Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases

PURPOSE: Evaluation of the treatment outcome after radiosurgery (RS) alone or in combination with whole-brain radiotherapy (WBRT) with special attention to prescribed dose and its influence on local control and survival. PATIENTS AND METHODS: Between September 1984 and January 1997, 236 patients with 311 brain metastases treated with radiosurgery met the following inclusion criteria: one to three brain metastases per patient; no previous WBRT; and Kamofsky performance status (KPS) > or = 50%. One hundred fifty-eight patients treated only with RS received a median dose of 20 Gy prescribed to the 80% isodose line; 78 patients received RS with a median dose of 15 Gy/80% and an additional course of WBRT. RESULTS: For the entire series, overall median survival was 5.5 months, with control of CNS disease achieved in 92% of the treated brain metastases; the results were not significantly different between patients treated by RS with or without WBRT. However, in patients without evidence of extracranial disease, median survival was increased for patients who received WBRT (15.4 vs 8.3 months; P=.08). Additionally, there was a suggestion that increased doses for patients treated with RS only resulted in improved outcome. Four lesions were suspicious for radiation necrosis by magnetic resonance imaging (MRI); in one of the four lesions, radiation necrosis was confirmed histologically. The incidence of transient low-grade toxicity was 18%; symptoms could be treated by the temporary administration of steroids. CONCLUSION: RS is an effective, noninvasive means of controlling brain metastases when used alone or in combination with WBRT. There is a trend for superior local control and especially in patients without extracranial disease for superior survival when RS is used in conjunction with WBRT. Randomized trials would seem to be warranted, comparing the benefit of RS with or without additional WBRT.     

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.     

Radiosurgery without whole brain radiotherapy in melanoma brain metastases. Club de Cancérologie Cutanée

To evaluate the effectiveness of radiosurgery without whole brain radiotherapy in the palliative treatment of melanoma brain metastases, we retrospectively assessed the results in 35 patients: 4 with a solitary brain metastasis, 13 with a single brain metastasis and metastases elsewhere and 18 with multiple brain metastases. The local control rate was 98.2% (55/56 metastases) at 3 months. Median survival was 22 months in patients with a solitary brain metastasis, 7.5 months in patients with a single brain metastasis and metastases elsewhere, and 4 months in patients with multiple brain metastases. Complications were unusual and surgery was required in 2 of 35 patients. These results show for the first time that melanoma patients with a unique brain metastasis with or without metastases elsewhere clearly benefit from tumour control easily obtained by radiosurgery. Although the comparison of radiosurgery with surgery and/or whole brain radiotherapy cannot be adequately addressed, radiosurgery alone seems to provide similar results with lower morbidity and impact on quality of life.     

Molecular and pharmacological characterization of recombinant rat/mice N-methyl-D-aspartate receptor subtypes in the yeast Saccharomyces cerevisiae

PURPOSE: To assess the local control and survival in patients who received pelvic irradiation for locally recurrent rectal carcinoma. METHODS AND MATERIALS: The records of 519 patients with locally recurrent rectal carcinoma treated principally with external-beam radiation therapy between 1975 to 1985 at a single institute were retrospectively reviewed. These included 326 patients who relapsed locally following previous abdominoperineal resection, 151 after previous low anterior resection, and 42 after previous local excision or electrocoagulation for the primary. No patients had received adjuvant radiation therapy or chemotherapy for the primary disease. Concurrent extrapelvic distant metastases were found in 164 (32%) patients at local recurrence and, in the remaining 355, the relapse was confined to the pelvis. There were 290 men and 229 women whose age ranged from 23 to 91 years (median = 65). Median time from initial surgery to radiation therapy for local recurrence was 18 months (3-138 months). Radiation therapy was given with varying dose-fractionation schedules, total doses ranging from 4.4 to 65.0 Gy (median = 30 Gy) over 1 to 92 days (median = 22 days). For 214 patients who received a total dose > or = 35 Gy, radiation therapy was given in 1.8 to 2.5 Gy daily fractions. RESULTS: The median survival was 14 months and the median time to local disease progression was 5 months from date of pelvic irradiation. The 5-year survival was 5%, and the pelvic disease progression-free rate was 7%. Twelve patients remained alive and free of disease at 5 years after pelvic irradiation. Upon multivariate analysis, overall survival was positively correlated with ECOG performance status (p = 0.0001), absence of extrapelvic metastases (p = 0.0001), long intervals from initial surgery to radiation therapy for local recurrence (p = 0.0001), total radiation dose (p = 0.0001), and absence of obstructive uropathy (p = 0.0013). Pelvic disease progression-free rates were positively correlated with ECOG performance status (p = 0.0001), total radiation dose (p = 0.0001), and previous conservative surgery for the primary (p = 0.02). CONCLUSIONS: Survival is poor for patients who develop local recurrence following previous surgery for rectal carcinoma. Pelvic radiation therapy provides only short-term palliation, and future efforts should be directed to the use of effective adjuvant therapy for patients with rectal carcinoma who are at high risk of local recurrence.     

Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer

PURPOSE: To identify predicting factors for local failure and increased risk of distant metastases by statistical analysis of the data after breast-conserving treatment for early breast cancer. METHODS AND MATERIALS: Between January 1976 and December 1993, 528 patients with nonmetastatic T1 (tumors < or = 1 cm [n = 197], >1 cm [n = 220]) or T2 (tumors < or = 3 cm [n = 111]) carcinoma of the breast underwent wide excision (n = 435) or quadrantectomy (n = 93) with axillary dissection (negative nodal status [n-]: 396; 1-3 involved nodes: 100; >3 involved nodes: 32). Radiotherapy consisted of 45 Gy to the entire breast via tangential fields. Patients with positive axillary lymph nodes received 45 Gy to the axillary and supraclavicular area. Patients with positive axillary nodes and/or inner or central tumor locations received 50 Gy to the internal mammary lymph node area. A boost dose was delivered to the primary site by iridium 192 Implant in 298 patients (mean total dose: 15.2+/-0.07 Gy, range: 15-25 Gy) or by electrons in 225 patients (mean total dose: 14.8+/-0.09 Gy, range: 5-20 Gy). The mean age was 52.5+/-0.5 years (range: 26-86 years) and 267 patient were postmenopausal. Histologic types were as follows: 463 infiltrating ductal carcinomas, 39 infiltrating lobular carcinomas, and 26 other histotypes. Grade distribution according to the Scarff, Bloom, and Richardson (SBR) classification was as follows: 149 grade 1, 271 grade 2, 73 grade 3, and 35 nonclassified. The mean tumor size was 1.6+/-0.3 cm (range: 0.3-3 cm). The intraductal component of the primary tumor was extensive (EIC = IC > or = 25%) in 39 patients. Tumors were microscopically bifocal in 33 cases. Margins were assessed in the majority of cases by inking of the resection margins and were classified as positive in 13 cases, close (< or = 2 mm) in 21, negative (>2 mm tumor-free margin) in 417, and indeterminate in 77. Peritumoral vascular invasion was observed in 40 patients. Tamoxifen was administered for at least 2 years in 176 patients. At least six cycles of adjuvant systemic chemotherapy were administered in 116 patients. The mean follow-up period from the beginning of the treatment was 84.5+/-1.7 months. RESULTS: First events included 44 isolated local recurrences, 8 isolated axillary node recurrences, 44 isolated distant metastases, 1 local recurrence with synchronous axillary node recurrence, 7 local recurrences with synchronous metastases, and 2 local recurrences with synchronous axillary node recurrences and distant metastases. Of 39 pathologically evaluable local recurrences, 33 were classified as true local recurrences and 6 as ipsilateral new primary carcinomas. Seventy patients died (47 of breast carcinoma, 4 of other neoplastic diseases, 10 of other diseases and 9 of unknown causes). The 5- and 10-year rates were, respectively: specific survival 93% and 86%, disease-free survival 85% and 75%, distant metastasis 8.5% and 14%, and local recurrence 7% and 14%. Mean intervals from the beginning of treatment for local recurrence or distant metastases were, respectively, 60+/-6 months (median: 47 months, range: 6-217 months) and 49.5+/-5.4 months (median: 33 months, range: 6-217 months). After local recurrence, salvage mastectomy was performed in 46 patients (85%) and systemic hormonal therapy and/or chemotherapy was administered to 43 patients. The 5-year specific survival rate after treatment for local recurrence was 78+/-8.2%. Multivariate analysis (multivariate generalization of the proportional hazards model) showed that the probability of local control was decreased by the following four independent factors: young age (< or = 40 yr vs. >40 yr; relative risk [RR]: 3.15, 95% confidence interval [CI]: 1.7-5.8, p = 0.0002), premenopausal status (pre vs. post; RR: 2.9, 95% CI: 1.4-6, p = 0.0048), bifocality (uni- vs. bifocal; RR: 2.7, 95% CI: 2.6-2.8,p = 0.018), and extensive intraductal component (IC <25% vs. IC > or = 25%; RR: 2.6, 95% CI: 13-5.2, p = 0     

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.     

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.     

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.     

Clerodane diterpenoids, long chain esters of coumaric acid and other compounds from Baccharis myrsinites

PURPOSE: To compare 1-year survival and acute toxicity rates between an accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions in patients with unresected brain metastasis. METHODS AND MATERIALS: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionation vs. standard fractionation from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastasis were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. For AH, 32 Gy in 20 fractions over 10 treatment days (1.6 Gy twice daily) was delivered to the whole brain. A boost of 22.4 Gy in 14 fractions was delivered to each lesion with a 2-cm margin. RESULTS: The average age in both groups was 60 years; nearly two-thirds of all patients had lung primaries. Of the 429 eligible and analyzable patients, the median survival time was 4.5 months in both arms. The 1-year survival rate was 19% in the AF arm vs. 16% in the AH arm. No difference in median or 1-year survival was observed among patients with solitary metastasis between treatment arms. Recursive partitioning analysis (RPA) classes have previously been identified and patients with a KPS of 70 or more, a controlled primary tumor, less than 65 years of age, and brain metastases only (RPA class I), had a 1-year survival of 35% in the AF arm vs. 25% in the AH arm (p = 0.95). In a multivariate model, only age, KPS, extent of metastatic disease (intracranial metastases only vs. intra- and extracranial metastases), and status of primary (controlled vs. uncontrolled) were statistically significant (at p < 0.05). Treatment assignment was not statistically significant. Overall Grade III or IV toxicity was equivalent in both arms, and one fatal toxicity at 44 days secondary to cerebral edema was seen in the AH arm. CONCLUSION: Although a previous RTOG Phase I/II report had suggested a potential benefit in patients with limited metastatic disease, a good Karnofsky performance status, or neurologic function when treated with an AH regimen, this randomized comparison could not demonstrate any improvement in survival when compared to a conventional regimen of 30 Gy in 10 fractions. Therefore, this accelerated hyperfractionated regimen to 54.4 Gy cannot be recommended for patients with intracranial metastatic disease.     

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.     

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.     

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.     

Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme

The purpose of this study was to compare the efficacy of stereotactic radiosurgery (SRS) and brachytherapy in the treatment of recurrent glioblastoma multiforme (GBM). The patients had either progressive GBM or pathologically proven GBM at recurrence after previous treatment for a lower grade astrocytoma. Thirty-two patients were treated with interstitial brachytherapy, and 86 received treatment with stereotactic radiosurgery (SRS). The patient characteristics were similar in the two groups. Those patients treated with SRS had a median tumor volume of 10.1 cm3 and received a median peripheral tumor dose of 13 Gy. Patients treated with brachytherapy had a median tumor volume of 29 cm3. Median dose to the periphery of the tumor volume was 50 Gy delivered at a median dose rate of 43 cGy/hour. Twenty-one patients (24%) treated with SRS were alive, with a median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with SRS was 10.2 months, with survivals of 12 and 24 months being 45 and 19%, respectively. A younger age and a smaller tumor volume were predictive of better outcome. The tumor dose, the interval from initial diagnosis, and the need for reoperation were not predictive of outcome after SRS. Five patients (16%) treated with brachytherapy were alive, with a median follow-up of 43.3 months. The median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals of 12 and 24 months were 44 and 17%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

p21 (WAF1/CIP1) expression is induced in newly nondividing cells in diverse epithelia and during differentiation of the Caco-2 intestinal cell line

The incidence of brain metastases secondary to small cell lung cancer (SCLC) is about 35% and the treatment strategy of brain irradiation with respect to dose and fractionation is controversial. In order to evaluate treatment outcome of brain irradiation in SCLC patients with brain relapse, we retrospectively evaluated all patients treated with brain irradiation in the eastern part of Denmark from 1988 to 1992 (PCI patients excluded). During this 5-year period, 101 evaluable patients were included (44 females, 57 males) (median age 61 years; range, 39-75 years). Forty-four patients, of whom 43 were in extracerebral complete remission (CR), received extended course (EC) brain irradiation (> 45 Gy, treatment schedule > 4 weeks). Fifty-seven patients received short course (SC) brain irradiation (< 30 Gy, treatment schedule < 1 week). Among the SC treated patients, 14 were in CR, 20 had partial remission or stable disease and 23 had progressive extracerebral disease. The median survival (from diagnosis of brain metastases) in the group receiving irradiation with EC (44 patients) was 160 days (range, 74-2021 days), while the 57 patients treated with SC had a median survival of 88 days (range, 20-948 days) (P = 0.00001, Log-Rank analysis). In a subgroup of 14 patients in extracerebral CR, receiving SC irradiation, the median survival was 83 days (range, 15-948 days). When the latter patients were compared to the 43 patients in CR in the group treated with EC, a statistically significant difference was shown (P = 0.034, Log-Rank analysis). Using Cox-hazard regression analysis with backward elimination, liver metastases and poor performance status were adverse prognostic signs, although the only significant parameters of survival were gender (female vs. male, relative risk of dying 1 and 1.52, P = 0.05) and schedule of brain irradiation (extended course vs. short course, relative risk of dying, 0.36 and 1, P < 0.001). Extended course irradiation of brain relapse secondary to SCLC seems in general to be of limited value, although a significant prolonged survival at approximately 7 weeks, was obtained. The prolongation of survival does not seem worthwhile considering the length of treatment time (5-6 weeks) compared to SC treatment (1 week). However, the data do not permit evaluation of the quality of life of the patients. This retrospective evaluation suggests the need for randomized trials with carefully planned quality-of-life assessments.     

Outcome of patients with brain metastases after combined modality therapy in small cell lung cancer (SCLC): a retrospective study

The authors evaluated the role of whole brain radiotherapy (WBRT) on the outcome of brain metastasis and survival in 41 patients with small cell lung cancer (SCLC) treated in their department. In addition to chemotherapy, radiotherapy was given to the primary site in all responder patients. Six patients presented brain metastasis initially and 10 patients after the fourth course of chemotherapy. Brain metastases were symptomatic in 12 of 16 patients with a median time of 5 months (1-14) until symptoms developed. All patients but 2 with brain metastasis received WBRT (30 Gy in 10 fractions) in addition to chemotherapy. The median survival time of patients with brain metastasis was 8.3 months (3.5 to 16) compared to 12 months (4 to 34+) for patients without brain metastasis. In addition, the median survival time for patients with brain metastasis who responded to systemic chemotherapy was better than that of nonresponders. The authors found no improvement in survival in patients who received concomitant WBRT after chemotherapy compared to patients who received WBRT after completion of chemotherapy. In conclusion, the role of consolidating cranial irradiation in addition to chemotherapy in SCLC patients is unclear and warrants prospective randomized studies.     

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.     

The correlation between microscopical examination and erythrocyte band 3 (AE1) gene deletion in South-east Asian ovalocytosis

Seventy-five patients with brain metastases from solid tumours were treated with whole-brain irradiation at our institution between 1990 and 1993. The primary cancers included 35 cases of lung cancer, 19 cases of breast cancer, nine cases of renal-cell cancer, six cases of melanoma and six cases of other primary sites. In each case the total dose to the whole brain was at least 25 gray (Gy). The primary site, age, performance status, number of brain metastases and the presence of extracranial disease were studied as prognostic factors for survival. The median survival for the whole population was 4 months (range 1-62 months). The patients with the brain as the only metastatic site had significantly better survival (P = 0.019) than those with both intracranial and extracranial metastatic sites. Poor performance status at the time of diagnosis of brain metastases was also related to short survival (P = 0.001). None of the other studied variables had prognostic significance. Four of the 75 patients with primary tumour sites in the breast (two patients) and the kidney (two patients) survived for more than 2 years. In general, patients with breast cancer had better survival than patients with other primary cancers. Our study confirms the generally poor prognosis of cancer with brain metastases, although individual patients may survive several years after whole-brain irradiation. Approximately two-thirds of the patients experienced a relief in symptoms allowing a reduction in the dose of corticosteroid medication, which clearly supports the use of whole-brain radiotherapy as a palliative treatment.     

Autologous hapten-modified melanoma vaccine as postsurgical adjuvant treatment after resection of nodal metastases

PURPOSE: To determine whether treatment with an autologous whole-cell vaccine modified with the hapten dinitrophenyl (DNP vaccine) is an effective postsurgical adjuvant treatment for melanoma patients with clinically evident nodal metastases. PATIENTS AND METHODS: Eligible patients had regional nodal metastases that were large enough (> or = 3 cm diameter) to prepare vaccine. Following standard lymphadenectomy, patients were treated with DNP vaccine on a monthly or weekly schedule. RESULTS: Of 62 patients with metastasis in a single lymph node bed (stage III), 36 are alive after a median follow-up time of 55 months (range, 29 to 76); the projected 5-year relapse-free and overall survival rates are 45% and 58%, respectively. Of 15 patients with metastases in two nodal sites, five are alive with a median follow-up time of 73 months. An unexpected finding was the significantly better survival of older patients; the projected 5-year survival of patients greater than 50 versus < or = 50 years was 71% and 47%, respectively (P = .011, log-rank test). The development of a positive delayed-type hypersensitivity (DTH) response to unmodified autologous melanoma cells was associated with significantly longer 5-year survival (71% v 49%; P = .031). Finally, the median survival time from date of first recurrence was significantly longer for patients whose subcutaneous recurrence exhibited an inflammatory response (> 19.4 v 5.9 months; P < .001). CONCLUSION: Postsurgical adjuvant therapy with autologous DNP-modified vaccine appears to produce survival rates that are markedly higher than have been reported with surgery alone. Moreover, this approach has some intriguing immunobiologic features that might provide insights into the human tumor-host relationship.     

Role of surgery in the treatment of brain metastases in patients with breast cancer

BACKGROUND: Patients whose brain metastases from breast cancer are treated nonsurgically have a median length of survival ranging from 2.5 to 7.5 months, and a median time to recurrence ranging from 2 to 5 months. Patients treated with radiotherapy have a median length of survival ranging from 3 to 4 months. Those treated with chemotherapy have a median length of survival ranging from 5.5 to 7.5 months. METHODS: We conducted a retrospective analysis on 63 patients treated over a 10-year period. Only patients who underwent surgery for nonrecurrent brain metastases were studied. Sixty-one patients (97%) underwent surgery within 2 weeks of diagnosis of the brain metastases. RESULTS: The median length of survival was 16 months (95% confidence interval [CI] 11 to 22 months), and the 5-year survival rate was 17% (CI 9% to 29%). Brain metastases recurred in 27 patients at a median interval of 15 months (CI 12 to 24 months). Eleven patients had local recurrence, 10 had distal recurrence, and seven developed leptomeningeal disease. Significant prognosticators of length of survival were age (p = 0.011), menopause status (p = 0.10), postoperative radiotherapy (p = 0.054), preoperative neurologic status (p = 0.011), and preoperative systemic disease status (p = 0.0003). Systemic disease status had a significant effect on the length of survival but not on the time to recurrence.     

Radiotherapy and local control in rectal cancer

Recurrence is a stage in the natural history of rectal cancer. Preoperative radiotherapy or postoperative radiochemotherapy lower the rate of recurrence, improving local control. From 1980 to 1997, at the "Divisione di Radioterapia" of the "Università Cattolica del S. Cuore" of Rome 380 patients with rectal cancer of early clinical stage T2-3, candidates for surgery for cure, underwent radiation therapy. 119 patients underwent postoperative radiotherapy (45-50 Gy); 45 patients underwent "sandwich" radiotherapy (45 Gy:27 Gy before and 28 Gy after surgery), of whom 7 were treated with preoperative radiotherapy alone; 145 patients underwent preoperative concomitant radiochemotherapy according to 3 different protocols, radiotherapy (38 Gy) combined with mitomycin C and 5-FU; radiotherapy (50.4 Gy) combined with cisplatin and 5-FU; radiotherapy (45 Gy) combined with 5-FU and folinic acid. 71 patients were treated with preoperative radiotherapy (38 Gy) combined with IORT (10 Gy). Median follow-up was 6 years. Overall local control was 85% at 3 years, 83% at 5 years, 81% at 10 years. The rate of local control at 5 years was: 76% for postoperative radiotherapy, 83% for "sandwich" radiotherapy, 84% for preoperative radiochemotherapy and 93% for preoperative radiotherapy combined with IORT. Local control was shown to be significantly better with preoperative treatment as compared to postoperative treatment (p = 0.02). The incidence of metastases was 35% in the patients with local recurrence and 16% in those with local control. The difference in survival was highly significant in patients with local control as compared to those with local recurrence: at 5 years 87% and 32% respectively. Patients with local control showed a lower incidence of metastasis and a better survival.