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Nothing is permanent except for change: Disease-free survival in cancer, time to change?


 Department of Cancer Registry and Epidemiology, Dr. B Borooah Cancer Institute, Guwahati, Assam, India

Date of Submission06-May-2019
Date of Acceptance23-Oct-2019
Date of Web Publication29-Jan-2020

Correspondence Address:
Manigreeva Krishnatreya,
Room No 2, Opd Block, Dr. B Borooah Cancer Institute, Gopinath Nagar, Guwahati - 781 016, Assam
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_318_19



How to cite this URL:
Krishnatreya M. Nothing is permanent except for change: Disease-free survival in cancer, time to change?. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 24]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=277241



Sir,

Cancer treatment aims to enable patients to live longer and better lives than they would without treatment.[1] The basic objective of any type of cancer-directed treatment is that it should allow patients to not only live longer lives but also with least possible associated morbidity. For achieving both objectives, clinical trials have provided a huge impetus. Above all, clinical trial endpoints should focus on the quality of life for patients. Endpoints of clinical trial studies are overall survival, patient-reported outcome (symptom endpoints), disease-free survival (DFS), progression-free survival, objective response, complete response, and clinical benefit rate.[2] Except for the overall survival, all the other clinical endpoints are surrogates of benefit of the supposed treatment. Surrogate endpoints can measure the efficacy of any clinical benefit of the treatment in shorter time frame, but there is the risk of interpreting misleading conclusions due to erroneous extrapolation from the results.[3] The outcomes of treatment in cancer are generally assessed by clinical, radiological, and biochemical responses. However, in clinical trials, responses in solid cancers are based only on radiological measures in an attempt to ensure objectivity.[2] DFS shows the duration for which patients are disease free and are widely accepted as correlating with a better quality of life if not longer life, and has been approved as surrogate endpoint in clinical trials.[4] The DATECAN initiative aimed to obtain standardized consensus definitions of time-to-event (TTE) endpoints for multiple cancer sites as follows: breast, sarcomas/gastrointestinal stromal tumors, pancreas, stomach/esophagus, head and neck, colon/rectum, kidney/bladder, and lung cancers.[5] One of the interesting fallout during the consensus meeting was that during the face-to-face meeting, the experts considered DFS irrelevant in the context of breast cancer. Thus, the two TTE endpoints for DFS adopted were invasive DFS (iDFS) and distant DFS. The iDFS which was initially named as “DFS” was renamed by the experts to distinguish DFS from in situ malignancy. A recent meta-analysis concluded that DFS might have good overall statistical validity to be used as a surrogate for overall survival in the adjuvant treatment of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.[6] Using DFS as surrogate for overall survival in patients with HER2 positive in early breast cancer in trials of adjuvant trastuzumab for up to 1 year will only widen disparity of assessing real benefit of cancer-directed treatment.

Cancer is a disease that occurs primarily due to genetic polymorphisms and mutations resulting in abnormal drivers that lead to malignant growth of cells. At present, all the treatments available do not alter this “basic” cancer driver. According to the Oxford dictionary, disease (noun) is a disorder of structure or function in a human, animal, or plant, especially one that produces specific symptoms or that affects a specific location and is not simply a direct result of physical injury.[7] The definition of disease clearly mentions about disorder of structure or function like that happens at the DNA level in cancer. Critics supporting the use of DFS will say “genetic abnormality without an adverse phenotypic manifestation is not a disease.” The definition states that “…. especially one that produces symptoms or that affects a specific location” which does not exclude structural disorders at DNA without clinical manifestations. So technically, cancer patients are actually never free from their disease biologically, which means, patients might not have malignant cells but healthy cells are prone to turn malignant. Moreover, in patients where recurrences or progression does not occur, it is either due to the failure of activation of the basic cancer driver or due to self-containment by immune check and other inherent mechanisms. Treatment in any form only salvages the diseases that are apparent by destruction either at the macrolevel or microlevel. At DNA level, the change that drives a cell to malignancy does persist even after the treatment. The issue of whether use of DFS is appropriate is not only about its semantics but also about evolving definitions of “disease” itself. Instead of DFS, the use of progression-free or relapse-free survival is more apt in the context of cancer. As we have evolved from describing minute objects from micro to nano, we must also evolve in our definitions of disease as well, especially in a disease like cancer. Is it the time to change for the use of DFS or just another wishful thinking?

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Booth CM, Tannock I. Reflections on medical oncology: 25 years of clinical trials – Where have we come and where are we going? J Clin Oncol 2008;26:6-8.  Back to cited text no. 1
    
2.
Wilson MK, Karakasis K, Oza AM. Outcomes and endpoints in trials of cancer treatment: The past, present, and future. Lancet Oncol 2015;16:e32-42.  Back to cited text no. 2
    
3.
Baker SG, Kramer BS. Surrogate endpoint analysis: An exercise in extrapolation. J Natl Cancer Inst 2013;105:316-20.  Back to cited text no. 3
    
4.
McKee AE, Farrell AT, Pazdur R, Woodcock J. The role of the U.S. Food and drug administration review process: Clinical trial endpoints in oncology. Oncologist 2010;15 Suppl 1:13-8.  Back to cited text no. 4
    
5.
Gourgou-Bourgade S, Cameron D, Poortmans P, Asselain B, Azria D, Cardoso F, et al. Guidelines for time-to-event end point definitions in breast cancer trials: Results of the DATECAN initiative (Definition for the assessment of time-to-event endpoints in CANcer trials). Ann Oncol 2015;26:873-9.  Back to cited text no. 5
    
6.
Saad ED, Squifflet P, Burzykowski T, Quinaux E, Delaloge S, Mavroudis D, et al. Disease-free survival as a surrogate for overall survival in patients with HER2-positive, early breast cancer in trials of adjuvant trastuzumab for up to 1 year: A systematic review and meta-analysis. Lancet Oncol 2019;20:361-70.  Back to cited text no. 6
    
7.
Oxford Dictionary. Available from: https://en.oxforddictionaries.com/definition/disease. [Last accessed on 2019 Apr 24].  Back to cited text no. 7
    




 

 
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