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Background: Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent., Methods: For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4-6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT)., Results: Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8-29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥95 % tumor necrosis) was observed in three patients (38 %)., Conclusion: Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).

Purpose: Although multimodal management of extremity soft tissue sarcoma (STS) is the standard of care, considerable variation exists in the sequencing of radiotherapy (RT) or chemotherapy (CT). Our goal was to identify factors responsible for this variation., Methods: Members of specialty societies with an interest in STS were emailed a questionnaire about multimodal treatment of STS. Survey responses were scored on a 5-point Likert scale (1 = always preoperative and 5 = always postoperative) and analyzed by specialty, years in practice, and percentage of practice consisting of STS., Results: The questionnaire was completed by 320 (65%) of 490 physicians, including medical oncologists (18%), radiation oncologists (8%), orthopedic oncologists (22%), surgical oncologists (45%), and others (7%). Respondents were evenly split on the use of neoadjuvant RT (mean 3.03 ± 0.06) and showed a slight preference for neoadjuvant CT (2.89 ± 0.06). Radiation oncologists (2.52 ± 0.18), physicians with a >75% STS practice (2.58 ± 0.17), and those in practice <5 years (2.79 ± 0.12) preferred neoadjuvant RT. Neoadjuvant CT was preferred by orthopedic oncologists (2.62 ± 0.12) and physicians with >75% STS practice (2.51 ± 0.16). Factors influencing the choice for neoadjuvant RT were well-defined treatment volume, increased acute morbidity, and decreased late morbidity, while for CT, they were in-situ disease monitoring and early treatment of micrometastases., Conclusions: Treatment sequencing in STS is influenced by specialty and clinical experience, with no clear consensus. These patterns may reflect the recent trend toward regionalization of STS care.

Background: Limited data exist regarding the radiographic and histologic response of soft tissue sarcoma (STS) to neoadjuvant radiotherapy (RT)., Methods: Between February 2000 and January 2009, a total of 25 patients aged >16 years with intermediate- or high-grade primary STS of all sites were treated with neoadjuvant RT followed by definitive resection. Patients receiving chemoradiotherapy were excluded. Cross-sectional images obtained before and after RT as well as pathologic specimens were reviewed for maximal change in tumor diameter and percentage tumor necrosis, respectively. Clinicopathologic variables were analyzed for their association with pathologic and radiographic response., Results: There were 18 extremity (72%) and 7 retroperitoneal (28%) tumors. Median maximal tumor size was 9 cm (range, 3.3-35 cm), and 88% were of high grade. There were 21 R0 resections (84%) and 4 R1 resections (16%). Radiographically, the median percentage change in tumor diameter was 0% (range, -25 to +86%). By Response Evaluation Criteria in Solid Tumors (RECIST), 5 patients demonstrated progressive disease, 20 demonstrated stable disease, and 0 demonstrated partial/complete response. The median pathologic percentage tumor necrosis was 30% (range, 5-100%). Two tumors (8%) demonstrated near-complete pathologic response (≥95% necrosis). Near-complete pathologic response was associated with favorable oncologic outcomes, although these associations were not statistically significant., Conclusions: Radiologic and near-complete pathologic responses are rare events after preoperative RT for STS. Near-complete pathologic response may be a potentially meaningful surrogate marker for disease outcome and is not predicted by RECIST response. Knowledge of these historical response rates is important for the evaluation of novel neoadjuvant therapies for patients with STS.