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Histologic Considerations for Individualized Systemic Therapy Approaches for the Management of Non-small Cell Lung Cancer FREE TO VIEW

Howard West, MD; David Harpole, MD, FCCP; William Travis, MD, FCCP
Author and Funding Information

Affiliations: From the Thoracic Oncology Program (Dr. West), Swedish Cancer Institute, Seattle, WA; Duke University Medical Center (Dr. Harpole), Durham, NC; and Memorial Sloan-Kettering Cancer Center (Dr. Travis), New York, NY.

Correspondence to: Howard West, MD, Medical Director, Thoracic Oncology Program, Swedish Cancer Institute, 1221 Madison St, Suite 1020, Seattle, WA 98104; e-mail: howard.west@swedish.org


Funding/Support:This research was sponsored by an educational grant from Eli Lilly and Company.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(4):1112-1118. doi:10.1378/chest.08-2484
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Over the past 5 to 10 years, we have reached a treatment plateau using standard platinum-based doublets in an unselected population of patients with advanced non-small cell lung cancer (NSCLC). Recent studies have focused on improving patient outcomes with new chemotherapeutic or targeted agents, as well as on individualizing therapy on the basis of patient characteristics such as tumor histology and biomarker analysis. This article summarizes recent data on histologic response determinants to chemotherapy and targeted therapy, with particular attention to the importance of standardized tissue collection, handling, storage, and analysis techniques, in order to best apply the results of tumor analysis to patient-care decisions. Such decisions are related to both improving patient safety and optimizing efficacy with standard chemotherapy as well as newer targeted therapy agents. This entails a change from a generalized approach in treating patients with NSCLC to an individualized strategy based on tumor histology.

Lung cancer is the leading cause of cancer death in the United States and accounted for approximately 161,840 deaths in 2008.1 Chemotherapy is the standard frontline treatment option for the majority of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC); platinum-based doublets improve survival compared with best supportive care.2 Several studies35 have demonstrated comparable results for several commonly used platinum-based doublets. Studies demonstrating one doublet as significantly superior to another in efficacy have been unusual,6,7 and typical guidelines do not make a distinction among particular platinum-based doublets to be recommended in this setting.8 Strategies for improving patient outcomes include using novel cytotoxic and targeted agents, optimizing current treatment regimens, or customizing treatment approaches using patient characteristics, tumor histology, and/or biomarker expression. Recent studies have focused on defining the attributes that contribute to the individualization of NSCLC management and the optimization of patient care, with some of this work revealing significant efficacy differences that may arguably drive clinical decisions.

NSCLC tumors are typically divided into the following three major histologic groups: adenocarcinomas (37 to 45%); squamous cell carcinomas (SCCs) [20 to 33%]; and large cell carcinomas (4 to 9%).9,10 Emerging data reveal that tumor histology impacts the benefit of specific chemotherapy or targeted therapy regimens.

Histology and Chemotherapy for NSCLC

In a phase III trial of patients with previously untreated advanced NSCLC that compared a platinum-based doublet of cisplatin (Platinol; Bristol-Myers Squibb Co; Princeton, NJ)/docetaxel (Taxotere; Sanofi-Aventis United States LLC; Bridgewater, NJ) to a nonplatinum doublet of docetaxel/gemcitabine (Gemzar; Eli Lilly and Co; Indianapolis, IN), the subset of patients with adenocarcinomas demonstrated a significantly higher response rate (RR) with the nonplatinum doublet, and those with nonadenocarcinomas responded significantly better to platinum-based chemotherapy.11

More recently, a randomized trial of patients with advanced NSCLC comparing second-line pemetrexed (Alimta; Eli Lilly and Co) with docetaxel was reviewed retrospectively by histology, showing significant differences by this variable.12 First, when results were pooled by treatment, patients with adenocarcinoma had the best median survival, followed by patients with SCC, then patients with other/mixed histology (9.1, 6.5, and 7.8 months, respectively; p = 0.004). Patients with adenocarcinoma histology had a superior median survival with pemetrexed (9.3 vs 8.0 months, respectively; p = 0.048); those with squamous histology had a better survival with docetaxel (7.4 vs 6.2 months, respectively; p = 0.018).12 The choice of first-line therapy (gemcitabine/platinum, taxane/platinum, or other) was not associated with significant differences in overall survival (OS) between histologic subgroups (p = 0.713).12

Following this retrospective analysis, a prospectively planned subset analysis was incorporated into a recently completed randomized phase III study13 of 1,725 chemotherapy-naive patients with advanced NSCLC that compared cisplatin/pemetrexed to cisplatin/gemcitabine therapy. This work revealed that those with adenocarcinoma or large cell carcinoma demonstrated improved survival on the pemetrexed-containing regimen compared with the cisplatin/gemcitabine reference arm (11.8 vs 10.4 months, respectively; p = 0.005). For patients with SCC, a borderline significant improvement in median OS was seen in the gemcitabine/cisplatin arm (10.8 vs 9.4 months, respectively; p = 0.05).13 On the basis of these results, pemetrexed was approved by the European Medicines Agency14 and the US Food and Drug Administration15 for the treatment of non-SCC in the first-line setting.

Although these results are compatible with the conclusion that pemetrexed is a considerably more effective therapy for patients with nonsquamous tumors, this prior work is limited by the fact that all patients received active therapy, so the effects are due to the relative contribution of both pemetrexed and the alternative chemotherapy regimen. As illustrated in Table 1, a phase III trial16,17 of maintenance pemetrexed vs placebo for nonprogressing patients after four cycles of platinum-based chemotherapy (without pemetrexed) demonstrated that the improvements in RR, progression-free survival (PFS), and OS were limited to patients with nonsquamous histology, in whom significant benefits were observed. In contrast, pemetrexed was associated with no improvement in any of these parameters compared to placebo in patients with squamous NSCLC. These results have led to restrictions of the previously broader NSCLC indication for second-line therapy to now include only patients with nonsquamous tumors, both by the European Medicines Agency and the US Food and Drug Administration.14,15

Table Graphic Jump Location
Table 1 Efficacy Results by Histologic Subgroups of a Phase III Trial Comparing Maintenance Pemetrexed Plus Best Supportive Care vs Placebo Plus Best Supportive Care

BSC = best supportive care; CR = complete response; Pcb = placebo; Pm = pemetrexed; PR = partial response; SD = stable disease. From Ciuleanu et al16 and Belani et al.17

Taken together, these data demonstrate that NSCLC histology has now emerged as a relevant factor in identifying optimal conventional chemotherapy and is relevant for general clinical decisions, at least for patients with advanced NSCLC. At the present time, it is unclear whether other commonly used chemotherapeutic agents will follow a similar pattern of histology-specific efficacy outcomes. The retrospective analysis of the trial12 comparing docetaxel to pemetrexed in the second-line setting shows no outcome differences between patients with squamous and adenocarcinoma tumors. However, other work on conventional chemotherapies has largely ignored the question of tumor histology, leaving us without any meaningful date to assess whether taxanes, gemcitabine, or vinorelbine may also be associated with histology-specific results. Regardless, there are now three large phase III trials12,13,17 that have all convincingly demonstrated that the efficacy of pemetrexed is significantly greater and potentially entirely limited to patients with nonsquamous NSCLC histologic subtypes.

These data also highlight that patients with squamous NSCLC consistently demonstrate lower survival than patients with adenocarcinoma or nonsquamous tumors. Because tumor histology is now increasingly specified and restricted in clinical trials in advanced NSCLC, it is critical when comparing results across different trials to consider the patient demographics and inclusion and exclusion criteria.

Relevance of Histology With Targeted Therapies for NSCLC

Several trials have revealed the impact of histology on treatment outcomes with epidermal growth factor receptor (EGFR)-based therapies. In the BR.21 trial randomizing previously treated patients with advanced NSCLC to the EGFR tyrosine kinase inhibitor (TKI) erlotinib (Tarceva; Genentech Inc; South San Francisco, CA; and OSI Pharmaceuticals Inc; Melville, NY) or placebo in a 2:1 fashion, erlotinib recipients with adenocarcinoma demonstrated an RR of 13.9%, which is more than three times the RR of 4.1% seen in patients with squamous or other tumor subtypes.18 Despite this difference in RRs, a similar relative survival benefit was seen in patients with squamous/other and adenocarcinoma subtypes (hazard ratio [HR], 0.8 and 0.7, respectively, for OS in squamous/other and adenocarcinoma patients). Further underscoring the distinction between RR and survival, a retrospective analysis of this trial19 demonstrated that single agent erlotinib was associated with a 2.1-month survival benefit among male smokers with squamous tumors, despite a very low RR of < 5% in this population.

Kim and colleagues20 recently reported results for the Iressa Versus Intravenous Docetaxel (Taxotere) [or INTEREST] phase III trial comparing second-line EGFR TKI gefitinib (Iressa; AstraZeneca Pharmaceuticals LP; Wilmington, DE) vs docetaxel in patients with advanced NSCLC but found not only no differences in OS in the overall patient populations, but also no differences between EGFR TKI therapy and conventional chemotherapy with a histology-specific analysis. However, patients with adenocarcinomas had a median OS that was 2 months longer than that seen among patients with NSCLCs with histologies other than adenocarcinoma (gefitinib, 8.5 vs 6.4 months, respectively; docetaxel, 8.9 vs 6.9 months). Furthermore, no differences in survival were seen in patients with high vs low EGFR copy number, positive vs negative EGFR protein expression, mutated vs wild-type EGFR, or mutated vs wild-type KRAS.21

Bronchioloalveolar carcinoma (BAC), a distinct subtype of NSCLC and specifically adenocarcinoma, has emerged as a unique histologically defined subgroup with particular relevance in the evolution of EGFR inhibitors. The BAC subtype was identified very early in multivariate analysis as one of the most favorable prognostic features for a favorable response to gefitinib.22 In a subsequent phase II prospective Southwest Oncology Group trial of gefitinib for advanced BAC,23 gefitinib was demonstrated to have an RR of approximately 15%, with several patients demonstrating no progression on ongoing gefitinib for > 4 years.24 It should be noted that the term BAC is used in these clinical studies to refer to advanced invasive adenocarcinoma with BAC features, as well as to “pure BAC,” a histologically noninvasive pattern of growth for lung adenocarcinoma.25,26

On the basis of these data, it is evident that tumor histology can be associated with significant differences in efficacy of specific anticancer therapies, but it is important to distinguish between clinical end points of response, which vary greatly by NSCLC histology,18 and survival, which is inconsistently associated with differences in clinical response to EGFR TKIs.18,27 Improved accuracy in histologic classification should help to clarify these associations between histology and patient outcomes and further refine individualized approaches to the management of patients with NSCLC. To clarify terminology issues in lung adenocarcinoma such as BAC, the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society are sponsoring a panel to develop an international multidisciplinary classification of lung adenocarcinoma, which should be completed in 2009.

Many therapies targeting tumor-associated angiogenesis are under investigation to improve the outcomes of patients with NSCLC. Despite their promise and limited data supporting a survival benefit with bevacizumab for some patients with previously untreated advanced NSCLC,28 the appropriate setting for the use of antiangiogenic agents must be clearly defined, especially because safety issues have been raised that require individualization of treatment recommendations on the basis of tumor histology, which requires an accurate identification of NSCLC subtype.

Bevacizumab

Bevacizumab (Avastin; Genentech Inc; South San Francisco, CA) is currently contraindicated in patients with SCC on the basis of the results of a phase II trial comparing carboplatin (Paraplatin; Bristol-Myers Squibb Co) plus paclitaxel (Taxol; Bristol-Myers Squibb Co) with or without bevacizumab.29 Although benefit was seen with bevacizumab treatment, this trial revealed that life-threatening or fatal hemoptysis was associated with bevacizumab in patients with SCC histology (4 of 13 patients; 31%), although it was not clear whether histology alone is the reason for increased bleeding risk. Excluding patients with SCC appeared to markedly limit the risk of life-threatening bleeding complications associated with bevacizumab in this setting.

The potential impact of histology on adverse events prompted several subsequent trials evaluating antiangiogenic agents to exclude patients with squamous cell histology. A large phase III trial, Eastern Cooperative Oncology Group (ECOG) E4599, randomized 878 previously untreated patients with advanced nonsquamous NSCLC to receive carboplatin/paclitaxel with or without bevacizumab and excluded patients with CNS metastases or a history of hemoptysis.28 Compared with chemotherapy alone, patients treated with bevacizumab demonstrated a significantly improved RR (35% vs 15%, respectively; p < 0.001), median PFS (6.2 vs 4.5 months, respectively; p < 0.001), and median OS (12.3 vs 10.3 months, respectively; p = 0.003). Despite a limitation of patients based on perceived risk of bleeding complications, there was still a significant increase in the incidence of hemorrhage observed in recipients of bevacizumab with chemotherapy (4.4% vs 0.7%, respectively; p < 0.001), and five cases (1.2%) of hemoptysis were fatal. Importantly, 20% of patients enrolled in ECOG 4599 had histology assigned as “NSCLC, not otherwise specified,” but there were no fatal bleeding complications among these patients (A. Sandler, MD; personal communication; June 2006).

The AVAstin in Lung cancer (or AVAiL) phase III trial evaluated the combination of cisplatin/gemcitabine with or without bevacizumab in previously untreated patients with nonsquamous advanced NSCLC.30,31 This trial randomized patients to the following three arms: cisplatin/gemcitabine plus placebo; cisplatin/gemcitabine plus low-dose bevacizumab (7.5 mg/kg); and cisplatin/gemcitabine plus high-dose bevacizumab (15 mg/kg). Patients in the cisplatin/gemcitabine plus placebo arm had a median PFS of 6.2 months, compared with 6.8 months for the patients in the low-dose bevacizumab arm (p = 0.0003 compared to placebo arm) and 6.6 months for patients in the high-dose bevacizumab arm (p = 0.0456). There was no significant difference in median OS between the study and the control arms (13.1, 13.6, and 13.4 months, respectively, for the placebo, low-dose bevacizumab, and high-dose bevacizumab arms). Serious bleeding complications were in the 1% range in the bevacizumab arms of this trial, indicating no unexpected toxicity issues.

BRIDGE is an open-label phase II study of bevacizumab plus carboplatin and paclitaxel in patients with advanced, previously untreated, SCC.32,33 Of 31 evaluable patients, 1 patient (3.2%) experienced a fatal pulmonary hemorrhage. Ongoing trials include PASSPORT, a phase II trial of bevacizumab combined with first-line or second-line therapy in patients with metastatic nonsquamous NSCLC with previously treated CNS metastases, and AVASQ, a phase II study of radiation followed by paclitaxel, carboplatin, and bevacizumab in patients with stage IIIB and IV squamous NSCLC.34,35

In the earlier disease setting, the ongoing ECOG E1505 phase III trial36 is evaluating the addition of bevacizumab to adjuvant cisplatin-based chemotherapy in patients with resected stage IB to IIIA NSCLC. Importantly, this study does not restrict by tumor histology because it is presumed that the tumor has been resected and does not represent a significant bleeding risk.

Small-Molecule Angiogenesis Inhibitors

With the emergence of serious bleeding events as a potential adverse event in patients with SCC receiving bevacizumab, trials investigating small-molecule angiogenesis inhibitors have paid close attention and reported bleeding-adverse events in an effort to determine whether these risks are a class effect or are particular to bevacizumab alone. Single-agent sunitinib (Sutent; Pfizer Inc; New York, NY) was evaluated in a phase II trial of 63 patients with advanced NSCLC who failed platinum-based chemotherapy and showed promising efficacy.37 With seven confirmed partial responses, the overall RR was 11.1%, and an additional 28.6% of patients experienced stable disease lasting at least 8 weeks. The median PFS was 12 weeks, and the median OS was 23.4 weeks. There were three deaths related to hemorrhage; two were pulmonary hemorrhages in patients with SCC, and the other was in a patient with adenocarcinoma and CNS metastases.

The ESCAPE phase III trial randomized chemotherapy-naive patients with advanced NSCLC of any NSCLC histology, including SCC, to carboplatin/ paclitaxel with or without the multikinase inhibitor sorafenib (Nexavar; Onyx Pharmaceuticals Inc; Emeryville, CA), which has antiangiogenic activity, in patients with advanced NSCLC.38,39 The trial was closed early when it was determined that the primary end point was not reached, but recently reported data from this trial showed no significant increase in PFS (HR, 0.97; p = 0.356) or OS (HR, 1.09; p = 0.849) between the trial arms, regardless of histology. In addition, there were nine grade 5 pulmonary hemorrhage events in patients with SCC (five occurred in the sorafenib arm; and four occurred in the placebo arm). Four instances of fatal pulmonary hemorrhage were observed in patients with nonsquamous histology receiving sorafenib and none was observed in the placebo arm. Overall, bleeding issues and potentially other excessive toxicity issues appear to be a broad concern with angiogenesis inhibitors as a class in patients with SCC, although more studies are needed to fully define the risks.

As therapy for NSCLC evolves into more individualized approaches that utilize patient characteristics such as biomarkers and tumor histology to drive treatment decisions, it becomes increasingly important to optimize the collection, handling, and storage of tissue in order to improve the consistency and accuracy of analysis. Furthermore, the type of downstream analysis is impacted by the choice of tissue sample and the method of preservation (Table 2) (W. Travis, MD, FCCP; personal communication; July 2008).40

Table Graphic Jump Location
Table 2 Recommendations for Tissue Collection and Fixation Based on Specific Tests

From Eberhard et al40; and W. Travis, MD, FCCP; personal communication; July 2008.

Adequate sampling of tumor tissue is important because lung tumors are often heterogeneous. At the molecular level, EGFR/EGFR protein expression, gene amplification, and mutational status can vary within the same tumor, complicating the interpretation of these analyses.4043 If available, it may be beneficial to evaluate multiple sections in order to assess tumor burden accurately within the entire sample.40 However, further research is needed on this topic. Prioritization of specimens for diagnosis, staging, and molecular analysis should also be considered, with an accurate diagnosis being the first priority.

Often, samples obtained by minimally invasive procedures, including cytology specimens such as fine-needle aspirates, are the only type available.40 This is particularly common in the setting of locally advanced and metastatic NSCLC. However, larger samples obtained by biopsy are preferred in order to provide adequate material for molecular assays.40 For cytology specimens, an onsite pathologist can make immediate decisions on whether tissue samples are adequate depending on the intended downstream analysis; however, it remains a challenge to balance these concerns against a need to minimize patient discomfort and procedural complications while obtaining larger, more adequate tumor samples. It is also not always possible to have a pathologist available onsite. Continued development of assay technologies to maximize the clinical utility of smaller samples is important.40

Accurate histologic classification of tumor tissue is critical, especially considering the safety concerns associated with the use of angiogenesis inhibitors in patients with SCC. However, in some poorly differentiated non-small cell carcinomas, the distinction between SCC and adenocarcinoma or large cell carcinoma may be very difficult even for experienced pathologists. This problem will be addressed in the upcoming International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society international multidisciplinary classification of lung adenocarcinoma.

Standardized protocols for tissue collection, fixation, and procurement are also necessary to improve the reproducibility and consistency of downstream diagnoses and analyses (Table 2). Standardized protocols should be accessible for all clinics, including community practices. Regarding fixation procedures, fresh-frozen samples have the advantage of avoiding fixation-related artifacts but must be procured and stored properly. Formalin-fixed samples are preferred for histologic classification and some molecular assays,40 but fixation times have not been standardized. Following paraffin embedding, samples should be stored as a block to maintain the integrity of the antigens being analyzed.40 Unstained slides can be used for immunohistochemistry (IHC) and, if sufficient tumor tissue is present on the sections, this material can also be used for fluorescence in situ hybridization (FISH) and mutation assays. However, the immunoreactivity of some antigens may be impaired with prolonged storage, particularly beyond 3 months.43,44

Similarly, standardized protocols should be used for molecular assays in order to improve consistency. Molecular techniques for tissue analysis have limitations; for example, the ISEL trial evaluating gefitinib vs placebo in patients that were evaluated for EGFR copy number compared two different EGFR-detecting antibodies and found that approach seemed to better predict for survival outcome with gefitinib.45 Thus, the choice of antibody as well as the choice of detection and scoring systems and cutoffs probably contributes to varying results in studies that test for EGFR expression. Commercially available assay kits may be a reasonable way to standardize EGFR IHC.40 In the same way, optimizing FISH analysis and mutational analysis also depends on proper sample handling, preparation, and analysis.40

The management of NSCLC is now moving from a standard of treatment based on stage and performance status to a much more individualized one based on clinical, histologic, and molecular factors. This movement is the result of a need to administer optimal chemotherapy for a particular patient, to address safety concerns with antiangiogenic agents, and to maximize the impact of targeted therapies like EGFR inhibitors by identifying subsets of patients more or less likely to benefit from these agents. Prior studies have laid the groundwork that justifies the need to obtain adequate tissue to assign a clear histologic diagnosis and conduct molecular testing, and ongoing and future trials will require having adequate tissue. In the setting of this changing standard of personalized treatment for patients with NSCLC, it is increasingly important to refine tissue sampling, collection, and handling techniques to ensure consistent, reproducible, and accurate downstream diagnoses and analyses. Personalized treatment for patients with NSCLC will require us to modify our expectations of what constitutes adequate tissue and to reevaluate our histologic classification of NSCLC tumors. This work will allow us to move beyond the impasse of several years of comparable results from a wide range of platinum-based doublets.

BAC

bronchioloalveolar carcinoma

ECOG

Eastern Cooperative Oncology Group

EGFR

epidermal growth factor receptor

FISH

fluorescence in situ hybridization

HR

hazard ratio

IHC

immunohistochemistry

NSCLC

non-small cell lung cancer

OS

overall survival

PFS

progression-free survival

RR

response rate

SCC

squamous cell carcinoma

TKI

tyrosine kinase inhibitor

Financial/nonfinancial disclosures: Dr. West has consulted for Eli Lilly and Co and ImClone Systems Inc, and has served on a speaker's bureau for Eli Lilly and Co. Dr. Travis has consulted for Genentech Inc. Dr. Harpole has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose produts or services may be discussed in this article.

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Bayer. Bayer and Onyx provide update on phase III trial of Nexavar in patients with non-small cell lung cancer.Accessed June 1, 2009 Available at:http://www.press.bayer.com/baynews/baynews.nsf/ID/2008-0063-e.
 
Hanna NH, von Pawel J, Reck M, et al. Carboplatin/paclitaxel with/without sorafenib in chemonaive patients with stage IIIB-IV non-small cell lung cancer (NSCLC): interim analysis (Ia) results from a randomized phase III trial (escape) [abstract]. J Thorac Oncol. 2008;11suppl:S268
 
Eberhard DA, Giaccone G, Johnson BE. Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol. 2008;26:983-994. [PubMed]
 
Italiano A, Vandenbos FB, Otto J, et al. Comparison of the epidermal growth factor receptor gene and protein in primary non-small-cell-lung cancer and metastatic sites: implications for treatment with EGFR-inhibitors. Ann Oncol. 2006;17:981-985. [PubMed]
 
Suzuki S, Dobashi Y, Sakurai H, et al. Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas: an immunohistochemical and fluorescencein situhybridization study. Cancer. 2005;103:1265-1273. [PubMed]
 
Varella-Garcia M. Stratification of non-small cell lung cancer patients for therapy with epidermal growth factor receptor inhibitors: the EGFR fluorescencein situhybridization assay. Diagn Pathol. 2006;1:19. [PubMed]
 
Bertheau P, Cazals-Hatem D, Meignin V, et al. Variability of immunohistochemical reactivity on stored paraffin slides. J Clin Pathol. 1998;51:370-374. [PubMed]
 
Hirsch FR, Dziadziuszko R, Thatcher N, et al. Epidermal growth factor receptor immunohistochemistry: comparison of antibodies and cutoff points to predict benefit from gefitinib in a phase 3 placebo-controlled study in advanced nonsmall-cell lung cancer. Cancer. 2008;112:1114-1121. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 Efficacy Results by Histologic Subgroups of a Phase III Trial Comparing Maintenance Pemetrexed Plus Best Supportive Care vs Placebo Plus Best Supportive Care

BSC = best supportive care; CR = complete response; Pcb = placebo; Pm = pemetrexed; PR = partial response; SD = stable disease. From Ciuleanu et al16 and Belani et al.17

Table Graphic Jump Location
Table 2 Recommendations for Tissue Collection and Fixation Based on Specific Tests

From Eberhard et al40; and W. Travis, MD, FCCP; personal communication; July 2008.

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Hanna NH, von Pawel J, Reck M, et al. Carboplatin/paclitaxel with/without sorafenib in chemonaive patients with stage IIIB-IV non-small cell lung cancer (NSCLC): interim analysis (Ia) results from a randomized phase III trial (escape) [abstract]. J Thorac Oncol. 2008;11suppl:S268
 
Eberhard DA, Giaccone G, Johnson BE. Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol. 2008;26:983-994. [PubMed]
 
Italiano A, Vandenbos FB, Otto J, et al. Comparison of the epidermal growth factor receptor gene and protein in primary non-small-cell-lung cancer and metastatic sites: implications for treatment with EGFR-inhibitors. Ann Oncol. 2006;17:981-985. [PubMed]
 
Suzuki S, Dobashi Y, Sakurai H, et al. Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas: an immunohistochemical and fluorescencein situhybridization study. Cancer. 2005;103:1265-1273. [PubMed]
 
Varella-Garcia M. Stratification of non-small cell lung cancer patients for therapy with epidermal growth factor receptor inhibitors: the EGFR fluorescencein situhybridization assay. Diagn Pathol. 2006;1:19. [PubMed]
 
Bertheau P, Cazals-Hatem D, Meignin V, et al. Variability of immunohistochemical reactivity on stored paraffin slides. J Clin Pathol. 1998;51:370-374. [PubMed]
 
Hirsch FR, Dziadziuszko R, Thatcher N, et al. Epidermal growth factor receptor immunohistochemistry: comparison of antibodies and cutoff points to predict benefit from gefitinib in a phase 3 placebo-controlled study in advanced nonsmall-cell lung cancer. Cancer. 2008;112:1114-1121. [PubMed]
 
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