Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials.

BACKGROUND: Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. PATIENTS AND METHODS: Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. RESULTS: Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. CONCLUSIONS: Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.

Testing new regimens in patients with advanced soft tissue sarcoma: analysis of publications from the last 10 years.

BACKGROUND: The prognosis of advanced soft tissue sarcoma remains poor. Many phase II trials investigating new regimens have been published in the last 10 years. MATERIALS AND METHODS: Full English-language reports of phase II clinical trials from January 1999 to October 2009 have been reviewed. We have defined those that provided 3- and 6-month progression-free survival rates (PFSR) >39% and 14%, respectively, as promising second-line regimens. For studies enrolling both chemonaive and pretreated patients, we have compared the reported PFSR3 to the expected PFSR3 of an active treatment administered in the same proportions of pretreated and nonpretreated patients. RESULTS: Forty-nine trials were identified. Among the trials investigating new regimens in pretreated patients alone, the promising second-line regimens were ifosfamide, brostallicin, pazopanib (except in liposarcoma), temozolomide, trabectedin, dacarbazine-gemcitabine and docetaxel (Taxotere)-gemcitabine combinations (in uterine leiomyosarcoma). Among the trials enrolling both chemonaive and pretreated patients, most regimens reached the level of efficacy; moreover, in three trials, the reported PFSR3 was particularly high: weekly paclitaxel (Taxol) in angiosarcoma, docetaxel-gemcitabine combination (in uterine leiomyosarcoma) and oral perifosine. CONCLUSIONS: In the past 10 years, several drugs or combinations have demonstrated promising activity in exploratory phase II trials and warrant further investigation in appropriate phase III trials.

First-line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histological soft tissue sarcoma subtypes and as a prognostic factor for MPNST: an EORTC soft tissue and bone sarcoma group study.

BACKGROUND: the role of chemotherapy in advanced malignant peripheral nerve sheath tumor (MPNST) is unclear. PATIENTS AND METHODS: chemotherapy-naive soft tissue sarcomas (STS) patients treated on 12 pooled nonrandomized and randomized European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials were retrospectively analyzed. Clinical outcomes, overall survival, progression-free survival (PFS) and response were determined for MPNST and other STS histotypes and compared. Additionally, prognostic factors within the MPNST population were defined. Studied cofactors were demographics, sarcoma history, disease extent and chemotherapy regimen. RESULTS: after a median follow-up of 4.1 years, 175 MPNST out of 2675 eligible STS patients were analyzed. Outcome was similar for MPNST versus other STS histotypes, with a response rate, median PFS and overall survival of 21% versus 22%, 17 versus 16 weeks and 48 versus 51 weeks, respectively. Performance status was an independent prognostic factor for overall survival. Chemotherapy regimen was an independent prognostic factor for response (P < 0.0001) and PFS (P = 0.009). Compared with standard first-line doxorubicin, the doxorubicin-ifosfamide regimen had the best response, whereas ifosfamide had the worst prognosis. CONCLUSION: this series indicates the role of chemotherapy in treatment of advanced MPNST. This first comparison showed similar outcomes for MPNST and other STS histotypes. The apparent superiority of the doxorubicin-ifosfamide regimen justifies further investigations of this combination in randomized trials.

Paclitaxel in patients with advanced angiosarcomas of soft tissue: a retrospective study of the EORTC soft tissue and bone sarcoma group.

RATIONALE: Angiosarcomas of soft tissue represent a heterogenous group of rare sarcomas with specific clinical behaviour and risk factors. Paclitaxel appears to induce tumour control in a higher proportion of patients with angiosarcoma, as compared to other sarcomas. The objective of this retrospective study was to assess the anti-tumour activity of this compound in a multicentre setting. METHOD: Clinical data from patients with angiosarcomas of soft tissue treated with single agent paclitaxel were collected from the centres of the soft tissue and bone sarcoma group of EORTC, using a standardised data collection form. Paclitaxel could be given every three weeks, or weekly. Statistical analysis was performed using SAS software. RESULTS: Data from 32 patients were collected from 10 centres. There were 17 males, 15 females, with a median age of 60.4 years (range, 25-91). Primary angiosarcomas were located in scalp and face in 8 patients (25%) and at other primary sites in 24 patients (75%). All patients had intermediate (n=13) or high grade (n=19) primary tumours. Thirteen (40%) patients had been pretreated with doxorubicin-based first-line-chemotherapy and three of them (9%) had also received second-line chemotherapy with ifosfamide. Eleven (34%) patients had been irradiated before as treatment for angiosarcoma. In 8 (25%) patients, the angiosarcoma occurred at sites of prior radiation therapy for other malignancies. The response rate was 62% (21/32) in the whole series, 75% (6/8) in scalp angiosarcomas and 58% (14/24) in other primary sites. The median time to progression was 7.6 months (range, 1-42) for the whole group. For the face/scalp group it was 9.5 months, and for patients with angiosarcomas at other sites it was 7.0 months, respectively. CONCLUSION: Paclitaxel was found to be an active agent in angiosarcoma of soft tissue in this retrospective analysis. These results need to be confirmed in a prospective randomised phase II study.

Exatecan in pretreated adult patients with advanced soft tissue sarcoma: results of a phase II--study of the EORTC Soft Tissue and Bone Sarcoma Group.

No standard treatment is established for patients with advanced soft tissue sarcoma after previous chemotherapy with anthracyclines and ifosfamide, given either in combination or sequentially. Exatecan (DX-8951f) is a totally synthetic analogue of the topoisomerase I-inhibitor camptothecin, which was synthesised to impart increased aqueous solubility, greater tumour efficacy, and less toxicity than camptothecin itself, topotecan or irinotecan. Since some activity against soft tissue sarcomas, especially leiomyosarcomas, has been reported for topoisomerase I-inhibitors, a study with a new and more potent agent seemed justified. We report on a prospective multicentre phase II study of Exatecan in adult soft tissue sarcomas failing 1 or 2 lines of chemotherapy in advanced phase, performed within the STBSG of EORTC. Thirty-nine patients (16 leiomyosarcomas and 23 other histologies) were included in two independent strata and received a total of 141 cycles (median 2). Median age was 61 years, range 25-76. Exatecan was given as i.v. infusion over 30 min at a dose of 0.5mg/m2 every day for five consecutive days, repeated every 21 days. Seventy-four percentage of cycles could be given without dose or schedule modification. The main toxicity was haematotoxicity with grade 3/4 neutropenia in 49%, grade 3/4 thrombocytopenia in 23%, and grade 3/4 anaemia in 15% of patients, respectively. Non-haematological toxicity consisted mainly of grade 2/3 dyspnoea in 36% of patients and grade 2/3 fatigue in 28%. One treatment-related toxic death due to septic shock was reported. Best overall response was no change with 60% in the leiomyosarcoma group and 53% in the non-leiomysarcoma group, respectively. The 3 months progression-free survival estimates are 56% for leiomysarcomas and 26% for other histologies, respectively. Using a two-step statistical design, the trial was stopped after the first step in both strata, due to lack of activity. In pretreated soft tissue sarcoma patients, Exatecan is well tolerated but does not achieve any objective responses. However, with respect to progression-free survival, Exatecan did show some activity in leiomyosarcomas.

Phase 1 European Organisation for Research and Treatment of Cancer study determining safety of pegylated liposomal doxorubicin (Caelyx) in combination with ifosfamide in previously untreated adult patients with advanced or metastatic soft tissue sarcomas.

This phase I study evaluated the toxicity of first-line combined pegylated liposomal doxorubicin (Caelyx) and ifosfamide in patients with advanced and/or metastatic soft tissue sarcomas. Five dose levels (L) were studied: Caelyx 30 mg/m2 (L1-4) or 40 mg/m2 (L5) 1-h infusion d 1 q 3 weeks + ifosfamide and mesna at X g/m2/4 h d 1-3 q 3 weeks at five doses: L1: X = 1.7 g; L2: X = 2 g; L3: X = 2.5 g; L4 and L5: X = 3 g. Cohorts of 3 patients were entered at each level unless a dose-limiting toxicity (DLT) occurred. In case of DLT in 1 of 3 patients a new cohort was added. Toxicity was evaluated by Common Toxicity Criteria (CTC). A total of 28 patients was included: 4 at dose L1, 8 at L2, 3 at L3, 6 at L4, and 7 at L5. Median age was 60 years (range 29-69 years). Male/female ratio was 12/16. Seventy-five percent of patients had a performance status of 1.0 and 36% had leiomyosarcomas. No DLT was observed at dose L1-4. Six patients developed a DLT at dose L5, and thus the recommended dose is level 4 (i.e. Caelyx 30 mg/m2/1 h d 1+ifosfamide at 3 g/m2/4 h d 1-3 q 3 weeks). Few haematological and biochemical events were observed and the principal toxicities were granulocytopaenia and leucopaenia. Five patients discontinued therapy because of toxicity, 4 of them at dose level 5. Non-haematological toxicities > grade 2 were also few. Palmar-plantar erythrodysesthesia (PPE) > grade 1 was not seen. Two patients obtained partial response (PR) and 13 stable disease (SD). Median overall survival (OS) was 333 d and median progression-free survival (PFS) 174 d. In conclusion, this seems to be a feasible combination in patients with advanced soft tissue sarcomas, allowing ifosfamide to be given in a dosage similar to that used when given alone. The recommended dose for future studies is Caelyx 30 mg/m2/1 h d 1+ifosfamide 3 g/m2/4 h d 1-3 q 3 weeks.

Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).

BACKGROUND: In 2004, level I evidence was established for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe (European Organization Research and Treatment of Cancer; EORTC) and the United States (Radiation Therapy Oncology Group; RTOG). Adjuvant chemotherapy-enhanced radiation therapy (CERT) was shown to be more efficacious than postoperative radiotherapy for these tumors in terms of locoregional control and disease-free survival. However, additional studies were needed to identify precisely which patients were most suitable for such intense treatment. METHODS: Both studies compared the addition of concomitant relatively high doses of cisplatin (on days 1, 22, and 43) to radiotherapy vs radiotherapy alone given after surgery in patients with high-risk cancers of the oral cavity, oropharynx, larynx, or hypopharynx. A comparative analysis of the selection criteria, clinical and pathologic risk factors, and treatment outcomes was carried out using data pooled from these two trials. RESULTS: Extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of CERT was significant in both trials. There was also a trend in favor of CERT in the group of patients who had stage III-IV disease, perineural infiltration, vascular embolisms, and/or clinically enlarged level IV-V lymph nodes secondary to tumors arising in the oral cavity or oropharynx. Patients who had two or more histopathologically involved lymph nodes without ECE as their only risk factor did not seem to benefit from the addition of chemotherapy in this analysis. CONCLUSIONS: Subject to the usual caveats of retrospective subgroup analysis, our data suggest that in locally advanced head and neck cancer, microscopically involved resection margins and extracapsular spread of tumor from neck nodes are the most significant prognostic factors for poor outcome. The addition of concomitant cisplatin to postoperative radiotherapy improves outcome in patients with one or both of these risk factors who are medically fit to receive chemotherapy.

RECIST vs. WHO: prospective comparison of response criteria in an EORTC phase II clinical trial investigating ET-743 in advanced soft tissue sarcoma.

The present study was set up just after the publication of the response evaluation criteria in solid tumors (RECIST) as a prospective validation exercise in soft tissue sarcoma. Forty-nine patients were entered into a phase II clinical trial aiming at determining the activity and safety of ET-743 (Ecteinascidin) in second line advanced soft tissue sarcoma. Response to treatment and progression were monitored following the WHO criteria and RECIST. Discordances between WHO and RECIST criteria for the best response were reported for two cases: one no-change (WHO) reported as partial response (RECIST) and one progression (WHO) reported as no-change (RECIST). In terms of date of progression, 3 patients progressed on WHO criteria while they were still stable with RECIST. Overall the results of the study would not have changed if RECIST had been used instead of WHO criteria. In conclusion, response criteria as defined by RECIST are adequate to measure response and progression in non-GIST soft tissue sarcoma and can be used instead of the modified WHO criteria.

Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO.

BACKGROUND: The management of gastrointestinal stromal tumors (GIST) has evolved very rapidly in the last 4 years. The objectives of this international consensus meeting were to describe the optimal management procedures for patients with GIST in localized and advanced stages, as well as research issues for the future. MATERIALS AND METHODS: A panel of experts from six specialties, including pathology, molecular biology, imaging, surgery, medical oncology and methodologists for clinical practice guidelines from different European and extra European sarcoma societies were invited to a 2-day workshop. Several questions were selected by the organizing committee prior to the conference. Selected panelists reviewed the current levels of evidence for each point, and presented their conclusions during the meeting. These proposals were discussed, and consensus points were identified and categorized according to the Standard Options Recommandations (SOR) of the French Federation of Cancer Centers and National Comprehensive Cancer Network (NCCN). RESULTS: Thirty-two consensus points were identified, most from categories 2A of the NCCN and B2 of the SOR. Among these, the standard histological examination with immunohistochemical analysis using CD117, CD34, PS100, desmin and smooth muscle actin is considered standard. Molecular biology for the identification of KIT and PDGFRA mutation is an optional diagnostic procedure for GIST with negative CD117 staining, and otherwise is considered a research procedure. Complete tumor resection with negative tumor margins is the standard surgical treatment. Adjuvant imatinib after optimal tumor resection as well as neo-adjuvant imatinib remain experimental approaches to be performed within prospective clinical studies. Imatinib should be started at the date of diagnosis of metastatic relapse and given until development of intolerance or progressive disease. The optimal criteria for tumor response to imatinib remain to be delineated, and should include not only tumor size reduction or disease stabilization, but also reduction of tumor density (Hounsfield Units) on computed tomography and metabolic activity (i.e. reduction of FDG uptake on positron emission tomography). In a substantial proportion of patients, stable disease and even increase in tumor size may be associated with pathologic response to imatinib therapy, and available survival data indicate that the survival of these patients is similar to that of patients with conventional tumor response. Metastasis resection is an experimental procedure. CONCLUSIONS: Consensus points in clinical management of GIST as well as questions for future clinical trials were identified during this consensus conference on GIST management.

Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial.

PURPOSE: This nonrandomized multicenter phase II study was performed to evaluate the activity and safety of Ecteinascidin (ET-743) administered at a dose of 1.5 mg/m(2) as a 24-hour continuous infusion every 3 weeks in patients with pretreated advanced soft tissue sarcoma. PATIENTS AND METHODS: Patients with documented progressive advanced soft tissue sarcoma received ET-743 as second- or third-line chemotherapy. Antitumor activity was evaluated every 6 weeks until progression, excessive toxicity, or patient refusal. RESULTS: One hundred four patients from eight European institutions were included in the study (March 1999 to November 2000). A total of 410 cycles were administered in 99 assessable patients. Toxicity mainly involved reversible grade 3 to 4 asymptomatic elevation of transaminases in 40% of patients, and grade 3 to 4 neutropenia was observed in 52% of patients. There were eight partial responses (PR; objective regression rate, 8%), 45 no change (NC; > 6 months in 26% of patients), and 39 progressive disease. A progression arrest rate (PR + NC) of 56% was observed in leiomyosarcoma and 61% in synovialosarcoma. The median duration of the time to progression was 105 days, and the 6-month progression-free survival was 29%. The median duration of survival was 9.2 months. CONCLUSION: ET-743 seems to be a promising active agent in advanced soft tissue sarcoma, with no cumulative toxicities. The 6-months progression-free survival observed in advanced soft tissue sarcoma compares favorably with those obtained with other active drugs tested in second-line chemotherapy in previous European Organisation for the Research and Treatment of Cancer trials. The median overall survival was unusually long in these heavily pretreated patients mainly due to the high number of patients who benefit from the drug in terms of tumor control.

A phase II study of ET-743/trabectedin ('Yondelis') for patients with advanced gastrointestinal stromal tumours.

Primary or secondary resistance to imatinib may occur in patients with gastrointestinal stromal tumours (GISTs) while these tumours have repeatedly been shown to be highly resistant to conventional doxorubicin- and ifosfamide-containing regimens. The investigation of new drugs is therefore warranted in GIST. A phase II study was conducted between May 1999 and November 2000 in eight centres of the EORTC STBSG group to establish the efficacy and safety of ET743 ('Yondelis') in GIST previously untreated with cytotoxic chemotherapy before the imatinib era. ET-743 was given was given at 1.5 mg/m(2) per course as a 24-h continuous intravenous infusion every 3 weeks. Twenty-eight patients were included, 16 males and 12 females. Median age was 54 years (range 25-73 years). Median performance status was 0 (range 0-1). 17 (63%), 4 (12%) and 7 (25%) patients, received 0-2, 3-5, and > or = 6 courses of ET-743, respectively. The best response was stable disease in 9 (33%) patients, and disease progression in 18 patients (67%), with a median time to disease progression and overall survival of 51 days and 589 days, respectively. The treatment was well tolerated: there were grades 3-4 neutropenia, thrombocytopenia, and transaminase increases in 13 (48%), 1 (4%) and 16 (59%) patients, respectively. There were no toxic deaths. ET-743 at this dose and schedule is not an effective treatment for advanced GIST.

Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group.

Previous studies have shown that activating mutations of c-KIT/PDGFRA, potential therapeutic targets for imatinib mesylate, are implicated in the pathophysiology of gastrointestinal stromal tumours (GISTs). In this study, GISTs from 37 patients enrolled in an European Organisation for Research and Treatment of Cancer (EORTC) phase I/II clinical study of imatinib were examined for mutations of c-KIT/PDGFRA in order to explore whether the mutational status of the tumour predicts the clinical response to therapy. Mutations were screened by denaturing high-pressure liquid chromatography (DHPLC) and characterised by bi-directional DNA sequencing. Activating mutations of c-KIT or PDGFRA were found in 29 (78%) and 2 (6%) GISTs, respectively. Most c-KIT mutations involved exon 11 (n=24; 83%), all but one being an in-frame deletion; no isolated point mutations were found. The other c-KIT mutations included exon 9 AY 502-503 duplication (n=4; 14%) and exon 13 Lys-->Glu(642) missense mutation (n=1; 3%). Two tumours with no detectable c-KIT mutations demonstrated PDGFRA Asp-->Glu(842) amino acid substitutions. Patients with GISTs harbouring exon 11 mutations were more likely to achieve a partial response (PR) on imatinib therapy (83%) than all of the others (23%). The overall survival and progression-free survival rates for the entire group at 106 weeks were 78.3% and 46.9%, respectively. Based on a Kaplan-Meier analysis, patients with GISTs harbouring c-KIT mutations had longer median survival times and were less likely to progress than the other patients. These findings indicate that the mutational status of the c-KIT/PDGFRA oncoproteins could be useful to predict the clinical response of patients imatinib therapy.

Long-term efficacy of the CHVmP/BV regimen used for aggressive non-Hodgkin's lymphoma in three randomised EORTC trials.

We analysed data from 936 newly-diagnosed patients with advanced, aggressive non-Hodgkin's lymphoma (NHL) treated in three randomised European Organisation for Research and Treatment of Cancer (EORTC) trials performed between 1980 and 1999 (median follow-up of 8.7 (0.2-20.4) years). The CHOP-like regimen CHVmP/BV (cyclophosphamide, doxorubicin, teniposide and prednisone with bleomycin and vincristine at mid-interval), was compared with CHVmP (CHVmP/BV without bleomycin and vincristine), ProMACE-MOPP (methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamide, vincristine, procarbazine and prednisone) and CHVmp/BV with additional, autologous stem-cell transplantation, respectively. Overall, treatment with CHVmP/BV resulted in a better long-term outcome with 63% complete responses being observed and an overall survival (OS) of 59 and 43% at 5 and 10 years, respectively. Remarkably, OS after CHVmP/BV improved across the trials, even after stratifying for the International Prognostic Index (IPI). This finding could not be directly related to better salvage treatments during the last decade. Selection bias appears to be responsible: stepwise corrections for small differences in inclusion criteria eliminated the difference in OS, especially when histological subgroups were studied. This systemic review underlines the difficulties encountered in retrospective sub-set analyses and the biases that can be introduced when recent studies are compared with older ones.

Advanced soft-tissue sarcoma: a disease that is potentially curable for a subset of patients treated with chemotherapy.

Adult patients with metastatic or locally advanced irresectable soft-tissue sarcoma (ASTS) are generally considered as incurable. Whether some of these patients achieve long-term survival after first-line treatment with chemotherapy is not known. Patients with ASTS still alive 5 years after initial treatment with a doxorubicin-containing regimen, i.e. long-term survivors, were analysed among the 2187 patients included in first-line chemotherapy protocols between 1976 and 1990 in seven trials of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC STBSG) group. 1888 patients were followed for at least 5 years. The initial clinical characteristics and the outcome of the long-term survivors were investigated. 66 of the 1888 patients were alive at 5 years and the projected 5-year survival was 8% in this series. Age or histological subtypes were similar in the long-term survivors compared with the other patients. The percentages of females (69%), of grade 1 tumours (35%), of patients with an initial performance status (PS) of 0 (63%) were significantly higher in the long-term survivors while liver metastasis (6% versus 21%) were significantly less frequent. Long-term survivors were observed in all subgroups of patients. 31, 31, 31 and 6% of the long-term survivors were in complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively, after the first-line regimen. A CR to a doxorubicin-containing regimen was the major parameter correlated to 5-year survival. In multivariate analysis using a logistic model, independent parameters correlated to 5-year survival were PS, female gender, grade I tumours, and the achievement of a CR after first-line treatment, which was retained as the most powerful predictor for 5-year survival. 10 of the 66 patients died after 5 years in this series, including 8 patients in PD or SD after first-line treatment versus 2 patients in PR or CR (P=0.01). 8% of patients with ASTS are alive 5 years after first-line chemotherapy with a doxorubicin-containing regimen. Long-term survivors are observed in all prognostic subgroups of patients, in particular those achieving a CR to first-line chemotherapy.

Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients.

The aim of this phase II study was to evaluate the efficacy and toxicity of two regimens of ifosfamide in metastatic soft tissue sarcoma patients given as first- and second-line chemotherapy. Two different schedules of ifosfamide were investigated in a randomised manner: Ifosfamide was given either at a dose of 5 g/m(2) over 24 h (5 g/m(2)/1 day), every 3 weeks or at a dose of 3 g/m(2) per day, administered over 4 h on three consecutive days (3 g/m(2)/3 days), every 3 weeks. Both schedules were given as first-line or second-line chemotherapy. A total of 182 patients was entered, 103 in first- and 79 in second-line, of whom 8 patients were ineligible, 5 in the first- and 3 in the second-line study. Most patients had a leiomyosarcoma, 46 of the 98 in the first-line and 34 of the 76 in the second-line. The two study arms were well balanced in both the first- and second-lines with respect to sex, age and performance status. In first-line treatment, 5 g/m(2)/1 day yielded five partial responses (PR) (Response Rate (RR) 10%), versus 12 PR (RR 25%) for the 3 g/m(2)/3 days. As second-line treatment, the 24-h infusion yielded: one CR and one PR (RR 6%) and the 3-day schedule one CR and two PR (RR 8%). Survival did not differ between the two regimens. The major World Health Organization (WHO) grade 3 and 4 toxicities encountered were: leucopenia in 19% of all courses in the first-line and 32% in the second-line with the 5 g/m(2)/1 day, while for the 3 g/m(2)/3 days schedule the rates were 57 and 63% respectively. Grade 3 or 4 infections were seen in 4% of patients treated with 5 g/m(2)/1 day first-line and 10% of patients given 3 g/m(2)/3 days, both as first- and second-lines. No such infections were seen in patients receiving 5 g/m(2)/1 day as second line treatment. In advanced soft-tissue sarcomas in the first-line, ifosfamide 3 g/m(2), given over 4 h on three consecutive days, is an active regimen with acceptable toxicity while the 5 g/m(2) over 24 hours schedule resulted in a disappointing response rate.

Progression-free rate as the principal end-point for phase II trials in soft-tissue sarcomas.

We have estimated progression-free rates (PFR) for various groups of soft-tissue sarcoma patients from our clinical trials database, to provide reference values for conducting phase II studies with PFR as the principal end-point. In 146 pretreated patients receiving an active agent, the PFR estimates were 39 and 14% at 3 and 6 months; with inactive regimens (234 patients), those estimates were 21 and 8% respectively. In 1154-non-pretreated patients, PFR estimates varied from 77% (synovial sarcoma) to 57% (malignant fibrous histiocytoma (MFH)) at 3 months, and from 56% (synovial sarcoma) to 38% (MFH) at 6 months. In 61 leiomyosarcomas from gastrointestinal origin, the corresponding figures were 44 and 30%, respectively. Consequently, for first-line therapy, a 6-month PFR of > or = 30-56% (depending on histology) can be considered as a reference value to suggest drug activity; for second-line therapy, a 3-month PFR of > or = 40% would suggest a drug activity, and < or = 20% would suggest inactivity.

Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group.

Gemcitabine (2'-deoxy-2'-difluorocytidine monohydrochloride) at a dose of 1250 mg/m(2) was given as a 30-min intravenous (i.v.) infusion on days 1 and 8 in a 3-weekly schedule to 32 patients with advanced soft-tissue sarcoma (STS) failing first-line chemotherapy. One patient was ineligible due to a delay between the previous chemotherapy and the start of treatment. Of the eligible patients, median age was 53 years (range 23-73 years). The predominant histological subtype was leiomyosarcoma in 12 patients (38%). The median number of cycles was three (range 1-8 cycles) with a median total dose of gemcitabine of 6.25 g/m(2) (range 1.25-19.97 g/m(2)). The relative dose intensity of gemcitabine was 96% (range 50-103%). Treatment was tolerated very well with non-complicated haematological toxicity as the most frequently observed side-effect. Only one partial tumour response was documented, giving a response rate of 3.23% (95% Confidence Interval (CI): 0.08-16.2%). The median overall survival was 268 days (95% CI: 129-377) and the median time to progression was 45 days (95% CI: 41-79). These results indicate that gemcitabine given at this dose and schedule is not active as second-line therapy in advanced STS.