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

(updated)

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 will 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 (bRFS) 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)

(10-yr update 4/2024) 

• 10-yr Freedom from Distant Metastases was 93% for ART and 90% for SRT, which are not statistically different.
• No difference in outcomes previously reported (bRFS and freedom from permanent ADT)
• Overall survival was not improved by ART.
• In addition to worse urinary incontinence, fecal incontinence was worse one year after ART, and remained worse 10 years later.

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 (SPPORT) showed that salvage radiation of pelvic lymph nodes with adjuvant ADT increased 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 prophecy - 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 (see this link). The patient must treat what is still too small to see.

Adjuvant ADT

RADICALS-HD explored the effect of various durations of adjuvant hormone therapy, and found that 6 months was no more beneficial than none! However,  GETUG-AFU-16 proved that adding at least 6 months of ADT improved results of SRT. RTOG 0534 (SPPORT) 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 metastatic risk may outweigh benefits when PSA is lower than 0.6 ng/ml. However, SPPORT found that men with a PSA above 0.35 (median, not a definitive cut-off) were more often cured if they got short-term ADT

See this link for updates on this topic.

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.

SABR to oligometastases slows progression via immune response

Stereotactic Ablative Body Radiation (SABR, or sometimes, SBRT) significantly slowed metastatic progression in men with 3 or fewer metastases (oligometastatic). SABR is a form of concentrated radiation accomplished in 1-5 treatments.

The ORIOLE trial has been previously described in detail here. To recap, it was a small (Phase 2) randomized trial with 36 men treated with SABR to bone scan/CT-detected oligometastases. There were 18 men in the untreated control group. The men were followed for 6 months to see if there was any progression of their cancer. Progression was defined as either PSA progression or new metastases detected on bone scan/CT or physical symptoms of decline (e.g., pain). Of course, with only 6 months of follow-up, most of the detected progression was PSA progression. Phuoc Tran, the lead investigator of the ORIOLE trial, reported the 6-month results here:

• Progression-free survival (PFS) was 81% in the SABR group vs 39% in the control group.
• Median PFS was not yet reached in the SABR group vs 5.8 months in the control group.
• The time to progression was increased by 70% by the treatment.
• Progression has not been reached among those treated patients followed for over a year.

Although patients were only treated for metastases discovered on a bone scan/CT, they were also given a PSMA-based PET scan (DCFPyL). Those in whom no additional metastases were discovered by the PET scan fared better:

• PFS was 84% in the fully treated group vs 36% in those with undiscovered metastases.
• Median PFS was not reached in the fully-treated group vs 11.8 months in those with undiscovered metastases.
• Distant metastasis-free survival (i.e., metastases distant from the ones that were treated) was 29 months in the fully-treated group vs 6 months in those with undiscovered metastases.

PFS in men in whom there were any untreated metastases was not improved compared to untreated men. This seems to be an all-or-nothing sort of thing.

SBRT has been found in lab studies to elicit a strong immune response. It releases cancer antigens into the bloodstream that are detected by T-cells, which become activated to find more cancer. That T cell response to radiation is thought to contribute to its effectiveness (called "the abscopal effect"). The investigators tracked the T cell response and found a significant response in the SABR-treated men.

Progression-free survival when most of the progression is PSA progression is not the endpoint we need to evaluate this therapy. SABR "treats" PSA. "Treating PSA" would occur if the radiation only provides excellent local control, while not necessarily delaying progression elsewhere. PSA is secreted in proportion to the size of the tumors, so treating only the tumors will do nothing to stop the micrometastases that are elsewhere. However, the strong T-cell response found by this study suggests that there may be a true delay in progression and not only a delay in PSA. Also, the fact that distant metastases were delayed by almost 2 years among those who had all of their PSMA-detected metastases irradiated, suggests a true response.

This is an important first step toward discovering whether oligometastasis-directed therapy provides a benefit, and how it works. It does not yet provide the answer to whether there is a survival benefit to such therapy. It also does not answer the question of whether ADT can be delayed when radiation has been given. There are several, larger clinical trials that will answer those questions more definitively. Meanwhile, the patient with rising PSA after prostate therapy should consider:

1. A PSMA-based PET scan (available in some clinical trials, and probably widely available within a year).
2. Talking to a radiation oncologist about SABR treatment of metastases if all discovered metastases are in places where it is entirely safe to treat them
3. Not forgoing ADT adjuvant to SABR treatment until there is more proof.