Anthem Blue Cross California GNRH Analogs for Oncologic Indications Form

Overview Clinical criteria Overview Coding Document history References This document addresses the use of gonadotropin releasing hormone (GnRH) analogs for the treatment of oncologic indications. GnRH analogs are a group of hormonal drugs consisting of GnRH agonists and antagonists, both of which suppress pituitary hormones. GnRH agonists typically act over several days and GnRH antagonists act quickly within several hours. Affecting the pituitary gland in the brain, GnRH analogs suppress function of the ovaries and testes, blocking the production of testosterone in males and estrogen in females. Repeated administration of these drugs will cause gonadal hormone dependent tissues/organs to reduce or cease activity, such as the normal prostate gland that is dependent on testosterone for growth and function. This effect is reversible on discontinuation of the drug therapy. The GnRH analogs included in the document include: Firmagon (degarelix), Zoladex (goserelin acetate), Vantas (histrelin acetate), Camcevi, (leuprolide mesylate) Eligard (leuprolide acetate), Lupron Depot (leuprolide acetate), and Trelstar, Trelstar LA (triptorelin pamoate). Breast Cancer Breast cancer is the most common cancer diagnosed in women today with the exception of skin cancer. Suppression of ovarian function with the use of luteinizing hormone-releasing hormone (LHRH) agonists has been shown to be effective in the treatment of hormone receptor positive breast cancer in pre- or peri-menopausal women. LHRH agonists currently available in the United States include goserelin acetate and leuprolide acetate. Breast cancer in men is a relatively rare disease. Due to this rarity, studies are limited in number and size. However, several authors (Giordano, 2002; Hotko, 2013) report that additive hormonal therapy has been shown to have substantial response rates in metastatic breast carcinoma in men. The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium and Clinical Practice Guidelines for Breast Cancer indicate that leuprolide acetate and goserelin acetate may be used to treat premenopausal women with hormone receptor- positive disease in combination with adjuvant endocrine therapy for recurrent or metastatic disease. Additionally, NCCN notes that men with breast cancer should be treated similarly to postmenopausal women, except that use of an aromatase inhibitor is ineffective without concomitant suppression of testicular steroidogenesis. These recommendations are NCCN category 1 and 2A. Two randomized phase III clinical trials) (TEXT and SOFT) (Pagani, 2014) demonstrated that the aromatase inhibitor exemestane plus ovarian suppression significantly reduced breast cancer recurrences as compared to tamoxifen plus ovarian suppression. The primary analysis combined data from 4690 subjects from the two trials. The rate of disease-free survival at 5 years was 91.1% (95% confidence interval [CI], 89.7 to 92.3) for subjects assigned to exemestane plus ovarian suppression, compared to 87.3% (95% CI, 85.7-88.7) for those in the tamoxifen plus ovarian suppression group. A GnRH analog was used for ovarian suppression in both groups. Based on results of these trials, NCCN included ovarian suppression plus an aromatase inhibitor for 5 years as adjuvant endocrine therapy option for premenopausal women with hormone receptor positive breast cancer at a higher risk of recurrence. Factors indicating a higher risk of recurrence include young age, high-grade tumor and lymph node involvement. One trial investigated whether or not 3-month depot was reliable as 6 cycles of CMF. In the trial, Lupron 11.25 mg subcutaneously was administered once every 3 months for 2 years in 589 patients. Leuprolide was compared to 6 cycles of CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant treatment in premenopausal patients with node-positive breast cancer (TABLE study) and was shown to be non-inferior for 2-year relapse free survival (63.9% vs. 63.4%; p=0.83). There are no trials currently comparing monthly injections to a 3-month depot injection. Ovarian Cancer 1 Leuprolide acetate is a viable option for treatment of ovarian cancer under certain circumstances (Rao, 2006; Yokoyama, 2013). Fishman (1996) evaluated 6 women with recurrent or persistent ovarian granulosa cell tumor who were treated with monthly leuprolide acetate injections. Cessation of disease progression was noted in 5 subjects. The 6th subject remained disease free after her primary cytoreductive surgery while on adjuvant therapy with leuprolide acetate for 24 months. There were no major side effects noted and the treatment was well tolerated. The authors concluded that a reasonable disease progression-free interval occurred, and leuprolide treatment should be considered for further trials of therapy. Balbi (2004) reported on a study in which 12 women with advanced ovarian cancer previously treated with paclitaxel were administered leuprolide on days 1, 8, and 28. Progression-free survival was 6 months, and the treatment was well tolerated. The authors noted: “the high tolerability and the results obtained with leuprolide versus platinum in second-line therapy might permit a better use of the analogs for advanced ovarian cancer.” The NCCN Drugs and Biologics Compendium and Clinical Practice Guidelines for Ovarian Cancer indicate that leuprolide acetate may be used for hormonal therapy as a single agent for persistent disease or recurrence of ovarian cancer (epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer) and for clinical relapse of stage II-IV granulosa cell tumors (2A recommendations). Prostate Cancer Prostate cancer is the most common form of cancer, other than skin cancer, among men. Wilt and colleagues (2008) report that approximately 90% of men with prostate cancer have disease confined to the prostate gland (clinically localized disease). GnRH analogs are commonly used in the treatment of prostate cancer under specific conditions as indicated by current FDA approved labels and NCCN. Men with prostate cancer are categorized according to their recurrence risk into those with clinically localized disease at low, intermediate and high risk of recurrence, or those with locally advanced disease at very high risk of recurrence, or those with metastatic disease. The NCCN Clinical Practice Guidelines for Prostate Cancer include the following additional information defining prostate cancer recurrence risk categories: Very low risk category includes individuals with tumors stage T1c, biopsy Gleason score (less than or equal to 6)/Gleason grade group 1 and serum PSA below 10 ng/ml, presence of disease in fewer than 3 biopsy cores, 50% or less prostate involvement in any core and PSA density less than 0.15 ng/ml/g. Low risk category includes individuals with tumors stage T1-T2a, Gleason score 6/Gleason grade group 1, and serum PSA level below 10 ng/ml. Intermediate risk category includes individuals with clinical stage T2b to T2c cancer, Gleason score 7/Gleason grade group 2-3, or PSA value of 10-20 ng/mL. Those with multiple adverse factors may be shifted into the high risk category. High risk category includes individuals with prostate cancer that is stage T3a, Gleason score 8-10/Gleason grade group 4-5, or PSA level greater than 20 ng/mL. Very high risk of recurrence (locally advanced) includes individuals with stage T3b to T4 disease, primary Gleason pattern 5, or more than 4 biopsy cores with Gleason score 8-10/Gleason grade group 4-5. Neoadjuvant androgen deprivation therapy (ADT) (which includes GnRH analogs) may be used to shrink the prostate to an acceptable size prior to brachytherapy, however increased toxicity would be expected from ADT and prostate size may not decline in some men (NCCN Clinical Practice Guidelines for Prostate Cancer). The American Academy of Urology (2008) indicates that there is evidence of benefit from hormone therapy prior to cryosurgery for downsizing purposes. Salivary Gland Tumors Salivary gland tumors can be found in the major salivary glands (for example, parotid, submandibular, sublingual) or in the minor salivary glands. Salivary gland carcinoma is rare and accounts for 6% of head and neck cancers in the United States (Dalin, 2017). Fushimi and colleagues (2017) performed the first prospective, phase II, open-label, single-arm study of a combined androgen blockade for androgen receptor-positive salivary gland carcinoma. A total of 36 subjects were included (33 with recurrent/metastatic disease and 3 with locally advanced disease). Inclusion criteria included: ≥ 20 years of age, ECOG performance status of 0-2, adequate organ function, measurable lesions, and at least a 3-month life expectancy. The researchers administered leuprorelin (another name for leuprolide) 3.75 mg every 4 weeks and bicalutamide 80 mg daily until the subjects’ disease progressed or they had unacceptable toxicities. Tumor response was assessed every 6 weeks using computed tomography or magnetic resonance imaging. The best overall response rate was 41.7% (n=15; 95% CI, 25.5% to 59.2%) and the clinical benefit rate was 75% (n=27, 95% CI, 57.8% to 87.9%). The median progression-free survival was 8.8 months (95% CI, 6.3 to 12.3) and median overall survival was 30.5 months (95% CI, 16.8 to not reached). Serious adverse events included elevated grade 3 liver transaminases and increased serum creatinine. The authors concluded that a combined androgen blockade may have antitumor activity in androgen-positive salivary gland carcinoma. The NCCN Drugs and Biologics Compendium and Clinical Practice Guidelines for Head and Neck Cancers indicate that leuprolide acetate may be used for salivary gland tumors for androgen receptor positive (AR+) recurrent disease with distant metastases and a 2 PS of 0-3 (2A recommendation). NCCN also recommends leuprolide to treat salivary gland tumors that are AR+, locally advanced, and unresectable (2A recommendation). Other Uses The uses of GnRH analogs considered to be medically necessary in this document have sufficient published evidence available to support them. However, there is a lack of scientific evidence found from which conclusions could be made concerning the safety and efficacy of treating various other oncologic indications, including, but not limited to cancers of the endometrium and liver. Currently there is a lack of evidence to support the use of leuprolide as monotherapy to treat salivary gland tumors. Definitions and Measures Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure; may include chemotherapy, radiation, hormone or biological therapy. Advanced prostate cancer: Disease that has spread beyond the prostate to surrounding tissues or distant organs. Androgen deprivation therapy (also known as androgen ablation or androgen suppression): Treatment to suppress or block the production or action of male hormones. This is done by having the testicles removed, by taking female sex hormones, or by taking drugs called antiandrogens or GnRH analogs. Brachytherapy (also known as internal radiation): A type of radiation treatment used to stop the growth of cancer cells by implanting radioactive material directly into the tumor or into the surrounding tissues. Cancer staging: The process of determining how much cancer there is in the body and where it is located; describes the extent or severity of an individual's cancer based on the extent of the original (primary) tumor and the extent of spread in the body. Clinically localized prostate cancer: Cancer presumed to be confined within the prostate based on pre-treatment findings such as physical exam, imaging, and biopsy findings. Cryosurgery (also called cryotherapy or cryosurgical ablation): Is the use of extreme cold produced by liquid nitrogen (or argon gas) to destroy abnormal tissue. Cryosurgery may be used to treat tumors on the skin (external tumors), such as basal cell carcinoma, or tumors inside the body (internal tumors), such as prostate cancer. ECOG Performance Status: A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale: • • • • • • 0= Fully active, able to carry on all pre-disease performance without restriction 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2= Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3= Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4= Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5= Dead External beam radiation therapy (EBRT) (also known as teletherapy): A form of therapy using radiation to stop the growth of cancer cells. A linear accelerator directs a photon or electron beam from outside the body through normal body tissue to reach the cancer and the radiation is given 5 days per week for a period of 3 to 8 weeks. Gleason Grade Group: Assigns grade groups from 1-5, derived from the Gleason score. Gleason grade group 1: Gleason score 6 and only individual discrete well-formed glands. Gleason grade group 2: Gleason score 3+4=7 and predominantly well-formed glands with lesser component of poorly formed/fused/cribriform glands. Gleason grade group 3: Gleason score 4+3=7 and predominantly poorly formed/fused/cribriform glands with lesser component of well- formed glands. Gleason grade group 4: Gleason score 4+4=8; 3+5=8; 5+3=8 • Only poorly formed/fused/cribriform glands; or • Predominantly well-formed glands and lesser component lacking glands1; or • Predominantly lacking glands and lesser component of well-formed glands1. Gleason grade group 5: Gleason score 9-10 and lack of gland formation (or with necrosis) with or without poorly formed/fused/cribriform glands2. 1Poorly formed/fused/cribriform glands can be a more minor component 2For cases with more than 95% poorly formed/fused/cribriform glands or lack of glands on a core or at RP, the component of less than 5% well-formed glands is not factored into the grade. 3 Gleason Grading System: A prostate cancer grading system. A primary and secondary pattern, the number range of each is from 1 to 5, are assigned and then summed to yield a total score. Gleason score: Represents the sum of the two most common Gleason grades observed by the pathologist on a specimen, the first number is the most frequent grade seen. Locally advanced disease (prostate cancer): Cancer that has spread from where it started to nearby tissue or lymph nodes. Metastatic: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread. Second primary cancer: a new primary cancer that occurs in a person who has had cancer in the past, second primary cancers may occur months or years after the original (primary) cancer was diagnosed and treated. Lupaneta has been discontinued by the manufacturer. Criteria will remain active until July 31, 2023 as claims can adjudicate several years after agent discontinuation. Vantas has been discontinued by the manufacturer. Criteria will remain active until September 20, 2023 as claims can adjudicate several years after agent discontinuation Clinical Criteria When a drug is being reviewed for coverage under a member’s medical benefit plan or is otherwise subject to clinical review (including prior authorization), the following criteria will be used to determine whether the drug meets any applicable medical necessity requirements for the intended/prescribed purpose. Firmagon (degarelix) Requests for Firmagon (degarelix) may be approved if the following criteria are met: I. Individual is using for the treatment of prostate cancer and any of the following are met: A. Used as androgen deprivation therapy as a single agent or in combination with an antiandrogen; OR B. Used for clinically localized disease with intermediate (T2b to T2c cancer, Gleason score of 7/Gleason grade group 2-3, or prostate specific antigen (PSA) value of 10-20 ng/mL) or higher risk of recurrence as neoadjuvant therapy with radiation therapy or cryosurgery; OR C. Used for progressive castration-naïve disease; OR D. Used for castration-recurrent disease; OR E. Other advanced, recurrent, or metastatic disease; OR II. III. IV. Individual is using in the preservation of fertility in pre-menopausal women; AND Individual currently has a cancer diagnosis; AND Individual meets one of the following: A. B. Individual will receive chemotherapy for cancer with a curative intent; OR Individual will receive radiation therapy for cancer with a curative intent. Trelstar (triptorelin pamoate) Requests for Trelstar (triptorelin pamoate) may be approved if the following criteria are met: I. Individual is using for the treatment of prostate cancer and any of the following are met: A. Used as androgen deprivation therapy as a single agent or in combination with an antiandrogen; OR B. Used for clinically localized disease with intermediate (T2b to T2c cancer, Gleason score of 7/Gleason grade group 2-3, or prostate specific antigen (PSA) value of 10-20 ng/mL) or higher risk of recurrence as neoadjuvant therapy with radiation therapy or cryosurgery; OR C. Used for progressive castration-naïve disease; OR D. Used for castration-recurrent disease; OR E. Other advanced, recurrent, or metastatic disease. OR II. OR III. IV. V. Individual is using for the treatment of men and pre-, or peri-menopausal women with hormone receptor positive breast cancer (Pagani, 2014); Individual is using in the preservation of fertility in pre-menopausal women; AND Individual currently has a cancer diagnosis; AND Individual meets one of the following: A. Individual will receive chemotherapy for cancer with a curative intent; OR 4 B. Individual will receive radiation therapy for cancer with a curative intent. Vantas (histrelin acetate implant) Requests for Vantas (histrelin acetate implant) may be approved if the following criteria are met: I. Individual is using for the treatment of prostate cancer and any of the following are met: A. Used as androgen deprivation therapy as a single agent or in combination with an antiandrogen; OR B. Used for clinically localized disease with intermediate (T2b to T2c cancer, Gleason score of 7/Gleason grade group 2-3, or prostate specific antigen (PSA) value of 10-20 ng/mL) or higher risk of recurrence as neoadjuvant therapy with radiation therapy or cryosurgery; OR C. Used for progressive castration-naïve disease; OR D. Used for castration-recurrent disease; OR E. Other advanced, recurrent, or metastatic disease. OR II. III. IV. Individual is using in the preservation of fertility in pre-menopausal women; AND Individual currently has a cancer diagnosis; AND Individual meets one of the following: A. B. Individual will receive chemotherapy for cancer with a curative intent; OR Individual will receive radiation therapy for cancer with a curative intent. Zoladex (goserelin acetate) Requests for Zoladex (goserelin acetate) may be approved if the following criteria are met: I. OR II. OR III. III. IV. Individual has a diagnosis of breast cancer, men and pre-, or peri-menopausal women with hormone receptor positive breast cancer; Individual is using for the treatment of prostate cancer and any of the following are met: A. Used as androgen deprivation therapy as a single agent or in combination with an antiandrogen; OR B. Used for clinically localized disease with intermediate (T2b to T2c cancer, Gleason score of 7/Gleason grade group 2-3, or prostate specific antigen (PSA) value of 10-20 ng/mL) or higher risk of recurrence as neoadjuvant therapy with radiation therapy or cryosurgery; OR C. Used for progressive castration-naïve disease; OR D. Used for castration-recurrent disease; OR E. Other advanced, recurrent, or metastatic disease. Individual is using in the preservation of fertility in pre-menopausal women; AND Individual currently has a cancer diagnosis; AND Individual meets one of the following: A. B. Individual will receive chemotherapy for cancer with a curative intent; OR Individual will receive radiation therapy for cancer with a curative intent. Leuprolide acetate (Eligard, Lupron Depot), leuprolide acetate (immediate release), or leuprolide mesylate (Camcevi) Requests for leuprolide acetate (Eligard, Lupron Depot) may be approved if the following criteria are met: I. Individual is using for the treatment of salivary gland tumors (NCCN 2A); AND A. B. Individual has androgen receptor positive recurrent disease with distant metastases; AND Individual has a current Easter Cooperative Oncology Group (ECOG) performance status of 0-3. Requests for leuprolide acetate (Eligard, Lupron Depot), leuprolide acetate (immediate release), or leuprolide mesylate (Camcevi) may be approved if the following criteria are met: I. Individual is using for the treatment of prostate cancer and any of the following are met: A. Used as androgen deprivation therapy as a single agent or in combination with an antiandrogen; OR B. Used for clinically localized disease with intermediate (T2b to T2c cancer, Gleason score of 7/Gleason grade group 2-3, or prostate specific antigen (PSA) value of 10-20 ng/mL) or higher risk of recurrence as neoadjuvant therapy with radiation therapy or cryosurgery; OR C. Used for progressive castration-naïve disease; OR D. Used for castration-recurrent disease; OR E. Other advanced, recurrent, or metastatic disease. Requests for leuprolide acetate (Lupron Depot) may be approved if the following criteria are met: 5 I. Individual is using for the treatment of ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) and the following are met: A. Hormonal therapy for clinical relapse in individuals with stage II-IV granulosa cell tumors; OR B. Hormonal therapy for treatment of epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer as a single agent for persistent disease or recurrence; OR II. Individual is using for the treatment of men and pre-, or peri-menopausal women with hormone receptor positive breast cancer. Requests for leuprolide acetate (Eligard, Lupron Depot), leuprolide acetate (immediate release) may be approved if the following criteria are met: I. II. III. Individual is using in the preservation of fertility in pre-menopausal women; AND Individual currently has a cancer diagnosis; AND Individual meets one of the following: A. B. Individual will receive chemotherapy for cancer with a curative intent; OR Individual will receive radiation therapy for cancer with a curative intent. Requests for leuprolide acetate (Lupron, Lupron Depot) may not be approved for the following: I. Individual is pre-menopausal and diagnosed with non-invasive ductal carcinoma in situ (DCIS) of the breast. Coding The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. Breast Cancer Treatment HCPCS J1950 J9202 J9218 S9560 Injection, leuprolide acetate (for depot suspension), per 3.75 mg [Lupron Depot 3.75 ] Goserelin acetate implant, per 3.6 mg [Zoladex] Leuprolide acetate, per 1 mg [Lupron] Home injectable therapy; hormonal therapy (e.g.; leuprolide, goserelin), including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem ICD-10 Diagnosis C50.011-C50.929 Malignant neoplasm of breast Z85.3 N95.9 Personal history of malignant neoplasm of breast Menopausal and other premenopausal disorders Ovarian Cancer Treatment HCPCS J1950 J9218 S9560 Injection, leuprolide acetate (for depot suspension), per 3.75 mg [Lupron Depot 3.75, Lupron Depot 3-month 11.25] Leuprolide acetate, per 1 mg [Lupron] Home injectable therapy; hormonal therapy (e.g.; leuprolide, goserelin), including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem ICD-10 Diagnosis C48.1-C48.8 Malignant neoplasm of peritoneum C56.1-C56.9 Malignant neoplasm of ovary 6 C57.00-C57.9 Malignant neoplasm of other and unspecified female genital organs Z85.4 N95.9 Personal history of malignant neoplasm of ovary Menopausal and other premenopausal disorders Prostate Cancer Treatment HCPCS J3315 J9155 J9202 J9217 J9218 J9225 J1952 S9560 Injection, triptorelin pamoate, 3.75 mg [Trelstar, Trelstar LA] Injection, degarelix, 1 mg [Firmagon] Goserelin acetate implant, per 3.6 mg [Zoladex] Leuprolide acetate (for depot suspension), 7.5 mg [Eligard, Lupron Depot 7.5, including 22.5 mg (3-month), 30 mg (4-month), 45 mg (6-month)] Leuprolide acetate, per 1 mg [Lupron] Histrelin implant (Vantas), 50 mg Leuprolide injectable, [Camcevi], 1 mg Home injectable therapy; hormonal therapy (e.g.; leuprolide, goserelin), including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem ICD-10 Diagnosis C61 Malignant neoplasm of prostate Z85.46 Personal history of malignant neoplasm of prostate Ovarian Preservation Treatment HCPCS J1675 J1950 J3315 J9155 J9202 J9217 J9218 Injection, histrelin acetate, 10 micrograms Injection, leuprolide acetate (for depot suspension), per 3.75 mg [Lupron Depot] Injection, triptorelin pamoate, 3.75 mg [Trelstar, Trelstar LA] Injection, degarelix, 1 mg [Firmagon] Goserelin acetate implant, per 3.6 mg [Zoladex] Leuprolide acetate (for depot suspension), 7.5 mg [Eligard, Lupron Depot] Leuprolide acetate, per 1 mg [Lupron] ICD-10 Diagnosis C00.0-C58 Malignant neoplasms C64.1-C96.9 Malignant neoplasms Z85.00-Z85.44 Personal history of malignant neoplasms Z85.50-Z85.9 N95.9 Personal history of malignant neoplasms Menopausal and other premenopausal disorders Salivary Gland Tumor Treatment HCPCS J9217 S9560 Leuprolide acetate (for depot suspension), 7.5 mg [Eligard 7.5 mg (1 Month), 22.5 mg (3 Month); Lupron Depot 7.5 mg (1 Month), 22.5 mg (3 Month)] Home injectable therapy; hormonal therapy (e.g.; leuprolide, goserelin), including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem ICD-10 Diagnosis C08.0-C08.9 Malignant neoplasm of other and unspecified major salivary glands 7 Z85.818-Z85.819 Personal history of malignant neoplasm of lip, oral cavity and pharynx Document History Reviewed: 05/19/2023