Early, adjuvant chemotherapy in high-risk patients after surgery

A paper presented yesterday at the now-completed annual meeting of the American Urological Association has given us new data on the role of adjuvant chemotherapy alone in the treatment of men with high-risk prostate cancer.

Lin et al. (abstract no. 740) presented the primary results of VA Cooperative Studies Group Study #553, a trial that had been designed to explore the value of early, adjuvant, docetaxel-based chemotherapy without androgen deprivation therapy for patients with prostate cancer who had received radical prostatectomy as first-line therapy, appeared to have responded well (i.e., no clear reason to believe that progression was imminent), but who were still at high risk for relapse. (See also this report on the MedPage Today web site.)

The fundamental enrollment criteria for this trial were as follows:

  • A initial histologic diagnosis of clinical stage T1 or T2 adenocarcinoma of the prostate prior to prostatectomy
  • Lymph node dissection at time of radical prostatectomy
  • One or more of the following poor prognostic features
    • Tumor extension into the seminal vesicles (pT3b) or the bladder neck (T4)
    • Established extracapsular extension (pT3a) with a Gleason score of 7 or higher
    • Organ-confined disease (pT2) with positive surgical margin and a Gleason score of 8 to 10
    • A preoperative PSA level > 20 ng/ml
  • A SWOG performance status of 0 or 1
  • A PSA nadir of ≤ 0.1 ng/ml at up to 30 days prior to randomization

Men with metastasis or lymph node-positive disease were not eligible for inclusion in this trial. In addition, the patients were required to be randomized to the trial within 120 days after their prostatectomy.

Patients were randomized either to simple monitoring, with “standard care” to address any clinical issues, but no further treatment of the prostate cancer or to adjuvant chemotherapy with docetaxel + prednisone every 3 weeks for 18 weeks (i.e., six cycles of chemotherapy). Randomization was stratified for PSA, Gleason score, tumor stage, and the presence of positive margins, within each of the 300 clinical study sites. The primary endpoint was progression-free survival.

It should be noted that the trial was initially designed to enroll 400 patients but this was later reduced to 300 patients because of “resource issues” (i.e., lack of appropriate funding).

Here are the core results reported by Lin et al.:

  • 297 patients enrolled and randomized between July 2006 and October 2011 were included in the analysis.
    • 157/297 (52.9 percent) received standard care.
    • 140/297 (47.1 percent) received adjuvant chemotherapy.
  • Average (median) follow-up was 62.4 months (range, 0.2 to 104.3 months), which is just over 5 years.
  • There was no statistically significant difference in median time to progression-free survival between the two groups.
    • 45.6 months in the standard care group
    • 55.5 months in chemotherapy group
  • Compared to standard care, subgroup analyses showed a clear benefit in progression-free survival for two sets of men receiving chemotherapy.
    • Men with a tumor stage ≥ T3b (hazard ratio [HR] = 0.58)
    • African Americans (HR = 0.54)
  • The most common adverse events of Grade 3 or higher that were related or possibly related to chemotherapy included neutropenia (in 40 percent of patients), hyperglycemia (in 18 percent), and fatigue (in 5 percent).
  • Febrile neutropenia was observed in 1.4 percent of chemotherapy patients.

It is apparent that this trial, in the end, was probably too small to show a benefit in the entire cohort of patients (if such a benefit was going to occur).

The authors conclude that:

Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone was well tolerated and did not lead to statistically significant improvement in progression-free survival for the ITT population as a whole. Subgroup analyses suggest potential benefit for patients with higher risk pathology (≥ pT3b) and African-American ancestry, supporting ongoing and planned trials of systemic chemotherapy for hormone-sensitive prostate cancer.

This trial clearly shows us that there may well be benefits associated with early, adjuvant chemotherapy (with or without androgen deprivation) in some carefully characterized subsets of patients with high-risk localized, lymph node-negative prostate cancer who receive standard forms of treatment. The problem is going to be teasing out which patients are most likely to benefit and (just as importantly) which patients are most likely to have significant risk for side effects and minimal potential for a survival benefit.

As discussed in the MedPage Today article referenced above, there are now multiple trials that are exploring the issue of exactly when and in whom to use early chemotherapy among high-risk, non-metastatic patients. Hopefully we will start to see some greater clarity about such issues in the near future. In the meantime, Dr. Lin and others are already stating that the data from this trial should be used to inform discussions with at least some patients at high risk after first-line treatment.

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