EBRT + total (combined) ADT in treatment of high-risk, localized and locally advanced prostate cancer

The big news today is the publication, in The Lancet, of the interim results of the NCIC CTG PR.3/MRC UK PR07 trial, originally presented by Warde et al. at the annual meeting of the American Society for Clinical Oncology in June 2010 and then by Mason et al. at the annual meeting of the American Society for Radiation Oncology (ASTRO) that September. We have previously discussed the results of this trial in some detail, but they merit a re-review.

Unfortunately, we do not have access to the full text of the article in The Lancet by Warde et al. — only to the abstract, and to a podcast of an interview between Dr. Warde and Richard Lane, the Editor of The Lancet. However, the details of this study are well understood. The problem is how we should be interpreting its findings.

The study was designed to test the hypothesis that the combination of external beam radiation therapy (EBRT; at a dose of 65-69 Gy and 45 Gy to the pelvic lymph nodes over a course of 35-37 treatments) with any form of lifelong total androgen deprivation therapy (ADT) would offer an all-cause and/or a prostate cancer-specific mortality benefit by comparison with any form of lifelong total ADT alone in men with high-risk, localized and locally advanced prostate cancer. The trial was designed in 1993 and enrolled patients from 1995 to 2005.

In this study, the study population was defined to encompass three groups of men:

  • Those with clinical stage T3/T4 disease
  • Those with clinical stage T2 disease and a PSA level > 40 ng/ml
  • Those with clinical stage T2 disease and a PSA level> 20 ng/ml and a Gleason score of 8 to 10

Furthermore, the trial very clearly showed some striking results:

  • Total study enrollment was 1,205 patients
    • 602 patients were randomized to receive ADT only.
    • 603 patients were randomized to receive ADT + EBRT.
  • Average (median) follow-up was 6.0 years.
  • At the time of analysis,
    • 175/602 men (29.1 percent) in the ADT only group had died.
    • 145/603 men (24.0 percent) in the ADT + EBRT had died.
  • Projected overall (all-cause) survival rates at 7 years were
    • 66 percent for men in the ADT only group
    • 74 percent for men in the ADT + EBRT group
    • This result was statistically significant (hazard ratio [HR] 0.77; p=0·033).
  • Toxicity and health-related quality-of-life results showed a small effect of RT on
    • Rectal bleeding of grade > 3 — 3 patients (0.5 percent) in the ADT only group; 2 patients (0.3 percent) in the ADT + EBRT group
    • Diarrhea of grade > 3 — 4 patients (0.7% percent) in the ADT only group; 8 patients (0.3 percent) in the ADT + EBRT group
    • Urinary toxicity of grade > 3 — 14 patients (2.3 percent) in each group.

We also know that this study clearly demonstrated that the addition of EBRT to ADT significantly reduced the risk of prostate cancer-specific mortality (HR = 0.57).

At first sight one could certainly come to the conclusion that this study has proven, in dramatic fashion, that the combination of EBRT + lifelong total ADT was the most appropriate form of treatment for men with high-risk, localized and locally advanced forms of prostate cancer … and that is true, so long as one realizes that this has only been proven by comparison to lifel0ng total ADT alone and using a now outmoded form of radiation therapy.

The problem, of course, is what has changed since this study was designed:

  • The introduction of much more sophisticated forms of radiation therapy, capable of delivering radiation to the prostate in doses of > 80 Gy (although one would not want to deliver doses of that level to the pelvic lymph nodes)
  • The demonstration that intermittent androgen deprivation is no less effective in delaying disease progression than lifelong, continuous androgen deprivation
  • The evidence that lifelong, continuous androgen deprivation is associated with significant cardiovascular risk in  at least some patients
  • The evidence that shorter courses of ADT may be sufficient (in combination with radiation therapy) to induce a curative effect even in men with high-risk localized and locally advanced disease
  • The evidence that other forms of therapy (e.g., surgery) may also be effective forms of curative treatment for selected men with high-risk, localized and locally advanced prostate cancer

So — what is the actual takeaway from the available data from this well-conducted and significant study by Warde and his colleagues? In our opinion, it is the following:

  • For men with high-risk, localized or locally advanced prostate cancer and a life expectancy in excess of 5 years
    • The combination of EBRT + ADT is a highly effective form of first-line treatment that should be considered by and discussed with all appropriate patients.
    • The most appropriate dose of radiation to the prostate is now likely to be > 70 Gy, and to other areas of the pelvis such as the pelvic lymph nodes is likely to be ~ 45 Gy.
    • The most appropriate form of ADT to be used in combination with EBRT is not well defined, but may include lifelong, total ADT and  intermittent, total ADT.
    • Shorter courses of total ADT may be appropriate for some patients.
    • Other forms of treatment may also be appropriate for carefully selected patients (e.g., first-line surgery with adjuvant radiation ± ADT).

A key factor in these decisions is that long-term ADT comes with a long list of potential adverse effects, which can be severe for many patients. Men who can achieve the survival benefits of initial therapy with EBRT + ADT as compared to ADT alone without the need for lifelong treatment with ADT should not be kept on ADT any longer than is actually necessary. The problem is that we don’t know whether most men in the above study would have achieved the same levels of outcome with (say) just 2, 3, or even 5 years of total ADT as opposed to the lifelong commitment.

To be fair to Dr. Warde and his colleagues, their written conclusion from this study in The Lancet states simply that, “The benefits of combined modality treatment—ADT and [EBRT]—should be discussed with all patients with locally advanced prostate cancer.”

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