose Vascular Anomaly (FAVA) Lesions

Shaikh et al (2016) stated that fibro-adipose vascular anomaly (FAVA) is a complex vascular malformation that typically presents with persistent pain, discomfort, contracture and other disabling symptoms.  There are no minimally invasive therapeutic options to effectively control these symptoms.  Image-guided percutaneous cryoablation, which has been used to control pain in patients with cancer, could be used for similar indications in FAVA.  In a retrospective cohort stud, these researchers examined the role of image-guided percutaneous cryoablation for control of symptoms in FAVA lesions. This trial included 20 children and young adults with FAVA who underwent percutaneous cryoablation at 26 sites, from September 2013 to August 2015.  The outcome was based on the brief pain inventory (BPI) scoring, concurrent symptoms, clinical response and patient satisfaction.  After cryoablation there was significant improvement in pain, which dropped by 3 points (pain now) to 3.7 points (pain in the last 24 hours).  Most patients indicated that pain interfered less in their everyday social life.  Concurrent symptoms like swelling, physical limitations and skin hyperesthesia also improved.  Clinical response was greatest at 2 to 5 months follow-up following cryoablation, with acceptable patient satisfaction thereafter.  Technical response was 100 %; and there were no major complications.  The authors concluded that image-guided percutaneous cryoablation was a safe and effective therapeutic option for symptomatic FAVA lesions.

Lipede et al (2021) described their experience in managing FAVA at a tertiary level pediatric hospital and offered a therapeutic algorithm.  These investigators carried out a retrospective review of 27 patients with proven FAVA.  All patients had undergone MRI and US evaluation.  Patient demographics, presenting concerns, treatment methods, and outcomes were recorded and evaluation with the pediatric outcomes data collection instrument (PODCI) completed a minimum of 12 months after definitive treatment.  Mean age at presentation was 8.9 years (range of 9 months to 17.4 years) and mean post-treatment follow-up was 7.4 years (range of 2 to 11.6 years); 20 of 27 lesions affected the lower limb.  Severe neurogenic-type pain was present in 23 cases and contractures across joints in 11 cases.  Sclerotherapy with sodium tetradecyl sulphate was used in 11 cases, with no improvement in symptoms.  Cryoablation provided pain relief in 3/4 cases; however, contracture subsequently increased in 1 patient and pain recurred in another; 14 cases underwent surgery (4 surgical excisions alone, 10 in combination with other procedures); 3 patients required 4 further surgical procedures that included 1 amputation for intractable pain and poor function.  PODCI evaluations suggested overall good function, with surgical management and interventional radiology that provided comparable results.  Surgery did correct deformity.  The authors concluded that if conservative measures or cryoablation failed to achieve symptomatic control, surgical excision should be considered, combined with adjunctive procedures, to correct contractures and balance muscle forces.  Relief of pain may compensate for the loss of muscle mass and overall improves function.

Furthermore, an UpToDate review on “Peripheral arteriovenous malformations” (Shortell and Geersen, 2021) states that “Fibro-Adipose Vascular Anomaly (FAVA) is a complicated vascular malformation gaining greater recognition, especially after initial therapies have failed or when the patient has had rapid recurrence, often resulting in the hallmark of a painful extremity with contracture, phlebectasia, and fibrofatty infiltration of muscle.  In studies first delineating the radiographic features of FAVA, it was noted to occur preponderantly in females, presenting from birth to 28 years of age, with sites in the extremities (calf, wrist, thigh) more common.  Many patients present with pain, limited joint movement, and imaging that demonstrates extra fascial features consisting of dense fibrous tissue, fat, and lymphoplasmacytic aggregates with atrophy of the muscle.  Adipose tissue tends to infiltrate the muscle at the periphery of the lesion.  Often, large, irregular, and excessively muscularized venous channels and clusters of veins are involved with lymphatic tissue, giving the lesions a "low-flow" lesion appearance.  Given the rapid recurrence with traditional treatments for FAVA, alternatives have been sought.  Cryoablation has been used, with improvement in pain and physical limitations and skin hyperesthesia in follow-up to five months from intervention”.

Intercostal Nerves for Post-Operative Analgesia After Placement of Left Ventricular Assist Device / Video-Assisted Thoracoscopic Surgery

An UpToDate review on “Anesthesia for placement of ventricular assist devices” (Maisonave and Nicoara, 2021) states that “Management of Postoperative Pain -- Patients remain intubated and sedated with controlled mechanical ventilation during the immediate postoperative period.  Standard systemic analgesic pain management strategies are employed.  Continuous erector spinae plane block has been described as an analgesic option after left ventricular assist device (LVAD) implantation”.  This review does not mention cryoablation as a management option.

Furthermore, an UpToDate review on “Practical management of long-term mechanical circulatory support devices” (Mancini, 2021) does not mention cryoablation as a management option.

Harbaugh et al (2018) examined post-operative outcomes after minimally invasive repair of pectus excavatum (Nuss procedure) using video-assisted intercostal nerve cryoablation (INC) compared to thoracic epidural (TE).  These researchers carried out a retrospective, single-center review of pediatric patients who underwent Nuss procedure with INC (n = 19) or TE (n = 13) from April 2015 to August 2017.  Pre-operative, intra-operative, and post-operative characteristics were collected.  The primary outcome was length of stay (LOS) and secondary outcomes were intravenous and oral opioid use, pain scores, and complications.  Opioids were converted to oral morphine milligram equivalents per kilogram (oral morphine equivalent [OME]/kg).  Mann-Whitney U test was used for continuous and Chi-square analysis for categorical variables.  There were no significant differences in patient characteristics, except Haller Index (INC: median [inter-quartile range] 4.3 [3.6 to 4.9]; TE: 3.2 [2.8 to 4.0]; p = 0.03).  LOS was shorter with INC (INC: 3 [3 to 4] days; TE: 6 [5 to 7] days; p < 0.001).  Opioid use was higher intra-operatively (INC: 1.08 [0.87 to 1.37] OME/kg; TE: 0.46 [0.37 to 0.67] OME/kg; p = 0.002) and unchanged post-operatively (INC: 1.78 [1.26 to 3.77] OME/kg; TE: 1.82 [1.05 to 3.37] OME/kg; p = 0.80), and prescription doses were lower at discharge in INC (INC: 30 [30 to 40] doses; TE: 42 [40 to 60] doses; p = 0.005).  There was no significant difference in post-operative complications (INC: 42.1 %; TE: 53.9 %; p = 0.51).  The authors concluded that INC during Nuss procedure reduced LOS, shifting post-operative opioid use earlier during admission.  This may reflect the need for improved early pain control until INC took effect.  Moreover, these researchers stated that prospective evaluation after INC is needed to characterize long-term pain medication requirements.   This was a retrospective, small (n = 19 in the video-assisted intercostal nerve cryoablation group) study; its findings need to be validated by well-designed studies.

Furthermore, an UpToDate review on “Overview of minimally invasive thoracic surgery” (Demmy and Dexter, 2021) does not mention cryoablation as a management option.    

Metastatic Hemangiopericytoma to the Lung

Kawamura et al (2006) noted that cryoablation of pulmonary metastases might be a useful therapy for non-surgical candidates.  The procedure was carried out following achievement of local anesthesia for 35 tumors in 20 patients (12 men and 8 women; mean age of 57 years).  The primary endpoint was the safety and feasibility of cryoablation, and the secondary endpoint was tumor control evaluated by follow-up dynamic computed tomographic (CT) scanning performed every 3 months.  Of the 22 sessions of cryoablation, pneumothorax occurred in 11, hemoptysis occurred in 8, and there was 1 case of phrenic nerve palsy.  The mean length of stay (LOS) in the hospital was 2.6 days.  There was local recurrence of 7 (20 %) tumors in 7 (35 %) patients during a 9- to 28-month (median of 21 months) follow-up period; and 1-year survival according to the Kaplan-Meier method was 89.4 %.  The authors concluded that percutaneous cryoablation therapy for metastatic lung tumors was feasible and minimally invasive, with satisfactory local control.

Yamauchi et al (2011) examined the safety and efficacy of cryoablation for metastatic lung tumors from colorectal cancer.  The procedures were carried out on 24 patients (36 to 82 years of age, with a median age of 62; 17 men and 7 women) for 55 metastatic tumors in the lung, during 30 sessions.  The procedural safety, local progression free interval, and overall survival (OS) were evaluated by follow-up CT scanning performed every 3 to 4 months.  The major complications were pneumothorax, 19 sessions (63 %), pleural effusion, 21 sessions (70 %), transient and self-limiting hemoptysis, 13 sessions (43 %) and tract seeding, 1 session (3 %).  The 1- and 3-year local progression free intervals were 90.8 % and 59 %, respectively.  The 3-years local progression free intervals of tumors of less than or equal to 15 mm in diameter was 79.8 % and that of tumors greater than 15 mm was 28.6 % (p = 0.001; log-rank test).  The 1- and 3-year OS rates were 91 % and 59.6 %, respectively.  The authors concluded that the findings of this study indicated that percutaneous cryoablation was a feasible therapeutic option; the local progression free interval was satisfactory at least for tumors that were less than or equal to 1.5 cm in diameter.

McDevitt et al (2016) identified risk factors for local recurrence and major complications associated with percutaneous cryoablation of lung tumors.  All cases between April 2007 and September 2014 at 1 institution were retrospectively reviewed.  Procedures were carried out using CT guidance and a double freeze-thaw protocol.  Tumor progression was determined via World Health Organization (WHO) guidelines, and complications were classified using SIR reporting standards.  Measures of efficacy were calculated via Kaplan-Meier analysis.  Predictors of local progression and major complications were identified by Cox proportional hazards and logistic regression.  There were 47 tumors (25 primary, 22 metastatic) treated with median follow-up of 11.1 months.  Mean diameter before treatment was 2.4 cm, and an average of 2.1 cryoprobes were used per procedure.  Major complications (most commonly, pneumothorax requiring chest tube) occurred in 12 (25 %) cases, and minor complications occurred in 13 (27 %) cases.  Median time to local progression was 14 months (16 months for primary tumors and 10 months for metastatic tumors), and median OS was 33 months (43 months for patients with primary tumors and 22 months for patients with metastatic tumors).  On multi-variate analysis, tumor diameter greater than 3 cm was associated with local progression (hazard ratio [HR] = 3.2, p = 0.013), and use of multiple cryoprobes (relative risk [RR] = 7.2, p = 0.045) and previous local therapy (RR = 15, p = 0.030) were associated with major complications.  The authors concluded that percutaneous cryoablation of lung tumors was technically feasible with a complication rate comparable to other percutaneous ablation techniques.  Percutaneous cryoablation was more effective and had fewer complications when offered to patients with small, previously untreated lesions.

Eiken and Welch (2019) reviewed the current indications for image-guided thermal ablation of pulmonary metastatic disease.  It also summarized data regarding the efficacy and complications of lung cryoablation and presented techniques for performing lung cryoablation as informed by the recent literature.  The authors stated that cryoablation offers potential advantages over radiofrequency ablation or microwave ablation in terms of ablation zone visualization with promising early reports of oncologic efficacy.  Based on the available literature, the authors recommended a triple-freeze protocol for pulmonary metastasis (less than or equal to 2.0 cm in maximum diameter) cryoablation with careful attention to employing a sufficient number of cryoprobes to achieve maximum efficacy.

Prud'homme et al (2019) reviewed the available options of percutaneous ablation of lung metastasis.  General indications, prognostic factors, and image guidance of percutaneous lung ablations were reviewed.  Specificities, technical aspects, advantages and limitations of each technic were highlighted.  Complications and follow-up where also reviewed.  Image-guided, percutaneous ablation is of interest for patients with a limit number (less than 3 to 5) small metastases (less than 2.0 to 3.0 cm).  Other predictive factors have been reported such as the disease-free interval, the primary tumor, or the proximity with large vessels or bronchus.  Radiofrequency ablation (RFA) is the most reported technic, with local control rate greater than 90 % for small tumors, and a very low complication rate.  Microwave (MWA) and cryoablation are alternative technics developed in the last 15 years to overcome RFA limitations, with encouraging results.  Larger ablations zones and less heat sink effect have been described with MWA.  On the other hand, cryoablation allows painless treatments under conscious sedation and/or local anesthesia, high accessibility of difficult locations and promising results on prospective, multi-center series.  Although irreversible electroporation (IRE) could be used for lesions close to main blood vessels as it is not limited by the heat sink effect and does not have significant effects on connective tissue, allowing to treat lesions near to vital organs, preliminary results for lung metastasis are disappointing.  The authors concluded that percutaneous ablation of lung metastases, whatever technique is used, is feasible, with high local control rate, and acceptable complication rate.  Although indications appeared clear enough, validation through controlled trials is mandatory.

In a retrospective, bi-institutional, cohort study, Leppelmann et al (2021) reported outcomes following percutaneous microwave and cryoablation of lung metastases from adenoid cystic carcinoma (ACC) of the head and neck.  This trial included 10 patients (6 women, median age of 59 years [range of 28 to 81]) who underwent 32 percutaneous ablation sessions (21 cryoablation, 11 microwave) of 60 lung metastases (median 3.5 tumors per patient [range of 1 to 16]) from 2007 to 2019.  Median tumor diameter was 1.6 cm [range of 0.7 to 4.0], significantly larger for cryoablation (2.2 cm, p = 0.002).  A median of 2 tumors were treated per session [range of 1 to 7].  Technical success, local control, complications, and OS were examined.  Primary technical success was achieved for 55/60 tumors (91.7 %).  Median follow-up was 40.6 months (clinical) and 32.5 months (imaging, per tumor).  Local control at 1, 2, and 3 years was 94.7 %, 80.8 %, and 76.4 %, respectively, and did not differ between ablation modalities; 5 of 15 recurrent tumors underwent repeat ablation, and secondary technical success was achieved in 4 (80 %).  Assisted local tumor control at 1, 2, and 3 years was 96.2 %, 89.8 %, and 84.9 %, respectively.  Complications occurred following 24/32 sessions (75.0 %) and 57.2 % Common Terminology Criteria for Adverse Events (CTCAE) lower than grade 3.  Of 13 pneumothoraxes, 7 needed chest tube placements.  Hemoptysis occurred after 7/21 cryoablation sessions, and bronchopleural fistula developed more frequently with microwave (p = 0.037).  Median hospital LOS was 1 day [range of 0 to 10], and median OS was 81.5 months (inter-quartile range [IQR] 40.4 to 93.1).  The authors concluded that percutaneous CT-guided microwave and cryoablation could treat lung metastases from ACC of the head and neck; complications were common but manageable, with full recovery expected.

Furthermore, an UpToDate review on “Image-guided ablation of lung tumors” (Dupuy, 2021) states that “Multiple image-guided ablative techniques are being developed for use in patients with primary non-small cell lung cancer (NSCLC) or oligometastatic pulmonary lesions in whom surgery is not an option.  Radiofrequency ablation is the most studied technique, but other approaches under development include microwave ablation, laser ablation, cryoablation, and irreversible electroporation”.

Osteoid Osteoma / Painful Bone Metastases

Cazzato et al (2018) stated that percutaneous image-guided cryo- (CA) and radiofrequency- (RFA) ablations have been widely used in the treatment of painful bone metastases (BM); however, paucity of data is available for the performance of these treatments when used with a curative intent.  In a retrospective review, these investigators examined the local progression free-survival (LPFS) after radical percutaneous image-guided ablation of BM in oligometastatic patients, and identified predictive factors associated with local tumor progression.  Subjects included patients who underwent percutaneous image-guided CA or RFA of BM with a radical intent between 2007 and 2018.  A total of 46 patients with a total of 49 BM underwent percutaneous image-guided CA (n = 37; 75.5 %) or RFA (n = 12; 24.5 %).  Primary malignancies included thyroid (n = 11, 22.5 %), breast (n = 21; 42.9 %), lung (n = 8; 16.3 %) and other (n = 9; 18.3 %) cancers.  Additional consolidation was performed after ablation in 20.4 % cases (n = 10).  Mean follow-up was 34.1 ± 22 months.  Local progression at the treated site was observed in 28.5 % cases (n = 14); 1- and 2-year LPFS was 76.8 % and 71.7 %, respectively.  Size of BM (greater than 2 cm) predicted local tumor progression (p = 0.002).  The authors concluded that percutaneous image-guided loco-regional therapies used in the radical treatment of BM in oligometastatic patients demonstrated significant rates of LPFS providing the size of BM of less than or equal to 2 cm.

Santiago et al (2018) examined the technical feasibility and efficacy of percutaneous cryoablation for the treatment of osteoid osteoma (OO) in adults.  A total of 21 patients (12 males and 9 females; mean age of 29.9 years) who underwent CT-guided percutaneous cryoablation for the treatment of OO were retrospectively evaluated.  Procedures were performed under local anesthesia and conscious sedation in 13 patients, and under general anesthesia in 8 patients.  Then, the ablation zone was examined with post-procedure magnetic resonance imaging (MRI) at 6 weeks.  Clinical outcome was assessed using a VAS to examine severity of pain before procedure, as well as at primary (6 weeks) and secondary follow-up (6 to 40 months).  All procedures were technically successful.  Median VAS scores were: 8 (range of 5 to 10) before procedure and after procedure, respectively, 0 (range of 0 to 2; p < .0001) and 0 (range of 0 to 7; p < .0001) at primary and secondary follow-up.  There were 3 minor complications (14.3 %) and no major complication.  A single patient reported symptom recurrence (4.8 %) at secondary follow-up and successfully underwent a 2nd cryoablation procedure.  The authors concluded that CT-guided percutaneous cryoablation was safe and effective in the treatment of OO in adults; and could be accomplished without general anesthesia in selected cases.

In a retrospective study, De Marini et al (2020) compared the safety profile of percutaneous image-guided RFA and cryoablation (CA) of bone metastases (BM) with and without a propensity score analysis.  Between January 2008 and April 2018, a total of 274 consecutive patients (mean age of 61.6 ± 12.1 years) with BM were treated at the authors’ institution with RFA (53 patients; 66 BM) or CA (221 patients; 301 BM) and included in this study.  Complications were assessed according to the type of ablation modality before and after applying a 1:1 propensity score method taking into account patient's demographics, BM features, procedural details and follow-up findings.  A total of 9 BM (2.5 %) reported major complications without significant difference between RFA (1/66; 1.5 %) and CA (8/301; 2.7 %; p = 1); 40 BM (10.9 %) showed minor complications, which were more common with RFA (22/66; 33.3 %) than with CA (18/301; 6.0 %, p < 0.001) mainly due to post-procedural pain occurring more frequently with RFA than CA (20/66; 30.3 % versus 7/301; 2.3 %, p < 0.001).  Following 1:1 matching, similar results were obtained, since there were similar rates of major complications with RFA and CA (1/66 [1.5 %] and 0/66 [0.0 %], respectively; p = 1); and higher rates of minor complications with RFA compared to CA [33.3 % (22/66) versus 2/66 (3 %); p < 0.001] due to preponderant post-procedural pain (90.9 % [20/22] minor complications with RFA).  The authors concluded that similarly low rates of major complications were expected with RFA and CA of BM.  In the post-operative period, RFA appeared more painful than CA, thus warranting for adoption of dedicated analgesic protocols for patients undergoing RFA.

Lindquester e al (2020) noted that although RFA is well-validated for treatment of osteoid osteoma, newer technologies, namely cryoablation, have been less thoroughly studied.  These researchers carried out a systematic review and pooled analysis of percutaneous ablation technologies for treatment of osteoid osteoma with subset analysis of intra-articular and spinal tumors.  A total of 36 of 79 identified manuscripts met inclusion criteria, comprising 1,863 ablations in 1,798 patients.  Inclusion criteria were (i) retrospective or prospective analysis of thermal ablation of osteoid osteomas in any location, (ii) at least 6 months of clinical follow-up, (iii) 10 or more patients, (iv) patients not included in a second study included in this review, and (v) English language or English translation available.  Success rate was defined as all ablations minus technical failures, clinical failures, and recurrences.  Subset analysis of intra-articular and spinal tumors was performed.  Overall success rate was 91.9 % (95 % CI: 91 % to 93 %).  Technical failure, clinical failure, and recurrence rates were 0.3 %, 2.1 %, and 5. 6% respectively.  Complications were observed in 2.5 % (95 % CI: 1.9 % to 3.3 %) patients.  There was no significant difference when comparing RFA and cryoablation (p = 0.92).  Success rates for intra-articular (RFA) and spinal tumors (RFA and cryoablation) were 97 % and 91.6 %, respectively.  The authors concluded that percutaneous ablation of osteoid osteomas was highly successful with low complication rates.  Efficacy of RFA and cryoablation was similar, which was consequential because cryoablation was associated with decreased pain, predictable nerve regeneration, and theoretical immunotherapy benefits.  Treatment of more challenging intra-articular and spinal lesions demonstrated similarly high success and low complication rates.

Meng et al (2021) noted that the traditional treatment for osteoid osteoma is the nidus' surgical resection, which was difficult to eradicate with more invasive and complications because of osteosclerosis surrounding the nidus.  These researchers examined the safety and effectiveness of percutaneous CT-guided cryoablation of osteoid osteoma at different sites (especially refractory sites such as the spine).  A total of 15 patients with osteoid osteoma who underwent cryoablation at the authors’ institution were analyzed retrospectively on their imaging data and clinical VAS pain scores before and after the procedure; 53 patients underwent surgical resection during the period were also included in this study as a control group.  Treatment efficacy was evaluated primarily by comparing the differences in VAS scores at different time-points in each group of patients by paired-sample t-test.  Differences in hospital length of stay (LOS) and complications between the 2 groups were also compared.  The technical success rate was 100 % in both the cryoablation and surgical resection group.  Cryoablation had a significantly shorter hospital LOS than surgery (p = 0.001).  Clinically, the post-operative VAS scores were all significantly improved compared to the pre-operative period, and the clinical cure was achieved in both groups.  Surgical operations had more complications than cryoablation, although there was no significant difference.  In the group of cryoablation, only 1 patient had mild numbness of the left lower extremity, which relieved itself; 2 patients had mild post-operative pain.  No patients in the cryoablation group experienced recurrence during the follow-up period.  In the surgery group, 3 of the patients experienced massive bleeding (greater than 500 ml), and 2 underwent transfusion therapy.  Only 1 patient in the surgical resection group experienced a recurrence at 29 months post-operatively and underwent a 2nd resection.  All patients had local scars on the skin after surgical resection.  The authors concluded that cryoablation was a minimally invasive, safe, and effective treatment strategy for osteoid osteoma, and was fully comparable to surgical resection.

In a systematic review and meta-analysis, Shanmugasundaram et al (2021) examined safety and effectiveness of percutaneous ablative therapy for the treatment for osteoid osteomas.  PubMed database, Web of Science, and SCOPUS were searched from their inception until November 2019 for articles describing osteoid osteoma.  Demographic data, success rates, pre- and post-procedure VAS scores, and complications were recorded.  A random-effects meta-analyses of the VAS pain score at various time points were calculated.  For radiofrequency ablation, visual analog scale (VAS) scores for pain at pre-procedure, 24 to 48 hours, and 3 to 6 months yielded cumulative pain scores of 7.64 +/- 0.175, 0.78 +/- 0.186, and 0.02 +/- 0.0196, respectively.  For cryoablation, VAS scores at pre-procedure, 24 to 48 hours, and 3 to 6 months yielded cumulative pain scores of 8.46 +/- 0.549, 0.975 +/- 0.66, and 0.112 +/- 0.08, respectively.  For laser ablation, VAS scores at pre-procedure and 24 to 48 hours yielded cumulative pain scores of 4.94 +/- 1.42, and 0.506 +/- 0.268, respectively.  For microwave ablation, VAS scores at pre-procedure, 24 to 48 hours, and 3 to 6 months yielded cumulative pain scores of 6.14 +/- 1.07, 1.636 +/- 1.215, and 0 +/- 0.0, respectively.  All ablation methods resulted in significant immediate and lasting pain reduction (p < 0.001).  Technical and clinical success rates and major complications for RFA, microwave ablation, laser ablation, and cryoablation did not differ significantly.  Overall recurrence of bone pain at the same site occurred in 4.06 % of all patients an average of 11 months post-procedure.  The authors concluded that percutaneous ablative therapies are safe and result in significant and lasting pain reduction as demonstrated through VAS pain scores.

Tepelenis et al (2021) noted that osteoid osteoma, the 3rd most common benign bone tumor, usually occurs in the cortex of long bones.  It consists of a radiolucent nidus surrounded by reactive osteosclerosis.  Generally, osteoid osteoma affects young males.  Nocturnal pain that eases with salicylates or non-steroidal anti-inflammatory drugs (NSAID) is the typical clinical presentation.  Sometimes, it remains undiagnosed for a long time.  Plain radiography and computed tomography (CT) are usually sufficient for the diagnosis of osteoid osteoma.  Initial treatment includes salicylates and NSAID because the tumor often regresses spontaneously over 2 to 6 years.  Surgical treatment is indicated in case of unresponsive pain to medical therapy, no tolerance of prolonged NSAID therapy due to side effects, and no willingness to activity limitations.  Nowadays, minimally invasive techniques have replaced open surgery and are considered the gold standard of surgical treatment.  Although cryoablation appeared superior in terms of the nerve damage and immunotherapy effect, RFA is the preferred technique.

Parmeggiani et al (2021) stated that osteoid osteoma is the 3rd most common benign bone tumor, with well-known clinical presentation and radiological features.  Although surgical excision has been the only therapeutic option for a long time, to-date it has been replaced by minimally invasive techniques, which proved satisfactory success rates and low complication occurrence.  In a literature review, these investigators described the main updates of these recent procedures in the field of interventional radiology, with particular attention paid to the results of the leading studies relating to the effectiveness, complications, and recurrence rate.  Moreover, they analyzed the peculiarities of each reported technique, with specific focus on the possible improvements and pitfalls.  Results proved that all mini-invasive procedures boast a high success rate with slight number of complications and a low recurrence rate; RFA is still considered the gold standard procedure for percutaneous treatment of osteoid osteoma, and it has the possibility to combine treatment with a biopsy.  Interstitial laser ablation's advantages are the simplicity of use and a lower cost of the electrodes, while cryoablation allows real-time visualization of the ablated zone, increasing the treatment safety.  Magnetic resonance-guided focused ultrasound surgery is the most innovative non-invasive procedure, with the unquestionable advantage to be radiation-free.

An UpToDate review on “Image-guided ablation of skeletal metastases” (Kurup and Callstrom, 2021) states that “Radiofrequency ablation (RFA), cryoablation, and focused ultrasound (FUS) are all effective ablative treatments for palliation of symptomatic skeletal metastases.  There are no randomized trials comparing these procedures, and the choice of ablation technique must consider availability, patient preference, and local expertise.  Microwave ablation, laser ablation, and irreversible electroporation are emerging ablation technologies that cannot yet be recommended with the same confidence as RFA, cryoablation, or FUS”.

An UpToDate review on “Nonmalignant bone lesions in children and adolescents” (Tis, 2021) states that “Treatment for osteoblastoma generally entails curettage and bone grafting.  En block excision may be warranted for more aggressive lesions or in regions that permit excision of the bone (e.g., fibula).  Radiation may be required for spinal lesions when the tumor cannot be completely resected.  Successful treatment has also been described with image-guided cryoablation”.

Furthermore, an UpToDate review on “Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors” (Yu and Hoffe, 2021) states that “Local Ablation -- For patients who have persistent or recurrent pain attributed to one or a few skeletal sites with small volume disease after palliative radiation therapy and who are not candidates for surgery or reirradiation with stereotactic techniques, local thermal ablation is an important therapeutic option.  Radiofrequency ablation, cryoablation, and focused ultrasound are all effective ablative treatments for palliation of symptomatic skeletal metastases.  When thermal ablation is applied to vertebral metastasis, the treatment volume should be at least 10 mm away from a neural structure to prevent neurologic complications.  There are no randomized trials comparing these procedures, and the choice of ablation technique should take into account availability, patient preference, and local expertise, as well as involvement of the multidisciplinary team”.

Pleural Lesions

In a prospective, single-arm, multi-center, phase-II clinical trial, Callstrom et al (2020) examined the safety and local recurrence-free survival (RFS) in patients after cryoablation for treatment of pulmonary metastases.  This study included 128 patients with 224 lung metastases treated with percutaneous cryoablation, with 12 and 24 months of follow-up.  Subjects were enrolled on the basis of the outlined key inclusion criteria, which include 1 to 6 metastases from extra-pulmonary cancers with a maximal diameter of 3.5 cm.  Time to progression of the index tumor(s), metastatic disease, and OS rates were estimated using the Kaplan-Meier method.  Complications were captured for 30 days after the procedure, and changes in performance status and QOL were also evaluated.  Median size of metastases was 1.0 +/- 0.6 cm (0.2 to 4.5) with a median number of tumors of 1.0 +/- 1.2 cm (1 to 6).  Local recurrence-free response (local tumor efficacy) of the treated tumor was 172 of 202 (85.1 %) at 12 months and 139 of 180 (77.2 %) at 24 months after the initial treatment.  After a 2nd cryoablation treatment for recurrent tumor, secondary local recurrence-free response (local tumor efficacy) was 184 of 202 (91.1% ) at 12 months and 152 of 180 (84.4 %) at 24 months.  Kaplan-Meier estimates of 12- and 24-month OS rates were 97.6 % (95 % CI: 92.6 to 99.2) and 86.6 % (95 % CI: 78.7 to 91.7), respectively.  Rate of pneumothorax that required pleural catheter placement was 26 % (44/169).  There were 8 grade-III complication events in 169 procedures (4.7 %) and 1 (0.6 %) grade-IV event.   The authors concluded that this report of the treatment of limited metastatic disease in the lung represented the largest, prospective, multi-center trial using image-guided percutaneous cryoablation.  The treatment was well-tolerated, and its effectiveness was encouraging.

The authors stated that drawbacks of this study included having mixed primary histologies, and as a result, the overall cancer-specific survival will require further analyses.  Analysis of tumor response using the Response Evaluation Criteria in Solid Tumors (RECIST) utilized the 1-month ablation zone measurement as the baseline for assessment of tumor response to the cryoablation treatment.  Over time, the ablation zone decreased in size with residual linear scar formation distinguishable from recurrent tumor.  Recurrence was noted as an increase in size of the ablation zone or as an enlarging focal nodule or presence of focal contrast enhancement.  As a result of scar formation at the ablation site, complete response to treatment included measurement of the residual scar rather than disappearance of the treated tumor.

Pulmonary Metastatic Lesions

In a Health Insurance Portability and Accountability Act (HIPAA) compliant, institutional review board (IRB)-approved, prospective, single-arm, multi-center study, de Baere et al (2015) examine the safety, feasibility, and local tumor control of cryoablation for treatment of pulmonary metastases.  This trial included 40 patients with 60 lung metastases treated during 48 cryoablation sessions, with currently a minimum of 12 months of follow-up.  Patients were enrolled according to the following key inclusion criteria: 1 to 5 metastases from extra-pulmonary cancers, with a maximal diameter of 3.5 cm.  Local tumor control, disease-specific survival (DSS) and overall survival (OS) rates were estimated using the Kaplan-Meier method.  Complications and changes in physical function and quality of life (QOL) were also evaluated using Karnofsky performance scale (KPS), Eastern Cooperative Oncology Group (ECOG) performance status classification, and Short Form-12 (SF-12) health survey.  Patients were 62.6 ± 13.3 years old (26 to 83).  The most common primary cancers were colon (40 %), kidney (23 %), and sarcomas (8 %).  Mean size of metastases was 1.4 ± 0.7 cm (0.3 to 3.4), and metastases were bilateral in 20 % of patients.  Cryoablation was carried out under general anesthesia (67 %) or conscious sedation (33 %).  Local tumor control rates were 56 of 58 (96.6 %) and 49 of 52 (94.2 %) at 6 and 12 months, respectively.  Patient's QOL was unchanged over the follow-up period; and 1-year OS rate was 97.5 %.  The rate of pneumothorax requiring chest tube insertion was 18.8 %.  There were 3 Common Terminology Criteria for Adverse Events grade-3 procedural complications during the immediate follow-up period (pneumothorax requiring pleurodesis, noncardiac chest pain, and thrombosis of an arterio-venous fistula), with no grade-4 or grade-5 complications.  The authors concluded that cryoablation was a safe and effective treatment for pulmonary metastases with preserved quality of life following intervention.

In a prospective, single-arm, multi-center, phase-II clinical trial, Callstrom et al (2020) examined the safety and local recurrence-free survival (RFS) in patients after cryoablation for treatment of pulmonary metastases.  This study included 128 patients with 224 lung metastases treated with percutaneous cryoablation, with 12 and 24 months of follow-up.  Subjects were enrolled on the basis of the outlined key inclusion criteria, which include 1 to 6 metastases from extra-pulmonary cancers with a maximal diameter of 3.5 cm.  Time to progression of the index tumor(s), metastatic disease, and OS rates were estimated using the Kaplan-Meier method.  Complications were captured for 30 days after the procedure, and changes in performance status (PS) and QOL were also evaluated.  Median size of metastases was 1.0 +/- 0.6 cm (0.2 to 4.5) with a median number of tumors of 1.0 +/- 1.2 cm (1 to 6).  Local RFS (local tumor efficacy) of the treated tumor was 172 of 202 (85.1 %) at 12 months and 139 of 180 (77.2 %) at 24 months after the initial treatment.  After a 2nd cryoablation treatment for recurrent tumor, secondary local recurrence-free response (local tumor efficacy) was 184 of 202 (91.1 %) at 12 months and 152 of 180 (84.4 %) at 24 months.  Kaplan-Meier estimates of 12- and 24-month OS rates were 97.6 % (95 % confidence interval [CI]: 92.6 to 99.2) and 86.6 % (95 % CI: 78.7 to 91.7), respectively.  Rate of pneumothorax that needed pleural catheter placement was 26 % (44/169).  There were 8 grade-3 complication events in 169 procedures (4.7 %) and 1 (0.6 %) grade-4 event.  The authors concluded that percutaneous cryoablation was a safe and effective treatment for pulmonary metastases.

In a retrospective, bi-institutional cohort study, Leppelmann et al (2021) reported outcomes following percutaneous microwave and cryoablation of lung metastases from adenoid cystic carcinoma (ACC) of the head and neck.  This trial included 10 patients (6 women, median age of 59 years [range of 28 to 81]) who underwent 32 percutaneous ablation sessions (21 cryoablation, 11 microwave) of 60 lung metastases (median 3.5 tumors per patient [range of 1 to 16]) from 2007 to 2019.  Median tumor diameter was 1.6 cm [range of 0.7 to 4], significantly larger for cryoablation (2.2 cm, p = 0.002).  A median of 2 tumors were treated per session [range of 1 to 7].  Technical success, local control, complications, and OS were assessed.  Primary technical success was achieved for 55/60 tumors (91.7 %).  Median follow-up was 40.6 months (clinical) and 32.5 months (imaging, per tumor).  Local control at 1, 2, and 3 years was 94.7 %, 80.8 %, and 76.4 %, respectively, and did not differ between ablation modalities; 5 of 15 recurrent tumors underwent repeat ablation, and secondary technical success was achieved in 4 (80 %).  Assisted local tumor control at 1, 2, and 3 years was 96.2 %, 89.8 %, and 84.9 %, respectively.  Complications occurred following 24/32 sessions (75.0 %) and 57.2 % Common Terminology Criteria for Adverse Events (CTCAE) lower than grade-3.  Of 13 pneumothoraxes, 7 needed chest tube placements.  Hemoptysis occurred after 7/21 cryoablation sessions, and bronchopleural fistula developed more frequently with microwave (p = 0.037).  Median length of stay (LOS) in the hospital was 1 day [range of 0 to 10], and median OS was 81.5 months (inter-quartile range [IQR] 40.4 to 93.1).  The authors concluded that percutaneous computed tomography (CT)-guided microwave and cryoablation could treat lung metastases from ACC of the head and neck; complications were common but manageable, with full recovery expected.

Furthermore, an UpToDate review on “Image-guided ablation of lung tumors” (Dupuy, 2021) states that “Surgery is the standard treatment option for most patients with resectable lung cancer and for the unusual patient with oligometastatic lung metastases.  However, surgery is not appropriate in many cases because of the presence of disseminated disease or because the patient’s age or comorbidity precludes a surgical approach.  In these settings, palliation of pulmonary symptoms may be beneficial … Among image-guided techniques, radiofrequency ablation is used more commonly than microwave ablation, laser ablation, cryoablation, and irreversible electroporation ... However, there are no trials comparing these image-guided techniques … A prospective multicenter trial evaluating the safety and efficacy of cryoablation for the treatment of metastatic lung tumors (ECLIPSE trial) showed local tumor control rates of 96.6 and 94.2 % at 6 and 12 months with a 1-year survival rate of 97.5 %.  A follow-up SOLSTICE trial with larger patient numbers and 2-year follow-up is ongoing … Multiple image-guided ablative techniques are being developed for use in patients with primary non-small cell lung cancer (NSCLC) or oligometastatic pulmonary lesions in whom surgery is not an option.  Radiofrequency ablation is the most studied technique, but other approaches under development include microwave ablation, laser ablation, cryoablation, and irreversible electroporation … For patients who have either a small primary NSCLC or a limited number of pulmonary metastases, and who are not candidates for surgery, use of radiofrequency ablation or another image-guided technique (e.g., stereotactic body radiotherapy) may be appropriate, depending on available expertise.  There are no comparative trials comparing these techniques with each other or with external beam stereotactic radiation therapy”.

Retinal Dialysis

Zhang et al (2005) examined the effect of external approach microsurgery in retinal dialysis.  A total of consecutive 30 eyes of 28 patients with retinal dialysis were enrolled for this study.  The progresses of the external approach microsurgery were following.  Under the surgical microscopy, the pre-placement of mattress sutures for buckling and/or encircling following retrobulbar anesthesia and scleral exposure, draining subretinal fluid, the cryotherapy of retinal breaks, checking the position of breaks on scleral buckle and gases injection were performed in turn.  After drainage of subretinal fluid, with scleral depression cryotherapy reaction around breaks could be observed clearly under the microscopy.  All breaks were located on anterior slope of the buckle.  Intra-operative complications were mild subretinal hemorrhage at drainage site and corneal epithelium exfoliation in 3 eyes, respectively.  Post-operative complications were mainly secondary glaucoma and retinal re-detachment.  The 1-operation re-attachment rate was 96.7 % (29 eyes), and the final re-attachment rate was 100 % after 1 eye had a second external approach microsurgery.  The post-operative vision acuity (VA) was significantly better than the pre-operative VA (Chi(2)= 9.529, p < 0.01).  The authors concluded that external approach microsurgery had favorable effect on the surgery of retinal dialysis.

In a retrospective study, James et al (2008) described buckle-related complications following surgical repair of retinal dialysis.  A total of 28 consecutive cryobuckle procedures for retinal detachments secondary to retinal dialysis were reported, with particular attention directed towards post-operative complications relating to the buckle.  Stata 8 statistical software and Fisher's exact test were used to analyze the data.  Of the 28 cases, anatomic success was achieved with a single procedure in 26 cases (92.9 %).  Post-operative complications were observed in 20 cases (71.4 %), with complications attributable to the buckle noted in 19 (67.9 %).  Buckle-related complications included exposure (7; 25 %), strabismus (5; 17.9 %), and infection (3; 10.7 %).  Surgical removal of the buckle was indicated in 13 cases (46.4 %), typically within the first 6 post-operative months.  Of these, the retina remained flat following removal of buckle in 12 cases (92.3 %), whereas the retina re-detached in 1 case (7.7 %).  The authors concluded that cryotherapy with explant was an effective primary procedure for the surgical repair of retinal detachment secondary to retinal dialysis; however, there was a high rate of post-operative complications relating to the buckle following this surgical approach, although the buckle can be safely removed without compromising the anatomic success of the primary surgery in the vast majority of cases.

Furthermore, an UpToDate review on “Retinal detachment” (Arroyo, 2021) states that “Patients who have a symptomatic retinal break (recent onset of flashing lights or hundreds of new floaters in affected eye) clearly benefit from laser retinopexy or cryoretinopexy to prevent retinal detachment”.

Spray Cryotherapy for the Treatment of Subglottic Stenosis and Cervical Tracheal Stenosis

Krimsky et al (2010) stated that functional partial occlusion of the glottic and subglottic areas by stenosis and strictures is challenging to manage despite a variety of surgical and endoluminal approaches that are prone to complications and inconsistent outcomes.  In an institutional review board (IRB)-approved clinical trial, these researchers described the first 3 human cases of glottic as well as subglottic narrowing treated with spray cryotherapy (SC) alone or in combination with balloon dilation.  A 42-year-old woman with idiopathic subglottic strictures, a 74-year-old woman with glottic strictures and vocal cord stenosis following neck radiation, and a 33-year-old woman with strictures from a previous tracheal stent were treated by 4 cycles of a 5-s cryotherapy spray alone or with balloon dilation.  The effects of treatment were observed up to 6 months, 12 weeks, and 9 months, respectively.  In all cases, patency of the stenosed areas was achieved with minimal bleeding and at least some degree of normalization of the glottic and subglottic mucosa.  Airway patency and laryngeal functions were restored without complications.  The authors concluded that the use of SC alone or in conjunction with balloon dilation was a promising and effective therapeutic approach to treating glottic and subglottic narrowing.

Fernando et al (2011) noted that benign airway strictures can be complex and challenging to manage.  Although resection is preferred, this is not always feasible, and hence, endoscopic therapies are often performed.  However, endoscopic therapies can be problematic, with granulation tissue and fibrosis leading to early failure.  Spray cryotherapy is a new approach that may modulate the healing response leading to less fibrosis and decrease the need, or the duration of time to intervention.  These investigators reported the initial results of SC for benign airway strictures.  Over a 22-month period, a total of 35 patients underwent SC; median age was 51 (18 to 81) years.  Prior therapy had been undertaken in 14 (41.2 %) of patients.  Stricture etiology included post-intubation (n = 5), prior tracheostomy (n = 6), radiation-induced (n = 2), prior surgery (n = 3), other causes (n = 12), or unknown etiology (n = 7).  Airway narrowing was graded as follows: 1 = 0 to 25 %, 2 = 26 to 50 %, 3 = 51 to 75 %, and 4 = 76 to 100 %.  For the purpose of analysis, this was treated as a continuous variable.  The usual treatment algorithm consisted of 3 to 4 SC cycles, followed by balloon dilation, and then by additional SC cycles.  Stricture locations were subglottic (n = 18), tracheal (n = 9), and bronchial (n = 8); 17 (49 %) patients required additional SC therapy, resulting in a total of 63 SC treatment sessions.  Only 2 (3.2 %) complications occurred including pneumothorax (n = 1) and intra-operative tracheostomy (n = 1).  Mean follow-up was available in 33/35 patients at a mean of 8.2 (1 to 19) months; 12 (of 33) patients (36.4 %) were asymptomatic, 16/33 (48.5 %) were improved, 4/33 (12.1 %) had no improvement or were worse, and 1/33 (3 %) patient died from an unrelated cancer.  On follow-up bronchoscopy, performed in 28 patients, airway narrowing improved significantly from 3.5 to 2.03 (p < 0.001).  The authors concluded that initial experience with SC for benign airway strictures suggested that this could be used safely.  This was effective in improving symptoms and reducing the severity of airway narrowing; however, re-intervention was still needed.  These researchers stated that further prospective studies are needed to determine factors that may be associated with success or failure as well as the relative efficacy of SC compared with other endoscopic therapies.

The authors stated that the major drawback of this trial was the use of a retrospective cohort with somewhat variable follow-up.   The effect of the therapy could also be exaggerated in observational studies.  These researchers stated that future investigation should ideally be performed comparing this approach to other common endoscopic approaches, such as dilation or stenting with silastic stents, with careful classification of stricture severity/type to determine success rates with each therapy.  However, an important advantage with SC may be that this modality will not adversely affect future intervention (in particular, surgery) because of the favorable wound response although, this was speculative.

Fernando et al (2010) stated that benign strictures of the airway can be complex and challenging to manage.  Although resection has the best long-term results, this is not always feasible, and there will be groups of patients who require additional therapy for failure after open operations or who are not surgical candidates; thus, requiring endoluminal management.  A number of stents are available; however, not all performed well for the longer duration that will be required for patients with benign compared with malignant strictures.  For this reason, stenting should be considered a temporary solution or a last resort for patients with benign airway strictures.  Combinational modalities hold promise; for example, radial laser incisions with dilatation and mitomycin C for tracheal stenosis.  Many techniques, however, have been associated with failure, especially for long strictures.  Spray cryotherapy is a new technique that may have advantages over other treatments by modulating the healing response and resulting in improved healing and less re-fibrosis. 

Bhora et al (2016) reported their early results for the use of SC in patients with benign tracheal stenosis.  Data were extracted from the medical records of a consecutive series of patients with benign airway stenosis secondary to granulomatosis with polyangiitis (GPA) (n = 13), prior tracheotomy or tracheal intubation (n = 8), and idiopathic strictures (n = 5) treated from September 1, 2013 to September 30, 2015, at a tertiary care hospital.  Airway narrowing was quantified on a standard quartile grading scale.  Response to treatment was evaluated by improvement in airway caliber and the time interval for re-intervention.  Intervention was delivery of 4 5-second SC cycles and 2 balloon dilatations.  A total of 26 patients (median [range] age of 53 [16 to 83] years; 20 [77 %] female) underwent 48 SC sessions.  Spray cryotherapy was successfully used without any substantial intra-operative or post-operative complications in all patients.  In a median (range) follow-up of 11 (1 to 26) months, all patients had improvement in symptoms.  Before the administration of SC, 23 patients (88 %) had grade III or IV stenosis.  At the last evaluation after induction of SC, 4 (15 %) had grade III or IV stenosis, with a mean (SD) change of 1.39 (0.51) (p < 0.001).  Patients with GPA required significantly fewer SC procedures (mean [SD], 1.38 [0.96] versus 2.31 [1.18]; p = 0.03) during the study period.  The authors concluded that SC was a safe adjunct modality to accomplish airway patency in patients with benign tracheal stenosis.  Moreover, these researchers stated that although efficacy evidence was limited for SC, it may be useful for patients who have experienced treatment failure with conventional modalities.  They stated that further analysis of this cohort will determine the physiologic durability of the reported short-term changes; additional trials are needed for further evaluation of this modality.

Furthermore, an UpToDate review on “Bronchoscopic cryotechniques in adults” (Colt, 2021) states that “As an alternative to direct contact cryoablation, a noncontact approach has been reported where liquid nitrogen is sprayed onto the lesion through a specially designed cryocatheter ("spray cryotherapy").  It has a potential advantage of treating large areas rapidly and uniformly.  Several case series report success treating nonmalignant airway strictures when combining this technique with mechanical dilation or ablative techniques.  However, complications are common and include barotrauma, nitrogen gas embolism, and death.  For example, in one study of 80 patients treated with spray cryotherapy, although rates of airway patency and hemostasis were high (> 90 %), 19 % had complications including hypotension, bradycardia, tachycardia, ST segment changes, desaturation, airway perforation, and death.  Consequently, this approach should be considered investigational with patients only treated as part of an investigational study”.

Sacral Chordomas

de Vries et al (1986) noted that sacrococcygeal chordoma is a rare malignant neoplasm situated in a location adjacent to important structures.  Distant metastases are usually rare and occur late.  The treatment of choice usually consists of radical surgery, sometimes followed by radiotherapy.  Extensive surgical resection is difficult and often causes bladder and/or bowel dysfunction, and the local recurrence (LR) rate remains high.  In an attempt to diminish both risks, these researchers introduced cryosurgery in-situ as a new treatment modality for chordoma in the sacrococcygeal region.  From 1974 to 1980, a total of 4 patients (2 male, 2 female) with sacrococcygeal chordoma were treated with cryosurgery without resection.  Two patients had extensive tumors (greater than 10 cm) and could be treated only palliatively.  Two other patients with smaller tumors (less than 10 cm) had radical cryosurgical treatment.  Both patients were disease-free 10 and 7 years after cryosurgical treatment.  One of the palliatively treated patients was alive with LR 4 years after cryosurgery, the other died of tumor after 5 years.  In a cryosurgical lesion, the tissue was completely devitalized; however, the architecture of the tissue in peripheral nerves, large vessels, and bone was preserved and remained as a perfect autograft.  Frozen tissue is very susceptible to the hematogenous spread of infection; therefore, infection prevention is of utmost importance.  The authors concluded that that cryosurgery should have a place in the treatment of sacrococcygeal chordoma.

Schwab et al (2009) noted that sacral chordomas are rare tumors presumed to arise from notochordal cells.  Local recurrence presents a major problem in the management of these tumors; and it has been correlated with survival.  Resection of sacral tumors is associated with significant morbidity.  In a retrospective, case-series study, these researchers examined factors that contribute to improved local control and survival.  Furthermore, they sought to define the expected morbidity associated with treatment.  A total of 42 patients underwent resection for sacral chordoma between 1990 and 2005; 12 had their initial surgery elsewhere.  There were 12 female and 30 male patients.  The proximal extent of the sacrectomy was at least S2 in 32 patients.  Median survival was 84 months, and 5-year DFS and DSF were 56 % and 77 %, respectively.  Local recurrence and metastasis occurred in 17 (40 %) and 13 (31 %) patients, respectively.  Local recurrence (p = 0.0001), metastasis (p = 0.0001), prior resection (p = 0.046), and higher grade (p = 0.05) were associated with a worse DSF.  Prior resections (p = 0.0001) and intralesional resections (p = 0.01) were associated with a higher rate of LR.  Intralesional resections were associated with a lower DSF (p = 0.0001).  Wide contaminated margins treated with cryosurgery and/or radiation were not associated with a higher LR rate.  Rectus abdominus flaps were associated with decreased wound complications (p = 0.01); 31 (74 %) patients reported of self-catheterization; and 16 (38 %) patients needed bowel training, while an additional 12 (29 %) patients had a colostomy; 28 (67 %) patients reported sexual dysfunction; and 2 (5 %) patients died due to sepsis.  The authors concluded that intralesional resection should be avoided as it was associated with a higher LR rate and worse survival.  Rectus abdominus flaps ought to be considered as they lower the wound complication rate.  Sacral resection was associated with significant morbidity.

Kurup et al (2012) reviewed the safety and effectiveness of cryoablation for the treatment of recurrent sacrococcygeal tumors.  The authors’ radiology departmental ablation database was retrospectively searched for cases of cryoablation performed to treat recurrences of sacrococcygeal tumors between January 1, 2010, and August 1, 2011.  Patient demographics, procedure technical parameters, and patient outcomes were reviewed.  A total of 5 cases of recurrent chordoma and 1 recurrent myxopapillary ependymoma were treated with cryoablation in 6 patients whose ages ranged from 31 to 80 years.  The tumors measured 1.4 to 3.9 cm in maximal dimension.  Cryoablation was performed with the use of CT guidance (n = 5) or a combination of US and MRI guidance (n = 1).  Sterile fluid was instilled to displace adjacent bowel and/or vagina in 4 cases, and electromyography (EMG) monitoring was performed in 2 cases with adjacent nerve roots; 2 patients with recurrent chordoma were treated for palliation of pain, with complete pain relief in 1 patient (pain recurred after 6 weeks) and immediate reduction in pain from a score of 6 to a score of 2 on a 10-point scale in the other (pain recurred after 7 months); 4 tumors were treated for local control, with no evidence of recurrence on follow-up imaging at 3, 6, 12, and 15 months.  No serious complication occurred.  The authors concluded that limited results suggested cryoablation to be a safe and relatively effective means of treating recurrent sacrococcygeal neoplasms for local control or palliation of pain in this small series with short-term follow-up.

Susa et al (2016) noted that historically, local control of recurrent sarcomas has been limited to radiotherapy when surgical re-resection is not feasible.  For metastatic carcinomas to the bone or soft tissue, radiotherapy and some interventional radiology treatment along with other systemic therapies have been widely advocated due to the possibility of disseminated disease.  These techniques are effective in alleviating pain and achieving local control for some tumor types, but it has not been effective for prolonged local control of most tumors.  Recently, cryoablation has been reported to have satisfactory results in lung and liver carcinoma treatment.  In this study, these researchers analyzed the clinical outcome of CT-guided cryoablation for malignant bone and soft tissue tumors to elucidate potential problems associated with this procedure.  Since 2011, a total of 11 CT-guided cryoablations in 9 patients were performed for locally recurrent or metastatic bone and soft tissue tumors (7 men and 2 women) at the authors’ institute.  Patients' average age was 74.8 years (range of 61 to 86) and the median follow-up period was 24.1 months (range of 5 to 48).  Histological diagnosis included RCC (n = 4), dedifferentiated liposarcoma (n = 2), myxofibrosarcoma (n = 2), chordoma (n = 1), HCC (n = 1), and thyroid carcinoma (n = 1).  Cryoablation methods, clinical outcomes, complications, and oncological outcomes were analyzed.  There were 5 recurrent tumors and 6 metastatic tumors, and all cases had contraindication to either surgery, chemotherapy or radiotherapy; 2 and 3 cycles of cryoablation were performed for bone and soft tissue tumors, respectively.  The average length of the procedure was 101.1 mins (range of 63 to 187), and the average number of probes was 2.4 (range of 2 to 3).  Complications included 1 case of urinary retention in a patient with sacral chordoma who underwent prior carbon ion radiotherapy, 1 transient femoral nerve palsy, and 1 minor wound complication.  At the final follow-up, 4 patients showed no evidence of disease, 2 were alive with disease, and 3 died of disease.  The authors concluded that reports regarding CT-guided cryoablation for musculoskeletal tumors were rare and the clinical outcomes have not been extensively studied.  In this case-series study, CT-guided cryoablation had analgesic effectiveness and there were no cases of LR post procedure during the follow-up period.  These investigators stated that although collection of further data regarding use of this technique is needed, these findings suggested that cryoablation is a promising option in medically inoperable musculoskeletal tumors.

In a retrospective study, Li et al (2020) examined the therapeutic effects of argon-helium cryoablation guided by CT in the treatment of sacral chordoma.  CT-guided argon-helium cryoablation was used to treat 9 sacral chordoma patients at the authors’ centers between January 2016 and June 2019.  These researchers collected data on treatment response and success.  Data from long-term follow-up of treatment outcomes were also assessed.  All patients were treated successfully according to the indicated technical parameters.  There were no reports of procedure-related complications from any of the patients.  Complete response was also achieved in all patients; 6 patients (66.7 %) achieved initial CR after 1 treatment session and 3 patients (33.3 %) achieved secondary CR after 2 treatment sessions.  The chordoma-related symptoms improved significantly in all patients after treatment.  The mean VAS score improved from 7.3 before treatment to 4.2 after treatment (p < 0.001).  The mean function score improved from 3.2 before treatment to 1.4 after treatment (p < 0.001).  The median length of follow-up for all patients was 33 months (range of 6 to 46 months).  All patients were alive during the follow-up; 2 (22.2 %) patients experienced LR at 6 and 9 months after treatment, respectively.  These patients had revised treatment with trans-arterial embolism (n = 1) or repeat ablation (n = 1).  The median PFS was 36.8 months.  The authors concluded that treatment of sacral chordoma with CT-guided argon-helium cryoablation was effective and offered a potentially beneficial therapeutic alternative for patients with the condition.

Spinal Metastases

In a retrospective study, Autrusseau et al (2021) examined pain relief and local tumor control (LTC) in spinal metastases (SM) undergoing cryoablation.  Between May 2008 and September 2020, a total of 46 metastases in 41 consecutive patients (mean age of 59.7 ± 4.4 [SD] years; range of 27 to 84) were treated with cryoablation in 42 interventional sessions.  Patient demographics, procedural data, complications, pain, and LTC were analyzed.  A total of 31 patients (36 SM; 32 sessions) were treated for pain relief and 10 (10 SM; 10 sessions) for LTC.  Clinical success was reached in 30/32 (93.8 %) interventional palliative sessions.  Mean pre-procedural numerical pain rate scale was 6.2 ± 1.7 (SD); and decreased significantly to 3.5 ± 1.8 (SD), 1.9 ± 1.7 (SD), and 1.9 ± 1.8 (SD) at 24-hour, 1-month and at the last available follow-up (median of 16.5 ± 23.2 [SD] months), respectively.  For patients requiring LTC, primary clinical success was reached in 6/10 (60 %) SM at median follow-up of 25-months.  The overall complication rate was 8 %, with no secondary fractures or iatrogenic thermal-mediated nerve injuries reported.  The authors concluded that percutaneous image-guided cryoablation of SM was safe and effective, providing high-rates of LTC at mid-term follow-up.

In a retrospective study, Cazzato et al (2022) reported on the safety and effectiveness of cryoablation for the treatment of SM in patients needing pain palliation or LTC.  All consecutive patients with SM who underwent cryoablation from May 2008 to September 2020 in 2 academic centers were identified and included in the present analysis.  Patient characteristics, goal of treatment (curative/palliative), SM characteristics, procedural details, and clinical outcomes (pain relief; LTC) were analyzed.  There were 74 patients (35 women; median age of 61 years) accounting for 105 SM.  Additional cementoplasty was used for 76 SM (76/105; 72.4 %).  There were 9 (8.5 %) complications (out of 105 SM; 2 major and 7 minor) in 8 patients.  Among the 64 (64/74; 86.5 %) patients with painful SM, the mean Numerical Pain Rating Scale dropped from 6.8 ± 2.2 (range of 0 to 10) at the baseline to 4.1 ± 2.4 (range of 0 to 9; p < 0.0001) at 24 hours, 2.5 ± 2.6 (range of 0 to 9; p < 0.0001) at 1 month, and 2.4 ± 2.5 (range of 0 to 9; p < 0.0001) at the last available follow-up (mean of 14.7 ± 19.6 months; median of 6).  A total of 34 patients (34/64; 53.1 %) were completely pain-free at the last follow-up.  At mean 25.9 ± 21.2 months (median of 16.5) of follow-up, LTC was achieved in 23/28 (82.1 %) SM in 21 patients undergoing cryoablation with curative intent.  The authors concluded that cryoablation of SM, often performed in combination with vertebral augmentation, was safe, achieved fast and sustained pain relief, and provided high rates of LTC at mean 2-year follow-up.

Sagoo et al (2022) noted that percutaneous cryoablation (PCA) is a minimally invasive technique that has been recently used in the treatment of SM with a paucity of data currently available in the literature.  These investigators carried out a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.  Prospective or retrospective studies concerning metastatic spinal neoplasms treated with current generation PCA systems and with available data on safety and clinical outcomes were included.  In the 8 included studies (7 retrospective, 1 prospective), a total of 148 patients (females = 63 %) underwent spinal PCA.  Tumors were located in the cervical (3/109 [2.8 %]), thoracic (74/109 [68.8 %]), lumbar (37/109 [33.9 %]), and sacrococcygeal (17/109 [15.6 %]) regions.  Overall, 187 metastatic spinal lesions were treated.  Thermo-protective measures (e.g., carbo-/hydro-dissection, thermocouples) were used in 115/187 [61.5 %] procedures.  For metastatic spinal tumors, the pooled mean difference (MD) in pain scores from baseline on the 0 to 10 NRS was 5.03 (95 % CI: 4.24 to 5.82) at a 1-month follow-up and 4.61 (95 % CI: 3.27 to 5.95) at the last reported follow-up (range of 24 to 40 weeks in 3/4 studies).  Local tumor control rates ranged widely from 60 % to 100 % at varying follow-ups.  Grade I to II complications were reported in 9/148 [6.1 %] patients and grade III to V complications were reported in 3/148 [2.0 %]) patients.  The authors concluded that PCA, as a stand-alone or adjunct modality, may be a viable therapy in appropriately selected patients with painful spinal metastases who were traditionally managed with open surgery and/or radiation therapy.

Giammalva et al (2022) noted that spine represents the most common site for metastatic disease involvement.  Due to the close relationship between the spinal cord and critical structures, therapeutical management of metastatic spinal cord disease remains challenging.  Spinal localization can lead to neurological sequelae, which can significantly affect the QOL in patients with a limited life expectancy.  The authors conducted a systematic literature review according to PRISMA guidelines in order to determine the impact of the most updated palliative care on SM.  The initial literature search retrieved 2,526 articles, manually screened based on detailed exclusion criteria.  A total of 65 studies met the inclusion criteria and were finally included in the systematic review.  In the wide scenario of palliative care, nowadays, recent medical or surgical treatments represent valuable options for ameliorating pain and improving patients QOL in such this condition.

These investigators stated that CA may be a minimal invasive treatment for patients with spinal tumors not responding to radiation therapy (RT).  CA can be used alone or combined with systemic or local therapies such as RT and vertebral augmentation.  CA resulted in fast and long-lasting pain relief as well as acceptable rates of LTC.  Main limitations of this technique are the limited experience and the risk of fracture.  Moreover, ablative techniques such as RFA or CA, are contraindicated for tumor location within 1 cm of important structures such as the spinal cord, major nerves, and blood vessels.

Knee Pain

Bellini and Barbieri (2015) noted that cryoanalgesia, also known as cryoneuroablation or cryoneurolysis, is a specialized technique for providing long-term pain relief.  In a retrospective study, these researchers presented data on pain relief and changes in function after cryoanalgesia techniques.  They described the effect of this procedure on articular facet syndromes, sacroiliac pain and knee pain.  These investigators reviewed the records of 18 patients with articular lumbar facet pain, knee pain and sacroiliac pain.  The VAS and Patient's Global Impression of Change (PGIC) scale showed satisfaction at 1 month after cryoablation, with the best scores after 3 months.  Only 3 patients showed a worse condition than the 1st month.  The authors concluded that the majority of patients experienced a clinically relevant degree of pain relief and improved function following percutaneous cryoanalgesia.

McLean et al (2020) stated that chronic, non-surgical, non-specific anterior knee pain is a common source of functionally limiting chronic ailment, especially in a young athletic and active-duty military population.  The infra-patellar branch of the saphenous is becoming a common therapeutic target for the diagnosis and treatment of anterior knee pain.  It is a nerve commonly injured during knee surgeries and trauma, resulting in neuroma formation and chronic neuropathic pain states, and it can also transmit nociceptive input from patients with non-surgical anterior knee pain of multiple etiologies.  Several methods have been used to treat this condition.  After the diagnosis of infra-patellar saphenous neuralgia, the nerve is safely ablated using RFA, neurolytic solutions, and, most recently, cryoablation using the hand-held iovera cryoablation system (Myoscience, Inc. Fremont, CA).  Cryoablation is an attractive technique because it is minimally invasive, not permanent, and well-tolerated by the patient with only local anesthesia.  These researchers have previously described a technique using a non-invasive peripheral nerve stimulator to identify and treat the exact location of the nerve more precisely, thereby optimizing treatment success and procedural simplicity.  The authors concluded that this case-series study (n = 11) showed their initial use and success with this technique.  Moreover, they stated that further follow-up and randomized sham-controlled trials are also planned.  These researchers stated that future studies will ideally be randomized, double-blind, and sham-controlled in design.  These studies could include the following cohorts: cryoablation using the novel nerve identification technique; cryoablation using the manufacturer’s (iovera) recommended treatment location; sham ablation using the novel nerve identification technique; and sham ablation using the iovera-recommended treatment location.

The authors stated that this case-series study had several drawbacks, including those that are inherent to case-series in general, such as the lack of control subjects making case-series prone to selection bias.  Furthermore, the lack of follow-up made it difficult to accurately determine the actual procedure success and delayed complication rate.  In additional, this case series lacked uniformed pre-defined follow-up duration after treatment because these patients had generally tended to appear for follow-up or repeat treatment only when they felt their symptoms had returned to a “significant” level.  Future studies should have pre-determined interval follow-ups to quantify the loss to follow-up, which can be an important factor in assessing study quality.  Furthermore, pre-set follow-ups may identify cases where patients no longer experienced satisfactory pain relief but still failed to return for re-evaluation or repeat treatment for whatever reason.  This case-series study had one sole outcome measure: change in Defense and Veterans Pain Rating Scale (DVPRS) numerical score.  Future study endpoints should include functional measures such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) as improvement in function in conjunction with pain relief has been widely accepted to yield a more meaningful assessment of the QOL than pain scores alone.

McMillan et al (2020) stated that cryoneurolysis is a process of addressing nerve-related pain via disruption of nerve conduction utilizing extreme cold temperatures.  Throughout the literature, cryoneurolysis has been described for decades across various specialties.  Within the past few years, a growing movement of its use within orthopedics has provided pain relief solutions in both the surgical as well as the non-surgical setting.  These investigators provided a review of the literature employing multiple medical search engines to identify relevant orthopedic articles related to the treatment of joint pain with cryoneurolysis or cryoanalgesia.  They provided a review of the cryoneurolysis, indications, effectiveness, and treatment gaps within the literature to furnish guidance for future research.

Furthermore, UpToDate reviews on “Approach to the adult with unspecified knee pain” (Covey and Shmerling, 2022), “Approach to the adult with knee pain likely of musculoskeletal origin” (Beutler and fields, 2022), and “Approach to chronic knee pain or injury in children or skeletally immature adolescents” (Hergenroeder, 2022) do not mention cryoablation as a management / therapeutic option.

Renal Mass for Suspected Renal Cell Carcinoma

On behalf of the American Society of Clinical Oncology, Finelli et al (2017) provided recommendations for the management options for patients with small renal masses (SRMs).  These investigators carried out a literature search and prospectively defined study selection; they sought systematic reviews, meta-analyses, randomized clinical trials, prospective comparative observational studies, and retrospective studies published from 2000 through 2015.  Outcomes included RFS, DSS, and OS.  A total of 83 studies, including 20 systematic reviews and 63 primary studies, met the eligibility criteria and formed the evidentiary basis for the guideline recommendations.  On the basis of tumor-specific findings and competing risks of mortality, all patients with an SRM should be considered for a biopsy when the results may alter management.  Active surveillance should be an initial management option for patients who have significant co-morbidities and limited life expectancy.  Partial nephrectomy (PN) for SRMs is the standard treatment that should be offered to all patients for whom an intervention is indicated and who possess a tumor that is amenable to this approach.  Percutaneous thermal ablation should be considered an option if complete ablation can reliably be achieved.  Radical nephrectomy for SRMs should only be reserved for patients who possess a tumor of significant complexity that is not amenable to PN or for whom PN may result in unacceptable morbidity even when performed at centers with expertise.  Referral to a nephrologist should be considered if chronic kidney disease (estimated glomerular filtration rate [eGFR] of less than 45 ml/min/1.73 m2) or progressive chronic kidney disease occurs after treatment, especially if associated with proteinuria.

Mershon et al (2020) noted that thermal ablation is increasingly employed as a management strategy for SRMs (less than 4 cm).  Partial nephrectomy is recognized as the gold standard; thermal ablation has been reserved for older patients with co-morbidities due to concern for local tumor recurrence.  As long-term data regarding the safety and effectiveness of ablative techniques accumulate with encouraging results, clinicians are widening their use in select patient populations.  These investigators examined the available evidence on these ablative technologies in terms of procedural differences, oncologic outcomes, renal function, and complication rates.  They carried out a structured literature review using PubMed and Web of Science, using the keywords: "renal cell carcinoma", "ablation techniques", "cryosurgery", "radiofrequency ablation", "microwave ablation", "outcomes assessment", "post-operative complication" and "hospital costs".  Articles were reviewed to summarize oncologic outcomes, complications, and impact on renal function of cryoablation, RFA, and microwave ablation.  Thermal ablation is a safe and effective management option for SRMs in select patients, especially in those with multiple tumors and/or those unable or unwilling to undergo more invasive surgery.  Slightly higher rates of local recurrence rates (approximately 1 % to 10 %) with thermal ablation were offset by lower complication rates and reduced morbidity, and equivalent or better renal function outcomes compared to surgery.  The authors concluded that the established modalities of cryoablation, RFA, and microwave ablation offer equivalent outcomes with similar complication rates; technique choice is primarily based on tumor characteristics and operator preference.

Leopold et al (2022) stated that while the gold-standard for management of localized renal cell carcinoma (RCC) is PN, recent ablative strategies are emerging as alternatives with comparable rates of complications and oncologic outcomes.  Thermal ablation, in the form of RFA and cryoablation, is being increasingly accepted by professional societies, and is especially recommended in patients with a significant co-morbidity burden, renal impairment, old age, or in those unwilling to undergo surgery.  Maturation of long-term oncologic outcomes has further allowed increased confidence in these management strategies.  New and exciting ablation technologies such as microwave ablation, stereotactic body radiotherapy, and irreversible electroporation are emerging.

Chan et al (2022) compared oncological outcomes in patients undergoing ablative therapies (AT) or PN for T1a or T1b SRM.  Medline, Embase, Cochrane CENTRAL and conference proceedings were searched on July 15, 2020 for comparative studies respective to the research question.  The ROBINS-I tool and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach were used to evaluate any risk of biases and certainty of evidence in the included studies.  A total of 1,748 records were retrieved: 32 observational studies and 1 RCT integrating 74,946 patients were included.  Patients undergoing AT patients were significantly older than PN patients (MD 5.70, 95 % CI: 3.83 to 7.58).  In T1a patients, AT patients had significantly worse OS (HR 1.64, 95 % CI: 1.39 to 1.95).  Local RFS was similar with PN in patients with longer than 5-years follow-up (HR 1.54, 95 % CI: 0.88 to 2.71).  AT patients also exhibited similar cancer-specific survival (CSS), metastasis-free survival, DFS, significantly fewer post-operative complications (RR 0.72, 95 % CI: 0.55 to 0.94), and a smaller decline in eGFR rate post-operatively (MD: -7.42, 95 % CI: -13.1 to -1.70) compared to those undergoing PN.  Evidence contradicted in T1b patients for oncological outcomes.  The authors concluded that AT had similar long-term oncological durability; lower rates of complications and superior kidney function preservation compared to PN.  These investigators stated that given the low quality of evidence, AT is a reasonable alternative to PN in frail and patients with co-morbidities.

Dong et al (2022) noted that minimally invasive PN (MIPN) and focal therapy (FT) are popular trends for SRMs; however, there is currently no systematic comparison between MIPN and FT of SRMs.  These investigators systematically examined the peri-operative, renal functional, and oncologic outcomes of MIPN and FT in SRMs.  They searched the Embase, Cochrane Library, and PubMed for articles between MIPN (robot-assisted PN and laparoscopic PN) and FT (RFA, microwave ablation (MWA), cryoablation (CA), irreversible electroporation, non-thermal [irreversible electroporation (IRE)] ablation, and stereotactic body radiation therapy (SBRT)).  These researchers calculated pooled mean difference (MD), ORs, and 95 % CIs.  A total of 26 articles (n = 4,420) were included in the study.  Compared with MIPN, the operating time (OP) of FT had significantly lower (SMD, -1.20; CI: -1.77 to -0.63; I2 = 97.6 %, p < 0.0001), estimated blood loss (EBL) of FT had significantly less (SMD, -1.20; CI: -1.77 to -0.63; I2 = 97.6 %, p < 0.0001), LOS was shorter (SMD, -0.90; CI: -1.26 to -0.53; I2 = 92.2 %, p < 0.0001), and eGFR rate of FT was significantly lower decrease (SMD, -0.90; CI: -1.26 to -0.53; I2 = 92.2 %, p < 0.0001).  However, FT possessed lower risk in minor complications (Clavien 1 to 2) (OR, 0.69; CI: 0.45 to 1.07; I2 = 47 %, p = 0.023) and overall complications (OR, 0.71; CI: 0.51 to 0.99; I2 = 49.2 %, p = 0.008).  Finally, there were no obvious difference between FT and MIPN in local recurrence, distant metastasis, and major complications (p > 0.05).  The authors concluded that FT had more advantages in protecting kidney function, reducing bleeding, shortening operating time, and shortening the LOS.  There was no difference in local recurrence, distant metastasis, and major complications.

Wu et al (2022) stated that there is growing evidence that PN and percutaneous CA (PCA) yield comparable outcomes for patients with cT1a RCC, although the cost-effectiveness of both treatments still needs to be assessed.  These investigators carried out a cost-effectiveness analysis of PN and PCA for patients with cT1a RCC.  A decision analysis was created over a 5-year span from a healthcare payer's perspective computing expected costs and outcomes of PN and PCA in terms of quality-adjusted life-years (QALYs) and incremental cost-effectiveness (ICER).  After each treatment, the following states were modelled using data from the recent literature: procedural complications, no evidence of disease (NED), local recurrence, metastases, and death from RCC- or non-RCC-related causes.  Probabilistic and deterministic sensitivity analyses were performed.  PCA and PN yielded health benefits of 3.68 QALY and 3.67 QALY, respectively.  Overall expected costs were $20,491 and $26,478 for PCA and PN, respectively.  On probabilistic sensitivity analysis, PCA was more cost-effective than PN in 84.78 % of Monte Carlo simulations.  PCA was more cost-effective until its complication risk was at least 38 % higher than PN.  PCA was more cost-effective than PN when PCAs annual local recurrence risk was less than 3.5 % higher than that of PN in absolute values; PCAs annual metastatic risk was less than 1.0 % higher than that of PN; or PCAs annual cancer-specific mortality risk was less than 0.65 % higher than that of PN.  PCA remained cost-effective until its procedural cost was above $13,875.  The authors concluded that PCA appeared to be more cost-effective than PN for the treatment of cT1a RCC, although the currently available evidence is of limited quality.  These researchers noted that PCA may be the better treatment strategy in the majority of scenarios varying procedural complications, recurrence, metastatic risk, and RCC-mortality in clinically plausible ranges.

Venous Malformations

In a retrospective, case-series study, Fujiwara et al (2021) examined the long-term effectiveness of percutaneous cryoablation for lower limb soft-tissue venous malformations (VMs).  A total of 9 patients (mean age of 36.6 years) with lower limb soft-tissue VMs were included.  Cryoablation was carried out percutaneously using an argon-based system; AE using the Common Terminology Criteria for AEs version 4.0 were evaluated.  The VAS scores and lesion volumes measured on MRI were also examined at 12 months and 5 to 6 years.  Technical success (i.e., complete coverage of the lesion by an iceball) was achieved in 8 of the 9 patients.  All patients developed a total of 14 grade-1 or grade-2 AEs.  The mean (± SD) VAS score was 6.0 (± 1.7) before therapy, whereas it was 0.14 (± 0.27) at 12 months and 0.97 (± 1.3) at 5 to 6 years (58 to 78 months).  Complete pain relief was obtained in 6 and 5 patients at 12 months and 5 to 6 years, respectively.  The median lesion volume was 2.49 ml before therapy, whereas it was 0.26 ml at 12 months and 0.35 ml at 5 to 6 years.  The authors concluded that percutaneous cryoablation of lower limb soft-tissue VMs achieved considerable pain relief and lesion shrinkage for 5 to 6 years in this small preliminary study.  Level of Evidence = IV.

The authors stated that this was a preliminary and exploratory study with several drawbacks.  First, the study population was small (n = 9) and biased.  Most of the lesions were relatively small and localized.  All lesions were located in the lower extremities or the hip; thus, there is a need to confirm whether similar effectiveness can be obtained in lesions that are large and diffuse, or present in other locations.  Second, cryoablation was carried out by a single operator.  Third, the previous therapy in 7 patients may have been a potential confounder.

In a systematic review, Fish et al (2022) examined the safety, effectiveness and technical aspects of cryoablation in the treatment of VMs and provided the groundwork for future studies.  These investigators carried out a literature search for clinical studies using percutaneous cryoablation of VMs.  All clinical studies related to primary or secondary treatment of VMs with percutaneous cryoablation were included in this review.  These selected studies were evaluated for patient characteristics, cryoablation technique, technical success, lesion size and pain scores before and after cryoablation, and adverse outcomes.  Random effects analysis of post-procedural changes in lesion volume and pain scores was performed.  There were 54 patients with 55 cases of cryoablation of VMs.  Of these cases, 27 recorded changes in lesion volume and 31 recorded changes in pain scores.  The weighted mean post-procedural decrease in lesion size was 92.0 % (raw average of 71.7 %).  The weighted mean reduction in pain score was 77% (raw average of 78.2 %).  Considering all treated cases (55), complete resolution of symptoms was observed in 35 cases (63.6 %) and overall (complete or partial) improvement in 52 cases (94.5 %).  Common post-procedural symptoms included pain, bruising, swelling and numbness lasting less than 2 weeks.  There were 2 major AEs (3.7 %), with both cases due to persistent dysesthesia.  Patients with a history of prior sclerotherapy demonstrated lower pre-procedural and post-procedural pain scores (4.7 and 1.3) than patients without prior treatments (5.8 and 2.8).  The authors concluded that cryoablation of VMs appeared to be potentially safe and effective on limited short-interval follow-up. These findings need to be validated by well-designed studies (larger sample size and follow-up duration).


Appendix

Stages of Prostate Cancer

Stage I (A)

Prostate cancer can not be felt by digital rectal exam, causes no symptoms, and is only in the prostate, usually found incidentally in a prostatectomy specimen when surgery is done for benign prostatic hyperplasia.

Stage II (B)

Cancer confined to the prostate gland found by a needle biopsy done for an elevated PSA level or after rectal examination reveals a mass in the prostate.

Stage III (C)

Cancer cells have spread outside the capsule of the prostate to tissues around the prostate, e.g., seminal vesicles.

Stage IV (D)

Cancer cells have metastasized to lymph nodes or to organs and tissues such as the bone, liver, or lungs.


References

The above policy is based on the following references:

Cryoablation of the Prostate

  1. Alberta Heritage Foundation for Medical Research (AHFMR). Cryosurgery for prostate cancer. Technote TN 16. Edmonton, AB: AHFMR; 2002.
  2. Alberta Heritage Foundation for Medical Research (AHFMR). Cryotherapy as primary treatment for localized prostate cancer (update). Technote TN 54. Edmonton, AB: AHFMR; 2005.
  3. Bahn DK, Lee F, Badalament R, et al. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60(2 Suppl 1):3-11.
  4. Bales GT, Williams MJ, Sinner M, et al. Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy. Urology. 1995;46(5):676-680.
  5. Barat M, Colleter L, Mongiat-Artus P, et al. Salvage cryoablation for local recurrence of prostatic cancer after curative therapy. Diagn Interv Imaging. 2019;100(11):679-687.
  6. BlueCross BlueShield Association (BCBS), Technology Evaluation Center. Cryoablation for the primary treatment of clinically localized prostate cancer. TEC Assessment Program. Chicago IL: BCBSA; 2001;16(6).
  7. Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Cryotherapy for prostate cancer. Pre-Assessment No. 32. Ottawa, ON: CCOHTA; February 2004.
  8. Carroll PR. Prostate cancer - many treatments but not enough answers. J Urol. 1995;154:454-455.
  9. Chin JL, Downey DB, Mulligan M, et al. Three-dimensional transrectal ultrasound guided cryoablation for localized prostate cancer in nonsurgical candidates: A feasibility study and report of early results. J Urol. 1998;159(3):910-914.
  10. Chuang CK, Chu SH, Chen HW, et al. Application of cryoablation in the management of prostate cancer. Chang Keng I Hsueh. 1997;20(3):201-206.
  11. Cohen JK, Miller RJ, Rooker GM, et al. Cryosurgical ablation of the prostate: Two year prostate-specific antigen and biopsy results. Urology. 1996;47(3):395-401.
  12. Cohen JK, Rooker GM, Miller RJ Jr, et al. Cryosurgical ablation of the prostate: Treatment alternative for localized prostate cancer. Cancer Treat Res. 1996;88:167-186.
  13. Corral DA, Pisters LL, von Eschenbach AC. Treatment options for localized recurrence of prostate cancer following radiation therapy. Urol Clin North Am. 1996;23(4):677-684.
  14. Cox RL, Crawford ED. Complications of cryosurgical ablation of the prostate to treat localized adenocarcinoma of the prostate. Urology. 1995;45:932-935.
  15. de la Taille A, Hayek O, Benson MC, et al. Salvage cryotherapy for recurrent prostate cancer after radiation therapy: The Columbia experience. Urology. 2000;55(1):79-84.
  16. Derakhshani P, Neubauer S, Braun M, et al. Cryoablation of localized prostate cancer. Experience in 48 cases, PSA and biopsy results. Eur Urol. 1998;34(3):181-187.
  17. Donnelly BJ, Saliken JC, Ernst DS, et al. Prospective trial of cryosurgical ablation of the prostate: Five-year results. Urology. 2002;60(4):645-649.
  18. Drachenberg DE. Treatment of prostate cancer: Watchful waiting, radical prostatectomy, and cryoablation. Semin Surg Oncol. 2000;18(1):37-44.
  19. Erlichman M, Handelsman H, Hotta SS. Cryosurgery for recurrent prostate cancer following radiation therapy - systematic review. Health Technology Assessment No. 13. AHCPR Pub. No. 99-0004. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); June 1999.
  20. Feldman M. Cryoablation of the prostate for the treatment of primary and recurrent localized prostate cancer. Technology Assessment. San Francisco, CA: California Technology Assessment Forum: June 15, 2005. Available at: http://www.ctaf.org/ass/viewfull.ctaf?id=54588264128. Accessed January 13, 2006.
  21. Foster KN. Cryotherapy for prostatic cancer. STEER: Succint and Timely Evaluated Evidence Reviews. Bazian Ltd., eds. London, UK: Wessex Institute for Health Research and Development, University of Southampton; 2001;1(4):1-10.
  22. Grubb RL 3rd, Vardi IY, Bhayani SB, Kibel AS. Minimally invasive approaches to localized prostate carcinoma. Hematol Oncol Clin North Am. 2006;20(4):879-895.
  23. Hummel S, Paisley S, Morgan A, et al. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: A systematic review. Health Technol Assess. 2003;7(33):1-170.
  24. Katz AE, Rewcastle JC. The current and potential role of cryoablation as a primary therapy for localized prostate cancer. Curr Oncol Rep. 2003;5(3):231-238.
  25. L'Agence Nationale d'Accreditation d'Evaluation en Sante (ANAES). Treatment of localised prostate cancer. Paris, France: ANAES; 2001:4.
  26. Long JP, Fallick ML, LaRock DR, et al. Preliminary outcomes following cryosurgical ablation of the prostate in patients with clinically localized prostate carcinoma. J Urol. 1998;159(2):477-484.
  27. Miller RJ, Cohen JK, Shuman B, et al. Percutaneous, transperineal cryosurgery of the prostate as salvage therapy for post radiation recurrence of adenocarcinoma. Cancer. 1996;77:1510-1514.
  28. National Institute for Health and Clinical Excellence (NICE). Cryotherapy as a primary treatment for prostate cancer. Interventional Procedure Guidance 145. London, UK: NICE; November 2005.
  29. National Institute for Health and Clinical Excellence (NICE). Cryotherapy for recurrent prostate cancer. Interventional Procedure Guidance No. 119. London, UK: NICE; May 2005.
  30. Onik GM, Cohen JK, Reyes GD, et al. Transrectal ultrasound-guided percutaneous radical cryosurgical ablation of the prostate. Cancer. 1993;72:1291-1299.
  31. Patel BG, Parsons CL, Bidair M, et al. Cryoablation for carcinoma of the prostate. J Surg Oncol. 1996;63(4):256-264.
  32. Saliken JC, Donnelly BJ, Brasher P, et al. Outcome and safety of transrectal US-guided percutaneous cryotherapy for localized prostate cancer. J Vasc Interv Radiol. 1999;10(2 Pt 1):199-208.
  33. Schmidt JD, Doyle J, Larison S. Prostate cryoablation: Update 1998. CA Cancer J Clin. 1998;48(4):239-253.
  34. Shelley M, Wilt TJ, Coles B, Mason MD. Cyrotherapy for localised prostate cancer. Cochrane Database Syst Rev. 2007;(3):CD005010.
  35. Shinohara K, Connolly JA, Presti JC Jr, et al. Cryosurgical treatment of localized prostate cancer (stages T1 to T4): Preliminary results. J Urol. 1996;156(1):115-121.
  36. Wong WS, Chinn DO, Chinn M, et al. Cryosurgery as a treatment for prostate carcinoma: Results and complications. Cancer. 1997;79(5):963-974.
  37. Zippe CD. Cryosurgical ablation for prostate cancer: A current review. Semin Urol. 1995;13(2):148-156.

Cryoablation for Malignant Endobronchial Obstruction

  1. National Institute for Health and Clinical Excellence (NICE). Cryotherapy for malignant endobronchial obstruction. Interventional Procedure Guidance No. 142. London, UK: NICE; November 2005. 
  2. Wood DE. Management of malignant tracheobronchial obstruction. Surg Clin North Am. 2002;82(3):621-642.

Cryoablation of the Kidney

  1. Aron M, Gill IS. Renal tumor ablation. Curr Opin Urol. 2005;15(5):298-305.
  2. Atwell TD, Farrell MA, Leibovich BC, et al. Percutaneous renal cryoablation: Experience treating 115 tumors. J Urol. 2008;179(6):2136-2140, discussion 2140-2141.
  3. Bishoff JT, Chen RB, Lee BR, et al. Laparoscopic renal cryoablation: Acute and long-term clinical, radiographic, and pathologic effects in an animal model and application in a clinical trial. J Endourol. 1999;13(4):233-239.
  4. Brett AS. Cryoablation for small renal tumors in older patients. Summary and Comment. JournalWatch General Medicine, July 3, 2008.
  5. Campbell SC. Renal cryosurgery: Experimental evaluation of treatment parameters. Urology. 1998;52(1):29-34.
  6. Cestari A, Guazzoni G, dell'Acqua V, et al. Laparoscopic cryoablation of solid renal masses: Intermediate term followup. J Urol. 2004;172(4 Pt 1):1267-1270.
  7. Chin JL, Pautler SE. New technologies for ablation of small renal tumors: Current status. Can J Urol. 2002;9(4):1576-1582.
  8. Cozzi PJ, Lynch WJ, Collins S, et al. Renal cryotherapy in a sheep model: A feasibility study. J Urol. 1997;157(2):710-712.
  9. Delworth MG, Pisters LL, Fornage BD, et al. Cryotherapy for renal cell carcinoma and angiomyolipoma. J Urol. 1996;155(1):252-255.
  10. Desai MM, Aron M, Gill IS. Laparoscopic partial nephrectomy versus laparoscopic cryoablation for the small renal tumor. Urology. 2005;66(5 Suppl):23-28.
  11. Desai MM, Gill IS. Current status of cryoablation and radiofrequency ablation in the management of renal tumors. Curr Opin Urol. 2002;12(5):387-393.
  12. Finley DS, Beck S, Box G, et al. Percutaneous and laparoscopic cryoablation of small renal masses. J Urol. 2008;180(2):492-498; discussion 498.
  13. Gill IS, Novick AC, Soble JJ, et al. Laparoscopic renal cryoablation: Initial clinical series. Urology. 1998;52(4):543-551.
  14. Gill IS, Remer EM, Hasan WA, et al. Renal cryoablation: Outcome at 3 years. J Urol. 2005;173(6):1903-1907. 
  15. Gulur D, Crow P, Keeley FX. Minimally invasive ablative technique for the treatment of small renal masses. Arch Ital Urol Androl. 2009;81(2):100-106.
  16. Harada J, Dohi M, Mogami T, et al. Initial experience of percutaneous renal cryosurgery under the guidance of a horizontal open MRI system. Radiat Med. 2001;19(6):291-296.
  17. Hinshaw JL, Shadid AM, Nakada SY, et al. Comparison of percutaneous and laparoscopic cryoablation for the treatment of solid renal masses. AJR Am J Roentgenol. 2008;191(4):1159-1168.
  18. Janzen N, Zisman A, Pantuck AJ, et al. Minimally invasive ablative approaches in the treatment of renal cell carcinoma. Curr Urol Rep. 2002;3(1):13-20.
  19. Johnson DB, Solomon SB, Su LM, et al. Defining the complications of cryoablation and radio frequency ablation of small renal tumors: A multi-institutional review. Urol. 2004;172(3):874-877.
  20. Kaouk JH, Aron M, Rewcastle JC, Gill IS. Cryotherapy: Clinical end points and their experimental foundations. Urology. 2006;68(1 Suppl):38-44.
  21. Klingler HC. Kidney cancer: Energy ablation. Curr Opin Urol. 2007;17(5):322-326.
  22. Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small renal mass: A meta-analysis. Cancer. 2008;113(10):2671-2680.
  23. Lee DI, McGinnis DE, Feld R, Strup SE. Retroperitoneal laparoscopic cryoablation of small renal tumors: Intermediate results. Urology. 2003;61(1):83-88.
  24. Littrup PJ, Ahmed A, Aoun HD, et al. CT-guided percutaneous cryotherapy of renal masses. J Vasc Interv Radiol. 2007;18(3):383-392.
  25. Long JP. Percutaneous cryoablation of the kidney in a porcine model. Cryobiology. 1999;38(1):89-93.
  26. Lowry PS, Nakada SY. Renal cryotherapy: 2003 clinical status. Curr Opin Urol. 2003;13(3):193-197.
  27. Moon TD, Lee FT Jr, Hedican SP, et al. Laparoscopic cryoablation under sonographic guidance for the treatment of small renal tumors. J Endourol. 2004;18(5):436-440.
  28. Mouraviev V, Joniau S, Van Poppel H, Polascik TJ. Current status of minimally invasive ablative techniques in the treatment of small renal tumours. Eur Urol. 2007;51(2):328-336.
  29. Nabi G, Cleves A, Shelley M. Surgical management of localised renal cell carcinoma. Cochrane Database Syst Rev. 2010;(3):CD006579.
  30. National Comprehensive Cancer Network (NCCN). Kidney cancer. NCCN Clinical Practice Guidelines in Oncology v.1.2009. Fort Washington, PA: NCCN; August 2008. 
  31. National Institute for Health and Clinical Excellence (NICE). Cryotherapy for renal cancer. Interventional Procedure Guidance 207. London, UK: NICE; January 2007. 
  32. National Institute for Health and Clinical Excellence (NICE). Percutaneous cryotherapy for renal cancer. Interventional Procedure Guidance 402. London, UK: NICE; July 2011. 
  33. Powell T, Whelan C, Schwartz BF. Laparoscopic renal cryotherapy: Biology, techniques and outcomes. Minerva Urol Nefrol. 2005;57(2):109-118.
  34. Rukstalis DB, Khorsandi M, Garcia FU, et al. Clinical experience with open renal cryoablation. Urology. 2001;57(1):34-39.
  35. Shingleton WB, Sewell PE Jr. Cryoablation of renal tumours in patients with solitary kidneys. BJU Int. 2003;92(3):237-239.
  36. Silverman SG, Tuncali K, vanSonnenberg E, et al. Renal tumors: MR imaging-guided percutaneous cryotherapy--initial experience in 23 patients. Radiology. 2005;236(2):716-724.
  37. Thiel DD, Winfield HN. State-of-the-art surgical management of renal cell carcinoma. Expert Rev Anticancer Ther. 2007;7(9):1285-1294.
  38. Uchida M, Imaide Y, Sugimoto K, et al. Percutaneous cryosurgery for renal tumours. Br J Urol. 1995;75(2):132-137.
  39. Weight CJ, Kaouk JH, Hegarty NJ, et al. Correlation of radiographic imaging and histopathology following cryoablation and radio frequency ablation for renal tumors. J Urol. 2008;179(4):1277-1281; discussion 1281-1283.

Cryoablation of the Breast

  1. Agnese DM, Burak WE Jr. Ablative approaches to the minimally invasive treatment of breast cancer. Cancer J. 2005;11(1):77-82.
  2. Bland KL, Gass J, Klimberg VS. Radiofrequency, cryoablation, and other modalities for breast cancer ablation. Surg Clin North Am. 2007;87(2):539-50, xii.
  3. Caleffi M, Filho DD, Borghetti K, et al. Cryoablation of benign breast tumors: Evolution of technique and technology. Breast. 2004;13(5):397-407.
  4. California Technology Assessment Forum (CTAF). Cryoablation for the treatment of breast fibroadenomas. A Technology Review. San Francisco, CA: CTAF; February 15, 2006. 
  5. Edwards MJ, Broadwater R, Tafra L, et al. Progressive adoption of cryoablative therapy for breast fibroadenoma in community practice. Am J Surg. 2004;188(3):221-224.
  6. Hall-Craggs MA, Vaidya JS. Minimally invasive therapy for the treatment of breast tumours. Eur J Radiol. 2002;42(1):52-57.
  7. Huston TL, Simmons RM. Ablative therapies for the treatment of malignant diseases of the breast. Am J Surg. 2005;189(6):694-701.
  8. Kaufman C, Bachman B, Littrup PJ, et al. Office-based ultrasound-guided cryoablation of breast fibroadenomas. Am J Surg. 2002;184(5):394-400.
  9. Kaufman CS, Littrup PJ, Freeman-Gibb LA, et al. Office-based cryoablation of breast fibroadenomas with long-term follow-up. Breast J. 2005;11(5):344-350.
  10. Kaufman CS, Littrup PJ, Freman-Gibb LA, et al. Office-based cryoablation of breast fibroadenomas: 12-month followup. J Am Coll Surg. 2004;198(6):914-923.
  11. Littrup PJ, Freeman-Gibb L, Andea A, et al. Cryotherapy for breast fibroadenomas. Radiology. 2005;234(1):63-72.
  12. Nurko J, Mabry CD, Whitworth P, et al. Interim results from the FibroAdenoma Cryoablation Treatment Registry. Am J Surg. 2005;190(4):647-652.
  13. Pfleiderer SO, Freesmeyer MG, Marx C, et al. Cryotherapy of breast cancer under ultrasound guidance: Initial results and limitations. Eur Radiol. 2002;12(12):3009-3014.
  14. Simmons R. Ultrasound in the changing approaches to breast cancer diagnosis and treatment. Breast J. 2004;10 Suppl 1:S13-4.
  15. Simmons RM. Ablative techniques in the treatment of benign and malignant breast disease. J Am Coll Surg. 2003;197(2):334-338.
  16. Simmons RM. Freezing breast cancers to enhance complete resection. Ann Surg Oncol. 2003;10(9):999.
  17. Singletary SE. Minimally invasive techniques in breast cancer treatment. Semin Surg Oncol. 2001;20(3):246-250.
  18. Whitworth PW, Rewcastle JC. Cryoablation and cryolocalization in the management of breast disease. J Surg Oncol. 2005;90(1):1-9. 

Cryoablation for Atrial Fibrillation

  1. Andrade JG et al. Efficacy and safety of cryoballoon ablation for atrial fibrillation: A systematic review of published studies. Heart Rhythm. 2011;8:1444-1451.
  2. Blomström-Lundqvist C, Johansson B, et al. A randomized double-blind study of epicardial left atrial cryoablation for permanent atrial fibrillation in patients undergoing mitral valve surgery: The SWEDish Multicentre Atrial Fibrillation study (SWEDMAF). Eur Heart J. 2007;28(23):2902-2908.
  3. Calkins H et al. 2012 HRS/EHRA/ECAS Expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints and research trial design. Heart Rhythm. 2012;9:632-696.
  4. Doll N, Kiaii BB, Fabricius AM, et al. Intraoperative left atrial ablation (for atrial fibrillation) using a new argon cryocatheter: Early clinical experience. Ann Thorac Surg. 2003;76(5):1711-1715; discussion 1715.
  5. Gaita F, Riccardi R, Caponi D, et al. Linear cryoablation of the left atrium versus pulmonary vein cryoisolation in patients with permanent atrial fibrillation and valvular heart disease: Correlation of electroanatomic mapping and long-term clinical results. Circulation. 2005;111(2):136-142.
  6. Gillinov AM, Saltman AE. Ablation of atrial fibrillation with concomitant cardiac surgery. Semin Thorac Cardiovasc Surg. 2007;19(1):25-32.
  7. Hazel S J, et al. A systematic review of intraoperative ablation for the treatment of atrial fibrillation. ASERNIP-S Report No.38. Stepney, SA: Royal Australasian College of Surgeons, Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S); 2004.
  8. Hoyt RH, Wood M, Daoud E, et al. Transvenous catheter cryoablation for treatment of atrial fibrillation: Results of a feasibility study. Pacing Clin Electrophysiol. 2005;28 Suppl 1:S78-S82.
  9. Kojodjojo P et al. Pulmonary venous isolation by antral ablation with a large cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: Medium term outcomes and non-randomized comparison with pulmonary venous isolation by radiofrequency ablation. Heart. 2010;96:1379-1384.
  10. Kuhne M et al. Cryoballoon versus radiofrequency catheter ablation of paroxysmal atrial fibrillation: biomarkers of myocardial injury, recurrence rates and pulmonary vein reconnection patterns. Heart Rhythm. 2010:7:1770-1776.
  11. Linhart M et al. Comparison of cryoballoon and radiofrequency ablation of pulmonary veins in 40 patients with paroxysmal atrial fibrillation: A case control study. J Cardiovasc Electrophys. 2009;20:1343-1348.
  12. Mack CA, Milla F, Ko W, et al. Surgical treatment of atrial fibrillation using argon-based cryoablation during concomitant cardiac procedures. Circulation. 2005;112(9 Suppl):I1-I6.
  13. National Institute for Health and Clinical Excellence (NICE). Cryoablation for atrial fibrillation in association with other cardiac surgery. Interventional Procedure Guidance 123. London, UK: NICE; May 2005. 
  14. Neuwirth R, Fiala M, Branny P, et al. Long term effectiveness of surgical cryoablation for chronic atrial fibrillation in patients undergoing surgery for severe mitral valve regurgitation. Vnitr Lek. 2007;53(2):151-156.
  15. Packer DL, Kowal RC, Wheelan KR, et al.; STOP AF Cryoablation Investigators. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: First results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol. 2013;61(16):1713-1723.
  16. Wann LS et al. 2011 ACCF/AHA/HRS Focused update on the management of patients with atrial fibrillation (updating the 2005 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice Guidelines. Circulation. 2011;123:104-123.

Cryoablation for Skin Cancers

  1. Morton C, Horn M, Leman J, et al. Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol. 2006;142(6):729-735.
  2. National Comprehensive Cancer Network (NCCN). Basal and squamous cell skin cancers. NCCN Clinical Practice Guidelines in Oncology v.1.2009. Fort Washington, PA: NCCN; 2009.
  3. Telfer NR, Colver GB, Morton CA, British Association of Dermatologists. Guidelines for the management of basal cell carcinoma. Br J Dermatol. 2008;159(1):35-48.

Cryoablation for Cervical Intraepithelial Neoplasia

  1. Lewis KD, Sellors JW, Dawa A, et al. Report on a cryotherapy service for women with cervical intraepithelial neoplasia in a district hospital in western Kenya. Afr Health Sci. 2011;11(3):370-376.
  2. Martin-Hirsch PP, Paraskevaidis E, Bryant A, et al. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2010;(6):CD001318.
  3. Sauvaget C, Muwonge R, Sankaranarayanan R. Meta-analysis of the effectiveness of cryotherapy in the treatment of cervical intraepithelial neoplasia. Int J Gynaecol Obstet. 2013;120(3):218-223.

Cryoablation for Other Indications

  1. Althausen PL, Schneider PD, Bold RJ, et al. Multimodality management of a giant cell tumor arising in the proximal sacrum: Case report. Spine (Phila Pa 1976). 2002;27(15):E361-E365.
  2. Arroyo JG. Retinal detachment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  3. Autrusseau P-A, Cazzato RL, De Marini P, et al. Pain relief and local tumour control following percutaneous image-guided cryoablation for spine metastasis: A 12-year single-centre experience. Clin Radiol. 2021;76(9):674-680.
  4. Bala MM, Riemsma RP, Wolff R, Kleijnen J. Cryotherapy for liver metastases. Cochrane Database Syst Rev. 2013;(6):CD009058.
  5. Beland MD, Mayo-Smith WW. Ablation of adrenal neoplasms. Abdom Imaging. 2009;34(5):588-592.
  6. Bellini M, Barbieri M. Percutaneous cryoanalgesia in pain management: A case-series. Anaesthesiol Intensive Ther. 2015;47(4):333-335.
  7. Beutler A, Fields KB. Approach to the adult with knee pain likely of musculoskeletal origin. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2022.
  8. Bhattacharyya N. Clinical presentation, diagnosis, and treatment of nasal obstruction. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2018.
  9. Bhora FY, Ayub A, Forleiter CM, et al. Treatment of benign tracheal stenosis using endoluminal spray cryotherapy. JAMA Otolaryngol Head Neck Surg. 2016;142(11):1082-1087.
  10. Birkenmaier C, Veihelmann A, Trouillier H, et al. Percutaneous cryodenervation of lumbar facet joints: A prospective clinical trial. Int Orthop. 2007;31(4):525-530.
  11. Bonthius DJ, Lee AG, Hershey AD. Headache in children: Approach to evaluation and general management strategies.  UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2017.
  12. Buethe JY, Abboud S, Brock K, et al. Percutaneous CT-guided cryoablation of the salivary glands in a porcine model. J Vasc Interv Radiol. 2016;27(12):1907-1912.
  13. Callstrom MR, Woodrum DA, Nichols FC, et al. Multicenter study of metastatic lung tumors targeted by interventional cryoablation evaluation (SOLSTICE). J Thorac Oncol. 2020;15(7):1200-1209.
  14. Cazzato RL, Auloge P, De Marini P, et al. Percutaneous image-guided ablation of bone metastases: local tumor control in oligometastatic patients. Int J Hyperthermia. 2018;35(1):493-499.
  15. Cazzato RL, Jennings JW, Autrusseau P-A, et al. Percutaneous image-guided cryoablation of spinal metastases: Over 10-year experience in two academic centers. Eur Radiol. 2022;32(6):4137-4146.
  16. Chan VWS, Abul A, Osman FH, et al. Ablative therapies versus partial nephrectomy for small renal masses - A systematic review and meta-analysis. Int J Surg. 2022;97:106194.
  17. Chang MT, Song S, Hwang PH. Cryosurgical ablation for treatment of rhinitis: A prospective multicenter study. Laryngoscope. 2020;130(8):1877-1884.
  18. Chen L, Gu YD, Xu L. Clinical application of axonal repair technique for treatment of peripheral nerve injury. Chin J Traumatol. 2004;7(3):153-155.
  19. Colangeli S, Parchi P, Andreani L, et al. Cryotherapy efficacy and safety as local therapy in surgical treatment of musculoskeletal tumours. A retrospective case series of 143 patients. J Biol Regul Homeost Agents. 2018;32(6 Suppl. 1):65-70.
  20. Colt HG. Bronchoscopic cryotechniques in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  21. Cornelis F, Petitpierre F, Lasserre AS, et al. Percutaneous cryoablation of symptomatic abdominal scar endometrioma: Initial reports. Cardiovasc Intervent Radiol. 2014;37(6):1575-1579.
  22. Coupal TM, Pennycooke K, Mallinson PI, et al. The hopeless case? Palliative cryoablation and cementoplasty procedures for palliation of large pelvic bone metastases. Pain Physician. 2017;20(7):E1053-E1061.
  23. Covey CJ, Shmerling RH. Approach to the adult with unspecified knee pain. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2022.
  24. Cunningham GR, Khera M. Treatment of male sexual dysfunction. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed September 2016.
  25. David Prologo J, Snyder LL, Cherullo E, et al. Percutaneous CT-guided cryoablation of the dorsal penile nerve for treatment of symptomatic premature ejaculation. J Vasc Interv Radiol. 2013;24(2):214-219.
  26. de Baere T, Tselikas L, Woodrum D, et al. Evaluating cryoablation of metastatic lung tumors in patients -- safety and efficacy: The ECLIPSE Trial -- interim analysis at 1 year. J Thorac Oncol. 2015;10(10):1468-1474.
  27. de Bruyns A, Li H, MacNeil A, et al. Evolving practice patterns over two decades (1993-2013) in the management of desmoid-type fibromatosis in British Columbia. Clin Oncol (R Coll Radiol). 2020;32(4):e102-e110.
  28. De Marini P, Cazzato RL, Auloge P, et al. Percutaneous image-guided thermal ablation of bone metastases: A retrospective propensity study comparing the safety profile of radio-frequency ablation and cryo-ablation. Int J Hyperthermia. 2020;37(1):1386-1394.
  29. de Vries J, Oldhoff J, Hadders HH. Cryosurgical treatment of sacrococcygeal chordoma. Report of four cases. Cancer. 1986;58(10):2348-2354.
  30. Demmy T, Dexter E. Overview of minimally invasive thoracic surgery. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  31. Domovitov SV, Chandhanayingyong C, Boland PJ, et al. Conservative surgery in the treatment of giant cell tumor of the sacrum: 35 years' experience. J Neurosurg Spine. 2016;24(2):228-240.
  32. Dong L, Liang WY, Ya L, et al. A systematic review and meta-analysis of minimally invasive partial nephrectomy versus focal therapy for small renal masses. Front Oncol. 2022;12:732714.
  33. Dupuy DE. Image-guided ablation of lung tumors. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  34. Eiken PW, Welch BT. Cryoablation of lung metastases: Review of recent literature and ablation technique. Semin Intervent Radiol. 2019;36(4):319-325.
  35. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines. Ann Oncol. 2016;27(suppl 5):v58-v68.
  36. Fan WZ, Niu LZ, Wang Y, et al. Initial experience: Alleviation of pain with percutaneous CT-guided cryoablation for recurrent retroperitoneal soft-tissue sarcoma. J Vasc Interv Radiol. 2016;27(12):1798-1805.
  37. Fernando HC, Dekeratry D, Downie G, et al. Feasibility of spray cryotherapy and balloon dilation for non-malignant strictures of the airway. Eur J Cardiothorac Surg. 2011;40(5):1177-1180.
  38. Fernando HC, Sherwood JT, Krimsky W. Endoscopic therapies and stents for benign airway disorders: Where are we, and where are we heading? Ann Thorac Surg. 2010;89(6):S2183-S2187.
  39. Ferrer-Mileo L, Luque Blanco AI, Gonzalez-Barboteo J. Efficacy of cryoablation to control cancer pain: A systematic review. Pain Pract. 2018;18(8):1083-1098.
  40. Fichman V, Valle ACFD, de Macedo PM, et al. Cryosurgery for the treatment of cutaneous sporotrichosis in four pregnant women. PLoS Negl Trop Dis. 2018;12(4):e0006434.
  41. Finelli A, Ismaila N, Bro B, et al. Management of small renal masses: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35(6):668-680.
  42. Fish A, Moushey A, Chan SM, et al. Cryoablation of venous malformations: A systematic review. J Vasc Interv Radiol. 2022;33(8):993-1000.
  43. Fujiwara H, Hiraki T, Matsui Y, et al. Percutaneous cryoablation of lower limb soft-tissue venous malformations: Preliminary results of long-term efficacy. Cardiovasc Intervent Radiol. 2021;44(9):1485-1490.
  44. Garza I, Schwedt TJ. New daily persistent headache. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2017b.
  45. Garza I, Schwedt TJ. Overview of chronic daily headache. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2017a.
  46. Giammalva GR, Ferini G, Torregrossa F, et al. The palliative care in the metastatic spinal tumors. A systematic review on the radiotherapy and surgical perspective. Life (Basel). 2022;12(4):571.
  47. Gomez FM, Patel PA, Stuart S, Roebuck DJ. Systematic review of ablation techniques for the treatment of malignant or aggressive benign lesions in children. Pediatr Radiol. 2014;44(10):1281-1289.
  48. Gosalia AJ, Martin P, Jones PD. Advances and future directions in the treatment of hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2017;13(7):398-410.
  49. Greenwald BD, Dumot JA, Abrams JA, et al. Endoscopic spray cryotherapy for esophageal cancer: Safety and efficacy. Gastrointest Endosc. 2010;71(4):686-693.
  50. Hamade N, Desai M, Chandrasekar VT, et al. Efficacy of cryotherapy as first line therapy in patients with Barrett's neoplasia: A systematic review and pooled analysis. Dis Esophagus. 2019;32(11):doz040. 
  51. Hamilos DL. Chronic rhinosinusitis: Management. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2018.
  52. Harbaugh CM, Johnson KN, Kein CE, et al. Comparing outcomes with thoracic epidural and intercostal nerve cryoablation after Nuss procedure. J Surg Res. 2018;231:217-223.
  53. Hergenroeder AC. Approach to chronic knee pain or injury in children or skeletally immature adolescents. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2022.
  54. Hwang PH, Lin B, Weiss R, et al. Cryosurgical posterior nasal tissue ablation for the treatment of rhinitis. Int Forum Allergy Rhinol. 2017;7(10):952-956. 
  55. Ierardi AM, Carnevale A, Angileri SA, et al. Outcomes following minimally invasive imagine-guided percutaneous ablation of adrenal glands. Gland Surg. 2020;9(3):859-866.
  56. Iguchi T, Sakurai J, Hiraki T, et al. Safety of percutaneous cryoablation in patients with painful bone and soft tissue tumors: A single center prospective study (SCIRO-1502). Acta Med Okayama. 2016;70(4):303-306.
  57. James M, O'Doherty M, Beatty S. Buckle-related complications following surgical repair of retinal dialysis. Eye (Lond). 2008;22(4):485-490.
  58. Kawamura M, Izumi Y, Tsukada N, et al. Percutaneous cryoablation of small pulmonary malignant tumors under computed tomographic guidance with local anesthesia for nonsurgical candidates. J Thorac Cardiovasc Surg. 2006131(5):1007-1013.
  59. Klem TM, Schnater JM, Schütte PR, et al. A randomized trial of cryo stripping versus conventional stripping of the great saphenous vein. J Vasc Surg. 2009;49(2):403-409.
  60. Koch G, Cazzato RL, Gilkison A, et al. Percutaneous treatments of benign bone tumors. Semin Intervent Radiol. 2018;35(4):324-332.
  61. Kompelli AR, Janz TA, Rowan NR, et al. Cryotherapy for the treatment of chronic rhinitis: A qualitative systematic review. Am J Rhinol Allergy. 2018;32(6):491-501.
  62. Krimsky WS, Rodrigues MP, Malayaman N, Sarkar S. Spray cryotherapy for the treatment of glottic and subglottic stenosis. Laryngoscope. 2010;120(3):473-477.
  63. Krummel T, Garnon J, Lang H, et al. Percutaneous cryoablation for tuberous sclerosis-associated renal angiomyolipoma with neoadjuvant mTOR inhibition. BMC Urol. 2014;14(1):77.
  64. Kujak JL, Liu PT, Johnson GB, Callstrom MR. Early experience with percutaneous cryoablation of extra-abdominal desmoid tumors. Skeletal Radiol. 2010;39(2):175-182.
  65. Kurup AN, Callstrom MR. Image-guided ablation of skeletal metastases. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  66. Kurup AN, Woodrum DA, Morris JM, et al. Cryoablation of recurrent sacrococcygeal tumors. J Vasc Interv Radiol. 2012;23(8):1070-1075.
  67. Lee JH, Stein M, Roychowdhury S. et al. Percutaneous treatment of a sacral metastasis with combined embolization, cryoablation, alcohol ablation and sacroplasty for local tumor and pain control. Interv Neuroradiol. 2013;19(2):250-253.
  68. Leopold Z, Passarelli R, Mikhail M, et al. Modern management of localized renal cell carcinoma -- Is ablation part of the equation? J Kidney Cancer VHL. 2022;9(3):5-23.
  69. Leppelmann KS , Levesque VM, Bunck AC, et al. Outcomes following percutaneous microwave and cryoablation of lung metastases from adenoid cystic carcinoma of the head and neck: A bi-institutional retrospective cohort study. Ann Surg Oncol. 2021;28(11):5829-5839.
  70. Li L, Jiang X-F, Sun L-J, et al. Computed tomography-guided argon-helium cryoablation for sacrum chordoma. Medicine (Baltimore). 2020;99(42):e22604.
  71. Lieberman PL. Chronic nonallergic rhinitis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2018.
  72. Lindquester WS, Crowley J, Hawkins CM. Percutaneous thermal ablation for treatment of osteoid osteoma: A systematic review and analysis. Skeletal Radiol. 2020;49(9):1403-1411.
  73. Lipede C, Nikkhah D, Ashton R, et al. Management of fibro-adipose vascular anomalies (FAVA) in paediatric practice. JPRAS Open. 2021;29:71-81.
  74. Luksanapruksa P, Buchowski JM, Singhatanadgige W, et al. Management of spinal giant cell tumors. Spine J. 2016;16(2):259-269.
  75. Maisonave Y, Nicoara A. Anesthesia for placement of ventricular assist devices. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  76. Mancini D. Practical management of long-term mechanical circulatory support devices. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  77. McDevitt JL, Mouli SK, Nemcek AA, et al. Percutaneous cryoablation for the treatment of primary and metastatic lung tumors: Identification of risk factors for recurrence and major complications. J Vasc Interv Radiol. 2016;27(9):1371-1379.
  78. McLean BC, Nguyen CD, Newman DP. Cryoablation of the infrapatellar branch of the saphenous nerve identified by non-invasive peripheral nerve stimulator for the treatment of non-surgical anterior knee pain: A case series and review of the literature. Cureus. 2020;12(6):e8747.
  79. McMillan S, Dwyer T, Amin NH, Ford E. The evolution of cryoneurolysis for the treatment of shoulder, hip, and knee pain: Where are we now and where will we go? A systematic review. Surg Technol Int. 2020;37:361-366.
  80. Meng L, Zhang X, Xu R, et al. A preliminary comparative study of percutaneous CT-guided cryoablation with surgical resection for osteoid osteoma. PeerJ. 2021;9:e10724.
  81. Mershon JP, Tuong MN, Schenkman NS, et al. Thermal ablation of the small renal mass: A critical analysis of current literature. Minerva Urol Nefrol. 2020;72(2):123-134.
  82. Miyazaki M, Saito K, Yanagawa T, et al. Phase I clinical trial of percutaneous cryoablation for osteoid osteoma. Jpn J Radiol. 2018;36(11):669-675.
  83. National Comprehensive Cancer Network (NCCN). Colon cancer. NCCN Clinical Practice Guidelines in Oncology, Version 1.2020. Fort Washington, PA: NCCN; 2020.
  84. National Comprehensive Cancer Network (NCCN). Esophageal and esophagogastric junction cancers. NCCN Clinical Practice Guidelines in Oncology, Version 5.2020. Plymouth Meeting, PA: NCCN; 2020.
  85. National Comprehensive Cancer Network (NCCN). Kidney cancer. NCCN Clinical Practice Guidelines in Oncology, Version 1.2018. Fort Washington, PA: NCCN; 2018.
  86. National Comprehensive Cancer Network (NCCN). Neuroendocrine and adrenal tumors. NCCN Clinical Practice Guidelines in Oncology, Version 1.2019. Fort Washington, PA: NCCN; 2019.
  87. National Comprehensive Cancer Network. Clinical practice guideline: Neuroendocrine and adrenal tumors. Version 3.2021. NCCN: Plymouth Meeting, PA.
  88. National Comprehensive Cancer Network. Clinical practice guideline: Soft tissue sarcoma. Version 2.2021. NCCN: Plymouth Meeting, PA.
  89. National Comprehensive Cancer Network (NCCN). Uterine neoplasms. NCCN Clinical Practice Guidelines in Oncology, Version 5.2019. Fort Washington, PA: NCCN; 2019.
  90. Onik G, Rubinsky B, Zemel R, et al. Ultrasound-guided hepatic cryosurgery in the treatment of metastatic colon carcinoma. Preliminary results. Cancer. 1991;67(4):901-907.
  91. Paprocka-Zjawiona M, Nowosielska-Grygiel J, Kikowski L, et al. Cryosurgery in the treatment of allergic and non-allergic rhinitis. Wiad Lek. 2018;71(6):1135-1140.
  92. Parmeggiani A, Martella C, Ceccarelli L, et al. Osteoid osteoma: Which is the best mininvasive treatment option? Eur J Orthop Surg Traumatol. 2021;31(8):1611-1624.
  93. Prud'homme C, Deschamps F, Moulin B, et al. Image-guided lung metastasis ablation: A literature review. Int J Hyperthermia. 2019;36(2):37-45.
  94. Quraishi NA, Giannoulis KE, Edwards KL, Boszczyk BM. Management of metastatic sacral tumours. Eur Spine J. 2012;21(10):1984-1993.
  95. Ravi V, Patel SR, Raut CP, DeLaney TF. Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2019; December 2020.
  96. Redifer Tremblay K, Lea WB, Neilson JC, et al. Percutaneous cryoablation for the treatment of extra-abdominal desmoid tumors. J Surg Oncol. 2019;120(3):366-375.
  97. Sagoo NS, Haider AS, Ozair A, et al. Percutaneous image-guided cryoablation of spinal metastases: A systematic review. J Clin Neurosci. 2022;96:120-126.
  98. Saltiel S, Bize PE, Goetti P, et al. Cryoablation of extra-abdominal desmoid tumors: A single-center experience with literature review. Diagnostics (Basel). 2020;10(8):556.
  99. Santiago E, Pauly V, Brun G, et al. Percutaneous cryoablation for the treatment of osteoid osteoma in the adult population. Eur Radiol. 2018;28(6):2336-2344.
  100. Sartor AO, DiBiase SJ. Bone metastases in advanced prostate cancer: Management. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2020.
  101. Schmitz JJ, Schmit GD, Atwell TD, et al. Percutaneous cryoablation of extraabdominal desmoid tumors: A 10-year experience. AJR Am J Roentgenol. 2016;207(1):190-195.
  102. Schwimer SR, Bassett LW, Mancuso AA, et al. Giant cell tumor of the cervicothoracic spine. AJR Am J Roentgenol. 1981;136(1):63-67.
  103. Schmitz JJ, Schmit GD, Atwell TD, et al. Percutaneous cryoablation of extraabdominal desmoid tumors: A 10-year experience. AJR Am J Roentgenol. 2016;207(1):190-195.
  104. Schwab JH, Healey JH, Rose P, et al. The surgical management of sacral chordomas. Spine (Phila Pa 1976). 2009;34(24):2700-274.
  105. Shaikh R, Alomari AI, Kerr CL, et al. Cryoablation in fibro-adipose vascular anomaly (FAVA): A minimally invasive treatment option. Pediatr Radiol. 2016;46(8):1179-1186.
  106. Shanmugasundaram S, Nadkarni S, Kumar A, Shukla PA. Percutaneous ablative therapies for the management of osteoid osteomas: A systematic review and meta-analysis. Cardiovasc Intervent Radiol. 2021;44(5):739-749.
  107. Shortell CK, Geersen D. Peripheral arteriovenous malformations. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  108. Simpson JL, Melia M, Yang MB, et al. Current role of cryotherapy in retinopathy of prematurity: A report by the American Academy of Ophthalmology. Ophthalmology. 2012;119(4):873-877.
  109. Smith HS. Painful boney metastases. Ann Palliat Med. 2012;1(1):14-31.
  110. Song ZG, Hao JH, Gao S, et al. The outcome of cryoablation in treatment of advanced pancreatic cancer: A comparison with palliative bypass surgery alone. J Dig Dis. 2014;15(10):561-569.
  111. Susa M, Kikuta K, Nakayama R, et al. CT guided cryoablation for locally recurrent or metastatic bone and soft tissue tumor: Initial experience. BMC Cancer. 2016;16(1):798.
  112. Tedesco D, Gori D, Desai KR, et al. Drug-free interventions to reduce pain or opioid consumption after total knee arthroplasty: A systematic review and meta-analysis. JAMA Surg. 2017;152(10):e172872.
  113. Tepelenis K, Skandalakis GP, Papathanakos G, et al. Osteoid osteoma: An updated review of epidemiology, pathogenesis, clinical presentation, radiological features, and treatment option. In Vivo. 2021;35(4):1929-1938.
  114. Thomas DM, Desai J. Giant cell tumor of bone. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed September 2016.
  115. Timmermans C, Manusama R, Alzand B, Rodriguez LM. Catheter-based cryoablation of postinfarction and idiopathic ventricular tachycardia: Initial experience in a selected population. J Cardiovasc Electrophysiol. 2010;21(3):255-261.
  116. Tis JE. Nonmalignant bone lesions in children and adolescents. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  117. Venkatesan AM, Locklin J, Dupuy DE, Wood BJ. Percutaneous ablation of adrenal tumors. Tech Vasc Interv Radiol. 2010;13(2):89-99.
  118. Venook AP. Nonsurgical local treatment strategies for colorectal cancer liver metastases. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2018.
  119. Welch BT, Atwell TD, Nichols DA, et al. Percutaneous image-guided adrenal cryoablation: Procedural considerations and technical success. Radiology. 2011;258(1):301‐307.
  120. Weller PF, Leder K. Hookworm infection. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2017a.
  121. Weller PF, Leder K. Hookworm-related cutaneous larva migrans. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed October 2017b.
  122. Westerveld DR, Nguyen K, Banerjee D, et al. Safety and effectiveness of balloon cryoablation for treatment of Barrett's associated neoplasia: Systematic review and meta-analysis. Endosc Int Open. 2020;8(2):E172-E178.
  123. Woolen S, Gemmete JJ. Treatment of residual facial arteriovenous malformations after embolization with percutaneous cryotherapy. J Vasc Interv Radiol. 2016;27(10):1570-1575.
  124. Wu X, Uhlig J, Shuch BM, et al. Cost-effectiveness of minimally invasive partial nephrectomy and percutaneous cryoablation for cT1a renal cell carcinoma. Eur Radiol. 2022 Nov 4 [Online ahead of print].
  125. Yamauchi Y, Izumi Y, Hashimoto K, et al. Percutaneous cryoablation for the treatment of medically inoperable stage I non-small cell lung cancer. PLoS One. 2012;7(3):e33223.
  126. Yamauchi Y, Izumi Y, Kawamura M, et al. Percutaneous cryoablation of pulmonary metastases from colorectal cancer. PLoS One. 2011;6(11):e27086.
  127. Yu MH, Hoffe SE. Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
  128. Zhang Y, Hu P, Shun L, et al. External approach microsurgery of retinal dialysis. Yan Ke Xue Bao. 2005;21(1):12-14, 26.