Neoadjuvant CHT + surgery for men with high-risk, localized prostate cancer

Eastham et al. have recently reported — in the Journal of Clinical Oncology — results from a randomized Phase III trial of the surgical treatment of men with high-risk forms of localized prostate cancer.

Some physicians have believed for quite a while that, when men are diagnosed with clinically localized, high-risk prostate cancer, it may be beneficial to treat them with neoadjuvant chemohormonal therapy (CHT), i.e., with androgen deprivation therapy (ADT) + docetaxel, and then with a radical prostatectomy, as opposed to just treating them with a radical prostatectomy alone.

Eastham et al. conducted a randomized Phase III trial to test this hypothesis. Patients diagnosed with clinically localized, high-risk prostate cancer were randomly assigned to neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m2 every 3 weeks for 6 cycles) and then a radical prostatectomy or to radical prostatectomy alone. The primary study end point was 3-year biochemical progression-free survival (bPFS). Biochemical failure was defined as a serum PSA level > 0.2 ng/mL that increased on two consecutive occasions that were at least 3 months apart. Secondary end points included 5-year bPFS, overall bPFS, local recurrence, metastasis-free survival (MFS), prostate cancer-specific mortality, and overall survival (OS).

While the full text of this article is not immediately accessible on line, there is also a report on the article that can be found on Cancer Therapy Advisor.

The core findings of the study to date are as follows:

  • 788 men were randomly assigned to one or the other form of treatment, and among these patients
    • The average (median) age was 62 to 63 years
    • 70 percent had a Kattan risk score of 3 or 4
    • 85 to 90 percent had a biopsy Gleason score of 8 to 10
    • 13 percent had previously received ADT
    • > 80 percent were clinical stage T1or T2
  • Average (median) follow-up was 6.1 years.
  • Overall rates of significant adverse events during chemotherapy were
    • 26 percent for grade 3 adverse events
    • 19 percent for grade 4 adverse events
  • There was no significant difference in 3-year bPFS between neoadjuvant CHT + radical prostatectomy and radical prostatectomy alone (0.89 v 0.84, respectively; P = 0.11).
  • There were no significant differences between the two study arms regarding 5-year bPFS and prostate-cancer specific mortality,
  • Compared to radical prostatectomy alone, neoadjuvant CHT + radical prostatectomy was associated with
    • Significant pathologic downstaging
    • Significantly fewer positive surgical margins
    • Improved overall bPFS (hazard ratio [HR] = 0.69)
    • Improved MFS (HR = 0.7
    • Improved OS (HR = 0.61)

However, the authors conclude that:

The primary study end point, 3-year bPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and [radical prostatectomy] in patients with clinically localized, high-risk [prostate cancer] at this time.

Having said all of this, it should also be noted that there was a significant study limitation mentioned by the authors. This was use of salvage therapy (most commonly radiation therapy with or without ADT) prior to meeting the primary endpoint. Such early salvage therapy occurred in 43 percent of patients receiveing neoadjuvant CHT + radical prostatectomy and in 52 percent of patients treated with radical prostatectomy surgery alone. Eastham et al. suggest that consequent early censoring of these patients may have compromised the power of the study.

The authors also note that a subsequent analysis of event-free survival in these two groups of patients, in which patients receiving salvage therapy were considered to have experienced treatment failure, showed a significantly longer event-free survival time for men treated with neoadjuvant CHT + surgery compared with surgery alone (HR = 0.61).

One does have to wonder whether, if there had been  a significantly larger number of patients enrolled into this trial, and a somewhat different set of criteria set for the definition of treatment failure necessitating salvage therapy, the trial might, in fact, have met its primary endpoint. But the question of whether neoadjuvant CHT prior to surgery for most high-risk patient with localized prostate cancer may still revolve around whether the risk for grade 3 and grade 4 adverse events negates what may be a relatively small set of survival benefits.

One Response

  1. Seems like the researchers were between a rock and a hard place here. They must have realized that permitting salvage therapy would significantly pollute results. However, how could they withold a key treatment proven to prevent disease advancement?

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