In patients with adult soft-tissue sarcoma (ASTS), the use and timing of adjuvant chemotherapy or chemoradiotherapy remains controversial. The appropriate target population is generally accepted as International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) stage III extremity or trunk sarcomas (ie, > 5 cm, grade 3/4, located deep to the superficial fascia, with no evidence of metastases). After definitive local treatment, the 5-year disease-free and overall survival rates in this population are approximately 52% and 56%.[1]

Meta-analysis

In 1997, the Sarcoma Meta-analysis Collaboration (SMAC)[2] reported a meta-analysis of survival outcomes of randomized trials of adjuvant chemotherapy (doxorubicin alone or in combination), for which accrual was completed before December 1992. Data were available on 1,544 patients in 14 trials. The investigators found a trend toward improvement in overall survival (hazard ratio [HR] = 0.89; 95% confidence interval [CI] = 0.76-1.03; P = .12), resulting in an absolute benefit in the chemotherapy arm of 4% at 10 years. Interestingly, significant improvements were seen in both local recurrence-free interval (HR = 0.73; 95% CI = 0.56-0.94; P = .016; absolute benefit of 6%); and distant recurrence-free interval (HR = 0.70; 95% CI = 0.57-0.85; P = .0003; absolute benefit of 10%).

An unplanned subgroup analysis of the cohort of 886 patients with extremity soft-tissue sarcoma revealed a significant improvement in overall survival (HR = 0.80; P = .029), for an absolute benefit of 7%. This meta-analysis had a number of limitations: (1) a possible dilution of the beneficial effects of chemotherapy for extremity ASTS by inclusion of tumors at all locations; (2) a similar dilution of effects of chemotherapy from inclusion of patients with low-grade (5%) or unknown grade (28%) tumors; (3) none of the chemotherapy regimens (except in one small unpublished study) included ifosfamide; (4) long accrual period back to 1973; (5) suboptimal chemotherapy compliance; and (6) variable protocol designs.

Italian Trial

Some of these limitations were addressed by an Italian Cooperative Group study, which included 104 patients with high-grade extremity ASTS ≥ 5 cm in size. Patients were randomized between postoperative high-dose epirubicin (Ellence) and ifosfamide for four cycles, or no chemotherapy. Because of the potential toxicity of the regimen, only patients ≤ 65 years old were included. Four patients did not complete therapy due to toxicity or refusal. Despite the use of granulocyte colony-stimulating factor (G-CSF, Neupogen), grade 4 leukopenia occurred in 35%, and neutropenic fever in 13%.

When the trial was first reported in 2001, the median follow-up was 60 months.[3] At 2 years, disease-free survival was 72% in the chemotherapy arm vs 45% in the control group (P = .04) but was not significantly different at 4 years (50% vs 37%; P = .19). For overall survival, the reverse was true—at 2 years, disease-free survival was 85% vs 72% (P = .10), and at 4 years, 69% vs 50% (P = .04), respectively. However, when the trial was reported at a longer follow-up of 90 months, overall survival was no longer significantly different—57% for chemotherapy recipients vs 42% for control patients.[4] This trial was originally designed to recruit twice the number of patients, but was discontinued halfway through recruitment due to an early-stopping rule based on disease-free survival.

EORTC Studies

The European Organisation for Research and Treatment of Cancer (EORTC) initiated a randomized phase II trial of neoadjuvant chemotherapy[5] with the intention of proceeding to a phase III study if progression during chemotherapy was infrequent and accrual was adequate. Poor accrual led to the study's termination after entry of 150 patients. Approximately 89% (134 patients) were deemed eligible, and had high-risk (> 8 cm, any grade; < 8 cm, grade 2/3; grade 2/3, local recurrence/inadequate first surgery) extremity, head and neck, trunk, and pelvis sarcomas. Patients were given three cycles of preoperative doxorubicin and ifosfamide or no chemotherapy, and then proceeded to surgery with or without postoperative radiotherapy. No postoperative chemotherapy was planned.

At a median follow-up of 7.3 years, 5-year actuarial outcomes for chemotherapy vs control were 56% vs 52% for disease-free survival (P = .36), and 65% vs 64% (P = .22) for overall survival. One toxic death occurred in the neoadjuvant chemotherapy group, but no difference was seen in postoperative complications. Approximately 12% of patients progressed on neoadjuvant chemotherapy. Isolated local recurrence rates were 12%, with no difference between the arms, but 25% of patients had local recurrence in the setting of distant metastases. Although underpowered to observe significant differences in disease-free or overall survival, this trial[5] was 50% larger than the Italian study.[3,4] Major criticisms of this study were that the dose of ifosfamide (5 g/m²) was low by current standards (whereas the doxorubicin dose was adequate at 75 mg/m²) and the total duration of chemotherapy was short.

Another major randomized trial of adjuvant chemotherapy, EORTC 62931, completed accrual in December 2003 but is not yet ready for analysis. Following surgery, 351 patients with grade 2/3 tumors of all sites were given postoperative doxorubicin/ifosfamide for five cycles or no chemotherapy. Radiotherapy, if needed, was postponed until the completion of chemotherapy. The duration of chemotherapy was longer than in the previous neoadjuvant EORTC study, but the doses of doxorubicin and ifosfamide per course were the same.