Clinical investigations: Prostate
Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: The combined experience of nine institutions in patients treated in 1994 and 1995

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Abstract

Purpose

To study the radiation dose–response as determined by Kaplan-Meier prostate-specific antigen (PSA) disease-free survival (PSA-DFS) estimates in patients with stage T1-T2 prostate cancer treated within a 2-year period (1994–1995).

Methods

Nine institutions combined data on 4839 patients with stage T1 and T2 adenocarcinoma of the prostate who received ≥60 Gy external beam radiation therapy (RT) as sole treatment. No patient received neoadjuvant androgen deprivation or planned adjuvant androgen deprivation. Of the 4839 patients, 1325 were treated in 1994 and 1995; 1061 were treated with <72 Gy and 264 with ≥72 Gy. The median RT doses for the <72 Gy and the ≥72 Gy groups were 68.4 Gy and 75.6 Gy, respectively. The median follow-up for the <72 Gy and the ≥72 Gy groups were 5.8 and 5.7 years, respectively. Risk groups, defined on the basis of T stage, pretherapy PSA level, and biopsy Gleason score (GS), were as follows: low risk—T1b, T1c, T2a, GS ≤6 and PSA ≤10 ng/mL; intermediate risk—T1b, T1c, T2a, GS ≤6 and PSA >10 ng/mL but ≤20 ng/mL or T2b, GS ≤6 and PSA ≤20 ng/mL or GS 7 and PSA ≤20 ng/mL; high risk—GS 8–10 or PSA >20 ng/mL. The endpoint for outcome analysis was PSA-DFS at 5 years after therapy using the American Society for Therapeutic Radiology and Oncology failure definition.

Results

Patients receiving ≥72 Gy had significantly more advanced cancers. The proportion of stage T2b/T2c cancers in the ≥72 Gy group was 42% compared with 32% in the <72 Gy group (p = 0.027). The mean pretherapy PSA was 11.4 ng/mL in the ≥72 Gy group compared with 10.7 ng/mL in the <72 Gy group (p = 0.001). The proportion of GS ≥8 cancers in the ≥72 Gy group was 9% compared with 7% in the <72 Gy group (p = 0.309). Overall, 15% of patients receiving <72 Gy had high-risk disease, compared with 22% of patients receiving ≥72 Gy (p = 0.034). The ≥72 Gy group had a greater number of follow-up PSA levels (mean 10.6/patient) compared with the <72 Gy group (mean 9.6/patient) (p = 0.007). For all 1325 patients, the 5- and 8-year PSA-DFS estimates were 64% and 62%, respectively. The 5-year PSA-DFS estimates for <72 Gy vs. ≥72 Gy were 63% vs. 69%, respectively (p = 0.046). Multivariate analysis for factors affecting PSA-DFS was performed for all cases using the following variables: pretherapy PSA (continuous), biopsy GS (continuous), stage (T1 vs. T2), radiation dose (continuous), and radiation technique (three-dimensional conformal vs. conventional). Pretreatment PSA (p < 0.001, chi-square 112.2), GS (p < 0.001, chi-square 12.8), radiation dose (p < 0.001, chi-square 13.5), and stage (p = 0.007, chi-square 7.2) were independent predictors of outcome. Radiotherapy technique was not (p = 0.50).

Conclusion

Differences in PSA-DFS estimates observed in multiple retrospective series have been attributed to differences in follow-up duration between patients treated to conventional doses (longer follow-up intervals) and those treated to higher doses (shorter follow-up intervals). In this report, the median follow-up duration in the ≥72 Gy group was essentially identical to the <72 Gy group, because the study included a large number of patients treated consecutively during a narrow time range (1994–1995). With similar follow-up duration, higher than conventional radiotherapy doses were associated with improved PSA-DFS when controlled for the influence of pretreatment PSA levels, biopsy GS, and clinical T stage.

Introduction

A significant controversy still exists in the radiation oncology community with respect to the impact of increasing radiation doses in the treatment of localized prostate cancers 1, 2, 3, 4, 5, 6, 7. Only one relatively mature randomized study, with a total of 301 cases, has been reported, and it showed an improved relapse-free survival rate with 78 Gy vs. 70 Gy in patients with localized prostate cancers (2). Most other retrospective studies addressing the issue of higher radiation doses, although typically including a greater number of cases, have been criticized in part because of differences in the length of follow-up periods between dose groups 8, 9, 10. Because dose escalation has gradually occurred over the past decade, patients treated with higher radiation doses have been treated more recently in comparison with patients treated with lower radiation doses. This implies that patients receiving higher doses would generally have shorter follow-up durations and would potentially include a higher proportion of patients with favorable features because of “stage migration” occurring over time 9, 10. Other criticisms have included improved radiotherapy (RT) techniques and increased use of androgen deprivation in more recent years.

In the absence of randomized studies, carefully conducted large-scale retrospective studies can still be useful to generate hypotheses related to dose escalation. In the current report, the outcomes of patients treated at nine major institutions over a short period (1994–1995) were combined in an attempt to minimize any biases introduced resulting from differences in follow-up durations or any biases introduced secondary to stage migration occurring over extended intervals during which patients would have been diagnosed and treated.

Section snippets

Patient population

Nine participating institutions with long-term follow-up of patients with prostate cancer collaborated on this study. These institutions included the Cleveland Clinic, Fox Chase Cancer Center, Mallinckrodt Institute of Radiology at Washington University, Massachusetts General Hospital, Mayo Clinic Rochester, Memorial Sloan-Kettering Cancer Center, University of Michigan, The University of Texas M. D. Anderson Cancer Center, and William Beaumont Hospital. Institutional Review Board approval was

Pretreatment characteristics

Table 1 summarizes the pretreatment clinical characteristics of all patients in the study sample. Overall, patients receiving ≥72 Gy had higher stage cancers and higher PSA levels. Risk groups, defined on the basis of initial (pretherapy) PSA levels (iPSA) and biopsy Gleason scores (GS), were as follows: low risk—T1b, T1c, T2a, GS ≤6 and iPSA ≤10 ng/mL; intermediate risk—T1b, T1c, T2a, GS ≤6 and iPSA >10 ng/mL but ≤20 ng/mL or T2b, GS ≤6 and iPSA ≤20 ng/mL or GS 7 and iPSA ≤20 ng/mL; and high

Discussion

The present study demonstrated that differences in follow-up duration and the number of follow-up PSA determinations were not factors that accounted for improved outcomes in patients receiving higher-than-standard radiation doses. In this large multi-institutional dataset, the study sample was limited to patients treated within a narrow 2-year period (1994–1995). The median follow-up periods were 5.7 and 5.8 years in the ≥72 Gy and <72 Gy groups. The treatment and follow-up durations were

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