Postgrad Med J: first published as 10.1136/pgmj.41.475.268 on 1 May 1965. Downloaded from POSTGRAD. MED. J. (1965), 41,268 THE CHEMOTHERAPY OF MALIGNANT DISEASE -PRACTICAL AND EXPERIMENTAL CONSIDERATIONS JOHN MATTHIAS, M.D., M.R.C.P., F.F.A., R.C.S. Physician, The Royal Marsden Hospital, London, S.W.3. THE TERM chemotherapy was introduced by positively charged alkyl (CH2) radicles of Ehrlich to describe the specific and effective the agent. treatment of infectious disease by chemical (a) The nitrogen mustards: mustine (HN2 substances. It is currently also applied to the 'nitrogen mustard', mechlorethamine, treatment of malignant disease. Unfortunately mustargen), trimustine (Trillekamin no aspect of tumour metabolism has been HN3), chlorambucil (Leukeran, phenyl discovered which has allowed the development butyric mustard), melphalan (Alkeran, of drugs capable of acting specifically upon the phenyl alanine mustard), uramustine malignant cell, so that cytotoxic drugs also (Uracil mustard), cyclophosphamide affect normal cells to a greater or lesser degree. (Endoxan or Cytoxan), mannomustine The most susceptible or sensitive of the normal (DegranoO). tissues are those with the highest rates of cell (b) The ethylenamines: tretamine (trie- turnover and include the haemopoietic and thanomelamine, triethylene melamine, lympho-reticular tissues, the gastro-intestinal TEM), thiotepa (triethylene thiopho- the the testis and the hair epithelium, ovary, sphoramide), triaziquone (Trenimon).by copyright. follicles. (c) The epoxides: triethyleneglycoldigly- Cancer chemotherapy may be said to encom- cidyl ether (Epodyl). pass all treatments of a chemical nature (d) The sulphonic acid esters: busulphan administered to patients with the purpose of (Myleran), mannitol myleran. restricting tumour growth or destroying tumour 2. The antimetabolites tissue. It is not proposed however in this The antimetabolites are substances of article to consider chemical substances active known chemical composition which closely by virtue of their physical emanations (i.e. resemble known naturally-occurring meta- bolites. Such a substance enters a radioisotopes). particularhttp://pmj.bmj.com/ The introduction of nitrogen mustard into metabolic pathway and interferes with medicine in 1946 as a direct result of chemical- subsequent biosynthetic steps by a process warfare research may be said to have heralded of competitive inhibition. the era of cancer chemotherapy, although the (a) Purine analogues: 6-mercaptopurine inhibitory effect of colchicine on cell mitosis (Puri-nethol), 6-chlorpurine. had been recognised since the latter part of (b) Folic acid antagonists: aminopterin. the nineteenth century. Subsequently many methotrexate (amethopterin), pyrime- thousands of naturally-occurring and laboratory- thamine. on September 26, 2021 by guest. Protected synthesized substances have been examined for (c) Pyrimidine analogues: 5-fluorouracil, anti-tumour potentiality. Of these only a limited 5-fluorodeoxyuridine, 6-azauracil. number have proved effective in clinical (d) Glutamine antagonists: azaserine, practice. Those in common use are listed diazo-oxo-norleucine (DON). below. B. Chemotherapeutic agents with obscure A. Chemotherapeutic agents, the actions of biochemical actions. which are, at least in part, understood. 1. Anti-mitotic substances extracted from 1. Alkylating agents plants: colchicine and its derivative deme- The alkylating agents are synthetic colcine (Colcemid), vinblastine (Velbe), substances of known chemical composition. vincristine (Oncovin). They react avidly with inorganic and 2. Antibiotics or agents synthesized by living organic radicles by a process known as organisms such as fungi and bacteria: alkylation, in which negatively charged actinomycin C (Sanamycin), actinomycin intra-cellular radicles combine with the D, mitomycin C. Postgrad Med J: first published as 10.1136/pgmj.41.475.268 on 1 May 1965. Downloaded from May, 1965 MATTHIAS: Chemotherapy of Malignant Disease 269 3. Miscellaneous cytotoxic chemicals: ure- malignant reticuloses, carcinoma of the ovary, thane, methylhydrazine, sodium vanadate. uterus, prostate and breast, plasma-cell mye- 4. Hormones loma, testicular tumours, melanoma and Chemical compounds with actions epithelioma. It is of interest that tumours similar to those of natural hormones may arising from tissues normally most susceptible be properly regarded as chemotherapeutic to chemotherapeutic agents are among those agents. This is particularly so when they most sensitive to treatment. are used in therapeutic rather than Following a remission, most authorities physiological or replacement dosage. Apart recommend continuing the drug in reduced from the lympholytic action of the corti- dosage as maintenance therapy. It has been costeroids, it is doubtful whether any of shown in acute leukaemia and in Hodgkin's the hormones used in cancer chemotherapy disease (Scott, 1963) that the duration of a affect the malignant cells directly. In the remission may be lengthened in this way. main, tumour cells seem to be inhibited There is no indication that prolonged use of by the withdrawal of certain natural a low dose hastens the appearance of resistance hormones, for example following ovariec- but the long term administration of potentially tomy or orchidectomy. Alternatively, the very toxic drugs may prove unnecessary in production of such hormones may be slowly growing tumours. In these cases it reduced by the suppression of internal would be reasonable to discontinue the drug secretions responsible for their control. So and await events. that the mode of action of many, if not all, There is little doubt that treatment with hormonal chemotherapeutic agents is chemotherapeutic drugs may prolong life. This possibly by means of a 'medical' hypophy- has been amply demonstrated in acute leukaemia sectomy, adrenalectomy, ovariectomy or where life expectancy is short (Haut, Altman, orchidectomy. Cartwright and Wintrobe, 1955 and 1959; (a) Oestrogens: stilboestrol, ethinyloes- Bernard and Boiron, 1962). However, when by copyright. stradiol. the untreated (b) Androgens: testosterone and esters, patient survives three, four or nandrolone (Deca-Durabolin). more years, it is more difficult to prove and the (c) Corticosteroids: prednisolone, pred- usefulness of a particular drug must rest on nisone. other criteria such as its ability to bring about (d) Thyroid hormones: thyroxine, tri- subjective and objective improvement. Where iodothyronine. improvement is marginal or equivocal or when (e) Progesterone: medroxyprogesterone two drugs of similar potential are to be com- ethisterone. pared, carefully conducted clinical trials are (Provera), required. http://pmj.bmj.com/ Hodgkin's disease and other reticuloses General Aspects unsuitable for radiotherapy by virtue of the Chemotherapeutic agents are most commonly degree of dissemination may commonly be used in cancer to treat disseminated disease controlled for considerable periods by alkylating unsuitable for surgery or radiotherapy. agents, of which chlorambucil (Scott, 1963), Radiotherapy remains the most effective means cyclophosphamide (Matthias, Misiewicz and of the volume of a tumour mass and Scott, 1960; Ravdin and reducing Coggins, Eisman, on September 26, 2021 by guest. Protected relieving localised bone pain, nerve pressure 1960), and melphalan are among those most or superior vena caval obstruction. widely used. Possibly the most rapid response Chemotherapeutic drugs may be administered is achieved by intravenous administration .;ystemically or locally. They may be given although oral therapy is usually effective. by mouth or injected into a vein or muscle. Methylhydrazine (Math6, Berumen, Schweis- Alternatively an agent may be instilled into guth, Brule, Schneider, Cattas, Amiel and an artery or a body cavity, may be injected Schwarzenberg, 1963) may be useful when the directly into a tumour mass or applied to its disease is resistant to the alkylating agents and surface. The development of agents which are relapses often respond to vinblastine (Warwick, effective by mouth has greatly simplified the Darte and Brown, 1960; Frost, Goldwein and mianagement of patients, many of whom may Bryan, 1962; Smart, Rochlin, Nahum, Silva and now be treated as out-patients. Wagner, 1964) or vincristine (Bohannon, Miller Substantial but temporary palliation has been and Diamond, 1963; Whitelaw and colleagues, achieved in acute leukaemia in children, chronic 1963). Methylhydrazine therapy tends to cause leukaemias, Hodgkin's disease and other troublesome nausea and vomiting, and the Postgrad Med J: first published as 10.1136/pgmj.41.475.268 on 1 May 1965. Downloaded from 270 POSTGRADUATE MEDICAL JOURNAL May, 1965 administration of vincristine is complicated by Gerhartz and Kortge, 1963; Rivers, Whittington a high incidence of neurotoxicity. Cyclopho- and Patno, 1963; Matthias, 1964b), and sphamide, vinblastine and vincristine possess melphalan (Bergsagel, Sprague, Austin and a relatively high therapeutic ratio as far as Griffith, 1962; Eridani, Carrara and Testero, the marrow is concerned and in particular may 1963; Brook, Bateman and Steinfeld, 1964; be more safely employed in patients with Waldenstrom, 1964; Speed, Galton and Swan, thrombocytopenia. As a rule maintenance 1964). This is possibly explained in part by therapy is indicated in Hodgkin's disease, the fact that either is well tolerated and may particularly as the remissions induced by single be persevered with for considerable