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Metastasis to the liver and lungs are the main causes of death in colorectal cancer.(1) I understand that colorectal cancer may have metastases. But how do these metastases cause death?
(1) A. Bolocan, D. Ion, D.N. Ciocan, D.N Paduraru. Chirurgia (2012) 107:555-563. Introduction.
Metastasis is the spreading of cancerous cells to a new site within the body where they form a secondary tumour. There is nothing special about how these metastases cause death, they do so in the same ways as the primary cancer eventually might:
- Replacing functional cells with non-functional cancerous cells
- Eroding into other tissues and disrupting normal body architecture
- Causing haemorrhage
- Putting pressure onto other structures
If we apply those principles to lung and liver secondary tumours, it is easy to see why they are likely to contribute significantly to mortality.
Cancerous masses in the lungs reduce the surface area available for gas exchange, reducing oxygen saturation of the patient. The tumour may also erode into a primary bronchus, which if obstructed would cause lung collapse, or into the mediastinum. If the mediastinum is involved then the great vessels or heart may be invaded into with significant consequences.
Liver metastases are more likely to cause problems due to the reduction of liver function as the cancer grows. This causes a plethora of problems as the liver is involved in so many pathways within the body. Examples of serious effects would include the patient becoming coagulopathic due to a reduction in production of clotting factors, making bleeding much more severe. The liver can begin to fail to clear toxins from the blood, leading to the risk of acidosis or hepatic encephalopathy (leading to coma and eventual death). If the tumour were to invade the portal vein, this can cause portal hypertension, which in turn shunts pressure into the systemic venous system. This can cause oesophageal varices which are prone to spontaneous and catastrophic bleeding. Similarly a tumour invading the common bile duct (or other part of the biliary tree) can cause obstructive jaundice and associated problems.
The reason your quote suggests that most deaths are from metastases than the primary tumour is probably because tumours in these locations have greater negative effects at a smaller size because they are in crucial tissues.
There may be another contributing factor in the form of data interpretation, however. Tumours are often 'staged' via the TNM staging system, the last component of which is the presence of metastases. The presence of distal metastases automatically makes colorectal cancer Stage 4. This is often considered not to be curable, meaning a move to more palliative treatment options. This may affect the survival curves for those with distal metastases and those without.
Lung cancer and liver metastases
Lung cancer with liver metastases refers to secondary or metastatic tumours that are formed from cancer cells that have broken away from a primary lung cancer and spread through the lymphatic system or blood stream to the liver.
Wendy is living with stage 4 lung cancer with liver metastases
Once your doctor suspects that cancer has spread to your liver, they may carry out different checks and tests to assess the extent and possible impact of the tumours.
These tests can help your medical team get a clearer picture of what’s going on, and help you think about what you want to do next. These tests may include:
What to know about liver metastases
The cancer cells that develop in liver metastases are not cells from the liver. They are cells from the part of the body where the cancer originated.
Because the cancer has spread to the liver from another part of the body, a doctor may refer to liver metastases as stage 4 or advanced cancer.
Primary liver cancer is less common than liver metastases. Typically, people with primary liver cancer have risk factors such as cirrhosis or hepatitis.
Share on Pinterest As the tumor advances, symptoms may include nausea, abdominal bloating, and loss of appetite.
The early stages of liver metastases may not present any noticeable symptoms. As the tumor in the liver advances, however, the liver may swell.
The swelling can cause an obstruction to blood and bile flow. When this occurs, a person may experience symptoms such as:
- weight loss
- dark urine
- loss of appetite
- abdominal bloating , or a yellowing of the skin and eyes
- nausea and vomiting
- enlarged liver
- pain in the right shoulder
- pain in the upper right side of the abdomen
A person with cancer in another area of the body who notices new symptoms should let their healthcare provider know as soon as possible.
If a person has symptoms of liver cancer, a healthcare provider might suspect liver metastases.
After performing an initial examination and asking some questions, they will need to run tests to confirm that liver cancer is present.
Some of the tests they may run include:
- a CT scan of the abdomen
- liver functions tests, which check how well the liver is functioning of the liver
- laparoscopy, which involves a flexible tube that allows the doctor to take a biopsy of the liver
- angiogram, wherein a doctor uses dye to make high-contrast images of the liver
- an MRI scan
Treating liver metastases typically aims to alleviate symptoms and increase life expectancy. In most cases, there is no way to cure liver metastases.
There are two treatment approaches for liver metastases: local and systematic. A person’s age and overall health status will determine what approach a doctor may suggest.
Treatment will also depend on where the primary cancer is, the size and number of tumors on the liver, and any past treatments the person has tried.
Some local treatment options include:
- radiofrequency ablation, which uses high-frequency electrical currents to create enough heat to kill cancer cells , which can be from injected radiation or machines that use a beam of radiation to target a tumor
Systematic treatments may target cancer throughout the body via the bloodstream. Some possible options for liver metastases include:
- biological response modifier therapy, which helps boost the body’s immune system , which uses drugs to target rapidly growing cells throughout the body
- hormone therapy, which targets cancers that rely on hormones to grow, such as breast cancer
- targeted therapy, which directly targets cancer cells
Life expectancy and prognosis for people with liver metastases are typically poor, as the cancer tends not to be curable.
However, treatments may help shrink the tumor, improve life expectancy, and relieve symptoms.
Overall 5 year survival rates depend on the cancer’s origin. Other factors include sex, age, and the overall health of the individual.
For example, according to one study , the 5 year survival rates for people with liver metastases originating from the colon are as follows:
A doctor is the best person to give a prediction on survival. In all cases, survival rates are only estimates. A person may live far longer or shorter than expected.
A person may experience more acute symptoms that indicate that they should seek medical attention immediately.
Some of these symptoms include:
- frequent vomiting, or vomiting two or more times per day for more than 1 day
- unusual swelling in the legs or abdomen
- trouble swallowing
- bloody vomit
- a black bowel movement
- unexplained weight loss
Liver metastases is a complication of more advanced cancers. It is an indication that cancer has spread from one area to another. Liver metastases are most common with the following cancer types:
Liver metastasis can occur years after successful treatment of the primary cancer. A person should get regular checkups to help ensure that they remain free of cancer.
A person should also know the signs of liver metastases and let their doctor know if they experience any of its symptoms.
Preventing liver metastases is not always possible.
Liver metastases occur when cancer has spread from another area of the body. In some cases, it can happen before the person has a diagnosis of the primary cancer. In other cases, it could take months or years for the cancer to spread to the liver.
Treating the primary cancer can help reduce the risk of the cancer spreading. However, this is not a guarantee, as liver metastases can develop years after successful treatment.
People should follow healthful living guidelines to help prevent cancer. Some behaviors to avoid include drinking in excess and smoking. People should maintain a healthful weight through diet and exercise.
Also, early detection of any cancer type often gives the best chance of successful treatment. A person should have regular checkups and discuss any unusual symptoms with their doctor.
Liver metastases means that cancer in one part of the body has spread to a person’s liver. In these cases, the person has advanced, or stage 4, cancer.
Prognosis for liver metastases tends to be poor, with a roughly 11% survival rate for 5 years.
Treatments can help reduce the symptoms and shrink the tumor, but typically, there is no cure for liver metastases.
Material and method
155 patients with cutaneous MM were investigated between 2008 and 2013. The classification of patients in one of the five clinical stages was done according to the 2009 TNM staging version developed by AJCC (American Joint Commission on Cancer) and approved by the UICC (Union for International Cancer Control) .
The diagnosis of MM was established by excisional biopsy of the primary tumor in 153 patients, by inguinal lymphadenectomy in a patient with achromic melanoma of the hallux nail bed, and by excisional biopsy of a subcutaneous tumor (either an in transit metastasis – stage III disease, or a subcutaneous metastasis – stage IV disease) in a patient with MM of unknown primary site. At diagnosis: 2 patients had in situ tumors, 31 were enrolled in stage I, 72 in stage II, 47 in stage III and 3 in stage IV.
After the appropriate treatment according to each clinical stage, patients were submitted to periodic controls, at every 6 months, which consisted in a complete physical exam, abdominal and regional lymphatic basin ultrasound and chest radiography. If these routine tests have raised suspicion of metastasis, then the investigations were supplemented with computed tomography and, in a few cases, with positron emission tomography.
The patient’s survival was calculated by using the Kaplan-Meier method with a confidence interval (CI) of 95%. Log-rank test (Mantel-Cox) and Wilcoxon were used in univariate analysis. Prognostic value (p) of each covariable was determined by applying Cox model of proportional hazards (multivariate logistic regression). P values < 0.05 were considered statistically significant.
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Hellman first proposed the theory of oligometastases in 1995 as a sequel to the spectrum theory of cancer metastasis. Hellman hypothesized that the process of cancer metastases occurred along a continuum, from locally confined cancer to widely metastatic disease. Although the phenomenon of limited and treatable cancer metastases had been noted historically, Hellman and Weichselbaum proposed the term oligometastases, suggesting that in some patients with a limited number of clinically detectable metastatic tumors, the extent of disease exists in a transitional state between localized and widespread systemic disease. In this model local control (LC) of oligometastases would have the potential to yield improved systemic control, going against the dogma that control of oligometastatic disease would not have a therapeutic benefit since it represents a clinical manifestation of a few detectable lesions in the setting of widespread occult disease. Oligometastasis continues to be defined as a state of metastatic disease that is limited in total disease burden, usually by number of clinically evident or radiographic sites (either 1𠄳 or 1𠄵), and that is not rapidly spreading to more sites. The clinical implication of oligometastasis suggests that if the primary site (if still present) is controlled, or resected, and the metastatic sites are ablated (surgically or with radiation), there will be a prolonged disease-free interval, and perhaps even cure. As the understanding of the mechanisms underlying cancer metastasis have evolved, possible mechanisms for the oligometastatic state must be explained and examined within that context.
Biological basis for oligometastasis
Theories of metastasis
Metastasis is the cause of most cancer-related deaths . In 1889, Stephen Paget  theorized that circulating tumor cells would “seed” to an amenable “soil”, suggesting that metastasis was not a matter of chance. Five years later, [3, 4], in 1894, Halstead theorized that cancer was an orderly disease that progressed in a contiguous manner, by direct extension from the primary tumor through the lymphatics, to the lymph nodes, and then to distant sites. Halstead proposed that breast cancer metastasis was a progressive, anatomical process of contiguous seeding his hypothesis supported the use of radical surgery and radiotherapy. Radical en bloc surgery, radical hysterectomy, and primary and regional irradiation for several tumor sites were all based on Halstead's theory of tumor spread . James Ewing, in 1928, complemented the Paget and Halstead theories to propose that cancer cells grow at a particular site because they are directed by the direction of blood flow and lymphatics. 
The ‘systemic’ theory of metastasis, first suggested by Keynes  and further developed by Fisher , held that clinically apparent cancer was a systemic disease, and that small tumors were an early manifestation of systemic disease . In this theory, nodal involvement was not part of an orderly contiguous extension but rather a marker of distant metastases. According to this theory, local control would not impact survival.
In contrast to the ‘Halsted’ theory and the ‘systemic’ theory, the ‘spectrum’ theory of cancer metastases, first described for breast cancer metastases in 1994, held that disease stage at the time of initial disease presentation fell into a spectrum ranging from indolent disease to widely metastatic, with the degree of clonal evolution determining the ability of the tumor to metastasize . The spectrum theory was refined just one year later to describe the limited metastasis of any solid tumor and the term ‘oligometastasis’ was coined.
The spectrum theory conceptualized the entire range of metastatic competence, analogous to a diapason, which is the entire range of an instrument. To that end, the social sciences concept of a diaspora has recently been utilized to inform biologic understanding and therapeutic paradigms of cancer metastasis . A diaspora refers to the scattering or movement of a population from its original homeland. In the case of systemic metastases, the diaspora resembles an imperial colonization in which the populations spread widely and eventually conquer the new host lands (aggressive cancer clones to multiple organs). Oligometastases resemble trading post diasporas, representing a limited number of outposts with limited growth potential (less aggressive cancer clones to few organs). (Table (Table1, 1 , Figure Figure1). 1 ). Systemic versus oligometastatic diasporas may be dependent on the types of mutations present in the cancer cells (quality of the diaspora migrants), the quality of the original tumor site (factors in the homeland that cause the population to migrate), and the quality of the new hostland (factors that allow immigrants to establish and flourish) (Table (Table2 2 ).
(left) Oligometastatic disease. Metastatic growth potential is limited. This could be (a) secondary to due to environmental conditions in the primary tumor forestalling evolutionary clonal pressure, (b) cancer cells that slough out of the primary tumor that do not have the properties necessary to survive the circulation and invade into target organ sites, and/or (c) the cancer cells land in inhospitable target organs. (right) Systemic disease. Widespread metastatic growth potential is unlimited. This could be (a) secondary to due to environmental conditions in the primary tumor creating many undifferentiated, aggressive clones, (b) cancer cells that actively migrate out of the primary tumor that have the properties necessary to survive the circulation and invade into target organ sites, and/or (c) the cancer cells land in hospitable target organs.
|Social Demography||Cancer Demography|
|Imperial Diaspora||Trading Post Diaspora||Trading Post Diaspora → Oligometastasis||Imperial Diaspora → Cancer metastasis|
|Large populations from a single homeland||Small population from a single homeland||Migrated from primary cancer in passive manner||Dispersed from a primary cancer in an active manner|
|Settle multiple countries in aggressive manner||Settle in few countries while avoiding upsetting host country||Mild hypoxia and unlimited nutrients Home niche conditions do not cause evolutionary clonal pressure||Hypoxia and lack of nutrients cause pressure to leave primary Evolving home niche conditions cause undifferentiated, aggressive clones.|
|Host country may or may not be receptive||Host country may or may not be receptive||Target organ may or may not be receptive||Target organ may or may not be receptive|
|Group maintains collective memory of their homeland and culture||Group maintains collective memory of their homeland and culture||Pathologists can identify where a cancer cell originated||Pathologists can identify where a cancer cell originated|
|Often assimilate the new homeland||Survive as distinct communities||Few distinct metastases||Multiple metastases as distinct masses|
|Relationship with host country is uneasy and degenerates over time||Relationship with host country may be uneasy but is maintained over time||Immune system may not see a threat||Immune system tries to destroy the cancer cells|
|Tied to the homeland by exchange of resources||Tied to the homeland by exchange of resources||Limited need for outside resources from homeland fewer cells trafficking||Multiple cell-type trafficking, trafficking of resources/info|
Table adapted from Pienta et al. Clin Can Research, 2013 
|Cancer dispersion||Quality of primary microenvironment [ΔQO][Δt]||Fitness of migrant cancer cells (EFnΔt) + (MFnΔt) + (SFnΔt)||Quality of metastatic sites (H1QnΔt)) + (H2QnΔt))…|
|Oligometastasis||ΔQO = little change||[(EFnΔt) > (MFnΔt) (SFnΔt)] [TR]||[(H1Qn)) + (H2Qn)] = low|
|Widespread metastasis||ΔQO = decreasing||[(EFnΔt) < (MFnΔt) (SFnΔt)] [TR]||[(H1Qn)) + (H2Qn)) = high|
|Primary microenvironment quality: ΔQO = the changing quality (ΔQ) of the primary cancer site over time (Δt). The quality of the primary microenvironment is dependent on multiple factors, including pH, oxygenation, amount of nutrients, interaction with supporting host cells, and the quality of the immune response. Primary nonlethal, epithelial cancer cells in a highly vascularized environment with rich nutrients are presumed to be less likely to evolve to a more aggressive clone by undergoing an epithelial to mesenchymal transition (EMT) and leave the primary over time. As the quality of the environment decreases, it is likely that the generation of lethal, mesenchymal clones increases.|
|Fitness of migrant cancer cells: EFnΔt = the number (n) and fitness (F) of passively shed epithelial cancer cells (E) over time (Δt). This represents the likelihood that a cancer cell passively shed into the circulation will survive transport to a target organ. MFnΔt = the number (n) and fitness (F) of actively emigrant cancer cells (M) over time (Δt). SFnΔt = number (n) and fitness (F) of cancer stem cells (S) over time. It is likely that the fitness of a passively shed cell is less than a migrating mesenchymal cell or stem cell that actively exits the primary tumor through the lymphatics, nerves, or circulation. Fitness depends on many variables, including EMT state, stemness, ability to secrete MMPs, ability to avoid anoikis, etc.|
|Quality of metastatic sites: HQn = the quality (Q) of the target organ or host-land sites (H1, H2…). Migrating cancer cells will land in multiple sites (n) within different target organs in order to immigrate. Success depends on the quality of the soil of each of these microenvironments as well as the host immune response.|
Table adapted from Pienta et al. Clin Can Research, 2013, 
Biology of systemic and oligometastases
It is now widely accepted that there are discrete steps in tumor metastasis. Initially there is a loss in cellular adhesion, followed by increased motility > invasiveness of the primary tumor > entry into and survival in the circulation > entry into new organs > eventual colonization of these organs [11, 12]. Shortfalls at any stage of this metastatic progression could result in phenotypes of limited metastatic potential . Gupta et al. described specific tumorigenic genes – initiation, progression, and virulence genes – that fulfilled specific roles in the metastatic cascade. Initiation genes afford a selective advantage to primary tumor cells to enter circulation. Progression genes fulfill rate-limiting steps for colonization. Virulence genes provide a selective advantage in cells to colonize a secondary site(s) . As Weichselbaum and Hellman noted, this paradigm suggests “that there may be primary tumor cells with a limited capability in one or more of the necessary biological requirements for metastasis thus proposing a possible biologic explanation of the origin of oligometastases” .
In 2000 and updated in 2011, Hanahan and Weinberg proposed the, widely accepted, ‘hallmarks of cancer’ . The original cancer hallmarks consisted of six transformations in cellular physiology that allow cells to survive, proliferate and disseminate, and together support carcinogenesis. The update posited that underlying the original hallmarks were two 𠆎nabling hallmarks’: ‘genome instability and mutation’ and ‘tumor-promoting inflammation’. Additionally, the update proposed two new 𠆎merging hallmarks’: regulation of cellular energetics’ and 𠆊voidance of immune destruction’ . The exact sequence in which the transformations occur, and thus the appearance of the ‘hallmarks’ (self-sufficiency in growth signals ↔ insensitivity to anti-growth signals ↔ tissue evasion and metastasis ↔ limitless replicative potential ↔ sustained angiogenesis ↔ evading apoptosis) can vary throughout the course of progression. Despite the ordering, collectively, the hallmarks can terminate into a cancer. However, the ordering and the degree of specific hallmarks, may potentially allow for a subsequent oligometastatic state. For example, cancer cells that lack the hallmarks to actively metastasize still may be able to slough into the circulation and inefficiently establish metastases. Other cells may be less efficient at proliferation, establishing slow growing metastases. Warburg (1956) suggested that “We may have cells which indeed look like cancer cells but are still energetically insufficient… such cells which are clinically not cancer cells, have lately been found not only in the prostate, but also in the lungs, kidney, and stomach of elderly persons such cells have been referred to as “sleeping cancer cells” .
Preclinical models of oligometastasis
Traditional clinicopathologic factors are inadequate when attempting to define the potential underlying biology of oligometastases. Several investigations have demonstrated the marked genetic and epigenetic heterogeneity present in metastatic cancer sites within the same patient . These studies demonstrate that cancer cells at different sites within a patient can have varied malignant potential . Preclinical models of tumors with varying degrees of metastatic potential, including low metastatic potential exist. Using a cell line derived from B16F1 melanoma, Fidler et al.  found that variant metastatic cells pre-exist in a heterogeneous primary tumor as opposed to originating through adaption during metastasis from an otherwise homogenous primary tumor. This finding was advanced in later work that showed the KHT sarcoma line demonstrated similar heterogeneity whether grown in vitro or in vivo, which suggested that clonal variation seen in vitro derived from heterogeneity present in the primary tumor . As an extension of this work in the KHT sarcoma line, it was demonstrated that effective metastatic variants developed at a high rate with low frequency, as opposed to the more frequent and stable subpopulations of metastatic variants . In comparing B16 cell lines, Cillo et al. showed that the more highly metastatic, and less genetically stable cell line, generated increased metastatic variants corresponding to increased chemotherapy resistance . Numerous in vitro studies and analyses of animal models have indicated that cells isolated from metastases differ greatly𠅋oth genetically and phenotypically𠅏rom cells isolated from their parental primary tumors . The preclinical models point toward variation in individual tumor cells' metastatic potential, which supports the concept of oligometastases .
Given that stochastic models have been used to predict biologic phenomena, a Bayesian model has been proposed to predict the chance of occult metastases in the presence of detectable oligometastases . Using the size and number of metastases, the proposed model inferred, (1) that the probability of occult metastases may increase substantially with minor increases in metastatic potential and (2) that extended disease-free periods were predictive of a substantial decrease in additional occult disease. Although compelling, such models are in their infancy and as yet remain in pre-clinical testing where the host, tumor and experimental factors are controlled. 
Clinical evidence of oligometastasis
Evidence for the evolution of the oligometastatic phenotype comes from various clinical and pre-clinical sources [26, 32]. Recent studies of the molecular biology of renal cell cancer metastasis have implied biologic differences between less and more aggressive metastases, as well as between fewer and multiple metastases. In order to better determine which patients presenting with localized RCC harbor an aggressive tumor and may not benefit from surgery, Kosari et al. using gene expression profiling, found gene expression alterations associated with an aggressive tumor and metastatic potential in the primary tumor . From a cohort of 20 resected pulmonary metastases taken from 18 patients, Wuttig et al demonstrated the predictive potential of identified gene signatures, when comparing disease-free intervals (DFI) and number of metastases, both of which are predictive of prognosis in metastatic RCC (mRCC). There were 306 differentially expressed genes in comparing DFI 𢙕 years and DFI 𢙉 months, and 135 differentially expressed genes in comparing multiple metastases () and few metastases (𢙈). 
In colorectal cancer, there is growing evidence that liver-limited disease is a distinct biological cohort that may benefit from aggressive management. While only a minority of patients are technically resectable, approximately 40% of patients with resected liver limited disease are alive 5 years after diagnosis compared with less than 1% for those with disseminated disease.  There is genetic evidence that patients undergoing hepatic resection for metastatic cancer had a different disease than those who did not . For example, it was noted that BRAF V600E mutant tumors, which were typically associated with aggressive biology, rarely came to liver resection [38, 39]. In addition, novel chromosomal aberrations have been identified that are associated with intra- and extra-hepatic recurrence after liver resection .
MicroRNAs, small non-coding RNA known to regulate tumor proliferation and apoptosis, are frequently dysregulated in cancer and metastasis . MicroRNA profiling has shown a possible method to distinguish patients with oligometastases from those with polymetastatic disease. Examples of pro-metastatic microRNAs include microRNA-10b (upregulated in primary breast tumors that had metastasized), microRNA-21 (correlated with advanced stage, incidence of metastases, and poor outcomes in breast and pancreatic tumors), and microRNA-373/520c (increased expression in breast metastases) . MicroRNA-210, a known transcriptional target of the HIF-1α signaling pathway, was elevated in sera from patients with metastatic castrate-resistant prostate cancer, as compared to controls, and was correlated with treatment response as assessed by change in PSA . Lussiter et al. found microRNA-200c was associated with polymetastatic progression in a oligometastatic cell line, derived from patients treated with high-dose radiotherapy, tested in a xenograft model . The investigators then stratified patients with resected pulmonary oligometastases into subgroups, based on high-risk versus low-risk of further metastatic progression. Differential microRNA expression patterns were identified between these two groups (high rate of progression (n = 16 prioritized microRNAs) and low rate of progression (n = 32 prioritized microRNAs) and, in an independent dataset, the expression patterns were associated with risk of progression and decreased overall survival.  Most recently, Uppal et al. identified three microRNAs overexpressed in clinical metastasis samples from patients with limited metastatic disease. MicroRNA-127𠄵p, microRNA-544a, and microRNA-655𠄳p were shown to limit, but not fully inhibit, metastasis in a model of breast cancer lung colonization .
Controversies surrounding the treatment of oligometastatic disease
Hellman theorized that, 1) whereas some tumors were destined to remain localized, 2) other tumors, as they increased in size, acquired an increasingly greater metastatic phenotype, suggesting at an early stage these tumors seeded distant sites with clones that had not reached full metastatic potential, and finally, 3) that some tumors already had occult distant dissemination at the time they are diagnosed. He also proposed that metastatic potential was not only directed by the tumor phenotype, but that it was also influenced by the tumor's location, venous drainage, and host factors [4, 46]. Based on Hellman's theory, later scientists further theorized that tumors in the oligometastatic disease state were tumors early in their evolution of metastatic progression therefore they produced metastases that were limited in number and location. These data support the presumption of a temporal evolution with an intermediate stage of limited metastatic capacity, where oligometastatic tumors may not have acquired the broad array of genetic changes required to develop widespread metastases [14, 47, 48].
The clinical implication of the oligometastatic state is that locally ablative therapies, given with the intent of targeting sites of clinically evident metastatic disease could result in long-term survival or cure [15, 49]. Treatment of oligometastatic disease may also result in decreased overall tumor burden, decreasing morbidity and increasing survival. These arguments are opposed by the concept that clinical metastases are evidence of systemic disease and locally directed treatment will not alter the natural history of the disease course within a patient. In this scenario, only systemic therapy may be beneficial. Indeed, oligometastatic treatment paradigms are controversial (due to the limited data available) [4, 34, 50, 51]. Without randomized studies, it is impossible to know if treatment of oligometastatic disease helps the patient. In addition, oligometastatic disease may represent indolent disease that does not require potentially toxic treatments [4, 34, 50, 51].
Patients are increasingly being diagnosed with oligometastatic disease due to the advent of sensitive imaging technologies as well as effective therapies that are allowing patients to live longer with the diagnosis of cancer [34, 52]. In addition, the fact that novel treatment options with acceptable safety profiles, such as stereotactic radiation, cryoablation, and minimally invasive surgery, are available to treat limited metastases, has led to a renewed interest in treating oligometastatic disease. Treatment of oligometastatic disease not only has the potential to prevent further evolution of genetically unstable clones and metastatic spread, it may improve overall disease control and delay more toxic systemic treatment [13, 34, 53, 54]. Finally, the definition of oligometastases had gradually evolved (Table (Table3), 3 ), which further inflates the increasing population of patients diagnosed with oligometastasis. In the absence of data to guide decisions, treatment of oligometastatic disease may be seen as a quality-of-life oriented approach, choosing personalized treatments with a reasonable risk to benefit ratio and taking into account the patient's own attitude in guiding them toward more or less, intensive therapy .
|Oligometastasis||“…metastases (from tumors early in the chain of progression) limited in number and location because the facility for metastatic growth has not been fully developed and the site for growth is restricted…”|||
|Oligometastatic disease||Solitary or few detectable metastatic lesions that are usually confined to a single organ|||
|Oligometastases||Due to limited metastatic competence and does not occur following otherwise successful systemic treatment. New metastases in this situation, albeit even limited, is likely to have more extensive malignant capabilities that were somehow spared from eradication by therapeutic means, or from the development of resistant clones|||
|Induced oligometastases||Occurs when widespread micrometastatic disease is mostly eradicated by systemic chemotherapy but drug resistant clones are left behind, or tumor foci is located in a site not accessed by chemotherapy|||
|Oligorecurrence||Limited metastases in the presence of a controlled primary lesion|||
|Sync-oligometastases||𢙅 metastatic or recurrent lesions in the presence of active primary lesions|||
|Synchronous oligometastasis||Oligometastatic disease is detected at the time of diagnosis of the primary tumor, therefore there is an active primary tumor|||
|Metachronous oligometastasis||Development of oligometastatic disease after treatment of the primary tumor interval for classification of metachronous versus synchronous is not standardized between Controlled primary lesion except for concomitant primary and distant recurrence|||
|Oligoprogression||Progression of a limited number of metastatic deposits, while remaining metastases are controlled with systemic therapy|||
|Oligometastasis (specific to prostate cancer)||Rising PSA following primary therapy, with oligometastasis on imaging, in whom local treatment (surgical metastasectomy (usually LN dissection), or SBRT for bony mets or LN recurrence) is required to defer initiation of ADT|||
|Oligometastasis (specific to prostate cancer)||Castrate resistant prostate cancer with a rising PSA and oligometastasis on imaging, in whom local treatment (surgical metastasectomy (usually LN dissection), or SBRT for bony mets or LN recurrence) may allow deferral of ADT|||
Abbreviations: LN = lymph node SBRT = stereotactic body radiation therapy mets = metastases ADT = androgen deprivation therapy PSA = prostate-specific antigen
Cellular Infiltration of Tumors and Metastases
The role of tumor infiltration by leukocytes in tumor growth and development is complex. Although tumor-associated macrophages (TAM) have tumoricidal activity and can stimulate antitumor T cells, tumor cells can block inflammatory cell infiltration and the function of infiltrating cells (77). Tumor-derived molecules can regulate the expansion of myeloid progenitors (Fig. 4), their mobilization from the marrow, chemo-attraction to tumors, and activation, resulting in the promotion of tumor survival, growth, angiogenesis, and metastasis. Numerous studies have shown that following activation, macrophages can kill tumor cells in vitro (78). Indeed, if a macrophage-activating agent is injected prior to isolation of macrophages from metastases, they have tumoricidal activity in vitro (78). However, tumor infiltration by macrophages seems to have predominantly a protumorigenic and/or metastatic phenotype this was initially shown in a study in which the macrophage content of six carcinogen-induced fibrosarcomas was reported to directly correlate with immunogenicity and, inversely, with metastatic potential (79). Other studies using human breast carcinomas and melanomas have been equivocal (80). One clinical study showed that patients with metastatic disease had a low macrophage infiltration (≤10%) of their primary neoplasm, whereas 13 patients with benign tumors and 6 out of 31 patients with malignant tumors and no clinical evidence of metastases had a TAM frequency of ≥10% (80). Thus, most (81–83), but not all studies (84), have shown that there is no relationship between immunogenicity, metastatic propensity, and TAM frequency. Macrophages differentiate from CD34 + bone marrow progenitors following expansion and commitment and are mobilized from the marrow into the periphery (56, 85), in which they differentiate into monocytes and following invasion into a tissue, mature into macrophages (86). Macrophage infiltration of primary tumors is regulated, at least in part, by cytokines, growth factors, and enzymes secreted by the primary tumor. The primary tumor can also regulate the function of TAMs, including tumor cell cytotoxicity, which can be tumor dependent (87).
Tumors can secrete growth factors and cytokines that result in the expansion and mobilization of myeloid progenitors from the marrow with trafficking to various extramedullary sites including the spleen, liver, lungs, and primary and metastatic tumor lesions. These committed myeloid progenitors (CMP) can mature into DCs, MDSCs, and macrophages including TAMs, as well as become activated, or “paralyzed,” within the tumor environment. These heterogeneous cells include progenitor cells, immature cells, mature, and activated cells. Dependent upon the infiltrating subset and extent of maturation and activation, these cells can be a critical component and regulator of angiogenesis, vascularogenesis, and tumor regression or growth.
Clinical studies of macrophage infiltration of tumors have suggested that it does not correlate with the immunogenicity and metastatic propensity (81–83, 88) rather, it is associated with a poor prognosis (89). Thus, a low frequency of macrophage infiltration does not guarantee that a tumor will metastasize as multiple factors are critical (90). Macrophage infiltration of tumors is regulated by tumor-associated chemoattractants such that host and/or tumor interactions may result in qualitative (87) or quantitative (91) regulation of macrophage infiltration, which can be obscured by the technologies used to assess macrophage infiltration (82, 92). Macrophages present in the extracellular matrix and capsular area of tumors can facilitate tumor invasion and are important during the development of early stage lesions (93). Further, the proteolytic enzyme secreted by activated macrophages facilitates tumor invasion and extravasation. Indeed, in vitro coculture of macrophages with tumor cells can accelerate tumor growth (94). Macrophage infiltration of some tumor models has been found to inversely correlate with relapse-free survival (RFS), microvessel density, and mitotic index (95). TAMs also express a number of factors (96) that stimulate tumor cell proliferation and survival and support angiogenesis, a process essential for tumor growth to a size larger than the 1 to 2 mm 3 size that can occur in the absence of angiogenesis.
Myeloid-derived suppressor cells (MDSC) have also been identified in the circulation of tumor-bearing hosts and infiltrating tumors. MDSCs in mice are CD11b + Gr-1 + (97, 98), whereas the human equivalents, which were originally described in the peripheral blood of squamous cell carcinoma of the head and neck patients (99), and, more recently, other cancer histiotypes, are DR − CD11b + (99–101). Tumor growth is associated with the expansion of this heterogeneous cellular population, which can inhibit T-cell number and function. The mechanisms of MDSC immunosuppression are diverse, including upregulation of reactive oxygen species (ROS), nitric oxide (NO) production, l -arginine metabolism, as well as secretion of immunosuppressive cytokines. The immunosuppressive functions of MDSCs were initially described in the late 1970s when they were identified as natural suppressor (NS) cells and defined as cells without lymphocyte-lineage markers that could suppress lymphocyte response to immunogens and mitogens (102, 103).
Granulocyte-macrophage colony stimulating factor (GM-CSF) has been directly associated with MDSC-dependent T-cell suppression (97), which can be reversed by blocking antibodies (104). Mice bearing transplantable tumors that secrete GM-CSF have increased numbers of MDSC and suppressed T-cell immunity (105), a finding that contrasts with the adjuvant activity of GM-CSF for tumor vaccines (106). This difference is associated with GM-CSF levels such that high levels expand MDSC numbers and reduce vaccine responses, whereas lower levels augment tumor immunity. Vascular endothelial growth factor (VEGF) has also been directly linked with MDSC expansion and tumor progression (107). VEGF can suppress tumor immunity (108) via an inhibitory effect on dendritic cell (DC) differentiation (109). Thus, there is a correlation between plasma VEGF levels in cancer patients, a poor prognosis (110), and VEGF-induced abnormalities in DC differentiation (111), resulting in an inverse correlation between DC frequency and VEGF expression (112). As expected, neutralizing VEGF antibodies can reverse not only VEGF-induced defects in DC differentiation (112), but also improve DC differentiation in tumor-bearing mice (113).
Recently, Finke and colleagues (114) reported that administration of sunitinib, a receptor tyrosine kinase inhibitor, resulted in a significant decrease in MDSC within patients with metastatic renal cell carcinoma (115). Whether this decrease was associated with a reduction in VEGF levels and neoangiogenesis or as an inhibition of Flt3-mediated expansion of MDSC remains to be addressed. Regardless of this observation there have been few studies that examined the infiltration of tumors by MDSCs. In one recent rodent study, it was shown that CCL2 mediated MDSC chemotaxis in vitro and that migration or chemotaxis of MDSCs could be blocked with neutralizing CCL2 antibodies (Abs) or by blocking CCR2. Sunitinib has also been shown to mediate reversal of MDSC accumulation in renal cell carcinoma (115). These observations suggest that the regulation of infiltrating myeloid cells has the potential to control the growth of primary tumors and metastasis (Fig. 5).
The clonal selection model of metastasis suggests that the cell populations in the primary tumor with all of the genetic prerequisites required for metastatic capacity are the subpopulations that metastasize. Further, both the cells within the primary tumor and the metastatic lesion(s) can continue to diversify as the lesions grow.
End-of-Life Care for People Who Have Cancer
What does end-of-life care mean for people who have cancer?
When a cancer patient’s health care team determines that the cancer can no longer be controlled, medical testing and cancer treatment often stop. But the person’s care continues, with an emphasis on improving their quality of life and that of their loved ones, and making them comfortable for the following weeks or months.
Medicines and treatments people receive at the end of life can control pain and other symptoms, such as constipation, nausea, and shortness of breath. Some people remain at home while receiving these treatments, whereas others enter a hospital or other facility. Either way, services are available to help patients and their families with the medical, psychological, social, and spiritual issues around dying. Hospice programs are the most comprehensive and coordinated providers of these services.
The period at the end of life is different for each person. The signs and symptoms people have vary as their illness continues, and each person has unique needs for information and support. Questions and concerns that family members have about the end of life should be discussed with each other, as well as with the health care team, as they arise.
Communication about end-of-life care and decision making during the final months of a person’s life are very important. Research has shown that if a person who has advanced cancer discusses his or her options for care with a doctor early on, that person’s level of stress decreases and their ability to cope with illness increases. Studies also show that patients prefer an open and honest conversation with their doctor about choices for end-of-life care early in the course of their disease, and are more satisfied when they have this talk.
Experts strongly encourage patients to complete advance directives, which are documents stating a person’s wishes for care. They also designate who the patient chooses as the decision-maker for their care when they are unable to decide. It’s important for people with cancer to have these decisions made before they become too sick to make them. However, if a person does become too sick before they have completed an advance directive, it’s helpful for family caregivers to know what type of care their loved one would want to receive. More information about advance directives can be found below in the Related Resources section of this fact sheet.
How do doctors know how long a person will continue to live?
Patients and their family members often want to know how long a person who has cancer will continue to live. It’s normal to want to be prepared for the future. But predicting how long someone will continue to live is a hard question to answer. A number of factors, including the type of cancer, its location, and whether the patient has other illnesses, can affect what will happen.
Although doctors may be able to estimate the amount of time someone will continue to live based on what they know about that person, they might be hesitant to do so. They may be concerned about over- or under-estimating the person’s remaining life span. They also might be fearful of giving false hope or destroying a person's will to live.
When should someone call for professional help if they’re caring for a person who has cancer at home?
People caring for patients at home should ask them if they’re comfortable, if they feel any pain, and if they’re having any other physical problems.
There may be times when the caregiver needs assistance from the patient's health care team. A caregiver can contact the patient's doctor or nurse for help in any of the following situations:
- The patient is in pain that is not relieved by the prescribed dose of pain medication.
- The patient is experiencing onset of new symptoms, such as nausea, vomiting, increasing confusion, anxiety or restlessness.
- The patient is experiencing symptoms that were previously well controlled.
- The patient shows discomfort, such as by grimacing or moaning.
- The patient is having trouble breathing and seems upset.
- The patient is unable to urinate or empty the bowels.
- The patient has fallen.
- The patient is very depressed or talking about suicide.
- The caregiver has difficulty giving medicines to the patient.
- The caregiver is overwhelmed by caring for the patient, is too sad, or is afraid to be with the patient.
- The caregiver doesn’t know how to handle a certain situation.
Keep in mind that palliative care experts can be called upon by the patient’s physician at any point in the person’s illness to help with these issues. They are increasingly available not only in the hospital, but also in the outpatient setting.
When is the right time to use hospice care?
Many people believe that hospice care is only appropriate in the last days or weeks of life. Yet Medicare states that it can be used as much as 6 months before death is anticipated. And those who have lost loved ones say that they wish they had called in hospice care sooner.
Research has shown that patients and families who use hospice services report a higher quality of life than those who don’t. Hospice care offers many helpful services, including medical care, counseling, and respite care. People usually qualify for hospice when their doctor signs a statement saying that patients with their type and stage of disease, on average, aren’t likely to survive beyond 6 months. More information about hospice can be found below in the Related Resources section of this fact sheet.
What are some ways to provide emotional support to a person who is living with and dying of cancer?
Everyone has different needs, but some worries are common to most dying patients. Two of these concerns are fear of abandonment and fear of being a burden. People who are dying also have concerns about loss of dignity and loss of control. Some ways caregivers can provide comfort to a person with these worries are listed below:
- Keep the person company. Talk, watch movies, read, or just be with him or her.
- Allow the person to express fears and concerns about dying, such as leaving family and friends behind. Be prepared to listen.
- Be willing to reminisce about the person's life.
- Avoid withholding difficult information. Most patients prefer to be included in discussions about issues that concern them.
- Reassure the patient that you will honor advance directives, such as living wills.
- Ask if there is anything you can do.
- Respect the person's need for privacy.
- Support the person’s spirituality. Let them talk about what has meaning for them, pray with them if they’d like, and arrange visits by spiritual leaders and church members, if appropriate. Keep objects that are meaningful to the person close at hand.
What other issues should caregivers be aware of?
It’s just as important for caregivers to take care of their own health at this time. Family caregivers are affected by their loved one’s health more than they realize. Taking care of a sick person often causes physical and emotional fatigue, stress, depression, and anxiety. Because of this, it’s important for caregivers to take care of their own body, mind, and spirit. Helping themselves will give them more energy, help them cope with stress, and cause them to be better caregivers as a result.
It’s also helpful if caregivers ask for support from friends and family members. Such help is important to help lessen the many tasks involved in taking care of a loved one who is sick or dying.
What are some topics patients and family members can talk about?
For many people, it’s hard to know what to say to someone at the end of life. It’s normal to want to be upbeat and positive, rather than talk about death. And yet, it’s important to be realistic about how sick the person may be. Caregivers can encourage their loved one without giving false hope. Although it can be a time for grieving and accepting loss, the end of life can also be a time for looking for meaning and rethinking what’s important.
During this period, many people tend to look back and reflect on life, legacies created, and loved ones who will be left behind. Some questions to explore with a patient at the end of life are the following:
- What are the happiest and saddest times we have shared together?
- What are the defining or most important moments of our life together?
- What are we most proud of?
- What have we taught each other?
Patients with serious, life-threatening illness have stated that being positive or adding humor remains an important outlet for them. Even at this challenging moment, laughter may still be the best medicine.
How should caregivers talk to their children about advanced cancer?
Children deserve to be told the truth about a family member’s prognosis so they can be prepared if their loved one dies. It’s important to answer all of their questions gently and honestly so they don’t imagine things that are worse than reality. They need to be reassured that they will be taken care of no matter what happens.
Caregivers need to be prepared to answer tough questions. To do this, they should know what their own feelings and thoughts are about the situation. They need to be able to show children how to hope for the best while preparing for and accepting that their loved one may die.
How does cancer cause death?
Every patient is different, and the way cancer causes death varies. The process can depend on the type of cancer, where it is in the body, and how fast it’s growing.
For some people, the cancer can’t be controlled anymore and spreads to healthy tissues and organs. Cancer cells take up the needed space and nutrients that the healthy organs would use. As a result, the healthy organs can no longer function. For other people, complications from treatment can cause death.
During the final stages of cancer, problems may occur in several parts of the body.
- Digestive system: If cancer is in the digestive system (e.g., stomach, pancreas, or colon), food or waste may not be able to pass through, causing bloating, nausea, or vomiting. If the cancer prevents food from being digested or absorbed, patients can also become malnourished.
- Lungs: If too little healthy lung tissue is left, or if cancer blocks off part of the lung, the person may have trouble breathing and getting enough oxygen. Or, if the lung collapses, it may become infected, which may be too hard for someone with advanced cancer to fight.
- Bones: If cancer is in the bones, too much calcium may go into the bloodstream, which can cause unconsciousness and death. Bones with tumors may also break and not heal.
- Liver: The liver removes toxins from the blood, helps digest food, and converts food into substances needed to live. If there isn’t enough healthy liver tissue, the body’s chemical balance is upset. The person may eventually go into a coma.
- Bone marrow: When cancer is in the bone marrow, the body can’t make enough healthy blood cells. A lack of red blood cells will cause anemia, and the body won’t have enough oxygen in the blood. A low white blood cell count will make it hard to fight infection. And a drop in platelets will prevent the blood from clotting, making it hard to control abnormal bleeding.
- Brain: A large tumor in the brain may cause memory problems, balance problems, bleeding in the brain, or loss of function in another body part, which may eventually lead to a coma.
In some cases, the exact cause can’t be pinpointed and patients simply decline slowly, becoming weaker and weaker until they succumb to the cancer.
Again, every patient is different and all processes have different stages and rates in which they advance. And some conditions have treatments that can help slow the process or make the patient more comfortable. It’s very important to keep having conversations with the patient’s health care team.
What are the signs that death is approaching, and what can the caregiver do to make the person comfortable during this time?
Certain signs and symptoms can help a caregiver anticipate when death is near. They are described below, along with suggestions for managing them. However, each person’s experience at the end of life is different. What may happen to one person may not happen for another. Also, the presence of one or more of these symptoms doesn’t necessarily mean that the patient is close to death. A member of the health care team can give family members and caregivers more information about what to expect.
Withdrawal from friends and family:
- People often focus inward during the last weeks of life. This doesn’t necessarily mean that patients are angry or depressed or that they don’t love their caregivers. It could be caused by decreased oxygen to the brain, decreased blood flow, and/or mental preparation for dying.
- They may lose interest in things they used to enjoy, such as favorite TV shows, friends, or pets.
- Caregivers can let the patient know they are there for support. The person may be aware and able to hear, even if they are unable to respond. Experts advise that giving them permission to “let go” may be helpful. If they do feel like talking, they may want to reminisce about joys and sorrows, or tie up loose ends.
- People may have drowsiness, increased sleep, intermittent sleep, or confusion when they first wake up.
- Worries or concerns may keep patients up at night. Caregivers can ask them if they would like to sit in the room with them while they fall asleep.
- Patients may sleep more and more as time passes. Caregivers should continue to talk to them, even if they’re unconscious, for the patient may still hear them.
- It may become harder to control pain as the cancer gets worse. It’s important to provide pain medication regularly. Caregivers should ask to see a palliative care doctor or a pain specialist for advice on the correct medicines and doses. It may be helpful to explore other pain control methods such as massage and relaxation techniques.
- Weakness and fatigue will increase over time. The patient may have good days and bad days, so they may need more help with daily personal care and getting around.
- Caregivers can help patients save energy for the things that are most important to them.
- As the body naturally shuts down, the person with cancer will often need and want less food. The loss of appetite is caused by the body’s need to conserve energy and its decreasing ability to use food and fluids properly.
- Patients should be allowed to choose whether and when to eat or drink. Caregivers can offer small amounts of the foods the patient enjoys. Since chewing takes energy, they may prefer milkshakes, ice cream, or pudding. If the patient doesn’t have trouble with swallowing, offer sips of fluids and use a flexible straw if they can’t sit up. If a person can no longer swallow, offer ice chips. Keep their lips moist with lip balm and their mouth clean with a soft, damp cloth.
- Near the end of life, people often have episodes of confusion or waking dreams. They may get confused about time, place, and the identity of loved ones. Caregivers can gently remind patients where they are and who is with them. They should be calm and reassuring. But if the patient is agitated, they should not attempt to restrain them. Let the health care providers know if significant agitation occurs, as there are treatments available to help control or reverse it.
- Sometimes patients report seeing or speaking with loved ones who have died. They may talk about going on a trip, seeing lights, butterflies, or other symbols of reality we can’t see. As long as these things aren’t disturbing to the patient, caregivers can ask them to say more. They can let them share their visions and dreams, not trying to talk them out of what they believe they see.
- There may be a loss of bladder or bowel control due to the muscles relaxing in the pelvis. Caregivers should continue to provide clean, dry bedding and gentle personal care. They can place disposable pads on the bed under the patient and remove them when soiled. Also, due to a slowing of kidney function and/or decreased fluid intake, there may be a decrease in the amount of urine. It may be dark and smell strong.
- Breathing patterns may become slower or faster, in cycles. The patient may not notice, but caregivers should let the doctor know if they are worried about the changes. There may be rattling or gurgling sounds that are caused by saliva and fluids collecting in the throat and upper airways. Although this can be very disturbing for caregivers, at this stage the patient is generally not experiencing any distress. Breathing may be easier if a person’s body is turned to the side and pillows are placed behind the back and beneath the head. Caregivers can also ask the health care team about using a humidifier or external source of oxygen to make it easier for the patient to breathe, if the patient is short of breath.
- Skin may become bluish in color and feel cool as blood flow slows down. This is not painful or uncomfortable for the patient. Caregivers should avoid warming the patient with electric blankets or heating pads, which can cause burns. However, they may keep the patient covered with a light blanket.
What are the signs that the person has died?
- The person is no longer breathing and doesn’t have a pulse.
- Their eyes don’t move or blink, and the pupils are dilated (enlarged). The eyelids may be slightly open.
- The jaw is relaxed and the mouth is slightly open.
- The body releases the bowel and bladder contents.
- The person doesn’t respond to being touched or spoken to.
- The person’s skin is very pale and cool to the touch.
What needs to be done after the person has died?
After the person has died, there is no need to hurry with arrangements. Family members and caregivers may wish to sit with the body, to talk, or to pray. When the family is ready, the following steps can be taken.
Progression of Metastases to the Liver
Liver metastases are foreign tissue growing within the liver. They either grow expansively (as a mass) or infiltratively (spreading through surrounding tissues). Physically, they grow and compress the surrounding liver tissue. A connective tissue rim is usually formed around the metastasis, and surrounding tissue is wasted away. Large metastases may even compress branches of the portal vein. Because they grow so quickly, liver metastases, like primary tumours, may outgrow their blood supply, resulting in death of the centre of the lesion.
Some specific cancer metastases have unique effects. Metastases from pancreatic and breast cancers result in fibrous scar formation. Some metastases throw off blood clots that may occlude the portal or hepatic veins. Others may cause areas of calcification that are readily detectable using radiographic imaging.
Metastases rarely cause death due to pure metastatic burden. Compression of the vena cava (hindering blood return to the heart), blockage of drainage outflows (resulting in lung infection, for example), and electrolyte imbalance caused by abnormal hormone secretion are some causes of death.
How do liver and lung metastases cause death? - Biology
There are many different kinds of cancer. Most cancers form solid tumors, and these tumors usually start with a series of mutation in one of the body's own cells. These mutations allow the affected cells to start dividing uncontrollably, and often to avoid the body's normal defenses against them. Sometimes just the physical presence of the tumor itself is the biggest problem. On the heart or brain, for example, a big tumor can prevent the organ from functioning normally and can even cause death.
More often, however, what ends up killing the cancer patient is what's known as metastasis. This is when cells from a tumor separate from it, find their way into the lymph system or the bloodstream, and spread throughout the body. When this happens, the tumor is said to be malignant. (Benign tumors are those that do not spread. They can still cause problems in some cases, like the heart or brain.) Particular types of malignant tumors often "metastasize" to particular organs--for example, colon cancer tumors often metastasize to the liver. But cancer cells from malignant tumors can invade many different tissues, such as bone, lungs, spleen, and more.
Each metastatic cell begins dividing and forming a new tumor in its new location. This is where the real problem is. Our bodies usually can't support the growth of that many tumors, and the tumors can disrupt the normal function of the organs they're growing in. If that happens, and if the disease is left untreated, the patient will die. Treating a patient who has malignant cancer is difficult, because the metastatic cells are actually the patient's own cells! Chemotherapies are usually designed to kill all rapidly dividing cells, but some rapidly dividing cells are normal, as in hair follicles and the stomach lining. This is why people taking chemotherapy often lost their hair and become nauseated. So the goal is to kill enough rapidly dividing cells to kill the tumors, but not so many that the patient is killed.
There are several ways it might. First, cancer cells metabolize (i.e. eat) other cells in the body, thus causing tissue damage to whatever they happen to be growing in. Second, cancer cells physically get in the way of other cells just by being there and not doing the job they are supposed to. Last, all tissues have functions, and the function of a tissue is lost because it is composed of cancer cells, that can be very bad.
Cancer results when a cell that is not growing suddenly decides to grow out of control and form a tumor. The way in which cancer kills varies, depending on what is affected. The most lethal cancers are those that are metastatic, where a single cell breaks off, migrates and starts a new tumor. Basically the tumor can fill up an organ and preclude it from functioning. The following is from cancerhelp.org.uk
Generally speaking, if cancer spreads to take over a part of the body that performs an essential function this can kill you. For example, if the cancer is growing in part of the digestive system, it can prevent the digestion and absorption of food. It can grow so that it blocks the digestive system and food cannot go through the intestines. If food cannot pass through, then the nutrients from the food cannot be absorbed.
If cancer is affecting the lungs, then eventually there is too little effective lung tissue to allow enough oxygen to be absorbed into the body to sustain life. Or the cancer can block off part of the lung. This part then collapses and often becomes infected. A person with an advanced cancer does not always have the strength to fight off such an infection, even with the help of antibiotics and so the infection can eventually lead to death.
If the cancer has spread to the liver or the bones, this can upset the body's delicate chemical balance. The human body operates within very fine limits of certain body salts and chemicals. For example, there has to be a certain amount of calcium in the circulating blood. Too much or too little can upset the whole system. If the cancer is affecting many of the bones in the body, then a lot of calcium is released into the blood stream.
Normally the body has mechanisms to fight this sort of imbalance. But when the balance becomes too much out of control, then the mechanisms to correct the imbalance can become overwhelmed. There are treatments to control too much calcium, but these too can become overwhelmed and then unfortunately the calcium will continue to rise in the blood until the person affected becomes unconscious and eventually dies.
The liver is the chemical factory of the body. It performs many different functions mostly to do with maintaining the balance of body chemicals. When there is not enough healthy liver tissue to keep the balance, for example in very advanced liver disease, patients may become unconscious when the body's chemical balance becomes severely upset.
When cancer is growing in the bone marrow, then eventually there will not be enough healthy bone marrow to make blood cells. This will cause anemia (not enough red blood cells) and not enough oxygen will be carried around the body. It will also cause a drop in white blood cells. As these fight infection, it becomes more and more difficult for the body to keep bacteria and viruses under control. A drop in platelets will prevent the body from controlling any abnormal bleeding. If a blood vessel in a vital part of the body is damaged, for example in the brain, then the resulting bleeding can cause a stroke which is likely to be fatal as the body cannot control the bleeding.
Some cancers produce particular substances directly which will upset the body balance. This can cause problems such as severe weight loss or dehydration which will eventually overwhelm the natural corrective mechanisms the body has.
Many treatments can control cancer for a long time even if they can't provide a cure. But if a cancer continues to grow, then unfortunately it can become too much for the body to cope with and ultimately the treatment can no longer keep it at bay.
Although this is a difficult subject for people to talk about (including doctors and nurses), it may help you to ask your specialist doctor or nurse about how you or your relative may die. It is something most people worry about at some point and talking about the way the cancer may affect your body can help to lessen at least some of those worries. Many people are relieved to find out that they (or their relative) are likely to become unconscious shortly before they die. It can be far more worrying to bottle up your fears - what you imagine may happen before death is often far worse than what actually will.
It is important to remember also that very good pain control is available and no one with cancer should die in pain.
First, it is useful to have a working definition. "Cancer" is actually a collection of diseases that share some common features (uncontrolled cell growth being the most obvious). Clinicians define cancer as unregulated cell growth leading to invasion of surrounding tissues and spread (metastasis) to other parts of the body.It is not always obvious how cancer kills. Most frequently, it is due to a disruption in the function of a vital organ -- wherever there is uncontrolled cell growth, the "normal" cells of that organ may be impaired either too many cells become cancerous and non function or the tumor cells deny proper nutrients to the remaining normal cells. This results in organ failure. But this does not explain, for example why bone metastases are so lethal. Typically, a cancer patient may suffer from "wasting" (called "cachexia") - this may be due to toxins that get released into the body - either from the tumor cells or in response to the tumor cells. There are many unanswered questions regarding causes of cancer and of course, prevention, treatment and cure. Just this week, it was announced that researchers had made a vaccine against a virus typically associated with cervical cancers! And as you probably know, most chemotherapy drugs are directed at fast dividing cells -- killing normal fast dividing cells as well as the cancer cells, leading to side effects. A new area of research, called cancer stem cell biology, offers some hope for new therapies based on the idea that tumors actually are derived from a slow dividing stem cell. I encourage you to check out the information on the websites at the National Institutes of Health and the American Cancer Society.
I used to ask myself this question, too. People often describe cancer as "uncontrolled cell growth". If cancer tumors really are just areas in the body where cells are growing out of check, how can this actually harm a person?
Technically, not all cancers are fatal. Many older men get prostate cancer but few die from it. (I think the actual number of men who will be diagnosed with prostate cancer before they die is around 17% the number of men who will die from it is around 3%. These statistics are from The American Cancer Society's web page.) This is mostly because the symptoms of prostate cancer are hard to ignore (pain during urination, impotence) and early diagnosis and treatment are effective in slowing the growth and spread of this type of cancer.
Scientists used to think that cancer was one disease with one primary cause. This would be nice, because then finding a cure would be that much easier. Unfortunately, we now know that different cancers have different causes, so each cancer needs to be researched separately to find out the causes and most effective treatments. For this reason, we are nowhere near a cure for cancer in general, although we may be close for certain types of cancer.Cervical cancer in women has been linked to infection by the human papilloma virus (HPV) Just recently, a vaccine for HPV has been developed that may, in fact, cure cervical cancer if used effectively. Certain people in the government are fighting this, however.
Because all types of fatal cancers are different, the way in which they are fatal is different. Some of the most fatal cancers are those which grow in a part of the body that is essential for life: the lungs, the intestines, the brain, the liver, bone marrow. Cancer in essential organs of the body can cause these organs to fail. The tumor, or area of rapid new cell growth, is not functional and can crowd out nearby functional cells or rob them of blood and nutrients. Lung cancer can cause a lung to collapse, stomach or intestine cancer can block your digestion, brain cancer can build pressure in your brain or crowd out vital brain tissue, liver cancer can cause your liver to fail, and bone marrow cancer can impede your body's ability to make blood cells, which in turn impedes your body's ability to transport oxygen and fight off infection. Because the major organs are so vital for life, these are all parts of the body that are hard to operate on. Assuming the operation is successful and you remove the tumor without lasting damage to the organ, the tumor may grow back. All it takes is a few cells of the original tumor remaining in the body. This is why surgery combined with chemotherapy are important for treating these cancers. Bone marrow cancer, or leukemia, is hard to treat because you can't operate to physically remove the cancerous cells, so chemotherapy and a bone marrow transplant are often the only options.
But why would a tumor growing in breast tissue or the skin of your face pose a life-threatening problem? One answer is that cancerous cells can often spread from the original site of the tumor to other parts of the body via the blood stream and lymph system. So a tumor growing in breast tissue or the skin on your face may actually cause a tumor to develop in your brain or lungs if left unchecked. Certain types of cancerous cells grow faster and/or spread more aggressively than others. Also, tumors are areas of rapidly growing cells and need a lot of blood supply and nutrients, so they can rob nearby cells of nutrients and kill them, causing damage near the tumor site. Some tumors produce toxins that can affect how nearby cells function, or even cause massive changes in the entire body, such as dehydration or rapid weight loss.
The American Cancer Society has a web page with a lot of information on cancer: American Cancer Society