Hideshi Sugiura

Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study.

BACKGROUNDnTrabectedin binds to the minor groove of DNA and blocks DNA repair machinery. Preclinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas. We aimed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma.nnnMETHODSnWe did a multicentre randomised open-label study in Japan. Eligible patients had pathological diagnosis of translocation-related sarcoma, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than four previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0 or 1, adequate bone marrow reserve, renal and liver functions, and had measurable lesions. Patients were randomly assigned (1:1) by the minimisation method to receive either trabectedin (1·2 mg/m(2) given via a central venous line over 24 h on day 1 of a 21 day treatment cycle) or best supportive care, which was adjusted centrally by pathological subtype. Investigators, patients, and the sponsor were unmasked to the treatment assignment. Progression-free survival and objective responses were assessed by a masked central radiology imaging review. Efficacy was assessed by masked central radiology imaging review. The primary endpoint was progression-free survival for the full analysis set population. Follow-up is ongoing for the patients under study treatment. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI-121850.nnnFINDINGSnBetween July 11, 2012, and Jan 20, 2014, 76 patients were enrolled and allocated to receive either trabectedin (n=39) or best supportive care (n=37). After central review to confirm pathological subtypes, 73 patients (37 in the trabectedin group and 36 in the best supportive care group) were included in the primary efficacy analysis. Median progression-free survival of the trabectedin group was 5·6 months (95% CI 4·1-7·5) and the best supportive care group was 0·9 months (0·7-1·0). The hazard ratio (HR) for progression-free survival of trabectedin versus best supportive care was 0·07 (90% CI 0·03-0·14 and 95% CI 0·03-0·16) by a Cox proportional hazards model (p<0·0001). The most common drug-related adverse events for patients treated with trabectedin were nausea (32 [89%] of 36), decreased appetite (21 [58%]), decreased neutrophil count (30 [83%]), increased alanine aminotransferase (24 [67%]), and decreased white blood cell count (20 [56%]).nnnINTERPRETATIONnTrabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population.nnnFUNDINGnTaiho Pharmaceutical Co., Ltd.

Inflammatory reaction in chondroblastoma

Abstractu2002Objective. The objective of this study was to evaluate the inflammatory reaction accompanying chondroblastoma and to define the value of the finding in clinical practice. Design. We reviewed the clinical, radiographic, and magnetic resonance (MR) findings in six patients with histologically proven chondroblastoma. Results. In all cases, MR imaging showed marrow and soft tissue edema. In four of six cases, periosteal reaction related to intra-osseous edema was more clearly demonstrated on MR imaging than on radiographs. Follow-up MR studies after surgery were available in three patients and all showed disappearance of inflammatory responses such as marrow and soft tissue edema, and reactive synovitis. Conclusion. We propose that these inflammatory reactions of chondroblastomas are important signs for detecting residual tumor in recurrences after surgery, as well as for making a precise diagnosis. The MR changes may also be valuable in demonstrating eradication of the tumor.

The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study.

Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large‐scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real‐life, postmarketing surveillance data.

A randomized, double-blind, placebo-controlled, Phase III study of pazopanib in patients with soft tissue sarcoma: results from the Japanese subgroup

Abstract Objective This analysis of the Japanese subpopulation of the PALETTE Phase III, randomized, placebo-controlled study investigated efficacy and safety of pazopanib in patients with metastatic soft tissue sarcoma after failure of standard chemotherapy. Methods Patients were randomly assigned in a 2:1 ratio to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Primary endpoint was progression-free survival. Secondary endpoints included overall survival and overall response rate. Efficacy analysis was by intent-to-treat. Safety was also investigated. Results Forty-seven patients received either pazopanib (n = 31) or placebo (n = 16). Median progression-free survival was 7.0 weeks (95% confidence interval: 4.0–11.7) for placebo and 24.7 weeks (95% confidence interval: 8.6–28.1) for pazopanib (hazard ratio = 0.41 [95% confidence interval: 0.19–0.90]; P = 0.002). Median overall survival was 14.9 months (95% confidence interval: 6.8—not calculable) for placebo and 15.4 months (95% confidence interval: 7.9–28.8) for pazopanib (hazard ratio = 0.87 [95% confidence interval: 0.41–1.83]; P = 0.687). More patients receiving pazopanib experienced best response of stable disease versus placebo. Adverse events were similar to the global population; those leading to dose reduction were more common and mean daily dose was lower in the Japanese population versus the global population (45 vs. 32% and 624.4 vs. 700.4 mg, respectively). Conclusions The efficacy and safety of pazopanib observed in the Japanese subpopulation of PALETTE were similar to those in the global population. Pazopanib is a new treatment option for Japanese patients with metastatic non-adipocytic soft tissue sarcoma after chemotherapy. Clinical trial Registration number NCT00753688; GSK study ID: VEG110727; http://www.gsk-clinicalstudyregister.com/study/VEG110727#ps.

Phase 2 study of eribulin in patients with previously treated advanced or metastatic soft tissue sarcoma

Objective: Eribulin, a microtubule dynamics inhibitor, is approved for the treatment of patients with breast cancer and soft tissue sarcoma. We investigated the efficacy and safety of eribulin in Japanese patients with soft tissue sarcoma. Methods: This open‐label, multicenter, nonrandomized, Phase 2 study enrolled Japanese patients with measurable, advanced/metastatic soft tissue sarcoma of high/intermediate grade and ≥1 prior chemotherapy for advanced disease. Patients received eribulin mesilate 1.4 mg/m2 intravenously over 2‐5 minutes on Days 1 and 8 of a 21‐day cycle. The primary endpoint was progression‐free rate at 12 weeks. Secondary endpoints included overall survival, progression‐free survival and safety. Efficacy analyses were stratified by histology (liposarcoma or leiomyosarcoma, and other subtypes). Results: Overall, 52 patients were enrolled and 51 patients were treated. Patients with liposarcoma/leiomyosarcoma (n = 35) had similar characteristics to those with other subtypes (n = 16), except for a higher proportion of women (63% vs 38%, respectively) and patients with Eastern Cooperative Oncology Group performance status 0 (57% vs 44%). Progression‐free rate at 12 weeks was 60% in liposarcoma/leiomyosarcoma patients, 31% in other subtypes and 51% overall. Median progression‐free survival was 5.5 months in liposarcoma/leiomyosarcoma patients, 2.0 months in other subtypes and 4.1 months overall. Median overall survival was 17.0 months in liposarcoma/leiomyosarcoma patients, 7.6 months in other subtypes and 13.2 months overall. The most common Grade 3‐4 adverse events were neutropenia (86%), leukopenia (75%), lymphopenia (33%), anemia (14%) and febrile neutropenia (8%). Conclusion: Eribulin showed clinical activity with a manageable safety profile in previously treated Japanese patients with advanced/metastatic soft tissue sarcoma.

Atypical and malignant granular cell tumors in Japan: a Japanese Musculoskeletal Oncology Group (JMOG) study

BackgroundMalignant granular cell tumors (MGCTs) are extremely rare neoplasms with only a limited number of studies published to date. The aim of this study is to elucidate the clinicopathological characteristics and prognostic factors of MGCTs.MethodsThis is a multi-institutional retrospective study of MGCTs with a central pathological review. A total of 18 cases were retrieved. Specimens were blindly reviewed by two pathologists based on the diagnostic criteria by Fanburg-Smith et al. Kaplan–Meier survival probabilities were calculated, and risk factors for poor prognosis were evaluated.ResultsThree and fifteen cases were diagnosed as atypical GCTs (AGCTs) and mGCTs according to the Fanburg-Smith et al. classification, respectively. Four (one atypical and three malignant) cases had metastasis at the first presentation, including lymph node metastasis. Three out of ten cases treated with wide resection developed local recurrence. Although prolonged static disease periods of ≥1xa0year were observed in four cases receiving chemotherapy, all cases with local recurrence or metastasis, including two atypical cases, eventually died of disease. The 5- and 10-year overall survival rates for localized MGCTs were 69.2 and 34.6xa0%, respectively. The presence of necrosis was revealed as a risk factor associated with adverse clinical outcomes.ConclusionsMGCTs have high rates of recurrence and metastasis including lymph node metastasis. As histologically atypical cases also have metastatic potential, close attention should be paid to AGCTs. The combination of histological evaluation and tumor size may lead to more accurate diagnosis of this rare neoplasm.

Non-rigid reconstruction of chest wall defects after resection of musculoskeletal tumors

PurposeWe analyzed the techniques used and the complications occurring in chest wall reconstruction after resection of musculoskeletal tumors to identify the optimal reconstruction method.MethodsThe medical records of 50 patients with primary or metastatic malignant tumors requiring chest wall full thickness resection were retrospectively reviewed. The surgical technique and rate of postoperative complications were investigated, and the factors influencing complications were identified.ResultsFlap transfer was used in 23 cases (46xa0%). For skeletal reconstruction, a prosthetic mesh was used in 19 cases. In 18 recent cases, no prosthetic mesh was used, and patients were treated using only suture stabilization. Postoperative complications were recognized in 11 cases (22xa0%). The analysis of factors influencing the development of complications identified the use of preoperative adjuvant chemotherapy (pxa0<xa00.05), the bone as the primary site (pxa0<xa00.05), an anterolateral location (pxa0=xa00.081) and resection of ≥3 ribs (pxa0=xa00.077) as significant factors. No significant difference in the rate of complications was noted between the groups divided based on whether mesh was used.ConclusionWe used non-rigid reconstruction for full thickness resection of the chest wall, and achieved good postoperative outcomes with no grade 4 complications or perioperative mortality. Non-rigid reconstruction using flap transfers and careful respiratory management is a useful method for treating patients requiring chest wall full thickness resection.

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

AIMnOur 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.nnnPATIENTS AND METHODSnThis was a single-arm study of the BSC patients of the randomised study in whom disease progressed. Trabectedin (1.2 mg/m(2)) 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.nnnRESULTSnThirty 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.nnnCONCLUSIONnTrabectedin 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.

Results of sub-analysis of a phase 2 study on trabectedin treatment for extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma

BackgroundTrabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase 2 study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted, which showed clinical benefit of trabectedin compared with best supportive carexa0(BSC). Extraskeletal myxoid chondrosarcoma (EMCS) and Mesenchymal chondrosarcoma (MCS) are very rare malignant soft tissue sarcomas, and are associated with translocations resulting in fusion genes. In addition, the previous in vivo data showed that trabectedin affect tumor necrosis and reduction in vascularization in a xenograft model of a human high-grade chondrosarcoma. The aim of the present analysis was to clarify the efficacy of trabectedin for EMCS and MCS subjects in the randomized phase 2 study.MethodsFive subjects with EMCS and MCS received trabectedin treatment in the randomized phase 2 study. Three MCS subjects were allocated to the BSC group. Objective response and progression-free survival (PFS) were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by central radiology imaging review.ResultsThe median follow-up time of the randomized phase 2 study was 22.7xa0months, and one subject with MCS was still receiving trabectedin treatment at the final data cutoff. The median PFS was 12.5xa0months (95 % CI: 7.4–not reached) in the trabectedin group, while 1.0xa0months (95 % CI: 0.3–1.0xa0months) in MCS subjects of the BSC group. The six-month progression-free rate was 100xa0% in the trabectedin group. One subject with MCS showed partial response, and the others in the trabectedin group showed stable disease. Overall survival of EMCS and MCS subjects was 26.4xa0months (range, 10.4–26.4xa0months) in the trabectedin group. At the final data cutoff, two of five subjects were still alive.ConclusionsThis sub-analysis shows that trabectedin is effective for patients with EMCS and MCS compared with BSC. The efficacy results were better than previously reported data of TRS. These facts suggest that trabectedin become an important choice of treatment for patients with advanced EMCS or MCS who failed or were intolerable to standard chemotherapy.Trial registrationThe randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).

Efficacy of Trabectedin in Patients with Advanced Translocation‐Related Sarcomas: Pooled Analysis of Two Phase II Studies

This analysis updates the results of two phase II studies of translocation‐related sarcomas to evaluate the efficacy of trabectedin against histological subtype and analyze overall survival.