Current Areas of Investigation
Is There a Role for Androgen-deprivation Therapy Combined With ART/SRT?
It is now clearly established that the standard nonoperative management for patients with high-risk prostate adenocarcinoma includes long-term ADT. Two previous cooperative group trials have demonstrated an overall survival advantage for high-risk patients with an intact prostate treated with 2–3 years of ADT.[49,50] It remains unknown if there is a benefit to the addition of adjuvant ADT for men with high-risk, node-negative prostate adenocarcinoma initially treated with a RP and pelvic lymph node dissection. The primary rationale for use of ADT post-RP is to:[51–53]
Improve local control by targeting disease that may be in hypoxic regions of the prostatic fossa given the altered vasculature postoperatively;
Target subclinical distant micrometastatic disease;
Alter PSA kinetics.
Previous studies have indicated a potential benefit for men with APFs treated with combination therapy. A secondary analysis of patients status post-RP enrolled on RTOG 85–31, a Phase III trial comparing standard external beam RT plus immediate ADT versus RT alone for patients with nonbulky PC, found a biochemical control advantage for patients who received combination therapy compared with men treated with RT alone. With a median follow-up of 5 years, the progression-free survival for men treated with combination therapy was estimated to be 65% compared with 42% for men treated with RT alone (p = 0.002). Similar results were seen in a retrospective study performed at Stanford University. A prospective study at the Mayo Clinic also revealed encouraging results for patients treated with 2 years of ADT and SRT (5-year freedom from PSA-relapse of 91.5%). A Phase III trial, RTOG 9601, also examined the benefit of 2 years of treatment with Casodex® for men with a pT2–3 N0 PC with a detectable PSA. This trial has reached target accrual and final results are currently pending. Preliminary results presented at the American Society of Clinical Oncology Genitourinary Symposium revealed a significant freedom-from PSA progression benefit for the cohort receiving long-term ADT (57 vs 40%; p < 0.0001). The EORTC currently has an ongoing Phase III trial (EORTC 22043) examining the role of postprostatectomy RT with or without concurrent and adjuvant ADT.
A current RTOG trial (0534) is investigating the benefit of short-term ADT as well as pelvic nodal irradiation in the SRT setting. In this trial, patients will be randomized to one of three treatment arms:
Prostatic fossa irradiation alone;
Prostatic fossa plus short-term ADT;
Prostatic fossa plus whole pelvic irradiation with short-term ADT.
The primary end points of this study are to determine the following:
Whether the addition of short-term androgen deprivation therapy to prostatic fossa irradiation improves freedom from progression for 5 years over that of prostatic fossa irRT alone;
Whether short-term ADT and whole pelvic RT improves freedom from progression over that of short-term ADT and prostatic fossa irradiation alone for men treated with SRT.
The target of accrual for this trial is 1764 patients and, to date, nearly 40% of the target-accrual goal has been met.
Can Treatment Time be Safely & Effectively Shortened?
Among patients, the long duration of external-beam RT for PC has been cited as a primary reason for selecting alternate therapies as first-line treatment. Currently, standard RT schedules deliver 66.6–70.2 Gy in 37–39 fractions over 7.5–8 weeks. Shortened courses of salvage RT may thus improve patient satisfaction and also offer the possibility of increasing local tumor control.
Shorter-course, or 'hypofractionated', RT is appealing based upon core radiobiological principles specific to PC that suggest the potential for reduced toxicity coupled with the ability to deliver a higher equivalent dose to PC cells through a shorter course and larger fraction RT schedules. Radiobiological models suggest that PC has an unusually low α:β ratio; approximately 1.5 Gy. By contrast, the α:β ratio of the bladder and rectum are thought be 3 Gy. The radiobiological concept of the α:β ratio, which characterizes damage repair after RT, is used in calculations of biological equivalent dose for RT schedules. For tissues with lower α:β ratios, such as PC, the biological equivalent dose is influenced more strongly by fraction size. That is, low α:β ratio cells are preferentially spared by more frequent, smaller fractions and are more sensitive to fewer, larger fractions. The difference between α:β ratios for PC (1.5 Gy) and late-responding normal tissues, such as the rectum (3 Gy), suggests a potential therapeutic window that can be exploited through hypofractionated (HypoFx) RT schedules. HypoFx RT schedules could therefore allow for RT dose escalation (without increasing expected normal tissue toxicity rates), or for decreasing the expected toxicity rates (without decreasing expected PC cure rates).
A recent Phase I–II trial performed in Italy found acceptable rates of acute and late GI and GU toxicity for patients receiving ART at a dose of 50 Gy in 2.5 Gy fractions. A similar study performed at the University of Wisconsin treated patients with RT delivered over 5 weeks (65 Gy in 2.5 Gy fractions). With a median follow-up of 32 months, the authors reported low rates of GI and GU toxicity and acceptable biochemical control.
As a smaller number of treatments are delivered, HypoFx RT is likely to result in substantially lower direct and indirect healthcare costs, in addition to less time away from the workplace and reduced use of transportation resources. The improved convenience of HypoFx RT may make salvage treatment more feasible for patients with limited access to RT facilities. Consequently, HypoFx is a promising area of research that will continue to be investigated over the ensuing years.
Is There a Role for Dose Escalation?
The predominant treatment failure pattern for patients treated with ART has been found to be local, within the prostatic fossa rather than distant metastatic disease. These data highlight the importance of identifying the optimal dose of RT to address microscopic disease within the prostatic fossa. It is well established that RT dose escalation results in increased biochemical control for patients treated in the with an intact prostate.[63,64] Thus, it is plausible that higher doses of RT in the postprostatectomy setting will also result in improved biochemical and local control rates.
In Milan, Italy, a recent retrospective, single-institutional analysis of 334 high-risk prostate carcinoma patients treated with early ART to either a dose of <70.2 or ≥70.2 Gy was performed. The 5-year biochemical relapse-free survival and disease-free survival rates were significantly higher in patients treated with ≥70.2 Gy. A multivariate analysis also identified treatment with RT doses of ≥70.2 Gy to be an independent prognostic factor predicting for an improved biochemical relapse-free survival and disease-free survival rates. A similar dose–response relationship was identified in patients treated with SRT at Stanford University. Moreover, other dosimetric studies have demonstrated that established normal tissue dose constraints for the bladder and rectum can be safely achieved using RT doses up to 72.0 Gy using IMRT.
What is the Prognostic Significance of a Detectable 'Ultrasensitive' PSA Level?
Several PSA assays currently in use allow for lower levels of PSA detection than what was previously possible. 'Hypersensitive' assays have a lower limit of detection of 0.1 ng/ml and 'ultrasensitive' PSA assays have a lower limit of detection of <0.1 ng/ml, sometimes detecting levels as low as 0.001 ng/ml. The prognostic significance of a detectable 'ultrasensitive' PSA level has been a source of confusion within the urologic-oncology community. Although some reports have suggested potential benefits for these assays, other reports have indicated that these results are unreliable and result in unwarranted patient and physician anxiety. However, more recent studies have demonstrated that an undetectable ultrasensitive PSA nadir is an independent predictor of biochemical recurrence-free survival that may be used to identify patients who will require salvage treatments. As data from institutions and clinical trials utilizing such assays materialize, we will be able to further characterize the prognostic significance of these values.
Future Oncol. 2011;7(12):1429-1440. © 2011 Future Medicine Ltd.