X-Ray Treatment of Chronic Leukemia
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Lindau Nobel Laureate Meetings37 / 340
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00:00
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Transcript: English(auto-generated)
00:11
Distinguished guests, ladies and gentlemen, I must first apologize for not giving my address in German.
00:23
I'm sure, however, that you will understand my Boston and perhaps Cambridge English much better than my German. I sort of feel that you might feel just now very much as I did quite a number of years ago
00:47
after listening to these two beautifully presented papers this morning with so much important information. Quite a number of years ago when I was taking my examinations to practice medicine in the state of Massachusetts,
01:07
part of the examination was an oral one. Each physician spent several minutes discussing their own subject with the candidate surgery,
01:25
internal medicine, pediatrics and so on. So after having been in conference with the surgeon for some minutes and not feeling too happy about the outcome, I approached the next man who asked me what I intended to do.
01:47
I said I thought I'd practice medicine. He said, are you interested in obstetrics? And I said, no, I hope I'd never have to deliver a baby. So he smiled and said, well, that happens to be my subject to examine you on.
02:08
And he said, I'd rather judge. You won't be very much interested in my questions, so let's just relax and talk a few minutes. So I feel perhaps that that's what we should do now is just relax
02:23
rather than trying to struggle through a discussion of the treatment of leukemia. The work that I want to present today was originally planned as a joint report
02:41
with the late Dr. Merrill Sossman who was Harvard Medical School Professor of Radiology at Peter Van Brigham Hospital. The work deals with certain data concerning 107 patients with chronic leukemia treated at the hospital
03:03
by Rankin Irradiation for the most part in cooperation with Dr. Sossman until his retirement in 1956. An attempt has been made to include in this group only those with chronic leukemia,
03:24
although it's a well-recognized fact that it's not always possible to distinguish between the chronic and the acute or subacute varieties. 60 of this group of patients were of the granulocytic variety, 47 of the lymphocytic.
03:48
May I have the first slide, please? The diagnosis was ordinarily made on the basis of the clinical evaluation and the peripheral blood picture.
04:03
This just shows a low-power photomicrograph of the picture in chronic lymphocytic leukemia. If there were blast forms present in any considerable degree or number,
04:22
the condition was considered to be acute rather than chronic. The next slide, please. I'm sorry that these do not show up well. The next slide. This is a high power of the lymphocytic and a low power of granulocytic.
04:41
And the next one shows higher power of the granulocytic. The next slide, please. You see an eosinophil in the far corner and a myelocyte in the center. It is not my intention today to try to discuss the nature of the leukemic process
05:10
or the etiology of the disease. Such a discussion would entail considerable speculation and perhaps theory
05:23
and would not help us to solve the problem of treatment, at least for the present. We do, however, now consider leukemia as a malignant cancer and we know that there are certain irritants that do tend to precipitate the disease.
05:48
That is, irradiation, chemical, physical and viral irritations have been shown to produce the disease in some instances.
06:02
During the earlier years, as was the prevailing custom, and occasionally later, treatment was directed either to the spleen, the chest, the long bones or masses of lymph nodes. Following the remission, treatment was usually withheld until another relapse occurred
06:24
and the general condition of the patient was poor. The rather large doses of x-rays required were frequently followed by anorexia, severe nausea and vomiting and general malaise. After recovery from this, there was a short period with some degree of well-being,
06:44
followed by the next relapse and then, of course, requiring another round of treatment. It was observed, however, that treatment over the long bones only was followed by a satisfactory response of the leukocytes,
07:03
but with less of the toxic effects so frequently observed following treatment to the spleen or chest. In view of these facts, it was decided that the method of treatment would be modified in two major respects,
07:21
in the belief that some of the unpleasant effects of therapy could be avoided and also that we might perhaps actually increase the lifespan. The first modification was to apply treatment in small dosage over the entire trunk from the mid-thighs upward
07:42
at one meter distance alternating front and back, so-called telorentgen therapy. The second modification was to start treatments when the leukocyte levels tended to rise above 40,000 cells per cubic millimeter,
08:01
rather than waiting until a more severe relapse, thus maintaining a rather uniformly near-normal leukocyte level. This we decided to refer to as spray technique, as opposed to the local application previously used.
08:23
Doses of from 15 to 50 or 60 retins were used depending upon the patient's condition and the effect anticipated. This method used was discussed in a paper in 1940.
08:41
The spray technique was introduced in the early part of 1934, and with few exceptions has been used as the principal method of treatment since that time in our clinic. Local treatment to masses of lymph nodes or to the spleen was used when it was indicated.
09:03
In order to compare the relative effects of the spray and local techniques, the patients treated by each method are considered separately according to the predominating technique used. 39 patients with granulocytic and 32 with lymphocytic leukemia
09:23
were treated by the spray technique. 21 with granulocytic and 15 with lymphocytic received only local treatment. A few of each group also received some form of chemical therapy at some time during the course of their illness.
09:45
May I have the fifth slide, the next slide please? The patients with granulocytic leukemia were divided equally in respect to sex. In the lymphocytic group there were 27 male and 20 female.
10:01
Now this slide shows the age at onset, or the first definite signs or symptoms recognized as manifestations of the disease. The age differed somewhat in the two groups. In the lymphocytic group we find only six of the patients
10:26
developing the disease before the fifth decade, whereas in the granulocytic group, to your right, over half of the patients develop the disease before the fifth decade.
10:44
In other words, granulocytic leukemia is a disease of younger people ordinarily, although again you see at the bottom, in the eighth decade, one patient in the lymphocytic group and two in the granulocytic.
11:05
The youngest patient in the lymphocytic was 36 and in the granulocytic 23. The oldest in each of the groups was 82 and 85 at time of onset.
11:23
May I have the next slide please? The results of treatment as indicated by length of survival after onset by the two techniques used are shown in these next two slides. The percentage of patients surviving three years,
11:42
these represent the years of survival, three to seven. The survival percentage in the two groups was about the same in the groups treated by spray or by local in both series,
12:05
78 and 80, 59 and 62%. However, at four years there is some difference, 69 as opposed to 60 in the locally treated group and in the granulocytic 36 as compared with 14.
12:27
Following through with the lymphocytic, at five years, 59% under spray treatment survived and only 27 under local treatment. The survival percentage was the same in both the forms of treatment
12:44
in the granulocytic group. And at seven years, 47% of the patients were still alive by the spray method and only 20 with the local treatment. The next slide please.
13:03
This shows the classification according to years, the number of patients still living at those intervals. The average survival rate in the lymphocytic leukemia patients treated by the spray method was 6.8 years
13:23
and in those treated by the local method 4.6. In the granulocytic group, the comparable figures are 3.1 and 2.8. Moffitt and Lawrence have cited 31 instances
13:41
of leukemia surviving at least five years. McGavran cited one instance of a patient surviving 25 years. Taking that into consideration, we have here five patients surviving 10 years,
14:04
1, 11, 12, 16, 17 and 26 years. That seems to be about the longest survival. In the granulocytic group, two patients survived nine years.
14:23
The figures indicating survival time as shown in these two slides compare favorably with those recorded in previously reported series. They also suggest some advantage in duration of survival time
14:40
for those treated by the spray method as opposed to the local technique, although this advantage is not striking. There has, however, been a great difference between the effects of the two techniques in respect to the condition of the patients during their illness.
15:00
Those treated in large dosage locally over the chest or spleen and at the time of severe relax have, as I have previously noted, experienced periods of rather disturbing malaise, anorexia, nausea and vomiting after their treatment with only brief periods of well-being between time.
15:27
Whereas those treated with the small dosage by spray technique have suffered few ill effects as the result of treatment and have in general lived normal lives carrying on their usual occupations
15:42
throughout their period of illness. The mild anorexia or nausea which occurred in an occasional patient was readily controlled by intramuscular injections of 50 to 100 milligrams of pyridoxine hydrochloride.
16:01
Those who experienced nausea or anorexia on the first exposure were after that treated an hour or two with pyridoxine before the next x-ray treatment was given.
16:20
It may be profitable to record briefly the regimen recommended for the management of treatment in the patient after the diagnosis has been established. This will of course vary depending on many circumstances. If the leukocyte level is high, the patient with all pertinent data
16:42
regarding history and blood picture is referred to the radiologist for treatment. Spray treatment may be applied daily or on alternate days and must be controlled by leukocyte counts before each exposure. Pyridoxine should be injected before each treatment if indicated.
17:04
Treatment is continued in small dosage until the leukocyte level has dropped to 30,000 or perhaps lower depending upon the rate of the drop. As one may expect the count to continue to drop for several days after treatment is stopped,
17:22
it is desirable to check the count in about a week as a guide to subsequent courses of treatment. The patient should be seen and the count checked thereafter every four to six weeks. When there is again a tendency for the leukocytes to increase,
17:43
one or more treatments may be sufficient to return the count toward normal. In this way an attempt is made to maintain fairly uniform and near normal leukocyte levels. This method of treatment, always carried out in consultation
18:01
between the physician and radiologist, is used for control of the leukocytes though massive enlargement of lymph nodes may require local therapy for their control. It is rarely necessary to treat the spleen locally even though it is slightly enlarged, for if one uses spray treatment regularly
18:26
the size of the spleen usually subsides also. If the leukocyte level is not high when the diagnosis is made, treatment should be delayed until such time as the patient
18:43
either shows definite indications of a relapse approaching or preferably as the leukocyte count rises to about 40,000. May I have the next slide?
19:01
This patient was followed for five years before treatment was started. This shows the five year period. Although his leukocyte count was tending to rise, treatment was not started for he was asymptomatic.
19:21
He did have arthritis, this was before the days of cortisone, but that was not very troublesome. The next slide shows the course of events during treatment which he was still living at the end of five years
19:41
and in all lived seven years during the course of treatment, during which time, as you will see, the leukocyte levels were maintained low and his general physical health was excellent. He worked regularly and subsequently died at a time
20:04
when the leukemia was well controlled of a coronary heart attack. This patient lived in all twelve years during the time that his disease was recognized.
20:23
May I have the next slide? If the lymph node enlargement is the presenting problem, such as in this patient, local application rather than spray will be indicated. This is illustrated by this patient whose complaint was of deafness.
20:45
His aureus thought this might be due to pressure from enlarged lymph nodes, which proved to be the case for when the lymph nodes were treated, his deafness totally disappeared. May I have the next slide?
21:02
And subsequently he was followed with spray treatment, but unfortunately circumstances were such that he died two years later. Death was not related to the leukemia, however,
21:22
but he had a hemorrhage, gastric hemorrhage, one very stormy, snowy night on his farm in Canada, which was twenty miles from the nearest medical attention. His history suggested that the hemorrhage was from a peptic ulcer.
21:46
He had been up to that time in excellent condition so far as the leukemia was concerned, and although he was then 72 years of age, I suspect that he would have had a rather long survival period.
22:03
The results of treatment in the granulocytic group have not been quite so satisfactory in general as those in the lymphocytic, and yet the majority have been remarkably well and able to carry on their usual activities throughout their illness.
22:21
An example of this, of the granulocytic well-controlled therapy, is this next slide, which shows the course of the blood picture in a man who is a model worker in a brass foundry
22:45
at which he continued to work throughout this three and a half year period, without periods of illness. The arrows at the bottom indicate when the treatments were given
23:01
in order to keep the leukocyte count low. As a terminal event, he developed severe pain in the head and abdomen. Sugar became present in the urine in large amounts.
23:21
He became comatose and for the first time during his illness was hospitalized, where he died a few days later from a condition which was diagnosed at post-mortem examination as cerebral thrombosis. I feel sure that this had nothing to do
23:42
with the leukemic process. Unfortunately, a few of our patients were not available for, or did not for one reason or another, follow up treatment in the prescribed manner and so our figures do not show up so well
24:02
as they might if we could have controlled them better. The causes of death, as observed in this series, are interesting, particularly in that they indicate that more than half of the patients died from diseases not directly related to leukemia.
24:21
Two patients with lymphocytic leukemia are living and in excellent conditions six and eleven years respectively after onset. May I have the next slide? Of the 105 patients who have died, the cause of death in 69 has been established
24:44
other than leukemia. Post-mortem examination confirmed the cause of death in 35 of this group. Perhaps those who died from pneumonia or hemorrhage, for example, should be included with those who died from a disease
25:02
directly related to leukemia. The cause of death for 35 patients is recorded as due to leukemia. Those with severe hemolytic anemia, localized infection, progression of the leukemia due to refusal of therapy,
25:21
and a few in whom no other cause could be determined are included in this group. Pneumonia was considered to be the cause of death in 11 patients, as you see at the top. This was the most frequent cause of death.
25:43
However, if one considers all of the cardiovascular group together, there were 21, which is by far the larger number. It is also of interest to note that of the 10 patients who died of multiple infarcts,
26:01
nine were in the granulocytic group and included splenic infarction. Five deaths are recorded as due to the unfavorable effects of treatment. One died of post-transfusion shock after receiving incompatible blood in another hospital.
26:26
The other four patients died of complications directly resulting from chemotherapy. Death followed the use of TEM, nitrogen mustard, aminopterin, and urethane,
26:42
together with intravenous injections of ACTH in one patient each. Four other patients died having severe bone marrow depression following chemotherapy. The causes of death are otherwise recorded in the table and so are not here considered as caused by chemotherapy.
27:07
Two under pneumonia, one cerebral vascular accident, and one myocardial infarction. Again, four different chemicals were responsible.
27:22
Nitrogen mustard, TEM, mercaptor purin with cortisone, and mylarin, each in one patient. The chemotherapy was not, however, carried out by us. You may take that slide off if you wish,
27:40
although I would like you to note particularly that five of our patients died from tuberculosis, and I'll mention those a little later on. One from renal failure, two from other malignant disease,
28:00
and several from hemorrhage, perhaps because of the severe anaemia, and six from sepsis. A solution of potassium arsenide, Fowler's solution, was used in a number of instances, particularly during the earlier years,
28:21
but was discontinued because of its unpleasant side effects. One patient with granulocytic leukemia had received Fowler's solution for two years when first seen by us. At no time during this period of treatment had he been free from severe anorexia and nausea
28:43
and malaise so that he had lost 40 pounds during that period of time. He was started on spray treatment and within a few weeks had regained his weight for he had no further nausea or vomiting
29:00
and lived two more years under spray therapy, four years in all. The published results of chemotherapy have not been sufficiently impressive to induce us to abandon spray x-ray therapy in its favour. Because we have had little personal experience
29:21
with the use of chemicals other than Fowler's solution, it is not our intention to attempt to evaluate the comparative effect of x-rays and chemotherapy. A brief record of the experience of some of our patients who received chemotherapy
29:40
may be of interest and instructive. These patients received it at some time during their period of illness, but not as the main course of treatment. Twelve patients, in addition to the eight recorded above, have received one or more chemicals
30:01
for varying periods of time. Urethane was discontinued after short periods of trial by six patients because of anorexia and nausea and vomiting. It was tolerated but had little clinical effect in one patient. TEM was discontinued in one patient
30:23
because of anorexia and nausea and in another after twice causing severe leukopenia. This second patient died of pulmonary tuberculosis after the last trial of TEM.
30:41
Aminopterin was used once but stopped because of unfavourable effects. Cortisone was given to four patients, two of whom also received antibiotics. Two of these died of miliary tuberculosis, one after a year of use, the other after a few weeks of use
31:02
together with an antibiotic. One died of septicemia while taking cortisone and an antibiotic, and the fourth of a cerebral vascular accident three weeks after starting cortisone. These unfavourable experiences with chemotherapy
31:22
are not sufficient to condemn this method, particularly in view of the fact that it has been given in a few instances in which the disease may have been in a terminal stage regardless of the type of therapy used. However, in comparison with the absence of toxic effects
31:42
following the use of x-rays in small dosage by the spray technique and because of the lack of evidence of superiority of chemotherapy over that of spray x-ray and reports thus far available, one may question the advisability of further experiment
32:02
with the chemicals presently in use. Lawrence has reported on the favourable experiences with the use of radioactive phosphorus, P32, and Osgoode has compared the effects of P32
32:20
to the spray therapy, showing no definite advantage of one over the other. Where spray treatment is available, it would seem to be the treatment of choice for the patient with chronic leukaemia. Unfortunately, the research during the past 40 years has not produced a strikingly important development
32:44
for the treatment of chronic leukaemia. Perhaps the most important development has been the introduction of the spray method of Rankin Irradiation, as used in this series of patients, which has tended to minimize some of the unpleasant side effects of therapy
33:03
and so allowed the patients to live more comfortably and normally throughout their illness. There may also have been added a few years to the life span and even more may be possible now that infections may be controlled
33:21
and the use of the sulfonamides and antibiotics available. The majority of the patients in this series were treated before these substances were generally available. Anemia has been a frequent and important complication,
33:41
as might be expected. Transfusions have been given when indicated. They have undoubtedly added both to the life span and to the comfort of the patient. Both iron and injections of either liver extract or vitamin B12 have been used in some patients
34:02
for control of the anemia, but probably not with strikingly beneficial effects, for we have seen the blood levels improve after spray therapy or x-ray therapy,
34:20
whether or not these substances were given. Experimental work in the future, in order to be successful in the management of leukemia, whether acute or chronic, must be directed toward finding a means of encouraging normal production or maturation of leukocytes
34:45
rather than their destruction. All of our methods of therapy up to date are designed to destroy cells rather than to increase their production or maturation
35:03
from a normal point of view. Or one must direct attention toward prevention of the disease by recognition of those factors which may initiate the abnormal growth of cells so that these may be avoided.
35:23
I've already commented on those irritants that are known and by controlling exposure to these I'm sure that some cases of leukemia can be prevented. I hope that we can learn more
35:41
of the mechanism by which these substances do produce irritation and so produce leukemia and in the near future be able to prevent rather than try to cure the disease which now of course is incurable.
36:03
Thank you.