Toru Hiruma

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

BACKGROUND Trabectedin 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. METHODS We 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. FINDINGS Between 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%]). INTERPRETATION Trabectedin 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. FUNDING Taiho Pharmaceutical Co., Ltd.

Carbon Ion Radiation Therapy for Unresectable Sacral Chordoma: An Analysis of 188 Cases

PURPOSE To evaluate the results of carbon ion radiation therapy administered to 188 patients with unresectable primary sacral chordomas. PATIENTS AND METHODS One hundred eighty-eight patients were treated with carbon ion radiation therapy at a single institute between 1996 and 2013 and retrospectively analyzed. The median age was 66 years. The highest proximal invasion reached past S2 level in 137 patients. The median clinical target volume was 345 cm(3). One hundred six patients received 67.2 gray equivalents (GyE)/16 fractions (fr), 74 patients received 70.4 GyE/16 fr, 7 patients received 73.6 GyE/16 fr, and 1 patient received 64.0 GyE/16 fr. RESULTS The median follow-up period was 62 months (range, 6.8-147.5 months). Seventy percent of patients were followed for 5 years or until death. The 5-year local control, overall survival, and disease-free survival rates were 77.2%, 81.1%, and 50.3%, respectively. Forty-one patients had a local recurrence. Sex, tumor volume, level of proximal invasion, and irradiated dose were unrelated to local control. There was grade 3 toxicity of the peripheral nerves in 6 patients and grade 4 toxicity of the skin in 2 patients. Ambulation remained in 97% of patients. CONCLUSIONS Carbon ion radiation therapy was safe and effective for unresectable chordoma and provided good local control and survival while preserving ambulation.

Changes in physical function after palliative surgery for metastatic spinal tumor: association of the revised Tokuhashi score with neurologic recovery.

Study Design. A retrospective study of patients undergoing palliative surgery for metastatic spinal tumors. Objective. To investigate short-term functional recovery and duration of improvement after palliative surgery, to correlate these outcomes with the revised Tokuhashi score, and to examine the relationship between function and neurologic deterioration. Summary of Background Data. The revised Tokuhashi score is a scoring system used to predict life expectancy for patients with metastatic spinal tumors. The relationship between the revised Tokuhashi score and physical functional improvement after palliative surgery has not been examined previously. Methods. The clinical charts of 86 patients were reviewed. The Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was used to assess physical function. Each score was documented before surgery and at every month after surgery. The duration of ECOG-PS improvement, defined as the period between surgery and deterioration to the preoperative ECOG-PS grade, was correlated with the revised Tokuhashi score. Results. The ECOG-PS grade improved in 44 (51.1%) patients at 1 month postoperative. When ECOG-PS improvement was found after surgery, it persisted above the preoperative level for an average of 9.3 months. At 1 month postoperative, patients scoring 0 to 8 on the total revised Tokuhashi score had significantly lower ECOG-PS improvement (26 of 55 patients) when compared to patients with higher scores (18 of 27 patients, P < 0.05). In 44 patients with ECOG-PS improvement, the existence of major internal organ metastases significantly shortened the duration of improvement (P < 0.05). Conclusion. Palliative surgery benefited half of the patients with metastatic spinal tumor, with a greater probability of benefit found in persons with a higher total revised Tokuhashi score (score 9–15) and/or primary cancers with longer survival times.

Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304)

OBJECTIVE The efficacy of perioperative chemotherapy for soft tissue sarcomas is controversial and only a few prospective studies of pre-operative chemotherapy for soft tissue sarcomas in the extremities have been reported. We therefore carried out Phase II study of perioperative chemotherapy for patients with soft tissue sarcomas in the extremities. METHODS Patients with Stage III non-round cell soft tissue sarcomas in the extremities were eligible. The patients were treated with pre-operative chemotherapy consisting doxorubicin 60 mg/m(2) and ifosfamide 10 g/m(2) for three courses. After the tumor resection, two additional courses of the same regimen were carried out. RESULTS A total of 72 patients were enrolled and 70 patients were eligible. The median age of the patients was 49 years. The major pathological subtypes were synovial sarcoma in 20 and undifferentiated pleomorphic sarcoma in 17 patients. The protocol treatments were completed in 74% of the eligible cases. The 2 and 5-year progression-free survival rates were 75.7% (95% CI, 63.9-84.1%) and 63.8% (95% CI, 51.3-73.9%), respectively. The 5-year overall survival was 82.6% (95% CI, 71.3-89.7%). There was no treatment-related death. Grade 3 or 4 hematological toxicities (leukopenia and neutropenia) were observed in most of the patients. CONCLUSIONS Although the toxicities of the regimen were significant, pre-operative chemotherapy followed by post-operative chemotherapy using doxorubicin and high-dose ifosfamide was feasible. The outcome of the trial for the patients with high-grade soft tissue sarcomas in the extremities was favorable, and this regimen is promising for further investigation. This trial was registered at the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) as C000000096.

Development and external validation of nomograms predicting distant metastases and overall survival after neoadjuvant chemotherapy and surgery for patients with nonmetastatic osteosarcoma: A multi‐institutional study

In this era of individualized cancer treatment, data that could be applied to predicting the survival of patients with osteosarcoma are still limited because of the rarity of the disease and the difficulty in accumulating a sufficient number of patients. Therefore, a multi‐institutional collaboration was implemented to develop and externally validate nomograms that would predict metastasis‐free survival (MFS) and overall survival (OAS) for patients with nonmetastatic osteosarcoma.

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

AIM Our 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 METHODS This 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. RESULTS Thirty 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. CONCLUSION Trabectedin 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.

Clear cell sarcoma‐like tumor of the gastrointestinal tract: A clinicopathological review

To the Editor: Clear cell sarcoma of soft parts (CCS) is a rare melaninproducing soft tissue sarcoma that was originally reported by Enzinger in 1968. Morphological and immunohistochemical features of CCS are similar to those of malignant melanoma. However, CCS is genetically distinct from melanoma as it lacks BRAF mutations, and has EWSR1/ ATF1 or EWSR1/CREB1 fusion transcripts. In 1993, Ekfors et al. reported a case of clear cell sarcoma of the duodenum, which was the first visceral case reported. Following this report, several clear cell sarcomas of visceral cases were reported with a variety of names (including malignant gastrointestinal neuroectodermal tumor, an osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcoma of soft parts). Clear cell sarcoma in the gastrointestinal tract is classified as a poor prognostic subtype of CCS in the World Health Organization Classification of Tumors-Tumors of Soft Tissue and Bone 4th edition. In contrast, it is classified as an independent disease, clear cell sarcoma-like tumor in gastrointestinal tract (CCSLGT) because of its different histological features, immunohistochemical expression, and poor prognosis, as described in Enzinger & Weisss Soft Tissue Tumors 6th edition. To the best of our knowledge, tumors belonging to the CCSLGT category have been reported in 58 cases in the English literature and in one case in the Japanese literature. Herein, we report our CCSLGT case and review 60 cases. The patient was a 32-year-old woman who had no history of malignancy. She visited the hospital because of fever and was diagnosed with anemia. She underwent gastrointestinal endoscopy. Lower gastrointestinal endoscopy revealed a tumor of the transverse colon. On admission, tumor marker levels (CA 19–9, <2.0U/mL; carcinoembryonic antigen [CEA], 1.6 ng/mL) were not elevated. Contrast-enhanced computed tomography showed a poorly enhanced tumor in the transverse colon and lymphadenopathy around the colon. Substantial organ metastasis was not found. Positron emission tomography showed that the tumor had an abnormal accumulation (standard uptake value: 13.7). There was no other abnormal accumulation, except in the lymph nodes. Tumor biopsy showed round to oval cells that were growing in solid sheets. The neoplastic cells contained clear to lightly eosinophilic cytoplasm. The nuclei had small nucleoli. Mitotic activity was brisk. Because the tumor was diagnosed as malignant using biopsy, the patient underwent transverse colon resection and lymphadenectomy. The resected specimen showed a well-circumscribed mass with ulcer formation, having a diameter of 65 40 25mm. On cut section, the tumor was a multinodular tan-gray mass. Pathological analysis showed round to oval cells with a high nucleus to cytoplasm ratio; the cells had grown in solid sheets with an area of short spindle cell proliferation. Some osteoclast-like multinucleated giant cells were identified (Fig. 1a–c). There was no pleomorphism or necrosis. Fifteen mitotic figures were noted per 10 high-power fields (HPFs). There were lymph node metastases around the intestinal tract (6/57). Immunohistochemical staining showed that the tumor cells were positive for S100 protein, vimentin, BCL2, and synaptophysin, focally positive for chromogranin A, CD56, and epithelial membrane antigen (EMA), and negative for AE1/AE3, CAM5.2, leukocyte common antigen, CD34, glial fibrillary acidic protein, c-kit, a-smooth muscle actin, desmin, transducer-like enhancer of split 1, CD99, melan A, human melanoma black 45 (HMB45), and neuron-specific enolase (Fig. 1d). The Ki-67 index was approximately 30%. Fluorescence in situ hybridization (FISH) using a Ewing sarcoma breakpoint region (EWSR) 1 probe showed split signals in 76% of tumor cells. The tumor cells contained EWSR1-ATF1 fusions with exon 11 of EWSR1 fused to exon 5 of ATF1, which were detected using reverse transcription polymerase chain reaction (RTPCR). Therefore, our case was finally diagnosed as clear cell sarcoma-like tumor of the colon. The patient received postoperative adjuvant chemotherapy (ifosfamide and doxorubicin). Recurrence was confirmed as liver metastasis 38 months after resection, and we are currently considering the possibility of further chemotherapy. We reviewed 60 cases that were classified into the CCSLGT category (Table S1). There were 32 male and 28 female patients, with ages ranging from 10 to 85 years (median, 40 years). In terms of clinical findings, abdominal pain, anemia and weight loss were reported in many cases. The tumors ranged from 15 to 150mm (median, 53mm). CCSLGT occurs everywhere in the gastrointestinal tract, but is most frequent in the small intestine (70%). Only seven patients survived for longer than 3 years, including our case, but there are insufficient cases to conclude that CCSLGT have a worse prognosis than CCS (Fig. S1). The frequency of lymph node metastases at the time of diagnosis of CCSLGT was 62% in comparison with 4% for CCS.

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.

Impact of geriatric factors on surgical and prognostic outcomes in elderly patients with soft-tissue sarcoma

Objective Patients aged ≥65 years requiring surgery for soft-tissue sarcoma are a concern in an aging society. We aimed to reveal the association of clinical/geriatric factors with survival period or postoperative events in such patients who underwent surgery. Methods We enrolled patients aged ≥65 years who underwent surgery for localized soft-tissue sarcoma at five institutions. We retrospectively collected clinical/geriatric factors and laboratory data, and analyzed their association with outcomes using univariate and multivariate analyses. Results Among the 202 patients included, mean age at presentation was 73 years. Surgical margin was R0 in 139 patients (69%). The Eastern Cooperative Oncology Group performance status was ≥2 in 15 (7%). Thirty patients (15%) showed thinness (body mass index <18.49 kg/cm2). High-sensitivity-modified Glasgow prognostic score ≥1 was seen in 52 patients (26%). Multivariate analysis showed that R1 surgical margin was significantly correlated with poor sarcoma-specific survival (hazard ratio for R1 vs. R0, 3.17; P = 0.001) and event-free survival (hazard ratio for R1 vs. R0, 2.56; P < 0.001). Higher Eastern Cooperative Oncology Group performance status was significantly associated with poor sarcoma-specific survival (hazard ratio for ≥2 vs. 0 or 1, 2.15; P = 0.038), and higher sensitivity-modified Glasgow prognostic score was significantly associated with poor event-free survival (hazard ratio for ≥1 vs. 0, 1.74; P = 0.046). Severe thinness (body mass index <16.00) was a risk factor for postoperative events (odds ratio for body mass index <16.00 vs. ≥16.00, 8.15, P = 0.010). Conclusions Negative surgical margin was associated with better survival. Coexisting conditions had an impact on outcomes in elderly soft-tissue sarcoma patients.

1422PDINTRA- AND INTER-PATIENT COMPARISON OF EFFICACY BETWEEN TWO PHASE II STUDIES OF TRABECTEDIN (T) IN PATIENTS (PTS) WITH TRANSLOCATION-RELATED SARCOMAS (TRS); A RANDOMIZED COMPARATIVE STUDY (STUDY-C) AND A SINGLE ARM STUDY (STUDY-S)

ABSTRACT Aim: T binds to the minor groove of DNA and blocks DNA repair machinery. In addition, T inhibits interactions of transcription factors with DNA. It has been reported that T is an active drug in TRS pts unresponsive to available chemotherapies with a significant increase in progression-free survival (PFS) and overall survival in study-C (ASCO 2014, Abstract: 10524). For pts with confirmed disease progression in best supportive care (BSC) arm of study-C, study-S as a rescue therapy was conducted to evaluate safety and efficacy of T. Efficacy for pts who were enrolled in both studies and efficacy difference for T between study-C and study-S were evaluated. Methods: Target population of study-C was pts with histologically proven TRS of 14 types and unresponsive or intolerable to standard chemotherapy. After confirmation of disease progression based on image assessments in study-C, pts who were assigned to BSC were enrolled in study-S if they signed a consent form. Pts received T as a 24-hour continuous infusion every 21 days. We analyzed intra-patient comparison between BSC in study-C (BSC/C) and T in study-S (T/S), and inter-patient comparison between T in study-C (T/C) and T/S. We used a multivariate Cox proportional hazard model adjusted by background factors to estimate hazard ratios (HRs) for PFS in these comparisons. Results: In study-C, 76 pts were randomized: 39 in T and 37 in BSC arm. Out of 37 pts in BSC arm of study-C, 31 pts were enrolled in study-S. Number of pts for efficacy analysis of T/C, BSC/C and T/S were 37, 29 and 29 respectively. Median PFS (95% confidence interval) for T/C, BSC/C and T/S were 5.6 month (m) (4.1-7.5), 0.9 m (0.9-1.0), and 7.3 m (2.9 -9.1), respectively. HRs for PFS in intra- (BSC/C vs T/S) and inter-patient (T/C vs T/S) comparison were 0.08 (P Conclusions: PFS was significantly prolonged in T/S compared with BSC/C, and was not different between T/C and T/S. Although contribution to survival is not evaluated, it is expected T could suppress progress of advanced TRS even at the late stage. Disclosure: T. Ueda: I disclose that I have a consultant or advisory relationship with Daiichi-Sankyo Pharmaceutical Co.Ltd.; A. Kawai: I disclose that I have received Honoraria from TAIHO, GSK, MSD and Eisai. All other authors have declared no conflicts of interest.