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Lead-In Phase to Randomized Trial of Motexafin Gadolinium and Whole-Brain Radiation for Patients With Brain Metastases: Centralized Assessment of Magnetic Resonance Imaging, Neurocognitive, and Neurologic End Points

From the Department of Human Oncology, University of Wisconsin, Madison, and Division of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; Barrow Neurologic Institute, Phoenix, AZ; University of Massachusetts, Amherst, MA; University of Kentucky, Lexington, KY; Psychiatry Service, H. Lee Moffitt Cancer Center, Tampa, FL; Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; Division of Radiation Oncology, Cross Cancer Institute, Alberta, Edmonton, Canada; Radiological Associates of Sacramento, Sacramento, Division of Radiation Oncology, UCLA, Los Angeles, and Pharmacyclics, Inc, Sunnyvale, CA; and Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA.

Address reprint requests to Minesh Mehta, MD, Department of Human Oncology, University of Wisconsin–Madison Medical School, K4/334 Clinical Science Center, 600 Highland Ave, Madison, WI 53792; email: mehta{at}mail.humonc.wisc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
PURPOSE: Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation therapy. This lead-in phase to a randomized trial served to evaluate radiologic, neurocognitive, and neurologic progression end points and to evaluate the safety and radiologic response of motexafin gadolinium administered concurrently with 30 Gy in 10-fraction whole-brain radiation therapy for the treatment of brain metastases.

PATIENTS AND METHODS: Motexafin gadolinium (5.0 mg/kg/d for 10 days) was administered before each radiation treatment in this prospective international trial. Patients were evaluated by MRI, neurologic examinations, and neurocognitive tests. Prospective criteria and centralized review procedures were established for radiologic, neurocognitive, and neurologic progression end points.

RESULTS: Twenty-five patients with brain metastases from lung (52%) and breast (24%) cancer, recursive partitioning analysis class 2 (96%), and an average of 11 brain metastases were enrolled. Neurocognitive function was highly impaired at presentation. Motexafin gadolinium was well tolerated. Freedom from neurologic progression was 77% at 1 year. Median survival was 5.0 months. In 29% of patients, the cause of death was brain metastasis progression. The radiologic response rate was 68%. Motexafin gadolinium’s tumor selectivity was established with MRI.

CONCLUSION: (1) Centralized neurologic progression scoring that incorporated neurocognitive tests was implemented successfully. (2) Motexafin gadolinium was well tolerated. (3) Local control, measured by radiologic response rate, neurologic progression, and death caused by progression of brain metastasis, seemed to be improved compared with historical results. A randomized phase III trial using these methods for evaluation of efficacy has just been completed.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
BRAIN METASTASIS is a common consequence of many cancers, occurring in as many as 24% of all cancer patients, according to autopsy data.¹ The outcome of patients with brain metastases is generally poor, with a median survival of approximately 4 months.^2-4 Local control of brain metastasis remains a problem, with approximately 30% to 55% of patients dying from progression of brain metastases despite the use of whole-brain radiation.³

Motexafin gadolinium (Xcytrin Injection; Pharmacyclics, Inc, Sunnyvale, CA), previously known as gadolinium texaphyrin or Gd-Tex,⁵ is a redox mediator that selectively targets tumor cells. Motexafin gadolinium catalyzes the oxidation of intracellular reducing metabolites such as ascorbate, glutathione, dihydrolipoate, nicotinamide adenine dinucleotide phosphate, and protein thiols, generating reactive oxygen species in a process known as futile redox cycling.^6-8 Previous studies have shown that motexafin gadolinium enhances radiation responsiveness in several animal tumor models.^8,9

The selective uptake and retention of motexafin gadolinium in tumors, but not in normal tissues, has been demonstrated in animal models⁹ and in patients using magnetic resonance imaging (MRI).^10-12 In a previously published phase Ib/II trial, motexafin gadolinium was administered with 30 Gy in 10-fraction whole-brain radiation to 61 patients with brain metastases.¹² The trial established that motexafin gadolinium 5 mg/kg/d was a safe and well-tolerated dose. A radiologic response rate of 72%, with only 12% of patients experiencing death caused by CNS tumor progression, suggested a potentially favorable effect on local control and efficacy.¹²

The purpose of the current study was to serve as the lead-in phase for an international, multicenter, prospective, randomized phase III trial evaluating the safety and efficacy of motexafin gadolinium in patients with brain metastasis receiving cranial irradiation. The lead-in phase was performed to confirm safety at the selected dose, to evaluate prospective progression criteria for radiologic, neurocognitive, and neurologic progression end points, and to establish the feasibility of centralized scoring for these novel end points.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
Study Design
This was a prospective, open-label, international, multicenter trial (see Appendix 1 for institutions and investigators). The protocol was reviewed and approved by institutional committees on human experimentation at each participating center in accordance with the Helsinki Declaration.¹³ Written informed consent was obtained from each patient before participation in the trial.

Patient Selection Criteria
Adult patients were eligible if they had radiologically demonstrated brain metastases from histologically proven solid tumors requiring whole-brain radiation therapy (WBRT) and if their Karnofsky performance status (KPS) was 70. Patients were excluded if they had small-cell cancer, lymphoma, or germ cell tumors, if their metastases had been partially or completely resected, if they had received prior cranial irradiation, if they had leptomeningeal metastases, or if they had two or more sites of extracranial metastases, except from breast cancer. They were also excluded if concurrent chemotherapy was planned during WBRT or the subsequent 14 days or if upfront radiosurgery was being contemplated.

Minimal laboratory requirements included the following: absolute granulocyte count 1,500/mm³; platelet count 50,000/mm³; total bilirubin, ALT, and AST two times the upper limit of normal; and serum creatinine 2.0 mg/dL.

Treatment Methods
Drug administration. Motexafin gadolinium, 2.3 mg/mL in 5% mannitol (pH 5.5), was filtered through a 0.45- to 5-µm filter (Millex HV; Millipore Corp, Bedford, MA) using a sterile technique and injected intravenously at a dose of 5 mg/kg/d for 10 to 30 minutes, at least 2 hours but no more than 5 hours before WBRT. Patients with nausea or vomiting after the first dose were premedicated with antiemetics before they received subsequent doses.

Radiation. WBRT was delivered Monday through Friday in 10 daily fractions of 3 Gy using megavoltage radiation. Treatments were delivered through parallel-opposed fields covering the entire cranial contents. The target volume covered the brain and meninges to 1 cm below the foramen magnum. Appropriate field arrangements and blocking were used to shield the patients’ eyes. Doses were specified at the central axis at midplane. Any photon energy could be used, but electrons were not permissible. Boosts were not allowed. Radiosurgery was only permitted at relapse.

Evaluation Methods
Clinical evaluation. All patients were evaluated at entry and after treatment until death. They were seen monthly until 6 months, then every 3 months. Adverse events were graded according to the National Cancer Institute’s common toxicity criteria, version 2. Any baseline neurologic deficits caused by the presence of brain metastases were documented at study entry. At every subsequent study visit, neurologic symptoms and signs found on history and neurologic examination were recorded. Signs and symptoms noted at study screening were tracked throughout the follow-up period. At every visit, investigators provided their clinical assessment of the effect the patient’s brain metastasis had on overall neurologic function. Investigators rated whether the patient experienced neurologic progression based on protocol-defined radiologic progression criteria or progressing neurologic signs or symptoms.

MRI. Standardized MRI scans were obtained at baseline, after WBRT completion, at 2, 4, and 6 months, and then every 3 months until death. T1- and T2-weighted images, with and without standard gadolinium contrast agents, were obtained using 5-mm slices without gaps. All MRI scans were analyzed at a central imaging laboratory (BioImaging Technologies, Newtown, PA) using electronic displays of digitally transferred images on high-resolution monitors. Patients with at least one follow-up MRI scan were assessable for their responses. The T1-gadolinium–enhanced images (using standard MRI contrast agents) were used for tumor measurement. The pretreatment MRI scan was used as the baseline study for numeric response assessment.

To determine the contours of each brain metastasis, a semiautomated intensity thresholding technique was used to segment each lesion from the surrounding normal tissue.¹⁴ A neuroradiologist counted all lesions and edited and confirmed lesion boundaries on every slice. The true area of the lesion was automatically determined and multiplied by the slice thickness to obtain the volume of each lesion per slice. These volumes were then added to obtain the lesion volume. Up to six lesions were chosen as indicator lesions. The volumes of the indicator lesions were added to evaluate the treatment response. The radiologist first reviewed the baseline scan, followed by the subsequent scans in random order. After the volumetric assessment was completed, the images were displayed in the proper temporal sequence to confirm the response based on volumetric data. Protocol-defined volumetric response criteria were complete disappearance of all assessable lesions for complete response, a 50% reduction in indicator lesion volume for a partial response, a less than 50% decrease and less than 25% increase in indicator lesion volume for stable disease, and 25% increase in indicator lesion volume, doubling of a single indicator lesion, new lesions, or the appearance of leptomeningeal metastasis for progressive disease. Conventional response criteria requiring a 65% decrease in tumor volume (the volumetric equivalent of a 50% decrease in the product of the greatest perpendicular cross-sectional diameters) for partial response, a 40% increase in tumor volume from nadir (the volumetric equivalent of a 25% increase in the product of the greatest perpendicular cross-sectional diameters) for progressive disease, and a less than 65% decrease and less than 40% increase for stable disease were collected as well. The semiautomated thresholding technique was selected because in at least one rigorous analysis, it has been demonstrated that tumor size is obtained more accurately and consistently between readers using an automated autocontour technique than between those using hand-held or electronic calipers.¹⁴

Neurocognitive function testing. All patients at each study visit underwent a battery of standardized neurocognitive tests administered by trained and certified nurses or clinical research associates. All individuals administering these tests underwent thorough training, including hands-on training, training manuals, and videotapes, followed by certification by one of the authors (C.A.M.). The tests included the Trailmaking Tests A and B,¹⁵ the Hopkins Verbal Learning Tests (HVLTs),^16,17 the Controlled-Oral Word Association (COWA),^15,18 and the grooved pegboard tests for dominant and nondominant hands.¹⁹ The two trailmaking tests require patients to connect circles in numerical (part A) or alternating numerical and alphabetical sequence (part B; eg, 1, A, 2, B, and so on) within a timed interval of no more than 5 minutes each. The HVLTs require patients to memorize a list of 12 items for three consecutive tests (recall), to identify the same 12 items from a list of semantically related or unrelated items (recognition), and to recall the 12 items after a 15-minute delay (delayed recall). COWA requires patients, in three 1-minute periods, to name words beginning with a specified letter, each increasing in associative difficulty. The grooved pegboard test requires patients to place pegs in the correct orientation into 25 slots using a single hand within a 5-minute period. The chosen tests assessed specific neurologic functional domains that may be impaired in patients with brain tumors. Trailmaking Test A assesses information processing efficiency, Trailmaking Test B and COWA assess executive function, the HVLTs (recall, recognition, and delayed recall) assess memory, and the grooved pegboard tests assess fine motor coordination. Completed tests were scored centrally (C.A.M.) at the University of Texas M.D. Anderson Cancer Center. Z-scores were derived from the patient’s scores in the individual neurocognitive tests using an age-adjusted (and, for COWA, education-adjusted) normative distribution of scores from an unimpaired population.^16,18,19 Individual z-scores from related tests were averaged to determine the overall z-score for a neurocognitive functional domain (memory, executive function, and fine motor coordination). When a patient could not attempt or did not complete any one 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 differentiated from all other causes.

Quality-of-life assessments. The Functional Assessment of Cancer Therapy with Brain Subscale^20,21 was self-administered, and the Barthel Index of activities of daily living (ADLs)²² was completed at each visit. The Barthel Index assesses a patient’s ability to carry out ADLs as reported by the patients, their families, or their caregivers. The Barthel ADL score ranges from 0 to 20, with 20 corresponding to a normal functional status.

Determination of neurologic progression by a centralized events review committee. An independent events review committee (ERC), consisting of four independent clinicians from institutions that did not enroll patients onto the trial, (one neurologist [R.A.P.], two neuro-oncologists [W.R.S. and M.J.G.], and a neuropsychiatrist [M.A.W.]) reviewed data for all patients. The ERC determined the end point of neurologic progression or death with neurologic progression, on the basis of prospectively established progression criteria. Patients were considered to have neurologic progression if they showed clinical deterioration that was related to worsening of their brain metastases during study follow-up or at the time of death. After viewing the presenting history and baseline brain MRI, the ERC evaluated a patient’s neurologic status in three domains: (1) neurocognitive function, (2) neurologic signs, and (3) neurologic symptoms. These data were provided to the ERC in an electronic format as a series of graphs and listings showing the patient’s neurologic examination and symptom data, neurocognitive test results, quality-of-life and Barthel scores, corticosteroid and narcotic use, and any additional chemotherapy, radiation therapy, or cancer-related surgeries over the course of the study follow-up period until death (see Appendix 2 for example screenshots). The ERC used these domains to identify patients who demonstrated clinical worsening in their neurologic status from any cause. Progression required deterioration in at least two of the three neurologic domains. The committee used the following specific guidelines to determine when deterioration occurred in each neurologic domain:

(1) Neurocognitive function: If a z-score average increased from baseline by 2 or more (indicating a deterioration by greater than 2 SDs) on two consecutive visits, or increased by 2 on the last follow-up visit before death, patients were considered to have had significant deterioration in their neurocognitive function at the time of the first z-score increase. Patients unable to complete testing because of a disability related to their brain metastases were considered to have had possible deterioration.

(2) Neurologic signs and (3) neurologic symptoms: Deterioration was only considered if clinically significant and consistent with the presence of brain metastases (eg, unilateral motor weakness) and if the findings were persistent. The ERC was empowered to supersede any of these rules if their clinical judgment disagreed with the outcome dictated by the rules. Confounding factors that might affect patients’ neurologic function, such as narcotic use, corticosteroid use, metabolic derangements, or continued treatment of their extracranial cancers, were provided to the ERC.

For patients with deterioration in at least two of the three neurologic domains, the ERC was given the MRI results showing tumor response, tumor volumes, and lesion counts over time, with medical narratives describing major medical events such as hospitalizations. In cases with inadequate follow-up data, the ERC also used investigator assessments of patient status to make their determinations. To meet the end point of neurologic progression, the ERC had to reach a consensus that the observed deterioration in the neurologic domains was related to the underlying brain metastases and not to alternative causes (eg, hepatic encephalopathy or other metabolic abnormalities).

For patients experiencing neurologic progression during study follow-up, the ERC assigned the date of neurologic progression as the date with the earliest evidence of progression. For patients who only showed neurologic progression at the time of death, the ERC assigned the date of neurologic progression as the date of death. Patients who received additional brain metastases–directed treatments, and did not have prior evidence of neurologic progression, were censored at the time of the additional treatment. However, they were followed up until death. Patients who died or terminated study follow-up and did not have prior evidence of neurologic progression were censored at the time of death or termination from follow-up. MRI results were used to confirm clinical findings and could not, as a sole result, be used to determine the specific clinical neurologic progression end point.

Statistical Methods
The sample size was chosen to obtain additional safety data at the motexafin gadolinium dose of 5 mg/kg/d before commitment to a randomized phase III trial. It was also chosen to evaluate the feasibility of the technical components of the trial, such as electronic data transfer (of MRI scans and case report forms), centralized end point review, and neurocognitive testing in an international multicenter setting. The survival data and time to neurologic progression or death with neurologic progression were plotted using the Kaplan-Meier method.²³

The specific rationale for setting up the ERC was to pilot centralized and blinded assessment of an important clinical end point, freedom from neurologic progression, specifically for the phase III component of the trial. Individual investigators are not blinded to treatment assignment and are therefore more likely to introduce bias in the measurement of a relatively subjective end point; the ERC members are blinded to treatment assignment and therefore would be less biased and apply standardized progression criteria for all patients, irrespective of treatment arm. Furthermore, the threshold for an individual investigator to designate neurologic progression may be quite variable; the ERC, on the other hand, because of its small composition and consistency of data reviewed, would have a much better defined and narrower threshold in this report.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
Twenty-five patients were enrolled onto the trial between November 1998 and April 1999. Their characteristics are shown in Table 1. There were nine men and 16 women, with a median age of 56 years (range, 33 to 78 years). The majority of patients in this trial had underlying lung or breast cancer, which is typical for patients with brain metastasis. One patient was classified as recursive partitioning analysis class 1 and the remainder (96%) as recursive partitioning analysis class 2, based on age, primary tumor status, or the presence of extracranial disease.² Primary tumors were uncontrolled in 56% of patients. Extracranial metastases in one site were found in 72% of patients and in two or more sites in 12% of patients. The median number of brain metastases was five (range, one to 51); the mean was 11. Five patients (20%) had single brain metastases; three patients (12%) had two brain metastases, and 17 (68%) had four or more lesions. Most patients were ineligible for radiosurgery by Radiation Therapy Oncology Group (RTOG) criteria, on the basis of location, size, and number of lesions. The mean lesion volume of the index lesions was 3.3 mL (range, < 0.8 to 51.2 mL), with a mean diameter of 1.7 cm. The mean volume of the tumor burden (sum of indicator lesions) was 10.8 mL (range, < 0.8 to 102.2 mL).

Tumor Selectivity
Noncontrast MRI scans (Figs 1A and 1B) obtained before the first and after the 10th motexafin gadolinium administration showed a characteristic tumor-specific signal enhancement in brain metastases, but not in normal brain, indicating selective targeting of tumors. The MRI signal enhancement is produced by the paramagnetic gadolinium ion contained within the motexafin gadolinium complex. Figure 1C shows a standard contrast-enhanced MRI scan of the same patient at 2 months, demonstrating a partial response.

View larger version (36K): [in this window] [in a new window]   Fig 1. T1-weighted brain MRI scans of a patient with non–small-cell lung cancer: (A) noncontrast scan at baseline; (B) noncontrast scan after the 10th administration of motexafin gadolinium; (C) gadolinium-enhanced contrast scan at 2 months.

View larger version (13K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates of time to all-cause mortality with 95% confidence intervals (dotted lines).

View larger version (47K): [in this window] [in a new window]   Fig 3. Percentage of patients with neurocognitive impairment, defined as a score at least 1.5 SDs worse than the normative mean in normal subjects, at baseline, by test.

View larger version (13K): [in this window] [in a new window]   Fig 4. Kaplan-Meier estimate of freedom from neurologic progression with 95% confidence intervals (dotted lines).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

A previous phase Ib/II study of motexafin gadolinium established 6.3 mg/kg/d as the maximum-tolerated dose.¹² More adverse events occurred at 6.3 mg/kg/d in that study than at 5.0 mg/kg/d, and doses above 6.3 mg/kg/d produced dose-limiting hepatotoxicity. A previous phase I trial found dose-limiting renal toxicity at a single dose above 22.3 mg/kg.¹⁰ The current study reported here found 10 doses of 5.0 mg/kg/d were well tolerated, drug-specific toxicity was minimal, and renal toxicity was not seen. Also, there were fewer occurrences of hepatotoxicity than in the phase Ib/II study. There was no grade 3 or greater hepatotoxicity definitely related to motexafin gadolinium administration in this study. This may be due to the lower drug dose or more stringent entry criteria—this study required a KPS 70, compared with a KPS 50 in the phase Ib/II trial. Patients in previous trials were hydrated with intravenous fluids; the omission of prehydration in this study did not have an adverse impact on renal function. Future studies should not require intravenous hydration before administration of motexafin gadolinium, unless the patient is dehydrated. In that case, oral or intravenous hydration with 500 to 1,000 mL of an appropriate fluid may be indicated.

Centralized reading of electronically transmitted MRI images using standard settings was successfully implemented in this study. An algorithm was developed in which the sequence of follow-up images was scrambled for each patient, requiring the neuroradiologist to compare each scan with the baseline scan for progression, without bias from the previous follow-up MRI scan. This algorithm is also being used in the phase III trial to blind the reader to treatment assignment, which might be associated with a survival difference and hence a different number of follow-up MRI scans. A semiautomated intensity thresholding technique was used to segment each lesion from the surrounding normal brain. The lesion boundary created in this fashion was edited as needed by the neuroradiologist. The program determined the true area of the lesion boundary and calculated the volume by multiplying the true area by the slice thickness and summing the subvolumes from each slice. The software also generated conventional cross-sectional diameter measurements using the lesion boundary on the image with the largest lesion area. Volumetric and cross-sectional response criteria resulted in identical response rates of 68%, confirming that the volumetric method does not overestimate the response rate. The radiologic response rate in this study is similar to the previous response rate of 72% reported in the phase Ib/II trial.¹² This response rate compares favorably with historical data. Using contrast-enhanced computed tomography scans, the RTOG reported a radiologic response rate of 47% in 633 patients treated with 30 to 70.4 Gy in RTOG studies 79-16, 85-28, and 89-05.² Nieder et al²⁴ reported a radiologic response rate of 43% in 138 patients treated with 30 Gy. Radiologic response in patients in this study was associated with better survival, consistent with reports in the literature. Gaspar et al² suggested that radiologic response was a favorable prognostic factor in predicting survival in univariate models, and Nieder et al²⁴ showed radiologic response to be an independent predictor of survival in a multivariate model.

Selective uptake and retention of the MRI-detectable motexafin gadolinium in brain metastases, but not in normal brain, was demonstrated by MRI, as previously reported.¹¹ Patients in this study had a median of 11 brain metastases; 68% had four or more lesions. This tumor burden is significantly greater than reported in prior clinical and autopsy experiences, which suggest that the majority of patients have three or fewer lesions. This may possibly be because most of the centers participating in this trial also use radiosurgery for brain metastases and patients with fewer lesions were not offered participation in this trial. An alternative explanation is that prior reports of lesion number are generally based on computer tomography scans, which may potentially underestimate lesion count.

This is one of the first reports of prospective neurocognitive functional analysis in patients with brain metastases, including baseline pretreatment assessment. Study nurses and data managers were trained to carry out the standardized neurocognitive testing in an international setting. The chosen battery of tests was completed with a high compliance rate by patients with brain metastases. The experience has now been emulated by the RTOG, which has completed enrollment onto its trial 00-18 (> 50 patients), a pilot trial to test the feasibility of administering a similar neurocognitive battery in a cooperative group, multi-institutional setting. These patients were found to have a high degree of baseline neurocognitive impairment, especially in verbal memory, fine motor coordination, and executive function. Since study entry required a KPS of 70, most patients were already "stabilized" on corticosteroids before the baseline neurocognitive testing. Therefore, this high level of impairment does not reflect an acute increase in intracranial pressure but more likely represents a global effect on the brain from the metastases or the advanced malignancy. A similar observation was reported for patients receiving chest irradiation and chemotherapy for limited-stage small-cell lung cancer.²⁵

This is the first report of an association of neurocognitive function with overall survival in patients with brain metastases. In univariate proportional hazards models, tests scores of executive function and fine motor coordination bilaterally were highly associated with survival. This preliminary finding needs to be confirmed and can be tested in multivariate models in the recently completed phase III study.

A novel algorithm was developed for scoring neurologic progression by a panel of experts. User-friendly, temporally sequenced computer graphics were developed and used to display all clinical data in a graphical format for rapid review by the panel. The panel developed prospective criteria to determine progression of neurocognitive function, neurologic symptoms, and neurologic signs. If clinical deterioration in any two of the three domains was evident, the radiologic data were used to confirm whether deterioration was due to progression of brain metastases. In the absence of neurologic progression as determined by the ERC, MRI progression was not sufficient for neurologic progression and patients were scored as progression-free with respect to this end point. The neurologic progression end point is therefore a clinical measure of the impact of brain metastasis progression on neurologic function. The actuarial rate of freedom from neurologic progression at 1 year was 77%.

Consistent with the high radiologic response rate of 68% and the high freedom from neurologic progression, only 29% of patients died from progression of brain metastases based on clinical assessment by the treating physician. The RTOG has previously reported brain metastases to be the direct cause of death in one third to one half of patients enrolled onto RTOG studies 79-16, 85-28, and 89-05.² Lagerwaard et al³ reported that 57% of 807 patients died from brain metastases progression.

Motexafin gadolinium was easily administered. When combined with WBRT of 30 Gy in 10 fractions, treatment resulted in a consistently high radiologic response rate and decreased deaths from brain metastasis progression relative to historic controls. Centralized, electronically driven, volumetric response assessment, prospective neurocognitive functional assessment, and independent clinical assessment of neurologic progression were successfully implemented in this multi-institutional international clinical trial.

	APPENDIX 1

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
The appendices listing participating institutions and investigators and screenshot examples of the electronic review tool used by ERC are available online at www.jco.org.

	APPENDIX 2

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

View larger version (61K): [in this window] [in a new window]   Fig 5.

View larger version (61K): [in this window] [in a new window]   Fig 6.

View larger version (54K): [in this window] [in a new window]   Fig 7.

View larger version (53K): [in this window] [in a new window]   Fig 8.

	ACKNOWLEDGMENTS

 
Supported by Pharmacyclics, Inc, Sunnyvale, CA.

We thank Art DeVault for critical review of the manuscript, Marilyn Ciraulo and David Eber for programming support, and Susan Caldwell for assistance in preparing the manuscript.

	NOTES

 
S.P, J.A.S., R.A.M., and M.F.R. are employees and shareholders of Pharmacyclics, Inc.

Presented in part at the Forty-Second Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Boston, MA, October 22-26, 2000.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX 1 APPENDIX 2 REFERENCES

 
1. Posner JB: Neurologic Complications of Cancer. Philadelphia, PA, F.A. Davis Company, 1999

2. Gaspar L, Scott C, Rotman M, et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37: 745-751, 1997[CrossRef][Medline]

3. Lagerwaard FJ, Levendag PC, Nowak PJ, et al: Identification of prognostic factors in patients with brain metastases: A review of 1292 patients. Int J Radiat Oncol Biol Phys 43: 795-803, 1999[CrossRef][Medline]

4. Nieder C, Nestle U, Motaref B, et al: Prognostic factors in brain metastases: Should patients be selected for aggressive treatment according to recursive partitioning analysis (RPA) classes? Int J Radiat Oncol Biol Phys 46: 297-302, 2000[CrossRef][Medline]

5. Mody TD, Fu L, Sessler JL: Texaphyrins: Synthesis and development of a novel class of therapeutic agents, in Karlin KD (ed): Progress in Inorganic Chemistry, Vol 49. New York, NY, John Wiley & Sons, 2001, pp 551-598

6. Magda D, Lepp C, Gerasimchuk J, et al: Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species. Int J Radiat Oncol Biol Phys 51: 1025-1036, 2001[CrossRef][Medline]

7. Sessler JL, Tvermoes NA, Guldi DM, et al: Pulse radiolytic studies of metallotexaphyrins in the presence of oxygen: Relevance of the equilibrium with superoxide anion to the mechanism of action of the radiation sensitizer motexafin gadolinium (Gd-Tex2+, Xcytrin). J Phys Chem 105: 1452-1457, 2001

8. Xu S, Zakian K, Thaler H, et al: Effects of motexafin gadolinium on tumor metabolism and radiation sensitivity. Int J Radiat Oncol Biol Phys 49: 1381-1390, 2001[CrossRef][Medline]

9. Miller RA, Woodburn K, Fan Q, et al: In vivo animal studies with gadolinium (III) texaphyrin as a radiation enhancer. Int J Radiat Oncol Biol Phys 45: 981-989, 1999[CrossRef][Medline]

10. Rosenthal DI, Nurenberg P, Becerra CR, et al: A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging. Clin Cancer Res 5: 739-745, 1999[Abstract/Free Full Text]

11. Viala J, Vanel D, Meingan P, et al: Phases IB and II multidose trial of gadolinium texaphyrin, a radiation sensitizer detectable at MR imaging: Preliminary results in brain metastases. Radiology 212: 755-759, 1999[Abstract/Free Full Text]

12. Carde P, Timmerman R, Mehta MP, et al: Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases. J Clin Oncol 19: 2074-2083, 2001[Abstract/Free Full Text]

13. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. Bull World Health Organ 79: 373-374, 2001[Medline]

14. Schwartz LH, Ginsberg MS, DeCorato D, et al: Evaluation of tumor measurements in oncology: Use of film-based and electronic techniques. J Clin Oncol 18: 2179-2184, 2000[Abstract/Free Full Text]

15. Lezak MD: Neuropsychological Assessment, ed 3 . New York NY, Oxford University Press, 1995

16. Benedict RHB, Schretlen D, Groninger L, et al: Hopkins Verbal Learning Test-Revised: Normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychologist 12: 43-55, 1998

17. Brandt J: The Hopkins Verbal Learning Test: Development of a new memory test with six equivalent forms. Clin Neuropsychologist 5: 125-142, 1991

18. Spreen O, Strauss E: A compendium of neuropsychological tests, ed 2 . New York, NY, Oxford University Press, 1998

19. Lafayette Instrument: Instruction/Owner’s Manual: Instructions for the 32025 Grooved Pegboard Test. Lafayette, IN, Lafayette Instrument, 1989

20. Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment of Cancer Therapy Scale: Development and validation of the general measure. J Clin Oncol 11: 570-579, 1993[Abstract/Free Full Text]

21. Weitzner MA, Meyers CA, Gelke CK, et al: The Functional Assessment of Cancer Therapy (FACT) scale: Development of a brain subscale and revalidation of the general version (FACT-G) in patients with primary brain tumors. Cancer 75: 1151-1161, 1995[CrossRef][Medline]

22. Wade DT: Measurement in Neurological Rehabilitation. Oxford, United Kingdom, Oxford University Press, 1992

23. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]

24. Nieder C, Berberich W, Nestle U, et al: Relation between local result and total dose of radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys 33: 349-355, 1995[CrossRef][Medline]

25. Komaki R, Meyers CA, Shin DM, et al: Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 33: 179-182, 1995[CrossRef][Medline]

Submitted July 30, 2001; accepted May 7, 2002.

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