Adding docetaxel to ADT and radiation therapy for high-risk prostate cancer

Earlier today, at the annual meeting of the American Society of Clinical Oncology (ASCO), we were given the results of RTOG 0521 — a large, randomized trial of adding docetaxel chemotherapy to androgen deprivation therapy (ADT) and radiation therapy for men with high-risk prostate cancer.

The late-breaking data presented by Sandler et al. will be discussed below, but we should be clear that there have been a number of highly positive media reports (see for example this one on the Medscape web site) about this presentation that do not reflect our view of the data — or the view of Dr. Ian Tannock, who was responsible for critiquing the study data at the actual presentation.

It had been hypothesized, back in the early 2000s, that adding adjuvant treatment with docetaxel + prednisone to long-term ADT (for 24 months) and radiation therapy might improve the overall survival of men with high-risk localized prostate cancer at time of diagnosis. The  RTOG 0521 trial was designed to address that question.

Between December 2005 and August 2009 the RTOG 0521 trial sought to enroll 600 men with high-risk, localized prostate cancer. The stated goal was to detect an improvement in 4-year overall survival from 86 to 93 percent with a 51 percent hazard reduction (i.e., an HR = 0.49) between men randomized to treatment with 24 months of ADT + radiation therapy and those randomized to ADT + radiation therapy + adjuvant chemotherapy.

Patients had to have a PSA level of ≤ 150 ng/ml and meet one of the following sets of criteria to be enrolled in the trial:

  • A Gleason score of 7 to 8, any T stage, and a PSA level > 20 ng/ml
  • A Gleason score of 8, a clinical stage of T2 or higher, and any PSA level
  • A Gleason score of 9 to 10, any T stage, and any PSA level.

All patients were treated with 75.6 Gy of radiation therapy, with an LHRH agonist for 2 years starting prior to the radiation therapy, and with an anti-androgen started at the same time as the LHRH agonist but stopped at the end of radiation therapy. The patients randomized to receive adjuvant chemotherapy were also treated with six 21-day cycles of docetaxel + prednisone starting 28 days after completion of radiation therapy.

Here are the study results:

  • 612 patients were actually enrolled as study participants, but 50 were excluded for eligibility issues, and so the total number of evaluable patients was 562.
  • The 562 evaluable patients had
    • An average (median) age of 66 years
    • An average (median) PSA level of = 15.1 ng/ml
  • In addition, 53 percent of the enrollees had a Gleason score of 9 or 10, and 27 percent had clinical stage T3 or T4 disease.
  • Average (median) follow-up was 5.5 years.
  • The 4-year overall survival rates were
    • 89 percent for men in the ADT + radiation therapy arm
    • 93 percent for men in the ADT + radiation therapy + chemotherapy arm
    • This difference was statistically significant (p = 0.03) based on a one-sided p-test (but see below).
  • The number of centrally-reviewed deaths in the study was
    • 52 among men in the ADT + radiation therapy arm
    • 36 among men in the ADT + radiation therapy + chemotherapy arm
  • There were fewer deaths due to prostate cancer or its treatment (20 vs. 16) and due to other causes/unknown (32 vs. 20) in the ADT + radiation therapy + chemotherapy arm.
  • The 5-year disease-free survival rates were
    • 66 percent for the men in the ADT + radiation therapy arm
    • 73 percent for men in the ADT + radiation therapy + chemotherapy arm
  • As one might expect, adverse events of Grades 3, 4, and 5 were notably more common in the ADT + radiation therapy + chemotherapy arm of the trial.

Sandler et al. conclude that

  • Adjuvant chemotherapy in addition to ADT + radiation therapy improved the overall survival of men with high-risk, localized prostate cancer from 89 to 93 percent at 4 years.
  • The toxicity of the adjuvant chemotherapy was “tolerable”.
  • The trial was designed with a short assessment period for overall survival and additional follow-up is warranted.

However, what is clear is that this trial did not in fact meet its original pre-specified endpoint for clinical benefit (4-year overall survival from 86 to 93 percent with a 51 percent hazard reduction). In addition, as pointed out by Dr. Tannock in discussing these trial results, the trial did not meet statistical criteria for success if one applied a standard two-sided p-test (in which case the statistical significance was p = 0.08)

Like Dr. Tannock, The “New” Prostate Cancer InfoLink finds the results of this trial to be interesting, but we do not feel that they can be used (yet) to justify adjuvant chemotherapy on top of ADT and radiation therapy as a routine form of treatment for all men with high-risk, localized prostate cancer. Longer follow-up will be needed to determine whether such a decision could possibly be justified.

3 Responses

  1. A few thoughts on this study …

    As a high-risk patient who chose a treatment just a couple of years ago (attempting a cure with radiation plus ADT and supportive tactics, based on better technology after about 13 years of successful IADT), I am reflecting what I would have done if these results had been available at the time. I believe I would have opted to bypass the chemo for reasons Sitemaster and Dr. Tannock have mentioned, especially the tentativeness of results and the added side effects of chemo for what appears to be a significant but not overwhelming advantage, especially considering advances that are now widely put to use over the radiation dose employed and imaging then likely used.

    Regarding the dose of RT used, 75.6 Gy: research has demonstrated an advantage and safety for a higher dose in the range of 78 to 81 Gy using IMRT/IGRT (image-guided RT). Therefore, based on use of a higher dose, whatever advantage there was in the chemo arm would be decreased by likely improvement in the arm without chemo. Moreover, there have been advances in pre-RT imaging to stage the patient more reliably, which also would have decreased any advantage in the chemo arm.

    As Sitemaster indicated, follow-up at 4 years is very short these days with survival of nearly 100% of non-metastatic patients at the 10-year point.

    Chemo probably does have some benefit, as was demonstrated in the impressive study last year that showed an advantage of ADT plus chemo for the first round of ADT for high-risk patients.

    The key will be the bang for the buck — the incremental benefit versus the costs (meaning mainly side effects). If I had been a Gleason 9 or 10 patient, as were many of the patients in this study, I believe I would have given results from this study very serious consideration in choosing a therapy.

  2. While the survival improvement is statistically significant, I don’t know if it’s clinically meaningful enough to change standard practice. Perhaps additional analysis will be able to identify a subset of men who are most likely to benefit from adjuvant docetaxel.

    I wanted to reiterate a point I made about docetaxel use with RT in your previous article on the STAMPEDE trial. I expect the best use of docetaxel + ADT + RT will turn out to be for newly diagnosed high-risk men with multiple metastases. Because RTOG 0521 screened out men with metastases, these data cannot be used to determine that.

    I also want to point out that the radiation dose used here is on the low side compared to today’s IMRT, which is typically around 80 Gy. Given the impressive results of combination brachytherapy + EBRT in the recent ASCENDE-RT trial, it is entirely possible that equivalent or better results could have been achieved without adding docetaxel to the mix.

  3. How can one know what this result means, with such a short follow-up period? We know that not all patients respond identically to Taxotere. What if there is a subset of this group (say 20%) that have a spectacular benefit from the Taxotere? We would never know it from this report. Longer follow-up is surely needed. Data on biochemical recurrence would also help.

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