Adding ADT to external beam radiation only benefits unfavorable risk patients

In 2013, Zumsteg et al. proposed a refinement in the NCCN “intermediate risk” classification into two subcategories, “favorable intermediate-risk (FIR)” and “unfavorable intermediate-risk (UIR).” Based on retrospective studies with short follow-up, they discerned that the two subgroups had divergent prognoses when treated with external beam radiation and adjuvant androgen deprivation therapy (ADT). Since then, others have found that it is also a useful division for deciding whether brachy boost therapy is beneficial (see this link), or whether it is beneficial to add ADT to brachytherapy (see this link). Some FIR patients may be suitable candidates for active surveillance.

It has also been found to be a useful division in terms of prognosis following surgery, brachytherapy, and SBRT (see this link). Some clinical trials use the definition to distinguish “favorable risk” (low risk or FIR) from “unfavorable risk” (UIR or high risk).  Since 2016, NCCN has incorporated the distinction in its risk stratification system.

The NCCN definitions are as follows:

  • NCCN intermediate-risk group
    • Stage T2b or T2c, or
    • PSA 10- 20 ng/ml, or
    • Gleason score = 7

(Note that if multiple risk factors are present, the clinician may optionally deem it high risk.)

  • Unfavorable intermediate risk (UIR) group
    • NCCN intermediate risk, as defined above, plus
    • Predominant Gleason grade 4 (i.e., Gleason score 4 + 3), or
    • Percentage of positive biopsy cores ≥ 50 percent, or
    • Multiple NCCN intermediate risk factors
  • Favorable intermediate risk (FIR) group
    • NCCN intermediate risk, as defined above, but only those with
    • Predominant Gleason grade 3 (i.e., Gleason score 3+4 or 3+3), and
    • Percentage of positive biopsy cores <50%, and
    • No more than one NCCN intermediate risk factor

Now, this classification system has been found to be a useful distinction in an unplanned secondary analysis of a randomized clinical trial, with 17.8 years of median follow-up. Such a long follow-up is unusual for a clinical trial and gives us the ability to see significant numbers of mortality and metastases even in intermediate-risk patients.

The trial, RTOG 9408, was originally conducted among 1,068 intermediate-risk patients who received 66.6 Gy to the prostate (low by today’s standards) and 46.8 Gy to the pelvic lymphatics. Half the patients received 4 months of adjuvant ADT, and half received none. The study lacked biopsy core information on 16 percent of the patients, who are excluded from the current analysis.

Zumsteg et al. found that adding 4 months of ADT to the radiation therapy:

  • More than doubled 15-year metastasis-free survival and prostate cancer-specific survival among UIR patients — and average (mean) overall survival was 0.7 years longer with ADT)
  • Had no statistically significant effect on 15-year metastasis-free survival, prostate cancer-specific survival, or overall survival among FIR patients

They also note that it took about 6 years for the differences to start to be noticeable.

Given all the retrospective studies we’ve seen before that all point to FIR vs UIR as a useful and significant distinction, this is not surprising. It did take a lot of work to review pathology reports on almost a thousand patients, and the authors are to be commended for doing so. If it spares some FIR men from being over-treated, it was a worthwhile effort.

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

3 Responses

  1. I don’t see where it says in the actual study, having read it, where 15 year survival for UIR is doubled? Did I miss something?


  2. Dear Clare:

    Have a look at the table and the figure in the SECOND of the two papers by Zumsteg et al. referred to in this commentary.

  3. Clare,

    I did not say that 15-year survival doubled. It increased by 0.7 years. In the table the Sitemaster refers to, the 15-year incidence and hazard ratio (HR) of PCSM and DM are less than half among those with UIR when ADT was used.

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