A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases.

PURPOSE: To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1 to 4 brain metastases treated with radiosurgery without whole-brain radiation therapy (WBRT). METHODS AND MATERIALS: Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase 2 trial of radiosurgery (15-24 Gy) and adjuvant temozolomide. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. RESULTS: Twenty-five patients were enrolled between 2002 and 2005; 3 were not evaluable for determining DBF. Of the remaining 22 patients, tumor types included non-small cell lung cancer (n = 8), melanoma (n = 7), and other (n = 7). Extracranial disease was present in 10 (45%) patients. The median number of tumors at the time of radiosurgery was 3 (range, 1-6). The median overall survival was 31 weeks. The median radiographic follow-up for patients who did not develop DBF was 33 weeks. Six patients developed DBF. The 1-year actuarial risk of DBF was 37%. CONCLUSIONS: In this study, there was a relatively low risk of distant brain failure observed in the nonmelanoma subgroup receiving temozolamide. However, patient selection factors rather than chemotherapy treatment efficacy are more likely the reason for the relatively low risk of distant brain failure observed in this study. Future trial design should account for these risk factors.

Management of brain metastases.

OPINION STATEMENT: As systemic cancer therapies have improved, the natural history and importance of treating brain metastases continues to evolve. Historically, most patients with brain metastases have been managed with whole brain radiation therapy (WBRT) with surgical resection or radiosurgery added for patients with single or few metastases. Because the potential late toxicity of WBRT is increasingly recognized when systemic tumor is more effectively controlled, there has been increased interest in the use of focal therapies such as radiosurgery with deferred WBRT even for patients with larger numbers of metastases. Although WBRT in combination with radiosurgery or surgical resection significantly reduces central nervous system recurrences at the treated site and elsewhere in the brain, it is not clear whether a patient's quality of life is more affected by tumor recurrence or by treatment with WBRT. In our practice, most patients with fewer than 7 to 10 tumors are treated with radiosurgery alone, with WBRT initially deferred because of concerns about its late toxicity. The ongoing technical improvements in radiosurgery have made this transition away from WBRT clinically feasible. This approach also allows patients to begin systemic therapy sooner, rather than waiting 2 to 4 weeks to complete WBRT. For patients with large or very symptomatic tumors, surgical resection is performed, followed by postoperative radiosurgery to the resection cavity, again initially deferring WBRT for many patients. This focal-only approach in the postoperative setting is associated with a higher rate of subdural dissemination and needs further prospective study, as some would argue that tumor progression is the major determinant of loss of function. Ultimately, better survival will require better systemic therapy that both controls extracranial disease and penetrates the brain to reduce intracranial recurrences. Unfortunately, many clinical trials of novel agents exclude patients with brain metastases.

Stereotactic body radiation therapy for liver metastases and primary hepatocellular carcinoma: normal tissue tolerances and toxicity.

BACKGROUND: There is growing interest in stereotactic body radiation therapy (SBRT) as a noninvasive means of treating inoperable hepatic metastases and primary intrahepatic hepatobiliary carcinomas. While initial outcomes are encouraging, the safety of delivering such large, ablative doses is still being studied. METHODS: We compiled all dose-volume constraints from seven prospective trials of liver SBRT and linked them to reported toxicities. Dose thresholds were made isoeffective, and grade 3 or higher toxicities for liver and adjacent normal tissues were correlated. RESULTS: Four cases of grade 3-5 radiation-induced liver disease (RILD) were identified, including 1 treatment related death, from all patients treated for metastasis. Three of these 4 cases were linked to excessive radiation doses in a large volume of liver. In 56 patients treated for hepatocellular carcinoma (HCC), 1 case of grade 5 RILD and 2 cases of grade 2 hepatic toxicity were reported. Additionally, a prominent retrospective series reported 3 cases of grade 5 RILD in 9 patients treated for HCC. CONCLUSIONS: SBRT appears to be safe for treatment of hepatic metastasis. The use of SBRT for HCC should be undertaken with caution or within the context of a clinical trial. Strict adherence to reported dose-volume constraints is advocated.

Adjuvant radiotherapy for pancreatic cancer is associated with a survival benefit primarily in stage IIB patients.

BACKGROUND: The role of adjuvant radiotherapy (RT) for pancreatic cancer remains controversial despite the completion of three multi-institutional randomized trials. This study examines the survival impact of postoperative RT in a large population-based database. METHODS: Patients with pancreatic cancer diagnosed from 1988 to 2003 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The cohort was limited to patients who underwent resection of nonmetastatic disease to yield a population of 3252 patients. The primary end point was overall survival. Survival analyses were conducted using corrections for perioperative mortality as well as a propensity score analysis to account for baseline differences in patient characteristics. RESULTS: Multiple independent factors were associated with RT use, including patient age and disease stage (P < 0.0001). In general, younger patients and those with more advanced disease were more likely to receive RT. Disease stage significantly affected survival (P < 0.0001). For patients who survived at least 6 months, adjuvant RT was associated with increased survival [hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.80-0.96]. On subgroup analysis, only stage IIB (T1-3N1) patients enjoyed a statistically significant benefit associated with RT (HR, 0.70; 95% CI, 0.62-0.79). CONCLUSIONS: Adjuvant RT is frequently given to patients in the United States after resection of their pancreatic cancer. Although RT is associated with a survival benefit for nonmetastatic patients as a whole, this trend appears to predominantly derive from a survival benefit in patients with stage IIB disease.

Locoregionally advanced head and neck cancer treated with primary radiotherapy: a comparison of the addition of cetuximab or chemotherapy and the impact of protocol treatment.

PURPOSE: The addition of platinum-based chemotherapy (ChRT) or cetuximab (ExRT) to concurrent radiotherapy (RT) has resulted in improved survival in Phase III studies for locoregionally advanced head and neck cancer (LAHNC). However the optimal treatment regimen has not been defined. A retrospective study was performed to compare outcomes in patients who were treated definitively with ExRT or ChRT. METHODS: Cetuximab with concurrent RT was used to treat 29 patients with LAHNC, all of whom had tumors of the oral cavity, oropharynx, or larynx. All patients were T2 to T4 and overall American Joint Committee on Cancer Stage III to IVB, with a Karnofsky Performance Status (KPS) score of 60 or greater. ChRT was used to treat 103 patients with similar characteristics. Patients were evaluated for locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS). Median follow-up for patients alive at last contact was 83 months for those treated with ExRT and 53 months for those treated with ChRT. Cox proportional hazard models were used to assess independent prognostic factors. RESULTS: The LRC, DMFS, and DSS were not significantly different, with 3-year rates of 70.7%, 92.4%, and 78.6% for ExRT and 74.7%, 86.6%, and 76.5% for ChRT, respectively. The OS was significantly different between the two groups (p = 0.02), with 3-year rates of 75.9% for ExRT and 61.3% for ChRT. OS was not significant when patients who were on protocol treatments of ExRT or ChRT were compared. Also, OS was not significant when multivariate analysis was used to control for potential confounding factors. CONCLUSION: In our single-institution retrospective review of patients treated with ExRT or ChRT, no significant differences were found in LRC, DMFS, DSS, or OS.

Stage-specific survival differences associated with postoperative radiotherapy for gastrointestinal cancers.

OBJECTIVE: To study the frequency and effect associated with postoperative radiotherapy (RT) for patients with resected gastrointestinal (GI) cancers. MATERIALS AND METHODS: In observational cohort from the Surveillance, Epidemiology, and End Results (SEER) program, a total of 23,049 patients were identified with resected pancreatic, gastric, esophageal, or rectal carcinomas diagnosed from 1988 to 2003. Using a propensity score analysis, survival differences associated with postoperative RT were analyzed. RESULTS: Adjuvant RT was given to 51.2%, 26.3%, 33.0%, and 58.0% of pancreatic, gastric, esophageal, and rectal cancer patients, respectively. Age and stage of disease were associated with RT use for each site (P < 0.001), with younger patients and those with advanced disease receiving RT more frequently. Postoperative RT was associated with a survival benefit for patients with pancreatic cancer (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96), gastric cancer (HR, 0.93; 95% CI, 0.87-0.99), and rectal cancer (HR, 0.84; 95% CI, 0.79-0.90). Subgroups of patients were also identified who experienced the greatest improvement in survival with RT (stage IIB pancreatic cancer, HR = 0.71 [95% CI 0.62-0.80]; stage IIIA and IV gastric cancer, HR = 0.86 [95% CI 0.77-0.97] and HR = 0.77 [95% CI 0.67-0.89], respectively; stages IIA, IIIB, and IIIC rectal cancer, HR = 0.87 [95% CI 0.78-0.97], HR = 0.71 [95% CI 0.63-0.80], and HR = 0.79 [95% CI 0.70-0.90], respectively). CONCLUSION: Postoperative RT is associated with improved survival for patients who undergo curative resection of pancreatic, gastric, and rectal malignancies. Significant differences are observed for this effect according to stage of disease, with more advanced cases in general experiencing a greater benefit with RT.

Predictors of distant brain recurrence for patients with newly diagnosed brain metastases treated with stereotactic radiosurgery alone.

PURPOSE: To ascertain predictors of distant brain failure (DBF) in patients treated initially with stereotactic radiosurgery alone for newly diagnosed brain metastases. We hypothesize that these factors may be used to group patients according to risk of DBF. METHODS AND MATERIALS: We retrospectively analyzed 100 patients with newly diagnosed brain metastases treated from 2003 to 2005 at our Gamma Knife radiosurgery facility. The primary endpoint was DBF. Potential predictors included number of metastases, tumor volume, histologic characteristics, extracranial disease, and use of temozolomide. RESULTS: One-year actuarial risk of DBF was 61% for all patients. Significant predictors of DBF included more than three metastases (hazard ratio, 3.30; p = 0.004), stable or poorly controlled extracranial disease (hazard ratio, 2.16; p = 0.04), and melanoma histologic characteristics (hazard ratio, 2.14; p = 0.02). These were confirmed in multivariate analysis. Those with three or fewer metastases, no extracranial disease, and nonmelanoma histologic characteristics (N = 18) had a median time to DBF of 89 weeks vs. 33 weeks for all others. One-year actuarial freedom from DBF for this group was 83% vs. 26% for all others. CONCLUSIONS: Independent significant predictors of DBF in our series included number of metastases (more than three), present or uncontrolled extracranial disease, and melanoma histologic characteristics. These factors were combined to identify a lower risk subgroup with significantly longer time to DBF. These patients may be candidates for initial localized treatment, reserving whole-brain radiation therapy for salvage. Patients in the higher risk group may be candidates for initial whole-brain radiation therapy or should be considered for clinical trials.

Reliability of language mapping with magnetic source imaging in epilepsy surgery candidates.

The external validity of a noninvasive language mapping protocol with magnetoencephalography (MEG) has been established through direct comparisons with invasive functional mapping techniques. This study examines the test-retest and interrater reliability of this protocol under realistic testing conditions in 21 epilepsy surgery candidates. Brain activation maps were obtained in the context of an auditory word recognition task and represented by temporally contiguous dipolar activity sources. Both the duration and strength of the associated magnetic flux were used as measures of the magnitude of regional brain activity. Hemispheric asymmetry indices based on these measures showed good interrater reliability and intraparticipant reproducibility. Similar findings were obtained with respect to the location of the geometric center of receptive language-specific cortex (Wernicke's) area in the dominant hemisphere. The results further support the adequacy of this MEG-based brain mapping protocol as a noninvasive tool for receptive language localization in epilepsy surgery candidates.

Dynamic brain activation patterns for face recognition: a magnetoencephalography study.

The present study used magnetoencephalography (MEG) to investigate the spatiotemporal profile of neurophysiological activity associated with recognition of recently encountered human faces in seventeen healthy right-handed adults. Activity sources modeled as instantaneous equivalent current dipoles were found in ventral occipito-temporal regions during the early stages of stimulus processing and in lateral temporal cortices during later stages. Hemispheric asymmetries in regional activity were restricted to ventral occipitotemporal areas. The magnitude of magnetic flux originating in these regions was greater in the right hemisphere during the first 350 ms post-stimulus onset. In addition, the duration of neurophysiological activity was greater in the right hemisphere after 600 ms post-stimulus onset. The results indicate right hemisphere predominance in the degree of engagement of neurophysiological processes involved in both the pre- and post-recognition phases of face processing.

In vivo hippocampal metabolic dysfunction in human temporal lobe epilepsy.

BACKGROUND: The nature of functional metabolic disturbances in mesial temporal lobe epilepsy remains unclear. OBJECTIVES: To compare in vivo measures of hippocampal metabolic abnormalities in mesial temporal lobe epilepsy, as acquired with fludeoxyglucose F 18 positron emission tomography and proton magnetic resonance spectroscopic imaging, and to determine the relationship between N-acetylaspartate (NAA) disturbances and well-established derangements of glucose metabolism. DESIGN: Measures of hippocampal glucose metabolism from fludeoxyglucose F 18 positron emission tomography were normalized to whole brain counts to provide a glucose uptake metabolic index. Proton magnetic resonance spectroscopic imaging was performed at 4.1 T, and measures of creatinine/NAA ratio were made from mostly hippocampal-only voxels. Direct comparisons and correlation analysis of measures were performed. SETTING: Presurgical evaluations for treatment of intractable epilepsy. PATIENTS: Twenty-nine patients between July 1994 and June 1996 who were candidates for anterior-medial temporal lobectomy at the epilepsy centers of the University of Alabama at Birmingham and Vanderbilt University schools of medicine were studied. RESULTS: The mean ipsilateral hippocampal glucose metabolic index (0.85) was normal, while the contralateral metabolic index (0.95) was nearly significant for an abnormally elevated measure. The mean ipsilateral hippocampal creatinine/NAA (1.26) was abnormally elevated; the mean contralateral creatinine/NAA (0.88) was normal. Hippocampal glucose and creatinine/NAA measures did not correlate; asymmetry measures also did not correlate. CONCLUSIONS: Hippocampal metabolic disturbances in mesial temporal lobe epilepsy as measured by fludeoxyglucose F 18 positron emission tomography vs proton magnetic resonance spectroscopic imaging reflect different mechanisms of biochemical dysfunction. This lack of correlation is hypothesized to reflect a differential effect of varying degrees of disturbed cellular energy metabolism on mechanisms of glucose use and biosynthesis of NAA.

Narcissism and depression: MMPI-2 evidence for the continuum hypothesis in clinical samples.

According to one hypothesis, self-report measures of narcissism help describe a psychological continuum related to self-esteem. Most of the previous support for this idea appeared in studies of undergraduates responding to the Narcissistic Personality Inventory (NPI; Raskin & Hall, 1981) along with other self-report instruments. In this project, results consistent with the continuum hypothesis were obtained when Minnesota Multiphasic Personality Inventory-2 (MMPI-2; Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) narcissism scales were correlated with depression in adults receiving treatment for alcoholism. Essentially identical outcomes emerged in a second sample of state psychiatric hospital patients. A third study upheld the hypothesis when narcissism scales were correlated with clinical assessments rather than self-reports of depression. None of these findings were easily explained in terms of alternative interpretations of self-reported narcissism, and these data demonstrate that empirical support for the continuum hypothesis was not limited to the NPI, undergraduates, or self-report measures.

Analysis of cognitive change: a commentary on Keith et al. (2002).

There have been significant advances in the study of cognitive change in recent years, evolving from traditional group-level parametric methods to new techniques such as the reliable change index (RCI) and the standardized regression-based (SRB) change score. In the very interesting study of cognitive change following cardiopulmonary bypass, Keith et al. (2002) opted for a more traditional group-level analysis of change (the mixed factor analysis of variance). They cited several limitations of the individual-level analytic techniques such as the RCI. In this commentary, the author attempts to address these specific concerns as well as some of the more general difficulties presented by the analysis of cognitive change. Advantages and disadvantages of the RCI and SRB methods are discussed.

Nonlinear Trends in Hippocampal Metabolic Function and Verbal Memory: Evidence of Cognitive Reserve in Temporal Lobe Epilepsy?

The present study explored the possibility of nonlinear trends in the relationship between verbal memory and hippocampal function in a series of 33 patients with temporal lobe epilepsy (TLE). Right and left hippocampal metabolic function was quantified using levels of hippocampal creatine to N-acetylaspartate (Cr/NAA) derived from (1)H magnetic resonance spectroscopic imaging. An exploratory neural network analysis (multi-layer perceptron) suggested the possibility of either a quadratic or cubic trend in the relationship between left hippocampal Cr/NAA and verbal retention. Using regression-based curve estimation, the cubic function was found to optimally fit the data, explaining 41% of the variance in the relationship between verbal memory and hippocampal metabolic function. This was contrasted to the 28% variance explained by simple linear regression. These findings suggest that (1) the relationship between verbal retention and hippocampal function in patients with TLE is nonlinear, and (2) this could be explained in terms of a possible "cognitive reserve." Clinical implications are discussed.