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.
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.
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.
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.
Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.
Primary malignant bone sarcomas (MBS) are rare and there are few studies examining their incidence and outcome. Here, the incidence and survival of all subtypes of MBS registered in England between ...1979 and 2007 were analysed from patient registry data held by the National Cancer Intelligence Network (NCIN). Over 11,002 new cases of MBS were registered, an average of 379 per year. There was no change in incidence demonstrated over the study period (p = 0.08). Although a peak incidence is observed in adolescence, approximately half of MBS are diagnosed in patients over 50 years. An improvement in outcome of MBS was observed between those patients registered from 1979 to 1983 and 1983 to 1987 (p < 0.0001), but there has been no improvement since. In the most recent period studied (patients diagnosed 1998–2002) 5‐year survival was 55% in Ewing sarcoma, 70% in chondrosarcoma, 56% in chordoma and 43% in osteosarcoma. Patients diagnosed with osteosarcoma over the age of 40 years or with a non‐extremity tumour have a significantly inferior outcome; 22% 5‐year survival >40 years compared with 53% <40 years (p < 0.0001) and 16% non‐extremity tumour compared to 48% extremity tumour (p < 0.0001). This population‐based study has allowed us to confidently define the English incidence and survival rates of both the commoner bone tumours such as osteosarcoma, and rarer entities such as chordoma as well as groups with inferior outcome. The lack of significant improvement over recent decades for these diseases is cause for concern and further research.
Consensus guidelines outline that patients with primary retroperitoneal sarcoma (RPS) should be managed within specialist sarcoma centres (SSC). There is, however, a paucity of population-based data ...detailing incidence and outcomes in these patients. Hence, we aimed to evaluate patterns of care among RPS patients in England and compare outcomes for those undergoing surgery in high-volume specialist sarcoma centres (HV-SSC), low-volume SSC (LV-SSC), and non-SSC (N-SSC).
Data on patients diagnosed with primary RPS between 2013 and 2018 were extracted from NHS Digital’s National Cancer Registration and Analysis Service using the national cancer registration dataset. Diagnostic pathways, treatment, and survival outcomes were compared between HV-SSC, LV-SSC, and N-SSC. Uni- and multivariate analyses were calculated.
Of 1878 patients diagnosed with RPS, 1120 (60%) underwent surgery within 12 months of diagnosis, with 847 (76%) operated on at SSC; of these, 432 patients (51%) were operated on in HV-SSC, and 415 (49%) in LV-SSC. One- and 5-year estimated overall survival (OS) rates for patients undergoing surgery in N-SSC were 70.6% (95% confidence interval CI: 64.8–75.7) and 42.0% (CI: 35.9–47.9), compared to 85.0% (CI: 81.1–88.1) and 51.7% (CI: 46.6–56.6) in LV-SSC (p < 0.01), and 87.4% (CI: 83.9–90.2) and 62.8% (CI: 57.9–67.4) in HV-SSC, (p < 0.01). After adjusting for patient- and treatment-related factors, patients treated in HV-SSC were found to have significantly longer OS than those treated at LV-SSC, with an adjusted hazard ratio of 0.78 (CI: 0.62–0.96, p < 0.05).
Patients with RPS undergoing surgery in HV-SSC have significantly better survival outcomes than those treated in N-SSC and L-SSC.
•24% of patients diagnosed with primary RPS are managed outside SSC.•HV-SSC had better survival outcomes compared to LV-SSC and N-SSC.•HV-SSC are independently associated with longer OS on the multivariate analysis.
Current questions in bone sarcomas Strauss, Sandra J; Whelan, Jeremy S
Current opinion in oncology,
07/2018, Letnik:
30, Številka:
4
Journal Article
Odprti dostop
Osteosarcoma and Ewing sarcoma, the most common primary bone tumours in young people, are curable in most patients. However, these tumours remain a significant challenge due to the complexity and ...intensity of treatment and its long-term morbidity and the significant proportion of patients in whom treatment is unsuccessful. This review addresses questions about current management and emerging therapeutic targets for patients with osteosarcoma, Ewing sarcoma and chondrosarcoma, the commonest bone sarcoma but more common in older patients.
The largest collaborative international study in osteosarcoma, EURAMOS-1 determined that treatment of patients with resectable disease should not be altered on basis of pathological response to neoadjuvant chemotherapy. In view of little improvement in outcome being evident in recent years, novel therapeutic approaches are required. Putative targets and clinical trials of novel agents are discussed, including emerging targets such as poly (ADP-ribose) polymerase inhibition and isocitrate dehydrogenase inhibition in Ewing sarcoma and chondrosarcoma, respectively. Newer radiotherapy techniques including proton beam and particle ion therapy may be important for local tumour control in selected patients.
Collaborative studies are essential to answer current questions and investigate novel therapies in these malignancies to improve outcome and quality of life for patients.
One approach to identifying cancer-specific vulnerabilities and therapeutic targets is to profile genetic dependencies in cancer cell lines. Here, we describe data from a series of siRNA screens that ...identify the kinase genetic dependencies in 117 cancer cell lines from ten cancer types. By integrating the siRNA screen data with molecular profiling data, including exome sequencing data, we show how vulnerabilities/genetic dependencies that are associated with mutations in specific cancer driver genes can be identified. By integrating additional data sets into this analysis, including protein-protein interaction data, we also demonstrate that the genetic dependencies associated with many cancer driver genes form dense connections on functional interaction networks. We demonstrate the utility of this resource by using it to predict the drug sensitivity of genetically or histologically defined subsets of tumor cell lines, including an increased sensitivity of osteosarcoma cell lines to FGFR inhibitors and SMAD4 mutant tumor cells to mitotic inhibitors.
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•Kinome-wide (714 gene) siRNA screens in 117 cell lines from ten cancer histotypes•Integrating genotype data reveals cancer driver gene dependencies•Integrating protein interaction data aids the interpretation of genetic dependencies•Identified dependencies enable prediction of mutant cell line responses to drugs
Campbell et al. use parallel siRNA screens to identify the kinase dependencies of 117 cancer cell lines from ten cancer types. They use this resource to identify kinase dependencies associated with specific cancer types or driver genes and show that the integration of protein interaction networks facilitates the interpretation of these dependencies.
Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of ...structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis. Using mathematical deconvolution strategies to unravel the complex copy-number profiles and mutational timing models we infer distinct evolutionary pathways of these rare cancers. In addition, 15% of tumors exhibited raised mutational burdens that correlated with gene expression signatures of immune infiltration, and good prognosis.
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•Undifferentiated sarcomas contain biologically relevant molecular subgroups•Identification of mismatch repair deficiency open up alternate avenues for therapy•Pseudohaploidization is a recurrent event in undifferentiated sarcomas•Copy-number signatures are useful for inferring states of sarcoma evolution
Steele et al. determine the molecular landscape of undifferentiated sarcomas. They identify tumors with high mutation burdens, which are enriched for activation of immune pathways and have good prognoses, and deduce four tumorigenic routes, all of which begin with driver mutations before whole genome duplication.
Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key ...pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.
Sarcomas are rare cancers with a spectrum of clinical needs and outcomes. We investigated care experiences and health-related quality of life (HRQoL) in sarcoma patients during the COVID-19 pandemic. ...Patients with appointments during the first two months of the UK lockdown were invited to complete a survey. Questions included views on care modifications, COVID-19 worry and psychosocial impact, and EORTC-QLQ-C30 items. 350 patients completed the survey; median age 58 (16–92) years. Care modifications included telemedicine (74%) and postponement of appointments (34%), scans (34%) or treatment (10%). Most felt the quality of care was not affected (72%), however, social life (87%) and emotional wellbeing (41%) were affected. Worry about COVID-19 infection was moderately high (mean 5.8/10) and significantly related to higher cancer-related worry; associated with lower emotional functioning irrespective of treatment intent. Curative patients (44%) with low resilient coping scores had significantly higher COVID-19 worry. Patients who did not know their treatment intent (22%) had significantly higher COVID-19 worry and insomnia. In summary, care experiences were generally positive; however, cancer-related worry, low resilient coping and uncertainty about treatment intent were associated with COVID-19 worry. These patients may benefit from additional psychological support during the pandemic and beyond.
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