Faculty Bibliography

PURPOSE: To evaluate the feasibility of and response rate to an intensified induction chemotherapy regimen for young children with newly diagnosed high-risk or disseminated medulloblastomas. PATIENTS AND METHODS: From January 1997 to March 2003, 21 patients with high-risk or disseminated medulloblastoma were enrolled. After maximal surgical resection, patients were treated with five cycles of vincristine (0.05 mg/kg/wk x three doses per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4 mg/kg/d x 2 days per cycle), cyclophosphamide (65 mg/kg/d x 2 days per cycle) with mesna, and methotrexate (400 mg/kg per cycle) with leucovorin rescue. Following induction chemotherapy, eligible patients underwent a single myeloablative chemotherapy cycle with autologous stem-cell rescue. RESULTS: Significant toxicities of this intensified regimen, including gastrointestinal and infectious toxicities, are described. Among the 21 patients enrolled, there were 17 complete responses (81%), two partial responses, one stable disease, and one progressive disease. The 3-year event-free survival and overall survival are 49% (95% CI, 27% to 72%) and 60% (95% CI, 36% to 84%), respectively. CONCLUSION: This intensified induction chemotherapy regimen is feasible and tolerable. With the majority of patients with disseminated medulloblastoma having M2 or M3 disease at diagnosis, the encouraging high response rate of this intensified induction regimen suggests that such an addition of methotrexate should be explored in future studies

Thymoma is an uncommon tumor of childhood. Stage of the tumor is an independent prognostic factor for survival. Surgery is the treatment of choice for stage I and stage II tumors. Chemotherapy is reserved for patients with refractory or metastatic disease. Thymomas are moderately radiosensitive. However, radiation therapy is not an attractive option for children due to its side-effects on developing organs. The authors describe 2 children with completely encapsulated thymoma who were successfully treated with surgery alone. Both patients remain free of disease 3 years after surgery. One of the patients also has nevus sebaceous. The authors also discuss the possible association between the two disease entities.

Thymoma is an uncommon tumor of childhood. Stage of the tumor is an independent prognostic factor for survival. Surgery is the treatment of choice for stage I and stage II tumors. Chemotherapy is reserved for patients with refractory or metastatic disease. Thymomas are moderately radiosensitive. However, radiation therapy is not an attractive option for children due to its side-effects on developing organs. The authors describe 2 children with completely encapsulated thymoma who were successfully treated with surgery alone. Both patients remain free of disease 3 years after surgery. One of the patients also has nevus sebaceous. The authors also discuss the possible association between the two disease entities.

Brain tumors are the second most common malignancy in children and the most common solid tumor. The majority of children are treated with surgery alone or in combination with radiation and/or chemotherapy. Recently investigators have used high dose chemotherapy with autologous stem cell rescue (ASCR) in patients with malignant brain tumors. This approach has been most successful in chemosensitive tumors including medulloblastoma, supratentorial primitive neuroectodermal tumors (SPNET) and central nervous system germ cell tumors (CNS GCT). In addition, the use of high dose chemotherapy has enabled the reduction and in many cases elimination of radiation therapy to very young children. To date there have been no prospective randomized studies comparing high dose chemotherapy and ASCR with conventional therapy. Radiation therapy is often not an option for patients with recurrent disease and conventional dose chemotherapy rarely if ever results in long-term survival. Unfortunately, the majority of studies using conventional therapy in order to delay irradiation in young children newly diagnosed with malignant brain tumors have been unsuccessful. Although the numbers are small, preliminary data suggest that not only is survival but also quality of life is superior with the use of high dose chemotherapy. Future studies will most likely include the use of new agents as part of the cytoreduction. In addition, through the use of peripheral blood stem cells and improvements in supportive care, multiple courses of high dose chemotherapy can be administered. High dose chemotherapy with ASCR is a foundation upon which many different types of therapies can be built. Several possibilities include the use of anti-angiogenesis agents, monoclonal antibodies and biologic response modifiers

PURPOSE: To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). PATIENTS AND METHODS: Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. RESULTS: Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. CONCLUSION: Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden

BACKGROUND: Recurrent non-cerebellar primitive neuroectodermal tumors (PNETs) carry a dismal prognosis when treated with conventional chemotherapy alone. XSWe tested the efficacy of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in this setting. PROCEDURE: Eligibility mandated either minimal residual disease or evidence of chemosensitivity before HDC. Conditioning consisted of carboplatin (CBDCA) (500 mg/m(2) or AUC = 7 mg/ml min using the Calvert formula) on days -8 to -6, thiotepa (300 mg/m(2)), and etoposide (250 mg/m(2)) on days -5 to -3. Irradiation was given post HDC selectively. RESULTS: Among 17 patients treated in this study, there were eight pineoblastoma(s) (pineo), seven cortical PNETs, and two arising elsewhere. Relapse was either local (nine) or metastatic to the brain (four) or spine (four). Two patients received HDC as the sole therapy for recurrence; additionally, eight underwent surgical debulking before HDC, and nine received irradiation, including six after HDC. Median age at ASCR was 3.9 years. Two patients died of toxicity (11%) and ten experienced tumor relapse (range: 23-361 days post ASCR). Five patients with cortical PNETs remain alive disease-free (median follow-up: 8.3 years); four of them received irradiation post HDC. The difference in 5-year event-free survival (EFS) between patients with pineo and other supratentorial PNETs was significant (0 vs. 62.5 +/- 17%, P = 0.0065). Both surgery at relapse and irradiation post HDC were favorable prognostic factors (P = 0.006 and 0.01, respectively). CONCLUSIONS: Patients with recurrent cortical PNETs can be cured with this strategy. Surgical debulking before, and irradiation after HDC play an important role in treatment success

PURPOSE: Anaplastic oligodendroglioma is a chemosensitive glial neoplasm. To improve disease control and postpone cranial radiotherapy, we designed a phase II study of intensive procarbazine, lomunstine and vincristine followed by high-dose thiotepa with autologous stem cell rescue for patients with newly diagnosed anaplastic or aggressive oligodendroglioma. PATIENTS AND METHODS: Sixty-nine patients with a median age of 42 (range: 18-67) and a median Karnofsky Performance Score of 90 (range: 70-100) were enrolled. Sixteen patients had a prior diagnosis of low-grade oligodendroglioma and 16 had mixed oligoastrocytoma pathology. Only patients with demonstrably chemosensitive enhancing tumors or those free of enhancing tumor after surgery and induction therapy were eligible to receive high-dose thiotepa. RESULTS: Thirty-nine patients (57%) completed the transplant regimen; their estimated median progression-free survival is 69 months and median overall survival has not been reached. Twelve transplanted patients (31%) relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with relapse; however, persistent non-enhancing tumor at transplant conferred an increased risk of relapse (p = 0.028). The transplant regimen was well-tolerated; median hospital stay was 20 days (range: 7-43) with a median time to ANC and platelet engraftment of 10 days. Thirty patients (43%) did not receive high-dose thiotepa because of stable or progressive disease (n = 21), excessive toxicity (n = 4), refusal of further therapy (n = 2), failure to obtain insurance coverage (n = 2), or other (n = 1). No treatment-related or long-term neurotoxicity was seen in the transplanted patients. CONCLUSIONS: High-dose chemotherapy with stem cell rescue as initial treatment for anaplastic oligodendroglioma is feasible and associated with prolonged tumor control in some patients