Streptozotocin for Islet-cell Carcinoma

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with benign insulinomas 6,7; it awaits evaluation in insulin-secreting carcinoma. A trial in combination with diazoxide may be worth while, since the mechanisms of action of the two drugs are different.7 No systematic study has yet been made of conventional cancer chemotherapeutic agents in malignant insulinoma, but isolated case-reports indicate that 5-fluorouracil and alkylating agents may be effective.2 The search for drugs selectively toxic to the islet cells has been guided by observations in normal animals. Alloxan proved disappointing in clinical practice 8; tubercidin, an antibiotic isolated from Streptomyces tubercidicus, has produced objective remissions in a few patients, but toxic side-

effects 2,9 are obstacles to extensive clinical trial. More success has been achieved with streptozotocin, an antibiotic isolated from Streptomyces acromogenes which produces a permanent diabetic state in several species through direct destruction of the pancreatic beta cells.10 MURRAY-LYON et al.11,12 were the first to use this drug to treat a patient with an islet-cell carcinoma. It not only reduced seruminsulin levels and controlled hypoglycasmic symptoms; it also measurably reduced the tumour size on hepatic scintiscans. Now BRODER and CARTER,13 from the National Cancer Institute, have presented the results of streptozotocin therapy in 52 patients with metastatic islet-cell carcinoma. Return towards normal plasma insulin and glucose was seen in 25 of the 39 evaluable patients (64%), and most were able to return to work. The maximum response was not usually seen for around 35 days. There was objective reduction in tumour mass in 15 of the 30 evaluable patients with functioning tumours and in 5 of 8 with no apparent endocrine activity. The duration of biochemical remission varied from 60 days to more than 2 years and tumour size was reduced for a similar period. Full evaluation of the duration of the benefits of the treatment and the effects on survival will not be possible for some time, for 22 of the 52 patients are still alive, but so far the one-year survival-rate, measured from diagnosis to last follow-up, is significantly better in those showing a biochemical response or a reduction in tumour mass after treatment than in those who did not so respond. The median survival in the responders (1268 days) was more than double that of the nonresponders (518 days), and this is similar to the median survival after onset of symptoms (308 days) in a series of 22 patients with insulin-secreting metastatic islet-cell carcinoma reported 14 before the advent of specific therapy. These benefits were achieved, however, at the cost of considerable drugrelated toxicity, which caused the death of 6 patients. In the first few hours after administration nausea and vomiting were almost invariable, and hypoglycxmia-presumably due to massive release of insulin from the damaged pancreatic islet cells-may be a further complication. The most important side-effect is renal damage, which was detected in 65% of the patients analysed by the National Cancer Institute. Proteinuria is an early and reversible sign, but if treatment is continued there may be proximal renal tubular damage with nephrogenic diabetes

Sircus, W. Gut, 1969, 10, 506. Schein, P. S., DeLellis, R. A., Kahn, C. R., Gorden, P., Kraft, A. R. Ann. intern. Med. 1973, 79, 239. Kernen, J. A., Scofield, G., Koucky, C., Benitez, R. E., Ackerman, L. V. Am. J. clin. Path. 1963, 39, 137. Graber, A. L., Porte, D., Williams, R. H. Diabetes, 1966, 15, 143. Pohl, J. E. F., Thurston, H. Br. med. J. 1971, iv, 142. Knopp, R. H., Sheinin, J. C., Freinkel, N. Archs intern. Med. 1973, 130, 904. Cohen, M. S., Bower, R. H., Fidler, S. M., Jonsonbaugh, R. E., Sode, J. Lancet, 1973, i, 40. Luckens, F. D. W. Physiol. Rev. 1948, 28, 304.

Bisel, H. F., Ansfield, F. J., Mason, J. H., Wilson, W. I. Cancer Res. 1970, 30, 76. 10. Rakieten, N., Rakieten, M. L., Nadkarni, M. V. Cancer Chemother. Rep. 1963, 29, 91. 11. Murray-Lyon, I. M., Eddleston, A. L. W. F., Williams, R., Brown, M., Hogbin, B. M., Bennett, A., Edwards, J. C., Taylor, K. W. Lancet, 1968, ii, 895. 12. Murray-Lyon, I. M., Cassar, J., Coulson, R., Williams, R., Ganguli, P. C., Edwards, J. C., Taylor, K. W. Gut, 1971, 12, 717. 13. Broder, L. E., Carter, S. K. Ann. intern. Med. 1973, 79, 108. 14. Howard, J. M., Moss, N. H., Rhoads, J. E. Int. Abst. Surg. 1950, 90, 417.

THE LANCET Streptozotocin for Islet-cell Carcinoma CARCINOMA of the pancreatic islets may be associated with several clinical syndromes, since the tumour cells may produce a variety of indigenous hormones (insulin, gastrin, glucagon) or ectopic hormones (A.C.T.H., M.S.H., secretin-like-material, and 5-H.T.) either singly or in combination. 1,2 Hyperinsulinism is the most frequent, and next the

Zollinger-Ellison syndrome. Long survival with an insulin-secreting carcinoma has been reported,3 but the hypoglycsemia is more often severe, unremitting, and hard to control. The presence of metastases usually makes operation only palliative. Medical treatment is aimed either at antagonising the effects of insulin or at destroying the tumour cells. The antagonistic approach includes frequent meals, corticosteroids, growth horDiazoxide acts mone, glucagon, and diazoxide.2 insulin release,4 and, chiefly by directly inhibiting relief may be achieved although good symptomatic for some time, the tumour continues to grow and metastasise. Furthermore, drug side-effects are often troublesome.5 The anticonvulsant diphenylhydantoin likewise inhibits insulin release, and has been used in

patients

1. 2. 3.

4. 5. 6. 7. 8.

9.

1064 or renal failure. Renal toxicity caused 5 deaths in this series. There was slight disturbance in liver-function tests in 67% of the patients and occasional mild anaemia or depression of the whitecell or platelet counts; marrow depression contributed to the death of 1 patient. These toxic side-effects were unpredictable, but large single intravenous doses and intra-arterial therapy were apparently sometimes to blame. The National Cancer Institute is therefore recommending an initial intravenous dose of 1 g. per sq.m. body-surface area weekly for 4 weeks with close monitoring of renal, hepatic, and

insipidus

hxmatological function. The response of 5 patients in whom evidence for the production of at least

there was one other hormone in addition to insulin, and the response of some non-functioning islet-cell tumours, suggest that streptozotocin may deserve trial in other situations. In one patient in whom there was also production of insulin and glucagon by the tumour,", 12 gastrin production and gastric hypersecretion were temporarily diminished after streptozotocin. Total gastrectomy, however, remains the treatment of choice for the Zollinger-Ellison syndrome. 15 Streptozotocin has been disappointing in various adenocarcinomas 16 and in carcinoma of the lung,13 but encouraging results have been reported in a small number of patients with the carcinoid syndromeY-19 In hyperinsulinism due to benign islet-cell tumours it should seldom be needed, since the results of surgical treatment are excellent-and, at any event, these tumours,18 like the normal pancreas,16 seem comparatively resistant to the action of the drug. The carcinogenic activity of streptozotocin in rats 20 should also be remembered if administration is contemplated in non-malignant disease.

Boxing Brains

_

AN extensive investigation of the physical and mental effects of boxing by the Royal College of Physicians in 1969 21,22 showed conclusively that repeated blows to the head cause brain damage, the severity of which is closely linked to the total number of bouts fought. This study was confined to the physical and psychological examinations of 250 men who boxed between 1929 and 1955. Now CORSELLIS and others 23 have produced a comple15. 16. 17.

18. 19. 20.

21. 22. 23.

Wilson, S. D., Ellison, E. H. Am. J. Surg. 1966, 111, 787. Moertel, C. G., Reitemeier, R. J., Schutt, A. J., Hahn, R. G. Cancer Chemother. Rep. 1971, 55, 303. Feldman, J. M., Quickel, K. E., Marecek, R. L., Lebovitz, H. E. Sth. med. J. 1972, 65, 1325. Piroska, E., Kollin, E. Ann. intern. Med. 1971, 75, 477. Iweze, F. I., Owen-Smith, M., Polak, J. Proc. R. Soc. Med. 1972, 65, 164. Rakieten, N., Gordon, B. S., Cooney, D. A., Davis, R. D., Schein, P. S. Cancer Chemother. Rep. 1968, 52, 563. The Medical Aspects of Boxing. Royal College of Physicians of London, 1969. Lancet, 1969, i, 88. Corsellis, J. A. N., Bruton, C. J., Freeman-Browne, D. Psychol. Med. 1973, 3, 270.

mentary report on the neuropathological findings in the brains of 15 retired boxers, all of whom fought time between 1900 and 1940, and half of whom had had at least 300 fights or a career of 15 years or more. 12 men had been professionals, of whom 2 were world champions. The careers of these men were during the heyday of British professional boxing, in an age when controls on the number of fights a man might have or the frequency with which he could box were few, and when little concern was shown about the amount of punishment he might receive during a contest. In addition to neuropathological investigations, the private lives and careers of the men were studied in detail by a psychiatric social worker. The first neuropathological report on the late effects of boxing appeared in 1954,24 and since then, as CoRSELLis and his colleagues comment, " a relatively stereotyped pattern of structural change in the brain has been identified ". The main findings include abnormalities of the septum pellucidum, focal scarring of the cerebral and cerebellar hemispheres, degeneration of the substantia nigra, and widespread neurofibrillary tangles within the substance of the brain. Cavitation or frank rupture of the septum pellucidum was found in most of the boxers’ brains, but in non-boxers such changes were seen where there was a history of head injury sufficient to cause permanent disability or to leave evidence of damage within the brain itself. Although the precise mechanism is unknown, trauma is clearly implicated as the primary cause for septal abnormalities. Small areas of focal scarring were found in both the cerebral and cerebellar hemispheres. Such changes are common in the cerebral hemispheres of older people with other evidence of degeneration, but they are far from common in the cerebellum-except in boxers. The inferolateral and tonsillar regions at some

particularly affected, although microscopy Purkinje and granular cells with of efferent fibres indicating more demyelinisation widespread damage. It is noteworthy that similar changes have been found in the brains of animals subjected to repeated low intensity blows given in rapid succession, but not after harder blows at longer intervals.25 It thus becomes possible to appreciate why disorders of coordination involving speech and gait began relatively early in the careers of the men investigated. At a higher level in the brain, substantial loss of pigmented nerve-cells from the substantia nigra in four boxers correlated with the presence of extrapyramidal disorders in life. Similar, though not identical, pathological changes are com-

were

showed loss of

in non-boxers with Parkinson’s disease, due either to primary degenerative processes or to encephalitis. Studies on boxers’ brains have therefore

mon

24.

Brandenburg, W., Hallervorden, J. Virchows Arch. path. Physiol. 1954, 325, 680. 25. Unterharnscheidt, D. Tex. Rep. Biol. Med. 1970, 28, 421.

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