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Trabectedin

Web Resources: Trabectedin
Recent Research Publications

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Recent Research Publications

Gronchi A, Maki RG, Jones RL
Treatment of soft tissue sarcoma: a focus on earlier stages.
Future Oncol. 2017; 13(1s):13-21 [PubMed] Related Publications
Surgery, with or without radiation therapy, is the standard of care for primary soft tissue sarcoma, with adjuvant/neodjuvant chemotherapy playing a role only in high-risk patients. Chemotherapy is generally the principal treatment modality for locally advanced or metastatic disease. Within this context, newer techniques and promising new treatments are challenging traditional treatment paradigms. For example, identification of histology-specific treatments is leading the field toward individualized care, with better outcomes. Patients over 65 years represent a sizable and largely undertreated sector of the soft tissue sarcoma population, with many being unsuited to receive anthracycline- or ifosfamide-based chemotherapy. First-line treatment options in this population are discussed.

Martín Broto J, Le Cesne A, Reichardt P
The importance of treating by histological subtype in advanced soft tissue sarcoma.
Future Oncol. 2017; 13(1s):23-31 [PubMed] Related Publications
While surgical resection (±radiotherapy) is standard treatment for localized soft tissue sarcomas (STS), chemotherapy is the mainstay for managing locally advanced and metastatic disease. Expanding knowledge of the biologies and sensitivities of STS histotypes, in conjunction with results from a growing collection of retrospective reviews and prospective randomized studies, point to the importance of treating in consideration of histological subtype. Doxorubicin ± ifosfamide continues to be standard first-line therapy for most STS subtypes. Main options for second- or later-line therapy include trabectedin, dacarbazine, gemcitabine combinations, pazopanib and, most recently, eribulin. Using illustrative case studies, treatment options are reviewed for three of the more common STS subtypes - uterine leiomyosarcoma, liposarcoma and synovial sarcoma - with a focus on use of trabectedin.

Demetri GD, Blay JY, Casali PG
Advances and controversies in the management of soft tissue sarcomas.
Future Oncol. 2017; 13(1s):3-11 [PubMed] Related Publications
Intensive clinical research in the sarcoma field has provided insight into the histopathological diversity of soft tissue sarcomas (STS) and led to the introduction of many new agents that promise to play an important role in the management of patients with STS. While an increasing body of scientific data has advanced our knowledge of this complex family of mesenchymal diseases, several controversies remain to be resolved: Is doxorubicin-based therapy still the definitive standard first-line treatment for all patients with unresectable and/or metastatic STS of all subtypes? Is histology-driven therapy beyond gastrointestinal stromal tumors a reality or are we pursuing an unachievable objective? Are we making practical headway in the establishment of sarcoma reference centers? Is it clearly established which is the best parameter to evaluate the efficacy of a new agent in STS?

Monk BJ, Lorusso D, Italiano A, et al.
Trabectedin as a chemotherapy option for patients with BRCA deficiency.
Cancer Treat Rev. 2016; 50:175-182 [PubMed] Related Publications
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.

Sheng JY, Movva S
Systemic Therapy for Advanced Soft Tissue Sarcoma.
Surg Clin North Am. 2016; 96(5):1141-56 [PubMed] Related Publications
Soft tissue sarcomas are rare tumors that present with distant metastasis in up to 10% of patients. Survival has improved significantly because of advancements in histologic classification and improved management approaches. Older agents such as doxorubicin, ifosfamide, gemcitabine, and paclitaxel continue to demonstrate objective response rates from 18% to 25%. Newer agents such as trabectedin, eribulin, aldoxorubicin, and olaratumab have demonstrated improvements in progression-free survival, overall survival, or toxicity profiles. Future studies on treatment of advanced soft tissue sarcoma will continue to concentrate on reducing toxicity, personalization of therapy, and targeting novel pathways.

De Sanctis R, Marrari A, Santoro A
Trabectedin for the treatment of soft tissue sarcomas.
Expert Opin Pharmacother. 2016; 17(11):1569-77 [PubMed] Related Publications
INTRODUCTION: Trabectedin, a marine-derived DNA-binding antineoplastic agent, has been registered by the EMA and recently also by the FDA for the treatment of patients with advanced soft-tissue sarcoma (STS), a rare and heterogeneous disease.
AREAS COVERED: The antitumor activity of trabectedin is related both to direct effects on cancer cells, such as growth inhibition, cell death and differentiation, and indirect effects related to its anti-inflammatory and anti-angiogenic properties. Furthermore, trabectedin is the first compound that targets an oncogenic transcription factor with high selectivity in mixoid liposarcomas. This peculiar mechanism of action is the basis of its clinical development. The clinical pharmacology of trabectedin, the subsequent phase I, II and III trials are summarized and put into perspectives in this review.
EXPERT OPINION: Trabectedin is a relevant pleiotropic antitumoral agent within the complex scenario of the management of STS. It can be used in advanced STS, either after failure of anthracyclines and ifosfamide or in patients unfit for these drugs, especially when reaching a high-tumor control and a long-term benefit is a priority. Toxicity profile is acceptable and manageable with no reported cumulative toxicities. Therefore, trabectedin has become one relevant therapeutic option in metastatic STS, especially in selected histologies.

Sugita S, Asanuma H, Hasegawa T
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.
Diagn Pathol. 2016; 11:37 [PubMed] Free Access to Full Article Related Publications
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.

Manji GA, Schwartz GK
Managing Liposarcomas: Cutting Through the Fat.
J Oncol Pract. 2016; 12(3):221-7 [PubMed] Related Publications
Liposarcomas are one of the most common of more than 50 histologic subtypes of soft tissue sarcomas that, themselves, are heterogeneous. Liposarcomas fall into four distinct histologic subtypes: atypical lipomatous tumor/well-differentiated liposarcoma, dedifferentiated liposarcoma, myxoid (round cell) liposarcoma, and pleomorphic liposarcoma. Definitive treatment remains surgical resection with negative margins for resectable disease. However, well-differentiated liposarcomas that are large or difficult to operate upon should be followed with close surveillance as long as there is no radiologic concern for a dedifferentiated component. In contrast, first-line chemotherapy with anthracycline with or without ifosfamide, or gemcitabine and docetaxel should be used for inoperable myxoid (round cell) or pleomorphic liposarcomas, which are relatively responsive to chemotherapy. In the second- and third-line setting, myxoid liposarcomas, in particular, seem to be sensitive to trabectedin, which was recently approved by the US Food and Drug Administration (FDA). Eribulin offered a survival benefit when compared with dacarbazine in the third-line setting in liposarcomas (other than the well-differentiated subtype) and is now FDA approved. Recent studies have identified distinct genetic aberrations that not only aid in the diagnosis of liposarcoma subtypes but represent actionable targets. Cyclin-dependent kinase 4 and murine double minute 2 are overexpressed in well-differentiated and dedifferentiated liposarcomas and offer opportunities that are being pursued in clinical trials. It is critical that liposarcomas are not approached by oncologists as one disease entity but rather subclassified into distinct subtypes using histologic and molecular tools before formalizing a treatment plan.

Kus T, Aktas G, Kalender ME, et al.
Complete response of a recurrent-metastatic liposarcoma with dedifferentiated histological features following the administration of trabectedin and review of literature.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):974-6 [PubMed] Related Publications
The present case report defines a rare case of a liposarcoma with bone metastasis resulting in a complete remission (CR) following trabectedin treatment. The patient was referred with abdominal swelling and pain. A retroperitoneal mass was detected and described as dedifferentiated liposarcoma (DDLS). The mass was surgically removed and consequently adjuvant chemotherapy was administered. Three months after the completion of chemotherapy, patient presented with bone metastasis in thoracic and lumbar vertebrae. Vertebroplasty and radiotherapy (RT) was performed. After these therapies, bone pain persisted and bone scintigraphy showed increased activity in L4, T11, and T12 vertebrae. Zoledronic acid was added to trabectedin treatment. CR has been detected on bone scintigraphy and positron emission tomography-computed tomography (PET-CT) after 18 weeks. Previous cases about liposarcoma treated with trabectedin were mostly about the myxoid/round cell type (former name, currently known as myxoid liposarcoma (MLS)) and mostly reported partial responses. In this study, trabectedin was used for the treatment of a metastatic retroperitoneal DDLS and a CR was achieved.

Araki N, Takahashi S, Sugiura H, et al.
Retrospective inter- and intra-patient evaluation of trabectedin after best supportive care for patients with advanced translocation-related sarcoma after failure of standard chemotherapy.
Eur J Cancer. 2016; 56:122-30 [PubMed] Related Publications
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.

Issels R, Kampmann E, Kanaar R, Lindner LH
Hallmarks of hyperthermia in driving the future of clinical hyperthermia as targeted therapy: translation into clinical application.
Int J Hyperthermia. 2016; 32(1):89-95 [PubMed] Related Publications
Regional hyperthermia is described as a targeted therapy and the definitions of six hallmarks of hyperthermia are proposed, representing the pleiotropic effect of this therapeutic modality to counteract tumour growth and progression. We recommend the considerations of these hallmarks in the design of clinical trials involving regional hyperthermia as targeted therapy. Randomised clinical studies using loco-regional hyperthermia as an adjuvant to radiotherapy or to chemotherapy for locally advanced tumours demonstrate the benefit of the combination compared to either of the standard treatments alone for tumour response, disease control, and patient survival outcome. These impressive results were obtained from proof-of-concept trials for superficial or deep-seated malignancies in unselected patients. None of these trials was designed as tailored approaches for the treatment of specified targets or to select potentially more sensitive subpopulations of patients using eligibility criteria. Based upon clinical examples of targeted chemotherapy, some guidelines are described for the successful development of targeted therapeutic combinations. We also retrospectively analyse the stepwise process of generating an ongoing new clinical trial using hyperthermia as targeted therapy to evade DNA repair in combination with a DNA damaging anticancer agent to implement this new vision.

Angarita FA, Cannell AJ, Abdul Razak AR, et al.
Trabectedin for inoperable or recurrent soft tissue sarcoma in adult patients: a retrospective cohort study.
BMC Cancer. 2016; 16:30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Trabectedin is an antineoplastic agent used for patients with soft tissue sarcoma (STS) who fail standard-of-care treatment. Real-world data of its performance is scarce. This study evaluates the safety and effectiveness of trabectedin for patients with advanced STS who were treated at a high-volume sarcoma center.
METHODS: A retrospective chart review was performed on 77 patients treated with trabectedin (24 h infusion q3w) between 01/2005 and 05/2014. Data regarding safety, objective radiological response, progression-free and overall survival were analyzed.
RESULTS: Median age at treatment onset was 52y [interquartile range (IQR): 45-61y]. Tumors included leiomyosarcoma (41.6%), liposarcoma (18.2%), and synovial sarcoma (13%). Trabectedin was provided as ≥ third-line chemotherapy in 71.4%. Median number of cycles was 2 (range: 1-17). Dose reduction and treatment delays occurred in 19.5 and 40.3%, respectively. Toxicities occurred in 78%, primarily for neutropenia or elevated liver enzymes. Two patients died secondary to trabectedin-induced rhabdomyolysis. Treatment was discontinued because of disease progression (84.7%), toxicity (10%), and patient preference (5%). Partial response or stable disease occurred in 14.1 and 33.8%, respectively, while 52.1% developed progressive disease. Median progression-free survival was 1.3 m (IQR: 0.7-3.5 m) and was significantly higher in patients lacking severe toxicities or progressive disease. Median overall survival was 6.7 m (IQR: 2.3-12.7 m) and was significantly higher in patients with leiomyosarcoma or liposarcoma relative to other histologies.
CONCLUSIONS: Trabectedin has an acceptable safety profile as an anti-tumor agent. Our data further suggest there may be some benefit in using trabectedin particularly in patients with leiomyo- or liposarcoma who failed standard-of-care agents.

Moriceau G, Rivoirard R, Méry B, et al.
Real-World Outcomes of Combination Chemotherapy with Trabectedin plus Pegylated Liposomal Doxorubicin in Patients with Recurrent Ovarian Cancer: A Single-Center Experience.
Chemotherapy. 2016; 61(3):122-6 [PubMed] Related Publications
BACKGROUND: Trabectedin plus pegylated liposomal doxorubicin (PLD) proved efficacious as second-line treatment for patients with recurrent ovarian cancer (ROC).
METHODS: We report a single-center retrospective analysis of the efficacy and tolerance of trabectedin 1.1 mg/m2 every 3 weeks in a cohort of real-life ROC patients.
RESULTS: From February 2012 to January 2014, 17 patients were treated with trabectedin alone or combined with PLD. Median age was 61 years (range: 48-78). Performance status was 0-1 in 16 patients (94%). Disease response rate was 53% and disease control rate was 76%. At the end of the follow-up, 8 patients (47%) were alive. Median overall survival was 17.6 months (95% CI 13.6 to not reached). Median progression-free survival was 6.7 months (95% CI 5.4-10.0). The most frequent grade 3-4 toxicities were neutropenia (n = 4, 24%) and nausea/vomiting (n = 4, 24%).
CONCLUSION: Trabectedin combined with PLD seems efficient in and well tolerated by real-life ROC patients.

Blum JL, Gonçalves A, Efrat N, et al.
A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer.
Breast Cancer Res Treat. 2016; 155(2):295-302 [PubMed] Related Publications
Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.

Bongiovanni A, Riva N, Ricci M, et al.
Long-lasting activity of trabectedin in refractory uterine leiomyosarcoma: a case report.
BMC Cancer. 2015; 15:998 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Leiomyosarcoma (LMS) is an aggressive soft tissue sarcoma derived from smooth muscle cells typically of uterine, gastrointestinal or soft tissue origin. The prognosis for this tumor is poor, with survival rates among the lowest of all soft tissue sarcomas. Surgery is the best approach for localized disease. The principal role of chemotherapy is prevalently in the treatment of metastatic disease. Trabectedin, a promising new DNA-damaging agent with a mechanism of action that differs from that of traditional alkylating agents, has been approved in Europe for the treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide,
CASE PRESENTATION: We report the case of a 53-year-old woman with metastatic well differentiated uterine leiomyosarcoma refractory to multiple treatments who underwent 22 cycles of trabectedin over 30 months, obtaining a partial response according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, with good tolerability, and maintaining the response for 10 months after trebectedin withdrawal.
CONCLUSION: This very prolonged response, which persisted after drug discontinuation, suggests that trabectedin exerts an oncostatic effect rather than the cytotoxic one produced by other chemotherapeutic agents. Our experience also raises the question of the best way to evaluate trabectedin efficacy.

Lorusso D, Scambia G, Pignata S, et al.
Prospective phase II trial of trabectedin in BRCA-mutated and/or BRCAness phenotype recurrent ovarian cancer patients: the MITO 15 trial.
Ann Oncol. 2016; 27(3):487-93 [PubMed] Related Publications
BACKGROUND: Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype.
PATIENTS AND METHODS: A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms [single-nucleotide polymorphisms (SNPs)] involved in DNA gene repair was analyzed.
RESULTS: Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1-2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported.
CONCLUSIONS: Our data prospectively confirmed that the signature of 'repeated platinum sensitivity' identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum.
EUDRACT NUMBER: 2011-001298-17.

Belli C, Piemonti L, D'Incalci M, et al.
Phase II trial of salvage therapy with trabectedin in metastatic pancreatic adenocarcinoma.
Cancer Chemother Pharmacol. 2016; 77(3):477-84 [PubMed] Related Publications
PURPOSE: No standard salvage chemotherapy has been identified for metastatic pancreatic adenocarcinoma (mPA), and there is an urgent need for active agents against this disease. This phase II trial explored the activity of trabectedin in mPA progressing after gemcitabine-based first-line chemotherapy.
METHODS: Patients with gemcitabine-resistant disease received trabectedin 1.3 mg/m(2) as a 3-h intravenous continuous infusion every 3 weeks until disease progression or unacceptable toxicity or for a maximum of 6 months. The primary endpoint was progression-free survival rate at 6 months (PFS-6). Since trabectedin modulates the production of selected inflammatory mediators, this study also aimed to identify inflammatory biomarkers predictive for response to trabectedin.
RESULTS: Between February 2011 and February 2012, 25 patients received trabectedin. PFS-6 was 4%, median PFS 1.9 months (range 0.8-7.4), and median overall survival 5.2 months (range 1.1-24.3). Grade >2 toxicity consisted of neutropenia in 44% of patients, febrile neutropenia and thrombocytopenia both in 12%, anemia in 8%, fatigue in 12%, and AST and ALT increase in 8 and 4%, respectively. Trabectedin was shown to modulate the production of inflammatory mediators, and at disease progression, levels of a subgroup of cytokines/chemokines were modified. Furthermore, tissue analysis identified 30 genes associated with better prognosis.
CONCLUSIONS: Although it has shown some ability to modulate inflammatory process, single-agent trabectedin had no activity as salvage therapy for mPA.

Maruzzo M, Brunello A, Diminutto A, et al.
Long-term response to first-line trabectedin in an elderly female patient with a metastatic leiomyosarcoma unfit for anthracycline.
Anticancer Drugs. 2016; 27(3):264-7 [PubMed] Free Access to Full Article Related Publications
Systemic chemotherapy comprising anthracycline monotherapy is the standard regimen for metastatic soft tissue sarcomas, particularly leiomyosarcomas, which have limited sensitivity to ifosfamide. However, the optimal chemotherapy regimen for elderly patients, especially those considered unfit for anthracyclines, is undefined. Trabectedin is a potent marine-derived antineoplastic drug with documented activity in liposarcomas and leiomyosarcomas. It is registered in Europe for the treatment of adult patients with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. We report the long-term response to first-line trabectedin therapy in an elderly patient with metastatic leiomyosarcoma unfit for standard therapy. A 66-year-old woman underwent resection of a pelvic epithelioid leiomyosarcoma with positive margins in December 2002, followed by postoperative radiotherapy. In February 2012, she was diagnosed with multiple lung lesions and local relapse in the pelvis. As she was considered unsuitable for both anthracycline and ifosfamide because of cardiovascular comorbidities and because she was highly anxious at the prospect of developing alopecia, vomiting, and fatigue, we commenced treatment with trabectedin at 75% of the standard dose of 1.5 mg/m every 3 weeks. Treatment was well tolerated, and the patient continued treatment for 25 cycles, with disease stabilization according to the RECIST criteria and a partial response according to the Choi criteria. Disease progression was observed in November 2013 and the patient died 20 months after the diagnosis of metastases. Trabectedin may represent an alternative option for highly selected elderly patients with metastatic sarcoma and unfit for anthracyclines; careful monitoring of toxicities is strongly recommended.

De Sanctis R, Marrari A, Marchetti S, et al.
Efficacy of trabectedin in advanced soft tissue sarcoma: beyond lipo- and leiomyosarcoma.
Drug Des Devel Ther. 2015; 9:5785-91 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Trabectedin is effective in leiomyosarcoma and liposarcoma, especially the myxoid variant, related to the presence of the FUS-CHOP transcript. We evaluated the efficacy of trabectedin in specific subgroups of patients with soft tissue sarcomas (STS).
METHODS: Seventy-two patients with advanced anthracycline-pretreated STS, who received trabectedin at a dose of 1.5 mg/m(2) every 3 weeks by continuous 24-hour infusion, were retrospectively analyzed. Best response rate according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria and severe adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.02) were evaluated. Secondary endpoints included progression-free survival and overall survival (OS).
RESULTS: Median age was 48 (range, 20-75) years, with a median Eastern Cooperative Oncology Group performance status of 0. The median number of previous chemotherapy regimens was 1 (range, 0-5). Median number of trabectedin cycles was 3 (range, 1-17). About 69/72 patients (95.8%) were evaluable for response: 9 patients (13%) achieved partial response and 26 (37.7%) stable disease. According to histotype, clinical benefit (partial response + stable disease) was reported in synovial sarcoma (n=5), retroperitoneal liposarcoma (n=10), myxoid liposarcoma (n=5), leiomyosarcoma (n=8), high-grade undifferentiated pleomorphic sarcoma (n=5), Ewing/peripheral primitive neuroectodermal tumor (n=1), and malignant peripheral nerve sheath tumor (n=1). Any grade AEs were noncumulative, reversible, and manageable. G3/G4 AEs included anemia (n=1, 1.4%), neutropenia (n=7, 9.6%), liver toxicity (n=6, 8.3%), and fatigue (n=2, 2.8%). With a median follow-up time of 11 (range, 2-23) months, median progression-free survival and OS of the entire cohort were 2.97 months and 16.5 months, respectively.
CONCLUSION: Our experience confirms trabectedin as an effective therapeutic option for metastatic lipo- and leiomyosarcoma and suggests promise in synovial sarcomas and high-grade undifferentiated pleomorphic sarcoma.

Miao X, Koch G, Straubinger RM, Jusko WJ
Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells.
Cancer Chemother Pharmacol. 2016; 77(1):181-93 [PubMed] Free Access to Full Article Related Publications
PURPOSE: This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions.
METHODS: Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter ψ was used to quantify the effects of the individual drugs and combinations.
RESULTS: Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant K max and the sensitivity constant KC50) for each drug. The interaction parameter ψ was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects.
CONCLUSIONS: The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug-specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations.

D'Incalci M, Zambelli A
Trabectedin for the treatment of breast cancer.
Expert Opin Investig Drugs. 2016; 25(1):105-15 [PubMed] Related Publications
INTRODUCTION: Trabectedin is an anti-tumor compound registered in Europe and in several other countries, for the second-line treatment of soft tissue sarcoma (STS) and for ovarian cancer in combination with liposomal doxorubicin. Trabectedin inhibits cancer cell proliferation mainly affecting the transcription regulation. Trabectedin also acts as a modulator of tumor microenvironment by reducing the number of tumor associated macrophages (TAM). Because of its unique mechanism of action, trabectedin has the potential to act as antineoplastic agent also in several solid malignancies, including breast cancer (BC).
AREAS COVERED: This article reviews the preclinical and clinical data of trabectedin focusing on development in metastatic BC (mBC). Comments regarding the nature and the results of these trials are included.
EXPERT OPINION: Trabectedin is thought to have a crucial activity with defective DNA-repair machinery and also in modulating the tumor micro-environment and the immune-system of cancer patients. From the current available data, we recognize a potential activity of trabectedin in mBC and support the renewed efforts to better elucidate the value of trabectedin in this indication.

Ducie JA, Leitao MM
The role of adjuvant therapy in uterine leiomyosarcoma.
Expert Rev Anticancer Ther. 2016; 16(1):45-55 [PubMed] Free Access to Full Article Related Publications
Uterine leiomyosarcoma (uLMS) is a rare mesenchymal tumor of the gynecologic tract. Although diagnosed in only 1-3% of patients with uterine cancer, uLMS accounts for the majority of uterine cancer-related deaths. The standard of care for patients with uLMS includes total hysterectomy and bilateral salpingo-oophorectomy (BSO). There are no standard recommendations regarding adjuvant or palliative therapy. Many cytotoxic and targeted agents have been studied in clinical trials in an effort to identify an effective therapy that may alter the natural history of this disease. Unfortunately, as of now, there are no adjuvant therapy regimens that improve overall survival in this patient population. There is, therefore, an unmet need to identify a novel therapy that will improve the survival of women diagnosed with this aggressive disease. Here we summarize the existing literature on adjuvant therapy in uLMS, specifically highlighting advances made in the last 5 years.

Acikgoz E, Guven U, Duzagac F, et al.
Enhanced G2/M Arrest, Caspase Related Apoptosis and Reduced E-Cadherin Dependent Intercellular Adhesion by Trabectedin in Prostate Cancer Stem Cells.
PLoS One. 2015; 10(10):e0141090 [PubMed] Free Access to Full Article Related Publications
Trabectedin (Yondelis, ET-743) is a marine-derived tetrahydroisoquinoline alkaloid. It is originally derived from the Caribbean marine tunicate Ecteinascidia turbinata and currently produced synthetically. Trabectedin is active against a variety of tumor cell lines growing in culture. The present study focused on the effect of trabectedin in cell proliferation, cell cycle progression, apoptosis and spheroid formation in prostate cancer stem cells (CSCs). Cluster of differentiation (CD) 133+high/CD44+high prostate CSCs were isolated from the DU145 and PC-3 human prostate cancer cell line through flow cytometry. We studied the growth-inhibitory effects of trabectedin and its molecular mechanisms on human prostate CSCs and non-CSCs. DU-145 and PC-3 CSCs were treated with 0.1, 1, 10 and 100 nM trabectedin for 24, 48 and 72 h and the growth inhibition rates were examined using the sphere-forming assay. Annexin-V assay and immunofluorescence analyses were performed for the detection of the cell death. Concentration-dependent effects of trabectedin on the cell cycle were also evaluated. The cells were exposed to the different doses of trabectedin for 24, 48 and 72 h to evaluate the effect of trabectedin on the number and diameter of spheroids. According to the results, trabectedin induced cytotoxicity and apoptosis at the IC50 dose, resulting in a significant increase expression of caspase-3, caspase-8, caspase-9, p53 and decrease expression of bcl-2 in dose-dependent manner. Cell cycle analyses revealed that trabectedin induces dose-dependent G2/M-phase cell cycle arrest, particularly at high-dose treatments. Three-dimensional culture studies showed that trabectedin reduced the number and diameter of spheroids of DU145 and PC3 CSCs. Furthermore, we have found that trabectedin disrupted cell-cell interactions via E-cadherin in prostasphere of DU-145 and PC-3 CSCs. Our results showed that trabectedin inhibits cellular proliferation and accelerates apoptotic events in prostate CSCs; and may be a potential effective therapeutic agent against prostate cancer.

Khalifa J, Ouali M, Chaltiel L, et al.
Efficacy of trabectedin in malignant solitary fibrous tumors: a retrospective analysis from the French Sarcoma Group.
BMC Cancer. 2015; 15:700 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Advanced malignant solitary fibrous tumors (SFTs) are rare soft-tissue sarcomas with a poor prognosis. Several treatment options have been reported, but with uncertain rates of efficacy. Our aim is to describe the activity of trabectedin in a retrospective, multi-center French series of patients with SFTs.
METHODS: Patients were mainly identified through the French RetrospectYon database and were treated between January 2008 and May 2013. Trabectedin was administered at an initial dose of 1.5 mg/m(2), q3 weeks. The best tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors 1.1. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS). The growth-modulation index (GMI) was defined as the ratio between the time to progression with trabectedin (TTPn) and the TTP with the immediately prior line of treatment (TTPn-1).
RESULTS: Eleven patients treated with trabectedin for advanced SFT were identified. Trabectedin had been used as second-line treatment in 8 patients (72.7 %) and as at least third-line therapy in a further 3 (27.3 %). The best RECIST response was a partial response (PR) in one patient (9.1 %) and stable disease (SD) in eight patients (72.7 %). Disease-control rate (DCR = PR + SD) was 81.8 %. After a median follow-up of 29.2 months, the median PFS was 11.6 months (95 % CI = 2.0; 15.2 months) and the median OS was 22.3 months (95 % CI = 9.1 months; not reached). The median GMI was 1.49 (range: 0.11-4.12).
CONCLUSION: Trabectedin is a very promising treatment for advanced SFTs. Further investigations are needed.

Moriceau G, Vallard A, Méry B, et al.
What makes real world outcomes in soft tissue sarcomas? A mono-institutional trabectedin experience.
Bull Cancer. 2015; 102(10):814-22 [PubMed] Related Publications
INTRODUCTION: Trabectedin proved its efficacy in relapsed advanced soft tissue sarcomas (STS) in 3 multicenter phase II studies with selected patients. The aim of the present study is to investigate trabectedin efficacy and tolerance in a cohort of "real-life" unselected patients with sarcoma.
METHODS: A single-center analysis was carried out on all consecutive patients with histologically proven unresectable advanced or metastatic STS, who received at least one cycle of trabectedin. Data on efficacy and tolerance were retrospectively reported.
RESULTS: From 2004 to 2014, data of 59 patients were reviewed. Median age was 62 years (from 23 to 87). A total of 317 cycles of trabectedin were administered. Twenty-five patients (42%) suffered grade 3-4 hematological toxicity, mainly with neutropenia (22 patients, 37%). Disease control rate was 24%, mainly with stable disease, and 45 patients (76%) experienced disease progression. Median overall survival was 6.6 months (95%CI [4.9-12.6]).
CONCLUSION: Trabectedin might be an option for patients without any other validated alternative, but phase III study evaluating trabectedin+best supportive care (BSC) versus BSC is necessary.

Demetri GD, von Mehren M, Jones RL, et al.
Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial.
J Clin Oncol. 2016; 34(8):786-93 [PubMed] Free Access to Full Article Related Publications
PURPOSE: This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen.
PATIENTS AND METHODS: Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response-as well as safety and patient-reported symptom scoring.
RESULTS: A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm.
CONCLUSION: Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.

Ceriani L, Ferrari M, Zangarini M, et al.
HPLC-MS/MS method to measure trabectedin in tumors: preliminary PK study in a mesothelioma xenograft model.
Bioanalysis. 2015; 7(15):1831-42 [PubMed] Related Publications
BACKGROUND: Trabectedin is an anticancer agent registered for the second-line treatment of soft tissue sarcoma and ovarian cancer. No preclinical data are available on its tumor distribution, so a method for quantification in neoplastic tissues is required.
METHODS/RESULTS: We validated an LC-MS/MS assay determining the recovery, sensitivity, linearity, precision and accuracy in mouse tumor and liver samples. The limit of quantification was 0.10 ng/ml with a curve range of 0.10-3.00 ng/ml (accuracy 96.1-102.1%). Inter-day precision and accuracy of QCs were 6.0-8.2 and 97.0-102.6% respectively. The method was applied in mesothelioma xenografts treated with therapeutic doses.
CONCLUSION: The method was validated for measuring trabectedin in tissues. In a mesothelioma xenograft model, trabectedin distributed preferentially in tumor compared with liver.

Obrador-Hevia A, Martinez-Font E, Felipe-Abrio I, et al.
RG7112, a small-molecule inhibitor of MDM2, enhances trabectedin response in soft tissue sarcomas.
Cancer Invest. 2015; 33(9):440-50 [PubMed] Related Publications
MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Selected sarcoma subtypes are being treated with Trabectedin in second line, which promotes DNA damage and p53-dependent apoptosis. The aim of this study was to evaluate the improvement of Trabectedin response with MDM2 inhibitors in soft tissue sarcomas. The antitumor effects of Trabectedin, Nutlin-3A and RG7112 as single agents or in combination were examined in vitro. RG7112 significantly synergized with Trabectedin in MDM2-amplified liposarcoma cells, representing a promising new therapeutic strategy for the treatment of sarcomas with MDM2 amplification.

Vincenzi B, Stumbo L, Maltese G, et al.
Lack of Correlation Between Liver Tests Abnormalities and Trabectedin Efficacy in the Treatment of Soft Tissue Sarcoma: a Retrospective Study.
Sci Rep. 2015; 5:12077 [PubMed] Free Access to Full Article Related Publications
Elevation in liver transaminases is common in patients treated with the marine antitumor agent trabectedin. However, the impact of trabectedin-related transaminase elevations on treatment outcomes is unclear. This retrospective study investigated the correlation between liver tests abnormalities and treatment outcomes in patients with unresectable advanced or metastatic soft tissue sarcomas (STS) treated with trabectedin 1.5 mg/m(2) once every 3 weeks at three reference centers in Italy. The effect of grade 3/4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) during the first two cycles and at any time during trabectedin treatment on progression-free survival (PFS) and overall survival (OS) were analyzed. Liver tests abnormalities during the first two cycles of chemotherapy or at any time during trabectedin treatment did not significantly affect PFS or OS. Nor were survival outcomes significantly different in the subgroups of patients with or without ALT/AST increases or with ALT/AST elevations ≥ 15 × the upper limit of normal (ULN) versus those with ALT/AST elevation < 15 × ULN. Although liver tests abnormalities are common in patients treated with trabectedin, elevations in ALT and AST are usually transient, occur during the first two cycles of treatment, and do not appear to affect survival.

Bonavita E, Galdiero MR, Jaillon S, Mantovani A
Phagocytes as Corrupted Policemen in Cancer-Related Inflammation.
Adv Cancer Res. 2015; 128:141-71 [PubMed] Related Publications
Inflammation is a key component of the tumor microenvironment. Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) are prototypic inflammatory cells in cancer-related inflammation. Macrophages provide a first line of resistance against infectious agents but in the ecological niche of cancer behave as corrupted policemen. TAMs promote tumor growth and metastasis by direct interactions with cancer cells, including cancer stem cells, as well as by promoting angiogenesis and tissue remodeling and suppressing effective adaptive immunity. In addition, the efficacy of chemotherapy, radiotherapy, and checkpoint blockade inhibitors is profoundly affected by regulation of TAMs. In particular, TAMs can protect and rescue tumor cells from cytotoxic therapy by orchestrating a misguided tissue repair response. Following extensive preclinical studies, there is now proof of concept that targeting tumor-promoting macrophages by diverse strategies (e.g., Trabectedin, anti-colony-stimulating factor-1 receptor antibodies) can result in antitumor activity in human cancer and further studies are ongoing. Neutrophils have long been overlooked as a minor component of the tumor microenvironment, but there is evidence for an important role of TANs in tumor progression. Targeting phagocytes (TAMs and TANs) as corrupted policemen in cancer may pave the way to innovative therapeutic strategies complementing cytoreductive therapies and immunotherapy.

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