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

Liposarcoma (LPS) is among the most common soft tissue sarcoma (STS) in adults, accounting for > 10% of all STS. In children and adolescents, however, LPS are a rarity. Limited data about best treatment of pediatric LPS are derived from the scarce single-centre reports encompassing no more than a dozen patients.

Between 10/1980-6/2008, 18 of > 3,500 patients < 19 years with sufficient clinical data registered with CWS in Germany and Poland had a first diagnosis of LPS confirmed by reference pathologic review.

Median age was 14 years, median follow-up for survivors as of 2/2009 seven years. Sixteen patients had localized, two metastatic LPS at diagnosis. Lymphnodes were affected in a single case. The most frequent primary site were the limbs (n=11), the remaining seven were trunk tumours (abdomen n=4, thorax n=3). 10/18 primary tumours were > 5cm. Thirteen LPS were completely resected at best surgery, and microscopically residual disease remained in two more tumours. Six individuals received radiation with a median dose of 45Gy, including one of the two R1-resected patients. Nine patients received multiagent chemotherapy (only two of them since 1996 onwards). Response to induction treatment could be assessed in three of these nine individuals, but tumour volume regression occured in a single case only. Four patients died of disease, among them two of the three patients who did not achieve a CR with primary treatment. Two relapses (one combined, one metastatic), both involving the lungs, occurred one years after diagnosis and these patients were not salvaged. Actuarial 5-year EFS and OS survival rates were 69±23 and 81±20%, respectively.

LPS account for < 0.1% of childhood STS. The golden standard of treatment and key to cure is complete surgical excision. The role of radiation and/or chemotherapy remains unclear, but both modalities do not appear to be indicated in completely resected, localized tumours.

Alveolar Rhabdomyosarcoma (RMA) are characterised by chromosomal translocations fusing the PAX3 or PAX7 gene with FKHR in ~85%. Previous studies have suggested that PAX3/7-FKHR fusion types are related to prognosis. In order to prove these findings we performed a retrospective analysis of the PAX-FKHR fusion status and its relation to outcome in patients treated in the CWS trials.

Between 1986 and 2004, out of 446 RMA patients treated in four consecutive CWS trials (CWS-86, -91, -96 or -2002-P), tumor samples from 121 patients with adequate quality for analysis of PAX-FKHR fusion status by RT-nested PCR were available. Survival analysis depending on clinical risk factors and fusion status was performed using the Kaplan-Meier Method, the log rank test and the Cox regression model.

There were no major differences in distribution of known risk factors in the analysed cohort of 121 patients compared to all patients enrolled in the CWS trials. PAX-FKHR fusions were detected in 83%: 72 PAX3-, 29 PAX7-FKHR fusions. Patients with PAX3-FKHR positive tumors more often showed a pattern of adverse clinical risk factors (age > 10 years, primary metastases, lymph node involvement) than the PAX7-FKHR positive group. The 5-year event free survival rate of patients with initially metastatic tumors positive for either of the two fusion transcripts was significantly lower compared with the fusion transcript negative cohort and the non-analysed RMA patients. There was no significant outcome difference between patients with PAX3-FKHR and PAX7-FKHR positive tumors in uni- and multivariate analysis.

In the present analysis, which is to our knowledge the largest reported so far, PAX-FKHR fusion type was no significant predictor for prognosis, thus not supporting results of previous studies.

Tumour volume reduction (i.e. response), assessed following induction chemotherapy, has been identified as a prognostic factor for localized embryonal rhabdomyosarcoma (RME) in the CWS studies. In combination with other risk factors, it has been used to stratify secondary local and systemic treatment. It is however unclear whether the poor outcome of non-responders is due to insufficient local and/or systemic post-induction treatment.

We analyzed post-induction therapy of RME-patients < 21 years with unresected localized tumours (IRS-III) and poor response (NR, i.e. < 33% tumour volume reduction) treated 1980–2005 in five consecutive CWS-trials. The NR were reviewed and subclassified (Objective Response (OR; i.e.< 33%–0%) vs. Stable Disease/Progression (PD; i.e. no reduction)).

From 758 IRS-III RME-patients, 59 were NR (n=34 OR, n=25 PD). Induction for NR included dactinomycin, vincristine, alkylators ± anthracyclines in all patients. There were no significant differences in comparison of the control group and NR with regard to age, size, TN-classification, apart from site (p=0.04), and no differences regarding these parameters between OR and PD. Twenty-four NR received continued induction chemotherapy, n=32 other combinations, and n=3 no further chemotherapy following response assessment. Four patients were treated with additional high-dose chemotherapy. Fourty-two NR were irradiated with a median dose of 48Gy (control group: 45Gy). In 20 NR, the tumours were completely resected. As of 9/2008, with a median follow-up of 4.5 years (range: 0.9–12.1) for NR survivors, 34 NR are alive in CR. Reasons for the 25 deaths were: local/combined failure (n=21), systemic failure (n=1), and other reasons (n= 3). 5-yrs-OS was 71±4% for the control group, 78±15% for OR, but only 43±15% for PD (p< 0.01).

Response is an important surrogate marker of outcome, but per se associated with a poor prognosis only in tumours without any volume regression to induction chemotherapy. Ineffective local control drives mortality in these patients.

Only few patients with osteosarcoma relapse with solitary skeletal lesions as only sign of recurrence. We used the COSS database to learn more about these rare occurrences.

This report covers all patients with high-grade osteosarcoma of the limbs or axial skeleton registered into the COSS database between 1980 and 2003 who developed 1st recurrences as solitary osseous lesions distant from the primary tumour before 01/2005. Patient-, tumour-, and treatment-related variables and outcomes were evaluated.

38 patients (27 male, 11 female) developed solitary osseous recurrences a median of 2.1 years (range:.5 – 14.3) from primary diagnosis. Primary sites had been limbs in 36 and axial in 2, relapses involved axial sites (24), limbs (10), or craniofacial bones (4). Treatment for osseous recurrence included surgery in 28 patients, radiotherapy in 10, and chemotherapy in 27. After a median follow-up of 1.9 years (range:.1–21.2) from 1st recurrence for all 38 patients and 5.5 years (.3–21.2) for 16 survivors (10 of these in continuous 2nd surgical remission), 2- & 5-year overall and event-free survival probabilities were 55% & 34% and 34% & 27%, respectively. A long interval to recurrence (> 1.5 years) predicted for better outcomes (p< .01). For those 21 patients achieving a 2nd complete surgical remission, 2- & 5-year overall and event-free survival probabilities were 81% & 61% and 52% & 49%, respectively, while only 1/17 patients failing to achieve a 2nd complete surgical remission survived beyond 5 years (p< .001) after additional radiotherapy. 14/16 survivors had also received 2nd-line chemotherapy.

1st solitary skeletal recurrences of osteosarcoma seem to have a favourable outcome provided treatment includes complete surgery as part of multimodal therapy. Some presumed bone metastases may rather represent second primary osteosarcomas.

The COSS studies that form the basis of this report were supported by Deutsche Krebshilfe.

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

EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) is the first prospective multicenter international study for patients 41–65 year old with high-grade bone sarcoma

Patients with HG Osteosarcoma (OS), HG sarcoma NOS (S), Fibrosarcoma, MFH, Leiomyosarcoma, Dedifferentiated Chondrosarcoma (DCh) were included. Chemotherapy: Combinations of cisplatin/doxorubicin (CDP 100mg/m2/ADM 60mg/m2), ifosfamide/CDP(IFO 6g/m2/CDP 100mg/m2) and IFO/ADM (IFO 6g/m2/ADM 60mg/m2) were repeated three times (9 cycles). Surgery was planned after 3 cycles. Methotrexate (8g/m2) was postoperatively added in poor responders. Immediate surgery was allowed and 9 cycles with CDP, ADM, IFO were postoperatively given.

At December 2007, 140 patients were registered (median age 51 years). OS (51%), S (16%), and DCh (11%) were the more frequent histotypes. Synchronous metastases in 30 (21%) patients, central location of tumor in 45(32%).Surgical complete remission (SCR) was achieved in 84% of patients, (localized 91%, meta-static 37%) without difference among the histology groups. One surgical-related and one chemotherapy-related death were reported.

Grade4 WBC and PLT incidence was 55% and 17%.Renal toxicity and peripheral neurotoxicity were reported in 16% and 20% of patients. With a median follow-up of 25 months (4–68) 3 year OS was 58% (95%CI 48–68%) [7% (95%CI 0–19%) without SCR]. In patients with SCR, 3-year OS and EFS were 46% (95%CI 9–83%) and 0% in case of synchronous metastases and 69% (95%CI58–80%) and 45% (95%CI33–57%) for localized patients; 50% (95%CI 29–71%) and 40% (95%CI 20–59%) for patients with central tumor, 73% (95%CI61–85%) and 44% (95%CI31–57%) for those with extremity tumor; 68% (95%CI 52–83%) and 46% (95%CI 32–54%) for OS, 64% (95%CI 42–85%) and 48% (95%CI 25–71%) for S, 48% (95%CI 13–82%) and 27% (95%CI 1–54%) for DCh.

The protocol is feasible, but the chemotherapy-related toxicity is remarkable. Surgical complete remission is the main factor influencing survival. Central location and synchronous metastases are negative prognostic factors, but 50% 3-year OS can be achieved with aggressive local and systemic treatment. Osteosarcoma and high-grade sarcoma NOS benefit from chemotherapy more than patients with dedifferentiated chondrosarcoma.

The experience of radiotherapy (RT) in the local treatment of osteosarcoma (OS) is limited. Data of 100 patients with RT for OS from the international COSS-Registry (1980–2007) were analysed. Survival and local control rates at five years were calculated. Univariate and multivariate analyses were performed.

The COSS-registry includes 3500 patients with histo-logically proven OS. A total of 175 patients were irradiated over the period of 1980 to 2007, 100 patients were eligible. Median age was 18 (3–66) years. Indication for RT was a primary tumor in 66, a local recurrence in 11 and metastases in 23 patients. 94 Patients got external photontherapy, 2 pats. protontherapy, 2 pats. neutrontherapy, and 2 pats. intraoperative RT. Seventeen patients received a samarium-153-EDTMP therapy. Median dose for external RT was 55.8 Gy All patients were treated with chemotherapy in accordance to different COSS-protocols.

Median follow-up is 1.5 (0.2–23) years. Overall survival rates at 5 years for the whole group, for treatment of primary tumours, local recurrence, and metastases are 36 %, 55%, 15%, and 0% respectively. Local control rate for combined surgery and RT is significantly better than for RT alone (48% vs. 22%, p=0.002). Local control for treatment of primary tumours, local recurrence, and metastases are 40%, 17%, and 0% respectively. Prognostic factors for survival are indication for RT, RT plus surgery vs. RT alone and localisation. Prognostic factors for local control are indication for RT, and RT plus surgery vs. RT alone.

Radiotherapy is an important option for local treatment of unresectable OS, after intralesional resection, or symptomatic metastases. Survival prognosis of these patients is poor. Combination of surgery, radiotherapy, and chemotherapy can be curative. Prognostic factors were identified.

Purpose: Compared to paediatric cancer patients adolescents and young adults may have disadvantaged access to care. Therefore we investigated the correlation of patient, tumour and institutional characteristics with the outcome of osteosarcoma in this age group.

Method: Analysis of consecutive patients aged 15–24 years with newly diagnosed high-grade osteosarcoma entered into the Cooperative Osteosarcoma Study Group(COSS) registry 1980–2004 and treated in pediatric (PO) or medical oncology institutions (MO). Standardised multimodal therapy according to a COSS-protocol. Event-free survival rates (EFS) evaluated in relation to patient demographics and registering institution (MO vs PO and treatment volume as: < 1, 1–3 or > 3 osteosarcoma/year).

Results: 944 patients identified (median age: 17.35 years; range: 15.01–24.99; 79% aged < 20 years). Patients > 20 years were more likely than younger patients to be treated in centers with low treatment volume (p< .0001) and MO (p< .0001) but otherwise comparable. After a median follow-up of 5.59 years (range: 0.12 – 27.92) for all patients and 8.08 years (range: 0.19 – 27.92) for 617 survivors, actuarial 5/10 year event-free survival probability (EFS) was 58%/54%. Upon univariate analysis of the total cohort neither of the institutional variables correlated significantly with EFS. There was a correlation between treatment in PO and improved EFS for patients > 20 years (p=.001) and for those with primary metastases (p=.009). Upon multivariate testing type of center (odds ratio: 1.26; p=.022) but not treatment volume were significant.

Conclusion: Within a framework of standardised regimens and consultation supportby our group’s infrastructure, similar EFS-probabilites were obtained regardless of institutional treatment volumes. Observed variations in outcome between PO and MO may be partly due to different distributions of presenting factors but deserve further investigation.

The development of local recurrence after multimodal treatment of osteosarcoma is associated with a very poor prognosis. The importance of clear surgical margins has been demonstrated in multiple studies, however up to date there are no studies defining which margin width is safe from an oncological perspective. The purpose of this retrospective analysis was to evaluate whether margin width or other surgical and tumour-related factors influence the development of local recurrence in osteosarcoma patients.

The files of 1867 consecutive patients with high-grade central osteosarcoma of the extremities, the pelvic bones and the shoulder girdle, who had achieved a complete surgical remission during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols between 1986 and 2005, were reviewed. Of those, the data required were available for 1369 patients, who were the subject of this analysis. Eighty of these patients developed a local recurrence during the course of their illness.

The median surgical margin width amounted to 45 mm (range, 0 to 140 mm) in the local recurrence (LR) group and 50 mm (range, 0 to 350 mm) in the non-local recurrence (NLR) group (p=0.106). No statistically significant difference between the two groups was found regarding tumour size (mean, 10.38 cm and 9.53 cm respectively, p=0.169), T-status (p=0.225) and presence of pathological fracture (p=0.231). However infiltration of the soft tissue beyond the periosteum was documented in 58.8% of the patients with local recurrence and only in 36.9% of the rest (p=0.003). Furthermore, in 50% of the LR group the biopsy had been performed in a centre other than the one performing the definitive tumour resection, compared to 30.2% of the NRL group (p=0.001).

In conclusion, the absolute metric width of surgical margins does not define oncological safety. Local recurrence is more likely to develop in patients with soft tissue infiltration beyond the periosteum or those biopsied in a centre other than the one performing the tumour resection.

Sclerosing epitheloid fibrosarcoma (SEF) is an extremely rare soft tissue sarcoma arising from connective tissue cells of mesenchymal origin. SEF mostly occurs in extraosseous sites in the soft tissue; however two cases of primary localization in the bone have been described. Despite benign cytological features the clinical course is complicated by a high local recurrence rate and late metastases. SEF represents a clinically challenging entity especially because no standardized treatment regimens are available.

We report a 16-year old female patient who showed persistent load-dependent pain focused on the right proximal tibia. Radiological evaluation revealed an osteolytic lesion and the diagnosis of a benign bone cyst was consented. The tumor was surgically removed. Only after recurrence of the tumor and repeated histopathological analysis diagnosis of SEF could be established.

Because of the bone localization of the tumor the patient underwent standardized neoadjuvant chemotherapy analogous to the European-American EURAMOS-1 protocol for the treatment of osteosarcoma followed by tumor resection and endoprothesis. Histopathological analysis of the resected tumor showed > 90% vital tumor cells suggesting no response to the neoadjuvant chemotherapy. Therefore, therapy was reassigned to the CWS protocol of the German Society for Pediatric Oncology and Hematology (GPOH) for treatment of soft tissue sarcoma. To date, the patient is alive and no metastases of the primary tumor can be detected.

SEF represents a taunting clinical entity due to deceptive histopathological features and rare occurrence. Localization in the bone represents an additional challenge with regards to the therapeutical approach. Standardized treatment regimens are currently not available for SEF. This case report, to our knowledge, is the first outlining a therapeutic approach in detail. Our data suggest that SEF may be resistant to a chemotherapy regimen containing Cisplatin, Doxorubicin and Metho-trexate despite close association to the bone, possibly indicative of the soft tissue histogenesis of this tumor. The response to the soft tissue sarcoma targeting CWS chemotherapy remains to be determined.