Stereotactic radiosurgery for brain metastasis from renal cell carcinoma.
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Brain Neoplasms↗
Biomedical subjects
C Nieder
Publications and source records attributed to C Nieder.
Hyperfractionated and accelerated-hyperfractionated radiotherapy for glioblastoma multiforme.
Because of promising radiobiological advantages allowing dose escalation and/or reduction of treatment time, hyperfractionated and accelerated-hyperfractionated radiotherapy (hf-rt, ahf-rt) were introduced as part of treatment of glioblastoma multiforme (gbm). In December 1988 we started a prospective study of hf-rt (total dose 78 Gy, two daily fractions of 1.3 Gy, interval between daily fractions 6 hr, treatment time 6 weeks, n = 34 patients). The results were compared with our previous regimen of conventionally fractionated radiotherapy (cf-rt: total dose 60 Gy, single dose 2 Gy, treatment time 6 weeks, n = 32 patients). In June 1990, the protocol was modified in order to reduce treatment time (ahf-rt: total dose 60 Gy, two daily fractions of 1.5 Gy, interval 6 hr, treatment time 4 weeks, n = 92 patients until December 1996). No chemotherapy was given. Entry criteria were: age > or = 17 years, pathological diagnosis of supratentorial gbm, and no previous treatment other than surgery. The ahf-rt group included significantly more patients with previous surgical resection instead of biopsy only. Compared with the cf-rt group, both the hf-rt and the ahf-rt group included significantly more patients with frontal tumor location. We found no significant survival difference between the groups (median survival 7-10 months, 1-year survival rate 19%-29%). Progression-free survival, clinical course, and toxicity were also not significantly different. Karnofsky performance status, age, and corticosteroid dose during radiotherapy were the most important prognostic factors. The results of this trial are in large agreement with most previous publications. It demonstrated no improved survival. However, it showed that treatment time can be reduced by ahf-rt without loss of survival benefit or intolerable toxicity. A short radiotherapy course might be appropriate for many patients with gbm who are not suitable for rather aggressive investigational therapies.
Adolescent↗
Radiation myelopathy: new perspective on an old problem.
This article discusses recent advances in basic research that alter the view of the pathogenesis of radiation myelopathy and summarizes the available data from developmental neurobiology and preclinical studies on demyelinating diseases. These studies have produced interesting insights into oligodendrocyte development, intercellular signaling pathways, and myelination processes. Current findings suggest that administration of cytokines as platelet-derived growth factor and basic fibroblast growth factor could increase proliferation of oligodendrocyte progenitors, enhance their differentiation, up-regulate synthesis of myelin constituents, and promote myelin regeneration in the adult central nervous system (CNS). Other compounds might also be able to modulate the progression of pathogenic processes that lead to myelopathy. In addition, several possible biological prevention or treatment strategies, for example stimulation of endogenous cellular regeneration and glial cell transplantation, are discussed. Rationally designed animal experiments pursuing such strategies could further elucidate the pathogenesis of radiation-induced CNS damage.
Animals↗
[Biological prevention and/or therapy possibility of radiation myelopathy. A discussion of recent perspectives].
BACKGROUND: Radiosensitivity of the spinal cord makes both curative first-line treatment of numerous malignancies and re-irradiation of recurrent or second tumors more difficult. This review discusses recent advances in basic research that alter the view on the pathogenesis of radiation myelopathy, possibly offering strategies for prevention and/or therapy. RESULTS: Available data of developmental neurobiology and preclinical studies of demyelinating diseases revealed interesting insights into oligodendrocyte development, intercellular signaling pathways, and myelination processes. Current findings suggest that administration of cytokines could increase proliferation of oligodendrocyte progenitor cells, enhance their differentiation, upregulate synthesis of myelin constituents, and promote myelin regeneration in the adult central nervous system (Table 1). Other compounds might also be able to modulate progression of pathogenic processes that eventually lead to radiation myelopathy. This offers several possible biological prevention and/or treatment strategies, which currently are being investigated in animal studies (Table 2). CONCLUSION: Technical options as well as optimization of fractionation parameters should be given priority in the attempt to reduce iatrogenic neurotoxicity. However, rational biological strategies could offer a new perspective for many patients.
Adult↗
Late radiation toxicity after whole brain radiotherapy: the influence of antiepileptic drugs.
This retrospective study had the following aims: (a) calculation of actuarial rate of late radiation toxicity after whole-brain radiotherapy (WBRT), (b) correlation of clinical symptoms with changes of computed tomography (CT) scans, and (c) analysis of potentially predictive factors with special regard to concomitant treatment with antiepileptic drugs. We analyzed 49 adult patients, selected from a preexisting data base. Inclusion criteria were as follows: no previous brain irradiation; WBRT without boost; CT, clinical, and neurologic examination before and more than 3 months after completion of WBRT. Uni- and multivariate tests of various patient- and treatment-related parameters as possible predictive factors for clinical symptoms of late radiation toxicity (scored according to the RTOG/EORTC system) as well as cerebral atrophy and white matter abnormalities were performed. Median age was 54 years. Patients were treated for brain metastases (n = 37), primary cerebral lymphoma (n = 2), primary brain tumors (n = 7), or with prophylactic intention (n = 3). Carbamazepine was given to 15 patients, phenytoin to 12, and barbiturate to 7, respectively; 42 patients also received corticosteroids. The median dose of WBRT was 30 Gy (range 27-66 Gy). Median fraction size was 3 Gy (1-3 Gy). Nine patients received two fractions per day. The biologically effective dose (BED) according to the linear-quadratic model ranged between 90 and 141 Gy (median, 120 Gy; alpha/beta value, 1 Gy). Median follow-up was 10 months (range, 4-130 months). In 16 cases, symptoms of late radiation toxicity grade I-III appeared. Actuarial rates were 32% after 1 year, 49% after 2 years, and 83% after 5 years. Actuarial rates of cerebral atrophy were 50% after 1 year and 84% after 2 years (white matter abnormalities: 25% and 85%, respectively). There was a significant correlation between atrophy and white matter abnormalities, but not between CT changes and clinical symptoms. CT changes were dependent on BED, absence of barbiturate use, and preexisting cerebral atrophy. Clinical symptoms usually were dependent on BED too, but treatment with carbamazepine was more important in the multivariate model. Neither other drugs nor other factors influenced late radiation toxicity. A detailed analysis showed that most carbamazepine-treated symptomatic patients took the drug during WBRT as well as during follow-up. Actuarial rates of grade I-III symptoms were 18% versus 50% after 1 year with or without carbamazepine. Even after exclusion of carbamazepine-treated patients, CT changes and clinical symptoms did not correlate. In conclusion, a BED <120 Gy was associated with a lower rate of late radiation toxicity after WBRT. The anticonvulsant drug carbamazepine showed a surprisingly clear influence on clinical symptoms of late radiation toxicity; that might be explained by the fact that the side effects of long-term drug treatment are indistinguishable from mild or moderate true radiation sequelae, rather than that it has a role in the pathogenesis of radiation-induced changes.
Actuarial Analysis↗
Radiomyelopathy after conventionally fractionated and hyperfractionated radiotherapy--experimental data and clinical consequences.
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Animals↗
[Palliative accelerated irradiation for advanced non-small-cell lung bronchial carcinoma: results of a pilot study].
In order to reduce the aggressivity of radiotherapy of very advanced non-small-cell lung cancer (NSCLC), and to shorten treatment time, a palliative accelerated irradiation regimen (PAIR) was developed. Before the onset of a randomised study, we performed a one-year pilot study, of which the paper presented here gives the results after complete follow-up. 34 patients (S) with locally inoperable advanced NSCLC stage III (74%) and IV (26%) were irradiated with accelerated fractionation schedule, focussing on tumour and mediastinum, with a total dose of 32 Gy (PAIR, 2 x 2 Gy/d). Treatment results were compared to those of a group of 178 controls (K) treated conventionally, who were selected from a preexisting database according to study inclusion criteria (tab. 2-5 stage III 65%, IV 35%). 105 of them had been treated with a total dose of 60 Gy (K60). After complete follow-up a final evaluation was made. Local control did not differ significantly between both groups, and not between groups S and K60 (tab. 6, fig. 2). Median survival for all patients (S + K) was 6 months. With 8.7 months, that of the study patients (S) was significantly longer than that of the controls (K, fig. 1). This was also true of stage III. Comparison with the 60-Gy-controls (K60) did not reveal significant survival differences. In Cox regression analysis independent prognostic factors were: Karnofsky index, UICC stage, and N stage. Concerning the palliation of tumour-related symptoms, both therapies were comparable (tab. 7). The side-effects were moderate and also comparable. These results induced us start a randomized study comparing both regimens in respect of prognosis and palliation.
Carcinoma, Non-Small-Cell Lung↗
Multivariate logistic analysis of dose-effect relationship and latency of radiomyelopathy after hyperfractionated and conventionally fractionated radiotherapy in animal experiments.
PURPOSE: We examined in rats whether the radiation tolerance of spinal cord is enhanced by using hyperfractionated radiotherapy compared to a conventional schedule. Higher tolerable doses to the spinal cord would allow dose escalation to the tumor and thus possibly lead to higher cure rates, especially in tumors with high cell proliferation. METHODS AND MATERIALS: Cervical spinal cord of 276 healthy rats was irradiated over 6 weeks hyperfractionally with single doses ranging from 0.75-2.5 Gy up to total doses ranging from 45-150 Gy (60 fractions) and conventionally with single doses of 1.5-4.0 Gy up to total doses of 45-120 Gy (30 fractions). The rats were examined neurologically and sacrificed when paralysis of the hind legs occurred. After fixation, spinal cord was removed and examined histologically. Dose-effect relationship and latency from the beginning of radiotherapy to the onset of paralysis were computed and analyzed using a multivariate logistic regression model. RESULTS: The model fitted the observed data excellently. There were highly significant effects both for the dose level and for the treatment regimen. Latency analysis showed earlier and more intense acute side effects after hyperfractionation but radiomyelopathy occurred markedly later. CONCLUSIONS: The sparing effect of hyperfractionation on spinal cord as predicted by radiobiologists could be confirmed in our experiments. Thus, it seems possible to escalate tumor doses using hyperfractionation without enhanced risk to spinal cord but with higher probability of tumor cure.
Animals↗
Patterns of relapse and late toxicity after resection and whole-brain radiotherapy for solitary brain metastases.
BACKGROUND: This retrospective analysis was performed in order to evaluate the pattern of relapse and the risk of late toxicity for solitary brain metastases treated with surgery and whole-brain radiotherapy and to correlate the results with those from radiosurgical trials. PATIENTS AND METHODS: From a total of 66 patients, 52 received 10 x 3 Gy and 10 were treated with 20 x 2 Gy whole-brain radiotherapy after resection of their brain metastases. RESULTS: The actuarial probability of relapse was 27% and 55% after 1 and 2 year(s), respectively. The local relapse rate (at the original site of resected brain metastases) was rather high for melanoma, non-breast adenocarcinoma, and squamous-cell carcinoma. No local relapse occurred in breast cancer and small-cell carcinoma. Failure elsewhere in the brain seemed to be influenced by extracranial disease activity. Size of brain metastases and total dose showed no correlation with relapse rate. Occurrence of brain relapse was not associated with a reduced survival time, because 10/15 patients who developed a relapse received salvage therapy. Of the patients, 11 had symptoms of late radiation toxicity (the actuarial probability was 42% after 2 years). CONCLUSIONS: Most results of surgical and radiosurgical studies are comparable to ours. Several randomized trials investigate surgical resection versus radiosurgery, as well as the effects of additional whole-brain radiotherapy in order to define the treatment of choice. Some data support the adjuvant application of 10 x 3 Gy over 2 weeks as a reasonable compromise when local control, toxicity, and treatment time have to be considered.
Actuarial Analysis↗
Dose/effect relationships for brain metastases.
PURPOSE: Only in selected patients with brain metastases, e.g. those with controlled or absent extracranial tumour, may application of higher total doses of radiotherapy improve survival. However, local control is the prerequisite for long-term survival. This study aimed to answer the question whether or not local control can be improved by dose escalation. METHODS: Computed tomography scans of 322 patients were analysed in order to evaluate the best local result after radiotherapy and the time to local progression. Total doses of 25-60 Gy were administered (single doses 1.8-5 Gy). The biologically effective dose (BED10) was calculated for statistical evaluation according to the linear-quadratic model assuming an alpha/beta-value of Gy. It ranged between 37.5 Gy and 72 Gy. RESULTS: The best local result was dependent on the number of brain metastases, BED and the histology of the primary tumour (small-cell and breast carcinoma had higher remission rates than squamous-cell carcinoma, non-breast adenocarcinoma and others). Partial remission rates significantly increased with BED, whereas complete remission rates did not improve. Histology was the only significant factor in multivariate tests. The 1-year-failure rate improved with increased BED from 44% to 31% (P > 0.05). Overall survival (median 3 months) was not dependent on total dose. CONCLUSIONS: Previous studies suggested that a prolongation of survival can be achieved through better local management (e.g. surgery plus radiotherapy, radiosurgery). However, it is still uncertain whether conventional external-beam radiotherapy with higher total doses leads to comparable results. The optimum dose level still has to be established. For squamous-cell carcinoma and adenocarcinoma a BED of at least 72 Gy seems to be necessary, for small-cell and breast carcinoma, doses between 48 Gy and 60 Gy might be sufficient. The important influence of tumour histology on local remission and progression-free survival should be considered when planning future clinical trials.
Adult↗
Radiotherapy of brain metastases from lung cancer.
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Brain Neoplasms↗
Comment on: Tumor volume as a response predictor in radiotherapy.
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Humans↗
Tumor-related prognostic factors for remission of brain metastases after radiotherapy.
PURPOSE: To study CT determined response to external beam radiotherapy as well as influence of tumor-related factors, especially of tumor volume, on remission and to evaluate whether particular subgroups of metastases are controlled by low-dose radiotherapy. METHODS AND MATERIALS: Contrast-enhanced CT scans before and after radiotherapy were analyzed. INCLUSION CRITERIA: brain metastases treated with whole-brain radiotherapy (10 fractions of 3 Gy over 2 weeks) since 1983; no additional treatment, for example, surgery or chemotherapy; at least one follow-up CT. Three hundred thirty-six metastases from 108 patients were evaluated with regard to their volume, extent of necrosis, histology of primary tumor, and interval between radiotherapy and follow-up CT. All parameters were correlated with best local result and progression-free survival by uni- and multivariate tests. Volume-response curves were calculated. RESULTS: In univariate analysis local result was significantly influenced by each of the four parameters mentioned above. Complete remission was observed in 37% of metastases from small-cell carcinoma, 35% of those from breast cancer, 25% of those from squamous-cell carcinoma, and 14% of those from nonbreast adenocarcinoma. The rate was 52% for metastases <0.5 cm3 and 0% for those >10 cm3. In multivariate analysis, small volume and no necrosis were the most important prognostic factors for complete remission. Progression-free survival was influenced by best local result. CONCLUSION: With radiotherapy to a total dose of 30 Gy even small metastases had a complete remission rate of 52% only. Therefore, patients should be treated with locally more effective dose and fractionation schedules when local control is the aim. However, partial remission rate was remarkable even for large and necrotic metastases. This should be considered when palliation is the aim of treatment.
Adenocarcinoma↗
[Brain metastases of colon and rectum carcinomas].
We analyzed 20 cases with brain metastases from colon or rectum carcinoma. Fourteen were treated with radiotherapy alone (total dose 30-60 Gy), six with neurosurgery plus radiotherapy (total dose 30-40 Gy). All patients had advanced primary tumours (T3 and T4), most of which were poorly differentiated; lymph node metastases were common. In 5 patients (25%) the brain was the first site of distant metastases. Ten patients (50%) had a solitary brain metastasis. As a tendency, the results of surgery plus radiotherapy were superior to those of radiotherapy alone, with respect to palliation of symptoms as well as to local tumour remission and survival. Overall median survival was only 51 days. The 1-year survival rate was 6%. In 5 of 14 cases (36%) symptomatic improvement was observed after radiotherapy alone. Partial remission of the brain metastases occurred in 3 of 14 cases (21%). The presence of extracerebral metastases was the most important prognostic factor. Selected patients considered to have a favourable prognosis may profit from combined treatment, i.e. neurosurgery plus radiotherapy. Despite the short survival time, stereotactic irradiation should be evaluated as an alternative to conventional radiotherapy in the remaining patients because the palliative effect of fractionated external irradiation is relatively disappointing.
Adult↗
Accelerated radiotherapy for brain metastases.
BACKGROUND AND PURPOSE: Two novel fractionation schedules for whole-brain irradiation were applied to patients with brain metastases. Both schedules were aimed at reduction of treatment time, whereby tumour control should be increasing with the application of a higher total dose (schedule 2). MATERIALS AND METHODS: We applied 2 x 2.5 Gy/day to a total dose of 30 Gy (schedule 1) or 2 x 1.8 Gy/day to a total dose of 50.4 Gy (schedule 2). The interval between daily fractions was 6 h. Treatment was interrupted on weekends. The 30 Gy schedule was also used in adjuvant treatment for resected brain metastases. We compared the results of 15 patients who underwent the 50.4 Gy schedule and 47 patients who were treated up to 30 Gy with those of a historical patient group, treated with one daily fraction of 3 Gy up to 30 Gy (n = 283). RESULTS: Local result, clinical course and survival were similar for the 30 Gy groups, whereby prognostic factors were equally distributed. Despite a favourable patient selection no therapeutic gain was seen for the 50.4 Gy group. Patients treated with the accelerated 30 Gy schedule had a significantly worse progression-free survival and a higher rate of late radiation toxicity than the historical group. In contrast, no severe acute toxicity was observed. CONCLUSIONS: Considering progression-free survival and late toxicity, the accelerated 30 Gy schedule can not be recommended without hesitation. Radiotherapy with a higher total dose (50.4 Gy) showed no advantage.
Adult↗
Rapid course radiation therapy vs. more standard treatment: a randomized trial for bone metastases.
PURPOSE: In a prospective randomized trial we examined whether radiotherapy of painful bone metastases can be shortened using larger single doses without impairing effectivity. METHODS AND MATERIALS: One hundred patients with painful bone metastases having no prior surgical intervention or treatment with x-ray therapy and had a median follow-up of 12 months were analyzed. The primary tumor was located in the breast in 43%, in the lung in 24%, and in the prostate in 14%. The most frequent sites of metastases were the pelvis (31%), the vertebral column (30%), and the ribs (20%). Further percentages of sites were: lower extremity 11%, upper extremity 6%, and skull 2%. Fifty-one patients received a short course radiotherapy with a total dose of 20 Gy in 1 week (daily dose 4 Gy), and 49 patients received 30 Gy in 3 weeks (daily dose 2 Gy). RESULTS: There were no significant differences in frequency, duration of pain relief, improvement of mobility, recalcification, frequency of pathologic fractures nor survival. There was a light trend favoring 30 Gy in frequency of pain relief and recalcification. Survival was mostly influenced by primary tumor site, Karnofsky performance status, and possibly by the response to radiotherapy (pain relief). CONCLUSIONS: Because of the very short life expectancy of patients with metastatic bone disease, we now use 20 Gy in 1 week as our standard to reduce hospital stay.
Adult↗
Ten years disease-free survival after solitary brain metastasis from breast cancer.
The unique case of a 51-year-old woman who developed a solitary brain metastasis as the first site of systemic disease 11 months after a total mastectomy for an undifferentiated infiltrating ductal carcinoma of her right breast is described. After surgery for the pT2pN0 carcinoma, the patient received radiotherapy of the internal mammary and supraclavicular lymph nodes. The brain metastasis was treated with surgery and adjuvant whole-brain radiotherapy to a total dose of 30 Gy in December 1984 and January 1985. Afterwards a hormonal treatment with tamoxifen was initiated, which still continues. Since then no further distant or lymph node metastases have developed. The patient is under regular after-care and undergoes various apparative examinations every 6 months. She is generally well and suffers only from a postoperatively persistent hemianopsia. This is the first case in which a disease-free survival for more than 10 years after brain metastases from breast cancer has been reported. It illustrates the specific biological behaviour of this tumour type and the chance of achieving long-term survival in very selected cases.
Antineoplastic Agents, Hormonal↗
A palliative accelerated irradiation regimen (PAIR) for advanced non-small-cell lung cancer (NSCLC).
In order to avoid overtreatment in advanced NSCLC we developed a palliative accelerated irradiation regimen (PAIR) applying a total dose of 32 Gy in 10 days with two daily fractions of 2 Gy. This paper reports on a 1-year pilot study carried out in preparation of a randomised trial. Data for the 34 patients receiving PAIR were compared to 179 conventionally irradiated historical controls selected from a pre-existing database according to identical inclusion criteria. Statistical analysis showed that PAIR patients had a significantly longer survival than controls (P = 0.0029). Median survival was 11.8 and 5.8 months, respectively, while 1-year survival was 45.6% vs. 21.2%. Compared to the subgroup of controls who had received the full planned dose of 60 Gy (n = 104) PAIR patients showed no significant difference in survival. In order to adjust for possible imbalances we used a comprehensive blinded prognostic rating design creating one score value per patient out of several known prognostic factors. After adjustment for the resulting prognostic score by means of the Cox proportional hazards model PAIR patients still showed significantly longer survival. We conclude that in advanced NSCLC survival after a palliative short-term regimen appears to be at least equivalent to that following conventional high-dose irradiation.
Carcinoma, Non-Small-Cell Lung↗