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Clin Cancer Res. Author manuscript; available in PMC 2013 Mar 15.
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PMCID: PMC3307146

Development and Use of Integral Assays in Clinical Trials


Clinical trials that include integral biomarkers to determine eligibility, assign treatment or assess outcome must employ robust assays to measure the molecular analyte of interest. The decision to develop a biomarker assay into a test suitable for use in humans should be driven by clinical need, i.e., there should be a clear clinical purpose to undertaking the test development. Supporting in vitro or in vivo research on the ability of the marker to distinguish subgroups of patients with a given characteristic is necessary. The magnitude of the difference in treatment effect expected with use of the marker should be sufficient to support differential treatment prescription for marker positive and negative patients. Analytical and clinical validation of the marker assay should be completed prior to initiating the clinical trial so that the assay is stable for clinical use throughout the trial. Clinical use of the assay requires that it be performed in a CLIA accredited laboratory and consideration should be given to whether submission of an application to the FDA for an Investigational Device Exemption is necessary. This article elaborates on the steps required to make a biomarker assay ready for use as an integral component of a clinical trial and gives an example of use of an integral assay in a phase III trial.


The elucidation of molecular signaling pathways that contribute to cancer initiation, progression and metastasis, and the development of drugs targeted to interrupt these pathways present the opportunity to conduct clinical trials that use these molecular features to select patients, assign treatment or assess treatment outcomes. Doing so potentially allows the design of clinical trials with larger effect sizes and smaller sample sizes that can be completed faster. Current research efforts focus on the characteristics of tumors and of the patient host that can provide insights into which treatment, even with standard therapy, is likely to benefit or harm a particular patient most. Integral assays are assays that must be performed for the clinical trial to proceed. The results of these assays may inform about eligibility, stratification, or treatment assignment (Text Box). They are distinct from “proof of mechanism” assays, which are research assays that assess whether a drug has impacted its target. They are also distinct from integrated assays, which may be performed on all or most patients in a clinical trial but the results will not impact the treatment of the patient on the trial; rather, the results are used to inform further research or clinical trials. Other types of markers may also be the subject of clinical research (1). This article will elucidate the analytical, clinical and regulatory issues that must be considered in the development of integral assays that will be used in a clinical trial to select patients, assign treatment, stratify patients or assess outcomes. Relevant definition of terms can be found in Table 1.

Text Box

Characteristics of Integral Markers

  • Integral markers are required for the trial to proceed and used for medical decision-making
  • Integral markers are used for:
    • patient eligibility (e.g., somatic mutation for a kinase inhibitor)
    • assignment to treatment (e.g., FLT3-ITD for risk assessment in pediatric trials with consequent assignment to specific treatment [17])
    • risk stratification if such stratification leads to different treatments (as in FLT3-ITD example)
    • risk classifier (as in FLT3-ITD example above)
  • Since assay is performed for medical decision-making with patient or physician informed of the result, a CLIA-certified laboratory is generally required for assay
  • Integrated markers are performed on all or a statistical subset of patients but not used for medical decision-making
  • Research markers include all other assays; often referred to as correlative research
Table 1
Relevant Definitions

Clinical Need

The development of any biomarker into an assay for use in humans, particularly an integral assay in a clinical trial, should be driven by the clinical need, e.g., will use of the assay result in better treatment outcomes than could be achieved without it? Our goal is to maximize the chance that a patient will benefit from the treatment and minimize the chance that he/she will not benefit. The choice of an integral assay in a clinical trial will vary depending on the objectives of the trial, the types of biospecimens to be studied, the analyte of interest and the complexity and analytical performance of the assay technology. Selection of an integral marker often relies on previous research findings, which have rarely been obtained with the goal of developing an assay that meets requirements for clinical utility. Thus, when the use of the assay to direct patient therapy is contemplated, a clinical assay must be developed, often under substantive time constraints, to be “ready” when the clinical trial begins accruing patients.

Before committing to the development of an assay for use in directing therapy, previous research should have demonstrated several qualities of the molecular marker (2). The biologic rationale for study of the marker should be strong – the marker should reflect the known biology and/or correlate with the relevant outcome (e.g., tumor shrinkage, tumor growth delay, disease free or overall survival). The prevalence of the abnormality in the tumor type to be studied should be determined. For example, if the prevalence of the targeted abnormality is 4% in NSCLC tumors and a drug is expected to provide benefit only to patients expressing the abnormality, the assay must be performed on 25 patients for every patient actually found to have the abnormality. This will increase cost and lengthen accrual time, compared to a more prevalent molecular abnormality, and may affect the stipulation of the necessary performance characteristics of the assay (i.e., optimizing assay specificity may be essential for detection of a low prevalence marker). If, on the other hand, the molecular abnormality exists in the great majority of tumors, performing the assay may not be necessary or useful, as most patients will be “positive” (assuming there is not a substantial risk in treating a patient who does not have the marker). The magnitude of the benefit obtained from using the marker/assay should also be great enough that patients and clinicians would find the assay useful in choosing between treatment alternatives. This is a difficult issue on which to have firm guidelines, because it is very context dependent and will vary based on the clinical situation, available therapies and their effectiveness, toxicities of available treatments and the impact of using the biomarker. An example of a marker/assay that might not be useful is one that predicts that marker positive patients have a survival of 6 months, whereas marker negative patients have a survival of 5 months. In addition, if both marker positive and marker negative patients benefit from a new treatment, but the magnitude of benefit is less in the marker negative patients, a clinician would not be likely to withhold the new treatment from marker negative patients. Ideally, before development of a “clinical grade” assay is undertaken, a research grade assay should be available that “works” in the types of human tissues to be used in the trial.

Analytical Validation

Analytical and clinical validation should be completed before patient accrual begins, to finalize and standardize the performance of the assay (lock down the assay) so that its use in the proposed clinical trial will provide reliable results.

Analytical validation involves documentation that the performance characteristics of the assay are reliable and suitable for the intended clinical use in the specimens of interest. The desired characteristics of the assay must be defined. For example, what are the clinical implications, for “wrong” results – i.e., for missing the abnormality when it is present, or for detecting the abnormality when it is absent (false negative and false positive)? The desired sensitivity and specificity of the assay must be defined. The desired limit of detection needs to be defined. If only 1% of cells possess the analyte, will the assay be able to detect this level? Is that level of detection necessary for the intended use? Specific acceptance criteria must be set in advance. “Pre-analytic” variables that may affect the assay performance must be defined: how much tumor tissue (or other biospecimen) is needed, how must the sample be collected (e.g., needle aspirate vs. core vs. open biopsy), how must tissue be handled and shipped, and how must the specimen be preserved? Clinical trials are often conducted at multiple institutions, or internationally and over several years of patient accrual, so the validation procedure must determine whether there are effects of storage time and storage conditions if this is relevant to the trial. Please see Hewitt et al (3) for further discussion of the role of pre-analytic factors.

The procedures to be followed for analytical validation depend on the technology platform. However, the assay must meet specifications for precision, accuracy, selectivity (quantification of the analyte in the presence of other substances) elucidation of any interfering substances, and stability of the analytes.

Accuracy is defined as the closeness of the mean test result to the true result. Assay precision documents how often the assay gives the same result when samples are repeatedly analyzed (within run, within day, between run, between days). Precision estimates may involve different operators, equipment, reagents, or laboratories. If possible, reference standards and a calibration curve for the range of potential assay results should be developed. Each step should be investigated to determine factors that affect variability. Standard operating procedures or a written protocol should be developed, and the assay should be “final” (“locked down”) prior to use in the trial. Please see Williams et al (4) elsewhere in this FOCUS section for further discussion of factors involved in developing and validating clinical assays.

With the more novel assay technologies, it may be necessary to periodically ascertain that the platform itself remains consistent. For example, has a recent software update resulted in changes in assay results that were previously stable? It is prudent to consider potential infringement on a patent or trade secret, as well as whether use of samples from patients treated with an investigational agent impact the intellectual property of the drug sponsor.

Several authors have published guidelines for validation of clinical use assays. (4-11). Sensitivity and specificity must be such that the assay result reliably classifies the tumor/patient with respect to the analyte.

Clinical Validation

Clinical validation refers to how well the assay result relates to the clinical outcome of interest. Initial attempts at clinical validation may use a “research” assay, and may use “samples of convenience” e.g., a collection of samples from the tumor of interest that may or may not have come from a clinical trial. Such samples may have biases that affect interpretation of the clinical utility of the assay (e.g., methods of specimen collection, differences in treatment, drug dosing, co-morbidities, performance status, and methods and timing of tumor assessment). When use in a clinical trial is contemplated, a marker clinical validation study requires a defined validation protocol with a specified analysis plan. As part of that plan, the assessment of performance should be focused on a completely defined specified biomarker, and the assay should be locked down. If the assay involves combinations of features then all parameters should specified prior to the evaluation. It is possible to perform clinical validation of an assay in a “prospective-retrospective” fashion, if an adequate number of samples can be obtained from relevant clinical trials that have already been completed and have outcome data available (12). The assay must be performed “blinded” with respect to patient outcome.

Samples from phase II trials of an agent could be useful to define the correlation of the assay result with the outcome of interest. However, if the Phase II study does not include an appropriate control group, it may not possible to assess if the marker is predictive of treatment efficacy or if it is prognostic only. Even with a randomized Phase II study, there is typically modest power to determine if a marker is predictive (test an interaction) or to identify the marker defined subgroup associated with greatest treatment efficacy.

Evaluation of clinical validity will demonstrate the variability of the biomarker in the intended population and in the population without the disease of interest.;

Assessment of Clinical Utility

Clinical utility refers to how useful the assay is for directing treatment. This can be determined with a prospective clinical trial or by using more than one prospective-retrospective trial (12, 13). For this assessment, the assay should be analytically and clinically validated (locked down). Analysis of more than one retrospective dataset will allow refinement of cut points, if these are necessary. A prospective clinical trial (see example, below) will also allow refinement of cut points for the assay. Clinical utility is generally the goal of trials using integral assays to guide treatment or to select patients for a given treatment.

While typically a test of significance of null hypothesis is conducted, evidence of a sufficiently strong effect for the assay to be of clinical utility is more relevant for the future use of the methodology. If there is substantial uncertainty from prospective-retrospective analyses of the magnitude of the marker’s predictiveness with respect to treatment efficacy then a prospective randomized trial that concurrently assesses the activity of a new drug and the biomarker should be considered (12,14). The clinical protocol for the prospective evaluation must include the important aspects related to use of the integral assay, including the impact on patient eligibility, statistical design (including implications for power and type one-error control if there are subgroup analyses), trial futility monitoring and logistical details such as sample preparation, submission details or timing and transmission of assay results. Various trial designs have been proposed for this purpose, including marker stratified designs (14) and Bayesian adaptive designs (15). In the marker stratified design, all patients have the marker measured, are stratified into marker negative or positive groups and each group is randomized to receive either the experimental or the standard therapy. A particular strength of this design is the possibility for retrospective assessment of a different cut point or potentially different biomarkers. Bayesian designs begin with an initial model of how the assay will perform relative to the primary outcome, and update the model with accruing data. These designs are being used particularly in earlier therapeutic development clinical trials and their efficiency relative to other designs is under study.

While enrichment designs, in which only a defined marker group is enrolled, can be an efficient strategy to assess a new drug or therapy in the biomarker positive subgroup, the design doesn’t allow a full assessment of the performance of the marker (drug effect in biomarker negative patients).

Legal, ethical and scientific standards

An integral assay or test must be performed in a Clinical Laboratory Improvement Amendments (CLIA) accredited laboratory. In addition, integral markers in clinical trials are often considered to pose a significant risk to the health of patients. The U.S. Food and Drug Administration (FDA) has recently increased its surveillance of the risk posed by integral markers in trials with risk defined in the Federal Code of Regulations as a marker and its assay “for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject” (16). Almost all integral markers are considered to be a “significant risk” and, as discussed by Meshinchi et al. (17) elsewhere in this FOCUS section, it is wise to contact the FDA early in the protocol development process and undergo a pre-Investigational Device Exemption (pre-IDE). If the FDA indicates a full IDE is needed, there are suggestions for how to facilitate the IDE application (17).


Increased expression of eicosanoids in non-small cell lung cancer (NSCLC) has been associated with adverse prognosis (18). The combination of cyclooxygenase (COX-2) inhibitors with lipoxygenase (LOX) inhibitors or with chemotherapy enhanced cytotoxicity in vitro (19). The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II study for patients with stage IIIb (pleural effusion) or stage IV chemotherapy-naïve NSCLC in which patients received standard cytotoxic chemotherapy (carboplatin and gemcitabine) with either celecoxib (a COX-2 inhibitor), zileuton (an anti-asthmatic drug that also inhibits 5-LOX) , or both. Although none of the three arms met the primary study endpoint of 50% failure-free survival at 9 months, an exploratory analysis showed that administration of celecoxib plus zileuton with chemotherapy resulted in longer failure free survival than the other two arms; the difference was of borderline significance (p=0.054) when adjusted for known prognostic factors (stage, performance status). Because tumor tissue and serum samples were collected in this study, subsequent retrospective-prospective analysis could determine that patients whose tumor overexpressed COX-2 had a worse prognosis and that patients whose tumor over-expressed COX-2 and received celecoxib (with or without zileuton), had superior survival compared with patients who did not receive celecoxib. The test for interaction between treatment (celecoxib) and marker (COX 2 index ≥ 4) was significant. (20) This provocative finding led to the design a phase III trial, CALGB 30801 “A Randomized Phase III Double Blind Trial Evaluating Selective Cox-2 Inhibition In Cox-2 Expressing Advanced Non-Small Cell Lung Cancer” in which COX-2 expression is used an integral biomarker to select patients for enrollment. This prospective trial begins with an enrichment design (COX2 > 2) and then randomizes patients to standard treatment with or without a COX-2 inhibitor. This trial will serve to confirm or refute an interaction between the expression of COX-2 in tumor and benefit from addition of a COX-2 inhibitor to standard treatment, and allows exploration of the cut point for the assay (FIG 1). The primary objective of CALGB 30801 is to evaluate the benefit of COX-2 inhibition combined with chemotherapy (arm A) compared to chemotherapy only (arm B) in advanced NSCLC patients whose tumors have “over-expressed” COX-2 (defined as COX-2 index ≥ 4). The trial also plans to evaluate the survival benefit of celecoxib in patients with a lower level of COX-2 expression (COX-2 index ≥ 2).

Fig 1
CALGB 30801 Randomized phase III trial for Stage IIIB or IV non small cell lung cancer (adenocarcinoma, large cell, squamous or mixture). The trial will allow evaluation of the cut point for COX2 assay.

All potentially eligible patients are pre-registered. The CALGB Molecular Pathology Reference Laboratory performs all COX-2 assays for the trial. The laboratory is CLIA certified and College of American Pathologists (CAP) accredited. At the time the trial was initiated the FDA was not requiring pre-IDE review for such NCI-supported studies.

COX-2 is measured by immunohistochemistry as previously described (20). Paraffin embedded tissue sections (4mm) are heated at 60 degrees, cooled, and deparaffinized and rehydrated through xylene and graded alcohol solutions to water. Endogenous peroxide is blocked with 3% hydrogen peroxide in water and antigen retrieval is performed with TRS (Dako) and steaming. Automated staining with antibody to Cox-2, clone SP21 (Labvision Corp) diluted 1:50 for an hour is performed at room temperature. The detection system is a labeled streptavidin-biotin complex. After immunohistochemistry is performed, images of the slides and the pathology reports are transferred to the reading pathologist by a virtual microscopy system. All slides are reviewed without knowledge of patient history. Scoring for COX-2 expression, established in the previous phase II trial, is semi-quantitative/ordered categorical. The neoplastic cells are scored for intensity (range of scores 0-3) and percentage of cells stained 0 (0%), 1 (1-9%), 2 (10-49%), 3 (50-100%). An IHC index (range of scores 0-9) is defined as the product of the intensity and percentage of cells staining. Two cut points will be evaluated in this trial, an index of COX-2 ≥2 and an index ≥4. Three expert pathologist members of the CALGB Pathology Committee will score each case using a digital slide scanning system.

Results are sent (within 72 hours of specimen receipt) to the CALGB Statistical Center and the institution is notified of the patient’s eligibility status within 72 hours. Once COX-2 testing is complete, those with an index of 2 or greater are registered and randomized with equal allocation to chemotherapy with celecoxib or placebo. Patients with a score less than 2 are not registered and are treated at the discretion of their physician.

Assay Validation

As mentioned previously, a locked down assay is necessary before it may be used as an integral assay in a clinical trial. Although the College of American Pathologists provides some proficiency standards for IHC assays, they were not available for this assay, nor was any standard or certified reference material (4). CALGB set up proficiency testing with a small set of cases that were tested by two different laboratories: the CALGB Molecular Pathology Reference Laboratory and the Ohio State University clinical immunohistochemistry laboratory.

Accuracy is generally determined by comparing the measurement of the analyte against the true or accepted value. Because there is currently no gold standard for measuring COX-2 protein in tissue, the accuracy of the COX-2 IHC assay was determined by showing that the monoclonal rabbit anti-human COX-2 antibody that was used for the assay was specific for the antigen as it was used to identify COX-2 in both western blotting and precipitation of COX-2 as determined by HPLC.

CALGB performed two forms of precision testing. First, a set of samples with a range of IHC indices was stained on consecutive days and analyzed by the study pathologists to determine the day-to-day variability and the consistency of performance. Second, a set of 26 specimens was re-read by two pathologists. A linear model was fitted with the measure from one pathologist as the outcome variable and that of the other pathologist as the explanatory variable. The 95% confidence interval for the intercept estimate contains 0, and that of the slope estimate contains 1. The joint test for the intercept=0 and the slope=1 was not statistically significant (p-value=0.5156). Similar findings held for COX-2 intensity and COX-2 percent positive cells. The intra-class correlation was 0.81260 for COX-2 index, 0.81308 for intensity, and 0.67726 for percentage. After dichotomizing COX-2 index at 2, the agreement between the pathologists as measured by Kappa coefficient (0.7797; 95%CI: 0.3666, 1.000) was good. Despite a wide confidence interval, these findings suggested that the reading of COX-2 expression is reproducible across different pathologists. COX-2 expression readings of two distinct runs on a tumor microarray of samples from 24 patients with NSCLC and 36 patients with colon cancer, also revealed similar reproducibility and accuracy.

Controls, assayed with each study specimen, included lung tissue typed as negative and positive and a non-specific matched isotype antibody used in place of the primary antibody.

If an assay provides un-interpretable results based on failed quality control, tissue staining or loss or distortion of the tissue from the slide, the assay is repeated. If the assay remains uninterpretable upon a second attempt, the pathology readout will indicate this, and the patient will not be enrolled.


Integral biomarker assays will likely become more common in future phase II and III clinical trials. Testing for molecular abnormalities in single genes or for copy number alterations is already fairly common in clinical practice for breast, lung, colon, melanoma and other tumors (e.g., estrogen and progesterone receptor expression, expression or amplification of Her2/neu, KRAS mutations, EGFR mutations, BRAF V600E mutation, expression of c-KIT and BCR/ABL, PML/RAR and EML4-ALK translocations). Several cancer centers and some companies sequence tumor DNA to identify “actionable targets”. The development of powerful technology that can perform massively parallel (Next Generation) sequencing in less time has brought the prospect of whole genome and whole exome sequencing to the clinical realm, with the possibility of identifying mutated genes that may be targets for therapy, or polymorphisms that may portend a greater risk for toxicity. The pace of technology development promises additional capabilities to molecularly characterize tumors in the near future. Thus, it will continue to be essential to assess the clinical utility of new putative biomarkers.

When an integral assay is contemplated, there should be a strong biological rationale and/or correlation with tumor biology or clinical outcome. The assay should be analytically validated in a CLIA accredited laboratory, in a manner adequate to support use in a clinical trial. Serious consideration must be given to obtaining an IDE and to consultation with the FDA (for trials conducted in the United States). Currently, not all trials with integral assays have met these criteria. However, if we are to attain the benefits of molecularly driven cancer treatment, we must invest in the development of assays that are robust, validated and that provide clinically useful information.


1. Poste G, Carbone DP, Parkinson DR, Verweij J, Hewitt S, Jessup JM. Leveling the playing field: bringing development of biomarkers and molecular diagnostics up to the standards for drug development. Clin Cancer Res. 2012;18 [PMC free article] [PubMed]
2. Taube SE, Clark GM, Dancey JE, McShane LM, Sigman CC, Gutman SI. A Perspective on Challenges nd Issues in Biomarker Development and Drug and Biomarker Codevelopment. J Natl Cancer Inst. 2009;101:1453–63. [PMC free article] [PubMed]
3. Hewitt SM, Badve SS, True LD. The impact of pre-analytic factors in the design and application of integral biomarkers for directing patient therapy. Clin Cancer Res. 2012;18 [PMC free article] [PubMed]
4. Williams PM, Lively TG, Jessup JM, Conley BA. Bridging the Gap: Moving predictive and prognostic assays from research to clinical use. Clin Cancer Res. 2012;18 [PMC free article] [PubMed]
5. Valentin MA, Ma S, Zhao A, Legay F, Avrameas A. Validation of immunoassay for protein biomarkers: bioanalytical study plan implementation to support pre-clinical and clinical studies. J Pharm Biomed Anal. 2011;55:869–77. [PubMed]
6. Lee JW, Weiner RS, Sailstad JM, Bowsher RR, Knuth DW, O’Brien PJ, et al. Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report. Pharm Res. 2005;22:499–511. [PubMed]
7. Lee JW, Devanarayan V, Barrett YC, Weiner R, Allinson J, Fountain S, et al. Fit-for-purpose method development and validation for successful biomarker measurement. Pharm Res. 2006;23:312–28. [PubMed]
8. Cummings J, Raynaud F, Jones L, Sugar R, Dive C. Fit-for-purpose biomarker method validation for application in clinical trials of anticancer drugs. Br J Cancer. 2010;103:1313–17. [PMC free article] [PubMed]
9. Chau CH, Rixe O, McLeod H, Figg WD. Validation of analytic methods for biomarkers used in drug development. Clin Cancer Res. 2008;14:5967–76. [PMC free article] [PubMed]
10. Wagner JA, Williams SA, Webster CJ. Biomarkers and surrogate end points for fit-for-purpose development and regulatory evaluation of new drugs. Clin Pharmacol Ther. 2007;81:104–7. [PubMed]
11. Williams SA, Slavin DE, Wagner JA, Webster CJ. A cost-effectiveness approach to the qualification and acceptance of biomarkers. Nat Rev Drug Discov. 2006;5:897–902. [PubMed]
12. Simon RM, Paik S, Hayes DF. Use of Archived Specimens in Evaluation of Prognostic and Predictive Biomarker. J Natl Cancer Inst. 2009;101:1446–1452. [PMC free article] [PubMed]
13. Garcia VM, Cassier PA, deBono J. Parallel Anticancer Drug Development and Molecular Stratification to Qualify Predictive Biomarkers: Dealing with Obstacles Hindering Progress. Cancer Discovery. 2011;1:207–12. online Aug 15, 2011. [PubMed]
14. Freidlin B, McShane LM, Korn EL. Randomized Clinical Trials with Biomarkers: Design Issues. J Natl Cancer Inst. 2010;102:152–60. [PMC free article] [PubMed]
15. Zhou X, Liu S, Kim ES, Herbst RS, Lee JJ. Bayesian Adaptive Design for Targeted Therapy Development in Lung Cancer – a Step Toward Personalized Medicine. Clin Trials. 2008;5:181–193. [PubMed]
16. Code of Federal Regulations - 21CFR 812.3m
17. Meshinchi S, Hunger SP, Aplenc R, Adamson PC, Jessup JM. Lessons learned from the Investigational Device Exemption (IDE) review of Children’s Oncology Group Trial AAML1031. Clin Cancer Res. 2012;18 [PMC free article] [PubMed]
18. Horn L, Backlund M, Johnson DH. Targeting Eicosanoids Pathway in Non-Small Cell Lung Cancer. Expert Opin Ther Targets. 2009;13(6):675–688. Doi 10.1517/1472822002915567. [PMC free article] [PubMed]
19. Soriano AF, Helfrich B, Chan DC, Heasley LE, Bunn PA, Jr, Chou T-C. Synergistic Effects of New Chemopreventive Agents and Conventonal Cytotoxic Agents against Human Lung Cancer Cell Lines. Cancer Res. 1999;59:6178–84. [PubMed]
20. Edelman MJ, Watson D, Wang X, Morrison C, Kratzke RA, Jewell S, Hodgson L, Mauer AM, Gajra A, Masters GA, Bedor M, Vokes EE, Green MJ. Eicosanoid Modulation in Advanced Lung Cancer: Cyclooxygenase-2 Expression is a Positive Predictive Factor for Celecoxib + Chemotherapy − Cancer and Leukemia Group B Trial 30203. J Clin Oncol. 2008;26(6):848–55. [PubMed]
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