The 2008 Genitourinary Cancers Symposium in San Francisco featured a session on anticipating failure in the patient with advanced prostate cancer. Anthony Zietman, MD, the Jenot and William Shipley Professor of Radiation Oncology at Harvard Medical School in Boston, made his case for the use of adjuvant external beam radiation therapy. Adam Kibel, MD, associate professor of surgery in the division of urologic surgery at Washington University School of Medicine in St. Louis, argues in favor of systemic treatment.
Systemic Therapy Most Appropriate
By Adam Kibel, MD
TODAY, THE management of high-risk prostate cancer following radical prostatectomy remains a treatment dilemma. Although many patients are cured by surgery alone, there are still a substantial number of patients who will experience recurrence and will eventually die of their disease. There is controversy when it comes to radiation therapy versus systemic therapy as adjuvant treatment; there is controversy surrounding immediate versus salvage therapy. However, there is no controversy surrounding the concept that systemic disease kills patients. The goal of any adjuvant treatment should be to prevent systemic disease.
Until recently, treatment options focused on improved local control with adjuvant radiation therapy (RT). However, patients at high risk for prostate cancer often have occult metastatic disease that is not controlled by additional local treatment. This phenomenon is reflected in the fact that large randomized adjuvant radiation therapy trials have demonstrated an improvement in local control but not in metastasis-free, disease-specific, or overall survival. Improved cure rates in this patient population will require improved systemic treatment.
Risk of treatment failure following radical prostatectomy can be categorized based on clinical characteristics. Patients with positive surgical margins, extracapsular disease, a high Gleason score, positive lymph nodes, or positive seminal vesicles have a less favorable outcome compared with patients who have organ-confined disease, a low Gleason score, or negative margins (J Urol. 2004;172:910-914). Also, the increased risk associated with adverse pathology translates into a decrease in biochemical-free survival and into a decrease in disease-specific and overall survival, believed to be secondary to micrometastatic disease at the time of diagnosis.
The key issue in the debate between the use of adjuvant radiation therapy and systemic therapy is whether the patient has residual local disease and/or has occult metastatic disease. If the patient has no residual disease then clearly no additional treatment is necessary. If disease is still confined to the pelvis, adjuvant RT has the potential to improve cure rates. If disease has spread, then only effective systemic therapy offers a chance for cure. Unfortunately, the malignant phenotype is established early and the molecular changes seen in the metastatic stage are already evident at early stages of cancer progression for patients with high-risk disease. The Southwest Oncology Group (SWOG) recently reported trial 8794, which treated men with high-risk localized disease with adjuvant radiation therapy. With a 10.6-year follow-up, biochemical-free survival was significantly improved. The median PSA relapse-free survival was 10.3 years for
radiotherapy compared with 3.1 years for observation. The study also found that disease recurrence was significantly reduced with adjuvant RT. The median recurrence-free survival was found to be 13.8 years for radiotherapy compared to 9.9 years for observation. However, metastasis-free and overall survival did not improve significantly, but the P values approached statistical significance, suggesting there may be a subset of patients who would benefit from adjuvant RT (JAMA. 2006;296:2329-2335).
Although SWOG has not examined this hypothesis, recent analysis of a second adjuvant RT (European Organization for Research and Treatment of Cancer 29911) demonstrates that improvements in progression-free survival are limited to patients with negative margins. This still needs to be confirmed, but these data support the conclusion that adjuvant RT will only be effective for patients with residual local disease (J Clin Oncol. 2007;25:4178-4186). It is important to note that these results are in line with evidence from other disease sites such as colorectal, breast, and lung. The evidence demonstrates that adjuvant radiation decreases local relapse but not disease-free survival.
It is well documented that patients with adverse pathology are at increased risk of PSA failure. They are also at increased risk of metastasis and increased risk of death from their disease. We know who these patients are. The evidence to date suggests that further improvements in cure rates for their disease will depend on improved systemic therapy. Initial work has focused on androgen deprivation therapy. Messing et al (Lancet Oncol. 2006;7:472-479) randomly assigned 98 men with positive lymph nodes at the time of radical prostatectomy to either immediate hormone ablation or ablation at the time of metastasis.
At a median follow-up of 11.9 years, men assigned to immediate ablation had an 84% improvement in overall survival, a fourfold increase in prostate cancer-specific survival, and a 3.4 times increase in progression-free survival. Since only patients with node-positive disease were treated, it is unclear if this should be the standard of care for all patients at high risk. However, in contrast to adjuvant radiation trials, this study demonstrated an improvement in overall survival. This is a very important issue that should be noted.
Introduction of chemotherapy has the potential to further improve survival. Recently, randomized prospective trials SWOG 9916 and TAX 327 demonstrated a survival advantage for chemotherapy (N Engl J Med. 2004;351:1502-1512;1513-1520). Earlier treatment may result in durable cures for men who were previously destined to fail. In a recently published phase II study of adjuvant docetaxel in prostate cancer patients at high risk of recurrence following radical prostatectomy, 46 of 76 evaluable patients (60.5%) experienced disease progression at a median follow-up of 28 months. The observed median progression-free survival was 15.7 months. This compared favorably with the predicted 10-month median progression-free survival (J Urol. 2007;177:1777-1781). Again, these findings are intriguing but do not prove that adjuvant chemo-therapy is effective.
Patients at high risk frequently have micrometastatic disease following primary local therapy with either surgery or radiation therapy. Only systemic treatment, however, can cure these patients. Systemic treatment with poor activity has proven to be somewhat efficacious and now better systemic treat-ments are available. In addition, more systemic treatments will be available shortly and these newer generation treatments may offer even greater promise and higher efficacy rates. These systemic agents will need to be studied in the adjuvant setting. Open trials need to be supported to prove that adjuvant/neoadjuvant systemic therapy works or doesn't work. Subjects in closed trials need to be followed to provide data on systemic therapy efficacy. It will take large, randomized prospective trials to improve cure rates for men at high risk of prostate cancer. These trials should be supported by the urologic oncology community.
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.”