Presentation and outcome of frequent and rare sarcoma histologic subtypes: A study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers.

BACKGROUND: The objective of this study was to describe characteristics at diagnosis and outcomes of adults with soft tissue sarcoma. METHODS: The authors conducted a retrospective multicenter study of 12,262 patients who were treated between January 1980 and 31 December 2013 in French Sarcoma Group centers and enrolled in the "Conticabase." Diagnoses were systematically reviewed by expert pathologists, and entities were classified according to the 2013 World Health Organization classification. Diagnostic characteristics, treatments, and outcomes are described for the entire cohort, for the subgroup of patients with translocation-related sarcomas, and for 9 different histologic subtypes. RESULTS: The results stressed the magnitude of heterogeneity among adult sarcomas. For example, compared with other sarcomas, translocation-related sarcomas (2143 tumors; 20.8%) were associated with a younger age at presentation (40.6 vs 60.0 years; P < .0001), a low rate of predisposing conditions (0.01% vs 22.3%; P < .0001), a higher rate of lymph node involvement (4.7% vs 1.3%; P < .0001), and a higher rate of synchronous metastasis (11.9% vs 6.7%; P < .001); and complete (R0) resection (41.6% vs 31.9%; P < .0001), receipt of (neo)adjuvant radiation therapy (62.6% vs 42.2%; P < .0001), and receipt of (neo)adjuvant chemotherapy (36.6% vs 22.3%; P < .0001) were significantly more frequent. Overall, translocation-related sarcomas were associated with a lower rate of local relapse (18.1% vs 26.0%; P < .0001) but a higher rate of metastatic relapse (42.0% vs 30.7%; P < .0001). CONCLUSIONS: Collaborative efforts are urgently needed to better assess the natural history and management options for every histologic subtype of sarcoma. Cancer 2018;124:1179-87. © 2017 American Cancer Society.

Translocation-Related Sarcomas.

Chromosomal translocations are observed in approximately 20% of soft tissue sarcomas (STS). With the advances in pathological examination technology, the identification of translocations has enabled precise diagnoses and classifications of STS, and it has been suggested that the presence of and differences in translocations could be prognostic factors in some translocation-related sarcomas. Most of the translocations in STS were not regarded as targets of molecular therapies until recently. However, trabectedin, an alkylating agent, has shown clinical benefits against translocation-related sarcoma based on a modulation of the transcription of the tumor's oncogenic fusion proteins. Many molecular-targeted drugs that are specific to translocations (e.g., anaplastic lymphoma kinase and tropomyosin kinase related fusion proteins) have emerged. The progress in gene technologies has allowed researchers to identify and even induce new translocations and fusion proteins, which might become targets of molecular-targeted therapies. In this review, we discuss the clinical significance of translocation-related sarcomas, including their diagnoses and targeted therapies.

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

BACKGROUND: Trabectedin is reported as effective, especially against translocation-related sarcomas (TRSs) after failure of or intolerance to standard chemotherapy. We conducted two phase II studies of TRS, confirming high efficacy of 1.2 mg/m2 trabectedin. The updated data of 66 patients in these studies was integrated to evaluate the efficacy of trabectedin against each histological subtype, and analyze final overall survival (OS). METHODS: Trabectedin was administered on day one of a 21-day cycle. Efficacy was assessed using progression-free survival (PFS), OS, and best overall response. An analysis of OS and PFS was performed for subgroups divided by baseline lymphocyte count (<1,000/µL, ≥1,000/µL) or number of previous chemotherapy regimens (0, 1, 2, ≥3 regimens), and a Weibull parametric model was used to estimate the numerical relationship between lymphocyte count and PFS and OS. RESULTS: Median PFS and OS in overall patients were 5.6 (95% confidence interval [CI]: 4.1-7.3) and 17.5 months (95% CI: 12.6-23.6), respectively. PFS in the myxoid and round-cell liposarcoma (MRCL) group (7.4 months [95% CI: 5.6-11.1]) was longer than in the other subtypes. The response rate was also highest in the MRCL group. Median OS was longer in patients with baseline lymphocyte counts ≥1,000/µL than in those with counts of <1,000/µL, but median PFS was not different between the two subgroups. CONCLUSION: Our updated and pooled data showed that trabectedin exerted prolonged disease control and antitumor effects in patients with advanced TRS, especially in MRCL. We consider that the subgroup analyses also provide important information for trabectedin treatment in patients with TRS. IMPLICATIONS FOR PRACTICE: The progression-free survival (PFS) for the integrated data of 66 patients with translocation-related sarcomas (TRSs) in two phase II studies of trabectedin 1.2 mg/m2 was 5.6 months (95% confidence interval: 4.1-7.3). PFS and response rate in myxoid/round-cell liposarcoma was longer than that of other subtypes. The overall survival (OS) in all TRS subtypes was similar to previous data of TRS patients. In subgroup analysis, the patients with baseline lymphocyte count ≥1,000/µL exhibited better OS, although PFS was not different by baseline lymphocyte count. Our data are considered important information for trabectedin treatment in TRS patients.

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

BACKGROUND: Trabectedin 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 care (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. METHODS: Five 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. RESULTS: The median follow-up time of the randomized phase 2 study was 22.7 months, and one subject with MCS was still receiving trabectedin treatment at the final data cutoff. The median PFS was 12.5 months (95 % CI: 7.4-not reached) in the trabectedin group, while 1.0 months (95 % CI: 0.3-1.0 months) in MCS subjects of the BSC group. The six-month progression-free rate was 100 % 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 26.4 months (range, 10.4-26.4 months) in the trabectedin group. At the final data cutoff, two of five subjects were still alive. CONCLUSIONS: This 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 REGISTRATION: The randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).

Translocation in bone and soft tissue sarcomas: a comprehensive epidemiological investigation.

BACKGROUND: Limited epidemiological research has focused on translocations in soft tissue sarcomas, with no studies on bone sarcomas. This study aimed to clarify the epidemiology, prognosis, and genetic information of translocation-related sarcoma (TRS) and non-TRS patients. MATERIALS AND METHODS: This retrospective cohort study used data from the Bone and Soft Tissue Tumor Registry in Japan (BSTTRJ) (2001-2019), the Kyushu University Hospital (KUH) repository (2001-2021), and a publicly available online dataset (MSK). The patients were categorized into TRS and non-TRS groups, and epidemiological, prognostic, and mutational diversity were compared. RESULTS: This study included 25 383 participants, of whom 4864 (19.2%) were TRS and 20 519 (80.8%) were non-TRS patients. TRS patients had significantly younger onset ages (median: 43 years, interquartile range: 29-59 years) than non-TRS patients (median: 63 years, interquartile range: 46-73 years). In the MSK cohort, microsatellite instability and tumor mutation burden scores in non-TRS were higher than in TRS, although they were rather low compared with the pan-cancer analysis. In the BSTTRJ cohort, survival analyses with the propensity score matching revealed that patients with TRS had better overall [hazard ratio (HR): 0.71, 95% confidence interval (CI) 0.63-0.81], metastasis-free (HR: 0.75, 95% CI 0.67-0.84), and recurrence-free (HR: 0.47, 95% CI 0.39-0.57) survival. CONCLUSIONS: This study highlights differences in the epidemiology and genetic rearrangements of sarcoma.

Long lasting response with trabectedin monotherapy in relapsed metastatic mesenchymal chondrosarcoma.

BACKGROUND: Mesenchymal chondrosarcoma is an exceedingly rare malignancy, accounting for around 5% of all patients with chondrosarcoma. It is a translocation-related sarcoma that tends to have both local and distant recurrences. Surgery is the mainstay of treatment in localised cases however treatment of advanced cases remains a challenge. The rarity of the disease precludes dedicated clinical trials and hence guidelines for its management are not well defined. The dearth in literature makes it pertinent that the cases treated with newer therapies must be reported to contribute to existing knowledge. CASE PRESENTATION: We hereby report a case of a 39-year old male without any comorbidity presenting with pelvic pain and was diagnosed as mesenchymal chondrosarcoma of the pelvis. He underwent an initial curative resection followed by a disease-free interval of 7 months. Subsequently, he was treated with pulmonary metastatectomy and local debulking surgery at time of initial relapse. He was then exposed to multiple lines of palliative chemotherapy, which limited our treatment options upon subsequent disease progression. Based on recent data, the patient was given trabectedin monotherapy as fourth line chemotherapy. He tolerated the therapy well and attained a progression-free survival of 12 months, which is an impactful figure in relapsed setting in this patient population. CONCLUSION: This report aims to present a comprehensive review into available and newer treatment choices for mesenchymal chondrosarcoma, and to highlight trabectedin monotherapy as a possible therapeutic option for mesenchymal chondrosarcoma in the relapsed setting.

Retrospective Analysis of Trabectedin Therapy for Soft Tissue Sarcoma.

BACKGROUND/AIM: Trabectedin is a synthetic antineoplastic agent approved for advanced soft tissue sarcoma (STS) in Japan. The aim of this study was to evaluate the efficacy and safety of the Japan-approved dose of trabectedin for advanced STS. PATIENTS AND METHODS: We retrospectively reviewed 38 patients with advanced STS who received salvage chemotherapy with trabectedin. RESULTS: The overall response and disease control rates were 16% (5 patients) and 67% (20 patients), respectively. The median progression-free and overall survival were 7.3 and 17.8 months, respectively. There were no significant differences between patients with liposarcoma or leiomyosarcoma and those without, or between patients with TRS and those without. The most common grade 3-4 AEs were elevated transaminases and neutropenia. CONCLUSION: Trabectedin 1.2 mg/m2, as the approved dose in Japan, showed similar efficacy to the dose of 1.5 mg/m2 used in Western countries. Trabectedin could be an option for advanced STS in Japan, regardless of histological subtype.

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.

Diagnostic use of fluorescence in situ hybridization in expert review in a phase 2 study of trabectedin monotherapy in patients with advanced, translocation-related sarcoma.

BACKGROUND: Fluorescence in situ hybridization (FISH) is one of the most powerful genetic analysis tools for pathological diagnoses. FISH can detect various genetic abnormalities including gene translocation that was specifically found in translocation-related sarcomas (TRSs). Here, we report the use of FISH in expert review in a phase 2 study of trabectedin monotherapy for patients with advanced TRS. METHODS: TRS patients (n = 76) were enrolled in the trial at 12 study sites after pathological diagnoses were made, including morphological examination with or without evidence of translocation by genetic testing. Following histological reviews of the representative specimens at the study sites, we performed immunohistochemistry using the appropriate antibodies and FISH for genetic confirmation of the tumor types in the expert review. RESULTS: Among the 76 TRS cases, no split signal for SS18 probe was detected by FISH in three synovial sarcoma cases that were diagnosed at the study sites. Malignant peripheral nerve sheath tumor (MPNST) was diagnosed in two cases and sarcomatoid carcinoma in one. One of the cases was a small round cell variant of MPNST. After excluding these three cases, we assessed the other 73. There were no split signals detected in 7 of the 73 cases by FISH analysis, due to decalcification and hyperfixation procedures. Excluding these seven cases, FISH detected translocations in 95 % (63/66) of the study cases with a high sensitivity. CONCLUSIONS: The diagnosis of TRS by FISH was highly sensitive and enabled genetic confirmation of the pathological diagnoses. We strongly recommend FISH as a confirmatory diagnostic test for TRS, which would enable the selection of patients with TRS in whom trabectedin is expected to be effective. This study was done in part that registered with Japan Pharmaceutical Information Center, number JapicCTI-121850.