Mell, Loren K

Rose, Brent S

Zakeri, Kaveh

eScholarship - University of California

UC San DiegoUC San Diego Previously Published WorksTitleDetecting a Survival Benefit to Dose Escalation.Permalinkhttps://escholarship.org/uc/item/0cq6z4d1JournalJAMA Oncology, 5(1)ISSN2374-2437AuthorsZakeri, KavehRose, Brent SMell, Loren KPublication Date2019DOI10.1001/jamaoncol.2018.5055 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of Californiaentries, as in the case of changing ambiguous outcome defi-nitions to specific ones. In addition, multivariable analyses ofthe factors associated with changes in ClinicalTrials.goventries were not feasible owing to the small number of stud-ies included in the analysis.AmongtrialssupportingFDAapprovalofcancerdrugs,modi-fications in study design after patient accrual has begun are com-mon,oftenunreported,andassociatedwithbreakthroughtherapydesignation, accelerated approval, and single-arm trials. Healthcare professionals, reviewers, journal editors, and regulatorsshould demand more transparent justification for changes to thetrial design after commencement of patient accrual.Daniel Shepshelovich, MDAriadna Tibau, MD, PhDConsolación Molto, MDHadar Goldvaser, MDAlberto Ocana, MD, PhDBostjan Šeruga, MD, PhDEitan Amir, MD, PhDAuthor Affiliations: Division of Medical Oncology & Hematology, Departmentof Medicine, Princess Margaret Cancer Centre, Toronto, Ontario, Canada(Shepshelovich, Goldvaser, Amir); Department of Internal Medicine, SacklerFaculty of Medicine, Tel Aviv University, Tel Aviv, Israel (Shepshelovich);Oncology Department, Hospital de la Santa Creu i Sant Pau, UniversitatAutònoma de Barcelona, Barcelona, Spain (Tibau, Molto); Department ofOncology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel(Goldvaser); Research Unit, Translational Oncology Laboratory, Regional Centerfor Biomedical Research (CRIB), Albacete University Hospital, Albacete, Spain(Ocana); Centro de Investigación Biomédica en Red Cáncer (CIBERONC),Castilla–La Mancha University, Albacete, Spain (Ocana); Department of MedicalOncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia (Šeruga);Department of Medicine, University of Toronto, Toronto, Ontario, Canada (Amir).Accepted for Publication: October 9, 2018.Corresponding Author: Eitan Amir, MD, PhD, Division of Medical Oncology &Hematology, Princess Margaret Cancer Centre, 700 University Ave, Floor 7,Ste 721, Toronto, ON M5G 1Z5, Canada (eitan.amir@uhn.ca).Published Online: December 6, 2018. doi:10.1001/jamaoncol.2018.5877Author Contributions: Drs Shepshelovich and Amir had full access to all of thedata in the study and takes responsibility for the integrity of the data and theaccuracy of the data analysis.Concept and design: Tibau, Ocana, Amir.Acquisition, analysis, or interpretation of data: Shepshelovich, Tibau, Molto,Goldvaser, Šeruga, Amir.Drafting of the manuscript: Shepshelovich.Critical revision of the manuscript for important intellectual content: All authors.Statistical analysis: Shepshelovich, Molto, Amir.Administrative, technical, or material support: Molto, Goldvaser, Amir.Supervision: Tibau, Ocana, Amir.Conflict of Interest Disclosures: Dr Ocana reported receiving personal fees fromDaiichi Sankyo, Servier, and Entrechem outside the submitted work. Dr Amirreported receiving personal fees from Genentech/Roche, Myriad Genetics, Agendia,and Apobiologix outside the submitted work. No other disclosures were reported.1. CONSORT statement, 6b: changes to outcomes. http://www.consort-statement.org/checklists/view/32--consort-2010/81-changes-to-outcomes.Accessed June 12, 2018.2. USFoodandDrugAdministration.Hematology/oncology(cancer)approvals&safetynotifications. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Updated October 16, 2018. Accessed October 28, 2018.3. Raghav KP, Mahajan S, Yao JC, et al. From protocols to publications: a studyin selective reporting of outcomes in randomized trials in oncology. J Clin Oncol.2015;33(31):3583-3590. doi:10.1200/JCO.2015.62.41484. Woloshin S, Schwartz LM, Bagley PJ, Blunt HB, White B. Characteristics ofinterim publications of randomized clinical trials and comparison with finalpublications. JAMA. 2018;319(4):404-406. doi:10.1001/jama.2017.206535. US Food and Drug Administration. Guidance for industry: expedited programs forserious conditions—drugs and biologics. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.PublishedMay2014. Accessed June 12, 2018.6. Liang F, Guo X, Zhang S, Xue H, Chen Q, Hu X. Comparison of primary endpointsbetween publications, registries, and protocols of phase III cancer clinical trials.Oncotarget. 2017;8(57):97648-97656. doi:10.18632/oncotarget.21459COMMENT & RESPONSEDetecting a Survival Benefit to Dose EscalationTo the Editor We commend Michalski et al1 for reporting the an-ticipated results of RTOG 0126, and in particular, for reporting theincidencesofbothall-causeandcause-specificmortality.Surpris-ingly, many trials do not report this vital information.2 The inci-dence of prostate cancer mortality was unexpectedly low in theirtrial, possibly owing to improvement in salvage therapies andchanges in the patient population. We are concerned that the pro-posed effect size (hazard ratio, 0.77) on overall survival (OS) was,in retrospect, mathematically infeasible, and therefore the truepower of this study to detect an OS benefit with dose escalationis much lower than 90%.The incidences of all-cause mortality and prostate cancermortality at 8 years were 25% and 4%, respectively, for a relativeincidence of cancer-specific to all-cause mortality of approxi-mately 0.16 (0.04/0.25). This relative incidence bounds themaximum effect a cancer treatment can have on a primary endpoint. Unless one postulates that mortality from cancer and non-cancer causes are positively correlated or that dose escalationsomehow reduces mortality from noncancer causes, the maxi-mum achievable hazard ratio in this population is greater than1 − 0.16 = 0.84, even if dose escalation were to entirely eliminatedeathfromprostatecancer.3 Therelativecause-specific incidencewould be much higher, of course, for biochemical progression-free survival, which would make an effect size of 0.77 more plau-sible. Thus, this trial seems underpowered for an OS primary endpoint and possibly overpowered for a biochemical progression-free survival primary end point.A power estimate is misleading if it proposes effect sizes thatare impossible. Post hoc, we estimate that even if dose escala-tion perfectly eliminated cancer deaths in this population, about5000 patients would be needed for 90% power with a 1-sided αof 0.025; with 1500 patients, this trial would have had less than50% power to observe any benefit on OS. Because OS is such aproblematic primary end point in populations with heavy com-peting risks,4 we propose that future trials use methods to iden-tify populations with a comparatively lower relative incidenceof competing mortality when OS is the desired primary endpoint.5 Before undertaking analysis, it may also be helpful tocheck the expected relative incidence against the hypothesizedeffect size to ensure that it is feasible.Kaveh Zakeri, MD, MASBrent S. Rose, MDLoren K. Mell, MDAuthor Affiliations: Department of Radiation Medicine and Applied Sciences,University of California San Diego, La Jolla.Corresponding Author: Loren K. Mell, MD, Division of Clinical and Translational Re-search,DepartmentofRadiationMedicineandAppliedSciences,UniversityofCaliforniaSan Diego, 3855 Health Sciences Dr, MC0843, La Jolla, CA 92093 (lmell@ucsd.edu).Lettersjamaoncology.com (Reprinted) JAMA Oncology January 2019 Volume 5, Number 1 109© 2018 American Medical Association. All rights reserved.Downloaded From: https://jamanetwork.com/ by a University of California - San Diego User  on 03/19/2019Published Online: November 15, 2018. doi:10.1001/jamaoncol.2018.5055Conflict of Interest Disclosures: None reported.1. Michalski JM, Moughan J, Purdy J, et al. Effect of standard vs dose-escalatedradiation therapy for patients with intermediate-risk prostate cancer: the NRGoncology RTOG 0126 randomized clinical trial. JAMA Oncol. 2018;4(6):e180039.doi:10.1001/jamaoncol.2018.00392. Mell LK, Lau SK, Rose BS, Jeong JH. Reporting of cause-specific treatmenteffects in cancer clinical trials with competing risks: a systematic review.Contemp Clin Trials. 2012;33(5):920-924. doi:10.1016/j.cct.2012.05.0133. Mell LK, Jeong JH. Pitfalls of using composite primary end points in thepresence of competing risks. J Clin Oncol. 2010;28(28):4297-4299. doi:10.1200/JCO.2010.30.28024. Zakeri K, Rose BS, Gulaya S, D’Amico AV, Mell LK. Competing event riskstratification may improve the design and efficiency of clinical trials: secondaryanalysis of SWOG 8794. Contemp Clin Trials. 2013;34(1):74-79. doi:10.1016/j.cct.2012.09.0085. Carmona R, Zakeri K, Green G, et al. Improved method to stratify elderlypatients with cancer at risk for competing events. J Clin Oncol. 2016;34(11):1270-1277. doi:10.1200/JCO.2015.65.0739In Reply We thank Dr Zakeri and colleagues for their interest inthe NRG/RTOG 0126 trial.1 After design, how a clinical trial playsout depends on accurate projections of several key para-meters. As mentioned by Zakeri et al and described in thereport,1 the overall survival (OS) was much better than antici-pated, owing largely to better-than-expected prostate cancerprognosis. This result, in turn, has major bearing on the haz-ard ratio (HR) for the composite end point of OS. Indeed, thebenefit on OS is bounded, and a simplified way to conceptu-alize this,2 similar to the argument by Zakeri et al, is that theHR of the composite outcome is a weighted average of effectson constituent end points:HROS = Proportion prostate cancer deaths × HRprostate cancer +Proportion other deaths × HRother deathsOne can reasonably assume a moderate to large effect on pros-tate cancer deaths and no effect on other-cause death. Assum-ing that 30% to 40% of deaths are attributable to prostate can-cer, a 23% reduction in mortality (HR, 0.77) would bemathematically achievable but ambitious. Revisiting the powercalculation, the key determinants are the failure rate (events/time) and rate ratio (ie, HR); thus, sample size was based onthese quantities. At the planned total of 715 events for defini-tive analysis, power for HR of 0.77 would be 93% (using theShoenfeld formula3; an alternate determination that was basedon time-varying event rates was used, yielding the original90%). The same number of events would afford 80% powerfor an HR of 0.81 and 70% power for an HR of 0.83. Thus, wecannot confirm the statement that “with 1500 patients, thistrial would have less than 50% power to observe any benefiton OS.” However, we do agree that the planning HR of 0.77 wasunrealistic in light of the much better-than-expected progno-sis of the patients, and less than 90% for more realistic HRs.Given the detailed development in the study protocol (avail-able via supplemental materials),1 there was certainly nointention to present a misleading power assessment, butwe acknowledge that, based on the observed study data, anunachievable target HR at 90% power was specified.As described, the trial was reported early (at 58% of events)owing to crossing of a futility monitoring boundary and addi-tional considerations that indicated little chance of the OS forthe high-dose radiation therapy (RT) arm proving to be supe-rior to a clinically material degree in this trial; this finding isunequivocal and not owing to a lack of statistical power. Giventhe low mortality rate and that high-dose RT has already beenwidely adopted, it was deemed useful to report the results atthis time. Further follow-up (in which the relative proportionof prostate cancer deaths may increase) will bear out the ulti-mate findings with respect to other end points, where benefitsare already apparent (eg, large prostate-specific antigen [PSA]failure reduction, leading to avoidance of salvage therapy) oremerging (eg, distant metastasis, cause-specific mortality).A PSA failure-based primary end point, while attractive be-cause it would have indeed led to a smaller trial, would then re-sult in lower power for the more substantive clinical end points.Thus, in conjunction with our partners at the National CancerInstitute, OS was selected as the primary end point.The ultimate determination of the worth of high-dose RTrests on weighing the realized benefits and risks, as observedin the trial. Design of future studies must strive to address thechallenging problem of identifying clinically meaningful inter-ventions for cancer patients with relatively low risk of cancermortality. Many, including Zakeri et al and others,4 continue towork on creative potential solutions to this problem.James J. Dignam, PhDKathryn A. Winter, MSJeff Michalski, MDAuthor Affiliations: NRG Oncology Statistics and Data Management Center,University of Chicago, Chicago, Illinois (Dignam); NRG Oncology Statistics andData Management Center, Philadelphia, Pennsylvania (Winter); WashingtonUniversity in St Louis, St Louis, Missouri (Michalski).Corresponding Author: Jeff Michalski, MD, Washington University in St Louis,4921 Parkview Pl, PO Box 8224, St Louis, MO 63110 (jmichalski@wustl.edu).Published Online: November 15, 2018. doi:10.1001/jamaoncol.2018.5093Conflict of Interest Disclosures: None reported.1. Michalski JM, Moughan J, Purdy J, et al. Effect of standard vs dose-escalatedradiation therapy for patients with intermediate-risk prostate cancer: the NRGoncology RTOG 0126 randomized clinical trial. JAMA Oncol. 2018;4(6):e180039.doi:10.1001/jamaoncol.2018.00392. Dignam JJ, Kocherginsky MN. Choice and interpretation of statistical testsused when competing risks are present. J Clin Oncol. 2008;26(24):4027-4034.doi:10.1200/JCO.2007.12.98663. Schoenfeld D. The asymptotic properties of nonparametric tests forcomparing survival distributions. Biometrika. 1981;68:316-319. doi:10.1093/biomet/68.1.3164. Xie W, Regan MM, Buyse M, et al; ICECaP Working Group. Metastasis-freesurvival is a strong surrogate of overall survival in localized prostate cancer.J Clin Oncol. 2017;35(27):3097-3104. doi:10.1200/JCO.2017.73.9987CompetingRisksforaDiagnosisofInvasiveBreastCancerTo the Editor In their recent article in JAMA Oncology, Brentnallet al1 reported on long-term results from a praiseworthy cohortstudy that observed women who completed a breast cancer riskassessment until the diagnosis of invasive breast cancer or cen-soring. Women were censored at death, diagnosis of ductalcarcinomainsitu,whentheyreached75yearsofage,orattheendof study follow-up.It is unclear if and how many women subsequentlyunderwent risk-reducing interventions, such as chemopro-Letters110 JAMA Oncology January 2019 Volume 5, Number 1 (Reprinted) jamaoncology.com© 2018 American Medical Association. All rights reserved.Downloaded From: https://jamanetwork.com/ by a University of California - San Diego User  on 03/19/2019

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