Commentary (Valicenti): Integrating Hormonal Therapy With External-Beam Radiation and Brachytherapy for Prostate Cancer

Icommend the authors for their excellent review and discussion regarding the integration of hormonal therapy with permanent prostate implants. They address several important issues relating to the sequence and duration of hormonal therapy in combination with externalbeam radiation therapy (EBRT) and its underlying relationships with permanent prostate implants. Therapeutic Rationale
The authors appropriately extrapolate the data of prospective randomized trials and apply the results in a different clinical context. Their motivation stems from a multiplicity of successfully completed and widely reported prospective randomized trials from the Radiation Therapy Oncology Group (RTOG). In particular, RTOG 86-10 and 85-31 have demonstrated a significant local tumor control and disease-free survival benefit in locally advanced prostate cancer patients (based primarily on clinical stage and Gleason score) with immediate neoadjuvant or adjuvant hormonal therapy and EBRT, as compared with EBRT alone.[1,2] To date, the most compelling results of the combined-modality treatment paradigm in prostate cancer are from a recent update of RTOG 85-31. With a median follow-up time of 7.3 years, EBRT with immediate adjuvant hormonal therapy (medical castration of indefinite duration) led to a 10-year absolute survival benefit of 47%, compared to 38%with EBRT alone (P = .0043). This survival outcome corresponded to approximately a 23% reduction in prostate cancer- specific mortality, implying that EBRT and long-duration adjuvant hormonal therapy was effective in prolonging survival in selected prostate cancer patients. This conclusion is most convincing given that it confirms a previously published and frequently cited prospective randomized trial by the European Organization for Research and Treatment of Cancer.[3] Important Related Issues
In light of the benefit of hormonal therapy with EBRT, the authors address central questions about patient selection for combined-modality therapy, the biologic interaction between hormonal therapy and EBRT, the optimal sequence of hormonal therapy, the volume to be irradiated, and finally, the optimal duration of hormonal therapy. In the absence of prospective randomized trials testing hormonal therapy and permanent prostate implants, it is essential to raise these important questions when considering the use of hormonal therapy or EBRT with permanent prostate implants. RTOG Risk Groups
In patient selection, there are a multitude of risk-stratification models using T stage, Gleason score, and pretreatment prostate-specific antigen (PSA). Most risk-stratification schemes are useful in determining prognoses after EBRT but are not commonly used to select patients for hormonal therapy. The authors point out that one notable exception is the RTOG risk group classification system (Table 1 in their article), in which the value of hormonal therapy has been studied.[4] According to the RTOG system, low-risk patients do not benefit from hormonal therapy, intermediate-risk patients benefit from short-duration hormonal therapy, and high-risk patients (groups 3 and 4) have an overall survival benefit with long-duration hormonal therapy. That said, several limitations of their conclusions include the absence of PSA data in the model, varying follow- up times, and a meta-analysis based primarily on the results of a single cooperative group's research. Finally, since all patients were treated with EBRT, the RTOG system simply does not pertain to permanent prostate implant patients. Extrapolation From Randomized Trials
Laboratory and clinical data strongly suggest that the biologic interaction between hormonal therapy and EBRT is multifaceted and has complex implications for primary tumor control as well as the eradication of micrometastases. Zietman et al demonstrated in a Shionghi mouse model that the dose of radiation to the tumor plus hormonal therapy could be halved and that the benefit was sequence-dependent, with greatest improvement after maximal hormonal therapy blockade.[5] Although the findings of RTOG 86-10 apparently support this conclusion, recent data from RTOG 94-13 suggest that the interaction between neoadjuvant hormonal therapy and EBRT applies to nodal micrometastases and does not occur primarily in the prostate.[6] Thus, if there is a plateau in improved local tumor control with neoadjuvant hormonal therapy and EBRT in the 70- to 80-Gy range, it is unlikely that neoadjuvant hormonal therapy would result in an observable benefit in dose-escalated prostate-targeted therapy, whether via permanent prostate implants or intensity-modulated radiation therapy. In addition, future development of the underlying concepts may have to take a new direction focusing on sites of prostate cancer micrometastases. RTOG 94-13 was the first phase III prospective randomized trial to address the sequence of 4 months of hormonal therapy and the use of pelvic nodal irradiation in prostate cancer patients at risk of nodal spread. This trial randomized patients to four treatment arms that included 4 months of neoadjuvant hormonal therapy and whole-pelvic irradiation, 4 months of neoadjuvant hormonal therapy and prostate-only radiotherapy, whole-pelvic irradiation and 4 months adjuvant hormonal therapy, or prostate-only irradiation and 4 months of adjuvant hormonal therapy. The authors summarized the results in their article, concluding that the evaluation of disease progression favored neoadjuvant hormonal therapy and pelvic nodal irradiation. This strongly suggests that there is a sequence- and volume-dependent interaction between neoadjuvant hormonal therapy and EBRT by which a therapeutic benefit is derived. In selected patients, the combination of EBRT, short-duration neoadjuvant hormonal therapy, and permanent prostate implants is justifiable, and it is perhaps necessary to use neoadjuvant hormonal therapy and pelvic- field irradiation with permanent prostate implants to fully maximize improved outcomes. However, this approach should be tailored to carefully address the possibility of additional acute and late toxicity by combining neoadjuvant hormonal therapy or adjuvant hormonal therapy with EBRT or permanent prostate implants.[7,8] Unfortunately, previous retrospective studies evaluating neoadjuvant hormonal therapy, EBRT, and permanent prostate implants did not routinely tailor the EBRT to pelvic nodal sites or uniformly use a certain sequence or duration of hormonal therapy. Because of varying combinations of treatment, patient selection, follow-up time, and definitions of outcome, the results of multiple studies are inconsistent and inconclusive with regard to determining the benefits of the addition of hormonal therapy to permanent prostate implants. In this clinical setting, patients and oncologist may have to depend on comparative reasoning and establish appropriate analogies with prospective data to orient themselves to optimal treatment solutions. Another pertinent question regarding permanent prostate implants and hormonal therapy is the optimal duration of hormonal therapy. This question has also been addressed by several prospective randomized trials and provides new insight to the trend for combining the two treatments. Recently, RTOG 92-02 demonstrated an improvement of disease-specific survival and overall survival (in patients with Gleason score 8 or higher) after long-duration adjuvant hormonal therapy (28 months) and EBRT compared with neoadjuvant hormonal therapy (4 months) and EBRT.[9] Furthermore, the Eastern Cooperative Oncology Group (ECOG) tested the effects of long-duration adjuvant hormonal therapy in a different patient population.[10] Messing et al reported on a prospective randomized trial of long-duration adjuvant hormonal therapy after radical prostatectomy in patients with nodal metastases. The study was significant for an improvement in survival with the addition of immediate adjuvant hormonal therapy compared to observation. Since longduration adjuvant hormonal therapy benefits selected patients with a wide range of demographic characteristics regardless of the primary treatment modality, it would seem reasonable that appropriately selected patients undergoing permanent prostate implants may derive a similar benefit. Conclusions
In summary, given the difficulty and pitfalls of interpreting and applying the results of retrospective data, the authors appropriately and justifiably extrapolate the prospective randomized data. In patients at high risk for nodal metastases (> 15%), the results of a single prospective randomized trial (RTOG 94-13) suggest using neoadjuvant hormonal therapy and pelvic field EBRT with permanent prostate implants. However, pursuit of this treatment recommendation should be attentive to the documented varying risk of additional toxicity. Finally, since multiple prospective randomized trials consistently support the use of long-duration adjuvant hormonal therapy after EBRT or radical prostatectomy, it would be reasonable to expect a similar benefit after permanent prostate implants.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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