Had radiation, or surgery then radiation, but my PSA has started rising – intermittent ADT or continuous ADT?

[JimJimJimJim]

Jim Marshall (not a doctor) said ...

In 1998, Crook and colleagues set out to find out if taking breaks from hormone treatment (intermittent androgen deprivation) was as good as taking hormone treatment continuously, for men who had rising PSA after radiation. They reported the results in 2012.

Men in this study had rising PSA after radiation.

• Some of the men had had radiation as their primary treatment.
  
• Some of the men had had surgery as their primary treatment, and were given radiation after that failed.
  
• All men went on hormone therapy (also called ADT, Androgen Deprivation Therapy) when their PSA started rising after their radiation.
  

After they started on the study, some men had ADT on and off (intermittent). Others had ADT continuously.

Another posting on this paper says what this may tell you in terms of "How long will I last?"

Here I will deal with what it may tell us about intermittent ADT vs continuous ADT after failing radiotherapy.

What this study tells us about intermittent vs continuous hormone therapy

• Overall survival (how long you will last) was about the same whether you were on intermittent hormone therapy or continuous hormone therapy.
  
• There was no significant difference between the groups in adverse events (serious side effects of treatment).
  
• Whichever treatment was chosen, half the men were still alive 9 years after they started. Of those who died in the first seven years, most died of other causes.
  
• Of those who did die of prostate cancer, more died in the intermittent group (18%) than the continuous group (15%).
  
• In the quality of life measures, the only significant differences were in hot flashes, sexual desire and urinary symptoms, all better in the intermittent men.
  
• In the intermittent group, only 35% of men had recovered their pre-treatment testosterone levels within 2 years of starting treatment.
  
• Of the men who had an erection good enough for penetration before treatment, only 29% recovered this.
  

What this study does not tell us

It does not tell us about prostate cancer that is locally advanced, metastatic to lymph nodes, or metastatic to other parts of the body.

• The men in this study had localized prostate cancer.
  

It does not tell us about intermittent ADT vs continuous ADT for men whose primary treatment is, or includes, ADT.

• All the men in this study had failed their primary treatment, and all the men had failed radiotherapy.
  

It does not tell us about other patterns of intermittent ADT.

• There are many patterns used.
  
  • Some patterns don't commence intermittent periods off treatment until the PSA has first been undetectable (less than 0.05) for 9 - 12 months.
    
  • Men were assigned to intermittent periods off treatment in this study if their PSA fell below 4 (and less than their starting PSA and not more than 1 more than their last PSA).
    
  • Some patterns continue the on-treatment time until a defined PSA is reached – say 4.
    
  • Others continue on-treatment time until a minimum is reached.
    
  • Others (like this one) have fixed on-treatment times. (On treatment periods are 8 months long in this study.)
    

  [*]Monitoring periods vary.

  • While this study used 2-monthly, monthly has been reported, with 3-monthly being common.
    

It does not tell us about results outside a trial setting.

Results in clinical trials are sometimes not duplicated in the doctor's clinic.

In this trial, for instance, prior to hormone resistance, all men had:

• Comprehensive medical examination, including scans and blood tests when they entered the study;
  
• A physical exam every 4 months for the first 2 years, then every 8 months after that;
  
• PSA and testosterone tests every 2 months;
  
• Monthly liver function tests while they were on an anti-androgen (We do not know how many had continuous anti-androgen vs anti-androgen only for 4 weeks for flare.)
  
• Annual:
  
  • Bone scan;
    
  • Hemoglobin
    
  • Fasting serum cholesterol.
    

This comprehensive health monitoring may be more stringent, and more frequent, than non-study doctors may do. As the authors suggest, with the "closer follow-up required, this follow-up may have undefined health benefits."

It does not tell us about when ADT after radiation failure should be commenced.

The authors chose a PSA that was both higher than 3 and higher than their lowest PSA after radiotherapy. The reason was simply that they thought this would get them volunteers quickly. We don't know from this study that a PSA of 0.1 or a PSA of 20 would have been better.

And finally, this study does not clearly demonstrate that intermittent hormone therapy will delay hormone resistance.

This seemed to be the case in cell studies in Petri dishes in the laboratory, and in studies in rodents, but this study in men has not clearly demonstrated this.

Caution with men with Gleason score 8, 9 or 10

Only 15% of the men had Gleason score of 8, 9 or 10.

Of these men with Gleason score of 8, 9 or 10, those on continuous ADT lived approximately 14 months longer than those on intermittent ADT.

There were not enough men with a Gleason score of 8, 9, or 10 to declare this statistically significant.

To decide for sure, a much larger number of men would have needed to start in the study.

However, it is something your doctor will bear in mind.

(Because Gleason score was not part of the original study, but retrieved from records later, this result is in the supplementary paper. )

You can purchase access for 24 hours to the full paper, the supplementary paper, and the protocol for $15.

... end Jim

N Engl J Med. 2012 Sep 6;367(10):895-903. doi: 10.1056/NEJMoa1201546.

Intermittent androgen suppression for rising PSA level after radiotherapy.

Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, Frymire E, Malone S, Chin J, Nabid A, Warde P, Corbett T, Angyalfi S, Goldenberg SL, Gospodarowicz MK, Saad F, Logue JP, Hall E, Schellhammer PF, Ding K, Klotz L.

Source

British Columbia Cancer Agency, Cancer Centre for the Southern Interior, 399 Royal Ave., Kelowna, BC V1Y 5L3, Canada. jcrook@bccancer.bc.ca

Erratum in

N Engl J Med. 2012 Dec 6;367(23):2262.

Abstract

BACKGROUND:

Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial.

METHODS:

We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals.

RESULTS:

Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24).

CONCLUSIONS:

Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).

Comment in

Androgen deprivation--continuous, intermittent, or none at all? [N Engl J Med. 2012]

Intermittent androgen suppression for rising PSA level. [N Engl J Med. 2012]

PMID: 22931259

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 (in this case $15, often $30+, sometimes free).

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

Jim is not a doctor.

From the Supplementary Appendix:

Gleason scores were not collected as part of the protocol design but were retrieved retrospectively from stored pathology reports and grouped as follows: unavailable: 9.2%, 2-6: 42.6%, 7: 33.0% and 8-10: 15.2%. Overall survival by treatment arm for 3 Gleason score groups, shows similar OS between treatment arms for Gleason score <6 (Fig. S3a) and 7 (Fig. S3b), while for Gleason score 8-10 (Fig. S3c), those on IAD had a trend to worse OS (HR of 1.21, p = 0.33). Cox regression model with treatment arm, Gleason score groups and their interaction terms show that there was no differential treatment effect among the 3 groups. The sample size of the study does not have the power to detect a small or moderate difference, but the approximately 14 month greater median survival for Gleason 8-10 receiving CAD suggests caution in this group.