Overdiagnosis is underestimated in screenings, a systematic review

Synthesis by Cancer Rose, April 2, 2023

According to this systematic review, randomized cancer screening trials are rarely designed to estimate overdiagnosis. Many trials used in the design of screenings have been biased toward underestimating the degree of overdiagnosis.

This is the first review and re-analysis of overdiagnosis in cancer screening trials.

Several authors (Danish, Portuguese, and Norwegian), including researchers from the Cochrane Collaboration, conducted this review.
Quantification of overdiagnosis in randomised trials of cancer screening: an overview and re-analysis of systematic reviews
Theis Voss, Mikela Krag, Frederik Martiny, Bruno Heleno, Karsten Juhl Jørgensen, John Brandt Brodersen 

The strength of this overview is that it included trials from the Cochrane systematic reviews, which are known for their comprehensive literature searches and structured assessment of the risk of bias, and a USPSTF systematic review, with high methodological standards[54]. The search strategy is updated, and the authors have verified the reference list of included trials, which increases the likelihood of presenting a comprehensive and up-to-date overview.
The degree of overdiagnosis in standard cancer screening trials is uncertain because of inadequate trial design, variable definition, and the methods used to estimate overdiagnosis.

The authors sought to quantify the risk of overdiagnosis for the most widely implemented cancer screening programs and to assess the implications of design issues and biases in the trials used for various screenings on estimates of overdiagnosis by conducting a new analysis of systematic reviews of cancer screening.

PubMed and the Cochrane Library were searched from their publication dates through November 29, 2021. The authors assessed the risk of bias using the Cochrane Collaboration's Cochrane Risk of Bias Tool.

Nineteen trials described in thirty articles were identified for review, reporting results for the following types of screening:
*mammography for breast cancer,
*chest x-ray or low-dose CT scan for lung cancer,
*alpha-fetoprotein and ultrasound for liver cancer,
*rectal examination, prostate specific antigen, and transrectal ultrasound for prostate cancer,
*CA-125 test and/or ultrasound for ovarian cancer.

No melanoma screening trials were eligible.

The magnitude of overdiagnosis ranged from 17% to 38% in cancer screening programs. On average, the authors found that:

-27% of breast cancers detected by mammography,
-31% of lung cancers detected by low-dose CT,
-27% of liver cancers detected by screening
-38% of prostate cancers detected by PSA and
-17% of ovarian cancers detected by CA-125

Here is a summary of the significant parts of the article published in Cancer Epidemiology, with tables, followed by Cancer Rose comments (additional figures are at the end).

1. Introduction

Overdiagnosis of cancer is the diagnosis of an indolent neoplastic pathology that would never progress to the point of causing symptoms and/or death during an individual's lifetime[1] and is the most serious harm of cancer screening[2],[3],[4] If a cancer is detected, clinicians cannot know which individuals are overdiagnosed because it is impossible to know how the cancer would have progressed without screening. Therefore, all patients are offered routine treatment or surveillance[5],[6]. Those who are overdiagnosed are therefore unnecessarily diagnosed and then overtreated, which is detrimental to them.

For this reason, knowing the magnitude of overdiagnosis in cancer screening is critical to making informed screening decisions, such as whether to participate individually or to implement a given screening program at the national level, such as prostate cancer screening[7],[8].

In theory, the most robust method for estimating overdiagnosis is to use data from randomized controlled trials with lifetime follow-up of all participants and without contamination of either the control or intervention group, i.e., without screening of both trial groups during and after the end of the study[5],[9]. [At the end of the active screening phase, an excess of cancers in the screened population is expected, as screening should advance the time of diagnosis (lead time) [5]. If there were no overdiagnosis, this excess of cancers should be offset over time, as they would all progress to a cancer that would be clinically detected after the active screening phase.
Thus, a persistent excess in the cumulative incidence of cancer in the screened population after a follow-up period sufficient to account for lead time is high-quality evidence of overdiagnosis[5],[8],[10].

The objective of this overview and re-analysis of systematic reviews of randomized controlled trials of cancer screening was to assess the extent of design limitations and biases in the randomized controlled trials included to quantify overdiagnosis and, if possible, to estimate the likelihood that the cancer detected by screening was overdiagnosed for the most common cancer screening programs. Many, if not all, types of cancer screening can lead to overdiagnosis. To our knowledge, we are the first to compile data on overdiagnosis in screening for different cancers. For this paper, we have chosen to focus on the most common cancer screening programs.

2. Methods used

This overview and re-analysis of systematic reviews was carried out on the basis of a protocol published before the present study was conducted[11].

Eligibility criteria

Systematic reviews of randomized trials were eligible if they:
1) studied screening to detect cancer earlier than it would appear clinically.
2) compared a cancer screening intervention with no screening.
3) reported the incidence of cancer in screened and unscreened participants, and the number of cancers detected by screening.
4) were conducted by the Cochrane Collaboration, i.e., Cochrane reviews, and included only randomized controlled trials. .....

Search strategy

We searched the Cochrane Library of Systematic Reviews (February 2016) using the search terms "screening" and "cancer" in the title, abstract, or keywords.

Risk of bias assessment for included trials

We extracted risk of bias assessments from included Cochrane systematic reviews. We used the Cochrane Risk of Bias Tool version 1.0[14] which includes the following six areas:

1. Selection bias: random sequence generation and allocation concealment
2. Performance bias: blinding of participants and staff (not extracted)
3. Detection bias: blinding of outcome evaluation
4. Attrition bias: incomplete outcome data
5. Reporting bias: selective reporting of outcomes
6. other possible sources of bias
We evaluated two additional biases that could affect the estimate of overdiagnosis (Table 1):
1. Control group contamination after randomization[15] Contamination was defined as the reported number of participants in the control group who were exposed to the same screening technology as the screened group. ......
2. Inadequate consideration of time delay (too short post-intervention follow-up or screening offered to the control group at the end of the trial)

Table 1

Other factors influencing estimates of overdiagnosis.
1. Different cancer risk at baseline between intervention and control groups (equivalent to the selection bias included in the Cochrane Risk of Bias tool).
2. Participation rate in screening rounds. Participation was not considered a bias in the estimation of overdiagnosis, but a component of screening.
3. Number of screening cycles and the interval between them.
4. Continuation of screening, i.e., whether participants continued with the proposed screening modality on their own initiative after screening ended.

3. Results

Of the 19 trials reviewed, the smallest trial had 3206 participants (ITALUNG [22]), the largest 202,546 participants (UKCTOCS [23]) and the median trial size was 26,602 participants (Stockholm [24]) (Table 2)

Estimates of overdiagnosis in included studies

For all trials and all types of cancer screening programs, estimates of overdiagnosis ranged from 6% to 67%.

* For breast cancer screening trials using mammography, estimates ranged from 10% to 30% .
* For lung cancer by low-dose CT, overdiagnosis ranged from 13% to 67% .
* For prostate cancer, estimates ranged from 12% to 63% .
* In ovarian cancer by CA-125, from 6 to 42%.
Only one trial of liver cancer screening and one trial of lung cancer screening by chest x-ray were included, and both showed that 27% of lung or liver cancers detected by screening were overdiagnosed, respectively (Table 4 and Figure 2 (at the end of the article)).

Click to enlarge

In our primary meta-analysis, we estimated that 28% (95% CI: 4-52%) of screen-detected breast cancers were overdiagnosed using data from the Malmö breast cancer screening trial. This trial had an overdiagnosis rate that was three percentage points higher than the meta-analysis based on all included trials (Table 4, Figure 2, Supplementary Figure A1, see end of article). [28], [29].

Our post hoc meta-analysis of the most reliable trials, i.e., excluding trials with high risk of bias in the areas of random sequence generation, assignment concealment, contamination, or turnaround time, included data from 12 trials reporting outcomes for six types of cancer screening. On average, 27% (95% CI: 8-45%) of breast cancers detected by mammography and 30% (95% CI: 2-59%) of lung cancers detected by low-dose CT were overdiagnosed.

For the other four types of screening, the results were not significant. We estimated that an average of 27% (95% CI -10% to 64%) of lung cancers detected by chest radiography, 27% (95% CI -4% to 58%) of liver cancers detected by screening, and 17% (95% CI -14% to 48%) of ovarian cancers detected by CA-125 are overdiagnosed.......

Meta-analysis of all trials included in the synthesis, regardless of risk of bias, showed that on average, 25% (95% CI 12-38%) of breast cancers detected by mammography, 27% (95% CI -10% to 64%) of lung cancers detected by chest radiography, 29% (95% CI 7-52%) of lung cancers detected by low-dose CT, 27% (95% CI 4%-58%) of liver cancers detected by ultrasound, 38% (95% CI 14-62%) of prostate cancers detected by PSA, 17% (95% CI -14%-48%) of ovarian cancers detected by CA-125, and 6% (95% CI -27%-39%) of ovarian cancers detected by ultrasound were overdiagnosed (Fig. 2, end of article).

4. Discussion

Main results

In our post-hoc meta-analysis of the most reliable trials, that is, excluding trials with a high risk of bias ......we found that:
-27% (95% CI 8-45%) of breast cancers detected by mammography,
-31% (95% CI 2-59%) of lung cancers detected by low-dose CT,
- 27% (95% CI -4% to 58%) of liver cancers detected by screening and
-17% (95% CI -14% to 48%) of ovarian cancers detected by CA-125 were overdiagnosed.

Many trials were at risk of bias because of poor randomization, control group contamination, or inadequate consideration of waiting time, i.e., insufficient follow-up time to account for slow-growing cancers.
Confidence in the estimates of overdiagnosis further decreased because of imprecision in the pooled estimate and inconsistency (heterogeneity) between trials (Figure 2, Supplementary Table A1, end of article).

Implications for Practice

Overdiagnosis is the most serious drawback of cancer screening.

Yet we found that many screening trials for various types of cancer were not adequately designed to estimate its magnitude. Many screening programs have been implemented on the basis of preliminary beneficial results. However, the adverse effects of screening, such as overdiagnosis, take many years to be adequately estimated. This overview underscores the need for continued evaluation (by the USPSTF, for example) of current and future cancer screening programs to take into account potential adverse effects that may require modifications or even termination of a screening program.

5. Conclusion

Randomized controlled trials are the most reliable model for quantifying overdiagnosis if they are designed for that purpose; however, our overview shows that confidence in estimates of overdiagnosis in randomized controlled trials of cancer screening is moderate to very low.
Two screening technologies (lung cancer by low-dose CT and breast cancer by mammography) showed significant overdiagnosis of 30% and 27%, respectively.

In addition, for prostate cancer screening with PSA, the estimate suggests that 38% of screen-detected prostate cancers were overdiagnosed, although the risks of bias are high in the included randomized clinical trials, which favors underestimation.

For ovarian cancer screening programs, our best estimates are that 17% of ovarian cancers screened by CA-125 and 6% of ovarian cancers screened by transvaginal ultrasound may be overdiagnosed.

Additional Figures

Click on the image to enlarge




Comments Cancer Rose

Three issues must be raised:

-First, regarding information for women, the National Cancer Institute's information documents remain insufficient and deficient in exposing complete data. Only the lowest ranges are disclosed to women, and overdiagnosis is largely minimized.

-The risks of breast cancer screening outweigh, when added to false alarms, morbidity and mortality secondary to overtreatment (hemopathies, cardiopathies, and cancers secondary to treatment), radiation-induced cancers, and the hypothetical benefit of this screening, treatments being recognized to be the cause of the relative decrease in mortality since the 1990s.
Therefore it is scandalous that the scientific controversy about this screening is, according to the French National Cancer Institute, among the "fake news."

A study on risk-stratified screening is financed to the tune of 12 million euros, which will be unable to quantify the over-diagnosis of breast cancer screening, giving women a choice between a (standard) screening and another (stratified) screening based on the principle that breast cancer screening must be maintained, and this in disregard of the demands of the citizens during the public consultation on breast cancer screening.
However, the fundamental question is: should we maintain these expensive screenings, most of which are services of little value to the population?

Another screening has not been addressed in this analysis because it is officially non-existent, that of thyroid cancer, which is widely practiced by systematic cervical ultrasound, despite a known and frightening risk of overdiagnosis (up to 84%!!!), and which is mainly borne by women.
In addition to the cost of human health, its economic cost in France was the subject of a study published in 'Value in Health'.
Here are the results:
Between 2011-2015, an estimated 33,911 women and 10,846 men in France were diagnosed with thyroid cancer, with an average cost per capita of €6,248.
Of those treated, 8,114-14,925 women and 1,465-3,626 men were treated due to overdiagnosis. The total cost of care for thyroid cancer patients was €203.5 million (€154.3 million for women and €49.3 million for men).

Overdiagnosis represents a clinical problem for the individual and a public health problem for the population not only in France but in the Western world, but also a colossal economic burden.

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