E L Korn1, M C Sachs2, L M McShane2. 1. Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, USA korne@ctep.nci.nih.gov. 2. Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, USA.
Abstract
BACKGROUND: A trial-level surrogate end point for a randomized clinical trial may allow assessment of the relative benefits of the treatment to be performed at an earlier time point and potentially with a smaller sample size. However, determining whether an end point is a reliable trial-level surrogate based on results of previous trials is not straightforward. The question of trial-level surrogacy is easily confused with the question of individual-level surrogacy, and this confusion can lead to controversy. A recent example concerns the evaluation of pathologic complete response (pCR) as a surrogate for event-free survival (EFS) and overall survival (OS) in early-stage breast cancer. MATERIALS AND METHODS: The differences between individual-level surrogacy (i.e. for patients receiving a specific treatment, the surrogate end point predicts the definitive end point) and trial-level surrogacy (the results of the trial for the surrogate end point predict the results of the trial for the definitive end point) are discussed. Trial-level data used in two previous meta-analyses evaluating pCR as a trial-level surrogate for EFS and OS were re-analyzed using methods that appropriately account for the variability in pCR rates as well as the variability in the hazard ratios for EFS and OS. RESULTS: There is no evidence that pCR is a trial-level surrogate for EFS or OS, nor is there evidence that pCR could be used reliably to screen out nonpromising agents from further drug development. CONCLUSIONS: At present, neoadjuvant RCTs should continue to follow patients to observe EFS and OS to assess clinical benefit, and they should be designed with sufficient sample size to reliably assess EFS. However, one cannot rule out the possibility that future meta-analyses involving more trials and in which the patient population or class of treatments is restricted could suggest the validity of pCR as a trial-level surrogate for EFS or OS in some focused settings. Published by Oxford University Press on behalf of the European Society for Medical Oncology 2015. This work is written by (a) US Government employee (s) and is in the public domain in the US.
BACKGROUND: A trial-level surrogate end point for a randomized clinical trial may allow assessment of the relative benefits of the treatment to be performed at an earlier time point and potentially with a smaller sample size. However, determining whether an end point is a reliable trial-level surrogate based on results of previous trials is not straightforward. The question of trial-level surrogacy is easily confused with the question of individual-level surrogacy, and this confusion can lead to controversy. A recent example concerns the evaluation of pathologic complete response (pCR) as a surrogate for event-free survival (EFS) and overall survival (OS) in early-stage breast cancer. MATERIALS AND METHODS: The differences between individual-level surrogacy (i.e. for patients receiving a specific treatment, the surrogate end point predicts the definitive end point) and trial-level surrogacy (the results of the trial for the surrogate end point predict the results of the trial for the definitive end point) are discussed. Trial-level data used in two previous meta-analyses evaluating pCR as a trial-level surrogate for EFS and OS were re-analyzed using methods that appropriately account for the variability in pCR rates as well as the variability in the hazard ratios for EFS and OS. RESULTS: There is no evidence that pCR is a trial-level surrogate for EFS or OS, nor is there evidence that pCR could be used reliably to screen out nonpromising agents from further drug development. CONCLUSIONS: At present, neoadjuvant RCTs should continue to follow patients to observe EFS and OS to assess clinical benefit, and they should be designed with sufficient sample size to reliably assess EFS. However, one cannot rule out the possibility that future meta-analyses involving more trials and in which the patient population or class of treatments is restricted could suggest the validity of pCR as a trial-level surrogate for EFS or OS in some focused settings. Published by Oxford University Press on behalf of the European Society for Medical Oncology 2015. This work is written by (a) US Government employee (s) and is in the public domain in the US.
Entities:
Keywords:
breast cancer; pathologic complete response; randomized clinical trial; screening trials; surrogate end point; trial-level surrogate end point
Authors: Lawrence V Rubinstein; Edward L Korn; Boris Freidlin; Sally Hunsberger; S Percy Ivy; Malcolm A Smith Journal: J Clin Oncol Date: 2005-10-01 Impact factor: 44.544
Authors: Marc Buyse; Geert Molenberghs; Xavier Paoletti; Koji Oba; Ariel Alonso; Wim Van der Elst; Tomasz Burzykowski Journal: Biom J Date: 2015-02-12 Impact factor: 2.207
Authors: Patricia Cortazar; Lijun Zhang; Michael Untch; Keyur Mehta; Joseph P Costantino; Norman Wolmark; Hervé Bonnefoi; David Cameron; Luca Gianni; Pinuccia Valagussa; Sandra M Swain; Tatiana Prowell; Sibylle Loibl; D Lawrence Wickerham; Jan Bogaerts; Jose Baselga; Charles Perou; Gideon Blumenthal; Jens Blohmer; Eleftherios P Mamounas; Jonas Bergh; Vladimir Semiglazov; Robert Justice; Holger Eidtmann; Soonmyung Paik; Martine Piccart; Rajeshwari Sridhara; Peter A Fasching; Leen Slaets; Shenghui Tang; Bernd Gerber; Charles E Geyer; Richard Pazdur; Nina Ditsch; Priya Rastogi; Wolfgang Eiermann; Gunter von Minckwitz Journal: Lancet Date: 2014-02-14 Impact factor: 79.321
Authors: Francesco Schettini; Tomás Pascual; Benedetta Conte; Nuria Chic; Fara Brasó-Maristany; Patricia Galván; Olga Martínez; Barbara Adamo; Maria Vidal; Montserrat Muñoz; Aranzazu Fernández-Martinez; Carla Rognoni; Gaia Griguolo; Valentina Guarneri; Pier Franco Conte; Mariavittoria Locci; Jan C Brase; Blanca Gonzalez-Farre; Patricia Villagrasa; Sabino De Placido; Rachel Schiff; Jamunarani Veeraraghavan; Mothaffar F Rimawi; C Kent Osborne; Sonia Pernas; Charles M Perou; Lisa A Carey; Aleix Prat Journal: Cancer Treat Rev Date: 2020-01-17 Impact factor: 12.111
Authors: Thomas Kieber-Emmons; Issam Makhoul; Angela Pennisi; Eric R Siegel; Peter D Emanuel; Bejotaloh Monzavi-Karbassi; Zenon Steplewski; J Thaddeus Beck; Laura F Hutchins Journal: Rev Recent Clin Trials Date: 2017
Authors: Chana Weinstock; Matthew D Galsky; Elaine Chang; Andrea B Apolo; Rick Bangs; Stephanie Chisolm; Vinay Duddalwar; Jason A Efstathiou; Kirsten B Goldberg; Donna E Hansel; Ashish M Kamat; Paul G Kluetz; Seth P Lerner; Elizabeth Plimack; Tatiana Prowell; Harpreet Singh; Daniel Suzman; Evan Y Yu; Hui Zhang; Julia A Beaver; Richard Pazdur Journal: Nat Rev Urol Date: 2021-09-10 Impact factor: 14.432
Authors: Z A Nahleh; W E Barlow; D F Hayes; A F Schott; J R Gralow; W M Sikov; E A Perez; S Chennuru; H R Mirshahidi; S W Corso; D L Lew; L Pusztai; R B Livingston; G N Hortobagyi Journal: Breast Cancer Res Treat Date: 2016-07-08 Impact factor: 4.872
Authors: Jairo M Montezuma-Rusca; John H Powers; Dean Follmann; Jing Wang; Brigit Sullivan; Peter R Williamson Journal: PLoS One Date: 2016-08-04 Impact factor: 3.240