Early chemotherapy after failure of first-line treatment — data from a Phase II trial

It remains unclear at this time whether the early use of chemotherapy in carefully selected men with intermediate- and high-risk forms of prostate cancer (while the cancer is still believed to be limited in its spread) is associated with superior clinical outcomes compared to other forms of therapy.

Nakabayashi et al. have just published data from a long-term follow-up from a Phase II study of combined chemohormonal therapy in 62 men with biochemical relapse after first-line treatment for potentially localized prostate cancer.

Patients were enrolled on failure of or biochemical progression after first-line treatment with either radical prostatectomy or external beam radiation therapy. All patients in this study received treatment with four cycles of docetaxel (at 70 mg/m2) once every 3 weeks and estramustine (280 mg) three times a day (on days 1 to 5 of the cycle) followed by 15 months of combined androgen deprivation therapy (ADT, with goserelin acetate and bicalutamide). The primary study endpoint was the percentage of patients with PSA levels < 0.1 and with recovered testosterone 5 years after completion of therapy.

The authors report the following results:

  • Average (median) follow-up was 8.6 years (range, 1.3 to 11.1 years).
  • At 5 years of follow-up,
    • 15/62 patients (24 percent) had not required re-initiation of ADT
      • 7/62 patients (11 percent) had PSA levels < 0.1 ng/ml.
      • 8/62 patients (13 percent) had PSA levels  > 0.1 but had not required re-initiation of ADT (their median PSA level was 0.37 ng/ml).
    • Of the 15 men without re-initiation of ADT, 14 had recovered testosterone levels within the normal range.
  • The average (median) time to biochemical progression for the entire cohort was 35.0 months.
  • The following baseline characteristics were associated with a longer time to biochemical progression
    • Baseline PSA levels < 3.0 ng/ml
    • No neoadjuvant or adjuvant ADT prior to study entry
    • Radical prostatectomy (as opposed to radiation therapy) as first-line treatment.
  • At the time of the most recent analysis
    • 42/62 patients (68 percent) had restarted ADT
    • 23/62 patients (37 percent) had castration-resistant prostate cancer (CRPC)
    • 11/62 patients (18 percent) had received additional chemotherapy for treatment of progressive disease.
    • The average (median) time to re-initiation of ADT was 32.6 months (range, 0 to 107.6 months).
    • 15/62 patients (24 percent) had died but median overall survival had not been reached.

The authors conclude that:

Chemotherapy plus ADT for BR resulted in durable (> 5 years) complete responses (< 0.1 ng/ml) in 7 men (11 percent). Twenty-four percent of men have not re-initiated ADT 5 years from completion of protocol therapy.

While the data suggest that a subset of this 62-patient cohort may have responded well to early chemotherapy, it is clearly not the majority of the patients in the cohort. As far as The “New” Prostate Cancer InfoLink can tell from the available data, this study does not offer us any truly helpful clinical insights with regard to which patients might actually benefit from the early use of chemotherapy in the treatment of progressive prostate cancer after failure of first-line therapy.

3 Responses

  1. I know of a couple of other studies where chemo was tried earlier.

    In one very small pilot study, 18 high-risk patients with no detectable metastases were treated with low-dose docetaxel (20 mg/m) during high-dose radiation therapy + neoadjuvant ADT. 94% achieved biochemical progression-free survival at 2 years, which is better than any numbers I’ve seen elsewhere for radiation + neoadjuvant ADT alone. So it’s possible that the docetaxel may work synergistically with radiation if used earlier.

    However, in a larger (n = 385) randomized controlled study of docetaxel + ADT vs ADT alone among men who had known metastases but were still hormone-sensitive, there was an overall survival advantage of almost 5 months, which was not statistically significant. There were many serious adverse toxicities, including deaths early in the study, mostly due to neutropenia. They found that early treatment with GM-CSF seemed to prevent such deaths. The authors conclude “Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer.” I don’t know whether the survival advantage would have reached significance if the, perhaps preventable, docetaxel-related deaths were excluded.

    Other studies have found that docetaxel may be more effective when there are no known mets, and in lower doses when used earlier.

    So questions remain:

    — Should low-dose docetaxel be used during RT (original or salvage) for high-risk patients?
    — Should earlier docetaxel treatment be used with hormone-sensitive, non-metastatic prostate cancer in high-risk men?
    — Should earlier docetaxel treatment be used with hormone-sensitive, metastatic prostate cancer? (I think the STAMPEDE study will address this.)
    — Should earlier docetaxel treatment be used with castrate-resistant, non-metastatic prostate cancer?
    — Should lower doses be used in earlier treatment?
    — With or without estramustane?
    — Should pre-treatment with GM-CSF (e.g., Leukine) be the standard of care?

  2. Dear Allen:

    There have been many small pilot studies over the years. However, as you are careful to point out, none of these studies have ever been large enough or long enough or stratified patients into subgroups with sufficient accuracy to define which patients might really benefit.

    You are correct that trial arm C of the STAMPEDE study may help to answer one of the questions you stipulate above — and possibly as early as some time in 2014.

  3. I did a similar protocol in 2008. At the time there were some Phase II studies that suggested a durable response was possible. I hoped to be one of the durable response guys. It seemed like a good bet at the time but for me I was back on ADT within a year.

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