Does cancer screening actually reduce all-cause mortality?

25th September 2023

Cancer screening is designed to detect the presence of disease at an early stage, but whether it actually has the desired effect of reducing mortality is up for debate. Clinical writer Rod Tucker investigates.

In medicine, screening is designed to identify the presence of a disease in healthy individuals who are not displaying any of the typical clinical signs or symptoms of a particular condition. Cancer screening, for instance, can therefore be considered to serve a dual purpose: on the one hand it is preventative, but it can also enable the early identification of cancer or precursor lesions and thus having the potential to improve prognosis.

Cancer screening is already well established for breast, prostate, lung, cervical and colorectal cancers, and many of the current tests are very accurate. For example, one novel prostate cancer screening test has an accuracy of 94%.

The fact that cancer screening has the potential to reduce cancer-related mortality and ultimately improve lifespan, has been the main focus in public health messaging. In the past, such messaging has been emotive, employing powerful and persuasive tools such as fear and guilt, engendering a sense of personal responsibility and convincing individuals to be screened.

And this approach has clearly worked. For instance, in a survey of 500 individuals that included women over 40 years of age and men over 50 years, without a history of cancer, the majority (87%) believed that routine cancer screening was almost always a good idea. In addition, 74% felt that finding a cancer early, through methods such as screening, saved lives most or all the time.

But does cancer screening actually extend lifetime? Five-year survival is often presented to the public as evidence of the value of early detection, but one analysis concluded that changes in five-year survival over time bear little relationship to changes in cancer mortality.

A recent meta-analysis attempted to shed further light on the relationship between cancer screening and all-cause mortality, which offered some surprising results.

Cancer screening and all-cause mortality

Most randomised controlled trials of cancer screening focus on disease-specific mortality as the outcome of interest. However, the validity of this outcome is highly dependant on an accurate ascertainment of death, which is not always clear.

This was highlighted in an analysis of 12 published randomised trials of cancer screening for which disease-specific and all-cause mortality data were available. The researchers identified major inconsistencies in both disease-specific and all-cause mortality but concluded that since all-cause mortality is not affected by bias in classifying the cause of death, it should be used as the main outcome of interest for randomised trials looking at cancer screening.

The most recent study to examine of the impact of cancer screening on all-cause mortality was conducted by a team based at the Institute of Health and Society, which is part of the University of Oslo in Sweden. The researchers performed a systematic review and meta-analysis of randomised clinical trials that reported on all-cause mortality to estimate the potential lifetime gained for six commonly used cancer screening tests when compared to no screening.

They focused on mammography screening for breast cancer; colonoscopy, sigmoidoscopy or faecal occult blood testing (FOBT) for colorectal cancer; computed tomography screening for lung cancer in smokers and former smokers; and prostate-specific antigen (PSA) testing for prostate cancer.

The team included trials with 10 to 15 years of follow-up and set the primary outcome of interest as lifetime in the screened group compared to the non-screening group based on all-cause mortality. Using these differences, the researchers calculated the absolute lifetime gained in days.

With the inclusion of just over 2.1 million individuals in the analysis for the six different cancer screening trials, the only screening test with a significant lifetime gain of 110 days (95% CI 0 – 274) was sigmoidoscopy. However, the lower 95% confidence interval extended to zero, so the effect was just significant.

Although there were gains in lifetime accrued for prostate (37 days) and lung (107 days) cancer screening, these increases were not significant.

Risk of death from other causes

Despite these largely negative findings, the researchers were quick to point out that they did not actually favour abandoning screening, merely that the current evidence did not substantiate the claim that common cancer screening tests saved lives by extending lifetime.

Although all-cause mortality has been suggested as a better study endpoint, a problem with using this metric is that the impact of screening on all-cause mortality, depends largely on the level of underlying risk of death from different causes, such as heart disease, within the population being screened.

Consequently, while there are clearly some limitations from focusing solely on cancer-related deaths as an outcome, this may be preferable with the caveat that deaths from other causes are carefully reviewed to identify potential cases of harm.

Nonetheless, a 2015 analysis concluded that currently available screening tests for diseases where death is a common outcome, reductions in disease-specific mortality are uncommon and either very rare or non-existent for all-cause mortality.

The use of all-cause mortality as a primary outcome may be more relevant for the multi-cancer early detection test, especially if deaths from the cancers targeted constitute a high proportion of expected deaths in the population recruited.

Perhaps the most important message from the recent cancer screening analysis is that in their discussions with patients, clinicians should no longer predicate the rationale for screening on the claim that it will both save lives and increase life expectancy. This may not always be the case.

Residual ctDNA predicts relapse in lung cancer

13th April 2022

Detection of ctDNA after treatment of patients with lung cancer is associated with greater disease recurrence and a reduced overall survival

The presence of residual ctDNA after treatment of patients with non-small cell lung cancer (NSCLC) is associated with a shorter recurrence-free survival and overall survival. This was the key finding of a study carried out in Cambridge, UK.

In 2020, there were over 2.2 million cases of lung cancer which resulted in nearly 1.8 million deaths. Lung cancer has two main forms; small cell and non-small cell, and in the UK, the latter accounts for around 85% of all cases.

Treatment options for NSCLC depend upon disease stage and range from surgical resection or radiotherapy (stage 1) through to surgery and adjuvant chemotherapy or chemo-radiotherapy for those with stage 3. However, an important consideration for any of the different forms of treatment, is the ability to detect the presence of post-therapy residual disease.

One emerging potential biomarker is circulating tumour DNA (ctDNA), which is a component of cell-free DNA shed by malignant tumours into the bloodstream and other bodily fluids. It has the potential for prognostication, molecular profiling and monitoring of patients with cancer and has, for example, been shown to be an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer.

In fact, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumour malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance.

For the present study, the researchers set out to assess ctDNA levels in patients with stage 1 to 3 NSCLC to determine whether detection of this DNA tumour fragment post-therapy could predict patient outcomes.

Using samples from the Lung cancer circulating tumour DNA study (Lucid), the team first determined the levels of ctDNA prior to lung cancer treatment and then sought to detect the DNA two weeks to four months after therapy.

Predictive value of ctDNA

A total of 363 plasma samples from 88 patients with early-stage NSCLC (stages 1, 2 and 3) treated with curative intent surgery (61), surgery and adjuvant chemotherapy/radiotherapy (8) and chemo-radiotherapy (19) were included in the study.

Prior to therapy, ctDNA was detected in 24%, 77% and 87% of patients with stage I, II and III disease respectively. Post-treatment, ctDNA was found in 64.3% of patients (28) who had a clinical recurrence of their cancer.

Detection of ctDNA within the time period of two weeks to 4 months post-treatment occurred in 17% of patients and was associated with shorter recurrence-free survival (hazard ratio, HR = 14.8, 95% CI 5.82 – 37.48, p < 0.00001) and a reduced overall survival (HR = 5.48, 95% CI 2.18 – 13.76, p < 0.0003).

Interestingly, ctDNA was also detected 1 – 3 days after surgery in 25% of patients but not associated with disease recurrence.

Among those where ctDNA was found before treatment, there was also a reduced overall survival (HR = 2.97, p = 0.01) and recurrence free survival (HR = 3.14, p = 0.003) compared to samples where ctDNA was not detected prior to treatment.

The authors concluded that their data supported the clinical utility of ctDNA testing to identify residual disease and recurrence and that this was a potentially sensitive tool to determine which patients were at high risk of relapse and who could benefit from additional adjuvant therapy.

Citation
Gale D et al. Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer Ann Oncol 2022