Combining Survival and Toxicity Effect Sizes from Clinical Trials: NCCTG 89-20-52 (Alliance)
DOI:
https://doi.org/10.6000/1929-6029.2018.07.04.4Keywords:
Survival, toxicity, quality of life, effect size, quality-adjusted life years, QALY.Abstract
Background: How can a clinician and patient incorporate survival and toxicity information into a single expression of comparative treatment benefit? Sloan et al. recently extended the ½ standard deviation concept for judging the clinical importance of findings from clinical trials to survival and tumor response endpoints. A new method using this approach to combine survival and toxicity effect sizes from clinical trials into a quality-adjusted effect size is presented.
Methods: The quality-adjusted survival effect size (QASES) is calculated as survival effect size (ESS) minus the calibrated toxicity effect sizes (EST) (QASES=ESS-EST). This combined effect size can be weighted to adjust for the relative emphasis placed by the patient on survival and toxicity effects.
Results: As an example, consider clinical trial NCCTG 89-20-52 which randomized patients to once-daily thoracic radiotherapy (ODTRT) versus twice-daily treatment of thoracic radiotherapy (TDRT) for the treatment of lung cancer. The ODTRT vs. TDRT arms had median survival time of 22 vs. 20 months (p=0.49) and toxicity rate of 39% vs. 54%, (p<0.05). The QASES of 0.18 standard deviations translates to a quality-adjusted survival difference of 5.7 months advantage for the ODRT arm over the TDRT treatment arm (22(16.3) months), p<0.05). Similar results are presented for the four possible case combinations of significant/non-significant survival and toxicity benefits using completed clinical trials.
Conclusions: We used a novel approach to re-analyze clinical trial data to produce a single estimate for each treatment that combines survival and toxicity data. The QASES approach is an intuitive and mathematically simple yet robust approach.
References
Braun MS, Seymour MT. Balancing the efficacy and toxicity of chemotherapy in colorectal cancer. Ther Adv Med Oncol 2011; 3(1): 43-52. https://doi.org/10.1177/1758834010388342 DOI: https://doi.org/10.1177/1758834010388342
Gelber RD, Gelman RS, Goldhirsch A. A quality-of-life-oriented endpoint for comparing therapies. Biometrics 1989; 45(3): 781-95. https://doi.org/10.2307/2531683 DOI: https://doi.org/10.2307/2531683
Sloan JA, Sargent DJ, Lindman J, et al. A new graphic for quality adjusted life years (Q-TWiST) survival analysis: the Q-TWiST plot. Qual Life Res 2002; 11(1): 37-45. https://doi.org/10.1023/A:1014401516011 DOI: https://doi.org/10.1023/A:1014401516011
Cole BF, Gelber RD, Gelber S, et al. A quality-adjusted survival (Q-TWiST) model for evaluating treatments for advanced stage cancer. Journal of Biopharmaceutical Statistics 2004; 14(1): 111-24. https://doi.org/10.1081/BIP-120028509 DOI: https://doi.org/10.1081/BIP-120028509
Revicki DA, Feeny D, Hunt TL, et al. Analyzing oncology clinical trial data using the Q-TWiST method: clinical importance and sources for health state preference data. Qual Life Res 2006; 15(3): 411-23. https://doi.org/10.1007/s11136-005-1579-7 DOI: https://doi.org/10.1007/s11136-005-1579-7
Sloan JA, Bonner JA, Hillman SL, et al. A quality-adjusted reanalysis of a Phase III trial comparing once-daily thoracic radiation vs. twice-daily thoracic radiation in patients with limited-stage small-cell lung cancer (1). Int J Radiat Oncol Biol Phys 2002; 52(2): 371-81. https://doi.org/10.1016/S0360-3016(01)01819-3 DOI: https://doi.org/10.1016/S0360-3016(01)01819-3
Radice D, Redaelli A. Q-TWiST analysis of cyclophosphamide, epirubicin, fluorouracil versus cyclophosphamide, methotrexate, fluorouracil treatment for premenopausal women with node-positive breast cancer. Pharmaco Economics 2005; 23(1): 69-75. https://doi.org/10.2165/00019053-200523010-00006 DOI: https://doi.org/10.2165/00019053-200523010-00006
Tate WR, Skrepnek GH. Quality-adjusted time without symptoms or toxicity (Q-TWiST): patient-reported outcome or mathematical model? A systematic review in cancer. Psychooncology 2014. DOI: https://doi.org/10.1002/pon.3595
Sloan JA, Sargent DJ, Novotny PJ, et al. Calibration of quality-adjusted life years for oncology clinical trials. J Pain Symptom Manage 2014; 47(6): 1091-99 e3. DOI: https://doi.org/10.1016/j.jpainsymman.2013.07.016
Jeff A Sloan DV-C, Celia C Kamath, Daniel J Sargent, Paul Novotny, Pamela Atherton, C Allmer, B L Fridley, Marlene Frost, C L Loprinzi. Detecting worms, ducks, and elephants: A simple approach for defining clinically relevant effects in quality-of-life measures. Journal of Cancer Integrative Medicine 2003; 1(1): 41-47.
Sloan JA, Major B. Combining survival and toxicity effect sizes from clinical trials into an interpretable,quality-adjusted survival effect size estimate of treatment efficacy [abstract]. Poster presentation. (2014 Jun 11) J Clin Oncol 2014; 32(15_suppl): 6630. DOI: https://doi.org/10.1200/jco.2014.32.15_suppl.6630
Bonner J, Sloan J, Shanahan T. Phase III comparison of twice-daily compared with once-daily thoracic radiotherapy in limited stage small-cell lung carcinoma. Journal of Clinical Oncology 1999; 17: 2681-91. https://doi.org/10.1200/JCO.1999.17.9.2681 DOI: https://doi.org/10.1200/JCO.1999.17.9.2681
Ajani JA, Rodriguez W, Bodoky G, et al. Multicenter Phase III Comparison of Cisplatin/S-1 With Cisplatin/Infusional Fluorouracil in Advanced Gastric or Gastroesophageal Adenocarcinoma Study: The FLAGS Trial. Journal of Clinical Oncology 2010; 28(9): 1547-53. https://doi.org/10.1200/JCO.2009.25.4706 DOI: https://doi.org/10.1200/JCO.2009.25.4706
Moore MJ, Goldstein D, Hamm J, et al. Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the
National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology 2007; 25(15): 1960-66. https://doi.org/10.1200/JCO.2006.07.9525 DOI: https://doi.org/10.1200/JCO.2006.07.9525
Baselga J, Cortes J, Kim S-B, et al. Pertuzumab plus Trasruzumab plus Docetaxel for Metastatic Breast Cancer. New England Journal of Medicine 2012; 366: 109-19. https://doi.org/10.1056/NEJMoa1113216 DOI: https://doi.org/10.1056/NEJMoa1113216
Bowling A. Research Methods in Health: Investigating Health and Health Services. Buckingham, UK: Open University Press 1997.
Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol 2014; 32(12): 1277-80. https://doi.org/10.1200/JCO.2013.53.8009 DOI: https://doi.org/10.1200/JCO.2013.53.8009
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Copyright (c) 2018 Brittny T. Major-Elechi, Paul J. Novotny, Jasvinder A. Singh, James A. Bonner, Amylou C. Dueck, Daniel J. Sargent, Axel Grothey, Jeff A. Sloan
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