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TRETAMINE IN THE TREATMENT OF INOPERABLE LUNG CANCER
206
Preliminary
workers have found it to be very toxic on the hxmopoietic tissues when so used. Wilkinsonregarded it as the most toxic of all agents he had tried. During the period July to November, 1959, 43 patients with advanced inoperable lung cancer have been treated with tretamine. Untreated the majority of these patients would have been dead within three months and many earlier than this. After some experiment a pattern of dosage that has given very encouraging results has been worked out. 30 patients have shown subjective improvement and in 10 of these very marked to complete regression of the tumour has occurred. In 4 cases the chest X-ray has returned to normal or near normal and it is these 4 results that have stimulated this preliminary report. Radiologically each patient had a large mass at one or other lung root with considerable enlargement of the superior mediastinal shadows. Tumour tissue was obtained from the bronchi or from neck glands or from both sites and in each instance was reported as an undifferentiated carcinoma. Additional details are given in the table and X-rays representative of the series are shown in figs. 1 and 2. Treatment of these 4 cases consisted of one or two large doses of tretamine given intravenously, with a total dose of 15 to 30 mg. This dose may be followed by severe nausea for twenty-four hours. Within three days subjective improvement was evident, and chest X-ray done routinely on the fifth day showed evident shrinkage of the tumour mass. This shrinkage continued over the next three weeks and at the end of a month the chest X-ray had returned to normal. 7. Wilkinson, J. F. Proc. R. Soc. Med. 1953, 46, 685.
Communications
TRETAMINE IN THE TREATMENT OF INOPERABLE LUNG CANCER THE first
use
of tretamine
(2 :4 :6-triethyleneimino-
s-triazine, triethylene melamine [T.E.M.]) in the control of clinical
its release for research Industries as the result of observations 23 on the inhibitory action of this and related compounds on the growth of experimental tumours. Other clinical reports4 followed independent parallel discoveries made at the Sloan-Kettering Research Institute, New York.
malignancyfollowed by Imperial Chemical
purposes
Experimental work on mice 5 showed that tretamine had very considerable activity against sarcoma 180 and lymphosarcoma L 1. The best response was obtained by large doses at infrequent intervals. In 15 cases of lung cancer treated with this drug 6 4 showed marked clinical improvement but no radiological change. In this and most subsequent reports the method of dosage has been frequent small doses over a period of a few weeks. Most 1. Paterson, E., Boland, J. Brit. J. Cancer, 1951, 5, 28. 2. Rose, F. L., Hendry, J. A., Walpole, A. L. Nature, Lond. 1950, 165, 993. 3. Hendry, J. A., Homer, R. F., Rose, F. L., Walpole, A. L. Brit. J. Pharmacol. 1951, 6, 357. 4. Karnofsky, D. A., Burchenal, J. H., Armistead, G. C., Jr., Southam, C. M., Berstein, J. L., Craven, L. F., Rhoads, C. P. Arch. intern. Med. 1951, 87, 477. 5. Goldberg, B., Schoenbach, E. B. Cancer, 1951, 4, 1125. 6. Saline, M., Baum, G. L. J. Amer. med. Ass. 1954, 156, 1493.
(b)
(a)
Fig. 1-Case 1: (a) X-ray one month before start of treatment, thereafter the (b) one month after treatment: (c) three months after treatment.
Fig. (a) Day before treatment; given; (c) one month later.
patient
bed-ridden and portable films
(b)
five days after 30 mg. tretamine, the chest
were
unsatisfactory;
(c)
(b)
(a) 2-Case 2:
(c) was
was not
aspirated and
no
other treatment
was
207 DETAILS OF
4
CASES OF INOPERABLE BRONCHIAL CARCINOMA TREATED WITH TRETAMINE
Of the other 6 patients whose tumours have undergone marked regression, 3 died within twelve days after the start of treatment, owing to hxmorrhage from the tumour which had undergone necrosis; the platelet-count was at a safe level at the time of these haemorrhages. The remaining patients were treated because of metastases from bronchial tumours previously removed. Only a clinical assessment of the regression of these metastases could be made since they were not radiologically visible. The patients, however, are all well and symptomless and the follow-up results are awaited. In every case there has been a depression of the white blood-cells and the platelets. The white blood-count falls to its lowest level about the twelfth day and if below 500 at this time prednisolone and penicillin have been given for a period of seven to ten days. The platelet-count has been more variable and usually reaches its lowest point about the fifteenth day. In 2 patients a slight purpuric rash occurred with a plateletcount of less than 25,000 per c.mm. Both were given a transfusion of fresh blood. Some of the early cases were treated with repeated small doses of tretamine; in 3 of these severe purpura occurred and blood-transfusion was urgently needed. It is considered advisable to watch very carefully for evidence of purpura from the twelfth day onwards. It was found expedient to do blood and platelet counts on alternate days until a moderate pancytopenia was present and then daily until the counts had returned to near normal. Pyridoxine (100 mg. intramuscularly once daily) and
SERUM-5-HYDROXYTRYPTAMINE LEVELS FOLLOWING EXPERIMENTAL INCREASE IN GASTROINTESTINAL ACTIVITY IN MAN THERE are good reasons for believing that much of the blood-5-hydroxytryptamine (5-H.T.) is derived from the enterochromaffin cells of the gastrointestinal tract. Haverback and Davidsonhave demonstrated low levels in a patient with extensive resection of large and small bowel. By means of a cardiac catheter, Erspamer and Testini2 found more 5-H.T. in the hepatic vein than in the inferior vena cava of patients. Experiments on the guineapig intestinehave shown that increased intra1. Haverback, B. J., Davidson, J. D. Gastroenterology, 1958, 35, 570.
2. 3.
Erspamer, V., Testini, A. J. Pharm., Lond. 1959, 11, 618. Bulbring, E., Crema, A. J. Physiol. 1959, 146, 18.
dimenhydrinate (’Dramamine’) (50 mg. six-hourly) has been given four hours after tretamine to control the nausea which occurs on the first day of treatment; and’ Villescon ’ (two tablets twice daily) has helped to restore a more than normal appetite by the fifth day of treatment. Tretamine in
single dose of 20-30 mg. (0-35 mg. per kg.) intravenously should be tried in inoperable undifferentiated cancer of the lung. The pancytopenia is manageable with prednisolone and penicillin and occasionally blood-transfusion. We do not yet know the duration of remission that this will produce nor have we a
the effects of a second course of problem of heemorrliage from necrotic tumour needs to be solved; and the possible place of this drug in combination with surgical excision must also be considered. any information treatment. The
on
We should like to acknowledge with thanks generous supplies of tretamine provided for this investigation by Imperial Chemical Industries Ltd., and much useful information from Dr. A. L. Walpole, of I.C.I. Research Laboratories.
Department of Thoracic Surgery, Baguley Hospital, Wythenshawe, Manchester
GORDON D. JACK M.B. Edin., F.R.C.S. L. DOYLE M.B. Dubl., M.R.C.P.I., D.C.H. M. M. PALEJWALLA M.B. Bombay
luminal pressure releases 5-H.T. from the gut, and Kowlessar et al. have reported an increase in the excretory product of 5-H.T. in the urine of patients with diarrhoea due to non-tropical sprue. It is possible, therefore, that 5-H.T. has some role in maintaining the motility of the intestine and that during increased small-bowel activity a larger quantity is released into the circulation. The were conducted to test this following experiments
hypothesis. METHODS
Volunteers were obtained from a group of healthy medical students. Serum-5-H.T. was extracted by the method of Hardisty and Stacey.5 The extracts were assayed on rat uteri 4. Kowlessar, O. D., WilHams, R. C., Law, D. H., Sleisinger, M. H. New Engl. J. Med. 1958, 259, 340. 5. Hardisty, R. M., Stacey, R. S. J. Physiol. 1955, 130, 711.
EFFECTS OF ADMINISTRATION OF CARBACHOL AND MAGNESIUM SULPHATE TO VOLUNTEERS
Preliminary
workers have found it to be very toxic on the hxmopoietic tissues when so used. Wilkinsonregarded it as the most toxic of all agents he had tried. During the period July to November, 1959, 43 patients with advanced inoperable lung cancer have been treated with tretamine. Untreated the majority of these patients would have been dead within three months and many earlier than this. After some experiment a pattern of dosage that has given very encouraging results has been worked out. 30 patients have shown subjective improvement and in 10 of these very marked to complete regression of the tumour has occurred. In 4 cases the chest X-ray has returned to normal or near normal and it is these 4 results that have stimulated this preliminary report. Radiologically each patient had a large mass at one or other lung root with considerable enlargement of the superior mediastinal shadows. Tumour tissue was obtained from the bronchi or from neck glands or from both sites and in each instance was reported as an undifferentiated carcinoma. Additional details are given in the table and X-rays representative of the series are shown in figs. 1 and 2. Treatment of these 4 cases consisted of one or two large doses of tretamine given intravenously, with a total dose of 15 to 30 mg. This dose may be followed by severe nausea for twenty-four hours. Within three days subjective improvement was evident, and chest X-ray done routinely on the fifth day showed evident shrinkage of the tumour mass. This shrinkage continued over the next three weeks and at the end of a month the chest X-ray had returned to normal. 7. Wilkinson, J. F. Proc. R. Soc. Med. 1953, 46, 685.
Communications
TRETAMINE IN THE TREATMENT OF INOPERABLE LUNG CANCER THE first
use
of tretamine
(2 :4 :6-triethyleneimino-
s-triazine, triethylene melamine [T.E.M.]) in the control of clinical
its release for research Industries as the result of observations 23 on the inhibitory action of this and related compounds on the growth of experimental tumours. Other clinical reports4 followed independent parallel discoveries made at the Sloan-Kettering Research Institute, New York.
malignancyfollowed by Imperial Chemical
purposes
Experimental work on mice 5 showed that tretamine had very considerable activity against sarcoma 180 and lymphosarcoma L 1. The best response was obtained by large doses at infrequent intervals. In 15 cases of lung cancer treated with this drug 6 4 showed marked clinical improvement but no radiological change. In this and most subsequent reports the method of dosage has been frequent small doses over a period of a few weeks. Most 1. Paterson, E., Boland, J. Brit. J. Cancer, 1951, 5, 28. 2. Rose, F. L., Hendry, J. A., Walpole, A. L. Nature, Lond. 1950, 165, 993. 3. Hendry, J. A., Homer, R. F., Rose, F. L., Walpole, A. L. Brit. J. Pharmacol. 1951, 6, 357. 4. Karnofsky, D. A., Burchenal, J. H., Armistead, G. C., Jr., Southam, C. M., Berstein, J. L., Craven, L. F., Rhoads, C. P. Arch. intern. Med. 1951, 87, 477. 5. Goldberg, B., Schoenbach, E. B. Cancer, 1951, 4, 1125. 6. Saline, M., Baum, G. L. J. Amer. med. Ass. 1954, 156, 1493.
(b)
(a)
Fig. 1-Case 1: (a) X-ray one month before start of treatment, thereafter the (b) one month after treatment: (c) three months after treatment.
Fig. (a) Day before treatment; given; (c) one month later.
patient
bed-ridden and portable films
(b)
five days after 30 mg. tretamine, the chest
were
unsatisfactory;
(c)
(b)
(a) 2-Case 2:
(c) was
was not
aspirated and
no
other treatment
was
207 DETAILS OF
4
CASES OF INOPERABLE BRONCHIAL CARCINOMA TREATED WITH TRETAMINE
Of the other 6 patients whose tumours have undergone marked regression, 3 died within twelve days after the start of treatment, owing to hxmorrhage from the tumour which had undergone necrosis; the platelet-count was at a safe level at the time of these haemorrhages. The remaining patients were treated because of metastases from bronchial tumours previously removed. Only a clinical assessment of the regression of these metastases could be made since they were not radiologically visible. The patients, however, are all well and symptomless and the follow-up results are awaited. In every case there has been a depression of the white blood-cells and the platelets. The white blood-count falls to its lowest level about the twelfth day and if below 500 at this time prednisolone and penicillin have been given for a period of seven to ten days. The platelet-count has been more variable and usually reaches its lowest point about the fifteenth day. In 2 patients a slight purpuric rash occurred with a plateletcount of less than 25,000 per c.mm. Both were given a transfusion of fresh blood. Some of the early cases were treated with repeated small doses of tretamine; in 3 of these severe purpura occurred and blood-transfusion was urgently needed. It is considered advisable to watch very carefully for evidence of purpura from the twelfth day onwards. It was found expedient to do blood and platelet counts on alternate days until a moderate pancytopenia was present and then daily until the counts had returned to near normal. Pyridoxine (100 mg. intramuscularly once daily) and
SERUM-5-HYDROXYTRYPTAMINE LEVELS FOLLOWING EXPERIMENTAL INCREASE IN GASTROINTESTINAL ACTIVITY IN MAN THERE are good reasons for believing that much of the blood-5-hydroxytryptamine (5-H.T.) is derived from the enterochromaffin cells of the gastrointestinal tract. Haverback and Davidsonhave demonstrated low levels in a patient with extensive resection of large and small bowel. By means of a cardiac catheter, Erspamer and Testini2 found more 5-H.T. in the hepatic vein than in the inferior vena cava of patients. Experiments on the guineapig intestinehave shown that increased intra1. Haverback, B. J., Davidson, J. D. Gastroenterology, 1958, 35, 570.
2. 3.
Erspamer, V., Testini, A. J. Pharm., Lond. 1959, 11, 618. Bulbring, E., Crema, A. J. Physiol. 1959, 146, 18.
dimenhydrinate (’Dramamine’) (50 mg. six-hourly) has been given four hours after tretamine to control the nausea which occurs on the first day of treatment; and’ Villescon ’ (two tablets twice daily) has helped to restore a more than normal appetite by the fifth day of treatment. Tretamine in
single dose of 20-30 mg. (0-35 mg. per kg.) intravenously should be tried in inoperable undifferentiated cancer of the lung. The pancytopenia is manageable with prednisolone and penicillin and occasionally blood-transfusion. We do not yet know the duration of remission that this will produce nor have we a
the effects of a second course of problem of heemorrliage from necrotic tumour needs to be solved; and the possible place of this drug in combination with surgical excision must also be considered. any information treatment. The
on
We should like to acknowledge with thanks generous supplies of tretamine provided for this investigation by Imperial Chemical Industries Ltd., and much useful information from Dr. A. L. Walpole, of I.C.I. Research Laboratories.
Department of Thoracic Surgery, Baguley Hospital, Wythenshawe, Manchester
GORDON D. JACK M.B. Edin., F.R.C.S. L. DOYLE M.B. Dubl., M.R.C.P.I., D.C.H. M. M. PALEJWALLA M.B. Bombay
luminal pressure releases 5-H.T. from the gut, and Kowlessar et al. have reported an increase in the excretory product of 5-H.T. in the urine of patients with diarrhoea due to non-tropical sprue. It is possible, therefore, that 5-H.T. has some role in maintaining the motility of the intestine and that during increased small-bowel activity a larger quantity is released into the circulation. The were conducted to test this following experiments
hypothesis. METHODS
Volunteers were obtained from a group of healthy medical students. Serum-5-H.T. was extracted by the method of Hardisty and Stacey.5 The extracts were assayed on rat uteri 4. Kowlessar, O. D., WilHams, R. C., Law, D. H., Sleisinger, M. H. New Engl. J. Med. 1958, 259, 340. 5. Hardisty, R. M., Stacey, R. S. J. Physiol. 1955, 130, 711.
EFFECTS OF ADMINISTRATION OF CARBACHOL AND MAGNESIUM SULPHATE TO VOLUNTEERS