Our analysis shows a statistically significant reduction in ≥ grade 2 GI toxicity with IMRT in intermediate- and high-risk prostate cancer treated with concurrent AD. Multivariable analysis showed that patients treated with 3DCRT were more than twice as likely to suffer a late grade ≥ 2 GI toxicity than patients treated with IMRT (HR = 2.1, CI: 1.1–4.3, p = 0.04) independent of other factors such as AD duration and diabetes. Al-Mamgani et al. (1
) have recently demonstrated that IMRT reduced toxicity compared to 3DCRT in patients treated with RT alone on the Dutch randomized dose escalation trial. This study also demonstrats a reduction in toxicity with IMRT when AD is used.
Several studies have shown a relationship between AD and GI toxicity. In the RTOG 92-02 study, a prospective randomized trial that evaluated the benefit of LTAD with advanced prostate cancer, all patients received STAD (2 months before and 2 months during radiotherapy) and were randomized to receive 2 further years of AD vs. no further therapy. This trial demonstrated a significant increase in late Grade 3 and higher toxicity associated with RT and LTAD (p = 0.037). Grade 3 or higher GI toxicity was 10% for STAD and 25% for LTAD (6
Initial reports from the RTOG 94-13 trial, a four arm study evaluating the optimal timing of STAD (2 months before and 2 months during radiation vs. 4 months starting after radiotherapy) and the role of elective nodal radiation for patients with a >15% risk of pelvic lymph nodes, had also demonstrated a trend toward increased GI toxicity at 2 years (p = 0.09) in patients receiving whole pelvis RT with concurrent ADT (21
). A recently published update of the same study demonstrated statistically significant differences in toxicity between the four arms with the neoadjuvant hormone therapy and whole pelvis RT group having the highest rate of late GI toxicity (11
). On the other had, a pooled analysis of the RTOG studies 85-31, 86-10 and 92-02 suggested a protective role for AD in terms of GI and GU toxicity (10
). It unclear as to whether these conflicting results is related to categorization of toxicity. While these studies largely report ≥ grade 3 toxicities, some have suggested the more important outcome is grade 2 or higher toxicity as being a critical outcome (9
). In any case, the results of Al-Mamgani et al. (1
) and the current study suggest that GI toxicity is reduced with IMRT.
Genitourinary toxicity has traditionally been more difficult to predict aside from clinical factors such as age and chronic obstructive uropathy. There was no apparent increase in GU toxicity associated with higher prescribed doses in the MD Anderson or Dutch randomized trials. While in general dose-volume effects likely exist, bladder dose-volume constraints that limit toxicity are not well established. One study in over 1,400 patients explored various dose-volume parameters as potential predictors of late GU toxicity (24
). Two methods were used to define the bladder: the entire bladder wall and it contents or the bladder wall alone. The authors concluded that increasing dose received by the entire volume or a higher proportion of the volume receiving 70 Gy were independent predictors irrespective of the contouring method used. At Fox Chase, IMRT bladder constraints have been to limit the volume of the bladder (and contents) receiving 65 Gy to 25%. Despite using these constraints with IMRT, our analysis was not able to demonstrate an improvement in GU toxicity with IMRT.
Our GI toxicity findings are consistent with the observations of a large retrospective series from the Memorial Sloan-Kettering Cancer Center in which an analysis of 1571 patients (of all risk groups, with or without concurrent AD) treated with either 3DCRT or IMRT was performed to assess incidence of and identify predictors for toxicity (25
). The 10-year incidence of ≥ grade 2 GI toxicity for 3DCRT 13% and for IMRT was 5% (p<0.001). The authors also noted that while increasing dose was associated with increased toxicity, there was a reduction in reported events at higher doses in the range of 75.6 to 81 Gy, which coincided with the implementation of treatment with IMRT. In the current study, the 5-year actuarial rate of ≥ grade 2 GI toxicity of 20% with 3DCRT and 8% with IMRT. These rates are promising given the high-risk population, universal use of concurrent AD, generally larger treated volumes, and larger fraction size (2 Gy vs. 1.8 Gy at Memorial).
Limitations of this study include the usual shortcomings associated with retrospective reviews. For example, treatment (3DCRT vs. IMRT and STAD vs. LTAD) was not randomized. A randomized comparison between 3DCRT and IMRT is unlikely to occur due to physician bias evidenced by the widespread adoption of IMRT. Despite the sequential nature of this study, the mean RT dose, an important factor in terms of toxicity, was very similar between the two groups (76 Gy for 3DCRT and 77 Gy for IMRT). But, treatment volumes were larger in the 3DCRT group with a greater proportion of patients receiving treatment to the regional lymph nodes. Furthermore, the PTV for all 3DCRT patients usually extended posteriorly by approximately 10 mm while the corresponding margin for IMRT was 3 – 5 mm. While this may favor IMRT, when considering only patients treated to the lymph nodes (3DCRT or IMRT), ≥ grade 2 GI toxicity was lower in the IMRT group (7% for IMRT, 21% for 3DCRT, p = 0.02). Furthermore, in multivariable analysis, the odds ratio of a late GI toxicity for 3DCRT was 2.3 (CI: 0.9–5.9; p = 0.09) compared with IMRT. In terms of AD, there was a greater proportion of patients in the IMRT group receiving LTAD, which based on our experience with 3DCRT+LTAD (9
) suggests this would bias results in favor of 3DCRT, and strengthens our finding that IMRT reduces toxicity. Last, a time-to-event analysis with the Cox method was used to account for loss of follow-up, censoring, and different follow-up rates. One disadvantage to this method is the assumption that loss to follow-up was unrelated to the outcome. One might reasonably assume that a patient with a late toxicity might not choose to return and seek care elsewhere.