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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3831-3837 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.8073 Symptom Improvement in Lung Cancer Patients Treated With Erlotinib: Quality of Life Analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21
From the Princess Margaret Hospital/University Health Network, University of Toronto, Toronto; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; and OSI Pharmaceuticals Inc, Melville, NY Address reprint requests to Andrea Bezjak, MD, 610 University Avenue, Room 5-810, Toronto, ON M5G 2M9 Canada; e-mail: andrea.bezjak{at}rmp.uhn.on.ca
PURPOSE: This report describes the quality of life (QOL) findings of a randomized placebo controlled study of erlotinib, an epidermal growth factor receptor inhibitor, in patients with non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This double-blind phase III trial randomly assigned 731 patients with NSCLC who had progressed after prior chemotherapy to erlotinib 150 mg daily or placebo, with survival as the primary study outcome. QOL was assessed by European Organisation for Research and Treatment of Cancer QLQ-C30 and the lung cancer module QLQ-LC13. The primary end points for QOL analysis were time to deterioration of three common lung cancer symptoms: cough, dyspnea, and pain. RESULTS: Survival was significantly longer (hazard ratio, 0.70; P < .0001) in the erlotinib arm. Compliance with QOL was 87% at baseline and more than 70% during treatment. Patients receiving erlotinib had significantly longer median time to deterioration for all three symptoms (4.9 v 3.7 months for cough [P = .04]; 4.7 v 2.9 months for dyspnea [P = .04], and 2.8 v 1.9 months for pain [P = .03]). QOL response analyses showed that 44%, 34%, and 42% of patients receiving erlotinib had improvement in these three symptoms, respectively. This was accompanied by a significant improvement in the physical function (31% erlotinib v 19% placebo, P = .01), and global QOL (35% v 26%, P < .0001). Patients with complete or partial response were more likely to have improvement in the QOL response than patients with stable or progressive disease (P < .01). CONCLUSION: Erlotinib not only improves survival in previously treated patients with NSCLC, but also improves tumor-related symptoms and important aspects of QOL.
Lung cancer continues to be a leading cause of cancer death1; despite improved outcomes with early-stage2 and locally advanced3 non–small-cell lung cancer (NSCLC), most patients present with incurable disease. Chemotherapy as first-line4 and second-line treatment5,6 prolongs survival, and improves symptoms and quality of life (QOL). However, third-line chemotherapy has shown less benefit.7 Molecularly targeted agents are promising agents.8-10 Erlotinib, a tyrosine kinase epidermal growth factor receptor inhibitor, prolonged survival compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) study BR.21.11 Detailed symptom and QOL analyses, an integral part of that study, are reported herein.
This phase III trial was coordinated by NCIC CTG, supported by funding from the NCIC, the Canadian Cancer Society, and OSI Pharmaceuticals Inc (Melville, NY). NCIC CTG maintained the trial database and conducted all analyses.
Patients
Study Procedures
QOL Assessment Patients from all countries were expected to complete QOL questionnaires, with the exception of Thailand (for any QOL assessments), and Romania and Brazil (for lung cancer module completion), since those questionnaires were not available in the local language; those patients are excluded from the calculation of compliance rates. Translations of the core questionnaire and/or lung module were previously performed and validated, according to the standard EORTC procedures. 14
Statistical Considerations
For each symptom, all patients who had a baseline and at least one follow-up QOL assessment for this symptom were included in the time-to-deterioration analysis. Patients were censored at the time of the last QOL questionnaire completion if they had not deteriorated before that. The unstratified log-rank test was the primary method to compare the time to deterioration in each symptom between the two treatment arms. The Hochberg procedure18 was used to adjust the P values of the log-rank tests for these three comparisons. As an exploratory analysis, the Cox regression model with treatment (erlotinib v placebo) and other covariates including performance status (0, 1 v 2, 3), best response to prior therapy (complete remission or partial remission v stable disease v progressive disease), number of prior regimens (one v two), exposure to prior platinum (yes v no), sex, age (
In a secondary analysis of QOL responses, patients were classified as improved, stable, or worsened for all of the symptom and function domains, global QOL, and single items, according to the NCIC CTG standard QOL analysis framework.19 Improvement in QOL function domains and global QOL was defined as a score 10 points or better than baseline at any time of QOL assessments; worsening a score minus 10 points or worse than baseline at any time without any improvement. Patients who had less than 10-point changes from baseline at every QOL assessment were considered as stable. Classification into improved/worsened categories was reversed for symptom domains and single items because a positive change indicates worsening (ie, more symptoms).
Patient Characteristics Seven hundred thirty-one patients were accrued onto BR.21 from 15 countries (488 receiving erlotinib and 243 in the placebo arm).11 There were no apparent imbalances in the patient characteristics between the arms: median age was 61 years, 65% of patients were male, 50% had adenocarcinoma, and performance status was predominantly 0 or 1.
Summary of Clinical Outcomes
QOL Compliance
Baseline QOL Results The two study arms had similar baseline QOL scores in all domains and items (Fig 1). The greatest impairment was seen in global QOL (mean scores, 55.3 and 53.5 in the erlotinib and placebo arms, respectively), role functioning (mean, 58.9 and 60.0) and physical functioning (mean, 65.4 and 64.4). Symptoms with the highest mean baseline scores were fatigue (mean, 42.5 and 45.4, respectively), pain (mean, 34.2 and 38.3), cough (mean, 43.4 and 39.0), and dyspnea (mean, 31.9 and 33.5).
Primary QOL Analysis: Response of Main Lung Cancer Symptoms Figure 2 summarizes the time to deterioration of the three main lung cancer symptoms. The median time to deterioration of cough was 4.9 months (95% CI, 3.8 to 7.4 months) for patients receiving erlotinib, and 3.7 months (95% CI, 2.0 to 4.9) for patients receiving placebo (Hochberg adjusted P = .04; Fig 2A). Median time to deterioration of dyspnea was 4.7 months (95% CI, 3.8 to 6.2 months) and 2.9 months (95% CI, 2.0 to 4.8 months), respectively (adjusted P = .04; Fig 2B); and of pain 2.8 months (95% CI, 2.4 to 3.0 months) and 1.9 months (95% CI, 1.8 to 2.8 months), respectively (adjusted P =.03; Fig 2C). Cox regression analyses showed that, besides treatment with erlotinib (P = .04 for cough; .004 for dyspnea; .02 for pain), the following factors were associated with longer time to deterioration of symptoms: for cough, never having smoked (P = .02); for dyspnea, performance status of 0 or 1 (P = .002) and stable disease after prior therapy (P = .01); and for pain, stable disease after prior therapy (P = .001).
Secondary QOL Analysis: Proportion of Patients Improved/Stable/Worse Table 2 details the QOL responses for all of the main QOL domains, global QOL, and single items of the core questionnaire and lung cancer module. Statistically significant differences favoring erlotinib were seen for physical functioning, pain, cough, dyspnea, and constipation. Multivariate logistic analyses showed that treatment with erlotinib (P = .006) was the only independent predictor for improvement in physical functioning. Treatment with erlotinib (P = .006) and performance status of 0 or 1 (P = .045) were independent predictors for pain; treatment with erlotinib (P = .004), never having smoked (P = .003), and performance status of 0 or 1 (P = .02) were predictors for cough; and treatment with erlotinib (P = .01) and more than one prior regimen (P = .02) were predictors for dyspnea. Female sex (P = .01) was the only independent predictor for improvement in constipation. Significantly more patients receiving erlotinib worsened, and fewer patients on placebo had improvement in diarrhea. Multivariate logistic analyses identified treatment with erlotinib (P < .0001), performance status 0 or 1 (P = .02), never having smoked (P = .02), female sex (P = .045), and adenocarcinoma (P = .007) as independent predictors for worsening diarrhea. Some domains and items had more patients treated with erlotinib in both improved and worsened categories. By grouping three categories into two (improved and not improved; worsened and not worsened) based on the category (improved or worsened) with larger difference between two treatment groups, we found that significantly more patients treated with erlotinib improved in global QOL (P = .04) and emotional functioning (P = .04) and worsened in sore mouth (P < .0001) and hair loss (P < .0001). Multivariate analyses identified that treatment with erlotinib (P = .045) and stable disease after prior therapy (P = .02) were independent predictors for improvement in global QOL. No predictor for improvement in emotional functioning was found from these multivariate analyses.
Correlation Between QOL Response and Objective Tumor Response Table 3 lists the distribution of number and percentage of patients who had improvement in global QOL, physical functioning, cough, pain, and dyspnea, across three objective tumor response categories. For all the QOL scale and domains analyzed, patients with complete remission/partial remission were more likely to have improvement in the QOL response than patients with either stable or progressive disease.
This large, randomized study of erlotinib versus placebo as second- or third-line treatment in NSCLC has demonstrated a survival benefit and a statistically and clinically significantly longer time to deterioration of thoracic symptoms and improvements in global QOL and physical functioning on the erlotinib arm that was correlated with response to erlotinib. The efficacy of chemotherapy in incurable malignancies is usually assessed through response rates, toxicity, disease-free survival, and OS. However, these parameters do not allow for an assessment of the overall therapeutic benefit because they do not provide information about the clinical condition of the patients, their experience while undergoing treatment, or the quality of their survival. Treatment choices that patients make are influenced by numerous factors,20,21 including the value they place on potential improvements in survival.22 Studies have shown that cancer patients want to have QOL information to help in their decision making,23 and that most oncologists are unwilling to prolong survival at the expense of worsening QOL,24 although QOL considerations play a relatively small role in treatment decisions in current practice.25 Toxicity reporting could be seen as an indirect indicator of QOL, and if toxicity is mild, prolonged survival time can be assumed to be of good quality. However, biochemical and laboratory changes may not have a direct impact on the patient. Moreover, critical examination of the validity and reliability of toxicity reporting reveals under-reporting and significant intraobserver variability.26 Studies that have compared QOL with toxicity reporting demonstrate lower rates of reporting by study personnel for symptoms such as fatigue, dyspnea, and pain.27 This suggests that tumor-related symptoms may not be captured adequately by most study case report forms, making any assumptions about QOL benefits dubious. Thus, the true palliative benefit of chemotherapy in incurable cancers cannot be deduced from response rates, survival benefits and other traditional end points alone, but needs to be assessed directly, through validated patient-reported tools. The QOL benefits seen in BR.21 are both statistically and clinically relevant, and correlated with response to erlotinib. The QOL benefits compare favorably with other studies using the same QOL questionnaire in first-line treatment of NSCLC, such as the study of cisplatinum-based versus noncisplatinum chemotherapy as first-line treatment for advanced NSCLC.28 Other studies that have reported QOL results for second-line chemotherapy describe small degrees of improvement,29,30 or more often less deterioration in the active therapy arm.31 Two studies reported on symptom and QOL effects of epidermal growth factor receptor inhibitors. In a nonrandomized study of 57 patients receiving erlotinib as second-line therapy,10 EORTC QOL questionnaires demonstrated improvements in pain and emotional functions, with responders to treatment showing sustained QOL for a longer time. In a phase II randomized study of 216 patients treated with gefitinib,9 Lung Cancer Symptom Scale (LCSS), and FACT-L (Functional Assessment of Cancer Therapy–Lung) questionnaires demonstrated 35% to 43% symptom improvement, particularly in pulmonary symptoms.17 The authors also describe correlation between symptom improvement and objective tumor response, with virtually all patients with partial remission showing symptom improvement, 61% to 81% of patients with stable disease reporting symptom improvement, and only 12% to 20% of patients with progressive disease reporting improvement. In our study, the primary QOL outcome was prospectively defined as time to a clinically significant deterioration in three common lung cancer symptoms. There is no consensus as to which aspect of QOL should be the primary outcome of QOL analyses; we chose tumor-related symptoms because one of the most important goals of second-/third-line chemotherapy is to palliate symptoms. Patients with advanced NSCLC who have previously been treated with (and progressed during or relapsed after) chemotherapy are expected to deteriorate. In that clinical setting, a benefit may be defined not only as an improvement in baseline symptoms, but also as a delay in progression of symptoms. There is general agreement that the end points for QOL analyses should be predefined in all trials so that the QOL analysis is hypothesis testing, rather than hypothesis generating.19 All of the predefined primary analyses of this study demonstrated statistically significant and clinically relevant benefits in favor of patients receiving erlotinib. Secondary analyses of all QOL domains also demonstrated an advantage to patients on erlotinib, with significantly more patients showing improvement in global QOL and physical function, and trends towards improvements of other symptoms, such as fatigue. Of interest is the proportion of patients whose QOL and symptoms improved on the placebo arm. In the absence of active systemic therapy for these patients, improvement was likely a result of other supportive measures such as palliative radiotherapy, pain medications, and so on. However, despite improvements in some patients on the placebo arm, all of the disease and patient-centered outcomes consistently favored the erlotinib arm. Thus, this QOL analysis supports the true palliative benefit of erlotinib in improving not only survival, but also symptoms and QOL of patients with previously treated stage IV NSCLC.
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
Supported in part by a grant to the National Cancer Institute of Canada–Clinical Trials Group from OSI Pharmaceuticals Inc. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18: 2354-2362, 2000 7. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol: Classic Papers and Current Comments 6: 87-96, 2001 8. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21: 2237-2246, 2003 9. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290: 2149-2158, 2003 10. Perez-Soler R, Chachoua A, Hammond LA, et al: Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J Clin Oncol 22: 3238-3247, 2004 11. Shepherd F, Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123-132, 2005 12. Aaronson NK, Ahmedzai S, Bergman B, et al: The European organization for research and treatment of cancer QLQ-C30: A quality-of-life instrument for use in international trials in oncology. J Natl Cancer Inst 85: 365-376, 1993 13. Bergman B, Aaronson NK, Ahmedzai S, et al: The EORTC QLQ-LC13: A modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer 30A: 635-642, 1994 14. Cull A, Sprangers M, Bjordal K, et al: EORTC Quality of Life Group Translation Procedure. EORTC Quality of Life Group Publication, 2002 15. Hopwood P, Stephens RJ: Symptoms at presentation for treatment in patients with lung cancer: Implications for the evaluation of palliative treatment—The Medical Research Council (MRC) Lung Cancer Working Party. Br J Cancer 71: 633-636, 1995[Medline] 16. Osoba D, Rodrigues G, Myles J, et al: Interpreting the significant changes in health-related quality-of-life scores. J Clin Oncol 16: 139-144, 1998 17. Cella D, Eton D, Fairclough D, et al: What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) study 5592. J Clin Epidemiol 55: 285-295, 2002[CrossRef][Medline] 18. Hochberg Y: A sharp Bonferroni procedure for multiple tests of significance. Biometrics 75: 800-802, 1988[CrossRef] 19. Osoba D, Bezjak A, Brundage M, et al: Analysis and interpretation of health-related quality-of-life data from clinical trials: Basic approach of the National Cancer Institute of Canada Clinical Trials Group. Eur J Cancer 41: 280-287, 2005[CrossRef][Medline] 20. Jansen SJ, Otten W, Stiggelbout AM: Review of determinants of patients' preferences for adjuvant therapy in cancer. J Clin Oncol 22: 3181-3190, 2004 21. Koedoot CG, de Haan RJ, Stiggelbout AM, et al: Palliative chemotherapy or best supportive care? A prospective study explaining patients' treatment preference and choice. Br J Cancer 89: 2219-2226, 2003[CrossRef][Medline] 22. Brundage MD, Davidson JR, Mackillop WJ: Trading treatment toxicity for survival in locally advanced non-small cell lung cancer. J Clin Oncol 15: 330-340, 1997 23. Brundage M, Leis A, Bezjak A, et al: Cancer patients' preferences for communicating clinical trial quality of life information: A qualitative study. Qual Life Res 12: 395-404, 2003[CrossRef][Medline] 24. Bezjak A, Ng P, Skeel R, et al: Predicting oncologists' use of quality-of-life (QOL) data: Results of a survey of Eastern Co-operative Group (ECOG) physicians. Qual Life Res 10: 1-13, 2001[CrossRef][Medline] 25. Detmar SB, Muller MJ, Schornagel JH, et al: Role of health-related quality of life in palliative chemotherapy treatment decisions. J Clin Oncol 20: 1056-1062, 2002 26. Brundage M, Pater J, Zee B: Assessing the reliability of two toxicity scales: Implications for interpreting toxicity data. J Natl Cancer Inst 85: 1138-1148, 1993 27. Butler L, Bacon M, Carey M, et al: Determining the relationship between toxicity and quality of life in an ovarian cancer chemotherapy clinical trial. J Clin Oncol 22: 2461-2468, 2004 28. Gridelli C, Gallo C, Shepherd F, et al: Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: A phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21: 3025-3034, 2003 29. Anderson H, Hopwood P, Stephens RJ, et al: Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer: A randomized trial with quality of life as the primary outcome—UK NSCLC Gemcitabine Group: Non-Small Cell Lung Cancer. Br J Cancer 83: 447-453, 2000[CrossRef][Medline] 30. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22: 1589-1597, 2004 31. Dancey J, Shepherd FA, Gralla RJ, et al: Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: Results of a prospective, randomized phase III trial. Lung Cancer 43: 183-194, 2004[CrossRef][Medline] Submitted January 25, 2006; accepted June 20, 2006. Related Correspondence
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 v > 60), ethnicity (Asian v others), prior radiotherapy (yes v no), histology (adenocarcinoma v others), and smoking history (smoker v nonsmoker v unknown), was used to identify independent factors associated with longer time to deterioration for each symptom. 
2 test was used to compare the distributions of these three categories between two arms; for the scale/domains with statistically significant differences between the arms, the logistic regression model with the afore-mentioned covariates was used to identified factors predictive of improvement or worsening. For global QOL, physical functioning, cough, dyspnea, and pain, the correlation between QOL response and objective tumor response was evaluated by 
