Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas

AimThis randomised phase III trial evaluated first-line trabectedin versus doxorubicin-based chemotherapy (DXCT) in patients with advanced/metastatic translocation-related sarcomas (TRS).MethodsPatients were randomly assigned (1:1) to receive trabectedin 1.5 mg/m² 24-h intravenous (i.v.) infusion every 3 weeks (q3wk) (Arm A), or doxorubicin 75 mg/m² i.v. q3wk, or doxorubicin 60 mg/m² i.v. plus ifosfamide (range, 6–9 g/m²) i.v. q3wk (Arm B). Progression-free survival (PFS) by independent review was the primary efficacy end-point.ResultsOne hundred and twenty-one patients were randomised; 88 of them had TRS confirmed by central pathology review (efficacy population). Twenty-nine PFS events were assessed by independent review (16 with trabectedin; 13 with DXCT). PFS showed non-significant difference between arms (stratified log rank test, p = 0.9573; hazard ratio = 0.86, p = 0.6992). At the time of this analysis, 63.9% and 58.3% of patients were alive in trabectedin and DXCT arms, respectively. There was no statistically significant difference in survival curves. Response rate according to Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0 was significantly higher in DXCT arm (27.0% versus 5.9%), but response according to Choi criteria showed fewer differences between treatment arms (45.9% versus 37.3%). Safety profile was as expected for both arms, with higher incidence of severe neutropenia, alopecia and mucositis in the DXCT arm.ConclusionNeither trabectedin nor doxorubicin-based chemotherapy showed significant superiority in the first-line treatment of patients with advanced translocation-related sarcoma.     

A retrospective statistical analysis of high-grade soft tissue sarcomas

Soft-tissue sarcomas have a mortality rate ranging from 40–60% for high-grade lesions. Prior identified risk factors for post-surgical mortality include tumor size, lesion histology, and margin status at resection. A better understanding of prognostic factors is needed to guide patient counseling and treatment. Data were collected from 129 patients surgically treated for high-grade extremity soft tissue sarcomas during 2002–2010. The primary endpoint was death related to high-grade soft tissue sarcoma. Thirteen variables were investigated: age, gender, race, tumor size, margin status, location, estimated blood loss, operative blood transfusions, pre-operative metastatic disease, pre-operative radiation, post-operative radiation, pre-operative chemotherapy, and post-operative chemotherapy. A Cox Survival Analysis model was created to determine the best predictors of survival time. Tumor size and the presence of pre-surgical metastasis were statistically significant predictors of overall survival. Patients with a tumor greater than 8 cm in any cross section had a 3.15 times greater chance of death. Presence of pre-surgical metastasis carried a 3.47 greater chance of death. The remaining variables did not predict patient outcomes in a statistically significant manner. The hazard ratios calculated add new data and can be used to more effectively guide patients in prognosis and treatment regimens.     

Retrospective inter- and intra-patient evaluation of trabectedin after best supportive care for patients with advanced translocation-related sarcoma after failure of standard chemotherapy

AimOur randomised phase II study showed the clinical benefit of trabectedin compared with best supportive care (BSC) in patients with advanced translocation-related sarcomas after the failure of standard chemotherapy. The aim of the present study was to evaluate efficacy and safety of trabectedin in the identical patients crossed over to trabectedin after disease progression in the BSC arm of the randomised study.Patients and methodsThis was a single-arm study of the BSC patients of the randomised study in whom disease progressed. Trabectedin (1.2 mg/m²) was administered over 24 h on day 1 of a 21-d treatment cycle. The efficacy and safety of trabectedin after BSC were evaluated and retrospectively compared with the results of the randomised study.ResultsThirty patients crossed over to trabectedin. Median progression-free survival (PFS) was 7.3 months (95% confidence interval [CI]: 2.9–9.1) after crossover compared with 0.9 months (95% CI: 0.9–1.0) at BSC in the randomised study. PFS in the present study was comparable to that of the trabectedin arm in the randomised study. The number of patients with growth modulation index ≥1.33 was 25 (86%). Individual tumour volume was decreased in 11 patients after crossover. Adverse drug reactions (ADRs) were observed in 27 patients (96.4%). ADRs of grade III–IV were mainly bone marrow suppression and abnormal liver functions.ConclusionTrabectedin was revealed to be effective and well tolerated in the identical patients crossed over to trabectedin after disease progression in BSC.The present study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121853.     

Comparison of Response Evaluation Criteria in Solid Tumours and Choi criteria for response evaluation in patients with advanced soft tissue sarcoma treated with trabectedin: A retrospective analysis

BackgroundTo assess the additional value of density measurement using contrast-enhancement sequences (Choi assessment) in a real-life cohort of adult soft tissue sarcoma patients treated with trabectedin.MethodsEligibility criteria included adults (age ⩾18) treated between 01/2007 and 12/2011, with at least two trabectedin cycles after failure or intolerance to doxorubicin/ifosfamide. Baseline and first computed tomography (CT)-scans were centrally reviewed by an experienced radiologist.ResultsThe retrospective cohort consists of 134 (73 female) patients treated with trabectedin 1.5 mg/m² given as a 24-h infusion every 3 weeks. Patients received a median of five trabectedin cycles (range: 2–33) and the main cause of discontinuation was progressive disease (PD) (n = 105, 78.4%). Response Evaluation Criteria in Solid Tumours (RECIST) assessment was feasible in 128 (95.5%) patients, with Choi assessment performed in 92 (68.7%) patients, generally due to inadequate sequences or exclusive lung metastases. Concordance between both methods was fair (Kappa = 0.290). We identified five patients with false PD (i.e. PD according to RECIST but stable disease/partial response as per Choi). Univariate analysis did not identify any predictive factors for false PD. Median overall survival (OS) of patients with PD as per RECIST but stable disease/partial response (SD/PR) according to Choi was better than for patients with PD according to both RECIST and Choi (14 months versus 8 months; p = 0.052).ConclusionsChoi assessment may identify patients with false PD who achieved improved efficacy outcomes, suggesting that trabectedin may delay tumour progression even in the case of non-dimensional response. Dual size and tumour density assessment may be more suitable to evaluate responses to trabectedin in sarcoma patients as well as to improve the decision-making strategies for the continuation of trabectedin therapy.     

Docetaxel and gemcitabine combination in 133 advanced soft-tissue sarcomas: a retrospective analysis

Advanced soft-tissue sarcomas are usually resistant to cytotoxic agents such as doxorubicin and ifosfamide. Antitumor activity has been observed for gemcitabine and docetaxel combination. We conducted a retrospective study on 133 patients (58 males/75 females) with unresectable or metastatic soft-tissue sarcoma. The median age at diagnosis was 51.7 (18-82), with 76 patients with leiomoyosarcoma and 57 patients with other histological subtypes. The initial localizations were limb (44), uterine (32), retroperitoneal (23) and organs or bone (34). Patients received 900 mg/m2 of gemcitabine (days 1 and 8) over 90 min plus 100 mg/m2 of docetaxel (day 8), intravenously every 21 days. Gemcitabine/docetaxel combination was well tolerated with an overall response of 18.4% and with no clear statistical difference between leiomyosarcomas and other histological subtypes (24.2% versus 10.4% (p=0.06)). No difference was found between uterine soft-tissue sarcomas versus others. The median overall survival was 12.1 months (1-28). Better overall survival was correlated with leiomyosarcoma (p=0.01) and with the quality of the response, even for patients with stable disease (p<10(-4)). No statistical difference was found for the initial localization. Response to treatment and overall survival were better for patients in World Health Organization (WHO) performance status classification (PS) 0 at baseline versus patients in WHO PS-1, 2 or 3 (p=0.023 and p<10(-4), respectively). Gemcitabine/docetaxel combination was tolerable and demonstrated better response and survival for leiomyosarcoma, especially for patients in WHO PS-0 at baseline. For the other histological subtypes, the response was not encouraging, but the survival for patients in response or stable suggests further investigation.     

Primary cardiac sarcomas: A retrospective study of the French Sarcoma Group

IntroductionPrimary cardiac sarcomas (PCS) are rare tumours of dismal prognosis.MethodsData of 124 patients with PCS referred to institutions of the French Sarcoma Group (FSG) from 1977 and 2010 were reviewed.ResultsMedian age was 48.8 years. PCS were poorly-differentiated sarcomas (N = 45, 36.3%), angiosarcomas (N = 40, 32.3%), leiomyosarcomas (N = 16, 12.9%) and others (N = 23, 18.6%). At diagnosis, 100 patients (80.6%) were localised and 24 (19.4%) metastatic. Tumours were located in the right (N = 47, 38.8%), left atrial cavities (N = 45, 37.2%) or encompassed several locations in nine cases (7.4%). Surgery was performed in 81 cases (65.3%). Heart transplant was performed in five patients. Radiotherapy adjuvant (N = 18, 14.5%) or alone (N = 6, 4.8%) was performed in non-metastatic patients only (N = 24, 19.4%). With a median follow-up of 51.2 months, median overall survival (OS) was 17.2 months for the entire cohort, 38.8 months after complete resection versus 18.2 after incomplete resection and 11.2 months in non-resected patients. Radiotherapy was associated with improved progression-free survival (PFS) on multivariate analysis. Chemotherapy was significantly associated with better OS only in non-operated patients but not in operated patients. In non-metastatic patients, surgery (hazard ratio [HR] = 0.42, p < 0.001), male gender (HR = 0.56, p = .032) was associated with better OS and surgery (HR = 0.61; p = .076), radiotherapy (HR = 0.43; p = .004) and chemotherapy (HR = 0.30, p = .003) improved PFS.ConclusionOnly surgical resection is associated with a perspective of prolonged survival. Chemotherapy is associated with a better outcome in non-resected patients.     

Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity

To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.     

19例子宫肉瘤临床分析

目的：探讨子宫肉瘤的诊治经验及预后分析，以改善其生存率。方法：作者对本院近12年来收治的19例子宫肉瘤的组织学类型、临床特点、治疗方法及预后进行分析。结果：该病的主要临床特点为异常阴道流血和子宫增大，并且易局部复发及远处转移，尤以肺转移为主。患者的3年及5年生存率分别为73.3%和41.7%。Ⅰ期与Ⅱ、Ⅲ、Ⅳ期的5年生存率有显著差异（P＜0.05)。术中快速病理学检查可减少误诊率。化疗对改善共预后的效果尚不理想。结论：子宫肉瘤较为罕见，其恶性程度高而预后差。子宫肉瘤主要的治疗方法是全子宫双附件切除辅助盆腔放疗或全身化疗。临床分期是影响子宫肉瘤预后的重要因素。辅助治疗在子宫肉瘤治疗中的作用有等进一步研究。     

65例复发及转移的子宫肉瘤分析

1960年5月至1994年4月，我院共收治153例子宫肉瘤。治疗后65例发生局部复发或远处转移，复发转移率42．5％平均复发转移时间12．9个月，中位时间7个月。76．9％的病人在2年内复发，单纯局部复发23例（354％），单纯远处转移28例（43．1％），局部加远处转移14例（21．5％）。本文分析了复发转移特点及复发有关因素。手术是子宫肉瘤主要治疗手段，术后输以放疗可降低盆腔复发率，尤其是内膜间质肉瘤，而术后加化疗未能降低远处转移率。复发转移与病理类型无关，与病变范围有一定关系。复发后积极治疗对延长病人生命有明显意义。     

A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children's Oncology Group

PurposeTo determine the toxicity, efficacy and pharmacokinetics of trabectedin given over 24 h every 3 weeks to children with recurrent rhabdomyosarcoma, Ewing sarcoma, or non-rhabdomyosarcoma soft tissue sarcomas.Patients and methodsTrabectedin was administered as a 24-h intravenous infusion every 21 days. Two dose levels were evaluated (1.3 and 1.5 mg/m²) for safety; efficacy was then evaluated using a traditional 2-stage design (10 + 10) at the 1.5 mg/m² dose level. Pharmacokinetics (day 1 and steady state) were performed during cycle 1.ResultsFifty patients were enroled, eight patients at 1.3 mg/m² and 42 at 1.5 mg/m². Dose limiting toxicities (DLTs) in the dose finding component included fatigue and reversible GGT elevation in 1/6 evaluable patients at 1.3 mg/m² and 0/5 at 1.5 mg/m². Efficacy was evaluated in 42 patients enroled at the 1.5 mg/m² dose of whom 22% experienced reversible grade 3 or 4 toxicities that included AST, ALT, or GGT elevations, myelosuppression and deep venous thrombosis.One patient with rhabdomyosarcoma had a partial response and one patient each with rhabdomyosarcoma, spindle cell sarcoma and Ewing sarcoma had stable disease for 2, 3 and 15 cycles, respectively.ConclusionTrabectedin is safe when administered over 24 h at 1.5 mg/m². Trabectedin did not demonstrate sufficient activity as a single agent for children with relapsed paediatric sarcomas.     

肾母细胞瘤369例回顾性分析

目的探讨肾母细胞瘤综合治疗方法,以期进一步提高存活率并改善生存质量。方法对１９５５～１９９６年３６９例肾母细胞瘤进行回顾性分析和随访,根据年代方法不同分为三个阶段。结果第一阶段１９５５～１９７２年以手术治疗为主,部分病人加放疗,４年无瘤存活率为２８．７％。第二阶段１９７３～１９８９年全组病人虽加用化疗,但仅有５３％（１０６/２００）完成全程规律化疗,４年无瘤存活率为６２．６％。第三阶段１９９０～１     

Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study

BACKGROUND: Previous studies have suggested that trabectedin (ecteinascidin-743) could have antitumour activity in soft-tissue sarcoma. We aimed to study the usefulness of trabectedin in the treatment of patients with myxoid liposarcomas, a subtype of liposarcoma that is associated with specific chromosomal translocations t(12;16)(q13;p11) or t(12;22)(q13;q12) that result in the formation of DDIT3-FUS or DDIT3-EWSR1 fusion proteins. METHODS: 51 patients with advanced pretreated myxoid liposarcoma who started treatment with trabectedin between April 4, 2001, and Sept 18, 2006 at five institutions in a compassionate-use programme were analysed retrospectively. Centralised radiological and pathological reviews were done for most patients. Trabectedin was given either as a 24-h continuous infusion or as a 3-h infusion, every 21 days, at 1.1-1.5 mg(2). 558 courses of trabectedin were given in total, with a median of ten courses for each patient (range 1-23). The primary endpoints were response rate and progression-free survival, and the secondary endpoint was overall survival. FINDINGS: According to Response Evaluation Criteria in Solid Tumors (RECIST), after a median follow-up of 14.0 months (IQR 8.7-20.0), two patients had complete responses (CR) and 24 patients had partial responses (PR); the overall response was 51% (95% CI 36-65). Five patients had early progressive disease. In 17 of the 23 patients who achieved PR or CR as defined by RECIST and who had centralised radiological review, tissue-density changes, consisting of a decrease in tumour density on CT scan or a decrease in contrast enhancement on MRI (or both), preceded tumour shrinkage. Median progression-free survival was 14.0 months (13.1-21.0), and progression-free survival at 6 months was 88% (79-95). INTERPRETATION: Trabectedin was associated with antitumour activity in this series of patients with myxoid liposarcoma. The noted patterns of tumour response were such that tissue density changes occurred before tumour shrinkage in several patients. In some patients, tissue-density changes only were seen. Long-lasting tumour control was noted in responsive patients. The compassionate-use programme is still ongoing. This analysis has resulted in the initiation of two prospective studies to assess the role of trabectedin in the treatment of patients with myxoid liposarcoma in preoperative and metastatic settings. Furthermore, the selective mechanism of action for trabectedin in this translocation-related sarcoma is being studied.     

Cimetidine enhancement of cyclophosphamide antitumour activity.

Male DBA2 mice were given 10(6) P-388 leukaemic cells i.p. and cimetidine (CMT) at 100 mg/kg 1 day for 10 days, or as a single 100 mg/kg injection 30 min before cyclophosphamide (CTX). CMT significantly prolonged the survival of groups of mice receiving 50, 100 and 200 mg/kg of CTX 3 days after tumour inoculation. Median survival increased by 5.5 days (P less than 0.05), 10 days (P less than 0.05) and 13 days (P less than 0.05) respectively. The addition of CMT had the effect of roughly doubling the CTX dose, without increasing the lethality. CMT produced the only long-term survival seen in the study (1-2/10) CMT alone had no apparent antitumour activity. CMT significantly prolonged mean pentobarbital sleep to 28.6-60 min vs only 10 min for phenobarbital treated mice. Both CMT regimens increased the plasma concentration time products for CTX-induced metabolites (NBP) by about 1.3 fold (in contrast to a 33% reduction with phenobarbital). On average the single-dose CMT regimen produced the greatest effect on survival, on pentobarbital sleep duration and on total NBP reactive species. Probable mechanisms for the CMT-CTX interaction include competitive microsomal enzyme inhibition and/or acutely depressed hepatic blood flow. Caution should be used in combining CMT with full doses of CTX and any other highly metabolized antineoplastic agents in man.     

Surgical treatment of pulmonary metastases from soft tissue sarcomas: A retrospective study in the Netherlands

Sixty-seven of 87 patients with soft tissue sarcoma underwent complete resection of the metastases in the lung. In this retrospective study, follow-up was for a median of 24 months. The 5-year overall, crude, and disease-free survival was 38%, 45%, and 41%, respectively. Twentyseven (40%) patients developed a recurrence in the lung. Of the six prognostic variables, the only factor significantly related to disease-free survival was grade. It is concluded that surgery for lung metastases of soft tissue sarcoma should be considered as standard therapy when preoperative evaluation predicts a complete resection. By adding chemotherapy to surgery, an improvement of prognosis probably can be achieved. © 1994 Wiley-Liss, Inc.     

A retrospective analysis of morphological tests in patients with interstitial cystitis

Cystoscopy, hydrobougieurage and biopsy of the urinary bladder were made in 80 female patients with interstitial cystitis (IC) aged 23-68 years. Endoscopic changes were estimated by an original scale. The analysis of the endoscopic findings revealed a correlation between duration of the process, cystoscopic picture and histopathological evidence. Clinical and cystoscopic pictures provide significant information on morphological changes in the wall of the urinary bladder depending on the disease stage. Histological study of urinary bladder biopsies in IC is used rather for excluding other diseases of the urinary bladder with similar clinical symptoms (primarily cancer and tuberculosis).     

N-methylformamide: antitumour activity and metabolism in mice.

The antitumour activities of N-methylformamide, N-ethylformamide and formamide against a number of murine tumours in vivo (Sarcoma 180, M5076 ovarian sarcoma and TLX5 lymphoma) have been estimated. In all cases N-methyl-formamide had significant activity, formamide had marginal or no activity and N-ethylformamide had no significant activity. N-methylformamide and N-ethylformamide were equitoxic to the TLX5 lymphoma in vitro. Formamide was found as a metabolite in the plasma and urine of animals given N-methylformamide and N-ethylformamide, but excretion profiles do not support the hypothesis that formamide is an active antitumour species formed from N-alkylformamides. No appreciable metabolism of N-methylformamide occurred under a variety of conditions with liver preparations in vitro. N-methylformamide, but not N-ethylformamide or formamide, reduced liver soluble non-protein thiols by 59.8% 1 h after administration of an effective antitumour dose.