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Risk Factors for Severe Neuropsychiatric Toxicity in Patients Receiving Interferon Alfa-2b and Low-Dose Cytarabine for Chronic Myelogenous Leukemia: Analysis of Cancer and Leukemia Group B 9013

From the Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, and New York Presbyterian Hospital, New York, NY; Cancer and Leukemia Group B Statistical Office, Durham, NC; The University of Chicago, Chicago, IL; and Wayne State University School of Medicine, Detroit, MI.

Address reprint requests to M.L. Hensley, MD, MSc, Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 426, New York, NY 10021; email hensleym{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: Recombinant interferon alfa-2b (rIFN2b) is a standard therapy for chronic myelogenous leukemia (CML). Severe neuropsychiatric toxicity has been described in patients receiving rIFN2b, although the frequency of and the risk factors for developing this toxicity are not well described. The purpose of this study was to identify predictors for the development of severe neuropsychiatric toxicity in CML patients receiving rIFN2b-based therapy.

PATIENTS AND METHODS: From a prospective cohort of 91 Philadelphia chromosome–positive, previously untreated, chronic-phase CML patients treated on Cancer and Leukemia Group B (CALGB) 9013, a phase II trial of rIFN2b plus cytarabine, the following were recorded at baseline: age, sex, race, pretreatment history of neurologic or psychiatric diagnosis, spleen size, blood counts, and peripheral blast count. Best response to treatment, rIFN2b cumulative dose, dose duration, and dose-intensity were recorded during follow-up. Severe neuropsychiatric toxicity was defined as grade 3 or 4 events, according to CALGB expanded common toxicity criteria. Univariate and multivariate logistic regression analyses were used to identify variables that were associated with the development of severe neuropsychiatric toxicity.

RESULTS: Severe neuropsychiatric toxicity developed in 22 patients (24.0%; 95% confidence interval [CI], 15.2% to 32.8%). Toxicity resolved after withdrawal of treatment in all patients. Five of six patients developed recurrence of symptoms with rechallenge. Twelve (63%) of 19 patients with a pretreatment neurologic or psychiatric diagnosis developed severe neuropsychiatric toxicity, as compared with 10 (14%) of 72 patients without a pretreatment neurologic or psychiatric diagnosis (P = .001), resulting in a relative risk of 4.55 (95% CI, 2.33 to 8.88) for developing severe neuropsychiatric toxicity. No other variables were independently associated with the development of neuropsychiatric toxicity.

CONCLUSION: CML patients with a pretreatment history of a neurologic or psychiatric diagnosis are at significantly increased risk of developing severe neuropsychiatric toxicity during therapy with rIFN2b plus cytarabine. Monitoring for neuropsychiatric symptoms and avoiding rechallenge are recommended measures for such patients receiving rIFN2b-based therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
ATTEMPTS TO PROLONG survival in patients with chronic myelogenous leukemia (CML) have necessitated a continued search for new agents and for novel combinations and dose schedules of existing active agents. Intensive myeloablative therapy followed by allogeneic bone marrow transplantation can result in complete remissions^1,2 but is applicable primarily to relatively young patients with compatible bone marrow donors and is associated with significant early morbidity and mortality. Recombinant interferon alfa-2b (rIFN2b), when given subcutaneously for prolonged periods, results in hematologic and cytogenetic responses. Ten percent to 31% of patients achieve complete (100% Philadelphia chromosome [Ph]–negative) cytogenetic responses.^3-5 The ability of rIFN2b to induce cytogenetic responses, delay the time to disease progression, and prolong overall survival has subsequently been demonstrated in several multicenter, randomized trials.^6-9 Low-dose cytarabine has shown in vitro inhibition of colony-forming units granulocyte-macrophage in CML cells.¹⁰ The combination of low-dose subcutaneous (SC) cytarabine and rIFN2b in a small group of heavily pretreated patients resulted in significant cytogenetic responses.¹¹ A large randomized trial comparing rIFN2b with the combination of low-dose cytarabine and rIFN2b demonstrated that the probability of achieving a major cytogenetic response (defined as < 35% Ph-positive cells) was higher and survival was longer (3-year survival 85.7% v 79.1%) in patients who received the combination regimen.¹² One recently published set of recommendations for the initial therapy of CML¹³ stated that a 12-month trial of rIFN2b would be appropriate for patients older than 50 years of age who lack allogeneic donors and for patients younger than 50 years with low- or intermediate-risk CML using Sokol’s criteria.¹⁴ Following this recommendation would result in at least 49% of all patients with newly diagnosed CML beginning therapy with rIFN2b annually.

Side effects frequently observed with the use of rIFN2b include fever, rigors, myalgia, weight loss, granulocytopenia, and thrombocytopenia. Nausea, vomiting, and diarrhea occur, particularly when rIFN2b is combined with SC cytarabine.¹⁵ Side effects that are generally considered to be rare include cardiovascular, dermatologic, and neuropsychiatric events. However, neurologic toxicity described as "dizziness or vertigo" was reported in 10% of patients treated with rIFN2b for CML in a Cancer and Leukemia Group B (CALGB) study involving 102 patients.³ In another study, neurologic symptoms described as moderate fatigue, depression, insomnia, reduced attention span, and memory deficits were reported in six of 14 patients receiving rIFN2b for CML.¹⁶ No neurologic toxicity was reported in the five patients treated with rIFN2b and low-dose cytarabine in the pilot study of this combination conducted by CALGB.¹¹ In a randomized trial of rIFN2b plus cytarabine compared with rIFN2b alone in 745 CML patients, protocol therapy was discontinued for neurologic or psychiatric toxicities in 10.3% versus 13.3% of patients, respectively.¹² Although it is recognized that cytarabine in high doses may cause reversible CNS dysfunction in some patients,¹⁷ neurotoxicity has not been reported at the low, subcutaneous cytarabine doses that are used to treat patients with CML. In a recent report of 140 CML patients treated with rIFN2b plus cytarabine, grade 2 neurologic changes were reported in 21% of patients, and grade 3 or 4 depression was reported in 4%.⁵

The lack of consensus regarding the frequency and severity of neuropsychiatric toxicity with rIFN2b and low-dose cytarabine, in addition to the paucity of data that assess risk factors for the development of neuropsychiatric toxicity, led us to assess the occurrence of and identify risk factors for this toxicity in a prospective cohort of CML patients who were uniformly treated on a phase II trial of rIFN2b and low-dose SC cytarabine conducted by CALGB. Therapeutic results of this trial have been reported elsewhere.¹⁵ Severe neuropsychiatric toxicity was found to be relatively frequent in this cohort. Our multivariate analysis shows that patients with a pretreatment history of a neurologic or psychiatric disorder were at significantly increased risk of developing this adverse outcome.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
From December 1990 to August 1993, 91 patients with previously untreated, Ph-positive CML were enrolled on CALGB 9013, a CALGB protocol designed to assess the efficacy of rIFN2b and low-dose cytarabine in terms of disease response, toxicity, and overall survival. Patients were enrolled from 39 different institutions, representing both academic medical centers and community hospitals. All patients gave written, informed consent before therapy was initiated. The data for the analyses reported here were compiled from prospective documentation of pretreatment patient characteristics, treatment details, and toxicities in all patients participating in the CALGB 9013 clinical trial. All toxicities, both neuropsychiatric and of other organ systems, were prospectively identified and recorded by individuals who were not involved with this study of risk factors for neuropsychiatric toxicity and who were blind to the present study’s hypothesis. The history of a pretreatment neurologic or psychiatric diagnosis was recorded before initiation of therapy, and before any patient’s status with respect to the outcome, severe neuropsychiatric toxicity, was known. Patients with currently active psychiatric illness or uncontrolled medical illness were not eligible for participation in the treatment protocol, although patients with a past medical history of a neurologic or psychiatric diagnosis were not excluded.

Eligibility Criteria
Initial evaluation of patients treated on CALGB 9013 included the following: history and physical examination, determination of performance status, complete blood cell count, biochemical profile, prothrombin time and partial thromboplastin time, and bone marrow aspirate and biopsy. Patients were required to have the Ph chromosome detected before enrollment. Exclusion criteria for participation in CALGB 9013 included the following: currently active psychiatric illness, uncontrolled medical illness, significant liver or renal dysfunction (defined as creatinine 1.8 mg/dL, AST, ALT, bilirubin, or alkaline phosphatase 1.5 times normal), or prior treatment with chemotherapy, radiation therapy, or IFN. Patients with a past medical history of a neurologic or psychiatric diagnosis remained eligible for trial participation.

Treatment
Participating patients received cytarabine 15 mg/m² SC twice daily and rIFN2b 5 million IU/m² SC daily. Six of the first 35 patients developed grade 3 gastrointestinal toxicity, which resulted in amendment of the protocol such that all subsequent patients received cytarabine 10 mg/m² SC twice daily.¹⁵ Blood counts were obtained weekly. The dose of cytarabine was increased by 50% if the WBC count did not decrease by 50%. Both drugs were discontinued whenever either the WBC count decreased to less than 2,000/µL or the platelet count decreased to less than 50,000/µL. Treatment was resumed when the WBC count was greater than 5,000/µL and the platelet count was greater than 100,000/µL. The time from beginning therapy to restarting therapy was defined as one cycle.

Monitoring
Spleen size was determined by physical examination and was measured in centimeters below the left costal margin. Weekly determinations of performance status and reporting of symptoms were performed at the time when blood counts were obtained until stable doses were determined. Thereafter, patients were seen approximately every 6 weeks for evaluation of blood counts, symptoms, and toxicities. Bone marrow aspirates and biopsies were performed on completion of the second cycle of treatment and every 6 months thereafter. Cytogenetics were performed by CALGB-approved cytogeneticists, and the karyotypes were reviewed by the cytogenetics committee. Treatment was maintained for at least 12 months for patients with stable disease and for at least 18 months for those with hematologic improvement, as defined under Response and Toxicity Definitions. All grade 4 toxicities, as defined in the CALGB expanded common toxicity criteria, were reported to the study chair (T.P.S.) for review. All patients were followed-up for survival.

Response and Toxicity Definitions
Best disease response to rIFN2b and cytarabine therapy was defined for CALGB 9013 as follows: complete biologic remission was defined as no detectable BCR rearrangement,¹⁸ 100% normal metaphases, and a normal bone marrow examination. Cytogenetic remission was defined as a complete clinical remission plus one of the following cytogenetic responses: (1) complete (100% normal metaphases), (2) partial (50% to 99% normal metaphases), or (3) cytogenetic improvement (1% to 49% normal metaphases). Complete clinical remission was defined as the disappearance of all signs and symptoms of disease with normal peripheral blood counts, bone marrow with less than 5% blasts and less than 10% blasts plus promyelocytes, and normal or decreased cellularity, without cytogenetic remission. Partial clinical remission was defined as WBC count 10,000/µL, no circulating immature cells, normal hemoglobin and platelets, less than 10% myelocytes plus promyelocytes in the bone marrow, and at least 50% decrease in spleen size, without cytogenetic remission. Hematologic improvement was defined as more than 50% reduction in WBC or platelet counts if initially abnormally high, no blasts in peripheral blood, and failure to achieve normalization of peripheral blood counts and the blast plus promyelocyte count in the bone marrow, without cytogenetic remission. Stable disease was defined as less than 50% reduction or an increase of less than 25% in WBC or platelet counts with no change in morphology or blast and promyelocytes in the bone morrow, without cytogenetic remission. Progression of disease was defined as an increase in WBC count to more than 50,000/µL on at least two occasions or an increase in WBC count to less than 50,000/µL accompanied by a decrease of hemoglobin or platelet count by more than 25% of best previous response, increasing peripheral blast count, increasing marrow blast plus promyelocyte count, basophils 20%, or emergence of new secondary clones, without cytogenetic remission.

Description, management, and outcome of severe neuropsychiatric toxicities were recorded. The occurrence of neuropsychiatric toxicity was determined from prospectively written notes in the chart that documented clinical findings. For the purposes of this study, we used CALGB expanded common toxicity criteria as follows: grade 1 neuropsychiatric toxicity was defined as headaches, minor irritability, or mild difficulty in concentration, with no interference with functioning. Grade 2 neuropsychiatric toxicity was defined as moderate difficulty in concentration, moderate changes in mood, and moderate anxiety or depression, with no interference with activities of daily living. Grade 3 neuropsychiatric toxicity was defined as major anxiety or depression associated with disorientation or confusion or significant impairment in activities of daily living. Grade 4 neuropsychiatric toxicity was defined as psychosis, delirium, or suicidal ideation.

Statistical Methods
The following variables were recorded at baseline for all 91 patients: CML risk factors (including age, baseline spleen size, platelet count, and percentage of peripheral blast count¹⁹ ), sex, race, WBC count, hemoglobin, and antecedent neurologic and psychiatric history. The following variables were recorded during follow-up: best response to therapy with rIFN2b and cytarabine, cumulative total rIFN2b dose, dose duration, and dose-intensity (total dose/treatment duration). Response was analyzed both as complete cytogenetic response rate and complete clinical response rate.

Demographic characteristics of the sample were described. Among those patients experiencing a neuropsychiatric toxicity, patient-specific descriptions of neuropsychiatric history, toxicity, and toxicity outcome were detailed. The overall incidence of severe (grade 3 or 4) neuropsychiatric toxicity and its 95% confidence interval (CI) were determined.

The correlation of each candidate variable with development of severe neuropsychiatric toxicity was assessed using the logistic regression model both univariately and multivariately. For those variables measured during follow-up, it was recognized that no implications of cause and effect could be made. The univariate association of each variable with neuropsychiatric toxicity was described with means and percentages of the variable according to whether neuropsychiatric toxicity was observed. The multivariate logistic regression was built using forward stepwise regression. The significance level for all tests was set at alpha = 0.05. No adjustment of the alpha level for multiple tests was made for this exploratory analysis. The association of neuropsychiatric toxicity with neurologic or psychiatric history was described with a risk ratio and its 95% CI.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Ninety patients received at least one dose of rIFN2b and cytarabine on CALGB 9013. One patient was enrolled onto the study but never received protocol therapy. The median age of all 91 patients was 48 years (range, 23 to 76 years). Fifty-seven percent of the patients were male. Eighty-seven percent of the patients were white, 9% were African-American, and 4% were Asian-American or American Indian.

Twenty-two of the 91 patients (24%; 95% CI, 15.2% to 32.8%), treated at 17 different institutions, developed grade 3 or 4 neuropsychiatric toxicity. No patient developed grade 5 neuropsychiatric toxicity. Table 1 lists the descriptions of the neuropsychiatric toxicities observed, the patients’ ages and pretreatment neurologic or psychiatric histories, the time from initiation of therapy to development of neuropsychiatric toxicity, and the outcome of the neuropsychiatric toxicity. Neuropsychiatric toxicity affected daily functioning in all patients. Withdrawal of protocol therapy resulted in eventual resolution of neuropsychiatric toxicity in all patients. Six patients were rechallenged with rIFN2b and cytarabine. With rechallenge, five of six patients developed recurrence or worsening of symptoms, which led to permanent discontinuation of rIFN2b and cytarabine in these five patients. In one patient who had arm weakness, ataxia, and vertigo, symptoms on rechallenge did not worsen, and protocol therapy was continued.

View this table: [in this window] [in a new window]   Table 1. Pretreatment Characteristics and Toxicity Descriptions of Patients Who Developed Severe Neuropsychiatric Toxicity During Treatment With rIFN2b and Low-Dose Cytarabine for CML

View this table: [in this window] [in a new window]   Table 2. Baseline Characteristics of Patients With and Without Neuropsychiatric Toxicity During Treatment With rIFN2b and Low-Dose Cytarabine for CML

View this table: [in this window] [in a new window]   Table 3. Treatment and Disease Response Characteristics of Patients With and Without Neuropsychiatric Toxicity During Treatment With rIFN2b and Low-Dose Cytarabine for CML

A pretreatment history of a neurologic or psychiatric disorder and patient age at time of initiation of therapy were significantly associated with the development of severe neuropsychiatric toxicity in univariate regression analyses. Pretreatment history was the only variable to enter into a regression model built using stepwise regression. Age was not a significant predictor after controlling for pretreatment history (P = .12), and the forced inclusion of age into the model had a negligible impact on the size of the pretreatment history effect.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
rIFN2b alone or in combination with low-dose cytarabine improves survival compared with conventional chemotherapy in patients with CML.^7,12,20,21 However, nonhematologic side effects, including influenza-like symptoms, gastrointestinal side effects, and neurologic toxicities, have led to discontinuation of therapy in 10% to 52% of patients in randomized, controlled trials.^6,9,12,22 In choosing initial therapy for patients with chronic-phase CML, it may be critical to identify which patients are more likely to suffer severe neuropsychiatric toxicity with rIFN2b-based therapy. This cohort of chronic-phase CML patients who were uniformly treated and uniformly evaluated for toxicities permitted the evaluation of potential risk factors for severe neuropsychiatric toxicity. In this phase II trial of rIFN2b and low-dose cytarabine, grade 3 or 4 neuropsychiatric toxicity was relatively frequent (24% of patients). Patients with a pretreatment history of a neurologic or psychiatric diagnosis were at significantly increased risk of developing severe neuropsychiatric toxicity (relative risk, 4.55; 95% CI, 2.33 to 8.88).

Baseline patient characteristics (including patient age, race, sex, and CML risk factors) and treatment factors (including rIFN2b cumulative dose, dose duration, and dose-intensity) were not found to have a significant association with neuropsychiatric toxicity. Similarly, cytogenetic and hematologic responses to rIFN2b and cytarabine did not differ significantly between patients who did and did not develop neuropsychiatric toxicity.

The frequency of severe neuropsychiatric toxicity observed in this trial is higher than that reported in other trials involving the use of rIFN2b for chronic-phase CML. In randomized controlled trials that compared single-agent rIFN2b with conventional chemotherapy for CML, the frequency of severe neuropsychiatric toxicity was consistently higher in patients receiving rIFN2b, as compared with patients assigned to treatment with conventional chemotherapy.^9,22,23 In a phase II trial of rIFN2b that involved 107 patients, severe neuropsychiatric toxicity was reported in 11% of patients during rIFN2b therapy.³ In other studies that provided rIFN2b-related toxicity details, the frequency of severe neuropsychiatric toxicity ranged from 1.2% to 13.3%.^9,12,22 One possible explanation for the higher incidence of neuropsychiatric toxicity observed in our study is that more patients with pretreatment neurologic or psychiatric histories may have been enrolled in our study than were enrolled in other studies involving rIFN2b treatment for CML. In the randomized trial comparing rIFN2b plus cytarabine to rIFN2b alone,¹² patients with a history of depressive illness or another psychiatric disorder were excluded from participation. Major neurologic or psychiatric toxicity that led to discontinuation of treatment occurred in 12% of patients, a percentage that approximates the incidence of neuropsychiatric toxicity (14%) observed among those patients without a pretreatment neurologic or psychiatric disorder in our study.

Although cerebellar toxicity associated with high-dose cytarabine has been well described,^24-27 cytarabine use is unlikely to explain the frequency of neuropsychiatric toxicity that was observed in this study. CNS toxicity has not been reported with the low doses of cytarabine used in this study. Reported risk factors for high-dose cytarabine–associated CNS toxicity include renal dysfunction, liver dysfunction, and increasing age.^17,28 Renal and liver dysfunction were rare in our patient population, because patient eligibility criteria excluded patients with creatinine 1.8 mg/dL or AST, ALT, bilirubin, or alkaline phosphatase 1.5 times normal. The median age (48 years) of patients in the cohort would place the patients at increased risk for high-dose cytarabine–associated CNS toxicity according to the model developed by Rubin et al.¹⁷ However, after adjusting for pretreatment neurologic or psychiatric history, age was not an independent risk factor for toxicity in the multivariate analysis for this study.

It is possible that the combination of low-dose cytarabine with rIFN2b potentiates the neuropsychiatric side effects of rIFN2b, leading to an increased severity and/or frequency of important toxicity. Among 140 early chronic-phase CML patients treated with the combination of rIFN2b and low-dose cytarabine, grade 2 neurologic toxicity was reported in 21% of patients and grade 3 or 4 neurologic change was reported in 4%.⁵ However, in a large randomized trial of rIFN2b alone versus rIFN2b and low-dose cytarabine for chronic-phase CML, the incidence of severe neuropsychiatric toxicity did not differ significantly between the two treatment arms of the study (13.3% v 10.3%, respectively).¹²

Neuropsychiatric complications, including depression, anxiety, paresthesias, confusion, and ataxia, have been reported in patients treated with varying doses, schedules, and preparations of rIFN2b for a variety of conditions including cancer, hepatitis, and amyotrophic lateral sclerosis.^29-32 These retrospective reports, culled from nonhomogeneous patient populations, have been unable to assess risk factors that predispose patients to these adverse outcomes or to assess dose relationships adequately. In a single prospective study that addressed neuropsychiatric complications of IFN2b treatment for chronic hepatitis, three of 58 patients developed delirium. Two patients had a history of psychiatric illness, and the third had a history of drug and alcohol abuse. All three patients returned to their baseline level of functioning after discontinuation of the IFN2b.³³

As the indications for the use of rIFN2b become broader, it may be important to identify patients who are at significant risk for developing severe neuropsychiatric complications. The approach used in this study is useful in understanding relatively uncommon diseases, new treatments, and unusual outcomes.³⁴ The prospective enrollment, uniform treatment, uniform follow-up and toxicity evaluation, and uniform eligibility criteria limit the selection bias and information bias in this study. Although generalizability of our results may be somewhat limited, the homogeneity of the population and the treatment regimen allow for a more reliable assessment of the risk factors and dose relationship. The identification of a pretreatment psychiatric or neurologic diagnosis as a significant risk factor for the development of severe neuropsychiatric toxicity may be generalizable to patients receiving IFN2b alone for CML, although we cannot test this from this CML cohort. For other diseases that require rIFN2b-based therapy, the presence of a pretreatment psychiatric or neurologic diagnosis should be investigated as a risk factor for severe neuropsychiatric toxicity.

Neuropsychiatric toxicity is a relatively frequent complication of treatment with rIFN2b and low-dose cytarabine for patients with chronic-phase CML. rIFN2b alone, or in combination with low-dose cytarabine, is a standard treatment for CML patients who are not candidates for initial allogeneic stem-cell transplantation. We have demonstrated that CML patients with a pretreatment history of a neurologic or psychiatric diagnosis are at significantly increased risk of developing severe neuropsychiatric toxicity during treatment with rIFN2b and low-dose cytarabine. All patients who receive rIFN2b should be monitored closely for the development of symptoms of neuropsychiatric toxicity, because discontinuation of rIFN2b seems to result in resolution of the toxicity.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following institutions participated in the study: CALGB Statistical Office (Stephen George, PhD; supported by CA33601) and Duke University Medical Center, Durham (Jeffrey Crawford, MD; supported by CA47577), Southeast Cancer Control Consortium Inc. CCOP, Goldsboro (James N. Atkins, MD; supported by CA45808), University of North Carolina at Chapel Hill, Chapel Hill (Thomas C. Shea, MD; supported by CA47559), and Wake Forest University School of Medicine, Winston-Salem, NC (David D. Hurd, MD; supported by CA03927); Christiana Care Health Services Inc. Community Clinical Oncology Program (CCOP), Wilmington, DE (Irving M. Berkowitz, DO; supported by CA45418); Community Hospital-Syracuse CCOP, Syracuse (Jeffrey Kirshner, MD; supported by CA45389), Long Island Jewish Medical Center, Lake Success (Marc Citron, MD; supported by CA11028), Mount Sinai School of Medicine, New York (James F. Holland, MD; supported by CA04457), North Shore University Hospital CCOP, Manhasset (Vincent Vinciguerra, MD; supported by CA35279), Roswell Park Cancer Institute, Buffalo (Ellis Levine, MD; supported by CA02599), State University of New York Health Science Center at Syracuse, Syracuse (Stephen L. Graziano, MD; supported by CA21060), and Weill Medical College of Cornell University, New York, NY (Ted P. Szatrowski, MD; supported by CA07968); Dana Farber Cancer Institute, Boston (George P. Canellos, MD; supported by CA32291), and University of Massachusetts Medical Center, Worcester, MA (F. Marc Stewart, MD; supported by CA37135); Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH (L. Herbert Maurer, MD; supported by CA04326); McGill Department of Oncology, Montreal, Quebec, Canada (Brian Leyland-Jones, MD; supported by CA31809); Milwaukee CCOP, Milwaukee, WI (Ronald Hart, MD; supported by CA45400); Rhode Island Hospital, Providence, RI (Louis A. Leone, MD; supported by CA08025); Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV (John Ellerton, MD; supported by CA35421); University of California at San Diego, San Diego, CA (Stephen L. Seagren, MD; supported by CA11789); University of Chicago Medical Center, Chicago, IL (Nicholas J. Vogelzang, MD; supported by CA41287); University of Iowa Hospitals, Iowa City, IA (Gerald H. Clamon, MD; supported by CA47642); University of Maryland Cancer Center, Baltimore, MD (David Van Echo, MD; supported by CA31983); University of Missouri/Ellis Fischel Cancer Center, Columbia (Michael C. Perry, MD; supported by CA12046) and Washington University School of Medicine, St. Louis, MO (Nancy L. Bartlett, MD; supported by CA77440); and University of Tennessee Memphis, Memphis, TN (Harvey B. Niell, MD; supported by CA47555).

	NOTES

 
The research for CALGB 9013 was supported in part by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (R.L.S., chairman), and by grants from CALGB Statistical Office (grant no. CA33601), The University of Chicago (grant no. CA41287), Weill Medical College of Cornell University (grant no. CA07968), and the Cancer and Leukemia Group B, Chicago, IL.

The contents of this study are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted August 5, 1999; accepted November 26, 1999.

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