Docetaxel

Number: 0956

Table Of Contents

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

Policy

  1. Criteria for Initial Approval

    Aetna considers docetaxel (Taxotere or generic docetaxel) medically necessary for the following indications:

    1. Anal cancer - for treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma;
    2. Breast cancer - for treatment of breast cancer in members when any of the following criteria are met:

      1. Member has human epidermal growth factor receptor 2 (HER2)-negative recurrent, unresectable or metastatic disease or no response to preoperative systemic therapy, as a single agent or in combination with capecitabine; or
      2. Member has human epidermal growth factor receptor 2 (HER2)-positive recurrent, unresectable or metastatic disease or no response to preoperative systemic therapy and the requested medication will be used in one of the following regimens (with or without endocrine therapy):

        1. In combination with pertuzumab and trastuzumab; or
        2. In combination with trastuzumab; or
      3. The requested medication will be used as adjuvant therapy; or
      4. The requested medication will be used as preoperative therapy; or
      5. The requested medication will be used as a substitute for other taxanes (e.g., paclitaxel or albumin-bound paclitaxel) in select members due to medical necessity;

    3. Bladder cancer, primary carcinoma of the urethra, upper genitourinary tract tumors, and urothelial carcinoma of the prostate:

      1. Bladder cancer; or 
      2. Primary carcinoma of the urethra - recurrent or metastatic primary carcinoma of the urethra; or
      3. Upper genitourinary tract tumors and urothelial carcinoma of the prostate - metastatic upper genitourinary tract tumors or urothelial carcinoma of the prostate; or

    4. Bone cancer:

      1. Ewing’s sarcoma - relapsed, progressive, or metastatic Ewing’s sarcoma; or
      2. Osteosarcoma - relapsed, refractory or metastatic osteosarcoma; or
    5. Cervical cancer - for subsequent treatment of persistent, recurrent, or metastatic cervical cancer as a single agent;
    6. Esophageal and esophagogastric junction cancers; or
    7. Gastric cancer; or
    8. Head and neck cancer - for treatment of head and neck cancer (including very advanced head and neck cancer, cancers of the lip (mucosa), oral cavity, salivary gland, oropharynx, hypopharynx, nasopharynx, glottic larynx, supraglottic larynx); or
    9. Non-small cell lung cancer (NSCLC); or
    10. Occult primary tumors (cancer of unknown primary); or   
    11. Ovarian cancer, fallopian tube cancer, and primary peritoneal cancer - for treatment of epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, carcinosarcoma (malignant mixed Mullerian tumors), clear cell carcinoma of the ovary, grade 1 endometrioid carcinoma, low-grade serous carcinoma/ovarian borderline epithelial tumor (low malignant potential), mucinous carcinoma of the ovary, malignant sex-cord stromal tumors, or malignant germ cell tumor residual disease; or
    12. Prostate cancer; or
    13. Small bowel adenocarcinoma - for treatment of advanced or metastatic small bowel adenocarcinoma; or
    14. Small cell lung cancer (SCLC); or
    15. Soft tissue sarcoma - for treatment of soft tissue sarcoma (including angiosarcoma, extremity/body wall, head/neck, retroperitoneal/intra-abdominal, pleomorphic rhabdomyosarcoma, dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous transformation, dedifferentiated chordoma, and solitary fibrous tumor; or
    16. Thyroid carcinoma - anaplastic carcinoma; or
    17. Uterine neoplasms - for treatment of uterine neoplasms (including endometrial carcinoma and uterine sarcoma).

    Aetna considers all other indications as experimental and investigational.

  2. Continuation of Therapy

    Aetna considers continuation of docetaxel (Taxotere or generic docetaxel) 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

Docetaxel (Taxotere) is supplied as follows:

  • Doxetaxel injection: Single-dose vials 20 mg/mL, 80 mg/4 mL, and 160 mg/8 mL
  • Taxotere: Single-dose vials 20 mg/mL and 80 mg/4 mL

Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over 1 hr every 3 weeks. PVC equipment is not recommended. Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial.

The recommended dosing is as follows:

Breast Cancer (BC)

  • BC locally advanced or metastatic: 60 mg/m2 to 100 mg/m2 single agent
  • BC adjuvant: 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles

Non-Small Cell Lung Cancer (NSCLC)

  • NSCLC: after platinum therapy failure: 75 mg/m2 single agent
  • NSCLC: chemotherapy-naive: 75 mg/m2 followed by cisplatin 75 mg/m2

Castration-Resistant Prostate Cancer (CRPC):

  • CRPC: 75 mg/m2 with 5 mg prednisone twice a day continuously

Gastric Adenocarcinoma (GC)

  • GC: 75 mg/m2 followed by cisplatin 75 mg/m2 (both on day 1 only) followed by fluorouracil 750 mg/m2 per day as a 24 hour IV (days 1-5), starting at end of cisplatin infusion

Squamous Cell Carcinoma of the Head and Neck (SCCHN)

  • SCCHN: 75 mg/m2 followed by cisplatin 75 mg/m2 IV (day 1), followed by fluorouracil 750 mg/m2 per day as a 24 hour IV (days 1-5), starting at end of cisplatin infusion; for 4 cycles
  • SCCHN: 75 mg/m2 followed by cisplatin 100 mg/m2 IV (day 1), followed by fluorouracil 1000 mg/m2 per day as a 24 hour IV (days 1-4); for 3 cycles

Source: sanofi-aventis, 2021; Sun Pharmaceutical Ind., 2021

Note: Docetaxel 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 - 96415 Chemotherapy administration, intravenous infusion technique

HCPCS codes covered if selection criteria are met:
J9171 Injection, docetaxel, 1 mg
J9172 Injection, docetaxel (ingenus) not therapeutically equivalent to j9171, 1 mg

Other HCPCS codes related to the CPB:
J9258 Injection, paclitaxel protein-bound particles (teva) not therapeutically equivalent to j9264, 1 mg
J9259 Injection, paclitaxel protein-bound particles (american regent) not therapeutically equivalent to j9264, 1 mg
J9264 Injection, paclitaxel protein-bound particles, 1 mg
J9267 Injection, paclitaxel, 1 mg

ICD-10 codes covered if selection criteria are met:
C00.0 - C09.9 Malignant neoplasm of lip and oral cavity
C10.0 - C10.9 Malignant neoplasm of oropharynx
C11.0 - C11.9 Malignant neoplasm of nasopharynx
C12 Malignant neoplasm of pyriform sinus
C13.0 - C13.9 Malignant neoplasm of hypopharynx
C14.0 - C14.9 Malignant neoplasm of other and ill-defined sites in lip, oral cavity and pharynx
C15.3 - C15.9 Malignant neoplasm of esophagus
C16.0 - C16.9 Malignant neoplasm of stomach
C17.0 - C17.9 Malignant neoplasm of small intestine
C30.0 - C31.9 Malignant neoplasm of nasal cavity and middle ear and accessory sinuses
C32. 0 - C32.9 Malignant neoplasm of larynx
C34.00 - C34.92 Malignant neoplasm of bronchus and lung
C41.0 - C41.9 Malignant neoplasm of bone and articular cartilage of other and unspecified sites
C44.520 Squamous cell carcinoma of anal skin
C46.2 Kaposi's sarcoma of palate
C47.0 Malignant neoplasm of peripheral nerves of head, face and neck
C48.1 - C48.8 Malignant neoplasm of retroperitoneum and peritoneum
C49.0 - C49.9 Malignant neoplasm of other connective and soft tissue
C49.A0 - C49.A9 Malignant neoplasm of gastrointestinal stromal tumor
C50.011 - C50.929 Malignant neoplasm of breast
C53.0 - C53.9 Malignant neoplasm of cervix uteri
C54.0 - C54.9 Malignant neoplasm of corpus uteri
C56.1 - C56.9 Malignant neoplasm of ovary
C57.00 - C57.02 Malignant neoplasm of fallopian tube
C61 Malignant neoplasm of prostate
C62.0 - C62.9 Malignant neoplasm of testis
C64.1 - C64.9 Malignant neoplasm of kidney and renal pelvis
C66.1 - C66.9 Malignant neoplasm of kidney and renal pelvis
C67.1 - C67.9 Malignant neoplasm of bladder
C69.00 - C69.92 Malignant neoplasm of eye and adnexa
C70.0 - C70.9 Malignant neoplasm of meninges
C71.0 - C71.9 Malignant neoplasm of brain
C72.0 - C72.9 Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system
C73 Malignant neoplasm of thyroid gland
C76.0 Malignant neoplasm of head, face and neck
C80.1 Malignant (primary) neoplasm, unspecified [occult primary tumors (cancer of unknown primary)]
D27.0 - D27.9 Benign neoplasm of ovary [ovarian borderline epithelial tumors (low malignant potential) with invasive implants]

Background

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

  • Breast Cancer (BC)

    • Docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.
    • Docetaxel in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.

  • Non-Small Cell Lung Cancer (NSCLC)

    • Docetaxel as a single agent is indicated for the treatment of patients with locally advanced or metastatic NSCLC after failure of prior platinum-based chemotherapy.
    • Docetaxel in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic NSCLC who have not previously received chemotherapy for this condition.

  • Prostate Cancer

    Docetaxel in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.

  • Gastric Adenocarcinoma (GC)

    Docetaxel in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.

  • Head and Neck Cancer

    Docetaxel in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Compendial Uses

  • Anal cancer
  • Bladder cancer, primary carcinoma of the urethra, upper genitourinary (GU) tract tumors, and urothelial carcinoma of the prostate
  • Bone cancer: Ewing’s sarcoma and osteosarcoma
  • Breast cancer
  • Cervical cancer
  • Esophageal and esophagogastric junction cancers
  • Gastric cancer
  • Head and neck cancer (including very advanced head and neck cancer and cancers of the lip (mucosa), oral cavity, salivary gland, oropharynx, hypopharynx, nasopharynx, glottic larynx, or supraglottic larynx)
  • Non-small cell lung cancer
  • Occult primary tumors (cancer of unknown primary)
  • Ovarian cancer/fallopian tube cancer/primary peritoneal cancer: epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, malignant germ cell tumors, malignant sex cord-stromal tumors, carcinosarcoma (malignant mixed Müllerian tumors), clear cell carcinoma of the ovary, mucinous carcinoma of the ovary, low-grade serious carcinoma/ovarian borderline epithelial tumor (low malignant potential) and grade 1 endometrioid carcinoma.
  • Prostate cancer
  • Small cell lung cancer
  • Soft tissue sarcoma (including angiosarcoma, extremity/body wall, head/neck, retroperitoneal/intra-abdominal, pleomorphic rhabdomyosarcoma, dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous transformation, dedifferentiated chordoma, and solitary fibrous tumor)
  • Thyroid carcinoma: anaplastic carcinoma
  • Uterine neoplasms: endometrial carcinoma and uterine sarcoma
  • Small bowel adenocarcinoma

Docetaxel (brand name Taxotere; brand name Docefrez has been discontinued) and is an antineoplastic agent belonging to the taxoid family that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. ) remove brand Docefrez from the title and the policy due to product discontinuation

Docetaxel is FDA approved for the treatment of breast cancer, non-small cell lung cancer (NSCLC), castration-resistant prostate cancer, gastric cancer, and squamous cell cancer of the head and neck; it also has several off-label indications. Treatment-related mortality is increased in patients with abnormal liver function, in patients receiving higher doses, and at a monotherapy dose of 100 mg/m2, in patients with NSCLC and a history of prior treatment with platinum-based chemotherapy. It should not be given to patients with increased liver function tests or in patients with neutrophil counts less than 1,500 cells/mm3. All patients should be premedicated with oral corticosteroids prior to each dose of docetaxel to reduce the incidence and severity of hypersensitivity, fluid retention, and skin toxicity.

Black Box Warnings

Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2. Docetaxel should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. LFTs should be obtained before each treatment cycle. Docetaxel should not be given if neutrophil counts are < 1500 cells/mm3 . Frequent blood counts should be obtained to monitor for neutropenia. Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of docetaxel Injection and administration of appropriate therapy. Docetaxel is contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80. Severe fluid retention may occur despite dexamethasone.

Breast Cancer

The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens). In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m2 every 3 weeks) or the combination of mitomycin (12 mg/m2 every 6 weeks) and vinblastine (6 mg/m2 every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The median survival time was 11.4 months in the docetaxel group compared with 8.7 months in the mitomycin/vinblastine group (p = 0.01; 95% CI:0.58-0.93). The median time to progression was 4.3 months in the docetaxel group compared with 2.5 months in the mitomycin/vinblastine group (p=0.01; 95% CI: 0.61-0.94). The overall response rate and complete response rates were 28.1% and 3.4%, respectively, in the docetaxel group compared with 9.5% and 1.6%, respectively in the mitomycin/vinblastine groups (p<0.0001).

In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m2 ) or doxorubicin (75 mg/m2 ) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The median survival time was 14.7 months in the docetaxel group (n=203)compared with 14.3 months in the doxorubicin group (p = 0.39; 95% CI:0.68-1.16). The median time to progression was 6.5 months in the docetaxel group compared with 5.3 months in the doxorubicin group (p = 0.45; 95% CI: 0.71-1.16). The overall response rate and complete response rates were 45.3% and 6.8% respectively, in the docetaxel group compared with 29.7% and 4.2%, respectively in the doxorubicin  groups (p<0.004).

In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m2 (n = 151), 75 mg/ m2 (n = 188) or 100 mg/ m2 (n = 188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with docetaxel dose: 19.9% for the 60 mg/ m2 group compared to 22.3% for the 75 mg/ m2and 29.8% for the 100 mg/ m2 group; pair-wise comparison between the 60 mg/ m2 and 100 mg/m2 groups was statistically significant (p = 0.037). Single Arm Studies Docetaxel at a dose of 100 mg/m2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0-44.8) and the complete response rate was 2.1%. Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m2 , in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2-55.7), similar to the response rate in single arm studies of 100 mg/m2 .

A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio = 0.74; 2-sided 95% CI = 0.60, 0.92, stratified log rank p = 0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients (see Figure 1). At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio = 0.69, 2-sided 95% CI = 0.53, 0.90) (see Figure 2). There will be further analysis at the time survival data mature.

Gastric Cancer

Locally advanced or metastatic stomach cancer has a poor prognosis with a low long-term survival of only 11.5 percent. The FDA based its decision on results from the TAX 325 study, the largest international phase III clinical trial in previously untreated advanced stomach cancer, involving 445 patients. This study was undertaken to evaluate the benefits of adding docetaxel to a standard chemotherapy regimen. The primary study endpoint was time to tumor progression (TTP), which was significantly improved with docetaxel based therapy (5.6 months) compared to standard treatment (3.7 months) with a 32 percent reduction in the risk of progression (log-rank test p=0.0004). The main secondary endpoint was to detect a statistically significant increase in overall survival. Patients treated with the docetaxel- based chemotherapy regimen (docetaxel plus cisplatin and 5-fluorouracil, TCF) experienced a significant 23 percent reduction in the risk of death compared to patients who received a current standard treatment of cisplatin and 5-fluorouracil (CF), (median follow-up: 23 months). The median overall survival was significantly longer with the docetaxel-containing regimen (9.2 vs 8.6 months, p=<0.02) with a hazard ratio of 1.29 (95% CI: 1.04-1.61). Time to disease progression was nearly two months longer in the docetaxel - containing arm (5.6 vs 3.7 months, p=0.0004), hazard ratio 1.47 (CF/TCF 95% CI/ 1.19 -1.83). Other secondary objectives included response rate, time to treatment failure, duration of response, safety profiles, quality of life and disease related symptoms.

In total, 81.4 percent of the patients experienced at least one Grade 3-4 (severe) side effect with the docetaxel- based regimen versus 75.4 percent in the control arm, with neutropenia being the most common Grade 3-4 side effect in the docetaxel- based regimen. The most common side effects (all grade) associated with the docetaxel- based regimen were anemia, neutropenia, diarrhea, and nausea. The most common side effects (all grade) associated with the cisplatin and 5-fluorouracil arm were anemia, neutropenia, nausea and vomiting. Primary prophylactic use of growth factor support (granulocyte-colony stimulating factor, G-CSF) was not allowed per the study protocol. G-CSF is a bone marrow growth factor that may be administered to reduce febrile neutropenia in patients receiving myelosuppressive chemotherapy. In the docetaxel arm, febrile neutropenia and/or neutropenic infection occurred in 12 percent of patients receiving secondary prophylactic G-CSF compared to 28 percent who did not, which represents a 57 percent reduction.

Head and Neck Cancer

The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 on Day 1, followed by fluorouracil (F) 750 mg/m2 per day as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 on Day 1, followed by fluorouracil (F) 1000 mg/m2 /day as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy-2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy. The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p = 0.0077 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively).

The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m2 /day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m2 /day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT. The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54 – 0.90].

Hormone Refractory Prostate Cancer

The safety and efficacy of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups: docetaxel 75 mg/m2 every 3 weeks for 10 cycles; docetaxel 30 mg/m2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles; Mitoxantrone 12 mg/m2 every 3 weeks for 10 cycles. All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously. In the docetaxel every three-week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone (median survival was 18.9 months in the docetaxel+prednisone group compared with 16.5 months in the mitoxantrone+prednisone; p= 0.0094). In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. 

Non-Small Cell Lung Cancer (NSCLC)

The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve. Monotherapy with docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy Two randomized, controlled trials established that a docetaxel dose of 75 mg/m2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy. Docetaxel at a dose of 100 mg/m2 , however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used. One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m2 . A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m2 or best supportive care. In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic nonsmall cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to docetaxel 75 mg/m2 , docetaxel 100 mg/m2 and a treatment in which the investigator chose either vinorelbine 30 mg/m2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m2 days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m2 .  Patients treated with docetaxel at a dose of 75 mg/m2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.

In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m2administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin. The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin.. Median survival was 10.9 months in the docetaxel+cisplatin compared with 10.0 months in the vinorelbine+cisplatin group (p=0.122; 95% CI: 0.74, 1.06). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival) was maintained.

The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression.

Docetaxel and Bevacizumab with or without Trastuzumab as First-Line Treatment for Metastatic Breast Cancer

Sun et al (2021) noted that although bevacizumab and trastuzumab have been widely added to the standard regimen for metastatic breast cancer (MBC), the clinical outcomes remain controversial.  In a meta-analysis, these investigators examined the safety and effectiveness of docetaxel and bevacizumab with or without trastuzumab as 1st-line treatment for patients with MBC.  All available literature of clinical studies regarding docetaxel, bevacizumab, trastuzumab and MBC was pooled from PubMed, Embase and Cochrane library database.  The meta-analysis combined the PFS, ORR and incidence of all grades adverse events (AEs) in MBC patients.  A total of 7 clinical studies were included by 2 reviewers.  Docetaxel and bevacizumab with trastuzumab had a pooled PFS of 16.53 months (95 % CI: 13.95 to 19.11 months), the pooled ORR was 0.75 (95 % CI: 0.69 to 0.80) in HER2-positive MBC patients.  Docetaxel and bevacizumab showed that the pooled PFS was 8.49 months (95 % CI: 7.80 to 9.18 months), the pooled ORR was 0.51 (95 % CI: 0.47 to 0.55) in HER2-negative MBC patients.  The authors concluded this meta-analysis found that trastuzumab combined with bevacizumab and docetaxel led to long PFS and high response rates in patients with HER2-positive MBC, while bevacizumab combined with docetaxel had a reliable effectiveness and lower incidence of AEs in patients with HER2-negative MBC.   Moreover, these researchers stated that as a consequence of the limitations of the quality of the included studies, more high-quality, large-sample studies are needed to verify the findings of this study.

The authors stated that this meta-analysis had several drawbacks.  First, more multi-center RCTs were needed for a meta-analysis.  Second, since the differences of AEs existed in the included studies, only 12 AEs were pooled in the HER2-positive MBC, and only 6 AEs were pooled in the HER2-negative MBC, while 2 studies were included on safety profile in the majority of including studies.  These researchers only pooled the incidence of AEs of all grades but did not pool the AEs of grade 3 and 4.  Third, due to the lack of relevant data, this meta-analysis could not effectively examine if patients had a longer OS; therefore, further investigation is needed to determine the OS rate of patients with MBC.

Metastatic, Hormone-Sensitive Prostate Cancer

Vale et al (2023) noted that the addition of docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer (PCa); however, uncertainty remains regarding who would benefit most.  These investigators obtained up-to-date estimates of the overall effects of docetaxel and examined if these effects varied according to pre-specified characteristics of the patients or their tumors.  The STOPCAP M1 Collaboration carried out a systematic review and meta-analysis of individual participant data.  These investigators searched Medline (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from January 1, 1990, to December 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomized studies that evaluated docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive PCa.  Detailed and updated individual participant data were requested directly from study investigators or via relevant repositories.  The primary outcome was OS.  Secondary outcomes were PFS and failure-free survival (FFS).  Overall pooled effects were estimated using an adjusted, intention-to-treat (ITT), 2-stage, fixed-effect meta-analysis, with 1-stage and random-effects sensitivity analyses.  Missing co-variate values were imputed.  Differences in effect by participant characteristics were estimated using adjusted 2-stage, fixed-effect meta-analysis of within-trial interactions based on PFS to maximize power.  Identified effect modifiers were also examined based on OS.  To evaluate multiple subgroup interactions and derive subgroup-specific absolute treatment effects , these researchers employed 1-stage flexible parametric modelling and regression standardization.  They examined the risk of bias using the Cochrane Risk of Bias 2 tool. 

These researchers obtained individual participant data from 2,261 patients (98 % of those randomized) from 3 eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE Trials), with a median follow-up of 72 months (inter-quartile range [IQR] of 55 to 85).  Individual participant data were not obtained from 2 additional small studies.  Based on all included trials and patients, there were clear benefits of docetaxel on OS (HR of 0.79, 95 % CI: 0.70 to 0.88; p < 0.0001), PFS (0.70, 0.63 to 0.77; p < 0.0001), and FFS (0.64, 0.58 to 0.71; p < 0.0001), representing 5-year absolute improvements of around 9 % to 11 %.  The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all 3 main outcomes.  The relative effect of docetaxel on PFS appeared to be greater with increasing clinical T stage (p interaction = 0.0019), higher volume of metastases (p interaction = 0.020), and, to a lesser extent, synchronous diagnosis of metastatic disease (p interaction = 0.077).  Considering the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing.  There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1 %, 95 % CI: -15 % to 12 %, for PFS; 0 %, -10 % to 12 %, for OS).  The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27 %, 95 % CI: 17 % to 37 %, for PFS; 35 %, 24 % to 47 %, for OS).  The authors concluded that the addition of docetaxel to hormone therapy was best suited to patients with poorer prognosis for metastatic, hormone-sensitive PCa based on a high volume of disease and potentially the bulkiness of the primary tumor.  There was no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently.  These findings will better characterize patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision-making, better informing treatment policy, and improving patient outcomes.

Sequential Intravesical Gemcitabine and Docetaxel Therapy in Patients with Non-Muscle Invasive Bladder Cancer

McElree et al (2022) stated that bacillus Calmette-Guerin (BCG) is currently recommended as adjuvant therapy following complete trans-urethral resection of bladder tumor for high-risk non-muscle-invasive bladder cancer (HR-NMIBC).  In response to the BCG shortage, gemcitabine (GEM) plus docetaxel (DOCE) has been used at the authors’ institution in the BCG-naive setting.  In a retrospective study, these investigators reported the outcomes of patients with BCG-naive HR-NMIBC treated with GEM/DOCE.  They reviewed patients with BCG-naive HR- NMIBC treated with GEM/DOCE from May 2013 through April 2021.  Subjects received 6 weekly intravesical instillations of sequential 1-g GEM and 37.5-mg DOCE following complete trans-urethral resection of bladder tumor.  Monthly maintenance of 2 years was initiated if disease-free at 1st follow-up.  The primary outcome was recurrence-free survival (RFS).  Survival was assessed with the Kaplan-Meier method, indexed from the 1st GEM/DOCE instillation; and AEs were reported using CTCAE (Common Terminology Criteria for Adverse Events) version 5.0 (National Cancer Institute, Bethesda, MD).  Differences were evaluated with the log-rank test.  The analysis included a total of 107 patients with a median follow-up of 15 months.  Patients had high-risk characteristics including 47 with any carcinoma in-situ, and 55 with T1 disease.  RFS was 89 %, 85 % and 82 % at 6, 12 and 24 months, respectively.  Recurrence rates were similar between patients with or without carcinoma in-situ (p = 0.42).  No patient had disease progression or died of bladder cancer; 1 patient underwent cystectomy due to end-stage lower urinary tract symptoms (LUTS); OS was 84 % at 24 months.  There were 92 AEs (1 grade-3 or more severe), and 4 (4 %) patients were unable to receive a full induction course.  The authors concluded that GEM/DOCE was an effective and well-tolerated therapy for BCG-naïve NMIBC.  Moreover, these researchers stated that these findings may serve as a benchmark for future prospective trial design examining GEM/DOCE as a 1st-line treatment for HR-NMIBC. 

The authors stated that this study had several drawbacks.  First, the retrospective nature allowed for selection bias and confounding.  Second, this study was limited by the lack of a direct comparator group and selection bias was possible.  Third, these findings were from a single high-volume institution with rigorous NMIBC protocols that may not be replicable in lower volume centers.  Fourth, this study was limited by relatively short-term (median of 15 months) follow-up.  Fifth, the retrospective design limited full confidence in classification of AEs per CTCAE criteria. 

In a prospective,  pilot study, Pareek et al (2022) examined intravesical GEM/DOCE versus BCG with respect to quality of life (QOL), safety, and effectiveness in NMIBC.  A total of 60 patients with NMIBC were evaluated between July 2019 and December 2020.  The sample size calculation was performed, keeping in mind the incidence of intravesical BCG-related complications of up to 50 5 to 60 % and 20 % to 30 % for GEM/DOCE combination.  The p value of 0.05 was used as statistically significant.  The enrollment ratio was kept at 1, and power of study was aimed at 80 %.  The study population was alternatively assigned to 2 groups (BCG versus GEM/DOCE) of 30 patients each.  Both groups received 6 weekly doses of induction therapy followed by 6 monthly doses of maintenance therapy if no recurrence was noted at interim follow-up.  QOL scores, safety, and effectiveness were examined at beginning of intravesical therapy, end of induction, and 6 months of maintenance therapy.  Cystoscopy examination and cytology were carried out at the end of induction therapy and 3-monthly thereafter.  The preliminary results at the end of 6 months following maintenance therapy demonstrated that the demographic profile, histological stage, and grade were comparable between 2 groups.  The QOL scores using QLQ-30 and QLQ-BLS-24 showed statistically significant differences with the GEM/DOCE arm showing better outcomes.  There were no progressions to higher stage, while 1 recurrence each was observed in both groups.  Patient-related side effects measured by CTCAE version 5.0 showed that the BCG group had higher toxicity profile as compared to GEM/DOCE group.  The authors concluded that combined GEM/DOCE intravesical therapy is a promising alternative to BCG for the treatment of patients with NMIBC, showing better QOL measures and lesser side effects. 

The authors stated that this trial being a pilot study lacked randomization and longer follow-up time-points; however, the findings for QOL were in accordance with existing literature.  Better QOL with safety profile in this trial will form the basis for future randomized studies with larger patient numbers to further define this promising option for the treatment of patients with NMIBC.  The long-term outcomes of this study are awaited.  Lastly, no study in these times can be exempt from the effect of pandemic.  This trial, like many other studies in world literature, pointed out towards this effect, which may range from recruitment of patients to providing timely care and follow-up.  These researchers recommended that a large-scale, multi-center study is needed to examine this effect on treatment and oncological outcomes of NMIBC. 

Kawada et al (2023) noted that shortages in intravesical BCG immunotherapy represent a challenge in the management of patients with HR-NMIBC.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of intravesical gemcitabine (GEM) and docetaxel (DOCE) for BCG-naive and unresponsive HR-NMIBC.  They identified 6 studies eligible for quantitative analysis via a systematic search according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement.  In the 2 studies in the BCG-naive setting, 1-year, and 2-year pooled RFS were 86 % and 84 %, respectively.  In the 2 studies in the BCG unresponsive setting, 6-month, 1-year, and 2-year pooled high-grade RFS (HG-RFS) were 80 %, 66 % and 51 %, respectively.  Cumulative data from 4 studies showed that 2.3 % of patients could not complete induction therapy and 6.9 % experienced treatment delay or dose reduction due to AEs.  The authors concluded that despite the preliminary data and based on a small sample size, intravesical GEM/DOCE therapy is a highly promising combination yielding an effective and well-tolerated alternative to BCG when indicated.  Moreover, these researchers stated that further large, well-designed comparative studies with BCG are needed.

References

The above policy is based on the following references:

  1. Fizazi K, Foulon S, Carles J, et al; PEACE-1 investigators. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): A multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707.
  2. Gil-Sierra MD, Alegre-Del Rey EJ, de la Lastra-Romero CA, Sánchez-Hidalgo M. Use of docetaxel in low- and high-burden metastatic hormone-sensitive prostate cancer: A systematic review and assessment of subgroup analyses. J Oncol Pharm Pract. 2021;27(7):1743-1750.
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  6. McElree IM, Steinberg RL, Martin AC, et al. Sequential intravesical gemcitabine and docetaxel for bacillus Calmette-Guerin-naive high-risk nonmuscle-invasive bladder cancer. J Urol. 2022;208(3):589-599.
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  11. Sun Z-W, Lan X-Y, Kong F-L, et al. Docetaxel and bevacizumab with or without trastuzumab as first-line treatment for patients with metastatic breast cancer: A meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25(17):5365-5373.
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