Adjuvant RT Is the Best Option
By Anthony L. Zietman, MD
In the hunt for a useful systemic therapy, clinicians should not lose sight of the one therapy proven to reduce recurrence and the need for subsequent castration. The best prospective, randomized evidence to date supports the use of adjuvant external beam radiation therapy (RT) for locally advanced prostate cancer. It is the only additional therapy currently available that offers a second chance for cure.
In addition, it does not preclude systemic therapy if judged necessary. The onus is on the urologist or oncologist to discuss adjuvant RT with the patient and to justify not using it.
Low-risk prostate cancer, as determined by preoperative factors, is often under-staged and thus pathologic T3 disease is subsequently discovered. Higher-risk prostate cancer, once considered a surgical taboo, is now frequently managed by initial prostatectomy and cancer eradication is often not achieved in a significant number of patients.
If a man with prostate cancer is at risk for local failure his options are rather limited. He can be treated with radiation early with adjuvant therapy or treated later with radiation in the form of salvage therapy.
Today, local recurrence as measured by a rising PSA level is common. The original intent of surgery for the patient and the surgeon was cure. Now, from the pathologic features of the prostatectomy specimen, we can quite reliably determine when this has not been achieved, and randomized trials have shown that adjuvant intervention with radiation reliably reduces the rate of subsequent relapse.
Two contemporary randomized trials have demonstrated that radiation to the tumor bed can reduce PSA levels and clinical failure at five and 10 years (Lancet. 2005;366:572-578 and J Clin Oncol. 2007;25:2225-2229). A survival advantage would not be anticipated until the second decade after surgery, but current reductions in the failure rate suggest that this will be achieved. Adjuvant radiation has the greatest chance of reducing relapse for a patient with positive surgical margins.
Even prostate cancer patients with the highest risk of distant relapse, such as those with positive seminal vesicles and high Gleason scores, have improvements in five-year outcomes. This all implies that there is a local component to the failure these patients experience that may well be several years ahead of the distant disease. The urinary and bowel morbidity of the radiation given in these trials appears to be low, although there is a reduction in the number of men recovering sexual potency.
It may be argued that adjuvant treatment for all patients at high-risk is less preferable to selective salvage radiation, the latter of which spares some patients unnecessary treatment. Unfortunately, late salvage rates are low and may not be as high as those achieved with early adjuvant therapy.
Researchers have looked at the efficacy of salvage radiation therapy “American style” and found that it can be selective but not effective. Stephenson et al conducted a study with 501 men treated with salvage radiation for detectable or rising PSA levels after radical retropubic prostatectomy (RRP).
The study, published in the Journal of the American Medical Association (2004;291:1325-1332), included pooled data from five academic centers in the United States. The mean follow-up was 45 months. The researchers found that 250 patients (50%) experienced disease progression after treatment, 49 (10%) developed distant metastases, 20 (4%) died from prostate cancer, and 21 (4%) died from other or unknown causes. The four-year progression-free probability (PFP) was 45%.
A British randomized trial has been launched to further investigate this issue. In addition, a European Organisation for Research and Treatment of Cancer (EORTC) trial has been initiated to determine whether the addition of a short course of androgen deprivation therapy may improve outcomes. In my opinion, this indicates an acknowledgement of the fact that many prostate cancer patients have systemic disease and that early introduction of systemic therapy may be beneficial. Adjuvant RT reduces the risk of a rising PSA level at five years by as much as 50%. Adjuvant RT also reduces the risk of clinical failure by 15%. The benefit appears to be concentrated among those prostate cancer patients with positive surgical margins.
At this time, it is too early to assess the effect on survival but it does reduce the need for subsequent androgen deprivation therapy. It is important to note that morbidity appears low and is certainly lower than the rate of morbidity associated with current systemic alternatives. When surgery has probably failed to cure the patient the best prospective data support the use of adjuvant radiation. Salvage RT cannot be more effective than adjuvant RT and actually may be less.
I find that this is an issue that is not addressed enough when urologists, oncologists, and surgeons discuss treatment options with their prostate cancer patients. It is important to note that radiation early after surgery may delay or prevent the recovery of erections which will be a disincentive for some men. Physicians are often reluctant because they don’t want to impair their handiwork and so they are not often anxious to advocate for more treatment. However, clinicians should know that several published studies clearly show that early treatment is preferable.
We are now in an era where urologists and oncologists need to discuss adjuvant external beam radiation therapy with their patients earlier in the course of their disease management and prepare them for a therapeutic option that may be coming down the road. This is an important issue because preparing the patient can help eliminate the significant disappointment they may experience when told later in the course of their disease management.
We have been counting on PSA levels to be our canary in the coal mine. However, I feel it is time to move past that way of thinking. We now have the clinical trial data to support the case for adjuvant external beam radiation therapy. We are supposed to practice evidence-based medicine, and the evidence suggests that early adjuvant external beam radiation therapy is superior to delayed treatment in terms of cure.
Prostate cancer success rates must be measured over decades. So, we are still many years away from declaring this debate over. Ultra-sensitive PSA assays may, in the future, clarify the distinction between adjuvant and salvage therapy ending the current argument. For now, however, I believe that you are less likely to see a prostate cancer patient suffer recurrence if you adopt this approach. Using adjuvant external beam radiation therapy may also significantly lower the risk of metastasis. At the end of the day, the message really is “think local.”