Anisman-Health-Psychology Part 2 PDF

11 Cancer Oh No, Why Me? Some diseases promote much greater fear than others, sometimes without a rationale basis. Ebola, despite still being fairly limited in its spread, seems to have created broad anxiety and worry. Influenza, which causes a much greater number of deaths annually, is...

11 Cancer Oh No, Why Me? Some diseases promote much greater fear than others, sometimes without a rationale basis. Ebola, despite still being fairly limited in its spread, seems to have created broad anxiety and worry. Influenza, which causes a much greater number of deaths annually, is taken far less seriously, and some illnesses, such as measles, although it can cause death, have been diminished by some individuals as ‘one of those things kids go through’, reinforcing their disposition to refuse vaccination for their children. Cancer falls into a unique class of illnesses that elicit shock and fear, possibly because it is so often fatal, has been associated with treatments that are fairly brutal, and patients are seen as being dehumanized. The very fact that ‘it can come back again’ even after a person has been ‘successfully’ treated, promotes continued anxiety, dread, and despair. In some instances, individuals may have a sense of helplessness, feeling as if they can’t do much to get rid of the disease, and a pervasive sense of hopelessness may develop as they realize that their doctors, despite considerable experience and technology behind them, also seem unable to deal with the illness. For that matter, the “Big C” (the disease whose name we dare not speak) can develop owing to factors entirely out of our control, including genes we happened to have inherited, or toxicants (e.g., certain herbicides) to which we had been exposed years earlier, well before we had known that they were dangerous. It wasn’t that long ago that cancer treatments, as horrendous and stressful as they were, provided individuals with only a brief extension of their lives. Treatments comprised gross surgical procedures, strong radiation, and nonspecific chemotherapeutic agents or a cocktail of several agents. In more recent times improvements have been made on many fronts. Surgical procedures are much better, chemotherapy can often be targeted at certain types of cancer, and indeed the specific treatments used may vary with multiple characteristics of the disease,  including its genetic constitution. Likewise, radiation treatments are more targeted, and medications to limit side effects, such as nausea and pain, have improved. For many years there had been a call for a change in the way diseases, such as cancer, were considered, but it wasn’t until the 1960s and 1970s that radical and profound changes occurred so that the focus of cancer research wasn’t just in finding better cures. Instead, increasingly greater efforts were made to prevent cancer occurrence. It’s actually quite remarkable that it took so long for this to occur, but individuals were made increasingly aware that cancers could be provoked as a result of environmental factors, and that as a result they could diminish cancer occurrence by changing their behaviors and their environments. This comprised giving up cigarette smoking, limiting sun exposure and using sun blockers, getting rid of environmental toxicants, as well as diminishing the consumption of unhealthy foods. This said, within Western countries about 20% of people continue to smoke and within other countries, such as Russia, the number exceeds 50%. However, smoking is only one of several factors that can cause cancer, and those who self-righteously wonder why anyone would be foolish enough to take such a risk might consider to what extent they’ve paid attention to other factors that increase or diminish cancer risk (e.g., particular foods eaten or others being avoided). I’d bet that like cigarette smokers and sun worshippers, they think “it won’t happen to me”, but if cancer does hit them, the response might be “Oh no, why me?”. Filling in a Few Blanks Cancer is among the most common ailments affecting humans and is among the top two or three (depending on the country) that lead to death among individuals beyond middle age. Although many biological and life-style factors have been implicated in the development of some types of cancer, most people are unaware of these linkages. This chapter will introduce: basic information related to the cancer process some of the presumed processes underlying cancer  several environmental and biological factors that influence illness occurrence life-style factors (stress, eating, exercise, sleep) that affect the occurrence and/or progression of cancer the psychological consequences associated with cancer and its treatments, and what options individuals have in dealing with their distress and with the illness itself the impact of psychological interventions on cancer-related treatments. What is Cancer and How Does it Develop? The term ‘cancer’ is often used as if in reference to a single illness. There are, however, more than 200 forms of this illness, involving different cell types, many different organs, diverse genetic and environmental contributions, differential influences of hormonal and immunological processes, each of which may call for a different treatment. Cancers are illnesses in which cells undergo uncontrolled growth, culminating in tumor development. Malignant cancer cells are defined by their ability to break away from the main tumor mass and travel to distant sites through the blood or lymphatic system, where they might establish a new cancer colony. This process, referred to as metastasis, distinguishes malignant from benign tumors, which don’t metastasize, although there are some exceptions (Kumar et al., 2014). Classifications Cancer subtypes can be broadly classified based on what types of tissue are affected (see Table 11.1) and the development/severity of the illness is usually described as falling into particular stages. Figure 11.1 Stages of cancer development using prostate cancer as an example Avoiding detection The battle between cancer cells and tumors can be ferocious, sometimes ending with our winning, but in too many cases, the cancers come out on top. Often the two seem to fight to a stalemate so that the tumor doesn’t appear (tumor dormancy), in some cases for up to 25 years, before a break- out occurs among cancer cells (e.g., D. Chen et al., 2014). As described in Chapters 3 and 10, the immune system ought to be able to detect and destroy cancer cells fairly readily. But, being wily, cancer cells have ways of avoiding detection so that they can flourish, eventually giving rise to a constellation of cells that make up a tumor. One early view, the immune surveillance hypothesis (Burnett, 1970), asserted that lymphocytes were continuously on alert for the presence of newly transformed cells, and that cancer occurred when these mutated cells were either not detected or not destroyed (Dunn et al., 2004). Being a mutated form of our own cells, these cancer cells might still maintain a sufficient self-identity so that they aren’t detected as foreign and thus avoid being attacked. Alternatively, they might engage disguises so that the immune system won’t recognize them as being dangerous or damaged, and needing to be eliminated. There are also occasions where the effectiveness of the immune systems is compromised, thus permitting increased tumor growth. In fact, some cancer cells may themselves shut down local immune responses, allowing them to multiply undisturbed. Still other cancers may develop in places such as the brain, where the immune cells don’t get to easily, and thus can grow with little interference. If all these clever devices weren’t sufficient to give cancer cells an edge, it now appears that they can also influence their neighbors. Cancer cells release small vesicles called exosomes that were believed to be akin to garbage being tossed out. However, they also contain DNA and RNA, which can infiltrate adjacent normal cells, turning those cancerous (Melo et al., 2014). Thus, despite the capacity of the immune system to deal with dangerous invaders, disruption of its components can increase the risk of cancer developing, and this is compounded by cancer cells acting more like terrorists than a conventional army. Figure 11.2 Immune system functioning could potentially affect the development of cancers. During the first of three phases, elimination, innate immune cells recognize the presence of a tumor that is growing (the immunosurveillance phase). Various components of the immune system are activated to deal with the cancer. The NK cells and macrophages stimulate one another, and through cytokine release call upon still more immune cells, including those of other varieties, to enter the battle, thereby furthering the tumor cell death. Still other factors, such as reactive oxygen species, are promoted that act against tumor cells. Dendritic cells cart off the dead tumor cells and deposit them in draining lymph nodes. In the next phase (equilibrium) various immune cells continue to be called upon (e.g., NK cells and various T cells) to deal with the threat. But, other processes are also occurring. The tumor cells present are genetically unstable and rapidly mutating, and lymphocytes and cytokines put selection pressure on them so that there is an increase in the generation of tumor cell variants that have increasingly greater capacity to escape and survive attacks by the immune system. Following the equilibrium phase, the surviving tumor cells that have escaped and are thus the most resilient are in the ‘Escape’ phase, during which they infiltrate the epithelium and thus continue growing in an uncontrolled fashion (shown by the large number of tumor cells over- running the T cells in the background). Adapted from Dunn, G.P., Bruce, A.T., Ikeda, H. Old, J. & Schreiber, R.D. (2002). Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunology 3, 991–998. Adapted from Dunn, G.P., Bruce, A.T., Ikeda, H. Old, J. & Schreiber, R.D. (2002). Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunology 3, 991–998. Genetic Contributions When we discussed DNA mutations in Chapter 3, the notion was introduced that the nucleotide sequence of a gene could be altered, even slightly, and these mutations could then appear in daughter cells of the initially mutated cell. Proofreading and editing occurs within cells so that these errors are relatively limited, but some mutations still sneak through. These mutations often appear in a portion of the DNA strand that has limited significance; however, they can also occur in aspects of genes that have much to say about the appearance of pathology. Our genes ordinarily contain a section which, upon being activated or expressed, initiates a constellation of biochemical changes that result in apoptosis (the cell’s death). This is a natural and beneficial process as the presence of damaged or unhealthy cells could potentially have negative consequences given that they use resources, but without providing any benefit. Should a mutation occur that hinders apoptosis, an essential regulatory mechanism would be lost and the cell could multiply repeatedly, culminating in the formation of a tumor mass (Macheret & Halazonetis, 2015). To a significant extent mutations occur randomly, but many factors can encourage the development of mutations (mutagenesis). Although cancers can develop owing to specific life-styles or environmental factors, in many instances they stem from a random process and are akin to ‘winning’ the wrong lottery. The longer certain cells live and the more divisions they undergo, the more likely it is that a cancer-producing mutation will evolve. As such, cancer should be more frequent in tissues that have stem cells that reproduce quickly than in those that are slower. In line with this supposition, an analysis of 31 tumor types determined that the lifetime risk for cancers was directly related to the rate of total stem cell division (Tomasetti & Vogelstein, 2015). Gene × environment interactions There are other ways in which inherited genes contribute to the development of cancer. For instance, the presence of BRCA1 and BRCA2 genes is involved in repair of chromosomal damage, and in this sense is involved in a tumor-suppressing capacity. However, when particular mutations occur in these genes, the risk for breast and ovarian cancer increases and the presence of these mutations thus serves as a formidable predictor of treatment outcomes (Zhong et al., 2014). These mutations have been associated with increased risk for the development of breast and ovarian cancer (55–65% of women with the BRCA1 mutation, and 45% with the BRCA2 mutation will likely develop breast cancer; Chen & Parmigiani, 2007). At the same time, as some women with a BRCA mutation might not develop cancer, suggests that additional factors contribute to illness development, including other gene mutations, the presence of certain hormones or immune factors, or environmental toxicants. It also appears that increased breast cancer risk is present among some women who use oral contraceptives, and hormone replacement therapy (estrogen plus progesterone) following menopause was likewise accompanied by increased cancer risk. Several other life-style variables, including drinking alcohol, being overweight following menopause, and low levels of physical activity promoted a small increase in the chance of cancer occurring, and while each of these has only a slight relation to the development of breast cancer, together they become a cause for concern, and it is possible that one or more of these variables interact with genetic factors in promoting cancer. As in the case of other illnesses we’ve discussed, it has been suspected that cancer has developed in response to several mutations and/or environmental contributions occurring concurrently or sequentially (a multi-hit hypothesis; Dent, 2013). One hit, for instance, might stimulate proto-oncogenes (a normal gene that has mutated and may become a cancer gene), which promotes cell proliferation, whereas a second mutation might inhibit tumor suppressing genes. Figure 11.3 depicts a possible sequence of events in which successive mutations lead to cells becoming cancerous. Ethnic and racial variations Appreciable differences exist across cultural groups with respect to the presence of the BRCA mutation. Among Ashkenazi Jews (i.e., primarily those of European descent) the mutation occurs in about 8% of women, whereas it occurs at a rate of 0.5% among Asian American women and 3.5% among Hispanic individuals (John et al., 2007). Ethnic differences have also been reported in relation to early detection of cancers. For instance, black and South Asian women are diagnosed with breast cancer later than white or Japanese women, and mortality rates have varied along these lines as well. Similarly, these differences were not accounted for by income or estrogen receptor status, but might reflect intrinsic differences in the features of tumors across ethnic groups (Iqbal et al., 2015). Figure 11.3 An initial mutation may inhibit genes that would ordinarily act against the development of factors that suppress tumor production, followed by a second mutation that limits DNA repair of damaged genes. This might lead to yet another mutation that favors a proto-oncogene becoming an oncogene, and when coupled with further activation of genes involved in tumor suppression, cancerous cells may develop. Ordinarily, proto- oncogenes have several different functions, such as providing signals that lead to cell division, or they may be involved in regulating programmed cell death (apoptosis). When a proto-oncogene is defective (referred to as an oncogene), unregulated cell division may occur, even in the absence of common growth signals that are normally provided by growth factors. In fact, even a single altered copy of an oncogene can instigate unregulated growth. Source: “Cancer requires multiple mutations from NIHen”. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Cancer_requires_multiple_m utations_from_NIHen.png#/media/File:Cancer_requires_multiple_mut ations_from_NIHen.png Source: “Cancer requires multiple mutations from NIHen”. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Cancer_requires_multiple_m utations_from_NIHen.png#/media/File:Cancer_requires_multiple_mut ations_from_NIHen.png Undoing Puzzles There are many puzzles concerning the processes by which cancers evolve and why some individuals are more likely to develop a cancer than others. When individual differences emerge in a relatively systematic way, it can give us important clues as to the processes leading to illness. Often, we can attribute the individual variability to life-style factors, exposure to environmental toxicants, or having inherited particular genes. So, it’s with some surprise that the occurrence of cancer among people with Alzheimer’s disease is about half the number expected based on simple probabilities, and, conversely, the risk of Alzheimer’s was diminished by 35% in people with some form of cancer. This seemed not to be a result of people dying of one disease before the other had an opportunity to emerge, nor a result of one illness obscuring symptoms of the other (Musicco et al., 2013). The source for this inverse relationship is presently hard to decipher, but it may have implications for determining preventive measures for both illnesses. A second puzzling finding is that if cancer development is largely due to random mutations, then why is it so often the case that those people struck with one type of cancer may in the end be affected by several types of cancer? It turns out that those individuals who seem to be affected by several types of cancer carry a genetic marker, dubbed the KRAS-variant. Among people with cancer 25% will carry this mutation, and of this group more than 50% will develop more than one cancer, usually of an aggressive variety (Chin et al., 2008). It seems that the presence of the KRAS mutation can be used to predict the occurrence of some types of cancer (e.g., Ratner et al., 2010), and a blood test to detect this variant is now possible, which can inform doctors and patients about the risk for particular types of cancer. So, while this puzzle has come to a good resolution, there are many other puzzles that have yet to be tackled. What to Do When…. When women test positive for the mutated forms of BRCA1 or BRCA2 they have several decisions and behaviors that ought to be made. They might begin screening for breast cancer earlier, but among these women mammography itself might pose a risk for cancer development, and MRI determinations might miss some types of cancer. Moreover, this gene also disposes women toward ovarian cancer, which is difficult to catch early (Evans et al., 2009). A second option is to have a double mastectomy to limit breast cancer, and removal of the ovaries and fallopian tubes to diminish risk of ovarian cancer, although these procedures don’t guarantee that cancer won’t develop (Domchek  et al., 2010). Women can use an estrogen receptor antagonist (e.g., tamoxifen used in cancer treatment) to diminish the risk of breast cancer in those with a BRCA mutation (Phillips et al., 2013), although such agents don’t eliminate the risk of cancer developing. Deciding to undergo mastectomy to prevent cancer is obviously a tough decision to make, but most individuals subsequently tend to be at peace with their decision (Boughey et al., 2015). Likewise, if a tumor is found to be present, the choice between mastectomy (with or without reconstructive procedures) versus breast-conserving surgery (e.g., lumpectomy) is also taxing. Following surgery, pain and fatigue may persist for some time, and women may be affected by changes of their body image and perceived stigma. With breast reconstruction, later body image has proved comparable to that of women who had breast- conserving surgery and better than that of women with mastectomy without this procedure (Fang et al., 2013). Individual differences regarding psychological consequences of surgery are pronounced, and what to do to diminish negative psychological states ought to be considered on an individual basis. Environmental Contributions There is a long list of carcinogen-provoked mutations that favor the development of several types of cancer. Particular living conditions or certain occupations, which bring people into contact with specific chemicals (e.g., endocrine disruptors or carcinogens), are associated with increased cancer incidence. Thus, even if it was observed that cancer runs through families, this wouldn’t necessarily mean that this cancer was due to genetic inheritance. Instead it might reflect a shared environment, such as living downwind from a carcinogen spewing factory or continued exposure to second-hand or even third-hand tobacco smoke comprising gases and particles that end up as dust within a room (Ramírez et al., 2014). Carcinogens Numerous environmental chemicals and stimuli (carcinogens) may cause cancer through their metabolic actions, or alternatively through the instigation of DNA mutations, interference with DNA repair processes, or the disruption of tumor suppressor genes. It is equally possible that carcinogens serve as a second hit that functions to promote cancer, disturb a cell’s ability to correct errors (mutations), or increase aging processes that could lead to pathologic outcomes (Pfeifer, 2015). Cigarettes have the worst reputation in this regard, while ultraviolet radiation from the sun is a distant second, followed by the many pollutants that we encounter daily. There are a great number of other carcinogens, such as asbestos, benzene, vinyl chloride, and gasoline, which we hear less about but which nonetheless can have powerful effects. Carcinogens may appear in the form of manufactured, synthetic, or natural products, such as aristolochic acid found in certain herbal medicines that have been linked to urothelial carcinomas (Pfeifer, 2015). The International Agency for Research on Cancer (IARC) has also warned that glyphosate, the most widely used herbicide world-wide, is “probably carcinogenic to humans”. Moreover, radiation (radium and plutonium, ionizing radiation such as that from X-rays and gamma rays) as well as immune-suppressing treatments, many of which are used during the course of medical treatments, can also promote different types of cancer. We’re obviously affected wherever we are, including at home and at work, despite the government legislation to protect us from these hazards. Epigenetics Just as random mutations can be instrumental in the production of tumors, so can epigenetic modifications of genes brought about by environmental toxicants, although it can be difficult to identify whether a particular epigenetic change is causally related to the appearance of a given type of cancer. In this regard, the ‘pattern’ of methylation that occurred in cancer cells was found to be in much greater disarray than in non-cancerous cells (many epigenetic changes occur concurrently, but without a systematic pattern). This diversity might not only help cancer cells deal with the multiple challenges that they encounter, but might also make it more difficult to target therapeutics at specific epigenetic marks (Landau et al., 2014). This roadblock in the treatment of cancer aside, considerable evidence has pointed to certain epigenetic modifications promoting the initial appearance and metastases of some types of cancer. Thus, it has become ever more important to identify these epigenetic marks so that classification systems can be established to determine prognosis and treatments of particular types of cancer (Szyf, 2012). Stressor experiences and diet can also affect epigenetic processes, which are being considered in the evolution of cancer occurrence and progression, as well as in the development of treatment strategies that target specific epigenetic processes (Day & Bianco-Miotto, 2013). Viral Factors In addition to carcinogens, several viruses have been implicated in the development of some cancers (oncovirus). Human papillomavirus (HPV) has been associated with cervical carcinoma, but it is also tied to cancer of the vagina, anus, penis, and throat (Schiffman et al., 2007). Considerable attention has been given to HPV because it is possible to immunize young women (and men) against this virus (Markowitz et al., 2007). Still other viruses, including hepatitis B and hepatitis C, have been linked to liver cancer, Epstein-Barr virus has been associated with several different types of cancer (Burkitt’s lymphoma, Hodgkin’s lymphoma, post-transplant lymphoproliferative disease, and nasopharyngeal carcinoma), and human T- cell leukemia virus-1, as the name implies, has been associated with leukemia. Moreover, Kaposi’s sarcoma herpes virus, an opportunistic infection often seen in patients with HIV/AIDS, has been associated with cancer development (Pagano et al., 2004). A Stress–Cancer Link Stressful events in predicting cancer The notion has been tossed around for years that cancer might develop as a result of stressful experiences. Perhaps individuals who were diagnosed with cancer, seeking a reason for their misfortune, ended up blaming past experiences for their lot, but there have been few scientific reports that support that contention. Although studies in animals have suggested that stressful experiences could modify the growth of induced or transplanted tumors, possibly owing to altered hormonal functioning or diminished immune responses against these tumor cells (Sklar & Anisman, 1979), there has been no convincing evidence of cancer being caused by stressors. Inflammatory responses have been implicated as important factors within the local environments in which cancer cells grow (Mantovani et al., 2008). Such inflammatory processes are thought to be linked to 15–20% of all deaths from cancer, and were associated with several different types of cancer, such as the incidence of breast cancer (Touvier et al., 2013), and breast cancer recurrence (Cole, 2009). Elevated levels of C-reactive protein (CRP) and other markers of inflammation have also been associated with increased mortality related to lung, colorectal, liver, and prostate cancer, and this is further exacerbated by smoking (Shiels et al., 2013). As stressors have the propensity to increase circulating cytokines and encourage inflammatory processes, they may also promote the progression of cancer growth. Several studies in humans have shown that stressful experiences were accompanied by increased cancer progression and cancer-related mortality (Hamer et al., 2009), and earlier death following stem cell transplantation applied in an effort to beat the disease (Park et al., 2010). It was likewise demonstrated in animal models that chronic stressors can diminish the effectiveness of treatments used to deal with prostate cancer (Hassan et al., 2013), and in humans stress-related psychological disorders (e.g., anxiety and depression) were predictive of a poorer response to neoadjuvant therapy (e.g., chemotherapy or hormone treatments) prior to the primary treatment being administered. The case has been made that stressful events, through their actions on hormones, neurotransmitters (particularly responses of epinephrine receptors), immune system functioning, as well as changes in tumor biology itself, could influence virtually every stage in the growth of existent tumors (Powell et al., 2013). Is there a Link Between Stressors and Metastases? During the course of fetal development, cells differentiate so that they can form particular organs and engage in particular functions. There’s a sense of order and organization of body cells, so that pancreatic cells know that they are part of the pancreas and they function in a predictable way (except when they don’t). Cells of the liver, or the breast or bone, don’t suddenly decide that they’d be more content as kidney or brain cells and then up and move. Cancer cells, in contrast, seem to be rebellious and travel to distant sites, where a new colony is established. So, what is it about them that supports their inclination to migrate and how is it that they survive? Do they have some sort of coating so that they aren’t recognized by immune cells that would otherwise destroy them? Or do they have protective factors that give them pardon to avoid proteins known as metastasis suppressors? Alternatively, are they politically astute to the extent that they hold hands with regular cells, fooling the immune cells which might react with ‘a friend of my friend is also my friend’ and thus won’t destroy these cancerous cells. It’s also possible that cancer cells use substances in the body, such as neurotransmitters, in an effort to ‘fit in’, or they might actually adopt the identity of other cells (e.g., expressing certain receptors on their surface), thereby going undetected. It also appears that lymphocytes can secrete a web of sticky DNA that captures cancer cells in circulation, but instead of killing these cells, they end up making them stronger and more aggressive, and more likely to reach organs that can then be colonized. Despite the science-fiction quality of these various alternatives, each has been advanced as a possible way by which cancer cells avoid detection and facilitate metastasis. In theory, dietary factors or stressors could affect tumor growth and metastases through hormones (e.g., cortisol) that diminish immune functioning, thus allowing for less restrained tumor growth and metastases (Moreno-Smith et al., 2010; Reiche et al., 2004) or by stimulation of norepinephrine receptors, which encourages cancer growth (Campbell et al., 2012). It is equally possible that metastasis can be facilitated through stressor- elicited hormonal changes. The migration and invasion of cancer cells could, for instance, be provoked by the release of epinephrine and norepinephrine following stressor exposure. When breast cancer cells were injected into the hearts of mice (thus simulating cancer cells that have left the main tumor mass), these cells increased subsequent cancer lesions on bones to a greater extent among stressed than nonstressed mice. However, when sympathetic activity was reduced by administration of the norepinephrine receptor blocker propranolol, the frequency of cancer lesions was attenuated. In line with these studies, there have been an increasing number of reports (albeit the number is still modest) suggesting that treatments in humans that interfere with norepinephrine functioning can limit metastasis (e.g., Ganz, 2011).  Not every environment is a welcoming one for cancer cells, but metastasis may be accompanied by the growth of a new network of blood vessels (angiogenesis) that feed the tumor cells, and it is possible that stress hormones could contribute to this process (Thaker et al., 2006). Indeed, pulmonary metastases have been seen to increase 5-fold among mice that had been exposed to a social stressor and later re-exposed to the negative event shortly after tumor cell inoculation, and these cancer-promoting effects of the stressor could be attenuated by pretreating mice with a drug that blocked the actions of epinephrine. Stressor-related biological changes associated with cancer The vast majority of studies that assessed the link between stressful events and cancer relied on retrospective procedures, which, as already detailed, can have serious limitations. The few studies that prospectively assessed this relationship, as in the case of a 20-year prospective study in Israeli individuals who had lost a son in war or by accident, revealed that this linkage was a weak one and could have been secondary to other factors related to the trauma, including life-style changes, rather than the distress experienced (Reiche et al., 2004). There have also been prospective reports indicating that appropriate coping and social support was predictive of slower cancer progression, but, once again, the data were not strong (Chida et al., 2008). While these findings suggest that stressors might not contribute to the emergence of cancer, data are available indicating that stressors may influence the course of cancer that is present or affect recovery from the illness. Consistent with the stress–cancer link, NK cell functioning was disturbed among breast cancer patients reporting high levels of psychological stress. Over the course of an 18-month period following surgery, women who indicated greater levels of distress exhibited diminished NK cell activity and reduced lymphocyte proliferative responses (Varker et al., 2007). As well, men who received stress management training exhibited enhanced mood following radical prostatectomy, coupled with recovery of NK cell activity (Thornton et al., 2007). As expected, coping indices, including social support, benefit finding, and optimism, were also directly related to NK cell activity and lymphocyte proliferative responses among individuals being treated for breast, gynecologic, prostate, gastrointestinal, digestive tract, and liver malignancies. A meta-analysis indeed confirmed that increased distress was accompanied by poorer survival across different types of cancer (Chida et al., 2008), and having a stress-prone personality, negative emotional responses, poor coping styles, or poor quality of life were related to higher cancer mortality. Owing to the difficulty of conducting prospective studies, another approach was adopted to determine whether stressful events were linked to cancer appearance. In this instance the patients’ stressor history was obtained when a tumor was first suspected and a biopsy performed, but before the biopsy results were available. As predicted, the appearance of malignant tumors (but not benign tumors) occurred more often in association with greater past stressors. Had the reported stressor experiences reflected biased appraisals on the part to those being assessed for possible cancer, then elevated negative life events would have been reported irrespective of whether the lump turned out to be benign or malignant, as both sets of women ought to have been equally distressed by the prospect of the cancer being malignant (Weinrib et al., 2010). In fact, however, vegetative and affective depressive symptoms were increased, as were nocturnal plasma cortisol among women with ovarian cancer relative to that which occurred among women with a benign disease (Lutgendorf et al., 2008), and diurnal cortisol levels among individuals with metastatic breast cancer predicted earlier mortality (Sephton et al., 2000). Although these findings support the view that stressful experiences, psychological changes, and cancer occurrence might be linked, there have also been reports that have been inconsistent with this perspective. As already indicated, the data supporting a causal connection between stressful experiences and the development of cancer have not been persuasive, whereas the findings pointing to stressor-elicited exacerbation of already-existent cancer have been more telling. Influence of early-life stressors on cancer Adverse early-life experiences in humans have been associated with increased incidence of breast cancer, just as this relationship was observed with other psychological and physical disorders. For instance, loss of a parent or poverty during early development was predictive of increased adult cancer incidence (Schuler & Auger, 2011), as were stressors that comprised physical or emotional abuse. Once again, these findings don’t point to causal relations; stressors, such as loss of a parent or poverty, can have multiple downstream consequences (altered diet or health-seeking behaviors) that could favor the development of cancer. Looking for Stressors at the Wrong Time and the Wrong Place When researchers conducted retrospective analyses in an effort to link stress and cancer, they typically focused on stressors experienced in recent years (e.g., the past 2 years), although in some studies lengthy time frames were assessed (20 years) in predicting later cancer occurrence. But let’s consider to what extent these are appropriate in the context of diseases such as cancer. The cancer process is a lengthy one, and cancer cells can be around for a long time before they go into a relatively rapid multiplication phase. The question that should be addressed is not whether there is an association with the relatively recent stressor experiences that could be recalled, but instead whether stressors preceded the first mutations that got the processes going or, alternatively, the events that occurred soon after a mutation appeared so that the growth and survival of those first malignant cells were enhanced. Early-life and prenatal stressful experiences cause multiple changes in the developmental course of many hormonal, neurochemical, and immunological systems, and may influence the response to later challenges encountered in adulthood. From this perspective, the root of stressor effects on pathology, including cancer, could potentially stem from these early experiences. Thus, trying to find a link between the occurrence of cancer and stressors experienced in the past few years might simply reflect looking in the wrong place at the wrong time. Stressor-provoked modification of therapeutic treatment responses It is of theoretical and practical importance that stressors may influence the effectiveness of treatments used in cancer therapy. As cancer patients typically experience considerable strain, it is conceivable that the beneficial effects of their treatment are limited owing to stressor-elicited epinephrine changes or variations of other hormones or immune factors. Moreover, it might be considered that treatment with a beta norepinephrine blocker, by reducing distress, might enhance the effectiveness of their cancer treatment. Consistent with this perspective, the effectiveness of the anti-cancer treatment bicalutamide in reducing prostate tumors in mice was diminished by a chronic stressor regimen, an outcome that could be attenuated by treatment with a β-norepinephrine blocker (Hassan et al., 2013). The Child’s Extra Burden Most severe, chronic illnesses, particularly if they involve intense treatment, can lead to PTSD symptoms. Among women with breast cancer, 1 in 4 developed signs of PTSD, and among children with cancer, 1 in 5 were at increased vulnerability to develop this disorder (Graf et al., 2013). Moreover, the risk for PTSD persists among childhood cancer survivors so that as adults new stressor experiences will be more likely to promote PTSD (Stuber et al., 2010). Beyond these psychological consequences, 60% of children treated for cancer experienced adult impairment of cardiac, pulmonary, endocrine, and nervous system disturbances, neurocognitive and auditory system problems, as well as other negative outcomes that likely came about owing to the treatments themselves, as well as to uncertainties and the development of PTSD (Lee et al., 2009). Overall, virtually all survivors of childhood cancer had at least one type of ongoing disturbance (Hudson et al., 2013), which could have encouraged the development of PTSD. While it might be important for all patients to receive stress reduction therapies as a part of their cancer treatment, this is especially true for children, who might not fully understand what is occurring and who probably don’t have effective ways of coping. Cognitive behavioral therapy has been found to be effective in children (Gillies et al., 2013) and could potentially serve in this capacity among children in cancer treatment. Hormones and hormone receptors in cancer Cancers may differ widely in their basic characteristics and the genes associated with the cancer, making them differentially amenable to particular types of treatment. Factors that influence reproductive hormones (use of oral contraceptives, pregnancy, having children, age when first child was born, breast feeding practice, age at first menstruation, age of menopause) can influence the occurrence and progression of some cancers, and thus therapy for some forms of breast and prostate cancer will include treatments that affect estrogen or testosterone functioning (e.g., Ricci et al., 2014). However, there are types of cancer that are less readily treatable in this manner. One form of breast cancer, referred to as triple-negative breast cancer, does not express the genes for the estrogen receptor (ER), progesterone receptor (PR), or HER2 (Hudis & Gianni, 2011), and treatment success is generally lower than in triple-positive instances. This said, even though there is a certain amount of uniformity to triple-negative cancers, they may actually comprise diverse attributes. Specifically, in most instances triple-negative breast cancers have a poor prognosis and require more aggressive therapy, but in others, oddly, prognosis may be as good as in hormone receptor positive breast cancers (Cheang et al., 2008). Given the link between hormones and some types of cancer, it would be expected that experiences that affect hormones, including eating, exercise, as well as medications being taken, could potentially influence cancer risk or progression. Hormone replacement therapy (HRT) among women in menopause, particularly if it involved a combination of estrogen and progesterone, increased the risk of breast cancer, and declined among women who had stopped using HRT (Narod, 2011). As stressful events influence multiple hormonal processes, including estrogen, it would be reasonable to suppose that such experiences could influence the progression of breast cancer, particularly among women using HRT. Cancer and the Pill Oral contraceptives come in two forms: the mini-pill contains only progesterone, whereas the combined pill, the far more popular of the two, contains both estrogen and progesterone. Not long after oral contraceptives were first introduced, it was argued that the hormonal changes provoked could favor the development of some cancers. However, with the concentrations of the hormones being reduced, the risk was diminished. Almost 20 years ago, a report from the Collaborative Group on Hormonal Factors in Breast Cancer (1996) and a subsequent study that tracked over 116,000 female nurses (Emons et al., 2000; Hunter et al., 2010) indicated that women using oral  contraceptives were still at somewhat elevated risk of developing breast cancer, but after stopping its use the risk declined, so that after 10 years the increased risk was entirely absent. One form of oral contraceptive in which the dose of hormones is changed in three stages during monthly cycles (‘triphasic pill’) was accompanied by higher risk for breast cancer (Hunter et al., 2010). Like breast cancer, cervical cancer was elevated among women using oral contraceptives, and then declined after termination of their use (Appleby et al., 2007). In line with other studies, oral contraceptive use, even for as long as 10 years, was not associated with an increase of breast cancer (Hankinson et al., 1997) and actually offered some protection against ovarian cancer (Hankinson et al., 1992). These findings were subsequently observed in other studies that involved varied hormone formulations. Hormonal treatments can have many benefits, some of which are related to certain forms of cancer, whereas others are unrelated to cancer. However, we don’t hear much about these beneficial actions of hormonally-related contraceptive methods (Bahamondes et al., 2015). Eating and Cancer Linking the consumption of particular foods to the development of cancer is difficult, just as it is in relation to heart disease. Given how many different foods we eat, how does one identify which, if any, are causing problems and which are simply bystanders? As well, the foods we eat may be influenced by other variables that could directly or indirectly influence the cancer process (e.g., living in poverty can influence the foods eaten). Finding answers to such issues obviously can’t be done through retrospective studies (do you remember what you ate 2 days ago, let alone 2 weeks ago?), and even prospective studies (e.g., using a food diary) can be unreliable. Despite these research limitations, it is thought that foods eaten or the accumulation of fat can affect cancer processes. According to Cancer Research UK (2014), some forms of cancer, including breast (among women after menopause), bowel, uterine, esophageal, gastric, pancreatic, renal, and gallbladder cancers, are connected to obesity in about 5% of cases. Some of these cancers might be exacerbated because fat tissues release cytokines that elicit inflammation, and our diet can also affect hormones (e.g., estrogen and testosterone) that in turn affect cell functioning and immune activity. Beyond these factors, certain foods may negatively interact with the stomach lining or, alternatively, the stomach doesn’t receive the stimulation it needs from certain chemicals, eventually favoring cancer development. Aspects of the diet also affect gut microbiota which can influence some cancers, such as colorectal cancer (Walsh et al., 2014). In this regard, the gut microbiota can either act against or aggravate cancer development, and may contribute to complications related to cancer treatment (Garrett, 2015). Perhaps it is especially significant that forms of bacteria Providencia and Fusobacterium may be linked to colon cancer and that identifying bacterial genes may be useful in predicting the occurrence of this type of cancer (M.B. Burns et al., 2015). It has also been maintained that certain foods, such as daily consumption of nuts, can reduce cancer risk somewhat (Bao et al., 2014), and some types of cancer, notably that of the mouth, esophagus, stomach and bowel, can be diminished by eating foods high in fiber as well as fruits and vegetables, and avoiding salt, red meat, and processed meats (Corpet, 2011). We occasionally hear about ‘superfoods’ that ward off multiple diseases, but these claims typically sound too good to be true, and typically have no scientific backing. As indicated in discussing the positive influence of particular diets, foods associated with cancer risk or benefits have been claimed far too often, and, as indicated earlier, it has been argued that many of these single studies offered “implausibly large effects” (Schoenfeld & Ioannidis, 2013). This doesn’t mean that particular foods don’t have positive attributes, nor that ‘biotherapeutics’ can’t be developed to prevent or treat certain cancers (Prakash et al., 2011) or modify responses to other therapies (Iida et al., 2013). However, it should be understood that complex interactions probably exist between gut bacteria, genetic, epigenetic, and immunologic factors, diet and age (Serban, 2014). Exercise and Cancer Given the positive effects of exercise on so many of our functions, including immune processes, there has been the question of whether an exercise regimen can influence quality of life among cancer patients, attenuate the development of cancer, or alter its course. There have been many scientific reports claiming the positive effects of exercise on factors secondary to cancer or its treatment (e.g., quality of life, diminished fatigue, improved muscle strength), which can diminish morbidity and mortality (Eyigor & Kanyilmaz, 2014). Positive outcomes might vary with numerous features and the type of cancer being assessed, as exercise interventions seem not to have particularly beneficial effects in the case of some cancers, such as colorectal cancer (Cramer et al., 2014). For other types of cancer, combined aerobic and resistance exercise regimens may diminish the fatigue that is otherwise common (Meneses-Echávez et al., 2015), and exercise can act against cancer cachexia (progressive weight loss, anorexia, and wasting) (Grande et al., 2014) and enhance health-related quality of life (Mishra et al., 2014). Although some of the positive attributes of exercise having been mentioned, but it should also be considered that different amounts of exercise can have varied health effects in patients, just as in non-ill individuals. Thus, it needs to be established whether certain doses of exercise are most practical and beneficial among those with cancer or those who have previously been treated. There is little information as to whether exercise can play some role in preventing the development of cancer, although there have been suggestions to this effect (Abioye et al., 2015). Studies still need to be conducted prospectively over extended periods, and once more, they need to distinguish between different types of cancer as they might not all be governed by the same processes. Furthermore, it is often difficult to establish whether the effects attributable to exercise in this context can be dissociated from related positive life-style factors (diet, stress experiences, sleep). Sleep and Cancer Sleep disturbances are accompanied by altered activity of inflammatory immune processes, and it might be expected that sleep alterations would influence cancer risk. This linkage has, however, received very limited support, although work-related variations of sleep patterns (e.g., among shift workers) have been proposed as a modest risk factor for breast, prostate, colon, and uterine malignancies as well as non-Hodgkin’s lymphoma (Haus & Smolensky, 2013). Although increased risk of prostate cancer was observed among men who had difficulties falling and staying asleep (Sigurdardottir et al., 2013), an association between sleep complaints or sleep duration and risk of breast cancer was not observed (Vogtmann et al., 2013). In still other studies, both short sleep (less than 5 hours) and long sleep (more than 9 hours) were associated with elevated colorectal cancer risk (Jiao et al., 2013). The data currently available are too scant and not sufficiently consistent to make causal connection between sleep disorders and cancer, or whether any effects of sleep disturbances are specific to only some types of cancer. Cancer Treatment and Psychological Factors Some types of cancer have been treated more successfully than others, potentially owing to improved early detection methods or to improved treatment (or illness management). It is also possible that improvements in general patient care and greater focus on psychological health might have contributed in this regard. The strain of cancer treatment Cancer treatment can be arduous, beset by obstacles, stumbles, and even backward steps. Soon after cancer is suspected, the individual is subjected to multiple tests, including biopsies; the treatments themselves can be exceptionally stressful, and both behavior and identity might change from one of an independent, self-sufficient person to that of a ‘victim’. Patients may have to undergo surgical procedures that range from limb amputation to removal of organs or parts of organs. As well, chemotherapeutic agents are highly toxic, killing healthy cells along with those that are cancerous, and many adverse outcomes can be expected. Normal fast-growing cells that are not cancerous, especially in the mouth, stomach, and intestines, will be most affected, as will blood cells and hair follicle cells (the latter is responsible for hair loss that occurs during treatment). The treatments may suppress the immune system (at times to dangerously low levels), provoke anemia and severe fatigue, and cause nausea and vomiting, anorexia, diarrhea, abdominal cramps, as well as constipation. Chemotherapy may also engender heart problems, infertility, peripheral neuropathy (pain, tingling, or numbness, usually in the hands and feet, that may not be reversible), and secondary neoplasms, such as acute myeloid leukemia. In addition, cognitive impairments may develop (sometimes referred to as chemo-brain), including disturbances of memory functioning (e.g., Paquet et al., 2013). These outcomes, as well as depression and PTSD that occur as a result of treatments, are all stressors that could potentially influence the effectiveness of the treatments themselves, and long-term disturbances (e.g., cardiovascular problems) aren’t uncommon (Yeh et al., 2004). Despite the hardships of treatment, the procedures will hopefully have positive effects and the patient will survive and resume their previous lives. To some extent, post-treatment symptoms, such as depression, have been related to trait optimism and how threatening individuals perceived their situation to be (Levkovich et al., 2014). However, even under ideal circumstances one shouldn’t be misled to believe that the patient can now feel entirely relieved. Getting to this point beats the alternative, but the battle isn’t over. Patients often have to spend time in physical or occupational rehabilitation, which in itself limits their usual activities, and additional tests are needed every few months to determine whether other adverse effects (e.g., cardiovascular problems) have emerged as a result of the treatment or whether the cancer has returned or metastasized. Understandably, these tests bring with them considerable distress as patients wait for the other shoe to drop. Being seen as a ‘cancer survivor’ doesn’t necessarily mean that the patient returns to their previous life exactly as it had been, and they soon realize that life has taken on a ‘new normal’. Thus, although the cancer survivors may develop a better appreciation for the good aspects of life, they often experience enormous strain and uncertainty about the future. The Stress of Surgery Many people are frequently fearful of medical procedures. For some, even a needle or the sight of blood makes them woozy; others are concerned with surgical procedures, either because of uncertainties regarding what things will be like after the surgery, or simply because when anaesthetized they would lose all control over the situation. There’s little question that surgical procedures and tools have become more precise. By example, in many instances large incisions to reach the abdominal cavity are replaced by keyhole (laparoscopic) surgery involving only a small incision, which allows for more rapid healing. For instance, patients who had a laproscopic procedure for gall bladder cancer had a longer survival than those who received other forms of surgery (Goetze & Paolucci, 2006). Still, cancer- related surgery is an invasive procedure, recovery isn’t always easy, and the procedures themselves aren’t always as successful as one would hope or may uncover still other problems. Despite  the improvements, for many people surgery is a major stressor, which can disturb immune functioning (e.g., Rosenberger et al., 2009). For that matter, simply treating patients with anesthetic or creating any sort of wound might affect the tumor process, and thus there’s something to be said for the use of immune- enhancing agents following surgery (Whelan, 2001). To improve surgical accuracy and diminish patient distress, robotic surgery has become increasingly well developed, and in many instances has yielded especially positive outcomes (e.g., Broholm et al., 2015). Novel approaches have also been proposed so that surgical procedures can be achieved through natural orifices (e.g., transluminal endoscopic surgery), which can also be enhanced through robotic control (Azizi Koutenaei et al., 2014). There’s the important issue of how comfortable patients will be in placing their trust in a heartless, soul-less robot in comparison to an understanding and compassionate human. Of course, the argument will also be made that human judgment is often necessary for complex decisions that need to be made during surgery, even if the surgeon graduated 94th in their class of 100, and miserably bombed the section on spleen because they didn’t think it would be on the exam. There’s another issue that needs to be considered in the context of surgical procedures. Given the distress and uncertainties that accompany surgery, it might seem surprising that such procedures are undertaken in patients with Stage 4 (metastasized) cancer. Sometimes this is done to relieve pain caused by obstructions, but at other times it might be to calm family members who demand something be done. Surely, the oncologists know that the patient’s case is terminal and not much can provide enhanced quality of life. However, the serious discussions that need to be undertaken with the patient and the family might not have occurred. In fact, only a small fraction of patients had issued a ‘Do Not Resuscitate’ order, possibly suggesting that a number still expected positive outcomes (Bateni et al., 2015). Psychological impact Being informed that one is stricken with cancer is distressing and may be associated with the subsequent development of depression, anxiety, and PTSD. When faced with such an experience, some individuals will succumb and remain depressed or anxious, whereas others might find effective ways of coping, and may even be able to find positive aspects from bad experiences (finding meaning). Considerable success has been achieved in the treatment of psychological disturbances secondary to cancer (Barrera & Spiegel, 2014), although it’s clear that there is still room for improvement (Galway et al., 2012). For many cancer patients collaborative care models, which included screening for depression and linking depression treatment programs, were found to be beneficial (Walker & Sharpe, 2014). Stress reduction treatments, such as cognitive behavioral therapy (CBT) and mindfulness-based stress reduction (MBSR), may also reduce distress and depression associated with cancer. Supportive group therapy likewise extended survival time among women with malignant melanoma (Fawzy et al., 1993), and similar findings were reported by a combination of psychotherapy and antidepressant drug treatments in relation to metastatic breast and gastrointestinal cancer. The enhanced subjective indices of psychological well-being may be accompanied by altered neuroendocrine functioning, lymphocyte proliferation, and pro- inflammatory cytokine production, as well as lengthening of telomeres (Matchim et al., 2011; McGregor & Antoni, 2009). Although psychological treatments often have positive effects on the individual’s psychological state, the benefits on the cancer process and survival have not always been realized. Some cancers might be entirely independent of stress-related processes, and in other instances it may have progressed to a point where psychological interventions were provided too late to have any effect. As indicated earlier, however, even if a psychological intervention doesn’t influence tumor progression, for many people it may help in coping with day-to-day burdens, and perhaps promote benefit finding that will allow them to consider their life experiences from a positive perspective. Given how devastating depression can be, coupled with reports that emotional factors can undermine cancer treatment, it is more than a bit surprising that 73% of cancer patients who experience depression are not treated for this (Walker et al., 2014).  Telomeres from a Different Perspective The finding that shortened telomeres were associated with poor health and earlier death prompted researchers to attempt to determine whether telomere length was simply a marker of poor well-being or was in some way causally related to the development of illness. In conducting such studies it was unexpectedly found that longer telomeres obtained from white blood cells were associated with an increased proclivity of dying from cancer. It is thought that people have long telomeres when their physical system is adept at repairing them. However, this very same process may act against our well-being when they serve to maintain and repair cancer cells. If this turns out to be correct, then it might be possible to limit cancer growth by undermining the ability of telomeres to maintain their length (Rode et al., 2015). There have been suggestions that telomeres may be involved in the development of cancer, and it was demonstrated that normal cell death, and by extension death of cells that may become cancer cells, can be manipulated by altering telomeres so that they lose their ability to protect cells (Hayashi et al., 2015). Social support Support from friends is especially valuable in cancer recovery, enhancing quality of life and improving adherence to treatment protocols (Le et al., 2014), and having larger social networks of friends and social support has been linked to reduced mortality following a diagnosis of breast cancer (Kroenke et al., 2012). Being married has likewise been associated with fewer health problems and greater longevity relative to being unmarried (or presumably individuals who are unhappily married), and this has also been observed in relation to some types of cancer (Inverso et al., 2014). A study of more than 734,000 patients diagnosed with the 10 leading types of cancer revealed that metastasis was lower by 17% among patients who were married than in those who were not (Aizer et al., 2013). There is, at times, the misconception that once a patient has gone through the rigors of cancer treatment and the primary tumor is no longer evident, that the battle has been won. Thus, it’s not unusual for social support that had been available from good friends to diminish, as these friends have their own problems to deal with. This is perfectly understandable, but as we’ve already seen, for many patients considerable uncertainty still remains as to whether the cancer will ‘come back’ in the next few months or years. Moreover, the distress experienced during the preceding months, coupled with the physical and psychological toll of the treatments, may leave patients drained, albeit happy that it seems over, even for the moment. These ‘cancer survivors’ need continued support, and other effective ways of coping with the ensuing months and years of uncertainty. Psychooncology The 1970s and 1980s saw the evolution of programs to link immune disturbances to psychological factors and specific brain processes. Some researchers focused on how psychosocial factors might influence the growth of an already existent cancer, whereas others considered the psychological ramifications of cancer and how to modify these outcomes. As already described, for many people psychological interventions enhanced quality of life, even if these treatments didn’t affect the course of the illness. Perhaps because clinical oncologists have witnessed repeated failures to develop cancer cures based on a standard medical model, there has been increased consideration that psychological treatments may have a role to play in extending life. Others, of course, continue to view the link between psychological processes and cancer as an interesting epiphenomenon, but might not consider it useful in achieving positive treatment outcomes. Nonetheless, it is being accepted that life-style and stressful experiences could negatively influence the course of cancer progression, and could potentially influence the treatment efficacy. As we’ll see in ensuing chapters concerning how to deal with illness as well as end-of-life treatments, enormous progress has been made in developing adjunctive psychosocial treatments in dealing with cancer-related well-being (Artherholt & Fann, 2012). While not necessarily diminishing the importance of psychological processes, some physicians feel that they should be doing what they were trained to do, namely treat the patient’s cancer and other aspects of the patient’s physical well-being, whereas psychological health should be dealt with by experts best suited to doing precisely that. It’s difficult to argue with this perspective, especially if the oncologists hadn’t received training to deal with the patients’ psychological issues. Yet the oncologist ought to appreciate that gravely ill patients are likely to look to their primary treating physician for signs of positive change and for support, and thus casting aside this responsibility is counterproductive. Being distraught and even desperate, some patients have opted for alternatives to standard medical treatments, even resorting to the most unlikely and ineffective therapies. ‘Natural medicines’ or ‘alternative medicines’ have been used as an adjunct to standard remedies or as a replacement for these procedures. It’s difficult to say to what extent these alternative approaches reflect hocus-pocus, and how much is real, but every time one turns around another odd treatment seems to appear. These range from imaging Pac-man-like characters gobbling up cancer cells, through to consumption of apricot pits or shark cartilage in the hope that these would provide a cure. Fasting for several days has been offered as a way to fight cancer, allegedly because this ‘kick-starts’ our immune system. Likewise, ancient Chinese medicines, green tea, red wine extracts, and herbal tonics including ginko biloba have all been suggested to either enhance standard cancer treatment or attenuate the side effects that might otherwise occur. This is not only worrisome because these treatments might not have any positive effect, but also because they might be used instead of possibly effective approaches. Moreover, some of these pseudo-treatments may actually have a negative influence on the actions of chemotherapy, or may increase risk of some cancers, as reported with respect to high levels of vitamin E or supplements containing selenium (Kristal et al., 2014). Dealing with Cancer-Related Pain Aside from so many other problems for the cancer patient, many cancers cause terrible pain. This may come about due to the growing tumor compressing or infiltrating sensitive regions of the body (e.g., bone), causing inflammation, or the release of chemicals that increase pain sensitivity. The intensity of pain increases with advanced cancers and more than 50% of individuals report pain sufficiently severe to disrupt day-to-day functioning. Thankfully, in most cases the degree of pain can be controlled by medications (e.g., opioids when the pain is severe), although these can also produce uncomfortable side effects. As well, various psychosocial and pain management techniques can be used, allowing for doses of medication to be  reduced, and antidepressant drugs have also been found to be helpful. Despite the low cost of pain medications, patients in large portions of the world (e.g., in parts of the Middle East, Africa, Asia, Latin America, and the Carribean) do not receive pain medications, either because of medicines not reaching their target audience, or because of over-regulation limiting their legitimate use (e.g., Cleary et al., 2013). These countries have serious challenges in relation to drug use, and a multipronged effort will be needed to alter regulatory policies and to provide educational reforms regarding the use of opioid acting agents. Patient decisions regarding treatments The shock of a cancer diagnosis sets most people into a shock reaction, and yet they are asked soon afterward what their wishes are concerning treatments they’re prepared to receive. Understandably, this is exceptionally difficult, and to facilitate this process the Mayo Clinic has offered a series of guidelines for patients that will help them make these decisions in collaboration with their doctor, who ought to be their partner in this process (see Table 11.2) (Mayo Clinic, 2015). Broad Consideration Regarding Cancer Treatment There are many reasons why cancer treatments might not work as well as one would hope. As we’ve already seen, aside from cancer cells’ ability to avoid detection by the body’s own immune cells, the treatment may not be attacking the root cause of the disease (e.g., the right gene or growth factors). As well, a second cancer-promoting mutation may develop so that a drug that targets the first mutation won’t be effective. It also seems that characteristics of cells that serve as a target for a chemotherapeutic agent may disappear (be suppressed), only to reappear again when the coast is clear and the drug is gone (Nathanson et al., 2014). A drug’s high toxicity may also limit its use, and its effectiveness may be compromised by the tumor’s ability to develop resistance to it. Treatments may also adversely influence normal cells in parts of the body beyond those affected by the cancer, which also limits their use. Efforts have been made to overcome these problems, such as nanotechnologies to deliver medicines to where they are needed (Wicki et al., 2014), thereby allowing low doses to be used to avoid toxic side effects and to eliminate the potential for tolerance to the drugs actions. However, given that for most cancers the treatments have been only moderately successful, much more effective methods are needed to outwit the cells working to harm us. Individualized treatment strategies The battle against some forms of cancer has recorded a number of wins over the past decades. Particular tumor types were linked to specific genes, hormones, or growth factors, leading to treatments based on the characteristics of the cancer, as in the case of estrogen sensitive HER2 positive breast cancer that is responsive to a drug cocktail that includes Herceptin (Trastuzumab). It likewise appears that a small molecule that fits precisely into a component of complex androgen receptors could have positive therapeutic effects in treating prostate cancer (Kulik, 2014). New treatments, such as those that target specific factors such as increasing AIM2, which ordinarily limits colon cancer growth, may serve to attenuate colon cancer (Wilson et al., 2015), although it will be some time before such compounds reach the clinic. Other cancers that had been considered a death sentence, such as chronic myelogenous leukemia, can frequently be treated successfully with Imatinib (Gleevec; Stenehjem et al., 2014), and newer compounds based on this agent are being developed (Wehrle et al., 2014). Pitted against such success stories are the many types of cancer for which the effectiveness of treatments have been limited, often adding only a few months to life. Lung and bronchial cancer, colon and rectal cancer, non- Hodgkin’s lymphoma, pancreatic, liver, and intrahepatic bile duct cancer are only a few of the many that haven’t realized the hoped for cure. Even when patients seemingly have the same type of cancer, there may be marked differences between them. Genetically and hormonally they may be worlds apart, and focused individualized treatment strategies based on such considerations have become common (e.g., Tuxen et al., 2014). This entails linking particular cancers to specific gene mutations that could potentially inform treatment strategies. However, because many mutations can contribute to the appearance of cancers, the connections between specific genes and the use of particular treatment strategies might not be obvious. Furthermore, the recurrence of cancer after initial treatment may involve the presence of still other characteristics, possibly resulting from epigenetic changes or the occurrence of multiple mutations, thus making the cancer, as in the case of non-Hodgkin’s lymphoma, non-responsive to chemotherapy (Pan et al., 2015). Despite these difficulties, there is the belief that advances will be seen as unique molecular genetic features of each cancer are identified (e.g., through the International Cancer Genome Consortium). In the interim, analyses of the individual differences related to psychological processes are necessary so that patients are emotionally and cognitively best equipped to deal with the illness. Cancer Screening The earlier cancer is detected the more likely that it can be treated successfully. Thus, it is essential that individuals are aware of their own bodies and symptoms, and when appropriate that they engage in screening for cancers. However, there have been divergent views concerning the effectiveness of some screening methods, and how often these should be conducted. As indicated in earlier chapters, there have also been concerns about the sensitivity and specificity of these screens, as false alarms or failures to detect cancers are not infrequent. Guidelines for mammograms (an x-ray of the breast) to catch breast cancer early have been revised so that it’s now recommended that routine screening begins at age 50 (instead of 40), is done every two years (instead of yearly), and is discontinued at age 74. This cut-off was based on the assumption that older women might not be able to handle the difficulties of cancer treatment, but if they are in good condition, then mammograms can be done. Reading an x-ray of the breast isn’t as simple as it sounds, and varies with the density of the breast, although newer technologies (e.g., molecular breast imaging; MBI) have been handling this effectively. There are occasions where false positives occur (i.e., the radiologist says that cancer is present when there isn’t actually any cancer), which can promote considerable distress and anxiety, sometimes persisting for several years. False negatives occur (i.e., saying there is no cancer when there actually is) in about 20% of cases (Mandelblatt et al., 2009), and the consequences are predictably deadly. Mammograms have advantages over no screening, but finding cancers early doesn’t necessarily lead to better outcomes, largely depending on the nature of the cancer. New screening strategies are being developed, including biomarkers from a blood test which predicted breast cancer appearance 2–5 years down the road. This test still needs improved sensitivity, but with increasing biomarkers becoming available this problem could be diminished (Bro et al., 2015). The usefulness of screening for prostate cancer, one of the leading causes of cancer death in men, has also been problematic. For years the standard approach was for the physician to assess enlargement of the prostate, or the presence of hard, lumpy, or abnormal areas through a digital rectal exam. As this didn’t allow for evaluation on the side of the prostate that was inaccessible to the doctor’s gloved finger, the prostate- specific antigen (PSA) test was developed, wherein the presence of this protein released from the prostate into the bloodstream was indicative of prostate cancer being present (Catalona et al., 1994). Although it had been widely used for more than two decades, elevated PSA levels were also associated with inflammation of the prostate (prostatitis) and enlargement of the prostate (benign prostatic hyperplasia), neither of which is predictive of cancer (Velonas et al., 2013). As a result, in many instances further invasive procedures were unnecessarily adopted, which often caused considerable distress. Proponents of PSA testing point out that we can’t afford not to do this testing given that the incidence of prostate cancer has been increasing, but this is not surprising as more cancers are being detected simply because more men are tested. It has also been suggested that the survival rate of men has increased with early testing, but it could equally be due to better treatment methods having become available. The fact is that while some prostate tumors are aggressive and lead to death relatively quickly, most grow slowly. Currently, the United States Preventive Services Task Force (USPSTF, 2012) and the Canadian Task Force on Preventive Health Care recommend against PSA testing as the harm it can create exceeds the possible good. Screening for other forms of cancer, such as colorectal cancer, should also be conducted among individuals over 50 years of  age, especially given the frequency of this type of cancer. According to the Centers for Disease Control, the frequency of people being screened for colorectal cancer through colonoscopy is still low, and those with mental health or physical disabilities receive still less attention in this regard (Ouellette-Kuntz et al., 2015). The procedure is intrusive, and it’s understandable that people are uncomfortable with having tubes travel around their intestine looking for abnormalities. However, the procedure is not painful and more often than not intravenous valium injection has the patient tripping slightly. Admittedly, the procedure necessary to void the bowel the day before a colonoscopy is no picnic, but things should be OK if individuals stay home with a clear path to the washroom. Typically, screening methods have focused on identifying the possibility of a type of cancer being present and following this up with further tests to establish whether it was actually malignant and what specific type of malignancy it was. Another potentially useful approach has emerged in which the full population of antibodies present in an individual’s blood is profiled, and based on this ‘immunosignature’ the presence of particular diseases can be determined with a high degree of accuracy (Stafford et al., 2014). Treatment Methods The amount of research concerning cancer treatments is staggering. Some of the research has focused on improvements of earlier treatments that are known to kill cancer cells, whereas others have focused on developing new approaches. These have ranged from immunotherapeutic and vaccine-based methods, attempts to use viruses (such as polio virus) to destroy some types of cancer, or offering a Trojan horse in which tumor cells take up nanoparticles that eventually cause their death. Still other methods have focused on finding weak spots on cancer cells that might make them more vulnerable to destruction. In this section we’ll consider some of the common methods currently used to treat cancers, and point to a few recent approaches being adopted. Chemotherapy Chemotherapy has long been a primary treatment method to deal with many cancers. These agents are effective because they influence the machinery responsible for cell division (Malhotra & Perry, 2003), and thus fast- growing types of tumor (e.g., acute myelogenous leukemia and aggressive lymphomas) are more likely to be altered by chemotherapy than relatively slow-growing cancers or slower dividing, non-cancerous cells. Typically, induction chemotherapy begins with the intent of achieving remission. This entails a combination chemotherapy in which a cocktail of several agents is administered, depending on the specific type of cancer being dealt with. Because each of the agents in this cocktail is used at a relatively moderate dosage, drug toxicity and the chances of resistance developing are diminished. Should a good response be achieved, with patients developing remission, the same chemotherapy may be continued (consolidation chemotherapy) in an effort to prolong the overall disease-free time and thus enhance survival. In other instances, intensification chemotherapy may be used to this same end, but using drugs different from those that had initially been employed. Too often, however, the treatments fail to produce remission, and the goal of therapy may change to diminishing symptoms or to prolonging life, but knowing that remission will likely not occur the doses are kept low enough to avoid producing toxicity (Airley, 2009). Getting a Boost from ‘Recycled’ Agents Bringing a drug to market can take many years and is typically enormously expensive. Estrogen receptor modulators are a class of drug that acts by blocking estrogen receptors, with Tamoxifen being the poster-drug for this class. However, the effectiveness of such agents may diminish with repeated use, in part because newly formed cancer cells following treatment may not express the estrogen receptors. Occasionally, a drug that has been used for other purposes is found to have a second use, including in cancer treatment. Bazodoxifene, for instance, which was initially used for the treatment of osteoporosis, has positive effects in relation to cancer, and many other compounds have been found to be effective in a variety of other illnesses. When drugs are being ‘recycled’ for a second purpose, this is advantageous as the clinical testing for side effects will already  have been established and perhaps the costs saved by drug companies will be passed on to consumers (maybe). Radiation therapy Another tool in the arsenal to deal with cancers is radiation therapy, which is generally used as a component of a broader treatment regimen, and is often adopted when the cancer is restricted (localized) to a portion of the body. It is used in the hope of eliminating the cancer, but it may be used in a palliative capacity to limit growth of the cancer and extend life. Radiation therapy destroys cancer cells by damaging their DNA (Lawrence et al., 2008), although there are some cancers that are not responsive to radiation treatment (e.g., melanoma and renal cell cancer). Typically, the treatment is applied over days to minimize radiation damage to healthy cells, and to increase the likelihood that cancer cells will be hit during parts of their cell cycle during which DNA damage is most likely to occur (Connell & Hellman, 2009). Radiation treatment may be preceded by neoadjuvant chemotherapy in an effort to shrink the size of the tumor and hence be more manageable by radiation therapy. As well, radiation therapy is often used following chemotherapy or surgery in an effort to diminish cancer recurrence. Because radiation therapy, like chemotherapy, operates by disrupting cell division, it may have some of the same side effects described earlier, ranging from fatigue, nausea, and vomiting to damage and sores on epithelial surfaces of the mouth, throat, and stomach, and may cause marked fluid retention and bloating. As well, the treatment may cause heart problems, bowel damage, and cognitive disturbances, and in infrequent instances radiation treatment itself may produce a secondary cancer (Lawrence et al., 2008). Forms of radiation therapy Several types of radiation therapy are available, and the choice of treatment depends on the type and size of the tumor, its location and proximity to normal tissues that are sensitive to radiation, as well as the distance into the body that the radiation will need to go. Of course, consideration is also given to what other treatments the patient will receive, their age, and their general health. Radiation therapy usually comprises the delivery of photon (e.g., gamma rays) or proton beams to specific sites over multiple sessions. Several beams of radiation are concurrently applied from different angles, and hence the full radiation dosage will only occur at the point at which the beams intersect, and thus the damaging effects can be limited to the site of tumor, although in some cases it is necessary to destroy cells along the margins of the cancer in case malignant cells have infiltrated the area. To achieve this specificity, the radiation procedure is combined with imaging procedures (e.g., three-dimensional conformal radiation therapy). For some procedures, the degree of sophistication is remarkable, as in the case of intensity-modulated radiation therapy, which delivers hundreds of small beams of radiation to maximize specificity and thus limit damage to healthy cells (Taylor & Powell, 2004). As the tumor may change over the course of treatment, variants of this procedure, such as image-guided radiation therapy (IGRT) and tomotherapy, which combine radiation therapy and imaging procedures, are used to hit cancer cells (Noda et al., 2009). When cancers are localized, yet another approach is used that consists of the insertion of radioactive pellets into the tumor area where they will kill off cancerous cells (brachytherapy) (Patel & Arthur, 2006). Immunotherapy A fundamental question in the development of some cancer therapies concerns why our immune system, which is thought to be so powerful, can’t handle cancerous cells. Thus, research efforts have been made to enhance immune functioning, such as by manipulating a newly discovered protein (Lymphocyte Expansion molecule; LEM), which may be effective in providing the energy needed for the massive expansion of T cells that go into battle against cancer cells (Okoye et al., 2015). As we’ve discussed, cancer cells sometimes are able to evade detection, but even when these cancer cells can be identified, there is a fine line between immune activation having beneficial versus harmful effects. For instance, the immune system could promote the course of cancer development by increasing a type of sugar that accumulates in tumor cells (Pearce et al., 2014). Further, in some instances, our own immune cells simply don’t do the right thing. In an effort to prevent excessive immune activity from causing an autoimmune response, regulatory T cells (Treg cells) may secrete cytokines that inhibit the actions of immune cells that could potentially destroy cancer cells. With this framework in mind, increasing research has focused on ways to facilitate the recognition and destruction of cancer cells by our own immune system, without having them ‘behave irrationally’. Vaccines Several vaccines have been created to catch and destroy cancerous cells before they can do much harm. However, vaccines can also be used to promote an elevated immune response targeted at particular antigens. This requires that cancerous cells carry markers on their surface so that these cells can be targeted by a vaccine tailored to precisely match these characteristics on the cells’ surface. The latter approach has seen some success against ‘neoantigens’, in which mutations have occurred in tumors making them different from other cells, and thus they can be recognized and attacked by T cells. Positive outcomes using this approach were achieved in brain cancer models (Bunse et al., 2015) and may go to a Phase I trial. Likewise, there have been promising results in Phase II trials of melanoma treatment (Carreno et al., 2015). A degree of success was also obtained through a vaccine-like treatment for some types of lung cancer that added several months to life, and still better results were obtained when it was combined with other types of anti-cancer agent (Herrera & Ramos, 2014). Other vaccines have been created for cancers and while promising results were obtained, to a considerable degree they have been overshadowed by other immunotherapeutic approaches. Cell-based therapy In addition to vaccines, several other forms of immunotherapy have been used which target cancer cells based on markers present on their surface. One of these approaches, referred to as cell-based therapies, comprises the removal of immune cells from the patient, growing them externally, and then returning them to the patient, whereupon they attack the tumor. One therapy that uses this approach, CAR T-cell therapy, received ‘breakthrough therapy’ designation from the Food and Drug Administration (FDA) in 2014, allowing for expedited development based on indications that it has advantages over existing methods (Park & Brentjens, 2013). Early trials with such treatments yielded remarkably positive outcomes. Among 30 patients (children and adults) with acute lymphoblastic leukemia (ALL) who had not done well with other treatments, a 90% rate of remission was achieved (Maude et al., 2014), sometimes within days or weeks of treatment (Davila et al., 2014). Given that the immune system sometimes turns itself off, an obvious (everything is obvious in retrospect) approach to cancer therapy is to prevent the immune inhibition. For instance, an antigen of T lymphocytes, dubbed CTLA-4, ordinarily resides within T cells, but when it appears on the surface of the cell, it signals immune activation to cease. Accordingly, if one could inhibit the actions of CTLA-4, then cancer treatment might be enhanced. The drug ipilimumab (an antibody for CTLA-4) inhibits the actions of this braking system, thus allowing for T cell activation and limiting the growth of late-stage melanoma (Egen et al., 2002). This treatment was effective in only a modest percentage of people, and could have side effects associated with too much immune functioning. Small trials in which this agent was combined with others that focused on pathways to take the brakes off the immune system engendered still better effects than ipilimumab (Porter et al., 2011), and could also be used in cancers other than melanoma. Monoclonal antibodies Another form of antibody therapy also targets cell surface receptors so that cancer cells can be destroyed. In this instance, antibodies are raised to specific antigens (markers) present on tumor cells, and when administered to patients the tumors can be destroyed (Scott et al., 2012). A related strategy has focused on modification of the brakes of the immune system, which ordinarily keeps immune activation in check, but in doing so also permits tumor cell growth. By engineering antibodies that shut down the proteins that form the brakes, effective treatment of one of the deadliest forms of cancer, melanoma, was observed (e.g., Tarhini et al., 2010), and positive initial results were observed in treating cancers of the lungs, bladder, and kidneys. Despite the remarkable success achieved through immunotherapy, we shouldn’t be lulled into complacency in this battle, nor should we fool ourselves about how good this treatment is. The treatment still only works in a subset of patients for reasons not yet known, and in some instances side effects have been markedly elevated, requiring that treatment be discontinued (Larkin, 2015). It will be essential to find biomarkers that predict who will benefit from immunotherapy and who won’t. Oncolytic Virotherapy Polio virus, the horror that affected so many people until a vaccine was developed, has now been resurrected for use in another way. A modified form of the virus, one that cannot cause the disease, has been used therapeutically in clinical trials in the treatment of solid tumors, such as glioblastoma, a brain tumor that is ordinarily untreatable. The altered polio virus is infused directly into the tumor site, and over the course of the next few months, assuming the right dosage is used and the tumor isn’t too large, it may shrink and perhaps even disappear entirely. This ‘oncolytic virotherapy’ seems to work because the virus directly kills tumor cells and, importantly, the virus activates our own immune system to fight the tumor (Brown et al., 2014). Essentially, following injection of the polio virus into the tumor, our immune system becomes engaged in eradicating the virus and concurrently destroys the tumor. Early data suggest that in addition to its effects on glioblastoma, this method might be effective in treating other forms of soft tissue sarcomas. A similar approach using a modified form of the herpes virus has also shown positive results in the treatment of melanoma (Andtbacka et al., 2015). Trials have now begun (e.g., at the Ottawa Hospital) in which two genetically modified viruses are used to attack cancer cells through somewhat different routes. One of the viruses being used in this trial is an adenovirus that was derived from the common cold, and the second is the Maraba virus, initially isolated from Brazilian sand flies, which has the ability to distinguish between normal cells and cancer cells that are attempting to hide from attack. Hopefully, this one-two punch will do what is hoped for. Too Old to Treat? There is the question concerning at what age should a person stop making efforts to beat cancer or, framed differently, when should oncologists stop trying to cure older people? This is a disease of aging, and so the majority of cancer patients will be more than 65 years of age, and many will be quite a bit older. With increasing life span, and with baby boomers now hitting older age, the issue of treating older people will soon be acute. It had been thought at one time that elderly people couldn’t withstand the hardships associated with cancer therapy, and so treatments were reluctantly administered, if at all. However,  many of the newer treatments are less brutal than they had once been, and with improved life-styles many older patients, even some in their 90s, are sufficiently strong to deal with the treatments. That said, should older people receive the same treatments as those who are younger? Do we even know whether the treatments are equally effective (or ineffective) in both populations, given that older patients have been under- represented in clinical trials (Klepin et al., 2009)? In light of the concerns that may exist about whether older patients should be treated, guidelines have been created to facilitate decisions related to whether the benefits of treatment will outweigh the risks (Hurria et al., 2014). Essentially, the value of treatment for the patient needs to be considered in relation to the physical and psychological costs incurred, and this needs to be discussed in detail with patients and family members. Summary Perspectives regarding the processes involved in cancer development and progression have evolved considerably over the past few decades, and increasingly greater attention has been devoted to cancer prevention, which had long been ignored. In this regard, there has been considerable focus on eliminating chemicals (and providing protection) that are carcinogenic, and this has been matched by efforts to change life-styles that might contribute to cancer appearance. As well, treatments have incorporated teams of health workers to deal with the multiple needs that patients might have, including efforts to maintain positive psychological health. But, have we been winning the ‘war on cancer’? I suppose that depends on whom you ask. Survivors probably think we are, and some physicians think so too, and for some types of cancer this is the case. For other types of cancer, the data haven’t been encouraging. Mutations of our DNA are essential for natural selection and thus in making us what we are, but some mutations are also fundamental in producing cancers. In essence, for us to continue evolving and adapt to changing environments, mutations are necessary, and bad mutations come with the package. It could be argued that we have steadily been winning some battles in the war (e.g., against certain cancers), and will win further as more genetic mutations are identified and appropriate treatments are developed. The treatment strategies used to deal with cancer have indeed seen considerable change. Rather than using chemicals that simply poison cells, somewhat indiscriminately, individualized treatments have evolved to deal with each cancer in a specific manner. Scientists working to treat cancer 50 years ago likely couldn’t have imagined some of the current technologies and medicines, and the notion of individualized medicine based on biological characteristics of each cancer wouldn’t even have been on the radar. To be sure, clinician scientists at that time would similarly have looked back 50 years and thought that their predecessors were fairly crude and naïve in their procedures. If we were to try to predict what medicine and cancer treatments would be like some years from now, we might envision that microbots the size of single cells would be used to target and destroy cancer, or methods would be available to sense the presence of a very small number of tumor cells and attack them through some form of very specific agent. Those of us who were around before computers were present in each home and office, and who preceded the genome being decoded, might be reluctant to make these predictions given that they know that there’s so much that they actually don’t know. Assuming that science moves at the pace that it has (and that global risks haven’t materialized as global damage), it’s likely that people 50 years from now will be wondering about the crude approaches that we used to deal with cancer.