Current treatments for malignant paediatric solid tumors involve a combination of chemotherapy, surgery and, in certain cases, radiotherapy. This multidisciplinary approach leads to an overall cure of approximately 70%. Nevertheless, cancer mortality remains the leading cause of disease-related death in children and adolescents between 1 and 19 years. This is due to diseases with a poor prognosis, such as metastatic neuroblastoma, sarcoma in soft tissue and bone and brain tumors. New effective treatments must be found in order to continue to increase the cure rate of children and adolescents treated for cancer, as well as to improve the cured patients' quality of life

Neuroblastoma (NB) is a malignant paediatric tumour derived from primordial neural crest cells. This tumor accounts for 8% to 10% of all cancers with a median age of onset of 22 months. The primary tumor may be located in different anatomic sites such as abdomen (65%), thorax (19%), pelvis (2%), and cervix (1%). The strongest prognostic factors are age and stage. Localized NB and those occuring in infants have a 90% survival rate when the biological profile is favorable. Conversely, in case of Myc-N amplification, survival is around 30% after conventional treatment and 70% after intensification. More than 50% of patients have a disseminated tumor at diagnosis, and Stage 4 neuroblastoma in patients older than 1 year of age represents the most frequent form. Neuroblastoma is a chemosensitive tumor. Chemotherapy is indicated in large primary tumours to reduce the volume and attempt a safe surgical resection and to eradicate tumour metastases in disseminated NB. The most frequently used drugs are alkylating and platinum agents (cyclophosphamide, melphalan, cisplatin, carboplatin), topoisomerase II inhibitors (doxorubicin, etoposide) and vinca-alkaloids (vincristine). High-dose chemotherapy (busulfan, melphalan, carboplatin, etoposide) with autologous bone marrow stem cell support is used as a consolidation treatment in patients with metastatic disease, as well as maintenance therapy with retinoid acid. Although such an intensive strategy, the probability of survival of patients over 1 year of age with Stage 4 neuroblastoma is less than 40%. New drugs are urgently needed for patients with recurrent neuroblastoma.

Central nervous system (CNS) tumors as an entity represent the second most frequent malignancy in childhood and adolescents. The incidence rate of childhood primary benign and malignant brain tumors is 3.9 cases per 100,000 person-years, and appears to be increasing. Two thirds of the new cases are in children less than 15 years of age. The morbidity associated with CNS tumors exceeds those of other malignancies and is undoubtedly a result of the neurological and cognitive deficits associated with both the tumor itself and aggressive multimodal therapy. Current treatment involves surgical resection, mostly combined with irradiation and/or chemotherapy. This multidisciplinary approach leads to a cure in about 55% of all brain tumour patients. However, the outcome in small children and certain malignancies, such as high grade astrocytomas, brain stem glioma and atypical teratoid/rhabdoid tumors and metastatic primary neuroectodermal tumors (PNET)/medulloblastoma is still dismal. In addition, treatment with irradiation and/or the combination of different chemotherapeutic agents is at the limit of tolerance inducing renal, hepatic, auditory, or hematological toxicity. Moreover, irradiation to the cerebral hemispheres, especially in small children, induces devastating sequelae. Clinical resistance to anticancer agents is the primary reason for treatment failure in childhood cancer and the development of new agents with a new profile of anti-tumour activity and toxicity is highly warranted.

Other relapsed/refractory non-CNS solid tumors include nephroblastoma, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma and soft-tissue sarcomas, and rarer tumours, such as hepatoblastoma, retinoblastoma, nasopharyngeal carcinoma, and germ-cell tumours. For most of these tumors, treatment protocols are available for first-line therapy; to a lesser extent, treatment recommendations are proposed in case of relapse. Depending on the disease, type, and localization of relapse, treatment may include combinations of salvage chemotherapy, including high-dose chemotherapy with stem cell rescue, radiotherapy, and surgery.

In several of these diseases, temozolomide (as well as topoisomerase I inhibitors, such as irinotecan and Topotecan) have shown single agent activity and may be used in combination schedules.