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Clinical trials in malignant disease
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Clinical Trials in Malignant Disease P A R T I . - - P R I N C I P L E S OF R A N D O M
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R A L S T O N P A T E R S O N , C.B.E., M.C., M.D., F.R.C.S., F.F.R. Christie Hospital and Holt Radium Institute, Manchester 20 THIs article attempts to analyse the relevant factors in any controlled clinical trial of the r a n d o m selection type where the subject of study is malignant disease. It is intended as a general introduction to a series of reports of such trials. Each study will be published separately as the material matures, but this outline of the factors c o m m o n to all the studies should save m u c h needless repetition. It m i g h t also be of value to anyone who contemplates setting up this type of experiment in future.
INTRODUCTION M a n y of our present-day beliefs about the value of individual methods of treatment of cancer, equally by surgery or by radiotherapy, are founded on pure impression or even on custom to a m u c h greater extent than is often realized. Moreover, m u c h evaluation is propagandist even although propagandist in the very best s e n s e - - n a m e l y , in the desire to convince others of what is sincerely believed good. W e need more demonstrable fact, objectively arrived at, to form a solid basis on which to build. In other branches of medicine, in the last decade or so, great use has been m a d e in this country of controlled and pre-planned experiments on statistically valid lines. Such experiments in the clinical field with patients as the subject of study have, for tactical reasons, gone by the n a m e of ' c l i n i c a l t r i a l s ' and have been exceptionally informative. As applied to the therapy of malignant disease such trials are fraught with greater difficulty and present greater problems than in other branches of medicine. M a n y of the clinical trials, such as those carried out with the antibiotics or with cortisone, for example, tend to yield a.fairly quick answer and where they do show differences between the two sides of any study that difference is often substantial. Studies affecting the treatment of malignant disease have two characters of importance. T h e y tend to be concerned with relatively narrow differences in results. T h e y also impose a latent period of years (conventionally five years in m a n y instances) from the end of a period of study to assessment of result. Moreover, to get significant statistical samples may, of itself, take two or three years. A final answer therefore requires from seven to ten years from initiation of the study and so calls for great patience. In addition cancer has ethical and emotional difficulties of no m e a n order. It has to be accepted as an inescapable premise that the only form of treatment that can be offered to any patient is that which at the time is sincerely believed to be the best available and to offer h i m the best chance of survival. It is, however, important to keep in m i n d that that which is new, even if apparently superior .(e.g. megavoltage), but for which optimal techniques
and optimal dosages are not yet solidly based on experience, is, o n that ground alone, at some disadvantage as compared to older techniques soundly based on previous extensive usage. In spite of the difficulties, however, cancer therapy has reached a stage of semi-stability at which progress is going to be s l o w e r - - a n d p a t c h y - - u n l e s s more determined efforts are made to m o u n t such really objective clinical experiments. It seemed to me, therefore, that a description of the principles employed in, and the experience gained from, some tentative studies of this type which were initiated at the Christie Hospital, Manchester, some eight to ten years ago, would be of interest. Some of the experiments appear genuinely informative and the results at times even surprising. Others are negative in failing to prove one approach better than another, but of interest in having indicated a probable equality. Others can be seen in retrospect to have been poorly conceived as experiments.
ETHICAL AND OTHER LIMITATIONS In this section I have tried to define certain of the limitations imposed on clinical trials in malignant disease by the nature of the material and by medical and public outlook towards cancer. i. T h e groups which form the two sides of any contrasting series m u s t be so designed, in the light of existing knowledge, as to be equally likely to be in the patient's best interests. If the answer is thought to be k n o w n by those responsible for the actual treatment any experiment becomes impossible. One illustration is that although there is great British controversy to-day between exponents of radical mastectomy and local mastectomy plus radiotherapy, no one has felt able to m o u n t a r a n d o m selection series. T h o s e who hold the one belief sincerely could not feel morally justified in offering any patient the alternative t r e a t m e n t - - a n d vice versa! 2. T h e group of patients to be included in the experiment m u s t be clearly defined by appropriate criteria. Simple examples of such criteria include : a. N o t over 70 years of age. b. Section proved. c. N o secondary lymph-nodes. d. N o t o v e r . . . (certain limiting d i m e n s i o n s either of patient or lesion). Once the group is suitably defined no other cases are admissible. Strictly any conclusions drawn from the ultimate results hold only for the material so defined. Deductions m a y be drawn, subsequently widening application of any findings, but these should be recognized as logical deductions, not as, of themselves, evidence. 3. At one time I held that even if the group under review had been so defined either tacitly or by
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defining criteria it was n o t essential t h a t every case coming w i t h i n t h e stated criteria be included. T h e exclusion of a n y case on a n y g r o u n d s whatsoever, social, political, or a n y other, did n o t seem to detract from t h e quality of the final s t u d y g r o u p p r o v i d e d only t h a t the exclusion was d o n e before t h e side of the e x p e r i m e n t into w h i c h the case w o u l d fall was known • T h e e x p e r i m e n t a l sample consisted only of those cases a d m i t t e d a n d w h o s e choice of t r e a t m e n t w i t h i n the g r o u p was d e t e r m i n e d b y absolute c h a n c e after inclusion. T h e statisticians have p o i n t e d out to m e t h a t while this is technically true, it has some u n d e s i r a b l e features. Certain of t h e exclusions m i g h t be so consistent as to f o r m a single g r o u p w h i c h would rob the total sample of its m o r e universal character. F o r example, to exclude all private p a t i e n t s could, in t h e o r y at least, give an a n s w e r t h a t w o u l d be true of one social s t r a t u m , b u t n o t necessarily t r u e of all classes; or if t h e severely ill are t a k e n o u t the results obviously apply only to the less ill. I t therefore seems desirable to t a b u l a t e in a d v a n c e and define clearly t h e types of case to b e excluded, in so far as these can b e foreseen. F o r example, one criterion suggested above was ' n o t over 70 '. T h i s b o t h avoids quite a n u m b e r of difficult decisions and, if c r u d e survival statistics are to be employed, deletes the increased incidence of d e a t h f r o m o t h e r causes in t h a t age group. 4. W h a t e v e r m a y have b e e n d e c i d e d as policy in relation to either p a r a g r a p h s 2 or 3 above, it has to be accepted t h a t all the possible c o m b i n a t i o n s of circumstances c a n n o t be set o u t i n a d v a n c e a n d so it still remains essential to review each a n d every case individually before it is accepted into the e x p e r i m e n t , to b e quite sure t h a t the p r o c e d u r e of either side of t h e series is equally a p p r o p r i a t e for t h a t patient. W h e r e this is n o t so, t h e case j u s t c a n n o t be i n c l u d e d in t h e sample. T h i s principle remains t r u e o n ethical g r o u n d s w h a t e v e r the damage to ideal statistical patterns. I t is very desirable to state t h e n a t u r e of cases so e x c l u d e d so t h a t t h e i r effect, if any, o n t h e sample could be assessed.
TECHNICAL LIMITATIONS I n p r e p a r i n g t h e studies referred to previously, I s o u g h t advice f r o m a n u m b e r of statisticians (including Professor B r a d f o r d Hill a n d D r . Doll, of L o n d o n , a n d M r . T i p p e t t , of t h e Shirley Institute, M a n c h e s t e r ) . T o all of t h e m I a m m o s t grateful. I n addition the general principles u n d e r l y i n g the p l a n n i n g of clinical trials i n general have b e e n outlined b y B r a d f o r d Hill (1955).* I n this section I have set o u t f r o m t h e n o n statistical clinicians' angle various principles w h i c h the medical statistician w o u l d like to see o b s e r v e d in t h e preparatio n of, or c o n d u c t of, any s u c h s t u d y in spite of t h e restrictions i m p o s e d b y clinical trials w h i c h involve p a t i e n t s w i t h m a l i g n a n t disease. I. T h e n u m b e r s of cases likely to be available for any s t u d y w i t h i n a reasonable p e r i o d of years m u s t be such as w o u l d b e c o m e statistically significant * Bradford Hill (I955), Principles of Medical Statistics, 6th ed., ch. VI.
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for m o d e s t differences in survival rates. T h e following table is a useful guide. Size of Group: Number of cases in each o f two contrasting series 25 50 IOO ~5o 200 300
Approximate Difference in Results required to ensure Significance at 5 per cent. Level ( P = ' o 5 ) per cent 3° 2o 15 ~2½ io 8
Several of o u r studies had, u n f o r t u n a t e l y , to b e a b a n d o n e d i n c o m p l e t e owing to lack of foresight in this respect. T h e difficulty is greatest for a single centre w o r k i n g on its o w n a n d w o u l d be eased b y collaborative effort or a n a t i o n - w i d e project. z. I f the i n d e x of result is to be " alive at five years (or t h r e e years) " the suitable type of disease for s t u d y is one w i t h an appreciable rate of expected survival to t h r e e or five years. F o r m a l i g n a n t diseases on o r t h o d o x t h e r a p y such figures are in general already well established. I n practical t e r m s this almost implies studies confined to the range 25 p e r c e n t to 75 p e r cent survival. Differences in survival levels w h e r e p r o b a b l e survival is u n d e r 5 p e r cent or even u n d e r i o p e r cent offer little g e n u i n e i n f o r m a t i o n unless v e r y large n u m b e r s can b e c o m pared. C o m p a r i s o n s of average survival t i m e in m o n t h s for s u c h diseases m a y offer useful i n f o r m a tion b u t m u s t n o t b e r e g a r d e d as an index of curability. 3. T h e allocation to one or o t h e r side of t h e s t u d y m u s t be b a s e d absolutely on ' c h a n c e ' - - a n d m a d e after t h e p a t i e n t has b e e n accepted into t h e study. 4. I n all later calculations statistical practice m u s t b e m e t i c u l o u s l y o b s e r v e d a n d s t a n d a r d errors, etc., indicated. 5. O n c e a p a t i e n t has b e e n accepted into the g r o u p a n d allocated to one or o t h e r side he remains in regardless of all o t h e r factors a n d w h e t h e r t r e a t e d in the p r e s c r i b e d m a n n e r or hot. W h a t is b e i n g assessed is the p e r c e n t a g e survival resulting f r o m a decision to a d o p t a certain policy a n d not t h e results of t h a t policy p u r s u e d to a conclusion. T h e following is a n i c e example : I n a breast series the stated criteria i n c l u d e d " no supraclavicular n o d e s " b u t t h e cases for t r e a t m e n t h a d to come to t h e C h r i s t i e Hospital, while some of t h e others did not. A supraclavicular n o d e f o u n d at hospital, even if it was o n t h e day after allocation, does n o t t h e n exclude the c a s e - - e v e n a l t h o u g h it m a y d e t e r m i n e an a d j u s t m e n t to t r e a t m e n t policy. T h e p o i n t is t h a t the n o n - t r e a t e d control case w o u l d n o t have b e e n similarly r e - c h e c k e d and t h u s was n e v e r in a position to b e similarly excluded. T h e i m p o r t a n c e of the p r i n c i p l e can scarcely b e overstressed, a n d failure to observe it is one of t h e likeliest sources of inaccuracy. T h e p o i n t to keep in m i n d is t h a t the p a t i e n t ' s t r e a t m e n t m a y have to be adjusted to m e e t a c h a n g e d situation (e.g., b y t h e discovery of metastases) f r o m w h a t was i n t e n d e d b u t t h a t he h i m s e l f r e m a i n s in the g r o u p to w h i c h he was allotted a n d is c o u n t e d w i t h t h e m . 6. I n w h a t has b e e n said so far the p a r a m e t e r to be n o t e d has b e e n p r e s u m e d as crude survival for ' X ' years. T h e same m e t h o d s of setting u p a s t u d y
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could be employed for other parameters such as n u m b e r of m o n t h s ' survival or length of remissions (e.g., comparing P.32 and chemotherapy in leuk~emia). T h e essential would then be that the criteria defining the parameter to be used as index be set out exactly in advance. 7. All concerned in the experiment must be i m b u e d by the need for complete objectivity and for the meticulous adherence to both spirit a n d letter of agreed rules governing the study. PRINCIPLES OF RANDOM SELECTION T h e r e would appear to be for our purposes two methods of selection by pure chance, both of which are statistically valid, but which are operated technically in rather different w a y s : (i) R a n d o m allocation of e a c h case in the total s a m p l e ; (2) R a n d o m allocation within stratified samples. I. I n d i v i d u a l R a n d o m A l l o c a t i o n . - - H e r e the choice of procedure is m a d e for each case separately and individually. T h e classical example of this is, of course, the tossing of a c o i n - - h e a d s or t a i l s - - b u t the n u m b e r of methods is legion. Sealed envelopes containing cards allocated to one or other side of the experiment using a table of random numbers are also often used for individual randomization. I n practice, however, unless some special m e c h a n i s m is devised, they are not without an element of clumsiness in operation, as a card has to be culled before the patient can be instructed as to what will happen to him. One useful variant in practice is to employ some characteristic of the actual patient as the determinant. T h i s must, however, be totally unrelated to the choice of procedures involved and not noted before registration into the experiment. I n the Christie Hospital series where individual random allocation was employed, the criterion has been the patient's birthday, odd or even, for the date of the day of the birthday. Occasionally the m o n t h of the birthday was used where there was possible overlap between two investigations. Usually ' odd ' was adopted as referring to the more unusual of any two methods! A rapid calculation of the Gregorian calendar will, of course, show that the n u m b e r s on each side are not quite equal (18.6 to i79 ) but they are near enough for all practical purposes. T h i s m e t h o d has proved very simple to operate. It is, however, open to the criticism that the birthday could be ascertained before decision. Equally, however, an envelope could be opened! T h e main advantage of individual randomization b y some simple determinant is that each patient is allocated independently of any other and that it can more-easily be operated by a n u m b e r of individuals in a n u m b e r of different places. It is also open to subsequent check. T h e numbers on each side of the study do not necessarily finish equal, but for large enough numbers they should come close to it according to the laws of chance. 2. S t r a t i f i e d S a m p l e s . - - H e r e the essence of the situation is that the expected material is divided in advance into a n u m b e r of defined groups with like qualities: Examples of such individual groups a r e : (a) Same age b r a c k e t ; (b) Same stage of disease; (c) Previous operation by same surgeon. T h e qualities selected for the stratification should obviously be of a nature estimated as likely to have
OF
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a bearing on results. T h e r e is no absolute rule as to n u m b e r in each ' sample ' - - a n y t h i n g from 2 upwards is statistically valid. F o r our purposes of malignant disease study, a useful working figure is IO or less. Equally, no rule can be laid down as to the n u m ber of samples, but this m u s t be kept within reason and use m a d e only of criteria likely to have a real bearing on results. Arrangements are then made to apply the r a n d o m decision within each sample with equal n u m b e r s in each sample for each side of the experiment. E v e n stratified samples could be randomized by individual random allocation of each case, but then this becomes in no way different from individual randomization of the whole sample, as already described. In practice the most c o m m o n m e t h o d of application of this system is the use of sealed envelopes containing cards giving the m e t h o d of treatment to be used and called seriatim. T h e name and identifying n u m b e r of the patient should be entered on the envelope before it is opened, and no envelope destroyed before the investigation is completed. T h e main advantage of stratified samples is that with relatively smaller total numbers, one has ensured some degree of equality in relation to important characteristics, and so can achieve answers with less material than is required by the unstratified method. S e q u e n t i a l M e t h o d . - - A third valuable m e t h o d of planning for clinical trials is the sequential method, by which the difference in results in the two samples is under constant current review and the experiment stops as soon as and if statistically significant results are reached. It is not easy to see how this could be applied t o cancer survival studies, because of the long latent period (3-5 years) between the end of the actual experiment and assessment of results. CONCLUSIONS Clinical experiments are fraught with considerable difficulty where the subject of study is malignant disease. O n this account there is severe restriction on the kind of experiment which can be mounted. Even so, there are m a n y situations in which something of this type can be ethically done. A further restriction is the substantial n u m b e r of cases of any one type which are required to give useful conclusions. T h e m e t h o d is therefore more applicable to c o m m o n diseases, for example, breast cancer, than to the rarities. F o r these less c o m m o n lesions something of a collaborative nature on a national or regional basis could be very rewarding. ADDENDUM T h e following experiments have been completed up to 1956, and where found informative, will be reported on reaching the 5-year interval. i. Breast C a n c e r : Prophylactic post-operative radiotherapy versus ' w a t c h ' policy (i.e., close followup and treatment only on need). 2. Breast Cancer : Simple X-ray castration versus no immediate castration. 3. Cervix Cancer : X - r a y therapy before r a d i u m versus after. 4. L a r y n x C a n c e r : R a d i u m (or Co 60) beam therapy versus beam-directed X-ray.
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5. L u n g C a n c e r : P o s t - p n e u m o n e c t o m y : p o s t operative r a d i o t h e r a p y v e r s u s n o i m m e d i a t e r a d i o theraPy. 6. X - r a y T e c h n i q u e : E q u a l d a i l y d o s a g e v e r s u s increasing daily dosage. 7. R a d i u m Dosage : Study of ' optimum ' dosage i n s k i n a n d m o u t h c a n c e r . Recently a new series of studies has been initiated, d e s i g n e d to c o n t r a s t m e g a v o l t a g e (4 M e V . l i n e a r
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accelerator) with conventional therapy (2oo-5oo kV.) wherever this seemed ethically acceptable. T h e l a t e n t p e r i o d to m a t u r i t y is still s o m e 6 - 7 y e a r s ! T h i s m e g a v o l t a g e g r o u p o f clinical trials h a s b e e n designed on strict random selection principles outlined above, and embodies the experience acquired in t h e first s e r i e s o f trials. T r i a l s a l r e a d y s t a r t e d include: Head and neck cancer; Bladder cancer; Cervix cancer (parametrial irradiation).
BOOK RE VIEWS Manual of Radiation Therapy. STENSTROM, P h . D . Springfield,
By K. WILHELM Ill. :
Charles
C.
Thomas. Tills little book is essentially a s u m m a r y of t h e radiotherapy techniques u s e d at t h e U n i v e r s i t y of M i n n e s o t a . Unfortunately an a t t e m p t is also m a d e to cover all t h e basic elements of radiotherapy. A general appreciation of the physical principles involved, e l e m e n t a r y radiochemistry and radio-biology, dose units, t h e collection and evaluation of t h e results of treatment, t h e place of the technician, a n d t h e possible f u t u r e of r a d i o t h e r a p y are all included in less t h a n 14 pages. T h e m a i n part of t h e v o l u m e is well arranged a n d easy to follow, b u t m a n y of t h e views p u t forward a n d t h e statements m a d e find little a g r e e m e n t in this c o u n t r y . T h e u s e of three fields in the t r e a t m e n t of neck glands with anterior a n d posterior obliques overlapping t h e lateral field by 5o per cent is pointless, as t h e r e will be no s p a r i n g of the skin a n d no increase in the d e p t h dose, and it is quite u n n e c e s s a r y to advise three fields w h e n treating a h~emangioma of the spine in order to achieve a depth dose of 80o r in seven to ten days. Controversial s t a t e m e n t s are e n c o u n t e r e d in m o s t chapters. C a r c i n o m a of the h a r d palate is n o t considered suitable for t r e a t m e n t b y a r a d i u m applicator because of the possible risk of necrosis of bone, a n d yet intensive X-ray t h e r a p y is r e c o m m e n d e d later in the t r e a t m e n t of unresectable palatal carcinomas. T h e r e is far less risk of bony necrosis u s i n g a r a d i u m applicator or telecobalt, and if external irradiation is necessary, t e l e c o b a l t w o u l d be m o r e suitable. C a r c i n o m a of t h e breast is staged in an u n u s u a l fashion with w h i c h m a n y will disagree. Stage I cases are those with histologically negative l y m p h - g l a n d s a n d Stage II those w i t h l y m p h - g l a n d invasion on microscopical examination. C a r c i n o m a of t h e uterine cervix is treated at first by external irradiation a n d later b y radium insertions and one of t h e reasons given is that the external irradiation will reduce any i n f l a m m a t o r y process in the pelvis. M o s t radiotherapists regard k n o w n pelvic infection as a contra-indication to radical X - r a y therapy, and doses large e n o u g h to destroy m e t a s t a t i c pelvic l y m p h - n o d e s are m u c h above t h o s e that were once c o m m o n l y r e c o m m e n d e d for t h e r e s o l u t i o n of infectious processes. Secondary skin cancer is discussed u n d e r two m a i n subdivisions: (a) C a r c i n o m a of t h e breast, a n d (b) L y m p h o b l a s t o m a . M a l i g n a n t m e l a n o m a is for s o m e reason included u n d e r this second h e a d i n g a n d no reference is m a d e to t h e possibility of other types of malignant t u m o u r s metastasizing to t h e skin.
T h e c h a p t e r on diseases of t h e eye is unsatisfactory. T h e usefulness of t h e beta-ray applicator is rightly e m p h a s i z e d , b u t t h e dosage delivered is prescribed in millicurie m i n u t e s , a n d it is r e c o m m e n d e d that t h e applicator be m o v e d slowly over t h e treated surface w h e n t h e applicator is smaller t h a n t h e diseased area. It is obviously impossible to have an accurate idea of t h e dose delivered by this m e t h o d . T h e r e are other i m p o r t a n t omissions in this chapter. Insufficient e m p h a s i s is laid on the avoidance of irradiation for b e n i g n conditions unless absolutely necessary. M o s t radiotherapists no longer treat any cases of so-called t h y m i c e n l a r g e m e n t in infants, a n d t h e illogical a n d u n p r o v e n practice of s t i m u l a t i n g t h e ovaries with 90 r s e e m s e x t e r m e l y inadvisable in the light of o u r p r e s e n t knowledge of t h e hazards f r o m irradiation. E v e n if it was considered, every care s h o u l d first be taken to e n s u r e that t h e patient is n o t already p r e g n a n t at t h e t i m e of irradiation. T h i s book is r e c o m m e n d e d on tlae fly leaf as a teaching guide for graduate s t u d e n t s of radiology. T h e reviewer does not consider it suitable reading material for t h e s t u d e n t radiotherapist in this country, a l t h o u g h it will p r e s u m a b l y be useful to t h o s e s t u d y i n g at t h e U n i v e r s i t y of M i n n e s o t a . M a n y of t h e t e c h n i q u e s described are n o t generally acceptable a n d a n y discussion, w h e r e it occurs, is brief a n d superficial, a n d therefore pointless. T h e r e are n o w several excellent text-books available covering t h e practice of radiotherapy and there does n o t s e e m m u c h need for this type of book, except as a reference book to the t e c h n i q u e s a n d m e t h o d s used at one particular centre.
Lithiase
de
la
Vole
Biliaire
Principale.
By
PABLO-L. MIRIZZI. Professor at the U n i v e r s i t y of C o r d o b a (Argentina). io × 6~ in. Pp. 162, with 79 illustratlons. 1957. P a r i s : M a s s o n . 22oo ft. THIS m o n o g r a p h f r o m t h e A r g e n t i n e is concerned with t h e surgical t r e a t m e n t of gall-stones. T h e work is very well illustrated a n d t h e quality of the radiographic reproductions is high. T h e value of operative cholangiog r a m s is stressed a n d t h e t e c h n i q u e described in detail. T h e surgical aspects of t h e m o n o g r a p h follow, for t h e m o s t part, accepted surgical practice in this country. C h o l e d o c h o t i t h o t o m y is described in detail at various levels, and attention is given to t h e value of choledochod u o d e n o s t o m y in suitable cases. Altogether a useful monograph. D. J. R.
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Clinical Trials in Malignant Disease P A R T I . - - P R I N C I P L E S OF R A N D O M
SELECTION
R A L S T O N P A T E R S O N , C.B.E., M.C., M.D., F.R.C.S., F.F.R. Christie Hospital and Holt Radium Institute, Manchester 20 THIs article attempts to analyse the relevant factors in any controlled clinical trial of the r a n d o m selection type where the subject of study is malignant disease. It is intended as a general introduction to a series of reports of such trials. Each study will be published separately as the material matures, but this outline of the factors c o m m o n to all the studies should save m u c h needless repetition. It m i g h t also be of value to anyone who contemplates setting up this type of experiment in future.
INTRODUCTION M a n y of our present-day beliefs about the value of individual methods of treatment of cancer, equally by surgery or by radiotherapy, are founded on pure impression or even on custom to a m u c h greater extent than is often realized. Moreover, m u c h evaluation is propagandist even although propagandist in the very best s e n s e - - n a m e l y , in the desire to convince others of what is sincerely believed good. W e need more demonstrable fact, objectively arrived at, to form a solid basis on which to build. In other branches of medicine, in the last decade or so, great use has been m a d e in this country of controlled and pre-planned experiments on statistically valid lines. Such experiments in the clinical field with patients as the subject of study have, for tactical reasons, gone by the n a m e of ' c l i n i c a l t r i a l s ' and have been exceptionally informative. As applied to the therapy of malignant disease such trials are fraught with greater difficulty and present greater problems than in other branches of medicine. M a n y of the clinical trials, such as those carried out with the antibiotics or with cortisone, for example, tend to yield a.fairly quick answer and where they do show differences between the two sides of any study that difference is often substantial. Studies affecting the treatment of malignant disease have two characters of importance. T h e y tend to be concerned with relatively narrow differences in results. T h e y also impose a latent period of years (conventionally five years in m a n y instances) from the end of a period of study to assessment of result. Moreover, to get significant statistical samples may, of itself, take two or three years. A final answer therefore requires from seven to ten years from initiation of the study and so calls for great patience. In addition cancer has ethical and emotional difficulties of no m e a n order. It has to be accepted as an inescapable premise that the only form of treatment that can be offered to any patient is that which at the time is sincerely believed to be the best available and to offer h i m the best chance of survival. It is, however, important to keep in m i n d that that which is new, even if apparently superior .(e.g. megavoltage), but for which optimal techniques
and optimal dosages are not yet solidly based on experience, is, o n that ground alone, at some disadvantage as compared to older techniques soundly based on previous extensive usage. In spite of the difficulties, however, cancer therapy has reached a stage of semi-stability at which progress is going to be s l o w e r - - a n d p a t c h y - - u n l e s s more determined efforts are made to m o u n t such really objective clinical experiments. It seemed to me, therefore, that a description of the principles employed in, and the experience gained from, some tentative studies of this type which were initiated at the Christie Hospital, Manchester, some eight to ten years ago, would be of interest. Some of the experiments appear genuinely informative and the results at times even surprising. Others are negative in failing to prove one approach better than another, but of interest in having indicated a probable equality. Others can be seen in retrospect to have been poorly conceived as experiments.
ETHICAL AND OTHER LIMITATIONS In this section I have tried to define certain of the limitations imposed on clinical trials in malignant disease by the nature of the material and by medical and public outlook towards cancer. i. T h e groups which form the two sides of any contrasting series m u s t be so designed, in the light of existing knowledge, as to be equally likely to be in the patient's best interests. If the answer is thought to be k n o w n by those responsible for the actual treatment any experiment becomes impossible. One illustration is that although there is great British controversy to-day between exponents of radical mastectomy and local mastectomy plus radiotherapy, no one has felt able to m o u n t a r a n d o m selection series. T h o s e who hold the one belief sincerely could not feel morally justified in offering any patient the alternative t r e a t m e n t - - a n d vice versa! 2. T h e group of patients to be included in the experiment m u s t be clearly defined by appropriate criteria. Simple examples of such criteria include : a. N o t over 70 years of age. b. Section proved. c. N o secondary lymph-nodes. d. N o t o v e r . . . (certain limiting d i m e n s i o n s either of patient or lesion). Once the group is suitably defined no other cases are admissible. Strictly any conclusions drawn from the ultimate results hold only for the material so defined. Deductions m a y be drawn, subsequently widening application of any findings, but these should be recognized as logical deductions, not as, of themselves, evidence. 3. At one time I held that even if the group under review had been so defined either tacitly or by
CLINICAL
TRIALS
IN
defining criteria it was n o t essential t h a t every case coming w i t h i n t h e stated criteria be included. T h e exclusion of a n y case on a n y g r o u n d s whatsoever, social, political, or a n y other, did n o t seem to detract from t h e quality of the final s t u d y g r o u p p r o v i d e d only t h a t the exclusion was d o n e before t h e side of the e x p e r i m e n t into w h i c h the case w o u l d fall was known • T h e e x p e r i m e n t a l sample consisted only of those cases a d m i t t e d a n d w h o s e choice of t r e a t m e n t w i t h i n the g r o u p was d e t e r m i n e d b y absolute c h a n c e after inclusion. T h e statisticians have p o i n t e d out to m e t h a t while this is technically true, it has some u n d e s i r a b l e features. Certain of t h e exclusions m i g h t be so consistent as to f o r m a single g r o u p w h i c h would rob the total sample of its m o r e universal character. F o r example, to exclude all private p a t i e n t s could, in t h e o r y at least, give an a n s w e r t h a t w o u l d be true of one social s t r a t u m , b u t n o t necessarily t r u e of all classes; or if t h e severely ill are t a k e n o u t the results obviously apply only to the less ill. I t therefore seems desirable to t a b u l a t e in a d v a n c e and define clearly t h e types of case to b e excluded, in so far as these can b e foreseen. F o r example, one criterion suggested above was ' n o t over 70 '. T h i s b o t h avoids quite a n u m b e r of difficult decisions and, if c r u d e survival statistics are to be employed, deletes the increased incidence of d e a t h f r o m o t h e r causes in t h a t age group. 4. W h a t e v e r m a y have b e e n d e c i d e d as policy in relation to either p a r a g r a p h s 2 or 3 above, it has to be accepted t h a t all the possible c o m b i n a t i o n s of circumstances c a n n o t be set o u t i n a d v a n c e a n d so it still remains essential to review each a n d every case individually before it is accepted into the e x p e r i m e n t , to b e quite sure t h a t the p r o c e d u r e of either side of t h e series is equally a p p r o p r i a t e for t h a t patient. W h e r e this is n o t so, t h e case j u s t c a n n o t be i n c l u d e d in t h e sample. T h i s principle remains t r u e o n ethical g r o u n d s w h a t e v e r the damage to ideal statistical patterns. I t is very desirable to state t h e n a t u r e of cases so e x c l u d e d so t h a t t h e i r effect, if any, o n t h e sample could be assessed.
TECHNICAL LIMITATIONS I n p r e p a r i n g t h e studies referred to previously, I s o u g h t advice f r o m a n u m b e r of statisticians (including Professor B r a d f o r d Hill a n d D r . Doll, of L o n d o n , a n d M r . T i p p e t t , of t h e Shirley Institute, M a n c h e s t e r ) . T o all of t h e m I a m m o s t grateful. I n addition the general principles u n d e r l y i n g the p l a n n i n g of clinical trials i n general have b e e n outlined b y B r a d f o r d Hill (1955).* I n this section I have set o u t f r o m t h e n o n statistical clinicians' angle various principles w h i c h the medical statistician w o u l d like to see o b s e r v e d in t h e preparatio n of, or c o n d u c t of, any s u c h s t u d y in spite of t h e restrictions i m p o s e d b y clinical trials w h i c h involve p a t i e n t s w i t h m a l i g n a n t disease. I. T h e n u m b e r s of cases likely to be available for any s t u d y w i t h i n a reasonable p e r i o d of years m u s t be such as w o u l d b e c o m e statistically significant * Bradford Hill (I955), Principles of Medical Statistics, 6th ed., ch. VI.
MALIGNANT
81
DISEASE
for m o d e s t differences in survival rates. T h e following table is a useful guide. Size of Group: Number of cases in each o f two contrasting series 25 50 IOO ~5o 200 300
Approximate Difference in Results required to ensure Significance at 5 per cent. Level ( P = ' o 5 ) per cent 3° 2o 15 ~2½ io 8
Several of o u r studies had, u n f o r t u n a t e l y , to b e a b a n d o n e d i n c o m p l e t e owing to lack of foresight in this respect. T h e difficulty is greatest for a single centre w o r k i n g on its o w n a n d w o u l d be eased b y collaborative effort or a n a t i o n - w i d e project. z. I f the i n d e x of result is to be " alive at five years (or t h r e e years) " the suitable type of disease for s t u d y is one w i t h an appreciable rate of expected survival to t h r e e or five years. F o r m a l i g n a n t diseases on o r t h o d o x t h e r a p y such figures are in general already well established. I n practical t e r m s this almost implies studies confined to the range 25 p e r c e n t to 75 p e r cent survival. Differences in survival levels w h e r e p r o b a b l e survival is u n d e r 5 p e r cent or even u n d e r i o p e r cent offer little g e n u i n e i n f o r m a t i o n unless v e r y large n u m b e r s can b e c o m pared. C o m p a r i s o n s of average survival t i m e in m o n t h s for s u c h diseases m a y offer useful i n f o r m a tion b u t m u s t n o t b e r e g a r d e d as an index of curability. 3. T h e allocation to one or o t h e r side of t h e s t u d y m u s t be b a s e d absolutely on ' c h a n c e ' - - a n d m a d e after t h e p a t i e n t has b e e n accepted into t h e study. 4. I n all later calculations statistical practice m u s t b e m e t i c u l o u s l y o b s e r v e d a n d s t a n d a r d errors, etc., indicated. 5. O n c e a p a t i e n t has b e e n accepted into the g r o u p a n d allocated to one or o t h e r side he remains in regardless of all o t h e r factors a n d w h e t h e r t r e a t e d in the p r e s c r i b e d m a n n e r or hot. W h a t is b e i n g assessed is the p e r c e n t a g e survival resulting f r o m a decision to a d o p t a certain policy a n d not t h e results of t h a t policy p u r s u e d to a conclusion. T h e following is a n i c e example : I n a breast series the stated criteria i n c l u d e d " no supraclavicular n o d e s " b u t t h e cases for t r e a t m e n t h a d to come to t h e C h r i s t i e Hospital, while some of t h e others did not. A supraclavicular n o d e f o u n d at hospital, even if it was o n t h e day after allocation, does n o t t h e n exclude the c a s e - - e v e n a l t h o u g h it m a y d e t e r m i n e an a d j u s t m e n t to t r e a t m e n t policy. T h e p o i n t is t h a t the n o n - t r e a t e d control case w o u l d n o t have b e e n similarly r e - c h e c k e d and t h u s was n e v e r in a position to b e similarly excluded. T h e i m p o r t a n c e of the p r i n c i p l e can scarcely b e overstressed, a n d failure to observe it is one of t h e likeliest sources of inaccuracy. T h e p o i n t to keep in m i n d is t h a t the p a t i e n t ' s t r e a t m e n t m a y have to be adjusted to m e e t a c h a n g e d situation (e.g., b y t h e discovery of metastases) f r o m w h a t was i n t e n d e d b u t t h a t he h i m s e l f r e m a i n s in the g r o u p to w h i c h he was allotted a n d is c o u n t e d w i t h t h e m . 6. I n w h a t has b e e n said so far the p a r a m e t e r to be n o t e d has b e e n p r e s u m e d as crude survival for ' X ' years. T h e same m e t h o d s of setting u p a s t u d y
82
JOURNAL
OF
THE
FACULTY
could be employed for other parameters such as n u m b e r of m o n t h s ' survival or length of remissions (e.g., comparing P.32 and chemotherapy in leuk~emia). T h e essential would then be that the criteria defining the parameter to be used as index be set out exactly in advance. 7. All concerned in the experiment must be i m b u e d by the need for complete objectivity and for the meticulous adherence to both spirit a n d letter of agreed rules governing the study. PRINCIPLES OF RANDOM SELECTION T h e r e would appear to be for our purposes two methods of selection by pure chance, both of which are statistically valid, but which are operated technically in rather different w a y s : (i) R a n d o m allocation of e a c h case in the total s a m p l e ; (2) R a n d o m allocation within stratified samples. I. I n d i v i d u a l R a n d o m A l l o c a t i o n . - - H e r e the choice of procedure is m a d e for each case separately and individually. T h e classical example of this is, of course, the tossing of a c o i n - - h e a d s or t a i l s - - b u t the n u m b e r of methods is legion. Sealed envelopes containing cards allocated to one or other side of the experiment using a table of random numbers are also often used for individual randomization. I n practice, however, unless some special m e c h a n i s m is devised, they are not without an element of clumsiness in operation, as a card has to be culled before the patient can be instructed as to what will happen to him. One useful variant in practice is to employ some characteristic of the actual patient as the determinant. T h i s must, however, be totally unrelated to the choice of procedures involved and not noted before registration into the experiment. I n the Christie Hospital series where individual random allocation was employed, the criterion has been the patient's birthday, odd or even, for the date of the day of the birthday. Occasionally the m o n t h of the birthday was used where there was possible overlap between two investigations. Usually ' odd ' was adopted as referring to the more unusual of any two methods! A rapid calculation of the Gregorian calendar will, of course, show that the n u m b e r s on each side are not quite equal (18.6 to i79 ) but they are near enough for all practical purposes. T h i s m e t h o d has proved very simple to operate. It is, however, open to the criticism that the birthday could be ascertained before decision. Equally, however, an envelope could be opened! T h e main advantage of individual randomization b y some simple determinant is that each patient is allocated independently of any other and that it can more-easily be operated by a n u m b e r of individuals in a n u m b e r of different places. It is also open to subsequent check. T h e numbers on each side of the study do not necessarily finish equal, but for large enough numbers they should come close to it according to the laws of chance. 2. S t r a t i f i e d S a m p l e s . - - H e r e the essence of the situation is that the expected material is divided in advance into a n u m b e r of defined groups with like qualities: Examples of such individual groups a r e : (a) Same age b r a c k e t ; (b) Same stage of disease; (c) Previous operation by same surgeon. T h e qualities selected for the stratification should obviously be of a nature estimated as likely to have
OF
RADIOLOGISTS
a bearing on results. T h e r e is no absolute rule as to n u m b e r in each ' sample ' - - a n y t h i n g from 2 upwards is statistically valid. F o r our purposes of malignant disease study, a useful working figure is IO or less. Equally, no rule can be laid down as to the n u m ber of samples, but this m u s t be kept within reason and use m a d e only of criteria likely to have a real bearing on results. Arrangements are then made to apply the r a n d o m decision within each sample with equal n u m b e r s in each sample for each side of the experiment. E v e n stratified samples could be randomized by individual random allocation of each case, but then this becomes in no way different from individual randomization of the whole sample, as already described. In practice the most c o m m o n m e t h o d of application of this system is the use of sealed envelopes containing cards giving the m e t h o d of treatment to be used and called seriatim. T h e name and identifying n u m b e r of the patient should be entered on the envelope before it is opened, and no envelope destroyed before the investigation is completed. T h e main advantage of stratified samples is that with relatively smaller total numbers, one has ensured some degree of equality in relation to important characteristics, and so can achieve answers with less material than is required by the unstratified method. S e q u e n t i a l M e t h o d . - - A third valuable m e t h o d of planning for clinical trials is the sequential method, by which the difference in results in the two samples is under constant current review and the experiment stops as soon as and if statistically significant results are reached. It is not easy to see how this could be applied t o cancer survival studies, because of the long latent period (3-5 years) between the end of the actual experiment and assessment of results. CONCLUSIONS Clinical experiments are fraught with considerable difficulty where the subject of study is malignant disease. O n this account there is severe restriction on the kind of experiment which can be mounted. Even so, there are m a n y situations in which something of this type can be ethically done. A further restriction is the substantial n u m b e r of cases of any one type which are required to give useful conclusions. T h e m e t h o d is therefore more applicable to c o m m o n diseases, for example, breast cancer, than to the rarities. F o r these less c o m m o n lesions something of a collaborative nature on a national or regional basis could be very rewarding. ADDENDUM T h e following experiments have been completed up to 1956, and where found informative, will be reported on reaching the 5-year interval. i. Breast C a n c e r : Prophylactic post-operative radiotherapy versus ' w a t c h ' policy (i.e., close followup and treatment only on need). 2. Breast Cancer : Simple X-ray castration versus no immediate castration. 3. Cervix Cancer : X - r a y therapy before r a d i u m versus after. 4. L a r y n x C a n c e r : R a d i u m (or Co 60) beam therapy versus beam-directed X-ray.
CLINICAL
T R I A L S IN M A L I G N A N T DISEASE
5. L u n g C a n c e r : P o s t - p n e u m o n e c t o m y : p o s t operative r a d i o t h e r a p y v e r s u s n o i m m e d i a t e r a d i o theraPy. 6. X - r a y T e c h n i q u e : E q u a l d a i l y d o s a g e v e r s u s increasing daily dosage. 7. R a d i u m Dosage : Study of ' optimum ' dosage i n s k i n a n d m o u t h c a n c e r . Recently a new series of studies has been initiated, d e s i g n e d to c o n t r a s t m e g a v o l t a g e (4 M e V . l i n e a r
83
accelerator) with conventional therapy (2oo-5oo kV.) wherever this seemed ethically acceptable. T h e l a t e n t p e r i o d to m a t u r i t y is still s o m e 6 - 7 y e a r s ! T h i s m e g a v o l t a g e g r o u p o f clinical trials h a s b e e n designed on strict random selection principles outlined above, and embodies the experience acquired in t h e first s e r i e s o f trials. T r i a l s a l r e a d y s t a r t e d include: Head and neck cancer; Bladder cancer; Cervix cancer (parametrial irradiation).
BOOK RE VIEWS Manual of Radiation Therapy. STENSTROM, P h . D . Springfield,
By K. WILHELM Ill. :
Charles
C.
Thomas. Tills little book is essentially a s u m m a r y of t h e radiotherapy techniques u s e d at t h e U n i v e r s i t y of M i n n e s o t a . Unfortunately an a t t e m p t is also m a d e to cover all t h e basic elements of radiotherapy. A general appreciation of the physical principles involved, e l e m e n t a r y radiochemistry and radio-biology, dose units, t h e collection and evaluation of t h e results of treatment, t h e place of the technician, a n d t h e possible f u t u r e of r a d i o t h e r a p y are all included in less t h a n 14 pages. T h e m a i n part of t h e v o l u m e is well arranged a n d easy to follow, b u t m a n y of t h e views p u t forward a n d t h e statements m a d e find little a g r e e m e n t in this c o u n t r y . T h e u s e of three fields in the t r e a t m e n t of neck glands with anterior a n d posterior obliques overlapping t h e lateral field by 5o per cent is pointless, as t h e r e will be no s p a r i n g of the skin a n d no increase in the d e p t h dose, and it is quite u n n e c e s s a r y to advise three fields w h e n treating a h~emangioma of the spine in order to achieve a depth dose of 80o r in seven to ten days. Controversial s t a t e m e n t s are e n c o u n t e r e d in m o s t chapters. C a r c i n o m a of the h a r d palate is n o t considered suitable for t r e a t m e n t b y a r a d i u m applicator because of the possible risk of necrosis of bone, a n d yet intensive X-ray t h e r a p y is r e c o m m e n d e d later in the t r e a t m e n t of unresectable palatal carcinomas. T h e r e is far less risk of bony necrosis u s i n g a r a d i u m applicator or telecobalt, and if external irradiation is necessary, t e l e c o b a l t w o u l d be m o r e suitable. C a r c i n o m a of t h e breast is staged in an u n u s u a l fashion with w h i c h m a n y will disagree. Stage I cases are those with histologically negative l y m p h - g l a n d s a n d Stage II those w i t h l y m p h - g l a n d invasion on microscopical examination. C a r c i n o m a of t h e uterine cervix is treated at first by external irradiation a n d later b y radium insertions and one of t h e reasons given is that the external irradiation will reduce any i n f l a m m a t o r y process in the pelvis. M o s t radiotherapists regard k n o w n pelvic infection as a contra-indication to radical X - r a y therapy, and doses large e n o u g h to destroy m e t a s t a t i c pelvic l y m p h - n o d e s are m u c h above t h o s e that were once c o m m o n l y r e c o m m e n d e d for t h e r e s o l u t i o n of infectious processes. Secondary skin cancer is discussed u n d e r two m a i n subdivisions: (a) C a r c i n o m a of t h e breast, a n d (b) L y m p h o b l a s t o m a . M a l i g n a n t m e l a n o m a is for s o m e reason included u n d e r this second h e a d i n g a n d no reference is m a d e to t h e possibility of other types of malignant t u m o u r s metastasizing to t h e skin.
T h e c h a p t e r on diseases of t h e eye is unsatisfactory. T h e usefulness of t h e beta-ray applicator is rightly e m p h a s i z e d , b u t t h e dosage delivered is prescribed in millicurie m i n u t e s , a n d it is r e c o m m e n d e d that t h e applicator be m o v e d slowly over t h e treated surface w h e n t h e applicator is smaller t h a n t h e diseased area. It is obviously impossible to have an accurate idea of t h e dose delivered by this m e t h o d . T h e r e are other i m p o r t a n t omissions in this chapter. Insufficient e m p h a s i s is laid on the avoidance of irradiation for b e n i g n conditions unless absolutely necessary. M o s t radiotherapists no longer treat any cases of so-called t h y m i c e n l a r g e m e n t in infants, a n d t h e illogical a n d u n p r o v e n practice of s t i m u l a t i n g t h e ovaries with 90 r s e e m s e x t e r m e l y inadvisable in the light of o u r p r e s e n t knowledge of t h e hazards f r o m irradiation. E v e n if it was considered, every care s h o u l d first be taken to e n s u r e that t h e patient is n o t already p r e g n a n t at t h e t i m e of irradiation. T h i s book is r e c o m m e n d e d on tlae fly leaf as a teaching guide for graduate s t u d e n t s of radiology. T h e reviewer does not consider it suitable reading material for t h e s t u d e n t radiotherapist in this country, a l t h o u g h it will p r e s u m a b l y be useful to t h o s e s t u d y i n g at t h e U n i v e r s i t y of M i n n e s o t a . M a n y of t h e t e c h n i q u e s described are n o t generally acceptable a n d a n y discussion, w h e r e it occurs, is brief a n d superficial, a n d therefore pointless. T h e r e are n o w several excellent text-books available covering t h e practice of radiotherapy and there does n o t s e e m m u c h need for this type of book, except as a reference book to the t e c h n i q u e s a n d m e t h o d s used at one particular centre.
Lithiase
de
la
Vole
Biliaire
Principale.
By
PABLO-L. MIRIZZI. Professor at the U n i v e r s i t y of C o r d o b a (Argentina). io × 6~ in. Pp. 162, with 79 illustratlons. 1957. P a r i s : M a s s o n . 22oo ft. THIS m o n o g r a p h f r o m t h e A r g e n t i n e is concerned with t h e surgical t r e a t m e n t of gall-stones. T h e work is very well illustrated a n d t h e quality of the radiographic reproductions is high. T h e value of operative cholangiog r a m s is stressed a n d t h e t e c h n i q u e described in detail. T h e surgical aspects of t h e m o n o g r a p h follow, for t h e m o s t part, accepted surgical practice in this country. C h o l e d o c h o t i t h o t o m y is described in detail at various levels, and attention is given to t h e value of choledochod u o d e n o s t o m y in suitable cases. Altogether a useful monograph. D. J. R.