Gemcitabine
Number: 0958
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
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Criteria for Initial Approval
Aetna considers gemcitabine (Gemzar, Infugem, or generic gemcitabine) medically necessary for the following indications:
- Ampullary Adenocarcinoma;
- Kaposi Sarcoma;
- B-Cell Lymphomas - including 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, AIDS-related B-cell lymphomas, and post-transplant lymphoproliferative disorders;
- Bladder Cancer - including primary carcinoma of the urethra, upper genitourinary tract tumors, transitional cell carcinoma of the urinary tract, urothelial carcinoma of the prostate, and non-urothelial and urothelial cancer with variant histology;
- Bone Cancer - including:
- Ewing's sarcoma - relapsed, progressive, or metastatic disease; or
- Osteosarcoma - relapsed, refractory or metastatic disease;
- Breast Cancer - members with no response to preoperative systemic therapy, recurrent, or metastatic disease;
- Cervical Cancer;
- Ovarian Cancer, Fallopian Tube Cancer, and Primary Peritoneal Cancer - advanced, persistent, or recurrent 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 tumors (low malignant potential), mucinous carcinoma of the ovary, or malignant germ cell tumor residual disease;
- Gestational Trophoblastic Neoplasia;
- Head and Neck Cancer - including very advanced head and neck cancer and cancer of the nasopharynx, and salivary gland tumors;
- Hepatobiliary and Biliary Tract Cancer - including intrahepatic and extrahepatic cholangiocarcinoma, and gallbladder cancer;
- Hodgkin Lymphoma - including:
- Classic Hodgkin lymphoma and pediatric Hodgkin lymphoma; or
- Nodular lymphocyte-predominant Hodgkin lymphoma - progressive, relapsed, or refractory disease;
- Kidney Cancer - relapsed or metastatic disease;
- Malignant Germ Cell Tumor;
- Malignant Pleural or Peritoneal Mesothelioma - including pericardial mesothelioma and tunica vaginalis testis mesothelioma;
- Non-Small Cell Lung Cancer (NSCLC);
- Occult Primary Tumors (cancer of unknown primary);
- Pancreatic Adenocarcinoma;
- Primary Cutaneous Lymphomas - including mycosis fungoides/Sezary syndrome and primary cutaneous CD30+ T-cell lymphoproliferative disorders;
- Small Cell Lung Cancer (SCLC);
- Soft Tissue Sarcoma - including angiosarcoma, extremity/body wall, head/neck, retroperitoneal/intra-abdominal, rhabdomyosarcoma, solitary fibrous tumor, and dermatofibrosarcoma protuberans (DFSP) with fibrosarcomatous transformation;
- Small Bowel Adenocarcinoma;
- T-Cell Lymphomas - including peripheral T-cell lymphomas, adult T-cell leukemia/lymphoma, hepatosplenic T-cell lymphoma, breast implant-associated anaplastic large cell lymphoma, and extranodal NK/T-cell lymphoma;
- Testicular Cancer;
- Thymomas and Thymic Carcinomas;
- Uterine Neoplasms - including uterine sarcoma and uterine leiomyosarcoma.
Aetna considers gemcitabine experimental and investigational for all other indications.
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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.
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)
- Hepatobiliary and biliary tract cancer
- Extrahepatic cholangiocarcinoma
- Intrahepatic cholangiocarcinoma
- Gallbladder cancer
-
Hodgkin lymphoma
- Classic Hodgkin lymphoma
- Nodular lymphocyte-predominant Hodgkin lymphoma
- Kidney cancer
- Malignant 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
- 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
- AIDS-Related B-Cell lymphomas
- Post-Transplant lymphoproliferative disorders
- Small bowel adenocarcinoma
- Malignant germ cell tumor
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.
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).
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:
- Clinical Pharmacology. Gemcitabine. Tampa, FL: Gold Standard/Elsevier; Updated periodically.
- DRUGDEX System [Internet database]. Gemcitabine. Armonk, NY: IBM Watson Health; Updated periodically.
- Eli Lilly and Company. Gemzar (gemcitabine) for injection, for intravenous use. Prescribing Information. Indianapolis, IN: Eli Lilly; revised May 2019.
- Lexicomp Online (Lexi-Drugs). Gemcitabine. Hudson, OH: UpToDate, Inc; Accessed July 20, 2022.
- Meitheal Pharmaceuticals. Gemcitabine for injection, for intravenous use. Prescribing Information. Chicago, IL: Meitheal Pharmaceuticals; August 2019.
- National Comprehensive Cancer Network (NCCN). Gemcitabine. NCCN Drugs & Biologics Compendium. Plymouth Meeting, PA: NCCN; July 2022.
- National Comprehensive Cancer Network (NCCN). Gestational trophoblastic neoplasia. NCCN Clinical Practice Guidelines in Oncology, Version 1.2022. Plymouth Meeting, PA: NCCN; October 2021.
- 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 Jul 27 [Online ahead of print].
- 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.
- Sun Pharmaceutical Industries, Inc. Infugem (gemcitabine in sodium chloride injection), for intravenous use. Prescribing Information. Cranbury, NJ: Sun Pharmaceutical Industries; revised January 2020.
- Sun Pharmaceutical Industries, Inc. Sun Pharma announces U.S. FDA approval of Infugem injection. Press Release. Cranbury, NJ: Sun Pharmaceutical Industries; July 18, 2018.
