In a phase I study, gemcitabine given concurrently with fixed-dose EBRT showed promising results following surgery in patients with high-risk soft-tissue sarcoma.
Using a method known as the toxicity severity weight method (TSWM), a new phase I study determined a maximum tolerated dose for gemcitabine given concurrently with fixed-dose external-beam radiation therapy (EBRT) in patients with resectable, high-risk extremity and trunk soft-tissue sarcoma. Outcomes following surgery were promising.
“Soft-tissue sarcoma accounts for only 1% of adult solid tumors; however, in affected patients, these tumors can often cause significant morbidity and death,” wrote study authors led by William W. Tseng, MD, of the University of Southern California in Los Angeles. Though gemcitabine has shown promise in sarcoma, “the safety and efficacy of neoadjuvant gemcitabine plus radiation therapy in patients with soft-tissue sarcoma is unknown.”
The new phase I trial included 36 patients with a median age of 53.5 years who had soft-tissue sarcoma of the extremity or trunk. Results were published online ahead of print in Cancer.
Patients received gemcitabine in doses ranging from 400 to 700 mg/m2, on days 1, 8, 22, 29, 43, and 50, in combination with a fixed EBRT dose of 50 Gy in total. Each successive cohort’s dose was determined using the TSWM, which “bases dose selection on the total toxicity burden. Each grade of each type of toxicity is assigned a severity weight based on clinical importance, and the total toxicity burden is equal to the sum of all the weights of each toxicity experienced by the patient.
In this case, six types of toxicity were included: myelosuppression without fever; myelosuppression with fever; dermatitis; hepatitis; nausea/vomiting; and fatigue. Using the TSWM, the maximum tolerated dose was determined to be 700 mg/m2. At that level, most observed toxicities were grade 3 or lower, and only four patients (24%) experienced a grade 4 toxicity.
All 36 patients underwent complete tumor resection following gemcitabine and EBRT; 47% of tumors showed a major pathologic response defined as greater than 90% tumor necrosis.
After a median follow-up of 6.2 years, the 5-year locoregional recurrence-free survival rate was 85%. The distant-metastasis-free survival rate was 80%, and the overall survival in the study was 86%.
The authors concluded that the TSWM is a useful method to help determine a maximum tolerated dose in a multimodal treatment regimen, though it is relatively labor-intensive and did not incorporate grade 1 and 2 toxicities.
“Gemcitabine combined with EBRT in the neoadjuvant setting for patients with resectable, high-risk extremity and trunk soft-tissue sarcoma appears to be feasible and safe with an maximum tolerated dose of 700 mg/m2,” they wrote. “Further evaluation of this treatment’s efficacy in a phase II trial is definitely warranted.”