A. Santoro

Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

PURPOSE The aim of this trial was to compare the activity and toxicity of single-agent doxorubicin with that of two multidrug regimens in the treatment of patients with adult advanced soft tissue sarcomas. PATIENTS AND METHODS This was a prospective randomized phase III trial performed by 35 cancer centers within the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer (EORTC). Six hundred sixty-three eligible patients were randomly allocated to receive either doxorubicin 75 mg/m2 (arm A), cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CYVADIC) (arm B), or ifosfamide 5 g/m2 plus doxorubicin 50 mg/m2 (arm C). RESULTS The overall response rate was 24% (95% confidence interval, 20.7% to 27.3%) among eligible patients and 26% among assessable patients. No statistically significant difference was detected among the three study arms in terms of response rate (arm A, 23.3%; arm B, 28.4%; and arm C, 28.1%), remission duration (median, 46 weeks on arm A, 48 weeks on arm B, and 44 weeks on arm C), or overall survival (median, 52 weeks on arm A, 51 weeks on arm B, and 55 weeks on arm C). The degree of myelosuppression was significantly greater for the combination of ifosfamide and doxorubicin than for the other two regimens. Cardiotoxicity was also more frequent in this arm, but other toxicities were similar. CONCLUSION In advanced soft tissue sarcomas of adults, single-agent doxorubicin is still the standard chemotherapy against which more intensive or new drug treatments should be compared. Combination chemotherapy cannot be recommended outside a controlled clinical trial with the exclusion of some subsets of sarcoma patients for whom significant tumor volume reduction may be an important end point of a chemotherapy regimen.

Prognostic Factors for the Outcome of Chemotherapy in Advanced Soft Tissue Sarcoma: An Analysis of 2,185 Patients Treated With Anthracycline-Containing First-Line Regimens—A European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study

PURPOSE A total of 2,185 patients with advanced soft tissue sarcomas who had been treated in seven clinical trials investigating the use of doxorubicin- or epirubicin-containing regimens as first-line chemotherapy were studied in this prognostic-factor analysis. PATIENTS AND METHODS Overall survival time (median, 51 weeks) and response to chemotherapy (26% complete response or partial response) were the two end points. The cofactors were sex; age; performance status; prior therapies; the presence of locoregional or recurrent disease; lung, liver, and bone metastases at the time of entry onto the trial; long time period between the initial diagnosis of sarcoma and entry onto the study; and histologic type and grade. RESULTS Univariate analyses showed (a) a significant, favorable influence of good performance status, young age, and absence of liver metastases on both survival time and response rate, (b) a significant, favorable influence of low histopathologic disease grade on survival time, despite a significantly lower response rate, (c) increased survival time for patients with a long time period between the initial diagnosis of sarcoma and entry onto the study, despite equivalent response rates, and (d) increased survival time with liposarcoma or synovial sarcoma, a decreased survival time with malignant fibrous histiocytoma, a lower response rate with leiomyosarcoma, and a higher response rate with liposarcoma (P < .05 for all log-rank and chi2 tests). The Cox model selected good performance status (P < .0001), absence of liver metastases (P = .0001), low histopathologic grade (P = .0002), long time lapse since initial diagnosis (P = .0004), and young age (P = .0045) as favorable prognostic factors of survival time. The logistic model selected absence of liver metastases (P < .0001), young age (P = .0024), high histopathologic grade (P = .0051), and liposarcoma (P = .0065) as favorable prognostic factors of response rate. CONCLUSION This analysis demonstrates that for advanced soft tissue sarcoma, response to chemotherapy is not predicted by the same factors as is overall survival time. This needs to be taken into account in the interpretation of trials assessing the value of new agents for this disease on the basis of response to treatment.

Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas

Ifosfamide (IFOS) 5 g/m2 and its parent analog Cyclophosphamide (CYCLO) 1.5 g/m2 were studied in a randomized phase II study, accruing 171 patients with advanced soft tissue sarcoma. Both drugs were administered as 24 hr infusions, every 3 weeks, with comcomitant Mesna 400 mg/m2 i.v. bolus 4 hourly X 9 doses. Twenty-four patients were ineligible and 12 were not evaluable. The groups were well matched for age, previous chemotherapy (42% of the total) or radiotherapy, the presence of distant metastases and performance status, but there were more females (59% vs. 45%) in the IFOS arm. Among the 68 evaluable patients receiving IFOS, there were 2 CR, 10 PR (overall response 18%), 27 SD and 29 PD. For CYCLO, the corresponding results in 67 patients were 1 CR, 4 PR (overall response 8%), 23 SD and 39 PD. Using the chi-square test the P values for response rate and linear trend were 0.13 and 0.04 respectively. Response rates were higher for females (20% vs. 5%, P = 0.01) and patients who had not received previous chemotherapy (19% vs. 4%, P = 0.01). Fourteen of the 17 responses came from a group of 43 females, who had not received previous chemotherapy, for whom the overall response rate was 37.5%. Remissions were noted in only 4 histological subtypes (centrally reviewed material), i.e., 5 of 17 synovial sarcomas, 7 of 13 mixed mesodermal sarcomas and 2 of 7 fibrosarcomas. One of the 31 leiomyosarcomas responded to Cyclophosphamide. Durations of response did not differ significantly between the 2 arms--median 26, range 10-81+ weeks. Leucopenia was significantly more severe on CYCLO, particularly in patients who had received previous chemotherapy (P = 0.007). Serious infections occurred in approx. 7% of patients with no difference between the two drugs, although there was one toxic death on CYCLO. Nausea and vomiting were significantly worse on IFOS and alopecia, related in extent to dose, was seen in both arms. Other side-effects, such as hematuria or rises in serum creatinine and encephalopathy, were infrequent and mild. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination therapy.

Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

PURPOSE To evaluate the benefit of adjuvant chemotherapy in adult patients with soft tissue sarcomas. The principal end points were freedom from local recurrence and/or metastases and overall survival. PATIENTS AND METHODS Between January 1977 and June 1988, 468 patients entered this randomized study and 317 were considered eligible. Following complete surgical resection with or without radiotherapy, outcome in 145 eligible patients receiving cyclophosphamide 500 mg/m2 intravenously (IV) bolus on day 1, vincristine 1.4 mg/m2 IV bolus on day 1, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) 50 mg/m2 IV bolus on day 1, and dacarbazine (DTIC) 400 mg/m2 by 1-hour infusion on days 1 to 3 (CYVADIC) cycles repeated every 28 days for eight courses was compared with that in 172 control patients. RESULTS With a median follow-up duration of 80 months (range, 39 to 165), actuarial percentage survival figures at 7 years were compared. Relapse-free survival rates were higher for CYVADIC, 56% versus 43% (P = .007), and local recurrence was significantly reduced in the CYVADIC arm at 17% versus 31% (P = .004). In contrast, distant metastases occurred with similar frequency in both arms, 32% for CYVADIC versus 36% for control patients (P = .42), and overall survival rates were not significantly different at 63% versus 56% (P = .64). A reduction in local recurrence was only apparent in the group of head, neck, and trunk sarcomas (P = .002), but not in limb tumors (P = .31). CONCLUSION Adjuvant chemotherapy with CYVADIC cannot be recommended outside the context of a clinical trial. Experience from this study has been used to plan a trial of neoadjuvant chemotherapy with doxorubicin/ifosfamide, which is currently in progress.

Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC soft tissue and bone sarcoma group☆

The objective of this randomized phase II/phase III study was to investigate the efficacy and toxicity of equimolar doses of adriamycin (ADM) and 4-epiadriamycin (EPI) in patients with locally advanced and/or metastatic soft tissue sarcoma. Doses of ADM and EPI were 75 mg/m2 given as an i.v. bolus injection every 3 weeks. Two hundred and ten patients were entered into the study by 18 institutions. Twenty-eight patients were ineligible and 15 were non-evaluable, leaving 167 evaluable patients. The two treatment groups were well balanced for sex, performance status, age, prior radiotherapy, extent and site of disease. Rates of response were similar, 25% in the ADM group compared to 18% in the EPI group (P = 0.33), and there were no significant differences between the ADM and EPI groups with respect to median duration of response (45 weeks vs. 77 weeks, P = 0.08), time to progression (15 weeks vs. 12 weeks, P = 0.945), and median survival (41 weeks vs. 48 weeks, P = 0.363). Myelotoxicity as shown by leucopenia was significantly more pronounced in the ADM treated patients (P = 0.002). Other toxicities such as alopecia and nausea/vomiting were also more severe in the ADM group (P = 0.02 and 0.06, respectively). In conclusion, the use of equimolar doses of ADM and EPI in advanced soft tissue sarcoma produced response rates which did not differ significantly and were only slightly in favour of ADM. However, this was achieved at the expense of higher toxicity.

Cyvadic in advanced soft tissue sarcoma: A randomized study comparing two schedules: A study of the EORTC soft tissue and bone sarcoma group

Two hundred forty‐six adults with advanced progressive soft tissue sarcoma received combination chemotherapy with cyclophosphamide, vincristine, Adriamycin (doxorubicin), and DTIC. They were randomly allocated to receive the four drugs simultaneously every 4 weeks (S1: CYVADIC), or pairs of drugs (S2: ADIC‐CYV) alternating at 4 weekly intervals. One hundred sixty‐two patients completed 8 weeks of chemotherapy, and were considered to be evaluable for response. There were 18 complete remissions and 25 partial remissions, an overall response rate of 26%, with a highly significant difference between the two arms in favor of S1 (38% versus 14%, P = 0.001). There were no significant differences between S1 and S2 in terms of median duration of remissions (62 versus 39 weeks), and median survival of responders (85 versus 80 weeks) and of all evaluable patients (43 versus 45 weeks). Karnofsky index (KI) was the single most important prognostic factor. Patients with KI 90–100 showed a remission rate of 41% (56% on the S1 regimen) in contrast with 14% in those with KI 50–80. No patient with a KI of 50 responded to chemotherapy. The main toxicities were nausea, vomiting, anorexia, alopecia and myelosuppression, but did not differ significantly between the two regimens. Our findings suggest that stratification according to KI is essential for studies on chemotherapy for advanced soft tissue sarcomas in order to make a valuable comparison of treatment results.

Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma

The objective of this phase II trial was to assess the therapeutic activity and toxicity of doxorubicin plus ifosfamide in previously untreated patients with advanced soft-tissue sarcoma. Treatment consisted of an intravenous bolus injection of doxorubicin at a dose of 50 mg/m2 followed by a 24-h infusion of ifosfamide at 5 g/m2 plus mesna, with therapy being repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Of the 203 patients entered, 175 were evaluable for response. The overall response rate was 35% (95% confidence interval, 28%-42%), with 9% of patients achieving complete responses and 26% showing partial responses. The median time to progression was 29 weeks for all evaluable patients and 67, 40, and 28 weeks for complete and partial responders and patients with stable disease, respectively. The median duration of survival was 58 weeks. Myelosuppression was the dose-limiting toxicity, resulting in leukopenia (World Health Organization grades 3 and 4) in 73% of the evaluable patients. Other side effects were rare and usually well manageable.

Carminomycin vs adriamycin in advanced soft tissue sarcomas: an EORTC randomised phase II study.

Eighty-three patients with advanced soft tissue sarcoma who had received no prior chemotherapy entered a randomised phase II study comparing carminomycin (CMM) 20 mg/m2 with adriamycin (ADM) 75 mg/m2, both administered i.v. bolus every 3 weeks. Six patients were ineligible and response could not be evaluated in 6 additional patients. Thirty-eight evaluable patients received ADM and 33 received CMM. There was one complete response to ADM and 10 partial responses, an overall response rate of 29%. CMM showed significantly (P = 0.01) lower antitumour activity--one partial response (3%). Stabilisation of disease was similar in both arms (47 and 45%), but fewer patients progressed on ADM (24 compared to 52%). Durations of response dating from the start of chemotherapy were 5 months for complete remission on ADM, a median of 7 months (range 4-17) for partial response on ADM and 14 months for the one partial remission on CMM. Although the median time to progression for all patients receiving CMM (2 months) was significantly (P = 0.001) shorter than for those receiving ADM (5 months), patients on ADM had only a marginally significant longer duration of survival (P = 0.06) than the patients receiving CMM. A leucocyte nadir less than 2.0 X 10(9)/l occurred in 38% of patients receiving ADM and 43% receiving CMM. Anaemia and thrombocytopoenia were uncommon. Other toxicities such as nausea, vomiting, anorexia and alopecia were more severe in the ADM group. There was one infective death secondary to leucopoenia in the ADM arm, and one patient who had received 109 mg/m2 CMM + 255 mg/m2 ADM developed progressively fatal cardiomyopathy.

European Experience of Adjuvant Chemotherapy for Soft Tissue Sarcoma: Interim Report of a Randomized Trial of Cyvadic Versus Control

A Multidisciplinary approach to the management of soft tissue sarcomas has led to improvements in the rates of local control, despite increasing use of limb salvage procedures. However, metastasis, which seems to correlate with higher histological grade, remains a distressingly frequent problem, occurring in approximately 30% of individuals, often in the absence of local failure.

Cyclophosphamide versus ifosfamide: preliminary report of a randomized phase II trial in adult soft tissue sarcomas

SummaryOne hundred and seventy-one patients with advanced soft tissue sarcoma entered a randomized crossover phase II study comparing cyclophosphamide (CYCLO) with a new analogue, ifosfamide (IFOS), both administered as 24 h i.v. infusions every 3 weeks. The doses used were CYCLO 1.5 g/m2 and IFOS 5 g/m2, with provision for dose escalation. All patients received mesna 400 mg/m2 as an i.v. bolus 4 hourly x 9 doses, commencing at the start of the oxazophosphorine infusion. Patients who had received previous chemotherapy were eligible provided this did not include a classical alkylating agent. There were 22 patients who were ineligible, and response could not be evaluated in 12 additional patients. IFOS produced two complete and ten partial remissions, for an overall response rate of 18%. CYCLO was significantly (P=0.04) less active, producing one complete and five partial remissions, an overall response rate of 9%. Stabilization of disease was similar in both arms (27% and 24% respectively), but fewer patients showed progression on IFOS. The response rate was higher (20% vs 5%) for patients who had not received previous chemotherapy, and also for female compared with male patients (21% vs 5%). When only patients who had not received previous chemotherapy were considered, the respective response rates for IFOS and CYCLO were 24% and 15%. There were no responses in previously treated patients receiving CYCLO. There were four partial responses in 33 patients crossing from CYCLO to IFOS, but no responses in 18 patients receiving CYCLO after IFOS. Leucopenia was significantly more pronounced (P=0.0004) with CYCLO, both after the first course and throughout treatment, although the incidence of severe infections, 6%, was the same in both arms. Nausea and vomiting were more severe with IFOS (P=0.022), but other toxicities were mild. Grade 1 or 2 bladder (haematuria) or renal (rise in serum creatinine) toxicity was slightly more frequent with IFOS (7 vs 3 patients) and was a reason for stopping treatment for one patient in each arm. Three episodes of mild to moderate drowsiness after IFOS were reported, but no severe encephalopathy. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination with such active agents as adriamycin.