Is whole pelvic radiation needed for primary treatment of Gleason 9/10?

Whether whole pelvic radiation therapy (WPRT) is beneficial for men newly diagnosed with Gleason 9/10 (Grade Group 5) is controversial. There is an ongoing randomized clinical trial (RTOG 0924) that will have results by 2027 at the earliest, but it includes intermediate and high-risk patients, very few of whom will have Gleason 9/10. Two previous randomized clinical trials (RCTs) gave conflicting results: RTOG 9413 showed a benefit to WPRT combined with ADT started before and continued through radiation treatment, while GETUG 01 found no benefit. However, neither RCT delivered doses of radiation that would be considered adequate by today's standards (70 Gy vs 80 Gy).

Sandler et al. analyzed the databases of 12 major institutions that treated 1170 Gleason 9/10 patients between 2000 and 2013.

• 299 received external beam radiation therapy (EBRT) boost to the prostate + WPRT
• 435 received EBRT only to the prostate + a small margin around it
• 320  received a brachytherapy boost (BBT) to the prostate + WPRT
• 116 received BBT only to the prostate + a small margin around it
• Patients were matched on age, T stage, PSA, Gleason score, and analyzed by ADT duration

After median follow-up of 5.6 years, 5-year biochemical recurrence-free survival (bRFS) was:

• 88% for BBT+WPRT
• 78% for BBT alone
• 66% for EBRT+WPRT
• 58% for EBRT alone
• WPRT was significantly improved by BBT (Hazard Ratio = 0.5, p=0.02) but not by EBRT (HR=0.8, p=0.4))
• Neither distant metastasis-free survival nor prostate cancer-specific survival were significantly improved by WPRT

In interpreting these findings, patients should discuss the following considerations with their radiation oncologists.

Lack of long-term follow-up

As we have observed before (see this link), it can take 15 or more years until over half of high risk patients have detectable metastases (by bone scan/CT) or have succumbed to prostate cancer. In this study, only 35% of those getting EBRT alone had been diagnosed with distant metastases, and only 23% had died of prostate cancer. The rates for all other groups were smaller. As the data mature, we expect that the now-evident and statistically significant differences in biochemical failure will eventually result in higher rates of metastases and mortality.

Lack of local control with EBRT only

ASCENDE-RT proved that prostate cancer is better controlled in high-risk patients by a brachytherapy boost than by EBRT alone. Local control (of cancer in the prostate) is obviously required because the high grade cancer easily progresses and metastasizes from the prostate.

Lack of regional control with surgery

As we have seen, prostatectomy, even when followed by radiation (see this link) seems to provide inferior cancer control compared to BBT with WPRT. This may be because the salvage radiation dose to the prostate bed (usually only 66-70 Gy) is inadequate compared to the primary radiation dose (see this link).

Inadequate coverage/detection of pelvic lymph nodes

In the present study, patients received WPRT to the standard pelvic lymph nodes. We have seen that this is inadequate to reach  the cancerous pelvic lymph nodes in over 40% of patients (see this link). Current methods do not allow us to find most of the cancerous lymph nodes (see this link). While PET scans are not yet FDA-approved for high-risk patients (as they are for recurrent patients), there are a few available in clinical trials.

Inadequate dose to pelvic lymph nodes

The dose to pelvic lymph nodes is often about 45-50 Gy given in 1.8 Gy increments. If it's true that perfect cancer control is achieved only with doses around 80 Gy, this treatment may be inadequate to control some of the larger lymph node metastases. This may be especially true because lymph node metastases are not well-oxygenated (hypoxic). As PET/CTs and PET/MRIs become available for high-risk patients, it may become possible to target known lymph node metastases with higher doses. Another fertile area for investigative research is radiosensitization with hyperthermia (see this link).

Toxicity

In RTOG 0534, late Grade 2 or worse gastrointestinal toxicity occurred in 7% of those receiving WPRT. While this is higher than the 2% experiencing this degree of toxicity with prostate-only EBRT treatment, it is nevertheless at a low level. In a large non-randomized, retrospective study comparing WPRT to prostate-only radiation, Parry et al. found no difference in the 3-year cumulative incidence of gastrointestinal and urinary toxicity among high risk and locally advanced patients.

Because we may never have more reliable data, patients and their radiation oncologists must make this decision based on this study and judgement for the foreseeable future.

note: Thanks to Amar Kishan for allowing me to see the full text.

For very high-risk patients, EBRT + BT is superior to surgery or EBRT only

A retrospective analysis of oncological outcomes among modern-era patients with a Gleason score of 9 or 10 demonstrates a clear advantage to a combination of external beam radiation therapy (EBRT) with a brachytherapy (BT) boost to the prostate and short–term androgen deprivation therapy (ADT).

Kishan et al. reported on 487 patients with biopsy Gleason scores of 9 or 10 who were consecutively treated between 2000 and 2013 at the University of California Los Angeles and Fox Chase Cancer Center. The patient characteristics were as follows:

• 170 were treated with radical prostatectomy (RP).
• 230 were treated with EBRT only.
• 87 were treated with EBRT + BT, and most of the BT was high dose rate.
• All patients were Gleason 9 or 10 on biopsy.
• RP patients were younger (median 62 years of age) compared to all radiation patients (median 70 years of age).
• RP patients had more favorable disease characteristics: lower initial PSA, and lower clinical stage.

The patient characteristics by treatment category are listed below.

For the RP patients:

• 11% had pre-surgery ADT or chemotherapy.
• 55% had adjuvant or salvage radiation therapy (68 Gy).
  • 39% of them had adjuvant ADT with radiation for a median of 22 months if adjuvant radiation, 12 months if salvage radiation.
• 85% with biochemical recurrence and no detected distant metastases had salvage radiation.
• 21% had a lower Gleason score (7 or 8) on final pathology, but 91 percent had any Gleason pattern 5 on final pathology.
• 78% were stage T3 or T4 on final pathology (vs. 12 percent clinically).
• 41% had positive surgical margins.
• 16% had positive lymph nodes
  • Among those, 64% received no immediate treatment because of patient preference.

For the EBRT patients:

• Median dose of radiation was 76.4 Gy.
• 94% had ADT starting before EBRT.
  • The median duration of ADT was 24 months.
• 76% had pelvic lymph nodes treated.
• 2 patients received salvage cryotherapy.

For the EBRT + BT patients:

• The median equivalent dose of radiation was 88.7 Gy
• 86% had ADT starting before radiation.
  • The median duration of ADT was 8 months.
• 78% had pelvic lymph nodes treated.
• 1 patient received salvage cryotherapy.

After a median follow-up of 4.6 years, the oncological outcomes were as follows:

• The 10-year biochemical recurrence rates (BCRs) were
  • 84% for RP
  • 40% for EBRT
  • 30% for EBRT + BT
  • Differences between RP and EBRT and between RP and EBRT + BT were statistically significant.
• Percentages of patients who began lifelong ADT after therapy failure were
  • 31% for RP
  • 21% for EBRT
  • 16% for EBRT + BT
  • Differences between RP and EBRT and between RP and EBRT + BT were statistically significant.
• The 10-year rates of distant metastases were
  • 39% for RP
  • 33% for EBRT
  • 10% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant, while the differences between RP and EBRT were not.
• The 10-year rates of prostate cancer-specific mortality were
  • 22% for RP
  • 20% for EBRT
  • 12% for EBRT + BT
  • None of the differences were statistically significant.
• The 10-year rates of overall survival were
  • 75% for RP (they were younger and healthier)
  • 65% for EBRT
  • 59% for EBRT + BT
  • None of the differences were statistically significant.

The authors conclude:

These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9–10 prostate cancer.

It will come as no surprise to readers that EBRT + BT boost has better outcomes than EBRT alone (see this link and this one). Dose escalation has been found to improve outcomes, and the use of ADT to radiosensitize the cancer, and to systemically clear up micrometastasis, seems to improve outcomes still further. However, ADT for as long as 2 years could not compensate for the lower radiation dose of EBRT used by itself. Longer duration of ADT was not associated with improved outcomes after accounting for the dose effect.

Those who were treated with EBRT + BT were at a considerable disadvantage in this study: they were older, had worse disease characteristics, and were given less local salvage, yet they performed much better. When controlling for those disparities, the total radiation dose emerged as the single most important variable, affecting biochemical recurrence, metastases-free survival, and prostate cancer-specific survival. No other variable – neither duration of ADT nor adjuvant/salvage radiation – was statistically significant.

Prostate cancer-specific mortality rates were cut in half by combining EBRT with a BT boost. While the combination therapy did not make a statistically significant difference in prostate cancer-specific survival, the study was probably under-powered to detect that with statistical significance. The survival curves between EBRT + BT and the other two therapies did consistently diverge throughout the follow-up period, so the difference might well be statistically significant on a larger sample size or longer follow-up.

Not everyone in this study received optimal therapy. The EBRT-only dose was sometimes low by today’s standards, salvage radiation was under-utilized, use of concurrent ADT with adjuvant/salvage radiation was low (see this link) and of too-short duration.  However, most were treated according to the standards of care. The authors looked at the subset of patients who were treated optimally and found no difference in conclusions. The conclusions were robust even excluding those who were lymph-node positive.

What is new here is the comparison of the three potentially curative treatments for very high-risk prostate cancer in the 21st Century. There have been several long-term database analyses that compared surgery to radiation therapy as offered in the 1990s, when radiation doses were often inadequate to achieve cures. We recently saw a comparative benefit to radiation over surgery in the modern era among high-risk patients at the University of Alabama Birmingham (see this link). Ideally, we would like to see a randomized comparative trial between surgery and radiation, but that is unlikely to occur. Meanwhile, this kind of analysis is about the best we have to inform our treatment decisions.

We understand that a future, expanded analysis will include data from other institutions, including Harvard, the Cleveland Clinic, and Memorial Sloan-Kettering Cancer Center. That analysis will also include toxicity data. We will certainly report on that when it is published.

note: Thanks to Drs. King and Kishan for allowing me to see the full text of this analysis, and responding to questions.