Cancer Screening—The Good, the Bad, and the Ugly

H. Gilbert Welch

doi:10.1001/jamasurg.2022.0669

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April 6, 2022

Cancer Screening—The Good, the Bad, and the Ugly

H. Gilbert Welch, MD, MPH¹

Author Affiliations Article Information

¹Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston, Massachusetts

JAMA Surg. 2022;157(6):467-468. doi:10.1001/jamasurg.2022.0669

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In clinical practice to say that a person has cancer gives as little information about the possible course of his disease as to say that he has an infection. There are dangerous infections that may be fatal and there are harmless infections that are self-limited or may disappear. The same is true of cancers. Cancer is not a single entity. It is a broad spectrum of diseases related to each other only in name.
George Crile, MD, cancer surgeon¹^(p128)

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4 Comments for this article

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April 12, 2022

Benefits and Harms of Cancer Screening

Eleftherios Diamandis, MD,PhD | Mount Sinai Hospital, University of Toronto, Toronto, oN Canada

Dr. Welch outlined masterfully the benefits and harms of cancer screening, using Dr. Criles recognition of cancer heterogeneity more than half a century ago (1). We also underlined previously that cancer biology plays a major role in the success of screening programs (2). I would like to add some contemporary information related to cancer screening. The last 10 years there are intense efforts from various multibillion dollar companies and prominent academic investigators/opinion leaders, to promote cancer screening by using a new cancer biomarker, circulating tumor DNA (ctDNA) under the umbrella of what is known as “liquid biopsy”. Although these new data are usually published in the top-tier journals, the results are fequently over-interpreted because the experimental designs that are used to evaluate these tests are based on case- control studies, not cohort studies. Case-control studies are known to over-estimate sensitivity, specificity, positive and negative predictive value of diagnostic testing, including cancer screening (3). In other commentaries we outlined the difficulty of early cancer detection by using ctDNA (4,5).
It should be realized, as Dr. Welch emphasizes too, that cancer screening does not just involve a successful test. The results must be interpreted by considering the benefits and harms, cost and most importantly, the ability of the screening to improve patient survival and/or quality of life (6,7). Simply detecting cancer, even with a highly sophisticated and accurate test, without parallel improvements in patient care would not be enough, as per the teachings of Wilson and Jungner (8).

References
1. Welch HG. Cancer Screening—The Good, the Bad, and the Ugly. JAMA Surg. Published online April 06, 2022. doi:10.1001/jamasurg.2022.0669
2. Diamandis EP. Cancer dynamics and the success of cancer screening programs. Clin Chem Lab Med. 2016 Aug 1;54(8):e211-2. doi: 10.1515/cclm-2015-1201. PMID: 26751900.
3. Fernandez-Uriate A, D. Pons-Belda O, Diamandis E. P. Cancer screening companies are rapidly proliferating: Are they ready for business? Cancer Epidemiol Biomarkers Prev (in press)
4. Ren AH, Fiala CA, Diamandis EP, Kulasingam V. Pitfalls in cancer biomarker discovery and validation with emphasis on circulating tumor DNA. Cancer Epidemiol Biomarkers Prev. 2020 Dec;29(12):2568-2574. doi: 10.1158/1055-9965.EPI-20-0074. Epub 2020 Apr 10. PMID: 32277003.
5. Fiala C, Diamandis EP. Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection. BMC Med. 2018 Oct 2;16(1):166. doi: 10.1186/s12916-018-1157-9. PMID: 30285732; PMCID: PMC6167864.
6. Diamandis EP, Li M. The side effects of translational omics: overtesting, overdiagnosis, overtreatment. Clin Chem Lab Med. 2016 Mar;54(3):389-96. doi: 10.1515/cclm-2015-0762. PMID: 26444364.
7. Fiala C, Taher J, Diamandis EP. Benefits and harms of wellness initiatives. Clin Chem Lab Med. 2019 Sep 25;57(10):1494-1500. doi: 10.1515/cclm-2019-0122. PMID: 30913033.
8. Wilson, J.M.G.; Jungner, G. Principles and Practice of Screening for Disease; Public Health Paper No. 34; World Health Organization: Geneva, Switzerland, 1968.

CONFLICT OF INTEREST: None Reported

April 19, 2022

It's Mostly Good

Paula Gordon, MD, FRCPC, FSBI | University of British Columbia

Dr. Welch [1] questions of the benefit of screening, and begins his viewpoint with birds, rabbits and turtles. The use of 40-60-year-old RCTs that showed mortality reduction eliminated biases that lead to artificially elevated survival statistics, so the claim that 5 year survival is used to promote screening is not true. In meta-analysis they showed 20% mortality reduction, but when the Canadian National Breast Screening Studies are omitted (now known to have been compromised [2]), results are considerably more favourable. Modern observational studies: cohort/case-control, trend and incidence-based mortality/staging show 40-50% reduction.

Welch implies that improved treatment reduces the need for early detection, but it has been shown that the “tumour stage at diagnosis of breast cancer still influences overall survival significantly in the current era of effective systemic therapy [3].” Moreover, women are aware, and care very much that early diagnosis allows the use of less harsh therapy: fewer mastectomies, fewer axillary dissections and lifelong lymphedema, and less chemotherapy [4].

He says that, "overdiagnosis is the most consequential harm of screening,” but says in the next paragraph that, "overdiagnosis remains, thankfully, a relatively rare event.” So he should endorse screening, which, after all, doesn’t diagnose cancer, but rather, detects it.

He confuses recalls from screening with incorrect diagnoses. The vast majority of recalled women will be assured that all is well, and that they may return to routine screening. Those found to have lesions which are associated with increased risk have the benefit of enhance screening. Women appreciate that; why doesn’t he?

He rightly states that screening is less effective at detecting rapidly-growing cancers, but is perhaps unaware of the movement toward functional imaging for women at elevated risk, which detects exactly those cancers often missed on mammography. The science is quite far along, with the European Society of Breast Imaging recommending that women with Category D density have contrast-enhanced MRI every 2-4 years [5].

Currently, 75% of women diagnosed with breast cancer have no indication of increased risk. Until such time as it can determined which women are of low risk, screening should be offered to the general population. Those of us who defend screening do so, not because we have "a genuine belief in its value,” but because we know the science, which clearly shows that the benefits outweigh the risks. Rather than his “back of the envelope calculations,” marginal cost per year of life saved supports screening.

1. Welch HG. Cancer Screening—The Good, the Bad, and the Ugly. JAMA Surg. Published online April 06, 2022. doi:10.1001/jamasurg.2022.0669

2. Seely JM, Eby PR, Gordon PB, Appavoo S, Yaffe MJ. Errors in Conduct of the CNBSS Trials of Breast
Cancer Screening Observed by Research Personnel. Journal of Breast Imaging, 2022, 1–9. Published Online: March 29, 2022. https://doi.org/10.1093/jbi/wbac009

3. Saadatmand S, Bretveld R, Siesling S, Tilanus-Linthorst MM. Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173,797 patients. BMJ. 2015 Oct 6;351:h4901. doi: 10.1136/bmj.h4901. PMID: 26442924; PMCID: PMC4595560.

4. Ahn S, Wooster M, Valente C, Moshier E, Meng R, Pisapati K, Couri R, Margolies L, Schmidt H, Port E. Impact of Screening Mammography on Treatment in Women Diagnosed with Breast Cancer. Ann Surg Oncol. 2018 Oct;25(10):2979-2986. doi: 10.1245/s10434-018-6646-8. Epub 2018 Jul 9. PMID: 299

CONFLICT OF INTEREST: Advisor: Dense Breasts Canada, DenseBreastInfo.org, Besins Healthcare. Stockholder: Volpara Solutions

June 9, 2022

Educating Physicians on Risk Literacy

Florence Lecraw, M.D. | Andrew Young School of Policy Studies, GA State University

I commend Dr. Welch regarding the cost of screening for cancer. As Dr. Welch mentioned, misleading conclusions are made by specifying relative risk and not absolute risk. For instance, in the 1960s in the U.K., it was widely communicated to the public that the third generation birth control pill had a relative risk increase of 100% for thrombosis when women took the third generation BCP compared to the first generation BCP. But few were informed that the absolute risk of thrombosis increased from 1 in 7000 users when using the first generation BCP to 2 in 7000 for the third generation BCP, i.e., 0.014% to 0.028%. Many women stopped taking BCP. This resulted an increase in unwanted pregnancies and 13,000 more abortions, especially among teenagers in England and Wales. I believe it would benefit our patients if we educated ourselves about risk literacy. This will allow us to more accurately communicate the incidence of risk and benefit of a procedure or laboratory test. I also believe we should encourage our medical schools to teach risk literacy. Accurate risk assessment is an important part of informed consent. Potential litigation can occur if a physician misleads the patient about the incidence of risk of a procedure vs the incidence benefit.

CONFLICT OF INTEREST: None Reported

June 11, 2022

Screening the Screening Tests

Pandiyan Natarajan, MBBS,DGO,MD,MNAMS. | Apollo 24/7, NOVA IVF FERTILITY, Chettinad Super Speciality Hospital (Retired)

Human life span increased significantly since 1950s due to several public health measures and the advent of vaccination and antibiotics. With significant reduction in deaths due to infectious diseases, deaths due to Life style diseases like Cardio vascular disease and Cancers became dominant causes of death.

Several Screening Tests were introduced in almost all the fields for early diagnosis with the assumption that Early Diagnosis would lead to more effective treatment of the conditions and cure in many patients. This priori was never subjected to proper validation.

Several decades after their introduction, usefulness of many of these Tests are still under debate. PGT-A, PSA, Mammography and Cardiac stress testing are some of these.

It is time these Screening Tests are properly screened and validated before their widespread application. This will help in saving considerable Anxiety, Cost and Time.

Professor Dr Pandiyan Natarajan.
Apollo 24/7, NOVA IVF FERTILITY,
Chettinad Super Speciality Hospital (Retired)
Los Angeles, Cary, USA, Chennai, India.

CONFLICT OF INTEREST: None Reported

Cancer Screening—The Good, the Bad, and the Ugly

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