Drs. Eulau and Corn comprehensively review the emerging use of combined androgen suppression and local therapies in locally advanced carcinoma of the prostate. These strategies have been developed since the recognition of the inadequacy of contemporary therapies in patients with clinical stage T2-T4 disease. Using strict biochemical end points, at least 80% of such patients will experience biochemical failure in the 10 years following radiation therapy, and there is further failure in the second decade.
High 10-year rates of metastatic disease have led many to believe that occult micrometastatic disease at the time of diagnosis is the principal problem and that these patients would be better served by improved systemic therapy. This is only partly true, however. Fuks et al have shown that metastases develop in two waves . The first wave, occurring over the first 5 years, is undoubtedly the result of occult, undiscovered micrometastases present at diagnosis. The second wave may well be the consequence of seeding from locally persistent disease at the primary site. Improved local control even in this locally advanced group may yield metastasis-free survival benefits.
3D Conformal Radiation Techniques
For the radiation oncologist, one reasonable approach to improving local control is to escalate the delivered radiation dose using three-dimensional (3D) conformal techniques. Such techniques are now being investigated at a number of major centers. Early resultsof 3D conformal techniques look promising when compared to historical controls, but these series are all currently very immature.
The only randomized trial of dose escalation in locally advanced prostate cancer, performed at Massachusetts General Hospital, was reported last year. A local control benefit was found for patients with poorly differentiated tumors but not for those with lower tumor grades . Despite this, 8-year overall survival and biochemical disease-free survival rates were identically poor in patients receiving 75.6 Gy of radiation and those receiving 67.2 Gy. The most notable difference between the two treatment arms was the increase in rectal morbidity observed in patients who were treated with the higher radiation dose.
This trial may have had negative results because the majority of patients had very advanced tumors and because dose escalation may simply have been insufficient. It does highlight the potential risks of dose escalation, however, and reminds us that this practice probably is advisable only in major academic centers.
Neoadjuvant Androgen Suppression
A far safer, more convenient, and widely applicable approach to locally advanced cancer is to hold the radiation dose at current levels and try to achieve tumor cytoreduction with neoadjuvant androgen suppression (NAS). As the authors point out, Radiation Therapy Oncology Group (RTOG) 86-10 was a landmark trial, and in the year since its publication, national practices for locally advanced disease have changed profoundly. This study showed significant improvements in both biochemical disease-free survival and local control in patients treated with NAS followed by irradiation, as compared with those who received irradiation alone.
Despite current enthusiasm for this approach, final judgment will have to be reserved, as this report represents only an interim analysis with a median follow-up of 4.5 years. An overall survival advantage has not yet been seen and may never emerge, as biochemical failure has already occurred in the vast majority of patients in both arms. The advantage in terms of local control also is not as clear-cut as it first seemed. Local failure was defined as either a palpable recurrence or a prostate-specific antigen (PSA) level more than 4 mg/mL in men with no evidence of metastatic disease. This latter criterion, in the absence of rebiopsy, may well overinflate the rate of local failure, and uncertainty remains as to what biases this definition has introduced.
These criticisms of RTOG 86-10 should not detract from its unique status as a positive randomized trial in prostate cancer. The trial's greatest merits is that it detected a small improvement and will guide us toward future studies that are more likely to yield greater improvements in outcome.
Much evidence is now emerging that longer periods of androgen suppression are more likely to significantly downsize the tumor than are shorter periods . The Vancouver group has demonstrated that there is a two-phase decline in serum PSA after the introduction of androgen suppression. A sharp reduction, principally due to decreased PSA synthesis, occurs in the first 3 months; this is followed by a slower decline, probably the result of continued tumor regression, over the subsequent 5 months.
If radical prostatectomies are performed in men with bulky T2 tumors, the positive surgical margin rate declines progressively from around 50% to 10% to 32% after 3 months of androgen suppression and to 4% after 8 months. Labrie et al reports that 6% of patients who undergo a radical prostatectomy after 8 months of androgen suppression will actually be rendered tumor-free. Canadian randomized studies are now exploring the issue of the duration of NAS prior to both radiation and surgery.
In addition to looking at the duration of NAS, its most appropriate and least costly form needs to be explored. Is maximal androgen blockade required? Smaller phase II studies have suggested that monotherapy may be sufficient.
Who Does and Does Not Benefit from Combination Therapy?
We also need to determine which tumor subgroups do not benefit from combined-modality therapy. It remains possible that many patients with clinical stage T3 or T4 disease do not need radiation at all. Their rate of occult metastasis is so high that indefinite androgen suppression may be the most appropriate management, with radiation withheld until symptomatic local progression occurs (if ever).
Future RTOG studies will also focus on the use of NAS in men with earlier-stage prostate cancer. If any gain is found in these patients, it will result largely from improved local control and should not be confounded by high levels of occult micrometastatic disease.
Conventional radiation therapy or radical prostatectomy currently offer high cure rates only in those with very early disease (T1-T2, Gleason 2-6, PSA less than 10 ng/mL). For the remaining T1-T4 tumors, these conventional approaches are insufficient. Neoadjuvant androgen suppression before radiation looks promising for these men, but the form of NAS and its duration have yet to be fully worked out. In addition, the specific subgroups with the most to gain from this combined-modality approach have yet to be defined. The next decade should yield answers to all of these clinical questions.
It is also tempting to speculate on a future in which patients with T1 or T2 disease could be treated with NAS and then offered radical therapy on the basis of their response. Those with a good response in terms of volume reduction and PSA would proceed to organ conservation with radiation, and the poor responders would undergo prompt surgery. Use of such intriguing sophisticated approaches, however, remains for the future.