Radiation After Prostatectomy: Debate Over Timing

Alexander M. Castellino, PhD

March 31, 2015

Among men with newly diagnosed prostate cancer who are offered radical prostatectomy (RP) with curative intent, around 60% of patients have high-risk features, which are associated with cancer recurrence. In these patients, radiation therapy (RT) after surgery is expected to improve cure rates.

In clinical practice, there is uncertainty about the timing of radiation. Should it be given soon after RP (adjuvant RT), or only after biochemical recurrence, when levels of the prostate-specific antigen (PSA) rise?

Two new studies could add to the debate on whether RT should be provided after surgery or after biochemical recurrence as salvage RT, but overall, both studies provide confidence to those who offer adjuvant RT.

The two longitudinal studies are based on analyses from Italian and Surveillance, Epidemiology, and End Results (SEER)–Medicare databases of cohorts of men who received RP and included men who received postsurgical radiation.

"The timing of radiation does not determine the risk for complication," radiation oncologist Timothy N. Showalter, MD, MPH, from the University of Virginia School of Medicine in Charlottesville, the corresponding author on both reports, told Medscape Medical News.

"In these large cohorts of patients, these studies importantly demonstrate that waiting for a period of time after prostatectomy to initiate radiation does not confer any additional benefit of fewer side effects, compared with giving it sooner," Michael J. Zelefsky, MD, professor of radiation oncology and vice-chair of clinical research in the Department of Radiation Oncology at the Memorial Sloan Kettering Cancer Center in New York City, told Medscape Medical News. He was not involved in either study, and was approached for comment.

The Italian study, published in the March 15 issue of the International Journal of Radiation Oncology, Biology, Physics, showed that the timing of radiation is not significant for any of the adverse-event outcomes associated with radiation — both gastrointestinal and genitourinary.

However, the analysis of the men in the SEER–Medicare linked database, published online February 23 in PLOS ONE, indicated that adjuvant RT is associated with lower rates of gastrointestinal events than salvage RT, with no increase in genitourinary events.

In both studies, erectile dysfunction rates were similar for adjuvant RT and salvage RT, and were similar to rates in patients undergoing only RP.

"These are both well-conducted studies," another expert approached for comment, Anthony V. D'Amico, MD, PhD, professor in the Department of Radiation Oncology and chief of genitourinary radiation oncology at the Dana-Farber Cancer Center and the Brigham and Women's Hospital in Boston, told Medscape Medical News.

The seemingly different conclusions from both studies arise from the fact that they were nonrandomized studies, so all patient confounders could not be adjusted for; each study can only generate a hypothesis that needs to be prospectively assessed in a randomized trial, Dr D'Amico explained.

Two such trials — RADICALS and RAVES — are ongoing, he noted.

"The authors should be congratulated on examining the relationship between the timing of radiation therapy after prostatectomy and side effects in two large datasets from different countries," Stacy Loeb, MD, MSc, assistant professor of urology and population health at New York University in New York City, also approached for comment, told Medscape Medical News.

"Both studies show clearly that any radiation therapy after prostatectomy increases the risk of urinary and gastrointestinal toxicity. They did not find a statistically significant difference in the risk of complications based on whether the radiation was given earlier or later after surgery," she commented. However, this does not mean that every man should be given adjuvant therapy, she added.

Analyzing an Italian Database

For the study of Italian men, Dr Showalter and colleagues accessed data from the Regione Emilia-Romagna Italian Longitudinal Health Care Utilization Database to identify men who underwent RP for prostate cancer from 2003 to 2009.

Of the 9876 men in the cohort, 7700 were treated with RP alone and 2176 were treated with RT after RP.

As expected, RT after RP led to significantly higher rates than RP alone for gastrointestinal (1.55 vs 0.99 events/100 person-years), urinary incontinence (2.34 vs 1.24 events/100 person-years), and genitourinary (0.77 vs 0.64 events/100 person-years) adverse events.

In a statistical analysis, the timing of when men received RT was not associated with any increased risk for these events.

Analyzing the SEER–Medicare Database

In the second study, Dr Showalter and colleagues identified 523,153 men in the SEER–Medicare linked database who were diagnosed with prostate cancer from 1992 to 2007.

From this cohort, 6137 men were eligible for analysis — 4509 treated with RP alone, 894 treated with adjuvant RT after RP, and 734 treated with salvage RT at least 12 months after RP.

As expected, adjuvant RT (13.87 events/100 person-years) and salvage RT (17.06 events/100 person-years) were associated with higher procedure-defined gastrointestinal event rates than RP alone (13.87 events/100 patient-years). A similar trend was seen for diagnoses-defined events. The event rate was higher for salvage RT than for adjuvant RT.

"This is probably related to the radiation doses patients received," Dr Showalter said. In their discussion, Dr Showalter and colleagues indicate that higher doses of radiation are typically used in salvage RT, and lead to better event-free survival but also to increased rates of gastrointestinal complications of grade 3 or higher. However, the actual radiation doses used were not available in the database.

Procedure-defined genitourinary event rates for incontinence were also lower for RP (5.88 events/100 person-years) than for adjuvant RT (6.58 events/100 person-years) or salvage RT (6.74 events/100 person-years).

Dr Loeb indicated that both studies had limitations. "The authors cannot actually determine whether the radiation therapy was given in an adjuvant or salvage scenario. They only know the date that it was received but not the actual clinical context," she told Medscape Medical News.

"In addition, we do not have any data on the extent to which patients' quality of life was affected," she said.

What These Data Mean for Clinical Practice

In an institution press release, Dr Showalter said that "urologists tend to prefer to forgo adjuvant radiation therapy because they fear the side effects, and radiation oncologists tend to prefer offering adjuvant radiation therapy because they fear the risk of metastasis."

"A lot of clinicians believe that if you wait 6 months, 12 months, 18 months, that each additional step gets you some benefit in terms of toxicity. That didn't make sense to me from a medical perspective, because I can't think of any other surgery where we think recovery requires a year or more. We often, for other cancers, deliver postoperative radiation very soon," Dr Showalter said.

Dr Zelefsky noted that not all patients with risk factors for biochemical recurrence ultimately develop a recurrence.

That is why it might be prudent to wait until the development of early biochemical recurrence, Dr Zelefsky told Medscape Medical News. This will spare others unnecessary RT, he added.

Dr Zelefsky explained that at Memorial Sloan Kettering, it is common practice to wait for early biochemical recurrence before initiating RT.

Dr Loeb agreed. "I believe in an early salvage approach for the majority of patients, and these studies will not change my practice," she said.

She indicated, as did Dr Showalter and colleagues in their introduction, that recurrence occurs in approximately 40% to 60% of men who have adverse pathology features at the time of surgery.

"This means that if we automatically give adjuvant radiation therapy to every man with adverse prostatectomy pathology, we will be overtreating the 40% to 60% of men who would not have recurred, subjecting them to a greater risk of genitourinary and gastrointestinal side effects, as this study shows," she told Medscape Medical News.

Dr Zelefsky noted that patients with high-risk factors for recurrence, such as those with positive surgical margins, should nevertheless be counseled on the potential benefit of immediate adjuvant RT.

"For these patients, these two studies provide further confidence that earlier treatment should not increase the risk of treatment-related toxicities," he told Medscape Medical News.

Dr D'Amico agreed. We are much more inclined to offer adjuvant RT than salvage RT to patients with high-risk factors, such as positive margins and a Gleason score of 8 or higher, he told Medscape Medical News.

Drs D'Amico and Zelefsky both indicated that the RADICALS and RAVES ongoing randomized clinical trials are comparing adjuvant with salvage RT to settle the timing of radiation.

RADICALS (NCT00541047), being conducted in Canada, Denmark, the Republic of Ireland, and the United Kingdom, is currently accruing patients with prostate cancer who are undergoing RP. It is expected to accrue 4000 patients.

RAVES (NCT00860652), being conducted by the Trans-Tasman Radiation Oncology Group in Australia and New Zealand, plans to accrue 470 men with prostate cancer who are undergoing RP and RT.

Dr Showalter noted that prostate cancer studies take a long time to complete because events occur over a long time. In fact, RAVES results are not expected until 2023.

In the meantime, what are clinicians supposed to do?

"The takeaway for men receiving prostate cancer treatment is that they should discuss the best strategy with their physicians based on their particular case," Dr Showalter said in the press release. In his clinical approach, Dr Showalter appears to agree with Drs D'Amico, Zelefsky, and Loeb.

"If someone's at generally low risk of prostate cancer reoccurrence and they have low-grade disease, it's probably still reasonable to take a delayed salvage radiation therapy approach," Dr Showalter said.

"Once there's a real, compelling reason to deliver radiation, there doesn't seem to be a benefit to delaying their radiation in terms of avoiding complications. And we know from other studies, the earlier radiation is delivered, the more effective it is for these patients, and the more likely it is to cure them," he concluded.

Dr Loeb added further context to the approach. She noted that postoperative RT increases the risk for urinary and gastrointestinal adverse effects and involves extra time and cost for the patient.

"Many men with adverse features at prostatectomy do not experience further progression. Therefore, an alternative option is to monitor patients' PSA levels initially and offer salvage radiation therapy selectively to those who need it at the earliest sign of recurrence," she said.

"Patients who have adverse pathology at radical prostatectomy should be counseled about these options, including adjuvant therapy and observation with early salvage therapy if needed," Dr Loeb added.

The study authors, Dr Zelefsky, and Dr D'Amico have disclosed no relevant financial relationships. Dr Loeb was an advisory board member for Xofigo.

Int J Radiat Oncol Biol Phys. 2015;91:752-759. Abstract

PLoS ONE. 2015;10:e0118430. Abstract

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