In Session I of the First Sonoma Conference on Prostate Cancer, a critical concern in prostate cancer management was addressed: improving the pretreatment prediction of patients outcomes in localized prostate cancer.
After a day of presentations, the participants met to outline general principles for the development of new outcomes-based models and predictive factors, based on the data presented. The goal of the discussions was to identify areas of agreement and areas for future research regarding models and pathologic predictors of outcome in prostate cancer.
I. Areas in Which There Was General Agreement About Models and Pathologic Predictors of Outcome
- Current staging systems inadequately predict outcomes for patients and need to be improved.
- Gleason grade and prostate-specific antigen (PSA) have been proven to improve the predictability of patients outcomes in addition to palpation stage and should be included in a new, unified model (a therapy-directed staging system) to replace the bin system. In a complex staging system, such as that used in prostate cancer, the possible number of bins is so large that it becomes too cumbersome to use efficiently. The participants believe that with multiple factors, the bin system becomes unmanageable and complex, reducing its applicability for individualized patient care.
- Components with interobserver variability (eg, histologic grading and T-staging by palpation) need to be systematized to eliminate subjectivity from the staging system and to improve reliability. Because of the intra- and interexaminer variability in interpretation of histologic grades and T-stages by palpation, these components of staging ultimately should be assigned less importance than other, more objective factors.
- Research into new genetic and molecular factors predictive of patient outcome is important for improving treatment decision making and directing care. The development of new predictive factors will also permit comparison of outcomes among various modalities (within or among institutions), improve our understanding of the biologic basis of prostate cancer, and guide the design of clinical trials.
- New study end points should be incorporated into clinical trials. Overall survival as an end point is confounded by co-morbid illness among prostate cancer patients. PSA failure is currently used as a clinical end point; however, it cannot be correlated with survival. Furthermore, the matching of treatment decisions to the magnitude of PSA failure varies among institutions. Surrogate end points that correlate with survival should be identified and incorporated in clinical trials. Additionally, the recognized important end points of cost-effectiveness and quality of life must be incorporated in new clinical trials.
II. Areas of Future Investigation
- The group supports mathematical and statistical research aimed at developing a new, unified model to improve prognostic predictions and guide the selection of therapy.
- Collaboration among institutions to develop new factors predictive of patients outcomes is also recommended. Shared databases should reflect data from both surgery and radiation therapy.
- Developing a common database linking multiple institutions and allowing them to share the results of radiation therapy and surgery is another important goal. Developing such a database will permit the pooling of data concerning PSA failure and survival as applied toward treatment decisions.
SESSION II: Androgen Deprivation with Radiation or Surgery
William U. Shipley, MD, Moderator
Department of Radiation Oncology, Massachusetts General Hospital, Boston, Mass.
In Session II, an area of prostate cancer management that is the focus of active investigation and debate was addressed: androgen deprivation with radiation or surgery. The goal was to assess existing data on this subject, present new findings, and propose consensus conclusions aimed at improving local control, survival, and quality of life in patients undergoing radiation or surgery for nonmetastatic prostate cancer.
After a day of presentations, participants were charged with distilling the data and identifying areas of agreement, areas where no agreement was reached, and areas in need of additional investigation.
I. Areas in Which There Was General Agreement About Androgen Deprivation with Radiation or Surgery
After actively discussing the current and future use of androgen deprivation in apparently nonmetastatic prostate cancer (with or without definitive local therapy), the participants deliberated over consensus conclusions that should be disseminated to the urology and radiation oncology communities. The discussions centered around four general areas: the use of neoadjuvant hormonal therapy (the participants chose to use the term combined androgen blockade to describe combination therapy with an LHRH-analog and antiandrogen) prior to surgery; the use of complete androgen blockade prior to radiation; the use of antiandrogens as monotherapy; and the use of androgen deprivation as an adjunct to radiation.
- Use of combined androgen blockade prior to surgery. For locally advanced prostate cancerie, clinical T3 diseaseno significant benefit of androgen deprivation has been demonstrated. However, the use of combined androgen blockade in T1 and T2 disease is the focus of six ongoing private Phase III trials. While early end points of PSA failure-free survival have not been encouraging, these studies need to be followed further before definitive conclusions can be drawn.
- Combined androgen blockade prior to external beam radiation therapy. The participants agreed that there is room for improvement in therapy for locally advanced prostate cancer (as clearly indicated by serum PSA failure results and rebiopsy findings). While no long-term survival benefit has yet been demonstrated, improved progression-free survival maintained for more than 5 years has been documented by the Radiation Therapy Oncology Group (RTOG) with 4 months of combined androgen blockade prior to, and during, external beam radiation therapy. These progression-free data are encouraging and support the use of androgen deprivation prior to radiation for locally advanced prostate cancer. (The benefits of combined androgen blockade prior to brachytherapy have not been the focus of large clinical trials. Therefore, the discussion focused on external beam radiation therapy.)
- Combined androgen blockade vs monotherapy. The participants agreed that the potential benefits of monotherapy with an antiandrogen vs combined androgen blockade should be actively investigated at all research junctures where adjuvant treatment is indicated. Investigators in Sweden are currently investigating the use of monotherapy with flutamide (Eulexin); the potential improvements in quality of life for patients treated with monotherapy vs combined androgen blockade have aroused much interest.
- Androgen deprivation as an adjuvant therapy to radiation. Long-term adjuvant luteinizing hormone-releasing hormone (LHRH) agonist treatment with external radiation therapy has shown survival advantages in patients with Gleason 8-10 (RTOG 8531) and T1-2, Gleason 8-10, T3-4 patients (European Organization for Research and Treatment of Cancer) with 1 to 3 years of treatment. However, the optimal duration of therapy has not been determined and the value of combined androgen blockade vs LHRH alone are not known.
II. Areas of Future Investigation
- Optimal duration of hormonal therapy (whether administered as neoadjuvant or adjuvant, or as monotherapy or combination therapy remains to be determined by future well-controlled trials. In addition, the use of early vs delayed hormonal therapy in patients with PSA only failure warrants investigation. Defining the particular pathologic stage appropriate for inclusion in adjuvant hormone trials after prostatectomy is another imperative.
- A more comprehensive measure of quality of life should be included as an end point in future research. Beyond potency, sexual quality of life (including libido), the incidence of fatigue, muscle loss, weight gain, osteoporosis, etc, as side effects of therapy, and cost-effectiveness of therapy need to be assessed. (The assessment should be made in terms of cost/unit improvement for combined androgen blockade vs LHRH alone, vs orchiectomy.) A more objective instrument for evaluating changes in potency is also necessary.
- The optimal treatment regimen, ie, combination or monotherapy with antiandrogens and/or an LHRH-analog, also remains to be determined.
- The benefits of androgen deprivation with brachytherapy have not been adequately studied. However, the principles of biological behavior (which resulted in the use of androgen deprivation with external beam radiation therapy) demonstrated an advantage in disease-free rate and survival and would also be expected to apply to brachytherapy. In addition, patients treated with brachytherapy also typically receive external beam radiation therapy, so benefits of androgen deprivation seen with external beam radiation therapy would be expected with brachytherapy as well.
- The role of antiandrogens in prostate intraepithelial neoplasia (PIN) is another possible application with potential promise. High-grade PIN on needle biopsy is considered a strong risk factor for prostate cancer. A number of studies (particularly in Canada) have demonstrated that androgen deprivation therapy can eliminate PIN or decrease it dramatically. Currently, the North Central Cancer Treatment Group is investigating the use of low-dose monotherapy with flutamide in men with high-grade PIN.