Sunday, September 30, 2018

Survival benefit to debulking the prostate with radiation in men with low metastatic burden

The term "debulking" denotes the radical treatment (via prostatectomy or radiation) of the cancerous prostate after distant metastases have been discovered. This first randomized clinical trial of debulking with external beam radiation found that there was no overall survival benefit.

Results of the STAMPEDE randomized clinical trial were published in the Lancet. Like the HORRAD trial (see below), they found there was no survival benefit to radiation debulking among all newly diagnosed men with metastases (Stage M1). Unlike the HORRAD trial, they utilized higher radiation doses.

Newly diagnosed men were treated with standard of care (which at the time meant ADT and docetaxel in 18% of the men) and were randomized to no radiation debulking or hypofractionated radiation, consisting of either:
  • 55 Gy in 20 daily treatments, or
  • 36 Gy in 6 weekly treatments (note: this bioequivalent dose is 15% higher)
However it made a big difference in survival if the men were oligometastatic (1-3 distant metastases). After 37 months median follow-up:
  • Survival increased by 32% (hazard ratio = 0.68) in 819 oligometastatic men
    • 3 yr survival was 81% with debulking vs 73% without debulking
  • No survival increase among the 1,120 polymetastatic men (defined as visceral metastases or 4 or more bone metastases with at least 1 outside the axial skeleton)
Survival increases were also noted among men with only pelvic lymph node metastases (N1M0), in whom whole pelvic radiation may be curative.

Adverse events from the radiation were generally mild:
  • 5% had grade 3 (serious) or higher acute urinary or rectal side effects
  • 4% had grade 3 (serious) or higher late-term urinary or rectal side effects

Based on this and their other randomized clinical trials, men with lower metastatic burden should be treated with ADT+Zytiga, followed in 2 months with local hypofractionated radiation. Men with higher metastatic burden should be treated with ADT+docetaxel (it is unknown whether Zytiga adds any additional benefit). Metastasis-directed therapy is under investigation.

Boevé et al. reported the results of 432 men with bone metastases at 28 centers in the Netherlands from 2004 to 2014 (the HORRAD trial). They had received no previous treatments. They all had PSA > 20 ng/ml at the start of treatment and were under 80 years of age. They were randomized to receive either:
  1. Lifelong ADT (an LHRH agonist, starting with 4 weeks of an anti-androgen)
  2. Lifelong ADT + external beam radiation therapy (EBRT) 
The EBRT dose was 70 Gy (35 treatments of 2 Gy each) or 57.8 Gy (19 treatments of 3.04 Gy each), which are biologically equivalent. No whole pelvic radiation or brachy boost therapy was given.

After 47 months median follow-up, the median overall survival was:

  • 45 months in the group that received ADT + EBRT
  • 43 months in the group that received ADT only
The difference was not significant

The authors also looked at survival differences based on:
  • Number of bone metastases (<5, 5-15, >15)
  • PSA at diagnosis (greater or less than 60 ng/ml)
  • Gleason score
  • Stage
  • Age
  • Performance status
  • Painful bone metastases

None made any significant difference in survival.

The time to PSA progression was slightly longer among those who received EBRT (15 months vs. 12 months), but the statistical significance vanished after correction for patient characteristics.

These disappointing results conflict with several retrospective database analyses. This once again illustrates that only prospective randomized clinical trials can prove a causal relation, and that observational studies are confounded by the vagaries of patient selection; i.e., patients who receive debulking in actual clinical practice are the ones who would do better anyway. It is worth noting that a similar thing had occurred with breast cancer. Several retrospective studies had suggested that resection of the breast tumor  plus axillary lymph nodes increased survival even when distant metastases were detected. However, Badwe et al. reported that when women were prospectively randomized to that treatment or no such treatment, there was no survival difference.

Because this trial began over a decade ago, it does not include radiation doses now considered to be curative (around 80 Gy). Nor does it include brachy boost therapy, which was shown to be superior to EBRT alone in high risk patients in the ASCENDE-RT randomized clinical trial. It is also unknown what effect whole-pelvic radiation or metastasis-directed therapy might have had, or whether prostatectomy with or without extended pelvic lymph node dissection (ePLND) may have increased survival.

This clinical trial began before CHAARTED, STAMPEDE, and LATITUDE clinical trials proved that early treatment with docetaxel and abiraterone improves survival in newly diagnosed metastatic men. It is unknown what effect debulking may have in men pre-treated with those systemic therapies.

Many of these unknowns are being explored in current clinical trials. The recently announced randomized clinical trial of debulking at MD Anderson will allow for either EBRT or surgery. This clinical trial in Canada allows for treatment with surgery, HDR brachytherapy, chemotherapy, and SBRT to metastases. This clinical trial in Europe allows for treatment with  docetaxel, and abiraterone. This clinical trial in Germany randomizes patients to prostatectomy + ePLND or best systemic therapy.

Because radiation and prostatectomy have adverse effects, this study should make patients cautious about having any kind of debulking outside of a clinical trial.

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