Showing posts with label unfavorable intermediate risk. Show all posts
Showing posts with label unfavorable intermediate risk. Show all posts

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.

Monday, October 15, 2018

Low Dose Rate Brachytherapy Monotherapy at the Mayo Clinic

The Mayo Clinic reported the 10-year oncological results on 974 consecutive low and intermediate risk patients treated with low dose rate brachytherapy (I-125 seeds) monotherapy from 1998 to 2013.

Patients were treated as follows:

  • 90% of the prostate received 159 Gy (median dose) of 1-125 seeds
  • 26% received some ADT (mainly to shrink the prostate)

Patient characteristics (number (%)) were as follows:

  • Gleason 6: 783 (80%)
  • Gleason 3+4 :153 (16%)
  • Gleason 4+3:  38 (4%)
  • Stage T 2b or 2c: 24 (2.5%)
  • PSA ≥ 10: 93 (10%)
  • Low risk: 693 (71%)
  • Intermediate risk: 281 (29%)

While they did not routinely collect data on the percent of positive biopsy cores, they did define an "unfavorable intermediate risk" cohort as having Gleason 4+3 or multiple intermediate risk factors.

With median follow-up of 6 years, there were only 45 cases of biochemical failure, and 10 deaths from any cause. The 10-year biochemical recurrence-free survival was:

  • 85% overall
  • 90% among low risk men
  • 74% among intermediate risk men

The following hazard ratios were significant on multivariate analysis:

  • Gleason score 4+3: 7.0
  • Use of ADT: 0.3
  • PSA (per unit increase): 1.17
  • Unfavorable intermediate risk : 3.75

Predominant Gleason pattern 4 also affected the rate of distant metastases and prostate cancer-specific survival. Use of ADT did not. Local recurrence was only 2%.

Radiation dose was consistently escalated, so the effect of dose differences failed to meet statistical significance. Patient selection has changed over the years. Low risk men are routinely steered towards active surveillance. Multiparametric MRI is now used to stage intermediate risk candidates in order to find those where cancer is likely to have escaped the prostate capsule or penetrated the seminal vesicles -- those patients may be offered multimodal radiation with both external beam therapy and a brachy boost. While use of monotherapy was rare among those with GS 4+3, it is probably much rarer today. Monotherapy seems to be sufficient in favorable intermediate risk men.

This study had similar results to those reported by Cleveland Clinic (see this link). It also affirms that monotherapy is all that's needed for favorable intermediate risk (see this link), and that brachy boost therapy is needed for unfavorable risk patients (see this link). These are reflected in current guidelines (see this link). The use of ADT beyond cytoreduction does not seem to be necessary, at least in high risk men receiving brachy boost therapy (see this link). This study did not address the toxicity of brachytherapy, which should be discussed with one's brachytherapist.

With thanks to Brian Davis for allowing me to read the full text of his study.

Monday, March 19, 2018

Escalated radiation dose doesn't improve 8-year overall survival in intermediate risk men (but does it matter?)

Last week, we saw that escalated dose did not improve 10-year overall survival in high-risk men (see this link). The latest published findings of the randomized clinical trial (RTOG 0126) prove that 8-year overall survival was not improved in intermediate risk men who received a higher radiation dose. In both studies, we are left wondering whether that matters.

Michalski et al. reported the results of RTOG 0126, a randomized clinical trial (RCT) designed to prove that escalated dose improves survival in intermediate risk men. It was a very large trial:
  • 1499 men
  • 104 sites in the US and Canada
  • Patients treated from 2002 to 2008
  • Median age was 71
The patients were all intermediate risk, defined as:
  • Stage T1b-T2b, and
  • Gleason score ≤ 6 and PSA ≥10 and <20 (16%), or
  • Gleason score = 7 and PSA < 15 (84%)
  • 71% were Gleason score 3+4
The treatment consisted of:
  • either low dose 70.2 Gy/ 39 treatments 
  • or high dose 79.2 Gy/ 44 treatments
  • delivered using 3D-CRT (66%) or IMRT (34%)
  • none had adjuvant ADT, but they may have had salvage ADT or other salvage therapies if RT failed
After a median follow-up of 8.4 years:
  • 8-year overall survival was 75% for the low-dose group vs. 76% for the high-dose group (not significantly different)
  • 8-year prostate cancer mortality was 4% for the low-dose group vs. 2% for the high-dose group (not significantly different)
  • 8-year biochemical failure was 35% for the low-dose group vs. 20% for the high-dose group (significantly different)
  • 8-year local progression (felt with DRE) was 6% for the low-dose group vs. 3% for the high-dose group (significantly different)
  • 8-year distant metastases (bone scan/CT detected) was 6% for the low-dose group vs. 4% for the high-dose group (significantly different)
  • 8-year salvage therapy was 22% for the low-dose group vs. 14% for the high-dose group (significantly different)
Toxicity outcomes were as follows;
  • Acute grade 2+ urinary toxicity was 17% for the low-dose group vs. 17% for the high-dose group (not significantly different)
  • Late-term grade 2+ urinary toxicity was 7% for the low-dose group vs. 12% for the high-dose group (significantly different)
  • Acute grade 2+ rectal toxicity was 5% for the low-dose group vs. 7% for the high-dose group (not significantly different)
  • Late-term grade 2+ rectal toxicity was 15% for the low-dose group vs. 21% for the high-dose group (significantly different)
In a separate analysis of the high-dose group:
  • Acute grade 2+ urinary and rectal toxicity was 15% among those treated with 3D-CRT vs. 10% among those treated with IMRT (a significant difference)
  • Late-term grade 2+ urinary toxicity was not significantly different among those treated with 3D-CRT vs. IMRT
  • Late-term grade 2+ rectal toxicity was 22% among those treated with 3D-CRT vs. 15% among those treated with IMRT (a significant difference)
This RCT raises many important questions about the design of clinical trials and the validity of conclusions drawn from them. Dr. Michalski addressed some of these concerns in an audio interview presented with the published study. This was an enormous undertaking, running almost two decades from design to reporting, and coordinating the treatments and reporting of 1,500 men in over 100 sites spread throughout Canada and the US.

The results show that dose escalation was not needed to increase 8-year survival in these intermediate risk patients. But this probably won't change practice for a number of reasons.

The intervening endpoints are of considerable importance to patients: the anxiety associated with rising PSA, the toxicity of all the salvage therapies, and the pain and possible crippling due to metastases all impact quality of life.

The median age of the men at treatment was 71, and they were screened for good performance status. The actuarial life expectancy in the US for a 71 year-old men is 14 years. This implies that they ought not make a decision based on expected survival for only 8 years. Also, as radiation-treated men get treated at a younger age, the gap will become more pronounced. According to the Memorial Sloan Kettering Life Expectancy Nomogram, a 71 year-old intermediate-risk man in good health has only a 8% probability of succumbing to prostate cancer in 10 years (vs 3% in 8 years in this study), and 12% at 15 years if he had no treatment whatever. At the same time, his probability of dying from other causes is 30% in 10 years, and 51% in 15 years. The overall survival improvement may not become apparent until median survival is reached in 15 years. And differences in prostate cancer survival are difficult to discern when numbers are this low. But it is difficult and costly to track patients for 15-20 years. We have to look to surrogate endpoints.

While 8-year overall survival and prostate cancer-specific survival did not improve, all the intervening endpoints did. Biochemical failure, local progression, distant metastases, and use of salvage therapies were all worse in the low-dose group.  It is very costly and difficult to run an RCT long enough to see a survival difference in men with localized prostate cancer. As we've seen, the few RCTs that have run the longest for each type of therapy have been single institution studies with much smaller sample sizes. Distant metastasis-free survival is probably a better surrogate endpoint if the study can't run for 15-20 years. There were enough metastatic events to see a difference. A recent analysis by the ICECaP Working Group of 12,712 patients in 19 clinical trials of radiation in localized prostate cancer showed that 5-year metastasis-free survival was almost perfectly correlated with overall survival. By reducing the time needed to accumulate data, this might increase the relevance of such trials while reducing their costs.

As Dr. Michalski points out, survival in both groups was much better than expected when the study was designed in 2001. This is largely because life-extending salvage therapies (e.g., docetaxel, GnRH agonists, Zytiga, Xtandi, Xofigo, and Provenge) have become prevalent in the interim.

Toxicity was markedly reduced by the introduction of IGRT/IMRT technology that became increasingly available, especially in the US, in the last 20 years. With the improvement in beam accuracy and the knowledge of the dose/toxicity relation of organs at risk, tighter dose constraints for organs at risk have been utilized. Because of the technology changes, a high-dose regimen today is probably no more toxic than a low-dose regimen. So, if there is little toxicity cost to the more effective treatment, why not use it? Rapidly adopted changes in radiation technology in the last 20 years, especially the shift from 3D-CRT to IMRT, render many of the findings irrelevant to today's standard practice.

Another RCT reported by Nabid et al. at the 2015 Genitourinary Conference had similar findings. They found that 10 year overall survival was no different for higher dose (76 Gy vs 70 Gy) or the addition of short-term ADT. Biochemical failures were actually worse in the higher dose group, but only if short-term ADT was not used with it. Zaorsky et al. conducted a meta-analysis of dose escalation trials in intermediate risk men and arrived at a similar conclusion. A contrary finding was noted by Kalbasi et al. in their analysis of the National Cancer Database. They found that there was a significant survival increase associated with higher dose (hazard ratio = 0.84). In fact, for every 2 Gy increase in dose, there was an 8% reduction in the hazard of death in intermediate-risk patients. Being retrospective, their analysis suffers from selection bias - it may be that the frailest patients got lower doses. However, they did include more unfavorable intermediate risk patients, including those treated with adjuvant ADT.

We are now recognizing that unfavorable intermediate risk patients may benefit from adjuvant ADT and higher doses, whereas the favorable intermediate risk patients may not. EORTC 2291 and the Nabid et al. trial established that short term (6 month) ADT markedly improved progression-free survival. Several retrospective studies (like this one and this and this) suggest that the benefit is limited to those with less favorable disease characteristics. It may well be that higher doses are necessary to overcome the radioresistance of high volumes of Gleason pattern 4.

The degree to which RTOG 0126 is irrelevant to contemporary decision-making is heightened by the success of hypofractionated IMRT and SBRT in intermediate risk patients. Both provide much higher biologically effective doses, equal efficacy to conventional IMRT, and about the same toxicity. Also, their cost is lower and patient convenience is higher. Unless a patient has an anatomical abnormality such that dose constraints cannot be met, it is hard to come up with a reason why higher biologically effective doses should not be used.

Note: Thanks to Dr. Howard Sandler for allowing me to see the full text of the study.

Saturday, May 20, 2017

Brachy boost therapy should be reserved for unfavorable risk patients

The ASCENDE-RT trial showed that oncological outcomes were improved among both intermediate risk and high risk men who were treated with external beam radiation (EBRT) and a brachytherapy boost (LDR-BT) to the prostate and adjuvant androgen deprivation therapy (ADT) (see this link). A new study from the University of Michigan suggests that the benefit in intermediate risk men is exclusively among those who have been diagnosed with unfavorable intermediate risk prostate cancer.

They used the NCCN definitions:
  • Favorable intermediate risk: Gleason score 3+4 and PSA< 10 ng/ml and stage T1/T2a and <50% of biopsy cores were positive
  • Unfavorable intermediate risk: All other intermediate risk

Abugharib et al. retrospectively reported the outcomes of 579 intermediate risk men treated with either EBRT alone or EBRT+LDR-BT between 1995 and 2012. After a median follow-up of 7.5 years:

  • The 10-year biochemical recurrence free survival was 92% for the brachy boost therapy vs. 75% for EBRT alone
  • Recurrences were cut in half (hazard ratio= 0.48) by the brachy boost after correcting for known confounders
  • The improvement due to the boost was only seen in the "unfavorable intermediate risk" group, but not in the favorable intermediate risk group.
  • 10-year distant metastasis-free survival did not differ by risk group.
  • 6-year cumulative incidence of grade 3 urinary toxicity was 3.5 times higher among men who received brachy boost therapy.
  • Toxicity was transient and resolved completely in 57%, partially in 29%, and persisted in only 1 patient.

We recall that ASCENDE-RT reported nearly identical oncological and toxicity outcomes:

  • Among those with intermediate-risk prostate cancer, 9-year bPFS was 94% for the brachy boost cohort vs. 70% for EBRT-only.
  • Late term Grade 3 GU toxicity reached 19% for the brachy-boost group vs. 5% for the EBRT-only group (3.8 times higher).

Although this was not a randomized clinical trial like ASCENDE-RT, the similarity helps lend credence to their study.

There was a randomized clinical trial RTOG 0232 (see this link) that also showed no benefit to the brachy boost among favorable intermediate risk men.

While ten years is not long enough to evaluate differential effects on metastases and mortality, we may infer from the large difference in the 10-year failure rate that those differences will probably eventuate in more metastases and deaths later on.

It appears that men with unfavorable intermediate risk prostate cancer may benefit from brachy boost therapy. However, men with favorable intermediate risk prostate cancer are at risk of much greater long-term urinary toxicity with no oncological benefit whatever. We can reasonably infer that men with low risk prostate cancer, who may be safely watched with active surveillance, would derive no benefit and only greater toxicity from the combination therapy. Unfortunately some clinics, notably the Radiotherapy Clinics of Georgia, infamously treat even low risk patients with brachy boost therapy (which they market as ProstRCision).

Wednesday, September 28, 2016

Brachytherapy alone is enough for favorable intermediate risk patients

RTOG 0232 was a large clinical trial conducted to determine whether low dose rate brachytherapy (BT) alone was of equal benefit compared to external beam radiation therapy with a brachytherapy boost (EBRT+BT) in intermediate risk patients.

The study was conducted at 68 cancer centers in the US and Canada from 2003 to 2012. 588 intermediate risk men were treated. For the purposes of this study, “intermediate risk” was defined as:
  • Stage T1c – T2b, and
  • Either Gleason Score of 7 and PSA less than 10 ng/ml, or
  • Gleason score of 6 and PSA between 10 and 20 ng/ml
They did not collect detailed data and report separately those who would now be classified as “favorable intermediate risk” by the Zumsteg definition (Gleason score 3+4, less than half the biopsy cores positive, and otherwise low risk). However, Howard Sandler, the Principal Investigator, wrote:
It was deliberately a favorable intermediate group largely. At the time (2002) we felt that combination therapy was mandatory for the more advance patients and we weren’t comfortable randomizing to brachy alone for those patients.

So it is important that we do not generalize their findings to unfavorable intermediate-risk or high-risk patients.

The patients were treated as follows:
  • BT: 145 Gy of I-125 seeds or 125 Gy of Pd-103 seeds
  • EBRT+BT: 45 Gy of EBRT and a boost with 110 Gy of I-125 seeds or 100 Gy of Pd-103 seeds
After 5 years of follow-up:
  • Progression-free survival was 85% for EBRT+BT patients, 86% for BT patients (no difference)
  • Acute grade 3 (serious) side effects were suffered by 8%  in each group.
  •  Late-term grade 3 (serious) side effects were higher (12%) in the EBRT+BT compared to 7% in the BT group
o   Urinary side effects: 7% in the EBRT+BT group vs. 3% in the BT group
o   Rectal side effects: 3% in the EBRT+BT group vs. 2% in the BT group

So, the addition of external beam radiation added nothing to cancer control, at least out as long as 5 years. While side effects were low for both groups, combination therapy increased them.

We saw recently in an analysis of the patients at Cleveland Clinic who were treated exclusively with BT only (see this link, especially the section on intermediate risk), that progression-free survival was very good for “low intermediate risk” patients. Furthermore, Drs. Stone and Zelefsky agreed that the combination therapy is unnecessary for this group, especially when treated with a sufficient brachytherapy dose. Radiotherapy Clinics of Georgia has built a business out of treating even low-risk patients with the combination therapy. This is now proved to be an overtreatment that is needlessly toxic.

Sunday, August 28, 2016

The optimal brachytherapy ADT pre-treatment for intermediate risk patients depends on whether they are “favorable” or “unfavorable.”

Anthony D’Amico has been advocating breaking up the intermediate risk category into “favorable” and “unfavorable,” and now offers yet another circumstance where the optimal treatment is different for each of the two groups, this time with brachytherapy.

First, let’s get clear about his definitions. He starts with the current NCCN definition of intermediate risk:
  • Clinical stage T2b or T2c, or
  • A PSA level of 10 to 20 ng/ml, or
  • A Gleason score of 7
(If multiple risk factors are present in a specific patient, the clinician may optionally deem such a patient to be high risk.)

D’Amico advocates for the intermediate-risk sub-grouping proposed last year by Zumsteg et al. (from the Memorial Sloan-Kettering Cancer Center):

Favorable Intermediate Risk:
  • NCCN intermediate risk, as defined above, but only those with
  • Predominant Gleason grade 3 (i.e., Gleason score 3 + 4 = 7), and
  • Percentage of positive biopsy cores < 50%, and
  • No more than one NCCN intermediate risk factor

Unfavorable Intermediate Risk:
  • NCCN intermediate risk, as defined above, plus
  • Predominant Gleason grade 4 (i.e., Gleason score 4 + 3 = 7), or
  • Percentage of positive biopsy cores ≥ 50%, or
  • Multiple NCCN intermediate risk factors

Keane et al. did a retrospective study using the dataset at Harvard of intermediate risk men treated with brachytherapy between 1997 and 2013. In that cohort, 1,902 fell into the “favorable intermediate risk” category, and 608 fell into the “unfavorable intermediate risk” category. After a median 7.8 years of follow-up, there 29 deaths attributable to prostate cancer. They found that:
·      Among “favorable intermediate risk” patients, there was no significant difference in prostate cancer mortality due to using ADT before brachytherapy vs, brachytherapy alone.
·      Among “unfavorable intermediate risk” patients, there was a significant decrease in prostate cancer mortality if they were pre-treated with ADT rather than if there was a combination therapy with external beam radiation (adjusted hazard ratio=0.34)

The authors conclude:
Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men.”

There are a few of important caveats:
·      This was a retrospective database analysis and not a randomized clinical trial, so the conclusions must be taken as provisional. This analysis is especially prone to selection bias: patients were chosen for their treatment based on an assessment of its probability of success.
·      There were only 29 deaths from prostate cancer in the follow-up period, so it is difficult to project what might have happened as the patients were tracked longer.
·      This study did not include a subgroup treated with all three therapies – early ADT and external beam RT and a brachytherapy boost. We saw in the ASCENDE-RT trial that that triple combination was very potent.

In spite of those caveats, there is nevertheless evidence of something very interesting happening here – the two subgroups that we had previously been treating equivalently respond, in fact, to very different treatment protocols.

We have seen in earlier studies (Castle et al. and Edelman et al.) that ADT confers no benefit when added to external beam radiation treatment unless the Gleason score is at least 4+3 or there is a large volume of cancer. This study provides evidence that that is also true for brachytherapy.

Unfavorable intermediate risk prostate cancer, on the other hand, seems to respond very well to the addition of ADT to brachytherapy. There is a randomized clinical trial (RTOG 0815) designed to determine if there is a benefit to adding ADT to dose-escalated external beam RT for intermediate risk patients as a whole, and sub-group analyses for unfavorable intermediate risk patients if there is a specific benefit. Zumsteg et al. demonstrated a benefit in a retrospective analysis.

Saturday, August 27, 2016

Distinguishing favorable vs. unfavorable intermediate risk

A randomized clinical trial (RTOG 9910) published by Pisansky et al sought to answer the question of whether 28 weeks of pre-treatment androgen deprivation therapy (ADT) is better than 8 weeks of pre-treatment ADT in intermediate risk men receiving primary radiation therapy (RT) for prostate cancer. The goal was to achieve a 33% decrease in PC-related deaths after 10 years of follow up. The results, supporting shorter duration pre-treatment ADT, were presented at the 2013 ASTRO meeting and reported in the New Prostate Cancer Infolink. A similar randomized clinical trial, DART 01/05 presented at the 2014 ASTRO meeting, reached a similar finding when intermediate risk men were treated with higher dose radiation. 

Now, Pisansky's peer-reviewed results have been published in the Journal of Clinical Oncology. What is especially interesting is Anthony D'Amico's accompanying editorial. Dr. D'Amico is well known for his risk stratification of prostate cancer into low, intermediate, and high risk categories. He, along with the National Comprehensive Cancer Network (NCCN), have since modified their original categories to include very low risk, low risk, intermediate risk, high risk, and very high risk categories.In the editorial, and in one last year, he makes the case for breaking up the intermediate risk category into favorable intermediate risk and unfavorable intermediate risk. He believes that the findings in such studies as Pisansky's may differ substantially between the two sub-categories. Favorable intermediate risk patients possibly require no ADT and possibly lower dosing (similar to RT treatment for low risk patients), while unfavorable intermediate risk patients may respond more like high risk patients to longer duration ADT coupled with higher doses of radiation.

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)

D'Amico advocates the intermediate risk subgrouping proposed by Zumsteg et al at Memorial Sloan Kettering (MSK) last year:

Unfavorable Intermediate Risk:
- 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:
- NCCN intermediate risk, as defined above, but only those with
- Predominant Gleason grade 3 (i.e., Gleason score 3+4), and
- Percentage of positive biopsy cores <50%, and
- No more than one NCCN intermediate risk factor

If the information on percentage of positive biopsy cores was collected, he would like to see a post-analysis with the new proposed subgroupings. He also calls for post-analysis of other studies among intermediate risk men, like the recently completed RTOG 0126 trial of dose escalation, the ongoing RTOG 0815 trial of short term ADT with high dose RT, and the above-mentioned DART 01/05 trial of long-term vs short-term ADT with high dose RT.

Another drawback associated with the Pisansky study is that only doses of 70 Gy were used, whereas 80 Gy has better oncological outcomes. This was proven by RTOG 0126 presented in September, but had already been incorporated into standard-of-care practice by many clinicians based on earlier studies. It is often the case in long-term clinical trials of radiation therapies that the findings have become irrelevant by the time they are published owing to technological advances, and enhancements in our understanding of oncology. It may be that Zumsteg's proposed improvement in risk stratification may already be outdated by the growing use of multiparametric MRI-targeted biopsies -- is 50% positive biopsy cores still a useful cutoff point when more cores are taken in suspicious areas?

Dr. Klotz has argued that favorable intermediate risk men also can safely choose Active Surveillance, given close monitoring with multiparametric MRI. With that inclusion, there really are no treatment choices that are different for low risk and favorable intermediate risk men - Active Surveillance/Watchful Waiting (if life expectancy is low), RP, focal therapy, brachy monotherapy, SBRT, IMRT or PBRT. Treatment choices for both unfavorable intermediate risk and high risk men are the same - brachy or PBRT boost therapy, SBRT, IMRT (all with adjuvant ADT), RP, or Watchful Waiting (if life expectancy is low). One could reasonably argue that only two risk categories are necessary - favorable risk or unfavorable risk. This binary distinction has been used in a number of clinical trials.

It is not necessary to have consensus on risk stratification. Indeed, even within the NCCN network, UCSF uses a CAPRA scoring system, and MSK uses Zumsteg's intermediate risk distinction. It is, however, useful to clinicians trying to apply the findings of such research studies to have a common terminology and to make distinctions where they might change treatment decisions. D'Amico's opinions on this subject carry a lot of weight.