Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines.

BACKGROUND: British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS: A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION: Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).

UK guidelines for the management of soft tissue sarcomas.

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.

Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata.

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.

First-line chemotherapy in advanced intra-abdominal well-differentiated/dedifferentiated liposarcoma: An EORTC Soft Tissue and Bone Sarcoma Group retrospective analysis.

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.

Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial.

BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. METHODS: In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. FINDINGS: Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. INTERPRETATION: Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. FUNDING: Cancer Research UK and AstraZeneca.

Safety and efficacy of Pazopanib in advanced soft tissue sarcoma: PALETTE (EORTC 62072) subgroup analyses.

BACKGROUND: PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS. METHODS: PALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory. RESULTS: A total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities. CONCLUSIONS: Longer mPFS was observed in patients receiving pazopanib following only 1 line of therapy. Additionally, mPFS with pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity. TRIAL REGISTRATION: NCT00753688 , first posted September 16, 2008 (registered prospectively).

Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database.

INTRODUCTION: As both anti-tumour effects and toxicity are thought to be dose-dependent, patients with the greatest toxicity may also have the best outcome. We assessed whether severity of doxorubicin-induced hematological toxicity is associated with outcome in advanced soft tissue sarcoma (STS) patients. In addition, risk factors for hematological toxicity were explored. METHODS: Worst haematological toxicities (anaemia, leukopenia, neutropenia and thrombocytopenia) seen during treatment were scored according to CTCAE toxicity score. Differences in overall survival (OS), progression free survival (PFS) and response rate (RR) between patients with or without high haematological toxicity (grades 0-2 vs. 3-4) were assessed using conventional statistical tests. Associations between baseline characteristics and hematological toxicity were established using logistic multivariate regression. RESULTS: In 557 patients eligible for this analysis, 47.2% of the patients received at least six cycles of treatment; 45% stopped treatment early due to progression, 3% because of toxicity. Relative dose intensity (RDI) was constant over the cycles. OS, PFS, and RR did not differ between patients with grade 3/4 toxicity during treatment versus those with grade 1/2. Risk factors for grade 3/4 haematological toxicity, in particular neutropenia, were age above 60 years, low BMI, and female gender. CONCLUSION: In this large series, risk factors for haematological toxicity in STS patients receiving doxorubicin monotherapy were revealed. The finding that there was no association between outcome and haematological toxicity during doxorubicin treatment may be useful to reassure advanced STS patients that failure to experience haematological toxicity during treatment does not equate to under-treatment.

Soft tissue sarcomas in adolescents and young adults: a comparison with their paediatric and adult counterparts.

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.

The spectrum of EWSR1-rearranged neoplasms at a tertiary sarcoma centre; assessing 772 tumour specimens and the value of current ancillary molecular diagnostic modalities.

BACKGROUND: EWSR1 rearrangements were first identified in Ewing sarcoma, but the spectrum of EWSR1-rearranged neoplasms now includes many soft tissue tumour subtypes including desmoplastic small round cell tumour (DSRCT), myxoid liposarcoma (MLPS), extraskeletal myxoid chondrosarcoma (EMC), angiomatoid fibrous histiocytoma (AFH), clear cell sarcoma (CCS) and myoepithelial neoplasms. We analysed the spectrum of EWSR1-rearranged soft tissue neoplasms at our tertiary sarcoma centre, by assessing ancillary molecular diagnostic modalities identifying EWSR1-rearranged tumours and reviewing the results in light of our current knowledge of these and other Ewing sarcoma-like neoplasms. METHODS: We retrospectively analysed all specimens tested for EWSR1 rearrangements by fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) over a 7-year period. RESULTS: There was a total of 772 specimens. FISH was performed more often than RT-PCR (n=753, 97.5% vs n=445, 57.6%). In total, 210 (27.9%) specimens were FISH-positive for EWSR1 rearrangement compared to 111 (14.4%) that showed EWSR1 fusion transcripts with RT-PCR. Failure rates for FISH and RT-PCR were 2.5% and 18.0%. Of 109 round cell tumours with pathology consistent with Ewing sarcoma, 15 (13.8 %) cases were FISH-positive without an identifiable EWSR1 fusion transcript, 4 (3.7%) were FISH-negative but RT-PCR positive and 4 (3.7%) were negative for both. FISH positivity for DSRCT, MLPS, EMC, AFH and CCS was 86.3%, 4.3%, 58.5%, 60.0% and 87.9%, respectively. A positive FISH result led to diagnostic change in 40 (19.0%) EWSR1-rearranged cases. 13 FISH-positive cases remained unclassifiable. CONCLUSIONS: FISH is more sensitive for identifying EWSR1 rearrangements than RT-PCR. However, there can be significant morphologic and immunohistochemical overlap between groups of EWSR1-rearranged neoplasms, with important prognostic and therapeutic implications. FISH and RT-PCR should be used as complementary modalities in diagnosing EWSR1-rearranged neoplasms, but as tumour groups harbouring EWSR1 rearrangements are increasingly characterised and because given translocations involving EWSR1 and its partner genes are not always specific for tumour types, it is critical that these are evaluated by specialist soft tissue surgical pathologists noting the morphologic and immunohistochemical context. As RT-PCR using commercial primers is limited to only the most prevalent EWSR1 fusion transcripts, the incorporation of high-throughput sequencing technologies into the standard diagnostic repertoire to assess for multiple molecular abnormalities of soft tissue tumours in parallel (including detection of newly characterised Ewing sarcoma-like tumours) might be the most effective and efficient means of ancillary diagnosis in future.

Pazopanib, a promising option for the treatment of aggressive fibromatosis.

Desmoid tumour/aggressive fibromatosis (DT/AF) is a rare soft-tissue neoplasm that is locally aggressive but does not metastasize. There is no standard systemic treatment for symptomatic patients, although a number of agents are used. Tyrosine kinase inhibitors have recently been reported to show useful activity. We reviewed our bi-institutional (Royal Marsden Hospital, Cambridge University Hospitals) experience with the tyrosine kinase inhibitor pazopanib in the treatment of progressing DT/AF. Eight patients with DT/AF were treated with pazopanib at Royal Marsden Hospital and Cambridge University Hospitals between June 2012 and June 2016. The median age of the patients was 37.5 (range: 27-60) years. The median duration of pazopanib treatment was 12 (range: 5-22) months and for three patients the treatment is ongoing. Three patients discontinued treatment early (patient preference, intolerable toxicity and logistical reasons, respectively). None of the patients showed radiological progression while on treatment, best responses according to Response Evaluation Criteria In Solid Tumors 1.1 were partial response in 3/8 and stable disease in 5/8 cases. Six patients derived clinical benefit from treatment in terms of improved function and/or pain reduction. Median progression-free survival was 13.5 (5-36) months. Only one patient experienced intolerable toxicity (grade 3 hypertension) leading to early treatment discontinuation. In our series of patients with DT/AF, pazopanib demonstrated important activity both in terms of symptom control (75%) and absence of radiological progression (100%). Results of ongoing confirmatory trials are eagerly awaited.

Treatment patterns and clinical outcomes with pazopanib in patients with advanced soft tissue sarcomas in a compassionate use setting: results of the SPIRE study.

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%.

Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organisation for Research and Treatment of Cancer 62012 study.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) 62012 study was a Phase III trial of doxorubicin versus doxorubicin-ifosfamide chemotherapy in 455 patients with advanced soft tissue sarcoma (STS). Analysis of the main study showed that combination chemotherapy improved tumor response and progression-free survival, but differences in overall survival (OS) were not statistically significant. We analyzed factors prognostic for tumor response and OS, and assessed histological subgroup and tumor grade as predictive factors to identify patients more likely to benefit from combination chemotherapy. METHODS: Central pathology review was performed by six reference pathologists. Gender, age, performance status, time from first presentation with sarcoma to starting palliative chemotherapy, tumor grade, histological subgroup, primary tumor site involvement, and sites of metastases were assessed as prognostic factors. RESULTS: Three hundred and ten patients were included in this study. Discordance between local and central pathology opinion of tumor histology and tumor grade was observed in 98 (32%) and 122 (39%) cases, respectively. In multivariate analysis, liposarcoma patients had improved tumor response compared to other histological subgroups, whilst patients with metastases other than lung, liver or bone had a poorer response [odds ratio (OR) 0.42, 95% confidence interval (CI) 0.23-0.78; p = 0.006]. Patients with bone metastases had reduced OS [hazard ratio (HR) 1.56, 95% CI 1.16-2.09; p = 0.003]. By central pathology review, patients with undifferentiated pleomorphic sarcoma (UPS) had improved tumor response and OS with doxorubicin-ifosfamide compared to single-agent doxorubicin (OR 9.90, 95% CI 1.93-50.7 and HR 0.44, 95% CI 0.26-0.79, respectively). Grade III tumors had improved response with combination chemotherapy but there was no interaction between chemotherapy and grade on OS. CONCLUSIONS: Prospective central pathology review of tumor histology should be integrated into future STS clinical trials. Doxorubicin-ifosfamide may be most appropriate for young, fit patients with poorly differentiated Grade III tumors including UPS.

Monogenic and polygenic determinants of sarcoma risk: an international genetic study.

BACKGROUND: Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. METHODS: In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). FINDINGS: The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29-58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24-1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95% CI 1·57-3·14, p=1·2 × 10(-6)) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance. INTERPRETATION: About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. FUNDING: Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.

Gene expression profiling identifies distinct molecular subgroups of leiomyosarcoma with clinical relevance.

BACKGROUND: Soft tissue sarcomas are heterogeneous and a major complication in their management is that the existing classification scheme is not definitive and is still evolving. Leiomyosarcomas, a major histologic category of soft tissue sarcomas, are malignant tumours displaying smooth muscle differentiation. Although defined as a single group, they exhibit a wide range of clinical behaviour. We aimed to carry out molecular classification to identify new molecular subgroups with clinical relevance. METHODS: We used gene expression profiling on 20 extra-uterine leiomyosarcomas and cross-study analyses for molecular classification of leiomyosarcomas. Clinical significance of the subgroupings was investigated. RESULTS: We have identified two distinct molecular subgroups of leiomyosarcomas. One group was characterised by high expression of 26 genes that included many genes from the sub-classification gene cluster proposed by Nielsen et al. These sub-classification genes include genes that have importance structurally, as well as in cell signalling. Notably, we found a statistically significant association of the subgroupings with tumour grade. Further refinement led to a group of 15 genes that could recapitulate the tumour subgroupings in our data set and in a second independent sarcoma set. Remarkably, cross-study analyses suggested that these molecular subgroups could be found in four independent data sets, providing strong support for their existence. CONCLUSIONS: Our study strongly supported the existence of distinct leiomyosarcoma molecular subgroups, which have clinical association with tumour grade. Our findings will aid in advancing the classification of leiomyosarcomas and lead to more individualised and better management of the disease.

Health-related quality-of-life results from PALETTE: A randomized, double-blind, phase 3 trial of pazopanib versus placebo in patients with soft tissue sarcoma whose disease has progressed during or after prior chemotherapy-a European Organization for research and treatment of cancer soft tissue and bone sarcoma group global network study (EORTC 62072).

BACKGROUND: Health-related quality of life (HRQoL) was an exploratory endpoint in the PALETTE trial, a global, double-blind, randomized, phase 3 trial of pazopanib 800 mg versus placebo as second-line or later treatment for patients with advanced soft tissue sarcoma (N = 369). In that trial, progression-free survival was significantly improved in the pazopanib arm (median, 4.6 vs 1.6 months; hazard ratio, 0.31; P < .001), and toxicity of pazopanib consisted mainly of fatigue, diarrhea, nausea, weight loss, and hypertension. METHODS: HRQoL was assessed using the 30-item core European Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline and at weeks 4, 8, and 12 in patients who received treatment on protocol. The primary HRQoL endpoint was the EORTC QLQ-C30 global health status scale. RESULTS: Compliance with HRQoL assessments was good, ranging from 94% at baseline to 81% at week 12. Differences in scores on the EORTC QLQ-C30 global health status subscale between the 2 treatment arms were not statistically significant and did not exceed the predetermined, minimal clinically important difference of 10 points (P = .291; maximum difference, 3.8 points). Among the other subscales, the pazopanib arm reported significantly worse symptom scores for diarrhea (P < .001) loss of appetite (P < .001), nausea/vomiting (P < .001), and fatigue (P = .012). In general, HRQoL scores tended to decline over time in both arms. CONCLUSIONS: HRQoL did not improve with the receipt of pazopanib. However, the observed improvement in progression-free survival without impairment of HRQoL was considered a meaningful result. The toxicity profile of pazopanib was reflected in the patients' self-reported symptoms but did not translate into significantly worse overall global health status during treatment.

Phase I study of nintedanib incorporating dynamic contrast-enhanced magnetic resonance imaging in patients with advanced solid tumors.

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.

Etoposide and carbo-or cisplatin combination therapy in refractory or relapsed Ewing sarcoma: a large retrospective study.

BACKGROUND: Patients with Ewing sarcoma (EWS) who develop refractory or relapsed disease have limited treatment options. In some sarcoma centres in Europe the combination of etoposide with carbo- or cisplatin is being used for these patients, however, there are no published data available yet. Here we investigated the outcome of the combination treatment for patients with advanced Ewing sarcoma in progression after standard treatment. PROCEDURE: All patients diagnosed with EWS between 1980 and 2012 in one of six major sarcoma centres in Europe and treated with either carboplatin and etoposide or cisplatin and etoposide were included and data were retrospectively collected for analysis. RESULTS: A total of 107 patients enrolled in this study of which 61 received the combination of etoposide and carboplatin and 46 received etoposide and cisplatin. The median overall survival (OS) was 23 months for both patient groups and the 5-year OS was 24.5% for the patients who received carboplatin and etoposide and 20% for those who received cisplatin and etoposide. The progression free survival was better in patients treated with the combination of carboplatin and etoposide (14.5 vs. 6.3 months P = 0.023). CONCLUSION: This is a retrospective study on the combination treatment of etoposide and carbo- or cisplatin in refractory Ewing sarcoma. The results justify exploring the combination in a prospective study with relapsed patients.

Primary cutaneous and subcutaneous Ewing sarcoma.

BACKGROUND: Primary cutaneous/subcutaneous Ewing sarcoma (scEWS) is extremely rare. We describe clinical features, treatment, and outcome of this Ewing localization. PROCEDURE: Retrospective study (1996-2012) on 56 patients. RESULTS: Most primary scEWS occurred in late adolescent/young adult females (F/M = 1.9; median age 21.5 years), with primary tumor in the extremity/trunk (48.5%/39%). Only 35/56 samples had Real-Time-Polymerase-Chain-Reaction/Fluorescent-In-Situ-Hybridization analysis, 32/35 had EWS-translocation. Most of them exhibited known favorable prognostic factors: localized disease (54/56), initial tumor volume < 200 ml (51/53). Thirty and 25 patients received chemotherapy according to Euro-Ewing99 or a shorter/less intense chemotherapy regimen associated with milder toxicity. One patient had not received chemotherapy. Surgery was performed at diagnosis in 37 patients (18/37 marginal/intra-lesional resections) followed by secondary surgery in 8/37 (three remained marginal). Nineteen other patients had an initial biopsy followed by chemotherapy, 15/19 underwent late surgery (4/15 marginal/intra-lesional resections). Overall, 27/56 patients received radiotherapy. Median follow-up was six years (1-15). Two patients with metastatic disease progressed at metastatic sites. Four patients with localized disease experienced progression/relapse (local n = 3, metastatic n = 1). Survival was excellent: 5y-OS and 5y-EFS were 93.8% (95%CI = 83-98%) and 88.5% (95%CI-= 77-95), respectively. CONCLUSIONS: Unplanned primary surgery should be avoided to try to minimize potential long term sequels due to secondary surgery or radiotherapy. Biopsy with molecular analysis and staging should be performed at diagnosis to inform treatment recommendations. Patients with metastases should be treated aggressively as for other metastatic EWS. Further studies are necessary to clarify whether a less intensive chemotherapy regimen could be safely used in localized disease to minimize acute/late toxicities.

Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.

BACKGROUND: Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. METHODS: We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18-60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m(2) by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m(2); 25 mg/m(2) per day, days 1-3) plus ifosfamide (10 g/m(2) over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs ≥50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984. FINDINGS: Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31-77) in the doxorubicin only group and 59 months (36-72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12·8 months [95·5% CI 10·5-14·3] in the doxorubicin group vs 14·3 months [12·5-16·5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0·83 [95·5% CI 0·67-1·03]; stratified log-rank test p=0·076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7·4 months [95% CI 6·6-8·3]) than for the doxorubicin group (4·6 months [2·9-5·6]; HR 0·74 [95% CI 0·60-0·90], stratified log-rank test p=0·003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228; p<0·0006). The most common grade 3 and 4 toxic effects-which were all more common with doxorubicin and ifosfamide than with doxorubicin alone-were leucopenia (97 [43%] of 224 patients vs 40 [18%] of 223 patients), neutropenia (93 [42%] vs 83 [37%]), febrile neutropenia (103 (46%) vs 30 [13%]), anaemia (78 [35%] vs 10 [5%]), and thrombocytopenia (75 [33%]) vs one [<1%]). INTERPRETATION: Our results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumour shrinkage. These findings should help individualise the care of patients with this disease. FUNDING: Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, Amgen.

Phase I trials in patients with relapsed, advanced upper gastrointestinal carcinomas: experience in a specialist unit.

BACKGROUND: Conventional therapeutic options for patients with advanced upper gastrointestinal cancers (UGIC) are limited. Following first-line treatments, some patients are offered experimental therapies, including participation in Phase I trials. This study aims to describe the experience of UGIC patients treated in a dedicated Phase I unit. METHODS: Patient, tumour and treatment characteristics, and clinical outcomes of UGIC patients treated consecutively at the Drug Development Unit, Royal Marsden Hospital, between 2005 and 2009, were recorded. RESULTS: Ninety-six patients who previously received a median of 2 (range 1-4) lines of chemotherapies were treated in 30 Phase I trials. Of 81 evaluable patients, 9 achieved RECIST-objective response (11 %) with a 6-month clinical benefit rate of 14 %. Median progression free and overall survival were 7.7 weeks [95 %CI 7.7 (6.4-9.0)] and 19.1 weeks (95 %CI 17.5-20.8), respectively. Grade 3 or 4 toxicities were observed in 37 patients (39 %) and led to trial discontinuation in 9 (9 %); no toxicity-related death was recorded. In the multivariate analysis, serum albumin (<35 g/dl, HR2.0, p = 0.002) and lactate dehydrogenase (>192 µmol/l, HR1.7, p = 0.016) were prognostic of overall survival. CONCLUSION: Phase I clinical trials can be considered a reasonable option in selected patients with relapsed UGIC. The use of objective prognosticators may improve selection and risk/benefit profile of patients.