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Why do patients with cancer die?

Nature Reviews Cancer (2024)Cite this article

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Abstract

Cancer is a major cause of global mortality, both in affluent countries and increasingly in developing nations. Many patients with cancer experience reduced life expectancy and have metastatic disease at the time of death. However, the more precise causes of mortality and patient deterioration before death remain poorly understood. This scarcity of information, particularly the lack of mechanistic insights, presents a challenge for the development of novel treatment strategies to improve the quality of, and potentially extend, life for patients with late-stage cancer. In addition, earlier deployment of existing strategies to prolong quality of life is highly desirable. In this Roadmap, we review the proximal causes of mortality in patients with cancer and discuss current knowledge about the interconnections between mechanisms that contribute to mortality, before finally proposing new and improved avenues for data collection, research and the development of treatment strategies that may improve quality of life for patients.

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Fig. 1: The proximal causes of mortality in patients with cancer.
Fig. 2: Recommendations for improving understanding of causes of cancer mortality.

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Acknowledgements

A.B. is funded by National Institutes of Health/National Cancer Institute P30 CA008748 and R01-CA245499. K.B. is employed by the UK National Health Service. T.R.C. acknowledges funding support from the National Health and Medical Research Council (NHMRC) Ideas (2000937), Project (1129766, 1140125), Development (2013881) and Fellowship (1158590) schemes, a Cancer Institute NSW Career Development Fellowship (CDF171105), Cancer Council NSW project support (RG19-09, RG23-11) and Susan G. Komen for the Cure (CCR17483294). T.G. is funded by the Cancer Prevention and Research Institute of Texas Grant 00011633. M.J.-H. has received funding from CRUK, NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR. T.J. acknowledges funding from Cancer Grand Challenges (NIH: 1OT2CA278690-01; CRUK: CGCATF-2021/100019), the Mark Foundation for Cancer Research (20-028-EDV), the Osprey Foundation, Fortune Footwear, Cold Spring Harbour Laboratory (CSHL) and developmental funds from CSHL Cancer Center Support Grant 5P30CA045508. R.K. is funded by the Intramural Research Program, the National Cancer Institute, NIH Clinical Center and the National Institutes of Health (NIH NCI ZIABC011332-06 and NIH NCI ZIABC011334-10). R.L. is supported by a Wellcome Early Career Investigator Award (225724/Z/22/Z). E.S. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2040), the UK Medical Research Council (CC2040) and the Wellcome Trust (CC2040) and the European Research Council (ERC Advanced Grant CAN_ORGANISE, Grant agreement number 101019366). E.S. reports personal grants from Mark Foundation and the European Research Council. C.S. is a Royal Society Napier Research Professor (RSRP\R\210001). His work is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041) and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (ERC Advanced Grant PROTEUS Grant agreement number 835297). M.G.V.H. reports support from the Lustgarten Foundation, the MIT Center for Precision Cancer Medicine, the Ludwig Center at MIT and NIH grants R35 CA242379 and P30 CA1405141.

Author information

Author notes

  1. These authors contributed equally: Adrienne Boire, Katy Burke, Thomas R. Cox, Theresa Guise, Mariam Jamal-Hanjani, Tobias Janowitz, Rosandra Kaplan, Rebecca Lee, Charles Swanton, Matthew G. Vander Heiden, Erik Sahai.

Authors and Affiliations

  1. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Adrienne Boire

  2. University College London Hospitals NHS Foundation Trust and Central and North West London NHS Foundation Trust Palliative Care Team, London, UK

    Katy Burke

  3. Cancer Ecosystems Program, The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia

    Thomas R. Cox

  4. School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia

    Thomas R. Cox

  5. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Theresa Guise

  6. Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK

    Mariam Jamal-Hanjani

  7. Department of Oncology, University College London Hospitals, London, UK

    Mariam Jamal-Hanjani & Charles Swanton

  8. Cancer Research UK Lung Centre of Excellence, University College London Cancer Institute, London, UK

    Mariam Jamal-Hanjani & Charles Swanton

  9. Cold Spring Harbour Laboratory, Cold Spring Harbour, New York, NY, USA

    Tobias Janowitz

  10. Northwell Health Cancer Institute, New York, NY, USA

    Tobias Janowitz

  11. Paediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Rosandra Kaplan

  12. Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK

    Rebecca Lee & Erik Sahai

  13. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Rebecca Lee

  14. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK

    Charles Swanton

  15. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Matthew G. Vander Heiden

  16. Dana-Farber Cancer Institute, Boston, MA, USA

    Matthew G. Vander Heiden

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  1. Adrienne Boire
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  2. Katy Burke
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Contributions

All authors researched data for the article. A.B., K.B., T.R.C., T.G., T.J., C.S., M.G.V.H, R.K., M.J.-H. and E.S. contributed substantially to discussion of the content. T.C., R.L. and E.S. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Thomas R. Cox or Erik Sahai.

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Competing interests

A.B. is an inventor on pending patents 63/449,817, 63/052,139 as well as awarded patents 11,305,014 and 10,413,522; all issued to the Sloan Kettering Institute. She has received personal fees from Apelis Pharmaceuticals and serves as an unpaid member of the Evren Technologies SAB. K.B., T.R.C., T.G., T.J. and R.K. declare no competing interests. M.J.-H. reports support from Achilles Therapeutics Scientific Advisory Board and Steering Committee, Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster and Bristol Myers Squibb outside the submitted work. R.L. reports personal fees from Pierre Fabre and has research funding from BMS, Astra Zeneca and Pierre Fabre outside the submitted work. E.S. reports grants from Novartis, Merck Sharp Dohme, AstraZeneca and personal fees from Phenomic outside the submitted work. C.S. reports grants and personal fees from Bristol Myers Squibb, AstraZeneca, Boehringer-Ingelheim, Roche-Ventana, personal fees from Pfizer, grants from Ono Pharmaceutical, Personalis, grants, personal fees and other support from GRAIL, other support from AstraZeneca and GRAIL, personal fees and other support from Achilles Therapeutics, Bicycle Therapeutics, personal fees from Genentech, Medixci, China Innovation Centre of Roche (CiCoR) formerly Roche Innovation Centre, Metabomed, Relay Therapeutics, Saga Diagnostics, Sarah Canon Research Institute, Amgen, GlaxoSmithKline, Illumina, MSD, Novartis, other support from Apogen Biotechnologies and Epic Bioscience outside the submitted work; in addition, C.S. has a patent for PCT/US2017/028013 licensed to Natera Inc., UCL Business, a patent for PCT/EP2016/059401 licensed to Cancer Research Technology, a patent for PCT/EP2016/071471 issued to Cancer Research Technology, a patent for PCT/GB2018/051912 pending, a patent for PCT/GB2018/052004 issued to Francis Crick Institute, University College London, Cancer Research Technology Ltd, a patent for PCT/GB2020/050221 issued to Francis Crick Institute, University College London, a patent for PCT/EP2022/077987 pending to Cancer Research Technology, a patent for PCT/GB2017/053289 licensed, a patent for PCT/EP2022/077987 pending to Francis Crick Institute, a patent for PCT/EP2023/059039 pending to Francis Crick Institute and a patent for PCT/GB2018/051892 pending to Francis Crick Institute. C.S. is Co-chief Investigator of the NHS Galleri trial funded by GRAIL. He is Chief Investigator for the AstraZeneca MeRmaiD I and II clinical trials and Chair of the Steering Committee. C.S. is cofounder of Achilles Therapeutics and holds stock options. M.G.V.H. is a scientific adviser for Agios Pharmaceuticals, iTeos Therapeutics, Sage Therapeutics, Faeth Therapeutics, Droia Ventures and Auron Therapeutics on topics unrelated to the presented work.

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Nature Reviews Cancer thanks Vickie Baracos, Clare M. Isacke, who co-reviewed with Amanda Fitzpatrick and Erica Sloan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis

An autoimmune encephalitis characterized by complex neuropsychiatric features and the presence of immunoglobulin G (IgG) antibodies against the NR1 subunit of the NMDA receptors in the central nervous system.

Atelectasis

Partial collapse or incomplete inflation of the lung.

Brain herniation

Pressure-induced movement of brain tissue.

Clonal haematopoiesis

An ageing-associated process in which haematopoiesis becomes dominated by one or a small number of genetically distinct stem or progenitor cells. Clonal haematopoiesis is linked to an increased risk of haematological malignancies.

Congestive heart failure

Inability of the heart to pump blood properly.

Coronary vasospasm

Constriction of the arteries that supply blood to the heart.

Corticotropin-releasing hormone

(CRH). One of the major factors that drives the response of the body to stress.

Disseminated intravascular coagulation

(DIC). A rare but serious condition in which abnormal blood clotting occurs throughout the blood vessels of the body.

Encephalitis

Inflammation of the brain.

Fistula

An abnormal connection that forms between two body parts, such as an organ or blood vessel and another often unrelated structure in close proximity.

Guillain–Barré syndrome

A rare disorder in which the immune system of a body attacks the nerves, which can lead to paralysis.

Haemostasis

The stopping of flow of blood, typically associated with the bodies response to prevent and stop bleeding.

Hydrocephalus

A build-up of fluid within the cavities of the brain.

Hypercalcaemia

Elevated calcium levels in the blood, often caused by overactive parathyroid glands. Hypercalcaemia is linked to kidney stones, weakened bones, altered digestion and potentially altered cardiac and brain function.

Hyperprogressive disease

(HPD). Rapid tumour progression sometimes observed during immune checkpoint inhibitor treatment.

Hyponatraemia

The condition that occurs when the level of sodium in the blood is low.

Iatrogenic effects

Harm, which is often unavoidable, caused by cancer treatments.

Immunoparesis

The marked suppression of polyclonal immunoglobulins in the body.

Lambert–Eaton myasthenic syndrome

(LEMS). A neuromuscular junction disorder affecting communication between nerves and muscles, which manifests as a result of a paraneoplastic syndrome or a primary autoimmune disorder. Many cases are associated with small-cell lung cancer.

Leptomeningeal metastases

When cancer cells spread to the tissue layers covering the brain and spinal cord (the leptomeninges).

Lung oedema

Also known as pulmonary oedema is a condition caused by excess fluid in the lungs. This fluid collects in the alveoli compromising function and making it difficult to breathe.

Midline shift

The observation of displacement of brain tissue across the centre line of the brain, suggestive of uneven intracranial pressure.

Myocardial infarction

Decreased blood flow to the myocardium, commonly called a heart attack.

Myocarditis

Inflammation specifically of the middle layer of the heart wall.

Paraneoplastic syndromes

A group of rare disorders that occur when the immune system reacts to changes in the body triggered by the presence of a neoplasm.

Peripheral nervous system

A dense network of nerves that transmit information from the brain (efferent neurons) to the periphery and conversely transmit information from the periphery to the brain (afferent neurons). A component of the peripheral nervous system is the autonomic nervous system.

Pleural effusion

A build-up of fluid between the tissues that line the lungs and the chest wall.

Sarcopenia

A condition characterized by loss of skeletal muscle mass and function.

Thromboembolism

The lodging of a circulating blood clot within a vessel leading to obstruction. Thromboembolisms may occur in veins (venous thromboembolism) and arteries (arterial thromboembolism).

Tissue factor

A key component of the pathway regulating blood clotting, specifically the receptor and cofactor for factor VII/VIIa.

Tumour lysis syndrome

A syndrome occurs when tumour cells release their contents into the bloodstream, either spontaneously or more typically, in response to therapeutic intervention.

Wearable technologies

Devices worn on the body, typically in the form of accessories or clothing, that incorporate advanced electronics and technology to monitor, track or enhance various aspects of human life. Examples include smartwatches and fitness trackers.

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Boire, A., Burke, K., Cox, T.R. et al. Why do patients with cancer die?. Nat Rev Cancer (2024). https://doi.org/10.1038/s41568-024-00708-4

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