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Phase I and Pharmacokinetic Study of Erlotinib for Solid Tumors in Patients With Hepatic or Renal Dysfunction: CALGB 60101

Antonius A. Miller, Daryl J. Murry, Kouros Owzar, Donna R. Hollis, Lionel D. Lewis, Hedy L. Kindler, John L. Marshall, Miguel A. Villalona-Calero, Martin J. Edelman, Raymond J. Hohl, Stuart M. Lichtman, Mark J. Ratain

From the Wake Forest University School of Medicine, Winston-Salem, NC; University of Iowa College of Pharmacy; University of Iowa Hospitals, Iowa City, IA; Department of Biostatistics and Bioinformatics and Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham, NC; Dartmouth Medical School, Lebanon, NH; Cancer and Leukemia Group B; University of Chicago Medical Center, Chicago, IL; Georgetown University Medical Center, Washington, DC; Ohio State University Medical Center, Columbus, OH; University of Maryland Cancer Center, Baltimore, MD; and North Shore–Long Island Jewish Health System, Manhasset, NY

Address reprint requests to Antonius A. Miller, MD, Comprehensive Cancer Center of Wake Forest University, Medical Center Blvd, Winston-Salem, NC 27157-1082; e-mail: aamiller{at}wfubmc.edu

	ABSTRACT

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Purpose We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction.

Patients and Methods Patients were assigned to one of three cohorts: cohort 1, AST 3x upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients.

Results Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin 1.5x baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean ± standard deviation) was cohort dependent as follows: 1.9 ± 0.2 L/h in cohort 1; 3.7 ± 4.7 L/h in cohort 1a; 2.4 ± 1.1 L/h in cohort 2; and 4.5 ± 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017).

Conclusion Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.

	INTRODUCTION

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The epidermal growth factor receptor (EGFR) is recognized as an important molecular target in cancer therapy.¹ Erlotinib is an orally active and potent inhibitor of the EGFR tyrosine kinase.² As in the development of other new drugs, erlotinib was initially tested in patients with adequate hepatic and renal function, and the recommended continuous daily dose is 150 mg for such patients.³ Erlotinib is a commonly used drug which, compared with placebo, improved survival as second- and third-line therapy for patients with advanced non–small-cell lung cancer in a randomized phase III trial.⁴ In another randomized phase III trial, gemcitabine plus erlotinib improved survival compared with gemcitabine plus placebo in advanced pancreatic cancer.⁵ Erlotinib is primarily metabolized in the liver (predominantly by cytochrome P450 3A4 [CYP3A4]). Urinary excretion is a minor (< 10%) route of elimination. We hypothesized that hepatic dysfunction would alter but renal dysfunction would not alter the pharmacokinetics and tolerability of erlotinib. Although patients with malignancies often present with abnormal hepatic or renal function, they were excluded from prior clinical trials of erlotinib. The objectives of this study were to determine a tolerable dose of erlotinib in patients with hepatic or renal dysfunction and to characterize its pharmacokinetics.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients were eligible if they had tumors commonly expressing EGFR, including glioma, mesothelioma, hepatocellular cancer, and epithelial malignancies such as non–small-cell lung, breast, head and neck, esophageal, pancreatic, bladder, prostate, ovarian, cervical, colorectal, and anal carcinomas. Patients with other tumors were eligible only if there was documentation of EGFR expression in the tumor tissue. The protocol required that patients had disease for which standard curative or palliative measures did not exist. Prior treatments were allowed under the following circumstances: 4 weeks must have elapsed since major surgery or since completion of radiation or chemotherapy (except 6 weeks for melphalan or mitomycin and 3 months for suramin); no prior nitrosoureas; and no prior EGFR-targeting therapies. Patients had to be 18 years of age with an Eastern Cooperative Oncology Group performance status of 0 to 2. Required laboratory values at entry included an absolute neutrophil count 1,500/µL and platelet count 100,000/µL. The study had to be approved by the institutional review board of each participating institution, and all patients gave written informed consent.

Exclusion Criteria
Patients who were pregnant or lactating were excluded. Concomitant medications known to cause hepatic or renal toxicity were not allowed on study. Other exclusion criteria included abnormalities of the cornea, GI tract disease resulting in an inability to take oral medication, HIV-positive patients on antiretroviral therapy, ingestion of potent CYP3A4 inhibitors within 7 days of protocol therapy, and evidence of biliary or renal obstruction.

Cohort Definitions
No widely accepted guidelines defining organ dysfunction in cancer patients were available when this study was designed. Our aim was to use laboratory values of organ dysfunction that are routinely available in clinical practice. Therefore, the initial cohort definitions were as follows: cohort 1, AST 3x upper limit of normal (ULN; normal direct bilirubin and normal creatinine); cohort 2, direct bilirubin of 1.0 to 7.0 mg/dL with any AST (normal creatinine); and cohort 3, creatinine of 1.6 to 5.0 mg/dL (AST < 3x ULN and direct bilirubin < 1.0 mg/dL). The amended cohort definitions were as follows: cohort 1a, albumin less than 2.5 g/dL (direct bilirubin < 1.0 mg/dL, any AST, and normal creatinine); cohort 2, direct bilirubin of 1.0 to 7.0 mg/dL with any AST (normal creatinine); and cohort 3a, creatinine of 2.5 to 5.0 mg/dL (albumin 2.5 g/dL, AST < 3x ULN, and direct bilirubin < 1.0 mg/dL). Patients who fit into more than one of these cohorts (eg, elevated bilirubin and elevated creatinine) were not eligible for this study.

Treatment
Erlotinib was administered as a single daily oral dose continuously. The first dose on day 1 was administered after an overnight fast. Otherwise, patients were instructed to take the tablet(s) in the morning with up to 200 mL of water 1 hour before or 2 hours after food. Patients were not allowed to take potent CYP3A4 inhibitors while on protocol treatment. Additionally, CYP3A4 substrates and inducers were avoided. Patients could only be registered to the study with approval of the study chair after review of the eligibility and exclusion criteria, cohort assignment, and other medications. The dose level was assigned at registration and depended on the cohort (Table 1). Patients were initially enrolled at dose level 0. If dose-limiting toxicity (DLT) was reached at dose level 0, more patients were to be enrolled at dose level –1. Escalation to the next dose level occurred in a new cohort of patients if the maximum-tolerated dose (MTD) had not been reached and all patients in a cohort had been treated for at least 4 weeks. Erlotinib (OSI-774) was manufactured by OSI Pharmaceuticals (Birmingham, United Kingdom) and distributed by the National Cancer Institute Division of Cancer Treatment and Diagnosis as 25-, 100-, and 150-mg tablets.

DLT
Because there are no rules to define DLT in patients with abnormal liver or renal function tests at entry onto trial, our definitions were empiric, but they were prospectively defined in the protocol. For cohorts 1, 1a, and 2, an increase in AST or alkaline phosphatase 2.5x baseline or an increase in bilirubin 1.5x baseline was considered dose-limiting hepatic toxicity unless unequivocally caused by tumor progression confirmed by imaging studies. For cohorts 3 and 3a, elevations in AST or alkaline phosphatase 5x ULN or bilirubin 2.5x ULN were defined as DLT. For cohorts 3 and 3a, an increase in creatinine 2.5x baseline was considered dose-limiting renal toxicity. For cohorts 1, 1a, and 2, an increase in creatinine 2x ULN was defined as DLT. Other grade 3 or greater nonhematologic toxicity was defined as DLT. Grade 3 or greater nausea, vomiting, diarrhea, and anorexia despite optimal supportive care were also considered DLTs. Grade 4 neutropenia and grade 4 thrombocytopenia were defined as DLTs.

Dose Escalation Rules
Dose escalation to the next dose level occurred in cohorts of patients when the MTD was not reached and after patients in a cohort had been treated for at least 4 weeks. If none of three patients developed DLT, three patients were entered at the next dose level. If two or more of three patients experienced DLT, dose escalation was stopped, and this dose level was the highest administered dose. If one of three patients developed DLT, at least three more patients were entered at this dose level. If none of these three additional patients experienced DLT, we proceeded to the next dose level. If one or more of these three additional patients experienced DLT, then dose escalation was stopped, and this dose was the highest administered dose. The MTD was prospectively defined as the dose level at which no more than one of six patients had DLT. The primary study end point was to assess patients for DLT in the first 4 weeks of treatment. Therefore, patients who discontinued protocol therapy within the first 4 weeks for reasons other than toxicity were replaced and not considered in the determination of MTD.

Pharmacokinetics
Blood samples were obtained at baseline and at 1, 2, 3, 4, 6, and 24 hours after the first dose of erlotinib on day 1. After centrifugation, the plasma was separated and frozen and sent to a laboratory at Wake Forest University (A.A.M.). Laboratory reference standards of erlotinib (OSI-774), its O-demethylated metabolite (OSI-420), and the internal standard (CP-292,597) were provided by OSI Pharmaceuticals. Plasma concentrations of erlotinib and OSI-420 were measured by isocratic high-performance liquid chromatography according to a published method.³ The lower limit of quantification of the assay was 10 ng/mL for both erlotinib and OSI-420. Erlotinib pharmacokinetic parameters were estimated using Adapt II software (available at http://bmsr.usc.edu/Software/Adapt/adptmenu.html) and maximum a posteriori Bayesian estimation methods. A two-compartment pharmacokinetic model was applied to estimate the total apparent oral clearance of erlotinib.

Measurement of Alpha-1-Acid Glycoprotein
The plasma obtained from the patient's blood sample taken just before treatment with erlotinib on day 1 (baseline) was also used for measurement of the alpha-1-acid glycoprotein (AAG) concentration using an immunoturbidometric method. This assay was performed using the Roche AAG Diagnostic Kit on a Cobas Integra 800 System (Roche Diagnostics, Alameda, CA).

Statistical Analysis
The marginal distributions of the pharmacokinetic parameters were summarized quantitatively using standard measures of central tendencies, location, and spread (eg, mean, median, and standard deviation). Given the small counts in some of the cohorts, the distribution of total clearance is depicted graphically using dot plots rather than box plots.⁹ The discrepancies among the distributions of apparent oral clearance of erlotinib with respect to factors (eg, cohorts and factors) were assessed using the Kruskal-Wallis test.¹⁰ Inference for the associations between total clearance and continuous measurements (eg, glomerular filtration rate and serum creatinine) was carried out using the Spearman rank correlation.¹⁰ Given the small sample size, the exact two-sided P values were approximated using B = 10,000 permutation replicates. The statistical analyses and plots were produced using the statistical computing environment R (version 2.3.1)¹¹ including package coin¹² for generating the conditional permutation P values.

	RESULTS

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Between December 2001 and May 2005, 55 patients were enrolled, but one patient never started therapy. The characteristics of the 54 treated patients are listed in Table 2. After the slow accrual of three patients to cohort 1, the protocol was amended to include patients with an albumin of less than 2.5 g/dL (cohort 1a), and three additional patients were accrued. In our experience, patients with such low albumin often did not meet the eligibility criteria for this study. Thirty patients were enrolled onto cohort 2. Their median direct bilirubin concentration at entry was 2.5 mg/dL (range, 1.1 to 8.4 mg/dL). After 12 patients were treated in cohort 3 (creatinine of 1.6 to 4.9 mg/dL) without adverse events, we amended the protocol to include six more patients with creatinine values between 2.5 and 5.0 mg/dL (cohort 3a). The median creatinine concentrations for cohorts 3 and 3a were 2.0 mg/dL (range, 1.6 to 4.9 mg/dL) and 2.7 mg/dL (range, 2.6 to 3.8 mg/dL), respectively. The distribution of patients in the various cohorts and dose levels is shown in Table 3. The attrition in cohorts 1 and 2 was a result of progressive disease before patients became assessable for toxicity. We observed four DLT events (Table 3).

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Dot plot of erlotinib clearance by cohort.

Besides the toxic events listed in Table 3, no other grade 4 toxicities were encountered over all therapy in patients on the hepatic cohorts, but the following other grade 3 toxicities were recorded: hemoglobin (n = 1), fatigue (n = 2), anorexia (n = 2), rash (n = 1), diarrhea (n = 1), nausea (n = 1), and GI bleed (n = 1). No grade 3 or 4 toxicities were observed over all therapy in patients on the renal cohorts, except for one grade 4 hemoglobin possibly related to erlotinib.

One partial response was observed in a patient with bladder cancer (cohort 3, dose level 2) who had received radiation therapy and two prior chemotherapy regimens. No other objective responses were observed.

	DISCUSSION

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The half-life and apparent oral clearance of erlotinib in patients with renal dysfunction (cohorts 3 and 3a in Table 4) are similar to the half-life and oral clearance in patients with adequate hepatic and renal function in a phase I study reported by Hidalgo et al.³ In patients with hepatic dysfunction (cohorts 1, 1a, and 2), the half-life was longer and the clearance reduced compared with the data for patients with renal dysfunction (Table 4, Fig 1). In addition, the phase I results listed in Table 3 support the notion that patients with hepatic dysfunction cannot tolerate the daily dose of 150 mg that is recommended for patients with normal organ function. These observations lead us to the following conclusions. Patients with renal dysfunction tolerate 150 mg daily and seem to have a normal clearance of erlotinib. Patients with hepatic dysfunction should initiate therapy at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance. Treatment with erlotinib was associated with elevation in bilirubin concentrations over baseline in three patients with hepatic dysfunction but not in patients with renal dysfunction (Table 3). Otherwise, erlotinib was well tolerated, and no unexpected toxicities were encountered.

Our study was intended to inform the clinician about the starting dose of erlotinib in patients with hepatic or renal dysfunction based on readily available laboratory information. In patients with hepatic dysfunction, the reduced dose of 75 mg daily should be considered the starting dose level. The dose may be escalated in an individual patient if the drug is well tolerated. A significant relationship between the skin rash associated with erlotinib and tumor response has been reported.¹⁵ Therefore, it seems reasonable to increase the dose of the drug to the occurrence of skin rash in patients who do not develop other serious toxicity.

Erlotinib is used for advanced pancreatic cancer in combination with gemcitabine, and patients with metastatic disease may have hepatic dysfunction. Treatment with gemcitabine in patients with elevated bilirubin levels resulted in an increased risk of hepatic toxicity in a prior Cancer and Leukemia Group B (CALGB) study.¹⁶ Such patients should initially be treated with a gemcitabine dose of 800 mg/m² and, subsequently, have dose escalation if tolerance to the 800-mg/m² dose is demonstrated.

Whereas all patients with renal dysfunction were assessable, many patients with hepatic dysfunction were unable to complete the first 4 weeks of continuous dosing (Table 3) and were deemed not assessable per protocol. This is consistent with studies classifying prognostic comorbidity in longitudinal studies. For instance, the commonly used Charlson risk index assigns higher points for liver disease than for renal disease.¹⁷ The worst possible risk for complications in the Charlson index is a metastatic solid tumor plus moderate or severe liver disease (6 + 3 points; very high risk 5 points).

Recently, Lu et al¹⁴ investigated the population pharmacokinetics of erlotinib in 1,047 patients with solid tumors treated on phase II or III studies and reported an oral clearance of 3.95 L/h in their final model. Of a total of 18 covariates, the total serum bilirubin and serum AAG had the largest effects in explaining the interindividual variability for clearance in their pharmacokinetic model. In their examination of the population pharmacokinetic data, elevated total bilirubin was correlated with lower clearance of erlotinib. In this study, direct bilirubin was not significantly correlated with apparent oral clearance, which may be a result of the limited number of patients and the difference in the patient populations. As pointed out by Lu et al,¹⁴ bilirubin itself is not expected to affect the metabolism of erlotinib through uridine diphosphate-glucuronosyl-transferase (UGT1A1) because erlotinib is first metabolized by phase I metabolizing enzymes (O-demethylation, acetylene oxidation, and aromatic hydroxylation) with subsequent phase II conjugation of metabolites. Therefore, bilirubin is only a biomarker for hepatic dysfunction. The Child-Pugh score also did not correlate with clearance. Pharmacogenomic variability should be investigated in future trials.

At the time of activation of this study, it was not known that cigarette smoking alters the pharmacokinetics of erlotinib. In healthy male volunteers, a 300-mg dose of erlotinib produced approximately the same area under the curve in smokers as a 150-mg dose in nonsmokers.¹⁸ Therefore, a limitation of our study is that we did not document smoking status. Another limitation of this study is the crude set of definitions for hepatic and renal dysfunction that evolved from a series of prior CALGB phase I and pharmacokinetic trials with paclitaxel, gemcitabine, and irinotecan.^16,19-21 Our current pharmacokinetic and phase I study of oral sorafenib for solid tumors and hematologic malignancies in patients with hepatic or renal dysfunction (CALGB 60301) has more detailed definitions for the following nine cohorts: (1) bilirubin ULN and AST ULN and creatinine clearance 60 mL/min; (2) bilirubin more than ULN but 1.5x ULN and/or AST more than ULN; (3) creatinine clearance between 40 and 59 mL/min; (4) bilirubin more than 1.5x ULN to 3x ULN (any AST); (5) creatinine clearance between 20 and 39 mL/min; (6) bilirubin more than 3x ULN to 10x ULN (any AST); (7) creatinine clearance less than 20 mL/min; (8) albumin less than 2.5 mg/dL (any bilirubin/AST); and (9) hemodialysis.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Hedy L. Kindler, OSI Pharmaceuticals, Genentech; John L. Marshall, Genentech; Martin J. Edelman, Genentech Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Antonius A. Miller, Daryl J. Murry, Lionel D. Lewis, Mark J. Ratain

Administrative support: Antonius A. Miller, Donna R. Hollis

Provision of study materials or patients: Antonius A. Miller, Lionel D. Lewis, Hedy L. Kindler, John L. Marshall, Miguel A. Villalona-Calero, Martin J. Edelman, Raymond J. Hohl, Stuart M. Lichtman, Mark J. Ratain

Collection and assembly of data: Antonius A. Miller, Kouros Owzar, Donna R. Hollis, Lionel D. Lewis

Data analysis and interpretation: Antonius A. Miller, Daryl J. Murry, Kouros Owzar, Donna R. Hollis, Lionel D. Lewis, Mark J. Ratain

Manuscript writing: Antonius A. Miller, Daryl J. Murry, Kouros Owzar, Donna R. Hollis, Lionel D. Lewis, Mark J. Ratain

Final approval of manuscript: Antonius A. Miller, Daryl J. Murry, Kouros Owzar, Donna R. Hollis, Lionel D. Lewis, Hedy L. Kindler, John L. Marshall, Miguel A. Villalona-Calero, Martin J. Edelman, Raymond J. Hohl, Stuart M. Lichtman, Mark J. Ratain

	Appendix

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The following members and institutions participated in this study: University of Chicago, Chicago, IL: Gini Fleming, MD, supported by CA 41287; Dartmouth Medical School–Norris Cotton Cancer Center, Lebanon, NH: Marc S. Ernstoff, MD, supported by CA 04326; Georgetown University Medical Center, Washington, DC: Edward Gelmann, MD, supported by CA 77597; University of Iowa, Iowa City, IA: Gerald Clamon, MD, supported by CA 47642; Long Island Jewish Medical Center, Lake Success, NY: Marc Citron, MD, supported by CA 11028; University of Maryland Greenebaum Cancer Center, Baltimore, MD: Martin Edelman, MD, supported by CA 31983; North Shore–Long Island Jewish Medical Center, Manhasset, NY: Daniel R. Budman, MD, supported by CA 35279; The Ohio State University Medical Center, Columbus, OH: Clara D. Bloomfield, MD, supported by CA 77658; Roswell Park Cancer Institute, Buffalo, NY: Ellis Levine, MD, supported by CA 02599; University of Massachusetts Medical School, Worcester, MA: William V. Walsh, MD, supported by CA 37135; and Wake Forest University School of Medicine, Winston-Salem, NC: David D. Hurd, MD, supported by CA 03927.

	NOTES

 
Supported by National Cancer Institute Grants No. CA 03927, CA 47642, CA 33601, CA 47577, CA 04326, CA 41287, CA 77597, CA 77658, CA 31983, CA 47642, CA 35279, and CA 31946.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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16. Venook AP, Egorin MJ, Rosner GL, et al: Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol 18:2780-2787, 2000[Abstract/Free Full Text]

17. Charlson ME, Pompei P, Ales KL, et al: A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 40:373-383, 1987[CrossRef][Medline]

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Submitted March 13, 2007; accepted April 17, 2007.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, A. A. Articles by Ratain, M. J. Search for Related Content PubMed PubMed Citation Articles by Miller, A. A. Articles by Ratain, M. J. Social Bookmarking                            What's this?