Allan F. Thornton

Management of Atypical and Malignant Meningiomas: Role of High-dose, 3D-conformal Radiation Therapy

AbstractObjective Atypical and malignant meningiomas are at high risk for local failure. The role of radiation therapy (RT) and dose levels required to improve tumor control are poorly defined. This study reviews our experience with RT. Material and methods Thirty-one patients underwent fractionated RT for atypical (AM, 15 patients) or malignant meningioma (MM, 16 patients) of the cranium. Sixteen patients presented with primary and 15 with recurrent disease. Eight patients received RT following total resection, 21 patients after subtotal resection and 2 patient following biopsy only. RT was given using megavoltage photons in 15 patients and combined photons and 160 MeV protons in 16 patients. Total target doses ranged from 50 to 68 (AM, mean 62) and from 40 to 72 (MM, mean 58) Gy or CGE (= cobalt-gray-equivalent). Results With mean observation time of 59 months (range: 7–155 months) actuarial local control rates at 5- and 8-years were similar for both histologies (38% and 19% for AM and 52 and 17% for MM). However, significantly improved local control was observed for proton versus photon RT (80% versus 17% at 5 years, p = 0.003) and target doses ≥60 Gy for both, atypical (p = 0.025) and malignant meningioma (p = 0.0006).At time of analysis, 14/15 patients (93%) with AM and 6/16 (38%) with MM were alive. Three patients (19%) with MM developed distant metastasis. Actuarial 5- and 8-year survival rates for MM were significantly improved by use of proton over photon RT and radiation doses ≥60 CGE. Three patients developed symptomatic radiation damage after 59.3, 68.4 and 72 Gy/CGE. Conclusion Conformal, high dose RT resulted in significant improvement of local control for atypical and malignant meningiomas. Increased local control resulted also in improved rates of survival for patients with malignant meningioma.

Chondrosarcoma of the head and neck

Chondrosarcoma is a malignancy rarely encountered in the head and neck. In an attempt to define this tumors characteristics and response to therapy, all cases of chondrosarcoma treated at the University of Michigan over the past 25 years were retrospectively studied. Fourteen cases originating in the nose and paranasal sinuses, mandible, temporal bone, and larynx were reviewed. Aggressive surgical resection was the mainstay of treatment, and resulted in an overall survival of 70%, with an average follow‐up of 3.5 years. Survival was highest in primary temporal bone lesions, and lowest in paranasal sinus lesions. Unre‐sectable lesions were not cured by other modalities. This study, therefore, continued to support the crucial role of wide surgical resection in the treatment of head and neck chondrosarcoma, but conservative resection, when needed to preserve important structures, has resulted in long‐term survival.

HYPOTHALAMIC/PITUITARY FUNCTION FOLLOWING HIGH-DOSE CONFORMAL RADIOTHERAPY TO THE BASE OF SKULL: DEMONSTRATION OF A DOSE-EFFECT RELATIONSHIP USING DOSE-VOLUME HISTOGRAM ANALYSIS

PURPOSE To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored. METHODS AND MATERIALS Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion. RESULTS The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction. CONCLUSION Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.

The clinical utility of magnetic resonance imaging in 3-dimensional treatment planning of brain neoplasms

Results of the clinical experience gained since 1986 in the treatment planning of patients with brain neoplasms through integration of magnetic resonance imaging (MRI) into computerized tomography (CT)-based, three-dimensional treatment planning are presented. Data from MRI can now be fully registered with CT data using appropriate three-dimensional coordinate transformations allowing: (a) display of MRI defined structures on CT images; (b) treatment planning of composite CT-MRI volumes; (c) dose display on either CT or MRI images. Treatment planning with non-coplanar beam arrangements is also facilitated by MRI because of direct acquisition of information in multiple, orthogonal planes. The advantages of this integration of information are especially evident in certain situations, for example, low grade astrocytomas with indistinct CT margins, tumors with margins obscured by bone artifact on CT scan. Target definitions have repeatedly been altered based on MRI detected abnormalities not visualized on CT scans. Regions of gadolinium enhancement on MRI T1-weighted scans can be compared to the contrast-enhancing CT tumor volumes, while abnormalities detected on MRI T2-weighted scans are the counterpart of CT-defined edema. Generally, MRI markedly increased the apparent macroscopic tumor volume from that seen on contrast-CT alone. However, CT tumor information was also necessary as it defined abnormalities not always perceptible with MRI (on average, 19% of composite CT-MRI volume seen on CT only). In all, the integration of MRI data with CT information has been found to be practical, and often necessary, for the three-dimensional treatment of brain neoplasms.

Benign meningioma: partially resected, biopsied, and recurrent intracranial tumors treated with combined proton and photon radiotherapy.

PURPOSE/OBJECTIVE To evaluate the recurrence-free survival and complications of combined proton and photon radiotherapy of patients with incompletely resected or recurrent histologically-confirmed benign meningioma. METHODS AND MATERIALS Between May 1981 and November 1996, 46 patients with partially resected, biopsied, or recurrent meningiomas (median age of 50 years; range 11-74 years) were treated with combined photon and 160-MeV proton beam therapy at the Massachusetts General Hospital (MGH) and the Harvard Cyclotron Laboratory, using computed tomography-based conformal 3D treatment planning. Nine patients were treated after incomplete tumor resection, 8 patients after tumor biopsy only, and 29 patients after tumor recurrence following gross total (10/29 patients) or progression after subtotal (19/29 patients) resection. All patients were classified as benign meningioma on review slides at MGH. The median dose to the macroscopic gross tumor volume was 59.0 CGE (range 53.1-74.1 CGE, CGE = proton Gy x 1.1 RBE). The median follow-up was 53 months (range 12-207). RESULTS Overall survival at 5 and 10 years was 93 and 77%, respectively, and the recurrence-free rate at 5 and 10 years was 100% and 88%, respectively. Survival without severe toxicity was 80% at 5 and 10 years. Three patients presented with local tumor recurrence at 61, 95, and 125 months. One patient developed distant intradural metastasis at 21 and 88 months. No patient died from recurrent meningioma; however, 4 patients died of other causes. A fifth patient died from a brainstem necrosis after 22 months. Eight patients developed severe long-term toxicity from radiotherapy, including ophthalmologic (4 patients), neurologic (4 patients), and otologic (2 patients) complications. All patients with ophthalmologic toxicity received doses higher than those allowed for the optic nerve structures in the current protocol. CONCLUSION Combined proton and photon radiotherapy is an effective treatment for patients with recurrent or incompletely resected benign intracranial menigiomas. Observed toxicity appears to be dose-related; with currently employed dose constraints, toxicity should not exceed that seen in patients treated with conformal fractionated supervoltage photon radiotherapy.

A quantitative assessment of the addition of MRI to CT-based, 3-D treatment planning of brain tumors

Quantitative 3-D volumetric comparisons were made of composite CT-MRI macroscopic and microscopic tumor and target volumes to their independently defined constituents. Volumetric comparisons were also made between volumes derived from coronal and axial MRI data sets, and between CT and MRI volumes redefined at a repeat session in comparison to their original definitions. The degree of 3-D dose coverage obtained from use of CT data only or MRI data only in terms of coverage of composite CT-MRI volumes was also analyzed. On average, MRI defined larger volumes as well as a greater share of composite CT-MRI volumes. On average, increases in block margin on the order of 0.5 cm would have ensured coverage of volumes derived from use of both imaging modalities had only MRI data been used. However, the degree of inter-observer variation in volume definition is on the order of the magnitude of differences in volume definition seen between the modalities, and the question of which imaging modality best describes tumor volumes remains unanswered until detailed histologic studies are performed. Given that tumor volumes independently apparent on CT and MRI have equal validity, composite CT-MRI input should be considered for planning to ensure precise dose coverage for conformal treatments.

Spinal cord astrocytomas : results of therapy

Spinal cord astrocytomas are rare lesions, usually of low grade, with a long natural history. Because of this, it is difficult to define the optimum approach to therapy based on available data. To provide more data, a retrospective review was performed. From 1975 through 1989, 21 patients were seen and treated (median age, 21 years), and 15 patients received radiation therapy after undergoing either biopsy or resection. The median time until death or the last follow-up examination was 41 months. The actuarial survival of all patients was 68% at 5 years. Of the five deaths, four were related to local tumor recurrence. The overall survival and recurrence-free survival of irradiated patients at 5 years was 57% and 44%, respectively. The age of the patient was a prognostic factor, with younger patients surviving substantially longer before recurrence. Of the 15 irradiated patients, 7 experienced recurrence of the tumor, which occurred within the irradiated portion of the spinal cord in all 7. Gross total resections were rarely achieved and, also, the extent of resection did not influence the risk for recurrence. In summary, we observed a long natural history for this disease, and although additional local therapy appears needed, it is unclear that either higher doses of radiation or more extensive surgery will decrease the risk of recurrence.

Neuroendocrine tumors of the sinonasal tract. Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy.

The authors report the results of a prospective study of patients with malignant neuroendocrine tumors of the sinonasal tract who received multimodality treatment incorporating high‐dose proton‐photon radiotherapy.

Results of primary and adjuvant CT-based 3-dimensional radiotherapy for malignant tumors of the paranasal sinuses.

PURPOSE This study reports our clinical experience supporting the normal tissue-sparing capability of 3-dimensional (3-D) treatment planning when applied to advanced neoplasms of the paranasal sinuses. METHODS AND MATERIALS Between 1986 and 1992, computed tomography (CT)-based 3-D radiotherapy was used to treat 39 patients with advanced stage malignant tumors of the paranasal sinuses as all or part of initial treatment. Fifteen unresectable patients were treated with primary radiotherapy to a median prescribed total dose of 68.4 Gy. Twenty-four patients were treated with postoperative adjuvant radiotherapy for close margins (< 5 mm), microscopic or gross residual disease. The median prescribed total doses were 55.8 Gy, 59.4 Gy and 67.8 Gy, respectively. Globe-sparing fields were used in the primary treatment plans of 37 patients (95%). The median follow-up is 4.5 years (range, 19-86 months). RESULTS For the unresectable patients who were treated with radiotherapy alone, the local control rate at 3 years is 32%. The actuarial overall survivals at 3 and 4 years are 32%. For the patients who received postoperative adjuvant radiotherapy, none of the five patients irradiated for close surgical margins recurred locally. Three of the 14 with microscopic residual (21%) recurred locally at 26, 63, and 74 months from the start of irradiation. Four of the five with gross residual (80%) recurred locally with a median time to recurrence of 2 years. The local control rates at 3 and 5 years for the adjuvant group are 75% and 65%, respectively. The actuarial overall survival at 3 and 5 years are 65% and 60%, respectively. None of the first sites of local disease progression were judged to have occurred outside the high-dose region. There was one case of mild osteoradionecrosis successfully treated with conservative treatment, one case of limited optic neuropathy and one case of possible radiation-induced cataract. There was no blindness related to irradiation. CONCLUSION This study indicates that computed tomography-based 3-D radiotherapy can preserve critical structures unaffected by tumor invasion and achieve the generally expected local control rates when it is used as all or part of initial treatment for extensive malignant tumors of the paranasal sinus. The presence of gross disease was a major adverse prognostic factor in this study. Additional therapeutic maneuvers are essential to improve the local control and survival rate in patients with advanced paranasal sinus carcinomas.

Three-dimensional treatment planning of astrocytomas: A dosimetric study of cerebral irradiation

To demonstrate that 3-dimensional planning is both practical and applicable to the treatment of high-grade astrocytomas, 50 patients over a 2-year period have received cerebral irradiation delivered in focussed, non-axial techniques employing from 2 to 5 beams. Astrocytomas have been planned using rapid, practical incorporation of CT data to define appropriate tumor volumes. Tumor + 3.0 cm and tumor + 1.5 cm volumes have been treated to conventional doses of 4500 cGy and 5940 cGy, respectively, using beam orientations that maximally spared normal remaining parenchyma. Analyses of 3-dimensionally calculated plans have been performed using integral dose-volume histograms (DVH) to help select treatment techniques. Using identical CT-based volumetric data as input for generation of Beams Eye View (BEV) designed blocks, DVH curves demonstrate dosimetric advantages of non-axial techniques over conventional parallel-opposed orientations. Assessment of the non-axial techniques in selected cases indicates that uniform target volume coverage could be maintained with a typical reduction of 30% in the total amount of brain tissue treated to high dose (95% isodose line).