Wednesday, September 9, 2020

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:

The NCCN intermediate-risk group is currently defined as having any of the following:
- Stage T2b or T2c, or
- PSA 10- 20 ng/ml, or
- Gleason score = 7 
(If multiple risk factors are present, the clinician may optionally deem it high risk)

Unfavorable Intermediate Risk (UIR):
- NCCN intermediate risk, as defined above, plus
- Predominant Gleason grade 4 (i.e., Gleason score 4+3), or
- Percentage of positive biopsy cores≥ 50%, or
- Multiple NCCN intermediate risk factors

Favorable Intermediate Risk (FIR):
- 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, it 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. They lacked biopsy core information on 16%, who are excluded from their analysis. Zumsteg et al. found that adding 4 months of ADT:

  • more than doubled 15-year metastasis-free survival and prostate cancer-specific survival among UIR patients. 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
  • 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 overtreated, it was a worthwhile effort.

6 comments:

  1. I thought that GS3+3=6 was a LOW risk.
    I know I am Unfavorable Intermediate Risk (UIR):because my GS4+3=7 and my PSA =20.0 ng/ml.
    I am on ADT(Lupron Depot 22.5 mg/12 weeks X 2 with VMAT 60 Gy/20 fx.

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    Replies
    1. Not necessarily. GS6 with a PSA between 10 and 20 or with Stage 2b or 2c is intermediate risk.

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    2. By this NCCN rules:
      The NCCN intermediate-risk group is currently defined as having any of the following:
      - Stage T2b or T2c, or
      - PSA 10- 20 ng/ml, or
      - Gleason score = 7
      (If multiple risk factors are present, the clinician may optionally deem it high risk)
      Since I am G(4+3=7) and my PSA is 13.7 (20.2 1 day post-biopsies) then I am with multiple risk factors I shoud be a High Risk.

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    3. NCCN puts that at the clinician's option. If your doctor wants to treat you as if you are a high-risk patient, that is reasonable. But it is also reasonable to treat you as a UIR patient. There are few differences in treatment options for those categories anyway. Brachy boost therapy has the best results for either. (It's strange that they would do a PSA test one day after a biopsy - that result should be ignored.)

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  2. Even if FIR patents showed no benefit of added ADT, there is very little harm in 4 months of ADT. Besides, the categorization of patients into FIR vs. UIR is flawed, since it is based typically on random biopsy, which may miss a 4+3 tumor. Takeaway: to be safe, get the ADT.

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    Replies
    1. The categorization is not flawed. The categories are based on what is detected on a random biopsy, not what is actually there. The randomized trial showed that 4 months is better than 0 months, not that 4 months is optimal. It is probable that 18 months is better. The harm it does depends on the patient. No one should take powerful drugs like ADT if they don't need them.

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