Adjuvant Radiotherapy Should Be Standard of Care in Postoperative Localized Prostate Cancer

Nick Mulcahy

January 27, 2009

January 27 2009 — Postoperative adjuvant radiotherapy should be the standard of care for men with localized prostate cancer who have undergone radical prostatectomy — whether the prostate-specific antigen (PSA) count is rising or not, according to the final results of a randomized clinical trial published online January 23 in the Journal of Urology.

In the study, adjuvant radiotherapy within 18 weeks of surgery significantly reduced the risk for PSA recurrence, metastasis, and the need for hormonal therapy, and significantly increased survival, compared with observation or a wait-and-see approach to radiotherapy, according to the authors, led by Ian Thompson, MD, professor and chair of the Department of Urology at the University of Texas Health Science Center at San Antonio.

Salvage radiotherapy, or the wait-and-see approach (where radiotherapy is administered only when PSA becomes detectable or rises to a threshold), may "place a patient at higher risk for metastasis and death," write Dr. Thompson and colleagues.

"I think this is a practice-changing study," J. Brantley Thrasher, MD, professor and chair of the Department of Urology at the University of Kansas School of Medicine, in Lawrence, told Medscape Oncology. "A critical question in urologists' minds has been: In patients who have had radical prostatectomy [yet have localized disease postoperatively], if I give adjuvant radiation before a rise in PSA, does it help? The answer is yes."

I think this is a practice-changing study.

Dr. Thrasher is a spokesperson for the American Urological Association and was not involved in the study.

In an interview with Medscape Oncology, Dr. Thompson pointed out the unique strengths of the new data: "There are very few studies in medicine that show an improved cure rate and an improved survival. But this is one of them."

There are very few studies in medicine that show an improved cure rate and improved survival. But this is one of them.

Despite their enthusiasms, both Dr. Thompson and Dr. Thrasher anticipated some reluctance on the part of urologists to implement this approach.

"The wait-and-see approach is well-entrenched," Dr. Thompson commented, but he emphasized that there are no data to support this approach.

"We all have preconceived notions about who will benefit in these circumstances and who won't," added Dr. Thrasher. Clinicians are hesitant to add radiotherapy soon after surgery and want to give patients time to heal, so that complications, such as urinary problems, are minimized — especially when PSA is not detectable, he added.

However, the study showed that quality of life, over time, was superior i the adjuvant-radiotherapy group, observed Dr. Thrasher. "We all thought that we would see more complications [in the radiation group]. But the differences are temporal, with the treatment group ultimately having better quality-of-life outcomes."

Dr. Thompson is clear about the need to offer these patients the option of adjuvant-radiation treatment. "Clinicians are obliged to discuss this with patients and offer a consult with a radiation oncologist," he said.

Better Metastasis-Free and Overall Survival

Extraprostatic disease will be manifest in one third of men after radical prostatectomy, Dr. Thompson and colleagues write. To determine if radiotherapy reduces the risk for subsequent metastatic disease and death, the investigators undertook a randomized trial in which 211 men were randomized to observation and 214 to adjuvant radiation. The radiation was a "modest" dose of 60 to 64 Gy to the pelvis fossa given in 30 to 32 fractions, write the study authors.

Eligible patients with clinical T1–2 prostate cancer must have undergone radical prostatectomy in the 16 weeks before randomization and must have met at least 1 criterion of pathological T3 disease, such as extracapsular tumor extension, positive margins, or seminal vesicle invasion.

Metastasis-free survival was significantly greater with radiotherapy (93 of 214 events in the radiotherapy group vs 114 of 211 events in the observation group; hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54 - 0.94; P = 0.016). Survival improved significantly with adjuvant radiation (88 deaths of 214 men in the radiotherapy group vs 110 deaths of 211 men in the observation group; HR, 0.72; 95% CI, 0.55 - 0.96; P = 0.023).

The median follow-up was 12.7 years for the radiation group and 12.5 years for the observation group.

The median survival benefit was 1.7 years, note the authors. "It is important to place this outcome in perspective," they write, and they point out, for comparison, that "in the realm of advanced prostate cancer, docetaxel, the only treatment proven to improve survival improves survival by only 1.9 to 2.3 months."

All the data in the newly published study are updates from the initial publication of the 2006 study results (JAMA. 2006:296;2329-2335).

Salvage Radiotherapy Also Beneficial

Of the men under observation, 70 ultimately received radiotherapy because of disease progression. Thus, the comparison in the study was ultimately between adjuvant radiation and observation/salvage therapy.

"This significant reduction [in risk for metastasis] was realized, despite the application of salvage radiotherapy, perhaps the most commonly used approach in these patients today, in a third of the patients in the observation group," the authors write.

"The salvage-therapy patients responded too. This is critically important," added Dr. Thrasher. "It is good to know that even in patients who have undergone surgery and have rising PSA that radiation is helpful. The nice thing about this study is that all of the subgroups appear to have benefited from radiotherapy," despite differences in timing.

The study authors also point out that the impressive final results for survival and metastasis-free survival occurred even though there was almost double the use of hormonal therapy in the observation group.

Undetectable PSA Not Required to Participate in Trial

Because an undetectable PSA after radical prostatectomy was not required for a man to participate in the trial, the investigators were able to compare the way adjuvant radiotherapy affected men with detectable PSA counts postsurgery with men with the way it affected men with undetectable PSA counts.

"Although there is a significant benefit to radiotherapy for the subset of patients with a detectable PSA after prostatectomy, that group's metastasis-free survival is inferior to that of those who received radiotherapy when PSA was still undetectable," write the authors.

This, along with the fact that patients who received adjuvant therapy eventually had higher quality-of-life scores and better survival, adds to the argument that adjuvant radiotherapy is clearly a better choice than watchful waiting, suggested the authors.

Surprise: Quality of Life Is Better for Adjuvant-Radiation Group

In a companion study by the investigators of about half the men in the larger clinical trial, treatment side effects and quality of life at baseline, 6 weeks, 6 months, and annually for 5 years were analyzed.

"Tenderness and urgency of bowel movements were significantly more common at the 6-week point (47% vs 5%) in the radiotherapy group, but by 2 years there was little difference between the groups," note the authors.

Urinary frequency was more common in the radiation group, but there was no differencein the rate of erectile dysfunction (common in both groups).

Global assessment of quality of life was initially worse in the adjuvant-radiotherapy group, but was similar by year 2 and became increasingly superior in the radiotherapy group in the subsequent 3 years. The authors detailed the reasons for the transition. "This gradual switch toward a superior quality of life in the adjuvant-radiotherapy group should be examined in the context of the increased rates of PSA recurrence, salvage radiotherapy, and hormonal therapy in the observation group, all of which have negative impacts on quality of life," they write.

Dr. Thompson will participate in a debate on the management of postoperative localized prostate cancer at the American Society of Clinical Oncology's Genitourinary Cancers Symposium on February 26 in Orlando, Florida.

The researchers have disclosed no relevant financial relationships.

J Urol. 2009:181;956-962.


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