Graziella Cefalo

High Response Rate to Cisplatin/Etoposide Regimen in Childhood Low-Grade Glioma

PURPOSE The aim of this study was to avoid radiotherapy and to induce an objective response in children with low-grade glioma (LGG) using a simple chemotherapy regimen based on cisplatin and etoposide. PATIENTS AND METHODS Thirty-four children (median age, 45 months) with unresectable LGG were treated with 10 monthly cycles of cisplatin (30 mg/m(2)/d on days 1 to 3) and etoposide (150 mg/m(2)/d on days 1 to 3). Tumor originated in the visual pathway in 29 patients, in the temporal lobe in two, in the frontal lobe in two, and in the spine in one. Eight children were affected by neurofibromatosis type 1. Objective tumor response and toxicity were evaluated by magnetic resonance imaging and neurologic and functional tests at 3-month intervals. RESULTS An objective response was obtained in 24 (70%) of 34 patients, whereas the others had stable disease. None of the children were electively irradiated. In 31 previously untreated children, overall survival was 100% and progression-free survival was 78% at 3 years, with a median follow-up of 44 months. Acute toxicity was unremarkable; 28% patients evaluated for acoustic neurotoxicity revealed a loss of perception of high frequencies. CONCLUSION Cisplatin and etoposide combined treatment is one of the most active regimens for LGG in children and allows avoidance of radiotherapy in the vast majority of patients.

Neoadjuvant Chemotherapy With Methotrexate, Cisplatin, and Doxorubicin With or Without Ifosfamide in Nonmetastatic Osteosarcoma of the Extremity: An Italian Sarcoma Group Trial ISG/OS-1

PURPOSE We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), and IFO 30 g/m(2)) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS). RESULTS From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B. CONCLUSION IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.

Adult-Type Soft Tissue Sarcomas in Pediatric-Age Patients: Experience at the Istituto Nazionale Tumori in Milan

PURPOSE Nonrhabdomyosarcoma soft tissue sarcomas are a heterogeneous group of tumors for which optimal treatment remains controversial. We report on a large group of 182 patients younger than 18 years old treated at a single institution over a 25-year period. PATIENTS AND METHODS In this relatively homogeneous subgroup of adult-type histotypes, surgery was the mainstay of treatment; radiotherapy was administered to 73 patients, and chemotherapy was administered to 114 patients (70 received chemotherapy as adjuvant therapy). RESULTS Overall survival at 5 years was 89% in patients who underwent complete resection at diagnosis, 79% in patients who had marginal resection, 52% in initially unresected patients, and 17% in patients with metastases at onset. Outcome was unsatisfactory in patients with large and high-grade tumors, even after gross resection; adjuvant chemotherapy seemed to improve the results in this group. Initially unresected patients who responded well to chemotherapy and subsequently underwent complete resection had an event-free survival rate of approximately 70%. The rate of response to chemotherapy was 58%. CONCLUSION The identification of prognostic variables should enable risk-adapted therapies to be planned. Patients with initially unresectable disease and patients with resected large and high-grade tumors are at high risk of metastases and treatment failure. Although the limits of this retrospective analysis are self-evident, our data would suggest that intensive chemotherapy (with an ifosfamide-doxorubicin regimen) might have a more significant role in these patients than what is generally assumed.

Hyperfractionated Accelerated Radiotherapy in the Milan Strategy for Metastatic Medulloblastoma

PURPOSE With a view to improving the prognosis for patients with metastatic medulloblastoma, we tested the efficacy and toxicity of a hyperfractionated accelerated radiotherapy (HART) regimen delivered after intensive sequential chemotherapy. PATIENTS AND METHODS Between 1998 and 2007, 33 consecutive patients received postoperative methotrexate (8 g/m(2)), etoposide (2.4 g/m(2)), cyclophosphamide (4 g/m(2)), and carboplatin (0.8 g/m(2)) in a 2-month schedule, then HART with a maximal dose to the neuraxis of 39 Gy (1.3 Gy/fraction, 2 fractions/d) and a posterior fossa boost up to 60 Gy (1.5 Gy/fraction,2 fractions/d). Patients with persistent disseminated disease before HART were consolidated with two myeloablative courses and circulating progenitor cell rescue. RESULTS Patients were classified as having M1 (n = 9), M2 (n = 6), M3 (n = 17), and M4 (n = 1) disease. Seven patients younger than 10 years old who achieved complete response after chemotherapy received a lower dose to the neuraxis (31.2 Gy). Twenty-two of the 32 assessable patients responded to chemotherapy; disease was stable in five patients and progressed in five patients. One septic death occurred before radiotherapy. Eight patients experienced relapse after a median of 12 months. Fourteen of the 33 patients underwent consolidation therapy after HART. With a median 82-month survivor follow-up, the 5-year event-free, progression-free, and overall survival rates were 70%, 72%, and 73%, respectively. No severe clinical complications of HART have emerged so far. CONCLUSION HART after intensive postoperative chemotherapy, followed by myeloablative chemotherapy in selected cases, proved feasible in children with metastatic medulloblastoma. The results of our treatment compare favorably with other series treated using conventional therapies.

Intrathecal methotrexate affects cognitive function in children with medulloblastoma

BackgroundCognitive impairment occurs after malignant brain tumor treatment in children, following brain radiotherapy and systemic and intrathecal chemotherapy. Objectives1) To compare two groups of children who underwent surgery for cerebellar medulloblastoma with their cousins and siblings, assessing intelligence, executive function, attention, visual perception, and short-term memory. Both groups were treated with the same combined radiotherapy–chemotherapy, but differed in that only one group received intrathecal methotrexate (MTX+). 2) To relate these measures to MRI findings (leukomalacia). ResultsThe two groups performed worse than their control subjects in all tests. The MTX+ group younger than 10 years performed significantly worse in all tests, particularly executive ones. The group older than 10 years performed significantly worse only in short-term memory. Younger patients without MTX performed significantly worse than controls only in some neuropsychological measures; there were no differences between older patients and control subjects. Only in the MTX+ group was there a direct correlation between extent of leukomalacia and performance in some tests. ConclusionsThe administration of intrathecal methotrexate to children with medulloblastoma worsens the cognitive deficits induced by chemotherapy and radiotherapy. The use of intrathecal methotrexate in the treatment of medulloblastoma and other malignancies should be reassessed.

Oophoropexy: a relevant role in preservation of ovarian function after pelvic irradiation.

OBJECTIVE To report on our experience with girls and young women who received treatment for Hodgkin lymphoma, underwent prior oophoropexy to preserve their ovarian function, and subsequently gave birth. DESIGN Retrospective monoinstitutional evaluation. SETTING National Cancer Institute. PATIENT(S) Eleven girls given treatment for Hodgkin lymphoma and undergoing bilateral ovarian transposition at a median age of 13 years. INTERVENTION(S) The ovaries were positioned behind the uterus by the general surgeon. MAIN OUTCOME MEASURE(S) Fourteen pregnancies were recorded among these 11 women, with 12 live births (1 twin) and 3 miscarriages. RESULT(S) None of these women needed the ovaries to be relocated, and none of them resorted to artificial insemination. Their median age at the time of first pregnancy was 31 years, and the median time elapsing since ovarian transposition was 14 years. CONCLUSION(S) This series confirms that oophoropexy can preserve ovarian function and enable future pregnancy. We encourage pediatric oncologists, surgeons, and radiotherapists to bear this option in mind when considering female patients for pelvic irradiation.

Malignant peripheral nerve sheath tumors in children: a single-institution twenty-year experience.

A retrospective series of pediatric patients with localized malignant peripheral nerve sheath tumors (MPNST) treated during a 20-year period at one institution is reported. Between 1976 and 1996, 24 consecutive children were treated by a multimodality approach. Conservative surgery was the treatment of choice: primary radical surgery was performed in 10. Postoperative radiotherapy was administered in 12 and adjuvant chemotherapy in 19. Eight patients were alive without evidence of disease, six in first complete remission and two in second complete remission, after a median follow-up of 230 months. The 10-year event-free survival (EFS) and survival were 29% and 41%, respectively. Survival was 80% for the patients who underwent radical surgery, and 14% for the others; 71% for patients with tumors smaller than 5 cm, and 29% for those with tumors 5 cm or larger. Local recurrence was the major cause for treatment failure (13 of 17; 76%); the rate of local relapse was 33% v 75% in patients who either received or did not receive radiotherapy. Complete surgical excision remains the most effective treatment for MPNST and represents the main prognostic factor along with tumor size. Radiotherapy seems to play a role in achieving local control, whereas the role of chemotherapy is uncertain.

Intensive, Very Short-Term Chemotherapy for Advanced Burkitt’s Lymphoma in Children

PURPOSE To improve the 63% event-free survival (EFS) achieved before 1986 in Murphys stage III to IV Burkitts lymphoma (BL), both chemotherapy and supportive care were intensified. PATIENTS AND METHODS From May 1987 to February 2001, 60 children, median age 9 years (range, 2.1 to 17 years), with advanced BL were enrolled onto two sequential institutional studies. From 1987 to 1992, 30 patients were stratified according to the absence (regimen IA, n = 19) or presence (regimen IB, n = 11) of bone marrow (BM) or CNS involvement. After 5-week cytoreductive chemotherapy consisting of vincristine, cyclophosphamide, doxorubicin, high-dose (HD) methotrexate (MTX), and intrathecal MTX or cytarabine, HD cytarabine and cisplatin were provided as a 4-day continuous infusion. Regimen IB was intensified by adding etoposide and HD ifosfamide and escalating MTX doses. Since 1992, regardless of BM or CNS status, 30 patients have been placed on regimen II, which is identical to IB but without ifosfamide. The scheduled duration of regimen II was 45 days. RESULTS EFS and disease-free survival at 5 years are 81% +/- 5% and 87% +/- 5%, respectively, for 59 assessable patients (73% +/- 8% and 85% +/- 7% for regimen IA + IB, 89% +/- 6%, EFS and disease-free survival, for regimen II; median follow-up, 6.7 years; range, 0.6 to 13.5 years). Six patients, two of whom were receiving regimen II, died as a result of initial treatment failure or relapse, and five patients, none receiving regimen II, died as a result of treatment-related complications. CONCLUSION This 45-day intensive chemotherapy program is the shortest schedule for disseminated BL and overcomes previously recognized risk factors such as BM and CNS infiltration.

Synovial sarcoma: Report of a series of 25 consecutive children from a single institution

BACKGROUND The role of postoperative radiotherapy and adjuvant chemotherapy in the treatment of synovial sarcoma remains to be determined. PROCEDURE Twenty-five children were treated during a 23-year period with a multimodality approach. All of them had resection of the primary tumor (three amputations), followed by surgical retreatment in eight. Postoperative radiotherapy was delivered to 16 patients and adjuvant chemotherapy was given to 22. RESULTS At the time of the report, 19 patients were alive and without evidence of disease. Six developed distant metastases (one associated with local recurrence); five of them died of their disease and one was alive in complete remission at 4 years from relapse. With a median follow-up of 9 years (range 2-23), the survival and the event-free survival at 5 years were 80% (SE 8.2) and 74% (SE 9.2), respectively. All relapsing patients had been classified as T2B. CONCLUSIONS Multimodality treatment yielded satisfying survival results using limb-preserving surgery in most cases. Tumor size > 5 cm and invasiveness, which defined stage T2B, were the most important predictors of poor outcome. Evaluation of the role of adjuvant chemotherapy and radiotherapy awaits prospective studies, even if T2B patients, as well as children having nonradical surgery, seem worth managing by adjuvant treatments.

Sequential chemotherapy, high-dose thiotepa, circulating progenitor cell rescue, and radiotherapy for childhood high-grade glioma

Childhood malignant gliomas are rare, but their clinical behavior is almost as aggressive as in adults, with resistance to therapy, rapid progression, and not uncommonly, dissemination. Our study protocol incorporated sequential chemotherapy and high-dose thiotepa in the preradiant phase, followed by focal radiotherapy and maintenance with vincristine and lomustine for a total duration of one year. The induction treatment consisted of two courses of cisplatin (30 mg/m2) plus etoposide (150 mg/m2) x 3 days and of vincristine (1.4 mg/m2) plus cyclophosphamide (1.5 g/m2) plus high-dose methotrexate (8 g/m2), followed by high-dose thiotepa (300 mg/m2 x 3 doses), with harvesting of peripheral blood progenitor cells after the first cisplatin/etoposide course. From August 1996 to March 2003, 21 children, 14 females and 7 males, with a median age of 10 years were enrolled, 18 presenting with residual disease after surgery. Histologies were glioblastoma multiforme in 10, anaplastic astrocytoma in nine, and anaplastic oligodendroglioma in two; sites of origin were supratentorial areas in 17, spine in two, and posterior fossa in two. Of the 21 patients, 12 have died (10 after relapse, with a median time to progression for the whole series of 14 months; one with intratumoral bleeding at 40 months after diagnosis; and one affected by Turcot syndrome for duodenal cancer relapse). Four of 12 relapsed children had tumor dissemination. At a median follow-up of 57 months, overall survival and progression-free survival at four years were 43% and 46%, respectively. Sequential and high-dose chemotherapy can be afforded in front-line therapy of childhood malignant glioma without excessive morbidity and rather encouraging results.