Comparison of two total body irradiation fractionation regimens with respect to acute and late pulmonary toxicity

BACKGROUND. Total body irradiation (TBI) is commonly used with autologous bone marrow transplantation (BMT) for treatment of hematologic malignancies. Pulmonary complications of TBI can cause long-term morbidity and mortality. The authors have compared the pulmonary toxicity and efficacy of two different TBI fractionation regimens in otherwise identical autologous BMT protocols. METHODS. Between 1990 and 1997 patients younger than 60 years of age with low-grade lymphoma at high risk of treatment failure were enrolled on one of two sequential protocols for autologous BMT differing only in their TBI regimens. The preoperative chemotherapy regimens were identical and consisted of intravenous etoposide (1500 mg/m²) for 1 day, intravenous cyclophosphamide (60 mg/kg) for 2 days, and mesna (10 mg/kg). The TBI used in protocol A consisted of twice-daily fractions of 1.7 grays (Gy) for 3 days to a total of 10.2 Gy through lateral fields, with no lung shielding. In protocol B, the TBI consisted of 3 Gy once daily for 4 days to a total of 12 Gy through anteroposterior fields, with lung shielding (5 half-value layers) during the third dose. Fifty-eight patients were treated on protocol A and 24 on protocol B. The groups were equivalent with regard to age, performance status (PS) and gender. Lung function was assessed objectively by pulmonary function tests (PFTs) before and at intervals after TBI. The pulmonary function parameters assessed included forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), forced expiratory flow between 25% and 75% of vital capacity (FEF_25-75), diffusing capacity for carbon monoxide (DL_CO), and total lung capacity (TLC). Each patient's post-TBI PFTs were normalized to the corresponding pre-TBI values and analyzed using a random effects model. Clinical pulmonary function status was scored according to Radiation Therapy Oncology Group criteria for acute and late lung toxicity. All clinical pulmonary toxicities such as pneumonitis, pneumonia, and diffuse alveolar hemorrhage, whether specifically related to TBI or not, were scored. Toxicity was classified as either acute (i.e., occurring within 90 days of TBI) or late (i.e., occurring more than 90 days after TBI). The endpoints of analysis were overall survival (OS), freedom from progression, and chronic pulmonary toxicity. Survival, progression, and complication free survival were computed using the method of Kaplan and Meier. RESULTS. Three-year actuarial OS rates were 66% and 67% for protocols A and B, respectively. Patients 50 years of age or older had a hazard ratio of death 3.5 times higher than younger patients. Freedom from progression was significantly different for the 2 TBI regimens (P < 0.001; log-rank test): 31% at 3 years in the protocol A group compared with 82% in protocol B group. Patients on protocol A had a rate of progression 4.7 times higher than patients on protocol B. The TBI protocols did not differ significantly in their effects on FVC, FEV₁, FEF_25-75, DL_CO, and TLC. Patients 45 years of age or older had lower average posttransplant values of FEV₁, FVC, and DL_CO than younger patients. There was no significant difference in acute or late toxicity rates between patients on the two protocols. Seven of the 57 patients in the twice-daily TBI (protocol A) group had acute pulmonary events (Grade 3 or greater), compared with 6 of the 24 patients in the once-daily (protocol B) group (P = 0.19). The 3-year freedom from late complications rate was 80% in the protocol A group and 70% in the protocol B group (P = 0.45). Patients with a PS of 1 had a hazard ratio of late complications 3.2 times greater than patients with a PS of 0 (P < 0.001). CONCLUSIONS. It is possible to intensify TBI from a total dose of 10.2 Gy delivered in 6 twice-daily fractions to 12 Gy delivered in 4 once-daily fractions without significantly increasing the risk of pulmonary toxicity. The increased dose may contribute to a decrease in the recurrence rate in these patients.