This study has been posted recently but now the Editorial Board of Advanced Prostate Cancer has commented on this study and I think the comments are interesting not only for the study but also as an example of how these experts discuss the study bringing in their own opinions.
TAKE-HOME MESSAGE
•This was a phase III randomized trial comparing adjuvant docetaxel plus prednisone with the standard of care (observation) in men at high risk of recurrence following radical prostatectomy. In the 298 patients recruited, median progression-free survival was not significantly longer in the treatment group compared with the control group (55.5 months vs 42.2; P=.21). Improved progression-free survival was observed in two prespecified subgroup analyses. These were patients with tumor stage ≥T3b and Gleason score ≤7.
•There was no significant improvement in survival with the use of adjuvant docetaxel in this high-risk population following surgery. The study had limited power due to poor accrual. Some subgroups did appear to benefit from the intervention. Further study is needed to identify the appropriate patients to consider for adjuvant chemotherapy in this setting.
– Jeffrey J. Tosoian, MD, MPH
Advanced Prostate Cancer
Written by Jonathan Silberstein MD, MBA Candidate 2018 Written by Brian E Lewis MD, MPH, FACP Written by Thomas J Guzzo MD, MPH.
The Editorial Board of Advanced Prostate Cancer discuss the Veterans Affairs cooperative study that was designed to assess the effect on progression-free survival of adjuvant docetaxel after prostatectomy in men with high-risk, localized prostate cancer.
Jon Silberstein: The study was designed to evaluate outcomes in post-prostatectomy patients at high risk of recurrence or progression who were randomized to either standard of care with observation or to chemotherapy with docetaxel and prednisone for six cycles. The study did not accrue as well as the investigators had hoped; fewer than half of the total intended patients were enrolled. There were various stratification factors.
The authors found no real difference in the study group overall with respect to their primary endpoint, which was progression-free survival. I need to look at how they define that; but, in any case, the study was hampered by the low accrual, and thus, the low number of events. In the chemotherapy group, there were fewer events than in the standard of care group (66 vs 84; 47% vs 53%), but the difference did not meet statistical significance. The time to progression also was a little bit longer in the patients receiving chemotherapy (55 vs 42 months). The secondary endpoints were metastases, all-cause mortality, and initiation of ADT, and there were very few events. No deaths were related to prostate cancer.
Because there are so few events here, none reach any statistical significance, although I suppose you could argue that there are fewer events for the patients who received chemotherapy in all of these groups. Survival probability seems to separate in the Kaplan-Meier curves.
What the authors did find, or at least put in their findings, was that, for the patients with particularly locally aggressive prostate cancer with seminal vesicle invasion or bladder neck invasion, there was a difference in terms of the progression-free survival favoring treatment with chemotherapy, with a ratio of 0.54 with a P-value of .022. And for patients with a lower Gleason score, there was benefit as well, which seems very odd to me. I don't understand that very well. I would think that the worst actors would be the ones who would benefit the most.
Tom Guzzo: Yes. I think it's got to be statistical, meaning it's a subset analysis of an underpowered study.
I would think that that might have a lot to do with it. I agree with you. Someone with Gleason 7 or less is more likely to have local recurrence than a systemic recurrence, and even the T3 being greater is obviously high risk. But, you know, even patients in this day and age with seminal vesicle involvement are not the systemic patients of 15 and 20 years ago. So, again, I think some of that has to be related to an underpowered study and a subset analysis.
JS: They define the primary outcome…I agree with everything that you're saying. So, it looks like in their forest plot in Figure 3 that the number of Gleason less than or equal to 7 totaled 200 patients with 93 events, and it looks like the hazard ratio comes very close to touching 1. But what I was going to say is that this progression-free survival is defined as initially a PSA of greater than 0.4 and then it was changed to 0.2.
All right. So, salvage therapy with any detectable PSA, how did they deal with adjuvant radiotherapy for any of these patients? Did anybody pick up on that? It's not typically what we do, but this study is around an era when we were doing it more for a patient with a high-risk localized prostate cancer. We might have offered some of these patients adjuvant radiotherapy, or even encouraged some of them to get it.
Brian Lewis: It seems a little bit strange, but I was thinking that same thing. Because, if you have like T3, like T3b, a positive margin or whatever with persistent PSA, you kind of feel inclined to give radiation. You know what I mean?
JS: Yes. I think the persistent PSA guys are going to be progressions. I think they're going to be failures, right, by their definition of 0.2.
They note that they had a high proportion of African Americans. I think the more interesting thing is to put this in the context of the PUNCH trial, where patients underwent docetaxel treatment prior to prostatectomy. The results showed questionable benefit for patients who were deemed to be high risk who were randomized to receive either 6 months of ADT plus docetaxel prior to prostatectomy or were randomized to prostatectomy alone.
It has been presented in meetings and demonstrated modest benefits, let's put it that way. So, you know, both of these studies suggest that, although docetaxel is associated with a tremendous survival advantage for patients with metastatic disease, for those with high-risk disease either prior to prostatectomy or following prostatectomy, it clearly has a limited role, if any.
TG: I agree with that, pending further studies.
JS: Further study and longer observation of Eastham's PUNCH trial, but yes.
BL: I'm not terribly excited about giving chemotherapy in the adjuvant setting, I have to confess.
I was just thinking that, in RTOG 0521 with chemotherapy post radiation therapy, there was an advantage in overall survival in the chemotherapy arm, but it seemed like they had much higher-risk patients in that study than in this study. Something like 85% of patients in that trial were Gleason 8, 9, 10, and I feel like, in this one, there are a lot of Gleason 7, as many as 50% or 60% or so. Then, I believe that the PSAs were all higher in the RTOG trial as well. Maybe the results would be a little bit different, favoring chemotherapy, if they had picked higher-risk patients.
JS: I definitely agree, although the authors point out that 34% had T3b prostate cancer or higher and 35% were in grades group 4 or 5, which still means that there are a lot of patients with less aggressive prostate cancers included in this trial. My hypothesis would be if there's going to be benefit, it's for the highest-risk patients.
BL: I don't know. This is an area that seems to have promise, but it doesn't seem like people are too excited about it.
JS: I think that there is a group of patients with localized prostate cancer who are destined to fail local treatment.
And there is a great deal of interest in either neoadjuvant or adjuvant treatment, and to date, as far as I know, there is no clear evidence of benefit with systemic chemotherapy.
Although I think that this is a really important study, it is essentially a negative study.
BACKGROUND
The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy.
OBJECTIVE
To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS).
DESIGN, SETTING, AND PARTICIPANTS
Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer-specific, and metastasis-free survival, and time to androgen deprivation therapy.
RESULTS AND LIMITATIONS
A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2-103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58-1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32-0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43-0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%.
CONCLUSIONS
Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b (ClinicalTrials.gov number NCT00132301).
PATIENT SUMMARY
In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.
European Association of Urology
Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-Risk Prostate Carcinoma: A Phase III Randomized Study
Eur Urol 2020 Jan 07;[EPub Ahead of Print], DW Lin, MC Shih, W Aronson, J Basler, TM Beer, M Brophy, M Cooperberg, M Garzotto, WK Kelly, K Lee, V McGuire, Y Wang, Y Lu, V Markle, U Nseyo, R Ringer, SJ Savage, P Sinnott, E Uchio, CC Yang, RB Montgomery
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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