Teenagers and young adults with cancer in Europe: from national programmes to a European integrated coordinated project.

Over 14 000 patients aged 15-24 are estimated to be diagnosed with cancer in the European Union (EU) each year. Teenagers and young adults (TYA) often fall down gaps between children's and adults cancer services. The specific challenges of providing optimal care to them are described, but we present a summary of recent progress. Progress to overcome these challenges is happening at different rates across Europe. We summarise the European national projects in this field but more recently we have seen the beginnings of European coordination. Within the EU 7th Funding Programme (FP7) European Network for Cancer Research in Children and Adolescents programme (ENCCA), a specific European Network for Teenagers and Young Adults with Cancer has held a series of scientific meetings, including professionals, patients and caregivers. This group has proposed unanswered research questions and agreed key features of a high-quality service that can improve outcomes for TYA with cancer, including the primacy of collaboration between adult and paediatric services to eliminate the gap in the management of TYA with cancer.

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders.

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

Osteosarcoma over the age of forty.

The European Musculo Skeletal Oncology Society (EMSOS) has carried out a retrospective review of patients over the age of 40 years with osteosarcoma. 481 patients from 12 centres or multicentric groups were included. 42 patients had osteosarcoma arising in Paget's disease, median survival was 9 months. Patients with axial or metastatic tumours also did badly whilst 41 patients with radiation-induced osteosarcoma had a prognosis paralleling conventional osteosarcoma matched for patient age and site of the tumour. 238 patients had high grade non-metastatic osteosarcoma and had a survival of 46% at 5 years. Older patients had less chemotherapy and fared worse. Osteosarcoma in the elderly is a curable condition and warrants intensive treatment with chemotherapy and surgical resection.

High dose ifosfamide in combination with high dose methotrexate, adriamycin and cisplatin in the neoadjuvant treatment of extremity osteosarcoma: preliminary results of an Italian Sarcoma Group/Scandinavian Sarcoma Group pilot study.

With the intention of starting an international protocol between Italy and Scandinavia on neoadjuvant treatment of extremity osteosarcoma using the four active drugs at maximum doses (doxorubicin 75 mg/m2 pre-operatively, and 90 mg/m2 post-operatively, cisplatin 120 mg/m2, methotrexate 12 g/m2, and ifosfamide 15 g/m2), a single center (the Rizzoli institute) performed a pilot study to closely monitor toxicity, safety, and tumor necrosis. Only 7 patients (10%) had a reduced number of the scheduled cycles. A total of 1,050 of the expected 1,076 cycles (98%) were administered. Delays and dose reduction were minimal, leading to a mean received dose intensity of 89%. Limb salvage surgery was performed in 59 cases (87%), with 6 amputations and 3 rotation plasties. Chemotherapy-induced necrosis higher than 95% was observed in 38 patients (56%). Eleven patients had total necrosis (16%). At a median follow-up of 60 months (range 50-65 months), 53 patients (73%) were continuously disease-free. Six of the relapsed patients were rescued with further treatments leading to an overall survival of 87%. Hematological toxicity was remarkable despite the use of G-CSF and hospitalization due to febrile neutropenia occurred in 25 patients (37%). Platelet transfusions were required in 77 of the 194 episodes of grade 4 thrombocytopenia, but no case of major bleeding was observed. Red blood cell transfusions were necessary in all patients (in 15 cases perioperatively only). Non-hematological toxicity comprised grade 1-2 nephrotoxicity in 3 cases, CNS toxicity in 2 cases, and dilata- tive cardiopathy leading to heart transplantation in 1 case. In conclusion, the pilot study was feasible in the vast majority of cases with toxicity not superior to that of the previous protocols where chemotherapy was given in lower doses. The rate of limb salvage procedures, event-free survival and overall survival seemed to be higher than in previous protocols. On the basis of this study, in March 1997 the Italian and Scandinavian Sarcoma Groups started a new protocol for osteosarcoma of the extremities.

Monitoring referral and treatment in soft tissue sarcoma: study based on 1,851 patients from the Scandinavian Sarcoma Group Register.

This report is based on 1.851 adult patients with soft tissue sarcoma (STS) of the extremities or trunk wall diagnosed between 1986 and 1997 and reported from all tertiary referral centers in Norway and Sweden. The median age at diagnosis was 65 years and the male-to-female ratio was 1.1:1. One third of the tumors were subcutaneous, one third deep, intramuscular and one third deep, extramuscular. The median size was 7 (1-35) cm and 75% were high grade (III-IV). Metastases at presentation were diagnosed in 8% of the patients. Two thirds of STS patients were referred before surgery and the referral practices have improved during the study. The preoperative morphologic diagnosis was made with fine-needle aspiration cytology in 81%, core-needle biopsy in 9% and incisional biopsy in 10%. The frequency of amputations has decreased from 15% in 198688 to 9% in 1995-1997. A wide surgical margin was achieved in 77% of subcutaneous and 60% of deep-seated lesions. Overall, 24% of operated STS patients had adjuvant radiotherapy. The use of such therapy at sarcoma centers increased from 20% 1986-88 to 30% in 1995-97. Follow-up has been reported in 96% of the patients. The cumulative local recurrence rate was 0.20 at 5 years and 0.24 at 10 years. The 5-year metastasis-free survival rate was 0.70.

Local recurrence of deep-seated, high-grade, soft tissue sarcoma: 459 patients from the Scandinavian Sarcoma Group Register.

This study was based on 459 adult patients with deep, high-grade, soft tissue sarcoma of extremities or trunk wall reported to the Scandinavian Sarcoma Group Register (1986-1993). All patients had their definitive surgery for primary tumor at a sarcoma center. The median follow-up was 7.5 (3-12) years. 204 patients are still alive. 68 patients had amputations and 391 underwent limb-sparing surgery. Among 183 patients with intralesional or marginal margins after limb-sparing surgery, 65% had postoperative radiotherapy and 9% of the 198 patients with wide margins. The local recurrence rate after limb-sparing surgery was 26%. The rate with an intralesional or marginal margin was 39% without postoperative radiotherapy versus 24% when radiotherapy was given. It was 25% after a wide margin, and no recurrences were noted among the 10 patients with a compartmental surgical margin. Among patients with a wide margin, a subset fulfilling criteria for a myectomy was defined. The local recurrence rate was 26% among these 62 and there was no advantage of myectomy over other wide margins. More radical surgical margins would improve the local recurrence rate, but this can hardly be achieved in center-operated patients without increasing the amputation rate. Instead, increased use of radiotherapy in all patients with inadequate margins, and to a larger extent in those with wide margins will improve local control.

Dedifferentiation of a well-differentiated liposarcoma to a highly malignant metastatic osteosarcoma: amplification of 12q14 at all stages and gain of 1q22-q24 associated with metastases.

Well-differentiated liposarcomas (WDLPS), especially those located in the retroperitoneum, may occasionally undergo dedifferentiation. Although this process is associated with a more aggressive clinical course, dedifferentiated liposarcomas rarely produces metastases. The case reported here is rather uncommon: A retroperitoneal WDLPS gave lung metastases that were diagnosed as highly malignant osteosarcomas. We used comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and Southern blot analyses to characterize the copy number changes and genetic aberrations occurring at different stages of the disease. In the primary tumor, the only detectable aberration was amplification of 12q13-q14, which was present only in a fraction of the cells and revealed by FISH analysis. High-level amplification of 12q13-q14, involving CDK4, MDM2, and HMGIC, was seen both in the relapse and the metastases. The second most common change, gain or high-level amplification of 1q22-q24, was detectable by CGH only in the osteogenic metastases, as was loss of the distal 2q. FISH analyses revealed considerable heterogeneity in the samples, and the percentage of cells showing aberrations was significantly higher in the metastatic samples. In particular, increased copy numbers of 789f2, a marker for 1q21 amplification in sarcomas, was observed in more than 65% of the cells in the metastatic samples, but in less than 10% of the cells from the recurrent samples. These observations could indicate that 1q amplification, in particular, may be indicative of a more malignant phenotype and ability of metastasis in WDLPS, as has also been suggested by others.

Biallelic inactivation of TP53 rarely contributes to the development of malignant peripheral nerve sheath tumors.

About 10% of the patients with neurofibromatosis type 1 (NF1) develop malignant peripheral nerve sheath tumors (MPNSTs), accounting for half of all MPNST cases. Several nonrandom chromosomal aberrations have been found, but the target genes remain mostly unrecognized. Mutations in the NF1 and TP53 genes have been found in some MPNSTs, and recent data from mouse models support a synergistic effect of these two genes in the development of MPNST. In the present study, we have analyzed 16 MPNSTs, including 11 from patients with NF1 and 5 sporadic cases, for mutations in the coding sequence of the TP53 gene (exons 2-11). We applied denaturing gradient gel electrophoresis and modifications of this technique for analyses of 12 genomic fragments, followed by direct sequencing for identification of the mutated base(s). None of the MPNSTs revealed mutations. The detection of control mutants for each fragment analyzed, the high sensitivity of the technique, the detection of polymorphisms in some samples, and the high content of tumor tissue in the biopsies imply that false negatives are highly unlikely. Although we cannot exclude that deletions including large parts of the gene remain undetected by the mutation analyses, previous comparative genomic hybridization (CGH), cytogenetic banding analysis, and/or loss of heterozygosity studies on 14 of the cases included here had revealed 17p deletions in only three. We thus conclude that TP53 biallelic inactivation is rare in MPNST, and that the potential impact of an altered TP53 pathway on the malignant transformation of a neurofibroma into an MPNST may more frequently occur by changes in other components of that pathway.

Computed tomography of pulmonary metastases from osteosarcoma: the less poor technique. A study of 51 patients with histological correlation.

BACKGROUND: The purpose is to evaluate the accuracy of computed tomography (CT) in the pulmonary staging of osteosarcoma. PATIENTS AND METHODS: Fifty-one patients presenting with osteosarcoma and at initial CT considered metastatic to the chest had lung surgery. Two teams of two senior radiologists independently reviewed all CT examinations. Their results were compared to the histological studies. RESULTS: One hundred nineteen CT's were reviewed. The 2 teams found 247 and 268 nodules on the initial. and 143 and 146 nodules on the preoperative CT. Histological studies confirmed metastatic nodules in 29 patients. Two hundred four nodules were excised and studied. One hundred nine were metastases. The 22 patients without metastases had 53 negative nodules removed. In the 29 patients with metastases, 151 nodules were removed, and 42 were non-metastatic. The positive predictive value was 53% with regard to 'nodules', and 57% with regard to 'patients'. Only 4 out of 13 patients with one nodule at surgery were metastatic, but all patients with more than 7 nodules were metastatic. The 46 cases with several available CT's, showed that no change in the number of nodules was more frequent in benign lesions. Other criteria revealed no significant difference. CONCLUSION: CT positive predictive value is limited, but as surgery is the only way to cure metastatic patients, CT will still be used as the reference technique until a more specific approach can be found.

Surgical margins, local recurrence and metastasis in soft tissue sarcomas: 559 surgically-treated patients from the Scandinavian Sarcoma Group Register.

The prognostic importance of surgical margins on local recurrence rates and metastasis-free survival (MFS) was studied in 559 patients with soft tissue sarcoma of the extremities and trunk wall. The patients were all surgically treated, but received no adjuvant treatment. The median follow-up for the survivors was 7.4 (range: 0.1 - 12.5) years. Independent prognostic factors for MFS were analysed by Cox models. The overall 5-year MFS was 0.72 (95% confidence intervals (CI) 0.68 - 0.76). High histopathological malignancy grade (relative risk (RR) 3.0; 95% CI 1.5 - 6.3) and an inadequate surgical margin (RR 2.9; 95% CI 1.8 - 4.6) were independent risk factors for local recurrence. High histopathological malignancy grade and large tumour size (> 7 cm) were the most important risk factors for metastasis. Local recurrence was associated with an increased risk of metastasis (RR 4. 4; 95% CI 2.9-6.8), but an inadequate surgical margin was not a risk factor for metastasis (RR 1.1; 95% CI 0.8-1.7). This study confirms that, as regards metastasis, tumour-related risk factors (malignancy grade and tumour size) are more important risk factors than treatment-related factors. Local recurrence was associated with an increased metastasis rate, whereas inadequate surgical margin was a risk factor for local recurrence but not for metastasis. Hence, the proposed causal association between local recurrence and metastasis is doubtful, and if it exists is a weak association.

Five-year results in Ewing's sarcoma. The Scandinavian Sarcoma Group experience with the SSG IX protocol.

The first Scandinavian protocol for Ewing's sarcoma, SSG IV, resulted in a local control rate of 74% and 5-year metastasis-free survival (MFS) of 43%. The second protocol, SSG IX, was started in order to improve upon these results. It featured four chemotherapy cycles, each consisting of two courses of VAI (vincristine, doxorubicin, ifosfamide) alternating with one course of PAI (cisplatin, doxorubicin, ifosfamide) at 3-weekly intervals. Total treatment time was 35 weeks. Local therapy was given at week 9. Inoperable or non-radically operated patients received hyperfractionated accelerated radiotherapy 1.5 Gy twice daily between chemotherapy courses to a total dose of 42-60 Gy, depending on surgical radicality and tumour localisation. 88 patients were included (58 male, 30 female, mean age 20 years; range 5-65 years). The tumour (73 M0 and 15 M1) was located centrally in 31 patients (35%), in the extremities in 34 (39%) and other sites in 23 (26%) of cases. The median size of tumour was 10 cm (range 2-23), soft tissue was invaded in 87%. Surgery was the local therapy for 60 (68%) patients: amputation in 8 and local excision in 52. The surgical margins were wide in 35 patients, marginal in 14 and intralesional in 3. Radiotherapy was given to 17 non-radically operated patients postoperatively and to 28 patients with inoperable tumours primarily. Histological responses were evaluated in 52 patients. 9 local recurrences were observed (10%). Distant metastases developed in 24 M0 patients (33%). The estimated 5-year MFS was 58% and overall survival (OS) 70% for M0 and 27% and 28% for M1 patients, respectively. Survival was favourable in patients with non-metastatic extremity tumours (90%) and tumours operated with wide margins (90%). Patients with a total necrosis after chemotherapy had a better OS than those with a partial or poor response (P=0.003). The toxicity (World Health Organisation) was acceptable (gastrointestinal G1-2; haematological G3-4). The SSG IX protocol gave better local control and survival rates than the SSG IV. Whether this is due to a higher therapeutic efficacy of the present protocol cannot be ascertained in this comparison with a historical control.

Neoadjuvant chemotherapy for osteosarcoma of the extremities with synchronous lung metastases: treatment with cisplatin, adriamycin and high dose of methotrexate and ifosfamide.

We report on the clinical course and outcome of 28 patients, treated at The Istituti Ortopedici Rizzoli between 1995 and 1997 for osteosarcoma of the extremities metastatic to the lung at presentation. The treatment for these patients was the following: primary chemotherapy with cisplatin, adriamycin and high dose of methotrexate and ifosfamide followed by simultaneous resection of primary and metastatic lesions (when feasible), and further chemotherapy. After primary chemotherapy, lung metastases disappeared in 6 patients, whereas metastases in 3 remained surgically unresectable. These 9 patients received surgical treatment of the primary tumor only. In the remaining 19 patients, after chemotherapy, a simultaneous resection of the primary and metastatic tumor was performed. The resection of metastatic lesions was complete in 18 cases and incomplete in one. Three of the 4 patients who did not achieve a tumor-free status died in a few months and one is still alive with uncontrolled disease. With a median follow-up of 32 months (19-43) of the 24 patients who achieved remission, 12 (55%) remained continuously free of disease, 11 relapsed with new metastases and 1 died of chemotherapy-related toxicity. The 2-year DFS and OS were 36% and 53% respectively. These results are much worse than those achieved in 114 contemporary patients with localised disease (2-year DFS: 81%) treated in the same period and they are superimposible to the results achieved in 23 patients previously treated with the same protocol, but with standard dose of ifosfamide (2-year DFS: 32%). However, it must be underlined that, as regards prognosis, patients with metastatic disease at presentation are a hetero-geneous group. The DFS was significantly higher for patients with only one or two metastatic lesions than for patients with 3 or more lesions (2 year DFS: 78% vs. 28%). In 12 of the 19 patients who had a complete simultaneous resection of the primary and metastatic tumor, a strong correlation between the degree of necrosis of the primary and metastatic lesions was found. We conclude that in patients with osteosarcoma of the extremity with lung metastases at presentation: a) the combination of aggressive chemotherapy with simultaneous resection of primary and metastatic tumors works very well only for those patients who present with one or two metastatic nodules whereas for patients with 3 or more pulmonary metastases the prognosis is very poor; b) within the 4-drug regimen used in this study, the increment of ifosfamide dose from 10 g/m2 to 15 g/m2 for cycle does not improve prognosis; c) the strong correlation found between the histologic response of the primary tumor and metastases supports the strategy, largely used nowadays in the neoadjuvant treatment of osteosarcoma, of tailoring postoperative chemo-therapy on the basis of the primary tumor histologic response to preoperative chemotherapy.

Consequences of local recurrence of soft tissue sarcoma: 205 patients from the Scandinavian Sarcoma Group Register.

From the Scandinavian Sarcoma Group Register, information on 1,224 surgically-treated patients with soft tissue sarcoma (STS) of the extremity or trunk wall, diagnosed between 1987 and 1995, was collected. 205 patients, one third of whom were referred to a center with a local recurrence, had a total of 284 local recurrences. This analysis describes the treatment for these local recurrences, complications and risk of further recurrences. 169 patients were surgically treated for their first local recurrence. An intralesional or marginal margin was achieved in 110 of these patients, 59 of whom were also given radiotherapy. 54 of the 169 patients had a second local recurrence. The second local recurrence rate was 0.50 if the first local recurrence had been treated with only surgery with a marginal margin, compared to 0.28 if treated with surgery with a marginal margin and radiotherapy or with a wide margin (p = 0.0008). In extremity STS, the crude amputation rate for local recurrences was 0.22 (31 of 142)-i.e., higher than for primary tumors 0.09 (96 of 1065) (p < 0.0001). A high local recurrence rate after treatment outside of sarcoma centers has earlier been shown. We conclude that the consequences of local recurrence in terms of morbidity and costs justifies referral of STS patients for multidisciplinary evaluation and multimodality treatment.

Extraskeletal myxoid chondrosarcoma: multimodal diagnosis and identification of a new cytogenetic subgroup characterized by t(9;17)(q22;q11).

Extraskeletal myxoid chondrosarcoma is a rare malignant soft tissue tumour that can be difficult to diagnose correctly, especially preoperatively. We describe four cases of extraskeletal myxoid chondrosarcoma of the extremities diagnosed by a multimodal approach. The cytological examination of fine-needle aspirates showed small and round, mildly pleomorphic cells lying in sheets and cords, but also dispersed within a myxoid and metachromatic intercellular substance. Histological, electron microscopic and immunocytochemical examination also yielded findings compatible with the diagnosis of extraskeletal myxoid chondrosarcoma. Cytogenetic analysis demonstrated a t(9;22)(q22;q12) in two tumours and a t(9;17)(q22;q11) in the third and fourth. The translocation t(9;22)(q22;q12) has been described repeatedly in extraskeletal myxoid chondrosarcoma but never in other tumours; hence, the detection of this pathognomonic chromosome abnormality in short-term cultured cells from fine-needle aspirates verified the diagnosis in two of the cases. The t(9;17)(q22;q11) found in the last two cases probably represents a new cytogenetic subgroup of extraskeletal myxoid chondrosarcoma as it, too, is unknown in other contexts. The multimodal approach taken in these four cases enabled a definite diagnosis of a rare malignant tumour whose cytological and histological features alone are usually not sufficiently distinct to rule out other differential diagnostic possibilities.