External beam radiation therapy (EBRT), conventional and more recently three-dimensional conformal radiation therapy (3D-CRT) with dose escalation, including intensity modulated radiation therapy (IMRT), has proven to be a highly effective treatment for men with localized prostate cancer. Treatment results from several series for patients with favorable prognostic factors of prostate-specific antigen (PSA) < 10ng/ml, Gleason score < 7 (i.e. well-moderately differentiated), and T1-T2a (i.e. locally-confined, low volume) disease, have been excellent. In a large series from MD Anderson Cancer Center, patients with favorable risk factors experienced a freedom from biochemical failure rate of 88% at 5 years and 84% at 10 years.2 Similar results have been seen in a number of other series across multiple institutions.3-5
Despite these reports showing the clinical benefit of RT in early-stage, low-risk prostate cancer, patients with intermediate risk prognostic factors and with high risk/locally advanced disease [i.e. clinical stage T2B, extensive unilateral disease, or Gleason score 7 (i.e. moderately-poorly differentiated), PSA 10-20 ng/ml; and clinical stage > T2C, bilateral often bulky disease, Gleason score > 8 (i.e. poorly differentiated) and PSA > 20 ng/ml] have a 25%-50% and a greater than 50% risk of biochemical recurrence in 5 years.6 Ten-year survival rates of only 40% have been observed with standard RT alone for patients with locally advanced disease.7'8 The rates of survival free of biochemical failure at 5 years were 69% for intermediate risk patients and 47% for high risk patients in a multi-institutional review.3
These relatively poor results of RT in patients with intermediate and high risk disease have led to trials investigating radiation dose-escalation using conformal RT methods, such as 3D-CRT and IMRT, and external beam combined with hormonal therapy, which is the main subject of this review.
In one trial of dose escalation performed at Fox Chase Cancer Center, an improvement in PSA-relapse free survival (RFS) was observed among the subgroup of patients with PSA > 10 when the RT dose was increased from 68 Gy to 79 Gy.9 The 5-year biochemical disease-free survival (DFS) was significantly improved for patients with pre-treatment PSA > 10 who received greater than 76 Gy. Patients with an initial PSA of 10.0-19.9 had a 5-year biochemical DFS of 29%, 57%, and 73% if they received <71.5 Gy, 71.5-75.6 Gy, and >75.6 Gy respectively (p = 0.02). Patients with an initial PSA > 20 had a 5-year biochemical DFS rate of 8%, 28% and 30% if they received <71.5 Gy, 71.5-75.6 Gy and >75.6 Gy, respectively (p = 0.02).10
Similar dose-response results have been observed at Memorial Sloan Kettering Cancer Center, indicating improvement in biochemical DFS for patients with intermediate and high-risk disease who received a dose of >75.6 Gy (p < 0.05).11 The study from Memorial Sloan Kettering showed that clinical response was dose dependent, with 90% of the patients receiving 75.6 Gy or 81.0 Gy achieving a PSA nadir < 1.0ng/ml compared with 76% and 56% for those treated with 70.2 Gy and 64.8 Gy (p< 0.001). Five-year actuarial PSA-RFS for patients with favorable prognostic indicators (stage T1-2, PSA < 10.0, Gleason score < 6/10) was 85% compared with 65% for those with intermediate prognosis and 35% for the group with unfavorable prognosis (> 2 indicators with high risk features) (p < 0.001).11 Positive biopsy rates also were significantly less in those receiving the higher doses.
In a large series of patients, analyzed at the University of Michigan,12 3D-CRT with dose escalation reduced the risk of biochemical failure among intermediate risk patients. Hormonal therapy was not associated with reduced rate of failure in patients with intermediate risk features, although for patients with high-risk features, adjuvant and neoadjuvant hormonal therapy significantly increased failure-free survival in radiation treated patients (p < 0.05), as is also reported in the randomized trial discussed below.
A French study accrued 164 patients to a dose escalation trial. The patients had clinical T1b-T3 disease and were prescribed doses ranging from 66 Gy to 80 Gy, with group 1 patients receiving a standard dose of 66-70 Gy, and group 2 patients receiving a dose of 74-80 Gy. Although mean follow-up was short for both groups (32 months for group 1, n = 46; 17.5 months for group 2, n = 118) the probability of achieving nadir PSA < 1 ng/ml was significantly higher for group 2 patients.13
The results of a randomized study from MD Anderson Cancer Center comparing 70 Gy vs. 78 Gy showed an improvement in 5-year freedom from PSA failure, most significant in patients with pre-treatment PSA > 10ng/ml.2,14 The 5-year freedom from failure (FFF) rate was 75% for the patients in the high risk arm vs. 48% for those in the control group (p = 0.011). Updated results at 60 months showed an improvement in crude biochemical failure rate for the experimental group (21% vs. 32%, p = 0.03).15 Kaplan-Meier analysis16 showed that although FFF rates were improved in the experimental group the differences narrowed, with longer follow-up, to 6% at 6 years. Improvements in FFF were most significant for patients with intermediate to high risk disease (6-year FFF rate of 43% vs. 62% for the control and experimental arms, respectively). There also appeared to be a reduction in freedom from distant metastasis at 6 years for patients with pre-treatment PSA > 10ng/ml (88% for the 70 Gy arm vs. 98% for the 78 Gy arm [p = 0.056]). There was no overall survival difference seen at 6 years.
Therefore, both radiation dose escalation and randomized series show a more pronounced effect of dose escalation in patients with intermediate risk prostate cancer. Patients with more favorable disease may not benefit from higher doses because conventional doses are adequate to eradicate these tumors. Patients with high risk disease may have a local control benefit from high dose RT; however, due to the high likelihood of occult metastases, long term biochemical no evidence of disease (NED) and DFS may not be affected. For this high-risk group of patients, adjuvant hormonal therapy and possibly chemotherapy may be necessary in addition to dose escalation. It is also not clear that dose escalation is without potential toxicity with longer follow-up15 and particularly when higher doses are used, although studies in general report an improvement in late sequelae of 3D-CRT and IMRT dose escalation.17-19
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