Luteinizing Hormone-Releasing Hormone (LHRH) Analogs

LCD Information Document Information Source LCD ID N/A LCD ID L39387 Original ICD-9 LCD ID Not Applicable LCD Title Luteinizing Hormone-Releasing Hormone (LHRH) Analogs Proposed LCD in Comment Period N/A Source Proposed LCD DL39387 Opens in a new window Original Effective Date For services performed on or after 02/19/2023 Revision Effective Date For services performed on or after 10/10/2024 Revision Ending Date N/A Retirement Date N/A Notice Period Start Date 01/05/2023 Notice Period End Date 02/18/2023 CPT codes, descriptions, and other data only are copyright 2025 American Medical Association. All Rights Reserved. Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of CPT, and the AMA is not recommending their use. The AMA does not directly or indirectly practice medicine or dispense medical services. The AMA assumes no liability for data contained or not contained herein. 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Issue Issue Description This LCD outlines limited coverage for this service with specific details under Coverage Indications, Limitations and/or Medical Necessity. Issue - Explanation of Change Between Proposed LCD and Final LCD Under Coverage Indications, Limitations and/or Medical Necessity added "palliative treatment of advanced prostate cancer" for Leuprolide Acetate, Goserelin implant and Triptorelin. Additionally, clarification was provided for Goserelin implant as it pertains to use in combination with flutamide. NCCN Clinical Practice Guidelines in Oncology® have been added and are cited. Palliative treatment of advanced prostate cancer has been removed from coverage for Histrelin acetate implant. Under Bibliography added #13-17. CMS National Coverage Policy Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. Title XVIII of the Social Security Act, §1862(a)(7) states Medicare will not cover any services or procedures associated with routine physical checkups. CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §50.3 Incident-to Requirements and §50.4.1 Approved Use Of Drug. CMS Internet-Only Manual, Pub. 100-08, Medicare Program Integrity Manual, Chapter 13, §13.5.4 Reasonable and Necessary Provision in an LCD. Coverage Indications, Limitations, and/or Medical Necessity Luteinizing Hormone-Releasing Hormone (LHRH) Analogs are synthetic analogs of the naturally occurring gonadotropin releasing hormone (GnRH) with greater potency than the naturally occurring hormone, that when given inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis. Leuprolide acetate (Lupron Depot®) Opens in a new window, goserelin acetate (Zoladex®) Opens in a new window, triptorelin pamoate (Trelstar Opens in a new window® Opens in a new window) Opens in a new window, histrelin acetate (Vantas Opens in a new window® Opens in a new window) Opens in a new window are synthetic LHRH agonists, analogs of the naturally occurring GnRH, and leuprolide mesylate (Camcevi Opens in a new window® Opens in a new window) Opens in a new window. They will be covered for Food and Drug Administration (FDA) approved indications. The dose and frequency of administration should be consistent with the FDA approved labeling. Covered Indications Leuprolide Acetate is covered for endometriosis, uterine fibroids, advanced prostate cancer, head and neck cancer (salivary gland tumors), ovarian cancer/fallopian tube cancer/primary peritoneal cancer, premenopausal breast cancer, male breast cancer, central precocious puberty (CPP) and palliative treatment of advanced prostate cancer.1 Leuprolide mesylate is covered for advanced prostate cancer.12 The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology for Breast Cancer®14, the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers®15, the NCCN Clinical Practice Guidelines in Oncology for Ovarian Cancer®16, and the NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer®17 are referenced for recommendations for coverage across each of these disease settings. Goserelin implant is covered for locally confined prostate cancer in combination with flutamide; for stage T2b-T4 (stage B2-C) flutamide is recommended only with radiation in this disease setting. Goserelin implant is covered for advanced breast cancer in premenopausal and perimenopausal women, endometriosis, to thin the endometrial lining of the uterus prior to endometrial ablation for dysfunctional uterine bleeding, and palliative treatment of advanced prostate cancer.2 The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer® is cited to nationally recognized guidelines to accommodate specific clinical scenarios.14 The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer® is cited to nationally recognized guidelines to accommodate specific clinical scenarios for “advanced prostate cancer.”17 Triptorelin pamoate is covered for palliative treatment of advanced prostate cancer.3 The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer® is cited to nationally recognized guidelines to accommodate specific clinical scenarios for “advanced prostate cancer.”17 Histrelin acetate implant is covered for CPP. Note: The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer® is cited to nationally recognized guidelines to accommodate specific clinical scenarios for “advanced prostate cancer.”17 Limitations Services that are not reasonable and necessary cannot be covered by Medicare in the following: The dose and frequency of administration is not consistent with the FDA approved labeling. Doses and frequencies that exceed the FDA recommended dosage/frequency as per the prescribing information, are considered not reasonable and necessary and not covered by Medicare. It is contraindicated to administer these products if you have experienced any type of allergic reaction to these drugs or to any of its ingredients. Summary of Evidence Lawrence, et al. (2020) conducted a systemic review to create the American Urological Association/American Society for Therapeutic Radiology and Oncology/Society of Urologic Oncology (AUA/ASTRO/SUO) Guideline to aid clinicians in the management of patients with advanced prostate cancer. Clinicians should offer ADT (androgen deprivation therapy) with either LHRH agonists or antagonists or surgical castration in patients with metastatic hormone sensitive prostate cancer (mHSPC) (strong recommendation; evidence level: grade B). The use of primary ADT for the management of mHSPC has been the standard of care (SOC) since its discovery by Huggins and colleagues in the 1940s.5 Conn, et al. (1991) review article reports the use of GnRH agonist analogues therapy to induce biochemical castration. The suppression of the normal pituitary-gonadal function is sought because physiologic levels of secretion of gonadal steroids which exacerbate an underlying medical condition, such as endometriosis, uterine fibroids, or prostate cancer.6 Guzick, et al. (2011) conducted a prospective, randomized, double-blind controlled trial to compare the efficacy of leuprolide and continuous oral contraceptives in the treatment of endometriosis associated pain. The major findings of this trial is that both treatment arms provided a significant reduction in pain from baseline and there was no significant difference in the extent of pain relief between the 2 treatment regimens. The strengths of this clinical trial include its study design (randomized, double-blind prospective, multicenter) and the choice of contemporary medical regimens currently in widespread clinical use in the United States. The greatest weakness of the study is its limited sample size, a direct result of significant challenges in subject recruitment.7 Kendzierski, et al. (2018) assessed the efficacy of leuprolide depot in combination with an aromatase inhibitor delivered monthly compared to once every 3 months in premenopausal women with estrogen receptor (ER)-positive breast cancer in a single center retrospective study. The Suppression of Ovarian Function Trial (SOFT)/Tamoxifen and Exemestane Trial (TEXT) trials solidified GnRH agonists as a definitive option in adjuvant therapy for premenopausal women with ER-positive breast cancer. They concluded leuprolide acetate depot administered every 3 months is as efficacious and tolerable as a monthly injection in combination with an aromatase inhibitor for premenopausal patients with hormone receptor-positive breast cancer. The study’s retrospective design comes with inherent limitations. The patient population was small, and they describe a single institution experience not a larger randomized, multicenter trial of adjuvant hormone therapy in breast cancer patients.9 Hassett, et al. (2020) convened an expert panel to develop clinical practice guideline recommendations based on a systematic review of the medical literature. To date, approaches to treating men with breast cancer have been extrapolated largely from research conducted in women with breast cancer. Guideline development involved a formal consensus process. The American Society of Clinical Oncology (ASCO) guideline offers recommendations on several key aspects of the management of male breast cancer.10 Francis, et al. (2018) reported the updated results from the SOFT and the TEXT. They concluded that among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence.11 Analysis of Evidence (Rationale for Determination) The analysis of evidence reviewed for LHRH analogs included the AUA/ASTRO/SUO Guideline, a prospective, randomized, double-blind controlled trial, a retrospective study, and the ASCO Guideline. The AUA/ASTRO/SUO Guideline has a strong recommendation for the use of primary ADT for the management of mHSPC.5 The article by Conn reports the use of GnRH agonist analogues therapy to suppress the normal pituitary gonadal function in medical conditions such as endometriosis, uterine fibroids, and prostate cancer.6 Kendzierski stated that the SOFT/TEXT trials solidified GnRH agonists as a definitive option in adjuvant therapy for premenopausal women with ER-positive breast cancer.9

Luteinizing Hormone-Releasing Hormone (LHRH) Analogs are synthetic analogs of the naturally occurring gonadotropin releasing hormone (GnRH) with greater potency than the naturally occurring hormone, that when given inhibits pituitary gonadotropin secretion and suppresses testicular and ovarian steroidogenesis. Leuprolide acetate (Lupron Depot ® ) , goserelin acetate (Zoladex ® ) , triptorelin pamoate (Trelstar ® ) , histrelin acetate (Vantas ® ) are synthetic LHRH agonists, analogs of the naturally occurring GnRH, and leuprolide mesylate (Camcevi ® ) . They will be covered for Food and Drug Administration (FDA) approved indications. The dose and frequency of administration should be consistent with the FDA approved labeling. Covered Indications Leuprolide Acetate is covered for endometriosis, uterine fibroids, advanced prostate cancer, head and neck cancer (salivary gland tumors), ovarian cancer/fallopian tube cancer/primary peritoneal cancer, premenopausal breast cancer, male breast cancer, central precocious puberty (CPP) and palliative treatment of advanced prostate cancer. 1 Leuprolide mesylate is covered for advanced prostate cancer. 12 The National Comprehensive Cancer Network ® (NCCN) Clinical Practice Guidelines in Oncology for Breast Cancer ® 14 , the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers ® 15 , the NCCN Clinical Practice Guidelines in Oncology for Ovarian Cancer ®16 , and the NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer ®17 are referenced for recommendations for coverage across each of these disease settings. Goserelin implant is covered for locally confined prostate cancer in combination with flutamide; for stage T2b-T4 (stage B2-C) flutamide is recommended only with radiation in this disease setting. Goserelin implant is covered for advanced breast cancer in premenopausal and perimenopausal women, endometriosis, to thin the endometrial lining of the uterus prior to endometrial ablation for dysfunctional uterine bleeding, and palliative treatment of advanced prostate cancer. 2 The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer ® is cited to nationally recognized guidelines to accommodate specific clinical scenarios. 14 The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer ® is cited to nationally recognized guidelines to accommodate specific clinical scenarios for “advanced prostate cancer.” 17 Triptorelin pamoate is covered for palliative treatment of advanced prostate cancer. 3 The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer ® is cited to nationally recognized guidelines to accommodate specific clinical scenarios for “advanced prostate cancer.” 17 Histrelin acetate implant is covered for CPP. Note : The NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer ® is cited to nationally recognized guidelines to accommodate specific clinical scenarios for “advanced prostate cancer.” 17 Limitations Services that are not reasonable and necessary cannot be covered by Medicare in the following: The dose and frequency of administration is not consistent with the FDA approved labeling. Doses and frequencies that exceed the FDA recommended dosage/frequency as per the prescribing information, are considered not reasonable and necessary and not covered by Medicare. It is contraindicated to administer these products if you have experienced any type of allergic reaction to these drugs or to any of its ingredients.