Jeffery A. Williams

Fractionated stereotactic radiotherapy for acoustic neuromas

PURPOSEnWhen compared with radiosurgery, fractionated stereotactic radiotherapy for acoustic neuroma (AN) offers escalation of the tumor dose and potential sparing of auditory and facial nerve functions.nnnMETHODS AND MATERIALSnBetween 1996 and 2001, 249 consecutive patients have received fractionated stereotactic radiotherapy for AN. One hundred twenty-five patients had follow-up >1 year and were the subject of this report. A noninvasive, repeat-fixation mask allowed simulation by way of spiral CT. Two distinct schedules for total dose and fractionation were used. For an AN <3.0 cm in diameter (volume 1.4 +/- 0.2 cm(3)), patients received 25 Gy given in 5 consecutive daily fractions of 5 Gy (111 patients), and for ANs >or=3.0 cm (volume 8.1 +/- 1.2 cm(3)), patients received 30 Gy given in 10 fractions of 3 Gy (14 patients).nnnRESULTSnThe percentage of decrease in tumor size was 12% +/- 2% (range 0-100%) vs. 13% +/- 3% (range 0-38%) for the 25 Gy vs. 30 Gy regimens, respectively. No patient had growth of the AN or developed facial weakness. Two patients developed transient decreases in facial sensation. The rates of hearing preservation were similar for the larger and smaller tumors.nnnCONCLUSIONnFractionated stereotactic radiotherapy may preserve normal function and control both small and large ANs.

Dosimetric properties of a novel brachytherapy balloon applicator for the treatment of malignant brain-tumor resection-cavity margins

PURPOSEnThis paper characterizes the dosimetric properties of a novel balloon brachytherapy applicator for the treatment of the tissue surrounding the resection cavity of a malignant brain tumor.nnnMETHODS AND MATERIALSnThe applicator consists of an inflatable silicone balloon reservoir attached to a positionable catheter that is intraoperatively implanted into the resection cavity and postoperatively filled with a liquid radionuclide solution. A simple dosimetric model, valid in homogeneous media and based on results from Monte Carlo photon-transport simulations, was used to determine the dosimetric characteristics of spherical geometry balloons filled with photon-emitting radionuclide solutions. Fractional depth-dose (FDD) profiles, along with activity densities, and total activities needed to achieve specified dose rates were studied as a function of photon energy and source-containment geometry. Dose-volume histograms (DVHs) were calculated to compare idealized balloon-applicator treatments to conventional 125I seed volume implants.nnnRESULTSnFor achievable activity densities and total activities, classical low dose rate (LDR) treatments of residual disease at distances of up to 1 cm from the resection cavity wall are possible with balloon applicators having radii between 0.5 cm and 2.5 cm. The dose penetration of these applicators increases approximately linearly with balloon radius. The FDD profile can be made significantly more or less penetrating by combining selection of radionuclide with source-geometry manipulation. Comparisons with 125I seed-implant DVHs show that the applicator can provide a more conformal therapy with no target tissue underdosing, less target tissue overdosing, and no healthy tissue hot spots; however, more healthy tissue volume receives a dose of the prescribed dosage or less.nnnCONCLUSIONSnThis device, when filled with 125I solution, is suitable for classical LDR treatments and may be preferable to 125I interstitial-seed implants in several respects. Manipulation of the dosimetric properties of the device can improve its characteristics for brain tumor treatment and may make it suitable for boosting the lumpectomy margins in conservative breast cancer treatment.

Fractionated stereotactic radiotherapy for acoustic neuromas: preservation of function versus size

For larger acoustic neuromas the preservation of cranial nerve function following radiosurgery remains a challenge. Fractionated stereotactic radiotherapy (FSR) for acoustic neuromas offers both higher total tumour dose (Gy) and potential sparing of the facial motor, sensory and auditory cranial nerves. Eighty consecutive patients (45 M, 35 F) (age 56.8+/-1.7 years) received FSR for AN and have a median follow up of 1.1 years. A prospective schedule permitted increased fractionation vs. size. For FSR 70 patients having AN < 3.0 cm in diameter had 5 daily fractions of 5 Gy (25 Gy total) and 10 patients having AN > or = 3 cm had 10 daily fractions of 3 Gy (30 Gy total). All treatments were prescribed to the 80% isodose and given via the dedicated 10 MeV accelerator. For both the larger and smaller AN, the percentage decrease in volume was similar. No tumour increased in size, no patient developed facial weakness and hearing was preserved. Using size-dependent fractionation, FSR may result in both tumour control and preservation of normal cranial nerve functions for both large and small AN.

Adenovirus-mediated wild-type p53 expression induces apoptosis and suppresses tumorigenesis of experimental intracranial human malignant glioma.

Adenoviral-mediated gene transfer for the treatment of experimental intrinsic malignant brain neoplasms holds promise. The role, however, of intracellular, adenoviral-mediated p53 expression to inhibit growth of experimental human intracranial malignant gliomas remains largely unexplored. Using the AdCMV.p53 vector we measured the in vitro expression of p53 and the resultant effect upon U251 human malignant glioma cellular proliferation. We further measured the survival of nude mice after intracranial injection of the infected vs. control U251 cells. The growth of the infected U251 cells was inhibited when compared to both the uninfected cells and cells infected with the control vector (AdCMV.Null). Agarose gel electrophoresis confirmed the AdCMV.p53-dependent cellular apoptosis. Nude mice having intracranial injections of the U251 cells infected with the control (AdCMV.Null) vector showed diminished survival. In contrast, mice having intracranial injections of the cells infected with the AdCMV.p53 vector showed 100% survivorship measured 100 days after treatment. Gene therapy via the AdCMV.p53 viral vector holds promise for the clinical treatment of human malignant gliomas.

Stereotactic radiosurgery for brain metastases: Comparison of lung carcinoma vs. non-lung tumors

In the medical literature, stereotactic radiosurgery (SRS) for brain metastases results in rates of local control of 65 to 85%. To define patient selection criteria, we measured the survival in a population with a high proportion of non-small cell lung carcinoma (NCS lung) metastases that occurred soon after primary diagnosis. Between 9/89 and 10/93 30 adults (21 M, 9 F) had SRS for metastatic NSC lung carcinoma (14 patients) vs. non-lung carcinomas (16 patients having breast (3), renal (3), melanoma (3), GI (2, thyroid (1) or carcinoma of unknown origin (4)). The metastases were solitary for 22 patients and multiple for 8 patients. Average ages (y) (± SD) were 58.6 ± 10.4 for NSC lung patients and 53.4 ± 12.5 (p=0.32) for non-lung patients. The average interval (months) from diagnosis of the primary to metastasis was 23.8 ± 41.4 for all patients. This interval was shorter for NSC lung patients: 3.1 ± 6.0 vs. 48.0 ± 51.7 (p < 0.001) for non-lung patients. Twenty seven patients had conventional radiotherapy (XRT) before (24 patients) or after (3 patients) SRS. Doses (cGy) were 3303 ± 841 for 13 NSC lung patients and 4256 ± 992 for 14 non-lung patients (p = 0.034). The median time from primary diagnosis to SRS was shorter for the NSC lung patients (11 mo) compared to the non-lung patients (35 mo). SRS was given for recurrence of metastases after XRT for 11/14 NSC lung patients and 13/16 non-lung patients. The doses (cGy) of SRS were 1579 ± 484 vs. 1682 ± 476 (p=0.45) for the NSC lung and non-lung groups, respectively. After SRS a decrease in metastasis diameter was observed in 10 of 14 NSC lung patients vs. 12 of 16 non-lung patients (p=0.85 Chi-square). Twenty-seven of the 30 patients have died. For all patients, the median survival after diagnosis of the primary and after radiosurgery was 31.3 and 8.4 months, respectively. The median survival (95% CI) from primary diagnosis was 24.3 months (13.2–27.3) for NSC lung patients and 46.5 months (39.2–65.5) for non-lung patients (p=0.005 logrank test). The median survival (95% CI) after SRS was 7.9 months (3.0–14.3) for the NSC lung patients and 8.4 (2.9–11.9) months for the non-lung patients (p=0.98 logrank test). Within the two groups, no difference in survival was observed for patients who had SRS sooner (< 1 yr for NSC lung; < 3 yr for non-lung) after primary diagnosis: 9.3 vs. 6.5 mo for NSC lung (p = 0.21) and 10.5 vs. 7.2 mo for non-lung (p=0.87). In this series, the shortened intervals from primary diagnosis to SRS for NSC lung metastases was associated with post-SRS survivorship that was equivalent to the more favorable non-lung group.

Synthetic, implantable polymers for local delivery of IUDR to experimental human malignant glioma.

PURPOSEnRecently, polymeric controlled delivery of chemotherapy has been shown to improve survival of patients with malignant glioma. We evaluated whether we could similarly deliver halogenated pyrimidines to experimental intracranial human malignant glioma. To address this issue we studied the in vitro release from polymers and the in vivo drug delivery of IUdR to experimental human U251 glioblastoma xenografts.nnnMETHODS AND MATERIALSnIn vitro: To measure release, increasing (10%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) polymer discs were serially incubated in buffered saline and the supernatant fractions were assayed. In vivo: To compare local versus systemic delivery, mice bearing flank xenografts had intratumoral or contralateral flank IUdR polymer (50% loading) treatments. Mice bearing intracranial (i.c.) xenografts had i.c. versus flank IUdR polymer treatments. Four or 8 days after implantation of polymers, mice were sacrificed and the percentage tumor cells that were labeled with IUdR was measured using quantitative microscopic immunohistochemistry.nnnRESULTSnIn vitro: Increasing percentage loadings of IUdR resulted in higher percentages of release: 43.7 + 0.1, 70.0 + 0.2, and 90.2 + 0.2 (p < 0.001 ANOVA) for the 10%, 30%, and 50% loadings, respectively. In vivo: For the flank tumors, both the ipsilateral and contralateral IUdR polymers resulted in similarly high percentages labeling of the tumors versus time. For the ipsilateral IUdR polymers, the percentage of tumor cellular labeling after 4 days versus 8 days was 45.8 +/- 7.0 versus 40.6 +/- 3.9 (p = NS). For the contralateral polymer implants, the percentage of tumor cellular labeling were 43.9 +/- 10.1 versus 35.9 +/- 5.2 (p = NS) measured 4 days versus 8 days after implantation. For the i.c. tumors treated with extracranial IUdR polymers, the percentage of tumor cellular labeling was low: 13.9 +/- 8.8 and 11.2 +/- 5.7 measured 4 and 8 days after implantation. For the i.c. tumors having the i.c. IUdR polymers, however, the percentage labeling was comparatively much higher: 34.3 +/- 4.9 and 35.3 +/- 4.0 on days 4 and 8, respectively. For the i.c. tumors, examination of the percentage cellular labeling versus distance from the implanted IUdR polymer showed that labeling was highest closest to the polymer disc.nnnCONCLUSIONnSynthetic, implantable biodegradable polymers provide the local, controlled release of IUdR and result in the high, local delivery of IUdR to experimental intracranial human malignant glioma. This technique holds promise for the local delivery of IUdR for radiosensitization of human brain tumors.

Fractionated Stereotactic Radiotherapy for Acoustic Neuromas

Fractionated stereotactic radiotherapy (FSR) for acoustic neuromas offers both higher tumor dose and potential sparing of the facial and auditory cranial nerve functions. Eighty consecutive patients (45 males and 35 females; age 56.8 ± 1.7 years) received FSR for acoustic neuromas and had a median follow-up of 2.9 years (range 2.3–6.5 years). For FSR, 70 patients had 5 daily fractions of 5 Gy (25 Gy total) and 10 patients had 10 daily fractions of 3 Gy (30 Gy total). Volume decreased by an average of 18%. No tumor increased in size, no patient developed facial weakness, and hearing was preserved.

Stereotactic Radiosurgery for Human Glioma: Treatment Parameters and Outcome for Low vs. High Grade

Stereotactic radiosurgery (SRS) offers the precise, local delivery of radiation for the treatment of recurrent gliomas. We examined the comparative characteristics, treatments, and outcome in a population having with low– and high–grade gliomas. Between September 1991 and December 1995, 20 patients (13 males, 7 females) had SRS for low-grade [9 patients: World Health Organization (WHO) grade II] vs. high-grade (11 patients: 9 WHO grade IV and 2 WHO grade III) gliomas. The patients with low-grade gliomas were younger (mean age ± SE, 39.6 ± 5.4 years; range, 11.4–61.0 years) than those with high-grade gliomas (51.3 ± 13.9 years; range, 32.9–78.5 years) (P = 0.09). Tumor locations were similar in the two groups: lobar for 7 of 9 low-grade vs. 9 of 11 high-grade gliomas (P = NS) and diencephalic or cerebellar for the remainder. The initial surgical treatments were biopsy, subtotal resection, and total resection for three, three, and three patients with low-grade gliomas, vs. three, seven, and one patients with high-grade gliomas, respectively (P = NS). Except for three patients with low-grade gliomas, all patients had conventional postoperative fractionated external-beam radiotherapy. The doses were 5583 ± 342 vs. 5345 ± 261 cGy (P = NS) for low- vs. high-grade gliomas, respectively. Intervals from surgery and conventional radiation (if given) to progression and SRS tended to be longer for low-grade gliomas: 37.5 ± 9.5 vs. 30.6 ± 11.1 months (P = NS) for low- vs. high-grade gliomas, respectively. High-grade gliomas were larger. The diameters of the collimators that allowed enclosure of the enhancing tumor volume within the specified treatment isodoses were 22.4 ± 2.0 mm for low-grade vs. 29.8 ± 2.8 mm for high-grade gliomas (P = 0.02, ANOVA). SRS doses and isodose percentiles were similar, however, for the two groups: 1650 ± 191 cGy and 79 ± 4.0% vs. 1932 ± 182 cGy and75 ± 3.5% for low- vs. high-grade gliomas, respectively (P = NS, dose and isodose). All patients with high-grade gliomas were followed until death. The mean survival after SRS was 11.6 ± 1.5 months (42 ± 12 months after surgery). Five of nine patients with low-grade gliomas expired 31.6 ± 6.0 months after SRS (P < 0.001, Kaplan–Meier log rank) (74.0 ± 16.0 months after surgery). The four survivors have been followed for 8, 13, 35, and 38 months after SRS, respectively. Multivariate analysis shows that the category of histologic grade correlates significantly with survival after radiosurgery (P = 0.01). SRS may be an important therapeutic option for patients with recurrent gliomas, regardless of their grade.