Dose escalation in the conformal treatment of prostate cancer: optimization is made possible by understanding the dose responses for control of cancer and late morbidity

Purpose: A prospective dose escalation study with conformal treatment was conducted in patients with prostate cancer to define the dose responses for biochemical control of disease (bNED) and for post treatment late radiation morbidity. With these observations it is possible to begin to optimize the radiation treatment of prostate cancer. Methods: Two hundred and thirty-three consecutive patients were treated in a prospective dose escalation study between 3/89 and 10/92. Every patient was treated in an individual immobilizing cast with the same 4-field conformal technique where the PTV was 1.0 cm around the CTV. Ninety-four patients received whole pelvic irradiation to 4500 Gy followed by prostate ± seminal vesicle boost, while 134 received treatment to the prostate plus or minus seminal vesicles. The whole pelvic radiation was given when clinical estimates of node involvement exceeded 15%. Center of prostate dose was escalated from 68 Gy to 79 Gy in ∼ 2Gy increments. Patient outcome (cancer control and late complications) is reported at 36 mo followup which is available in all alive patients. Serial post treatment PSA's are available at six month intervals in all patients and no patient has been lost to followup. Dose response for bNED survival and late morbidity at 3 years are reported by logit response models. Multivariate analysis using censoring data are based on Cox Regression models. bNED failure is defined as a PSA >1.5 and rising on two consecutive values. Grade 2 GI and GU morbidity is reported based on the recent late effects scale (LENT) while the reporting of Grade(3(4)) GI and GU morbidity includes our modification of the LENT GI scale including patients with chronic rectal bleeding, requiring >2 coagulations as a grade 3 complication. Results: The probit analysis of 36 mo bNED is shown in Figure 1 by pretreatment PSA level grouping. There was no dose response for patients with pretreatment PSA <10 on probit analysis or on multivariate analysis and they are not included. The 50% bNED response at three years for the PSA grouping 10-19.9 is 64 Gy, it is 76 Gy for the PSA grouping 20+. The slopes of the responses are 13% and 9% respectively. Probit plots of morbidity are shown in Figure 2. At 76 Gy grade 2 GI events are 50%, grade 2 GU events are 17%, and grade(3(4)) GI and GU are 9%. The slopes of the morbidity plots are steeper than the bNED survival plots and are 19-21%. The individual late Grade(3(4)) GI/GU complications include one colostomy, one sigmoid resection, one severe urinary incontinence, 4 transfusions alone and 4 with >2 coagulations alone. Conclusions: This is the first prospective dose escalation study in prostate cancer reporting dose responses for bNED survival and morbidity thereby allowing optimization of treatment. No dose response is demonstrated for patients with pretreatment PSA's <10 and we do not recommend treatment beyond 71 Gy where our grade 3,4 late GI and GU complications are <4%. Dose response is observed for patients with pretreatment PSA's 10-19.9 and 20+ ngm/ml. However, since dose beyond 76 Gy is associated with an increasing grade (3(4)) morbidity beyond 9%, we strongly recommend special protection of the rectal mucosa when treating above this dose level. Since observing these dose responses, we have elected to restrict the dose to the rectum by special blocking techniques to 72 Gy while delivering 76 Gy to the prostate plusor minus seminal vesicles. This limitation of dose to the rectum will result in late grade 3,4 morbidity of <5%. It is not known whether the quantitative reduction in bNED survival that we will observe beyond 3 years followup will alter the qualitative shape of the bNED dose response. It is unlikely that longer followup will alter the rate of late complications