Theoretical Foundations Of The Treatment Of Tumours

It is incorrect to affirm that ‘cancer is the bankruptcy of medi­cine’, firstly, because the gap between morbidity, and mortality grows wider and wider, and many cancers of the skin, for instance, are almost entirely absent from the list of causes of death in Europe, America and many countries in Asia.

Secondly, one can only speak of ‘bankruptcy’ with the provision that cancer is not just a me­dical problem but also a general biological one with its roots in the principal problems of life on the Earth, in the broad problems of biology, ecology, and sociology. It might be more proper to speak of ‘bankruptcy’ of the narrow medical approach to the pro­blem of cancer, expressed in the collecting of causes of the phe­nomenon without due attention to the nature of the latter. How­ever we take it, cancer is not more ‘bankruptcy’ than the cardio­vascular diseases of man.

To understand the success of the various methods of treating cancer one has to take into account how long the ‘cancer disease’ lasts, once it has it has been diagnosed. But here we come up against major difficulties owing to the great variety of the different loca­lization of cancer, the individuality of the bearer, and so on. Ac­cording to Gummel, expectation of life with cancer of the breast is often 25 to 30 years; periods of six to fourteen years are usual after palliative operations for that cancer, and for those of the uterus and stomach.

The most widely used method of treatment at present is surgery, i.e. the total removal of the tumour by mechanical means. The real results achieved in this respect are expressed in the signifi­cant reduction of total cancer mortality. The results for women are particularly indicative, because surgical approach to cancers of the female reproductive organs is easier, and because there is a predominance in men of cancers that are difficult to operate on.

According to data for the USA, one cancer patient in four was cured surgically at the beginning of the century; at present one pa­tient in three is cured, though, of course, other methods than sur­gery are used as well.

The very possibility of radical excision of tumours indicates the leading significance of local factors in their origin. Even when we take into account data obtained by the statistical sampling, which point to a rela­tive susceptibility of cancer bearer to cancers in general, still complete excision as a rule saves the individuum. In other words, the surgical method of treatment refutes the proposition that a ‘tumour develops as the consequence of disease in the organism as a whole, and during the whole of its development is most intimately linked with the organism’.

A tumour of an organ is not a tumour of the organism, and, even in certain tumours, like chorionepitheliomas, controlled by the organism, complete surgical excision is still quite feasible. Morphological processes in organs, and disturbances of these pro­cesses have no close or obligatory correlative links with the orga­nism as a whole; we do not surely regard persons with maldeveloped organs or parts of the body as defective organisms.

There are reasons to doubt that tumours developing in the sto­mach, liver, and intestine are always tumours of those organs as integral formations. As a rule, they can be resected with the part of the organ affected without any danger either to the organism or to the future of the remaining part of the organ; and that empha­sizes once more the local origin of the process and its limited chara­cter and, consequently, the complete justification of surgical meth­ods of treatment.

But even in cases when the tumour develops, for instance, in intimate association with some hormonal stimuli of general significance, the tumour actively affects the organism, and its surgical removal often proves effective. The fact that almost all attempts to ‘act on the tumour through the organism’ have been unsuccessful can be taken as indirect refutation of the thesis of the intimate connection between tumours and the organism.

Failures of surgical treatment are usually due to late interven­tion or to the difficulty of ensuring complete extirpation of the neoplasm. Failures are often caused by defective post-operaive regeneration; recurrence of the tumour is then associated not with poor surgical technique, but with the fact that the ‘cambial’, nor­mal, tissues that are the initial material for healing of the surgical wound produce the same pathological product, tumour growth. In other words, the rudiment of a tumour develops there again in the course of regeneration as a defective process of form production or as an obligatory precancer.

Treatment with radiant energy is a successful rival of surgery, and has displaced other techniques in treating many forms and localizations of cancer. The essence of the treatment is the direct action of their radiation on the prolifera­ting cells in accordance with the general law of Bergonie and Tribondeau that sensitivity to radiation is directly related to the rep­roductive activity of the tissue. The direct effect of radiation is seen two days after exposure as arrest of mitosis.

Three possible effects of irradiation on growing cells have been described, depending on its intensity, the exposure time, and the state of the cells in relation to the mitotic cycle. They are: (1) direct destruction of the cell; (2) inhibition of developing mitosis, followed by pathological forms and death of the cell; (3) loss of proliferative capacity only in succeeding generations.

Mitosis often resumes on the third or fourth day, but it is already pathological in form and is usually confined to the metaphase. Chromosomes prove to be fragmented; and the spindles take on the form of uncoordinated threads. Such abortive mitoses terminate in dissolution of the chromatin and of the whole cell. Common pictures of necrosis are seen in areas near the site of irradiation; at a distance from the site a large increase of cell protoplasm and an enlargement of the nucleus are noted, and numerous variants of pathological forms of mitosis.

Mitosis generally disappears in seven or eight days, while degenerative changes progress in the protoplasm and nucleus, provoking reactive processes in the form of leukocytic infiltration. Later, at the site of a tumour only loose connective-tissue stroma is noted, in which complexes of dead neoplastic cells are immured, often impregnated with calcium salts. That is followed by intensification of sclerosis and hyalinosis. Some authors see these phenomena as the princi­pal moment, since the fibrous tissues compress the cells of the tu­mour parenchyma.

For all that, histological analysis demonstrates that individual deformed tumour cells may persist even in marked sclerosis and hyalinosis of both the tumour tissues and of the underlying ones. That explains the comparative frequency of recurrence following radiation therapy.

It has been demonstrated from tumours with marked anaplasia that their sensitivity to radiation needs to be distinguished from their curability; the two do not coincide.

The general favourable effect of radiation on the organism of a cancer patient, and indirectly upon the tumour, cannot be denied; but the mechanism and significance of its general action remains obscure. A negative aspect, however, is also often observed in treat­ment by X-rays and radium in the form of progressive aplastic anae­mia and leukopenia as special manifestations of radiation sickness.

Ulcers of the skin with a torpid course, necroses, diffuse scleroses of the internal organs, etc., are also encountered, and neoplasms may develop on their basis. Thus, X-rays and ra­dium radiation can not only be therapeutic agents, but also means of evoking cancer, i.e. carcinogens.

The radiosensitivity of tumours varies widely according to their localization and structure. Not only their general histological dia­gnosis is, therefore, of great significance, but also their detailed characteristics.

Chemotherapy has been widely applied to treat tumours. The aim is to act selectively on the metabolic processes, taking account of their peculiarities, for example the nucleoprotein metabolism in tumour cells. Because of lack of attention to these features thou­sands of chemotherapeutic drugs already tested have proved use­less, which has led many authors to take a sceptical attitude to them. There is talk of drug-resistant populations of cancer cells, of the high adaptability of cancer cells to new envi­ronmental conditions, of the impossibility of creating any general ‘cancerostatic agent’, since each cancer has individual features not only in respect of the organ in which it occurs, but also as re­gards the organism.

There are three lines of research: search for cytotoxic agents, search for chemical antagonists, and hormone therapy. Many pre­parations have been synthesized, but they have not been parti­cularly successful.

Certain, albeit modest, results have been obtained with various derivatives of chlorethylamine, like sarcolysine. When tumours sensitive to sarcolysine are treat­ed with it there is a marked reduction in the size of these neoplasms through necrobiosis of the tumour cells, and activation of the resorptive function of macrophages, leading to scarring.

The ideal of chemotherapy is to act only upon the tumour cells and on all of them as well. But the degree of chemical and morpho­logical anaplasia in the various cells of the tumour is not conside­red, and the real actual possibility of penetrating the tumour mass with the drug is neglected. As these agents do not arrest the supply of nutrients to the tumour, and since chemotherapeutic preparations produce extensive breakdown, the tumour cells that remain viable receive a powerful stimulus to accelerated synthesis, and to accelerated rates of multiplication.

Attempts to substantiate chemotherapy of cancer by analogy with the correspon­ding methods of treating infectious diseases are theoretically not quite justified, since cancer cells are cells of the organism, and micro-organisms are themselves integral organisms.

Attempts have been made to act selectively on cancer cells thro­ugh the administration of radio-active substances, radio-active iodine for instance, in carcinoma of the thyroid gland, working on theoretical concepts of the significance of iodine in the cellular metabolism of that gland. It has appeared, however, that only 2 per cent of the cancers accumulate an amount of radio-active iodine sufficient to have a therapeutic effect. In general, the effect corresponds to the degree of differentiation of the cancer cells; un­differentiated forms accumulate very little of the isotope, and only complete resection of the normally functioning part of the gland ‘compels’ the cancerous part to absorb iodine intensely and to concentrate it in itself.

These observations demonstrate that cancer does not, in prin­ciple, possess ‘uncontrollable’ growth, and that it is possible in practice to affect that growth by means of certain metabolites. But the same experiments indicate that there are considerable difficulties in solving this problem, since an adequate concentra­tion of the appropriate growth inhibitors does not occur in the metabolism of undifferentiated forms, which are the main group of malignant neoplasms. In other words, their sensitivity to isotopes differs according to the degree of differen­tiation of the individual cells of one and the same cancer.

It is also necessary to take into consideration the changing sen­sitivity of cancers to various inhibitors. That is shown by clinical observations on radiotherapy and hormone therapy of certain tu­mours. Even radio-sensitive tumours, as is known, rapidly become radio-resistant, which means, in principle, that a tumour, like any other biological process, is quite stable. That is sometimes occa­sioned by a number of special circumstances outside the tumour, these are seen with particular clarity in observations on hormone therapy of cancer of the breast.

Treatment of this carcinoma in young women by means of testosterone, and in older women with oestrogens, like stilbestrol, often has an amazing effect as regards decline of proliferation in already developed nodes, infiltrates, and metastases; extensive foci disappear almost completely, the patient’s well-being improves, her working capacity is restored, and so on.

Auerbach showed that complexes of cancer cells ‘melt away’, and are replaced by microliths, the stroma of the former tumour acquiring the features of physiological stroma on a background of general revival of the latter in the form of a proliferation of lymphoid and plasma cells and fibroblasts. The fact that this is a general hormonal action, and that it acts on the ‘local’ through the ‘general’, is demonstrated by the change in the appearance of women treated with testosterone: hair begins to grow on the face, the voice deepens, and other signs of virilism are noted.

But even hormonal therapy of cancer of the breast does not lead to complete recovery. That is linked on the one hand with the relative stability of the cancerous process and on the other with the factor of habituation of the organism to any preparation, including hormones.

The absence of any significant success with hormone therapy of other cancers, particularly with treatment by sex hormones, is an indication of the great variety of the general and local precondi­tions determining the development of one tumour or another, the time and the place where it develops, its structure, and its clini­cal course.

It must be borne in mind that hormones can not only have a therapeutic effect but can also have a carcinogenic action, parti­cularly oestrogens. Experimental extirpation of the hypophysis and of the testes has an inhibitory effect on the development of tumours, but the thyrotropic hormone, on the contrary, has an activiting action.