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Quality of Life Analysis of Patients With Non–Small-Cell Lung Cancer 5. Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, Bonomi P. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer. 1995;12(3):199-220. 6. Butt Z, Webster K, Eisenstein AR, et al. Quality of life in lung cancer: the validity and cross-cultural applicability of the Functional Assessment Of Cancer Therapy-Lung scale. Hematol Oncol Clin North Am. 2005;19(2):389-420, viii. 7. Cella D, Eton DT, Fairclough DL, 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. 2002;55(3):285-295. 8. Agresti A. Categorical Data Analysis. 2nd ed. Hoboken, NJ: John Wiley & Sons Inc; 2002. 9. Fletcher A, Gore S, Jones D, Fitzpatrick R, Spiegelhalter D, Cox D. Quality of life measures in health care. II: Design, analysis, and interpretation. BMJ. 1992;305(6862):1145-1148. 10. Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions. Hoboken, NJ: John Wiley & Sons Inc; 2003. 11. Giobbie-Hurder A, Gelber RD, Regan MM. Challenges of guarantee-time bias. J Clin Oncol. 2013;31(23):2963-2969. 12. Dafni U. Landmark analysis at the 25-year landmark point. Circ Cardiovasc Qual Outcomes. 2011;4(3):363-371. 13. Little RJ, Rubin DB. Statistical Analysis With Missing Data. 2nd ed. New York, NY: WileyInterscience; 2002. 14. Sarna L, Swann S, Langer C, et al. Clinically meaningful differences in patient-reported outcomes with amifostine in combination with Original Investigation Research chemoradiation for locally advanced non-small-cell lung cancer: an analysis of RTOG 9801. Int J Radiat Oncol Biol Phys. 2008;72(5):1378-1384. 15. Basch E, Iasonos A, McDonough T, et al. Patient versus clinician symptom reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events: results of a questionnaire-based study. Lancet Oncol. 2006;7 (11):903-909. 16. Movsas B, Moughan J, Sarna L, et al. Quality of life supersedes the classic prognosticators for long-term survival in locally advanced non-small-cell lung cancer: an analysis of RTOG 9801. J Clin Oncol. 2009;27(34):5816-5822. 17. Coates A, Porzsolt F, Osoba D. Quality of life in oncology practice: prognostic value of EORTC QLQ-C30 scores in patients with advanced malignancy. Eur J Cancer. 1997;33(7):1025-1030. 22. Hallqvist A, Bergman B, Nyman J. Health related quality of life in locally advanced NSCLC treated with high dose radiotherapy and concurrent chemotherapy or cetuximab: pooled results from two prospective clinical trials. Radiother Oncol. 2012;104(1):39-44. 23. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol. 2011;29(3):279286. 24. Movsas B, Hunt D, Watkins-Bruner D, et al. Can electronic web-based technology improve quality of life data collection? analysis of Radiation Therapy Oncology Group 0828. Pract Radiat Oncol. 2014;4 (3):187-191. 18. Cella D, Herbst RS, Lynch TJ, et al. Clinically meaningful improvement in symptoms and quality of life for patients with non-small-cell lung cancer receiving gefitinib in a randomized controlled trial. J Clin Oncol. 2005;23(13):2946-2954. 25. Yom SS, Liao Z, Liu HH, et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2007;68(1):94-102. 19. Werner-Wasik M, Swann RS, Bradley J, et al. Increasing tumor volume is predictive of poor overall and progression-free survival: secondary analysis of the Radiation Therapy Oncology Group 93-11 phase I-II radiation dose-escalation study in patients with inoperable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008;70(2):385-390. 26. Grills IS, Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL. Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small-cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat Oncol Biol Phys. 2003;57(3):875-890. 20. Siddiqui F, Liu AK, Watkins-Bruner D, Movsas B. Patient-reported outcomes and survivorship in radiation oncology: overcoming the cons. J Clin Oncol. 2014;32(26):2920-2927. 27. Jiang ZQ, Yang K, Komaki R, et al. Long-term clinical outcome of intensity-modulated radiotherapy for inoperable non-small cell lung cancer: the MD Anderson experience. Int J Radiat Oncol Biol Phys. 2012;83(1):332-339. 21. Fayers PM, Curran D, Machin D. Incomplete quality of life data in randomized trials: missing items. Stat Med. 1998;17(5-7):679-696. Editor's Note The Importance of Quality of Life Assessment Charles R. Thomas Jr, MD, PhD Dose escalation of an antineoplastic modality such as radiotherapy (RT) may result in an increased therapeutic ratio with the use of effective strategies to mitigate normal tissue toxic effects. Successful execution of dose escalation using Related article page 359 external beam RT (EBRT) approaches has yielded unintended outcomes.1,2 While increased disease control and survival are a focus of such strategies to increase the therapeutic ratio, quality of life (QOL), as measured by appropriate patientrelated outcomes tools, are nearly as important. To that end, Movsas et al,3 in this issue of JAMA Oncology, document that an attempt to deliver nearly a quarter higher total dose (74 Gy vs 60 Gy) of EBRT given concomitantly with a platinumtaxane doublet for locally advanced non–small-cell lung cancer (LA-NSCLC) results in a clinically meaningful decrement in QOL at 3 months.3 However, the Radiation Therapy Oncology Group 0617 trial is not the definitive treatise regarding the RT dosejamaoncology.com escalation question for LA-NSCLC. The QOL assessments, as well as the survival results, likely were influenced by numerous factors that are difficult to control for in a multi-institutional, cooperative group clinical trial setting. Emerging data on molecular signatures that may predict radiosensitivity and/or radioresistance of tumor, as well as normal tissues, may be helpful in future assessment of baseline patient characteristics for those enrolled in prospective, large-scale cancer clinical trials of RT-based treatment. Moreover, not all modes of potential RT delivery and dose escalation are equal. Currently, radiation oncologists see patients on a weekly basis and basically assess symptoms as a “snapshot in time.” This is fraught with recall bias and other factors that contribute to a diminished appreciation of real-time patient-related outcomes, which should ideally be recorded on a continuous 24/7 basis to assess QOL during treatment. Movsas and colleagues are to be congratulated for executing a trial that will help in the design of next-generation QOL trials for LA-NSCLC. (Reprinted) JAMA Oncology March 2016 Volume 2, Number 3 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935080/ on 05/05/2017 367 Research Original Investigation Quality of Life Analysis of Patients With Non–Small-Cell Lung Cancer Conflict of Interest Disclosures: None reported. a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187-199. REFERENCES 2. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20(5): 1167-1174. 1. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): 3. Movsas B, Hu C, Sloan J, et al. Quality of life analysis of a radiation dose–escalation study of patients with non–small-cell lung cancer: a secondary analysis of the Radiation Therapy Oncology Group 0617 randomized clinical trial [published online November 25, 2015]. JAMA Oncol. doi:10.1001/jamaoncol.2015.3969. Invited Commentary Dose Escalation in Stage III Non–Small-Cell Lung Cancer Patients Agree With the Clinical Results David Cella, PhD As we conduct clinical research to continue to “move the dial” of progress against lung cancer, it has become increasingly important to consider the patient’s perspective alongside that of more standard efficacy and safety end points. Besides the Related article page 359 obvious reason of patient centricity, there are several compelling clinical reasons to do so. In this issue of JAMA Oncology, the article by Movsas and colleagues1 provides us with more evidence to illustrate the importance of the patient’s perspective on efficacy and safety in clinical trials, and especially the importance of studies in advanced disease. The results reaffirm a few principles of quality-of-life measurement in advanced tumor oncology that can now be considered teachable facts, supported by robust results, reproduced in multiple studies, using various questionnaires. Three such facts are (1) quality-of-life reports taken at the start of a new therapy for advanced disease are predictive of survival; (2) clinicianrated toxicity on the Common Terminology Criteria for Adverse Events (CTCAE) grading system underestimates the adverse effects of treatments on patients’ lives; and (3) dose escalation, whether chemotherapeutic or radiotherapeutic, has predictable, deleterious effects on quality of life, as reported on a well-validated lung cancer questionnaire. To frame these “facts,” I will discuss them in the context of the article by Movsas et al.1 Despite promising phase 2 trial data in patients with unresectable stage III non–small-cell lung cancer (NSCLC), escalating dose of radiation therapy (RT) and adding cetuximab did not lengthen survival when compared with standard dose RT with concurrent and consolidation chemotherapy.2 This article1 presents detail on the quality-of-life data from the same study.2 The authors1 used the Trial Outcome Index (TOI) from the Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS) quality-of-life instrument. The FACT-LCS produces 5 individual subscale scores and 2 summary scores: one (TOI) to reflect the physical dimension of life quality, and the other (FACT-LCS total score) to reflect an overall summary of health-related quality of life. Movsas et al1 chose to administer and focus only on 368 the physical dimension, using the 3 subscales that comprise the TOI: Physical Well-Being, Functional Well-Being, and Lung Cancer Symptoms. Lessons learned: 1. Quality-of-life reports taken at the start of a new therapy for advanced disease are predictive of survival. As has been shown in several prior studies,3 across many groups of patients with advanced disease, baseline patient report of quality-of-life (TOI score) was associated (P = .046) with survival time. It has also been shown in several investigations,3 although not apparently analyzed in this investigation, that change in patient report while on therapy is also predictive of survival, above and beyond the baseline report. Analysis of both baseline scores and early change in scores can shed further light on which patients benefits, and which do not, from therapy in early treatment, perhaps contributing to clinical decision-making after initiation of treatment. 2. Clinician-rated toxic effects on the CTCAE grading system underestimates the adverse effects of treatments on patients’ lives. On the one hand, Movsas and colleagues1 reported that very few of the clinician-rated adverse events were worse in the treatment arm receiving the escalated dose of RT. On the other hand, patient report of symptoms, adverse effects, and functioning, as manifest in the FACTLCS TOI and its components, were significantly and meaningfully worse in the arm receiving the escalating dose. Significantly more patients in the arm receiving 74-Gy (45% vs 30%) had clinically meaningful decline in FACT-LCS at 3 months than those receiving 60 Gy (P = .02). 3. Dose escalation, whether chemotherapeutic or radiotherapeutic, has predictable, deleterious effects on quality of life. Here are some of the most novel and interesting findings by Movsas et al.1 Those clinicians planning future studies that include dose escalation can learn from these results, especially with regard to making hypotheses and then measuring and testing them. To their credit, these investigators1 studied several patient-reported toxic effects, and they asked the right questions to answer their questions. Several dosimetric factors were associated with clinically meaning- JAMA Oncology March 2016 Volume 2, Number 3 (Reprinted) Copyright 2016 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/oncology/935080/ on 05/05/2017 jamaoncology.com