Whole pelvic salvage radiation + short-term ADT improves oncological results

We didn't expect to see this for another two years, but they hit their recruitment goal early and were able to provide 5-year results. Alan Pollack, the lead investigator, presented the preliminary findings of NRG Oncology/RTOG 0534 (or SPPORT) trial at the ASTRO meeting, and in Medpage Today. It proved that salvage whole pelvic radiation (sWPRT) with short term ADT  (STADT) is superior to either prostate-bed only salvage radiation (PBRT) or prostate-bed only salvage radiation with short term ADT.

They randomly assigned 1,792 men with a recurrence after prostatectomy in 2008-2015 at 460 locations in the US, Canada, and Israel to one of 3 therapies:

1. sWPRT+STADT
2. PBRT + STADT
3. PBRT

• ADT consisted of 4-6 months of a combination of an anti-androgen and an LHRH agonist starting 2 months before salvage radiation.
• Radiation dose to the prostate was 64.8-70.2 Gy at 1.8 Gy per fraction.
• Radiation dose to the pelvic lymph nodes was 45 Gy at 1.8 Gy per fraction.
• The treated pelvic lymph node area was per RTOG guidelines and did not include the recently recommended expansion. 

The oncological results were:

• 5-year freedom from progression (biochemical or clinical) was 89% for sWPRT+STADT, 83% for PBRT+STADT, and 72% for PBRT (all significantly different). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
• 8-year incidence of metastases was 25 for sWPRT+STADT (HR=0.52), 38 for PBRT+STADT (HR=0.64), and 45 for PBRT (sWPRT+STADT was significantly better than the other two)

The reported toxicity results were:

• GI grade 2 or higher: 7% for sWPRT+STADT vs. 2% for PBRT
• Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT
• Bone marrow grade 3: 2.6% for sWPRT+STADT vs. 0.5% for PBRT
• Late term bone marrow grade 2 or higher was 4% for sWPRT+STADT

There were some caveats. The researchers found that the benefit of salvage whole pelvic treatment and ADT was not maintained in men with very low PSA. There are further analyses expected based on patient risk characteristics and genomic biomarkers. We previously saw in a retrospective study that prostatectomy Gleason score had a significant influence. With better PET scans now, we can have more assurance that whole pelvic radiation is necessary. But at very low PSA (<0.2), even our best PET scans may not find the cancer. Also, it may be that long-term ADT may improve results even further, and that dose escalation may improve results. While this changes the standard of care for many men with persistent PSA and recurrences after prostatectomy, the patient and his radiation oncologist still must rely on judgment.

EBRT works better with ADT for intermediate/high-risk prostate cancer

The EORTC trial 22991 compared EBRT + short-term ADT vs. EBRT alone in intermediate and high-risk men. The preliminary report by Bolla et al. was posted at the 2016 GU Conference. There are more details of the clinical trial available here. There were 819 patients in the European multi-institutional study:

• ·      407 received EBRT only, 403 received EBRT+6 months of ADT
• ·      Radiation dose: 70, 74, or 78 Gy (at discretion of each institution)
• ·      Pelvic node radiation: at discretion of each institution
• ·      75% intermediate risk, 25% high risk

After a median follow-up of 7.2 years,

• ·      5-year biochemical progression-free survival was 82.5% with the ADT, 69.3% without it.
• ·      Improvement was irrespective of radiation dose.
• ·      5-year clinical progression-free survival was improved by 7.9 percentage points.
• ·      Late urinary toxicity was 5.9% with the ADT, 3.6% without it (not statistically significant)
• ·      Severe sexual function impairment was 27.0% with the ADT, 19.4% without it (statistically significant)
• ·      Symptoms of hormone treatment, sexual activity and functioning were impaired at 6 months with ADT, but there was no difference at 2 years.

The authors conclude:

“The addition of 6 months of medical castration to primary irradiation improves BPFS and PFS in intermediate- and high-risk localized T1b-cT2a N0M0 prostatic carcinoma with no persistent detriment on HRQOL or sexual function.”

Unfortunately, this preliminary report doesn’t break out the intermediate and high-risk men separately.

We have previously looked at the DART 01/05 clinical trial that proved that at escalated radiation doses, long-term (28 months) androgen suppression improved cancer control better than short-term (4 months), at least for high-risk men. The benefit of longer duration ADT was not established for intermediate risk men at 5-year follow-up.

Nabid et al. focused on intermediate risk men and found a clear benefit to adding 6 months of ADT rather than none (after 10 years of follow-up).

It now seems clear that short-term androgen suppression improves results in intermediate risk men, while longer androgen suppression is necessary in high risk men. It would be helpful to know whether the improvement in intermediate risk men was only among the subgroup classified as “unfavorable intermediate risk.” ADT seems to have a more powerful effect than radiation dose, but it is unclear if that effect is maintained with therapies like SBRT and brachy boost that treat with much higher biologically effective doses. We are getting closer to defining an optimal duration of adjuvant ADT by risk level, and future trials using genetic classification data may provide better definition.

EBRT with 2 years of ADT better than 4 months in patients treated for locally advanced prostate cancer

It will come as no surprise that long-term ADT improved outcomes among men treated for locally advanced prostate cancer with external beam radiation. While this study is largely irrelevant now because a more recent study, DART 01/05 (discussed here), proved much the same thing with dose-escalation, this study also included pelvic lymph node treatment and has a median of 20 years of follow up.

The final results of RTOG 0902 were reported at the recent ASTRO meeting by Lawton et al. and in a news release. In this multi-institutional study, 1,992 patients were treated between 1992 and 1995. They were all high risk (T2c-T4) with no detectable distant metastases and PSA<150. All patients ere treated according to the following protocol:

• ·      44-46 Gy to the pelvic lymph nodes
• ·      65-70 Gy to the prostate
• ·      The short-term ADT group (STADT) received 4 months of flutamide and goserelin, starting 2 months before EBRT.
• ·      The long-term ADT group (LTADT) received 24 additional months of goserelin.

At 15 years after treatment:

• ·      Disease-free survival was 16% for the LTADT group vs. 10% for the STADT group, and was statistically significant.
• ·      PSA increase was 45% for the LTADT group vs. 61% for the STADT group, and was statistically significant.
• ·      Local progression was 13% for the LTADT group vs. 23% for the STADT group, and was statistically significant.
• ·      Distant metastases rate was 17% for the LTADT group vs. 26% for the STADT group, and was statistically significant.
• ·      Disease-specific survival was 10% higher for the LTADT group vs. the STADT group, and was statistically significant.
• ·      Overall survival was 30% for the LTADT group vs. 27% for the STADT group, and was not statistically significant.
• ·      No difference in urinary toxicity and minimal difference in bowel toxicity between the two groups.

While all the survival numbers are very low in both groups, it should be recalled that the radiation dose received back then was well below the dose now considered curative. Also, most of such men would now be diagnosed at a much earlier stage of disease progression. There was a clear benefit to long-term compared to short-term androgen suppression, and DART 01/05 proved that the benefit was still true with dose escalation in high-risk patients.