Stereotactic radiosurgery for recurrent malignant gliomas

PURPOSE: To evaluate the role of stereotactic radiosurgery in the management of recurrent malignant gliomas. PATIENTS AND METHODS: We treated 35 patients with large (median treatment volume, 28 cm3) recurrent tumors that had failed to respond to conventional treatment. Twenty-six patients (74%) had glioblastomas multiforme (GBM) and nine (26%) had anaplastic astrocytomas (AA). RESULTS: The mean time from diagnosis to radiosurgery was 10 months (range, 1 to 36), from radiosurgery to death, 8.0 months (range, 1 to 23). Twenty-one GBM (81%) and six AA (67%) patients have died. The actuarial survival time for all patients was 21 months from diagnosis and 8 months from radiosurgery. Twenty-two of 26 patients (85%) died of local or marginal failure, three (12%) of noncontiguous failure, and one (4%) of CSF dissemination. Age (P = .0405) was associated with improved survival on multivariate analysis, and age (P = .0110) and Karnofsky performance status (KPS) (P = .0285) on univariate analysis. Histology, treatment volume, and treatment dose were not significant variables by univariate analysis. Seven patients required surgical resection for increasing mass effect a mean of 4.0 months after radiosurgery, for an actuarial reoperation rate of 31%. Surgery did not significantly influence survival. At surgery, four patients had recurrent tumor, two had radiation necrosis, and one had both tumor and necrosis. The actuarial necrosis rate was 14% and the pathologic findings could have been predicted by the integrated logistic formula for developing symptomatic brain injury. CONCLUSION: Stereotactic radiosurgery appears to prolong survival for recurrent malignant gliomas and has a lower reoperative rate for symptomatic necrosis than does brachytherapy. Patterns of failure are similar for both of these techniques.     

Arnold-Chiari malformation in a captive African lion cub

PURPOSE: Surgery and systemic chemotherapy offer modest benefit to patients with recurrent glioblastoma multiforme. These tumors are associated with rapid growth and progressive neurological deterioration. Radiosurgery offers a rational alternative treatment, delivering intensive local therapy. A pilot protocol to treat recurrent glioblastoma was developed using fractionated stereotactic radiosurgery with concurrent intravenous (i.v.) Taxol as a radiation sensitizer. METHODS AND MATERIALS: The treatment outcome was analyzed in 14 patients with recurrent glioblastoma treated with fractionated stereotactic radiosurgery and concurrent Taxol. Median tumor volume was 15.7 cc and patients received a mean radiation dose of 6.2 Gy at 90% isodose line, 4 times weekly. The median dose of Taxol was 120 mg/m2. RESULTS: The median survival was 14.2 months, 1-year survival was 50%. CONCLUSIONS: Survival for this small group of patients was similar to or better than historical controls or patients treated with single-fraction radiosurgery alone. This data should stimulate the investigation of both fractionated radiosurgery and the development of radiation sensitizers to further enhance treatment.     

Comparison of parental and health care professional preferences for the acellular or whole cell pertussis vaccine

PURPOSE: To evaluate the efficacy and toxicity of gamma knife radiosurgery in the treatment of melanoma metastases to the brain. PATIENTS AND METHODS: We retrospectively reviewed 55 patients with single or multiple intracranial melanoma metastases treated at the University of California, San Francisco, with gamma knife radiosurgery from 1991 through 1995. Sixteen patients were treated with gamma knife radiosurgery for recurrence following previous radiation therapy, 11 received radiosurgery as a boost to whole-brain radiation therapy, and 28 had radiosurgery alone for initial management of brain metastases. The median minimum radiosurgery tumor dose for 140 treated lesions was 19 Gy (range, 10-22 Gy) prescribed at the 35% to 90% isodose contour (median, 50%). The median total target volume per patient was 6.1 cc (range, 0.25-28.3 cc). RESULTS: With a median follow-up of 75 weeks in living patients, the median survival times were 35 weeks overall: 35 weeks for patients with solitary metastases versus 33 weeks for those with multiple metastases. A factor that was significant in univariate analysis of survival was total target volume treated. This parameter remained significant on multivariate analysis. The actuarial median freedom from progression analyzed by lesion for 113 lesions in 46 patients with imaging follow-up was 89 weeks with 6-month and 1-year actuarial freedom from progression rates of 89% (95% confidence interval, 80%-95%) and 77% (95% confidence interval, 62%-87%). In univariate analysis, improved freedom from progression was associated with smaller target volume treated, smaller maximum diameter, or higher prescribed dose. Four patients (7%) developed acute Radiation Therapy Oncology Group grade > or = 2 morbidity, and five patients (9%) developed late grade > or = 2 morbidity. DISCUSSION: Median survival and freedom from progression in patients treated with radiosurgery for melanoma metastatic to the brain are comparable to results in published radiosurgery series of grouped histologies. For melanoma patients, total intracranial tumor volume appears to be of greater prognostic significance than the absolute number of metastases treated. We conclude that gamma knife radiosurgery is effective and should be considered among various management strategies.     

Risk analysis of linear accelerator radiosurgery

PURPOSE: To evaluate the toxicity of stereotactic single-dose irradiation and to compare the own results with already existing risk prediction models. METHODS AND MATERIALS: Computed tomography (CT) or magnetic-resonance (MR) images, and clinical data of 133 consecutive patients treated with linear accelerator radiosurgery were analyzed retrospectively. Using the Cox proportional hazards model the relevance of treatment parameters and dose-volume relationships on the occurrence of radiation-induced tissue changes (edema, localized blood-brain barrier breakdown) were assessed. RESULTS: Sixty-two intraparenchymal lesions (arteriovenous malformation (AVM): 56 patients, meningioma: 6 patients) and 73 skull base tumors were selected for analysis. The median follow-up was 28.1 months (range: 9.0-58.9 months). Radiation-induced tissue changes (32 out of 135, 23.7%) were documented on CT or MR images 3.6-58.7 months after radiosurgery (median time: 17.8 months). The actuarial risk at 2 years for the development of neuroradiological changes was 25.8% for all evaluated patients, 38.4% for intraparenchymal lesions, and 14.6% for skull base tumors. The coefficient: total volume recieving a minimum dose of 10 Gy (VTREAT10) reached statistical significance in a Cox proportional hazards model calculated for all patients, intraparenchymal lesions, and AVMs. In skull base tumors, the volume of normal brain tissue covered by the 10 Gy isodose line (VBRAIN10) was the only significant variable. CONCLUSIONS: These results demonstrate the particular vulnerability of normal brain tissue to single dose irradiation. Optimal conformation of the therapeutic isodose line to the 3D configuration of the target volume may help to reduce side effects.     

Trends in surgical management of astrocytomas and other brain gliomas

PURPOSE: Retrospective analysis of the influence of clinical and technical factors on local control and survival after radiosurgery for brain metastasis. PATIENTS AND METHODS: From January 1994 to December 1996, 42 patients presenting with 71 metastases underwent radiosurgery for brain metastasis. The median age was 56 years and the median Karnofsky index 80. Primary sites included: lung (20 patients), kidney (seven), breast (five), colon (two), melanoma (three), osteosarcoma (one) and it was unknown for three patients. Seventeen patients had extracranial metastasis. Twenty-four patients were treated at recurrence which occurred after whole brain irradiation (12 patients), surgical excision (four) or after both treatments (eight). Thirty-six sessions of radiosurgery have been realized for one metastasis and 13 for two, three or four lesions. The median metastasis diameter was 21 mm and the median volume 1.7 cm3. The median peripheral dose to the lesion was 14 Gy, and the median dose at the isocenter 20 Gy. RESULTS: Sixty-five metastases were evaluable for response analysis. The overall local control rate was 82% and the 1-year actuarial rate was 72%. In univariate analysis, theoretical radioresistance (P = 0.001), diameter less than 3 cm (P = 0.039) and initial treatment with radiosurgery (P = 0.041) were significantly associated with increased local control. Only the first two factors remained significant in multivariate analysis. No prognostic factor of overall survival was identified. The median survival was 12 months. Six patients had a symptomatic oedema (RTOG grade 2), only one of which requiring a surgical excision. CONCLUSION: In conclusion, 14 Gy delivered at the periphery of metastasis seems to be a sufficient dose to control most brain metastases, with a minimal toxicity. Better results were obtained for lesions initially treated with radiosurgery, theoretically radioresistant and with a diameter less than 3 cm.     

Permanent I-125 brain stem implants in children

Between 1988 and 1997, 28 children have had iodine-125 implants for CNS tumors performed in our institution. Ten had stereotactic implantation in the brain stem region, and nine had the diagnosis of brain stem glioma (8 diffuse pontine, 1 midbrain tumor). Their ages ranged from 1.8 to 12 years. All patients had histological confirmation of malignancy (7 high-grade glioma, 2 low-grade glioma, 1 PNET). Diffuse pontine glioma patients received external beam radiation (50 Gy) followed by a fractionated stereotactic boost of 3 Gyx4 fractions. After 4-6 weeks, patients were reevaluated for stereotactic interstitial I-125 therapy. The planned implant dose was 82.9 Gy to the enhancing tumor (4 cGy per h). Preliminary results indicated that no surgical complications were associated with the catheter placement. Four patients have died (7-9 months from diagnosis) and four patients remain alive (5-38 months from diagnosis, median 10 months). Two autopsies confirmed the presence of progressive glioblastoma multiforme and intralesional necrosis. In one patient who received an implant alone for midbrain LGA, necrosis without tumor was found on biopsy after 36 months. He was successfully treated with hyperbaric oxygen therapy. The implementation of permanent I-125 implants appears to have a role in the management of pediatric CNS malignancy. This study confirms the results of previous reports regarding the safety of stereotactic interstitial brachytherapy in the brain stem. Tumor control for patients with high-grade brain stem glioma remains poor even with high focal radiation doses.     

Analyses of neuro-otological complications after radiosurgery for acoustic neurinomas

PURPOSE: To find out the optimum treatment parameters and the proper indications for treatment of acoustic neurinomas, univariate and multivariate actuarial analyses of neuro-otological complications after stereotactic radiosurgery for acoustic neurinomas were performed. METHODS AND MATERIALS: The subjects were 46 patients with acoustic neurinomas who underwent unilateral radiosurgery between June 1990 and June 1994 and were followed up at the University of Tokyo. Age ranged from 13 to 77 years (median, 54 years). Tumor diameter ranged from 0 to 25 mm (mean, 12 mm) at the cerebellopontine angle and from 2 to 15 mm (mean, 8.3 mm) in the internal auditory meatus. Maximum tumor doses ranged from 20 to 40 Gy (mean, 31.4 Gy), and peripheral doses from 12 to 25 Gy (mean, 16.8 Gy). One to eight isocenters were used (mean, 3.2). Median follow-up was 39 months. Eight events concerning neuro-otological complications were chosen, and the potential risk factors for them were analyzed by the actuarial analyses (univariate and multivariate). The events examined include hearing loss, vestibular function loss, facial palsy, and trigeminal nerve dysfunction. In order to point out potential risk factors for neuro-otological complications, univariate analyses were performed using both the Wilcoxon test and the log rank test, and multivariate analyses were performed with the Cox proportional hazards model. Variables nominated as potential risk factors were 1) demographic variables such as patient age and sex, 2) tumor dimensions, 3) treatment variables such as tumor doses and number of isocenters, and 4) pretreatment hearing levels. A variable with significant p-values (p < 0.05) in two or more of the three actuarial analyses (two univariate and one multivariate) was considered a possible risk factor. RESULTS: The possible variables that increase the risk for each event analyzed were: neurofibromatosis type II (NF2) and the number of isocenters for total hearing loss; experience of prior operation, the tumor diameter in the internal auditory meatus, and NF2 for hearing threshold elevation; peripheral tumor dose for vestibular function loss; patient age or midporus transverse tumor diameter (the two variables were correlated), and the number of isocenters for facial palsy; and the number of isocenters for trigeminal neuropathy. CONCLUSION: NF2 and the tumor diameter were the common risk factors for hearing loss in previous studies and ours. For the 5th/7th nerve dysfunction, the tumor diameter was the common risk factor. The risk of using more isocenters remains controversial. The difference in risk factors for hearing impairment and vestibular function loss suggests different mechanisms for the two. Further studies with larger populations and longer follow-up periods are required in order to draw conclusions on the risk factors in radiosurgery.     

Chronic lymphocytic leukemia presenting as pyogenic arthritis of the proximal interphalangeal joint

PURPOSE: To evaluate the results of 125I brachytherapy in colorectal cancers recurrent in the pelvis and paraortics. METHODS AND MATERIALS: From September 1989 to January 1997, 29 patients with colorectal adenocarcinoma recurrent in the pelvis or the paraortic nodes were treated intraoperatively with permanent 125iodine seed implantation at the James Cancer Center of The Ohio State University (OSU). All patients had undergone prior surgery; 72% had prior EBRT. The implanted residual tumor volume was microscopic in 38% and gross in 62%. The implanted area (median 25 cc) received a median minimal peripheral dose of 140 Gy to total decay. An omental pedicle was used to minimize irradiation of the bowel. Five patients received additional postimplant EBRT (20-50 Gy; median 30 Gy). RESULTS: The 1-, 2-, and 4-year actuarial local-regional control rates were 38%, 17%, and 17%, respectively, with a median time to local failure of 11 months (95% CI 10-12 months). The first manifestation of disease progression in 52 % of the patients was local-regional. In addition, 22 patients (75%) developed distant metastases. The 1-, 2-, and 4-year actuarial overall survival rates were 70%, 35%, and 21%, (median = 18 months; 95% CI: 14-22 months). Overall survival was better for patients smaller volume implants (p = 0.007), with a lower total activity implanted (p = 0.0003), with a smaller number of implanted sites (p = 0.004), and with microscopic residual disease (p = 0.01). Patients receiving additional EBRT also had a better prognosis (p = 0.005). Local tumor progression was the cause of death in 34% of the patients who have died at the time of this report and 56% died of distant metastases. Of the patients, 13 (45%) experienced 15 toxic events, including 3 patients (10%) with enteric fistula. Neuropathy was not observed. CONCLUSIONS: 125I brachytherapy can be successfully used for salvage in patients with recurrent colorectal cancer. Patients with isolated, microscopic, or minimal gross residual disease requiring small-volume implants and those receiving additional EBRT have a better prognosis. Postimplant EBRT is now routinely added, even for previously irradiated patients, in an attempt to improve local control. Compared to IOERT and IOHDR, 125I brachytherapy is not associated with clinical neuropathy, probably due to the continuous low dose rate irradiation delivered by the 125I seeds.     

Genetics of male infertility

This study was undertaken to analyze the influence of total skin dose and dose-fractionation schedules on the response rate, survival and skin toxicity of patients with mycosis fungoides [MF] treated with total skin electron irradiation [TSEI]. From 1979 to 1992, 40 patients with MF were treated with TSEI using a modified Christie Hospital technique. Mean follow-up time was 48 months [median 20 months]. 37/40 patients completed TSEI; three died due to non-treatment-related conditions during therapy. 34/37 [92%] treated patients achieved complete remission [CR] and 16/40 [40%] are alive with no evidence of disease. Over the years, changes in dose-fractionation schedules were made and correlated with the pattern of CR and skin toxicity. The 5-year actuarial survival [Stanford staging] was 84% in Stages IA-IB [all Stage IA patients are alive] and 59% in Stage II. The probability of survival of Stage III-IV patients was 30% at 30 months. Late skin toxicity was mild to moderate in 60% and severe in 25% of patients. A reduction of the total dose and dose-per-fraction resulted in an acceptable CR rate and a significantly lower toxicity. TSEI is effective in early stage MF. Skin control and late skin toxicity seem to be dose-fractionation-schedule related. For the early stages, the optimal treatment schedule seems to be 24-30 Gy to the whole skin surface in 2.4-3.0 Gy fractions, given twice weekly over a period of four to six weeks. Total doses of 24-30 Gy at 2.4-3.0 Gy per fraction yielded comparable skin control rates with lower skin toxicity.     

Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas

PURPOSE: To retrospectively evaluate the initial clinical results of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) for pituitary adenomas with regard to tumor and hormonal control and adverse effects of the treatment. SUBJECTS AND METHODS: Forty-eight patients with pituitary adenoma who underwent SRS or SRT between September 1989 and September 1995 were analyzed. Of these, 18 received SRS and 30 received SRT. The median tumor volumes were 1.9 cm3 for SRS and 5.7 cm3 for SRT. Eleven of the SRS and 18 of the SRT patients were hormonally active at the time of the initial diagnosis. Four of the SRS and none of the SRT patients had a history of prior radiation therapy. Both SRS and SRT were performed using a dedicated stereotactic 6-MV linear accelerator (LINAC). The dose and normalization used for the SRS varied from 1000 cGy at 85% of the isodose line to 1500 cGy at 65% of the isodose line. For SRT patients, a total dose of 4500 cGy at 90% or 95% of the isodose line was delivered in 25 fractions of 180 cGy daily doses. RESULTS: Disease control-The three year tumor control rate was 91.1% (100% for SRS and 85.3% for SRT). Normalization of the hormonal abnormality was achieved in 47% of the 48 patients (33% for SRS and 54% for SRT). The average time required for normalization was 8.5 months for SRS and 18 months for SRT. Adverse effects-The 3-year rate of freedom from central nervous system adverse effects was 89.7% (72.2% for SRS and 100% for SRT). Three patients who received SRS for a tumor in the cavernous sinus developed a ring enhancement in the temporal lobe as shown by follow-up magnetic resonance imaging. Two of these cases were irreversible and were considered to be radiation necrosis. None of the 48 patients developed new neurocognitive or visual disorders attributable to the irradiation. The incidence of endocrinological adverse effects were similar in the two groups, resulting in 3-year rates of freedom from newly initiated hormonal replacement of 78.4% (77.1% for SRS and 79.9% for SRT). CONCLUSION: Considering the relatively high incidence of morbidity observed in the SRS group, we recommend SRT as the primary method of radiation therapy for pituitary tumors. When treating a lesion in the cavernous sinus with SRS, special attention should be paid to dose distribution in the adjacent brain parenchyma. Longer follow-up is necessary before drawing any conclusions about the advantages of these techniques over conventional external beam radiation therapy.     

Treatment of hemangioblastomas in von Hippel-Lindau disease with linear accelerator-based radiosurgery

OBJECTIVE: Stereotactic radiosurgery is increasingly being used to treat hemangioblastomas, particularly those that are in surgically inaccessible locations or that are multiple, as is common in von Hippel-Lindau disease. The purpose of this study was to retrospectively evaluate the effectiveness of radiosurgery in the treatment of hemangioblastomas. METHODS: From 1989 to 1996, 29 hemangioblastomas in 13 patients with von Hippel-Lindau disease were treated with linear accelerator-based radiosurgery. The mean patient age was 40 years (range, 31-57 yr). The radiation dose to the tumor periphery averaged 23.2 Gy (range, 18-40 Gy). The mean tumor volume was 1.6 cm3 (range, 0.07-65.4 cm3). Tumor response was evaluated in serial, contrast-enhanced, computed tomographic and magnetic resonance imaging scans. The mean follow-up period was 43 months (range, 11-84 mo). RESULTS: Only one (3%) of the treated hemangioblastomas progressed. Five tumors (17%) disappeared, 16 (55%) regressed, and 7 (24%) remained unchanged in size. Five of nine patients with symptoms referable to treated hemangioblastomas experienced symptomatic improvement. During the follow-up period, one patient died as a result of progression of untreated hemangioblastomas in the cervical spine. Three patients developed radiation necrosis, two of whom were symptomatic. CONCLUSION: Although follow-up monitoring is limited, stereotactic radiosurgery provides a high likelihood of local control of hemangioblastomas and is an attractive alternative to multiple surgical procedures for patients with von Hippel-Lindau disease.     

Dose-volume histogram analysis of high dose rate intracavitary brachytherapy for uterine cervix cancer

PURPOSE: We retrospectively analyzed the relationship between dose distribution and local control using a dose-volume histogram (DVH) in patients with cancer of the uterine cervix treated by definitive radiotherapy including intracavitary brachytherapy. METHODS AND MATERIALS: Twenty-five patients with squamous cell carcinoma of the uterine cervix who underwent definitive radiotherapy between August 1987 and April 1994 were selected for the present study. They included 15 patients with local control and 10 patients with local recurrence. In principle, these patients were treated with 50 Gy of external beam pelvic radiotherapy and a point A dose of 24 Gy, in four fractions, of intracavitary brachytherapy. The DVHs of tumor volumes were calculated by superimposing three-dimensional (3D) dose distributions on computed tomography (CT) images taken before brachytherapy. RESULTS: Differential DVHs revealed a tendency for the portion of the total tumor volume to which the delivered dose was low to be larger in patients with local recurrence. The tumor volumes and the absolute dose volumes of which the absorbed dose was less than 24 Gy [DV (< 24 Gy)] were significantly larger in patients with local recurrence than those in local control patients (p = 0.02 and 0.03, respectively). The percent DV (<24 Gy) was not significantly different in the two groups. In patients with larger tumor volume, the absolute DV (<24 Gy) was also larger and a strong linear correlation was noted between them. CONCLUSIONS: The analysis of dose distribution of brachytherapy using DVH was useful to evaluate the quality of dose distribution quantitatively. The absolute dose volume was considered more important than the percent dose volume for evaluation of the clinical outcome. Our study suggested that unfavorable dose distribution for the tumor volume in brachytherapy was one of the reasons of poor local control in patients with large tumor volume.     

United States Thrombotic Thrombocytopenic Purpura Apheresis Study Group (US TTP ASG): multicenter survey and retrospective analysis of current efficacy of therapeutic plasma exchange

PURPOSE: Clinical experiences in interstitial 192-iridium HDR brachytherapy for the treatment of unresectable pancreatic carcinoma are presented. Brachytherapy has been used as boost irradiation in a multimodality treatment concept together with external radiotherapy and simultaneous chemotherapy. Practicability during clinical routine, tolerability and toxicity of treatment are investigated. PATIENTS AND METHODS: Nineteen patients (9 female, 10 male, median age 67 years) with unresectable carcinoma of the pancreas have been treated with interstitial brachytherapy. Distribution according to UICC stages showed 4, 10 and 5 patients in stage II to IV respectively. In all cases afterloading technique with 192-iridium in HDR-modus was used. A total dose of 10 to 34 Gy to the reference isodose was delivered (single dose 1.88 to 5 Gy, median 2.5 Gy). Brachytherapy was followed by external radiotherapy, delivering an additional dose of 40 to 58 Gy. Nine patients received simultaneous chemotherapy (5-fluorouracil, leucovorin). Treatment planning was performed based on CT scans, allowing spatial correlation of isodose curves to the patient's anatomy. RESULTS: Median survival time was 6 months. A trend of lower survival rates with advanced stage of disease (median survival stage IV 4 months, stage II and III 6.5 months) was seen. Local control rate was 70%. Brachytherapy treatment was well tolerated, severe acute side effects were not observed. One patient developed pancreatic fistulae 4 months and 1 patient a gastric ulcer 7 months after treatment. Pain release was achieved in all patients. CONCLUSIONS: 192-iridium HDR-brachytherapy is an effective tool in the treatment of unresectable pancreatic carcinoma with a high rate of local control and a low rate of side effects and is comparable IORT or seed implantation.     

Results of high-dose thoracic irradiation incorporating beam's eye view display in non-small cell lung cancer: a retrospective multivariate analysis

PURPOSE: To review the University of Michigan clinical experience in nonsmall cell lung cancer using high-dose thoracic irradiation (> or = 60 Gy) so that a starting dose for our prospective dose-escalation study could be determined. METHODS AND MATERIALS: Eighty-eight consecutive patients diagnosed with medically inoperable or locally advanced, unresectable nonsmall cell lung cancer were identified who were treated with thoracic irradiation alone to a minimum total dose of 60 Gy (uncorrected for lung density). All patients except four (95%) underwent computed tomography scanning for treatment planning that included beam's eye view display for tumor and critical structure localization. All patients were treated with standard fractionation in a continuous course to uncorrected total doses ranging from 60 to 74 Gy (median, 67.6 Gy). RESULTS: The median follow-up exceeds 24 months for all surviving patients (range, 12 to 78 months). The median survival time was 15 months, and the 2- and 3-year overall actuarial survival rates were 37% and 15%, respectively. Survival was significantly different between stage of disease (p = .004) and N-stage (p = .002) by univariate analysis. In a multivariate analysis, stage becomes the only characteristic significantly associated with outcome. The median time to local progression for 86 evaluable patients was 29 months. Stage (p = .0003), T-stage (p = .0095) and N-stage (p = .027) were significantly different with respect to local progression-free survival by univariate analysis. However, only stage was prognostic for local progression-free survival by multivariate analysis. There was no difference between large volume treatment (inclusion of the contralateral hilar and supraclavicular lymph nodes) and small volume treatment (exclusion of these elective nodal sites) with respect to local progression-free survival (p = .507) or survival (p = .520). With regard to dose, there was no significant difference between patients who received > 67.6 Gy and patients who received < or = 67.6 Gy with respect to local progression-free survival (p = .094) or survival (p = .142). Within the Stage III subgroup, local progression-free survival (p = .018) and survival (p = .061) were longer favoring the high-dose group of patients. Despite these doses, disease progression within the irradiated field was the predominant first site of treatment failure. CONCLUSION: This retrospective study has shown that it is feasible to deliver uncorrected tumor doses as high as 70 Gy using standard fractionation in NSCLC with acceptable morbidity. Local control remains a significant problem. These data indicate justification for a starting dose in a prospective radiation dose-escalation study.     

Effects of gamma knife radiosurgery for brain tumors: clinical evaluation

BACKGROUND: Gamma knife radiosurgery is a safe and effective alternative to microsurgery in the management of selected intracranial lesions. In our initial three-year experience with gamma knife radiosurgery, 431 patients were treated using this method. This report presents the treatment results for three different types of brain tumors: benign meningiomas, malignant metastases and gliomas. METHODS: A retrospective study was performed to analyze a consecutive series of 71 meningiomas, 31 metastatic tumors and 21 gliomas treated by gamma knife radiosurgery between March 1993 and May 1996. The treatment results were investigated using regular magnetic resonance examinations and tumor volume measurement at six-month intervals to observe sequential changes of the tumors. Patients with meningiomas were further divided into three groups according to the peripheral radiation doses: high-dose (20-17 Gy, n = 18), medium-dose (16-15 Gy, n = 33) and low-dose (14-12 Gy, n = 20). The Generalized Estimation Equation was applied to compare treatment results in these three groups with different doses and tumor volumes. RESULTS: Volume measurements of the 71 meningiomas showed that 76% decreased in size, 16% stabilized and 8% increased in size. The volumes increased most frequently in the early stage (6-12 months) after treatment and subsequently regressed after the twelfth month. The tumor control rate for meningiomas in our three-year follow-up was over 90%. For meningiomas, the statistical analysis showed that both the radiation dose and tumor volume were significantly related to the development of adverse radiation effects (p < 0.05). In metastatic tumors, rapid tumor regression after radiosurgery was found in 87% of the patients. In gliomas, radiosurgery effectively inhibited tumor growth in selected patients with small, circumscribed, less infiltrative tumors. Ependymomas and low-grade astrocytomas had more favorable outcomes than other gliomas. CONCLUSIONS: Gamma knife radiosurgery is effective for controlling tumor growth in benign meningiomas for up to three years after surgery. In selected cases of malignant metastasis and gliomas, most patients appeared to benefit from the treatment with symptomatic improvement and prolonged survival. Treatment strategy and dose selection in radiosurgery should be adjusted to optimize tumor control and avoid adverse radiation effects.     

Changes with age in the modulation of natural killer activity of murine leukocytes by gastrin-releasing peptide, neuropeptide Y and sulfated cholecystokinin octapeptide

From Jan. 1993 to Sept. 1995 23 patients suffering from brain metastases from renal cell carcinoma were treated with the Leksell Gamma Knife at the University of Vienna. At the time of diagnosis 13 patients had single and 10 patients presented with multiple metastatic lesions with a total of 44 metastases in MRI scans. Median tumour volume was 5500 cmm (range 100-24000 cmm). Predominant neurological symptoms and signs were different forms of hemiparesis, focal and generalized seizures, cognitive deficit, headache, dizziness, ataxia and CN XII paresis. Fourteen patients received Gamma Knife Radiosurgery (GKRS) with a median dose of 22 Gy (range 8-30 Gy) at the tumour margin. Nine patients underwent a combined treatment of a radiosurgical boost with a median dose of 18 Gy (range 10-22 Gy) at the tumour margin followed by Whole Brain Radiotherapy (total dose 30 Gy/2 weeks). In 20 patients tumour volume reduction up to 30% of the primary tumour volume was found after 4 weeks, evaluated on CT or MRI. A total remission was seen in 4 cases 3 months after GKRS. We achieved a local tumour control of 96%. Rapid neurological improvement after GKRS was seen in 17 patients. The median survival time was 11 months; the one-year actual survival in this unselected group was 48%. Five long term survivors were still alive, 18 patients had subsequently died, 15 of them of general tumour progression. GKRS induces a significant tumour remission accompanied by rapid neurological improvement and therefore provides the opportunity for extended high quality survival. Neither local tumour control was improved nor CNS relapse free survival was prolonged significantly by additional WBRT.     

Stereotactic radiosurgery for tentorial meningiomas

Radical microsurgical resection is the procedure of choice for tentorial meningiomas. Despite advances in microsurgery, tentorial meningiomas continue to challenge surgeons and patients. To evaluate the response of tentorial meningiomas, we evaluated 41 patients who had Gamma knife stereotactic radiosurgery during a 9 year period. Patient age varied from 32 to 79 years. Headache, trigeminal neuralgia, or facial paraesthesia were the most common presenting symptoms. Sensory deficits in the distribution of the trigeminal nerve were the most common finding. Eighteen patients (44%) had undergone between 1 and 5 (mean, 1.9) resections prior to radiosurgery; 23 had tumors diagnosed by neuroimaging. The average tumor diameter in this series was 20 mm. The maximum tumor dose varied from 24 to 40 Gy (mean, 30.5 Gy), and the tumor margin dose varied from 12 to 20 Gy (mean, 15.3 Gy). During the average follow-up interval of 3 years (range, 1-8 years), 19 patients had clinical improvement, 20 remained stable, and 2 patients deteriorated. Follow-up imaging showed a reduction in tumor size in 18 patients, no further tumor growth in 22, and an increase in tumor size in one (overall tumor control rate of 98%). Stereotactic radiosurgery using the Gamma Knife was a safe and effective primary or adjuvant treatment for patients with tentorial meningiomas.     

Combined treatment of inoperable carcinomas of the uterine cervix with radiotherapy and regional hyperthermia. Results of a phase II trial

AIM: The disappointing results for inoperable, advanced tumors of the uterine cervix after conventional radiotherapy alone necessitates improving of radiation therapy. Simultaneous chemotherapy or altered radiation fractionation, such as accelerated regimen, increase acute toxicity and treatment is often difficult to deliver in the planned manner. The purpose of this phase II study was to investigate the toxicity and effectiveness of a combined approach with radiotherapy and regional hyperthermia. PATIENTS AND METHODS: From January 1994 to October 1995 18 patients with advanced carcinomas of the uterine cervix were treated in combination with radiotherapy and hyperthermia. The patients were treated with 6 to 20 MV photons delivered by a linear accelerator in a 4-field-box technique to a total dose of 50.4 Gy in 28 fractions. In the first and fourth week 2 regional hyperthermia treatments were each applied with the Sigma-60 applicator from a BSD-2000 unit. After this a boost to the primary tumor was given with high-dose-rate iridium-192 brachytherapy by an afterloading technique with 4 x 5 Gy at point A to a total of 20 Gy and for the involved parametrium anterioposterior-posterioanterior to 9 Gy in 5 fractions. RESULTS: The acute toxicity was low and similar to an external radiotherapy alone treatment. No Grade III/IV acute toxicity was found. The median age was 47 years (range 34 to 67 years). In 16 of 18 patients a rapid tumor regression was observed during combined thermo-radiotherapy, which allowed the use of intracavitary high-dose-rate brachytherapy in these cases. Complete and partial remission were observed in 13 and 4 cases, respectively. One patient did not respond to the treatment. The median follow-up was 24 months (range 17 to 36 months). The local tumor control rate was 48% at 2 years. Median T20, T50 and T90 values were 41.7 degrees C (range 40.3 to 43.2 degrees C), 41.1 degrees C (range 39.2 to 42.5 degrees C) and 39.9 degrees C (range 37.7 to 41.9 degrees C), respectively. Cumulative minutes of T90 > 40 degrees C (Cum40T90) and cumulative minutes, which were isoeffective to 43 degrees C, were calculated (CEM43T90, CEM43T50, CEM43T20). CEM43T90 was found to be a significant parameter in terms of local tumor control for the 4 hyperthermia treatments (p = 0.019). CONCLUSIONS: This treatment modality has proved to be feasible and well tolerable. The rapid tumor shrinkage in the combined approach of radiotherapy with hyperthermia before beginning brachytherapy seems to be a good prerequisite for improving of the disappointing results in cure of advanced cancer of the uterine cervix.     

Interim report on the radiosurgical treatment of cerebral arteriovenous malformations. The influence of size, dose, time, and technical factors on obliteration rate

During the authors' initial 4-year experience with radiosurgery using the Leksell cobalt-60 gamma unit, they treated 121 patients with cerebral arteriovenous malformations (AVMs). The radiosurgical dose to the margin of the nidus was 20 Gy for lesions less than 2.0 cm in diameter (volume < or = 4.2 cm3); 18 Gy for malformations 2.1 to 3.0 cm in diameter (volume 4.2-14.1 cm3); and 16 Gy for malformations greater than 3.0 cm (volume > 14.1 cm3). Fifty-one patients underwent follow-up angiography between 1 and 3 years after treatment, and complete obliteration of the nidus was confirmed in 38 (74.5%) of these patients. Thirty-two (74.4%) of 43 AVMs with volumes of 10 cm3 or less and six (75%) of eight larger AVMs (volume 11-30 cm3) showed complete obliteration. Analysis of the time course of AVM nidus shrinkage and obliteration showed that most of the radiosurgically induced effect had occurred by 36 months after treatment. Retrospective analysis of the dose plans for 10 AVMs that were not obliterated by 36 months after gamma knife radiosurgery at the authors' institution (eight cases) or elsewhere (two cases) revealed that six AVMs had not been covered completely by the prescribed isodose. Six (5%) of the 121 patients developed neurological deficits as a direct result of radiosurgical treatment. The authors infer from these data that malformations up to 30 cm3 in volume (approximately 4.0 cm in average diameter) can be treated effectively with an acceptably low complication rate using a radiosurgical dose of 16 Gy to the margin of the nidus. The obliteration rate for the larger malformations that were treated with a dose of 16 to 18 Gy appears to be similar to that for smaller ones treated with 18 to 20 Gy. As more experience accrues using radiosurgery to treat AVMs, patient selection criteria and the variables associated with successful obliteration of the nidus should become more clearly defined.     

Stereotactic radiosurgery for patients with nonsmall cell lung carcinoma metastatic to the brain

BACKGROUND: A retrospective study of patients undergoing stereotactic radiosurgery for one to four brain metastases from nonsmall lung cell carcinoma (NSCLC) was performed to document outcomes and risks. METHODS: Seventy-seven patients underwent radiosurgery during a 7-year interval; 71 also underwent whole brain radiation therapy. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. RESULTS: The overall median survival was 10 months after radiosurgery, and 15 months from the diagnosis of brain metastases. Five factors significantly affected survival: extent of systemic disease, presence of a neurologic deficit, size of the intracranial tumor, initial imaging appearance of intratumoral necrosis, and initial resection of the primary tumor of the chest. Median survival time was 26 months in a subgroup of patients with no extracranial metastases, no neurologic deficits, and a small tumor without necrosis. The authors evaluated 91 tumors with imaging. Local tumor control was achieved in 77 lesions (85%) and tumoral radiation necrosis developed in 4 lesions (4.4%). Nineteen new metastatic tumors developed during the observation interval. CONCLUSIONS: Stereotactic radiosurgery for NSCLC brain metastases is effective and is associated with few complications. The early detection of brain metastases and treatment with radiosurgery combined with radiation therapy provide the opportunity for extended high quality survival.