Date Published: November 1, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Ariel E. Marciscano, Matthew E. Hardee, Nicholas Sanfilippo.
Traditionally, patients with high-risk localized prostate cancer have been an extremely challenging group to manage due to a significant likelihood of treatment failure and prostate cancer-specific mortality (PCSM). The results of multiple large, prospective, randomized trials have demonstrated that men with high-risk features who are treated in a multimodal fashion at the time of initial diagnosis have improved overall survival. Advances in local treatments such as dose-escalated radiotherapy in conjunction with androgen suppression and postprostatectomy adjuvant radiotherapy have also demonstrated benefits to this subset of patients. However, therapeutic enhancement with the addition of chemotherapy to the primary treatment regimen may help achieve optimal disease control.
Prostate cancer is the most common noncutaneous malignancy and is the second leading cause of cancer-related mortality among men in the USA . In 2010, it is estimated that 217,730 men were newly diagnosed and 32,050 men died of prostate cancer . Simply stated, roughly 1 in 6 American men will be confronted with a diagnosis of prostate cancer during their lifetime. Prostate cancer exhibits a broad spectrum of clinical behaviors, ranging from microscopic, well-differentiated indolent tumors to aggressive malignancies with significant potential for recurrence and metastasis. Most prostate cancers are localized at the time of diagnosis which is likely to continue with increasing emphasis on screening and improving technology for early detection.
Traditionally, single modality regimens for treating high-risk patients have resulted in poor treatment responses and high failure rates . These poor clinical outcomes are observed irrespective of the primary treatment type, either a surgical approach with radical prostatectomy (RP) or radiotherapy with external-beam radiation therapy (EBRT) or brachytherapy. A study by Pisansky et al., assessed disease relapse in 500 patients with clinically localized prostate cancer treated solely with radiotherapy. The total RT dose administered was dependent on tumor stage: T1 received a median dose of 64 Gy (range 60–70.7 Gy); T2 64.8 Gy (range, 50–70.2 Gy); T3-4, 66.3 Gy (range, 55.8–70.4 Gy). Amongst high-risk patients, a 24% relapse-free probability at 5 years as well as a much higher incidence of clinical and biochemical relapse was reported when compared to their low and intermediate risk counterparts . Furthermore, a 2005 multi-institutional review by Soloway and Roach further delineated the need to improve existing therapeutic interventions. High-risk patients undergoing monotherapy with curative intent with RP, EBRT, or brachytherapy had high rates of both clinical and biochemical progressions (>50% at 5 years). Importantly, this paper also alluded to the increasing importance of adjuvant therapy and multimodal approaches in order to improve control of high-risk localized disease .
The need to improve high-risk disease management has prompted the development of novel agents, several of which may be genuine contenders to impact disease outcomes in the future. Initial studies in castration-refractory disease have been useful in order to characterize the efficacy and safety of these potential therapeutic agents.
While considerable progress has been made in the treatment of high-risk prostate cancer, there is a clear need to continue prospective randomized clinical trials in order to optimize treatments. Combination therapies involving radiotherapy, androgen deprivation therapy, surgery and chemotherapy have yielded varied success. Importantly, the combination of long-term ADT and radiotherapy and has been particularly successful and chemotherapy may have the potential further improve outcomes. As we continue to appreciate the additive and synergistic effects of multimodality therapy, we must also acknowledge the potential for additive toxicities.