Dose-escalation with proton/photon irradiation for Daumas-Duport lower-grade glioma: results of an institutional phase I/II trial.

PURPOSE: The role of dose escalation with proton/photon radiotherapy in lower-grade gliomas was assessed in a prospective Phase I/II trial. We report the results in terms of local control, toxicity, and survival. MATERIALS AND METHODS: Twenty patients with Grade 2/4 (n = 7) and Grade 3/4 (n = 13) gliomas according to the Daumas-Duport classification were treated on a prospective institutional protocol at Massachusetts General Hospital/Harvard Cyclotron Laboratory between 1993 and 1996. Doses prescribed to the target volumes were 68.2 cobalt Gray equivalent (CGE, 1 proton Gray = 1.1 CGE) to gross tumor in Grade 2 lesions and 79.7 CGE in Grade 3 lesions. Fractionation was conventional, with 1.8 to 1.92 CGE once per day. Eligibility criteria included age between 18 and 70 years, biopsy-proven Daumas-Duport Grade 2/4 or 3/4 malignant glioma, Karnofsky performance score of 70 or greater, and supratentorial tumor. Median age of the patient population at diagnosis was 35.9 years (range 19-49). Ten tumors were mixed gliomas, one an oligodendroglioma. RESULTS: Five patients underwent biopsy, 12 a subtotal resection, and 3 a gross total resection. Median interval from surgery to first radiation treatment was 2.9 months. Actuarial 5-year survival rate for Grade 2 lesions was 71% as calculated from diagnosis (median survival not yet reached); actuarial 5-year survival for Grade 3 lesions was 23% (median 29 months). Median follow-up is 61 months and 55 months for 4 patients alive with Grade 2 and 3 patients alive with Grade 3 lesions, respectively. Three patients with Grade 2 lesions died from tumor recurrence, whereas 2 of the 4 survivors have evidence of radiation necrosis. Eight of 10 patients who have died with Grade 3 lesions died from tumor recurrence, 1 from pulmonary embolus, and 1 most likely from radiation necrosis. One of 3 survivors in this group has evidence of radiation necrosis. CONCLUSION: Tumor recurrence was neither prevented nor noticeably delayed in our patients relative to published series on photon irradiation. Dose escalation using this fractionation scheme and total dose delivered failed to improve outcome for patients with Grade 2 and 3 gliomas.

Chondrosarcoma of the base of the skull: a clinicopathologic study of 200 cases with emphasis on its distinction from chordoma.

Conventional chondrosarcoma (CSA) of the skull base is an uncommon neoplasm that can resemble chordoma, and indeed it is misdiagnosed frequently as such. This has important clinical implications, because when treated with similar aggressive treatment strategies, CSA has a much better prognosis than chordoma. In an effort to identify those morphologic and immunohistochemical features that help to identify conventional skull base CSA correctly and to understand its prognosis better, particularly compared with chordoma, when treated with surgery and proton beam irradiation, the authors performed a clinicopathologic analysis of 200 CSAs. The patients ranged in age from 10 to 79 years (mean, 39 years), 87 patients were male and 113 patients were female, and most presented with symptoms related to the central nervous system. Approximately 6% of the tumors arose in the sphenoethmoid complex, 28% originated in the clivus, and 66% developed in the temperooccipital junction. Histologically, 15 tumors (7.5%) were classified as hyaline CSA, 59 (29.5%) as myxoid CSA, and 126 (63%) as mixed hyaline and myxoid CSA. A total of 101 (50.5%) tumors were grade 1, 57 (28.5%) had areas of grades 1 and 2, and 42 (21%) were pure grade 2 neoplasms. The vast majority of patients originated from referring hospitals, and the diagnosis was changed prospectively at our institution to CSA from chordoma in 74 patients (37%). Of the tumors studied immunohistochemically, 96 of 97 (98.9%) stained for S-100 protein, 0 of 97 (0%) stained for keratin, and faint staining for epithelial membrane antigen was seen in 7 of 88 tumors (7.95%). All patients underwent high-dose postoperative fractionated precision conformal radiation therapy with a dose that ranged from 64.2 to 79.6 Cobalt-Gray-equivalents (median, 72.1 Cobalt-Gray-equivalents, given in 38 fractions. The 200 patients had a median follow-up of 63 months (range, 2.1 mos - 18.5 yrs). Tumor control was defined as lack of progression by clinical and radiographic assessment. Based on this definition, there were three local recurrences, and two of these patients died of tumor-related complications. The 5- and 10-year local control rates were 99% and 98% respectively, and the 5- and 10-year disease-specific survival rates were both 99%. In contrast to CSA, the 5- and 10-year survival rates of chordoma have been reported to be approximately 51 % and 35% respectively, and in our institution intensive treatment has resulted in 5- and 10-year progression-free survival rates of 70% and 45% respectively. CSA of the skull base can be distinguished reliably from chordoma, and this distinction is important because skull base CSA has an excellent prognosis when treated with surgery and proton beam irradiation, whereas chordomas have a substantially poorer clinical course despite similar aggressive management.

Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial.

OBJECT: After conventional doses of 55 to 65 Gy of fractionated irradiation, glioblastoma multiforme (GBM) usually recurs at its original location. This institutional phase II study was designed to assess whether dose escalation to 90 cobalt gray equivalent (CGE) with conformal protons and photons in accelerated fractionation would improve local tumor control and patient survival. METHODS: Twenty-three patients were enrolled in this study. Eligibility criteria included age between 18 and 70 years, Karnofsky Performance Scale score of greater than or equal to 70, residual tumor volume of less than 60 ml, and a supratentorial, unilateral tumor. Actuarial survival rates at 2 and 3 years were 34% and 18%, respectively. The median survival time was 20 months, with four patients alive 22 to 60 months postdiagnosis. Analysis by Radiation Therapy Oncology Group prognostic criteria or Medical Research Council indices showed a 5- to 11-month increase in median survival time over those of comparable conventionally treated patients. All patients developed new areas of gadolinium enhancement during the follow-up period. Histological examination of tissues obtained at biopsy, resection, or autopsy was conducted in 15 of 23 patients. Radiation necrosis only was demonstrated in seven patients, and their survival was significantly longer than that of patients with recurrent tumor (p = 0.01). Tumor regrowth occurred most commonly in areas that received doses of 60 to 70 CGE or less; recurrent tumor was found in only one case in the 90-CGE volume. CONCLUSIONS: A dose of 90 CGE in accelerated fractionation prevented central recurrence in almost all cases. The median survival time was extended to 20 months, likely as a result of central control. Tumors will usually recur in areas immediately peripheral to this 90-CGE volume, but attempts to extend local control by enlarging the central volume are likely to be limited by difficulties with radiation necrosis.

Locally challenging osteo- and chondrogenic tumors of the axial skeleton: results of combined proton and photon radiation therapy using three-dimensional treatment planning.

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.