Clinical Investigations
Temporal Lobe (TL) Damage Following Surgery and High-Dose Photon and Proton Irradiation in 96 Patients Affected by Chordomas and Chondrosarcomas of the Base of the Skull

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Abstract

Purpose: To determine the temporal lobe (TL) damage rate in 96 patients treated with high-dose proton and photon irradiation for chordomas and chondrosarcomas of the base of the skull.

Methods and Materials: The records of 96 consecutive patients treated at Massachusetts General Hospital (MGH) and Harvard Cyclotron Laboratory (HCL) between June 1984 and 1993, for chordomas and chondrosarcomas of the base of the skull were reviewed. All the patients had undergone some degree of resection of the tumor prior to radiation therapy. Seventy-five patients were classified as “primary tumors” and 21 as recurrent or regrowing tumors after one or more surgical procedures. All the patients were randomized to receive 66.6 or 72 cobalt Gray equivalent (CGE) on a prospective dose-searching study by proton and photon irradiation (Radiation Therapy Oncology Group #85-26) with conventional fractionation (1.8 CGE/day, 5 fractions/week). All treatments were planned using the three-dimensional (3D) planning system developed at the Massachusetts General Hospital, and the dose was delivered using opposed lateral fields for the photon component and a noncoplanar isocentric technique for the proton component. Clinical symptoms of TL damage were classified into 4 grades. Computerized tomography (CT) and magnetic resonance imaging (MRI) scans were evaluated for white matter changes. Abnormalities associated with persistent or recurrent tumor were distinguished from radiation-induced changes. TLs were delineated on the original scans of the 10 patients with damage and those of a group of 33 patients with no clinical or MRI evidence of injury. Dose distributions were calculated and dose–volume histograms were obtained for these patients.

Results: Of the patients, 10 developed TL damage, with bilateral injury in 2 and unilateral injury in 8. The cumulative TL damage incidence at 2 and 5 years was 7.6 and 13.2%, respectively. The MRI areas suggestive of TL damage were always separated from the tumor bed. Symptoms were severe to moderate in 8 patients. Several baseline factors, tumor- or host-related, were analyzed to evaluate their predictivity for TL damage: age, gender, tumor site, histology, type of presentation, type and number of surgical procedures, primary tumor volume, prescribed dose, normal tissue involvement, and volume of TL receiving doses ranging between 10 and 50 CGE or more. Only gender, in a univariate analysis (log rank) was a significant predictor of damage (0.0155), with male patients being at significantly higher risk of TL injury. In a stepwise Cox regression that included gender as a variable, no other baseline variable improved the prediction of damage.

Conclusions: The 2- and 5-year cumulative TL damage rates were 7.6 and 13.2%, respectively. Despite the different TL damage rates related to age, tumor volume, number of surgical procedures prior to radiation therapy, and prescribed doses to the tumor, only gender was a significant predictor of damage (p = 0.0155) using a univariate (log rank) test. Chordomas and chondrosarcomas of the base of the skull may represent an interesting model to evaluate the TL damage rates because of their extradural origin, displacing the white matter instead of infiltrating it as gliomas do, because of their longer local recurrence-free survival other than gliomas and other brain tumors and because of the high doses of irradiation delivered to the target volume to obtain local control.

Introduction

The physical properties of the proton beam that make it attractive for radiation therapy are represented by their finite range in tissues due to the Bragg peak and sharply defined lateral beam edges. These features provide the basis for proton dose distributions that are superior to those obtainable with photons in many tumor to healthy tissue relationships, particularly at the base of the skull. The dose delivered to a tumor using protons can, consequently, be increased to a certain extent, with proton beam therapy (PBT), relative to that which can be delivered with photon therapy while maintaining a comparable rate of treatment-related morbidity. This difference in volume of healthy tissues included in comparison to photons is primarily due to minimal dose beyond the target due to the Bragg peak of the proton radiation.

Chordomas and chondrosarcomas of the base of the skull present a worthy challenge to the neurosurgeon and the radiation oncologist and are judged to be a good example of tumors that may likely benefit from high-dose proton radiation. With photon radiation therapy, only moderate doses of radiation can be delivered to the primary target, and most of these patients die with locally progressive disease [1]. The total dose that can safely be delivered to the tumor is limited by the close proximity of healthy structures, such as the brain stem, temporal lobes, and optic chiasm and nerves. As a consequence of these particular tumor-healthy tissue relationships, and of the vital importance of the nervous structures, clinicians limit the radiation dose to levels tolerated by these structures (although the dose–response relationship for the central nervous system (CNS) has not yet been completely assessed) [2]. Irradiation of the CNS can, in fact, produce a wide range of clinically expressed, as well as silent, injuries in the brain 3, 4, 5, which have been described in patients receiving doses in excess of 45 Gy [6].

Identification of radiation damage as a distinct entity from the effects of the tumor growth, surgical procedures, or other incidental pathologies is crucial to devise new protocols for dose-escalation studies, and to evaluate retrospectively the cost-benefit of the clinical achievements. The knowledge of the tolerance dose of the healthy tissues is essential to maximize the dose prescribed to the targets and, thereby, achieve the highest tumor control with a low probability of damaging healthy surrounding tissues.

To contribute to the comprehension of CNS late effects, after high-dose irradiation, we report our experience based on an analysis of 96 consecutive patients affected by chordomas or chondrosarcomas of the base of the skull who were treated with high-dose proton and photon irradiation and were randomized to receive 66.6 or 72 CGE on a controlled, prospective dose-searching study. The aim of the present study was to examine the correlation between clinical and imaging signs of temporal lobe damage and dose, features of the tumor, distortion of the normal anatomy induced by the tumor, number of surgical procedures, and other host characteristics.

Section snippets

Methods and Materials

Ninety-six consecutive patients with chordomas and chondrosarcomas of the base of the skull were randomized to receive 66.6 or 72 CGE in a prospective dose-searching study (RTOG-Radiation Therapy Oncology Group #85-26) by proton and photon techniques at the Massachusetts General Hospital (MGH) and Harvard Cyclotron Laboratory (HCL) between July 1984 and July 1993.

The patients ranged in age from 11 to 80 years, with a median of 44 years; there were 51 males and 45 females. Of the tumors, 41 were

Results

The 2- and 5-year cumulative TL damage rates were 7.6 and 13.2%, respectively (standard errors 2.8 and 4.1, respectively). Ten patients with TL damage were identified, 1 with MRI white matter changes only, and 9 with both MRI changes and clinically evident TL injury. One had Grade 2 and 8 had Grade 3 injury. One patient developed multiple Grade 2 symptoms and 7 suffered Grade 3 symptoms (4 of 7 one Grade 3 only, 2 of 7 multiple Grade 3, and 1 of 7 Grade 3 and 2). Epilepsy and deterioration of

Discussion

The classical late adverse effect of therapeutic or incidental brain irradiation is localized necrotic reaction, which occurs typically at a few months to several years after irradiation and is usually associated with neurological symptoms that cannot be attributed to recurrent tumor [14].

After high-dose radiation therapy, “the specific endpoint chosen for complication of the brain is radionecrosis” [2]. Burger et al. [15]provided a clear description of the histological modifications associated

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