Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

Abstract

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Chemotherapy for metastatic soft tissue sarcomas – another full circle?

“…Because of variability in patient populations, direct comparisons between studies have limited value. However, a response rate of 27% is in keeping with many other studies of intermittent high dose ADR (Bramwell et al, 1983;Mouridsen et al, 1987;Santoro et al, 1990), and is similar to the respose rate for ADIC (30%) in this second ECOG trial (Bordon et al, 1987) and for ADIC (33%) in the SWOG trial (Baker et al, 1987). Benjamin's editorial (1987) suggested that 'IFOS intensification' might produce better results.…”

“…Although the response rate for single agent ADR was higher than the 19% achieved with the second combination regimen (VCR + ADR + CYCLO) used in this study, the difference was not significant. A later trial by SWOG, randomising 335 patients (Baker et al, 1987), showed that adding CYCLO or DACT to the ADIC regimen did not significantly improve response rates, which were respectively 33% (ADIC), 34% (CYCLO/ADIC) and 24% (DACT/ADIC).…”

Chemotherapy for adult soft tissue sarcoma

“…Finally, many investigators are of the opinion that some histological types of ASTS respond poorly to chemotherapy, in particular leiomyosarcomas of gastrointestinal origin. However, convincing evidence for this is difficult to find in the literature [8,10,12]. Dose-response relationships Is there a strong proven dose-response relationship in ASTS, so that the effect of chemotherapy can be increased by simply increasing the dose?…”

“…There are indications that some cytostatic agents may have higher activity for certain histological types, including ifosfamide and doxorubicin for synovial sarcomas [4,10], and OTIC-containing combinations for leiomyosarcomas [II,12].…”

Chemotherapy of Soft Tissue Sarcoma

“…Yap et al treated 125 ae ORIGINAL ARTICLE ae advanced STS patients with a combination of doxorubicin, dacarbazine, cyclophosphamide, and vincristine, the socalled 'CYVADIC regimen', with a reported RR of 50% (8). In 1976 Á/1979, in a randomized study by the Southwest Oncology Group (SWOG) comprising 112 patients, three treatment combinations were compared, i.e., doxorubicin'/ dacarbazine vs. doxorubicin'/dacarbazine'/cyclophosphamide vs. doxorubicin'/dacarbazine'/actinomycin D, but no statistically significant differences in RR were found (33%, 34%, and 24%) (9). In a randomized study comprising 663 patients with advanced STS conducted by the European Organization for Research and Treatment of Cancer (EORTC), it was concluded that single-agent doxorubicin should be the standard treatment.…”