Toxicity of high-dose chemotherapy with etoposide, thiotepa and CY in treating poor-prognosis Ewing's sarcoma family tumors: the experience of the Bambino Gesù Children's Hospital.

We report the toxicity of high-dose chemotherapy (HDC) based on etoposide, thiotepa and CY (ETC) in children with poor-prognosis Ewing's sarcoma family tumors (ESFTs). A total of 26 patients with high-risk ESFT (metastasis or axis localization or tumor volume >200 ml or necrosis <95%) were reviewed. The conditioning was based on etoposide (600 mg/m(2)), thiotepa (750 mg/m(2)) and CY (120 mg/kg) followed by autologous BM or PBSC rescue. The conditioning regimen was well tolerated, without any toxic deaths. The median time from transplant to a neutrophil count of >0.5 x 10(9)/l was 10 days (range 6-27) and 22.5 days (range 9-114) for a plt count of >50 x 10(9)/l. Oral mucositis was recorded in 20 patients, grade 1/2 in 19 and grade 3 in the last patient. Diarrhea grade 1/2 was recorded in four patients and grade 1/2 liver toxicity in four patients. Sepsis was documented in four cases and skin toxicity in three. Lung and tubular toxicity, respectively, were reported in one patient each. We conclude that the ETC regimen presented a limited and manageable toxicity. Further studies would confirm the role of ETC in high-risk ESFT.

Congenital glioblastoma.

We describe the case a 2-day-old female with congenital glioblastoma. Total resection was followed by adjuvant and high dose chemotherapy, as indicated by the current Italian infant protocol. The child is alive and well 18 months after diagnosis. A review of 67 selected congenital brain tumors showed the mortality rate was 82%. Even though the majority of patients had glioblastoma, only 5/67 had received adjuvant therapy. To ensure optimal outcomes, we recommend total or subtotal surgical resection, followed by adjuvant and high dose chemotherapy. Given the lack specific protocols for congenital brain tumors an international consensus seems to be needed, starting with congenital glioblastoma.

Temozolomide in resistant or relapsed pediatric solid tumors.

PURPOSE: We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day x 5 days or 180 mg/m2/day x 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. RESULTS: Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1-37) and median time to progression was 3.4 months (range 1-20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3-4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. CONCLUSION: Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy.

Ifosfamide/carboplatin/etoposide (ICE) as front-line, topotecan/cyclophosphamide as second-line and oral temozolomide as third-line treatment for advanced neuroblastoma over one year of age.

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front-line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second-line treatment for children with relapsed neuroblastoma, particularly after high-dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty-one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty-one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow-up is needed to confirm a survival advantage. Second-line treatment was effective in obtaining remissions, some of them long lasting. Third-line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.

Neurovesical dysfunction in children after treating pelvic neoplasms.

OBJECTIVE: To evaluate 10 years of experience, and thus define the occurrence and causes, of neurogenic lower urinary tract dysfunction in children with pelvic neoplasms treated by surgery. PATIENTS AND METHODS: From 1991 to 2000, 33 children were operated by the same surgeons for pelvic neoplasms; 11 were analysed, comprising four each with sacrococcygeal teratoma (ST) and ganglioneuroma, and one each with yolk sac tumour (YST), neuroblastoma and myofibroblastic bladder sarcoma (MBS). The other patients were not assessed because eight had died or were in severe progression, three were treated by bladder substitution and the others were lost to follow-up or refused a urological evaluation. All 11 children were evaluated at >/= 6 months after surgery with a questionnaire about bowel and voiding habits, a neurological and orthopaedic assessment, a noninvasive urodynamic study, renal ultrasonography and spinal and pelvic magnetic resonance imaging (MRI). All patients with signs of bladder dysfunction were evaluated by a pressure-flow study. The results were analysed for surgical approach and anatomical involvement, i.e. group A, extensive surgery for complete tumour excision in the sacral area (ST and YST); group B, surgery for tumour resection in the paraspinal ganglia area (neuroblastoma and ganglioneuroma); and group C, bladder tumour with partial bladder resection (MBS). RESULTS: Eight patients had signs or symptoms related to bladder sphincter dysfunction. One child refused the invasive urodynamic evaluation, leaving seven for analysis (two each ST and ganglioneuroma, one each YST, neuroblastoma and MBS). The urodynamic findings were normal in three children. On spinal and pelvic MRI a presacral lipoma with syringomyelia was discovered in one child with ST. Eight children had bladder dysfunction and two had no neurogenic damage (which was only in sacral tumours); in one child it was related to an upper motor neurone lesion from spinal dysraphism and in the other to a lower motor neurone lesion from surgical injury to the splanchnic nerves. Patients operated for paraspinal tumours had more bladder dysfunction but no signs of neurogenic damage, as did the patient with partial bladder resection. However in Group B, there may have been a transient or incomplete nerve injury in one patient. CONCLUSIONS: Deficits of parasympathetic, sympathetic and somatic innervation of the bladder and the urethra may occur in children after surgery for pelvic neoplasms, related to minor or major surgical trauma. In ST, a tethered cord may be associated with mixed neurogenic damage. Knowledge of bladder dysfunction in anorectal malformations, spinal dysraphism, etc. and the clinical protocol used in these patients also seemed to be useful for understanding the development of voiding dysfunction in patients with neoplasm.