Francisco S. Pardo

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.

Intrinsic radiation sensitivity may not be the major determinant of the poor clinical outcome of glioblastoma multiforme

Abstract Purpose: Many radiobiologic mechanisms may contribute to the clinical radiation resistance of Glioblastoma Multiforme. One of them is considered to be an unusually low intrinsic radiation sensitivity. This is a collaborative study between three laboratories to evaluate the intrinsic radiation sensitivity of 85 cell lines derived from human malignant gliomas as the major cause of the poor clinical results of radiation treatment to these tumors. Methods and Materials: Fifty-one cell lines were early passage. The distribution by histologic type was: 58 glioblastoma, 17 anaplastic astrocytoma, six oligodendroglioma and four astrocytoma grade 2. The intrinsic radiation sensitivity will be expressed by the surviving fraction at 2 Gy (SF 2 ). The SF 2 has been determined for single dose irradiation for cell lines on exponential phase, under aerobic conditions, growing on plastic. The patient age, Karnofski Status, histological grade, survival, dose of irradiation for 50 patients are investigated for correlation with SF 2 of the corresponding newly established cell lines. Results: The mean SF 2 of the 85 cell lines was 0.46 (0.12 – 0.87). The mean SF 2 by histologic type was 0.50, 0.34, 0.54 and 0.38 for glioblastoma, anaplastic astrocytoma, oligodendroglioma and astrocytoma grade 2 cell lines, respectively. No correlation was found between SF 2 and the patient age or Karnofski status. The difference in SF 2 between the 58 glioblastoma and 17 anaplastic astrocytoma cell lines was significant p = 0.002. The difference in actuarial survival between glioblastoma and anaplastic astrocytoma patients was borderline of significance ( p = 0.08). The difference in SF 2 of cell lines derived from these two groups of patients was of borderline significance ( p = 0.08). The difference in radiation sensitivity for anaplastic astrocytoma and glioblastoma cell lines was clearly reflected in the difference in survival for the two groups of patients from where the cell lines were derived. However, no correlation was found between SF 2 and survival within each grade. In a multivariate analysis the age, grade and Karnofski status were found to be significant prognostic values for survival with a p values of 0.032, 0.03 and 0.038, respectively, however, the In SF 2 was not significant ( p = 0.40). The mean SF 2 of the 6 oligodendroglioma cell lines (0.54) was comparable to that of glioblastoma multiforme (0.50). The high SF 2 for oligodendroglioma does not accord with the much better clinical outcome of these tumors. Conclusions: These data on 85 malignant glioma cell lines show a very broad distribution of SFZ values for irradiation in vitro . SF 2 reflected the difference in sensitivity between AA (Grade 3) and GBM (Grade 4). This may suggest that the parameter SF 2 is useful to discriminate between the sensitivity of different grades or types of histology in vitro . However, SF 2 was not a predictor of the clinical outcome on individual basis for malignant gliomas. The in vitro studies will need to be supplemented by physiologic characterization of the tumors in vivo . Such conclusions would limit the predictive value of current radiation sensitivity assays based on in vitro dose-survival measurement for at least high grade malignant gliomas.

Echo-Planar MR Cerebral Blood Volume Mapping of Gliomas: Clinical utility

Neovascularization is a common phenomenon in gliomas. MR imaging cerebral blood volume (CBV) mapping utilizes ultrafast echo-planar imaging and simultaneous use of gadolinium-based contrast material. To determine the utility of MR CBV mapping in the clinical evaluation of gliomas, we followed 15 patients with serial studies. This technique provided functional information that was not evident with conventional CT or MR imaging. Low-grade tumors demonstrated homogeneously low CBV, while high-grade tumors often showed areas of both high and low CBV The maximum tumor CBV/white matter ratio was compared between low- (n = 3) and high-grade gliomas (n=5) in patients without previous treatment and with histologic verification (n=8) and was significantly higher in high-grade gliomas (p<0.01). High CBV foci in nonenhancing tumor areas were present in 2 cases. The distinction between radiation necrosis and active tumor could be made correctly in 3 of 4 cases. The information provided by MR CBV mapping has the potential to be an adjunct in the clinical care of glioma patients.

IN VITRO INTRINSIC RADIATION SENSITIVITY OF GLIOBLASTOMA MULTIFORME

Glioblastoma multiforme is one of the most resistant of human tumors to radiation whether used alone or in combination with surgery and/or chemotherapy. This resistance may be caused by one or more of several different factors. These include inherent cellular radiation sensitivity, an efficient repair of radiation damage, an increased number of clonogens per unit of volume, a high hypoxic fraction, high [GSH] concentration, and rapid proliferation between fractions. In the present study, we evaluate the intrinsic radiation sensitivity (surviving fraction at 2 Gy or mean inactivation dose) of malignant human glioma cells in vitro. The in vitro radiation sensitivity of 21 malignant glioma cell lines (early and long term passages) has been measured using colony formation as the end-point of cell viability. The survival curve parameters (SF2 measured and calculated, alpha, beta, D0, n and MID) have been determined for single dose irradiations of exponential phase cells (18-24 hr after plating) under aerobic conditions and growing on plastic. The mean SF2 of the 21 cell lines is 0.51 +/- 0.14 (with a range of 0.19 to 0.76). This value may be compared to the mean SF2 of 0.43-0.47 for SCC, 0.43 for melanoma, and 0.52 for glioblastoma as reported from other authors when using colony formation of cells in exponential phase on plastic. Although glioblastoma is almost invariably fatal, our data demonstrate a very wide range of intrinsic radiosensitivities. These broadly overlap the radiation sensitivities of cell lines from tumors that are often treated successfully. We conclude that standard in vitro measurements of cellular radiation sensitivity (SF2) do not yield values that track in a simple manner with local control probability at the clinical level and that, for at least some of the tumors, other parameters and/or physiological factors are more important.

A new miniature x-ray device for interstitial radiosurgery: dosimetry.

A miniature, battery operated 40 kV x-ray device has been developed for the interstitial treatment of small tumors ( < 3 cm diam) in humans. X rays are emitted from the tip of a 10 cm long, 3 mm diameter probe that is stereotactically inserted into the tumor. The beam, characterized by half-value layer (HVL), spectrum analysis, and isodose contours, behaves essentially as a point isotropic source with an effective energy of 20 keV at a depth of 10 mm in water. The absolute output from the device was measured using a parallel plate ionization chamber, modified with a platinum aperture. The dose rate in water determined from these chamber measurements was found to be nominally 150 cGy/min at a distance of 10 mm for a beam current of 40 microA and voltage of 40 kV. The dose in water falls off approximately as the third power of the distance. To date, 14 patients have been treated with this device in a phase I clinical trial.

Prognostic significance of proliferative indices in meningiomas

The prognostic value of tumor proliferative indices in meningiomas was assessed by mitotic counts and by immunocytochemistry using a monoclonal antibody against the proliferating cell nuclear antigen (PCNA) (clone 19A2), a 36-kd nuclear protein involved in DNA synthesis. Sixty-three intracranial meningiomas were classified as benign (26), with atypical features (24) or as malignant (13). The patients included 24 men and 39 women, mean age 54.2 ± 1.7 (mean ± SEM) (range 15–78) at initial presentation. Twenty-four of the 63 primary tumors recurred locally, including 23.1% (6/26) of the benign, 37.5% (9/24) of the atypical, and 69.2% (9/13) of the malignant meningiomas. Among tumors that recurred, 1/9 (11%) of the atypical and 5/9 (55.5%) of the malignant tumors had had macroscopical total excision at the initial surgery. The mean interval to recurrence was 52 ± 11.8 months. The mean progression-free follow-up period for patients without tumor recurrence was 82 ± 8.5 months. Analysis of variance revealed that significant differences existed between tumor grades for both PCNA indices (1.16 ± 0.29% for benign; 14.14 ± 2.07% for atypical and 21.37 ± 5.47% for malignant) and mitotic indices (total counts per ten high power fields) (0.08 ± 0.05 for benign, 4.75 ± 0.91 for atypical and 19.00 ± 4.07 for malignant). Multivariate regression analysis indicated that mitotic index >6 was the single most important factor (p < 0.05) for shorter disease-free interval. Age, sex and total surgical excision were not significant factors. PCNA index was a significant factor in the univariate model, but not in the multivariate model. However, a two-factor-interaction model with PCNA >5% and mitoses >6 was highly significant as a predictor of outcome (p < 0.0001). We conclude that PCNA index may be used as an adjunct with mitotic counts in predicting the clinical course of patients with meningiomas.

Functional cerebral imaging in the evaluation and radiotherapeutic treatment planning of patients with malignant glioma

PURPOSE Functional magnetic resonance imaging (MRI) and positron emission tomography are relatively new modalities of great potential value in the evaluation, treatment, and subsequent follow-up care of patients with malignant glioma. We report our experience with the incorporation of functional imaging data into radiation therapy three-dimensional (3-D) treatment planning. METHODS AND MATERIALS Over a 24-month period, a total of 37 positron emission tomography and 29 functional MRI studies have been conducted on eight consecutive patients prior to, during, and following the completion of radiation therapy. Functional imaging was conducted prior to radiation therapy treatment planning and at approximate 3-month follow-up time intervals. RESULTS In two patients, functional imaging provided additional information over conventional imaging modalities and resulted in subsequent modification of conventional radiation therapy treatment planning. CONCLUSION Although it is premature to make definitive statements regarding the use of these new imaging parameters in the prognostic setting, functional imaging may likely prove to be a useful adjunct in the initial evaluation, radiation treatment planning, and follow-up care of patients with malignant glioma.

Transfection of rat embryo cells with mutant p53 increases the intrinsic radiation resistance

Dominant oncogenic sequences have been shown to modulate the intrinsic radiation sensitivity of cells of both human and murine tumor cell lines. Whether transfection with candidate tumor-suppressor genes can modulate intrinsic radiation sensitivity is unknown. The data presented here demonstrate that transfection of rat embryo cells with a mutant p53 allele can increase the intrinsic radiation resistance of cells in vitro. First, transfection with mutant p53 resulted in transformed cellular morphology. Second, the transfected clone and the corresponding pooled population of transfected clones were more resistant to ionizing radiation in vitro. Last, analyses of the parameters of cell kinetics suggested that the radiobiological effects were unlikely to be due to altered parameters of cell kinetics at the time of irradiation, suggesting that mutant p53 altered the intrinsic radiation resistance of transfected cells by a more direct mechanism. Further experimentation will be necessary to develop a mechanistic approach for the study of these alterations.

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.

Dosimetric results from a feasibility study of a novel radiosurgical source for irradiation of intracranial metastases

PURPOSE A feasibility study addressing the role of a new miniature x-ray device, the Photon Radiosurgery System (PRS), for interstitial radiosurgical treatment of intracranial metastatic neoplasms, was conducted at our institution. To gain insight into the role of PRS vis-à-vis other currently available radiosurgical treatment modalities, dosimetric comparisons of Linac Radiosurgery and proton beam therapy were performed in the treatment of a small approximately spherical metastasis. METHODS AND MATERIALS The photon radiosurgery system is a miniature, battery operated, high-voltage x-ray generator that produces low-energy x-rays with an effective energy of 10-20 keV emanating from the tip of a probe stereotactically inserted into small tumors (< 3 cm in diameter) in humans. Patients, 18 years or older, with supratentorial mass lesions less than 3 cm in diameter were eligible if they were likely to survive their systemic cancer and be capable of self-care for more than 4 months. Patients were ineligible if presenting with infratentorial lesions, contraindications for biopsy, or receipt of chemotherapy or radiotherapy within 4 weeks were ineligible. RESULTS Fourteen patients with metastatic supratentorial lesions were treated from December 1992 to December 1993 for metastatic tumors to the brain. Single doses of 10-20 Gy were delivered to spherical targets of 10 to 35 mm in diameter. Treatment, including biopsy, pathologic review and radiation treatment, generally took less than 3 h. One patient, later found to have an ischemic stroke, developed a small hemorrhage from the biopsy that preceded interstitial irradiation. There were no other complications. Median survival was 10 months. Three locally recurrent lesions failed at 3.5, 4, and 10 months after treatment. All patients had stable or improved Karnofsky status for 2 weeks to 21 months after treatment. The PRS dosimetry appears at least as good as that obtained using 6 MV Linac or 160 MeV protons. Analyses of dose-volume histograms comparing the volumes of normal CNS tissue irradiated employing each of the respective modalities suggest a small sparing of normal tissue with PRS, as opposed to linac or protons, in this patient population with small, approximately spherical tumors. CONCLUSIONS The PRS device provides a unique cost and time efficient procedure for providing interstitial radiation therapy immediately following histologic confirmation of malignancy in patients undergoing biopsy of intracranial lesions. The PRS treatment appears safe, and preliminary data suggest no evidence of treatment-related morbidity within the life span of the selected patient population. When treating small, spherical lesions, PRS appears to offer a modest dosimetric advantage over Linac or proton beam therapy in sparing normal tissue. These encouraging results have prompted a Phase II trial that is currently underway. Further efforts are necessary in the design of a clinically relevant trial addressing the role of fractionated external beam radiation therapy with boost vs. PRS treatment with WBRT in the treatment of single metastases.