Combinations of Hormones and Local Therapies in Locally Advanced Prostate Carcinoma
Combinations of Hormones and Local Therapies in Locally Advanced Prostate Carcinoma
Until recently, newly diagnosed patients with prostate cancer were faced with one of four basic management options: observation, radiation therapy, radical prostatectomy, or hormonal manipulation. The exact option chosen by an individual patient depended on his symptoms and life expectancy, stage of disease, and (for organ-confined cancers) degree of tumor differentiation. In more recent years, combinations of therapies have been examined more extensively. These trials are now reaching a maturity sufficient for preliminary evaluation.
The review by Eulau and Corn addresses treatment options for patients with locally advanced prostate cancer. Their review places emphasis on data derived from clinical trials using hormonal therapy in combination with radiation or surgery.
Staging, End Point, and Patient Selection Issues
Patients with locally advanced prostate cancer are an extremely heterogeneous group within a disease known for its heterogeneity. The extent and manner of staging are critical for the accurate determination of prognosis. When patients with clinical stage C (T3,NX,M0) disease undergo a pelvic lymph node dissection, approximately 50% are found to have pathologic stage D1 (TX,N1,M0) disease . If immunohistochemical stains or molecular-based pathologic methods were routinely used, node-positive disease would be detected even more frequently. Thus, when evaluating treatment efficacy, it is essential to realize that 50% of patients with clinical stage C disease actually have early-stage metastatic cancer and that poor long-term outcomes can be expected for the majority of these patients if treated with radiation or surgery only.
As with any clinical trials, comparisons of nonrandomized studies in prostate cancer are difficult. Trials with distinct end points may or may not be comparable; ie, trials evaluating outcomes based on prostate-specific antigen (PSA) are very different from trials evaluating clinical-based outcomes. In addition, patient selection can have a profound influence on outcome. Protocols conducted at the Mayo Clinic, for example, cannot readily be compared to those conducted at Charity Hospital in New Orleans. When taken together, issues related to staging, end points, and patient selection conspire to make comparisons of nonrandomized trials extremely difficult.
Given these facts, evidence for treatment efficacy can best be derived from adequately powered, prospective, multicenter randomized trials with clearly defined, clinically relevant end points. With this guiding dictum, a review of locally advanced prostate cancer protocols is vastly simplified.
The RTOG Trials
The studies meeting these criteria in locally advanced prostate cancer have been conducted under the auspices of the RTOG or the EORTC Radiotherapy Therapy and Genitourinary Tract Cancer Cooperative Groups. To these organizations' credit, these trials are well executed and appropriately analyzed.
What data are available and sufficiently mature to analyze? The end points cited in most trials include locoregional control and progression-free survival. When these end points are used, several randomized trials suggest that the combination of hormones and radiation is more effective than radiation alone for clinically staged locally advanced prostate cancer. In particular, RTOG trials 85-31 and 86-10 demonstrate that adjuvant goserelin (Zoladex) or neoadjuvant goserelin plus flutamide (Eulexin) can decrease local relapse rates and increase progression-free survival rates. Based on data from the excellently executed RTOG 86-10 trial , the addition of approximately 4 months of goserelin plus flutamide to external-beam radiation therapy can increase the 5-year progression-free survival rate from 15% to 36% (P less than .001). A significant decrease in the rate of local progression (from 71% to 46%, P less than .001) was also noted with combination therapy.
Much will be learned from continued follow-up of patients treated in the randomized RTOG trials. Will there be survival advantages? Will the survival curves plateau? Will prior hormonal therapy decrease the duration of response to subsequent hormonal therapy?
Results from the EORTC study have not yet been published in the peer-reviewed literature, but preliminary results presented at the American Society of Clinical Oncology's 1996 meeting are particularly noteworthy . In this trial, patients with high-grade T1-T2 tumors or any-grade T3-T4 tumors (and no known nodal or distant metastases) were randomized to receive radiation alone or radiation plus 3 years of hormonal therapy. The hormonal therapy started at the beginning of radiation and consisted of 3 years of goserelin injections. One month of an antiandrogen (cyproterone acetate) was also administered during the first month of therapy. Median follow-up was only 33 months. However, estimated overall 5-year survival in patients receiving combined hormonal and radiation therapy was 78%, as compared with 56% for those receiving radiation alone (P = .001). Local control was achieved in 95% of those treated with combined therapy and 75% of those given radiation alone (P less than .001).
These preliminary data are extremely impressive and are the first to indicate that an overall survival advantage may be conferred by the combinations of hormones and radiation in patients with locally advanced prostate cancer. The peer-reviewed publication of these important data and additional reports concerning analysis of more mature data are eagerly anticipated.
Trials of Neoadjuvant Hormonal Therapy
The review by Eulau and Corn also covers randomized trials of neoadjuvant hormonal therapy prior to radical prostatectomy. These trials are not of sufficient maturity to make clinically relevant conclusions. In the preliminary analyses, the addition of hormonal therapy favorably influences pathologic, but not clinical, end points. More mature data from these studies are eagerly anticipated.
Importance of the RTOG Data
In the absence of any conflicting data, the RTOG and the EORTC studies assume even more importance. For patients with clinically staged locally advanced prostate cancer, these data provide hope that combinations of hormonal and radiation therapy will provide better disease control than radiation therapy alone. In fact, according to Eulau and Corn, the RTOG has accepted a combination of radiation and maximal androgen blockade as standard treatment for future trials, and the FDA recently granted approval for the treatment of stage B2/C prostate cancer with flutamide in combination with a luteinzing hormone-releasing hormone (LHRH) agonist and radiation. If the EORTC trial's survival data continue to hold true with additional follow-up, combinations of radiation and hormonal therapy should be regarded as the standard of therapy for patients with locally advance prostate cancer for many years to come.
Much progress is still needed for patients with locally advanced prostate cancer. The optimal timing and extent of hormonal therapy has yet to be determined. In addition, no trial has assessed the utility of hormonal treatment alone for patients with locally advanced prostate cancer. Until such a study is performed the contribution of radiation therapy to improved patient outcome cannot be objectively assessed. I also note that despite the best of current treatments, a majority of patients will have progressive cancer within 5 years of treatment. Innovative approaches in combination with appropriately designed and adequately powered clinical trials are needed to improve this dismal prognosis.
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2. Pilepich MV, Krall JM, Al-Sarraf M, et al: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: A randomized comparative trial of the Radiation Therapy Oncology Group. Urology 45:616-623, 1995.
3. Bolla M, Gonzalez D, Warde P, et al: Immediate hormonal therapy improves locoregional control rates and survival in patients with locally advanced prostate cancer. Results of a randomized phase III clinical trial of the EORTC radiotherapy and genitourinary tract cancer cooperative groups. Proceedings American Society of Clinical Oncology 15:591A, 1996.