Volume 71, Issue 1 , Pages 16-22, 1 May 2008
Effect of Increasing Radiation Doses on Local and Distant Failures in Patients With Localized Prostate Cancer
Article Outline
Purpose
To study the effect of radiation dose on local failure (LF) and distant metastasis (DM) in prostate cancer patients treated with external beam radiotherapy.
Methods and Materials
The study sample consisted of 919 Stage T1-T3N0M0 patients treated with radiotherapy alone. Three separate dose groups were analyzed: <72 Gy (n = 552, median dose, 68.4 Gy), ≥72 but <82 Gy (n = 215, median dose, 78 Gy), and ≥82 Gy (n = 152, median dose, 83 Gy). The median follow-up period for all patients and those receiving <72 Gy, ≥72 but <82 Gy, and ≥82 Gy was 97, 112, 94, and 65 months, respectively.
Results
For all patients, the LF rate at 10 and 15 years was 6% and 13%, respectively. The 7-year LF rate stratified by dose group (<72 Gy, ≥72 but <82 Gy, and ≥82 Gy) was 6%, 2%, and 2%, respectively (p = 0.012). For all patients, the DM rate at 10 and 15 years was 10% and 17%, respectively. The 7-year DM rate stratified by dose group (<72 Gy, ≥72 but <82 Gy, and ≥82 Gy) was 9%, 6%, and 1%, respectively (p = 0.008). Multivariate analysis revealed T stage (p < 0.001), pretreatment prostate-specific antigen level (p = 0.001), Gleason score (p < 0.001), and dose (p = 0.018) to be independent predictors of DM. For all 919 patients, multivariate analysis revealed only Gleason score (p = 0.009) and dose (p = 0.004) to be independent predictors of LF.
Conclusion
Although the effect of increasing radiation doses has been documented mostly for biochemical failure rates, the results of our study have shown a clear association between greater radiation doses and lower LF and DM rates.
Prostatic neoplasms, Radiotherapy, Dose, Local control, Distant metastasis
Introduction
Greater than conventional radiation doses (i.e., >70 Gy) are associated with lower rates of failure after external beam radiotherapy for localized prostate cancer 1, 2, 3, 4, 5. However, in the prostate-specific antigen (PSA) era, few outcomes analyses have examined the effect of radiation dose on clinical endpoints such as local control and distant metastases (DMs). To demonstrate the benefit of greater than conventional doses for patients with localized prostate cancer, the prevention of clinical events such as local failure (LF) and DM will have a more significant impact than would biochemical failure (bF) alone. With greater than conventional doses having been in use for >10 years, the observation of the effect of high radiation doses on clinical outcomes such as LF and DM is possible. We examined the effect of dose on these clinical events in a large cohort of consecutively treated patients with clinically localized prostate cancer during a 14-year period.
Methods and Materials
Between 1986 and 2000, 919 patients with clinical Stage T1-T3N0M0 adenocarcinoma of the prostate were treated with external beam radiotherapy. All patients had pretreatment PSA levels (iPSA) and biopsy Gleason scores (bGS) available, and none had undergone androgen deprivation. The mean patient age at presentation was 69 years (range, 44–86 years). African Americans constituted 23% of all patients. The clinical stage (2002 American Joint Committee on Cancer staging system) at presentation was T1-T2a in 70%, T2b-T2c in 24%, and T3 in 6%. The median PSA level at presentation was 8.5 ng/mL (range, 0.4–692.9 ng/mL). The PSA distribution at presentation was as follows: ≤4.0 ng/mL in 9%, 4.1–10.0 ng/mL in 52%, 10.1–20.0 ng/mL in 24%, and >20.0 ng/mL in 15%. The bGS distribution at presentation was ≤6 in 68%, 7 in 24%, and ≥8 in 8%. Using the D'Amico risk grouping, 36% of patients were considered to be at low risk, 25% at intermediate risk, and 39% at high risk (6). None of the patients in this cohort had received any neoadjuvant or adjuvant androgen deprivation. Because the institution's policy beginning in the mid-1990s was to use androgen deprivation only for patients with high-risk disease, a significant number of patients with high-risk features were excluded from this analysis. This was particularly true for the patients receiving the greatest doses in the more recent years. However, because the aim of the study was to document the effect of radiation dose alone, excluding the patients who had undergone hormonal therapy would render the analysis more reliable. Even then, 39% of patients (n = 356) in this analysis had tumors with high-risk features.
The radiation dose was delivered with standard fractionation (1.8–2.0 Gy/fraction) in 767 patients to a dose of 60–78 Gy and with hypofractionation (2.5 Gy/fraction) in 152 patients to a dose of 70 Gy. A dose of 70 Gy at 2.5 Gy/fraction is equivalent to approximately 83 Gy at 2.0 Gy/fraction for prostate cancer tissue, according to the linear-quadratic model if an α/β ratio of 1.8 is used. A high-dose hypofractionated schedule is therefore a method of dose escalation (7). In this analysis, patients receiving 70 Gy at 2.5 Gy/fraction were considered to have received ≥82 Gy at conventional fractionation and were grouped as such. Hence, none of the patients received a nominal dose of ≥82 Gy, but an equivalent dose. Therefore, all patients grouped as having received ≥82 Gy in this study received a nominal dose of 70 Gy but an equivalent dose of about 83 Gy. Therefore, three separate dose groups were analyzed: <72 Gy (n = 552; median dose, 68.4 Gy), ≥72 but <82 Gy (n = 215; median dose, 78 Gy), and ≥82 Gy (n = 152; median dose, 83 Gy).
The patients were typically seen in follow-up 6 weeks after treatment completion and then every 3 months for the first year, every 6 months for the subsequent 4 years, and annually thereafter. Toxicity was assessed at each visit. The median follow-up for all 919 patients was 97 months (range, 0–224 months); that is >8 years. The proportion of patients with <6, ≥6 but <12, ≥12 but <18, and ≥18 but <24 months of follow-up was 0.8%, 0.2%, 1.3%, and 2.1%, respectively. Therefore, 99% of patients had a follow-up period >12 months, and 96% had a follow-up period >24 months. A total of 11,866 follow-up PSA levels were available for analysis (mean, 13/patient). Because the implementation of increasing radiation doses occurred over time, the median follow-up of patients receiving increasing radiation doses was different. The median follow-up period for patients receiving <72 Gy, ≥72 but <82 Gy, and ≥82 Gy was 112, 94, and 65 months, respectively. Therefore, the analysis of the clinical endpoints would be most reliable for the groups receiving <72 Gy and ≥72 but <82 Gy.
The primary endpoint for analysis was DM. LF was a secondary endpoint, because it is a more difficult endpoint to assess. LF was defined as positive biopsy findings or clinical presentation (clear recurrence on physical examination). Consequently, the documentation of LF was relatively inconsistent compared with the documentation of DM. However, this inconsistency in the documentation of LF did not change during the study period. Given the limitations of a retrospective study and the difficulty in dealing with the inconsistencies of the varying treating physicians with respect to the workup and treatment of bF, DM was a more solid endpoint. The documentation of DM was more obvious and clinically more relevant to patients. bF was assessed with the Phoenix bF definition of PSA nadir plus 2 ng/mL (8). With respect to bF, which was nearly invariably the first manifestation of failure, 332 patients (36%) had bF at the last follow-up visit. The proportion of patients with bF throughout the entire follow-up period was 50%, 22%, and 5% for patients receiving <72 Gy, ≥72 but <82 Gy, and ≥82 Gy, respectively.
Acute and late toxicities were measured using the Radiation Therapy Oncology Group scores. Survival was assessed with the Kaplan-Meier method, with statistically significant differences measured with the log–rank test. Multivariate analyses were done using the Cox proportional hazards method. Hazard rates were estimated using actuarial (life-table) methods.
Results
Biochemical failure rates
Table 1 shows the distribution of pretreatment and treatment parameters by radiation dose group. Patients treated to lower doses had tumors with greater risk features, because they had been treated earlier in the study. For all 919 patients, the 10-year biochemical relapse-free survival rate was only 49% (95% confidence interval, 44–54%). The 7-year biochemical relapse-free survival rate stratified by dose group (<72 Gy, ≥72 but <82 Gy, and ≥82 Gy) was 50%, 79%, and 91%, respectively (p < 0.001). Figure 1 demonstrates the different bF rates during the 10 years according to radiation dose group. A multivariate time-to-failure analysis for bF using the Cox proportional hazards model was performed using the following categorization of parameters: T stage (T1-T2 vs. T3), iPSA (continuous variable), bGS (2–6 vs. 7–10), and radiation dose (continuous variable). These parameters were used in this manner to mirror the analysis performed by Morgan et al. (9). They reported on the effect of dose on outcomes in a similar manner. For example, some parameters (such as the year of therapy, race, or age) were excluded from the analysis to keep the comparison of these analyses consistent. In our study, for all 919 patients, the multivariate analysis revealed T stage (p < 0.001), iPSA level (p < 0.001), bGS (p < 0.001), and radiation dose (p < 0.001) to be predictors of bF (Table 2).
Table 1. Distribution of pretreatment and treatment parameters by radiation dose group
| Variable | <72 Gy | ≥72 but <82 Gy | ≥82 Gy | p |
|---|---|---|---|---|
| Clinical T stage | 0.003 | |||
 T1-T2 | 512 (93) | 199 (93) | 152 (100) | |
| T3 | 40 (7) | 16 (7) | 0 (0) | |
| iPSA level (ng/mL) | <0.001 | |||
| ≤4 | 50 (9) | 14 (7) | 13 (8) | |
| >4 to ≤10 | 233 (42) | 135 (63) | 112 (74) | |
| >10 to ≤20 | 147 (27) | 50 (23) | 26 (17) | |
| >20 | 122 (22) | 16 (7) | 1 (1) | |
| bGS | <0.001 | |||
| 2–6 | 350 (63) | 149 (69) | 122 (80) | |
| 7–10 | 202 (37) | 66 (31) | 30 (20) | |
| Risk group | <0.001 | |||
| Low | 161 (29) | 96 (45) | 99 (65) | |
| Intermediate | 134 (24) | 51 (24) | 43 (28) | |
| High | 257 (47) | 68 (31) | 10 (7) | |
| Total | 552 (100) | 215 (100) | 152 (100) |
Fig. 1.
Biochemical failure rates by radiation dose group.
Table 2. Multivariate analysis of factors affecting biochemical failure using nadir plus 2 ng/mL PSA relapse definition, local failure, and distant failure
| bF | LF | DM | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Variable | p | HR | 95% CI | p | HR | 95% CI | p | HR | 95% CI |
| T stage (T3 vs. T1-T2) | <0.001 | 3.12 | 2.18–4.44 | 0.841 | 0.89 | 0.30–2.69 | <0.001 | 3.60 | 2.07–6.25 |
| iPSA (continuous; 1 ng/mL increase) | <0.001 | 1.01 | 1.00–1.01 | 0.154 | 1.00 | 1.00–1.01 | <0.001 | 1.01 | 1.00–1.01 |
| bGS (7–10 vs 2–6) | <0.001 | 2.02 | 1.62–2.51 | 0.009 | 2.13 | 1.21–3.76 | <0.001 | 2.44 | 1.55–3.83 |
| Radiation dose (continuous; 1 Gy increase) | <0.001 | 0.89 | 0.86–0.91 | 0.004 | 0.89 | 0.82–0.96 | 0.018 | 0.93 | 0.88–0.99 |
Local failure rates
For all patients, the LF rate at 10 and 15 years was 6% and 13%, respectively. As shown in Fig. 2, the 7-year LF rate stratified by dose group (<72 Gy, ≥72 but <82 Gy, and ≥82 Gy) was 6%, 2%, and 2%, respectively (p = 0.012). As seen in Fig. 2, it is clear that for patients receiving <72 Gy, LF occurred persistently beyond 10 years. Only one documented LF occurred after 10 years among patients receiving ≥72 but <82 Gy. It is relatively early to comment on the long-term LF rates in patients receiving ≥82 Gy, because of the still relatively short follow-up period compared with the follow-up for the other dose groups. For the ≥82-Gy group, at 5–7 years after radiotherapy, the LF rates were similar to those of the ≥72 but <82 Gy group. The multivariate time-to-failure analysis using the Cox proportional hazards model was performed using the following parameters: T stage (T1-T2 vs. T3), iPSA level (continuous variable), bGS (2–6 vs. 7–10), and radiation dose (continuous variable). For all 919 patients, the multivariate analysis revealed only bGS (p = 0.003) and radiation dose (p = 0.004) to be predictors of LF. T stage (p = 0.84) and PSA level (p = 0.15) were not predictive of LF (Table 2).
Fig. 2.
Local failure rates by radiation dose group.
Distant metastasis rates
For all patients, the DM rate at 10 and 15 years was 10% and 17%, respectively. As shown in Fig. 3, the 7-year DM rate stratified by dose group (<72 Gy, ≥72 but <82 Gy, and ≥82 Gy) was 9%, 6%, and 1%, respectively (p = 0.008). As seen in Fig. 3, similar to the findings for LF, it is clear that for patients receiving <72 Gy, DM occurred persistently beyond 10 years. No DMs were documented beyond 10 years among patients receiving ≥72 but <82 Gy. For the ≥82-Gy group, up to 5–7 years, the DM rates have been encouragingly low >5 years after radiotherapy, with a median follow-up in this group of >5 years. A multivariate time-to-failure analysis using the Cox proportional hazards model was performed using the following parameters: T stage (T1-T2 vs. T3), iPSA level (continuous variable), bGS (2–6 vs. 7–10), and radiation dose (continuous variable). For all 919 patients, the multivariate analysis revealed T stage (p < 0.001), iPSA level (p = 0.001), bGS (p < 0.001), and radiation dose (p = 0.018) to all be predictors of DM (Table 2).
Fig. 3.
Distant metastasis rates by radiation dose group.
Because the assumption behind the effect of radiation dose on DM is through local control, the DM rates were analyzed by local control versus LF. The data in Fig. 4 demonstrated that of the patients who had LF, nearly 50% had DM by 15 years compared with about 12% of patients with local disease control. Because of the imperfect methods of documentation of LF (i.e., without a systematic approach of biopsies performed at defined intervals after radiotherapy), definite observations on this issue are difficult. The sequence of LF and DM is impossible to determine in an absolute manner. However, even with these obvious limitations, a difference in DM was observed between patients with LF vs. those without.
Fig. 4.
Distant metastasis rates by local failure vs. no local control.
Finally, to study the effect of radiation dose on the pattern of DM, the hazard rates for DM were estimated in 2-year intervals for the three radiation dose groups (Fig. 5). The patients receiving <72 Gy had an initially high rate of failure and a second high rate at between 10 and 15 years. With the available follow-up period, patients receiving >72 Gy did not exhibit the same pattern.
Fig. 5.
Interval hazard rates for distant metastasis during 2-year intervals after therapy by radiation dose group.
Discussion
The use of bF for the clinical management of an individual patient, as well as for the purpose of serving as a study endpoint, has been questioned 10, 11, 12, 13, 14, 15. This is particularly important in the context of evaluating the benefit of greater than conventional radiation doses that have been in use for the past 10 to 15 years. The principal justification for the use of greater than conventional radiation doses has mostly come from the demonstrated reduction in bF rates with the use of high radiation doses 3, 5, 16, 17. However, the interpretation of PSA increases after radiotherapy has been difficult, particularly in the context of predicting for clinical events (10). The analysis of the relationship between bF and clinical failure has already led to a change in the definition of bF itself (8). The bF definition was changed from three consecutive rises in post-treatment PSA values to a post-treatment PSA value of the nadir plus 2 ng/mL, largely to increase its correlation with clinical events.
Because the delivery of greater than conventional doses carries the risk of greater toxicity, increasingly sophisticated radiation planning and delivery techniques (such as three-dimensional conformal and intensity-modulated radiotherapy) have been required 18, 19, 20, 21. Such approaches would be even more justified if dose escalation was clearly demonstrated to be associated with decreased LF rates and, consequently, decreased DM rates. To date, greater radiation doses have been shown to result in decreased positive prostate biopsy rates in subsets of patients treated with external beam radiotherapy and brachytherapy 22, 23. A decrease in DM rates would be the strongest argument to support dose escalation, and this has already been reported by Morgan et al. 9, 24.
The present series of patients, with a relatively long follow-up, is the largest to clearly demonstrate a benefit from dose escalation with respect to a significant effect in decreasing LF and DM. The present series of patients was retrospective and subsequently had the limitations of any retrospective study, specifically that lower doses were delivered in the chronologically earlier patients in the PSA era. Therefore, patients treated with lower doses had the longest follow-up and the patients treated with the greatest doses had the shortest follow-up. Because failure occurred in the low-dose group even beyond 10 years, the long-term outcomes are important to document in all dose groups. In the greatest dose group (≥82 Gy), the median follow-up period of >5 years allowed for a preliminary positive assessment of clinical outcomes after therapy. However, additional follow-up is needed to validate these observations. In addition, the difference between the follow-up periods for patients receiving <72 Gy and ≥72 but <82 Gy was relatively small at 94 vs. 112 months. Therefore, at a minimum, the comparison between <72 Gy and ≥72 but <82 Gy should be reliable. Most observations made in this study were truly based on these two groups. The addition of the ≥82-Gy group was only helpful in establishing that with the relatively short follow-up, the observed outcomes were trending toward improved cure rates with greater doses.
The benefit from radiotherapy is obviously through local control, and the documentation of local control is notoriously difficult after therapy of localized prostate cancer. Radiologic studies are of limited value because intraprostatic imaging is still imperfect with respect to reliably identifying cancer recurrence. Physical examination will only detect a minority of gross recurrences within the prostate gland. Biopsies are probably the best method to document LF. However, the interpretation of post-radiation biopsies and the significance of biopsies performed randomly throughout the prostate gland with negative findings render biopsy only an imperfect method of assessing LF. In the present report, the evaluation of LF was not consistent, because biopsy was not systematically performed. However, during the study period, the documentation of LF did not change and remained mostly dependent on physical examination and/or biopsy findings, largely prompted by increasing PSA levels. This is clearly an imperfect process, but it did not change during the study period. Therefore, differences in outcomes can be assumed to be probably related to the differing radiation doses rather than the endpoint evaluation method. In the future, documentation of local control should be performed by random prostate biopsy obtained in every patient at specific intervals after radiotherapy.
The most compelling observation in the present study was that the DM rates were lower with greater radiation doses. More importantly, they seemed to plateau after 10 years in patients receiving doses >72 Gy. Although the cutoff dose was 72 Gy, it is crucial to realize that the median dose in the group receiving ≥72 but <82 Gy was 78 Gy compared with only 68 Gy for the group receiving <72 Gy. The benefit from greater radiation doses is not dependent on cutoffs such as 72, 78, or 82 Gy but clearly increases on a continuous scale (25). The decrease in DM rates is particularly encouraging because, unlike LF, the documentation of DM is relatively straightforward. The major question that needs to be addressed in this context is whether the DM rates were lower because of patient selection rather than as a result of the greater local disease control with the greater radiation doses (i.e., a greater proportion of low-risk patients in more recent years when greater radiation doses were used). This did not seem to be the case, because the multivariate analysis of iPSA level, bGS, and T stage still demonstrated a clear benefit from greater radiation doses with respect to decreasing DMs. As shown in Fig. 4, of patients with LF, nearly 50% had DM by 15 years compared with about 12% of patients without LF. The hazard rates for DM demonstrated an initial high rate for patients receiving low radiation doses (Fig. 5). This was most probably a result of pre-existing metastases at treatment in this group of patients with relatively higher risk disease compared with patients receiving the greater doses (Table 1). However, a clear increase was seen in the hazard rate between 10 and 15 years, suggesting a wave of DMs, possibly from an uncontrolled primary tumor. A similar observation was made by Morgan et al. (9). Patients treated to doses >72 Gy had an increase in the hazard rate only between 5 and 10 years. The lack of an initial high hazard rate compared with patients treated to doses <72 Gy could reflect the more favorable nature of the tumors generally treated with higher doses compared with the patients receiving 72 Gy or, possibly, better staging. More importantly, the absence of a second increase beyond 10 years could reflect better local control with the greater doses. This should be confirmed with longer follow-up, particularly for patients treated to doses of about 80 Gy.
The most disconcerting aspect of the use of increasingly greater radiation doses is that with the limited data available today, even with the highest range of doses currently used (i.e., >80 Gy in conventional fractionation), the positive biopsy rate is about 10% even in the absence of documented bF (23). It is obviously unclear whether this is a result of the intrinsic radioresistance of some prostate cancers, a consequence of geographic misses due to still imperfect planning and delivery techniques, or evidence of the need for even greater radiation doses >85 Gy or, even, 90 Gy (25). However, it is clear that there is still room for improvement in the local control rates achieved by external beam radiotherapy for localized prostate cancer. Trials testing doses in the 85–90 Gy range with adequate targeting techniques, using either conventional or altered fractionation schedules are probably justified.
Conclusion
Although the effect of increasing radiation doses has been mostly documented for bF, a clear association was found between greater radiation doses and lower LF and DM rates. In patients receiving relatively low radiation doses, the DM rates continued to increase during a 15-year period. Although greater than conventional radiation doses have been associated with lower rates of LF and DM rates, it is unclear whether the currently used doses are sufficient. Doses greater than the ones currently used should be tested in the treatment of localized prostate cancer.
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Note—An online CME test for this article can be taken at http://asro.astro.org under Continuing Education.
Conflict of interest: none.
PII: S0360-3016(07)04242-3
doi:10.1016/j.ijrobp.2007.09.020
© 2008 Elsevier Inc. All rights reserved.
Volume 71, Issue 1 , Pages 16-22, 1 May 2008