Aim

The percentage of adolescents and young adults with sarcoma enrolled in multicenter clinical trials is reportedly much lower than that of younger children. We intended to determine if this remained true despite the availability of a study open to patients up to the age of 40 years

Osteosarcoma is the most common malignant bone tumour in children and young people. Approximately 40% patients respond poorly to highly toxic preoperative MAP (methotrexate adriamycin, cisplatin) chemotherapy with consequent inferior survival. The role of genetic polymorphisms in drug response and toxicity is reported in acute leukaemia and some solid tumours. Recent evidence in osteosarcoma suggests increased chemotherapy toxicity is associated with improved survival. The aim of this pilot study is to investigate the influence of drug target and metabolising gene polymorphisms on tumour response and chemotherapy toxicity in osteosarcoma.

Patients who have completed MAP chemotherapy are eligible. Chemotherapy toxicity (CTCAE grade) is collected from patient records. Tumour response is graded as good (> 90% necrosis) or poor (< 90% necrosis) in resection specimen. Peripheral blood DNA is typed for genome-wide single nucleotide polymorphisms (SNP) using the Illumina 610 Quad array and analysed using Bead Studio software. Standard PCR techniques are used to genotype the Thymidylate synthase (TS) gene (folate pathway) for the presence of 2 or 3 copies of a 28 base pair repeat (2R/3R) and a G/C SNP in the 3R allele.

52 patients have entered to date: 33 good responders, 12 poor and 7 unevaluable for response. Median age 18 years (range 10–51), males:females 1.3:1. Median follow up is 39 months (range 2–76) with 11 patients relapsing. 23 patients have TS genotype 2R/2R, nineteen 2R/3R, six 3R/3R, three 2R/4R and one 2R/7R. Neither TS repeat or G/C SNP genotype correlated with histological response or degree of methotrexate stomatitis. Interestingly, presence of the 2R allele was significantly related to relapse (p=0.01) but may reflect small patient numbers. Recurrent methotrexate stomatitis (> 2 episodes of CTCAE grade 2) was weakly correlated with no relapse (p=0.07). Analysis of SNP array data with emphasis on MAP pathway polymorphisms will be presented when complete.

The Euro-E.W.I.N.G. 99 trial aimed to improve the dismal prognosis of patients with primary disseminated multifocal Ewing tumors (PDM-ET) with a dose-intense treatment concept.

From 1999 to 2005, 281 patients with PDM-ET were enrolled onto the EURO-E.W.I.N.G. 99 trial. Median age was 16.2 years (0.4–49). Recommended treatment consisted of 6 VIDE, one VAI cycle, local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by autologuous stem cell transplantation (HDT/SCT).

After a median follow up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27%±3% and 34%±4%. Six VIDE cycles were completed by 250 patients (89%); 169 (60%) received HDT/SCT. Forty-six children less than 14 years and HDT/SCT achieved a 3-year EFS of 45%. Cox regression analyses demonstrated increased risk at diagnosis for patients over 14 years (HR 1.6), a primary tumor volume > 200ml (HR 1.8), more than one bone metastatic site (hazard ratio: HR 2.0, bone marrow metastases (HR 1.6) and additional lung metastases (HR 1.5). An “up front” risk score based on these HR factors identified three groups with EFS rates of 50% for score ≤3 (82 patients), 25% for score > 3 to < 5 (102 patients), and 10% for score ≥5 (70 patients), p< 0.0001.

PDM-ET patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of meta-static spread are relevant risk factors. A score based on these factors identifies PDM-ET patients may facilitate risk adapted treatment approaches.

The European and American Osteosarcoma study group (EURAMOS) was formed by four multinational study groups (COG, COSS, EOI, SSG) based upon a common understanding that broad international collaboration facilitating randomised trials was important for further progress in the field of osteosarcoma. Representatives from each group reached quick agreement on a study design; to determine whether altering post-operative therapy based on response to pre-operative chemotherapy improves outcome. Additionally, a quality-of-life sub-study was included in the project. After a three-year process to resolve regulatory and organisational issues the study opened for accrual in April 2005. Important for an efficient conduction of the trial a common infrastructure was established with central sponsorship (Medical Research Council, UK), one coordinating data centre (MRC Clinical Trials Unit, UK) and a common Safety Desk and a coordinating Quality-of-life data centre (Münster, DE).

As of Dec 2008, a total of 1268 patients from 290 institution in 15 countries have been registered into the trial (AUS 16 patients; B 27; CAN 54; CH 26; D 266; DK 12; FIN 3; H 14; NL 61; NOR 23; NZ 8; OST 7; SWE 25; UK 174; USA 552) and 937 patients participate in the quality-of-life evaluation. 697 patients have been randomized and 53% are assessed as good histological responders. Due to a lower than expected randomisation rate and a higher than expected number of patients with a good histological response the accrual time will be extended by one year to summer 2010.

In conclusion, EURAMOS-1 may serve as a model for a successful non-commercial multinational clinical trial in times of increasing economic and regulatory pressure. It is the fastest accruing and largest osteosarcoma trial ever. In addition, to addressing important questions in a randomised setting a common language in osteosarcoma has been established.

Supported by the European Science Foundation (ESF) under the EUROCORES Program European Clinical Trials (ECT), through contract No. ERASCT-2003-980409 of the European Commission, DG Research, FP6

Sarcomas account for 10% of cancers occurring in 15–24 year olds. Within this group there is considerable clinical and biological heterogeneity and incomplete understanding of optimal treatments.

Most clinical research attention has focused on the management of bone sarcomas, particularly osteosarcoma and Ewing’s tumours. Several factors have been studied which consistently identify patient groups with differing outcomes. Age at diagnosis appears to affect prognosis in Ewing’s tumours but less obviously in localised extremity osteosarcoma. Any underlying biological or treatment delivery variables which may explain these observations have yet to be elucidated. Whether different treatment approaches for bone sarcomas should be adopted for teenagers and young adults (TYA) is unclear and will require systematic prospective evaluation.

Soft tissue sarcomas affect all ages. The numerous histiotypes are not evenly distributed across all age ranges. In the progression from childhood through adolescence to adulthood, rhabdomyosarcoma is replaced as the commonest subtype by the many different subtypes recognised by adult oncologists. There is little guidance about appropriate management of ‘adult-type’ soft tissue sarcomas occurring in TYA and this group have not been systematically studied. Their representation within clinical trials may be biased towards those with adverse features. There is considerable variation in practice particularly regarding the use of adjuvant chemotherapy. Few studies address whether specific approaches to treatment are appropriate for TYA with soft tissue sarcoma.

In the future, biologists and clinicians familiar with sarcomas affecting TYA and adults need to work together to share understanding and to design rational treatment programmes aimed at improving outcomes for TYA.

Medical records of children < /=5 years, treated by the London sarcoma service for malignant primary bone tumours (average new cases osteosarcoma (OS)/Ewings sarcoma (ES), all ages: 125/year) between 1999 and 2009, were reviewed.

Results: 5 OS and 6 ES. Mean age – 4.2 years (range 2.1–5.8), 8/11 males. OS primary sites: distal femur (2), proximal femur (1) and proximal humerus (2); localised tumours only. Primary sites in the ES cohort included 1 distal femur, 2 chest wall (1 – spinal extension), 1 buttock (spinal extension), 1 temporal bone and 1 ulna; 1 had bone/bone marrow involvement, 1 had chest metastases. 4/5 OS (Euramos, MRC B007) and 5/6 ES (Euro-Ewings 99) were entered into phase III clinical trials. Delayed surgery for OS occurred at mean 12.1 weeks (range 11–13) – 4 limb salvage prostheses with 2/4 non-invasive growers, 1 forequarter amputation. All had a good (> 90% necrosis) histologic response to neoadjuvant therapy. Delayed surgery for ES occurred at mean 21.7 weeks (range 12.8 – 35), 1 limb salvage with prosthesis (non-invasive grower), 1 biological reconstruction; remainder had tumour resections. Histologic response: 50% good. In the OS cohort, 1 child died a toxic death; 1 developed pulmonary metastases and died 2 years from diagnosis; 1 has a metastatic recurrence in the opposite humerus 2 years from diagnosis and starts 2nd line therapy; 1 had local recurrence 1 year from diagnosis but alive at 7.4 years;1 alive/disease free at 2.5 years. In the ES cohort 5/6 are alive disease free -1, 4.1, 5.2, 6.9 and 7 years from diagnosis; 2 needed 2nd line therapy for recurrent distant disease 4.5 and 5.8 years off therapy, 1 of whom has just recurred again (6.1 years from diagnosis).

Conclusion- improving early survival rates in the very young with OS remains a significant challenge. Quality of survival requires further age-appropriate study.