The aggressive treatment of high-risk localized and node-positive prostate cancer

Long-term follow-up data have just been published from two studies designed to provide preliminary information on the potential use of very aggressive forms of treatment in men with high-risk categories of prostate cancer.

In the first of these reports, Dibiase et al. offer us data from a prospective, Phase II trial of androgen deprivation therapy (ADT) + pelvic radiotherapy (EBRT) + a permanent transperineal prostate brachytherapy boost (PBB) + adjuvant docetaxel in patients with high-risk prostate cancer. (We will call this Study A.) In the second report, Hussain et al. provide data on a trial of  paclitaxel + concurrent EBRT + ADT in patients with high-risk prostate cancer who may or may not have been given a prior radical prostatectomy (RP). (We shall refer to this trial as Study B.)

Studies A and B were not randomized, controlled, blinded clinical trials. To all intents and purposes they were two small case series, and so the conclusions that can be drawn on the basis of these two studies are limited. Furthermore, the patient populations recruited in these two trials encompassed a wide group of “high risk” patients, making specific conclusions even more difficult. However, with those two provisions, let’s look at the data with some care.

In Study A, patients had to have biopsy-proven adenocarcinoma of the prostate and needed to meet one or more of the following eligibility criteria:

• A PSA level of > 20 ng/ml or
• A Gleason score of 7 and a PSA level of >10 ng/ml or
• A Gleason score of 8, 9, or 10 or
• Clinical stage T2b to T3 (regardless of their Gleason score or their PSA).

Their treatment followed the following course:

• Initial treatment with 45 Gy of pelvic EBRT and the initiation of ADT, followed 1 month later by
• A PBB using iodine-125 or palladium-103 seeds, followed 1 month later by
• Three cycles of docetaxel chemotherapy (35 mg/m² per week, on days 1, 8, and 15 every 28 days).

All patients received ADT for 2 years, and biochemical relapse was defined using the Phoenix criteria (i.e., the PSA nadir + 2 ng/ml).

The major results of Study A are as follows:

• Total enrollment was just 42 patients (between August 2000 and March 2004), 42 patients were enrolled.
• Median overall follow-up was 5.6 years (range, 0.9 to 7.8 years).
• Acute Grade 2 and Grade 3 genitourinary and gastrointestinal  toxicities occurred in  50.0 and 14.2 percent of patients, respectively.
• There were no Grade 4 genitourinary or gastrointestinal  toxicities.
• Acute Grade 3 and Grade 4 hematologic toxicities occurred in 19.0 and 2.4 percent of patients, respectively.
• 36/42 patients (85.7 percent) completed the planned multimodality treatment.
• 5- and 7-year actuarial freedom from biochemical failures rates were 89.6 and 86.5 percent, respectively.
• 5- and 7-year actuarial rates for disease-free survival were 76.2 and 70.4 percent, respectively.
• 5- and 7-year actuarial overall survival rates were 83.3 and 80.1, respectively, respectively.
• 5- and 7-year actuarial rates of late Grade 2 genitourinary and gastrointestinal toxicity were 7.7 percent (with no evidence of Grade 3, 4 or 5 toxicities).

The authors conclude that 2 years of ADT, combined with EBRT, PBB, and adjuvant docetaxel chemotherapy was well tolerated and produced “encouraging long-term results” in this series of 42 patients.

In Study B, patients again had to have biopsy-proven adenocarcinoma of the prostate and needed to meet one or other of two sets of eligibility criteria:

• Completion of a radical prostatectomy and
• Locally advanced prostate cancer defined by one or more of

Treatment of these patients included:

• ADT (for either 4 or 24 months)
• Weekly paclitaxel (at 40, 50, or 60 mg/m² per week)
• Pelvic EBRT (for a total dose of 64.8 Gy among the prior-RP patients; or 70.2 Gy among the patients who’d had no surgical treatment).

The major results of Study B are as follows:

• A total of 59 patients were enrolled.
• Baseline patient characteristics were:
• > 95 percent of patients received their prescribed doses of paclitaxel together with radiation and ADT; dose modifications were primarily needed among patients who had had a prior radical prostatectomy.
• No acute Grade 4 toxicities occurred.
• Grade 3 toxicities included diarrhea (in 15 percent of patients), urinary urgency/incontinence (10 percent), tenesmus (5 percent), and leukopenia (3 percent).
• Median follow-up was 75.3 months.
• Biochemical progression occurred in 24/59 patients (41 percent)
• Clinical progression (i.e., clear evidence of metastatic disease) occurred in 11 patients (19 percent).
• 5- and 7-year overall survival rates were 83 and 67 percent, respectively.
• There were no differences in overall survival between the groups of patients who did or did not have a radical prostatectomy, nor between the groups of patients who received 4 or 24 months of ADT.

In their conclusions, the authors state that concurrent ADT, radiation, and weekly paclitaxel is feasible and well-tolerated in this group of patients, with the provision that the dose of paclitaxel is limited to 40 mg/m² per week.

So what is the take-away from these two studies? We believe that the following conclusions are reasonable:

• Cancer progression was still apparent in a significant percentage of the patients in each of these studies, but most particularly in Study B. To that extent, even this form of aggressive therapy isn’t good enough to prevent progression in these high-risk patients.
• For many of the patients in these two studies who did appear to have progression-free survival, this form of aggressive treatment may well have been “overkill.” An example would be a patient with T2bN0M0 prostate cancer and a Gleason score of 8 but a PSA of 10 or less.
• All we really know from these two studies is that this type of aggressive therapy is feasible. We don’t even know whether it has any specific benefits in a subset of the wide range of patients treated.

The bottom line is that some 7 years after the approval of docetaxel for the treatment of castration-resistant prostate cancer, we still have no idea whether there is a specific subset of men with an aggressive form of prostate cancer who would really benefit from early, adjuvant, taxane-based chemotherapy in combination with hormone therapy. It’s a shame.