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A subgroup analysis of treatment efficacy according to whether patients had low-, intermediate-, or high-risk disease, showed that the addition of short-term ADT to radiotherapy conferred the greatest clinical benefit in the intermediate-risk subgroup, with an increase in the 10-year rate of overall survival from 54 to 61% (hazard ratio for death with radiotherapy alone, 1.23; 95% CI, 1.02 to 1.49) and a reduction in the 10-year disease-specific mortality from 10 to 3% (hazard ratio, 2.49; 95% CI, 1.50 to 4.11). No significant benefit was shown in the low-risk subgroup, with an increase in the 10-year rate of overall survival from 64 to 67% (hazard ratio for death with radiotherapy alone, 1.07; 95% CI, 0.83 to 1.39) and an increase in the 10-year disease-specific mortality from 1 to 3% (hazard ratio, 0.63; 95% CI, 0.21 to 1.92). An interaction test revealed no significant interaction effect between treatment and risk category for overall survival (P = 0.71) and only a weak suggestion of a differential benefit according to risk group for disease-specific mortality (P = 0.08). In all three risk subgroups, short-term ADT was associated with a significant reduction in biochemical failure (Table 2). The incidence of positive findings on repeat prostate biopsy in the lowrisk, intermediate-risk, and high-risk subgroups was fairly uniform in the radiotherapy-alone group, at 35%, 41%, and 39%, respectively, as compared with 12%, 24%, and 30% in the combined-therapy group. Analyses of treatment efficacy separately in white and black patients and in patients who were 70 years of age or younger and those who were older than 70 years were also performed.

The addition of short-term ADT was associated with a benefit in all these subgroups, with the 10-year rate of overall survival increasing from 57 to 62% among white patients (hazard ratio for death with radiotherapy alone, 1.19), 55 to 61% among black patients (hazard ratio, 1.15), 64 to 70% among patients who were 70 years of age or younger (hazard ratio, 1.23), and 50 to 54% among those older than 70 years of age (hazard ratio, 1.11), with no statistical evidence of a differential benefit between whites and blacks (interaction test, P = 0.79) or between age subgroups (P = 0.47). Among black patients, the addition of shortterm ADT to radiotherapy was associated with a decrease in the 10-year disease-specific mortality from 7 to 5% (hazard ratio with radiotherapy alone, 1.27) and a decrease in the 10-year rate of biochemical failure from 40 to 19% (hazard ratio, 2.27).

The multivariate analysis showed that a Gleason score of 7 or higher was a negative prognostic factor for overall survival, disease-specific mortality, distant metastases, and biochemical failure. Other identified negative prognostic factors were older age and nonwhite race or ethnic group for overall survival, clinical T2 lesions for diseasespecific mortality, and a PSA level of 4 ng per milliliter or higher for biochemical failure. A total of 439 patients (44%) in the combinedtherapy group and 404 (41%) in the radiotherapyalone group underwent a repeat prostate biopsy at 2 years. The initial Gleason scores, PSA values, and rates of biochemical failure at 2 years were similar between the patients who underwent biopsy and those who did not undergo biopsy. Persistent cancer was detected in 20% of the biopsy specimens in the combined-therapy group as compared with 39% in the radiotherapy-alone group (P<0.001).

Patient-Reported Erectile Dysfunction
At the pretreatment, 1-year, and 2-year evaluations, the Sexual Adjustment Questionnaire completion rates were 88%, 70%, and 27%, respectively. Before treatment, 48% of the respondents in the combined-therapy group and 54% of those in the radiotherapy-alone group reported that they were “always or almost always able to have an erection” (P = 0.15); the respective rates at 1 year were 21% and 31% (P = 0.004) (Table 3). Scores at 1 year, as compared with the pretreatment scores, were improved in 9% of the patients, the same in 33%, and worse in 58%, with no significant differences between the groups.

Toxic Effects
In the group treated with short-term ADT, the proportions of patients who had acute hepatic toxic effects (occurring up to 90 days after the start of radiotherapy) of grade 1, 2, 3, and 4 were 20%, 5%, 3%, and less than 1%, respectively; late hepatic toxic effects were seen in 4%, 1%, less than 1%, and 0 of these patients, respectively, as compared with 1%, 0, 0, and 0 in the radiotherapy-alone group. In both groups, the incidences of grade 3 or higher acute and late gastrointestinal toxic effects were 1% and 3%, respectively, with grade 5 toxic effects in three patients; two patients receiving radiotherapy alone died of obstruction of the colon, and one patient treated with radiotherapy plus short-term ADT died of colorectal bleeding. Acute grade 3 or higher genitourinary toxic effects were seen in 2% of patients in both groups, with late toxic effects in 8% of patients in the combined-therapy group and 6% of those in the radiotherapy-alone group. During the 8 weeks of short-term ADT before the start of radiotherapy (in the combined-therapy group), 55% of patients had hot flashes, 3% had rash, and the incidences of hepatic toxic effects, decreased hemoglobin levels, and elevated whitecell counts were 16%, 16%, and 4%, respectively (all grade 1). Grade 1 cardiac toxic effects were observed in 11 patients (1%) within 2 years after treatment.

Statistical Analysis
On the basis of previous studies, we expected patients treated with radiotherapy alone to have an 8-year overall survival rate of 60%. Adding short-term ADT was projected to increase this rate to at least 67%. Accordingly, the trial was designed to provide 90% power to detect a 7-percentage-point absolute difference in the 8-year survival rate, with the use of a one-sided log-rank test at the 0.025 significance level, requiring 1980 patients and 716 deaths for definitive analysis. We conducted three planned interim analyses with a significance level of P<0.001 as the criterion for early stopping, which was not met in any of these analyses. The primary end point, overall survival, was estimated by means of the Kaplan–Meier approach, and in the multivariate analyses, hazard ratios with 95% confidence intervals were estimated
with the use of the Cox regression model.

The end points of disease-specific mortality, distant metastases, and biochemical failure were estimated by means of the cumulative incidence function to account for competing risks. The Fine–Gray model was used to estimate hazard ratios for competing risks. The chi-square test was used to test differences in patients’ responses to the Sexual Adjustment Questionnaire. Three subgroup analyses of treatment efficacy were conducted. One was planned: a comparison of treatments within racial groups (white and black). Two were unplanned; one compared treatments within three risk categories defined according to baseline characteristics, and the other evaluated treatments within two age groups (≤70 years and >70 years). The likelihood-ratio test was used to assess whether there was a statistically significant difference in the magnitude of treatment benefit (i.e., interaction effect) according to patient subgroups.

Characteristics of the Patients
Between October 1994 and April 2001, a total of 2028 patients from 212 centers in the United States and Canada were randomly assigned to radiotherapy plus short-term ADT (the combined-therapy group) or radiotherapy alone. Forty-nine patients were ineligible, withdrew consent, or were lacking pretreatment data, leaving 1979 eligible patients who were available for evaluation (992 in the radiotherapy-alone group and 987 in the combined- therapy group).

Compliance
Compliance with the radiotherapy protocol was assessed in a random sample of 61% of the patients in the combined-therapy group and 64% in the radiotherapy-alone group. Compliance was balanced between the two treatment groups; 65% of the patients were treated per protocol, 19% were treated with acceptable variations, and 5% were treated with unacceptable variations. Data were incomplete in 1% of the patients because of death or progressive disease or because the patient declined radiotherapy, and 9% were not available for evaluation. Compliance with hormonal therapy was reviewed in all randomly assigned patients; the therapy was delivered per protocol in 78% of the patients, with acceptable variation in 17% and unacceptable deviation in 4%. Data were incomplete or were not available for evaluation in 1% of these patients.

Outcomes
The median follow-up for surviving patients was 9.1 years (range, 0.01 to 13.5) in the group of patients who received radiotherapy plus short-term ADT and 9.2 years (range, 0.2 to 14.1) in the group of patients who received radiotherapy alone. The 10-year rate of overall survival was 57% in the radiotherapy-alone group and 62% in the combined-therapy group (hazard ratio for death with radiotherapy alone, 1.17; 95% confidence interval [CI], 1.01 to 1.35; P = 0.03). The 10-year disease-specific mortality was 8% in the radiotherapy-alone group and 4% in the combined-therapy group (hazard ratio, 1.87; 95% CI, 1.27 to 2.74; P = 0.001). The 10-year rate of biochemical failure was 41% in the radiotherapy-alone group and 26% in the combined-therapy group (hazard ratio, 1.74; 95% CI, 1.48 to 2.04; P<0.001). The 10-year cumulative incidence of distant metastases was 8% in the radiotherapy-alone group and 6% in the combined-therapy group (hazard ratio, 1.45; 95% CI, 1.03 to 2.06; P = 0.04). The 10-year cumulative incidence of death from causes other than prostate cancer was 37% in the radiotherapy-alone group and 34% in the combined-therapy group (P = 0.56).

Treatment
All patients began treatment within 21 days after randomization. Radiotherapy, administered in daily 1.8-Gy fractions prescribed to the isocenter of the treatment volume, consisted of 46.8 Gy delivered to the pelvis (prostate and regional lymph nodes), followed by 19.8 Gy to the prostate, for a total dose of 66.6 Gy. Treatment of the regional lymph nodes was omitted in patients with negative lymph-node dissections or with a PSA level of less than 10 ng per milliliter and a Gleason score of less than 6. The study cochairs reviewed the simulation and portal films for each treatment field. Patients assigned to short-term ADT received flutamide at a dose of 250 mg orally three times a day and either monthly subcutaneous goserelin at a dose of 3.6 mg or intramuscular leuprolide at a dose of 7.5 mg for 4 months. Radiotherapy commenced after 2 months of androgen deprivation. Flutamide was discontinued if the level of alanine aminotransferase increased to more than twice the upper limit of the normal range.

Assessments
At the beginning and end of radiotherapy, assessments included a history taking and physical examination, performance status, complete blood count, and levels of alkaline phosphatase, alanine aminotransferase, PSA, and serum testosterone. Follow-up visits occurred at intervals of 3 months during the first year, 4 months during the second year, 6 months in years 3 through 5, and then annually. PSA values were obtained at each visit, along with the serum testosterone level and complete blood count during the first 2 years and the alkaline phosphatase level yearly. Repeat prostate biopsy 2 years after treatment was planned for patients without medical contraindications or evidence of local or distant disease and for patients who had not undergone orchiectomy or received hormonal treatment. Acute and late toxic effects were assessed with the use of the RTOG toxicity scales.

At each visit during the first 2 years, the first 793 patients enrolled in the study completed the Sexual Adjustment Questionnaire. Erectile dysfunction was assessed with the question, “When sexually excited, are you able to get an erection?” The five levels of response were: always or almost always, sometimes, almost never or never, did not try, and no answer.

End Points
All end points were measured from the date of randomization. Overall survival, the primary end point, was calculated at the date of death from any cause. Secondary end points included diseasespecific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years. Disease-specific mortality included all deaths from prostate cancer or treatment complications, as well as deaths from unknown causes in patients with either active cancer or a previously documented relapse. The study cochairs reviewed the reported causes of death, and complicated cases were reviewed by committee. The scoring of distant metastasis required documentation of metastatic disease. The Phoenix Consensus Conference definition (an increase in the PSA level of >2 ng per milliliter above the nadir) was used to define biochemical failure.