Significant Reduction of Late Toxicities in Patients With Extremity Sarcoma Treated With Image-Guided Radiation Therapy to a Reduced Target Volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial

Abstract

Purpose: We performed a multi-institutional prospective phase II trial to assess late toxicities in patients with extremity soft tissue sarcoma (STS) treated with preoperative image-guided radiation therapy (IGRT) to a reduced target volume.

Patients and methods: Patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Daily pretreatment images were coregistered with digitally reconstructed radiographs so that the patient position could be adjusted before each treatment. All patients received IGRT to reduced tumor volumes according to strict protocol guidelines. Late toxicities were assessed at 2 years.

Results: In all, 98 patients were accrued (cohort A, 12; cohort B, 86). Cohort A was closed prematurely because of poor accrual and is not reported. Seventy-nine eligible patients from cohort B form the basis of this report. At a median follow-up of 3.6 years, five patients did not have surgery because of disease progression. There were five local treatment failures, all of which were in field. Of the 57 patients assessed for late toxicities at 2 years, 10.5% experienced at least one grade ≥ 2 toxicity as compared with 37% of patients in the National Cancer Institute of Canada SR2 (CAN-NCIC-SR2: Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) trial receiving preoperative radiation therapy without IGRT (P < .001).

Conclusion: The significant reduction of late toxicities in patients with extremity STS who were treated with preoperative IGRT and absence of marginal-field recurrences suggest that the target volumes used in the Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity) study are appropriate for preoperative IGRT for extremity STS.

Trial registration: ClinicalTrials.gov NCT00589121.

Fig 1.

CONSORT diagram for cohort B from Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity). CAN-NCIC-SR2, National Cancer Institute of Canada SR2 (Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma); RT, radiation therapy.

Fig 2.

Treatment schema for patients in Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity). Chemotherapy was allowed at the discretion of the treating medical oncologist for deep (≥ 8 cm) sarcomas in maximum dimension with intermediate- to high-grade histology (grade 3 or 4; American Joint Committee on Cancer, 6th edition). Treating centers were certified by the RTOG for sarcoma image-guided radiation therapy (RT) as well as for 3-dimensional conformal radiation therapy (3D-CRT) and/or intensity-modulated RT (IMRT). Radiation therapy technique (3DCRT v IMRT) was at the discretion of the treating radiation oncologist. CT, computed tomography; EBRT, external beam RT; HDR, high-dose rate; IORT, intraoperative RT; LDR, low-dose rate; MRI, magnetic resonance imaging.

Fig 3.

(A) Cumulative incidence of local, regional, and distant failure and second primary tumor (SPT) per Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity) definitions of failure. (B) Kaplan-Meier estimates of disease-free survival (DFS) and distant disease-free survival per RTOG-0630 definitions of failure. (C) Kaplan-Meier estimates of local recurrence, regional/distant recurrence, and progression-free survival (PFS) per National Cancer Institute of Canada SR2 (CAN-NCIC-SR2; Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) definitions of failure. (D) Kaplan-Meier estimates of overall survival. In the CAN-NCIC-SR2 trial, patients who did not have surgery or had an amputation to remove the primary tumor were not included in analysis, so (C) has fewer patients (73) than (A), (B), and (D), which have 79. Event No. indicates distant, local, or regional failure or second primary.