Extracranial Disease Status Research Articles

Triple-negative breast cancer with brain metastases: a comparison between basal-like and non-basal-like biological subtypes

The aim of this study was to divide the group of triple-negative breast cancer patients with brain metastases into basal-like and non-basal-like biological subtypes in order to compare clinical features and survival rates in those two groups. A comprehensive analysis of 111 consecutive triple-negative breast cancer patients with brain metastases treated in the years 2003–2009 was performed. In 75 patients, immunohistochemistry was used as a surrogate of microarray in order to evaluate the expression of three basal markers: cytokeratin 5/6 (CK 5/6), EGFR/HER1 and c-KIT. The basal-like (ER/PgR/HER2-negative, CK5/6positive and/or HER1-positive) and non-basal-like (ER/PgR/HER2-negative, CK5/6-negative, HER1-negative) subsets were selected. Clinical features and survivals were compared in both groups. In the group of 111 triple-negative breast cancer patients, median DFS, OS and survival from brain metastases were 20, 29 and 4 months, respectively. In 75 patients who were evaluable for basal markers, median DFS, OS and survival from brain metastases were 18, 26 and 3.2 months, respectively. In the basal-like subtype, the survival rates were 15, 26 and 3 months, respectively, and in the non-basal-like subtypes, they were 20, 30 and 2.8 months, respectively. No statistically significant differences in survivals were detected between the basal-like and non-basal-like biological subtypes. Factors influencing survival from brain metastases were: Karnofsky performance status (KPS), the status of extracranial disease and age. Biological markers differentiating triple-negative group into basal-like and non-basal-like subtype (CK 5/6, HER1, c-KIT) had no influence on survival. In patients with triple-negative breast cancer and brain metastases, well-known clinical, but not molecular, features correlated with survival.

Salvage stereotactic radiosurgery (SRS) after previous whole-brain radiation therapy (WBRT) for breast cancer brain metastases: Outcomes and prognostic factors including tumor phenotype.

581 Background: Salvage SRS is often considered in breast cancer patients (pts) previously treated with WBRT for brain metastases. The goal of this study was to analyze clinical outcomes and prognostic factors for survival in the salvage setting. Methods: We retrospectively examined all breast cancer pts who underwent SRS at DF/BWCC between 2000 and 2010. We identified 79 consecutive female pts who received salvage SRS (interval of > 3 months after initial therapy), 76 of whom (96%) received prior WBRT. Overall survival (OS) and CNS progression-free survival was calculated from the date of SRS using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results: Median age was 50.5 years. Subtype distribution was: ER+, 46; HER2+, 27; triple negative, 8). 97% had a KPS ≥70%. 95% had extracranial metastases at the time of SRS, 81% at other visceral sites (lung/pleura/liver). 48% had stable extracranial disease at the time of SRS. Median interval from WBRT to SRS was 8.4 months. Median follow-up for survivors was 16.7 months. Median CNS progression-free survival was 5.7 months (IQR 3.6-11 months) and median OS was 9.8 months (IQR 3.8-18 months). 82% of evaluable pts received further systemic therapy after SRS. 92% of patients were in RPA class II. RPA class was not found to be a useful prognostic index in this population. Median OS in RPA class II pts was 10.4 months. HER2 status (adjusted HR 2.4, p=0.008) and extracranial disease status (adjusted HR 2.7, p=0.004) were significant prognostic factors for survival on multivariate analysis. Conclusions: In patients with good KPS, salvage SRS at the time of CNS recurrence should be strongly considered. HER2 positivity and status of extracranial disease are prognostic factors for survival following SRS in the salvage setting after prior WBRT. Prognostic factors for OS. Univariate Multivariate HR P value HR P value Age >65 y 3.4 0.02 1.8 0.3 Extracranial disease Progessing 2.9 <0.001 2.7 0.004 Stable 1 HER2+ Yes 1 No 2.3 0.002 2.4 0.008 ER+ Yes 0.73 0.2 No 1 Triple-negative Yes 3.8 0.001 1.6 0.3 No 1 KPS <80% 4.2 <0.001 1.9 0.11 N lesions treated SRS 1.1 0.76 Time to SRS 1.0 0.77

Stereotactic 125Iodine Brachytherapy for the Treatment of Singular Brain Metastases: Closing a Gap?

Brain metastases represent the most common intracranial tumors and are associated with very poor prognosis. To investigate the feasibility, survival, and cerebral disease control of patients with singular brain metastases treated with stereotactic 125iodine brachytherapy (SBT), to identify prognostic factors, and to compare results with other local treatment methods. Complications, survival (overall and separated by recursive partitioning analysis [RPA] classes), and local and distant disease control were evaluated retrospectively in 90 patients. Prognostic factors were identified by forming subgroups of patients based on age, Karnofsky Performance Status, status of extracranial disease, interval since initial diagnosis, absence/presence of prior whole-brain radiation therapy, localization, morphology, and tumor volume. There was no treatment-related mortality, and morbidity was transient and low (3.3%). Median survival was 8.5 months overall and 18.1 months for RPA class 1 patients. After 1 year, the actuarial incidence of local and distant cerebral relapse was 5.4% and 46.4%, respectively. Karnofsky Performance Status ≥ 70 (P < .002), stable systemic disease (P < .02), RPA class 1 (P < .02), and a prolonged (> 12 month) interval between initial diagnosis and SBT (P < .05) significantly improved survival. No significant influence of previous whole-brain radiation therapy on survival or cerebral disease relapse was found. SBT represents a safe, minimally invasive, and, compared with SRS and microsurgery, a similarly effective local treatment option in terms of survival and cerebral disease control. It allows histological (re-)evaluation and treatment within 1 stereotactic operation. Because it is less restricted by tumor localization or size, it greatly advances local treatment options, and on the basis of its favorable biological irradiation effect, SBT does not limit additional irradiation treatment in the event of disease relapse.

Linear accelerator-based stereotactic radiosurgery for brainstem metastases: the Dana-Farber/Brigham and Women’s Cancer Center experience

To review the safety and efficacy of linear accelerator-based stereotactic radiosurgery (SRS) for brainstem metastases. We reviewed all patients with brain metastases treated with SRS at DF/BWCC from 2001 to 2009 to identify patients who had SRS to a single brainstem metastasis. Overall survival and freedom-from-local failure rates were calculated from the date of SRS using the Kaplan-Meier method. Prognostic factors were evaluated using the log-rank test and Cox proportional hazards model. A total of 24 consecutive patients with brainstem metastases had SRS. At the time of SRS, 21/24 had metastatic lesions elsewhere within the brain. 23/24 had undergone prior WBRT. Primary diagnoses included eight NSCLC, eight breast cancer, three melanoma, three renal cell carcinoma and two others. Median dose was 13Gy (range, 8-16). One patient had fractionated SRS 5Gy ×5. Median target volume was 0.2cc (range, 0.02-2.39). The median age was 57years (range, 42-92). Follow-up information was available in 22/24 cases. At the time of analysis, 18/22 patients (82%) had died. The median overall survival time was 5.3months (range, 0.8-21.1months). The only prognostic factor that trended toward statistical significance for overall survival was the absence of synchronous brain metastasis at the time of SRS; 1-year overall survival was 31% with versus 67% without synchronous brain metastasis (log rank P=0.11). Non-significant factors included primary tumor histology and status of extracranial disease (progressing vs. stable/absent). Local failure occurred in 4/22 cases (18%). Actuarial freedom from local failure for all cases was 78.6% at 1year. RTOG grade 3 toxicities were recorded in two patients (ataxia, confusion). Linac-based SRS for small volume brainstem metastases using a median dose of 13Gy is associated with acceptable local control and low morbidity.

Linear Accelerator-based Stereotactic Radiosurgery for Single Brainstem Metastases: The Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) Experience

To review the safety and efficacy of linear accelerator-based stereotactic radiosurgery (SRS) for single brainstem metastases. We reviewed all patients with brain metastases treated with SRS at DF/BWCC from 2001-2009 to identify patients who had SRS to a single brainstem metastasis. Overall survival and freedom-from-local-failure rates were calculated from the date of SRS using the Kaplan-Meier method. Prognostic factors were evaluated using the log-rank test and Cox proportional hazards model. A total of 24 consecutive patients with brainstem metastases had SRS. All had single lesions in the brainstem (10 midbrain, 13 pons and 1 medulla). At the time of SRS, 21/24 had metastatic lesions elsewhere within the brain. 23/24 had undergone previous whole-brain radiotherapy. Primary diagnoses included 8 NSCLC, 8 breast cancer, 3 melanoma, 3 renal cell carcinoma and 2 others. Median dose was 13 Gy (range, 8-16). One patient had fractionated SRS 5 Gy x 5. Median target volume was 0.2 cc (range, 0.02-2.39). At least 98% of the target was covered by the prescription dose in all cases. Median normalization was 73% (range, 52-90). Median conformity index (prescription isodose volume/PTV) and homogeneity index (maximum dose/prescribed dose) were 1.81 (range, 1.36-2.60) and 1.39 (range, 1.22-1.92), respectively. Fourteen patients were female (58%). The median age was 57 years (range, 42-92). Follow-up information was available in 22/24 cases. At the time of analysis, 18/22 patients (82%) had died. The median overall survival was 5.3 months (range, 0.8-21.1 months). The 4 surviving patients have been followed for 5, 8, 14, and 21 months. The only prognostic factor that trended toward statistical significance for overall survival was the absence of synchronous brain metastasis at the time of SRS (1-year overall survival 31% with vs. 67% without synchronous brain metastasis, log-rank p = 0.11). Non-significant factors included primary tumor histology and status of extracranial disease (progressing vs. stable/absent). Local failure occurred in 4/22 cases. Actuarial freedom-from local failure for all cases was 78.6% at 1 year. RTOG grade 3 toxicities were recorded in two patients (ataxia, confusion). Both patients progressed at distant sites within the brain. Linac-based SRS for small-volume brainstem metastases using a median dose of 13 Gy is associated with acceptable local control and low morbidity.

EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer

A small subset of patients with nonsmall cell lung cancer (NSCLC) harbors mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The characteristics and behavior of brain metastases (BMs) in these patients have not been well described. The longitudinal records of all NSCLC patients who underwent EGFR mutation screening at our center from August 2004 to November 2008 were reviewed for eligibility, and 93 patients were identified who developed BM during the course of their disease. Survival was estimated using the Kaplan-Meier method and the log-rank test. Multivariable predictors were assessed via the Cox proportional hazards model. Among the 93 patients with BM, 41 (44%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations. Eighty-three percent of patients with BM were treated initially with whole brain radiation, either alone (53%) or in combination with craniotomy for neurosurgical resection (22%) or stereotactic radiosurgery (8%). Median survival from the time of BM was 11.7 months and was longer for patients with an EGFR mutation (14.5 vs 7.6 months, P = .09). On multivariable analysis, EGFR mutation (HR: 0.50, 95% CI: 0.30-0.82), age (HR: 1.03, 95% CI: 1.00-1.05), and active extracranial disease (HR: 3.30, 95% CI: 1.70-6.41) were independently associated with survival. In NSCLC patients with BM, EGFR mutation status is associated with improved survival, independent of age, functional status, extracranial disease status, and number of BMs.

EGFR mutation status and survival after diagnosis of brain metastasis in non-small cell lung cancer.

7542 Background: Non-small cell lung cancer (NSCLC) is the most frequent site of origin for brain metastases (BM), which affect 30%-40% of pts with advanced disease. A small subset of pts with NSCLC harbor mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyroskine kinase inhibitors (TKIs). The characteristics and behavior of BM in this population have not been well described. Methods: From August ‘04 to November ‘08, 373 NSCLC pts underwent EGFR mutation screening at our center; 93 of these developed BM at some time during their course. Clinical and treatment variables were collected by chart review. Survival was estimated using the Kaplan-Meier method and log-rank test. Multivariate predictors were assessed via Cox proportional hazards models. Results: Among the 93 pts with BM, 41 (44%) had an EGFR mutation, including 13 exon 19 del and 12 L858R. Brain was the first site of metastasis in 55/93 pts (59%) and the proportion did not differ by mutation status. 83% of pts with BM were treated initially with whole brain radiation, either alone (53%) or in combination with surgery (22%) or stereotactic radiosurgery (8%). 6 pts were treated with TKIs alone; all but 1 were EGFR mutant. Median survival from the time of BM was 10.5 mo. On univariate analysis, EGFR-mutated pts had prolonged survival after BM (12.0 mo vs. 7.3 mo, p = 0.05). Additional predictors of survival included age, performance status, number of BM and status of extracranial disease. On multivariate analysis, EGFR mutation status (HR 0.36, 95% CI 0.20- 0.63), age (HR 1.03, 95% CI 1.01-1.06) and active extracranial disease (HR 3.72, 95% CI 1.84-1.75) remained strong independent predictors of survival. The rate of development of leptomeningeal disease (7%) did not vary by EGFR mutation status, nor did the rate of intracranial recurrence. Cause of death was isolated intracranial progression in 9%; combined intra- and extracranial in 31%; and isolated extracranial in 38%. Conclusions: EGFR mutation status is a strong prognostic factor in NSCLC pts developing BM, independent of known prognostic factors including age, functional status, extracranial disease status and number of BM. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Gatekeeper Biogen Idec, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, MedImmune, Millennium, Roche, Schering-Plough, Telik Novartis

The Management of Brain Metastases in Patients with Non-small Cell Lung Cancer—is it Time to go Back to the Drawing Board?

Unless confirmation of a solitary brain metastasis is made in the context of absent extracranial disease and good performance status, patients with metastatic brain disease from non-small cell lung cancer fare badly. There are no level I recommendations for the management of those with multiple brain metastases. The role of whole brain radiotherapy is not certain in those of poorer performance status. This overview assesses what we know and what we are uncertain of in the context of a changing paradigm for some subsets of patients who may obtain superior palliation with treatments targeted at the histological or molecular level. Once the standard treatment is established (steroids plus or minus whole brain radiotherapy), those who are of better performance status may be considered for comparison of this standard with or without systemic management.

Management of brain metastases

Brain metastases represent a common and devastating complication of cancer. With advances in surgery, radiology, and medical and radiation oncology, the number of treatment options have greatly increased. In addition, the prognosis for patients can vary widely depending on factors such as the number of lesions, extent of extracranial disease, age, and functional status. Recently, the possible impairment of whole brain radiation therapy on neurocognitive function has been a subject of concern and debate. Thus, the use of whole brain radiation therapy in conjunction with other treatment modalities should be optimized to ensure the best outcomes with regard to tumor control and functional status. As a result, patient management has become controversial, with strong opinions often dictating "optimal" therapy. This review of the management of brain metastases focuses on whole brain radiation therapy, surgery, stereotactic radiosurgery, radiation sensitizers, and clinical trials.

Gamma Knife surgery for metastatic brain tumors

The authors compared results of Gamma Knife surgery (GKS) for brain metastases obtained at 2 institutions in Japan. They analyzed a consecutive series of 2390 patients with brain metastases who underwent GKS from 1998 through 2005 in 2 institutes (1,181 patients in Chiba; 1,209 in Mito). In the 2 facilities, 1 neurosurgeon each was responsible for diagnosis, patient selection, GKS procedures, and follow-up (T.S. in Chiba, M.Y. in Mito). Even if tumor numbers exceeded 4, all visible lesions were irradiated with a total skull integral dose (TSID) of <or= 10-12 J. No prophylactic whole-brain radiotherapy (WBRT) was applied. If new distant lesions were detected, salvage GKS was appropriately performed. The distributions of patient and treatment factors did not differ between institutes. The most common primary tumors were lung cancer (1,572 patients), followed by gastrointestinal tract (316), breast (211), kidney (113), and other cancers (159). The median survival periods were 7.7 months in Chiba and 7.0 months in Mito (p = 0.0635). The significant poor prognostic factors for overall survival were active extracranial disease status, male sex, and low initial Karnofsky Performance Scale score on multivariate analysis (all p < 0.0001). The neurological survival rates at 1 year were 86.6% in Chiba and 84.2% in Mito (p = 0.3310). This 2-institute study demonstrated no significant institutional differences in any of the treatment result items. Gamma Knife surgery for brain metastases without prophylactic WBRT prevents neurological death and allows a patient to maintain good brain condition. However, there is 1 important patient selection criterion: regardless of how many tumors there are, all lesions can be irradiated with a TSID of <or=12 J.

Have Changes in Systemic Treatment Improved Survival in Patients with Breast Cancer Metastatic to the Brain?

Newly developed systemic treatment regimens might lead to improved survival also in the subgroup of breast cancer patients that harbour brain metastases. In order to examine this hypothesis, a matched pairs analysis was performed that involved one group of patients, which were treated after these new drugs were introduced, and one group of patients, which were treated approximately 10 years earlier. The two groups were well balanced for the known prognostic factors age, KPS, extracranial disease status, and recursive partitioning analysis class, as well as for the extent of brain treatment. The results show that the use of systemic chemotherapy has increased over time, both before and after the diagnosis of brain metastases. However, such treatment was performed nearly exclusively in those patients with brain metastases that belonged to the prognostically more favourable groups. Survival after whole-brain radiotherapy has remained unchanged in patients without further active treatment. It has improved in prognostically better patients and especially patients that received active treatment, where the 1-year survival rates have almost doubled. As these patient groups were small, confirmation of the results in other series should be attempted. Nevertheless, the present results are compatible with the hypothesis that improved systemic therapy might contribute to prolonged survival in patients with brain metastases from breast cancer.

Treatment and Prognosis of Brain Metastases From Gynecological Cancers

Brain metastases from gynecological cancers were retrospectively investigated in 18 patients who were treated between 1985 and 2006. Six patients received surgical resection followed by radiotherapy, and 12 patients received only radiotherapy. The median survival for all patients was 4.1 months (range 0.7-48.2 months), and the actuarial survival rates were 11% at both 12 months and 24 months. Univariate analysis showed that treatment modality, extracranial disease status, total radiation dose, number of brain metastases, and Karnofsky performance status (KPS) all had statistically significant impacts on survival. Two patients survived for more than 2 years, and both had single brain metastasis, inactive extracranial disease, 90-100% KPS, and were treated with surgical resection followed by radiotherapy. Improvements in neurological symptoms were observed in 10 of the 12 patients treated with palliative radiotherapy, with median duration of 3.1 months (range 1.5-4.5 months). The prognoses for patients with brain metastases from gynecological cancers were generally poor, although selected patients may survive longer with intensive brain tumor treatment. Palliative radiotherapy was effective in improving the quality of the remaining life for patients with unfavorable prognoses.

Treatment and prognosis of brain metastases from breast cancer

To analyze retrospectively the results of treatments for patients with brain metastases from breast cancer. The records of 65 breast cancer patients with brain metastases who were treated between 1985 and 2005 were reviewed. For brain metastases, 11 patients (17%) were treated with surgical resection followed by radiotherapy, and the remaining 54 patients were treated with radiotherapy alone. Systemic chemotherapy was also administered to 11 patients after brain radiotherapy. The overall median survival for all patients was 6.1 months (range, 0.4-82.2 months). In univariate analysis, treatment modality, Karnofsky performance status (KPS), administration of systemic chemotherapy, extracranial disease status and total radiation dose each had significant impact on overall survival, and in multivariate analysis, treatment modality, KPS and administration of systemic chemotherapy were significant prognostic factors. Eight patients survived for more than 2 years after the diagnosis of brain metastases, and all these patients were treated with surgical resection and/or systemic chemotherapy in addition to radiotherapy. For the 45 patients treated with palliative radiotherapy (without systemic chemotherapy), the improvements in neurological symptoms were observed in 35 patients (78%), with the median duration of improvement of 3.1 months (range, 1.5-4.4 months). The prognoses for patients with brain metastases from breast cancer were generally poor, although selected patients may survive longer with intensive brain tumor treatment, such as surgical resection and/or systemic chemotherapy in addition to brain radiotherapy. For patients with unfavorable prognoses, palliative radiotherapy was effective in improving the quality of the remaining lifetime.

Integration of chemotherapy into current treatment strategies for brain metastases from solid tumors.

Patients with brain metastases represent a heterogeneous group where selection of the most appropriate treatment depends on many patient- and disease-related factors. Eventually, a considerable proportion of patients are treated with palliative approaches such as whole-brain radiotherapy. Whole-brain radiotherapy in combination with chemotherapy has recently gained increasing attention and is hoped to augment the palliative effect of whole-brain radiotherapy alone and to extend survival in certain subsets of patients with controlled extracranial disease and good performance status. The randomized trials of whole-brain radiotherapy vs. whole-brain radiotherapy plus chemotherapy suggest that this concept deserves further study, although they failed to improve survival. However, survival might not be the most relevant endpoint in a condition, where most patients die from extracranial progression. Sometimes, the question arises whether patients with newly detected brain metastases and the indication for systemic treatment of extracranial disease can undergo standard systemic chemotherapy with the option of deferred rather than immediate radiotherapy to the brain. The literature contains numerous small reports on this issue, mainly in malignant melanoma, breast cancer, lung cancer and ovarian cancer, but very few sufficiently powered randomized trials. With chemotherapy alone, response rates were mostly in the order of 20–40%. The choice of chemotherapy regimen is often complicated by previous systemic treatment and takes into account the activity of the drugs in extracranial metastatic disease. Because the blood-brain barrier is partially disrupted in most macroscopic metastases, systemically administered agents can gain access to such tumor sites. Our systematic literature review suggests that both chemotherapy and radiochemotherapy for newly diagnosed brain metastases need further critical evaluation before standard clinical implementation. A potential chemotherapy indication might exist as palliative option for patients who have progressive disease after radiotherapy.

Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial

Brain metastases occur in up to 40% of all patients with systemic cancer. We aimed to assess whether stereotactic radiosurgery provided any therapeutic benefit in a randomised multi-institutional trial directed by the Radiation Therapy Oncology Group (RTOG). Patients with one to three newly diagnosed brain metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic radiosurgery boost. Patients were stratified by number of metastases and status of extracranial disease. Primary outcome was survival; secondary outcomes were tumour response and local rates, overall intracranial recurrence rates, cause of death, and performance measurements. From January, 1996, to June, 2001, we enrolled 333 patients from 55 participating RTOG institutions--167 were assigned WBRT and stereotactic radiosurgery and 164 were allocated WBRT alone. Univariate analysis showed that there was a survival advantage in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6.5 vs 4.9 months, p=0.0393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months' follow-up than were patients allocated WBRT alone (43% vs 27%, respectively; p=0.03). By multivariate analysis, survival improved in patients with an RPA class 1 (p<0.0001) or a favourable histological status (p=0.0121). WBRT and stereotactic boost treatment improved functional autonomy (KPS) for all patients and survival for patients with a single unresectable brain metastasis. WBRT and stereotactic radiosurgery should, therefore, be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases.

Posterior Fossa Metastases: Risk of Leptomeningeal Disease When Treated with Stereotactic Radiosurgery Compared to Surgery

Leptomeningeal disease (LMD) represents a diffuse form of central nervous system metastatic disease that is often associated with poor quality of life and prognosis. Our objective was to compare the incidence of LMD in patients with posterior fossa metastases (PFM) following stereotactic radiosurgery (SRS) versus surgical resection. The medical records of 93 patients aged 57.9 +/- 10.8 years (mean +/- SD) with PFM treated at the Cleveland Clinic from 1995 to 2001 were analyzed retrospectively. Treatments consisted of surgery with whole brain radiation therapy (WBRT) or SRS with or without WBRT. The impact of age, Karnofsky performance status (KPS) at presentation, Radiation Therapy Oncology Group, recursive partitioning analysis (RPA) class, status of extracranial disease, number, size, volume, pathology of brain metastases and steroid use were studied using univariate and multivariate analyses. There were 80 evaluable patients (10 lost to follow-up and three excluded for supratentorial surgery with subsequent LMD). LMD occurred after the surgical removal of the PFM in 9 of 18 patients (50%), whereas LMD occurred after SRS in 4 of 62 patients (6.5%) (p = 0.0028). Multivariate analysis also showed that patients who had surgery were more likely to develop LMD compared to patients treated with SRS (p = 0.0024). Patients had a median KPS decline of 30 points after LMD was diagnosed. There was no statistically significant difference in survival of patients with LMD and the rest of the patients (13.5 vs. 11.7 months, p = 0.7659). Patients treated surgically had significantly larger lesions (3.43 +/- 0.74 vs. 1.96 +/- 0.95 cm maximum diameter, p < 0.0001). All surgical patients belonged to RPA class II at diagnosis. Their survival was not different from the RPA class II patients in the SRS group. Surgery and SRS had comparable complication rates (8.1% vs. 5.6%, p = 0.99), although the surgical complications were more serious (e.g. hemorrhage, CSF leak). The duration of steroid use was longer after SRS compared to surgery (2.1 +/- 3.6 vs. 1.3 +/- 2.4 months); however, the difference was not statistically significant. Myopathy and psychosis in one patient after SRS, were the only steroid-related complications. There was no statistically significant association between the primary tumor type and the presence of LMD. In this retrospective analysis of patients with PFM, SRS was associated with a lower incidence of LMD than was surgery. Although LMD was associated with rapid and considerable decline in the quality of life, it did not influence the overall survival. SRS was associated with less serious complications than surgery. Surgery in this study was performed on patients with larger lesion sizes and a trend toward poorer initial performance status, which could bias these results. A prospective study directly comparing surgery and SRS and further evaluating the significance of LMD in PFM is warranted.

Linac Radiosurgery for Brain Metastasis of Melanoma

Purpose: To evaluate the efficacy and toxicity of stereotactic radiotherapy in the treatment of brain metastases of melanoma. Patients and Methods: From 1994 to 2001, 25 patients presenting with 61 metastases of cutaneous melanoma were treated with radiosurgery. Median age was 47 years (range: 25–73 years) and median Karnofski performance status 80 (range: 50–100). Twenty patients had one radiosurgery, 5 had two or three. Median metastasis diameter was 21 mm (range: 6–54.4 mm), and median metastasis volume was 1.7 cm³ (range: 0.4–25.6 cm³). Irradiation was delivered by a linear accelerator. Median minimal dose was 14.1 Gy (range: 10–19.4 Gy), and median maximal dose was 20.5 Gy (range: 16–48 Gy). Results: Mean follow-up was 12.6 months (range: 1–85 months). Five metastases progressed (9.8%), 2–12 months after radiosurgery. Three-, 6- and 12-month local control rates were 95 ± 3, 90 ± 5 and 84 ± 7%, respectively. By univariate analysis, only absence of extracranial tumor was a prognostic factor of local control. Three-, 6- and 12-month brain-disease-free survival rates were 75 ± 9, 68 ± 11 and 38 ± 13%, respectively. According to univariate analysis, only the Score Index for Radiosurgery in brain metastases (SIR) was a prognostic factor of brain-event-free survival (p = 0.03). Median survival was 8 months. Three-, 6- and 12-month overall survival rates were 75 ± 9, 53 ± 10, and 29 ± 10%, respectively. According to univariate analysis, extracranial controlled disease status (p = 0.03), and SIR (p = 0.04) were prognostic factors for overall survival. According to multivariate analysis, none was an independent prognosticator for overall survival. Complications were minimal. Conclusion: Radiosurgical treatment of brain metastases of melanoma is effective and accurate. The use of radiosurgery alone is an appropriate management strategy for many patients with brain metastases of melanoma.

Brain metastases from esophageal carcinoma: natural history, prognostic factors, and outcome.

Brain metastases from esophageal carcinoma are extremely rare, and information regarding the natural history, results of treatment, and possible prognostic factors in these patients is limited. The records of 36 patients with brain metastases from esophageal carcinoma who were treated between 1986 and 2000 were reviewed. For brain metastases, 12 patients (33%) were treated with surgical resection followed by radiation therapy (S+RT), and the remaining 24 patients were treated with radiation therapy alone. At the initial diagnosis of esophageal carcinoma, the median primary tumor length was 8 cm (range, 2-19 cm), and 26 of 32 available patients (81%) had clinical Stage III-IV tumors according to the International Union Against Cancer 1997 criteria. At time brain metastases appeared, lung metastases were not demonstrated in 25 of 36 patients (69%) who were assessed by chest computed tomography (CT) scans. The overall median survival for all patients was 3.9 months (range, 0.6-36.8 months), and the actuarial survival rates at 12 months and 24 months were 14% and 3%, respectively. In univariate analysis, treatment modality, Karnofsky performance status (KPS), and extracranial disease status each had a statistically significant impact on survival, and, in multivariate analysis, treatment modality and KPS were statistically significant prognostic factors for survival. Five patients (14%) survived more than 1 year, all of whom were treated with S+RT. These five patients had inactive extracranial disease and, four of five patients (80%) had a 90-100% KPS. Brain metastases from esophageal carcinoma tended to occur in patients with a large primary tumors and/or disease in advanced clinical stages. With the appearance of brain metastases, an absence of lung metastasis frequently was observed on chest CT scans. The prognoses for these patients were generally poor, although selected patients may survive longer with intensive brain tumor treatment.

The role of radiosurgery for multiple brain metastases

The authors evaluated the role of stereotactic radiosurgery (SRS) in patients with multiple brain metastases by analyzing prognostic factors that predict survival. Between March 1991 and January 1999, 83 patients with multiple brain metastases underwent SRS in which they used a 6 mV linear accelerator. The median radiation dose of 15 Gy (range 6-50 Gy) was delivered to the 40 to 90% (median 87%) isodose line encompassing the target. Actuarial overall survival was calculated from the date of SRS by using the Kaplan-Meier method. Univariate comparisons of survival between different groups were performed using a log-rank test. All 83 patients were included in the calculation of overall survival. Actuarial overall survival was 22% at 1 year and 13% at 2 years, and a median survival of 5.4 months (range, 0.3-28.8 months) was demonstrated. Variables that predicted survival were Karnofsky Performance Scale (KPS) score, extracranial disease status, and the number of intracranial metastases. Median survival in patients with a KPS score greater than as compared with less than 70 was 9.1 and 2.7 months, respectively (p = 0.002). Median survival when comparing absence and presence of extracranial disease was 9.9 and 4.1 months, respectively (p = 0.02). Median survival in patients harboring two, three, or four or more lesions was 6.6 months, 5.4 months, and 2.7 months, respectively (p = 0.02). In patients with a KPS score greater than or equal to 70 and with three or fewer lesions, median survival was 7 months or longer. In patients with four or more lesions median survival was 7.4 months for those with no extracranial disease and 2.4 months for those with extracranial disease. Other variables tested (sex, histological tumor type, previous resection, location of metastases, treatment modality, and tumor status) did not influence outcome. The absence of extracranial disease, a KPS score greater than or equal to 70, and fewer number of metastases were shown to be significant predictors of longer survival. Stereotactic radiosurgery appears to be a reasonable therapeutic option in patients with up to three lesions when their KPS score is greater than or equal to 70, regardless of extracranial disease status. In those with four or more metastases, however, SRS should be limited to those with no extracranial disease.

Radiation therapy in the management of brain metastases from breast cancer.

A retrospective analysis of 99 patients treated at Radiumhemmet, Karolinska Hospital 1979-1990 with palliative radiotherapy for brain metastases from breast cancer was performed. A relief of symptoms was obtained in 45% of patients. Median time from diagnosis of breast cancer until CNS metastases was 33 months. Median survival time with CNS metastases after diagnosis was 5 months. Prognostic indicators for survival were studied. Patients operated for a singular brain metastasis and irradiated postoperatively had a mean survival of 21 months while patients with multiple brain metastases and meningeal spread displayed a short median survival. Extracranial disease status influenced prognosis significantly. Radiation dose (CRE) did not correlate with survival.