Proffered Papers— Young Investigator

RESULTS OF TWO CONSECUTIVE PHASE II STUDIES AND INTERIM ANALYSIS OF A PHASE III INTERGROUP STUDY OF NEOADJUVANT TREATMENT INCLUDING REGIONAL HYPERTHERMIA (RHT) IN HIGH RISK SOFT TISSUE SARCOMA (HR-STS) PATIENTS

Wendtner CM, Abdel-Rahman S, Falk MH, Lang NK, Krych M, Hiddemann W, Issels RD (Med. Klinik III/Grosshadern, Ludwig-Maximilians-University and KKG Hyperthermie, GSF, D-81377 Munich, Germany)

We report upon 113 patients with HR-STS (non-resectable primary/S1, recurrent/S2, inadequately resected/S3) located within extremities, trunk or abdomen who were treated within a neoadjuvant phase II protocol (RHT-91 or RHT-95). HR-criteria were: tumor grade II/III + tumor size (>8cm for RHT-91; >5cm for RHT-95) + extracompartmental extension. The neoadjuvant RHT-91 protocol (59 pts) included 4 cycles of preoperative chemotherapy (XT) plus RHT, followed by surgery and 4 cycles of adjuvant XT plus RHT. In addition, R1/R2-resected pts received radiation. The RHT-95 protocol (54 pts) was identical except that pts after surgery obtained XT without RHT and adequate radiation regardless of resection status. XT of both studies consisted of etoposide (125mg/m2) on day 1+4, ifosfamide (1500mg/m2) on day 1 to 4, and adriamycin (50mg/m2) on day 1 (EIA). RHT (1hr at 42.5oC) was given on day 1+4. Radiographic response in 52 evaluable pts of the RHT-91 (42%) and in 36 assessable pts of the RHT-95 study (33%) included 1+2 CR, 8+6 PR, 13+4 MR, 17+10 SD and 13+14 PD, respectively. Among 74 pts undergoing surgery, amputation rate was <15%. After different median observation times (RHT-91: 58mo/ RHT-95: 30mo) probability of overall survival (42% vs 48%; p=0.392) and distant progression free survival (51% vs 64%; p=0.357) are quite similar for both studies. Subgroup analysis (S3 vs S1, S2) for overall survival revealed also no significant difference (47% vs 48%; p=0.616). Interestingly, local relapse free survival was in favour of the RHT-91 study which included pre- and postoperative RHT (58% vs 57%; p=0.021).

Based on these results, a randomized prospective phase III intergroup study (EORTC 62961 /ESHO RHT-95) with transatlantic participation is ongoing comparing EIA +/- RHT in previously defined (S1-S3) risk groups and includes pre- and postoperative RHT in the experimental treatment arm with local relapse free survival as the main study endpoint. Since July 1997 more than 100 pts have been randomized. Feasibility of preoperative XT was 95% (270 of 284 cycles in 71 pts evaluable) and of postoperative XT 74% (115 of 156 cycles in 39 pts evaluable), respectively. In all pts assessed so far, no grade IV hematological toxicity was observed. Three pts died of acute non-hematological toxicity (4%). Feasibility of preoperative RHT was 90% (133 of 148 cycles in 37 pts evaluable) and of postoperative RHT 59% (45 of 76 cycles in 19 pts evaluable), respectively, while almost no severe reactions directly attributed to hyperthermia were reported. Taken together, treatment within this international phase III protocol is a feasible and safe approach for HR-STS patients while impact on local disease control and survival has to be awaited.