[en] Purpose: Tumors of the axial skeleton are at high risk for local failure. Total surgical resection is rarely possible. Critical normal tissues limit the efficacy of conventional photon therapy. This study reviews our experience of using combined high dose proton and photon radiation therapy following three-dimensional (3D) treatment planning. Methods and Materials: Between December 1980 and September 1992, 47 patients were treated at the Massachusetts General Hospital and Harvard Cyclotron Laboratory for primary or recurrent chordomas and chondrosarcomas (group 1, 20 patients), osteogenic sarcomas (group 2, 15 patients) and giant cell tumors, osteo- or chondroblastomas (group 3, 12 patients). Radiation treatment was given postoperatively in 23 patients, pre- and postoperatively in 17 patients, and 7 patients received radiation therapy as definitive treatment modality following biopsy only. The proton radiation component was delivered using a 160 MeV proton beam and the photon component using megavoltage photons up to 23 MV energy with 1.8-2.0 Cobalt Gray Equivalent (CGE) per fraction, once a day. Total external beam target dose ranged from 55.3 CGE to 82.0 CGE with mean target doses of 73.9 CGE (group 1), 69.8 CGE (group 2), and 61.8 CGE (group 3). Results: Group 1 (chordoma and chondrosarcoma): Five of 14 patients (36%) with chordoma recurred locally, and 2 out of 5 patients developed distant metastasis, resulting in 1 death from disease. A trend for improved local control was noted for primary vs. recurrent tumors, target doses > 77 CGE and gross total resection. All patients with chondrosarcoma achieved and maintained local control and disease-free status. Five-year actuarial local control and overall survival rates were 53% and 50% for chordomas and 100% and 100% for chondrosarcomas, respectively. Group 2 (osteogenic sarcoma): Three of 15 patients (20%) never achieved local control and died within 6 months of completion of radiation treatment. Only 1 out of 12 patients who were controlled for more than 6 months failed locally, yielding a 5-year local control rate of 59% for 15 patients. Overall, 4 patients (27%) developed distant metastasis (two in patients with uncontrolled primary); 4 patients succumbed to their disease, 3 patients died of intercurrent disease, resulting in overall survival of 44% at 5 years. Group 3 (giant cell tumors, osteo- and chondroblastoma): One of 8 patients with giant cell tumor failed locally, 1 patient distantly, and all patients are alive. Three of 4 patients with osteo- or chondroblastoma are alive and well. One patient suffered local recurrence and died of disease. Local control rate and overall survival for this group of 12 patients was 76% and 87% and local control for patients with giant cell tumors 83% at 5 years. In the majority of cases radiotherapy was well tolerated. However, one patient with a large base of skull tumor developed retinopathy, one patient required enucleation of a previously blind eye, and another patient with sacral tumor developed chronic diarrhea. Conclusion: Combined proton and photon radiation therapy optimized by 3D treatment planning, allows the delivery of higher radiation doses to tumors of the axial skeleton, while respecting normal tissue constraints. High radiation doses can result in improved long-term local control

[en] Purpose: To evaluate the outcome of children with base of skull or cervical spine chordomas treated by high dose irradiation. Methods and Materials: Eighteen children, 4 to 18 years of age, with base of skull or cervical spine chordomas, received fractionated high-dose postoperative radiation using mixed photon and 160 MeV proton beams. The median tumor dose was 69 Cobalt Gray-equivalent (CGE) with a 1.8 CGE daily fraction. Results: The median follow-up was 72 months. The 5-year actuarial survival was 68% and the 5-year disease-free survival (DFS) was 63%. The only significant prognostic factor was the location: patients with cervical spine chordomas had a worse survival than those with base of skull lesions (p = 0.008). The incidence of treatment-related morbidity was acceptable: two patients developed a growth hormone deficit corrected by hormone replacement, one temporal lobe necrosis, and one fibrosis of the temporalis muscle, improved by surgery. Conclusion: Chordomas in children behave similarly to those in adults: children can receive the same high-dose irradiation as adults with acceptable morbidity

[en] Purpose: To determine the patterns of failure and outcome following relapse of chordomas of the base of skull and cervical spine. Methods and Materials: Between November 1975 and October 1993, 204 patients were treated for chordoma of the base of skull or cervical spine, of which 63 have developed relapse. These 63 patients constitute the main focus of this study. Forty-five patients presented with base of skull and 18 with cervical spine tumors. All patients received combined proton and photon beam radiation. The median prescribed dose was 70.1 cobalt-Gray equivalent (CGE) (range 66.6-77.4). There were 25 males and 38 females, with a median age of 41 years (range 7-66). Median follow-up was 54 months (range 8-158). Results: Sixty-three of the 204 patients treated (31%) had treatment failure. Among the 63 patients who relapsed, 60 (95%) experienced local recurrence, and in 49 patients (78%), this was the only site of failure. Two of 63 patients (3%) developed regional lymph node relapse and 3 of 63 (5%) developed surgical pathway recurrence (1 left neck, 1 palate and 1 nasal cavity). Thirteen of 204 patients relapsed in distant sites, accounting for 20% (13 of 63) of all patients with recurrence in this series. The most common metastatic sites were lungs and bones presenting in 7 of 13 and 6 of 13 patients, respectively. Only 2 of 13 patients failed with isolated distant metastasis. The actuarial 3- and 5-year survival rates after local relapse (60 patients) were 44 and 5%, respectively. Following distant failure (13 patients), the 3- and 5-year survival rates were 25 and 12%, respectively. After any relapse (63 patients) the corresponding survival rates were 43 and 7%. Following local relapse, 49 of 60 patients underwent salvage therapy consisting of subtotal resection in most patients (46 of 49). The remaining 11 of 60 patients received supportive care only. Salvage therapy resulted in stable or improved status without subsequent disease progression in 7 of 49 (14%), stable or improved status with subsequent disease progression in 26 of 49 (53%), and progressive disease in 16 of 49 patients (33%). The actuarial 2- and 5-year overall survival rates following relapse for the 49 patients who underwent salvage treatment were 63 and 6%, which favorably compared to the 2-year survival rate of 21% for those who received supportive care only (p 0.001). Conclusion: Local relapse is the predominant type of treatment failure for chordomas of the base of skull and cervical spine. Salvage treatment may relieve symptoms; however, most patients will ultimately succumb to their disease. Poor long-term survival rates following relapse emphasize the importance of a combined treatment approach with experienced surgeons and radiation oncologists at the time of primary treatment. For most patients, only permanent local tumor control will offer a chance of cure

[en] Purpose: Low grade chordomas and chondrosarcomas require high radiation doses for effective, lasting tumor control. Fractionated, 3-D planned, conformal proton radiation therapy has been used for lesions along the base of skull and spine to deliver high target doses, while respecting constraints of critical, normal tissues. In this study, we sought to determine the incidence of myelopathy after high dose radiotherapy to the cervical spine and investigated the influence of various treatment parameters, including dose-volume relationship. Methods and Materials: Between December 1980 and March 1996, 78 patients were treated at the Massachusetts General Hospital and Harvard Cyclotron Laboratory for primary or recurrent chordomas and chondrosarcomas of the cervical spine using combined proton and photon radiation therapy. In general, the tumor dose given was between 64.5 to 79.2 CGE (Cobalt Gray Equivalent). The guidelines for maximum permissible doses to spinal cord were: ≤ 64 CGE to the spinal cord surface and ≤ 53 CGE to the spinal cord center. Dose volume histograms of the spinal cord were analyzed to investigate a possible dose and volume relationship. Results: With a mean follow-up period of 46.6 months (range: 3 - 157 months), 4 of 78 patients (5.1%) developed high-grade (RTOG Grade 3 and 4) late toxicity: 3 patients (3.8%) experienced sensory deficits without motor deficits, none had any limitations of daily activities. One patient (1.2%) developed motor deficit with loss of motor function of one upper extremity. The only patient, who developed permanent motor damage had received additional prior radiation treatment and therefore received a cumulative spinal cord dose higher than the treatment guidelines. No patient treated within the guidelines experienced any motor impairment. Six patients (7.7%) experienced transient Lhermitt's syndrome and 1 patient (1.2%) developed asymptomatic radiographic MR findings only. Time to onset of symptoms of radiographic changes was between 2 and 8.5 months after radiation therapy. Two risk factors appeared to have significant impact when all incidences were considered: proton portion of tumor dose > 55 CGE (p=.023), and spinal cord surface dose ≥ 60 CGE (p=.045). For patients receiving 55 CGE to >1.5cc of spinal cord, the risk of developing imaging changes was significantly higher (p=.0074). Age < 40 years was found to be correlated with higher incidence of Lhermitt's syndrome (p=.002). No variable was significant for predicting incidence of sensory or motor deficits. Conclusions: For chordomas and chondrosarcomas of the cervical spine, requiring high radiation doses, the guidelines of limiting maximum spinal cord surface dose to ≤ 64 CGE and maximum spinal cord center dose to ≤ 53 CGE appears safe. For the patients who had been treated within the above tolerance dose, none of them had developed motor deficits. Both a significant dose response relationship as well as volume effect for symptomatic or asymptomatic spinal cord changes were observed. The incidence of 1 patient, who developed motor damage after higher radiation doses to the spinal cord than generally allowed, emphasizes the importance of strict guidelines for critical, normal tissues in high dose, conformal radiation treatment

[en] Purpose: The dose constraints to the critical structures that are lower than the prescribed dose may cause dose inhomogeneity in the tumor volume at the tumor-critical structure interface, if the tumor abuts or displaces the normal structure. The low dose region in the tumor volume may be one of the reasons for local failure. The aim of this study is to quantitate the effect of the tumor dose inhomogeneity on local control. Materials and Methods: 133 patients with skull base chordoma were treated with photon and proton irradiation between 1978 and 1993. This study reviews 88 whose dose volume data are available. The prescribed doses ranged from 66.6 Cobalt-Gray-Equivalent (CGE) to 79.2 CGE (average of 70.2CGE). The dose to the optic structures (optic nerves and chiasm), the brain stem surface and the brain stem center was limited to 60, 64 and 53 CGE, respectively. We used the dose volume histogram data derived with the three-dimensional treatment planning system to evaluate the prescribed dose, the mean tumor dose, the tumor volume, and the volume receiving less than 66CGE (V < 66CGE) in relation to local control. Results: Local failure developed in 24 of 88 patients, with the actuarial local control rates at 5 and 10 years being 66.6% and 47%, respectively. The prescribed dose, the mean tumor dose and the tumor volume were not significantly different in patients with local control and those with local failure. The absolute V < 66CGE was significantly larger in the patients with local failure (average of 11.9 cc) than in those with local control (average of 5.7cc) (p=0.0002). There was a significant difference in the local control rate depending on the volume receiving less than 66CGE: local control in patients with V < 66CGE < 7.4cc was significantly higher than in patients with V < 66CGE >= 7.4cc at 10 years (71.5% vs. 33%, respectively, p=0.04). Conclusion: This study suggested that the size of the low dose region in the tumor volume was a significant factor for local control of skull base chordoma

[en] Purpose: When irradiating a tumor that abuts or displaces any normal structures, the dose constraints to those structures (if lower than the prescribed dose) may cause dose inhomogeneity in the tumor volume at the tumor-critical structure interface. The low-dose region in the tumor volume may be one of the reasons for local failure. The aim of this study is to quantitate the effect of tumor dose inhomogeneity on local control and recurrence-free survival in patients with skull base chordoma. Methods and Materials: 132 patients with skull base chordoma were treated with combined photon and proton irradiation between 1978 and 1993. This study reviews 115 patients whose dose-volume data and follow-up data are available. The prescribed doses ranged from 66.6 Cobalt-Gray-Equivalent (CGE) to 79.2 CGE (median of 68.9 CGE). The dose to the optic structures (optic nerves and chiasma), the brain stem surface, and the brain stem center was limited to 60, 64, and 53 CGE, respectively. We used the dose-volume histogram data derived with the three-dimensional treatment planning system to evaluate several dose-volume parameters including the Equivalent Uniform Dose (EUD). We also analyzed several other patient and treatment factors in relation to local control and recurrence-free survival. Results: Local failure developed in 42 of 115 patients, with the actuarial local control rates at 5 and 10 years being 59% and 44%. Gender was a significant predictor for local control with the prognosis in males being significantly better than that in females (P 0.004, hazard ratio = 2.3). In a Cox univariate analysis, with stratification by gender, the significant predictors for local control (at the probability level of 0.05) were EUD, the target volume, the minimum dose, and the D_5cc dose. The prescribed dose, histology, age, the maximum dose, the mean dose, the median dose, the D_90% dose, and the overall treatment time were not significant factors. In a Cox multivariate analysis, the models including gender and EUD, or gender and the target volume, or gender and the minimum target dose were significant. The more biologically meaningful of these models is that of gender and EUD. Conclusion: This study suggests that the probability of recurrence of skull base chordomas depends on gender, target volume, and the level of target dose inhomogeneity. EUD was shown to be a useful parameter to evaluate dose distribution for the target volume

[en] Purpose: To predict the organ at risk (OAR) dose levels achievable with proton beam therapy (PBT), solely based on the geometric arrangement of the target volume in relation to the OARs. A comparison with an alternative therapy yields a prediction of the patient-specific benefits offered by PBT. This could enable physicians at hospitals without proton capabilities to make a better-informed referral decision or aid patient selection in model-based clinical trials. Methods and Materials: Skull-base tumors were chosen to test the method, owing to their geometric complexity and multitude of nearby OARs. By exploiting the correlations between the dose and distance-to-target in existing PBT plans, the models were independently trained for 6 types of OARs: brainstem, cochlea, optic chiasm, optic nerve, parotid gland, and spinal cord. Once trained, the models could estimate the feasible dose–volume histogram and generalized equivalent uniform dose (gEUD) for OAR structures of new patients. The models were trained using 20 patients and validated using an additional 21 patients. Validation was achieved by comparing the predicted gEUD to that of the actual PBT plan. Results: The predicted and planned gEUD were in good agreement. Considering all OARs, the prediction error was +1.4 ± 5.1 Gy (mean ± standard deviation), and Pearson's correlation coefficient was 93%. By comparing with an intensity modulated photon treatment plan, the model could classify whether an OAR structure would experience a gain, with a sensitivity of 93% (95% confidence interval: 87%-97%) and specificity of 63% (95% confidence interval: 38%-84%). Conclusions: We trained and validated models that could quickly and accurately predict the patient-specific benefits of PBT for skull-base tumors. Similar models could be developed for other tumor sites. Such models will be useful when an estimation of the feasible benefits of PBT is desired but the experience and/or resources required for treatment planning are unavailable.

[en] Purpose/Objective: To evaluate the risk of radiation injury to the optic pathway following high dose radiation therapy (RT) for base of skull tumors with regard to the following variables: diabetes, hypertension, number of surgical procedures, use of patch, patch distance, radiation dose, and volume of optic structures receiving 50, 55, or 60 Cobalt Gray Equivalent (CGE). Materials and Methods: A total of 359 patients with base of skull chordoma or low grade chondrosarcoma received high dose radiation therapy. Patients were treated with external beam radiotherapy utilizing protons alone or combined protons and photons. Protons of 160 MeV were delivered at the Harvard Cyclotron Laboratory using a modulated Bragg peak. The tumor dose ranged from 61 to 76 CGE. CGE was used because modulated protons have an RBE of 1.1 compared to ⁶⁰Co. Among 359 patients, 85 patients were excluded from evaluation based on age, tumor location, and pre-RT treatment criteria. All 274 evaluable patients had a minimum follow up of 12 months. Medical records were reviewed to determine the actual cause of vision changes. A total of 12 patients with grade II, III, and IV radiation-induced optic neuropathy were identified. Twenty-four patients without complications who closely matched the aforementioned 12 cases with optic neuropathy were selected from the 274 patients as a control group. Dose volume histograms of 12 cases and 24 controls were reviewed to determine minimum, median, and maximum dose to the optic apparatus as well as dose volume at 50, 55, and 60 CGE. Other information regarding remaining potential risk factors, such as diabetes, hypertension, number of surgical procedures, use of patch, and patch distance, was also obtained. Results: A total of 12 patients (4.4%) developed radiation-induced optic neuropathy: 1 grade II, 9 grade III, and 2 grade IV. Specific sites of involvement were left optic nerve in 9, right optic nerve in 5, and chiasm in 4 cases. The duration to the onset of impairment ranged from 7 to 40 months following the completion of therapies, with a median duration of 12 months. The maximum dose to the optic apparatus ranged from 50.21 to 69.60 CGE, with a median value of 59.43 CGE. By Student t-test analysis, patch distance was the only variable significantly related to radiation-induced optic neuropathy. While the proportion of patients with patches was not different in the two groups, the patch distances were significantly smaller (p = 0.0284) in the cases than in the controls. Conclusion: Twelve of 274 patients (4.4%) who received high dose external beam proton and photon radiotherapy for skull base tumors developed radiation-induced optic neuropathy in 7 to 40 months from the completion of therapies. Patch distance was a significant risk factor for developing optic neuropathy (p = 0.0284)

[en] Purpose/Objective: The purpose of this study was to perform a detailed evaluation of auditory complications and audiological changes in patients undergoing high-dose radiotherapy to base of skull tumors. Materials and Methods: Twenty-five patients receiving high-dose skull-base proton radiotherapy at the Harvard Cyclotron Laboratory (HCL) met this study's strict inclusion criterion. These included: a) radiation doses over 15 CGE to the ipsilateral auditory structures, b) normal pre-treatment audiograms, c) performance of sequential post-treatment audiogram(s), with the first being a minimum of one year after treatment, and d) no local tumor failure near auditory structures. Eight individual hearing structures were contoured by a neuroanatomist (BCF) on each patient's 1-3 mm treatment-planning CT slices, and dose-volume histograms were developed. The dose calculated was that dose received by 50% of each structure. Results: Moderate to severe hearing loss was seen in 6 patients. Of these six, five were under 39, and four were female. Intervals to hearing loss ranged from 8 months to 5 years and the deficit was progressive rather than acute. Each had received cochlea and auditory nerve doses greater than 60 CGE. Doses to the cochlea nucleus and middle ear were infrequently over 60 CGE in this patient population. No hearing loss was seen in any patient whose dose to the cochlea, eighth nerve, cochlear nucleus, or middle ear was under 60 CGE. There was no clear-cut dose response in the dose range 60-72 CGE for the cochlea or eighth nerve. Clinical courses and correlations, as well as surgical and radiotherapeutic treatment variables, will be discussed. Conclusions: Given the limitations of the study including small numbers and selection bias (particularly selection for post-treatment audiograms with severe hearing loss), this study, with its exact anatomical localization and contouring, indicates that doses of less than 60 Gy with standard fractionation can be safely administered to any part of the auditory pathway. A significant risk of hearing loss, particularly for the younger patient, exists if more than 60 Gy is given to at least 50% of the auditory nerve or cochlea

[en] 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 no. 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