New data from the randomized FinnProstate Study VII trial comparing outcomes of men randomized to treatment with either intermittent (IAD) or continuous (CAD) androgen deprivation therapy are going to further confuse physicians and patients about the relative merits of these two types of androgen deprivation therapy.
Regular readers will remember that, earlier in the year, at the ASCO annual meeting, Hussain et al. presented data suggesting that IAD was significantly less clinically effective than CAD for the initial treatment of most men with metastatic prostate cancer. This finding set off something of a firestorm in the professional and the lay prostate cancer communities because other trials had suggested that the relative efficacies of the two forms of therapy were very similar.
Salonen et al. initiated the FinnProstate Study VII by enrolling 852 men with locally advanced or metastatic prostate cancer who all received therapy with 12.5 days of antiandrogen therapy (using cyproterone acetate) to prevent a flare reaction and 24 weeks (6 months) of androgen deprivation with the LHRH agonist goserelin acetate (Zoladex). These 852 men were enrolled into the study between 1997 and 2003.
To be specific, the men initially enrolled into the trial had to meet at least one of the following criteria:
- M1 disease and any PSA level
- M0 disease and a PSA level ≥ 60 ng/ml
- T3-4M0 disease and a PSA level ≥ 20 ng/ml
In theory it was also possible to enroll patients who had received prior treatment with surgery or radiation therapy for localized prostate cancer and a recurrent PSA level ≥ 20 ng/ml (with no prior hormonal or other medical treatment). However, no such patients weere, in fact, enrolled into this trial.
After the initial 24 weeks of therapy,
- 554/852 men (65 percent) had a PSA than had declined to < 10 ng/ml or by ≥ 50 percent if their original PSA was < 20 ng/ml at baseline.
- 298/852 men (35 percent) did not meet the above eligibility criteria for a sufficient decline in their PSA and were excluded from randomization.
The 554 men who did have a sufficient initial decline in their PSA levels at 24 weeks were randomized to either CAD (n = 280) or IAD (n = 274) and followed until January 2010. The results of the study with respect to effectiveness are as follows:
- Average (median) follow-up was 65 months (5.4 years).
- Average (mean) age of patients was 71.5 years and there was no difference in the ages of patients in the two arms of the study.
- No patients were lost to follow-up, and one patient was followed for a total of 11.4 years.
- 79 percent of patients randomized had PSA levels of ≤ 4.0 ng/ml at the time of randomization.
- For the men treated with IAD
- The average number of cycles of IAD was 3 (range, 0 to 14 cycles).
- 392/554 patients (71 percent) died of all causes during follow-up.
- 186/274 patients who died (68 percent) had been treated with IAD.
- 206/280 patients who died (74 percent) had been treated with CAD.
- This difference was not statistically significant.
- 248/554 patients (54 percent) died of prostate cancer during follow-up.
- 117/274 patients who had been treated with IAD (43 percent) died of prostate cancer .
- 131/280 patients who had been treated with CAD (47 percent) died of prostate cancer.
- Again, this difference was not statistically significant
- The average (median) times from randomization to progression or death were as follows:
- 34.5 months from randomization to disease progression for the men on IAD
- 30.2 months from randomization to progression for the men on CAD
- 45.2 months from randomization to death from all causes for the men on IAD
- 45.7 months from randomization to death from all causes for the men on CAD
- 45.2 months from randomization to prostate cancer-specific death for the men on IAD
- 44.3 months from randomization to prostate cancer-specific death for the men on CAD
- 22.9 months from randomization to treatment failure for the men on IAD
- 30.5 months from randomization to treatment failure for the men on CAD
Note that the definitions of treatment failure and disease progression are complex but are listed in full in Appendix 2 of the full text of the paper in the Journal of Urology.
Now let’s look at the adverse effect and quality of life results from the second of the two papers. Salonen et al. report that:
- There were no significant differences in the prevalence of serious adverse effects between the two groups of patients.
- 87/274 men treated with IAD (32 percent) had adverse cardiovascular effects.
- 95/280 men treated with CAD (34 percent) had adverse cardiovascular effects.
- 24/274 men treated with IAD (9 percent) withdrew from the trial after adverse cardiovascular effects.
- 29/280 men treated with CAD (10 percent) withdrew from the trial after adverse cardiovascular effects.
- 19/274 men treated with IAD (7 percent) had bone fractures.
- 15/280 men treated with CAD (5 percent) had bone fractures.
- Hot flashes and/or night sweats were reported by 47.1 percent of patients treated with IAD.
- Hot flashes and/or night sweats were reported by 50.4 percent of patients treated with CAD.
- Interestingly, however:
- Erectile dysfunction was reported by 15.7 percent of men treated with IAD.
- Erectile dysfunction was reported by 7.9 percent of men treated with CAD.
- Depressed mood was reported by 2.2 percent of men treated with IAD.
- Depressed mood was reported by no men treated with CAD.
- These differences are statistically significant.
- Significant differences favoring men treated with IAD as opposed to CAD were evident with regard to
- Limitations on activity
- Physical capacity
- Sexual function
Based on the data from these two papers, Salonen et al. conclude that, compared to CAD:
- IAD is “a feasible, efficient and safe method to treat advanced prostate cancer.”
- IAD “showed benefits” with respect to quality of life.
- IAD was associated with a similar prevalence of adverse effects.
Now it does have to be clearly pointed out that the FinnProstate Study VII was based on a significantly smaller study population than the data reported by Hussain at ASCO. Furthermore, in the trial reported by Hussain, men’s PSA levels had to drop to < 4.0 ng/ml before they were eligible for randomization, whereas in the Finnish trial men’s PSA levels only had to drop to < 10 ng/ml (although, as noted earlier, 79 percent of the men in the Finnish trial did have PSA levels of ≤ 4.0 ng/ml at the time of randomization). It is not really possible to make an accurate comparison of the “meaningfulness” of the results of the two trials, as a consequence.
What is clear is that — depending on people’s perspectives — they are going to use one or other of these sets of data to argue that CAD or IAD may be a “better” option for specific patients. It is going to be difficult for most men to really appreciate the distinctions between these two sets of data, let alone use them to make clinically appropriate decisions for themselves as individuals.
It should be noted that Salonen et al. do state in their conclusions that:
[P]atients with the most advanced and the most aggressive prostate cancer with a high pre-treatment PSA do not show an adequate biochemical PSA response to androgen deprivation therapy, and are not candidates for IAD.