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Combined Therapy in Malignant Disease
797
LEADING ARTICLES
professional reserve from speaking about his patients. Nor is it unreasonable that fear of publicity, natural to most people, is the greater for the doctor because, when things go wrong, he may have to face litigation. The emotions which plague the doctor are passed (perhaps too readily) to the hospital administrator, who is naturally inclined towards protecting his medical staff (whose representative he feels he is) and the good name proper
THE LANCET LONDON
10
OCTOBER
1964
Why Don’t We
Tell ? WHEN and how should medical information be given to the public ? This question has recurred sharply after a series of pseudomonas infections at the Birmingham Eye Hospital had caused six patients to lose the sight of one eye and an operating-theatre to be closed. The problem of informing the public is not new; another recent example-admittedly in rather different formarose in the early stages of the Aberdeen typhoid epidemic when it was felt by Press and public that the possibility of an epidemic had been played down. It seems that rumour of trouble at the Birmingham Eye Hospital began to spread six weeks after the infection was first detected. A Sunday Mercury reporter then telephoned the hospital and put two questions to the hospital secretary. " Is there a virus infection in the hospital ? ": to which the answer was " no ". This was followed by "Have five people died ? " : again the answer was no ".i The secretary may have been relieved that the questions were so framed that he could answer " no in a literally truthful sense. But he can hardly have missed the reporter’s intent. The hospital management committee have endorsed their administrator’s action; but The Birmingham Post has suggested 2 that such grave matters as this infection are of public interest and that the public has a right to be informed. Information is withheld to avoid alarm-so it is said. What is this state of alarm which must be avoided at the cost of not being informed ? Do people run madly in the streets, faint in public places, or pine through fear in privacy ? Alarm must not be allowed to become a plausible excuse with which to escape odium or inconvenience. In reality such events cause concern-and that is a proper reaction which nobody should wish to avoid or suppress. Concern may be increased to alarm when information is concealed or incompletely given, as the public’s uncertainty revealed at the outset of the Aberdeen typhoid epidemic. The motives for withholding information are complex. Possibly the most potent lies in a professional attitude and in inhibition of the doctor. In his hospital practice the consultant does not always do as much as he should to inform patients and relatives about the illness and its treatment; and he is even less inclined towards informing a wider public through the Press. Indeed, he may not "
"
"
"
perceive that there is a comparable duty in the two situations. It is this attitude that may be to blame for the not uncommon failure in relations between the Press and the hospitals, to which we refer again in an annotation this week. The doctor may also be inhibited by a 1. Birmingham Post, Oct. 2. ibid. Sept. 30, 1964.
1, 1964.
of his institution. In fact he is often the last person who should be expected to answer the Press, for he has neither the authority to deal with questions suddenly posed over the telephone for which he may be quite unprepared, nor the time to confer with his medical colleagues. His position is untenable: it might be better if inquiries of this kind were answered from regionalboard headquarters by someone not living cheek by jowl with those working in the hospital itself. Certainly, whoever answers should, if possible, have had the advantage of discussing the situation with all those closely concerned. As WHITE FRANKLIN has urged 3, a very unusual case or event in hospital should be recognised as of legitimate public interest and preparations made for informing the Press. And the conference of doctors and Press organisations, organised by the B.M.A. in 1955, recommended that " all hospitals should ensure that a sufficiently senior and responsible officer of the hospital is at all times available, whether in person or by telephone, to answer Press inquiries ".4 Though public interest in hospital and medical affairs is at times trying and even tiresome to doctors, it is a proper development in a civilised society with a national health service. The intentions of the Press are almost always good; and it is not trite to recall that the Press constitutes a vital insurance of individual liberty. It is very unlikely that a more open attitude from the medical side would be abused: some fear that unnecessary prying would hamper work and inhibit that internal criticism within an institution that is so necessary for maintaining high standards; but we very much doubt it. A solution must be found: it will come more readily when doctors and administrators are prepared to. give the Press the trust-and the information-it deserves.
Combined
Therapy in Malignant Disease
CAN the combined use of radiotherapy and a cytotoxic drug do more for the patient with malignant disease than radiotherapy alone ? Some detailed reviews 5-7 of this subject indicate that the evidence is often conflicting. " Synergism " simply means " working together ", but in medical usage it has often come to stand for " the joint action of agents, so that their combined effect is greater than the algebraic sum of their individual effects ".8 Words like " enhancement ", " potentiation ", and " sensitisation " are also freely used in discussing combined radiation and chemotherapy, but 3. White Franklin, A. Lancet, 1960, i, 1065. 4. See ibid. 1955, ii, 921. 5. Bane, H. N., Conrad, J. T., Tarnowski, G. S. Cancer Res. 1957, 6. Hodnett, E. M. Cancer Chemother. Rep. 1963, 32, 55. 7. Foye, L. A. in Cancer: progress volume, 1963 (edited by R. W. p. 203. London, 1963. 8. Dorland’s Illustrated Medical Dictionary. Philadelphia, 1957.
17, 551. Raven);
798
monitis after doses of radiation that would not normally produce it. More recently, another group,18 using the anti-mitotic same drug in most cases, reported a series of 99 patients, 47 with lung cancer. Toxic reactions were common and, although there were a few excellent responses, the general picture was not very encouraging. VON ESSEN et a1.19 concluded that their controlled study of patients with multiple metastatic tumours " failed to demonstrate a significant alteration in the tumour response by the addition of fluorouracil to X-radiation ". LATOURETTE and LAWTON 10 reported 24 cases of more effective), safer, easier, or more comfortable for advanced malignancy (mostly of the head and neck) the patient, if 5000 rads had been given without any treated by combined radiation and fluorouracil (given drug. If this second method of treatment had been locally by intra-arterial injection). Regression of the adopted, it is unlikely that anybody would say that the lesion was usually more rapid than would have been first 2000 rads of radiation had potentiated the effect of expected after radiation alone, but the response was often the other 3000 rads. Obviously the effect is purely short-lived. They are doubtful whether any true " additive ". But is the action of combined therapy only synergism was demonstrated and they feel that the additive, or is it truly synergistic ? Even if synergism has therapeutic ratio was not significantly altered. Several been convincingly demonstrated in the laboratory, there other workers 21 22 share their view that the response is no benefit to the patient unless there has been a change to combined treatment is often more rapid than to in the differential between the response of normal cells radiation alone, but it is still an open question whether and that of malignant cells (PATERSON’S " therapeutic the benefit is sufficiently lasting to justify the added ratio 9). In radiotherapy, the limit to the dose of radia- discomforts and possible dangers. tion that can safely be given is set-broadly speakingActinomycin D is another cytotoxic drug that has by fear of local tissue damage (when the area being been thought to provide encouraging potentiation of treated is small) or constitutional and hasmopoietic radiation effects.10 13 Laboratory evidence, largely disturbances (when it is large). Combined therapy based on observations in animals, has been conflicting makes no real progress unless it produces the same and hard to assess 24; but some striking clinical results effect on the tumour with less unwanted actions. In have been reported, especially in children with metaother words, if the synergistic effect is as great in stases from Wilms tumour.25 Toxic effects have been normal cells as in malignant cells, nothing of value has frequent and sometimes distressing, but the prolonged been achieved. It is surprising therefore that the control (and possible cure) of such advanced disease discovery of increased radiation reactions in the skin have been thought to justify them. after the administration of actinomycin D,10 for example, Renewed efforts to assess the true worth of combined should have been regarded as a hopeful sign of its therapy by controlled clinical trials deserve careful therapeutic possibilities. study. FLETCHER 21 chose accessible (and thus measur11 Nearly five years ago HALL and his colleagues in able) squamous-cell tumours of the head and neck and San Francisco described " excellent initial responses " he did a double-blind study in which those assessing the in malignant disease of various kinds, including lung results did not know which patients had had fluorouracil The and which had had only placebo injections. cancer, when intravenous 5-fluorouracil was combined with radiotherapy. Others 12-16 used the same combina- importance of controls was illustrated by a group of 5 tion and were encouraged by at least some of their advanced carcinomas of the pharyngeal wall, all of results; but the hopes of these earlier series, mostly which did surprisingly well, healing completely after rather small and without adequate controls, have not treatment. As FLETCHER points out, if all these patients been fully realised. GOLLIN et al." described a had had the drug as well as the radiation, this would have randomised clinical trial in lung cancer of either radio- seemed impressive evidence for combined therapy; but therapy alone or radiation plus fluorouracil. There in fact it was found that 2 of the 5 had had only placebo was some suggestion that the combined therapy injections with their radiotherapy. FRIEDMAN 211 and achieved longer survival, but it might have been due to VON EssEN et ap9 have both used what FRIEDMAN calls chance. Of the 13 patients given the combined therapy, " interior controls "-that is to say, a part of the patient’s 2 died of toxic effects and others had radiation pneu- disease is treated by radiation only and another part by their meaning is not always defined. Suppose a dose of 3000 rads is combined with the latest drug and the effect is found to be consistently and dramatically better than when the same dose of radiation is given without the drug. The uncritical observer might then feel that he has all the evidence he needs to announce that the drug has potentiated the effect of the radiation, or that it possesses the property of increasing the radiosensitivity of tumours, even that a " major breakthrough " has been achieved. It may be so: but it may also be that it would have been just as effective (perhaps
9. 10. 11.
12. 13. 14. 15. 16. 17.
Paterson, R. The Treatment of Malignant Disease by Radiotherapy; p. 14. London, 1963. Liebner, E. J. Amer. J. Roentgenol. 1962, 87, 94. Hall, B. E., Foye, L. V., Roth, M., Willett, F. M., Hales, D. R., Ward, J. H., Butler, H. T., Godfrey, M. H. Lancet, 1960, i, 115. Griffing, J., Sayler, C., Vann, P., Sensenbrenner, L. Cancer Chemother. Rep. 1961, 12, 63. Crews, Q. E. ibid. 1961, 14, 45. Allaire, F. J., Thieme, E. T., Korst, D. R. ibid. p. 59. Helsper, J. T., Sharp, G. S. ibid. 1962, 20, 103. Frank, W., Newcomer, K. L., Cirksena, W. J., Bauer, A. J., Blom, J. ibid. 1962, 22, 55. Gollin, F. F., Ansfield, F. J., Curreri, A. R., Heidelberger, C., Vermund, H. Cancer, 1962, 15, 1209.
18.
Langdon,
E. A.,
Ottoman, R. E., Rochlin, D. B. Radiology, 1963, 81,
1008. 19. 20. 21.
22. 23. 24. 25. 26.
Essen, C. F., Kligerman, M. M., Calabresi, P. ibid. p. 1018. Latourette, H. B., Lawton, R. L. J. Amer. med. Ass. 1963, 186, 1057. Fletcher, G. H., Suit, H. D., Howe, C. D., Samuels, M., Jesse, R. H., Jr., Villareal, R. U. Cancer, 1963, 16, 355. Malherbe, E., Sealy, R., Helman, P., Anderson, J. Clin. Radiol. 1963, 14, 240. D’Angio, G. J. Amer. J. Roentgenol. 1962, 87, 106. Schoeniger, E. L., Salerno, P. R., Friedell, H. L. Radiat. Res. 1961, 14, 499. Farber, S., D’Angio, G. J., Evans, A., Mitus, A. Ann. N.Y. Acad. Sci. 1960, 89, 421. Friedman, M., Daly, J. F. Amer. J. Roentgenol. 1963, 90, 246.
von
799
therapy. Lesions that were clinically or have to be done before the innumerable combinations radiologically measurable were chosen and the results and dosage schedules can be properly assessed. Meancompared. The only objection to this method is that it is while, those working on this important subject must by no means unknown in cancer therapy for the same keep a close eye on toxic effects. It is true that these are determined almost as much by the dosage level selected treatment to produce different results in different areas. FRIEDMAN, using mainly oral methotrexate with as by the drug used, but they are common and can radiotherapy, makes a number of interesting observa- be very difficult to predict. Caution is particularly tions. Usually he waited until he saw how the tumour necessary when renal or hepatic function is poor, when the patient is debilitated, or when bone-marrow function was responding to the start of chemotherapy before of his cases has radiation. About already been impaired by earlier treatment. In 10% of squamousadding cell carcinoma of the head and neck regressed dramatically one randomised trial,33 patients on the combined before radiation was begun, but histological evidence of therapy had more infections than those receiving radia" focal chemoresistance " was seen in some, and tion alone, and they also showed a greater tendency to FRIEDMAN feels that this .accounts for those conditions lose weight. Such effects as nausea, vomiting, diarrhoea, which respond quickly, but recur within a month. stomatitis, and alopecia can greatly increase a patient’s In the management of inoperable lung cancer, intra- mental and physical suffering, and they must give cause venous nitrogen mustard or other chemotherapy is for great concern, unless there is some very useful sometimes given in general medical wards with the idea clinical benefit to compensate for them. Modern radioof starting treatment before the patient goes to a radio- therapy, provided the radiotherapist exercises good therapy centre. This policy may sometimes provide clinical judgment as well as technical care and skill, can useful immediate relief-for example, in superior vena quite often be a remarkably easy treatment for the caval obstruction-but it may also cause the white- patient, compared with what happened some years ago. cell count to fall more than usual during the sub- It would be a great pity if the over-enthusiastic and sequent radiotherapy; and it must be remembered that unselective use of combined therapy were to revive old CHALMERS,27 for example, reporting a large controlled fears of the treatment being worse than the disease. trial by four cooperating hospitals, found that the addition of nitrogen mustard to radiotherapy appeared Recurrent Cerebral Ischæmia to increase toxicity, without improving survival, and As long ago as 1914 HUNT 34 remarked that " attacks without " contributing enough positive effects to of threatened hemiplegia and cerebral intermittent warrant the extra labour and toxicity ". claudication are some of the vascular symptoms which In retinoblastoma, the rare malignant eye tumour of should suggest the possibility of carotid obstruction ". childhood, postoperative or bilateral cases seem to be With this quotation, MARSHALL 35 introduces a valuable responding better to combined therapy than they used survey of the natural history of transient ischaemic to do to radiation alone. REESE et who have treated combined
-
a1.,28
numbers of these children with X-rays and tretamine, have recorded remarkable 90% " curerates ". STALLARD 29 has used radiation and cyclophosphamide. In this condition, apart from varying survival-rates, there may be differences in the proportion of children who retain useful vision; and here again combined therapy may score. But a 72% ten-year survival-rate has been reported in 79 cases treated by radiotherapy alone,3O and the superiority of the combined method cannot be said to be completely established. Chlorambucil 31 and thiotepa 32 have been effectively used with radiation in the treatment of disseminated malignant disease of the ovary. Like every other drug we have mentioned, these two may depress the bone-marrow and therefore must be watched with special care when they are given with radiation; but they are much less likely to produce other side-effects than many of the newer agents which have received more attention. In all these conditions it seems that the individual response to combined therapy is even more variable than it is to radiotherapy alone, and much more work will
large
27. Chalmers, 28.
29. 30. 31. 32.
cerebrovascular attacks. He recalls that FISHER 36 37 emphasised that fleeting paralysis, paraesthesiae, and dysphasia could be prodromal episodes in patients with carotid-artery disease, but these premonitory symptoms received little attention at first. Similarly, although KuBiK and ADAMs,38 in 1946, described in detail the syndrome of occlusion of the basilar artery, it was not until some years later that the occurrence of repeated ischxmic episodes involving the vertebrobasilar territory was widely recognised and accepted. DENNY-BROWN 39 suggested that episodic insufficiency in the circle of Willis is responsible for such ischxmic attacks. The causes of episodes of this type have been variously held to include falls in systemic blood-pressure, polycythxmia, and intermittent compression of the vertebral artery in the intervertebral canal resulting from spondylosis; but the view which now holds favour is that most of them are due to recurrent inicroembolism.40 In many such cases the emboli arise from areas of mural
thrombosis forming on an atheromatous plaque in the intima of one of the large vessels-often the carotid or vertebral arteries themselves. Such emboli have been 33.
T. C. Cancer Chemother.
Rep. 1962, 16, 463. Reese, A. B., Tapley, N. du V., Forrest, A. W. Arch. Ophthal. Chicago, 1958, 60, 897. Stallard, H. B. Trans. Ophthal. Soc. U.K. 1962, 82, 573. Halnan, K. E. Clin. Radiol. 1962, 13, 19. Miller, S. P., Brenner, S. M. Cancer Chemother. Rep. 1962, 16, 455. Kottmeier, H. L. in Carcinoma of the Uterine Cervix, Endometrium, and Ovary; p. 285. Chicago, 1962.
34. 35. 36. 37. 38. 39. 40.
Hosley, H. F., Marangoudakis, S., Ross, C. A., Murphy, W. T., Holland, J. F. Cancer Chemother. Rep. 1962, 16, 467. Hunt, J. R. Amer. J. med. Sci. 1914, 147, 704. Marshall, J. Quart. J. Med. 1964, 33, 309. Fisher, C. M. Arch. Neurol. Psychiat. 1951, 65, 346. Fisher, C. M. ibid. 1954, 72, 187. Kubik, C. S., Adams, R. D. Brain, 1946, 69, 73. Denny-Brown, D. Med. Clin. N. Amer. 1951, 35, 1457. Fisher, C. M. Neurology, Minneap. 1959, 9, 333.
LEADING ARTICLES
professional reserve from speaking about his patients. Nor is it unreasonable that fear of publicity, natural to most people, is the greater for the doctor because, when things go wrong, he may have to face litigation. The emotions which plague the doctor are passed (perhaps too readily) to the hospital administrator, who is naturally inclined towards protecting his medical staff (whose representative he feels he is) and the good name proper
THE LANCET LONDON
10
OCTOBER
1964
Why Don’t We
Tell ? WHEN and how should medical information be given to the public ? This question has recurred sharply after a series of pseudomonas infections at the Birmingham Eye Hospital had caused six patients to lose the sight of one eye and an operating-theatre to be closed. The problem of informing the public is not new; another recent example-admittedly in rather different formarose in the early stages of the Aberdeen typhoid epidemic when it was felt by Press and public that the possibility of an epidemic had been played down. It seems that rumour of trouble at the Birmingham Eye Hospital began to spread six weeks after the infection was first detected. A Sunday Mercury reporter then telephoned the hospital and put two questions to the hospital secretary. " Is there a virus infection in the hospital ? ": to which the answer was " no ". This was followed by "Have five people died ? " : again the answer was no ".i The secretary may have been relieved that the questions were so framed that he could answer " no in a literally truthful sense. But he can hardly have missed the reporter’s intent. The hospital management committee have endorsed their administrator’s action; but The Birmingham Post has suggested 2 that such grave matters as this infection are of public interest and that the public has a right to be informed. Information is withheld to avoid alarm-so it is said. What is this state of alarm which must be avoided at the cost of not being informed ? Do people run madly in the streets, faint in public places, or pine through fear in privacy ? Alarm must not be allowed to become a plausible excuse with which to escape odium or inconvenience. In reality such events cause concern-and that is a proper reaction which nobody should wish to avoid or suppress. Concern may be increased to alarm when information is concealed or incompletely given, as the public’s uncertainty revealed at the outset of the Aberdeen typhoid epidemic. The motives for withholding information are complex. Possibly the most potent lies in a professional attitude and in inhibition of the doctor. In his hospital practice the consultant does not always do as much as he should to inform patients and relatives about the illness and its treatment; and he is even less inclined towards informing a wider public through the Press. Indeed, he may not "
"
"
"
perceive that there is a comparable duty in the two situations. It is this attitude that may be to blame for the not uncommon failure in relations between the Press and the hospitals, to which we refer again in an annotation this week. The doctor may also be inhibited by a 1. Birmingham Post, Oct. 2. ibid. Sept. 30, 1964.
1, 1964.
of his institution. In fact he is often the last person who should be expected to answer the Press, for he has neither the authority to deal with questions suddenly posed over the telephone for which he may be quite unprepared, nor the time to confer with his medical colleagues. His position is untenable: it might be better if inquiries of this kind were answered from regionalboard headquarters by someone not living cheek by jowl with those working in the hospital itself. Certainly, whoever answers should, if possible, have had the advantage of discussing the situation with all those closely concerned. As WHITE FRANKLIN has urged 3, a very unusual case or event in hospital should be recognised as of legitimate public interest and preparations made for informing the Press. And the conference of doctors and Press organisations, organised by the B.M.A. in 1955, recommended that " all hospitals should ensure that a sufficiently senior and responsible officer of the hospital is at all times available, whether in person or by telephone, to answer Press inquiries ".4 Though public interest in hospital and medical affairs is at times trying and even tiresome to doctors, it is a proper development in a civilised society with a national health service. The intentions of the Press are almost always good; and it is not trite to recall that the Press constitutes a vital insurance of individual liberty. It is very unlikely that a more open attitude from the medical side would be abused: some fear that unnecessary prying would hamper work and inhibit that internal criticism within an institution that is so necessary for maintaining high standards; but we very much doubt it. A solution must be found: it will come more readily when doctors and administrators are prepared to. give the Press the trust-and the information-it deserves.
Combined
Therapy in Malignant Disease
CAN the combined use of radiotherapy and a cytotoxic drug do more for the patient with malignant disease than radiotherapy alone ? Some detailed reviews 5-7 of this subject indicate that the evidence is often conflicting. " Synergism " simply means " working together ", but in medical usage it has often come to stand for " the joint action of agents, so that their combined effect is greater than the algebraic sum of their individual effects ".8 Words like " enhancement ", " potentiation ", and " sensitisation " are also freely used in discussing combined radiation and chemotherapy, but 3. White Franklin, A. Lancet, 1960, i, 1065. 4. See ibid. 1955, ii, 921. 5. Bane, H. N., Conrad, J. T., Tarnowski, G. S. Cancer Res. 1957, 6. Hodnett, E. M. Cancer Chemother. Rep. 1963, 32, 55. 7. Foye, L. A. in Cancer: progress volume, 1963 (edited by R. W. p. 203. London, 1963. 8. Dorland’s Illustrated Medical Dictionary. Philadelphia, 1957.
17, 551. Raven);
798
monitis after doses of radiation that would not normally produce it. More recently, another group,18 using the anti-mitotic same drug in most cases, reported a series of 99 patients, 47 with lung cancer. Toxic reactions were common and, although there were a few excellent responses, the general picture was not very encouraging. VON ESSEN et a1.19 concluded that their controlled study of patients with multiple metastatic tumours " failed to demonstrate a significant alteration in the tumour response by the addition of fluorouracil to X-radiation ". LATOURETTE and LAWTON 10 reported 24 cases of more effective), safer, easier, or more comfortable for advanced malignancy (mostly of the head and neck) the patient, if 5000 rads had been given without any treated by combined radiation and fluorouracil (given drug. If this second method of treatment had been locally by intra-arterial injection). Regression of the adopted, it is unlikely that anybody would say that the lesion was usually more rapid than would have been first 2000 rads of radiation had potentiated the effect of expected after radiation alone, but the response was often the other 3000 rads. Obviously the effect is purely short-lived. They are doubtful whether any true " additive ". But is the action of combined therapy only synergism was demonstrated and they feel that the additive, or is it truly synergistic ? Even if synergism has therapeutic ratio was not significantly altered. Several been convincingly demonstrated in the laboratory, there other workers 21 22 share their view that the response is no benefit to the patient unless there has been a change to combined treatment is often more rapid than to in the differential between the response of normal cells radiation alone, but it is still an open question whether and that of malignant cells (PATERSON’S " therapeutic the benefit is sufficiently lasting to justify the added ratio 9). In radiotherapy, the limit to the dose of radia- discomforts and possible dangers. tion that can safely be given is set-broadly speakingActinomycin D is another cytotoxic drug that has by fear of local tissue damage (when the area being been thought to provide encouraging potentiation of treated is small) or constitutional and hasmopoietic radiation effects.10 13 Laboratory evidence, largely disturbances (when it is large). Combined therapy based on observations in animals, has been conflicting makes no real progress unless it produces the same and hard to assess 24; but some striking clinical results effect on the tumour with less unwanted actions. In have been reported, especially in children with metaother words, if the synergistic effect is as great in stases from Wilms tumour.25 Toxic effects have been normal cells as in malignant cells, nothing of value has frequent and sometimes distressing, but the prolonged been achieved. It is surprising therefore that the control (and possible cure) of such advanced disease discovery of increased radiation reactions in the skin have been thought to justify them. after the administration of actinomycin D,10 for example, Renewed efforts to assess the true worth of combined should have been regarded as a hopeful sign of its therapy by controlled clinical trials deserve careful therapeutic possibilities. study. FLETCHER 21 chose accessible (and thus measur11 Nearly five years ago HALL and his colleagues in able) squamous-cell tumours of the head and neck and San Francisco described " excellent initial responses " he did a double-blind study in which those assessing the in malignant disease of various kinds, including lung results did not know which patients had had fluorouracil The and which had had only placebo injections. cancer, when intravenous 5-fluorouracil was combined with radiotherapy. Others 12-16 used the same combina- importance of controls was illustrated by a group of 5 tion and were encouraged by at least some of their advanced carcinomas of the pharyngeal wall, all of results; but the hopes of these earlier series, mostly which did surprisingly well, healing completely after rather small and without adequate controls, have not treatment. As FLETCHER points out, if all these patients been fully realised. GOLLIN et al." described a had had the drug as well as the radiation, this would have randomised clinical trial in lung cancer of either radio- seemed impressive evidence for combined therapy; but therapy alone or radiation plus fluorouracil. There in fact it was found that 2 of the 5 had had only placebo was some suggestion that the combined therapy injections with their radiotherapy. FRIEDMAN 211 and achieved longer survival, but it might have been due to VON EssEN et ap9 have both used what FRIEDMAN calls chance. Of the 13 patients given the combined therapy, " interior controls "-that is to say, a part of the patient’s 2 died of toxic effects and others had radiation pneu- disease is treated by radiation only and another part by their meaning is not always defined. Suppose a dose of 3000 rads is combined with the latest drug and the effect is found to be consistently and dramatically better than when the same dose of radiation is given without the drug. The uncritical observer might then feel that he has all the evidence he needs to announce that the drug has potentiated the effect of the radiation, or that it possesses the property of increasing the radiosensitivity of tumours, even that a " major breakthrough " has been achieved. It may be so: but it may also be that it would have been just as effective (perhaps
9. 10. 11.
12. 13. 14. 15. 16. 17.
Paterson, R. The Treatment of Malignant Disease by Radiotherapy; p. 14. London, 1963. Liebner, E. J. Amer. J. Roentgenol. 1962, 87, 94. Hall, B. E., Foye, L. V., Roth, M., Willett, F. M., Hales, D. R., Ward, J. H., Butler, H. T., Godfrey, M. H. Lancet, 1960, i, 115. Griffing, J., Sayler, C., Vann, P., Sensenbrenner, L. Cancer Chemother. Rep. 1961, 12, 63. Crews, Q. E. ibid. 1961, 14, 45. Allaire, F. J., Thieme, E. T., Korst, D. R. ibid. p. 59. Helsper, J. T., Sharp, G. S. ibid. 1962, 20, 103. Frank, W., Newcomer, K. L., Cirksena, W. J., Bauer, A. J., Blom, J. ibid. 1962, 22, 55. Gollin, F. F., Ansfield, F. J., Curreri, A. R., Heidelberger, C., Vermund, H. Cancer, 1962, 15, 1209.
18.
Langdon,
E. A.,
Ottoman, R. E., Rochlin, D. B. Radiology, 1963, 81,
1008. 19. 20. 21.
22. 23. 24. 25. 26.
Essen, C. F., Kligerman, M. M., Calabresi, P. ibid. p. 1018. Latourette, H. B., Lawton, R. L. J. Amer. med. Ass. 1963, 186, 1057. Fletcher, G. H., Suit, H. D., Howe, C. D., Samuels, M., Jesse, R. H., Jr., Villareal, R. U. Cancer, 1963, 16, 355. Malherbe, E., Sealy, R., Helman, P., Anderson, J. Clin. Radiol. 1963, 14, 240. D’Angio, G. J. Amer. J. Roentgenol. 1962, 87, 106. Schoeniger, E. L., Salerno, P. R., Friedell, H. L. Radiat. Res. 1961, 14, 499. Farber, S., D’Angio, G. J., Evans, A., Mitus, A. Ann. N.Y. Acad. Sci. 1960, 89, 421. Friedman, M., Daly, J. F. Amer. J. Roentgenol. 1963, 90, 246.
von
799
therapy. Lesions that were clinically or have to be done before the innumerable combinations radiologically measurable were chosen and the results and dosage schedules can be properly assessed. Meancompared. The only objection to this method is that it is while, those working on this important subject must by no means unknown in cancer therapy for the same keep a close eye on toxic effects. It is true that these are determined almost as much by the dosage level selected treatment to produce different results in different areas. FRIEDMAN, using mainly oral methotrexate with as by the drug used, but they are common and can radiotherapy, makes a number of interesting observa- be very difficult to predict. Caution is particularly tions. Usually he waited until he saw how the tumour necessary when renal or hepatic function is poor, when the patient is debilitated, or when bone-marrow function was responding to the start of chemotherapy before of his cases has radiation. About already been impaired by earlier treatment. In 10% of squamousadding cell carcinoma of the head and neck regressed dramatically one randomised trial,33 patients on the combined before radiation was begun, but histological evidence of therapy had more infections than those receiving radia" focal chemoresistance " was seen in some, and tion alone, and they also showed a greater tendency to FRIEDMAN feels that this .accounts for those conditions lose weight. Such effects as nausea, vomiting, diarrhoea, which respond quickly, but recur within a month. stomatitis, and alopecia can greatly increase a patient’s In the management of inoperable lung cancer, intra- mental and physical suffering, and they must give cause venous nitrogen mustard or other chemotherapy is for great concern, unless there is some very useful sometimes given in general medical wards with the idea clinical benefit to compensate for them. Modern radioof starting treatment before the patient goes to a radio- therapy, provided the radiotherapist exercises good therapy centre. This policy may sometimes provide clinical judgment as well as technical care and skill, can useful immediate relief-for example, in superior vena quite often be a remarkably easy treatment for the caval obstruction-but it may also cause the white- patient, compared with what happened some years ago. cell count to fall more than usual during the sub- It would be a great pity if the over-enthusiastic and sequent radiotherapy; and it must be remembered that unselective use of combined therapy were to revive old CHALMERS,27 for example, reporting a large controlled fears of the treatment being worse than the disease. trial by four cooperating hospitals, found that the addition of nitrogen mustard to radiotherapy appeared Recurrent Cerebral Ischæmia to increase toxicity, without improving survival, and As long ago as 1914 HUNT 34 remarked that " attacks without " contributing enough positive effects to of threatened hemiplegia and cerebral intermittent warrant the extra labour and toxicity ". claudication are some of the vascular symptoms which In retinoblastoma, the rare malignant eye tumour of should suggest the possibility of carotid obstruction ". childhood, postoperative or bilateral cases seem to be With this quotation, MARSHALL 35 introduces a valuable responding better to combined therapy than they used survey of the natural history of transient ischaemic to do to radiation alone. REESE et who have treated combined
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a1.,28
numbers of these children with X-rays and tretamine, have recorded remarkable 90% " curerates ". STALLARD 29 has used radiation and cyclophosphamide. In this condition, apart from varying survival-rates, there may be differences in the proportion of children who retain useful vision; and here again combined therapy may score. But a 72% ten-year survival-rate has been reported in 79 cases treated by radiotherapy alone,3O and the superiority of the combined method cannot be said to be completely established. Chlorambucil 31 and thiotepa 32 have been effectively used with radiation in the treatment of disseminated malignant disease of the ovary. Like every other drug we have mentioned, these two may depress the bone-marrow and therefore must be watched with special care when they are given with radiation; but they are much less likely to produce other side-effects than many of the newer agents which have received more attention. In all these conditions it seems that the individual response to combined therapy is even more variable than it is to radiotherapy alone, and much more work will
large
27. Chalmers, 28.
29. 30. 31. 32.
cerebrovascular attacks. He recalls that FISHER 36 37 emphasised that fleeting paralysis, paraesthesiae, and dysphasia could be prodromal episodes in patients with carotid-artery disease, but these premonitory symptoms received little attention at first. Similarly, although KuBiK and ADAMs,38 in 1946, described in detail the syndrome of occlusion of the basilar artery, it was not until some years later that the occurrence of repeated ischxmic episodes involving the vertebrobasilar territory was widely recognised and accepted. DENNY-BROWN 39 suggested that episodic insufficiency in the circle of Willis is responsible for such ischxmic attacks. The causes of episodes of this type have been variously held to include falls in systemic blood-pressure, polycythxmia, and intermittent compression of the vertebral artery in the intervertebral canal resulting from spondylosis; but the view which now holds favour is that most of them are due to recurrent inicroembolism.40 In many such cases the emboli arise from areas of mural
thrombosis forming on an atheromatous plaque in the intima of one of the large vessels-often the carotid or vertebral arteries themselves. Such emboli have been 33.
T. C. Cancer Chemother.
Rep. 1962, 16, 463. Reese, A. B., Tapley, N. du V., Forrest, A. W. Arch. Ophthal. Chicago, 1958, 60, 897. Stallard, H. B. Trans. Ophthal. Soc. U.K. 1962, 82, 573. Halnan, K. E. Clin. Radiol. 1962, 13, 19. Miller, S. P., Brenner, S. M. Cancer Chemother. Rep. 1962, 16, 455. Kottmeier, H. L. in Carcinoma of the Uterine Cervix, Endometrium, and Ovary; p. 285. Chicago, 1962.
34. 35. 36. 37. 38. 39. 40.
Hosley, H. F., Marangoudakis, S., Ross, C. A., Murphy, W. T., Holland, J. F. Cancer Chemother. Rep. 1962, 16, 467. Hunt, J. R. Amer. J. med. Sci. 1914, 147, 704. Marshall, J. Quart. J. Med. 1964, 33, 309. Fisher, C. M. Arch. Neurol. Psychiat. 1951, 65, 346. Fisher, C. M. ibid. 1954, 72, 187. Kubik, C. S., Adams, R. D. Brain, 1946, 69, 73. Denny-Brown, D. Med. Clin. N. Amer. 1951, 35, 1457. Fisher, C. M. Neurology, Minneap. 1959, 9, 333.