Otto W.M. Meijer

Single-fraction vs. fractionated linac-based stereotactic radiosurgery for vestibular schwannoma: a single-institution study

PURPOSE In this single-institution trial, we investigated whether fractionated stereotactic radiation therapy is superior to single-fraction linac-based radiosurgery with respect to treatment-related toxicity and local control in patients with vestibular schwannoma. METHODS AND MATERIALS All 129 vestibular schwannoma patients treated between 1992 and June 2000 at our linac-based radiosurgery facility were analyzed with respect to treatment schedule. Dentate patients were prospectively selected for a fractionated schedule of 5 x 4 Gy and later on 5 x 5 Gy at the 80% isodose in 1 week with a relocatable stereotactic frame. Edentate patients were prospectively selected for a nonfractionated treatment of 1 x 10 Gy and later on 1 x 12.5 Gy at 80% isodose with an invasive stereotactic frame. Both MRI and CT scans were made in all 129 patients within 1 week before treatment. All patients were followed yearly with MRI and physical examination. RESULTS A fractionated schedule was given to 80 patients and a single fraction to 49 patients. Mean follow-up time was 33 months (range: 12-107 months). There was no statistically significant difference between the single-fraction group and the fractionated group with respect to mean tumor diameter (2.6 vs. 2.5 cm) or mean follow-up time (both 33 months). Only mean age (63 years vs. 49 years) was statistically significantly different (p = 0.001). Outcome differences between the single-fraction treatment group and the fractionated treatment group with respect to 5-year local control probability (100% vs. 94%), 5-year facial nerve preservation probability (93% vs. 97%), and 5-year hearing preservation probability (75% vs. 61%) were not statistically significant. The difference in 5-year trigeminal nerve preservation (92% vs. 98%) reached statistical significance (p = 0.048). CONCLUSION Linac-based single-fraction radiosurgery seems to be as good as linac-based fractionated stereotactic radiation therapy in vestibular schwannoma patients, except for a small difference in trigeminal nerve preservation rate in favor of a fractionated schedule.

Volumetric Modulated Arc Radiotherapy for Vestibular Schwannomas

PURPOSE To evaluate volumetric modulated arc radiotherapy (RapidArc [RA]), a novel approach allowing for rapid treatment delivery, for the treatment of vestibular schwannoma (VS). METHODS AND MATERIALS The RA plans were generated for a small (0.5 cm(3)), intermediate (2.8 cm(3)), and large (14.8 cm(3)) VS. The prescription dose was 12.5 Gy to the encompassing 80% isodose. The RA plans were compared with conventional radiosurgery plans using both a single dynamic conformal arc (1DCA) and five noncoplanar dynamic conformal arcs (5DCA). Conformity indices (CI) and dose-volume histograms of critical organs were compared. The RA plan for the medium-sized VS was measured in a phantom using Gafchromic EBT films and compared with calculated dose distributions. RESULTS The RA planning was completed within 30 min in all cases, and calculated treatment delivery time (after patient setup) was 5 min vs. 20 min for 5DCA. A superior CI was achieved with RA, with a substantial decrease in low-dose irradiation of the normal brain achieved relative to 5DCA plans. Maximum doses to critical organs were similar for RA and 5DCA but were higher for 1DCA. Film measurements showed the differences between calculated and measured doses to be smaller than 1.5% in the high-dose area and smaller than 3% in the low-dose area. CONCLUSION The RA plans consistently achieved a higher CI and decrease in areas of low-dose irradiation. This, together with shorter treatment delivery times, has led to RA replacing our conventional five-arc radiosurgery technique for VS.

Fractionated stereotactic radiation therapy and single high-dose radiosurgery for acoustic neuroma: early results of a prospective clinical study

PURPOSE To prospectively assess the local control and toxicity rate in acoustic neuroma patients treated with linear accelerator-based radiosurgery and fractionated stereotactic radiation therapy. METHODS AND MATERIALS We evaluated 37 consecutive patients treated with stereotactic radiation therapy for acoustic neuroma. All patients had progressive tumors, progressive symptoms, or both. Mean tumor diameter was 2.3 cm (range 0.8-3.3) on magnetic resonance (MR) scan. Dentate patients were given a dose of 5x4 Gy or 5x5 Gy and edentate patients were given a dose of 1x10 Gy or 1x12.50 Gy prescribed to the 80% isodose. All patients were treated with a single isocenter. RESULTS With a mean follow-up period of 25 months (range 12-61), the actuarial local control rate at 5 years was 91% (only 1 patient failed). The actuarial rate of hearing preservation at 5 years was 66% in previously-hearing patients. The actuarial rate of freedom from trigeminal nerve toxicity was 97% at 5 years. No patient developed facial nerve toxicity or other complications. CONCLUSION In this unselected series, fractionated stereotactic radiation therapy and linear accelerator-based radiosurgery give excellent local control in acoustic neuroma. It combines a high rate of preservation of hearing with a very low rate of other toxicity, although follow-up is relatively short.

Radiosurgery of brain arteriovenous malformations in children

ObjectiveThe authors describe their experience in treating 22 children with a single brain arteriovenous malformation (bAVM) using a dedicated LINAC stereotactic radiosurgery unit.MethodsThe findings of 22 consecutive patients ≤ 18 years of age who underwent radiosurgery for a single bAVM and with at least 24 months of follow-up, or earlier proven obliteration,were reviewed. The median age at radiosurgery was 13.8 years,with a hemorrhagic presentation in 86%. Median bAVM-volume was 1.8 ml, with a median prescribed marginal dose of 19.0 Gy.ResultsThe crude complete obliteration-rate was 68% (n = 15) after a median follow-up of 24 months. The actuarial obliteration- rate was 45 % after two years and 64 % after three years. Patients with a radiosurgery-based AVM score ≤ 1 more frequently had an excellent outcome than patients with a bAVM score > 1 (71% vs. 20%, P = 0.12), as well as an increased obliteration rate (P = 0.03) One patient died from a bAVM-related hemorrhage 27 months after radiosurgery, representing a postradiosurgery hemorrhage rate of 1.3%/year for the complete followup interval. Overall outcome was good to excellent in 68% (n = 15). Radiation-induced changes on MR imaging were seen in 36% (n = 8) after a median interval of 12.5 months, resulting in deterioration of pre-existing neurological symptoms in one patient.ConclusionsRadiosurgery is a relatively effective, minimally invasive treatment for small bAVMs in children. The rebleeding rate is low, provided that known predilection places for bleeding had been endovascularly eliminated.Our overall results compare unfavourably to recent pediatric microsurgical series, although comparison between series remains imprecise. Nevertheless, when treatment is indicated in a child with a bAVM that is amenable to both microsurgery or radiosurgery, microsurgery should carefully be advocated over radiosurgery, because of its immediate risk reduction.

The clinical utility of prognostic scoring systems in patients with brain metastases treated with radiosurgery

PURPOSE The RTOG recursive partitioning analysis (RPA) classification is the gold standard for assessing the prognosis of patients with brain metastases (BM). Newer prognostic scoring systems for BM patients have been proposed, but their superiority over RPA needs to be established for patients treated with radiosurgery. METHODS 380 patients with 1-3 BM were treated at the VUmc with radiosurgery (RS) from 2002 to 2011. Using baseline characteristics, patient scores were calculated for RPA, the Rotterdam-system, the score index for radiosurgery (SIR), the basic score for BM (BSBM), the graded prognostic assessment (GPA), the diagnosis-specific GPA, the Rades score, and the Golden grading system (GGS) for comparison with survival time and survival classification (≤3 months or ≥12 months). RESULTS Median survival after RS was 7.7 months, with 3-month and 1-year overall survival (OS) of 76% and 39%, respectively. Multivariate analysis confirmed the prognostic value of performance status, age, absence of extracranial metastases, primary tumor site, gender, and steroid response for OS. The percentage of patients included within the intermediate prognostic classes ranged from 48% to 77%, and was 64% for the RPA. All scoring systems highly correlated with OS (p<0.001). The specificity for predicting early death ranged from 85% to 98% (RPA 88%), with the unfavorable classes of Rades, GGS, BSBM and SIR performing best. The sensitivity for predicting long-term survival ranged from 10% to 69% (RPA 29%), and was highest for the favorable classes of Rades and GGS. CONCLUSIONS All prognostic scoring systems correlated very well with OS. All scores shared the limitation of unbalanced proportions of patients within the prognostic classes. As the clinical superiority of more recently developed prognostic scoring systems was only modest in predicting early death and long term survival, the well-known and easy to use RPA system currently remains the standard.

Stereotactic radiation therapy for large vestibular schwannomas.

BACKGROUND AND PURPOSE To evaluate the morbidity and tumor-control rate in the treatment of large vestibular schwannomas (VS) after stereotactic radiation therapy in our institution. MATERIAL AND METHODS Twenty-five consecutive patients (17 men, 8 women) with large VS (diameter 3.0 cm or larger), treated with stereotactic radiotherapy (SRT) or stereotactic radiosurgery (SRS) between 1992 and 2007, were retrospectively studied after a mean follow-up period of three years with respect to tumor-control rate and complications. RESULTS Actuarial 5-year maintenance of pre-treatment hearing level probability of 30% was achieved. Five of 17 patients suffered permanent new facial nerve dysfunction. The actuarial 5-year facial nerve preservation probability was 80%. Permanent new trigeminal nerve neuropathy occurred in two of 15 patients, resulting in an actuarial 5-year trigeminal nerve preservation probability of 85%. Tumor progression occurred in four of 25 (16%) patients. The overall 5-year tumor control probability was 82%. CONCLUSION Increased morbidity rates were found in patients with large VS treated with SRT or SRS compared to the published series on regular sized VS and other smaller retrospective studies on large VS.

Proliferation and clonal survival of human lung cancer cells treated with fractionated irradiation in combination with paclitaxel

PURPOSE This study was performed to determine the effects of a continuous exposure to paclitaxel (taxol) in combination with fractionated irradiation on cell proliferation and survival. METHODS AND MATERIALS Human lung carcinoma cells (SW1573) were given a daily treatment with 3 Gy of x-rays during 5 days in the continuous presence of 5 nM taxol. The surviving fraction and the total number of cells were determined every 24 h before and immediately after irradiation. RESULTS Irradiation with 5 x 3 Gy and 5 nM taxol cause approximately the same inhibition of cell proliferation. In combination these treatments have an additional effect and the cell population increases no further after the first 24 h. Whereas the cells become more resistant to taxol after the first 24 h with a minimum survival of 42%, taxol progressively reduces the population of surviving cells in combination with x-rays when the number of fractions increases, up to 25-fold relative to irradiation alone. The enhancement effect of 5 nM taxol is likely to be attributed to an inhibition of the repopulation during fractionated irradiation and not to an increased radiosensitivity. Only after treatment with 10 or 100 nM taxol for 24 h, which is attended with a high cytotoxicity, is moderate radiosensitization observed. CONCLUSION Taxol, continuously present at a low concentration with little cytotoxicity, causes a progressive reduction of the surviving cell population in combination with fractionated irradiation, mainly by an inhibition of the repopulation of surviving cells between the dose fractions.

Clinical outcome after repeated radiosurgery for brain arteriovenous malformations

INTRODUCTION We assessed the clinical and radiological outcome after repeated radiosurgery for brain arteriovenous malformations (bAVMs) after failure of initial radiosurgery. MATERIALS AND METHODS Fifteen patients underwent repeated radiosurgery. The mean bAVM volume at first radiosurgery (S1) was 4.6 +/- 4.3 ml and that at second radiosurgery (S2) was 2.1 +/- 2.5 ml. The median marginal dose was 18 Gy at S1, and 21 Gy at S2. Modified Rankin Scale (MRS) score was determined in all patients at last follow-up (FU). RESULTS Complete obliteration was reached in nine patients (60%). Median time to obliteration was 50 months after S2. An excellent outcome (no new neurologic deficiencies, complete obliteration) was reached in seven patients (47%). Eleven patients (73%) showed a MRS1. Radiation-induced complications occurred in 20%, of which 13% occurred after S2. Radiological complications included cyst formation (n = 1), radiation-related edema (n = 4), and radiation necrosis (n = 1), resulting in an increasing mean MRS of 0.5 at S1, 0.6 at S2, to 0.8 at FU. No (re-)bleedings were encountered during 137-patient years at risk. DISCUSSION Repeated radiosurgery is a viable option for the treatment of small remnant bAVMs. We report 20% permanent radiation-induced complications. Such complications were mainly seen in relatively large, and therefore difficult to treat, bAVMs.

Phase I clinical trial to determine the feasibility and maximum tolerated dose of panitumumab to standard gemcitabine-based chemoradiation in locally advanced pancreatic cancer

Purpose: Epidermal growth factor receptor (EGFR) inhibitors may improve both the therapeutic efficacy of radiotherapy and the radiosensitizing activity of gemcitabine. Based on this rationale and the nonoverlapping toxicity profiles of gemcitabine and the monoclonal EGFR antibody panitumumab, we designed a phase I trial to investigate the maximum-tolerated dose (MTD), safety, and activity of panitumumab added to gemcitabine-based chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer (LAPC). Experimental Design: Patients with LAPC and WHO performance status 0 to 1 were treated with weekly panitumumab at four dose levels (1–2.5 mg/kg), combined with weekly gemcitabine 300 mg/m2 and radiotherapy (50.4 Gy in 28 fractions) for 6 weeks, followed by gemcitabine 1,000 mg/m2 weekly for 3 weeks every 4 weeks until disease progression or unacceptable toxicity. Each cohort was monitored during the combination therapy to establish dose limiting toxicity. Tumor evaluation was performed after CRT and during gemcitabine monotherapy. Results: Fourteen patients were enrolled; 14 were evaluable for toxicity and 13 for response. The MTD for panitumumab was 1.5 mg/kg. Three of the 6 patients, treated at MTD, experienced grade 3 adverse events during the combination therapy; neutropenia (n = 2; 33%), fatigue (n = 1; 17%), nausea (n = 1; 17%), and vomiting (n = 1; 17%). Partial response was achieved by 3 patients (23%), 1 in each dose cohort. Median progression free survival of the three cohorts together was 8.9 months. Conclusions: The addition of panitumumab to gemcitabine-based chemoradiotherapy in LAPC has manageable toxicity and potential clinical efficacy. Clin Cancer Res; 21(20); 4569–75. ©2015 AACR.

Imaging-documented repeated intratumoral hemorrhage in vestibular schwannoma: a case report.

Intratumoral hemorrhage in vestibular schwannomas is rare. Symptoms often have an acute onset and include headache, nausea, vomiting, vertigo, and depressed consciousness. Intratumoral hemorrhage is probably caused by vascular fragility associated with tumor characteristics and growth. With hemorrhage in VS being rare, repeated hemorrhage has only been reported twice, and on clinical grounds only. The present report details the case of acute neurological deterioration in a patient with repeated intratumoral hemorrhage inside a vestibular schwannoma with computed tomography and magnetic resonance imaging confirmation. To our knowledge, repeated hemorrhage in vestibular schwannoma with radiological confirmation has not been reported before.