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The incidence and mortality due to the major cancers such as lung, breast, colon-rectum, prostate, and ovary have changed very little over the past 20-30 years, in spite of the introduction of important new treatments and apparent prolongation of survival of patients with these cancers. The new strategies focus on earlier detection and primary prevention of cancer. Three approaches for prevention are receiving increasing prominence as an approach to reducing the incidence of cancer: (1) control of common source environmental carcinogens, (2) modification of personal health behavior believed to increase or decrease the risk of cancer, and (3) identification of specific genotypes that increase the risk of cancer. All of these approaches offer some hope of reducing cancer incidence and morbidity. All will be costly and, therefore, require careful evaluation. It is likely that the changes in personal health behaviors will have the greatest overall impact on cancer incidence. Identification of specific genotypes will be of importance for high risk families. At present, it is unlikely that control of environmental common sources will substantially reduce cancer incidence without better measures of exposure and risk of disease.

Free radicals, intermediates in the tissue damage caused by radiation, are formed, inter alia, in interactions catalyzed by iron, which synergizes with radiation and some cytostatics (anthracyclins) in causing cell damage. Conversely, iron chelators can counteract cell damage. Similarly, antioxidants can slow atherogenesis, caused in part by oxidative stress and free radicals. Cell damage is also prevented by physiological defense systems like superoxide dismutase, against endogenous free radicals formed by granulocytes, monocytes, etc. Iron can thus induce free radicals which cause DNA double strand breaks and oncogene activation. This is suggested by four epidemiological studies suggesting a higher cancer risk in patients with larger iron stores than in those with small iron stores. In addition to its effect on carcinogenesis, iron can also maintain the growth of malignant cells as well as growth of pathogens. Breast cancer cells, for instance, display 5-15 times more transferrin receptors than normal breast tissue. Iron-carrying transferrin is in fact a growth factor. Hyposideremia in patients with cancer or infection is not a paraphenomenon but a functioning defense mechanism ('nutritional immunity'). If this immunity is broken by iron administration, relapses of diseases like tuberculosis, brucellosis, and malaria have been described. While iron-deficiency anemia should of course be diagnosed, treated and if possible prevented, there are good reasons to avoid over-utilization of medicamental iron.

Verapamil (240 mg daily orally) was tested in a phase II trial to restore vincristine sensitivity in 9 patients with myeloma, chronic lymphatic leukemia and immunocytoma. These tumors were selected because treatment response and tumor progression can easily be ascertained with the help of electrophoresis and marrow studies, blood counts and lymph node examination. All patients were clinically refractory to vincristine-cytoxan-prednisolone combinations, to which adriamycin had been added in 2 patients. One patient was refractory to adriamycin, VM 26, and prednisone. In 2/9 patients a side effect-free second response lasting 5-10 months was observed, with a doubtful response in two additional patients. It is suggested that occasional clinical responses can be seen, despite the fact that in vitro the mean verapamil concentration required to affect vincristine efflux from malignant lymphocytes in 5 mumols/1 and the mean in vivo serum concentration only 1 mumole. Hypothetically, the clinical response can be explained by an overlapping in some patients of an unusually high serum concentration with an unusually low verapamil requirement.

No decade has seen as great advances as the 1970's in the understanding of cancer and in treatment results. The discovery of the role of oncogens, of some viruses, carcinogenic chemicals, and life-style in carcinogenesis and the increased cure rates in childhood tumors, leukemias, lymphomas, and breast and testicular carcinomas are some examples. The National Cancer Act must be credited for these advances to an appreciable degree.

Currently, the most probable theory of tumor surveillance is neither the existence of any tumor-specific, antigen-dependent, T-cell-mediated cytotoxic effect that could eliminate spontaneous tumors in man and that could be used for some kind of vaccination against tumors, nor the complete absence of any surveillance or defense systems against tumors. What is probable is the cooperation of a number of antigen-independent, relatively weakly cytotoxic or possibly only cytostatic humoral and cellular effects, including nutritional immunity, tumor necrosis factor, certain cytokines, and the cytotoxic effects mediated by macrophages, NK cells, NK-like cells, and certain stimulated T-cells. One question remaining to be solved is why these antigen-independent effects do not attack normal cells. A number of plausible hypotheses are discussed. The hypothetical surveillance system is modulated both by traditional cancer treatment and by attempts at immunomodulation. Radiotherapy reduced the T-helper cell function for almost a decade, but not those of macrophages or NK cells. T-cell changes have no prognostic implication, supporting, perhaps, the suggestion of a major role for macrophages and NK cells. Cyclic adjuvant chemotherapy reduces the peripheral lymphocyte population and several lymphocyte functions but not NK activity. Most of the parameters were normalized some years following treatment, but NK activity remained elevated and Th/Ts cell ratio was still decreased. This might possibly be taken to support the surveillance role of NK cells. Bestatin increases the frequency of lymphocytes forming rosettes with sheep red blood cells (but not their mitogenic responses), enhances NK activity, and augments the phagocytic capacity of granulocytes and monocytes (but not their cytotoxic activity). Improved survival with Bestatin treatment following chemotherapy has been observed in patients with melanoma Stages 1b and II and in patients with acute nonlymphatic leukemia, where BCG also seems active, although possibly only in patient groups with less than 49% complete remissions.

If Skipper's exponential growth and 'log-kill' hypothesis is replaced by one assuming an S-shaped growth curve and a growth inhibition proportional to the product of the growth fraction and the tumor volume, little growth inhibition can be achieved in minimal tumors. This 'kinetic refractoriness' may explain why minimal residual tumors cannot be eradicated by adjuvant chemotherapy.

So-called complete remission of acute leukemia and other tumors frequently leaves minimal residual disease cells, sometimes causing an inflammatory response and often relapse. Although the remaining cells often have long generation times or may even be in G0 condition, they may form a new tumor mass. This can be explained by cell kinetics alone, or by an escape from immunologic or other control mechanisms, or by a new promoting event. Maintenance chemotherapy beyond the first 6 months seemed only to have an effect where induction chemotherapy was weak and palliative, but not since it has become intensive and sometimes curative: it only increases the relapse incubation time, not the survival. Relapse cells may be refractory to cytostatics previously not given, in part because of alternative metabolic pathways or enzyme induction, in part because of tumor cell progression, and any chemotherapy seems to be able to play a significant role in this progression. The result is a relatively high residual tumor mass and a short duration of rare second remissions. Adjuvant immunotherapy, despite controversies about its results, seems to work in some tumors, but the statistical methods applied and the monitoring have been criticized. The strategy proposed for potentially 'curable' tumors (leukemias, lymphomas, embryomas) with short cell generation times is therefore intensive remission induction aiming at the smallest possible residual disease cell number. It is conceivable that this induction might mean accepting risks comparable to those accepted for transplant patients. Manipulation of the bioimmunological response can be effective even against cells in the G0 phase. New methods are proposed to manage residual disease of solid tumors with long generation times, and only maintenance chemotherapy active on cells with a long generation time is suggested.

Adjuvant chemotherapy. The frequent 6 month complete remission induction chemotherapy is not discussed here. What is under debate at present is the prolonged maintenance or adjuvant chemotherapy, which in comparative trials with 5 year follow-up does not appear to improve survival prognosis in leukemia, myeloma, non-Hodgkin lymphoma or post-menopausal breast cancer. However, it may prolong the duration of the first remission. It is suggested that the sensitivity to chemotherapy might depend on cells being induced into the G2 or M phases by growth growth promotor(s), such as estrogens in breast carcinoma. Their presence before the menopause could explain why this neoplasia in this condition is one of the few tumoral diseases transitorily sensitive to adjuvant chemotherapy. Adjuvant immunotherapy is also under debate. Immunotherapy has been reported to give a significant improvement in remission duration and/or overall survival and/or survival after relapse in several tumors and in several trials. However, for almost every trial reporting a statistically significant effect there is one (or more) which shows no significant effect. Theoretically, immunotherapy has several advantages over chemotherapy. It may be effective in minimal residual disease if tumor cells are in the G0 phase. So-called kinetic refractoriness (see separate chapter in this volume) may not apply to immunotherapy. Finally, tumor cells appear to be more sensitive than normal cells to some cytotoxic mechanisms which form a part of the biological response to tumors.

The lipid-associated sialic acid (LASA) level in serum was increased in 663 out of 794 patients (83.5%) of which 55.1% were CEA negative. There were 16.5% LASA (possibly false) negative, CEA positive patients. There were 24.1% false positives in 116 patients without malignant tumors. In manifest prostatic carcinoma 94.2% of the LASA values but only 36.5% of the prostatic acid phosphatase values were increased. Similarly, in breast and pulmonary carcinoma, LASA was more sensitive than CEA. In 499 patients with minimal residual disease, 203 (41.5%) were LASA-negative, of which 180 were CEA-negative. Out of 180 LASA positive patients, 70 have relapsed, as have 70 out of 219 patients with increases in both LASA and CEA. The sensitivity of LASA (87%) in lymphoma was higher than that of the erythrocyte sedimentation rate (53.3%), of C-reactive protein (51.2%), serum copper (64.7%) and of six other markers.

It is well known that even after maximal surgical and/or cytostatic treatment, and even in patients with an apparently complete remission, what is known as minimal residual disease often remains. Adjuvant chemotherapy given for periods longer than six months after the induction of complete remission does not appear, in comparative trials with a five-year follow-up, to improve the final prognosis either in leukaemia or in solid tumours. It is suggested here that the reason may be that minimal residual tumours may consist of cells in the G-O phase. Breast cancer before the menopause may be an exception, since oestrogens present before, but not during, menopause are promotors. This could explain why premenopausal breast cancer seems to be the only tumour transitorily sensitive to adjuvant chemotherapy. Immunotherapy given during complete remission seems to result in longer remission duration and/or overall survival and/or survival after relapse in some but not in all properly conducted trials. It is well known that large tumour masses are not influenced by immunotherapy. In contrast, it is known that cells in G-O, refractory to chemotherapy, may be sensitive to immunotherapy.

Reduced serum concentrations of nutrients like iron, zinc and folates and of albumin and cholesterol are found, as well as emaciation, both in malnutrition and in cancer. In patients with leukemia, a depletion of intracellular potassium and hypo-potassemia are found in addition. The use of hyperalimentation in cancer was originally based on the concept that too little food is the cause of these disturbances in the nutrition state. However, there is also a disturbed metabolism of nutrients in patients with tumors and inflammatory disease. In the case of folic acid, the disturbed metabolism could not be normalized by hyperalimentation. The more advanced the disease, the more pronounced is the disturbed nutrient metabolism, and this disturbance is related to the macrophage activity. It is not self-evident, therefore, that hyperalimentation can normalize the nutritional state in cancer. Emaciation in cancer patients is not caused exclusively by malnutrition.

Thirty-four patients with cancer (30) or ARC (4) with severe T cell defect or imbalance persisting a long time after completion of any cytostatic treatment were treated by bestatin 30 mg/day 3 days per week during three weeks. The drug has no toxicity of any kind. Reassessment of T cell subsets after completion of bestatin therapy showed a significant improvement of the absolute number of CD4 cells in peripheral blood. CD8 subsets wether initially increased or decreased were modified towards normalisation but the modification reached statistical significance only in the subgroup with initial absolute defect of CD8 cells. CD4/CD8 ratio was significantly increased whether considering all cycles of therapy, or all those given to patients with initially high or normal CD8 subsets. Bestatin appears to have immunomodulating properties which might be useful in cancer patients.

Although every second patient with leukemia or a solid tumor has lymphocytes which can recognize or can be induced to recognize autologous tumor cells, it has been difficult to demonstrate that this recognition is, in man, due to tumor specific antigens. Other immunological abnormalities, such as lineage infidelity or maturation asynchrony, are more likely explanations. Moreover, immunological heterogeneity is pronounced among human tumor cells. For these reasons, antibody independent tumor surveillance is receiving increased attention. It is mediated by cytotoxic macrophages, NK-cells and the so called NK-like, pre-induced cytotoxic T-cells. NK-cells, probably a T-cell subpopulation sharing a marker with macrophages, have a cytotoxic effect mainly on certain cell-lines, but hardly on viable human tumor cells. In contrast, different degrees of pre-stimulation with allogeneic lymphocytes, lectins or interleukin 2 can induce, in human T-cells, both HLA-restricted and non-restricted cytotoxicity against viable human tumor cells. This indication is active even in T-cell populations that are either monoclonal or pre-depleted of NK cells.

Zinc is an trace metal necessary for T cell differentiation and maturation. Forty-two patients, with Aids Related Complex or malignancy in remission and with severe and stable CD4 lymphoid cells cytopenia were submitted to zinc gluconate, 125 mg twice daily orally for three weeks. Reevaluation of T cell subsets one week after the end of zinc intake showed non significant modification of total lymphocyte counts nor of CD4 subsets. CD8 cells however were significantly increased in absolute number in those patients with initially low counts of the cells while they were significantly reduced in those patients with initially normal or high CD8 cells counts. Zinc gluconate in short courses appear to act as a regulator of CD8 lymphoid cells subsets.