Why Do Cancer Patients Die?

Cancer is a significant contributor to mortality on a global scale. But what actually causes a cancer patient to die? Here, we summarize the elegant review “Why do cancer patients die?” from Boire and colleagues [1], highlighting severe acute events, systemic factors, and their underlying causes in this context.

Cancer metastasis is often cited as the primary cause of cancer-related mortality [2]. However, this term is over simplistic, not completely precise and not largely supported by published literature. While it is true that patients with metastatic cancer are more likely to die than those with locally confined disease, cancer is intriguingly complex and results in a variety of symptoms, including acute single events or patient deterioration through systemic (organ) dysfunction. To effectively mitigate the destructive impact of cancer, it is essential to gain a deeper understanding of the physiological responses involved and identify more precisely the various cancer-related causalities.

Most advanced cancers can be considered as a chronic and systemic disease. However, it is likely that up to half of the cancer-induced deaths are functionally related to severe events such as vascular coagulation and cardiac failure, obstruction of vital organs, bacterial infection, or paraneoplastic syndromes. For instance, patients with cancer have an elevated risk of thromboembolic events, which may lead acutely to fatal strokes or pulmonary emboli and chronically to coronary heart disease and, subsequently, heart failure. Furthermore, congestive heart failure may also occur due to excessive loss of cardiac muscle, a phenomenon associated with and often caused by cancer cachexia. In addition, growing tumours can impair vital organ function. This can particularly be observed in primary brain cancers, where uncontrolled growth increases intracranial pressure, which can ultimately cause irreversible brain damage. A similar phenomenon can be observed in the lung, where pulmonary metastases can reduce gas exchange, resulting in severe respiratory distress. Because cancer patients often have compromised immune systems, both from the disease itself and from cancer therapy, they are at an increased risk for bacterial, viral, or fungal infections that can cause life-threatening complications. Moreover, paraneoplastic syndromes can irreversibly damage critical organs as a consequence of tissue dysfunction in the surrounding area of the tumour. For example, an inappropriate production of pro-inflammatory cytokines, hormones, or antibodies can result in severe adverse effects, potentially leading to critical organ damage and ultimately, death. Despite the principle objective of cancer treatments to target tumour cells, almost every therapeutic agent has unwanted adverse effects, including acute neutropenia (potentially leading to bacterial sepsis) or platelet depletion, which can also be life-threatening in some cases.

Nevertheless, these fatal events are accelerated or initiated by underlying factors that have previously disrupted major physiological organ systems in the affected patients. One such system is the immune and haematopoietic system. In patients with cancer, immune exhaustion is frequently observed as a consequence of a progressively degrading immune system. The secretion of chemokines and pro-inflammatory cytokines by cancer cells and non–transformed cells of the tumour microenvironment (TME) can lead to an altered composition of subsets of leukocytes. Prolonged alteration of leukocyte compositions can strain the ability of haematopoietic stem cells (HSCs) to produce sufficient amounts of the appropriate cell type. Additionally, the proliferation and cytotoxic granule secretion of cytotoxic T cells may be impaired due to an immunosuppressive TME or upon chronic stimulation with cancer neoantigens. A second major physiological system that can be disrupted in patients suffering from cancer is the nervous system. Tumours in the brain have the potential to impair the brain structure and disrupt neural connections, which may result in cognitive deficits, sensory dysfunction or even personality changes. Furthermore, circadian rhythms may be disrupted, which could have an adverse effect on memory and sleep, and thus on overall well-being.

Another significant physiological system that can exert substantial influence on various organs is cellular and systemic metabolism. Patients with advanced cancers frequently experience involuntary loss of muscle and fat mass, resulting in substantial loss of body weight, also known as cachexia. This phenomenon is caused by a negative energy balance, which is the result of increased energy consumption by the body combined with a reduced appetite. For instance, an increased production of lactate by the tumour can prompt the liver to convert lactate back to glucose via the Cori cycle. This process requires energy and is therefore not only increasing the overall energy demand, but also exerting a burden on liver function. Prolonged caloric deficits result in the breakdown of essential fat and muscle tissue. In severe cases, this results in the loss of cardiac or intercostal muscle, which can ultimately be fatal due to an associated loss of pulmonary and cardiac function. Furthermore, recent studies have indicated that cachexia can exert additional effects on other organs and systems, including the brain and the immune system. Despite the incomplete understanding of the molecular mechanisms underlying cachexia in cancer, there is accumulating evidence suggesting that transforming growth factor-β (TGF-β) pathway is centrally involved, as increased concentrations of members of the TGF-β superfamily have shown to correlate with cachexia development in lung cancer patients. Currently, clinical trials are being conducted with the objective to deepen the understanding of the role played by the TGF-β pathway in cancer-associated cachexia. Of particular interest is one preclinical study, which showed that blocking the TGF-β pathway leads to decreased metabolic changes and reduced mortality in murine models of pancreatic cancer cachexia [3]. However, there are also other cytokines that are assumed to contribute to cachexia, including the tumour necrosis factor (TNF), nuclear factor ‘kappa light chain enhancer’ of activated B-cells (NF-κB), interleukin-1 (IL-1), or IL-6. These cytokines act through various mechanisms such as the ubiquitin-mediated proteolysis of muscle protein or the corticotropin releasing hormone (CRH).

Even though it is important to identify the specific causalities of cancer-related deaths, it makes sense to consider whole body dysfunction as a cause of cancer mortality. For instance, several pro-inflammatory cytokines have multifaceted functions and are involved in different pathways, thereby impairing several vital organs or systems simultaneously. The prolonged cumulative strains on these systems deteriorates the patient's condition and can ultimately induce the patients demise.

To further deepen the understanding of specific causes of cancer-related mortality, Boire and colleagues underscore the importance of implementing systematic monitoring of patients as they transition to palliative care, ideally with noninvasive procedures to not further increase patient discomfort at the end of their lives. Additionally, autopsies, including warm autopsies, could provide insights into undetected causes of death, such as thromboembolic events, and support research into biological processes of mortality. Finally, with advancing technology, the identification of novel molecular predictors of survival becomes feasible and once identified, these markers could be monitored and interfered with in preclinical studies or clinical trials. It will be of special importance to improve the clinical/translational relevance of preclinical trials by constantly optimizing disease models. Currently, the majority of models exhibit an accelerated disease progression with a narrow window between disease onset and mortality, which is not optimal for the investigation of chronic disease conditions in patients.

Taken together, the elegant review by Adrienne Boire and her 10 equally contributing co-authors (among them key opinion leaders in the fields of basic cancer research, cancer genetics, cancer metabolism and cancer cachexia) addresses a topic of paramount importance in oncology. The phrase “metastasis accounts for the vast majority of cancer-related deaths” is omnipresent in the published literature. Strikingly, robust clinical evidence to support this claim is, at best, scarce. Boire and colleagues provide a comprehensive analysis of why cancer patients die and re-enforce the central role of cachexia in this context. We are sure that this article will prove extremely valuable for a wide range of readers and hope that it will inspire research groups with different backgrounds to jointly identify the causes and molecular mechanisms of cancer mortality. The final aim, of course, should be to develop innovative and effective therapies to extend the lives of our patients with cancer.

Timon Rausch: conceptualization, writing – first draft. Thorsten Cramer: conceptualization, writing – review and editing.

The authors declare no conflicts of interest.