Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium.

AIM: To explore imatinib efficacy and pharmacokinetics in children and adolescents with refractory/relapsing solid tumours, expressing imatinib-sensitive receptor tyrosine kinases. METHODS: Exploratory study on imatinib in tumours expressing, at least, one of the receptors KIT or platelet-derived growth factor receptor (PDGFR). Standard radiological response evaluation, pharmacokinetics, gene mutations and positron emission tomography imaging were assessed. RESULTS: Thirty-six patients (median age: 13.7 years) with brain (12), mesenchymal/bone (14) or other solid tumours, received imatinib 340 mg/m(2)/d over a total of 255 months. Fifteen tumours expressed KIT in 30% cells, 19 expressed PDGFRA and 25 expressed PDGFRB. Twenty patients experienced grades 1-2 treatment-related toxicities. Ten patients achieved stable disease; one chordoma had metabolic response. Pharmacokinetic data showed high inter-patient variability (variation coefficient: 44% and 53% for plasma imatinib and CGP 74588 AUCs, respectively). CONCLUSIONS: Imatinib was tolerated well, but failed to show efficacy according to standard criteria in paediatric malignancies expressing KIT or PDGFR.

Testicular function of survivors of childhood cancer: a comparative study between ifosfamide- and cyclophosphamide-based regimens.

PURPOSE: This study aimed at comparing gonadal toxicity of ifosfamide versus cyclophosphamide received during childhood. METHODS: The evaluation was based on basal FSH measurement. LH and testosterone were also measured in most of the patients. One hundred patients had received ifosfamide and 59 had received cyclophosphamide. RESULTS: Median age at treatment was 11.2 years. The median interval since treatment was 10.7 years (range 4.1-20.2) and median age at evaluation was 21.4 years (17.5-36.1). The median dose of ifosfamide and of cyclophosphamide was 54 g/m(2) (18-114) and 8.3 g/m(2) (4.6-22), respectively. All but two males had normal testosterone levels. FSH was abnormal in 28/59 patients (47.5%) after receiving cyclophosphamide and was within the normal range in 94/100 patients (94%) after receiving ifosfamide. CONCLUSIONS: These results show that ifosfamide is associated with a lower risk of gonadal damage than cyclophosphamide. The risk of abnormal FSH increased with the cumulative dose of cyclophosphamide.

A phase II study of irinotecan in children with relapsed or refractory neuroblastoma: a European cooperation of the Société Française d'Oncologie Pédiatrique (SFOP) and the United Kingdom Children Cancer Study Group (UKCCSG).

PURPOSE: To evaluate the efficacy and safety of irinotecan in paediatric recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Thirty seven patients aged between 6 months and < or = 20 years, with relapsed or refractory neuroblastoma, received irinotecan at 600 mg/m(2) administered as a 60-min infusion, every 3 weeks. Tumour response was evaluated by conventional radiological and mIBG scans every two cycles. RESULTS: No objective response was observed during the study. Stable disease was observed in 13% of evaluable patients. Median times to progression and survival were 1.4 months (range, 1.2-1.5 months) and 8.8 months (range, 6.7-11.3 months), respectively. One forty two cycles were administered, with a median of two cycles per patient (range, 1-17 cycles). The most common grade 3-4 toxicities were neutropenia (65% of patients), anaemia (43%), thrombocytopenia (38%), vomiting (14%), abdominal pain or cramping (8%), and nausea (5%). CONCLUSION: Irinotecan administered intravenously as a single agent every 3 weeks induced no objective response in relapsed or refractory neuroblastoma.

Phase I study of weekly oxaliplatin in relapsed or refractory pediatric solid malignancies.

PURPOSE: To explore feasibility, maximum-tolerated dose (MTD), and recommended dose (RD) for phase II studies of weekly oxaliplatin for the treatment of relapsed or refractory pediatric solid malignancies. PATIENTS AND METHODS: Eligible patients were 6 months to 21 years old, had a diagnosis of a solid malignancy, and had experienced treatment failure with at least two or more previous lines of therapy. The phase I study was multicentric, open-label, and nonrandomized. It foresaw two phases: a dose-escalation phase (comprising six levels) to find the RD and an extension at the RD to evaluate the cumulative toxicity. Oxaliplatin was administered intravenously over 2 hours on days 1, 8, and 15 of a 28-day cycle. RESULTS: Forty-five patients were enrolled: 29 patients in the dose-escalation phase and 16 patients in the extension at the RD. Median age was 9.5 years (range, 2.8 to 20.0 years) and 7.8 years (range, 1.8 to 19.2 years), respectively. The dose-limiting toxicities during the first treatment cycle were grade 3 (G3) sepsis at 50 mg/m(2), G3 dysesthesia at 90 mg/m(2), and G3 dysesthesia and G3 paresthesia at 110 mg/m(2), thus the MTD and RD was 90 mg/m(2). No case of ototoxicity was reported. Stable disease was reported in seven patients (16.3%), and confirmed partial response was observed in two patients (4.7%), one with neuroblastoma and one with osteosarcoma. CONCLUSION: Oxaliplatin administered in a weekly schedule has an acceptable safety profile, different from cisplatin and carboplatin, and shows activity in children with relapsed or refractory solid tumors, suggesting further investigation in pediatric malignancies.

Surgical resection of thalamic tumors in children: approaches and clinical results.

OBJECTIVES: Thalamic tumors are uncommon, and although gross total removal (GTR) is a prospective goal, its interest is debated because the thalamus constitutes a highly functional region. The relation of choice of the surgical approach, achievability of GTR, and operative morbidity to the anatomic location of the tumor has received little attention in the medical literature. MATERIALS AND METHODS: We reviewed retrospectively the cases of pediatric patients treated for thalamic tumor, with pre- and postoperative magnetic resonance imaging, and who were operated with the aim of maximal surgical removal. CONCLUSION: We reviewed 16 cases operated between 1992 and 2003. The clinical presentation was dominated by intracranial hypertension and hemiparesis. Fifteen children were operated through transcortical approaches: transfrontal in six cases, transparietal in six, and transtemporal in three. The remaining patient was operated through an infratemporal approach. All operations performed since 1998 used intraoperative neuronavigation. Complete or near-total resection was achieved in 11 cases; only subtotal resection was achieved in the remaining five cases. The most common postoperative morbidity was visual field defect. Hemiparesis was unchanged or improved in all the cases. Seven children died of tumor progression, in relation with high histological grade, and one died of acute hydrocephalus. The approach to thalamic tumors needs to be planned according to the location of critical neural structures. GTR of thalamic tumors in children bears acceptable morbidity and may even improve preoperative deficits. Surgery alone can be curative in low-grade tumors; in high-grade or infiltrating tumors, GTR is only part of the overall oncological management.

Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group.

PURPOSE: This phase II study was designed to evaluate the efficacy of irinotecan administered intravenously once every 3 weeks in pediatric patients with recurrent or refractory rhabdomyosarcoma. PATIENTS AND METHODS: A total of 35 patients younger than age 20 years, with refractory or relapsed rhabdomyosarcoma for which standard treatments have failed, received irinotecan at 600 mg/m2 administered as a 60-minute infusion every 3 weeks. Concomitant treatments included atropine for cholinergic symptoms, loperamide for diarrhea at the first liquid stool, and preventive antiemetic treatment. Tumor response was assessed every two cycles until progression according to WHO criteria. RESULTS: The best overall response rate to irinotecan was 11.4% (95% CI, 3.2 to 26.7%; 2.9% complete responses, 8.5% partial responses) from all patients recruited. The median times to progression and survival were 1.4 and 5.8 months, respectively. A total of 112 cycles were administered, with a median number of two cycles per patient (range, 1 to 16). The most common grade 3/4 toxicities were neutropenia (46%), abdominal pain or cramping (17%), cholinergic syndrome (14%), nausea/vomiting (11%), anemia (11%), thrombocytopenia (9%), and diarrhea (6%). CONCLUSION: In heavily pretreated children with a high tumor burden who have been treated with multiagent chemotherapy, irinotecan administered intravenously as a single agent, at 600 mg/m2 every 3 weeks, showed an interesting objective response rate and a good tolerance profile in rhabdomyosarcoma.

SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients.

The SFOP-OS94 randomised multi-centre trial was designed to determine whether preoperative chemotherapy regimen combining high-dose methotrexate courses and etoposide-ifosfamide could improve the proportion of good histologic response (5% viable cells) compared to a regimen based on high-dose methotrexate and doxorubicin, in children/adolescents with localised high-grade limb osteosarcoma. Postoperative chemotherapy was adapted to the histologic response. Overall, 234 patients were randomised between 1994 and 2001. There were 56% good responders in the etoposide-ifosfamide arm versus 39% in the doxorubicin arm (p-value=0.009). With a median follow-up of 77 months, the 5-year event-free survival of the entire population was 62%, slightly greater in the etoposide-ifosfamide arm than in the doxorubicin arm, but the difference was not significant (Hazard Ratio: HR=0.71, 95%CI: 0.5-1.06, p-value=0.09). Five-year overall survival of the entire population was 76%, similar in both arms (HR=0.95, 95%CI: 0.6-1.6, p-value=0.85). Toxicity was manageable with different acute toxicity profiles between treatment arms. No acute toxicity related death was reported. About 43% of the patients in the etoposide-ifosfamide arm were event-free at 3 years without having received any doxorubicin or cisplatin, thus avoiding the risk of long-term cardio- and ototoxicity.

Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children.

BACKGROUND: Morbidity and mortality are high in young children with medulloblastoma who receive craniospinal radiotherapy. We aimed to assess whether adjuvant treatment with protracted chemotherapy alone could replace radiotherapy. METHODS: We enrolled 79 children aged younger than 5 years who had had surgical resection of medulloblastoma onto a multicentre trial. Patients were treated with combination chemotherapy, which did not include methotrexate, for more than 16 months irrespective of the extent of disease. Early postoperative imaging defined three groups: R0M0 (no residual disease, no metastasis), R1M0 (radiological residual disease alone), and RXM+ (presence of metastases). Patients who did not relapse did not receive radiotherapy. Patients who relapsed or had disease progression received salvage treatment, which consisted of high-dose chemotherapy and stem-cell transplantation followed by local or craniospinal radiotherapy. For children classified as R0M0, the primary endpoint was 5-year overall survival and the secondary endpoint was 5-year progression-free survival. For children classified as R1M0 or RXM+, the primary endpoint was best radiological response and the secondary endpoints were 5-year overall survival and 5-year progression-free survival. Analyses were done by intention to treat. FINDINGS: Two of 15 patients classified as RXM+ and four of 17 patients classified as R1M0 had a complete radiological response. 5-year progression-free survival was 29% (95% CI 18-44) in the R0M0 group, 6% (1-27) in the R1M0 group, and 13% (4-38) in the RXM+ group. 5-year overall survival was 73% (59-84) in the R0M0 group, 41% (22-64) in the R1M0 group, and 13% (4-38) in the RXM+ group. In the R0M0 group, 5-year progression-free survival was 41% (26-58) for the 34 patients who underwent gross total resection compared with 0% for the 13 patients who had subtotal resection (relative risk 2.7 [1.3-5.6], p=0.0065). INTERPRETATION: Conventional chemotherapy alone can be used to cure children with non-metastatic medulloblastoma who have gross total resection confirmed by early radiological assessment, but is not sufficient for treatment of those with metastatic or incompletely resected medulloblastoma. Salvage treatment followed by posterior-fossa radiotherapy can effectively treat local relapses or progression.

Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results of the first French prospective study for the French Society of Pediatric Oncology.

PURPOSE: To evaluate a strategy aimed at avoiding radiotherapy during first-line treatment of children with progressive optic pathway tumors (OPT), by exclusively administering multiagent chemotherapy during 16 months. PATIENTS AND METHODS: Between 1990 and 1998, 85 children with progressive OPT were enrolled onto this multicenter nationwide trial. Chemotherapy alternating procarbazine plus carboplatin, etoposide plus cisplatin, and vincristine plus cyclophosphamide was given every 3 weeks. At the time of relapse or progression, second-line chemotherapy was authorized before recourse to radiotherapy. RESULTS: Objective response rate (partial response [PR] + complete response [CR]) to chemotherapy was 42%. Five-year progression-free survival (PFS) and overall survival rates were 34% and 89%, respectively. The 5-year radiotherapy-free survival rate was 61%. In the multivariate analysis of the 85 patients that entered onto the study, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.047) and absence of neurofibromatosis type 1 (P =.035). In the multivariate analysis of the 74 patients that remained on study after the first cycle of chemotherapy, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.0053) and no objective response to chemotherapy (P =.0029). Three-year PFS was 44% in infants < or = 1 year versus 66% in children older than 1 year. Three-year PFS was 53% in the absence of an objective response to chemotherapy versus 68% after a PR or CR. CONCLUSION: A significant proportion of children with OPT can avoid radiotherapy after prolonged chemotherapy. Deferring irradiation with chemotherapy protocols did not compromise overall survival of the entire population or visual function.

[Frequency of genetic diseases and cancer antecedents in 493 adults with visceral or soft tissue sarcomas]. / Fréquence des génopathies et des antécédents carcinologiques chez 493 adultes atteints de sarcomes viscéraux ou des tissus mous.

Little is known about epidemiology of adults soft tissue and visceral sarcomas (ASTS). The frequency of previous cancers and associated genetic diseases has been analyzed out of 493 ASTS, treated between 1997 and 2002 at Oscar Lambret Cancer Center. Median age is 51, sex ratio is close to 1. Liposarcomas and malignant fibrous histiocytofibromas are the two main types (respectively 104 and 86 cases). Upper and lower limbs are the two main locations (respectively 176 and 75 cases). Fifteen patients had associated genetic disease, including 12 cases of Recklinghausen diseases. 7 out of those 15 patients have neurosarcoma. 30 patients have previous cancers, including 7 breast cancers, 3 lymphomas and 3 chronic lymphocytic leukemias. Four out of those 30 patients have two different previous cancers. 13 patients have radiation-induced sarcomas, after an average 10-year-period, and an average dose of 53 Gy. Undifferenciated sarcomas are the main histologic type (8/13), followed by angiosarcomas (2/13). Radiation-induced sarcomas are located in the chest wall (7/13), in pelvis (2/13) and head and neck (2/13). Those sarcomas are high grade (10 grade III tumours). ASTS epidemiology is complex with different risk factors depending on histologic type.