Osteosarcoma (OS), chondrosarcoma, and chordoma are characterized by multiple challenges to the investigator, clinician, and patient. One consequence of their rarity among sarcomas, as well as their ...biologic and clinical heterogeneity, is that management guidelines are inadequate to inform the range of individual patient-treatment decisions from diagnosis, approaches to surgery, chemotherapy, radiotherapy, treatment of recurrence, palliative care, and quality of survivorship. Of high-grade sarcomas, OSs are among the most curable, with more than two-thirds of patients with localized disease likely to achieve long-term survival. Neoadjuvant chemotherapy comprising cisplatin, doxorubicin, and methotrexate with intercalated surgery is the standard of care for resectable OS in those younger than 40 years. Outcomes for OS presenting with unresectable metastases or recurrent disease, or in those older than 40 years are generally poor. Overall results have improved little for all patients with OS, and new treatments are needed. Surgical resection remains the cornerstone of management for chondrosarcoma and chordoma. However, the application of new biologic insights to therapeutic development indicates that improved treatments may soon be routine for patients with chondrosarcoma and chordoma for whom surgery alone is inadequate. For all these uncommon diseases, patients should be offered specialist expert care delivered by experienced multidisciplinary teams in high-volume centers.
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.
In high‐income countries, cancer remains the commonest cause of disease‐related death in adolescents and young adults (AYAs) despite survival improvements. With more than 1,000,000 new diagnoses of ...cancer in AYAs annually worldwide, and their number of life‐years affected by cancer being greatest of all ages, the global burden of cancer in AYAs exceeds that in all other ages. In low‐ and middle‐income countries, where the great majority of the world's 3 billion AYAs reside, the needs of those with cancer have been identified and demand attention. Unique to the age group but universal, the psychosocial challenges they face are the utmost across life's spectrum.
This lead‐off article of a new series in Pediatric Blood and Cancer on AYA oncology attempts to assess the global status of this emerging discipline. The review includes the changing incidence and survival of the common cancers in AYAs—there is no other age group with a similar array of malignancies—and the specific challenges to quality and quantity of life that compromise their lives.
Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary ...approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.
Summary 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/m2 by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m2 ; 25 mg/m2 per day, days 1–3) plus ifosfamide (10 g/m2 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.
The expanding role of primary care in cancer control Rubin, Greg, Prof; Berendsen, Annette, PhD; Crawford, S Michael, MD ...
Lancet oncology/Lancet. Oncology,
09/2015, Letnik:
16, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Summary The nature of cancer control is changing, with an increasing emphasis, fuelled by public and political demand, on prevention, early diagnosis, and patient experience during and after ...treatment. At the same time, primary care is increasingly promoted, by governments and health funders worldwide, as the preferred setting for most health care for reasons of increasing need, to stabilise health-care costs, and to accommodate patient preference for care close to home. It is timely, then, to consider how this expanding role for primary care can work for cancer control, which has long been dominated by highly technical interventions centred on treatment, and in which the contribution of primary care has been largely perceived as marginal. In this Commission, expert opinion from primary care and public health professionals with academic and clinical cancer expertise—from epidemiologists, psychologists, policy makers, and cancer specialists—has contributed to a detailed consideration of the evidence for cancer control provided in primary care and community care settings. Ranging from primary prevention to end-of-life care, the scope for new models of care is explored, and the actions needed to effect change are outlined. The strengths of primary care—its continuous, coordinated, and comprehensive care for individuals and families—are particularly evident in prevention and diagnosis, in shared follow-up and survivorship care, and in end-of-life care. A strong theme of integration of care runs throughout, and its elements (clinical, vertical, and functional) and the tools needed for integrated working are described in detail. All of this change, as it evolves, will need to be underpinned by new research and by continuing and shared multiprofessional development.
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.
Summary Background We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% ...viable tumour) improved event-free survival in patients with high-grade osteosarcoma. Methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2 , doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2 ) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00134030. Findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio HR 0·98 95% CI 0·78–1·23); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 89% patients in MAP vs 268 90% in MAPIE), thrombocytopenia (231 78% in MAP vs 248 83% in MAPIE), and febrile neutropenia without documented infection (149 50% in MAP vs 217 73% in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 12% of 301 in the MAP group vs 71 24% of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.
EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response ...(good response) to induction chemotherapy.
At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary).
Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model.
At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.
Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease ...monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.
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