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TREATMENT OF SECONDARY HEPATIC TUMOURS BY LIGATION OF HEPATIC ARTERY AND INFUSION OF CYTOTOXIC DRUGS
172
TREATMENT OF SECONDARY HEPATIC TUMOURS BY LIGATION OF HEPATIC ARTERY AND INFUSION OF CYTOTOXIC DRUGS
IAIN M. MURRAY-LYON J. L. DAWSON M. O. RAKE V. A. PARSONS L. M. BLENDIS J. W. LAWS ROGER WILLIAMS Medical Research Council Group on Metabolism and
Hœmodynamics of Liver Disease, and Departments of Surgery, Chemical Pathology, and Radiology, King’s College Hospital,
previously been removed or was resected at the time of hepatic-artery ligation (table). Aortography and selective hepatic arteriography were used to define the vascular anatomy, and immediately before laparotomy each patient had an intravenous infusion of glucose and insulin to ensure adequate hepatic glycogen stores. The hepatic artery was ligated at several sites distal to the gastroduodenal and right gastric branches, and in some patients the left and right branches were ligated separately. The gallbladder was removed at operation because necrosis of the gallbladder has been described after hepatic-artery ligation. A nylon catheter was placed in the umbilical vein (six cases), a gastroepiploic vein (one case), or an omental vein (one case) and brought out through the skin.
London S.E.5
patients with symptoms due secondary tumour deposits in the liver were treated by ligation of the hepatic artery, and in five this was followed by infusion of the portal vein with 5-fluorouracil. Liver function was moderately disturbed in all patients but none went into hepatic failure, and the one postoperative death was due to a cardiac arrythmia. The surviving ten achieved good relief of abdominal pain for up to 10 months, and Serial scintiscans showed most gained weight. reduction in size of the deposits, and tumour necrosis was demonstrated on liver biopsy. In three patients with the carcinoid syndrome the necrosis was reflected biochemically by an immediate and striking rise in urinary 5-hydroxyindoleacetic-acid excretion followed by a return towards normal levels, and in these patients it is preferable to precede hepatic-artery ligation by a period of hepatic-artery infusion with cytotoxic drugs to ensure more controlled release of Summary
Eleven to
metabolites. Introduction
THE
hepatic artery provides the major bloodsupply to primary and secondary malignant tumours of the liver in man, and in 1952 Markowitz2 suggested ligation of the hepatic artery as a possible method of Tumour tissue does become necrotic after this procedure,3 and a few patients have been treated in this way in Thailand4 and Swedenwith convincing symptomatic relief. Secondary tumour deposits may also derive some blood-supply from the portal vein, and Bengmark6 suggested infusing the portal vein with cytotoxic drugs, after ligation of the hepatic artery, to treat any areas of surviving tumour tissue. We describe here the results of such therapy in eleven patients with secondary hepatic tumours. Serial measurement of liver function by bromsulphthalein (B.S.P.) clearance, urinary 5-hydroxyindoleacetic acid (5-H.l.A.A.) output in three patients with functioning carcinoid tumours, and hepatic scintiscanning have been used as objective measures of improvement. treatment.
Patients and Methods All patients had lost weight and were experiencing severe upper abdominal pain attributable to hepatic metastases. The three patients with carcinoid tumours were having troublesome attacks of flushing and diarrhoea not controllable by medical measures. No patient had evidence of metastases beyond the liver except patient 10 in whom radiographs were suggestive of a metastasis in the lumbar spine. Except for case 3 the primary tumour had either
Immediate
There
Postoperative
Results Period
postoperative death on the third day cardiac arrhythmia. At necropsy the tumour tissue showed extensive necrosis, although in metastases extending to the liver capsule there was a rim of surviving tumour. Liver cells adjacent to was one
(case 9), due
to a
some metastases
showed
recent
necrosis but most of
the
hepatic parenchyma was normal (fig. 1). Changes in liver function occurred in all patients and were maximal during the first 3 days after operation. The plasma-bilirubin rose transiently to 3-5, 1-3, and I’lmg. per 100 ml. in three patients and the serum-alkaline-phosphatase rose in eight patients; the most striking changes were in the serum-aspartatetransaminase (fig. 2). Liver-function tests had returned towards normal by the tenth day. B.S.P. clearance 2-4 weeks after hepatic-artery ligation was better in five of the seven patients in whom this was estimated (fig. 3). Liver biopsy in case 1 at 6 weeks showed viable tumour tissue only, but in cases 9, 3, and 6 samples of liver taken 3 days, and 2 and 4 weeks, respectively, after ligation of the hepatic artery showed extensive tumour necrosis with little inflammatory response. Preoperative biopsies in these cases had shown viable tumour tissue only. In case 7, at 2 months, there was also extensive necrosis. Fever was present before operation in eight patients and was probably due to hepatic metastases as there
Fig. 1-Case
9: Histological section showing normal liver (left) and necrotic tumour tissue (right) 3 days after ligation of the hepatic artery.
The marginal zone shows some necrotic liver cells and inflammatory cell infiltrate. Viable tumour cells are seen at the extreme right. (Haematoxylin and eosin; reduced to 3/6 of 150.)
173
Fig. 3-Serial B.S.P. excretion tests in eight patients. The percentage retention in the plasma at 45 minutes determined after intravenous injection of 5 mg. B.S.P. per
was
kg.
body-weight. few hours after return to the ward. In retrospect this clinical state was clearly due to a massive release of 5-hydroxytryptamine and other vasoactive compounds from the tumour, for the urinary excretion of 5-H.I.A.A. in the first 24 hours after operation was 2600 mg. By day 3 she was better, and although she required a further laparotomy on day 13 for drainage of a wound abscess which was in continuity with a necrotic cavity in the liver, her condition steadily improved. Histology of an operative liver biopsy taken on day 13 showed extensive necrosis of tumour and liver cells, and viable tumour cells were seen only beneath the capsule. After the initial peak, urinary 5-H.I.A.A. levels fell rapidly to within the normal range and she had no further symptoms of the carcinoid syndrome until the sixth month when minor symptoms returned with some rise in the urinary 5-H.I.A.A. excretion. Because of this experience we attempted to control the release of tumour products in cases 6 and 11 by a period of preoperative hepatic artery infusion with 5-fluorouracil (table). Also, methysergide and flufenamic acid were given orally as pharmacological antagoa
Fig. 2-Serum-aspartate-transaminase levels after ligation of the hepatic artery and before infusion with 5-fluorouracil. Dotted line denotes change of scale. Shaded area shows normal range. ____________
evidence of infection. After the operation there was a rise in temperature in all patients, but this had returned to normal in seven by the time of discharge. It had been planned to start infusion of the portal venous system with 5-fluorouracil as soon as the serum-aspartate-transaminase returned to normal, but because of displacement of the catheter during this time only five cases were treated. The doses used are given in the table. Patients with Carcinoid Syndrome The first patient operated on (case 3) became shocked with severe sweating and generalised cyanosis was no
TYPES OF PRIMARY
TUMOUR, CYTOTOXIC THERAPY, AND CLINICAL RESULTS
174 a biopsy from case 2 at 11 months there extensive tumour necrosis. Unfortunately in none of these cases were biopsies done during the earlier postoperative period so comparison is not possible. Courses of 5-fluorouracil were given at the time of relapse, either systemically or by hepatic arterial or portal venous infusion (table), but objective evidence of further remission in these cases was slight.
although in was
Liver Scintiscans and
Aortography
Hepatic scintiscans, using technetium-99m-labelled sulphur colloid, were done before and at intervals after ligation of the hepatic artery in nine patients. Serial measurements obtained by planimetry showed that the tumour area was reduced by a mean of 41-4 sq. cm., representing approximately 10% of the total liver Some reduction in the area of normal liver was also noted, though this less than in the tumour area (mean reduction 10 sq. cm.). During the succeeding months there was little change in the area of normal liver but the tumour area gradually returned to the preoperative value. In six patients aortography was done between 7 and 9 months after ligation of the hepatic artery. In each case some filling of the intrahepatic branches of the hepatic artery was obtained, but there was considerable delay and they were smaller than before the ligation. The collateral supply to the liver was carried by enlarged right phrenic and intercostal arteries in two cases (cases 1 and 5), by a leash of local collaterals around the site of ligation in four cases (cases 2, 4, 5, and 8), and in one patient (case 3) the hepatic artery filled through a previously undemonstrated branch of the superior mesenteric artery whereas before it had filled from the coeliac axis. area.
Fig. 4-Case
6: serial measurements of 24-hour urine 5-H.I.A.A.
output.
Note the rise during infusion of the hepatic artery with 5-fluorouracil and the further peak after ligation of the hepatic arterv.
nists of 5-hydroxytryptamine and kinins, respectively. No severe symptoms occurred, and serial urinary 5-H.I.A.A. estimations demonstrated an increase in excretion during the period of infusion (fig. 4). The postoperative course in these patients was uneventful, and the rise in serum-aspartate-transaminase was mirrored by a peak in urinary 5-H.i.A.A. output which then fell towards normal (fig. 4). Later
All
Changes
patients who survived the operation derived symptomatic benefit. Most striking was the almost immediate loss of abdominal pain and improvement in wellbeing. Most patients gained weight (table) ten
lost their fever as described above. This improvement is well illustrated by the following and
seven
case-history : A 54-year-old man (case 8) had a left orbital clearance in 1965 for a malignant melanoma. He remained well until January, 1969, when he started to get recurrent bouts of severe right upper abdominal pain often associated with rigors. He felt generally unwell and lost weight. In July, 1969, the hepatic artery was ligated-the liver was extensively infiltrated by melanoma deposits, and lymph-nodes at the hilum of the liver were also involved. From the second to eighteenth postoperative days the liver was infused with 5-fluorouracil via a catheter placed in a gastroepiploic vein. The right-upper-quadrant pain disappeared within a few days of hepatic-artery ligation and the fever which had been persistently present preoperatively had settled by the time of discharge. He gained 4 kg. in weight and returned to work. He remains well in the tenth month although recently there has been some increase in the size of the liver, and B.s.p. retention has increased.
The shortest period of remission was in case 7 in whom abdominal pain was completely relieved for only 3 months after operation. In the other seven long-term survivors the remission of symptoms varied from 5 to 10 months (table). Relapse was usually characterised by a combination of weight-loss, and abdominal pain. It was always associated with increasing B.s.p. retention (fig. 3), and rising levels of serum-alkaline-phosphatase. Liver biopsies from cases 4 and 5 during clinical relapse at 8 and 9 months, respectively, showed viable tumour tissue only,
malaise,
Discussion
When tumour metastases are confined to one lobe of the liver, resection may offer the best chance of
cure,6 but, unfortunately, they are usually scattered through both lobes. The results of systemic cytotoxic therapy are disappointing, and although prolonged local infusion of the liver 8 may be more successful this is often attended by serious complications, and the patients require close supervision. In a review of the surgical literature in 1933, Graham and Cannell 9 drew attention to the high mortality which followed ligation of the hepatic artery. Severe hepatic necrosis is likely to result if the artery is ligated during an extensive abdominal operation and if the postoperative course is complicated by hypotension and sepsis.1O More recent experience, however, has shown that, except in these circumstances, relatively little disturbance of the liver function follows this procedure," and our patients tolerated hepatic-artery ligation well. Dogs almost always die after ligation of the hepatic artery, due to septic liver infarction which can be largely prevented by penicillin therapy. 12 With the possible exception of case 3 there was no evidence of septicaemia or hepatic sepsis in our patients. Nevertheless it would seem wise to give antibiotics routinely during the first week. Using an intrahepatic injection of radioxenon to measure liver blood-flow Gelin et al.13 showed that ligation of the hepatic artery reduced flow through
175 tissue almost to zero whilst that through normal liver was only slightly reduced. In our series necrosis of tumour deposits was demonstrated on liver biopsy in four patients up to 11 months after operation. The presence of viable tumour tissue in the subcapsular region in two cases shows that collateral circulation through the capsule may provide an important blood-supply to such metastases. The sharp rise in serum-aspartate-transaminase after hepatic-artery ligation indicates that some necrosis of normal hepatic parenchyma did occur, and this was demonstrated in the early postoperative liver biopsies from cases 3 and 9. Furthermore serial liver scans showed that the area of normal liver fell in tumour
patients. ten patients who returned home were considerably improved symptomatically and had clinical remissions lasting up to 10 months. The most striking changes were the loss of abdominal pain and the gain in weight. The three patients with the carcinoid syndrome were relieved of their distressing symptoms and the immediate postoperative rise in urinary
with hepatic metastases is very poor, with a median survival time of 75 days in one series 16 although occasional patients survive for long periods. A controlled trial is needed to establish that life expectancy is prolonged, but it is clear that worthwhile symptomatic improvement can be achieved by hepatic-artery ligation. Furthermore, this is relatively easy to carry out, rarely upsets the patients for more than a few days, requires no special apparatus, and is attended by few
complications. We thank Mr. N. H. Porter for permission to include details case 11 and to Dr. Merton Sandler for his help with the patients with the carcinoid syndrome.
of
Requests
for
reprints should
some
The
5-H.I.A.A. output was a clear biochemical marker of the extent of the tumour necrosis. The subsequent drop in output towards normal levels suggests that a major part of the tumour mass had been destroyed. The main indication for this form of therapy is pain due to hepatic tumour deposits in patients who do not have clinical evidence of widespread metastatic disease. The presence of small peritoneal seedlings in several of our cases did not seem to detract from the benefits of the treatment. It is clearly not possible to assess the independent effect of the cytotoxic therapy and the hepatic-artery ligation in many of these patients. Five cases, however, did not have 5-fluorouracil at first and yet showed good symptomatic and biochemical improvement. After clinical relapse further local or systemic 5-fluorouracil seemed to have little effect though more benefit would be expected from portal-vein
infusion immediately following hepatic-artery ligation when the surviving tumour tissue is receiving its
blood-supply largely from the portal vein. Several technical problems were encountered in the portalvein infusion, including displacement of the catheters from thin-walled venous tributaries. The umbilical vein is thicker walled, but, usually, only the left lobe of the liver can be infused by this route. Nylon catheters tend to harden after some weeks and kink at the site of ligatures, and we are now trying catheters made of siliconised rubber. It is arterial
probably impossible completely to cut off the blood-supply to the liver. Michels 14 described twenty-six routes by which arterial blood can reach the liver and the development of a collateral circulation has been demonstrated in man by arteriography as soon as one week after hepatic-artery ligation.15 Repeat angiography in our cases showed that the arterial supply was considerably reduced even months after ligation. The enlargement of the phrenic artery seen in case 1 has also been observed in dogs after hepatic-artery ligation. Nilsson et all reported a doubling in survival-times of rats with secondary malignant tumours after ligation of the hepatic artery. In man the prognosis of patients
be addressed
to
R. W.
REFERENCES G. Am.
Breedis, C., Young, J. Path. 1954, 30, 969. Markowitz, J. Surgery Gynec. Obstet. 1952, 95, 644. Mori, W., Masuda, M., Miyanaga, T. Surgery, St. Louis, 1966, 59, 359. 4. Plengvanit, U., Limwonges, K., Viranuvatti, V., Hitanant, S., Chearanai, O. 3rd int. Symp. int. Ass. Study Liver; p. 490. Antwerp, 1967. 5. Nilsson, L. A. V. Rev. Surg. 1966, 23, 374. 6. Bengmark, S. Schweiz. med. Wschr. 1969, 99, 571. 7. Moertel, C. G. in Year Book of Drug Therapy (edited by H. Beckman); p. 129. Chicago, 1969. 8. Sullivan, R. D., Zurek, W. Z. J. Am. med. Ass. 1965, 194, 481. 9. Graham, R. R., Cannell, D. Br. J. Surg. 1933, 20, 566. 10. Brittain, R. S., Marchioro, T. L., Hermann, G., Waddell, W. R., Starzl, T. E. Am. J. Surg. 1964, 107, 822. 11. Almersjö, O., Bengmark, S., Engevik, L., Hafstrom, L. O., Loughbridge, B. P., Nilsson, L. A. V. Ann. Surg. 1968, 167, 9. 12. Markowitz, J., Rappaport, A., Scott, A. C. Proc. Soc. exp. Biol. Med. 1949, 70, 305. 13. Gelin, L.-E., Lewis, D. H., Nilsson, L. Acta hepato-splenolo. 1968, 15, 21. 14. Michels, N. A. J. Am. med. Ass. 1960, 172, 125. 15. Loughbridge, B. P., Almersj&oacgr;, O., Bengmark, S., Hafström, L. O. J. Okla. St. med. Ass. 1968, 61, 207. 16. Jaffe, B. M., Donegan, W. L., Watson, F., Spratt, J. S. Surgery Gynec. Obstet. 1968, 127, 1. 17. Nilsson, L. A. V., Rudenstam, C-M., Zettergren, L. Bibl. anat. 1967, 9, 425. 1. 2. 3.
EVALUATION OF IRON SUPPLEMENTS IN PREVENTION OF IRON-DEFICIENCY ANÆMIA P. C. ELWOOD
W. E. WATERS
W. J. W. GREENE Medical Research Council
Epidemiology Cardiff CF2 3AS
Unit
(South Wales),
In many countries an attempt is made a national level to prevent iron deficiency by enriching food with iron. The amount by which iron intake should be increased is unknown, and decisions seem to be based on very inadequate evidence. Trials of iron supplements in two at-risk groups revealed an effect on hæmoglobin level of a supplement of 10 mg. iron per day, but gave no clear evidence of an effect of a smaller supplement.
Summary
at
Introduction
By how much should the daily iron intake be increased to prevent iron deficiency in the community ? The Committee on Iron Deficiency of the Council on Foods and Nutritionhas recommended a mean dietary intake of 20 mg. per day in women in the U.S.A., even though they recognise that this could at
TREATMENT OF SECONDARY HEPATIC TUMOURS BY LIGATION OF HEPATIC ARTERY AND INFUSION OF CYTOTOXIC DRUGS
IAIN M. MURRAY-LYON J. L. DAWSON M. O. RAKE V. A. PARSONS L. M. BLENDIS J. W. LAWS ROGER WILLIAMS Medical Research Council Group on Metabolism and
Hœmodynamics of Liver Disease, and Departments of Surgery, Chemical Pathology, and Radiology, King’s College Hospital,
previously been removed or was resected at the time of hepatic-artery ligation (table). Aortography and selective hepatic arteriography were used to define the vascular anatomy, and immediately before laparotomy each patient had an intravenous infusion of glucose and insulin to ensure adequate hepatic glycogen stores. The hepatic artery was ligated at several sites distal to the gastroduodenal and right gastric branches, and in some patients the left and right branches were ligated separately. The gallbladder was removed at operation because necrosis of the gallbladder has been described after hepatic-artery ligation. A nylon catheter was placed in the umbilical vein (six cases), a gastroepiploic vein (one case), or an omental vein (one case) and brought out through the skin.
London S.E.5
patients with symptoms due secondary tumour deposits in the liver were treated by ligation of the hepatic artery, and in five this was followed by infusion of the portal vein with 5-fluorouracil. Liver function was moderately disturbed in all patients but none went into hepatic failure, and the one postoperative death was due to a cardiac arrythmia. The surviving ten achieved good relief of abdominal pain for up to 10 months, and Serial scintiscans showed most gained weight. reduction in size of the deposits, and tumour necrosis was demonstrated on liver biopsy. In three patients with the carcinoid syndrome the necrosis was reflected biochemically by an immediate and striking rise in urinary 5-hydroxyindoleacetic-acid excretion followed by a return towards normal levels, and in these patients it is preferable to precede hepatic-artery ligation by a period of hepatic-artery infusion with cytotoxic drugs to ensure more controlled release of Summary
Eleven to
metabolites. Introduction
THE
hepatic artery provides the major bloodsupply to primary and secondary malignant tumours of the liver in man, and in 1952 Markowitz2 suggested ligation of the hepatic artery as a possible method of Tumour tissue does become necrotic after this procedure,3 and a few patients have been treated in this way in Thailand4 and Swedenwith convincing symptomatic relief. Secondary tumour deposits may also derive some blood-supply from the portal vein, and Bengmark6 suggested infusing the portal vein with cytotoxic drugs, after ligation of the hepatic artery, to treat any areas of surviving tumour tissue. We describe here the results of such therapy in eleven patients with secondary hepatic tumours. Serial measurement of liver function by bromsulphthalein (B.S.P.) clearance, urinary 5-hydroxyindoleacetic acid (5-H.l.A.A.) output in three patients with functioning carcinoid tumours, and hepatic scintiscanning have been used as objective measures of improvement. treatment.
Patients and Methods All patients had lost weight and were experiencing severe upper abdominal pain attributable to hepatic metastases. The three patients with carcinoid tumours were having troublesome attacks of flushing and diarrhoea not controllable by medical measures. No patient had evidence of metastases beyond the liver except patient 10 in whom radiographs were suggestive of a metastasis in the lumbar spine. Except for case 3 the primary tumour had either
Immediate
There
Postoperative
Results Period
postoperative death on the third day cardiac arrhythmia. At necropsy the tumour tissue showed extensive necrosis, although in metastases extending to the liver capsule there was a rim of surviving tumour. Liver cells adjacent to was one
(case 9), due
to a
some metastases
showed
recent
necrosis but most of
the
hepatic parenchyma was normal (fig. 1). Changes in liver function occurred in all patients and were maximal during the first 3 days after operation. The plasma-bilirubin rose transiently to 3-5, 1-3, and I’lmg. per 100 ml. in three patients and the serum-alkaline-phosphatase rose in eight patients; the most striking changes were in the serum-aspartatetransaminase (fig. 2). Liver-function tests had returned towards normal by the tenth day. B.S.P. clearance 2-4 weeks after hepatic-artery ligation was better in five of the seven patients in whom this was estimated (fig. 3). Liver biopsy in case 1 at 6 weeks showed viable tumour tissue only, but in cases 9, 3, and 6 samples of liver taken 3 days, and 2 and 4 weeks, respectively, after ligation of the hepatic artery showed extensive tumour necrosis with little inflammatory response. Preoperative biopsies in these cases had shown viable tumour tissue only. In case 7, at 2 months, there was also extensive necrosis. Fever was present before operation in eight patients and was probably due to hepatic metastases as there
Fig. 1-Case
9: Histological section showing normal liver (left) and necrotic tumour tissue (right) 3 days after ligation of the hepatic artery.
The marginal zone shows some necrotic liver cells and inflammatory cell infiltrate. Viable tumour cells are seen at the extreme right. (Haematoxylin and eosin; reduced to 3/6 of 150.)
173
Fig. 3-Serial B.S.P. excretion tests in eight patients. The percentage retention in the plasma at 45 minutes determined after intravenous injection of 5 mg. B.S.P. per
was
kg.
body-weight. few hours after return to the ward. In retrospect this clinical state was clearly due to a massive release of 5-hydroxytryptamine and other vasoactive compounds from the tumour, for the urinary excretion of 5-H.I.A.A. in the first 24 hours after operation was 2600 mg. By day 3 she was better, and although she required a further laparotomy on day 13 for drainage of a wound abscess which was in continuity with a necrotic cavity in the liver, her condition steadily improved. Histology of an operative liver biopsy taken on day 13 showed extensive necrosis of tumour and liver cells, and viable tumour cells were seen only beneath the capsule. After the initial peak, urinary 5-H.I.A.A. levels fell rapidly to within the normal range and she had no further symptoms of the carcinoid syndrome until the sixth month when minor symptoms returned with some rise in the urinary 5-H.I.A.A. excretion. Because of this experience we attempted to control the release of tumour products in cases 6 and 11 by a period of preoperative hepatic artery infusion with 5-fluorouracil (table). Also, methysergide and flufenamic acid were given orally as pharmacological antagoa
Fig. 2-Serum-aspartate-transaminase levels after ligation of the hepatic artery and before infusion with 5-fluorouracil. Dotted line denotes change of scale. Shaded area shows normal range. ____________
evidence of infection. After the operation there was a rise in temperature in all patients, but this had returned to normal in seven by the time of discharge. It had been planned to start infusion of the portal venous system with 5-fluorouracil as soon as the serum-aspartate-transaminase returned to normal, but because of displacement of the catheter during this time only five cases were treated. The doses used are given in the table. Patients with Carcinoid Syndrome The first patient operated on (case 3) became shocked with severe sweating and generalised cyanosis was no
TYPES OF PRIMARY
TUMOUR, CYTOTOXIC THERAPY, AND CLINICAL RESULTS
174 a biopsy from case 2 at 11 months there extensive tumour necrosis. Unfortunately in none of these cases were biopsies done during the earlier postoperative period so comparison is not possible. Courses of 5-fluorouracil were given at the time of relapse, either systemically or by hepatic arterial or portal venous infusion (table), but objective evidence of further remission in these cases was slight.
although in was
Liver Scintiscans and
Aortography
Hepatic scintiscans, using technetium-99m-labelled sulphur colloid, were done before and at intervals after ligation of the hepatic artery in nine patients. Serial measurements obtained by planimetry showed that the tumour area was reduced by a mean of 41-4 sq. cm., representing approximately 10% of the total liver Some reduction in the area of normal liver was also noted, though this less than in the tumour area (mean reduction 10 sq. cm.). During the succeeding months there was little change in the area of normal liver but the tumour area gradually returned to the preoperative value. In six patients aortography was done between 7 and 9 months after ligation of the hepatic artery. In each case some filling of the intrahepatic branches of the hepatic artery was obtained, but there was considerable delay and they were smaller than before the ligation. The collateral supply to the liver was carried by enlarged right phrenic and intercostal arteries in two cases (cases 1 and 5), by a leash of local collaterals around the site of ligation in four cases (cases 2, 4, 5, and 8), and in one patient (case 3) the hepatic artery filled through a previously undemonstrated branch of the superior mesenteric artery whereas before it had filled from the coeliac axis. area.
Fig. 4-Case
6: serial measurements of 24-hour urine 5-H.I.A.A.
output.
Note the rise during infusion of the hepatic artery with 5-fluorouracil and the further peak after ligation of the hepatic arterv.
nists of 5-hydroxytryptamine and kinins, respectively. No severe symptoms occurred, and serial urinary 5-H.I.A.A. estimations demonstrated an increase in excretion during the period of infusion (fig. 4). The postoperative course in these patients was uneventful, and the rise in serum-aspartate-transaminase was mirrored by a peak in urinary 5-H.i.A.A. output which then fell towards normal (fig. 4). Later
All
Changes
patients who survived the operation derived symptomatic benefit. Most striking was the almost immediate loss of abdominal pain and improvement in wellbeing. Most patients gained weight (table) ten
lost their fever as described above. This improvement is well illustrated by the following and
seven
case-history : A 54-year-old man (case 8) had a left orbital clearance in 1965 for a malignant melanoma. He remained well until January, 1969, when he started to get recurrent bouts of severe right upper abdominal pain often associated with rigors. He felt generally unwell and lost weight. In July, 1969, the hepatic artery was ligated-the liver was extensively infiltrated by melanoma deposits, and lymph-nodes at the hilum of the liver were also involved. From the second to eighteenth postoperative days the liver was infused with 5-fluorouracil via a catheter placed in a gastroepiploic vein. The right-upper-quadrant pain disappeared within a few days of hepatic-artery ligation and the fever which had been persistently present preoperatively had settled by the time of discharge. He gained 4 kg. in weight and returned to work. He remains well in the tenth month although recently there has been some increase in the size of the liver, and B.s.p. retention has increased.
The shortest period of remission was in case 7 in whom abdominal pain was completely relieved for only 3 months after operation. In the other seven long-term survivors the remission of symptoms varied from 5 to 10 months (table). Relapse was usually characterised by a combination of weight-loss, and abdominal pain. It was always associated with increasing B.s.p. retention (fig. 3), and rising levels of serum-alkaline-phosphatase. Liver biopsies from cases 4 and 5 during clinical relapse at 8 and 9 months, respectively, showed viable tumour tissue only,
malaise,
Discussion
When tumour metastases are confined to one lobe of the liver, resection may offer the best chance of
cure,6 but, unfortunately, they are usually scattered through both lobes. The results of systemic cytotoxic therapy are disappointing, and although prolonged local infusion of the liver 8 may be more successful this is often attended by serious complications, and the patients require close supervision. In a review of the surgical literature in 1933, Graham and Cannell 9 drew attention to the high mortality which followed ligation of the hepatic artery. Severe hepatic necrosis is likely to result if the artery is ligated during an extensive abdominal operation and if the postoperative course is complicated by hypotension and sepsis.1O More recent experience, however, has shown that, except in these circumstances, relatively little disturbance of the liver function follows this procedure," and our patients tolerated hepatic-artery ligation well. Dogs almost always die after ligation of the hepatic artery, due to septic liver infarction which can be largely prevented by penicillin therapy. 12 With the possible exception of case 3 there was no evidence of septicaemia or hepatic sepsis in our patients. Nevertheless it would seem wise to give antibiotics routinely during the first week. Using an intrahepatic injection of radioxenon to measure liver blood-flow Gelin et al.13 showed that ligation of the hepatic artery reduced flow through
175 tissue almost to zero whilst that through normal liver was only slightly reduced. In our series necrosis of tumour deposits was demonstrated on liver biopsy in four patients up to 11 months after operation. The presence of viable tumour tissue in the subcapsular region in two cases shows that collateral circulation through the capsule may provide an important blood-supply to such metastases. The sharp rise in serum-aspartate-transaminase after hepatic-artery ligation indicates that some necrosis of normal hepatic parenchyma did occur, and this was demonstrated in the early postoperative liver biopsies from cases 3 and 9. Furthermore serial liver scans showed that the area of normal liver fell in tumour
patients. ten patients who returned home were considerably improved symptomatically and had clinical remissions lasting up to 10 months. The most striking changes were the loss of abdominal pain and the gain in weight. The three patients with the carcinoid syndrome were relieved of their distressing symptoms and the immediate postoperative rise in urinary
with hepatic metastases is very poor, with a median survival time of 75 days in one series 16 although occasional patients survive for long periods. A controlled trial is needed to establish that life expectancy is prolonged, but it is clear that worthwhile symptomatic improvement can be achieved by hepatic-artery ligation. Furthermore, this is relatively easy to carry out, rarely upsets the patients for more than a few days, requires no special apparatus, and is attended by few
complications. We thank Mr. N. H. Porter for permission to include details case 11 and to Dr. Merton Sandler for his help with the patients with the carcinoid syndrome.
of
Requests
for
reprints should
some
The
5-H.I.A.A. output was a clear biochemical marker of the extent of the tumour necrosis. The subsequent drop in output towards normal levels suggests that a major part of the tumour mass had been destroyed. The main indication for this form of therapy is pain due to hepatic tumour deposits in patients who do not have clinical evidence of widespread metastatic disease. The presence of small peritoneal seedlings in several of our cases did not seem to detract from the benefits of the treatment. It is clearly not possible to assess the independent effect of the cytotoxic therapy and the hepatic-artery ligation in many of these patients. Five cases, however, did not have 5-fluorouracil at first and yet showed good symptomatic and biochemical improvement. After clinical relapse further local or systemic 5-fluorouracil seemed to have little effect though more benefit would be expected from portal-vein
infusion immediately following hepatic-artery ligation when the surviving tumour tissue is receiving its
blood-supply largely from the portal vein. Several technical problems were encountered in the portalvein infusion, including displacement of the catheters from thin-walled venous tributaries. The umbilical vein is thicker walled, but, usually, only the left lobe of the liver can be infused by this route. Nylon catheters tend to harden after some weeks and kink at the site of ligatures, and we are now trying catheters made of siliconised rubber. It is arterial
probably impossible completely to cut off the blood-supply to the liver. Michels 14 described twenty-six routes by which arterial blood can reach the liver and the development of a collateral circulation has been demonstrated in man by arteriography as soon as one week after hepatic-artery ligation.15 Repeat angiography in our cases showed that the arterial supply was considerably reduced even months after ligation. The enlargement of the phrenic artery seen in case 1 has also been observed in dogs after hepatic-artery ligation. Nilsson et all reported a doubling in survival-times of rats with secondary malignant tumours after ligation of the hepatic artery. In man the prognosis of patients
be addressed
to
R. W.
REFERENCES G. Am.
Breedis, C., Young, J. Path. 1954, 30, 969. Markowitz, J. Surgery Gynec. Obstet. 1952, 95, 644. Mori, W., Masuda, M., Miyanaga, T. Surgery, St. Louis, 1966, 59, 359. 4. Plengvanit, U., Limwonges, K., Viranuvatti, V., Hitanant, S., Chearanai, O. 3rd int. Symp. int. Ass. Study Liver; p. 490. Antwerp, 1967. 5. Nilsson, L. A. V. Rev. Surg. 1966, 23, 374. 6. Bengmark, S. Schweiz. med. Wschr. 1969, 99, 571. 7. Moertel, C. G. in Year Book of Drug Therapy (edited by H. Beckman); p. 129. Chicago, 1969. 8. Sullivan, R. D., Zurek, W. Z. J. Am. med. Ass. 1965, 194, 481. 9. Graham, R. R., Cannell, D. Br. J. Surg. 1933, 20, 566. 10. Brittain, R. S., Marchioro, T. L., Hermann, G., Waddell, W. R., Starzl, T. E. Am. J. Surg. 1964, 107, 822. 11. Almersjö, O., Bengmark, S., Engevik, L., Hafstrom, L. O., Loughbridge, B. P., Nilsson, L. A. V. Ann. Surg. 1968, 167, 9. 12. Markowitz, J., Rappaport, A., Scott, A. C. Proc. Soc. exp. Biol. Med. 1949, 70, 305. 13. Gelin, L.-E., Lewis, D. H., Nilsson, L. Acta hepato-splenolo. 1968, 15, 21. 14. Michels, N. A. J. Am. med. Ass. 1960, 172, 125. 15. Loughbridge, B. P., Almersj&oacgr;, O., Bengmark, S., Hafström, L. O. J. Okla. St. med. Ass. 1968, 61, 207. 16. Jaffe, B. M., Donegan, W. L., Watson, F., Spratt, J. S. Surgery Gynec. Obstet. 1968, 127, 1. 17. Nilsson, L. A. V., Rudenstam, C-M., Zettergren, L. Bibl. anat. 1967, 9, 425. 1. 2. 3.
EVALUATION OF IRON SUPPLEMENTS IN PREVENTION OF IRON-DEFICIENCY ANÆMIA P. C. ELWOOD
W. E. WATERS
W. J. W. GREENE Medical Research Council
Epidemiology Cardiff CF2 3AS
Unit
(South Wales),
In many countries an attempt is made a national level to prevent iron deficiency by enriching food with iron. The amount by which iron intake should be increased is unknown, and decisions seem to be based on very inadequate evidence. Trials of iron supplements in two at-risk groups revealed an effect on hæmoglobin level of a supplement of 10 mg. iron per day, but gave no clear evidence of an effect of a smaller supplement.
Summary
at
Introduction
By how much should the daily iron intake be increased to prevent iron deficiency in the community ? The Committee on Iron Deficiency of the Council on Foods and Nutritionhas recommended a mean dietary intake of 20 mg. per day in women in the U.S.A., even though they recognise that this could at