Brainstem Toxicity Research Articles

SU‐E‐T‐274: Dosimetric Indicators of Radiation‐Induced Toxicity in Meningioma Patients

Purpose: In this study, we retrospectively reviewed treatment plans and normal tissue toxicities for patients who were treated for meningiomas to investigate the correlation between DVH parameters and late Grade 3 radiation‐induced brainstem toxicity and hearing or vision changes. Methods: We analyzed data from 26 patients treated for brain meningiomas with either proton radiation or photon IMRT (11 were treated to 54Gy and 15 to 59.4Gy or higher) between 2009 and 2012 at the University of Pennsylvania. Five patients developed late Grade 3 toxicity with the remaining patients having late Grade 2 toxicity or less. Eight patients experienced hearing changes and seventeen experienced vision changes. We evaluated the maximum brainstem dose and volume of brainstem receiving more than 50∼54Gy for late Grade 3 toxicities. We also evaluated maximum and mean doses to the optic structures and cochlea. Statistical significance of the correlation between late Grade 3 toxicity or hearing and vision changes and the above mentioned DVH constraints was evaluated using Fisher exact test (two‐tailed). Results: The proportion of patients with Dmax > 45Gy or Dmean > 30 Gy for the cochlea was significantly greater in patients with hearing changes (p < 0.05 and p < 0.1 respectively). While for the brainstem a difference in the proportion of patients with and without late Grade 3 toxicity and with V54Gy > 5% was observed, this difference did not reach statistical significance. Conclusion: Differences were observed in the DVHs of meningioma patients who experienced radiation injury after radiation therapy. The mean dose to the cochlea is related to the likelihood of developing hearing changes. Based on the results of this study, dose volume parameters (that is, V54Gy) for the brainstem may be expected to be associated with Grade 3 toxicity in a larger cohort of patients.

Radiation Associated Brainstem Injury

Publications relating brainstem radiation toxicity to quantitative dose and dose-volume measures derived from three-dimensional treatment planning were reviewed. Despite the clinical importance of brainstem toxicity, most studies reporting brainstem effects after irradiation have fewer than 100 patients. There is limited evidence relating toxicity to small volumes receiving doses above 60-64 Gy using conventional fractionation and no definitive criteria regarding more subtle dose-volume effects or effects after hypofractionated treatment. On the basis of the available data, the entire brainstem may be treated to 54 Gy using conventional fractionation using photons with limited risk of severe or permanent neurological effects. Smaller volumes of the brainstem (1-10 mL) may be irradiated to maximum doses of 59 Gy for dose fractions <or=2 Gy; however, the risk appears to increase markedly at doses >64 Gy.

Effectiveness and Safety of Spot Scanning Proton Radiation Therapy for Chordomas and Chondrosarcomas of the Skull Base: First Long-Term Report

To evaluate effectiveness and safety of spot-scanning-based proton radiotherapy (PT) in skull-base chordomas and chondrosarcomas. Between October 1998 and November 2005, 64 patients with skull-base chordomas (n = 42) and chondrosarcomas (n = 22) were treated at Paul Scherrer Institute with PT using spot-scanning technique. Median total dose for chordomas was 73.5 Gy(RBE) and 68.4 Gy(RBE) for chondrosarcomas at 1.8-2.0 Gy(RBE) dose per fraction. Local control (LC), disease specific survival (DSS), and overall survival (OS) rates were calculated. Toxicity was assessed according to CTCAE, v. 3.0. Mean follow-up period was 38 months (range, 14-92 months). Five patients with chordoma and one patient with chondrosarcoma experienced local recurrence. Actuarial 5-year LC rates were 81% for chordomas and 94% for chondrosarcomas. Brainstem compression at the time of PT (p = 0.007) and gross tumor volume >25 mL (p = 0.03) were associated with lower LC rates. Five years rates of DSS and OS were 81% and 62% for chordomas and 100% and 91% for chondrosarcomas, respectively. High-grade late toxicity consisted of one patient with Grade 3 and one patient with Grade 4 unilateral optic neuropathy, and two patients with Grade 3 central nervous system necrosis. No patient experienced brainstem toxicity. Actuarial 5-year freedom from high-grade toxicity was 94%. Our data indicate safety and efficacy of spot-scanning based PT for skull-base chordomas and chondrosarcomas. With target definition, dose prescription and normal organ tolerance levels similar to passive-scattering based PT series, complication-free, tumor control and survival rates are at present comparable.

A Retrospective Study of Surgery and Reirradiation for Recurrent Ependymoma

To report disease control for patients with recurrent ependymoma (EP) treated with surgery and a second course of radiation therapy (RT(2)). Thirty-eight pediatric patients (median age, 2.7 years) with initially localized EP at the time of definitive RT underwent a second course of RT after local (n = 21), metastatic (n = 13), or combined (n = 4) failure. Reirradiation included radiosurgery (n = 6), focal fractionated reirradiation (n = 13), or craniospinal irradiation (CSI; n = 19). Initial time to failure was 16 months, and median age at second treatment was 4.8 years. Radiosurgery resulted in significant brainstem toxicity and one death (median dose, 18 Gy). Progression-free survival ratio was greater than unity for 4 of 6 patients; there was one long-term survivor. Three of 13 patients treated using focal fractionated reirradiation (median combined dose, 111.6 Gy) experienced metastasis. The CSI was administered to 12 patients with metastatic failure, 3 patients with local failure, and 4 patients with combined failure. The 4-year event-free survival rate was 53% +/- 20% for 12 patients with metastatic failure treated with CSI. Failure after CSI was observed in 1 of 3 patients with a history of local failure and 3 of 4 patients with a history of combined failure. Patients with locally recurrent EP experience durable local tumor control, but remain at risk of metastasis. Patients with metastatic EP failure may receive salvage therapy that includes a component of CSI. Durability of disease control and long-term effects from this approach require further follow-up.

A CASE-CONTROL AUDITORY EVALUATION OF PATIENTS TREATED WITH ARTEMETHER-LUMEFANTRINE

Artemether-lumefantrine is the first registered, fixed, artemisinin-based combination treatment. Artemisinin derivatives are highly effective antimalarials with a favorable safety profile. Concerns remain over their potential neurotoxicity, although there has been no clinical evidence of this in humans. In animals (rats, dogs, and monkeys) artemether, a derivative of artemisinin is associated with an unusual toxicity pattern in specific brain nuclei involving the auditory and vestibular pathways. A recent report from Mozambique described a small but significant and irreversible hearing loss in patients exposed to artemether-lumefantrine. To explore this issue, we conducted a case-control study using tympanometry, audiometry and auditory brain-stem responses. We assessed 68 subjects who had been treated with artemether-lumefantrine within the previous five years and 68 age- and sex-matched controls living in the malarious region along the Thailand-Myanmar border. There were no differences in the test results between cases and controls. There was no neurophysiologic evidence of auditory brainstem toxicity that could be attributed to artemether-lumefantrine in this study population.

Audiometric changes associated with the treatment of uncomplicated falciparum malaria with co-artemether

Animal studies have demonstrated artemisinin brain stem toxicity with auditory centres being especially affected; there has, to date, been no evidence of such toxicity with oral artemisinins in humans. Subjects working at a construction site in Mozambique had audiometric assessments taken on joining and leaving the project. Subjects with uncomplicated malarias received co-artemether (artemether–lumefantrine) ( n=150) while age-, gender-, weight- and race-matched controls ( n=150) neither suffered malaria nor received antimalarial therapy. Hearing thresholds were measured at predefined frequencies in treated subjects and controls. Subjects receiving co-artemether had a significantly greater heating loss than controls at all frequencies except 250 Hz and 500 Hz ( P values ranging from <0.001 to 0.04, Mann–Whitney U). Mean changes at the different frequencies in subjects ranged from −6.50 dB (95% CI −8.19 to −4.81) [at 1 kHz frequency] to −0.07 dB (95% CI −2.19 to 2.05) [at 6 kHz frequency]. Mean changes in the control group ranged from −4.20 dB (95% CI −5.97 to −2.43) [at 1 kHz frequency] to +2.7dB (95% CI −0.93 to 4.47) [at 6 kHz frequency]. Treatment of uncomplicated malaria with co-artemether is associated with hearing loss, possibly from synergy between potentially ototoxic agents in combination. The safety and neurotoxicity of artemesinins and other endoperoxides needs to be more fully evaluated.

Clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain-stem function in Vietnamese patients.

The qinghaosu (artemisinin) group of drugs is the most important new class of antimalarials developed in the last fifty years. Although there has been no clinical evidence of neurotoxicity, an unusual pattern of damage to specific brain-stem nuclei has been reported in experimental animals receiving high doses of arteether or artemether. Detailed clinical examinations, audiometry, and brain stem auditory evoked potentials (BSAEPs) were assessed in 242 Vietnamese subjects who had previously received up to 21 antimalarial treatment courses of artemisinin or artesunate alone and 108 controls from the same location who had not received these drugs. There was no evidence of a drug effect on the clinical or neurophysiological parameters assessed. In this population there was no clinical or neurophysiological evidence of brain-stem toxicity that could be attributed to exposure to artemisinin or artesunate.

The integral biologically effective dose to predict brain stem toxicity of hypofractionated stereotactic radiotherapy

Objective : The aim of this work was to develop a parameter for use during fractionated stereotactic radiotherapy treatment planning to aid in the determination of the appropriate treatment volume and fractionation regimen that will minimize risk of late damage to normal tissue. Materials & Methods : We have used the linear quadratic model to assess the biologically effective dose at the periphery of stereotactic radiotherapy treatment volumes that impinge on the brain stem. This paper reports a retrospective study of 77 patients with malignant and benign intracranial lesions, treated between 1987 and 1995, with the dynamic rotation technique in 6 fractions over a period of 2 weeks, to a total dose of 42 Gy prescribed at the 90% isodose surface. From differential dose-volume histograms, we evaluated biologically effective dose-volume histograms and obtained an integral biologically-effective dose (IBED) in each case. Results : Of the 77 patiens in the study, 36 had target volumes-positioned so that the brain stem received more than 1% of the prescribed dose, and 4 of these, all treated for meningioma, developed serious late damage involving the brain stem. Other than type of lesion, the only significant variable was the volume of brain stem exposed. An analysis of the IBEDs received by these by these 36 patients shows evidence of a threshold value for late damage to the brain stem consistent with similar thresholds that have been determined for external beam radiotherapy. Conclusion : We have introduced a new parameter, the IBED, that may be used to represent the fractional effective dose to structures such as the brain stem that are partially irradiated with stereotactic dose distributions. The IBED is easily calculated prior to treatment and may be used to determine appropriate treatment volume and fractionation regimens minimizing possible toxicity to normal tissue.

Brainstem tolerance to conformal radiotherapy of skull base tumors

The aim of this study was to analyze the long-term incidence of brainstem toxicity in patients treated for skull base tumors with high dose conformal radiotherapy. Between 1974 and 1995, 367 patients with chordomas (n = 195) and chondrosarcomas (n = 172) of the base of skull have been treated with combined megavoltage photon and 160 MeV proton radiotherapy. Following 3D treatment planning with delineation of target volumes and critical nontarget structures dose distributions and dose-volume histograms were calculated. Radiotherapy was given an 1.8 Gy or CGE (=Cobalt Gray Equivalent) dose per fraction, with prescribed target doses ranging from 63 CGE to 79.2 CGE (mean = 67.8 CGE). Doses to the brainstem surface were limited to < or = 64 CGE and to the brainstem center to < or = 53 CGE. Follow-up time ranged from 6 months to 21.4 years (mean = 42.5 months). Brainstem toxicity was observed in 17 of 367 patients attributable to treatment, resulting in death of three patients. Actuarial rates of 5 and 10-year high-grade toxicity-free survival were 94 and 88%, respectively. Increased risk of brainstem toxicity was significantly associated with maximum dose to brainstem, volume of brainstem receiving > or = 50 CGE, > or = 55 CGE, and > or = 60 CGE, number of surgical procedures, and prevalence of diabetes or high blood pressure. Multivariate analysis identified three independent factors as important prognosticators: number of surgical procedures (p < 0.001), volume of the brainstem receiving 60 CGE (p < 0.001), and prevalence of diabetes (p < 0.01). Tolerance of brainstem to fractionated radiotherapy appears to be a steep function of tissue volume included in high dose regions rather than the maximum dose of brainstem alone. In addition, presence of predisposing factors as well as extent of surgical manipulation can significantly lower brainstem tolerance in the individual patient.

Light-emitting diodes as a light source for intraoperative photodynamic therapy.

The development of more cost-effective light sources for photodynamic therapy of brain tumors would be of benefit for both research and clinical applications. In this study, the use of light-emitting diode arrays for photodynamic therapy of brain tumors with Photofrin porfimer sodium was investigated. An inflatable balloon device with a light-emitting diode (LED) tip was constructed. These LEDs are based on the new semiconductor aluminum gallium arsenide. They can emit broad-spectrum red light at high power levels with a peak wavelength of 677 nm and a bandwidth of 25 nm. The balloon was inflated with 0.1% intralipid, which served as a light-scattering medium. Measurements of light flux at several points showed a high degree of light dispersion. The spectral emission of this probe was then compared with the absorption spectrum of Photofrin. This analysis showed that the light absorbed by Photofrin with the use of the LED source was 27.5% of that absorbed with the use of the monochromatic 630-nm light. Thus, to achieve an energy light dose equivalent to that of a laser light source, the LED light output must be increased by a factor of 3.63. This need for additional energy is the difference between a 630- and 677-nm absorption of Photofrin. Using the LED probe and the laser balloon adapter, a comparison of brain stem toxicity in canines was conducted. LED and laser light showed the same signs of toxicity at equivalent light energy and Photofrin doses. The maximal tolerated dose of Photofrin was 1.6 mg/kg, using 100 J/cm2 of light energy administered by laser or LED. This study concludes that LEDs are a suitable light source for photodynamic therapy of brain tumors with Photofrin. In addition, LEDs have the potential to be highly efficient light sources for second-generation photosensitizers with absorption wavelengths closer to the LED peak emission.

1015 The integral biologically effective dose to predict brain stem toxicity of hypofractionated stereotactic radiotherapy

1015 The integral biologically effective dose to predict brain stem toxicity of hypofractionated stereotactic radiotherapy

The role of photodynamic therapy in posterior fossa brain tumors. A preclinical study in a canine glioma model.

Photodynamic therapy was studied in dogs with and without posterior fossa glioblastomas. This mode of therapy consisted of intravenous administration of Photofrin-II at doses ranging from 0.75 to 4 mg/kg 24 hours prior to laser light irradiation in the posterior fossa. Tissue levels of Photofrin-II were four times greater in the tumor than in the surrounding normal brain. Irradiation was performed using 1 hour of 500 mW laser light at a wavelength of 630 nm delivered through a fiberoptic catheter directly into the tumor bed via a burr hole. All animals receiving a high dose (4 or 2 mg/kg) of Photofrin-II developed serious brain-stem neurotoxicity resulting in death or significant residual neurological deficits. A lower dose (0.75 mg/kg) of Photofrin-II produced tumor kill without significant permanent brain-stem toxicity in either the control animals or the animals with cerebellar brain tumors receiving photodynamic therapy.

Brainstem Toxicity With Reversible Locked-In Syndrome After Intrascalene Brachial Plexus Block

Brainstem Toxicity With Reversible Locked-In Syndrome After Intrascalene Brachial Plexus Block

Chronic effects of phenytoin on brain-stem auditory evoked potentials in man

The effects of phenytoin (PHT) on brain-stem auditory evoked potentials (BAEPs) were studied in 65 epileptic patients who received long-term PHT monotherapy at therapeutic and supra-therapeutic levels with no clinical evidence of brain-stem toxicity. Abnormal BAEPs were found in 7.5% and 33.3% of patients with therapeutic and supra-therapeutic PHT levels respectively. Serum PHT levels had a trend towards a positive relationship with the I–V interpeak latency (IPL), and a significant negative relationship with the amplitudes of waves I and V. at supra-therapeutic levels, both I–V and I–III IPLs were significantly prolonged while at therapeutic evels onl I–III IPLs were prolonged. The absolute latency of wave I was prolonged in both the therapeutic and the supra-therapeutic groups. These results suggest that PHT acts both peripherally on either the auditory nerve or the cochlea, and centrally on brain-stem conduction.

Changes in Auditory Brainstem Responses in Hyperbilirubinemic Infants Before and After Exchange Transfusion

Auditory brainstem responses (ABR) were evoked, before and after exchange transfusion, in an effort to determine whether hyperbilirubinemia is associated with acute effects on brainstem function of neonates. Nine full-term infants with hemolytic disease received exchange transfusion for conventional serum bilirubin concentration indications (mean 22.3 +/- 1.4 mg/dL). In three infants, wave-absence before exchange transfusion was followed by appearance of the waves after exchange transfusion. Other significant alterations observed in the group after exchange transfusion were increase of wave amplitudes and reduction of interpeak latencies (brainstem transmission time 5.80 +/- 0.36 ms after exchange transfusion compared with 6.25 +/- 0.30 ms before exchange transfusion, P less than 0.001). These improvements are considered to have been brought about by removal of bilirubin from the body and from the brainstem during exchange transfusion. Acute brainstem toxicity appears to occur in a percentage of infants with hyperbilirubinemia at serum levels commonly seen in clinical practice. These changes appear to be rapidly reversible with exchange transfusion.