Gemcitabine

Number: 0958

Table Of Contents

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


Policy

Scope of Policy

This Clinical Policy Bulletin addresses gemcitabine for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

  1. Criteria for Initial Approval

    Aetna considers gemcitabine (Gemzar, Infugem, or generic gemcitabine) medically necessary for the treatment of the following indications:

    1. Ampullary adenocarcinoma;
    2. Kaposi sarcoma;
    3. B-cell lymphomas - including:

      1. Follicular lymphoma [grade 1-2]
      2. Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma
      3. Mantle cell lymphoma
      4. Diffuse large B-cell lymphoma
      5. High-grade B-cell lymphomas
      6. Burkitt lymphoma
      7. HIV-related B-cell lymphomas
      8. Post-transplant lymphoproliferative disorders;
    4. Bladder cancer - including:

      1. Primary carcinoma of the urethra
      2. Upper genitourinary tract tumors
      3. Transitional cell carcinoma of the urinary tract
      4. Urothelial carcinoma of the prostate
      5. Non-urothelial and urothelial cancer with variant histology;
    5. Bone Cancer 

      1. Ewing's sarcoma - relapsed, progressive, or metastatic disease
      2. Osteosarcoma - relapsed, refractory, or metastatic disease;
    6. Breast cancer - members with no response to preoperative systemic therapy, recurrent, or metastatic disease;
    7. Cervical cancer;
    8. Ovarian cancer, fallopian tube cancer, and primary peritoneal cancer
       
      1. Advanced, persistent, or recurrent epithelial ovarian cancer
      2. Fallopian tube cancer
      3. Primary peritoneal cancer
      4. Carcinosarcoma (malignant mixed Mullerian tumors)
      5. Clear cell carcinoma of the ovary
      6. Grade 1 endometrioid carcinoma
      7. Low-grade serous carcinoma/ovarian borderline epithelial tumors (low malignant potential)
      8. Mucinous carcinoma of the ovary
      9. Malignant germ cell tumor residual disease;
    9. Gestational trophoblastic neoplasia;
    10. Head and neck cancer - including:

      1. Very advanced head and neck cancer
      2. Cancer of the nasopharynx
      3. Salivary gland tumors;
    11. Biliary tract cancer - including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer;
    12. Hodgkin Lymphoma - including:

      1. Classic Hodgkin lymphoma and pediatric Hodgkin lymphoma
      2. Nodular lymphocyte-predominant Hodgkin lymphoma - progressive, relapsed, or refractory disease;
    13. Kidney cancer - relapsed or metastatic disease;
    14. Malignant germ cell tumor;
    15. Pleural or peritoneal mesothelioma - including pericardial mesothelioma and tunica vaginalis testis mesothelioma;
    16. Non-small cell lung cancer (NSCLC);
    17. Occult primary tumors (cancer of unknown primary);
    18. Pancreatic adenocarcinoma;
    19. Primary cutaneous lymphomas (including mycosis fungoides/Sezary syndrome and primary cutaneous CD30+ T-cell lymphoproliferative disorders);
    20. Small cell lung cancer (SCLC);
    21. Soft tissue sarcoma - including angiosarcoma, extremity/body wall, head/neck, retroperitoneal/intra-abdominal, rhabdomyosarcoma, solitary fibrous tumor, dedifferentiated chordoma, and dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous transformation);
    22. Small bowel adenocarcinoma;
    23. T-cell lymphomas - including:

      1. Peripheral T-cell lymphomas
      2. Adult T-cell leukemia/lymphoma
      3. Hepatosplenic T-cell lymphoma
      4. Breast implant-associated anaplastic large cell lymphoma
      5. Extranodal NK/T-cell lymphoma;
    24. Testicular cancer;
    25. Thymomas and thymic carcinomas;
    26. Uterine neoplasms - including uterine sarcoma and uterine leiomyosarcoma;
    27. Vulvar cancer - as concurrent chemoradiation as a single agent if cisplatin is unavailable.

    Aetna considers gemcitabine experimental and investigational for all other indications.

  2. Continuation of Therapy

    Aetna considers continuation of gemcitabine (Gemzar, Infugem, or generic gemcitabine) therapy medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Gemcitabine (Gemzar) is supplied as 200 mg or 1 gram lyophilized powder in single-dose vials for reconstitution for intravenous infusion. Additionally, gemcitabine (Infugem) is supplied as single-dose premixed infusion bags containing 10 mg/mL of gemcitabine in 0.9% sodium chloride: 1200 mg in 120 mL, 1300 mg in 130 mL, 1400 mg in 140 mL, 1500 mg in 150 mL, 1600 mg in 160 mL, 1700 mg in 170 mL, 1800 mg in 180 mL, 1900 mg in 190 mL, 2000 mg in 200 mL, and 2200 mg in 220 mL for intravenous infusion.

The recommended dosing is as follows:

Ovarian Cancer

Administer 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle.

Breast Cancer

Administer 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle.

Non-Small Cell Lung Cancer

Administer 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle.

Pancreatic Cancer

Administer 1000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly on days 1, 8, and 15 of each 28-day cycle.

Source: Eli Lilly, 2019; Meitheal Pharmaceuticals, 2019

Note: Gemcitabine is also available as a generic formulation.


Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Other CPT codes related to the CPB:

96413 - 96417 Chemotherapy administration, intravenous infusion technique

HCPCS codes covered if selection criteria are met:

J9196 Injection, gemcitabine hydrochloride (accord), not therapeutically equivalent to j9201, 200 mg
J9198 Injection, gemcitabine hydrochloride, (infugem), 100 mg
J9201 Injection, gemcitabine hydrochloride, 200 mg

Other HCPCS codes related to the CPB:

J8610 Methotrexate; oral, 2.5 mg
J9060 Injection, cisplatin, powder or s0lution, 10 mg
J9250 Methotrexate sodium, 5 mg
J9255 Injection, methotrexate (accord) not therapeutically equivalent to j9250 or j9260, 50 mg
J9260 Methotrexate sodium, 50 mg

ICD-10 codes covered if selection criteria are met:

C00.0 - C00.9 Malignant neoplasm of lip
C01 - C03.9 Malignant neoplasm of tongue and gum
C04.0 - C04.9 Malignant neoplasm of floor of mouth
C05.0 - C05.9 Malignant neoplasm of palate
C06.0 - C06.9 Malignant neoplasm of other and unspecified parts of mouth
C07 - C10.9 Malignant of parotid gland, other and unspecified major salivary gland, tonsil and orophanrynx
C11.0 - C11.9 Malignant neoplasm of nasopharynx
C12 - C14.8 Malignant neoplasm of pyriform sinus, hypopharynx, other and ill-defined sites in the lip, oral cavity and pharynx
C17.0 - C17.9 Malignant neoplasm of small intestine [small bowel adenocarcinoma]
C22.0 - C22.9 Malignant neoplasm of liver and intrahepatic bile ducts
C23 Malignant neoplasm of gallbladder
C24.0 - C24.9 Malignant neoplasm of other and unspecified parts of biliary tract
C25.0 - C25.9 Malignant neoplasm of pancreas
C30.0 Malignant neoplasm of nasal cavity
C30.1 Malignant neoplasm of middle ear
C34.00 - C34.92 Malignant neoplasm of bronchus and lung
C37 Malignant neoplasm of thymus
C40.00 - C40.92 Malignant neoplasm of bone and articular cartilage of limbs
C41.0 - C41.9 Malignant neoplasm of bone and articular cartilage of other and unspecified sites
C44.00 – C44.99 Other and unspecified malignant neoplasm of skin [Dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous transformation]
C45.0 - C45.9 Mesothelioma
C46.0 - C46.9 Kaposi's sarcoma
C48.0 - C48.8 Malignant neoplasm of retroperitoneum and peritoneum
C49.0 Malignant neoplasm of connective and soft tissue of head, face and neck [undifferentiated pleomorphic sarcoma][Dedifferentiated chordoma]
C49.10 - C49.9 Malignant neoplasm of other connective and soft tissue [undifferentiated pleomorphic sarcoma][Dedifferentiated chordoma]
C50.011 - C50.919 Malignant neoplasm of breast
C51.0 - C51.9 Malignant neoplasm of vulva
C53.0 - C53.9 Malignant neoplasm of cervix uteri
C54.0 - C54.9 Malignant neoplasm of corpus uteri
C55 Malignant neoplasm of uterus, part unspecified
C56.1 - C56.9 Malignant neoplasm of ovary [Clear cell carcinoma of the ovary, mucinous carcinoma of the ovary and malignant germ cell tumor residual disease]
C57.00 - C57.02 Malignant neoplasm of fallopian tube
C57.7 Malignant neoplasm of other specified female genital organs [Malignant mixed Mullerian tumors]
C58 Malignant neoplasm of placenta
C61 Malignant neoplasm of prostate
C62.00 - C62.92 Malignant neoplasm of testis
C64.1 - C64.9 Malignant neoplasm of kidney, except renal pelvis
C67.0 - C67.9 Malignant neoplasm of bladder
C68.0 Malignant neoplasm of urethra
C68.9 Malignant neoplasm of urinary organ, unspecified
C76.0 Malignant neoplasm of head, face and neck
C80.0 - C80.2 Malignant neoplasm without specification of site
C81.00 - C81.99 Hodgkin lymphoma
C82.10 - C82.19 Follicular lymphoma grade II
C83.00 - C83.09 Small cell B-cell lymphoma
C83.10 - C83.19 Mantle cell lymphoma
C83.30 - C83.39 Diffuse large B-cell lymphoma
C83.70 - C83.79 Burkitt lymphoma
C84.00 - C84.09 Mycosis fungoides
C84.10 - C84.19 Sezary disease
C84.40 - C84.49 Peripheral T-cell lymphoma, not classified
C84.A0 - C84.A9 Cutaneous T-cell lymphoma, unspecified
C84.7A Anaplastic large cell lymphoma, ALK-negative, breast
C85.10 - C85.19 Unspecified B-cell lymphoma
C86.0 - C86.6 Other specified types of T/NK-cell lymphoma
C88.4 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue [MALT-lymphoma]
C91.50 - C91.52 Adult T-cell lymphoma/leukemia (HTLV-1-associated)
D00.08 Carcinoma in situ of pharynx
D01.5 Carcinoma in situ of liver, gallbladder and bile ducts
D01.7 Carcinoma in situ of other specified digestive organs [pancreas]
D02.2 Carcinoma in situ of bronchus and lung
D04.0 Carcinoma in situ of skin of lip
D04.10 - D04.122 Carcinoma in situ of skin of eyelid, including canthus
D04.20 - D04.22 Carcinoma in situ of skin of ear and external auricular canal
D04.30 - D04.39 Carcinoma in situ of skin of other and unspecified parts of face
D04.4 Carcinoma in situ of skin of scalp and neck
D04.60 - D04.62 Carcinoma in situ of skin of upper limb, including shoulder [thymus]
D05.00 - D05.92 Carcinoma in situ of breast
D06.0 - D06.9 Carcinoma in situ of cervix uteri
D07.0 Carcinoma in situ of endometrium
D07.39 Carcinoma in situ of other female genital organs
D07.5 Carcinoma in situ of prostate
D07.69 Carcinoma in situ of other male genital organs
D09.0 Carcinoma in situ of bladder
D09.19 Carcinoma in situ of other urinary organs
D21.9 Benign neoplasm of connective and other soft tissue, unspecified [solitary fibrous tumor]
D25.0 - D25.9 Leiomyoma of uterus
D27.0 – D27.9 Benign neoplasm of ovary [ovarian borderline epithelial tumors (low malignant potential)]
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
D49.2 Neoplasm of unspecified behavior of bone, soft tissue, and skin [solitary fibrous tumor]

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

  • Ovarian cancer - In combination with carboplatin for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy
  • Breast cancer - In combination with paclitaxel for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated
  • Non-small cell lung cancer - In combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer (NSCLC)
  • Pancreatic cancer - As first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemzar, Infugem, or gemcitabine is indicated for patients previously treated with fluorouracil.

Compendial Uses

  • Ampullary adenocarcinoma
  • Bladder cancer, primary carcinoma of the urethra, upper genitourinary tract tumors, transitional cell carcinoma of the urinary tract, urothelial carcinoma of the prostate, non-urothelial and urothelial cancer with variant histology
  • Bone cancer

    • Ewing sarcoma
    • Osteosarcoma

  • Breast cancer
  • Cervical cancer
  • Head and neck cancers (including very advanced head and neck cancer, cancer of the nasopharynx. and salivary gland tumors)
  • Biliary tract cancer

    • Extrahepatic cholangiocarcinoma
    • Intrahepatic cholangiocarcinoma
    • Gallbladder cancer

  • Hodgkin lymphoma

    • Classic Hodgkin lymphoma
    • Nodular lymphocyte-predominant Hodgkin lymphoma

  • Kidney cancer
  • Pleural or peritoneal mesothelioma
  • Non-small cell lung cancer (NSCLC)
  • Occult primary tumors (cancer of unknown primary)
  • Ovarian cancer, fallopian tube cancer, and primary peritoneal cancer: epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer
  • Pancreatic adenocarcinoma
  • Small cell lung cancer (SCLC)
  • Soft tissue sarcoma

    • Angiosarcoma
    • Extremity/Body wall, head/neck
    • Retroperitoneal/intra-abdominal
    • Rhabdomyosarcoma
    • Solitary fibrous tumor
    • Dedifferentiated chordoma
    • Dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous transformation

  • Testicular cancer
  • Thymomas and thymic carcinomas
  • Uterine neoplasms (including uterine sarcoma and uterine leiomyosarcoma)
  • Kaposi Sarcoma
  • Primary cutaneous lymphomas

    • Mycosis fungoides/Sezary syndrome
    • Primary cutaneous CD30+ T-Cell lymphoproliferative disorders

  • T-Cell lymphomas

    • Peripheral T-Cell lymphomas
    • Adult T-Cell leukemia/lymphoma
    • Breast implant-associated anaplastic large cell lymphoma
    • Extranodal natural killer (NK)/T-Cell lymphoma
    • Hepatosplenic T-Cell lymphoma

  • Gestational trophoblastic neoplasia
  • B-Cell lymphomas

    • Follicular lymphoma (grade 1-2)
    • Histologic transformation of indolent lymphomas to diffuse large B-Cell lymphoma
    • Mantle cell lymphoma
    • Diffuse large B-Cell lymphoma
    • High-Grade B-Cell lymphomas
    • Burkitt lymphoma
    • Human immunodeficiency virus (HIV)-Related B-Cell lymphomas
    • Post-Transplant lymphoproliferative disorders

  • Small bowel adenocarcinoma
  • Malignant germ cell tumor
  • Vulvar cancer

Gemcitabine (brand name Gemzar) is a nucleoside metabolic inhibitor that kills cells undergoing DNA synthesis and blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate deoxynucleoside triphosphates for DNA synthesis, resulting in reductions in deoxynucleotide concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP by the action of the diphosphate enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strands, which eventually results in the initiation of apoptotic cell death (Eli Lilly 2019).

The FDA has approved gemcitabine for the following indications:

  • in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy
  • in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated
  • in combination with cisplatin, for the treatment of non-small cell lung cancer
  • as a single agent for the treatment of pancreatic cancer.
On July 18, 2018, the U.S. Food and Drug Administration (FDA) granted approval for Infugem (gemcitabine in 0.9% sodium chloride injection) 10 mg/mL, for intravenous use in a ready-to-administer (RTA) bag (Sun Pharmaceutical Industries, 2018).

Breast Cancer

The efficacy of gemcitabine was evaluated in a multinational, randomized, open-label trial (Study 2) conducted in women receiving initial treatment for metastatic breast cancer and who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated. Patients were randomized to receive either gemcitabine 1250 mg/m2 on Days 1 and 8 of each 21-day cycle with paclitaxel 175 mg/m2 administered on Day 1 before gemcitabine administration (n=267) or paclitaxel 175 mg/m2 on Day 1 of each 21-day cycle (n=262). The major efficacy outcome measure was time to documented disease progression. A total of 529 patients were enrolled. Demographic and baseline characteristics were similar between treatment arms. The addition of gemcitabine to paclitaxel resulted in statistically significant improvement in median time to documented disease progression (5.2 months in the gemcitabine/paclitaxel group compared with 2.9 months in the paclitaxel group; p < 0.0001) and overall response rate (40.8% in the gemcitabine/paclitaxel group compared with 22.1% in the paclitaxel group; p < 0.0001) compared to paclitaxel alone. There was no significant difference in overall survival (18.6 months in the gemcitabine/paclitaxel group compared with 15.8 months in the paclitaxel group) (Eli Lilly 2019).

Non-Small Cell Lung Cancer

The efficacy of gemcitabine was evaluated in two randomized, multicenter trials (Eli Lilly 2019).

Study 3: 28-Day Schedule A multinational, randomized trial (Study 3) compared gemcitabine with cisplatin to cisplatin alone in the treatment of patients with inoperable Stage IIIA, IIIB, or IV NSCLC who had not received prior chemotherapy. Patients were randomized to receive either gemcitabine 1000 mg/m2 on Days 1, 8, and 15 of each 28-day cycle with cisplatin 100 mg/m2 on Day 1 after gemcitabine administration (N=260) or cisplatin 100 mg/m2 on Day 1 of each 28-day cycle (N=262). The major efficacy outcome measure was overall survival. A total of 522 patients were enrolled. Demographics and baseline characteristics were similar between arms with the exception of histologic subtype of NSCLC, with 48% of patients on the cisplatin arm and 37% of patients on the gemcitabine with cisplatin arm having adenocarcinoma. The median survival was 9.0 months in the gemcitabine/cisplatin group compared with 7.6 months in the cisplatin group for Study 3; p = 0.008. The tumor response rate was 26% in the gemcitabine/cisplatin group compared with 10% in the cisplatin group for Study 3; p < 0.0001.

Study 4: 21-Day Schedule A randomized (1:1), multicenter trial (Study 4) was conducted in patients with Stage IIIB or IV NSCLC. Patients were randomized to receive either gemcitabine 1250 mg/m2 on Days 1 and 8 of each 21-day cycle with cisplatin 100 mg/m2 on Day 1 after gemcitabine administration or etoposide 100 mg/m2 intravenously on Days 1, 2, and 3 with cisplatin 100 mg/m2 on Day 1 of each 21 -day cycle. The major efficacy outcome measure was response rate. A total of 135 patients were enrolled. There was no significant difference in survival between the two treatment arms (8.7 months in the gemcitabine/cisplatin group compared with 7.0 months in the etoposide/cisplatin group for Study 4; p = 0.18). The median survival was 8.7 months for the gemcitabine with cisplatin arm versus 7 months for the etoposide with cisplatin arm. Median time to disease progression for the gemcitabine with cisplatin arm was 5 months compared to 4.1 months on the etoposide with cisplatin arm (Log rank p=0.015, two-sided). The objective response rate for the gemcitabine with cisplatin arm  was 33% compared to 14% on the etoposide e with cisplatin arm (Fisher’s Exact p=0.01, two-sided). The tumor response rate was 33% in the gemcitabine/cisplatin group compared with 14% in the etoposide/cisplatin group for Study 4; p = 0.01.

Ovarian Cancer

The efficacy of gemcitabine was evaluated in a randomized trial (Study 1) conducted in women with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle with carboplatin AUC 4 on Day 1 after gemcitabine administration (n=178) or carboplatin AUC 5 on Day 1 of each 21-day cycle (n=178). The major efficacy outcome measure was progression-free survival (PFS). A total of 356 patients were enrolled. The addition of gemcitabine to carboplatin resulted in statistically significant improvements in PFS (8.6 months in the gemcitabine/carboplatin group compared with 5.8 months in the carboplatin group; p = 0.0038) and overall response rate by investigator review (46.2% in the gemcitabine/carboplatin group compared with 30.9% in the carboplatin group; p = 0.0016). Approximately 75% of patients in each arm received additional chemotherapy for disease progression; 13 of 120 patients in the carboplatin alone arm received gemcitabine for treatment of disease progression. There was no significant difference in overall survival between the treatment arms (18 months in the gemcitabine/carboplatin group compared with 17.3 months in the carboplatin group; p = 0.8977) (Eli Lilly 2019).

Pancreatic Cancer

The efficacy of gemcitabine was evaluated in two trials (Studies 5 and 6), a randomized, single-blind, two-arm, active-controlled trial (Study 5) conducted in patients with locally advanced or metastatic pancreatic cancer who had received no prior chemotherapy and in a single-arm, open-label, multicenter trial (Study 6) conducted in patients with locally advanced or metastatic pancreatic cancer previously treated with fluorouracil or a fluorouracil-containing regimen. In Study 5, patients were randomized to receive either gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles (n=63) or fluorouracil 600 mg/m2 intravenously over 30 minutes once weekly (n=63). In Study 6, all patients received gemcitabine 1000 mg/m2 intravenously over 30 minutes once weekly for 7 weeks followed by a one-week rest, then once weekly for 3 consecutive weeks every 28-days in subsequent cycles. The major efficacy outcome measure in both trials was “clinical benefit response”. A patient was considered to have had a clinical benefit response if either of the following occurred: The patient achieved a ≥50% reduction in pain intensity (Memorial Pain Assessment Card) or analgesic consumption, or a 20-point or greater improvement in performance status (Karnofsky Performance Status) for a period of at least 4 consecutive weeks, without showing any sustained worsening in any of the other parameters. Sustained worsening was defined as 4 consecutive weeks with either any increase in pain intensity or analgesic consumption or a 20-point decrease in performance status occurring during the first 12 weeks of therapy. OR the patient was stable on all of the aforementioned parameters and showed a marked, sustained weight gain (≥7% increase maintained for ≥4 weeks) not due to fluid accumulation. Study 5 enrolled 126 patients. Demographics and baseline characteristics were similar between the arms. Patients treated with gemcitabine had statistically significant increases in clinical benefit response, survival, and time to disease progression compared to those randomized to receive fluorouracil. No confirmed objective tumor responses were observed in either treatment arm (Eli Lilly 2019).

Eshmuminov et al (2023) stated that pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC); neoadjuvant systemic therapy is recommended as initial treatment.  Presently, it is unclear what chemotherapy should be preferred for patients with BRPC or LAPC.  These investigators carried out a systematic review and meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC.  Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based.  A total of 23 studies comprising 2,930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment.  OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001).  In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001).  This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens.  The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO.  In patients with LAPC, resection rates were 0.19 with gemcitabine and 0.28 with FIO.  In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083).  A similar trend was observed in resected patients converted from LAPC.  The authors concluded that in patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with gemcitabine-based chemotherapy appeared to provide a survival benefit for patients who were ultimately unresectable.  For patients who underwent surgical resection, outcomes were similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

Gemcitabine with Pazopanib or Gemcitabine with Docetaxel for the Treatment of Soft-Tissue Sarcoma

Somaiah et al (2021) noted that therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited.  In an open-label, randomized, multi-center, phase- II clinical trial, these researchers examined the safety and effectiveness of combined gemcitabine plus pazopanib, a multi-tyrosine kinase inhibitor (TKI) with activity in STS.  This trial enrolled patients with advanced non-adipocytic STS who had received prior anthracycline-based therapy.  Subjects were assigned 1:1 to receive gemcitabine at a dose of 1,000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks.  Cross-over was allowed at the time of disease progression.  This trial employed a non-comparative statistical design based on the precision of 95 % confidence intervals (CIs) for reporting the primary endpoints of median PFS and rate of grade 3 or worse adverse events (AEs) for these 2 regimens based on the intent-to-treat (ITT) patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events).  A total of 90 patients were enrolled: 45 patients on each treatment arm.  The median PFS was 4.1 months for each arm (p = 0.3, log-rank test).  The best overall response of stable disease (SD) or better (complete response [CR] + partial response [PR] + SD) was the same for both treatment arms (64 % for both the G+T and G+P arms).  The rate of related grade 3 or worse AEs was 82 % for the G+T arm and 78 % for the G+P arm.  Related grade 3 or worse AEs occurring in 10 % or more of patients in the G+T and G+P arms were anemia (36 % and 20 %, respectively), fatigue (29 % and 13 %, respectively), thrombocytopenia (53 % and 49 %, respectively), neutropenia (20 % and 49 %, respectively), lymphopenia (13 % and 11 %, respectively), and hypertension (2 % and 20 %, respectively).  The authors concluded that the findings of this trial suggested the similarity of the G+P regimen compared with G+T with regard to effectiveness and tolerability.  In patients who are unsuitable for treatment with G+T (because of a contraindication or intolerance to docetaxel), G+P would be a reasonable alternate regimen for the 2nd-line treatment of those with metastatic non-adipocytic sarcomas.

Nivolumab, Gemcitabine, and Cisplatin or Nivolumab and Ipilimumab in Previously Untreated Advanced Biliary Cancer

Sahai et al (2022) stated that gemcitabine and cisplatin has limited benefit as treatment for advanced biliary tract cancer (BTC).  The addition of an anti-programmed death receptor (PD-1)/PD-ligand (L1) antibody to either systemic chemotherapy or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody has shown benefit in multiple solid tumors.  In a phase-II clinical trial, patients 18 years of age or older with advanced BTC without prior systemic therapy and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 1 were randomized across 6 academic centers.  Patients in Arm A received nivolumab (360 mg) on day 1 along with gemcitabine and cisplatin on days 1 and 8 every 3 weeks for 6 months followed by nivolumab (240 mg) every 2 weeks.  Patients in Arm B received nivolumab (240 mg) every 2 weeks and ipilimumab (1 mg/kg) every 6 weeks.  Of 75 randomized patients, 68 received therapy (Arm A = 35, Arm B = 33); 51.5 % women with a median age of 62.5 years.  The observed primary outcome of 6-month PFS rates in the evaluable population was 59.4 % in Arm A and 21.2 % in Arm B.  The median PFS and OS in Arm A were 6.6 and 10.6 months, and in Arm B 3.9 and 8.2 months, respectively, in patients who received any treatment.  The most common treatment-related grade-3 or higher hematologic AE was neutropenia in 34.3 % (Arm A) and non-hematologic AEs were fatigue (8.6 % Arm A) and elevated transaminases (9.1 % Arm B).  The authors concluded that the addition of nivolumab to chemotherapy or ipilimumab did not improve 6-month PFS.  Although median OS was less than 12 months in both arms, the high OS rate at 2 years in Arm A suggested benefit in a small cohort of patients.


References

The above policy is based on the following references:

  1. Clinical Pharmacology. Gemcitabine. Clinical Pharmacology powered by Clinical Key. Philadelphia, PA: Elsevier; 2023. Available at: https://www.clinicalkey.com/pharmacology/. Accessed July 14, 2023.
  2. Eli Lilly and Company. Gemzar (gemcitabine) for injection, for intravenous use. Prescribing Information. Indianapolis, IN: Eli Lilly; revised May 2019.
  3. Eshmuminov D, Aminjonov B, Palm RF, et al. FOLFIRINOX or gemcitabine-based chemotherapy for borderline resectable and locally advanced pancreatic cancer: A multi-institutional, patient-level, meta-analysis and systematic review. Ann Surg Oncol. 2023;30(7):4417-4428.
  4. Lexicomp. Gemcitabine. Lexi-Drugs. Lexicomp Online. Hudson, OH: Lexicomp; 2023. Avaiable at: https://online.lexi.com. Accessed July 14, 2023.
  5. Meitheal Pharmaceuticals. Gemcitabine for injection, for intravenous use. Prescribing Information. Chicago, IL: Meitheal Pharmaceuticals; August 2019.
  6. Meritave LP. Gemcitabine. In-Depth Answers. Merative Micromedex. Ann Arbor, MI: Merative; 2023. Available at: https://www.micromedexsolutions.com. Accessed July 14, 2023.
  7. National Comprehensive Cancer Network (NCCN). Gemcitabine. NCCN Drugs & Biologics Compendium. Plymouth Meeting, PA: NCCN; October 2023.
  8. National Comprehensive Cancer Network (NCCN). Gestational trophoblastic neoplasia. NCCN Clinical Practice Guidelines in Oncology, Version 1.2023. Plymouth Meeting, PA: NCCN; December 2022. 
  9. Sahai V, Griffith KA, Beg MS, et al. A randomized phase 2 trial of nivolumab, gemcitabine, and cisplatin or nivolumab and ipilimumab in previously untreated advanced biliary cancer: BilT-01. Cancer. 2022;128(19):3523-3530.
  10. Somaiah N, Van Tine BA, Wahlquist AE, et al. A randomized, open-label, phase 2, multicenter trial of gemcitabine with pazopanib or gemcitabine with docetaxel in patients with advanced soft-tissue sarcoma. Cancer. 2021;127(6):894-904.
  11. Sun Pharmaceutical Industries, Inc. Infugem (gemcitabine in sodium chloride injection), for intravenous use. Prescribing Information. Cranbury, NJ: Sun Pharmaceutical Industries; revised January 2020.
  12. Sun Pharmaceutical Industries, Inc. Sun Pharma announces U.S. FDA approval of Infugem injection. Press Release. Cranbury, NJ: Sun Pharmaceutical Industries; July 18, 2018.