Gemcitabine (Gemzar)

Number: 0958

Policy

Aetna considers gemcitabine medically necessary for the following indications:

  • AIDS-Related Kaposi Sarcoma
  • B-Cell Lymphomas, including follicular lymphoma (grade 1-2), histologic transformation of nodal marginal zone lymphoma 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; and
    • Osteosarcoma - relapsed, refractory or metastatic

  • Breast Cancer - recurrent or metastatic disease
  • Cervical Cancer when either of the following criteria are met:

    • The disease is advanced, recurrent or persistent; or
    • Gemcitabine will be used in combination with cisplatin as neoadjuvant therapy

  • Epithelial Ovarian Cancer, Fallopian Tube Cancer, and Primary Peritoneal Cancer -  advanced, persistent, or recurrent disease
  • Gestational Trophoblastic Neoplasia
  • Head and Neck Cancer, including, including very advanced head and neck cancer and cancer of the nasopharynx
  • Hepatobiliary and Biliary Tract Cancer, including intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary cancer
  • Hodgkin Lymphoma, including:

    • Classic Hodgkin lymphoma; and
    • Nodular lymphocyte-predominant Hodgkin lymphoma - progressive, relapsed, or refractory

  • Kidney Cancer - relapsed or metastatic disease 
  • Malignant Pleural 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 undifferentiated pleomorphic sarcoma (UPS)
  • Small bowel adenocarcinoma
  • T-Cell Lymphomas, including peripheral T-Cell lymphomas, adult T-Cell leukemia/lymphoma, hepatosplenic gamma-delta T-Cell lymphoma, and extranodal NKT/T-Cell lymphoma, nasal type
  • Testicular Cancer
  • Thymomas and Thymic Carcinomas
  • Uterine Neoplasms, including uterine sarcoma and uterine leiomyosarcoma.
Aetna considers continued treatment with the requested medication medically necessary in members requesting reauthorization for a medically necessary indication when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers gemcitabine experimental and investigational for all other indications because its effectiveness for other indications has not been established.

Dosing Recommendations

  • Ovarian Cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle
  • Breast Cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle
  • Non-Small Cell Lung Cancer: 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: 1000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly for 3 weeks of each 28-day cycle

Source: Eli Lilly and Company; 2019.

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 or gemcitabine is indicated for patients previously treated with fluorouracil.

Compendial Uses

  • 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
  • Head and neck cancers (including very advanced head and neck cancer and cancer of the nasopharynx)
  • Hepatobiliary and biliary tract cancer

    • Extrahepatic cholangiocarcinoma
    • Intrahepatic cholangiocarcinoma
    • Gallbladder cancer
    • Ampullary cancer

  • Hodgkin lymphoma
  • Classic Hodgkin lymphoma
  • Nodular lymphocyte-predominant Hodgkin lymphoma
  • Kidney cancer
  • Malignant pleural 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
  • Undifferentiated pleomorphic sarcoma (UPS)
  • Testicular cancer
  • Thymomas and thymic carcinomas
  • Uterine neoplasms (including uterine sarcoma and uterine leiomyosarcoma)
  • AIDS-Related 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
  • Extranodal NK/T-Cell lymphoma, nasal type
  • Hepatosplenic Gamma-Delta T-Cell lymphoma
  • Gestational trophoblastic neoplasia
  • B-Cell lymphomas
  • Follicular lymphoma (grade 1-2)
  • Histologic transformation of nodal marginal zone lymphoma 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
  • Cervical cancer
  • Small bowel adenocarcinoma

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).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

Other CPT codes related to the CPB:

96413 - 96417 Chemotherapy administration, intravenous infusion technique

HCPCS codes covered if selection criteria are met:

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
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
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]
C49.10 - C49.5,
C49.8 - C49.9
Malignant neoplasm of other connective and soft tissue [undifferentiated pleomorphic sarcoma]
C49.6 Malignant neoplasm of connective and soft tissue of trunk, unspecified [undifferentiated pleomorphic sarcoma]
C50.011 - C50.919 Malignant neoplasm of breast
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
C57.00 - C57.02 Malignant neoplasm of fallopian tube
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
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
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
D49.2 Neoplasm of unspecified behavior of bone, soft tissue, and skin [solitary fibrous tumor]

The above policy is based on the following references:

  1. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; Updated periodically.
  2. DRUGDEX System [Internet database]. Ann Arbor, MI: Truven Health Analytics Micromedex; updated periodically.
  3. Eli Lilly and Company. Gemzar (gemcitabine) for injection, for intravenous use. Prescribing Information. Indianapolis, IN: Eli Lilly and Company; revised May 2019.
  4. Gold Standard, Inc. Overview Name. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed: July 7, 2020.
  5. Hospira, Inc. Gemcitabine for injection, for intravenous use. Prescribing Information. Lake Forest, IL: Hospira, Inc.; June 2019.
  6. Lexicomp [database online]. Hudson, OH: Lexi-Comp, Inc [available with subscription].
  7. Meitheal Pharmaceuticals. Gemcitabine for injection, for intravenous use. Prescribing Information. Chicago, IL: Meitheal Pharmaceuticals, Inc.; August 2019.
  8. National Comprehensive Cancer Network (NCCN). Gemcitabine. NCCN Drugs & Biologics Compendium. Fort Washington, PA: NCCN; 2019.
  9. National Comprehensive Cancer Network (NCCN). Gemcitabine. NCCN Drugs & Biologics Compendium. Fort Washington, PA: NCCN; 2020.
  10. National Comprehensive Cancer Network (NCCN). Gestational Trophoblastic Neoplasia. NCCN Clinical Practice Guidelines in Oncology, version 1.2020. Fort Washington, PA: NCCN; 2020.