Clinical UM Guideline


Subject:Gonadotropin Releasing Hormone (GnRH) Analogs
Guideline #:  CG-DRUG-15Current Effective Date:  07/09/2013
Status:ReviewedLast Review Date:  05/09/2013

Description

Gonadotropin releasing hormone (GnRH) analogs are synthetic analogs of naturally occurring GnRH with greater potency than the natural hormone.  

The following agents are addressed in this document:

Note:
This document does not address infertility treatment. Please see the following document for additional information: CG-DRUG-11 Injectable Infertility Drugs

Clinical Indications

I. Breast Cancer –Goserelin acetate or leuprolide acetate 

Medically Necessary 

Goserelin acetate or leuprolide acetate is considered medically necessary for the treatment of hormone receptor positive breast cancer in pre- or peri-menopausal women. 

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 

Medically Necessary 

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 

Medically Necessary 

  1. Degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate, or triptorelin pamoate is considered medically necessary for the treatment of prostate cancer when any of the following indications are met:
    • Clinically localized disease* with intermediate (T2b to T2c cancer, Gleason score of 7, or prostate specific antigen (PSA) value of 10-20 ng/mL) or higher risk of recurrence; or
    • Locally advanced disease*; or
    • Other advanced*, recurrent, or metastatic* disease; or
    • In combination with antiandrogen (flutamide or bicalutamide) for locally confined stage T2b-T4 (stage B2-C) disease; or

      *See definition section below for description of term

  2. Degarelix, goserelin acetate, histrelin acetate (Vantas), leuprolide acetate or triptorelin pamoate is considered medically necessary to shrink an enlarged prostate to an acceptable size prior to brachytherapy, cryosurgery or external beam radiation therapy for the treatment of prostate cancer.

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)

Medically Necessary 

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 or nafarelin acetate 

Medically necessary: 

  1. Goserelin acetate, leuprolide acetate or nafarelin acetate is considered medically necessary when any of the following indications are met:
    • 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])-not to continue beyond 3 months if there is no symptomatic relief; or
    • Endometriosis (for goserelin acetate the 3.6 mg implant only should be used); or
    • To induce amenorrhea in women in certain populations, including menstruating women diagnosed with severe thrombocytopenia or aplastic anemia.
  2. Goserelin acetate is considered medically necessary for any of the following additional indications:
    • Dysfunctional uterine bleeding; or
    • Endometrial thinning prior to endometrial ablation for dysfunctional uterine bleeding (3.6 mg implant only).
  3. Leuprolide acetate is considered medically necessary for any of the following additional indications:
    • Preoperative treatment as adjunct to surgical treatment of uterine fibroids (leiomyoma uteri). May be used to reduce size of fibroids to allow for a vaginal procedure; or
    • Prior to surgical treatment (myomectomy or hysterectomy) in individuals with documented anemia.

Not Medically Necessary 

Goserelin acetate, leuprolide acetate or nafarelin acetate is considered not medically necessary for gynecological uses when the criteria above are not met.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference.  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.

HCPCS 
J1675Injection, histrelin acetate, 10 micrograms
J1950Injection, leuprolide acetate (for depot suspension), per 3.75 mg [Lupron Depot, Lupron Depot-Ped]
J3315Injection, triptorelin pamoate, 3.75 mg [Trelstar, Trelstar Depot, Trelstar LA]
J9155Injection, degarelix, 1 mg [Firmagon]
J9202Goserelin acetate implant, per 3.6 mg [Zoladex]
J9217Leuprolide acetate (for depot suspension), 7.5 mg [Eligard, Lupron Depot, Lupron Depot-Ped]
J9218Leuprolide acetate, per 1 mg [Lupron, Eligard]
J9225Histrelin implant (Vantas), 50 mg 
J9226Histrelin implant (Supprelin LA), 50 mg 
S9560Home 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]
  
ICD-9 Diagnosis 
 All diagnoses
  
ICD-10 DiagnosisICD-10-CM draft codes; effective 10/001/2014:
 All diagnoses
  
Discussion/General Information

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 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 (The 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

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 (Jonat, 2002; Jakesz, 2002) compared ovarian suppression hormones, such as GnRH analogs to conventional chemotherapeutic agents, such as a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Five years after the completion of one study, no difference between goserelin acetate (Zoladex) and CMF was established in the final outcome review. Converting subjects from an estrogen receptor positive to negative state, CMF induces significantly better disease free survival and overall survival. 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 (NCCN, 2013).

Ovarian Cancer 

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 six women with recurrent or persistent ovarian granulosa cell tumor who were treated with monthly leuprolide acetate injections. Cessation of disease progression was noted in five subjects. The sixth 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 six 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 

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 2013 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.

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 (which includes GnRH analogs) may be used to shrink the prostate to an acceptable size prior to brachytherapy (NCCN Clinical Practice Guideline for Prostate Cancer, 2013). 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 androgen deprivation therapy may be used before radiation to shrink the prostate cancer to make other treatments more effective. In addition, several early studies demonstrated reduction of the size of the prostate with GnRH prior to cryosurgery or external beam radiation therapy for treatment of prostate cancer. Shearer and colleagues (1992) reported a significant reduction in prostate volume achieved with GNRH (goserelin) in 20 of 22 individuals prior to external beam radiotherapy. These authors also noted that hormonal therapy allows for reduction of tumor volume and hence the size of the radiotherapy field. Wong and colleagues (1997) treated 47 cases of prostate cancer with androgen ablation (leuprolide acetate) prior to cryosurgery to shrink the gland. Wilson and colleagues (2004) report that GnRH antagonists clearly provide efficacy in downsizing the prostate and urologists are utilizing androgen deprivation therapy before surgical and radiation procedures for prostate cancer. Specialty consensus review also recommends short-term use of androgen deprivation therapy prior to brachytherapy, cryosurgery or external beam radiation therapy in men with large prostates (50 grams or more) for a period of 3-9 months prior to therapy to shrink the gland in order to make radiation or cryotherapy feasible. If the gland is too large, therapy may be inadequate.

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 eight years of age in girls and nine 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 eight or nine. 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)."

Gynecology Uses 

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:

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

The effect of GnRH analogs on fertility preservation during chemotherapy has also been investigated. Del Mastro and colleagues (2011) indicated 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 six 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. Published data regarding the efficacy of GnRH in protecting the ovaries during chemotherapy is conflicting and it unclear at this time if these agents are able preserve fertility.

Conclusion

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; male castration, and to stop pubertal development in order to maximize growth for children of short stature on growth hormones.

Definitions

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 a 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):

Low risk of recurrence: Men with tumors stage T1-T2a, low Gleason score (less than or equal to 6), and serum PSA level below 10.

Intermediate risk of recurrence: Men with any T2b to T2c cancer or Gleason score of 7 or PSA value of 10-20 ng/mL.

High risk of recurrence: Men with prostate cancer that is clinically localized stage T3a or Gleason score 8-10, or PSA level greater than 20 ng/mL after definitive therapy.

Very high risk of recurrence: Men with Stage T3b to T4 (locally advanced) disease.

References

Peer Reviewed Publications:

  1. Balbi G, Piano LD, Cardone A, Cirelli G. Second-line therapy of advanced ovarian cancer with GnRH analogs. Int J Gynecol Cancer. 2004; 14(5):799-803.
  2. Carel JC. Can we increase adolescent growth? Eur J Endocrin. 2004; 151:U101-U108.
  3. Carel JC. Management of short stature with GnRH agonist and co-treatment with growth hormone: a controversial issue. Mol Cell Endocrinol. 2006; 254-255:226-233.
  4. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009; 123(4):e752-762.
  5. Chudecka-Głaz A, Rzepka-Górska I. Favorable effects of long-term therapy with gonadoliberin analogues in three patients with advanced and recurrent ovarian cancer. Eur J Gynaecol Oncol. 2009; 30(5):589-591.
  6. Del Mastro L, Boni L, Michelotti A, et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA. 2011; 306(3):269-276.
  7. Donnez J, Vilos G, Gannon MJ, et al. Goserelin acetate (Zoladex) plus endometrial ablation for dysfunctional uterine bleeding: a large, randomized double-blind study. Fertil Steril. 1997; 68(1):29-36.
  8. Eugster EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J Clin Endocrinol Metab. 2007; 92(5):1697-1704.  
  9. Fishman A, Kudelka AP, Tresukosol D, et al. Leuprolide acetate for treating refractory or persistent ovarian granulosa cell tumor. J Reprod Med. 1996; 41(6):393-396.
  10. Franke HR, van de Weijer PH, Pennings TM, van der Mooren MJ. Gonadotropin-releasing hormone agonist plus "add-back" hormone replacement therapy for treatment of endometriosis: a prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000; 74(3):534-539.
  11. Gerber B, von Minckwitz G, Stehle H, et al; German Breast Group Investigators. Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol. 2011; 29(17):2334-2341.
  12. Jakesz R, Hausmaninger H, Kubista E, et al. Austrian Breast and Colorectal Cancer Study Group Trial 5. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol. 2002; 20(24):4621-4627.
  13. Jonat W, Kaufmann M, Sauerbrei W, et al. Zoladex Early Breast Cancer Research Association Study. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol. 2002; 20(24):4628-4635.
  14. Ling, FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol. 1999; 93(1):51-58.
  15. Meirow D, Rabinovici J, et al. Prevention of severe menorrhagia in oncology patients with treatment-induced thrombocytopenia by luteinizing hormone-releasing hormone agonist and depo-medroxyprogesterone acetate. Cancer. 2006; 107(7):1634-1641.
  16. Messing E, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer: results at 10 years of EST 3886. J Urol. 2003; 169: 396, A1480.
  17. Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer. N Engl J Med. 1999; 341(24):1781-1788.
  18. Phillip M, Lazar L. Precocious puberty: growth and genetics. Horm Res. 2005; 64 Suppl 2:56-61.
  19. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma- long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys. 2005; 61(5):1285-1290.
  20. Quaas AM, Ginsburg ES. Prevention and treatment of uterine bleeding in hematologic malignancy. Eur J Obstet Gynecol Reprod Biol. 2007; 134(1):3-8.
  21. Roach M III, deSilvio M, Lawton C, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol. 2003; 21(10):1904-1911.
  22. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer. a systematic review and meta-analysis. Ann Internal Med. 2000; 132(7):566-577.
  23. Shearer RJ, Davies JH, Gelister JS, Dearnaley DP. Hormonal cytoreduction and radiotherapy for carcinoma of the prostate. Br J Urol. 1992; 69(5):521-524.
  24. Thompson I, Thrasher JB, Aus G, et al; AUA Prostate Cancer Clinical Guideline Update Panel. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007; 177(6):2106-2131.
  25. van Gool SA, Kamp GA, Visser-van Balen H, et al. Final height outcome after three years of growth hormone and gonadotropic-releasing hormone agonist treatment in short adolescents with relatively early puberty.  J Clin Endocrinol Metab. 2007; 92(4):1402-1408.
  26. Wheeler JM, Knittle JD, Miller JD. The Lupron Endometriosis Study Group. Depot leuprolide acetate versus danazol in treatment of women with symptomatic endometriosis: a multicenter, double-blind, randomized clinical trial II. Assessment of safety. Am J Gynecol Obstet. 1993; 169(1):26-33.
  27. Wilson S. Downsizing and prostate cancer. Rev Urol. 2004; 6 Suppl 7:S19-24.
  28. Wilt TJ, MacDonald R, Rutks I, et al. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med. 2008; 148(6):435-448.
  29. Wit JM, Visser-van Balen H, Kamp GA, Oostdijk W. Benefit of postponing normal puberty for improving final height. Eur J Endocrin. 2004; 151:S41-S45.
  30. Wong WS, Chinn DO, Chinn M, et al. Cryosurgery as a treatment for prostate carcinoma: results and complications. Cancer. 1997; 79(5):963-974.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Albuquerque LE, Saconato H, Maciel MCR. Depot versus daily administration of gonadotropin releasing hormone agonist protocols for pituitary desensitization in assisted reproduction cycles. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD002808.
  2. American College of Obstetrics and Gynecology Committee on Practice Bulletins -- Gynecology. ACOG Practice Bulletin No. 51. Chronic pelvic pain. Obstet Gynecol. 2004 (reaffirmed 2008); 103(3):589-605.
  3. American College of Obstetrics and Gynecology Committee on Practice Bulletins -- Gynecology. ACOG Practice bulletin no. 114: management of endometriosis. Obstet Gynecol. 2010; 116(1):223-236.
  4. Babaian RJ, Donnelly B, Bahn D, et al. Best practice statement on cryosurgery for the treatment of localized prostate cancer. J Urol. 2008; 180(5):1993-2004.
  5. Bayram N, van Wely M, Van der Veen F. Pulsatile gonadotropin releasing hormone for ovulation induction in subfertility associated with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD000412.
  6. Degarelix Acetate. In: DrugPoints® System [Internet database]. Truven Health Analytics, Greenwood Village, CO. Last Modified: March 25, 2013. Available at: http://www.micromedexsolutions.com. Accessed on April 14, 2013.
  7. Eligard [Product Information], Bridgewater, NJ. Sanofi-aventis US, LLC; February 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021343s027,021379s025,021488s025,021731s023lbl.pdf. Accessed on April 14, 2013.
  8. Firmagon [Product Information], Parsippany, NJ. Ferring Pharmaceuticals Inc.: March 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022201s002lbl.pdf. Accessed on April 14, 2013.
  9. Goserelin acetate Monograph. February 2012. American Hospital Formulary Service®. Available at: http://www.ashp.org/ahfs/. Accessed on April 14, 2013.
  10. Goserelin acetate (Zoladex®). In: DrugPoints® System [Internet database]. Truven Health Analytics, Greenwood Village, CO. Last modified March 18, 2013. Available at: http://www.micromedexsolutions.com. Accessed on April 14, 2013.
  11. Histrelin acetate (Vantas®, Supprelin®, Supprelin® LA). In: DrugPoints® System [Internet database]. Truven Health Analytics, Greenwood Village, CO. Last modified April 12, 2013. Available at: http://www.micromedexsolutions.com Accessed on April 14, 2013.
  12. Lee SJ, Schover LR, Partridge A, et al. American Society of Clinical Oncology Recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006; 24(18):2917-2931.
  13. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001; (2):CD000547.
  14. Leuprolide acetate Monograph. February 2012. American Hospital Formulary Service®. Available at: http://www.ashp.org/ahfs/. Accessed on April 14, 2013.
  15. Leuprolide acetate (Lupron®, Lupron Depot®, Lupron Depot-Ped®, Eligard®). In: DrugPoints® System [Internet database]. Truven Health Analytics, Greenwood Village, CO. Last modified March 13, 2013. Available at: http://www.micromedexsolutions.com. Accessed on April 14, 2013.
  16. Loblaw DA, Virgo KS, Nam R, et al. American Society of Clinical Oncology. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007; 25(12):1596-1605.
  17. Lupron Depot [Product Information], North Chicago, IL. Abbott Laboratories; January 2013. Available at: http://www.rxabbvie.com/pdf/lupron3_4_6month.pdf. Accessed on April 14, 2013.
  18. Lupron Depot-Ped [Product Information], North Chicago, IL. Abbott Laboratories; August 2011. Available at: http://www.rxabbott.com/pdf/lupronpediatric.pdf. Accessed on April 14, 2013.
  19. Nafarelin acetate Monograph. February 2012. American Hospital Formulary Service®. Available at: http://www.ashp.org/ahfs/. Accessed on April 14, 2013.
  20. Nafarelin acetate (Synarel Nasal Spray®). In: DrugPoints® System [Internet database]. Truven Health Analytics, Greenwood Village, CO. Last modified February 19, 2013. Available at: http://www.micromedexsolutions.com. Accessed on April 14, 2013.
  21. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium (electronic version). 2013. For additional information visit the NCCN website: http://www.nccn.org. Accessed on April 14, 2013.
    • Degarelix
    • Goserelin acetate
    • Histrelin acetate
    • Leuprolide acetate
    • Triptorelin pamoate
  22. National Comprehensive Cancer Network® (NCCN). Clinical Practice Guidelines in Oncology. 2013. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 14, 2013.
    • Breast Cancer (V.2.2013). Revised March 11, 2013.
    • Ovarian Cancer (V.1.2013). Revised October 12, 2012.
    • Prostate Cancer (V.2.2013). Revised March 11, 2013.
  23. Royal College of Obstetricians and Gynaecologists (RCOG). The initial management of chronic pelvic pain. RCOG Guideline No. 41. London, UK: RCOG; April 2005.
  24. Sagsveen M, Farmer JE, Prentice A, Breeze A. Gonadotropin-releasing hormone analogues for endometriosis: bone mineral density. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD001297.
  25. Sowter MC, Lethaby A, Singla AA. Pre-operative endometrial thinning agents before endometrial destruction for heavy menstrual bleeding. Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD001124.
  26. Supprelin LA [Product Information], Chadds Ford, PA. Endo Pharmaceuticals, Inc.; April 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022058s011lbl.pdf. Accessed on April 14, 2013.
  27. Synarel [Product Information], New York, NY. GD Searle LLC.; January 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019886s030lbl.pdf. Accessed on April 14, 2013.
  28. Trelstar [Product Information], Parsippany, NJ. Watson Pharma, Inc.; February 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020715s030,021288s027,022437s007lbl.pdf. Accessed on April 14, 2013.
  29. Triptorelin pamoate Monograph. February 2012. American Hospital Formulary Service®. Available at: http://www.ashp.org/ahfs/. Accessed on April 14, 2013.
  30. Triptorelin pamoate (Trelstar®, Trelstar LA®, Trelstar Depot®). In: DrugPoints® System [Internet database]. Truven Health Analytics, Greenwood Village, CO. Last modified March 27, 2013. Available at: http://www.thomsonhc.com. Accessed on April 14, 2013.
  31. Vantas (histrelin) Implant [Product Information], Chadds Ford, PA. Endo Pharmaceuticals, Inc.; April 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021732s018lbl.pdf. Accessed on April 14, 2013.
  32. Zoladex (goserelin acetate) Implant 3.6 mg. [Product Information], Wilmington, DE. AstraZeneca; November 2012. Available at: http://www1.astrazeneca-us.com/pi/zoladex3_6.pdf. Accessed on April 14, 2013.
  33. Zoladex (gosarelin acetate) Implant 10.8 mg. [Product Information], Wilmington, DE. AstraZeneca; November 2012. Available at: http://www1.astrazeneca-us.com/pi/zoladex10_8.pdf. Accessed on April 14, 2013.
Web Sites for Additional Information
  1. American Cancer Society. Prostate Cancer. Hormone (androgen deprivation) therapy. Last Revised: 01/17/2013. Available at: http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-treating-hormone-therapy. Accessed on April 14, 2013.
Index

Breast Cancer
Central Precocious Puberty (CPP)
Chronic Pelvic Pain
Degarelix
Dysfunctional Uterine Bleeding
Endometrial Thinning
Eligard
Endometriosis
Firmagon
Gonadotropin Releasing Hormone (GnRH) Analogs
Goserelin Acetate
Histrelin Acetate
Depot
Lupron Depot-Ped
Nafarelin Acetate
Ovarian Cancer
Prostate Cancer
Supprelin LA
Synarel Nasal Spray
Trelstar
Trelstar Depot
Trelstar LA
Triptorelin Pamoate
Uterine Fibroids
Vantas
Zoladex

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.

Document History
StatusDateAction
Reviewed05/09/2013Medical Policy & Technology Assessment Committee (MPTAC) review. Discussion and Reference sections updated
Reviewed05/08/2013Hematology/Oncology Subcommittee review. Discussion and Reference sections updated.
Revised05/10/2012MPTAC review. Medically necessary statement for central precocious puberty clarified. Added "or" between medically necessary statements for prostate cancer. Discussion and Reference sections updated.
Revised11/17/2011MPTAC review.
Revised11/16/2011Hematology/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.
Revised11/18/2010MPTAC review.
Revised11/17/2010Hematology/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.
 10/01/2010Updated Coding section with 10/01/2010 ICD-9 changes.
Revised05/13/2010MPTAC review.
Revised05/12/2010Hematology/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.
 11/11/2009Removed the table of FDA-approved indications.
Reviewed05/21/2009MPTAC review. No change to clinical indications. Removed the additional table of FDA approved drugs with dosing and labeling information. Updated Reference section.
 10/01/2008Updated Coding section with 10/01/2008 ICD-9 changes.
Reviewed05/15/2008MPTAC 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).
 01/01/2008Updated Coding section with 01/01/2008 HCPCS changes.
Revised05/17/2007MPTAC review. Document was revised to delete delayed puberty as a medically necessary indication for GnRH therapy. References and coding were also updated. 

Reviewed

 

03/08/2007MPTAC review. No change to clinical indications. Removed dosage table. References and coding were updated (updated coding; removed HCPCS S0133 deleted 03/31/2006).
New03/23/2006MPTAC initial guideline development. 
Pre-Merger OrganizationsLast Review DateDocument NumberTitle
Anthem, Inc.  No document
Anthem BCBS  No document
WellPoint Health Networks, Inc.10/03/2005Pharmacology ToolkitGoserelin (Zoladex ®)
 10/03/2005Pharmacology ToolkitLeuprolide acetate (Lupron®, Lupron depot®)