Progestins

Progestins

PEP Topic 
Hot Flashes
Description 

Progestins are synthetic hormones that have activity that simulates progesterone, the female hormone that is elevated during pregnancy. Progestin has a steroid structure and is the main component of birth control medications. Progestins have been evaluated for effect in patients with cancer for anorexia, CINV, hot flashes, and fatigue.

Effectiveness Not Established

Research Evidence Summaries

Bertelli, G., Venturini, M., Del Mastro, L., Bergaglio, M., Sismondi, P., Biglia, N., … Rosso, R. (2002). Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: A randomized study. Annals of Oncology, 13, 883–888.

doi:10.1093/annonc/mdf151
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Study Purpose:

The study was designed to compare injected medroxyprogesterone vs. oral megestrol to control hot flashes in women with breast cancer.

Intervention Characteristics/Basic Study Process:

Participants were randomized to two groups. Group 1 received I.M. depot MPA (500 mg on days 1, 14, and 28) and Group 2 received oral megesterol acetate (40 mg po daily days 1-42).

Sample Characteristics:

Eligible patients were postmenopausal females with a history of breast cancer, without evidence of relapse, whom had been suffering from hot flashes for at least 1 month prior to study entry. Group 1 enrolled 3 , and Group 2 enrolled 34.  Major Inclusion/Exclusion Criteria:

  • Concurrent adjuvant tamoxifen 20 mg/day was allowed if started at least 1 month before study entry and if the planned residual duration of treatment was at least 6 months.
  • No concurrent treatment with estrogens, androgens, progestins, corticosteroids, clonidine, veralipride, or ciclophenile was allowed.
  • Patients who had received adjuvant chemotherapy had to have concluded treatment for more than 2 months.

Setting:

Not described

Measurement Instruments/Methods:

The primary endpoint was the proportion of responding patients after 6 weeks of treatment (7 weeks after randomization). A patient was classified as a responder if she achieved a greater than 50% reduction in frequency of hot flashes and hot flash score. Frequency and severity of hot flashes were monitored through self compiled diaries. The three main efficacy parameters were:

  1. Changes in average number of hot flashes per day
  2. Average daily ‘hot flash score’ compared to baseline
  3. Proportion of participants who obtained greater than 50% reduction in frequency and reduction in HF score as compared to baseline score

Results:

The mean number of hot flashes and hot flash scores did not differ significantly at baseline between the two groups. Differences between the two groups at week six were not statistically significant. Good control by both treatments was apparent. No significant difference in the proportion of responders between the two arms was observed (p=0.567) Overal,l 50 of 71 patients (70.4%, 95% CI 58-81%) achieved a response as previously defined.Maintenance of response in the group of 50 initial responders was assessed at 2-monthly follow up visits for 6 months after randomization. By patient report, a difference in the duration of response was observed: out of 28 responding patients in the MPA group, 25 (89.3%) were still responding at 6 months. In the megestrol group, only 10 of the initial 22 responders (45.4%) were still in response after 6 months.

Limitations:

For an 80% power and two sided 5% significance, 90 subjects were planned. Only 71 were accrued. After randomization, five patients in each group refused to start the assignment and withdrew from the study. Two more patients, both in group one, were found ineligible (one for medical contraindication and one not postmenopausal) and withdrawn. Six patients did not provide complete diary recordings during treatment (five patients who dropped out before completion for side effects and one who was lost to follow-up). Treatment allocation was not double-blinded because this would have required administration of I.M. placebo in group 2 which was judged impractical.

Goodwin, J.W., Green, S.J., Moinpour, C.M., Bearden, J.D., III, Giguere, J.K., Jiang, C.S., … Albain, K.S. (2008). Phase III randomized placebo-controlled trial of two doses of megestrol acetate as treatment for menopausal symptoms in women with breast cancer: southwest oncology group study 9626. Journal of Clinical Oncology, 26, 1650–1656.

doi:10.1200/JCO.2006.10.6179
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Intervention Characteristics/Basic Study Process:

Southwest Oncology Group Study 9626 evaluated  megestrol for management of menopausal symptoms in women with breast cancer. It compared two doses of megestrol acetate  versus placebo over six months. Participants were randomized to placebo, megestrol 20 mg, or megestrol 40 mg daily for three months. If success was achieved, treatment continued for three additional months. If not, the patient was unblinded and given megestrol 20 mg daily.

Sample Characteristics:

Participants: 288 patients with T 1-3, N0-1 breast cancer following surgery, chemotherapy, and at least four months of tamoxifen, if prescribed, were enrolled. 225 completed the trial.

Study Design:

This was a phase III, randomized, placebo-controlled, double-blind trial.

Measurement Instruments/Methods:

At the initial evaluation, patients completed a seven-day patient daily log of hot flashes with re-evaluation at three and six months. The primary endpoint was differences in the probability of hot flash reduction in three comparison groups.  Instruments included:

  • The patient report of menopausal symptoms
  • The symptom log
  • National Cancer Institute Common Toxicity Criteria, version 2.
  • Performance status assessed using ECOG scale

Results:

At three months, improvement was 14% with placebo, 65% withmegestrol acetate 20 mg, and 48% with megestrol acetate 40 mg. Both doses were superior to placebo (p < .0001). Duration of effectiveness continued at six months. Megestrol 40 mg was not superior to megestrol 20 mg.

Conclusions:

The recommended daily dose is 20 mg.

Limitations:

The study was not designed to evaluate long-term toxicities or relapse of symptoms with long-term use. Concern remains regarding the use of progestins in women with a history of breast cancer.

Irani, J., Salomon, L., Oba, R., Bouchard, P., & Mottet, N. (2010). Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet Oncology, 11(2), 147-154.

doi:10.1016/S1470-2045(09)70338-9
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Study Purpose:

Compare the efficacy of 3 drugs in preventing hot flashes in men receiving  hormone treatment for prostate cancer

Intervention Characteristics/Basic Study Process:

Patients were randomly assigned to receive wither venlafaxine delayed release 75 mg/day, medroxyprogesterone 20 mg/day or cyproterone acetate 100 mg/day in addition to leuprorelin injections.  Patients were followed up at 4, 8 and 12 weeks.  Patients completed daily hot flush diaries and categorised hot flush severity

Sample Characteristics:

  • N  309 AGE   Not reported
  • MALES (%) 100%         FEMALES (%)
  • KEY DISEASE CHARACTERISTICS All had prostate cancer treated with hormonal therapy for at least 6 months.  All had experienced 14 or more hot flushes in the week before study entry

Study Design:

 Double blind randomized controlled trial

Measurement Instruments/Methods:

  • Daily hot flush diary
  • European Organization for Research and Treatment of Cancer Quality of life questionnaire ( EORTC-QLC 30)
     

Results:

Patients in the medroxyprogesterone group had higher hot flash scores at baseline.  The reduction in daily hot flush scores at 4 weeks was significantly lower for all 3 groups (p<.0001).  Improvements were significantly lower in the venlafaxine group than either of the other 2 groups ( p = .0006), and patients ratings of efficacy of treatment showed that significantly fewer patients in the venlafaxine group rated the treatment as good ( p<.0001) compared to the other 2 groups. Adverse events related to the study drugs were not significantly different between groups, though cyproterone led to a non significantly higher number of vascular adverse events.  The most frequent adverse events were gastrointestinal, including pain, constipation, diarrhea and nausea.  GI events were more frequent with venlafaxine.

Conclusions:

Men with significant hot flushes during androgen suppression for prostate cancer appeared to respond better to cyproterone acetate and medroxyprogesterone acetate than to venlafaxine

Limitations:

  • Baseline sample/group differences of import
  • Risk of bias (no control group)
  • Other limitations/*explanation  No control or placebo group precluded observation of placebo effect.  The sample was limited to patients who sought treatment for hot flashes.  This was a short follow up period - longer term efficacy is not known. Effects of hormonal treatment for hot flashes on prostate cancer are not known.

Nursing Implications:

It appears that hormonal treatment is more effective in than venlafaxine for management of hot flashes in patients who are receiving androgen suppression for prostate cancer.  Results also showed that many men did not seek treatment for this problem, suggesting that nurses may need to directly assess these patients for problems with hot flash symptoms.  Effects of steroidal anti androgens on prostate cancer are not clear, and patients receiving both androgen suppression and cyproterone or medroxyprogesterone could have increases in prostate specific antigen concentrations.

Loprinzi, C.L., Michalak, J.C., Quella, S.K., O’Fallon, J.R., Hatfield, A.K., Nelimark, R.A., … Oesterling, J.E. (1994). Megestrol acetate for the prevention of hot flashes. New England Journal of Medicine, 331, 347–352.

doi:10.1056/NEJM199408113310602
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Study Purpose:

The study was done to assess the efficacy and short-term toxicity of low-dose megestrol acetate as a treatment for hot flashes in women with breast cancer and in men who had undergone androgen-deprivation therapy for prostate cancer.

Intervention Characteristics/Basic Study Process:

Subjects were randomly assigned to receive megestrol 20 mg twice a day for 4 weeks followed by placebo for 4 weeks.or placebo for 4 weeks then megestrol for 4 weeks. Subjects received no medication for the first 7 days.

Sample Characteristics:

Of the enrolled subjects, 163 cpmpleted the study. They included women with a history of breast cancer and men who had undergone surgical or medical orchiectomy. All had at least one hot flash per month. Women were stratified according to duration of hot flashes (9 months cut point). Men were stratified by medical or surgical orchiectomy and duration of androgen ablation.

Study Design:

The study was a double-blind, randomized, crossover trial.

Measurement Instruments/Methods:

Participants kept hot flash diaries,  recording the number and severity of hot flashes each day. They also recorded  appetite changes, fluid retention, and vaginal problems.

Results:

During the first 4 week medication period, megestrol was associated with decreased frequency of hot flashes for both men and women. Crossover analysis was not performed because of carryover effects of medication.

Limitations:

There was an insufficient washout period to allow for crossover analysis.

Systematic Review/Meta-Analysis

Frisk, J. (2010). Managing hot flushes in men after prostate cancer--a systematic review. Maturitas, 65(1), 15-22.

doi:10.1016/j.maturitas.2009.10.017
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Purpose:

To describe hot flushes in men with prostate cancer and their treatment methods.

TYPE OF STUDY Systematic review

Search Strategy:

DATABASES MEDLINE, ISI Web of Knowledge, Cinahl & PsycINFO

KEYWORDS  Prostate cancer, androgen deprivation therapy, vasomotor symptoms, hot flashes treatment

INCLUSION CRITERIA All studies were randomized controlled studies (RCT) that addressed hot flashes (HF) in men with any stage of prostate cancer, treated with androgen deprivation therapy either medically or surgically. The studies addressed treatment for hot flashes where the main outcomes were frequency of hot flushes, distress from hot flushes, or hot flash score.

EXCLUSION CRITERIA Studies were limited to human studies and publications appearing between 1966 - 2009. Excluded were reviews & meta-analysis.

Literature Evaluated:

TOTAL REFERENCES RETRIEVED: 252

METHOD OF STUDY EVALUATION The Jadad score was used to assess the quality of the randomized controlled trial (RCT), on a five-point scale, and the QUORUM guidelines for systematic review were considered.

This summary did not include the measures that were used by the participants in reporting their hot flashes: i.e, diaries, skin temperature measurements, QOL surveys.
 

Sample Characteristics:

FINAL NUMBER STUDIED INCLUDED; N = 5   TOTAL SAMPLE SIZE: N = : 328 men were analyzed.   SAMPLE RANGE ACROSS STUDIES : Sample sizes ranged from 12 - 177.

KEY SAMPLE CHARACTERISTICS: Samples included men with prostate cancer who had undergone surgical or medical castration and were currently experiencing hot flushes.
 

Phase of Care and Clinical Applications:

PHASE OF CARE Active Treatment

APPLICATIONS Late Effects and Survivorship; Elderly Care
 

Results:

In the five studies analyzed, the treatments that were studied included cyproterone acetate (CA), megestrol acetate (MA), gabapentin, transdermal clonidine, and diethylstilbestrol (DES). Unfortunately, none of the studies analyzed the same treatment. Because the studies looked at different interventions to relieve hot flushes (HF) in castrated men with prostate cancer, it was not possible to combine the studies to strengthen the outcomes. The studies' outcomes demonstrated varying degrees of success in relieving the hot flushes: Cyproterone acetate 100 mg, once per day, yielded 75% fewer HF than placebo  (p<0.001), and 100% of men on CA had a 50% or greater reduction of mean number of HF, compared to placebo group. Megestrol acetate  20 mg, twice per day, yielded an 80% reduction of the  median number of HF compared to a 19% reduction in the placebo group (p<0.001), an 87% reduction of median HF score vs. a 16% reduction for placebo (p<0.001), and a 50% or greater reduction of median number of HF (p<0.001) reported by 79% of MA group and 12% of placebo group. Gabapentin (4 schedules) achieved a 45.5% reduction of the median number of HF with 900mg gabapentin per day vs. 21.5% with placebo (p=0.02). Transdermal clonidine demonstrated no difference between the  treated group and placebo. Diethylstilbestrol (1 mg) yielded a 100% reduction in the median number of HF vs.13% with placebo. 100% of DES and 14% of placebo reported a 50% or greater reduction of the median number of HF.

Conclusions:

The systematic review of studies on treatment approaches to managing hot flushes in men after castration for prostate cancer showed very few such studies. Only five RCT studies were identified, and none of them analyzed the same treatment approach. Several of the studies that were presented demonstrated successful treatment approaches, including DES as the most effective, followed closely by MA and CA. However, these medications are linked to side effects that are not well tolerated by all patients.

Limitations:

Only five RCT studies were identified, and none of them analyzed the same treatment approach. 

Nursing Implications:

Large randomized placebo controlled studies are needed to clarify the data and provide clearer direction to managing HF in men who have been castrated as a treatment for prostate cancer. The summary, although providing insight for possible medical management, addressed only briefly the drop-out rates due to side effects. Further investigations of the drop-out subgroup could explore correlations among the medications to reveal unacceptable side effects  in managing the participants’ hot flash symptoms. Further investigations comparing medications used and providing more specific information about measurements of QOL and hot flash reporting by participants are warranted.


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