Sunday, September 29, 2019

"Adjuvant" similar to "Early Salvage" Radiation Outcome in Meta-analysis

Although at least three randomized clinical trials have told us that adjuvant radiation after prostatectomy often affords better results than just taking a "wait-and-see" approach, most radiation oncologists have been reluctant to immediately treat every man with poor post-prostatectomy pathology results (positive margins, stage T3/4, high Gleason score).  Now, some early combined results (called a meta-analysis) of three more randomized clinical trials suggest that oncological outcomes may be no worse if men wait to be treated until certain PSA cut-offs are reached.

The three randomized clinical trials were RADICALS-RT (UK & Canada), GETUG-AFU-17 (France), and RAVES (Australia & NZ). The meta-analysis, called "ARTISTIC" (critique here). comprised 2151 men, of whom 1074 were randomized to adjuvant radiation and 1077 were randomized to early salvage radiation. There have been 5 years of follow-up so far. ARTISTIC analyzed the early data based on "event-free survival," which for the most part meant freedom from a PSA-defined recurrence after radiation.

"Adjuvant" radiation (ART) was defined by all three trials as treatment within 6 months of prostatectomy. Note that this can be longer than the "immediate" treatment often given.

"Early salvage" radiation (eSRT) was defined variously as treatment when PSA ≥ 0.1ng/ml or 3 consecutive rises (RADICALS-RT), PSA≥0.2 ng/ml and rising (GETUG-AFU-17), or PSA≥0.2 ng/ml (RAVES).

Patients in all three trials had positive surgical margins, extracapsular extension, or penetration into the seminal vesicles. Most patients were intermediate risk:
  • Most (77%) had a Gleason score of 7
  • Very few (9-17%) had a Gleason score of 8-10
  • About 1 in 5 had seminal vesicle invasion

After 5 years of median follow-up:
  • Event-free (mostly PSA) survival was about the same for ART and eSRT (HR=1.1, p=0.47)
  • 57% of patients randomized to SRT never had it because they didn't have biochemical progression

The following are the results for RADICALS-RT (1,496 patients followed up for 4.9 years):
  • 64% of the patients randomized to receive eSRT, never experienced PSA progression
  • At 5 years, biochemical progression-free survival was 85% for ART and 88% for eSRT (p=0.56, not statistically different)
  • At 5 years, freedom from permanent ADT was not different (93% for ART, 92% for eSRT)
  • Urinary incontinence at one year was 5.3% for ART vs 2.7% for eSRT (p=0.008, statistically different)
  • Serious or life-threatening urethral stricture was 6% for ART vs 4% for eSRT (p=0.02, statistically different)

The following are the results for GETUG-AFU-17 (424 patients with 6.3 yrs of follow-up):
  • 41% of the patients randomized to receive SRT, never experienced PSA progression
  • 5-yr event-free survival (no PSA or clinical relapse) was the same (92% for ART, 90% for SRT)
  • Late-term urinary toxicity (any grade) was worse for ART (73% for ART, 29% for SRT)
    • incontinence:  54% for ART, 17% for SRT
    • frequency: 39% for ART, 15% for SRT
  • Late-term rectal toxicity (any grade) was worse for ART (44% for ART, 20% for SRT)
  • Late-term erectile dysfunction (any grade) was worse for ART (36% for ART, 13% for SRT)

The following are the results for RAVES (333 patients with 6.1 yrs of follow-up):
  • 47% of the patients randomized to receive SRT, never experienced PSA progression
  • 5-yr freedom from biochemical relapse was the same (86% for ART, 87% for SRT)
  • Late-term urinary toxicity (grade 2+) was worse for ART (70% for ART, 54% for SRT)
  • Late-term rectal toxicity (grade 2+) was the same (14% for ART, 10% for SRT)

Pelvic lymph nodes

If pelvic lymph node dissection during prostatectomy revealed any positive nodes, or if scans suggest enlarged, cancerous pelvic lymph nodes, there is no question that adjuvant radiation is required. RTOG 0534 showed that salvage radiation of pelvic lymph nodes with adjuvant ADT increase progression-free survival even when there were no detected cancerous lymph nodes, but only if PSA was high enough.

It is never worth waiting for PSA to rise to a point where newer PET scans can detect metastases just to find out where the largest sites of recurrence are. That would be a self-fulfilling prophesy - the goal is curative treatment before the cancer has time to metastasize. A/SRT must be given to the prostate bed, and possibly an extended pelvic lymph node field. The patient must treat what is still too small to see.

Adjuvant ADT

Other arms of RADICALS, not yet reported, explored the effect of various durations of adjuvant hormone therapy. GETUG-AFU-16 proved that adding at least 6 months of ADT improved results of SRT. RTOG 0534 also showed that adding ADT to SRT was often beneficial. But RTOG 9601 showed that adjuvant ADT did not improve results when postprostatectomy PSA was below 0.7 ng/ml. A recent analysis by Spratt et al. suggested that adjuvant ADT is always necessary when PSA ≥ 1.5 ng/ml, but that risks may outweigh benefits when PSA is lower than 0.6 ng/ml.

Radiation Dose

GETUG-AFU-17 and RADICALS-RT used a radiation dose of 66 Gy in 33 treatments. RADICALS-RT also allowed a moderately hypofractionated dose (52.2 Gy in 20 treatments). RAVES used a slightly lower dose: 64 Gy in 32 treatments. SAKK 09/10 found that the salvage dose in the RAVES trial had equivalent biochemical outcomes. The effect of the higher dose on toxicity using the best linacs is unknown.

High Risk/Decipher

Most of the men in these trials were originally intermediate risk. It is entirely possible that originally high-risk men (Gleason 8-10, PSA≥20 or cT3/T4) may benefit more from ART rather than eSRT.  Men who were originally low risk (Gleason 6 and PSA<10 and T1/2) may be able to wait longer or indefinitely before SRT.

If the Decipher score is very high, that should also be taken into account in deciding between ART and eSRT. Genome Dx also provides scores that suggest whether the cancer is amenable to SRT, but those scores have yet to be prospectively validated.

We are starting to get a better handle on the ART vs eSRT decision, but none of what we have learned gives us hard-and-fast guidelines. Thee trial results do provide more fodder for discussion between the patient and his radiation oncologist.

Exceptions: see this link.

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