John F. Kuttesch

A quantitative meta-analysis of neurocognitive sequelae in survivors of pediatric brain tumors†‡

Deficits in neurocognitive functioning are an important area of late effects in survivors of pediatric brain tumors, but a quantitative analysis of the magnitude of these deficits has yet to be conducted.

Utility of Fdg-pet/ct in Follow-up of Children Treated for Hodgkin and Non-hodgkin Lymphoma

Positron emission tomography using 18F-flurodeoxyglucose (FDG-PET) is considered an excellent tool for staging and monitoring disease status in adults with lymphoma. We retrospectively reviewed results of PET/CT and diagnostic computed tomography (CT) scans performed during follow-up after completion of therapy in 41 children <18 years of age with Hodgkin lymphoma and non-Hodgkin lymphoma. PET/CT scan with uptake greater than that of the liver was considered positive. Uptake that increased over the background but less than in the liver was equivocal. Clinical outcomes were obtained from medical records. Thirteen (32%) had a positive PET/CT scan and an equal number had equivocal scans in a median follow-up of 2.3 years. Diagnostic CT scans revealed new findings in 13 (32%) and persistent abnormalities in 21 (51%) of the children. Five children developed recurrent disease, and one developed a second cancer. No children with equivocal positivity developed recurrent disease. PET/CT scan was 95% sensitive, with a positive predictive value (PPV) of 53%. Diagnostic CT was 79% sensitive, with a PPV of 52%. We conclude that a negative PET/CT scan during routine follow-up for lymphoma in children strongly suggests absence of recurrence but a positive PET/CT and diagnostic CT scans have low PPV and should be interpreted with caution in this setting.

Phase I Study of Combination Topotecan and Carboplatin in Pediatric Solid Tumors

PURPOSE We conducted a phase I trial of escalating doses of topotecan (TOPO) in association with a fixed systemic exposure of carboplatin (CARBO) with or without granulocyte colony-stimulating factor (G-CSF) in children. PATIENTS AND METHODS Two separate cohorts of patients (pts) with solid tumors were studied: (A) pts with refractory or recurrent disease and (B) pts with no prior myelosuppressive therapy or newly diagnosed tumors for which there was no standard chemotherapy. CARBO was given on day 1 at an area under the curve of 6.5, followed by TOPO as a continuous infusion for 3 days; the starting dose of TOPO was 0.50 mg/m(2)/d. Cycles were repeated every 21 days. G-CSF was given at a dose of 5 microg/kg/d starting on day 4. RESULTS Forty-eight of 51 pts were assessable for toxicity. In group A, dose-limiting myelosuppression persisted despite de-escalation of TOPO to 0.3 mg/m(2)/d and use of G-CSF. In group B, the maximum-tolerated dose of TOPO was 0.5 mg/m(2)/d for 3 days, and 0.6 mg/m(2)/d for 3 days with G-CSF. No significant nonhematologic toxicities were observed. Among 46 pts assessable for response, one had complete response, five had partial response, and 18 had stable disease. CONCLUSION Although this combination possesses antineoplastic activity in pediatric solid tumors, hematologic toxicity precluded any meaningful TOPO dose escalation. The addition of G-CSF did not alter this. The potential for preservation of activity and diminution of toxicity with alternative sequences and schedules of administration (topoisomerase followed by alkylating or platinating agents) should be evaluated.

P-glycoprotein expression at diagnosis may not be a primary mechanism of therapeutic failure in childhood rhabdomyosarcoma.

PURPOSE To evaluate the prognostic significance of tumor cell P-glycoprotein (Pgp) expression at diagnosis in children with rhabdomyosarcoma. PATIENTS AND METHODS A panel of three anti-Pgp monoclonal antibodies (mAb) (C219, C494, and JSB-1) that recognize different Pgp epitopes was used to measure Pgp expression in rhabdomyosarcoma specimens obtained at diagnosis from 76 patients treated at St Jude Childrens Research Hospital from 1969 to 1991. Two separate experiments using different immunohistochemical methods (immune alkaline phosphatase and immunoperoxidase) were performed to evaluate Pgp expression. The immunostaining was graded using a semiquantitative scale corresponding to the percentage of tumor cells with detectable staining. The influence of Pgp expression on outcome was assessed by the Kaplan-Meier method and Cox regression analysis with stepwise selection. The relationship between Pgp expression and clinical features was assessed using the Mantel-Haenszel method. RESULTS Pgp expression at diagnosis did not predict worse overall survival or progression-free survival when tested in either experiment with C219, C494, or JSB-1 separately. No association was shown between Pgp expression and clinical features (clinical group, primary site, or histology) or response. However, in the immune alkaline phosphatase experiment, patients whose tumors had more than 10% tumor cell staining with all three mAbs had a significantly higher rate of estimated 5-year survival (78% +/- 10%) than did all other patients (38% +/- 8%; P = .025). In this instance, Pgp expression had independent prognostic value after adjusting for clinical group. CONCLUSION We found no strong association between Pgp expression at diagnosis and clinical features or extent of disease in pediatric rhabdomyosarcoma. Depending on the criteria used to define it, high Pgp expression at diagnosis does not predict poor outcome. Although a large prospective study is needed to provide definitive conclusions, our findings suggest that Pgp-mediated multidrug resistance may not be a primary mechanism of therapeutic failure in rhabdomyosarcoma.

Neurocognitive Late Effects of Pediatric Brain Tumors of the Posterior Fossa: A Quantitative Review

Deficits in neurocognitive functioning are an important area of late effects in survivors of pediatric brain tumors; however, a quantitative analysis of the magnitude of these deficits in survivors of brain tumors of the posterior fossa has not been conducted. Despite tumor locations in the posterior regions of the brain, individual studies have documented deficits in a variety of domains, reflective of impairment in other brain regions. The current study provides a comprehensive meta-analysis of literature on neurocognitive late effects found in survivors of posterior fossa tumors. Results indicated significant deficits in both specific and broad indices of neurocognitive functioning, and the overall magnitude of effects across domains ranged from medium to large (g = -0.62 to -1.69) with a large mean overall effect size (g = -1.03). Moderator analyses indicated significantly greater effects for survivors diagnosed at a younger age and those who received radiation therapy. These findings underscore the importance of monitoring neurocognitive late effects in survivors of pediatric brain tumors of the posterior fossa, as well as the need for more consistent consideration of demographic, diagnostic, and treatment-related variables to allow for examination of factors that moderate these deficits.

Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium

PURPOSE To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. PATIENTS AND METHODS This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m(2)) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m(2)/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. RESULTS Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m(2) weekly plus irinotecan 16 mg/m(2)/d (pediatric) or 20 mg/m(2)/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). CONCLUSION The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.

Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: A Children's Oncology Group study†

A Phase II trial was developed to determine the efficacy and toxicity of intravenous vinorelbine, a semi‐synthetic vinca alkaloid, in children, adolescent, and young adults with recurrent or refractory solid malignancies.

Tumor-cell DNA content predicts outcome in children and adolescents with clinical group III embryonal rhabdomyosarcoma. The Intergroup Rhabdomyosarcoma Study Committee of the Children's Cancer Group and the Pediatric Oncology Group.

PURPOSEThe prognostic value of tumor-cell DNA content (ploidy) was evaluated in children with unresectable, nonmetastic rhabdomyosarcoma of embryonal histology.PATIENTS AND METHODSFlow-cytometric techniques were used to estimate the ploidy of tumor specimens from 34 patients with embryonal rhabdomyosarcoma who were enrolled in the intergroup rhabdomyosarcoma study III (IRS III) from 1985 to 1991. Tumors were classified as diploid or hyperdiploid (DNA content, 1.1 to 1.8 times that of normal diploid cells). The influence of ploidy on clinical outcome was assessed by the Kaplan-Meier technique and Cox regression analysis with stepwise selection.RESULTSTwelve of the tumor specimens were diploid and 22 were hyperdiploid. The patient groups defined by diploid or hyperdiploid tumors had similar presenting characteristics (eg, age, tumor size, and anatomic site). Significantly more children with hyperdiploid tumors achieved a complete response than did children with diploid tumors (85% v 42%; P = .01). The proba...

Phase 2 study of safety and efficacy of nimotuzumab in pediatric patients with progressive diffuse intrinsic pontine glioma

BACKGROUND The prognosis of diffuse intrinsic pontine glioma (DIPG) remains poor, with no drug proven to be effective. METHODS Patients with clinically and radiologically confirmed, centrally reviewed DIPG, who had failed standard first-line therapy were eligible for this multicenter phase II trial. The anti-epidermal growth factor receptor (EGFR) antibody, nimotuzumab (150 mg/m(2)), was administered intravenously once weekly from weeks 1 to 7 and once every 2 weeks from weeks 8 to 18. Response evaluation was based on clinical and MRI assessments. Patients with partial response (PR) or stable disease (SD) were allowed to continue nimotuzumab. RESULTS Forty-four patients received at least one dose of nimotuzumab (male/female, 20/24; median age, 6.0 years; range, 3.0-17.0 years). All had received prior radiotherapy. Treatment was well tolerated. Eighteen children experienced serious adverse events (SAEs). The majority of SAEs were associated with disease progression. Nineteen patients completed 8 weeks (W8) of treatment: There were 2 PRs, 6 SDs, and 11 progressions. Five patients completed 18 weeks (W18) of treatment: 1 of 2 patients with PR at W8 remained in PR at W18, and 3 of 6 children with SD at W8 maintained SD at W18. Time to progression following initiation of nimotuzumab for the 4 patients with SD or better at W18 was 119, 157, 182 and 335 days, respectively. Median survival time was 3.2 months. Two patients lived 663 and 481 days from the start of nimotuzumab. CONCLUSIONS Modest activity of nimotuzumab in DIPG, which has been shown previously, was confirmed: A small subset of DIPG patients appeared to benefit from anti-EGFR antibody treatment.

Tumor-Cell DNA Content Predicts Outcome in Children and Adolescents With Clinical Group III Embryonal Rhabdomyosarcoma

PURPOSE The prognostic value of tumor-cell DNA content (ploidy) was evaluated in children with unresectable, nonmetastic rhabdomyosarcoma of embryonal histology. PATIENTS AND METHODS Flow-cytometric techniques were used to estimate the ploidy of tumor specimens from 34 patients with embryonal rhabdomyosarcoma who were enrolled in the intergroup rhabdomyosarcoma study III (IRS III) from 1985 to 1991. Tumors were classified as diploid or hyperdiploid (DNA content, 1.1 to 1.8 times that of normal diploid cells). The influence of ploidy on clinical outcome was assessed by the Kaplan-Meier technique and Cox regression analysis with stepwise selection. RESULTS Twelve of the tumor specimens were diploid and 22 were hyperdiploid. The patient groups defined by diploid or hyperdiploid tumors had similar presenting characteristics (eg, age, tumor size, and anatomic site). Significantly more children with hyperdiploid tumors achieved a complete response than did children with diploid tumors (85% v 42%; P = .01). The probability of progression-free survival at 5 years (+/- SE) was 91% +/- 6% for the hyperdiploid group, compared with 17% +/- 11% for the diploid group (P < .001). Hyperdiploidy was also associated with a significantly higher overall survival rate at 5 years: 96% +/- 4% versus 50% +/- 14% (P = .004). Ploidy retained its prognostic significance after adjustment for tumor site in the Cox regression model. CONCLUSION Tumor-cell ploidy strongly correlates with outcome in children with nonmetastic, unresectable embryonal rhabdomyosarcoma. The two biologically distinct groups identified by this measure would benefit from further refinements in risk-directed therapy.