Stephen W. Gilheeney

Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma.

PURPOSE We previously reported excellent local control for treating medulloblastoma with a limited boost to the tumor bed. In order to decrease ototoxicity, we subsequently implemented a tumor-bed boost using intensity-modulated radiation therapy (IMRT), the clinical results of which we report here. PATIENTS AND METHODS A total of 33 patients with newly diagnosed medulloblastoma, 25 with standard risk, and 8 with high risk, were treated on an IMRT tumor-bed boost following craniospinal irradiation (CSI). Six standard-risk patients were treated with an institutional protocol with 18 Gy CSI in conjunction with intrathecal iodine-131-labeled monoclonal antibody. The majority of patients received concurrent vincristine and standard adjuvant chemotherapy. Pure-tone audiograms were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS Median age was 9 years old (range, 4-46 years old). Median follow-up was 63 months. Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) rates for standard-risk patients who received 23.4 or 36 Gy CSI (not including those who received 18 Gy CSI with radioimmunotherapy) were 81.4% and 88.4%, respectively, at 5 years; 5-year PFS and OS rates for high-risk patients were both 87.5%. There were no isolated posterior fossa failures outside of the boost volume. Posttreatment audiograms were available for 31 patients, of whom 6%, at a median follow-up of 19 months, had developed Grade 3 hearing loss. CONCLUSION An IMRT tumor-bed boost results in excellent local control while delivering a low mean dose to the cochlea, resulting in a low rate of ototoxicity.

Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma

We previously reported promising pilot results treating patients with stage 4a metastatic retinoblastoma with combined intensive conventional chemotherapy, high‐dose chemotherapy with autologous hematopoietic stem cell rescue, and radiation therapy and now present an expanded and updated series.

Reirradiation for recurrent medulloblastoma

Previously irradiated recurrent medulloblastoma (MB) is a highly lethal disease. Reirradiation is often not considered secondary to its potential toxicity and uncertain efficacy. Analysis of retreatment could help identify the feasibility and role of reirradiation for recurrent MB.

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.

A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies.

Previous clinical and pre‐clinical research has demonstrated synergy between anti‐angiogenic agents and cytotoxic chemotherapy. This trial was undertaken to investigate whether the combination of cyclophosphamide and thalidomide would be active against pediatric tumors.

Thiotepa/topotecan/carboplatin with autologous stem cell rescue in recurrent/refractory/poor prognosis pediatric malignancies of the central nervous system.

Thiotepa and carboplatin are known to be active in central nervous system tumors. Topotecan potentiates the anti‐cancer effects of alkylators and crosses the blood–brain barrier. We present ten patients with recurrent or progressive central nervous system malignancies treated on a myeloablative regimen using these drugs.

A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors

The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.

Extraneural metastases of medulloblastoma: Desmoplastic variants may have prolonged survival

Extraneural metastases from CNS medulloblastoma are rare and poorly described. The purpose of this study is to describe the clinical and radiological characteristics of a large single institution series of patients with medulloblastoma who developed extraneural metastases.

Diffusion-weighted imaging to assess treatment response in a child with trilateral retinoblastoma

Trilateral retinoblastoma (TRb) is a rare condition in which children with bilateral retinoblastoma develop primary midline intracranial neuroblastic tumors. The intracranial lesions are difficult to follow after treatment due to residual mass-like enhancement that may represent persistent tumor or treated disease. We highlight a case where close evaluation of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) characteristics accurately depicted the extent of treated disease versus residual tumor after chemotherapy.

A phase II study of radioimmunotherapy with intraventricular 131I-3F8 for medulloblastoma

High‐risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell‐surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131I‐labeled 3F8 in patients with MB on a phase II clinical trial.