Faculty Bibliography

PURPOSE: This single-institution Phase III study conducted from 1989 to 1995 evaluates the feasibility of a multimodality protocol combining hyperfractionated craniospinal radiotherapy (HFRT) followed by adjuvant chemotherapy in 23 patients with newly diagnosed primitive neuroectodermal tumors (PNET) arising in the central nervous system. METHODS AND MATERIALS: All 23 patients had a histologically confirmed PNET and were over 3 years of age at diagnosis. The eligibility criteria for PNET patients with cerebellar primaries (medulloblastoma) included either a high T stage (T3b or 4) or high M stage (M1-3). All patients with noncerebellar primaries were eligible regardless of T or M stage. The median age of the 23 patients was 9 years (mean 3-25); 11 were female. The primary tumor arose in the cerebellum in 19. Of these medulloblastoma patients, 15 had high T stages (T3b or T4) with large locally invasive tumors and no evidence of metastases (M0), constituting Group 1. Thirteen (86%) of these patients had gross total resections. Four other medulloblastoma patients had both high T and high M stages, constituting Group 2. Group 3 consisted of four other patients with exocerebellar primaries (two brain, one brain stem, and one cauda equina), three of whom were M3. Hyperfractionated radiotherapy was administered within 4 weeks of surgery. Twice-daily 1-Gy fractions were administered separated by 4-6 h. The total dose to the primary intracranial tumor and other areas of measurable intracranial disease was 72 Gy. The prophylactic craniospinal axis dose was 36 Gy, and boosts of 44-56 Gy were administered to metastatic spinal deposits. Following radiotherapy, monthly courses of multiagent chemotherapy were administered sequentially (cyclophosphamide-vincristine followed by cisplatin-etoposide followed by carboplatin-vincristine) for a total of 9 months. RESULTS: All patients completed radiotherapy as planned. Only three patients lost >10% of their body weight. One patient had clinically apparent radiation-induced esophagitis. The mean white blood count (WBC) nadir was 2.5/dl, and hematologic recovery occurred in all within 4 weeks of completing HFRT without the need of granulocyte-colony-stimulating factor. Two patients refused adjuvant chemotherapy, 3 patients experienced tumor progression during chemotherapy, and 2 of 18 remaining patients could not tolerate the full 9 months owing to hematologic toxicity. Of the 15 patients (93%) in Group 1, 14 remain in continuous remission for a median of 78 months, and none have died. Two of four patients in Group 2 are in continuous remission at 67 and 35 months, and two died at 18 and 30 months. One of the two patients in Group 2 who died refused adjuvant chemotherapy and developed tumor progression in the bone marrow. None of the three patients in Group 3 with evaluable disease (M3) had a complete response to therapy, and eventually all four died of progressive or recurrent disease. CONCLUSION: This multimodality protocol is feasible in the short term, and long-term monitoring of neurocognitive and neuroendocrine effects are in progress. Excellent long-term disease control has been achieved for medulloblastoma patients with high T stages who were M0 at diagnosis (Group 1), the majority of whom had gross total resections. This group has a progression-free survival of 95% after a median period of follow-up of 6.5 years. Alternative treatment strategies must be developed for patients with high M stages, as five of seven patients died of progressive or recurrent disease

Over a 13-year period extending from 1980 to 1993, 27 children less than 3 years of age underwent operation for removal of an intramedullary spinal cord tumor (IMSCT). The majority (18 of 27) of children had undergone surgery before being referred to New York University (NYU) Medical Center. The most common reasons for radiological investigation were pain (42%), motor regression (36%), gait abnormalities (27%), torticollis (27%), and progressive kyphoscoliosis (24%). Forty procedures were performed in 27 children. Nine children underwent two operations and two children underwent three procedures. A gross-total resection was achieved in 72% of the procedures. There was no surgical mortality. A comparison of the preoperative and 3-month postoperative functional grades for the first NYU procedure (NYU-1) yielded the following findings: 20 patients' conditions remained the same, five patients improved, and two patients deteriorated. The functional outcomes of a second operation (NYU-2) were similar. The majority of the children (24 of 27, 89%) had histologically determined low-grade lesions. There were 12 patients with low-grade astrocytomas (Grades I-III), eight with gangliogliomas, two with ganglioglioneurocytomas, one with a glioneurofibroma, and one child with a mixed astro/oligodendroglioma. Two children had anaplastic astrocytomas (Grades II-III) and one child had a glioblastoma multiforme. In a median follow-up review of 76 months, two patients died and two patients were lost to follow up. The 3- and 5-year progression-free survival (PFS) rates were 81.7% (standard error of the mean (SEM) 0.083) and 76.2% (SEM 0.094), respectively. Eight of 24 patients suffered a recurrence within a mean time of 45.4 +/- 28.9 months. All were treated with surgery (NYU-2). Lesions recurred in three of 12 children with low-grade astrocytomas, two of eight children with gangliogliomas, one child with an anaplastic astrocytoma, one child with a ganglioglioneurocytoma, and one child with a glioblastoma multiforme. At follow-up review, most of these children were doing well. Sixteen are in functional Grades I or II and 18 children attend a normal school system. The authors conclude that surgery for the removal of IMSCTs in children less than 3 years of age can be performed radically and safely. The postoperative functional performance is determined by the degree of the preoperative deficit. It is, therefore, of utmost importance to diagnose and treat these children as early as possible. Spinal cord tumors should be recognized as potentially excisable lesions on their initial presentation and when they recur. The optimum treatment for malignant lesions is still to be determined

Radical surgery is the most important treatment modality for ependymoma. The benefit of adjuvant radiotherapy and/or chemotherapy following a gross total resection of a low grade intracranial ependymoma is uncertain. Since 1990 we elected to defer adjuvant therapy in 7 pediatric patients with a median age of 7 years (range 3-16 years) who had a radical resection of an intracranial ependymoma and no evidence of central nervous system metastases. The primary tumor site was the cerebral hemisphere (6) and the cerebellum (1). A gross total resection was radiologically confirmed in 5 of the 7 patients. Two of the patients had a blood clot in the resection site on the postoperative magnetic resonance imaging scan. All patients are alive after a median follow-up of 44 months and the median progression-free survival is 38+ months. Five of the patients remain in continuous remission. The 2 patients with postoperative blood clots developed subclinical local recurrences, 10 and 11 months, respectively, after diagnosis. They remain in remission for 13+ and 27+ months after subsequent radical surgical procedures. Involved field radiotherapy was administered to 1 patient. After a limited period of follow-up, radical surgery alone appears to be sufficient for the majority of children with low grade ependymomas diagnosed at > 3 years of age when postoperative imaging confirms a gross total resection. This is more likely to occur in supratentorial ependymomas arising in older children

Radiotherapy has remained the mainstay of treatment for children with intrinsic, diffuse pontine tumors in spite of over 20 years of clinical trials attempting to validate the additional role of chemotherapy. Conventional phase II clinical trials conducted in patients with recurrent or progressive brainstem gliomas using single chemotherapy agents such as cyclophosphamide, carboplatin, cisplatin, etoposide and thiotepa or combinations of chemotherapy agents have produced low response rates in the range of 15-20%. Preradiotherapy chemotherapy phase II trials in newly diagnosed patients have yielded similar results with a therapeutic window as long as 4 months. Preliminary data from protocols employing high-dose chemotherapy with stem cell support have also met with disappointment. The one published phase III trial conducted by the Children's Cancer Study Group comparing radiotherapy with radiotherapy plus chemotherapy (CCNU, vincristine and prednisone) failed to establish a benefit to multimodality therapy. Current studies include the use of radiosensitizing chemotherapy (carboplatin, estramustine and cisplatin) in newly diagnosed patients and more intensive neoadjuvant chemotherapy trials. Major advances in our management await insights into molecular vulnerability of high-grade gliomas

PURPOSE: To determine clinical characteristics and response to treatment for children with supratentorial primitive neuroectodermal tumors (S-PNETs). PATIENTS AND METHODS: After surgery and staging, 55 patients aged 1.5 to 19.3 years with S-PNETs were randomized to receive craniospinal radiotherapy (RT) followed by eight cycles of 1-(2-chloro-ethyl)-3-cyclohexylnitrosourea (CCNU), vincristine (VCR), and prednisone (standard treatment) or two cycles of 8-in-1 chemotherapy followed by RT and then eight additional cycles of 8-in-1. RESULTS: Three-year Kaplan-Meier estimates (estimate +/- SE) of survival and progression-free survival (PFS) rates for patients with confirmed diagnoses of S-PNET were 57% +/- 8% and 45% +/- 8%, respectively; survival and PFS rates for children with PNETs located in the pineal region were 73% +/- 12% and 61% +/- 13%, respectively, and were significantly different from the other S-PNETs (P < .03). The 8-in-1 arm had greater toxicity than the standard-treatment arm. Distributions of PFS between the two treatment groups were not significantly different (P > .5). Other univariate prognostic factors that influenced PFS included metastasis (M) stage (P < .03: M0 50% +/- 9% v M1-4 0%) and age (P < .02: 1.5 to 2 years 25% +/- 13% v > or = 3 years 53% +/- 9%). CONCLUSION: In this first randomized treatment trial for S-PNETs in children, no significant differences were detected between the two treatment groups. M0 and pineal site of involvement were independent predictors of a better outcome. However, survival was better than previously reported.

A new analytical affinity chromatography method was developed for measuring the free [Zn2+] concentration in bovine milk. The column was generated by immobilizing avidin and attaching biotinylated metallothionein (MT) on controlled-pore glass beads. Zinc bound to the MT column at physiological free [Zn2+] concentration and was dissociated again in an elution buffer of pH 2. The distributions of extrinsically added 65Zn and native zinc in different fractions of milk were virtually identical, validating the use of extrinsic labeling in studies of the free [Zn2+] concentration in milk. Extrinsically labeled whey fractions were mixed with standard solutions whose free [Zn2+] concentrations were calculated by computer model. 65Zn retained by the column provided an indication of free [Zn2+] concentration in the mixture, and by interpolation, in the original milk. The free [Zn2+] concentration measured by the affinity chromatography method in the milk of a group of six cows was 90.4 +/- 29.7 pM. This value is similar to estimates of free [Zn2+] concentrations in other biological fluids by entirely different methods. Measurement of free [Zn2+] may be helpful in understanding the physiology and biochemistry of zinc metabolism.