MED. THE CHEMOTHERAPY OF MALIGNANT DISEASE · nandrolone (Deca-Durabolin). (c) Corticosteroids: prednisolone, pred-nisone. (d) Thyroid hormones: thyroxine, tri-iodothyronine. (e)

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 byEhrlich to describe the specific and effectivetreatment of infectious disease by chemicalsubstances. It is currently also applied to thetreatment of malignant disease. Unfortunatelyno aspect of tumour metabolism has beendiscovered which has allowed the developmentof drugs capable of acting specifically upon themalignant cell, so that cytotoxic drugs alsoaffect normal cells to a greater or lesser degree.The most susceptible or sensitive of the normaltissues are those with the highest rates of cellturnover and include the haemopoietic andlympho-reticular tissues, the gastro-intestinalepithelium, the ovary, the testis and the hairfollicles.

Cancer chemotherapy may be said to encom-pass all treatments of a chemical natureadministered to patients with the purpose ofrestricting tumour growth or destroying tumourtissue. It is not proposed however in thisarticle to consider chemical substances activeby virtue of their physical emanations (i.e.radioisotopes).The introduction of nitrogen mustard into

medicine in 1946 as a direct result of chemical-warfare research may be said to have heraldedthe era of cancer chemotherapy, although theinhibitory effect of colchicine on cell mitosishad been recognised since the latter part ofthe nineteenth century. Subsequently manythousands of naturally-occurring and laboratory-synthesized substances have been examined foranti-tumour potentiality. Of these only a limitednumber have proved effective in clinicalpractice. Those in common use are listedbelow.

A. Chemotherapeutic agents, the actions ofwhich are, at least in part, understood.

1. Alkylating agentsThe alkylating agents are synthetic

substances of known chemical composition.They react avidly with inorganic andorganic radicles by a process known asalkylation, in which negatively chargedintra-cellular radicles combine with the

positively charged alkyl (CH2) radicles ofthe agent.(a) The nitrogen mustards: mustine (HN2

'nitrogen mustard', mechlorethamine,mustargen), trimustine (TrillekaminHN3), chlorambucil (Leukeran, phenylbutyric mustard), melphalan (Alkeran,phenyl alanine mustard), uramustine(Uracil mustard), cyclophosphamide(Endoxan or Cytoxan), mannomustine(DegranoO).

(b) The ethylenamines: tretamine (trie-thanomelamine, triethylene melamine,TEM), thiotepa (triethylene thiopho-sphoramide), triaziquone (Trenimon).

(c) The epoxides: triethyleneglycoldigly-cidyl ether (Epodyl).

(d) The sulphonic acid esters: busulphan(Myleran), mannitol myleran.

2. The antimetabolitesThe antimetabolites are substances of

known chemical composition which closelyresemble known naturally-occurring meta-bolites. Such a substance enters a particularmetabolic pathway and interferes withsubsequent biosynthetic steps by a processof competitive inhibition.(a) Purine analogues: 6-mercaptopurine

(Puri-nethol), 6-chlorpurine.(b) Folic acid antagonists: aminopterin.

methotrexate (amethopterin), pyrime-thamine.

(c) Pyrimidine analogues: 5-fluorouracil,5-fluorodeoxyuridine, 6-azauracil.

(d) Glutamine antagonists: azaserine,diazo-oxo-norleucine (DON).

B. Chemotherapeutic agents with obscurebiochemical actions.

1. Anti-mitotic substances extracted fromplants: colchicine and its derivative deme-colcine (Colcemid), vinblastine (Velbe),vincristine (Oncovin).

2. Antibiotics or agents synthesized by livingorganisms such as fungi and bacteria:actinomycin C (Sanamycin), actinomycinD, mitomycin C.

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MATTHIAS: Chemotherapy of Malignant Disease

3. Miscellaneous cytotoxic chemicals: ure-thane, methylhydrazine, sodium vanadate.

4. HormonesChemical compounds with actions

similar to those of natural hormones maybe properly regarded as chemotherapeuticagents. This is particularly so when theyare used in therapeutic rather thanphysiological or replacement dosage. Apartfrom the lympholytic action of the corti-costeroids, it is doubtful whether any ofthe hormones used in cancer chemotherapyaffect the malignant cells directly. In themain, tumour cells seem to be inhibitedby the withdrawal of certain naturalhormones, for example following ovariec-tomy or orchidectomy. Alternatively, theproduction of such hormones may bereduced by the suppression of internalsecretions responsible for their control. Sothat the mode of action of many, if not all,hormonal chemotherapeutic agents ispossibly by means of a 'medical' hypophy-sectomy, adrenalectomy, ovariectomy ororchidectomy.(a) Oestrogens: stilboestrol, ethinyloes-

stradiol.(b) Androgens: testosterone and esters,

nandrolone (Deca-Durabolin).(c) Corticosteroids: prednisolone, pred-

nisone.(d) Thyroid hormones: thyroxine, tri-

iodothyronine.(e) Progesterone: medroxyprogesterone

(Provera), ethisterone.

General AspectsChemotherapeutic agents are most commonly

used in cancer to treat disseminated diseaseunsuitable for surgery or radiotherapy.Radiotherapy remains the most effective meansof reducing the volume of a tumour mass andrelieving localised bone pain, nerve pressureor superior vena caval obstruction.Chemotherapeutic drugs may be administered

.;ystemically or locally. They may be givenby mouth or injected into a vein or muscle.Alternatively an agent may be instilled intoan artery or a body cavity, may be injecteddirectly into a tumour mass or applied to itssurface. The development of agents which areeffective by mouth has greatly simplified themianagement of patients, many of whom maynow be treated as out-patients.

Substantial but temporary palliation has beenachieved in acute leukaemia in children, chronicleukaemias, Hodgkin's disease and other

malignant reticuloses, carcinoma of the ovary,uterus, prostate and breast, plasma-cell mye-loma, testicular tumours, melanoma andepithelioma. It is of interest that tumoursarising from tissues normally most susceptibleto chemotherapeutic agents are among thosemost sensitive to treatment.

Following a remission, most authoritiesrecommend continuing the drug in reduceddosage as maintenance therapy. It has beenshown in acute leukaemia and in Hodgkin'sdisease (Scott, 1963) that the duration of aremission may be lengthened in this way.There is no indication that prolonged use ofa low dose hastens the appearance of resistancebut the long term administration of potentiallyvery toxic drugs may prove unnecessary inslowly growing tumours. In these cases itwould be reasonable to discontinue the drugand await events.There is little doubt that treatment with

chemotherapeutic drugs may prolong life. Thishas been amply demonstrated in acute leukaemiawhere life expectancy is short (Haut, Altman,Cartwright and Wintrobe, 1955 and 1959;Bernard and Boiron, 1962). However, whenthe untreated patient survives three, four ormore years, it is more difficult to prove and theusefulness of a particular drug must rest onother criteria such as its ability to bring aboutsubjective and objective improvement. Whereimprovement is marginal or equivocal or whentwo drugs of similar potential are to be com-pared, carefully conducted clinical trials arerequired.Hodgkin's disease and other reticuloses

unsuitable for radiotherapy by virtue of thedegree of dissemination may commonly becontrolled for considerable periods by alkylatingagents, of which chlorambucil (Scott, 1963),cyclophosphamide (Matthias, Misiewicz andScott, 1960; Coggins, Ravdin and Eisman,1960), and melphalan are among those mostwidely used. Possibly the most rapid responseis achieved by intravenous administrationalthough oral therapy is usually effective.

Methylhydrazine (Math6, Berumen, Schweis-guth, Brule, Schneider, Cattas, Amiel andSchwarzenberg, 1963) may be useful when thedisease is resistant to the alkylating agents andrelapses often respond to vinblastine (Warwick,Darte and Brown, 1960; Frost, Goldwein andBryan, 1962; Smart, Rochlin, Nahum, Silva andWagner, 1964) or vincristine (Bohannon, Millerand Diamond, 1963; Whitelaw and colleagues,1963). Methylhydrazine therapy tends to causetroublesome nausea and vomiting, and the

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administration of vincristine is complicated bya high incidence of neurotoxicity. Cyclopho-sphamide, vinblastine and vincristine possessa relatively high therapeutic ratio as far asthe marrow is concerned and in particular maybe more safely employed in patients withthrombocytopenia. As a rule maintenancetherapy is indicated in Hodgkin's disease,particularly as the remissions induced by singlecourses of mustine, methylhydrazine, vinblas-tine and vincristine, are not uncommonly onlyof four to eight weeks duration.Progressive lymphoproliferative disorders such

as lymphosarcoma and chronic lymphaticleukaemia are generally relatively more sensitivethan Hodgkin's disease to the alkylating agentsso that smaller doses should be used initially.Corticosteroids may be used alone or in con-junction with cytotoxic drugs. However, theyare usually less effective in reducing thelymphocyte count and the volume of tumourmasses but are often preferred in the face ofa significant thrombocytopenia because of theireffect in reducing capillary permeability.Nevertheless if the deficiency of platelets isdue to interference with the megakaryocytes inthe marrow by tumour cells, a case may bemade for the cautious use of cytotoxic agents.The frequency of troublesome side effects

due to long-term therapy, such as osteoporosis,vertebral collapse, myopathy, diabetes mellitusand steroid obesity, suggests that corticosteroidsshould not be used too readily in patients witha relatively good outlook.

Corticosteroids are also of value for treatingthe anaemia of cancer. This common comp-lication is in part hiemolytic and the incidenceof both anaemia and undue hamolysis increasesas the disease progresses. Prednisone orprednisolone in therapeutic doses will oftenreduce the rate of fall of, and sometimesincreases, the hemoglobin level. The explana-tion for this effect is almost certainly complexbut in part may be due to a reduction of lossesof red cells from the circulation (Matthias,1964a).There seems little value in using doses of

prednisolone or prednisone larger than 40-60mg. a day in the treatment of malignant disease.Indeed it has been shown that doses in therange of 250 mg. a day in acute leukaemia areassociated with an increased risk of over-whelming infection (Medical Research CouncilWorking Party, 1963).The most successful drugs in plasma-cell

myeloma are cyclophosphamide (Matthias,Misiewicz and Scott, 1960; Algenstaedt,

Gerhartz and Kortge, 1963; Rivers, Whittingtonand Patno, 1963; Matthias, 1964b), andmelphalan (Bergsagel, Sprague, Austin andGriffith, 1962; Eridani, Carrara and Testero,1963; Brook, Bateman and Steinfeld, 1964;Waldenstrom, 1964; Speed, Galton and Swan,1964). This is possibly explained in part bythe fact that either is well tolerated and maybe persevered with for considerable periodsrather than to any other reason. Some 50-6b%of patients will improve objectively and onethird may be returned to gainful occupation.Busulphan induces consistent and worthwhile

remissions in chronic myelocytic leukaemia. Itis more easily controlled and more consistentthan mercaptopurine (Shullenberger, 1961) andshould be continued in maintenance doses.Prednisolone (or prednisone) is the drug ofchoice in acute leukemia. 70-80% of childrenand 10-20% of adults will remit. If a remissionis not achieved, mercaptopurine or methotrexateshould be added and on occasion cyclophos-phamide (Hoogstraten, 1962; Fernbach andcolleagues, 1962) or vincristine (Selawry andHananian, 1963; Whitelaw and colleagues,1963) may be effective. Corticosteroid remis-sions can be extended by the addition ofmercaptopurine in maintenance doses, andZuelzer (1964) has shown that there is someadvantage in ringing the changes at regularintervals between mercaptopurine and metho-trexate. In 1963 Elion and her co-workersintroduced the xanthine oxidase inhibitor,hydroxypyrazole pyrimidine (HPP or allo-purinol). It is not of itself effective in inducingremissions but potentiates the action ofmercaptopurine several fold. HPP inhibits thedegradation of 6-mercaptopurine to 6-thiouricacid.

In general the response of the solid tumoursto cytotoxic drugs is disappointing. Ovariancarcinoma responds with reasonable regularityto alkylating agents and worthwhile responsesoccur from time to time in a number of otherconditions including mammary and lungcarcinomata. Adenocarcinoma of the alimentary system has proved extremely resistant totherapy, although it is claimed that successfulpalliation may be achieved in 20-30% with5-fluorouracil or related compounds (Wilson,1960; Ansfield and Curreri, 1963). 5-fluorouracilis toxic and must be used with particular care.5-fluorodeoxyuridine has a more favourabletherapeutic index but it is expensive and notgenerally available.

Cytotoxic drugs and radiation usuallyproduce additive effects but there is some

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indication that actinomycin D (D'Angio, Farberand Maddock, 1959) and 5-fluorodeoxyuridine(Foye, Willett, Hall and Roth, 1960) maypotentiate the effects of radiotherapy in asynergistic fashion. Such combinations mayprove useful in resistant solid tumours. How-ever, it is doubtful whether tumour cells aresensitised in preference to normal cells.The best results in breast cancer developing

before the menopause or in the subsequent fiveor ten years are achieved by measures whichreduce the output of natural oestrogens suchas ablative surgery and the administration ofandrogens and corticosteroids. When thedisease arises ten or more years after themenopause, oestrogen therapy is usuallypreferred. The controlling factor in the choiceof therapy is the degree of natural oestrogenactivity present at the time. On occasionhormonal therapy may stimulate rather thansuppress tumour growth so that the patientsshould be followed carefully. Recently someseparation of the anabolic and virilisingactivities of androgens has been achieved andit has been found that relatively non-virilisingpreparations may retain their ability to arrestbreast cancer. It is often said that hormonalmeasures are most effective in the control ofmetastases in bone but it should be rememberedthat whereas a relatively minor reduction inthe volume of a bone secondary may beassociated with the relief of pain, a comparableeffect on metastases in soft tissues and organsmay pass unnoticed. Chemotherapeutic agentsare usually advocated for this type of diseaseand some success may be expected fromthiotepa (Moore, 1958; Sears, 1961), metho-trexate (Wright, Cobb, Golomb, Gumport,Lyall and Safadi, 1959) or 5-fluorouracil (Ivy,1962; Dao and Grinberg, 1963) in 15-30% ofpatients.Measures designed to reduce the output of

natural androgens (castration and oestrogentherapy) continue to be the treatment of choicein disseminated carcinoma of the prostate.Recently attempts have been made to enhancethe effectiveness of treatment by deliberatelystimulating the tumour with testosterone priorto the administration of radio phosphorus.It has been known for many years that a smallpercentage of patients with well-differentiatedtumours of the thyroid respond to theadministration of thyroid hormones, thelimiting factor being the general metaboliceffects. (Balme, 1954; Crile, 1957; Thomas,1957). There is hope that the antithyroid andmetabolic effects may eventually be successfully

divorced. This has to some extent already beenachieved in the propionic and acetic acidderivatives of thyroxine and triiodothyronine.Progesterone derivatives have been claimed tobring about objective remissions in one thirdof patients with disseminated carcinoma of thebody of the uterus (Baker, 1961) and also tobe useful on occasion in carcinoma of thekidney.The concept of 'cure' by chemotherapy

Until the advent of radiotherapy, surgeryoffered the only possibility of 'cure' in cancer.Already radiotherapy has replaced surgery inthe treatment 'of some malignant conditions(e.g. basal cell carcinoma). In others it hasproduced comparable results and cases unsuit-able for surgery show increasing numberssurviving five, ten or even twenty years withoutrecurrence after treatment. In particular,conditions previously considered of multifocalorigin and therefore 'incurable', such as thereticuloses, are showing impressive survivalfigures when treated as if they were of unicentricorigin. Large doses of radiation are given tothe site of disease and the adjacent regions oflymphatic drainage are also treated. Usingthis principle Peters and Middlemiss claim a71% five-year survival, a 58% ten-year survivaland 33% twenty-year survival in Hodgkin'sdisease confined clinically to one lymphaticregion at the time of presentation and treatment(Peters, 1950; Peters and Middlemiss, 1958).The Manchester results are equally impressive(Easson and Russell, 1963).Wide dissemination, however, may occur

before local control can be achieved. It islogical therefore to attempt the elimination ofsuch cells even when the disease is localisedclinically and apparently amenable to curativesurgery or radiotherapy. In practice it hasproved difficult to demonstrate that a com-bination of chemotherapy and curative surgery(Curreri, 1962; Higgins and colleagues, 1962;Holden and Dixon, 1962; Longmire, 1962), orradiotherapy improves the patient's chances ofsurvival. However, the published series suggestthat 'adjuvant' chemotherapy (Shapiro andFugmann, 1957) may be of value in particularinstances; for example, the use of thiotepawith radical mastectomy in carcinoma of thebreast (Noer, 1962), thiotepa and surgery inovarian carcinoma (Masterton, 1962), actino-mycin D and radiation in Wilm's tumour(Farber, D'Angio, 1vans and Mitus, 1960;Altman, 1961), and tretamine (TEM) andradiation in retinoblastoma (Reese and



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colleagues, 1958; Hyman, Elsworth and Reese,1962).However, in general it has not been shown

clearly to be of use and in view of the hazardsaccompanying the administration of such agentsit should be considered an experimental pro-cedure and restricted to carefully conductedclinical trials. The injudicious use of chemo-therapeutic agents at the time of surgery mayincrease the morbidity and mortality of theprocedure and there is some suggestion that onoccasion the natural immunological defence ofthe body against the tumour may be impaired.Further, with particular regard to radiotherapy,the effects of the systemic agent on the bonemarrow may severely limit the amount ofradiation that can be given to the tumour.Some forms of malignant disease in animals

may be cured by chemotherapeutic agentsalone. In patients, survival in good healthwithout evidence of recurrence for five yearsor more has been achieved in choriocarcinomaand allied conditions (Hertz and colleagues,1959, 1961, 1963; Bagshaw, 1963). Thesetumours arise from homologous foetal tissueand are almost certainly less securely establishedand more easily influenced than autologoustumours. Large doses of methotrexate arerequired. 20 or 30 mg. are given intra-muscularly on each of five consecutive days.In some resistant cases as many as ten orfifteen courses have been given. Despite acomplete clinical response the gonadotrophinoutput may remain elevated. In some of thesepatients it has fallen to normal after hysterec-tomy and residual tumour has been found inthe resected specimen. The particular sensitivity-of this tumour to chemotherapeutic agents isevidenced by the high percentage of subsequentremissions (40-50%) which can be obtainedby the use of other agents such as actinomycinD, chlorambucil, vinblastine or DON (Hertz,Lipsett and May, 1960; Ross, Stolbach andHertz, 1962). In contradistinction gonado-trophin-producing tumours in the male areusually resistant to treatment.

It has been suggested that the judicious useof currently available drugs may:be able toeliminate malignant cells in other cancers.Experimental work, however, suggests thattumours contain a spectrum of cells of varyingsensitivity and that it becomes progressivelymore difficult to destroy all the neoplastic cells(Hauschka, 1957). There is evidence that thehigher the dose the more effective the treatment(Ferrebee and Thomas, 1960; Skipper, Schabeland Wilcox, 1964) but the systemic use of large

doses of cytotoxic drugs is extremely hazardous,requiring the provision of adequate supportivemeasures such as red cell and platelet trans-fusions, electrolyte replacement and protectionagainst infection by pathogens (reversed-barrier nursing) and commensals. The useful-ness of marrow transplantation is controversial(Mathe, 1960; Kurnick, 1962). It seems thatultimate recovery is little improved evenfollowing the use of autologous marrowalthough the rate of recovery may be accelerated(Sprague, 1960). The administration of testo-sterone may allow larger doses of chemothera-peutic drugs to be given with less than theexpected degree of depression of the peripheralcount (Brodsky, Dennis and Khan, 1964).The volume of tumour present has been

shown to have a considerable effect on the curerates achieved by chemotherapeutic agents inanimals. When the tumours are small and ofrecent origin the greater the chance of cure.In patients the principle may be exploited bythe earlier treatment of a recurrence or metas-tasis and by the excision of tumour masses.Further, the effect of a drug may be greatlymodified by varying the intervals between dosesquite apart from any consideration of the totaldosage employed (Jones, Woodrow, Lessnerand Rane, 1962). For example, in the case ofmitomycin, correct spacing of the dose pro-longs the survival time of animals even whenthe total dosage is reduced.A combination of chemotherapeutic drugs

may be more likely to succeed than a singleagent (Martin, 1960). Some workers are usingas many as five drugs simultaneously in thetreatment of acute leukaemia, and some successhas 'been reported with a combination ofchlorambucil, actinomycin D and methotrexatein resistant testicular (Li, Whitmore, Golbeyand Grabstald, 1960) and ovarian tumours.

Nevertheless, it may be possible by suchmeasures to reduce the number of malignantcells to such a degree that there may be achance of eliminating residual cells by othermeans. Animal experiments have shown thatantitumour antibodies enhance the effectivenessof chemotherapy but little has been achievedto date in patients (Graham and Graham, 1959;Buinaskos, McCredie, Brown and Cole, 1959).However, the circumstances are complex and itmay well be necessary to prepare a specificantiserum for each tumour. Further, theantigenic determinants of a tumour may changeduring the course of the disease.Regional ChemotherapyHigh concentrations of chemotherapeutic

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agents in the region of the tumour may bemore safely achieved by introducing the drugdirectly into the arterial supply. Drugs givenin this way are more likely to be effective thanwhen used systemically so the techniques areto be recommended for inoperable butrelatively localised tumours. Two methods areused. The first is known as infusion, when thedrug is instilled into the arterial supply of thetumour without recirculation. A single injectionmay be given, or alternatively an indwellingcatheter may be introduced and a continuousinfusion or repeated injections given over aperiod of time. (Freckman, 1963; Oettgen,Clifford and Candler, 1963; Sullivan, Miller,Chryssochoos and Watkins, 1962; Sullivan andZurek, 1964). Systemic effects are restrictedby dilution in the general circulation andinactivation of a proportion of the drug duringits passage through the tumour-thus drugswith a short action are favoured. Alternatively,antidotes may be given systemically to inhibitthe general effects, for example, folinic acid maybe given when using methotrexate (Sullivan,Miller and Sykes, 1959; Duff and colleagues,1961; Trussell and Mitford-Barberton, 1961),thymidine with 5-fluorodeoxyuridine (Miller,Sullivan, Young and Burchenal, 1961), andthiosulphate or cysteine when using radio-mimetic drugs. Protection of the body mayalso be attempted by hypothermia.The second method is that of perfusion

(Creech, 1959, a and b). The tumour vasculatureis isolated as completely as possible and thedrug is circulated mechanically in a closedcircuit by means of a pump in association withan oxygenator. When the region can beisolated completely, the tolerance of normaltissues proves the limiting factor to the amountof drug that can be used. However, except withperipherally situated limb lesions, considerableleakage into the general circulation cannot beavoided. The advantages of the perfusiontechniques lie in the relative isolation and thepossibility of some control over the localenvironment. For example, the anti-tumoureffects of some agents may be enhanced byincreasing the temperature, oxygen tension orglucose concentration or by lowering the pH(Krementz, Harlin and Knudsen, 1960).Many ingenious methods have been intro-

duced for the infusion and perfusion of thelimbs, the head and neck including the brain,the liver, the pelvis and the lungs: the mostcommonly employed techniques are the inter-mittent or continuous infusion of cancers ofthe head and neck with methotrexate, 5-

fluorouracil or a short acting alkylating agentsuch as mustine or Epodyl, alone or in com-bination, and the perfusion of malignantmelanoma of the limbs with melphalan. Thedevelopment of micro-pumps which can beattached to the person or implanted sub-cutaneously has allowed the ambulant patientto avoid spending prolonged periods in hospital(Rose and Nelson, 1955; Sullivan and Zurek,1964).Regional chemotherapy is usually a palliative

procedure. It is consistently successful inrelieving pain and obstruction. It may provea valuable means of improving the results ofsurgery and perhaps may eventually becomethe curative treatment of choice for sometumours (for example, peripherally situatedmelanomata, see Stehlin, Smith and Clark,1960).However, the crux of the problem lies in

the development of drugs with a specific actionon malignant tissue. It has already been shownthat it is possible to separate to some degreethe cytotoxic effects of such drugs on tumourand normal tissue. In animals, if the minimumdose which effectively prolongs life (MED) orcures (MCD) is compared with the minimumlethal dose (MLD), the figures for mustine,chlorambucil and melphalan in moles/kg. arerespectively, MCD/MLD, 16/15, 50/174 and50/140 and MED/MLD, 5.2/15, 1.7/174 and19/140 (Jones and colleagues, 1960), showingthe superiority of chlorambucil and melphalanover mustine.

It must be emphasised that to date no patientwith malignant disease may be said to havebeen cured by chemotherapeutic drugs. Thereis, nevertheless, high hope that success willeventually be realised. Already the eliminationof malignant trophoblastic disease may havebeen achieved and regional chemotherapy hasbeen advocatdd as the definitive treatment formalignant melanoma of the extremities.Undoubtedly at the present time, in those

situations in which surgery or radiotherapyoffer a reasonable chance of cure, such treat-ment should be advised. However, it seemslikely that the cure rates of both surgery andradiotherapy may be improved in certaincircumstances by the judicious use of adjuvantchemotherapy designed to destroy undetecteddisseminated disease, to prevent the dissemi-nation of viable malignant cells at operationand to reduce the site of the tumour tofacilitate the technical aspects of operation.Possibly the preoperative administration oftherapeutic drugs will allow the more extensive



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and mutilative forms of surgery to be replacedby lesser procedures without prejudicing thepatient's chances of survival.

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ALTMAN, D. H. (1961): Actinomycin D and Roentgen-ray Therapy in Treatment of Metastatic Wilm'sTumour, Amer. J. Roentgenol., 86, 673.

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BALME, H. W. (1954): Metastatic Carcinoma of theThyroid Successfully Treated with Thyroxine,Lancet, i, 812.

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BUINASKOS, P., MCCREDIE, J. A., BROWN, E. R., andCOLE, W. H. (1959): Expermental Treatment ofTumours with Antibodies, Arch. Surg. (Chicago),79, 432.

COGGINS, P. R., RAVDIN, R. G., and EIsMAN, S. H.(1960): Clinical Evaluation of a New AlkylatingAgent Cytoxan (cyclophosphamide), Cancer, 13,1254.

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CRILE, G. (1957): The Endocrine Dependency ofCertain Thyroid Cancers and the Danger thatHypothyroidism may Stimulate their Growth,Cancer, 10, 1119.

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DUFF, I. K., SULLIVAN, R. D., MILLER, E., ULM,A. H., CLARISON, B. D., and CLIFFoRD, P. (1961):Metabolite Cancer Chemotherapy using ContinuousIntra-arterial Methotrexate with IntermittentIntramuscular Citrovorum Factor, Cancer, 14, 744.

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ELION, G. B., CALLAHAN, S., NATHAN, H., BIEBER, S.,RUNDLES, R. W., and HITCHINGS, G. H. (1963):Potentation by Inhibition of Drug Degradation:6-substituted Purines and Xanthine Oxidase.Biochem. Pharmacol., 12, 85.

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276 POSTGRADUATE MEDICAL JOURNAL May, 1965

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