ABSTRACT
Soft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues and can occur almost anywhere in the body. Their rarity, and the heterogeneity of subtype and location, means that developing evidence-based guidelines is complicated by the limitations of the data available. This makes it more important that STS are managed by expert multidisciplinary teams, to ensure consistent and optimal treatment, recruitment to clinical trials, and the ongoing accumulation of further data and knowledge. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field. These guidelines are an update of the previous versions published in 2010 and 2016 [1, 2]. The original guidelines were drawn up by a panel of UK sarcoma specialists convened under the auspices of the British Sarcoma Group (BSG) and were intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. This iteration of the guidance, as well as updating the general multidisciplinary management of soft tissue sarcoma, includes specific sections relating to the management of sarcomas at defined anatomical sites: gynaecological sarcomas, retroperitoneal sarcomas, breast sarcomas, and skin sarcomas. These are generally managed collaboratively by site specific multidisciplinary teams linked to the regional sarcoma specialist team, as stipulated in the recently published sarcoma service specification [3]. In the UK, any patient with a suspected soft tissue sarcoma should be referred to a specialist regional soft tissues sarcoma service, to be managed by a specialist sarcoma multidisciplinary team. Once the diagnosis has been confirmed using appropriate imaging and a tissue biopsy, the main modality of management is usually surgical excision performed by a specialist surgeon, combined with pre- or post-operative radiotherapy for tumours at higher risk for local recurrence. Systemic anti-cancer therapy (SACT) may be utilised in cases where the histological subtype is considered more sensitive to systemic treatment. Regular follow-up is recommended to assess local control, development of metastatic disease, and any late effects of treatment.
ABSTRACT
BACKGROUND: Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer. METHODS: Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon's two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata. RESULTS: Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events. CONCLUSIONS: Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials. CLINICAL TRIAL REGISTRATION: ISRCTN 60791336.
Subject(s)
Hemangiosarcoma , Leiomyosarcoma , Sarcoma, Synovial , Sarcoma , Soft Tissue Neoplasms , Humans , Axitinib/adverse effects , Leiomyosarcoma/drug therapy , Sarcoma, Synovial/chemically induced , Sarcoma, Synovial/drug therapy , Hemangiosarcoma/chemically induced , Hemangiosarcoma/drug therapy , Vascular Endothelial Growth Factor A , Sarcoma/drug therapy , Soft Tissue Neoplasms/drug therapy , Soft Tissue Neoplasms/pathology , Angiogenesis Inhibitors/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: No prospective trial with anthracycline-based chemotherapy has individually assessed response in a well-differentiated (WD)/dedifferentiated (DD) liposarcoma patient cohort. We conducted a retrospective analysis of first-line chemotherapy in liposarcoma of intra-abdominal origin (IA-LPS) in patients who had entered the European Organisation for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG) trials. METHODS: We searched for all adult patients treated with first-line chemotherapy for advanced IA-LPS in the EORTC STBSG phase 2 and 3 trials from 1978. Treatment was aggregated into 5 groups: anthracycline alone, ifosfamide alone, doxorubicin plus ifosfamide (D+IFO), doxorubicin/cyclophosphamide/vincristine/dacarbazine, and "other" (brostallicin, trabectedin). Response was assessed prospectively by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. RESULTS: A total of 109 patients with IA-LPS from 13 trials were identified (104 evaluable for response). Overall, there were 10/109 (9.2%) responders: 3/48 (6.3%) in the anthracycline alone group, 2/15 (13%) in the ifosfamide alone group, and 4/18 (22%) in the D+IFO group. At the 10-month median follow-up (interquartile range, 6-24), the median OS was 19 months (95% CI, 15-21) and median PFS 4 months (95% CI, 3-6). D+IFO achieved a not statistically significant longer median PFS (12 months) and median OS (31 months) than observed with other regimens. Univariate/multivariate analysis did not identify prognostic factors. CONCLUSIONS: Cytotoxic chemotherapy, in particular anthracycline alone, had marginal activity in advanced IA-LPS. Ifosfamide-containing regimens showed higher activity, although it was not statistically significant and in a small number of cases, with the combination of doxorubicin and ifosfamide appearing to be the more active regimen available in fit patients. This series provides a benchmark for future trials on new drugs in WD/DD liposarcoma.
Subject(s)
Bone Neoplasms , Liposarcoma , Osteosarcoma , Sarcoma , Adult , Antibiotics, Antineoplastic , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/drug therapy , Doxorubicin , Humans , Ifosfamide , Lipopolysaccharides/therapeutic use , Liposarcoma/drug therapy , Osteosarcoma/drug therapy , Retrospective Studies , Sarcoma/pathologyABSTRACT
BACKGROUND/AIM: Distinguishing true oligometastatic disease from early polymetastatic disease is vital in patients with soft tissue sarcoma as contemporary treatment strategies differ significantly. Clinical factors such as tumour biology, organ involved, number of lesions, and patient fitness influence clinical decisions. PATIENTS AND METHODS: A retrospective search of a prospective database identified patients with new distant relapse, treated between 2009 and 2012. RESULTS: A total of 223 patients were included, and oligometastases were diagnosed in 81 (36%) patients, which were pulmonary in just over half of cases. These were treated with local therapy in 66 of 89 cases, and 7 patients received subsequent treatment for additional oligometastases. Metastasectomy was the most common treatment modality. A total of 16/66 patients (24%) underwent active surveillance for >6 months prior to local therapy. CONCLUSION: Patients with oligometastatic disease can experience durable disease control with timely multimodality treatment approaches for evolving metastatic disease, where disease biology allows.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Metastasectomy/mortality , Sarcoma/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Retrospective Studies , Sarcoma/pathology , Sarcoma/therapy , Survival Rate , Young AdultABSTRACT
Importance: The association between quality of surgery and overall survival in patients affected by localized gastrointestinal stromal tumors (GIST) is not completely understood. Objective: To assess the risk of death with and without imatinib according to microscopic margins status (R0/R1) using data from a randomized study on adjuvant imatinib. Design, Setting, and Participants: This is a post hoc observational study on patients included in the randomized, open-label, phase III trial, performed between December 2004 and October 2008. Median follow-up was 9.1 years (IQR, 8-10 years). The study was performed at 112 hospitals in 12 countries. Inclusion criteria were diagnosis of primary GIST, with intermediate or high risk of relapse; no evidence of residual disease after surgery; older than 18 years; and no prior malignancies or concurrent severe/uncontrolled medical conditions. Data were analyzed between July 17, 2017, and March 1, 2020. Interventions: Patients were randomized after surgery to either receive imatinib (400 mg/d) for 2 years or no adjuvant treatment. Randomization was stratified by center, risk category (high vs intermediate), tumor site (gastric vs other), and quality of surgery (R0 vs R1). Tumor rupture was included in the R1 category but also analyzed separately. Main Outcomes and Measures: Primary end point of this substudy was overall survival (OS), estimated using Kaplan-Meier method and compared between R0/R1 using Cox models adjusted for treatment and stratification factors. Results: A total of 908 patients were included; 51.4% were men (465) and 48.6% were women (440), and the median age was 59 years (range, 18-89 years). One hundred sixty-two (17.8%) had an R1 resection, and 97 of 162 (59.9%) had tumor rupture. There was a significant difference in OS for patients undergoing an R1 vs R0 resection, overall (hazard ratio [HR], 2.05; 95% CI, 1.45-2.89) and by treatment arm (HR, 2.65; 95% CI, 1.37-3.75 with adjuvant imatinib and HR, 1.86; 95% CI, 1.16-2.99 without adjuvant imatinib). When tumor rupture was excluded, this difference in OS between R1 and R0 resections disappeared (HR, 1.05; 95% CI, 0.54-2.01). Conclusions and Relevance: The difference in OS by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse OS. Trial Registration: ClinicalTrials.gov Identifier: NCT00103168.
Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/surgery , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/surgery , Imatinib Mesylate/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Chemotherapy, Adjuvant , Digestive System Surgical Procedures/standards , Female , Humans , International Cooperation , Male , Middle Aged , Quality of Health Care , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: A named patient program (NPP) was designed to provide patients with advanced soft-tissue sarcoma (aSTS) access to pazopanib, a multitargeted tyrosine kinase inhibitor. The SPIRE study was a retrospective chart review of participating patients. PATIENTS AND METHODS: Eligibility criteria for the NPP and SPIRE mirrored those of the pivotal phase-III study, PALETTE, which compared pazopanib with placebo in patients ≥18 years with aSTS and whose disease had progressed during or following prior chemotherapy or were otherwise unsuitable for chemotherapy. Outcomes of interest included treatment patterns, treatment duration, relative dose intensity, progression-free survival (PFS), overall survival (OS), clinical benefit rate, adverse events (AEs) and reasons for treatment discontinuation. RESULTS: A total of 211 patients were enrolled (median age 56 years; 60% female). Most patients received pazopanib in second- and third-line therapy (28.0% and 28.4%, respectively), followed by fourth line (19.0%) and ≥ fifth line (18.5%). The median duration of pazopanib treatment was 3.1 months (95% CI: 2.8-3.8), with a mean daily dose of 715 mg equating to 92% of recommended dose. Median OS was 11.1 months and clinical benefit rate was 46%. There was evidence of some clinical benefit across most histological subtypes. At study end, 40% of patients were alive and of these, 18% remained on pazopanib. Thirteen percent (13%) of patients discontinued pazopanib due to AEs. CONCLUSIONS: The SPIRE study demonstrated activity of pazopanib in heavily pretreated aSTS patients in a compassionate use setting. No new safety concerns were noted. Reassuringly, the relative dose intensity of pazopanib was 92%.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Sarcoma/drug therapy , Sulfonamides/therapeutic use , Compassionate Use Trials , Disease-Free Survival , Female , Hemangiosarcoma/drug therapy , Hemangiosarcoma/pathology , Humans , Indazoles , Leiomyosarcoma/drug therapy , Leiomyosarcoma/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Male , Middle Aged , Retrospective Studies , Sarcoma/pathology , Sarcoma, Synovial/drug therapy , Sarcoma, Synovial/pathology , Solitary Fibrous Tumors/drug therapy , Solitary Fibrous Tumors/pathology , Survival Rate , Time Factors , Uterine Neoplasms/drug therapy , Uterine Neoplasms/pathologyABSTRACT
Purpose To report on the long-term results of a randomized trial comparing a standard dose (400 mg/d) versus a higher dose (800 mg/d) of imatinib in patients with metastatic or locally advanced GI stromal tumors (GISTs). Patients and Methods Eligible patients with advanced CD117-positive GIST from 56 institutions in 13 countries were randomly assigned to receive either imatinib 400 mg or 800 mg daily. Patients on the 400-mg arm were allowed to cross over to 800 mg upon progression. Results Between February 2001 and February 2002, 946 patients were accrued. Median age was 60 years (range, 18 to 91 years). Median follow-up time was 10.9 years. Median progression-free survival times were 1.7 and 2.0 years in the 400- and 800-mg arms, respectively (hazard ratio, 0.91; P = .18), and median overall survival time was 3.9 years in both treatment arms. The estimated 10-year progression-free survival rates were 9.5% and 9.2% for the 400- and 800-mg arms, respectively, and the estimated 10-year overall survival rates were 19.4% and 21.5%, respectively. At multivariable analysis, age (< 60 years), performance status (0 v ≥ 1), size of the largest lesion (smaller), and KIT mutation (exon 11) were significant prognostic factors for the probability of surviving beyond 10 years. Conclusion This trial was carried out on a worldwide intergroup basis, at the beginning of the learning curve of the use of imatinib, in a large population of patients with advanced GIST. With a long follow-up, 6% of patients are long-term progression free and 13% are survivors. Among clinical prognostic factors, only performance status, KIT mutation, and size of largest lesion predicted long-term outcome, likely pointing to a lower burden of disease. Genomic and/or immune profiling could help understand long-term survivorship. Addressing secondary resistance remains a therapeutic challenge.
Subject(s)
Antineoplastic Agents/administration & dosage , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Imatinib Mesylate/administration & dosage , Adult , Aged , Cross-Over Studies , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Gastrointestinal Neoplasms/pathology , Gastrointestinal Stromal Tumors/pathology , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Metastasis , PrognosisABSTRACT
Survival outcomes for adolescent and young adult patients with soft tissue sarcomas lag behind those of children diagnosed with histologically similar tumours. To help understand these differences in outcomes, we discuss the following issues with regard to the management of these patients with soft tissue sarcomas: delays in diagnosis, trial availability and participation, aspects of the organisation of care (with an emphasis on age-specific needs), national centralisation of sarcoma care, international consortia, and factors related to tumour biology. Improved understanding of the causes of the survival gap between adolescents and young adults with sarcomas will help drive new initiatives to improve final health outcomes in these populations. In this Review, we specifically focus on embryonal and alveolar rhabdomyosarcoma, synovial sarcoma, and adult soft tissue sarcomas diagnosed in adolescents and young adults, and discuss the age-specific needs of these patients.
Subject(s)
Sarcoma/pathology , Soft Tissue Neoplasms/pathology , Adolescent , Adult , Child , Humans , Young AdultABSTRACT
Purpose Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients and Methods Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m2 intravenously day 1 plus palifosfamide 150 mg/m2/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. Results In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (hazard ratio, 1.05; 95% CI, 0.79 to 1.39; P = .74). There was a higher incidence of grade 3 to 4 adverse events in the doxorubicin plus palifosfamide arm (63.6% v 50.9%) including a higher rate of febrile neutropenia (21.4% v 12.6%). Conclusion No significant difference in PFS was observed in patients receiving doxorubicin plus palifosfamide compared with those receiving doxorubicin plus placebo. The observed median PFS and overall survival in this large, international study can serve as a benchmark for future studies of doxorubicin in metastatic soft tissue sarcoma.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Doxorubicin/therapeutic use , Sarcoma/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Drug Administration Schedule , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Phosphoramide Mustards/administration & dosage , Phosphoramide Mustards/adverse effects , Placebos , Sarcoma/pathologyABSTRACT
PURPOSE: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery patients with localized, high- or intermediate-risk GI stromal tumor (GIST). PATIENTS AND METHODS: Patients were randomly assigned to 2 years of imatinib 400 mg daily or no further therapy after surgery. The primary end point was overall survival; relapse-free survival (RFS), relapse-free interval, and toxicity were secondary end points. In 2009, given the concurrent improvement in prognosis of patients with advanced GIST, we changed the primary end point to imatinib failure-free survival (IFFS), with agreement of the independent data monitoring committee. We report on a planned interim analysis. RESULTS: A total of 908 patients were randomly assigned between December 2004 and October 2008: 454 to imatinib and 454 to observation. Of these, 835 patients were eligible. With a median follow-up of 4.7 years, 5-year IFFS was 87% in the imatinib arm versus 84% in the control arm (hazard ratio, 0.79; 98.5% CI, 0.50 to 1.25; P = .21); RFS was 84% versus 66% at 3 years and 69% versus 63% at 5 years (log-rank P < .001); and 5-year overall survival was 100% versus 99%, respectively. Among 528 patients with high-risk GIST by local pathologist, 5-year IFFS was 79% versus 73%; among 336 centrally reviewed high-risk patients, it was 77% versus 73%, respectively. CONCLUSION: This study confirms that adjuvant imatinib has an overt impact on RFS. No significant difference in IFFS was observed, although in the high-risk subgroup there was a trend in favor of the adjuvant arm. IFFS was conceived as a potential end point in the adjuvant setting because it is sensitive to secondary resistance, which is the main adverse prognostic factor in patients with advanced GIST.
Subject(s)
Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Imatinib Mesylate/therapeutic use , Molecular Targeted Therapy , Neoplasm Recurrence, Local/drug therapy , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Australasia , Chemotherapy, Adjuvant , Disease-Free Survival , European Union , Female , Follow-Up Studies , Humans , International Cooperation , Kaplan-Meier Estimate , Male , Middle Aged , Molecular Targeted Therapy/methods , Neoplasm Recurrence, Local/prevention & control , Odds Ratio , Salvage Therapy/methods , Treatment FailureABSTRACT
BACKGROUND: This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors. METHODS: Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28. RESULTS: Fifty-one patients received nintedanib 100-450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily. CONCLUSION: Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Indoles/therapeutic use , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Contrast Media , Drug Administration Schedule , Enzyme Inhibitors/therapeutic use , Humans , Indoles/administration & dosage , Indoles/adverse effects , Indoles/pharmacokinetics , Magnetic Resonance Imaging , Maximum Tolerated Dose , Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND: We retrospectively reviewed data from nine pre-treated metastatic desmoplastic small round cell tumour (DSRCT) patients who received pazopanib. PATIENTS AND METHODS: Three patients received pazopanib within the EORTC phase II 62043, three in the EORTC phase III 62072, and three in the context of UK named patient program. RESULTS: Nine patients were retrieved from the databases, the median age was 30 years (range: 21-47), they were all males. All had received prior chemotherapy. At the time of treatment start, 4 patients (44%) had ECOG PS 0, 4 (44%) PS 1, 1 (11%) PS 2. Best response was partial response (PR) in 2/9 (22%) patients, stable disease (SD) in 5/9 (56%) and progressive disease (PD) in 2/9 (22%) with a clinical benefit rate (PR + SD > 12 weeks) of 78%. Median PFS and OS were 9.2 (95%CI: 0-23.2) and 15.4 (95%CI: 1.5-29.3) months respectively. With a median follow-up of 20 months, 2/9 (22%) patients are still alive, all progressed. The most common toxicities included neutropenia (G1-2 45%; G3-4 11%), anaemia (G1-2 45%), fatigue (G1-2 67%), diarrhoea (G1-2 45%; G3-4 11%), nausea (G1-2 45%), hypertension (G1-2 45%) and increase in liver enzymes (G1-2 34%; G3-4 11%). Three patients (34%) required a dose reduction. One of the patients discontinued treatment because of persistent increase in total bilirubin level, one due to patient's choice. CONCLUSION: In this series, pazopanib showed interesting activity in DSRCT patients who progressed after prior chemotherapy without major toxicity.
ABSTRACT
Soft-tissue sarcoma (STS) is a rare and heterogeneous group of tumours that comprise approximately 1% of all adult cancers, and encompass over 50 different subtypes. These tumours exhibit a wide range of differing behaviours and underlying molecular pathologies, and can arise anywhere in the body. Surgical resection is critical to the management of locoregional disease. In the locally advanced or metastatic disease settings, systemic therapy has an important role in the multidisciplinary management of sarcoma. Cytotoxic therapy that usually consists of doxorubicin and ifosfamide has been the mainstay of treatment for many years. However recent advances in molecular pathogenesis, the development of novel targeted therapies, changes in clinical trial design and increased international collaboration have led to the development of histology-driven therapy. Furthermore, genomic profiling has highlighted that some STS are driven by translocation, mutation or amplification and others have more complex and chaotic karyotypes. In this Review, we aim to describe the current gold standard treatment for specific STS subtypes as well as outline future promising therapies in the pipeline.
Subject(s)
Sarcoma/drug therapy , Algorithms , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Vaccines/therapeutic use , Combined Modality Therapy , Drug Resistance, Neoplasm/drug effects , Histone Deacetylase Inhibitors/therapeutic use , Humans , Immunotherapy , Immunotherapy, Adoptive , Molecular Targeted Therapy , Prodrugs/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Sarcoma/genetics , Sarcoma/pathology , Sarcoma/therapyABSTRACT
BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. METHODS: This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. FINDINGS: 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. INTERPRETATION: Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. FUNDING: GlaxoSmithKline.
Subject(s)
Antineoplastic Agents/therapeutic use , Pyrimidines/therapeutic use , Sarcoma/drug therapy , Soft Tissue Neoplasms/drug therapy , Sulfonamides/therapeutic use , Adolescent , Adult , Aged , Cross-Over Studies , Disease-Free Survival , Double-Blind Method , Female , Humans , Indazoles , Kaplan-Meier Estimate , Male , Middle Aged , Sarcoma/mortality , Sarcoma/secondary , Soft Tissue Neoplasms/mortality , Soft Tissue Neoplasms/secondary , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Epithelioid sarcoma is a rare soft tissue sarcoma subtype. The response of this disease to chemotherapy is not well described. The aim of this study was to investigate the response rate and progression-free survival in a series of epithelioid sarcoma patients treated with chemotherapy at a single referral center. METHODS: A retrospective search of a prospectively maintained database was made to identify epithelioid sarcoma patients treated with chemotherapy between 1990 and 2009. Radiological response and histological diagnosis were re-reviewed for this study. RESULTS: Twenty-one epithelioid sarcoma patients treated with chemotherapy were identified; follow-up data on palliative chemotherapy was available on 20 of these patients. The median age was 36.5 years (range, 17.4 to 64.8 y) and the male/female ratio was 19:2. Ten patients (50%) were treated with single-agent anthracycline, 9 patients (45%) were treated with a combination therapy (anthracycline and ifosfamide), and 1 patient received trabectedin (5%). Three patients achieved a partial response, 12 had stable disease, and 5 progressed. The median progression-free survival was 29 weeks (95% confidence interval [CI]: 23-35). Seven and 3 patients received second-line and third-line palliative chemotherapy, respectively. The median overall survival from commencing palliative chemotherapy in our series was 51 weeks (95% confidence interval; 29-73). CONCLUSIONS: Systemic chemotherapy provides satisfactory palliation in patients with epithelioid sarcoma. However, this is an aggressive disease, responses to chemotherapy are of short duration and there is a need for more effective novel therapies in the treatment of this condition.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Palliative Care , Sarcoma/drug therapy , Sarcoma/mortality , Adolescent , Adult , Aged , Dioxoles/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Ifosfamide/administration & dosage , Male , Middle Aged , Neoplasm Staging , Prognosis , Prospective Studies , Retrospective Studies , Sarcoma/pathology , Survival Rate , Tetrahydroisoquinolines/administration & dosage , Trabectedin , Young AdultABSTRACT
Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and are in mid-late stage trials for other cancers. The HDAC inhibitors LAQ824 and SAHA increase phosphocholine (PC) levels in human colon cancer cells and tumor xenografts as observed by magnetic resonance spectroscopy (MRS). In this study, we show that belinostat, an HDAC inhibitor with an alternative chemical scaffold, also caused a rise in cellular PC content that was detectable by (1)H and (31)P MRS in prostate and colon carcinoma cells. In addition, (1)H MRS showed an increase in branched chain amino acid and alanine concentrations. (13)C-choline labeling indicated that the rise in PC resulted from increased de novo synthesis and correlated with an induction of choline kinase α expression. Furthermore, metabolic labeling experiments with (13)C-glucose showed that differential glucose routing favored alanine formation at the expense of lactate production. Additional analysis revealed increases in the choline/water and phosphomonoester (including PC)/total phosphate ratios in vivo. Together, our findings provide mechanistic insights into the impact of HDAC inhibition on cancer cell metabolism and highlight PC as a candidate noninvasive imaging biomarker for monitoring the action of HDAC inhibitors.
Subject(s)
Biomarkers, Tumor/analysis , Choline Kinase/metabolism , Colonic Neoplasms/metabolism , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Phosphorylcholine/analysis , Phosphorylcholine/metabolism , Prostatic Neoplasms/metabolism , Animals , Cell Line, Tumor , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy/methods , Male , Mice , Mice, Nude , Sulfonamides , Xenograft Model Antitumor AssaysABSTRACT
Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response.
ABSTRACT
Clear cell sarcoma is a rare translocation-related sarcoma. There have been few studies documenting the response rate and progression-free survival in clear cell sarcoma patients treated with palliative chemotherapy. The prospectively maintained databases of two referral centres were searched to identify clear cell sarcoma patients treated with chemotherapy. Twenty-four patients were treated with palliative first-line chemotherapy with a median age of 30 years at diagnosis. There were 18 men and 6 women. One (4%) achieved a partial response and 9 (38%) had stable disease. Fourteen patients (58%) progressed on therapy. The median progression-free survival was 11 weeks (95% CI, 320 weeks). The median overall survival from commencing first-line chemotherapy was 39 weeks (95% CI, 3445 weeks). Second-line chemotherapy was administered to 12 patients, 11 (92%) of these progressed and one (8%) had stable disease. Of the 5 patients treated with third-line chemotherapy, 4 (80%) progressed and one (20%) had stable disease. One patient received fourth-line chemotherapy and maintained stable disease for 4 months. Conventional chemotherapy has minimal activity in clear cell sarcoma as documented by the response rate of 4% and median progression-free survival of 11 weeks in this retrospective series. These data provide a reference for response and outcome in the assessment of novel agents in this histological subtype.