High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients

Abstract

$\text{Purpose:}$ To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT).

$\text{Methods and Materials:}$ Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6–60 months).

$\text{Results:}$ Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of ≥ late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of ≥ late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively.

$\text{Conclusions:}$ These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be significantly reduced compared with what has been observed with conventional three-dimensional conformal radiotherapy techniques. Short-term PSA control rates seem to be at least comparable to those achieved with three-dimensional conformal radiotherapy at similar dose levels. Based on this favorable risk:benefit ratio, IMRT has become the standard mode of conformal treatment delivery for localized prostate cancer at our institution.

Introduction

High-dose three-dimensional conformal radiotherapy (3D-CRT) has been shown to improve local control and disease-free survival in patients with localized prostate cancer 1, 2, 3, 4. Dose levels of 75.6 Gy and higher have been associated with improved outcomes for patients with favorable, intermediate, and unfavorable prognostic risk features (5). Although the rate of severe (≥ Grade 3) late toxicities was low for patients treated at these dose levels, a higher incidence of Grade 2 rectal and urinary toxicities was observed when the dose was escalated from 64.8 to 81 Gy with conventional 3D-CRT techniques. The incidence of late Grade 2 rectal bleeding among patients who received 75.6–81 Gy was 17% compared to 6% for those treated to lower dose levels 1, 6.

Several investigators have shown that the volume of normal tissue exposed to higher radiation dose levels may represent the most significant factor affecting the development of late Grade 2 toxicity. Jackson et al. (7) found that in patients treated to 70.2 and 75.6 Gy with 3D-CRT, the mean rectal dose-volume histogram was significantly increased in patients who had rectal bleeding as compared to nonbleeders. Storey et al. (8) reported that rectal toxicity was observed more often among those patients treated to ≥70 Gy who had 30% or more of the rectum exposed to higher doses. Together, these data have corroborated the importance of the volume effect and its impact on late toxicity development in the setting of dose escalation strategies.

Recognizing that dose escalation was associated with greater risk of toxicity if a greater volume of normal tissue was treated to high dose levels, we implemented intensity-modulated radiotherapy (IMRT) to further improve the conformality of the dose distribution and thereby facilitate dose escalation for patients with localized prostate cancer. We reported previously that this enhancement in technology was associated with a significantly lower incidence of acute and late rectal toxicities (9). Subsequently, more than 700 patients have been treated with IMRT at our institution. In this report, we present the preliminary tolerance outcome of these patients who were treated to dose levels of 81 and 86.4 Gy. The data indicate that to date, the acute and late toxicity profiles are excellent, and despite the enhanced conformality associated with IMRT, the biochemical outcome is apparently not compromised.