Proffered Papers— Surgical Treatment of Sarcomas

COMBINED MODALITY MANAGEMENT OF RETROPERITONEAL SARCOMAS: PHASE I TRIAL OF PREOPERATIVE DOXORUBICIN-BASED CONCURRENT CHEMORADIATION, SURGICAL RESECTION, AND INTRAOPERATIVE ELECTRON-BEAM RADIATION THERAPY (IORT)

Pisters PWT, Patel SR, Crane C, Feig BW, Hunt KK, Burgess MA, Papadopoulos NE, Plager C, Benjamin RS, Pollock RE, Janjan NE. (University of Texas M. D. Anderson Cancer Center, Houston, TX 77030)

Background: Patterns of failure for patients with retroperitoneal sarcomas (RPS) demonstrate that the majority of patients develop local recurrence. Strategies to enhance to efficacy / intensity of local therapies are needed. One approach involves the use of pre-operative chemoradiotherapy (chemoXRT). This protocol explores the use of pre-operative doxorubicin given by protracted venous infusion (PVI) with concurrent external beam radiotherapy (EBRT). This approach takes advantage of the benefits of preoperative radiotherapy, the activity of doxorubicin in STS, and the radiosensitizing properties of doxorubicin. When chemo XRT is combined with surgical resection and IORT, local therapy is maximized. Objectives of this phase I trial included: 1) define the toxicities of preoperative PVI doxorubicin and concurrent EBRT followed by surgical resection with IORT and 2) establish the maximum tolerated dose (MTD) of EBRT when combined with PVI doxorubicin.

Methods: Patients with localized, resectable, grade II or III primary or recurrent RPS are eligible. Preoperative continuous infusion doxorubicin is administered (4 mg/m₂ over 24 hours x 4 days/week for 4 weeks) with concomitant escalating doses of EBRT (1.8 Gy/fraction). The dose escalation scheme (and number of patients treated) for successive cohorts of patients has been: 18 Gy (3 patients), 30.6 Gy (3 patients), 36 Gy (3 patients), 41.4 Gy (3 patients), 46.8 Gy (12 patients), and 50.4 Gy (2 patients).

Results: 26 patients have been treated. The median tumor size was 12 cm (range 6-31 cm). Histologies included leiomyosarcoma (n=8), liposarcoma (n=5), malignant fibrous histiocytoma (n=5), unclassified soft tissue sarcoma (n=5), and other RPS’s (n=3). The MTD has not yet been defined. Only one patient experienced grade IV neutropenia at 18 Gy and there were no episodes of febrile neutropenia. Grade III gastrointestinal toxicities have included diarrhea (1 patient each at 18, 30.6, and 50.4 Gy) and nausea (1 patient each at 46.8 and 50.4 Gy); no patients have experienced grade IV gastrointestinal toxicities. Twenty-one patients have undergone surgical resection. IORT (15 Gy) was provided to 15 patients with no identifiable toxicities. No major wound complications have been observed.

Conclusions: 1) Doxorubicin-based concurrent chemoradiation can be given to a dose of 46.8 Gy with minimal grade III/IV toxicities, 2) MTD has not yet been defined, 3) No identifiable toxicities are attributed to IORT. This combined modality approach appears to have an acceptable overall toxicity profile and capitalizes on all of the advantages of pre-operative/intraoperative treatment to enhance the therapeutic ratio of surgery and radiotherapy in the management of RP STS.