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Veterans affairs cooperative studies program study #553: chemotherapy after prostatectomy for high-risk prostate carcinoma: a phase III randomized study

  • Daniel W. Lin 1,
  • Mei-Chiung Shih 2,
  • William Aronson 3,
  • Joseph Basler 4,
  • Tomasz M. Beer 5,
  • Mary Brophy 2,
  • Matthew Cooperberg 6,
  • Mark Garzotto 5,
  • W. Kevin Kelly 7,
  • Kelvin Lee 2,
  • Valerie McGuire 8,
  • Yajie Wang 2,
  • Ying Lu 8,
  • Vivian Markle 1,
  • Unyime Nseyo 9,
  • Robert Ringer 2,
  • Stephen J. Savage 10,
  • Patricia Sinnott 2,
  • Edward Uchio 7,
  • Claire C. Yang 1,
  • R. Bruce Montgomery 1
1 VA Puget Sound Health Care System, Seattle, WA, USA 2 VA Cooperative Studies Program, Albuquerque, NM, USA 3 West LA VA, Los Angeles, CA, USA 4 San Antonio VA, San Antonio, TX, USA 5 Portland VA, Portland, OR, USA 6 San Francisco VA, San Francisco, CA, USA 7 West Haven VA, West Haven, CT, USA 8 Stanford University, Stanford, CA, USA 9 Gainesville VA, Gainesville, VA, USA 10 Charleston VA, Charleston, SC, USA

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).

The Chemotherapy after Prostatectomy (CAP) study explored the use of a chemotherapy medication called docetaxel in patients who have undergone an operation to remove high-risk, localized (=restricted to the prostate) prostate cancer. The findings indicate that docetaxel doesn’t offer patients any survival advantages and thus should remain to be prescribed in case of metastatic cancer, cancer that has spread to other parts of the body, only. Docetaxel should not be used as a safety procedure after prostate cancer surgery.

Commented by Prof. Tsaur

The Chemotherapy after Prostatectomy (CAP) study is a randomized prospective controlled phase 3 trial assessing adjuvant treatment with 6 cycles of docetaxel after prostatectomy in high-risk patients with prostate cancer. At least one of the following high-risk defining criteria had to be met for enrollment: pT3b/4 disease, pT3a and Gleason score (GS) 7-10, pT2 and GS 8-10 with positive surgical margin, and preoperative PSA >20 ng/ml. Furthermore, PSA nadir ≤0.1 ng/ml as well as no evidence of nodal involvement were required. Patients were randomized to receive chemotherapy or standard of care with observation within 120 d after surgery with progression-free survival (PFS) as a primary end-point.

Only 298 out of estimated 636 patients were finally randomized, whereby neither PFS nor secondary end-points of metastasis-free survival, all-cause mortality as well as initiation of androgen deprivation treatment (ADT) differed significantly between the study arms in the overall intention-to-treat population. The prespecified subgroup analyses yielded a PFS advantage in the cohorts with pT3b/4 disease as well as GS ≤7 favoring cytotoxic therapy.

One reason for the lack of the therapy benefit in the study cohort could be a lower than anticipated accrual reducing the power of the study to detect statistically significant differences. Another critical aspect is that no ADT has been concomitantly utilized for fear of cell cycle arrest potentially leading to alleviated efficacy of docetaxel. If concurrent ADT would alter the efficacy of docetaxel in the current setting is unknown. Surprising is moreover the counterintuitive finding of the benefit of docetaxel for patients with a less aggressive disease. This finding might be attributable to some imbalance in PFS-relevant characteristics of the prespecified cohorts with GS ≤7 and ≥8 resulting from insufficient accrual.  All-in-all, no indication exists for docetaxel to be used in the adjuvant setting after prostatectomy so far. Further research is warranted to reliably identify patients with a high-risk (often micrometastatic) disease who could benefit from adjuvant strategies.