Palliative treatment of liver tumoursReview
Department of Surgery, Lund University Hospital
In a recent article by professor Bengmark on the palliative management of hepatic tumours the objective of such a treatment was highlighted (1). It was stated that palliative treatment should be developed which is simple, can be performed on a ambulatory basis for life, involves active participation by the patient and which has monimal or no side effects. Such treatment should not reduce mental or physical activity. No such treatment exist today.
What should be the goals for palliative treatment? The ultimate goal is to prolong symptoms-free survival, but also to relieve symptoms, an effect which is not defined or observed in many of the studies performed.
The resectability rate of primary liver cancer and metastasis is low and mostly below 20% (2). The natural history of patients with untreated primary liver cancer and metastases is also low. For primary liver cancer a median survival of 6 months is often reported and for metastases at the most 18 months. Therefor, the majority of patients with liver tumors will be referred for palliative treatment. When talking about liver metastases in this context it almost refers to colorectal liver metastases.
Many palliative treatments have been suggested and I will give my opinion on a few shown in table 1. The multitude of therapies indicates that no one is clearly effective.
Tabl.1 - Palliative treatment
ChemotherapySystemic chemotherapy in primary liver cancer has usually included doxorubicin or epirubicin. Response rates of 10 to 50% are generally reported but no prolongation of survival has been achieved. The toxic side effects are also considerable (3).
Several regimens of systemic chemotherapy have been used in the treatment of colorectal liver metastases and they iclude 5-FUDR, BCNU, Mitomycin, Methotrexat and Cisplatin. Response rates are generally lower than for primary liver cancer and no prolongation of survival has been achieved so far (4). Prospective randomized control trials in this group of patients are lacking. Nonetheless it appers that systemic chemotherapy results in relative low response rates for colorectal liver metastases with some but minimal effect on survival. In a recent study it was shown that the systemic chemotherapy could be performed with an improvement or stabilization of quality of life in more than half of patients with advanced colorectal cancer (5).
The administration of cytotoxic drugs and degradable starch microspheres (DSM) in the hepatic artery causes a selective increase in tumor concentration not by reduction in the elution but instead of increasing tumour perfusion. A number of phase 2 studies have now been undertaken in patients with hepatic metastases using DSM with a variety of cytotoxic agents. Objective response in terms of partial or complete tumor regression is reported in between 20 and 50% of patients (6). The number of patients is small however. Side effects include nausea, vomiting and epigastric pain. Hepatic artery tromboses and gastritis have also been reported. This route of therapy must be further exploited and the role of sequential administration should be evaluated. The use is not restricted to the delivery of conventional cytotoxic drug but also monoclonal antibodies and to produce regional hypothermia.
primary liver cancer has not been widely applied. The regional aplication of doxyrubicin has no advantage compared to systemic administration (7). Other combination have been used with FUDR and Mitomycin C. Some prolongation of life has been proposed bu no control study has been performed. Some has shown though that this treatment can be performed with good quality of life for the patients. It must be confirmed however in carefully controlled studies. Local intraarterial chemotherapy of colorectal liver metastases with 5-FUDR has been tried extensively. Response rates of 50 to 90% have been observed and the survival benefits compared to historic controls and compared to intravenous infusion have been achieved (8,9). There is however high complication rate especially with the use of implantable pumps with biliary sclerosis etc. Randomized studies with untreated controls areremarkably rare. It is hard to explain the lack of demostrable survival advantages with such high response rates because the presence of liver metastases has a significant negative impact on survival compared with metastases in other non-vital organs which rarely cause the death of patients. Several factors may explain this:
1 - De novo resistance.
Approximately 50% of patients never respond to arterial infusion despite adequate concentration of FUDR in the liver. The reasons for the de novo resistance are not clear.
2 - Acquired resistance.
Acquired resistance may be manifested by an initial response to therapy and the subsequent emergence of resistance. These two problems may by prevented or modulated with the addition of interferon alfa.
3 - Extra hepatic tumour progression.
Despite adequate response in the liver systemic failure has been reported in up to 50% pf patients, most commonly in the lungs. Some combination with systemic therapy may be advisable.
4 - Toxicity.
Hepatico-biliary and other toxicity may limit treatment benefit.
Chemotherapy has also been applied in a regional isolated perfusion system. Only small series of patients with liver tumors of different origins have been presented (10,11). The complication rate is rather high and today the isolation procedure is a major surgical intervention and I do not think it is applicable to this group of patients until the isolation can be performed percutaneously. Besides this many drugs have a dose limiting hepatotoxicity in the isolated system and this therefore futher hampers the effect. By using drugs whick lack hepatic toxicity but have severe systemic side effects, the isolated perfusion system may offer some advantage. We have performed a series of experiments where have tried to metabolically manipulate the liver tumors by interfering with glycolysis and protein synthesis (12).
Interstitial therapyInterstitial therapy may be defined as a method of treatment where the therapeutic stimulus is delivered to the liver directly to the selected site of intended tissue damage. The intent is to reduce the volume of viable tumor or preventing futher tumor growth and improve length of survival. The attractions of the use of hypothermia are the increased heat sensitivity of neoplastic cells. There seems to be little consistent difference between the response if normal and neoplastic cells with the exclusion possibly at low pH. Therefore hyperthermia must be applied locally. Radiofrequency and microwave technique and application of ultrasound have been used but they are impractical because they are invasive when used in the liver. Lasertherapy is more attractive since it can be used by a percutaneous approach. Single fibre treatment can produce areas of necrosis up to 1,5 cm and with fibres activated simultaneously this can be increased to 4 cm. Several studies have been using this technique. The first two studies have used it at surgery in patients with primary and secondary tumours (13,14).
In both studies a decrease in AFP and CEA levels was achieved but follow up was short. In the study by Schröder there were complications with infections and air embolus (14). In the study from U.K. a percutaneous approach was used and a tumour response was see in 60% of the patients. 40% did not respond at all. In two out of 13 patients disseminated disease was apparent (15). It is difficult to judge effect on survival and it can be concluded that laserhyperthermia is still at the stage of pilot clinical studies.
Cryotherapy is the application of a cooling agent, usually liquid nitrogen. This leads to irreversible cell damage but also more remote effect within the body with immunological response to recidual viable tumour. This is thought to be the result of liberation of antigen but it is not clear if this has any clinical relevance (10). Several studies using this technique in the laboratory animal have published. In a first clinical study by Zhou et al.(17) of primary liver cancer a one year survival rate of 52% was achieved, in other studies with metastatic lesions a decrease in CEA levels could be observed (18). The main disadvantage of the technique is that patients have to undergo laparotomy. Modern technology may the application devises.
Percutaneous alcohol injection has gained wide spread use and is of potential interest. It can be applied to tumours of less than 3 cm in diameter and usually volumes of 5 to 10 ml up to 99 ml per lesion have been used. If larger lesions are injected a high incidence of remaining malignant cells and no evidence of regression is observed. It has been used with very few complications and impressive results in patients with irresectable primary liver cancer have been achieved with one year survival rates of 92% and 5 years survival rate of 60% (19-22). There are some reports of implantation metastases along the injection needle tract but this can probably be avoided by an improved technique. Alcohol is toxic and pain and some damage to surrounding liver tissue us observed.
The case for alcohol injection is becoming stronger. Its advantages are many including minimal demand on manpower and equipment. A futher improvement in results may be by combination with embolization.
Radiotherapy. Conventional external radiotherapy has little to recommend for palliation of hepatic tumours. There is a limit to the dose that can be applied. In an attempt to overcome this problem the technique of intraoperative radiotherapy (IORT) has been used (23). The rationale is that a much higher dose can be delivered to the tumour with little effect on the normal surrounding parenchyma or other organs (24). No controlled studies are available on liver tumours and we do not know any effect on survival or symptom relief. Another way of local radiotherapy is by interstitial radiotherapy. This is used by local application of 192 Iridium seeds (25) and Ytrium-90 microspheres (26,27). Any number of lesions can be treated at laparotomy with the seeds. The microspheres are injected at angiography. There are few uncontrolled studies but all that can be said from these is that the techniques are feasible but the follow up is too short to comment on survival.
Biological treatmentsBiological treatment of cancer has evolved during the last decade and is based on a stimulation of the natural immune reactions against the disease. It can be defined as a cancer treatment that acts primarily through natural host defense mechanisms or the administration of natural mammalian substances (28). This therapy includes administration of interleukin 2 (IL-2), lymphokine activated killer cells (LAK) or tumour necrosis factor (TNF) either systemically or locally. Although the treatment is attractive results so far have been disapoiting with no response in colorectal liver cancer with administration of IL-2 alone and a response rate of 13% when combining IL-2 and LAK cells (29). The side effects with the systemic administrations are also significant.
The administration of TNF experimentaly is associated with a greater antitumour activity (30). However also here the dose limiting toxicity is severe (31). The regional application of TNF intraarterially seems attractive and it has been used in some case reports in the treatment of hepatocellular carcinoma combined with embolization and local hyperthermia (32). The results in colorectal liver metastases are not good (33,34). The rate of objective is however not impressive and the duration is very short.
It is well known that primary liver cancer express several hormone receptors such as estrogen receptors, androgen receptors among others. It is therefore attractive to treat irresectable primary liver cancers with tamoxifen. In one randomized study some encouraging results was reported with one year survival rate of 40% in a group of patients treated with tamoxifen 30 mg/day compared to 0 in an untreated control group (35). If these results are confirmed they represent an excellent advantage. However another study from King°s College has not been able to confirm this where in a controlled trial involving 59 patients comparing tamoxifen + doxorubicin with doxorubucin alone. There was no difference in the response rate and the survival rate of the two groups, unfortunately (36). A more recent study confirm the effectiveness of tamoxifen as a palliative measure and I think it should be tried in patients not possible to treat otherwise (37).
Ischaemic therapyHepatic artery embolization in combination with chemotherapy was developed in Japan for unresectable cases of hepatocellular carcinoma. Embolization is performed either with gelatin sponges in combination with cytotoxic drugs doxorubicin or mitomycin with the combination of Lipiodol or by Lipiodol and doxorubucun. Several studies have shown that this treatment achieves high concentrations of chemotherapeutic agent in the tumour and induce tumour necrosis (38,39). Several studies have shown very beneficial effects of this treatment. One year survival rates ranging from 40% to 100% have been achieved and 5 years survival rates of 5% to 20% in irresectable primary liver cancer. It has also been used in the treatment of local recurrencies in the liver after resection with remarkable results (40). Several studies have proven its efficacy versus systemic chemotherapy and embolization without Lipiodol (41). The tumour size is of no importance for the effectiveness of embolization but uninodular tumours have better results (42). The morbidity rate is between 10% and 15% and the major complications include liver failure with encephalopathy and ascites, cholecystitis and renal insufficiensy. It is important to note that many reports include symptomatic improvement in abdominal pain and general improvement in patients who were debilitated prior to treatment (43).
The use of embolization in patients with liver metastases has not been so effective. Usually a similar approach has been applied as for primary liver cancer but the effect on survival is very limited. The principal indication for its use is the amelioration of symptoms directly attributable to liver metastases such as local pain or the unpleasant humoral effects produced by secondary deposits from active endocrine tumours. The amelioration of symptoms can be achieved in 75% of the patients (44,45). This is especially true in patients with metastases from endocrine tumours. Complications are frequent and include pain, pyrexia, leucocytosis in half of the patients but more serious complication such as infection, gastrointestinal complications and renal failure are rare between 2% and 5%. Mortality rates of 1% to 22% have been reported.
The difference between blood supply of normal and tumour tissue can be utilized also in other ways. A true ischaemic insult can be inflicted by hepatic arterial ligation. Preformed arterial collaterals make the ischaemic effect only transient and therefore a more complete dearterialization of the liver has been proposed. This is a large operative procedure and performed alone or in combination with cytotoxic drug therapy, no survival benefit has been proven either in primary liver cancer or in metastatic liver disease. A rather high complication rate has also been reported (46). Since a few years we have tried to modify this concept by performing the dearterialization procedure repeatedly and transiently. For this purpose we have constructed a small vascular balloon occluder which is placed around the hepatic artery at laparotomy. Complete mobilization of the liver is also performed. Therafter pulsed ischaemic periods can be instituted by the patient himself by inflating the balloon. This can then be combined with cycling of cytotoxic drug administration. In animal experiments we have shown that short episods of ischaemia up to 2 hours do not induce the formation a-v collaterals. Upon occlusion there seems to be a generation of oxygen free radicals that might be cytotoxic in the tumour tissue upon reestablishment of the arterial circulation and increased DNA synthesis occurs which can be utilized when combined with cytotoxic drug therapy. With this therapy we have treated 25 patients in a first trial (47). Four patients with primary liver cancer all had signs of tumour regression, in one patients so much that he could be resected 6 months after institution of therapy. In patients with colorectal liver metastasis diseases the response is more varied with an overall median survival of 18 months and an objective tumour response in about 50% of the patients. Symptomatic relief is achieved in the majprity of patients with reduction of hepatomegaly. The psychological benefit which the patient gets from performing the treatment himself may also be of value. A randomized trial comparing this treatment to regional cytotoxic alone is in progress.
In summary, it can be stated that in the palliative treatment of liver tumours control studies are lacking, therefore fopefully in the future more patients will be inckuded in controlled studies. There is some support to recommend that in patients with irresectable primary liver cancer a palliative effect can be reached by administration of tamoxifen, alcohol injection or chemoembolization. For metastatic liver disease recommendations are harder to given. There is some evidence that regional chemotherapy may be beneficial. Alcohol injection technique can be applied and percutaneous laser application should be evaluated.
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Department of Surgery
Lund University Hospital
221 85 LUND - Sweden
(První díl v čísle 94-3.)
Portal Hypertension - State of the Art(2nd part)
Hans-Kalk Hospital, Bad Kissingen
Role of liver transplantationLiver transplantation (LT) is hypothetically the most logical treatment for bleeding esophageal varices in patients with advanced liver disease in recent reports (82,83). Starzl°s group has described their experience in 1000 patients undergoing LT. Of these 302 had a history of variceal hemorrhage before LT and all were Child class C. The overall predicted five years survival of these patients was 71%. This is considerably better than estimated survival curves for most reported series treating variceal hemorrhage using any non-transplant modality. This is even further excentuated with aspect to the markly improved survival of Child class C patients after LT. Of particular importance is the observation that the original liver disease did not influence survival after LT.
Liver transplantation should be only offered to a small and selected number of patients with portal hypertension (84). Its indication has been discussed in patients with liver cirrhosis and Child-Pugh class C or advanced B with progression. However this decision is given independently if the patient has a portal hypertension with esophageal varices or not. Contraindications are continuing alcohol abuse, high morbidity and extrahepatic manifestation of a hepatocellular carcinoma. Furthermore the patients should be very compliant. If the indication for shunt operation in Child-pugh A and B patients because od sclerotherapy failure is discussed the possibility or necessity of a later LT should not be forget. Suitable shunt types for later LT are distal splenorenal shunt and small diameter mesocaval or portocaval shunts with 10 or 12 mm PTFE prothesis side-to-side (82-83). There is no role for an acute transplantation in patients with acute variceal hemorrhage (84). These are candidates for emergency sclerotherapy, TIPS or emergency surgery. Bleeding should be stopped by these modalities to be able to perform later elective LT. However, these data are representative of the subsest of patients with endstage liver failure and must be analysed against the potential limitation of organ procurement. Thus, the role and the application of LT to the therapy of acute variceal hemorrhage is as yet undefined.
Management of the acute bleeding patientThe overall therapeutic goal is to control hemorrhage as rapidly and reliable as possible with minimal complications. The initial resuscitation should include critical monitoring for the sequelae of hepatocellular failure. Thus the patient must be hemodynamically stabilized measures must be institute to provent encephalopathy, coagulation defects should be corrected and electrolyte hemostasis should be monitored.
Emergency endoscopy is mandatory. The suspicion of varices may require inition of combined intravenous vasopressin (0,4 U/min.) and subliqual nitroglycerine (1 Tbl./1/2hourly for 6 hrs.) or Octreotide prior to endoscopy. If the diagnosis is confirmed endoscopically and the expertice is available, immediate sclerotherapy or ligation should be performed. Should the necessary expertise not be available, bleeding should be temporalily controlled by the use of balloon tamponade or drug therapy. Delayed sclerotherapy should be performed within 24 hours. Patients who continue to bleed or who rebleed after sclerotherypy or ligation require rapid identification or preparation for either emergency meso- or portocaval shunt or devascularisation, possibly in combination with staple transsection. Individuals whose bleeding is controlled by sclerotherapy should undergo repeat endoscopic evaluation and injected as needed at weekly or monthly intervals until all visible varices are obliterated or protected by scar tissue. Thereafter appropriate long-term management and follow-up should be instituted. This may include repeated sclerotherapy or ligation or elective planned operation like distal spleno-renal or narrow-lumen mesocaval or portocaval shunt or later LT.
In conclusion, when the ballad of Sir Andrew:
"Fight on, my men, Sir Andrew says,
a little I am hurt, but yet not slane,
I will but lie down and bleed awhile,
and then a arise and fight again"
ballad of Sir Andrew Barton (85)is rephrased: we need to reliable predict that who will be hurd and not stand, and prevent them from bleeding awhile but if they should, we need to be sure that they will rise and fight again. Clearly, in odrer to rationalize prophylactic therapeutic intervention, a clearer definition of the patients subsets within the broad classification of esophageal varices is required. Most investigators have been unsuccessful in identifying the one third of patients whose cause will be complicated by hemorrhage (86). Prophylactic intervention will become a realistic goal, when a mean of identifying those at high risk for either hemerrhage or death becomes clear. Hopefully, using similar predictive criteria, preemptive and prioritized LT will become a pragmatic aim. Realistically, the development of rational strategies for surgical therapy in this disease will require a better understanding of the fundamental reason why varices bleed and therapy fails. This, along with improvement in non-operative management and improvement in technology to correct the hepatocellular component, will hopefully help to reduce the discouraging over-all outlook in this disease.
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Zobrazování jaterních metastáz pomocí značených monoklonálních protilátekRubeš T., * Bláha V.
Chirurgická klinika 3.LF UK v Praze
* Klinika nukleární mediciny 3.LF UK v Praze
SouhrnJednou z možností detekce jaterních metastáz je metoda imunoscintigrafická využívající značené monoklonální protilátky. Tato diagnostická metoda je vhodná i k zobrazení primárního nádoru a jeho recidiv.
Autoři uvádějí své zkušenosti s monoklonální antiCEA protilátkou BW 431/26 - Scintium CEA firmy Behring u 54 onkologických nemocných. Z jejich výsledků vyplývá, že imunoscintigrafické vyšetření je výhodnější při vyhledávání metachronních metastáz jater než při zobrazování metastáz synchronních. Nejvýhodnější je užít imunoscintigrafickou metodu k detekci lokální recidivy nádoru.
Klíčová slova : imunoscintigrafie - monoklonální protilátky - jaterní metastázy
SummaryImmunoscintigraphy based on monoclonal antibodies is one of the methods used to the detection of liver secundarities. This method is available also for the detection of primary tumor and its recurrence.
Authors describe their experience with monoclonal antiCEA antibody BW 431/26 - Scintium CEA Behring on 54 oncologic patients. On the base of their results authors conclude that immunoscintigraphy is more available for looking up of metachronic liver secundarities than for the detection of synchronic metastatic tumors. The most available is the use of imunoscintigraphy for the diagnosis of local recurrence.
Key words: immunoscintigraphy - monoclonal antibodies - liver metastatic tumors