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.

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).

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.

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.

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.