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 treatments 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.