Lupron

1. Aetna considers Lupron (leuprolide) medically necessary for the following indications subject to the specified limitations:

   1. Endometriosis (see appendix)
   2. To decrease fibroid size prior to surgery (see appendix).
   3. To decrease endometrial thickness prior to endometrial ablation (see appendix).
   4. For palliative treatment of members with advanced (Stage III or Stage IV) prostate cancer that has metastasized or has recurred after treatment, or member refuses orchiectomy (see appendix).
   5. For true (central) precocious puberty, defined as sexual maturation before age 8 in girls and age 10 in boys, and tumor has been ruled out by lab tests, CT, MRI, or ultrasound (see appendix).
   6. Infertility (used in conjunction with urofollitropin or menotropins) to suppress luteinizing hormone (LH) production in members with documented premature LH surge, or used in “super-ovulation” regimens associated with in vitro fertilization (see appendix).
   7. For treatment of metastatic breast cancer, when the member is pre-menopausal and the disease has progressed or recurred after a trial of at least 3 months of tamoxifen (see appendix).
   8. To suppress onset of puberty in cases where the adolescent meets medical necessity criteria for growth hormone supplementation and has early onset of puberty and is not within target growth range (within 1 standard deviation of mean height for age and sex) (see appendix).
   9. For the treatment of women with chronic refractory pelvic pain (see appendix).
   10. For treatment of relapsed granulosa cell tumors of the ovary (see appendix).
   11. For treatment-resistant paraphilias (see appendix).

   12. For use in leuprolide stimulation test for diagnosing hypogonadism and central precocious puberty (see appendix).

2. Aetna considers leuprolide experimental and investigational for all other indications, including any of the following conditions, since limited information has been published and further research including randomized, controlled trials is required to determine its efficacy:

   1. Precocious pubarche alone, or pseudoprecocious puberty (gonadotropin independent precocious puberty); or
   2. Polycystic ovarian disease; or
   3. Pre-menstrual syndrome; or
   4. Endometrial cancer (including endometrial stromal sarcoma); or 
   5. Preservation (suppression) of ovarian function during chemotherapy; or
   6. Preservation (suppression) of testicular function during chemotherapy; or
   7. Epilepsy; or
   8. Alzheimer's disease; or
   9. Hypermenorrhea; or
   10. Sickle cell anemia-associated priapism; or
   11. Autoimmune progesterone dermatitis of pregnancy; or
   12. Osteosarcoma.

Zoladex

1. Aetna considers Zoladex (goserelin) medically necessary for any of the following indications:

   1. Advanced (metastatic) prostatic carcinoma; or
   2. Advanced (metastatic) breast cancer in pre-menopausal members; or
   3. Endometriosis, Stage III or IV; or
   4. Uterine fibroids (leiomyoma uteri) (preoperative adjunct to surgical treatment) (short-term (less than 6 months) use); or

   5. Endometrial ablation or hysterectomy (preoperative adjunct) (short-term (less than 6 months) use). (See also CPB 091 - Endometrial Ablation).

2. Aetna considers goserelin experimental and investigational for preservation of ovarian or testicular function during chemotherapy and for all other indications because its effectiveness for these indications has not been established.

Histrelin

1. Aetna considers histrelin implant medically necessary for the following indications:

   1. For true (central) precocious puberty, defined as sexual maturation before age 8 in girls and age 10 in boys, and tumor has been ruled out by lab tests, CT, MRI, or ultrasound (see appendix).

   2. For palliative treatment of members with advanced (Stage III or Stage IV) prostate cancer that has metastasized or has recurred after treatment, or member refuses orchiectomy (see appendix).

2. Aetna considers histrelin acetate implant experimental and investigational for all other indications.

Plenaxis

1. Aetna considers Plenaxis (abarelix) medically necessary for the treatment of men with advanced prostate cancer who cannot take other hormone therapies and who have refused surgical castration.

2. Aetna considers abarelix experimental and investigational for all other indications.

This policy is based on the FDA-approved indications for Plenaxis.

Degarelix

1. Aetna considers degarelix medically necessary for the treatment of men with advanced prostate cancer who cannot take other hormone therapies and who have refused surgical castration.

2. Aetna considers degarelix experimental and investigational for all other indications.

For gonadotropin-releasing hormone antagonists for infertility, see CPB 327 - Infertility.

Lupron:

Leuprolide (Lupron) is a gonadotropin-releasing hormone analog, which may be indicated for treatment of certain conditions, which are hormonally regulated.

Leuprolide may be indicated in advanced cancer (palliative treatment) in patients who have inoperable prostate tumor, or refuse orchiectomy. The available literature suggests combined therapy with leuprolide and an anti-androgen (e.g., megestrol, flutamide) appears to produce additive effects and to be more effective than leuprolide therapy alone in the treatment of advanced prostate cancer. According to established guidelines, recommended dosing of leuprolide for palliative treatment of advanced prostate cancer is 1 mg given subcutaneously daily. According to established guidelines, if patient is receiving leuprolide acetate suspension (Lupron depot) dosing is 7.5 mg IM once monthly.

Leuprolide has been used in the treatment of true (central) precocious puberty, defined as sexual maturation less than age 8 in girls, and sexual maturation less than age 10 in boys. The available literature suggests tumors should be ruled out by lab tests, CT, MRI, or ultrasound. Leuprolide is not indicated for precocious pubarche alone or pseudoprecocious puberty (gonadotropin-independent precocious puberty). According to established guidelines, recommended starting doses are: Lupron Depot Ped: 0.3 mg/kg every four weeks (minimum 7.5 mg), or Lupron injection: 50 mcg/kg daily. Doses may be titrated upwards in order to achieve hormonal down-regulation.

Studies of leuprolide for endometriosis indicate that six months is an appropriate length for therapy. Because of lack of safety data with long-term use, and because of concerns expressed in the available literature regarding effects on bone density, treatment after six months is typically not recommended. According to established guidelines, recommended dosing of leuprolide for endometriosis is 3.75 mg as a single monthly IM injection.

Leuprolide has been studied for the treatment of uterine fibroids (leiomyoma uteri), as a preoperative adjunct to surgical treatment. Clinical studies have demonstrated the benefit of leuprolide in reducing vascular and surgical complications secondary to obstructive fibroid size. In tests, GnRH agonists have effectively reduced the fibroid size, but their use was accompanied by a rapid regrowth following discontinuation. The available literature states Leuprolide therapy does not prevent or replace the eventual need for surgery. If used as a pre-operative adjunct, the available literature states short-term treatment only is recommended (i.e., 1-3 months).

Leuprolide also has been shown to be an effective preoperative adjunct to decrease endometrial thickness prior to endometrial ablation. If used as a pre-operative adjunct, short-term treatment only (i.e., 1-2 months) is indicated.

Leuprolide is used in conjunction with urofollitropin or menotropins in patients with infertility. It has been used to suppress LH production in patients with documented premature LH surge. In addition, it has been used in “super-ovulation” regimens associated with in vitro fertilization. Treatment of infertility may be subject to limitations under some benefit plans. Some HMO contracts, with or without a separate infertility benefit such as the Advanced Reproductive Technology (ART) Rider, specifically exclude injectable infertility drugs.

Leuprolide has been shown to be useful in the treatment of metastatic breast cancer in pre-menopausal patients whose disease has progressed or recurred despite a 3 or more month trial of tamoxifen.

Consensus guidelines from the National Comprehensive Cancer state that leuprolide may be an appropriate option for persons with stage II-IV granulosa cell tumors of the ovary that have relapsed after platinum-based chemotherapy (NCCN, 2007). Granulosa cell tumors are frequently hormonally active and often demonstrate estrogen receptor positivity. Thus, leuprolide been used as a method of reducing estrogen production in salvage therapy for recurrent, advanced stage granulosa cell tumors.

Leuprolide has been used as treatment for various other conditions (e.g., polycystic ovarian disease, hypermenorrhea, premenstrual syndrome, paraphilias, and endometrial cancer). At this time limited information has been published to show efficacy for conditions other than those mentioned in the clinical criteria above. Further research with randomized, controlled trials is required to determine efficacy in these other conditions.

The American Society of Clinical Oncology's recommendations on fertility preservation in cancer patients (Lee, et al., 2006) stated that sperm and embryo cryopreservation are considered standard practice. On the other hand, the use of GNRH analogs or antagonists for testicular or ovarian suppression is considered investigational. ASCO guidelines state: “At this time, since there is insufficient evidence regarding the safety and effectiveness of GnRH analogs and other means of ovarian suppression on female fertility preservation, women interested in ovarian suppression for this purpose are encouraged to participate in clinical trials.” The guidelines also noted that there is insufficient evidence of the effectiveness of GnRH analogues in preventing chemotherapy-induced gonadal damage in men: “The efficacy of gonadoprotection through hormonal manipulations has only been evaluated in very small studies in cancer patients.”

In a review of the literature, Sonmezer and Oktay (2006) explained that there are a limited number of prospective studies of GNRH analogues in preventing chemotherapy-induced gonadal damage, “which are flawed because of short-term follow-up and/or because of lack of control subjects.” The review notes that “[i]n addition to the lack of consistent support from clinical studies, there is currently no biological explanation for who GNRHa [GNRH analogues] can affect ovarian reserve.” The authors concluded that “[i]n the absence of a prospective randomized study with sufficient power, we do not rely on ovarian suppression as an effective means of fertility preservation.”

Leuprolide has been employed as a therapeutic option for individuals with paraphilia who have failed pharamcotherapies such as cyproterone acetate (CPA), medroxyprogesterone acetate (MPA), and selective serotonin reuptake inhibitors (SSRIs). Leuprolide is thought to decrease sexual drive in men afflicted with paraphilas by decreasing testosterone production. Briken et al (2003) stated that in addition to psychotherapy, pharmacotherapy is an important treatment option for paraphilias, especially in sexual offenders. They noted that research has showed that luteinizing hormone-releasing hormone (LHRH) agonists may offer a new treatment option for treatment of paraphilic patients. These investigators performed a literature review on the use of LHRH agonist a new treatment option for treatment of paraphilic patients. They found 4 case reports, 1 case- control study, 7 open uncontrolled studies, and 1 study comparing patients receiving CPA with those receiving LHRH agonist treatment in forensic hospitals. In total, the studies reported on a sample of 118 treated patients with different forms of paraphilias  -- sadism, pedophilia, exhibitionism, voyeurism. Nearly all of the studies used self-reports to measure the effects of medication. Duration of follow-up was between 6 months and 7 years and revealed that there were no relapses if patients remained under treatment. Patients previously treated with other agents like CPA, MPA, or SSRIs reported better effects when taking LHRH agonists. The authors concluded that although there is a need for further research, LHRH agonists offer a treatment option for patients with severe paraphilia. Furthermore, in a review on medications that may alter behaviors of sex-offenders, Scober and colleagues (2006) stated that therapeutic drugs include LHRH inhibitors (e.g., leuprolide acetate, CPA, and triptorelin), synthetic estrogens (e.g., diethylstilbestrol), and progesterones (e.g., MPA).

Leuprolide has also been tried for the treatment of seizures (Akaboshi and Takeshita, 2000) as well as Alzheimer's disease (Casadesus et al, 2006). However, there is currently insufficient evidence to support its use for thes indications.

Available evidence on the effectiveness of leuprolide for the treatment of endometrial stromal sarcoma is limited to case reports. Guidelines on systemic therapy for uterine sarcoma from Cancer Care Ontario included no recommendation for the use of leuprolide in uterine stromal sarcomas (Kanjeekal et al, 2004). Furthermore, the National Cancer Institute's PDQ on uterine sarcoma (2008) did not include leuprolide or gonadotropin-releasing hormone analogs as treatment options for uterine sarcoma.

Zoladex:

Goserelin (Zoladex) is a gonadotropin releasing hormone (GnRH) (also known as gonadorelin and luteinizing hormone releasing hormone or LHRH) analog, which is indicated in certain conditions requiring suppression of estrogen or testosterone secretion. At this time it is available only in a continuous-release subcutaneous implant which releases drug over a period of about 28 days.

Goserelin is approved by the FDA for treatment of advanced metastatic prostate cancer and advanced endometriosis. Goserelin has also been shown to be effective for treatment or palliation of breast cancer in pre-menopausal patients.

Goserelin has been studied for the treatment of uterine fibroids. Clinical studies have demonstrated the benefit of leuprolide in reducing vascular and surgical complications secondary to obstructive fibroid size. In tests, GnRH agonists have effectively reduced the fibroid size, but their use was accompanied by a rapid regrowth following discontinuation. Therefore, the literature states that goserelin therapy does not prevent or replace the eventual need for surgery. If used as a pre-operative adjunct, the literature recommends short-term treatment (six months or less).

Goserelin has been shown to be effective for the short-term (less than 6 months) preoperative adjunct to endometrial ablation or surgery for leiomyomata uteri (uterine fibroids).

Goserelin is under investigation as a method of prevention of chemotherapy-induced gonadal damage. In a prospective pilot study (n = 5), Franke, et al. (2005) explore the effects of goserelin acetate in women with Hodgkin's disease (HD) receiving chemotherapy while taking a continuous combined estrogen-progestin preparation as add-back on the prevention of premature ovarian failure (POF). Pre-menopausal women with HD received goserelin and add-back until polychemotherapy was completed. Every 4 weeks during treatment and thereafter, a hormonal profile (follicle-stimulating hormone (FSH), LH, 17beta-estradiol, progesterone and inhibin B) was measured until resumption of menstruation or the development of a hyper-gonadotropic state (2 x FSH greater than 30 U/l). All patients reached pre-pubertal status during treatment. Following cessation of goserelin therapy, 1 patient developed a hyper-gonadotropic state and 4 patients resumed menstruation. One of those patients became pregnant and delivered a healthy son. These investigators concluded that the effectiveness of GnRH agonist plus add-back on the prevention of POF during polychemotherapy in women with HD needs further elucidation in randomized controlled trials.

Del Mastro, et al. (2006) noted that standard methods to prevent chemotherapy-induced early menopause in young, breast cancer patients are unavailable to date. Pre-clinical data has suggested that LHRH analogs given during treatment can decrease the gonado-toxicity induced by chemotherapy. In a phase II clinical trial, these investigators evaluated the activity of such a method in young, breast cancer patients undergoing adjuvant chemotherapy. Pre-menopausal patients received goserelin 3.6 mg every 4 weeks before and during chemotherapy. According to 2-stage optimal phase II Simon design, treatment was considered clinically interesting if it was able to prevent menopause in 19 out of 29 patients of the study population. The resumption of ovarian function was defined by a resumption of menstrual activity or by a FSH value less than or equal to 40 IU/l within 12 months after the last cycle of chemotherapy. A total of 30 patients were enrolled and 29 were evaluable. Median age was 38 years (range 29 to 47 years). All but one patient received CEF regimen (cyclophosphamide, epirubicin, 5-fluorouracil). Resumption of menstrual activity was observed in 21 patients (72%; 95% CI 52 to 87%) and a FSH value less than or equal to 40 IU/l in 24 patients (83%; 95% CI 63 to 93%). Menses resumption was observed in 16 out of 17 patients (94%) with age less than 40 years and in 5 out of 12 patients (42 %) with age 40 years or over. These researchers concluded that goserelin given before and during chemotherapy may prevent premature menopause in the majority of patients. However, the different success rate by age indicates the need of a prospective evidence of the effectiveness of such a strategy.

Histrelin Acetate (Supprelin LA, Vantas):

Histrelin, an LH-releasing hormone (LH-RH) agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses. Continuous administration of histrelin causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. These inhibitory effects result in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. These decreases occur within 2 to 4 weeks after initiation of treatment.

The histrelin implant is designed to provide continuous subcutaneous release of histrelin at a rate of 50 to 60 mcg/day (Vantas) or approximately histrelin 65 mcg per day (Supprelin LA) over 12 months.

Children with central precocious puberty (neurogenic or idiopathic) have an early onset of secondary sexual characteristics (earlier than 8 years of age in females and 9 years of age in males). They also show a significantly advanced bone age, which can result in diminished adult height attainment.Supprelin LA was approved by the FDA for the treatment of children with central precocious puberty based on the results of a single-arm, open-label study involving 36 patients ranging in age from four to eleven years. The primary endpoint of the study was hormonal suppression below pubertal levels by month three with continued suppression upon GnRH challenge. All patients in the study were suppressed within the first month of treatment.

Prior to initiation of treatment, a clinical diagnosis of central precocious puberty should be confirmed by measurement of blood concentrations of total sex steroids, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) following stimulation with a gonadotropin-releasing hormone (GnRH) analog, and assessment of bone age versus chronological age. Baseline evaluations should include height and weight measurements, diagnostic imaging of the brain(to rule out intracranial tumor), pelvic/testicular/adrenal ultrasound (to rule out steroid secreting tumors), human chorionic gonadotropin levels (to rule out chorionic gonadotropin secreting tumor), and adrenal steroids to exclude congenital adrenal hyperplasia.

Vantas has been approved by the FDA for the palliative treatment of advanced prostate cancer. The FDA approval was based upon an open-label, multicenter study evaluating 138 patients with advanced prostate cancer and mean baseline serum levels of 388.3 ng/dL for testosterone and 83.6 ng/mL for PSA. Patients were treated with a single histrelin acetate implant and were evaluated for at least 60 weeks. Of the 138 patients, 37 had Jewett stage C disease, 29 had stage D disease, and 72 had an elevated or rising serum PSA after definitive therapy for localized disease. Ninety percent of patients were 65 years of age or older. Efficacy was determined by the number of patients who attained the criterion level of chemical castration (defined as serum testosterone 50 ng/dL or less) at week 4 and maintained this level through week 52. The study found that all evaluable patients (n=134) attained chemical castration after four weeks of treatment. A statistically significant low mean testosterone level of less than 16 ng/dL (p < 0.0001) was achieved by week 4, and testosterone levels maintained below 20 ng/dL through week 52 of the study. The investigators reported that all patients experienced a decrease in PSA levels after they began treatment with histrelin implant. By week 24, 93% of patients (n= 103) experienced a decrease in serum PSA to within normal limits.

The FDA labeling recommends that response to Vantas should be monitored by measuring serum concentrations of testosterone and PSA periodically, especially if the anticipated clinical or biochemical response to treatment has not been achieved.

Plenaxis:

Plenaxis (abarelix) is a gonadotropin-releasing hormone antagonist approved by the FDA in November 2003. It is indicated for the treatment of the symptoms of men with advanced prostate cancer who cannot take other hormone therapies and who have refused surgical castration. Plenaxis is marketed under a voluntary risk management program agreed to and administered by the sponsor that will restrict the use of Plenaxis to patients with advanced prostate cancer, who have no alternative therapy, because of an increased risk of serious, and potentially life-threatening, allergic reactions associated with its use.

In a phase III clinical study (n = 269), McLeod et al (2001) evaluated the levels of testosterone and other hormones in men with prostate cancer treated with abarelix versus leuprolide acetate. The authors concluded that treatment with abarelix produced a higher percentage of patients who avoided a testosterone surge and had a more rapid time to testosterone suppression with a higher rate of medical castration 1 day after treatment and greater reductions in testosterone, LH, follicle-stimulating hormone, and dihydrotestosterone during the first 2 weeks of treatment compared with leuprolide acetate. The achievement and maintenance of castration was comparable between the two groups.

In another phase III clinical trial (n = 255), Trachtenberg et al (2002) reported that abarelix as monotherapy achieved medical castration significantly more rapidly than combination therapy (LHRH agonist and a non-steroidal anti-androgen) and avoided the testosterone surge characteristic of agonist therapy. Both treatments were equally effective in reducing serum prostate specific antigen, and achieving and maintaining castrate levels of testosterone.

Koch, et al. (2003) stated that abarelix provided a safe and effective medical alternative to surgical castration in symptomatic patients (n = 81) with advanced prostate cancer without the risk of the clinical flare associated with LHRH agonists.

Degarelix:

On December 29, 2008, the FDA approved degarelix, a GnRH receptor inhibitor, for the treatment of patients with advanced prostate cancer. The effectiveness of degarelix was established in a clinical trial in which patients with prostate cancer received either degarelix or leuprolide.

In a 12-month, comparative, randomized, open-label, parallel-group phase III study, Klotz et al (2008) assessed the safety and effectiveness of degarelix versus leuprolide for achieving and maintaining testosterone suppression in a 1-year phase III trial involving patients with prostate cancer. A total of 610 patients with adenocarcinoma of the prostate (any stage; median age of 72 years; median testosterone of 3.93 ng/ml, median prostate-specific antigen, PSA, level of 19.0 ng/ml) were randomized and received study treatment. Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator's assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intra-muscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12-month study. Both the intent-to-treat (ITT) and per protocol populations were analyzed. The primary endpoint of the trial was suppression of testosterone to less than or equal to 0.5 ng/ml at all monthly measurements from day 28 to day 364, thus defining the treatment response. This was achieved by 97.2 %, 98.3 % and 96.4 % of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population). At 3 days after starting treatment, testosterone levels were less than or equal to 0.5 ng/ml in 96.1 % and 95.5 % of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (p < 0.001). The hormonal side-effect profiles of the 3 treatment groups were similar to previously reported effects for androgen-deprivation therapy. The s.c. degarelix injection was associated with a higher rate of injection-site reactions than with the i.m. leuprolide injection (40 % versus less than 1 %; p < 0.001, respectively). There were additional differences between the degarelix and leuprolide groups for urinary tract infections (3 % versus 9 %. p < 0.01, respectively), arthralgia (4 % versus 9 %, p < 0.05, respectively) and chills (4 % versus 0 %, p < 0.01, respectively). There were no systemic allergic reactions. The authors concluded that degarelix was not inferior to leuprolide at maintaining low testosterone levels over a 1-year treatment period. Degarelix induced testosterone and PSA suppression significantly faster than leuprolide; PSA suppression was also maintained throughout the study. Degarelix represents an effective therapy for inducing and maintaining androgen deprivation for up to 1 year in patients with prostate cancer, and has a different mechanism of action from traditional GnRH agonists. Its immediate onset of action achieves a more rapid suppression of testosterone and PSA than leuprolide. Furthermore, there is no need for anti-androgen supplements to prevent the possibility of clinical "flare". The findigns of Klotz et al (2008) are in agreement with those of Gittelman et al (2008) as well as Van Poppel et al (2008).

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