Salvage RT After Prostatectomy Prevails in Long-Term Comparison With Adjuvant RT

Adjuvant radiotherapy (RT) after radical prostatectomy did not improve outcomes in prostate cancer as compared with salvage RT but added toxicity, according to long-term follow-up from a randomized trial.

Freedom from distant metastasis (FFDM) at 10 years was 93% with adjuvant RT and 90% with salvage treatment. After a median follow-up of 7.8 years, 52 patients in the adjuvant RT arm had died as compared with 57 in the salvage group, resulting in nearly identical overall survival (HR 0.98). Biochemical progression-free survival and non-protocol hormone therapy, both secondary outcomes, also did not differ significantly between the treatment arms.

As reflected in patient-reported outcomes, adjuvant RT was associated with significantly more urinary incontinence at 1 year (P=0.001) and more fecal incontinence through 10 years (P=0.017), reported Chris Parker, MD, of the Royal Marsden Hospital in Sutton, England, and co-authors in Annals of Oncology.

“Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity but does not meaningfully improve disease control,” the authors concluded. “An observation policy with salvage RT for PSA [prostate-specific antigen] failure should be the current standard after radical prostatectomy.”

The findings confirm earlier reports from RADICALS-RT and are consistent with those of the RAVES trial from Australia, which showed similar rates of freedom from biochemical recurrence with adjuvant or salvage RT, said Bridget Koontz, MD, of East Carolina University in Greenville, North Carolina. Older comparative studies showed an advantage for adjuvant RT, but those trials had much longer delays to salvage treatment.

Not all patients received RT, for reasons that remain unclear, Koontz continued. Also, more patients in the salvage arm received androgen deprivation therapy (ADT), raising a question about whether best evidence-based practices were followed.

“The take home is that, as in all medicine, we are getting better at determining who is most going to benefit from a treatment and minimizing treating those who will not benefit,” Koontz, an American Society for Radiation Oncology (ASTRO) expert, told MedPage Today via email. “Radiotherapy is very safe, has a low side-effect profile, and when appropriately prescribed to those whose PSA has risen after prostatectomy (or as a curative therapy on its own) is very effective at curing prostate cancer. However, many patients with risk factors for cancer recurrence do not recur and, in general, no ground is lost to closely monitor PSA and treat only those whose PSA does progress.”

“Radiotherapy is still critically important and is the only proven treatment that can cure prostate cancer if it recurs after prostatectomy,” she noted.

Currently, postoperative RT is underutilized in the U.S., according to Amar U. Kishan, MD, of the University of California Los Angeles. Even so, “these data suggest that for many patients, with a standard risk of recurrence after surgery, it would be appropriate to follow closely, with an approach of early salvage therapy taken soon after rising PSAs are seen. The data overall support a very favorable safety and efficacy profile for early salvage therapy.”

The main limitation of the study is underrepresentation of high-risk patients — high grade, seminal vesicle invasion, nodal involvement.

“It is not clear if adjuvant versus early salvage is truly superior in this group of patients,” added Kishan, who also is an ASTRO expert.

Multiple studies have addressed the issue of whether adjuvant RT is necessary after radical prostatectomy or will salvage RT lead to similar outcomes. Early trials produced conflicting results, reflected in the vote of an expert panel that considered the evidence: 48% favored adjuvant RT versus 52% who did not. More recent trials lacked adequate sample size or sufficient follow-up to assess long-term. As a result, optimal timing of RT after prostatectomy remains unclear, Parker and co-authors noted in their introduction.

RADICALS-RT involved 1,396 patients enrolled from November 2007 to December 2016 at sites in England, Europe, and Canada. Patients were randomized to adjuvant RT or to close observation and salvage RT in the event of PSA failure, defined as two consecutive rising PSA values of >0.1 ng/mL or three consecutive PSA increases.

In both groups, treatment consisted of RT to the prostate bed with a total dose of 66 Gy in 33 fractions or 52.5 Gy in 20 fractions. Treatment began within 26 weeks of prostatectomy for the adjuvant RT group and within 2 months of PSA failure for the salvage RT group.

The primary outcome was FFDM. Secondary outcomes included initiation of non-protocol ADT, treatment toxicity, patient-reported outcomes, and biochemical progression-free survival (bPFS), defined as freedom from PSA ≥0.4 ng/mL after adjuvant RT or PSA >2.0 ng/mL at any time, or clinical progression, initiation of non-protocol ADT, or death from any cause.

The analysis of 10-year FFDM yielded a nonsignificant hazard ratio (HR) of 0.68 for adjuvant versus salvage RT (95% CI 0.43-1.07, P=0.095). Adjuvant versus salvage RT also did not differ with respect to bPFS (HR 0.972) or non-protocol ADT (HR 0.832).

Grade 3/4 urethral stricture occurred in 6% of patients and other routinely reported grade 3/4 toxicities in ≤5%, with no differences between groups. Overall toxicity occurred more often with adjuvant RT, primarily as a result of grade 1/2 toxicity. Late toxicity remained significantly higher with adjuvant RT.

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