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Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 157-165 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.128 Neurocognitive Function and Progression in Patients With Brain Metastases Treated With Whole-Brain Radiation and Motexafin Gadolinium: Results of a Randomized Phase III TrialFrom the M.D. Anderson Cancer Center, Houston, TX; Pharmacyclics Inc, Sunnyvale; California Cancer Care, Greenbrae, CA; University of Wisconsin Medical School, Madison, WI; New Mexico Hematology-Oncology Consultants, Albuquerque, NM; North Memorial Research Center, Robbinsdale, MN; University of Colorado, Denver, CO; Thomas Jefferson University, Philadelphia, PA; Princess Margaret Hospital, Toronto; Ottawa Regional Cancer Centre, Ottawa, Canada; Wessex Cancer Centre, Southampton, United Kingdom; Western General Hospital, Edinburgh, Scotland; Medisch Spectrum Twente, Enschede, The Netherlands; and Centre Léon Bérard, Lyon, France. Address reprint requests to Christina A. Meyers, PhD, M.D. Anderson Cancer Center, Department of Neuro-Oncology, Unit 431, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: cameyers{at}mdanderson.org
PURPOSE: To report the neurocognitive findings in a phase III randomized trial evaluating survival and neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to receive WBRT 30 Gy in 10 fractions with or without MGd 5 mg/kg/d. Monthly neurocognitive testing for memory, executive function, and fine motor skill was performed. RESULTS: Four hundred one patients were enrolled (251 with non–small-cell lung cancer, 75 with breast cancer, and 75 with other cancers); 90.5% patients had impairment of one or more neurocognitive tests at baseline. Neurocognitive test scores of memory, fine motor speed, executive function, and global neurocognitive impairment at baseline were correlated with brain tumor volume and predictive of survival. There was no statistically significant difference between treatment arms in time to neurocognitive progression. Patients with lung cancer (but not other types of cancer) who were treated with MGd tended to have improved memory and executive function (P = .062) and improved neurologic function as assessed by a blinded events review committee (P = .048). CONCLUSION: Neurocognitive tests are a relatively sensitive measure of brain functioning; a combination of tumor prognostic variables and brain function assessments seems to predict survival better than tumor variables alone. Although the addition of MGd to WBRT did not produce a significant overall improvement between treatment arms, MGd may improve memory and executive function and prolong time to neurocognitive and neurologic progression in patients with brain metastases from lung cancer.
Brain metastases are a frequent complication of many cancers, occurring in as many as 24% of all patients on the basis of autopsy data [1]. In lung cancer, the most common cause of brain metastases, up to 50% of patients develop CNS involvement [2-4]. Brain metastases occur early in lung cancer and sometime produce neurologic symptoms at disease presentation, in contrast to other cancers in which CNS spread is usually a later complication [1]. Other tumor types commonly associated with brain metastases include breast cancer (15% to 20%), unknown primary tumor (2% to 15%), melanoma (10%), and colon cancer (5%) [5-9]. The median survival of patients with brain metastases treated with whole-brain radiation therapy (WBRT) is only approximately 4 months [10-12]; clinical trials comparing various radiation therapy regimens and radiosensitizers have not demonstrated a survival benefit [13-19]. The majority of patients with brain metastases have neurologic and neurocognitive impairment [20]. In patients with primary brain tumors, neurocognitive impairments preventing functional independence have been shown to be more common than physical disability [21]. Any treatment that would reduce the severity of neurologic and neurocognitive impairments would therefore potentially enhance the quality of life of patients with brain metastases. Brain metastases not amenable to surgical resection are often treated with radiation therapy. However, normal tissue tolerance limits radiation dosage. Use of a tumor-selective agent that enhances radiation effect in tumors but spares normal brain might improve the therapeutic ratio of WBRT, improving local control of the tumor without increasing radiation toxicity. Motexafin gadolinium (MGd) targets tumors selectively and generates reactive oxygen species intracellularly, lowering the apoptotic threshold to radiation and chemotherapy. It increases tumor radiation response in vivo in preclinical models [22-24]. MGd is paramagnetic, and previous clinical studies have demonstrated tumor localization using magnetic resonance imaging (MRI) [25-27]. A randomized phase III study was conducted to determine if MGd, administered with WBRT, would improve outcome for patients with brain metastases [28]. Because patients with brain metastases frequently die as a result of systemic disease progression, a survival end point may be of limited value in assessing the clinical benefit of a new treatment for brain metastases. This study, therefore, employed tests of neurologic function and neurocognitive function (NCF) to evaluate the effect of improved local tumor control. Although, as reported elsewhere [28], no significant difference in survival was observed between the two treatment arms, differences in time to neurologic progression and NCF were observed between the two treatment arms. The relationship between NCF and clinical variables, as well as the results of treatment with MGd on NCF, are summarized in this report. This is the first large clinical trial in which neurocognitive assessments have been studied in patients with brain metastases.
Study Design The study design, treatment, and assessments have been described previously [28]. In brief, this was a prospective, open-label, multicenter clinical trial (institutions and investigators are listed in the Appendix). The protocol was reviewed and approved by institutional ethics committees at each participating center in accordance with the Helsinki Declaration. Written informed consent was obtained from each patient before participation in the trial.
Adult patients were eligible to participate if they had an MRI that demonstrated brain metastases from histologically proven solid tumors, required WBRT, and had a Karnofsky performance score (KPS) Patients were excluded if they had small-cell lung cancer, lymphoma, or germ cell tumors; had brain metastases that had been resected; had received prior cranial irradiation, including stereotactic radiosurgery; had leptomeningeal or liver metastases; or had two or more sites of extracranial metastases, except when breast was the primary cancer.
Treatments
Efficacy Assessments Patients were evaluated at entry, at monthly intervals for the first 6 months, and then every 3 months until death. MRI scans were obtained at baseline, at 2, 4, and 6 months, and then every 3 months, and were reviewed in a blinded manner [28]. Up to six measurable brain metastases were selected at presentation as indicator lesions, the sum of which is referred to in the text and tables that follow as indicator lesion volume. Data on postrandomization use of corticosteroids, anticonvulsants, and anticancer therapies were collected. All patients underwent a battery of standardized neurocognitive tests administered by trained and certified nurses or clinical research associates at each study visit [28]. All individuals administering these tests underwent thorough training by review of training manuals, videotapes, and hands-on instruction followed by certification. Completed neurocognitive tests were scored centrally by a blinded, central reviewer to remove potential treatment bias in assessing outcomes. z scores were derived from the patient's scores in the individual neurocognitive tests, using an age-adjusted (and for controlled oral word association [COWA], education-adjusted) normative distribution of scores from an unimpaired population. When a patient could not attempt or did not complete any of these tests, the primary cause of the missed assessment was recorded. Causes considered by investigators to be related to a disability resulting from a brain metastasis were included as progression in the analysis.
Patients were considered to be impaired in a particular neurocognitive test at baseline if their z score was
Statistical Methods and Sample Size Calculation
Predictors of neurocognitive impairment at baseline.
Univariate and stepwise logistic regression analyses were conducted to identify potential predictors of neurocognitive impairment (binary variable; Neurocognitive progression analysis. Tests were grouped into three domains of functioning: three memory domain tests were the Hopkins Verbal Learning Test (HVLT) for immediate recall, delayed recall, and recognition [29]; two executive function tests were COWA [30] and Trailmaking Test B [31]; two fine motor tests were pegboard dominant hand, pegboard nondominant hand [31]. Visual-motor scanning speed was measured by Trailmaking Test A [31]. Time-to-progression analysis used three progression definitions for each of the eight tests, thereby increasing the power and generalizability of the results. The three progression definitions were a worsening in each test's score from baseline by 3, 4.5, or 6 SDs in the test's normative distribution. In addition, each worsening only counted as a progression if it was confirmed by a subsequent assessment or if it was the last measurement before termination. Time to neurocognitive progression was analyzed using SUDAAN software (Release 8.0.1, Research Triangle Institute, Research Triangle Park, NC) by a repeated measures time-to-event Cox regression analysis with the tests in each domain and with the three levels of progression included as repeated measures. Patients were censored at the earliest occurrence of termination from the study, additional brain-related treatment, or death.
Survival analysis.
Factors predictive of survival were analyzed using Cox regression analysis. Both univariate and stepwise multivariate analyses were conducted. The following variables were included in the models: site of the primary tumor (lung v breast); sex; baseline albumin (low v normal); low, normal, or high baseline serum lactate dehydrogenase (LDH); KPS (70 to 80 v 90 to 100); age; baseline hemoglobin (low v normal); volume of indicator brain metastases; number of assessable brain metastases (
Patient Characteristics A total of 401 patients (251 patients with lung cancer, 75 patients with breast cancer, and 75 patients with other cancers) were randomly assigned to receive either MGd and WBRT (193 patients) or WBRT alone (208 patients). The two groups were balanced with respect to known prognostic features (Table 1). Brain was the only site of metastases in 50.8% of patients and the majority (80.1%) had multiple metastases. The majority of patients enrolled onto the study had non–small-cell lung cancer (NSCLC; n = 251). As previously reported, the clinical features of patients with lung cancer were found to differ significantly from patients with breast or other cancers [28]. More lung cancer patients had brain metastases at the time that their primary tumors were diagnosed, had brain as the only site of metastases, had a much shorter median time from primary cancer diagnosis to enrollment, had less prior systemic therapy, and had smaller median indicator lesion volume in the brain. There was no difference in the postrandomization use of corticosteroids, anticonvulsants, or anticancer therapy by treatment arm.
Compliance Baseline neurocognitive tests were completed by 87% to 98% of patients (Table 2). Completion rates of neurocognitive tests remained high at subsequent visits. For example, 77% to 87% of patients completed the tests at their 6-month visit.
NCF Test Results Baseline NCF was balanced between treatment arms for the overall study population and for each tumor strata. NCF was commonly impaired in patients at baseline; in particular, fine motor control, executive function, and memory (Table 2). Nearly all patients had some evidence of neurocognitive impairment at baseline: 363 (90.5%) patients had impairment of one or more neurocognitive tests at baseline, with 170 (42.4%) of the patients having impairment in four or more tests. Analyses of NCF versus the volume of indicator lesions at baseline and the number of brain metastases at baseline are shown in Table 3. NCF at baseline was not statistically correlated with the number of brain metastases at baseline, but each of seven neurocognitive tests demonstrated a high degree of correlation with the volume of the indicator lesion at baseline (P = .0036 for memory recognition, P = .0002 for COWA, and P < .0001 for each of the other five neurocognitive tests; Table 3).
Univariate and stepwise logistic regression analyses of global neurocognitive impairment (binary variable,  three or > three tests impaired) at baseline were performed using the following variables: age, sex, smoking history, prior chemotherapy (yes or no), number of prior chemotherapy cycles, number of prior chemotherapy regimens, prior neurotoxic chemotherapy (eg, vincristine or cisplatin; yes or no), number of brain metastases, time from primary tumor diagnosis to enrollment, and baseline indicator lesion volume. Lesion volume was the only predictor of global neurocognitive impairment at baseline in this model (P < .0001 for the univariate analysis, and P = .0014 for stepwise analysis).
Time to Neurocognitive Progression
Neurocognitive Test Scores and Lesion Volume Changes in NCF 2 months after treatment correlated with indicator lesion volume (Fig 3); patients with progressive disease had greater median changes in z scores for each neurocognitive test than did patients with partial response. Only patients with partial response demonstrated improvement in executive function (Trail B) and visual motor scanning (Trail A) tests.
NCF and Survival Analysis of neurocognitive test scores at baseline as univariate predictors of survival is shown in Table 5. Neurocognitive tests at baseline that were predictive of survival in univariate analysis included memory (HVLT recognition, recall, and delayed recall), motor speed and dexterity (pegboard test for dominant and nondominant hands), executive function (Trailmaking Test B), and global neurocognitive impairment (> three tests impaired; Table 5). A multivariate Cox proportional hazards analysis of survival with all eight neurocognitive tests included in the model demonstrated that HVLT recognition and recall remained as independent predictors of survival (P = .0323 and P = .0342, respectively).
When clinical as well as neurocognitive parameters are included, the pegboard dominant hand test at baseline was predictive of survival in a stepwise multivariate analysis (P = .0233; Table 6). Other factors predictive of survival included sex, number of brain metastases (one to two v > two), KPS (70 to 80 v 90 to 100), high LDH, low LDH, low albumin, time from primary tumor diagnosis to enrollment, and breast cancer. Impaired pegboard test scores, male sex, more than two brain metastases, low KPS, primary tumor other than breast cancer, high LDH, low albumin, and intermediate time to primary tumor diagnosis were associated with shorter survival (Table 6).
This study used several measurements of NCF and neurologic progression to determine the potential benefit of MGd when added to WBRT to address the limitations of a survival end point in assessing the value of a treatment aimed at improving tumor control in the brain. The neurologic progression end point provided a clinical measure of the impact of brain metastases progression on neurologic function. NCF was assessed because it is objective and not dependent on self-reporting, which could be unreliable because of impairment caused by tumor growth and treatment. Although never previously measured in patients with brain metastases, in glioblastoma multiforme, neurocognitive progression is predictive for survival [32]. Performance on neurocognitive tests is related to the patient's ability to manage finances, recognize safe and unsafe behaviors, and remember and comply with medication regimens [21,33]. This is one of the first reports of prospective neurocognitive testing and analysis in patients with brain metastases, including baseline pretreatment assessments. Nearly all patients had some degree of neurocognitive impairment at baseline and multiple neurocognitive impairments were common. NCF at baseline was highly correlated with the volume of the indicator lesions at baseline but not statistically correlated with the number of brain metastases. This suggests that NCF is more affected by tumor burden than by number of lesions. This is a reasonable finding considering these mass effects occur within a fixed intracranial space. NCF at baseline was predictive of overall survival duration in patients with brain metastases. Neurocognitive tests at baseline that were predictive of survival in univariate analysis included memory, motor speed and dexterity, executive function, and global neurocognitive impairment. Only memory was predictive of survival in the multivariate analysis. Pegboard dominant hand performance at baseline was also found to be predictive of survival in a stepwise multivariate analysis that included clinical as well as neurocognitive variables. The finding that memory performance was significant in the model with only neurocognitive tests but not in the model that included clinical variables reflects a statistical dependence between memory performance and the included clinical variables. This suggests that memory function, tumor biology, extent of spread, prior therapy, or other clinical features have an overlapping effect on survival. These neurocognitive results are consistent with those of Mehta et al [20] who reported that test scores of executive function and fine motor coordination bilaterally are significantly associated with survival. Meyers et al [32] have similarly reported that cognitive function, specifically performance on a test of verbal memory, is an important prognostic factor in predicting survival in patients with recurrent malignant glioma. The relation between cognitive functioning and survival, observed in these different studies, suggests that cognitive tests are a relatively sensitive measure of the functioning of the brain and that a combination of tumor prognostic variables and brain function assessments seem to predict survival better than tumor variables alone in patients with brain metastases. Neurocognitive testing revealed a benefit in prolonging time to neurocognitive progression in six tests of memory and executive function for patients with brain metastases from lung cancer (but not from breast or other tumor types) treated with MGd and WBRT compared with WBRT alone. A significant delay in time to neurologic progression for patients treated with the MGd and WBRT as assessed by the investigators (P = .018, unadjusted) has been found. This benefit was primarily seen in the lung cancer patient group (P = .025, unadjusted), as previously reported. In that study, a statistically significant benefit with MGd treatment in the prespecified lung cancer subgroup was found by both a blinded review committee and clinical investigators [28]. Although death is a competing end point that is censored in these analyses, the similarity in overall survival between treatment arms minimizes concern that censoring influenced the results. There are several possible reasons why a benefit was observed favoring the MGd and WBRT treatment arm in lung cancer patients for time to both neurocognitive and neurologic progression. Patients with lung cancer in this trial differed substantially from patients with breast and other cancers; lung cancer patients more often presented with brain metastases at their initial primary tumor diagnosis, had brain as the only known site of metastases, had smaller lesion volume, and had less prior therapy [28]. It is likely that less extensive intracranial disease, more rapid and reversible development of CNS signs and symptoms, and less exposure to potentially neurotoxic chemotherapies provide a greater opportunity to demonstrate a benefit in this subgroup. Recently, Sperduto et al [34], in a study of WBRT with or without stereotactic radiosurgery in patients with one to three brain metastases, similarly observed a treatment benefit in a lung cancer subgroup. This study demonstrates that the combination of neurocognitive tests and tumor prognostic variables predicts survival better than tumor variables alone. Addition of MGd to WBRT appeared to improve memory and executive function and prolong time to neurocognitive progression in patients with brain metastases from lung cancer. A randomized phase III trial in patients with brain metastases from NSCLC has been initiated to confirm the benefits seen in this study.
The following investigators and institutions participated in the study: T. Batchelor, Massachusetts General Hospital, Boston, MA; A. Bezjak, Princess Margaret Hospital, Toronto, Ontario, Canada; M. Brada, The Royal Marsden NHS Trust, Surrey, United Kingdom; H. Brereton, Radiation Medicine Association of Scranton, Scranton, PA; C. Carrie, Centre Léon-Bérard, Lyon, France; J. Caudrelier, Centre Oscar Lambret, Lille, France; A. Cmelak, Vanderbilt University, Nashville, TN; C. Collier, Amsterdam Community Cancer Program, Amsterdam, NY; I. Crocker, Emory University, Atlanta, GA; M. Croghan, Arizona Oncology Associates, Tucson, AZ; P. Eisenberg, Marin Oncology Associates, Greenbrae, CA; B. Fisher, London Regional Cancer Centre, London, Ontario, Canada; J. Ford, University of California Los Angeles Medical Center, Los Angeles, CA; A. Frank, Riverview Cancer Care Medical Associates, Rexford, NY; L. Gaspar, University of Colorado, Denver, CO; C. Haie-Meder, Institut Gustave Roussy, Villejuif, France; T. Illidge, Wessex Cancer Centre, Southampton, United Kingdom; M. Katin, Radiation Therapy Services Inc, Fort Myers, FL; R. Komaki, University of Texas M.D. Anderson Cancer Center, Houston, TX; P. Kumar, Cancer Institute of New Jersey, New Brunswick, NJ; I. Kunkler, Western General Hospital, Edinburgh, United Kingdom; F. Lagerwaard, Daniel den Hoed Kliniek, Rotterdam, the Netherlands; Q. Le, Stanford University School of Medicine, Stanford, CA; M. Leibenhaut, Radiological Associates of Sacramento, Sacramento, CA; J. Liebmann, New Mexico Hematology Oncology, Albuquerque, NM; K. Levin, Wayne State University, Detroit, MI; E. Levine, Christie Hospital NHS Trust, Manchester, United Kingdom; J. Mazeron, Hôpital de la Pitié-Salpêtrière, Paris, France; S. McCachren, Thompson Cancer Survival Center, Knoxville, TN; J. Meerwaldt, Medisch Spectrum Twente, Enschede, the Netherlands; M. Mehta, University of Wisconsin, Madison, WI; F. Mott, Scott & White Hospital, Temple, TX; R. Pezner, City of Hope National Medical Center, Duarte, CA; P. Pickens, Abington Hematology Oncology Associates, Meadowbrook, PA; A. Rao, Kaiser Permanente, Los Angeles, CA; J. Rieke, Virginia Mason Medical Center, Seattle, WA; W. Roa, Cross Cancer Centre Institute, Edmonton, Alberta, Canada; P. Rodrigus, Dr Bernard Verbeeten Instituut Tilburg, the Netherlands; S. Sagar, Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada; M. Saunders, Tyler Cancer Center, Tyler, TX; A. Schorer, Department of Veterans Affairs Medical Center, Minneapolis, MN; C. Schultz, Medical College of Wisconsin, Milwaukee, WI; M. Seiler, Hematology Oncology, New Orleans, LA; R. Siemers, North Memorial Research Center, Minneapolis, MN; L. Souhami, Montreal General Hospital, Montreal, Quebec, Canada; L. Stalpers, Academisch Medisch Centrum, Amsterdam, the Netherlands; J. Suh, Cleveland Clinic, Cleveland, OH; C. Terhaard, Academisch Ziekenhuis, Utrecht, the Netherlands; R. Timmerman, Indiana University Medical Center, Indianapolis, IN; Y. Ung, Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada; and M. Werner-Wasik, Thomas Jefferson University, Philadelphia, PA.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): J. Smith, Pharmacyclics; S. Phan, Pharmacyclics; R. Miller, Pharmacyclics; M. Renschler, Pharmacyclics. Acted as a consultant within the last 2 years: M. Mehta, Pharmacyclics; W. Curran, Pharmacyclics. Performed contract work within the last 2 years: C. Meyers, Pharmacyclics. Served as an officer of the Board of a company: R. Miller, Pharmacyclics. Received more than $2,000 a year from a company for either of the last 2 years: C. Meyers, Pharmacyclics; M. Mehta, Pharmacyclics.
We thank Matt Downs and Heidi Christ-Schmidt at Statistics Collaborate Inc for their invaluable help with the analysis plan, and Gary Koch, PhD, at the Department of Biostatistics, University of North Carolina (Chapel Hill, NC) for his helpful suggestions regarding the SUDAAN analysis.
The study drug and funding for this research were provided by Pharmacyclics Inc. This study was presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18–21, 2002, Orlando, FL; 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 6–10, 2002, New Orleans, LA; and 7th Annual Meeting of the Society of Neuro-Oncology, November 21–24, 2002, San Diego, CA. C.A.M and J.A.S. contributed equally to this manuscript. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
70. 
