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.

Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application. METHODS: Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS). RESULTS: Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54-5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19-3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42-3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01-4.68, P = 0.04). CONCLUSIONS: This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies.

Magnetic resonance imaging of trunk and extremity myxoid liposarcoma: diagnosis, staging, and response to treatment.

Myxoid liposarcoma (MLS) accounts for approximately 30% of all liposarcomas. The majority are intermediate-grade tumours, but the presence of >5% round cell component renders it a high-grade sarcoma with subsequent poorer outcome. MLS most commonly arises in the lower extremities, has a predilection for extra-pulmonary sites of metastatic disease, and is recognized to be radiosensitive. The purpose of the current article is to review the role of MRI in the management of MLS, including the characteristic features of the primary tumour, features which help to identify a round cell component and thus determine prognosis, the role of whole-body MRI for evaluation of extra-pulmonary metastatic disease, and the utility of MRI for assessing treatment response. The MRI differential diagnosis of MLS is also considered.

A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in high-grade uterine sarcoma after stabilization or response to doxorubicin ± ifosfamide following surgery or in metastatic first line treatment (EORTC62113).

BACKGROUND: Uterine sarcomas are a group of rare tumors that include different subtypes. Patients with histopathological high-grade diseases are at high-risk of recurrence or progression, and have a poor prognosis. We aim to explore the most appropriate management in patients with uterine high-grade sarcomas. PRIMARY OBJECTIVE: To assess the efficacy of maintenance treatment with cabozantinib in patients with high-grade uterine sarcomas who achieved clinical benefit after standard chemotherapy. STUDY HYPOTHESIS: Maintenance treatment with cabozantinib after standard chemotherapy given as an adjuvant treatment after curative surgery, or in locally advanced or metastatic disease, increases progression-free survival compared with placebo TRIAL DESIGN: This is a randomized double blinded phase II trial. MAJOR INCLUSION/EXCLUSION CRITERIA: The study is enrolling adult patients with high-grade undifferentiated uterine sarcomas, high-grade endometrial stromal sarcomas, high-grade leiomyosarcoma, and high-grade adenosarcoma, FIGO (Federation International gynecologue Obstétricien) stage II/III to IV in stable disease or who achieved complete or partial response with doxorubicin ± ifosfamide, who are assigned 1:1 to 60 mg daily cabozantinib (experimental arm) or placebo (control arm), as maintenance therapy. Exclusion criteria include low-grade sarcoma. PRIMARY ENDPOINT: Progression-free survival at 4 months. SAMPLE SIZE: The study plans to enroll 90 patients to allow the randomization of 54 patients to detect an improvement in 4-month progression-free survival from 50% to 80% with 15% significance level and 85% power. Estimated dates for accrual completion: recruitment for the trial started in February 2015, and has currently enrolled 83 patients, of whom 35 patients have been randomized. The end of recruitment is anticipated for December 2020. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT01979393.

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.

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma.

BACKGROUND: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. METHODS: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression. RESULTS: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis. CONCLUSIONS: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity.

Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.

BACKGROUND: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. METHODS: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m2 on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m2 on days 1 and 8 and intravenous docetaxel 75 mg/m2 on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. FINDINGS: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7-29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5-54·6] vs 46·4% [37·5-54·8]); median progression-free survival (23·3 weeks [95% CI 19·6-30·4] vs 23·7 weeks [18·1-20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99-1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. INTERPRETATION: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. FUNDING: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.

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.

First-line treatment in advanced or metastatic disease: one size fits all or adapted to specific histiotypes?

PURPOSE OF REVIEW: This article evaluates the supporting evidence for adapting choice of first-line chemotherapy to specific histological subtypes in advanced or metastatic soft tissue sarcoma (STS). RECENT FINDINGS: The evidence for the current standard of care for first-line chemotherapy in STS is reviewed. This is followed by an overview of the evidence for use of specific chemotherapy drugs in a number of specific STS histological subtypes. The more recent literature on newer drugs being used in the first-line setting in STS is then reviewed, and finally an assessment is made as to whether it is possible at this time to tailor first-line chemotherapy to histiotype. SUMMARY: The review shows that at present there is insufficient evidence to support the concept of adapting choice of first-line chemotherapy in advanced or metastatic STS to specific histiotypes.

Follow-up practices for high-grade extremity Osteosarcoma.

BACKGROUND: The optimal conduct of follow-up (FU) of patients with osteosarcoma is uncertain. In the absence of any formal validation of optimal timing and method of surveillance, guidance is provided by oncology societies' recommendations. FU is designed to detect either local recurrence or metastatic disease at a time when early treatment is still possible and might be effective. METHODS: We performed a retrospective analysis of 101 patients with high-grade extremity osteosarcoma in a single centre. Chest x-ray (CXR) was used as routine surveillance method; however patients with initial lung metastases or previous suspicious findings had computed tomography (CT) scans. RESULTS: With a median FU time of 30.7 months 34 patients relapsed. Relapse-free survival after 5 years was 61% (CI 52%; 73%), late relapses occurred in only two patients between 2 and 5 years of FU. Twenty-five of the 34 relapses were detected at routine FU appointments. All 8 local recurrences were noted clinically. Twenty-two patients had metastases confined to the lungs, either detected on CXR or CT. Thirty-two percent of patients with lung metastases only were salvaged successfully. CONCLUSIONS: Routine FU in high-grade osteosarcoma results in clinical detection of local relapse, and detection of lung metastases by CXR at a time when metastatectomy is possible. The optimal time interval for FU appointments is not known, however we recommend more frequent surveillance visits during the two years after treatment. We hypothesize that routine CT scans are not required and propose CXR for detection of lung metastases.

Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib.

BACKGROUND: The objectives of this study were to provide sunitinib to patients with gastrointestinal stromal tumor (GIST) who were otherwise unable to obtain it and to collect broad safety and efficacy data from a large population of patients with advanced GIST after imatinib failure. (ClinicalTrials.gov identifier NCT00094029). METHODS: Imatinib-resistant/intolerant patients with advanced GIST received sunitinib on an initial dosing schedule of 50 mg daily in 6-week cycles (4 weeks on treatment, 2 weeks off treatment). Tumor assessment frequency was according to local practice, and response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.0. Overall survival (OS) and safety were assessed regularly. Post hoc analyses evaluated different patterns of treatment management. RESULTS: At final data cutoff, 1124 patients comprised the intent-to-treat population, and 15% of these patients had a baseline Eastern Cooperative Oncology Group performance status ≥2. The median treatment duration was 7.0 months. The median time to tumor progression was 8.3 months (95% confidence interval [CI], 8.0-9.4 months), the median OS was 16.6 months (95% CI, 14.9-18.0 months), and 36% of patients were alive at the time of analysis. Patients for whom the initial dosing schedule was modified exhibited longer median OS (23.5 months) than those who were treated strictly according to the initial dosing schedule (11.1 months). The most common treatment-related grade 3 and 4 adverse events were hand-foot syndrome (11%), fatigue (9%), neutropenia (8%), hypertension (7%), and thrombocytopenia (6%). Treatment-related adverse events associated with cardiac function (eg, congestive heart failure and myocardial infarction) were reported at frequencies of ≤1% each. CONCLUSIONS: This treatment-use study confirms the long-term safety and efficacy of sunitinib in a large international population of patients with advanced GIST after imatinib failure.

Gynecologic Cancer InterGroup (GCIG) consensus review for endometrial stromal sarcoma.

Endometrial stromal sarcoma (ESS) accounts for approximately 20% of all uterine sarcomas and presents, at a mean age, around 50 years of age. Half of the patients are premenopausal. ESS often manifests as an endometrial polyp and 60% of cases present with FIGO stage I disease. The natural history is one of slow growing indolent disease. Typical microscopic findings include a uniform population of endometrial stromal-type cells invading the myometrium and myometrial vessels. Imaging studies cannot reliably diagnose ESS preoperatively, so surgical resection for a presumed fibroid is a common scenario. Hysterectomy is the cornerstone of treatment for localized ESS, but morcellation should be avoided. Systematic lymphadenectomy in ESS does not improve the outcome. Leaving the ovaries in situ does not worsen survival and this is of importance especially for young women. The data support the current practice to administer adjuvant hormonal treatment, although several questions remain, such as optimal doses, regimens (progestins or aromatase inhibitors) and duration of therapy. Repeat surgery for recurrent disease that is indolent and hormone sensitive appears to be an acceptable approach. Systemic treatment for recurrent disease is mainly hormonal.

The IMRiS Trial: A Phase 2 Study of Intensity Modulated Radiation Therapy in Extremity Soft Tissue Sarcoma.

PURPOSE: Primary soft tissue sarcoma (STS) is rare, with many tumors occurring in extremities. Local management is limb-sparing surgery and preoperative/postoperative radiation therapy (RT) for patients at high risk of local recurrence. We prospectively investigated late normal tissue toxicity and limb function observed after intensity modulated RT (IMRT) in extremity STS. METHODS AND MATERIALS: Patients with extremity STS, age ≥16 years. Two treatment cohorts: IMRT 50 Gy in 25 × 2 Gy fractions (preoperative) or 60/66 Gy in 30/33 × 2 Gy fractions (postoperative). The primary endpoint was the rate of grade ≥2 late soft tissue fibrosis (subcutaneous tissue) at 24 months after IMRT (Radiation Therapy Oncology Group late radiation morbidity scoring). RESULTS: One hundred sixty-eight patients were registered between March 2016 and July 2017. Of those, 159 (95%) received IMRT (106, 67% preoperative RT; and 53, 33% postoperative RT) with a median follow-up of 35.2 months (IQR, 32.9-36.6); 62% men, median age 58 years. Of 111 patients assessable for the primary endpoint at 24 months, 12 (10.8%; 95% CI, 5.7%-18.1%) had grade ≥2 subcutaneous fibrosis. The overall rate at 24 months of Radiation Therapy Oncology Group late skin, bone, and joint toxicity was 7 of 112 (6.3%), 3 of 112 (2.7%), and 10 of 113 (8.8%), respectively, and for Stern's scale edema was 6 of 113 (5.3%). More wound complications were observed with preoperative than postoperative RT (29.2% vs 3.8%). Overall survival at 24 months was 84.6%, and the local recurrence event rate at 24 months was 10%. CONCLUSIONS: The rate of grade ≥2 subcutaneous fibrosis at 24 months after IMRT was 10.8%, consistent with other recent trials of IMRT and lower than historically reported rates in patients treated with 3-dimensional conformal RT. This trial provides further evidence for the benefits of IMRT in this patient population.

Best clinical management of tenosynovial giant cell tumour (TGCT): A consensus paper from the community of experts.

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive, mesenchymal tumor arising from the joints, bursa and tendon sheaths. TGCT comprises a nodular- and a diffuse-type, with the former exhibiting mostly indolent course and the latter a locally aggressive behavior. Although usually not life-threatening, TGCT may cause chronic pain and adversely impact function and quality of life (QoL). CSFR1 inhibitors are effective with benefit on symptoms and QoL but are not available in most countries. The degree of uncertainty in selecting the most appropriate therapy and the lack of guidelines on the clinical management of TGCT make the adoption of new treatments inconsistent across the world, with suboptimal outcomes for patients. A global consensus meeting was organized in June 2022, involving experts from several disciplines and patient representatives from SPAGN to define the best evidence-based practice for the optimal approach to TGCT and generate the recommendations presented herein.

Heritable defects in telomere and mitotic function selectively predispose to sarcomas.

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.

Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis.

BACKGROUND: Pigmented villonodular synovitis (PVNS) (also known as diffuse-type giant cell tumor) and tenosynovial giant cell tumors (TGCT) are rare, usually benign neoplasms that affect the synovium and tendon sheaths in young adults. These tumors are driven by the overexpression of colony stimulating factor-1 (CSF1). CSF1 is expressed by a minority of tumor cells, which, in turn attract non-neoplastic inflammatory cells that express CSF1 receptor (CSF1R) through a paracrine effect. METHODS: Imatinib mesylate (IM) blocks CSF1R, and previous case reports indicated that it also exerts antitumor activity in PVNS. The authors conducted a multi-institutional retrospective study to assess the activity of IM in patients with locally advanced/metastatic PVNS/TGCT. RESULTS: Twenty-nine patients from 12 institutions in Europe, Australia, and the United States were included. There were 13 men, the median age was 41 years, and the most common site of disease was the knee (n = 17; 59%). Two patients had metastatic disease to the lung and/or bone. Five of 27 evaluable patients had Response Evaluation in Solid Tumor (RECIST) responses (overall response rate, 19%; 1 complete response and 4 partial responses), and 20 of 27 patients (74%) had stable disease. Symptomatic improvement was noted in 16 of 22 patients (73%) who were assessable for symptoms. Despite a high rate of symptomatic improvement and a favorable safety profile, 6 patients discontinued because of toxicity, and 4 patients decided to discontinue IM for no clear medical reason. CONCLUSIONS: IM displayed interesting activity in patients with PVNS/TGCT, providing proof of concept for targeting CSF1R in this disease. The authors concluded that the benefits of alleviating morbidity in patients with localized PVNS/TGCT must be balanced against the potential toxicity of chronic drug therapy.

Survival after high-dose chemotherapy for refractory and recurrent Ewing sarcoma.

BACKGROUND: outcome of primary refractory or recurrent Ewing sarcoma (RRES) is poor and the role of high-dose therapy (HDT) remains uncertain. We retrospectively reviewed all patients treated for RRES in the London Sarcoma Service (LSS) over a 22-year period with the aim of adding to the current literature and developing a prognostic risk score to aid clinical decision-making. METHODS AND RESULTS: One hundred and ninety-six patients were included; 64 patients received HDT, 98 standard non-HDT chemotherapy and 34 no systemic therapy. At RRES, median age was 20 years and seventy-four per cent of patients had progressed or relapsed within 24 months. Median overall survival for HDT and non-HDT patients was 76 months (95% CI 34.8-117.2) and 10.5 months (95% CI 8.9-12.1), respectively. Two and five-year post-relapse survival (PRS) for HDT patients was 67.9% (SE 5.9) and 52.7% (SE 6.5), and for non-HDT patients, 20.5% (SE 4.2) and 2% (SE 1.5). Four prognostic factors significant on multivariate analysis were assigned a score of one point each, creating good (score 0), intermediate (score 1-2) and poor (score 3-4) prognosis groups. The increased score was significantly associated with reduced PRS. CONCLUSION: Our study demonstrates that in RRES, HDT is associated with superior outcomes compared with non-HDT chemotherapy. RRES patients can be risk-stratified according to a predictive prognostic index we have developed, with the potential benefit of HDT observed even in patients with poor prognostic scores.

DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours.

AIMS: The histopathological diagnosis of gastrointestinal stromal tumours (GIST) is typically made based on a combination of clinical and morphological features supported by immunohistochemistry studies. The aim of this study was to examine the staining quality, sensitivity, specificity and utility of antibodies used commonly in GIST diagnosis. METHODS AND RESULTS: Immunohistochemistry with a panel of antibodies [CD117, DOG1, protein kinase C (PKC)-theta, nestin, CD34, smooth muscle actin (SMA), desmin, S100 and CD171] was performed on whole sections from 187 GIST and 29 gastrointestinal mesenchymal tumours, and on several microarrays including 355 GISTs and 120 soft tissue sarcomas. Results showed that DOG1 and CD117 were the most sensitive and specific antibodies used in GIST diagnosis. PKC-theta and nestin were sensitive, but less specific, also staining other spindle cell tumours commonly considered in the differential diagnosis of GIST. CD34 staining was less sensitive than many of the other antibodies and of limited aid in diagnosis. The smooth muscle markers SMA and desmin, together with the neural marker S100, were unhelpful in confirming a diagnosis of GIST, but were particularly useful in the exclusion/diagnosis of other gastrointestinal mesenchymal tumour types. CONCLUSIONS: In the majority of histologically suspected GISTs a combination of CD117 and DOG1 immunostaining is sufficient to confirm the histological diagnosis.

Guidelines for the management of soft tissue sarcomas.

These guidelines were drawn up following a consensus meeting of UK sarcoma specialists convened under the auspices of the British Sarcoma Group and are intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. The guidelines published by the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) were used as the basis for discussion and adapted according to UK clinical practice and local requirements. Note was also taken of the National Institute for Health and Clinical Excellence (NICE) improving outcomes guidance (IOG) for people with sarcoma and existing technology appraisals. The guidelines are not intended to challenge NICE guidance but discrepancies may exist where current guidance does not reflect an international standard of care owing to the ever-evolving nature of cancer treatment. It is acknowledged that these guidelines will require updating on a regular basis. An appendix lists the key recommendations which are summarised below. Any patient with a suspected soft tissue sarcoma should be referred to a diagnostic centre and managed by a specialist sarcoma multidisciplinary team. Surgical excision followed by post operative radiotherapy is the standard management of high grade limb sarcomas although occasionally amputation remains the only option. Pre-operative treatment with chemotherapy or radiotherapy should be considered for patients with borderline resectable tumours. Isolated limb perfusion may permit limb salvage in some cases where amputation is the only other option. Adjuvant chemotherapy is not routinely recommended but may be considered in certain specific situations. Regular follow up is recommended to assess local control and the development of metastatic disease. Single agent doxorubicin is the standard first line therapy for metastatic disease. Ifosfamide is an alternative if anthracyclines are contraindicated. Combination therapy may be considered in individual patients. Second line agents include ifosfamide, dacarbazine, trabectedin and the combination of gemcitabine + docetaxel. Surgical resection of local recurrence and pulmonary metastases should be considered in individual patients. There is specific guidance on the management of retroperitoneal and uterine sarcomas.