Clinical UM Guideline
|Subject:||Gonadotropin Releasing Hormone (GnRH) Analogs|
|Guideline #:||CG-DRUG-15||Current Effective Date:||01/13/2015|
|Status:||Revised||Last Review Date:||11/13/2014|
Gonadotropin releasing hormone (GnRH) analogs are synthetic analogs of naturally occurring GnRH.
The following agents are addressed in this document:
Note: This document does not address infertility treatment. Please see the following document for additional information:
I. Breast Cancer–Goserelin acetate or leuprolide acetate
Goserelin acetate or leuprolide acetate is considered medically necessary for the treatment of men and pre- or peri-menopausal women with hormone receptor positive breast cancer.
Not Medically Necessary:
Goserelin acetate or leuprolide acetate is considered not medically necessary for the treatment of breast cancer when the criteria above are not met.
II. Ovarian Cancer (including fallopian tube cancer and primary peritoneal cancer)–Leuprolide acetate
Leuprolide acetate is considered medically necessary for ovarian cancer when any of the following are met:
Not Medically Necessary:
Leuprolide acetate is considered not medically necessary for ovarian cancer when the criteria above are not met.
III. Prostate Cancer-Degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate, or triptorelin pamoate
*See definition section below for description of term.
Not Medically Necessary:
Degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate, or triptorelin pamoate is considered not medically necessary for treatment of prostate cancer when the criteria above are not met.
IV. Central Precocious Puberty- Leuprolide acetate (Lupron Depot-Ped), nafarelin acetate, or histrelin acetate subcutaneous implant (Supprelin LA)
Leuprolide acetate (Lupron Depot-Ped), nafarelin acetate or histrelin acetate subcutaneous implant (Supprelin LA) is considered medically necessary for the treatment of children known to have central precocious puberty (defined as the beginning of secondary sexual characteristics before age 8 in girls and 9 in boys)*.
*See discussion section below for additional information.
Not Medically Necessary:
Leuprolide acetate (Lupron Depot-Ped), nafarelin acetate or Supprelin LA (histrelin acetate subcutaneous implant) is considered not medically necessary for the treatment of central precocious puberty when the criteria above are not met.
V. Gynecology Uses-Goserelin acetate, leuprolide acetate, leuprolide acetate for depot suspension and norethindrone (Lupaneta Pack), or nafarelin acetate
Not Medically Necessary:
Goserelin acetate, leuprolide acetate, leuprolide acetate for depot suspension and norethindrone acetate tablets or nafarelin acetate is considered not medically necessary for gynecological uses when the criteria above are not met.
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.
|J1675||Injection, histrelin acetate, 10 micrograms|
|J1950||Injection, leuprolide acetate (for depot suspension), per 3.75 mg [Lupron Depot, Lupron Depot-Ped]|
|J3315||Injection, triptorelin pamoate, 3.75 mg [Trelstar, Trelstar Depot, Trelstar LA]|
|J9155||Injection, degarelix, 1 mg [Firmagon]|
|J9202||Goserelin acetate implant, per 3.6 mg [Zoladex]|
|J9217||Leuprolide acetate (for depot suspension), 7.5 mg [Eligard, Lupron Depot, Lupron Depot-Ped]|
|J9218||Leuprolide acetate, per 1 mg [Lupron, Eligard]|
|J9225||Histrelin implant (Vantas), 50 mg|
|J9226||Histrelin implant (Supprelin LA), 50 mg|
|S9560||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|
|No code for Nafarelin acetate [Synarel Nasal Spray]|
|No code for Leuprolide acetate for depot suspension and norethindrone acetate tablets [Lupaneta Pack]|
|ICD-9 Diagnosis||[For dates of service prior to 10/01/2015]|
|ICD-10 Diagnosis||[For dates of service on or after 10/01/2015]|
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.
Drugs classified as GnRH analogs include, but are not limited to: degarelix (Firmagon®), goserelin acetate (Zoladex®), histrelin acetate (Vantas® 12 month implant; Supprelin® LA 12 month implant), leuprolide acetate (Lupron Depot®, Lupron Depot-Ped®, Eligard®), nafarelin acetate (Synarel Nasal Spray®), and triptorelin pamoate (Trelstar ®, Trelstar LA®, Trelstar Depot®). Currently, the brand Lupron (leuprolide acetate) is not being marketed in the United States; however, the brands Lupron Depot, Lupron Depot-Ped and Eligard remain available. There are both U.S. Food and Drug Administration (FDA) approved and non-FDA approved indications for these drugs. The non-FDA approved indications listed in this document are based on drug compendia (National Comprehensive Cancer Network® NCCN Drugs & Biologic Compendium™, DrugPoints® Compendium, and the American Hospital Formulary Service®) and published peer reviewed literature as detailed in CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use.
Although GnRH products may differ in specific labeled indications and dosing requirements, clinical evidence does not support differential effectiveness of one product over the other for FDA approved clinical indications.
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 goserelin acetate or leuprolide acetate has been shown to be effective in the treatment of hormone receptor positive breast cancer in pre- or peri-menopausal women. Two clinical studies (Jakesz, 2002; Jonat, 2002) compared ovarian suppression hormones, such as GnRH analogs to conventional chemotherapeutic agents, such as a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). CMF induced significantly better disease free survival and overall survival when subjects were converted from an estrogen receptor positive to negative state.
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) demonstrate that additive hormonal therapy has been shown to have substantial response rates in metastatic breast carcinoma in men. In addition, NCCN (2014) recommends that men with breast cancer be treated similarly to postmenopausal women, except that use of an aromatase inhibitor is ineffective without concomitant suppression of testicular steroidogenesis.
There are several small studies in the peer-reviewed published literature assessing the role of leuprolide acetate as a treatment for ovarian cancer. 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 since 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."
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.
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 2015 NCCN Prostate Cancer Guideline includes the following additional information defining prostate cancer recurrence risk categories:
Low risk category includes men with tumors stage T1-T2a, low Gleason score (less than or equal to 6), and serum PSA level below 10 ng/ml.
Intermediate risk category includes men with any T2b to T2c cancer, Gleason score of 7, or PSA value of 10-20 ng/ mL. Those with multiple adverse factors may be shifted into the high risk category.
Men with prostate cancer that is clinically localized Stage T3a or Gleason score 8-10 or preoperative PSA level greater than 20 ng/mL are categorized by the NCCN Guideline Panel as high risk for recurrence after definitive therapy, and those at very high risk of recurrence have Stage T3b to T4 (locally advanced) disease.
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 (NCCN Clinical Practice Guideline for Prostate Cancer, V1.2015). The American Academy of Urology (2008) indicates that there is evidence of benefit from hormone therapy prior to cryosurgery for downsizing purposes. The American Cancer Society (2013) reports that ADT may be used before radiation to shrink the prostate cancer to make other treatments more effective.
Central Precocious Puberty
Central precocious puberty (CPP) refers to premature activation of the hypothalamic-pituitary-gonadal axis (Eugster, 2007; Phillip, 2005). Carel and colleagues (2009), on behalf of members of the European Society for Pediatric Endocrinology, indicated that precocious puberty is the development of secondary sexual characteristics before 8 years of age in girls and 9 years of age in boys. Treatment may be initiated following the establishment of a clinical diagnosis of CPP; however, the condition may not be detected or evaluated at onset and treatment can sometimes be started after age 8 or 9. Discontinuation of therapy is a clinical decision and there is insufficient evidence to rely on any one clinical variable to make that decision. In studies examined, wishes of the individual receiving treatment, family and the physician's decision were stated as deciding factors for cessation of treatment. However, discontinuation guidance is provided in the product label. For example, the Supprelin LA product label indicates that discontinuation "should be considered at the discretion of the physician and at the appropriate time point for the onset of puberty (approximately 11 years for females and 12 years for males)."
Guidelines from the Royal College of Obstetricians and Gynaecologists (2005) state women with cyclical pelvic pain should be offered a therapeutic trial, using the combined oral contraceptive pill or a GnRH agonist for a period of 3-6 months before having a diagnostic laparoscopy.
The American College of Obstetrics and Gynecology (ACOG) (2004; reaffirmed 2008) practice bulletin for chronic pelvic pain includes the following Level A recommendation and conclusion which is stated to be based on good and consistent scientific evidence:
Level B recommendations which are based on limited or inconsistent scientific evidence include the following:
The ACOG (2010) practice bulletin for the management of endometriosis includes the following Level A recommendations and conclusions:
Level B recommendations include the following:
FDA approved labels for goserelin acetate, leuprolide acetate, leuprolide acetate for depot suspension and norethindrone (Lupaneta Pack), and nafarelin acetate all specify a time limit for duration of treatment for endometriosis. Leuprolide acetate and leuprolide acetate for depot suspension with norethindrone (Lupaneta Pack) are approved for an initial 6 month course and a 6 month course of retreatment if necessary. Goserelin acetate and nafarelin acetate are limited to a 6 month duration of treatment.
The Ling (1999) study is a small, short-term, randomized controlled trial (RCT) used for support of empiric therapy for management of chronic pelvic pain.
Fertility Preservation during Chemotherapy
The effect of GnRH analogs on fertility preservation during chemotherapy has been investigated in multiple randomized clinical trials with conflicting conclusions. Del Mastro and colleagues (2011) reported that the use of triptorelin to induce temporary ovarian suppression during chemotherapy in premenopausal women with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause. In another study, Gerber and colleagues (2011) concluded that premenopausal women with breast cancer receiving goserelin acetate during chemotherapy did not experience statistically significantly less amenorrhea 6 months after end of chemotherapy compared with those receiving chemotherapy alone. Although the resumption of menses was more favorable in the triptorelin study, the actual number of live births between both groups was not significantly different.
Several recent meta-analyses reported on randomized trials which used GnRH for the prevention of chemotherapy induced ovarian failure. Vitek and colleagues (2014) analyzed the use of GnRH agonists for the preservation of ovarian function in women with breast cancer who did not use tamoxifen after chemotherapy. Four randomized studies were analyzed (Del Mastro, 2011; Elgnidy, 2013; Gerber, 2011; Sverrisdottir, 2009). The authors concluded that concurrent GnRH agonists with chemotherapy may not preserve ovarian function in women with breast cancer.
However, Del Mastro and colleagues (2014) analyzed nine randomized studies, including four from the Vitek meta-analysis and concluded that temporary ovarian suppression induced by GnRH reduced the risk of chemotherapy induced primary ovarian failure in young women with cancer. In addition to the studies previously addressed in the Vitek meta-analysis, Del Mastro included other randomized trials for breast cancer (Badawy, 2009; Munster, 2012), as well as ovarian cancer (article not published in U.S.) and Hodgkin's or non-Hodgkin's lymphoma (Behringer, 2010; Demeestere, 2013).
Gerber and colleagues (2014) reviewed a recently presented and not yet published phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of GnRH analog during chemotherapy to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer. The main strength of the study was reported to be the demonstration of resumption of ovarian function after 2 years and an increased pregnancy rate after using GnRH. Numerous weaknesses of the study were noted, including early trial closure due to lack of recruitment and financial support and a high drop-out rate. Out of 214 subjects, follow-up data from only 135 were available with a drop-out rate as high as 38%. The authors reported "even after after POEMS, there is no additional clarity regarding preservation of ovarian function during chemotherapy by GnRHa."
In an update of a clinical practice guideline on fertility preservation for individuals with cancer, American Society of Clinical Oncology 2013 states:
Currently, there is insufficient evidence regarding the effectiveness of GnRHa and other means of ovarian suppression in fertility preservation. GnRHa should not be relied upon as a fertility preservation method. However, GnRHa may have other medical benefits such as a reduction of vaginal bleeding when patients have low platelet counts as a result of chemotherapy. This benefit must be weighed against other possible risks such as bone loss, hot flashes, and potential interference with response to chemotherapy in estrogen-sensitive cancers. Women interested in this method should participate in clinical trials, because current data do not support it. In a true emergency or rare or extreme circumstances where proven options are not available, providers may consider GnRHa an option, preferably as part of a clinical trial.
Published data regarding the efficacy of GnRH in protecting the ovaries during chemotherapy is conflicting and it is unclear at this time if these agents are able preserve fertility.
The uses of GnRH analogs considered to be medically necessary in this document have sufficient 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 indications, including, but not limited to: premenstrual syndrome, fertility preservation during chemotherapy, menopause or mood related disorders, cancer of the endometrium, cancer of the liver, benign prostatic hypertrophy, and to stop pubertal development in order to maximize growth for children of short stature on growth hormones.
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.
Central precocious puberty: The beginning of secondary sexual characteristics before age 8 in girls and age 9 in boys.
Chronic pelvic pain: Noncyclical pain lasting 6 or more months that localizes to the anatomic pelvis, anterior abdominal wall at or below the umbilicus, the lumbosacral back, or the buttocks, and is of sufficient severity to cause functional disability or lead to medical care (ACOG, 2004).
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.
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 Grading System: A prostate cancer grading system based on a number range from one to five; the lower the number, the lower the grade, and the slower the cancer growth.
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.
Risk of recurrence (prostate cancer):
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
Central Precocious Puberty (CPP)
Chronic Pelvic Pain
Dysfunctional Uterine Bleeding
Gonadotropin Releasing Hormone (GnRH) Analogs
Synarel Nasal Spray
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Revised||11/13/2014||Medical Policy & Technology Assessment Committee (MPTAC) review.|
|Revised||11/12/2014||Hematology/Oncology Subcommittee review. Medically necessary statements for prostate cancer clarified. Discussion and Reference sections updated.|
|Revised||05/14/2014||Hematology/Oncology Subcommittee review. Medically necessary statement for leuprolide acetate for depot suspension and norethindrone acetate tablets (Lupaneta Pack) added. Limits for treatment duration of endometriosis added. Medically necessary statement in breast cancer section of position statement updated to include breast cancer in men. Description, Discussion, Reference and Index sections updated.|
|Reviewed||05/09/2013||Medical Policy & Technology Assessment Committee (MPTAC) review. Discussion and Reference sections updated.|
|Reviewed||05/08/2013||Hematology/Oncology Subcommittee review. Discussion and Reference sections updated.|
|Revised||05/10/2012||MPTAC review. Medically necessary statement for central precocious puberty clarified. Added "or" between medically necessary statements for prostate cancer. Discussion and Reference sections updated.|
|Revised||11/16/2011||Hematology/Oncology Subcommittee review. Added medically necessary statements to the prostate cancer indications for use in combination with antiandrogen (flutamide or bicalutamide) and to shrink an enlarged prostate to an acceptable size prior to brachytherapy, cryosurgery or external beam radiation therapy. Discussion, Definitions and Reference sections updated.|
|Revised||11/17/2010||Hematology/Oncology Subcommittee review. Clarified the not medically necessary statements for ovarian cancer, prostate cancer and gynecological uses by removing the words "any of". "Intermediate risk of recurrence" defined in prostate cancer medically necessary statement. Clarified prostate cancer clinical indication statements by adding the brand name of Vantas. Note added below prostate cancer medically necessary statement referring reader to definition section for description of terms. Clarified the precocious puberty clinical indication statement by adding the brand name Lupron Depot-Ped. Description, Discussion, Definitions, and References updated. Index added.|
|10/01/2010||Updated Coding section with 10/01/2010 ICD-9 changes.|
|Revised||05/12/2010||Hematology/Oncology Subcommittee review. Reformatted the clinical indication section by adding specific GnRH analogs for each indication. Added degarelix to the GnRH analogs considered medically necessary for prostate cancer. Removed infertility treatment indications and added a note in the description section referring to CG-DRUG-11 Oral and Injectable Infertility Drugs. Removed a note in the description section stating this document does not address the combined use of gonadotropin releasing hormone (GnRH) analogs and anti-androgens. Removed Viadur® from description section. Removed the medically necessary indication for GnRH analogs and breast cancer which stated: "Breast cancer patients who are not on concurrent aromatase inhibitor therapy for: Treatment of advanced or metastatic breast cancer in premenopausal and perimenopausal women; or Treatment in premenopausal women with hormone receptor positive disease with or without concurrent tamoxifen for ovarian suppression" and replaced with "Goserelin acetate or leuprolide acetate is considered medically necessary for the treatment of hormone receptor positive breast cancer in pre- or peri-menopausal women." Added medically and not medically necessary statements for the use of leuprolide acetate for ovarian cancer. Removed prostate cancer indications for "palliative treatment of advanced or metastatic prostate cancer and neoadjuvant or adjuvant therapy with radiation therapy in the management of localized prostate cancer in men" and replaced with "when any of the following indications are met: clinically localized disease with intermediate or higher risk of recurrence; or locally advanced disease; or other advanced, recurrent, or metastatic disease." Added a medically necessary statement for goserelin acetate stating it is considered medically necessary for the treatment of prostate cancer in combination with flutamide for locally confined stage T2b-T4 (stage B2-C) disease. Added a medically necessary statement for goserelin acetate and dysfunctional uterine bleeding. Wording of "precocious puberty" in medically necessary statements updated to "central precocious puberty" and removed the precocious puberty requirement stating "tumor has been ruled out by lab tests, CT, MRI, or ultrasound". Updated definition of precocious puberty by changing age limit from before age 10 to before age 9 in boys. Description, Discussion, Coding and References updated. Definition section added.|
|11/11/2009||Removed the table of FDA-approved indications.|
|Reviewed||05/21/2009||MPTAC review. No change to clinical indications. Removed the additional table of FDA approved drugs with dosing and labeling information. Updated Reference section.|
|10/01/2008||Updated Coding section with 10/01/2008 ICD-9 changes.|
|Reviewed||05/15/2008||MPTAC review. Added Supprelin® LA (histrelin acetate) to the GnRH agents considered medically necessary for precocious puberty. References were updated including the change from USP DI reference information to DrugPoints® and the American Hospital Formulary Service (AHFS).|
|01/01/2008||Updated Coding section with 01/01/2008 HCPCS changes.|
|Revised||05/17/2007||MPTAC review. Document was revised to delete delayed puberty as a medically necessary indication for GnRH therapy. References and coding were also updated.|
|03/08/2007||MPTAC review. No change to clinical indications. Removed dosage table. References and coding were updated (updated coding; removed HCPCS S0133 deleted 03/31/2006).|
|New||03/23/2006||MPTAC initial guideline development.|
|Pre-Merger Organizations||Last Review |
|Anthem, Inc.||No document|
|Anthem BCBS||No document|
|WellPoint Health Networks, Inc.||10/03/2005||Pharmacology Toolkit||Goserelin (Zoladex ®)|
|10/03/2005||Pharmacology Toolkit||Leuprolide acetate (Lupron®, Lupron depot®)|