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 b one 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 diff erent TBI fractionation regimens in otherwise identical autologous BMT prot ocols. METHODS. Between 1990 and 1997 patients younger than 60 years of age with l ow-grade lymphoma at high risk of treatment failure were enrolled on one of two sequential protocols for autologous BMT differing only in their TBI re gimens. The preoperative chemotherapy regimens were identical and consisted of intravenous etoposide (1500 mg/m(2)) for 1 day, intravenous cyclophosph amide (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 tot al 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 throu gh 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 stat us (PS) and gender. Lung function was assessed objectively by pulmonary fun ction tests (PFTs) before and at intervals after TBI. The pulmonary functio n parameters assessed included forced vital capacity (FVC), forced expirato ry volume in I second (FEV1), forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), diffusing capacity for carbon monoxide (DLCO), 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 mo del. Clinical pulmonary function status was scored according to Radiation T herapy Oncology Group criteria for acute and late lung toxicity. All clinic al pulmonary toxicities such as pneumonitis, pneumonia, and diffuse alveola r hemorrhage, whether specifically related to TBI or not, were scored. Toxi city 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 an alysis were overall survival (OS), freedom from progression, and chronic pu lmonary toxicity. Survival, progression, and complication free survival wer e 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 d eath 3.5 times higher than younger patients. Freedom from progression was s ignificantly different for the 2 TBI regimens (P < 0.001; log-rank test): 3 1% 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 pa tients on protocol B. The TBI protocols did not differ significantly in the ir effects on FVC, FEV1, FEF25-75, DLCO, and TLC. Patients 45 years of age or older had lower average posttransplant values of FEV1, FVC, and DL, than younger patients. There was no significant difference in acute or late tox icity rates between patients on the two protocols. Seven of the 57 patients in the twice-daily TBI (protocol A) group had acute pulmonary events (Grad e 3 or greater), compared with 6 of the 24 patients in the once-daily (prot ocol B) group (P = 0.19). The 3-year freedom from late complications rate w as 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 d elivered in 6 twice-daily fractions to 12 Gy delivered in 4 once-daily frac tions without significantly increasing the risk of pulmonary toxicity. The increased dose may contribute to a decrease in the recurrence rate in these patients. (C) 2001 American Cancer Society.