To the issue of decision-making in palliative medicine based on the study of immediate causes of death, mechanisms of fatal pathological processes in cancer patients

Introduction

Malignant neoplasms (MNs) are one of the leading causes of death worldwide. Despite progress in cancer treatment, in many cases life expectancy is reduced, and at the end of life patients have numerous distant metastases. The cause of death is often referred to as dissemination of the process, “metastases.” However, more precise causes of deterioration and death in cancer patients remain poorly understood [1].

Who needs to know this and why? First of all, physicians working in palliative care units, as well as in intensive care units, for timely assessment of the patient’s condition, decision‑making, and prescribing adequate therapy. By definition, palliative medicine aims to relieve symptoms and improve the patient’s quality of life. But not only in the last days or weeks of life! There is often a need for palliative medicine throughout the trajectory of a progressive chronic disease [2]. However, it is impossible to do this professionally without knowing what is happening in the patient’s body at the present moment and which mechanisms need to be targeted to achieve the goal. It is very important to determine what our task is at a given moment — active or even intensive therapy in the presence of an acute condition/sudden deterioration, when the patient can be brought out of an emergency state; or relief of suffering when all reserve capacities of the body are exhausted. Palliative medicine is not a formal approach to the situation using opioids and oxygen at the end of life, with physicians already believing that “the patient will die anyway, and soon.” It is an independent and complex branch of medicine, at the interface with intensive care, where the physician must decide what to do: take measures for an acutely life‑threatening condition and refer to intensive care or to a surgeon (myocardial infarction, stroke, pulmonary embolism, abdominal catastrophe, etc.); identify complications of recent antitumor therapy, e.g., febrile neutropenia, and refer to chemotherapists; or understand and accept that the deterioration is due to MN progression and the patient needs only symptomatic therapy. But even in the latter case, it is desirable to know what scenario the disease progression follows, what to do, and what to expect. Moreover, symptomatic therapy cannot be effective without considering the pathogenesis of any distressing symptom.

Decision‑making and choice of tactics require knowledge and responsibility, because there are situations where, with appropriate therapy, even patients with stage IV MNs can not only improve their quality of life but also prolong it. It must be recognized that sometimes even a month or a week of life is of great importance to the person and their loved ones. A physician has no moral right to approach the treatment of a patient with advanced MN with the attitude “they will die anyway,” as often happens, but should act differently — “I must do everything as it should be, according to all the canons of skill, to provide timely and adequate assistance.”

Lack of knowledge and information, lack of understanding of the pathological processes in the patient’s body / mechanistic concepts / complicates the choice of the right strategy to improve the quality and potentially prolong the life of cancer patients at a late stage of the disease. Moreover, in practice, it is highly desirable to implement the chosen strategy as quickly as possible [1].

The factors that determine the process of vital function decline in MNs are numerous and often begin to act from the very onset of the disease. Understanding the mechanisms leading to deterioration and ultimately often to death provides us with information for performing / or refraining from / interventions that can prolong the patient’s life, reduce suffering, or, conversely, not prolong meaningless agony.

Unfortunately, a systematic analysis of the main causes of death in cancer patients is very difficult to find, partly because death certificates often do not contain sufficient information about the immediate cause of death [1, 3–6].

In disseminated disease, dysfunction of all body systems occurs to varying degrees. This is probably due to excessive activation of local and systemic inflammatory, protective, and immunosuppressive mechanisms.

The occurrence of death in disseminated MN is certainly correlated with the severity of the patient’s condition caused by the malignant process itself. However, our practice shows that the situation is more complex and multifaceted. The physician needs to understand how the MN affects (or does not affect) vital functions and ultimately leads to fatal changes. Different scenarios of disease progression and deterioration are primarily determined by the location of the primary tumor and metastatic foci, which may remain undetected. For example, brain metastases can lead to dysfunction of various parts of the central nervous system, and peritoneal metastases can cause intestinal obstruction. It should be noted that the size and number of metastases may not impair the function of the organ in which they are located for some time [7]. Individual patient characteristics, such as general condition, presence and severity of comorbidities, genetic, psychological, and even socioeconomic status, are certainly of great importance [8]. All these factors determine the course of the disease and the body’s response to the situation/cancer process/ and have a great impact on the condition, limiting available treatment options and/or the patient’s ability to undergo treatment [9, 10].

There are cases where the deterioration leading to death depends not on the presence of metastases but on local tumor spread and events complicating this process (bleeding from stomach or intestinal cancer, tumor obstruction of the bronchial or tracheal lumen, etc.). The physician is faced with the task of disentangling the knot of causes and effects that initiate and shape the development of the fatal pathological process.

The cause of death in cancer patients may be an acute condition, and it is possible to influence the main mechanisms that cause it, or even prevent their development. In terminal‑stage cancer patients, after a sufficiently long period of deterioration, the causes of death are different / the dying process itself is formed differently / which gives us the opportunity for targeted intervention [1]. Therefore, early integration of palliative care into the treatment system improves survival [11]. Ultimately, a deeper understanding of the processes occurring in the body of patients with progressive MN will enable the development of new strategies to alleviate suffering at the end of life. In addition, patients and their loved ones should be able to discuss the prognosis and express their wishes and preferences regarding treatment tactics at the final stage, the main goal of which is to improve quality of life [12].

Acute conditions as a cause of death

Although MN can be considered a chronic disease, and many patients live with it for years, the immediate cause of death is often (up to 50% of cases) an acute condition [13, 14].

Cardiovascular conditions and coagulation disorders

As is known, cancer patients are at increased risk of thromboembolism, resulting in respiratory failure, strokes, heart failure, or myocardial infarction [15]. In some cases, disseminated intravascular coagulation can lead to thrombotic obstruction of small and medium‑sized vessels, leading to dysfunction of one or another organ [16]. We often forget about the possibility of these complications. Hemorrhagic complications caused by depletion of the platelet lineage, decreased levels of coagulation system proteins, and other factors can also be life‑threatening [16]. Congestive heart failure can also be an immediate cause of death, with various reasons for its development. These include myocardial wasting (associated with cachexia and intoxication), electrolyte disturbances, and thromboembolic events [17]. It should be noted that the main mechanism leading to progressive deterioration and death in cancer patients with bone metastases remains unclear. However, it is assumed that cardiovascular disturbances are the leading factors in pathogenesis [18]. In the practice of a palliative care physician, there are many cases where, with multiple bone metastases from prostate cancer and the absence of other metastases, patients progressively weaken, lose interest in life, and gradually experience a decline and fading of consciousness. Tumor invasion into blood vessels can lead to impaired blood supply to a particular organ or catastrophic bleeding [19–22].

Impaired organ function due to tumour growth: displacement, compression, obstruction

The presence and growth of the tumor itself can impair the function of vital organs. This may occur, for example, in the case of brain metastases or primary brain MNs, with extensive invasion, brain herniation, or edema leading to increased intracranial pressure [22–24]. In addition, seizure disorder can be life‑threatening for patients [25, 26]. However, such a picture is not always observed. For example, with leptomeningeal metastases, intracranial pressure is rarely increased, and there is no change in brain structure; however, cerebrospinal fluid circulation is impaired, leading to hydrocephalus, progression of neurological symptoms, and ultimately death [26].

Large lung metastases can cause respiratory failure, whereas patients with numerous small foci, even countless, can live without respiratory dysfunction for quite a long time until a critical point is reached, after which rapid deterioration follows [27]. As with brain metastases, organ dysfunction is often determined not only by tumor volume. For example, even a relatively small tumor volume (<100 ml of altered tissue in the lungs compared to a total volume of 4–5 L) can be fatal [28]. Pulmonary edema associated with other pathologies, such as pneumonia or heart failure, can also be fatal. Another cause of progressive deterioration in cancer patients may be hydrothorax, which is caused not only by pleural involvement but also by the MN of the lung itself [29].

In ovarian cancer, colorectal cancer, and other MNs of the gastrointestinal tract, due to peritoneal involvement, intestinal obstruction may be the cause of death [30]. Death may occur as a result of hepatic and/or renal failure. Dysfunction of these organs is usually caused by obstruction of the bile ducts or ureters by metastases, therapy‑induced intoxication leading to impaired normal organ function, and reduced tissue perfusion due to hypotension and dehydration [31–34]. Furthermore, one should not forget that sepsis may develop as a result of bile duct or ureteral obstruction, which occurs unpredictably and usually progresses rapidly, leading to multiple organ failure and ultimately death.

Thus, according to Seible DM et al., among deceased patients with pancreatic cancer, local disease progression was the cause of death in 56% of cases (29% gastrointestinal bleeding, 2% intestinal perforation, 8% small bowel obstruction, 6% intestinal ischemia, and 13% extrahepatic bile duct obstruction). Stage at diagnosis, tumor size, location (head or body/tail), and previous surgical treatment did not correlate with the cause of death [35].

Infections

Bacterial infections develop more often in cancer patients than we think, due to impaired immune system function caused both by the MN itself and by some of its treatments, such as chemotherapy, which can lead to myelosuppression and leukopenia. Cancer patients are at increased risk of opportunistic viral, fungal, and protozoal infections. While these may be relatively mild in healthy individuals, they can cause serious complications in cancer patients. Pneumonia and other infectious processes in the lungs leading to respiratory failure, which are not diagnosed during life, are often cited as causes of death in cancer patients [36, 37].

Paraneoplastic syndromes

Paraneoplastic syndromes are a group of rare disorders that are systemic in nature and can cause irreversible pathological changes leading to death. They most often develop in patients with neuroendocrine tumors, small‑cell lung cancer, kidney cancer, breast cancer, ovarian cancer, lymphoma, and other MNs of the blood system. The development of paraneoplastic syndromes is based on various mechanisms, including the production of cytokines, hormones, and antibodies. For example, excessive production of parathyroid hormone‑related peptide (PTHrP) can lead to hypercalcemia. Inappropriate production of antidiuretic hormone, which occurs in small‑cell lung cancer, leads to hyponatremia, and some neuroendocrine tumors of the pancreas secrete large amounts of insulin (insulinomas) [38–41]. Tumors can also cause abnormal production of autoantibodies, leading to Lambert‑Eaton myasthenic syndrome, anti‑NMDA receptor encephalitis², and myasthenia gravis [42, 43]. Paraneoplastic syndromes are often untreatable and lead to death [44].

² Anti‑NMDA receptor encephalitis is an autoimmune disease caused by increased levels of IgG autoantibodies to the NR1 subunit of the N‑methyl‑D‑aspartate receptor, observed predominantly in young people (more often in women) under 45 years of age and often associated with tumors (in particular, in 20% with ovarian teratoma).

Complications caused by antitumor therapy

Almost all methods of antitumor treatment have negative effects on tissues and organs, impairing their function. In some cases, therapy can lead to life‑threatening consequences and death. Few people think that autoimmune reactions resulting from therapy can have fatal consequences, including myocarditis and encephalitis [45–47]. Death can occur from sepsis due to chemotherapy‑related febrile neutropenia [48]. Therapy‑induced thrombocytopenia can lead to fatal bleeding [49]. Arrhythmias, cardiomyopathy, and coronary spasm, which are complications of some anticancer treatments such as the use of 5‑fluorouracil and capecitabine, can also be fatal [50–52].

British researchers (O’Brien M et al., 2006) followed patients who died within 30 days of starting chemotherapy (8.1% of cases). Of these, 75.6% of deaths were caused by disease progression, 7.5% by chemotherapy complications (of which 4.3% developed sepsis due to neutropenia). In 15.5% of deaths occurring within 30 days of treatment initiation, the cause of death was not determined [53].

Kuciejewska A et al. evaluated the effectiveness of chemotherapy in patients with breast cancer. The mortality rate within 30 days of treatment initiation in this group of patients receiving third‑line chemotherapy was 12.6% [54].

Main causes of death

To determine the immediate cause of death, it is necessary to know the basic factors that, in a particular situation, lead to a terminal condition and, ultimately, how the action of these factors is initiated and progresses in disseminated MN. In a recently published article, Boire A et al. propose to consider how the function of three main body systems progressively deteriorates in patients with MNs, and how this leads to death [1].

Immune and hematopoietic systems. In cancer patients, the immune system gradually becomes less capable of responding effectively to infectious agents. This phenomenon is often called “immune exhaustion.” As a result, patients with disseminated disease develop increased susceptibility to a wide range of infections and, as a rule, suffer more serious consequences than would be observed in healthy individuals [55]. Many mechanisms reduce the ability of the immune system to respond to infection. The formation of cancer cells in various organs triggers processes at the cellular and molecular levels similar to those occurring in a wound healing process [56]. Production of cytokines, including IL‑6, G‑CSF, and GM‑CSF, by both tumor cells and other cells of the tumor microenvironment, disrupts hematopoiesis, leading to a shift in the white blood cell differential [57]. Long‑term hematopoietic impairment inhibits the ability of stem cells to generate sufficient numbers of the right type of cells to fight infections, with an increase in the myeloid‑to‑lymphoid ratio. Clonal hematopoiesis may be increased in cancer patients, with suppression of the myeloid lineage and a decrease in the reservoir of naive T‑cells [57].

In addition, many patients have thrombocytopenia and impaired iron metabolism (in 30–60% of patients and even up to 90% in some groups), leading to impaired oxygen delivery by red blood cells [58, 59]. Immunodeficiency occurs, often observed in patients with multiple myeloma [60]. Furthermore, comorbid diseases that either suppress immunity or lead to the development of autoimmune processes can enhance the negative effect of MNs on the immune system. T‑cell responses to infection are impaired in cancer patients, usually with decreased proliferation and expression of granzyme B³ [61]. Long‑term stimulation of T‑cells by tumor antigens can also contribute to their functional exhaustion. Moreover, the immune system’s response to tumor aggression leads to the production of immunosuppressive factors by cancer cells, further weakening immunity [62].

³ Granzymes are serine proteases found in the specialized lytic granules of cytotoxic T‑lymphocytes and natural killer cells.

Other causes related to MNs may also contribute to the development of infections. For example, tumor compression leads to impaired circulation of fluids such as bile, urine, and lymph, creating a favorable environment for the development of pathogenic flora. Impaired patency of the bronchial tree leads to pneumonia [63]. Invasive tumor growth often leads to the formation of fistulas (e.g., rectovaginal in colorectal cancer), resulting in systemic spread of infection and sepsis. In addition, the loss of mobility of cancer patients as the disease progresses leads to infectious complications and atelectasis due to reduced ventilation, as well as pressure ulcers and progression of existing lymphedema [64].

Impaired hematopoiesis leads to failure of the coagulation and hemostasis systems. Thrombocytosis is often observed in cancer patients and is considered a marker of poor prognosis. High levels of inflammatory cytokines caused by MNs can potentially enhance megakaryopoiesis by increasing the production of thrombopoietin (TPO) by the liver, leading to increased platelet production. The risk of hypercoagulation may be further enhanced by the production of tissue factor, which is responsible for initiating the coagulation cascade [65]. These mechanisms increase the likelihood of fatal thromboembolic complications [65].

Immunodeficiency may also be iatrogenic. Cytotoxic therapy interferes with the proliferation and division of hematopoietic stem cells and may result in the immune system being unable to respond to pathogenic factors, leading to fatal outcomes [66]. In severe cases, pancytopenia, severe anemia, increased susceptibility to infections, and a high probability of bleeding occur [48, 67, 68]. Thrombocytopenia leads to hypocoagulation and increases the likelihood of bleeding and the development of hemorrhagic syndromes [67]. Thus, both the MN itself and its treatment lead to coagulation disorders. Neutropenia increases mortality in cancer patients from infections, which in many cases are thought to arise from the growth of resident mucosal flora [69, 70].

In addition, corticosteroids, often prescribed for symptom relief or as concomitant therapy for anticancer treatment, can also contribute to immune suppression and worsen the risk of infectious complications [71]. Chemotherapy further enhances clonal hematopoiesis, which is common in cancer patients [72]. Opioid analgesics prescribed to cancer patients with pain syndrome can also suppress the functions of various body systems, including immunity [73]. Finally, an additional risk factor for infection is the placement of drains, stents, or central venous catheters for therapy. According to foreign authors, the incidence of port‑associated infections is 0.5–10 per 1,000 port‑days [74, 75]. According to Topuzov E.E. et al., infectious complications were observed in 1.07% of all port‑system placements [76].

Immunotherapy, compared to traditional treatment methods, leads to a different list of immune complications. They are primarily associated with excessive activation of the immune system, leading to the development of autoimmune reactions and, in some cases, the development of cytokine storm, which require the use of anticytokine therapy, such as tocilizumab, anakinra, and ruxilitinib, which in turn further suppress the immune response [77]. However, fatal cases associated with autoimmune adverse effects of immune checkpoint inhibitors are rare (about 1%), especially if the drug toxicity is resolved quickly [78, 79]. Among the causes of death associated with the use of checkpoint inhibitors are potentially life‑threatening conditions such as colitis (can lead to intestinal perforation), Guillain‑Barré syndrome, hepatitis, and myocarditis [80–82]. High‑dose corticosteroids are first‑line drugs for treating autoimmune adverse effects in patients receiving immunotherapy. In some patients, rapid disease progression is observed after immunotherapy, the reasons for which are still unclear [83]. Cellular immunotherapy can also lead to bone marrow dysfunction and the development of myelosuppression [84].

Nervous system. Tumors of the brain or its membranes, including metastatic ones, can significantly disrupt neural connections, leading to cognitive deficits, motor/sensory dysfunction, and personality change. Tumor growth causes cerebral edema and dislocation, disruption of the function of vital centers, resulting in progressive neurological deficits, paralysis, seizure disorder, cognitive impairment, depression of consciousness, and, ultimately, respiratory and cardiac arrest due to brainstem compression.

Brain function may also be impaired in patients without brain tumors or metastases, with dysfunction of the autonomic nervous system often reported. However, among other things, brain dysfunction may contribute to the progression of anorexia, and reduced nutrition affects many other physiological and pathophysiological processes [85, 86].

Psychological and social factors can have a serious impact on patients with incurable cancer. This is manifested in a more than three‑fold increase in the number of suicides among cancer patients, more often among women [87]. It should be noted that these rates are higher in cancer patients from unfavorable social environments. Anhedonia and depression are common, affecting overall well‑being, treatment adherence, and outcomes, including mortality [88]. Mental disorders often complicate somatic disorders, aggravating the severity of each. Studies are emerging that conclude that mortality from MNs is also determined by stress‑related psychosocial factors [89, 90].

Research into the role of psychosocial aspects in the treatment of cancer patients, including emotional and cognitive well‑being, still receives insufficient attention. Integrating a psychosocial component into the care system, including screening and targeted therapy, as well as access to quality palliative care, improves emotional well‑being and alleviates physical suffering in patients and will certainly help reduce mortality rates among cancer patients. A deeper understanding of the mechanisms underlying the functioning of neuropsychological systems, and understanding the mutual influence of the disseminated malignant process and the functioning of the nervous system and psyche, will be crucial.

Impairment of the body's functions as a whole

When discussing the causes of death from MNs, it is necessary to consider the impairment of the body’s functions as a whole, not just the dysfunction of individual systems. Such an analysis will help us understand cases of death from cancer without an obvious acute cause. Cytokines, with their effects on the immune system and their appetite‑reducing potential, can contribute to the development of cachexia. Therefore, tumors affect both immune and metabolic function. The immune and nervous systems are very sensitive to nutrient deficiencies; for example, the brain has a high demand for glucose. Excess lactic acid and impaired kidney function can lead to systemic acidosis, which is life‑threatening, especially in patients with hematological MNs. The situation may be exacerbated by cytotoxic therapy, leading to tumor lysis syndrome, which can be fatal. Consequently, metabolic disturbances and cachexia affect the body’s vital functions as a whole. Over time, the cumulative growth of metabolic changes caused by metastatic organ damage, chronic changes in cytokine levels, continuous generation of tumor antigens, aggressive therapy, and incidental infections leads to exhaustion of the adaptive immune system and impedes the regenerative capacity of many organs, whose function becomes depleted [18]. This multifaceted exhaustion of the whole system ultimately leads to death.

Do the causes of death depend on the location of the tumor process?

The location of the primary tumor and metastatic foci determines different scenarios of disease progression and patient deterioration.

For example, according to Chuong MD et al., in pancreatic cancer, the most common cancer‑related causes of death were liver failure due to liver metastases (20.4%), brain metastases (7.4%), lung metastases (5.6%), and peritoneal carcinomatosis causing intestinal obstruction (4.6%). Sepsis was a common cause of death (31.5%), without specifying the cause leading to sepsis (it is known that local recurrence and cholangitis are common causes of sepsis) [99]. Other studies indicate that the common cause of death in patients with pancreatic cancer, even in the presence of limited distant metastases, is local or regional recurrence (56%) [35].

However, the main cause of death in cancer patients is progressive multiple organ failure and wasting. This process is undoubtedly influenced by the comorbidities present in cancer patients. Thus, according to pathologists (Kardanova A.T. et al., 2020), the causes of death from MNs in most cases, across various locations, were: multiple organ failure (74%), bleeding (12%), pulmonary embolism (8%), peritonitis and sepsis (6%). The authors note that the spectrum of causes of death in oncological pathology is due to the development of organ or multiple organ failure depending on the combination of complications, often incompatible with life, such as obstructive asphyxia, massive bleeding, pulmonary embolism, peritonitis, and sepsis [100].

It should be noted that practical experience in the intensive care unit (ICU) of a city hospital shows that the most common reason for ICU admission of palliative cancer patients is hypovolemia of alimentary origin, resulting in unstable hemodynamics, hypotension, and, as a consequence, the development of multiple organ failure due to low perfusion pressure in organs and tissues. This raises the question of preventing these conditions and, consequently, the need for follow‑up of this group of patients.

Conclusion

Providing care to cancer patients with disseminated disease is a very complex task. Most often, this task is performed by palliative care physicians. In practice, there are cases where a patient requires active or even intensive therapy in the presence of an acute condition. To make a decision, it is necessary to establish a correct diagnosis and understand the events occurring against the background of MN progression. Furthermore, even palliative/symptomatic therapy cannot be effective without considering the pathogenesis of any distressing symptom. Therefore, it is necessary to increase knowledge to understand the pathological processes occurring in the patient’s body, even at a late stage of the disease, in order to choose the right care strategy. This requires careful observation of the patient, study and understanding of the causes and mechanisms leading to deterioration and death, knowledge of the scenarios of events depending on the location of the tumor and its metastases, and potential complications of antitumor therapy.