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
    • Pathological stage T3 disease or
    • A rising PSA level ≥ 0.5 ng/ml post-surgery
  • Locally advanced prostate cancer defined by one or more of
    • Clinical stage T2b-T4N0M0 or T2b-T4N+M or
    • A Gleason score of 8, 9, or 10 or
    • A Gleason score of 7 and a PSA level of 10-20 ng/ml or
    • A PSA level of between 20 and 150 ng/ml (but no actual evidence of metastatic prostate cancer).

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.
    • 30 men had received a prior radical prostatectomy; 29 had not.
    • 30 men received 24 months of ADT; 29 were given just 4 months of ADT.
  • Baseline patient characteristics were:
    • Median age 67 years (range, 45-86 years)
    • Median PSA level 5.9 ng/ml (range, 0.1-92.1 ng/ml)
    • Median Gleason score 8 (range, 6-9).
  • > 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.

7 Responses

  1. Mike: I promise to keep banging the same drum. Prostate cancer studies typically are immature to give us that all important piece of information — prostate cancer-specific mortality. And in being too short they are of little use for us 44-years-old at diagnosis guys. I fit perfectly into both study criteria and decided to be more aggressive with my therapies — RALP, IMRT, ADT for 28 months. I even considered entering the Sanofi-Aventis study using Taxotere but decided to not join because at the time (February 2007) they would not allow the radiation for my positive margins. While I am somewhat encouraged by study A, 7 years is not my goal. 37 years is. I guess I’ll have to be my own study….

    Oh yes, the drum. … Prostate cancer studies, and the physicians doing them, need to focus on longer terms than they do today. These studies could be very helpful with follow up in another in a decade or so.

  2. Tony:

    You are going to need to help to persuade people to fund these 20-year-long studies. I agree with your premise, but I also know what the costs are. And if we are going to do 20-year-long studies, I sincerely hope they would be much better designed than these two case series.

  3. Another study that makes you scratch your head. Look into the 2010 recap and click on the 12-year brachytherapy results. Those outcomes are significantly better than these, at 12 years instead of 5-7, and with men of Gleason 8+. It looks from that information that the “throw everything at it” approach of this study did not result in better outcomes and at an incredible price in terms of dollars and suffering. I would say that the 40% progression in 6 years is among the worst I have ever seen for any treatment modality at any risk level.

  4. i would hope that the advocacy groups would be that help. So far I run into very little resistance from anyone with a prostate cancer advocacy background when I talk about this subject. We ask the government for research dollars by signing petitions all of the time. Short-term research studies are important, but so is making sure that the research monies granted by the government will help fund the longer terms of certain studies. Just a silly thought I guess.

  5. Radiation doses: Regarding Study A, the pelvic dose was 45 Gy; regarding Study B, “pelvic radiation therapy (total dose: RP = 64.8 Gy; LAPC = 70.2 Gy).” I’m wondering if that would be considered enough, in view of the concurrent therapy, from the viewpoint of current radiation standards. Maybe it’s enough to the pelvis, considering the other therapies employed.

    Androgen deprivation therapy: Neither abstract describes the type of ADT. I suspect it was just single ADT, either an LHRH agonist or orchiectomy. I wonder what the results would have been if an antiandrogen, or perhaps triple ADT, had also been employed.

  6. Tony, I think that in today’s medical world the treatments available in 10 more years may be so different than what we have now that any information on them would be nearly useless. Using RP data from 1990 might be worth something; radiation data is available at +10 years and that technology has improved. Most studies show a real leveling off of recurrence rates after 5 years and certainly after 10. Best wishes, PC in your 40s is a tough deal.


    Hi especially to Tony and Sitemaster regarding your 11/29 7:18 PM (Tony) 11/29 11:27 PM (Sitemaster) and 11/30 1:44 PM posts regarding length of follow-up.

    I’m sitting back scratching my head about follow-up today after watching the whole FDA advisory committee hearing which ended up with a thumbs down for both finasteride and dutasteride label changes covering prevention.

    Those of us who think about these things have realized for some time that follow-up was grossly inadequate for both the PLCO and ERSPC (have I got the acronym right) screening trials published in the New England Journal of Medicine last year. While those short follow-up times (among other flaws) seriously undermined the conclusions in both studies, both were cited today at least twice as authoritative in the FDA hearing.

    On the other hand, some presenters as well as members of the advisory panel rightly noted that 4 years of follow-up (REDUCE for Avodart prevention of PC) was on the short side.

    I’m thinking maybe the PLCO and ERSPC trialists had their sleeves rolled up, gave a special handshake, and winked when they submitted for publication whereas the PCPT and REDUCE trialists did not.

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