Cosudex (+3%) vs Androcur (-3%) in long term use

[JimmyToowong]

Standard ADT (Androgen Deprivation Therapy) is most often an LHRH agonist implant given every few months.

• LHRH agonists used in standard ADT: Zoladex (Goserelin), Lupron (leuprolide), Eligard (leuprolide), Suprefact (buserelin), Suprecor (buserelin), Synarel (nafarelin), histrelin (Supprelin), Suprelorin (deslorelin), Ovuplant(deslorelin), Triptorelin
  

Very often a short course of antiandrogen for a few weeks is given at the beginning, to prevent 'flare'.

• Antiandrogens often used to prevent flare: Casodex (bicalutamide), Eulexin (Flutamide), both nonsteroidal, and Androcur (Cyproterone, a steroid),
  

Some doctors continue to use the antiandrogen for the whole period of ADT.

This is called by various names, including Complete Androgen Deprivation (CAD), Maximal androgen blockade (MAB) and ADT2.

These doctors have decided, hopefully in consultation with their patients, that given the health of their patient, and the extra side effects and expense of the antiandrogen, on balance CAD is worth it.

The extract below reports a study that tried to quantify the benefit of CAD.

It reports an approximate 3% survival advantage to non-steroidal antiandrogens (like Cosudex and Flutamide) and an approximate 3% survival disadvantage in the use of the steroidal antiandrogen Androcur. (This is long-term use being reported, not short-term use for 'flare'.)

The authors' conclusion is that the 3% survival advantage is not worth the health and financial cost, and that standard practice should remain use of a single LHRH agonist (like Zoladex, Lupron, Eligard etc.) usually implanted every few months (though sometimes monthly).

Curr Oncol. 2006 Jun;13(3):81-93.

Maximal androgen blockade for the treatment of metastatic prostate cancer--a systematic review.

Lukka H, Waldron T, Klotz L, Winquist E, Trachtenberg J; Genitourinary Cancer Disease Site Group; Cancer Care Ontario Program in Evidence-based Care.

Source

Juravinski Cancer Centre, 699 Concession Street, Hamilton, Ontario L8V 5C2.

Abstract

INTRODUCTION:

Maximal androgen blockade (MAB) versus castration alone in patients with metastatic prostate cancer has been extensively evaluated in randomized trials. The inconsistent results have led to the publication of multiple meta-analyses. The present review examines the evidence from meta-analytic reports to determine whether MAB using agents such as flutamide, nilutamide, and cyproterone acetate (CPA) is associated with a survival advantage.

METHODS:

We conducted a systematic review of the literature (MEDLINE, EMBASE, and the Cochrane Library through July 2004; CANCERLIT through October 2002) for meta-analyses that compared MAB with castration alone in previously untreated men with metastatic prostate cancer (D1 or D2, N+/M0 or M1). Two reviewers selected papers for eligibility; disagreement was resolved by all the authors through consensus.

RESULTS:

The literature search identified six meta-analyses that met the eligibility criteria of the review. Two of those reports were based on individual patient data (IPD), and four were based on data from the published literature. All six meta-analyses pooled data on overall survival. The best evidence came from the largest meta-analysis, conducted by the Prostate Cancer Trialists Collaborative Group and based on IPD (8725 patients) from 27 trials. That analysis detected no difference in overall survival between mab and castration alone at 2 or 5 years. However, a subgroup analysis showed that MAB with nonsteroidal anti-androgens (NSAAS) was associated with a statistically significant improvement in 5-year survival over castration alone (27.6% vs. 24.7%; p = 0.005). {jm: the famous 3% difference which indicates inclusion as standard treatment in breast cancer, but exclusion in prostate cancer } The combination of MAB with CPA, a steroidal anti-androgen, was associated with a statistically significant increased risk of death (15.4% vs. 18.1%; p = 0.04). Compared with castration alone, MAB was associated with more side effects (that is, gastrointestinal, endocrine function) and reduced quality of life in domains related to treatment symptoms and emotional functioning.

CONCLUSIONS:

The small survival benefit conferred by MAB with NSAA is of questionable clinical significance given the added toxicity and concomitant decline in quality of life observed in patients treated with MAB. Therefore, combined treatment with flutamide or nilutamide should not be routinely offered to patients with meta-static prostate cancer beyond the purpose of blocking testosterone flare. Monotherapy, consisting of orchiectomy or the administration of a luteinizing hormone-releasing hormone agonist is recommended as standard treatment.

PMID: 17576447 Forum: Primary hormone therapy Title: ADT2 3% non-steroidal (Casodex, Cosudex)

In the article above, CPA refers to cyproterone acetate (brand name Androcur).

The statistically significant increased risk of death associated with cyproterone acetate/Androcur referred to above concerns its long term use.

There is no evidence presented that the use of cyproterone acetate/Androcur for a few weeks to prevent flare from an ADT implant is harmful.

This extract can be found on http://PubMed.com, and is in the public domain.

On PubMed.com there will be a link to the full paper (often $30, sometimes free).

Any highlighting (except the title) is not by the author, but by Jim Marshall.

Jim is not a doctor.

This page was found on the Advanced Prostate Cancer Community for Australian men at http://advancedprost...lia.ipbhost.com.

The link is hard to remember.

An easier way to find it is to go to JimJimJimJim.com and click on Prostate.

That's the word Jim four times, no spaces, followed by .com.

If you need other help - to perhaps find someone to talk to or a local support group:

Click on the Contact Jim button at http://JimJimJimJim.com.

[Admin]

It is now known that some antiandrogens have a changing relationship with some prostate cancers.

Where they kill the prostate cancer cells for a long while, eventually some prostate cancer cells evolve which not only to resist, but use the antiandrogen as a fuel.

So, when PSA begins to rise, the antiandrogen is stopped, and in about 30% of cases that PSA goes down, because the prostate cancer cells had learned to use the antiandrogen for fuel.

It occurs to me that in many of the reported trials from the 1990s, the antiandrogen may not have been stopped when PSA rose, making the MAB (or CAB or ADT2) figures not as good as they could have been.

[Admin]

The main study the authors quote was reported with different results in 1995 and 2000, the difference being in the type of antiandrogen being used.

Lancet. 1995 Jul 29;346(8970):265-9.

Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Prostate Cancer Trialists' Collaborative Group.

[No authors listed]

Abstract

A systematic overview, or meta-analysis, of the randomised evidence on maximum androgen blockade (MAB) in advanced prostate cancer identified 25 trials that compared conventional castration (surgical or medical) versus MAB (castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide). Individual patient data were obtained from 22 of the trials. Median follow-up was 40 months, during which 57% of patients died (3283/5710). Crude mortality rates were 58% for castration alone and 56% for MAB. Life-table estimates of the corresponding 5-year survival rates were 22.8% and 26.2%, representing a non-significant improvement of 3.5% (95% CI 0-7%). Logrank time-to-death analyses found no significant heterogeneity between trials (or between the effects of different types of MAB) and no significant evidence of additional benefit in an overview of all these MAB trial results (2p > 0.1). The currently available evidence from randomised trials does not show that MAB results in longer survival than conventional castration.

Comment in

Lancet. 1999 Apr 3;353(9159):1184.

Lancet. 1995 Oct 14;346(8981):1030.

Lancet. 1995 Oct 14;346(8981):1030-1.

Lancet. 1995 Oct 14;346(8981):1031.

PMID: 7630245

Lancet. 2000 Apr 29;355(9214):1491-8.

Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group.

[No authors listed]

Abstract

BACKGROUND:

In advanced prostate cancer, androgen suppression (AS) by surgery or drugs controls testicular hormone secretion, and the further addition of an antiandrogen such as nilutamide, flutamide, or cyproterone acetate is referred to as maximum androgen blockade (MAB). The aim of this overview was to compare the effects on the duration of survival of MAB and of AS alone.

METHODS:

The collaborative meta-analysis of 27 randomised trials involved central reanalysis of the data on each of 8275 men (98% of those ever randomised in trials of MAB vs AS) with metastatic (88%) or locally advanced (12%) prostate cancer. Half were over 70 years of age, and follow-up was typically for about 5 years.

FINDINGS:

5932 (72%) men have died; of the deaths for which causes were provided, about 80% were attributed to prostate cancer. 5-year survival was 25.4% with MAB versus 23.6% with AS alone, a non-significant gain of 1.8% (SE 1.3; logrank 2p=0.11). There was no significant heterogeneity in the treatment effect (MAB vs AS) with respect to age or disease stage. The results for cyproterone acetate, which accounted for only a fifth of the evidence, appeared slightly unfavourable to MAB (5-year survival 15.4% MAB vs 18.1% AS alone; difference -2.8% [sE 2.4]; logrank 2p=0.04 adverse), whereas those for nilutamide and flutamide appeared slightly favourable (5-year survival 27.6% MAB vs 24.7% AS alone; difference 2.9% [sE 1.3]; logrank 2p=0.005). Non-prostate-cancer deaths (although not clearly significantly affected by treatment) accounted for some of the apparently adverse effects of cyproterone acetate.

INTERPRETATION:

In advanced prostate cancer, addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit runs from about 0% to about 5%.

Comment in

Lancet. 2000 Apr 29;355(9214):1474-5.

ACP J Club. 2001 Jan-Feb;134(1):23.

Lancet. 2000 Jul 22;356(9226):341-2.

PMID: 10801170

[Admin]

So we know that non-steroidal antiandrogens are best in this long term use.

But these studies had a wide range of antiandrogens.

Today the most common antiandrogens are Cosudex, Casodex (bicalutamide) and Eulexin (flutamide).

Is there any comparison of these two?

Good question.

Luckily there is a comparison.

Urology. 1997 Sep;50(3):330-6.

Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group.

Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ.

Source

Department of Urology, Eastern Virginia Medical School, Norfolk 23507-1999, USA.

Abstract

OBJECTIVES:

To compare the efficacy and tolerability of bicalutamide and flutamide, each combined with luteinizing hormone-releasing hormone analogue (LHRH-A) therapy, in patients with metastatic (Stage D2) prostate cancer.

METHODS:

This was a randomized, double-blind (for antiandrogen therapy), multicenter study with a two-by-two factorial design. Eight hundred thirteen patients were allocated 1:1 to bicalutamide (50 mg once daily) and flutamide (250 mg three times daily) and 2:1 to goserelin acetate (3.6 mg every 28 days) and leuprolide acetate (7.5 mg every 28 days).

RESULTS:

The median times to progression and death were

97 and 180 weeks for the bicalutamide plus LHRH-A group compared with

77 and 148 weeks for the flutamide plus LHRH-A group.

{jm: highlighting and line breaks mine}

The hazard ratio for time to progression for bicalutamide plus LHRH-A to flutamide plus LHRH-A was 0.93 (95% confidence interval [CI] 0.79 to 1.10, P = 0.41) and that for survival time was 0.87 (95% CI 0.72 to 1.05, P = 0.15). The therapies were generally well tolerated. The most common adverse event in the two groups was hot flashes. The incidence of hematuria was significantly higher for the bicalutamide plus LHRH-A group than for the flutamide plus LHRH-A group (12% versus 6%, P = 0.007), but no patient withdrew from therapy because of hematuria. There was a significantly (26% versus 12%, P < 0.001) higher incidence of diarrhea and more withdrawals for diarrhea (25 patients versus 2) for the flutamide plus LHRH-A group relative to the bicalutamide plus LHRH-A group.

CONCLUSIONS:

With a median follow-up time of 160 weeks, the combination of bicalutamide plus LHRH-A was well tolerated and had equivalent time to progression and survival compared with flutamide plus LHRH-A. Treatment with bicalutamide plus LHRH-A resulted in longer median survival than treatment with flutamide plus LHRH-A.

Comment in

Urology. 1999 Mar;53(3):662-3.

PMID: 9301693

[Admin]

So bicalutamide/Cosudex is better than flutamide/Eulexin when added to treatment with an LHRH agonist implant like Zoladex, Lucrin etc.

1. But is there a study that lets me know how much better the combined androgen deprivation (CAD) is than using an implant alone?
   
2. If not, why not?
   
3. If not, is one underway?
   
4. If not, can someone make an educated guess?
   

1. Study? Sadly, there is no such study.
   
2. Why not? Until recently combined androgen deprivation (CAD) was standard practice. It was considered unethical to deprive half the people in a study of the antiandrogen.
   
3. One underway? The bicalutamide patent ran out in 2011. No drug company invests in studies unless it has a patent with a few years to run.
   
4. Educated guess? Laurence Klotz and Paul Schellhammer have calculated a probable benefit.
   

On applying this analysis the balance of evidence suggests that there is a high probability (98.5%) that bicalutamide as part of combined therapy provides a survival advantage over castration alone. The HR is 0.80, indicating a 20% reduction in the risk of death, with a 95% CI of 0.66–0.98, indicating that this benefit could range from an absolute benefit of 2% to 34% (Fig. 4).

...

When considering therapeutic options the clinician and patient must consider many factors. These include the patient’s disease status, benefits of therapy, treatment side effects, quality-of-life issues and cost. Individual trial and meta-analysis data suggest that there is a modest improvement in overall survival with combined therapy using nonsteroidal antiandrogens over castration alone in advanced disease, although these do not appear until after 2 years.

So, in my rehash of Klotz and Schellhammer's recalculation of the data:

After 5 years, adding bicalutamide/Cosudex to a LHRH agonist implant (Like Zoladex, Lupron) will likely extend life by an average of 4-7 months. (Average here is the median. Half the men will get less than this, half the men will get more, a few considerably more.)

However, the uncertainty introduced by the statistics means that that median man could really be anywhere from 2 weeks to 1 year.

So, you and your doctor have no absolute guidance from the research.

You depend here on your doctor's clinical experience and wisdom.

Recent guidelines just advise:

Given that the bicalutamide CAB has minimal, if any, additional toxicity over castrate therapies alone and is significantly cheaper than the newer systemic therapies, until the results of a trial designed to address the potential survival benefit is available, patients should be made aware of the findings described herein, and bicalutamide CAB should be considered.

[Admin]

But what about the cost? Is it cost effective?

To address the issue of cost-effectiveness, Nishimura et al.(29) constructed a Markov model that examined the prognosis of untreated prostate cancer and estimated the cost-effectiveness of CAB in comparison with that of LHRH-A monotherapy. The model showed that the expected costs of CAB and LHRH-A monotherapy were 5.24 and 3.66 million yen (approximately US$55 851 and US$39 010), respectively, with expected survival durations of 7.45 and 6.44 years, respectively. The incremental cost-effectiveness ratio (ICER) for CAB compared with LHRH-A monotherapy was 1.56 million yen ⁄ life-year-saved (approximately US$16 627), and was lower than the ICER threshold set in the study (6 million yen ⁄ life-yearsaved [approximately US$63 952]), which demonstrates that the cost-effectiveness of CAB is superior to that of LHRH-A monotherapy. Similar results were found in a study conducted by Penson et al.(30)

So, on a system wide basis, it makes economic sense.

What about personal economics?

Ignoring the health costs, that depends upon the price you pay for your bicalutamide.

I understand that in Australia, PBS meets most of the cost if you have metastatic disease.

If you have to pay for it yourself, it costs around $128 per 30 days.

You do the math.

If any member wishes to know more, see the following reviews that the above information has been drawn from:

Combined androgen blockade for prostate cancer: Review of efficacy, safety and cost-effectiveness, Hideyuki Akaza 2010

A re-assessment of the role of combined androgen blockade for advanced prostate cancer, L. Klotz, P. Schellhammer, K. Carroll 2004