Introduction

The term "psychological factors" (PFs) refers both to internal characteristics, such as personality, attitude and reactions, as well as to external non-physical factors that affect internal characteristics (e.g. stressful life events, social support). These will be the independent variables. A restriction applies: if a psychological factor is associated with a physical carcinogen, it will not be considered an independent variable, although it may be regarded as a possible confounder. For example, it is claimed that certain traits predispose one to smoking. Those traits will not be of interest insofar as they affect smoking and its carcinogenic consequences, but only insofar as they may affect cancer independently of smoking.

The dependent variables will be cancer incidence and mortality and, for prognosis among cancer patients, disease-free interval and survival time. The known or suspected risk factors for cancer (radiation, genetic attributes, viruses, smoking, chemicals, etc.) will be regarded as possible confounders, as cofactors or as primary etiologic agents, in conjunction with which psychological factors may act.

To deal with this topic, we need to consider the long natural history of malignancies. Incidence of cancer is determined either by clinical diagnosis or at autopsy. In both cases, the malignancy has to grow to the point of detection. If it is a blood or lymphatic cancer, enough cells have to be transformed to be detected, and if it is a solid tumour, it has to grow large enough to be detected by x-ray, palpation, sonogram, visualization, etc.

The first actual mutation of a cell to malignancy, however, has taken place months or years before.1,2 For example, the median time to detection of leukemia incidence after Hiroshima was between six and seven years.3 The estimated median growth time to detection for breast cancer is seven to eleven years, depending on the researchers.1,4 According to Steel,1 in a mix of several cancers with lung heavily represented, the median was about 5.5 years.

In many PF studies, the authors fail to consider whether the psychological factors existed before malignant transformation. In addition, very few mention the possibility that the factor itself may have arisen from the biologic effect of the cancer 5,6 or the patient's knowledge that he or she had the disease.

We also need to consider study design. In case-control studies a group of cancer patients or survivors or patients with recurrence is selected, together with a control group that does not have cancer, has not died or has had no recurrence. The researcher measures some putatively discriminating attribute in both groups to see if they differ in respect to that attribute.

In cohort studies an attribute is measured in all members of the cohort before the outcome of disease, death or a recurrence, and the researcher follows the cohort to determine which members get cancer, survive or suffer recurrences. The proportion who get cancer during the given follow-up period in those with the risk factor (e.g. stressful event) is compared with the proportion who get cancer during this period among those without the risk factor. Cohort studies are generally subject to fewer biases than case-control studies, their findings are usually more trustworthy and they are the design to be preferred in PF studies.

The Variety of Psychological Factors

Stress

Stress in Animals
Although the earliest work on the effect of PFs on cancer dealt mainly with humans, a number of studies soon appeared in which the relationship of stress and cancer in animals was explored. Important early work was done by Riley 7 and Seifter.8 They and others found clear evidence that stress in rodents caused faster growth both of virally induced and transplanted tumours. In addition, survival time was shorter in stressed rodents. Nevertheless, some workers (Newberry and Sengbusch,9 for example) found stress to inhibit tumour development and growth under some conditions. Justice,10 in a thorough review of the topic, presented an extensive list of variables that stimulate and inhibit tumour development. His most important inference, now well confirmed, was that viral tumours in animals were adversely affected by stress and that those induced by chemical carcinogens were favourably influenced by stress.

In view of the role attributed to the immune system in protecting against cancer growth, and possibly initiation, one might be tempted to transfer these findings to humans. Several facts, however, suggest caution.

• Humans, guinea pigs and certain other animals are considerably less sensitive to high corticosteroid levels than the major rodent species used in the laboratory.11 Even among rodents, various strains differ in their sensitivity to glucocorticoids. Thus the major findings of Riley,7 Seifter 8 and others that stress-induced high glucocorticoid levels in rodents led to increased tumour growth might not be duplicated in humans, even if human cortisol levels did rise with stress.
• Humans are outbred, with a variety of responses to many physiologic stimuli; mice and rats used in laboratories were historically inbred to produce cancer-prone strains.
• Tumour transplants or heavy doses of carcinogens introduce strong antigens, that is, stimuli to immune recognition and response, with consequent greater protection against the tumour; spontaneous human tumours take a long time to develop and probably involve limited or even absent immune recognition and response.
• Immunosuppressed animals develop tumours in excess of normal at many sites, each strain being susceptible to concentration of tumours at the site peculiar to that strain-liver, lung and testes, for example; immunosuppressed humans also develop tumours in excess of normal, but most frequently lymphoreticular tumours. The focus of the immunosuppressive stimulus is the immune system itself.
• Many stress experiments in animals involve viral tumours, with associated stimulation of tumour growth. In humans, however, the proportion of viral tumours is small, in the order of 3-4% of all tumours. If one extrapolated directly to humans from animal findings, one would conclude that stress is a depressant of tumour development and growth (as found by Newberry 9 and others in animals), rather than a stimulant to tumour growth as suggested by most psychological studies. For a number of reasons, such a conclusion should not be drawn.

The animal findings, nevertheless, are important; they should, however, form the bases for hypotheses, not conclusions, about humans.

Human Stress
This discussion will report on some case-control studies, but will focus on cohort studies. There are several reasons for giving little emphasis to case-control studies when considering PFs. First, cancer can and does produce physical, psychological and attitudinal changes, mostly negative, that can bias conclusions.12 Second, these changes in patients are known to increase reports of stressful events when compared to reports of controls.13 Third, one can never be sure that the patient group is not made up of a biased sample. Last and perhaps most important, one cannot be sure that the control group is matched to the patient group in regard to variables that might lead to erroneous conclusions.

Early case-control studies reported a greater number of stressful events earlier in life in the cancer group than in the controls.14,15 However, most later case-control studies showed no excess of traumatic events among patients.16,17 Interestingly, Priestman et al.18 reported opposite results-controls reported more stressful events than the group with benign tumours, who in turn experienced more than those with cancer.

The earlier cohort studies found no more cancers among stressed than among unstressed members of cohorts. Keehn et al.,19 for example, found no greater cancer mortality among 9813 soldiers of World War II discharged for psychoneurosis than among 9942 controls over the period January 1946 to December 1969.

Keehn 20 studied cancer mortality among World War II prisoners of war from 1946 through 1975 and in the Korean conflict from 1954 through 1978. No excess cancer mortality was found for either Pacific or European World War II veterans (n = 6023) or for Korean veterans (n = 3959) over their respective controls (n = 5223 and n = 3953). Joffres et al.21 looked at 4581 Japanese men in Hawaii and found no association between stressful events and cancer incidence.

There have been relatively few recent cohort studies. Grossarth-Maticek et al.,22 in a widely cited series of studies, found a relationship between stressful events and later cancer. Their work has been severely criticized 23 and will not be further dealt with here.

Concerning stress and survival or disease-free interval, several case-control studies have been done. Ramirez et al.,24 for example, found an excess of prior traumatic events among women with recurrence of breast cancer. But Funch and Marshall 25 obtained variable results; survival following breast cancer was related to stress for the oldest and youngest patients, but not those in middle age.

Only two cohort studies exploring the relationship between stressful events and survival or disease-free interval could be found. Hislop et al.26 reported no relationship between recent stressful life events and either survival or disease-free interval in 133 breast cancer patients followed up over four years. Barraclough et al.27 also found no relationship between traumatic events and disease-free interval in 204 breast cancer patients followed up over 42 months.

It is quite likely that, on the whole, cancer patients tend to recall more stressful events than non-cancer controls, even though some studies report that they do not.28 Only a few defining studies have been done to show that their reports are not a reflection of actual events experienced. A thorough and intensive review of memory as it is influenced by affect has been written by Blaney,29 one of whose conclusions was that people with negative affect report more negative events than people with average or positive affect. Examples of studies reflecting his conclusions are those of Brett et al.13 and Cohen et al.30

Almost all those who have cancer and know it have negative affect to varying degrees. If this is true of a substantial number, but not all cancer patients, their excessive recall of negative events would still be enough to bias the average recall level of the whole cancer group.

We can summarize the findings on stress as follows.

• Case-control studies on this topic have yielded mixed results, but are subject to bias.
• Almost all cohort studies show no excess stressful events associated with later cancer incidence, mortality or survival.
• People with negative affect report having experienced more stressful events than those with average or positive affect, when the true frequencies are alike.

The last finding explains much if not all of the case-control results. It is also the basis for predicting that in the absence of such bias, there will be no excess of stressful events among the cancer group. The prediction is confirmed by the results of the cohort studies, which are not subject to that particular bias. The conclusion is that it is almost certain stressful events do not occur more often among those who later get cancer, die of it or survive a shorter time than controls.

Bereavement

Some of the earlier case-control studies reported increased cancer incidence among widowed persons. These have been intensively analyzed, as have prospective studies up to 1986, and their problems have been delineated.32

Large cohort studies of bereaved spouses carried out over an extended period have shown no excess cancer deaths when compared with still-married spouses. In the exceptions, the excess lasted from six months to two years. As we know that the development time to diagnosis of most cancers is in the order of as much as 15 years, those findings could not have referred to cancer initiation. A large 1987 Finnish cohort study on 95,647 persons widowed in 1972 showed no excess deaths during the next four years among 7600 cancer cases.33 In another study, in Washington County, Maryland, 4032 white persons widowed between 1963 and 1974 were followed for approximately 12 years and showed no excess cancer deaths.34 A third large cohort study reported a similar lack of excess cancer deaths over 10 years among widowed persons of either sex.32 In a study of 1782 breast cancer patients and 1738 controls, Ewertz 35 found no difference in the death rates of married and widowed patients.

In summary, while some studies have reported short-term excess of cancer following bereavement, the large cohort studies have, in general, not found excess cancer incidence or death over the long term. This conclusion is consistent with the previous one that stress other than bereavement cannot be said to increase later cancer incidence or death.

A few studies (Neale,36 for example) have looked at survival or disease-free interval among widowed persons. The results have been mixed, some finding reduced survival among the widowed and some not. They cannot be applied to the issue of bereavement as a PF, since none of the studies on survival mention time of bereavement in respect to the cancer. Only marital status at the time of diagnosis was considered; the cancer could have been detected one day after bereavement, or 20 years later. We can thus draw no conclusions from marital status studies with regard to bereavement as a PF.

Psychosis, Especially Schizophrenia

The appropriate analysis would be to compare the absolute cancer death rate in a mental patient cohort with the age-equivalent population's absolute cancer death rate. Eight of the studies analyzed by the proportionate mortality method reported enough data that absolute mortality rates could be determined. The newly analyzed data showed either no deficiency of cancer deaths or a slight, though non-significant, excess among the hospitalized samples.37,38 Thus, one can lay to rest the often repeated view that psychotics, especially schizophrenics, have fewer cancer deaths than normal.

Depressed Mood

The first was by Shekelle et al.42 on a cohort of 2018 male workers at an electric plant in Chicago. Those workers whose results on the MMPI (Minnesota Multiphasic Personality Inventory) showed depressed mood, had a cancer death rate 2.3 times the remainder of the cohort over a 17-year period. This 1981 finding stood alone until 1988 and 1989, when a series of further cohort studies appeared. Persky et al.43 followed the Shekelle et al. cohort another three years and observed a substantial decline in the relative risk of cancer deaths, although the overall cancer risk of those with depressed mood was still in excess of that of the remainder of the cohort. However, of four other cohort studies, all with greater cohort size, none showed an excess of cancer deaths among people with depressed mood.

An editorial in the Journal of the American Medical Association concluded: "the combined evidence is consistent with a null or weak relationship, the relative risks being distributed around a value of 1.0 or slightly more. It is clearly not consistent with a strong relationship between depressive symptoms and cancer among major segments of the population."44 Special circumstances in the electric plant where the Shekelle et al. cohort worked could have biased their results: ubiquitous electric fields and widespread distribution of PCB vapours from condenser and transformer manufacture, both of which have been shown to yield neurological symptoms and to stimulate cancer in animals.

Suppression of Emotion, Especially Anger

Temoshok carried out several experiments on melanoma patients and reported that those with a Type C personality (opposite in character to the better known Type A) had a worse survival experience than others.47 The term "Type C" was first used by Morris and Greer in 1980 48 to describe people who were "emotionally contained," especially when confronted by stress. Temoshok has described people with this personality as "cooperative and appeasing, unassertive, patient, unexpressive of negative emotions (particularly anger), and compliant with external authorities."47

A further set of data, however, puts into doubt the whole concept that the basic personality of the cancer patient both before and after diagnosis involves the tendency to suppress emotion, especially anger, whether that tendency arose through heredity or environment. Several such studies point to two conditions.

• Prior strong belief by the patient as to the future benign or malignant biopsy result and consequent effect on emotional suppression
• Attitude change among those diagnosed with cancer upon learning of the outcome, that is, increased emotional suppression and defensiveness

The first condition was shown by Schwarz in a 1993 paper.49 The second condition was shown by Kreitler et al. in a study of patients before and after surgery.50 They examined three groups of women, two possible breast cancer groups and a group with surgery unrelated to cancer. All three groups were tested before and after surgery on anxiety and suppression of emotions. The possible cancer patients were told their status after surgery with regard to malignancy. None of the groups differed in their test results before surgery. After surgery the groups did not differ on the anxiety measure. In the cancer group alone, however, defensiveness and emotional suppression increased significantly.

Kreitler et al. concluded: "Our results suggest that cancer patients probably do not have an intrinsic tendency for suppression, at least not for suppression as defined and assessed in terms of the new conceptualization based on anxiety defensiveness."50 While several studies confirm the findings of Schwarz, those of Kreitler et al. need further confirmation before we can be confident that they are reliable.

Helplessness and Hopelessness

Later studies have yielded varied results. Cassileth et al. measured the helpless-hopeless attitude in two groups. No relationship was found between degree of helplessness-hopelessness and either survival in Group I (a mixed-site group of 100) or disease-free interval in Group II (60 stage II breast cancer patients and 40 intermediate or high-risk melanoma patients). In a later follow-up study three to eight years after diagnosis, Cassileth et al. reported: "No psychosocial factor consistently was associated with the length of survival or remission."51

They did report that people who scored in the middle third of the range of scores on the hopelessness scale experienced longer disease-free intervals than those whose scores were higher or lower. The meaning of this is obscure. It cannot be held to support the Greer and Morris finding, but is consistent with Cassileth et al.'s conclusion. Their tentative hypothesis, that the relationship between survival and hopelessness has an inverted U shape, is certainly possible. A more recent longitudinal study 52 showed no relation between coping style (depressive coping, self-encouragement and distraction, and problem-tackling) and three-year course of disease (metastasis or death).

Social Support

Some of the measures examined are number of social contacts, number of supportive friends, number of support persons, employment status, size of social network, frequency of contact with friends and with relatives, level of need for social support, difference between level of need and level of received support. Studies differ in terms of controlling for other factors affecting survival. Ell et al. say of their study: "Findings showed different factors related to survival for those with breast versus lung or colorectal cancer and for those with localized versus non-localized cancers. Results provide important evidence that social relations and social support may operate differently, depending on cancer site and extent of disease."53

Reynolds and Kaplan 54 studied cancer survival among 154 men and 185 women from an initial cohort of 6848 adults after measuring 11 social support elements: social network index level (four levels, from least connected to most connected), number of contacts, feeling of isolation, marital status, friend/relative contacts, church group membership, other group memberships and church attendance. They controlled for age at diagnosis and stage at diagnosis and found that men who were least connected survived a significantly shorter time than those at other levels, but that women showed no such relationship. None of the other social support variables were related to survival.

Funch and Marshall 25 studied 20 white female breast cancer patients, measuring social support in an interview at diagnosis that covered the five previous years. Social support (except involvement in organizations) was not related to survival after 20 years in the group as a whole. Those in the youngest and oldest groups (15-45 years and 61-90 years) survived longer when their social involvement was high. Those in the peri-menopausal group (46-60 years) showed no difference in survival with regard to social involvement. This demonstrates the variability in these studies; of eight studies on this topic, three showed a clear relationship, four showed mixed or uncertain relationships and one 51 showed no relationship.

Reynolds and Kaplan 54 also studied social support factors as they related to cancer incidence over a 17-year period. The degree of men's social support showed no relationship to their subsequent cancer incidence, but among women, those reporting social isolation had a greater cancer incidence than those not isolated. Those women who reported both the fact and the feeling of social isolation were at especially high risk of later cancers, particularly hormone-related ones.

I am inclined to the position that there is a weak relationship between social support and cancer incidence and survival, and that it probably stems from more basic cancer variables, such as diet, spouse's or own occupation and level of exposure to various carcinogens. I believe that if there is a relationship, the population relative risk is small, perhaps in the order of 1.1 or 1.2. Such a level in the population would produce the mixed results observed in the various samples examined in the studies.

Psychotherapeutic Interventions

At 10-year follow-up, analysis was carried out according to the "intention-to-treat" paradigm, where length of survival of all 86 patients was calculated, even though some had died, moved away or were too ill to enter psychotherapy. Of the 50 randomized to intervention, only 36 entered therapy, and of the 36 randomized to control, only 24 remained. Mean survival from time of randomization was 36.6 months for the intervention patients and 18.9 months for the controls. Divergence in survival did not begin until 20 months after randomization, or 8 months after the end of the group therapy sessions. Currently, Spiegel is well into a study designed to try to replicate these findings.

Fawzy et al.56 carried out a series of just six weeks, rather than a year, of group therapy sessions with melanoma patients. They found a death rate over the five to six years of follow-up of 10 out of 34 for controls and 3 out of 34 for the treatment group. Although this was a significant difference, neither of the death frequencies is particularly large.

In a randomized trial of individual counselling done on 120 end-stage male cancer patients, 62 assigned to counselling and 58 controls, treatment patients improved in quality-of-life measures, but did not differ from controls in survival over a year's time.57

Another study, by Gellert et al.58 on breast cancer patients, examined the effectiveness of Bernie Siegel's group therapy sessions in a follow-up study to an earlier one that showed practically no improved survival for the therapy group when compared to a control group. The earlier result had emerged after correcting for a difference in intervals between diagnosis and treatment of the two groups.

The Gellert et al. study improved the selection of controls by using historical controls matched with the treatment patients on several important variables, and extended the observed survival time by 10 years. Three controls were matched to each of the 34 treatment patients. No difference in survival was observed after matching the duration of antecedent survival of the two groups at the time of entry into therapy. Without that matching, the treatment group showed spuriously longer survival.

In a recent study by Ilnyckyj et al.,59 96 cancer patients were randomly assigned to a treatment group and 31 to a control group, with weekly psychotherapy extending to six months for the treatment group. One treatment group (n = 31) was led by a professional social worker for six months; a second (n = 30) was led for three months, then the group continued to meet for three months without a leader; a third treatment group met for six months without professional leadership. The control group (n = 31) had no treatment other than the normal oncological care that all groups received. Mean survival from time of randomization was 70.7 months in the professionally led group, 62.0 months in the unled groups and 82.4 months in the control group. None of these means differed significantly from any other.

It is clear that the issue of extension of life among cancer patients by psychotherapeutic intervention is unsettled. Too many differences exist in procedures, samples, disease types, stages, experimental designs, approaches to therapy and durations of treatment to allow a clear conclusion.

Some Considerations

The reaction of the body to stress is the proliferation of corticosteroids, which seems to depress immune competence in various degrees. Rats and mice react strongly to their corticosteroid, corticosterone, while humans react considerably less strongly to their hormone, cortisol. This suggests that we should not extrapolate to humans the tumour-stimulating findings regarding stress in animals.

As for other possible cancer-initiating PFs, there is evidence from a Russian study,60 confirmed in an American study,61 that sister-chromatid exchange is increased in mice under stress. Other studies have suggested that increased sister-chromatid exchange might increase cancer susceptibility. One study 62 has shown that, in humans, one of the DNA repair enzymes falls off under stressful conditions. Theoretically, unrepaired mutated DNA (for example, in cancer-inhibiting genes) may increase chances of cancer or reduce it in cancer-stimulating genes. If, however, these events are random, the chances of cancer arising from failure to repair DNA is small, since current theory says that the number of such cancer-prone or cancer-inhibiting genes is a tiny fraction of the total number of genes.

As for prognosis, the theory espoused in most of the recent papers on presumably negatively acting PFs is that immune system activity may be depressed in people with such factors, and hence the cancer tends to grow faster in them. Positively acting PFs would tend to do the opposite. This is an oversimplification. The few studies looking at both immune system activity and survival have reported that even if responsiveness of one or several immune system elements (T4 cells, T8 cells, T4/T8 ratio, natural killer cells, mitogen-responsive mononuclear cells in general) declines, no corresponding reduction in survival time has appeared.56 Among the few intervention studies, to my knowledge, none of the PF measures given to the treatment and control groups of patients have predicted survival differences in the groups.55,56

It has been suggested 4 that the influence of PFs might act as an intrinsic concomitant of the known influence of various carcinogens, selectively causing certain people to get cancer among all those exposed to the risk factor (for example, which smokers get lung cancer?). Such an interaction is very difficult to justify across the large array of PFs, the equally large array of known and unknown carcinogens and the more than 100 types of cancer, each peculiar to the cytologic and hormonal characteristics of particular cancer patients. Such a notion must remain a speculation at present, but should not be discarded.

Thus, in regard to the basic question of possible influence of PFs on cancer, it seems clear that for a few factors there is, at most, very little influence. For other factors the position is uncertain. In my opinion, some people, under some conditions, for some cancer types, may well be affected by PFs, such that cancer is more or less likely to occur in them than in others, or it may progress faster or slower than in other patients. I feel, moreover, that such cases are probably quite rare, and it would be quite impossible, at present, to identify them individually.

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