Limb Function Not Improved by Lower Volume Radiation for Extremity STS

A lower dose of radiation therapy following surgery did not improve limb function and was not found to be non-inferior compared with standard dose radiation 2 years post procedure in patients extremity soft tissue sarcoma. 

A slight trend toward lower recurrence favoring the research arm was seen at 2 years but it did not reach the statistical significance required to determine non-inferiority. The 2-year local recurrence-free rates (LRFR) were 94% (95% CI, 87-97) in the control versus 91% (95% CI 83, 95) with standard radiation (univariate HR, 1.35; 90% CI, 0.69-2.61). After adjusting for tumor grade and margin the adjusted HR was 1.47 (90% CI, 0.75-2.86).

“The research hypothesis was that a smaller volume of radiotherapy treatment would reduce treatment toxicity and the overall level of post surgical disability but is not inferior to standard treatment in terms of disease-free and overall survival,” explained Beatrice Seddon, PhD, Consultant Clinical Oncologist on the Sarcoma Unit at University College Hospital, UCLH NHS Trust.

Seddon presented results for the VORTEX trial that randomized 218 patients with extremity STS to receive the standard biphasic volume of radiation or a hypofractionated dose. In the standard arm, radiotherapy was delivered post surgically at 50 Gy in 25 fractions to clinical target volume 1 (CTV1) followed by 16 Gy in 8 fractions to CTV2 (control arm). In the investigational arm, patients received 66 Gy in 33 fractions to CTV2 only. Prior to randomization, patients were stratified by tumor grade, adequacy of surgical margin, and treatment center.

Co-primary outcome measures were limb function at 2 years by TESS and the time to local recurrence. Secondary outcomes were soft tissue and bone toxicity, disease-free survival (DFS), overall survival (OS), and level of disability.

All patients registered for preoperative tumor and normal tissue collection and baseline TESS questionnaire. Histopathology revealed 55 myxofibrosarcoma, 28 myxoid liposarcoma, 74 undifferentiated pleomorphic, and 61 ‘other’ tumor types (leiomyosarcoma, pleomorphic liposarcoma, dedifferentiated liposarcoma). In both cohorts, the tumor sites were arm, buttock, pelvis, thigh, knee, and lower leg and the mean tumor size was 9cm; 10% were grade 1 and 90% of tumors were grade 2.

Fresh frozen paraffin embedded tissue was collected from 98% of randomized patients, and matched tumor and normal tissue was obtained from 88% of patients for planned evaluation of hypoxia markers CA-IX, HIF-1alpha, and GLUT-1 by immunohistochemistry.

“No difference between treatment arms in TESS at 2 years was observed,” she pointed out.

TESS comprises 30 questions that contribute to a highest score of 100. TESS was completed 7 times by the patients from baseline, post-surgery, and at intervals to 24 months.

A sharp decline from baseline in TESS of approximately -16 points immediately post-surgery was reported for all patients. TESS reflected recovery at 3 months with a score of -10 reported for both arms. The absolute change from baseline was similar and continued to show improvement in the control and research arms at 6, 12, and 18 months.

TESS at 24 months, the primary outcome, was nearly equivalent at -5.0 in the control arm versus -4.9 in the research arm. OS was also similar between the cohorts. The 5-year OS rates of 70% for the control arm versus 72% in the research arm (adjusted HR, 0.99; 90% CI, 0.65-1.50). A trend toward improved DFS was seen: the 2-year DFS rates were 69% versus 71% in the control versus research arms, respectively (adjusted HR, 0.95; 90% CI, 67-1.38).

“There is no evidence that smaller margins for post operative radiotherapy in extremity soft tissue sarcoma improves limb function,” commented Seddon.

Late radiation morbidity at 2 years was evaluated using the RTOG/EORTC radiation morbidity score on a scale of 0 to 5. Late events grade ≥2 were reported for the skin (29% vs 28%), subcutaneous region (43% vs 32%), bone (1% vs 1%), and joints (9% vs 4%) of patients in the control versus research arms, respectively.

“Toxicity of grade 2 or higher predicted lower TESS and poorer function,” said Seddon.

TESS associated significantly with toxicity scores at 2 years for subcutaneous and joint events (P≤.001 andP= .002, respectively) but did not reach statistical significance for skin and bone toxicities.

Seddon summarized: “There was no difference in local recurrence, overall survival and disease free survival, but lower patient numbers means we cannot confirm that the research arm is non-inferior for local recurrence; this trial did demonstrate that large multi-center trials of local treatment in rare tumors are challenging, but possible and can provide a feasible opportunity for bio-banking.”

Robinson M, Gaunt P, Grimer R, et al. VORTEX trial: a trial of volume of post-operative radiotherapy given to adult patients with extremity soft tissue sarcoma (STS). Presented at: CTOS Annual Meeting; Lisbon, Portugal, from November 9 to 12, 2016. Paper 004.