Phase III randomised trial Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma Aileen M. Davis a,j,* , Brian O’Sullivan b,j , Robert Turcotte c , Robert Bell b,d,j , Charles Catton b,j , Pierre Chabot e , Jay Wunder b,d,j , Alex Hammond f , Veronique Benk g , Rita Kandel d,j , Karen Goddard h , Carolyn Freeman c , Anna Sadura i , Benny Zee i , Andrew Day i , Dongsheng Tu i , Joseph Pater i , A Canadian Sarcoma Group and NCI Canada Clinical Trials Group Randomized Trial a Toronto Rehabilitation Institute, Canada, b Princess Margaret Hospital, Toronto, Canada, c McGill University Health Center, Montreal, Canada, d Mount Sinai Hospital, Toronto, Canada, e Hopital Maisonneuve-Rosemont, Montreal, Canada, f London Regional Cancer Centre, Ont., Canada, g Toronto-Sunnybrook Regional Cancer Centre, Ont., Canada, h BC Cancer Agency, Vancouver, Canada, i NCI Canada Clinical Trials Group, Cancer Research Institute, Ont., Canada, j University of Toronto, Canada Abstract Background and Purpose: This study compared late radiation morbidity in patients with extremity soft tissue sarcoma randomized to treatment by pre- (50 Gy) or postoperative (66 Gy) radiotherapy in combination with surgery. The morbidities evaluated included fibrosis, joint stiffness and edema at 2 years following treatment. The impact of morbidity on patient function as measured by the Musculoskeletal Tumor Rating Scale (MSTS) and the Toronto Extremity Salvage Score (TESS) was also evaluated. Patients and methods: 129 patients were evaluated. Toxicity rates were compared by treatment arm using the Fisher’s exact test. Function scores by toxicity were analyzed using the Wilcoxon rank sum test. Multivariate logistic regression was used to evaluate the joint effect of treatment arm, field size, and dose on subcutaneous tissue fibrosis, joint stiffness and edema. Results: 27 of 56 patients (48.2%) in the postoperative arm compared to 23 of 73 (31.5%) in the preoperative arm had grade 2 or greater fibrosis (PZ0.07). Although not statistically significant, edema was more frequent in the postoperative arm, 13 of 56 (23.2%) versus 11 of 73 (15.1%) in the preoperative arm, as was joint stiffness, 13 of 56 (23.2%) versus 13 of 73 (17.8%). Patients with significant fibrosis, joint stiffness or edema had significantly lower function scores on both measures (all P-values !0.01). Field size was predictive of greater rates of fibrosis (PZ0.002) and joint stiffness (PZ0.006) and marginally predictive of edema (PZ0.06). Conclusions: Patients treated with postoperative radiotherapy tended to have greater fibrosis. Fibrosis, joint stiffness and edema adversely affect patient function. q 2005 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 75 (2005) 48–53. Keywords: Radiotherapy; Toxicity; Randomized trial; Extremity soft tissue sarcoma Patients with extremity soft tissue sarcoma are com- monly treated with limb preservation surgery in combination with adjuvant radiotherapy [13,14,16,19,22,23,26,32,33]. While adjuvant radiotherapy may be given with external beam or brachytherapy, external beam techniques continue to be used at most centers in Europe and North America [13–15,21,26,32]. These modalities achieve optimum local tumor control; however, physical disability and reduced quality of life may result from treatment morbidity [7,15]. In patients with extremity soft tissue sarcoma, these morbidities may include major wound complications [3,4,15,18,20] and late radiation effects such as subcutaneous tissue fibrosis, edema, joint stiffness, and bone changes including osteoradionecrosis and fracture [2,5,15,17,21,25]. There is limited documentation of the effects of late radiation morbidity on extremity function in soft tissue sarcoma patients in the literature. Three retrospective studies evaluated function in relation to radiation dose and morbidity but these studies included patients treated as early as 1975 in one study and 1983 in the remaining studies [14,21,25]. With the advent of computerized tomography 0167-8140/$ - see front matter q 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.12.020 Radiotherapy and Oncology 75 (2005) 48–53 www.elsevier.com/locate/radonline