The potential life-saving impact of reducing Stage IV disease and detecting more cancers at Stage III
When people think about cancer screening, the emphasis is almost always on finding cancers as early as possible. That goal makes intuitive sense, but it can lead to an important oversight. The greatest threat to improving patient outcomes is not failing to detect every cancer at Stage I; it is allowing cancers to progress to Stage IV, when treatment options are limited and mortality is high. There is a major difference between cancers that have metastasized to distant sites (Stage IV) and those that have not (Stage I-III). Doctors use staging to describe how advanced a cancer is, usually with the TNM system which describes 1) T = tumor size / local invasion; 2) N = lymph node involvement; and 3) M = metastasis (spread to distant organs). When cancers are stage III, they are considered “locally advanced” (sometimes called “regional spread”), which often means a larger tumor and/or spread to nearby lymph nodes. These cancers are often curable. When cancers are stage IV, however, in addition to larger tumor size and lymph node involvement, the tumor has broken off and spread to other organs, typically the liver, lung, bone, or brain. These cancers are possibly treatable but are generally not curable. Thus, among cancers considered to be diagnosed at later stages, the difference between diagnosing a Stage III versus a Stage IV cancer can be profound.
Reducing late-stage cancer diagnoses has therefore long been a central objective of effective screening programs; the NHS-Galleri trial has been explicitly designed with this goal in mind. What is often underappreciated is just how much clinical value lies in preventing cancers from reaching Stage IV. Even without shifting diagnoses to the very earliest stages, fewer metastatic cancers has the potential to translate into substantial clinical and public health gains.
This perspective is especially important because late-stage cancer remains a stubborn problem. In contrast to decades-long progress in cancer treatment, there has been surprisingly little improvement in reducing advanced-stage diagnoses. In both the US and England, roughly one in five cancers (about 20 percent) is still diagnosed at Stage IV, a figure that has barely changed in recent years. As populations age and cancer incidence rises, the absolute number of people diagnosed with advanced disease continues to grow. The underlying reason is straightforward: most cancers still lack effective population-wide screening tests, and many are only detected once symptoms appear, by which point disease is often already advanced for many cancer types.
Treatments for locally advanced disease have improved dramatically in recent years. For most Stage III cancers, curative-intent treatment is possible, often combining surgery, radiation, and systemic therapy; by contrast, Stage IV disease is usually managed with palliative intent, with the primary goal of prolonging life rather than achieving cure. Indeed, across multiple cancer types, clinical trials in patients with locally advanced disease increasingly demonstrate meaningful survival benefits from immunotherapy given after surgery or chemoradiation, as well as from targeted therapies matched to tumour biology. These advances have translated into higher rates of long-term remission and cure for patients with Stage III disease. AS a consequence of these clinical trial results the number of new cancer drugs approved for use in both the US and UK in the NHS has risen sharply in recent years, many of them specifically indicated for locally advanced cancers. Finding cancer earlier allows patients to benefit from the full potential of modern cancer therapy.
The survival gap between these stages across many common cancers is also striking. For example, in colorectal cancer, five-year survival is more than 50 percentage points higher at Stage III than at Stage IV. In stomach cancer, survival improves by more than 30 percentage points. Even in lung cancer, one of the deadliest malignancies, five-year survival for Stage III disease is approximately 37 percent, compared with just 10 percent for Stage IV disease. Across all cancer types combined, the American Cancer Society estimates that five-year relative survival for locally advanced (regional) disease increased from 54 percent in the mid-1990s to 69 percent in 2015–2021.
These differences are not merely statistical. At the population-level, shifting cancers currently diagnosed at Stage IV to Stage III could be associated with an overall reduction in cancer deaths by approximately 15 percent every five years (Clarke et al. 2020, Clarke et al, 2022), which could result in a reduction in annual cancer deaths of about 5,000 in the UK and 24,000 in the US population of screening age (Chang et al. 2024). For context, reducing deaths by this amount would have enormous public health impact, equivalent to entirely eliminating all deaths from accidents and unintentional injuries or diabetes (Clarke et al. 2020).
Traditional screening programmes have understandably focused on a small number of cancer types, including breast, cervical, colorectal, and lung cancer in selected populations. Yet many of the deadliest cancers, such as pancreatic, ovarian, liver, and esophageal cancer, still lack effective screening options. New approaches, including multi-cancer early detection tests, aim to help address this gap by identifying cancers – including aggressive cancers that lack recommended screening tests – before symptoms arise, and before disease has spread. Earlier diagnosis expands treatment options, increases the likelihood of curative intent, and reduces the need to default to palliative care.
Cancer outcomes are shaped not only by better drugs, but by when cancer is found. After years of limited progress in reducing advanced-stage disease, emerging screening technologies offer a rare opportunity to finally shift the stage at diagnosis. Reducing Stage IV cancer diagnoses is not merely a clinical aspiration; it is one of the most powerful levers available to improve cancer survival at scale. Increasingly, it is also within reach.
References
Chang ET, Clarke CA, Colditz GA, Kurian AW, Hubbell E. Avoiding lead-time bias by estimating stage-specific proportions of cancer and non-cancer deaths. Cancer Causes Control. 2024 May;35(5):849-864.
Clarke CA, Hubbell E, Kurian AW, Colditz GA, Hartman AR, Gomez SL. Projected Reductions in Absolute Cancer-Related Deaths from Diagnosing Cancers Before Metastasis, 2006-2015. Cancer Epidemiol Biomarkers Prev. 2020 May;29(5):895-902.
Clarke CA, Patel AV, Kurian AW, Hubbell E, Gomez SL. Racial/Ethnic Differences in Cancer Diagnosed after Metastasis: Absolute Burden and Deaths Potentially Avoidable through Earlier Detection. Cancer Epidemiol Biomarkers Prev. 2022 Mar 1;31(3):521–527.
Neal RD, Johnson P, Clarke CA, et al. Cell-Free DNA-Based Multi-Cancer Early Detection Test in an Asymptomatic Screening Population (NHS-Galleri): Design of a Pragmatic, Prospective Randomised Controlled Trial. Cancers (Basel) 2022; 14(19).
Siegel RL, Kratzer TB, Wagle NS, Sung H, Jemal A. Cancer statistics, 2026. CA Cancer J Clin. 2026 Jan–Feb;76(1):e70043.