Chemoembolisation when and how? Mr. S. J. Wigmore University Department of Surgery RIE and Dr. D. Redhead Dept of Clinical Radiology RIE

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1 Chemoembolisation when and how? Mr. S. J. Wigmore University Department of Surgery RIE and Dr. D. Redhead Dept of Clinical Radiology RIE

2 Publisher Edinburgh Univesity Press Office Editorial and Production Director Klavs Zarins Publication Date October 2004

3 Chemoembolisation when and how? Chemoembolisation is widely used in the management of patients with hepatocellular carcinoma. Embolisation combined with chemotherapy enables tumour drug concentrations to attain much higher levels than would occur with IV chemotherapy. Furthermore the dwell-time of the drug within the tumour, is prolonged if the bloodflow to it is stopped. The aim is to treat the tumour, the whole tumour and nothing but the tumour, where anatomy allows this. Indications: (for HEPONE trial see protocol) 1 - Patients with irresectable HCC : ( too large for RFA ie > 4cms). 2 - Patients with radiologically resectable disease but considered unfit for surgery by virtue of comorbid conditions/age etc. 3 - Patients awaiting liver transplantation who have tumor/s within acceptable limitations for transplantation at the time of presentation and who are within 1cm of exceeding these limits ie 1 tumour less than 5cms but greater than 4cms or fewer than three lesions each less than 3cms but 1 or more greater than 2cms. 4 - Patients unsuitable for surgery who are symptomatic from the lesion/s 5 - Spontaneous rupture of HCC. (Fig 1,2) Fig 1 - Spontaneous rupture of HCC- CT scan. Fig 2 - Hepatic angiogram showing hypervascular HCC - same patient as Fig 1. 3

4 Contraindications to Chemoembolisation: 1 - Patients with main portal vein occlusion. 2 - Patients with ascites- which may reflect the degree of liver disease or peritoneal spread of the disease. 3 - Patients with extrahepatic spread of disease who are not symptomatic. 4 - Blood results- In a previous study we demonstrated on the basis of multivariate analysis that 3 factors were associated with poor prognosis for chemoembolisation for HCC: age >60 years, alkaline phosphatase > twice the upper limit of normal and the albumin <35g/l. Based on these criteria, patients were allocated a score for each factor with a minimum of 0 and a maximum of 3. This scoring system provides different prognoses and the median survival of patients based on this score is as follows: score 0= 20months, score 1= 12months, score 2 =7months, score 3 = 4months. Based on this we feel that it is not warranted to use chemoembolisation to treat patients with a score of 3 unless there is a specific symptomatic target of therapy. Table 1 - Kaplan Meier survival curves of patients ( in Group 1) with liver cancer who underwent treatment by TACE, stratified by a treatment scoring system. Log rank = 35.8, df=3, P<

5 Preparation: 1 - Clotting parameters should be checked and corrected as far as possible. Platelet level should ideally be >100,000 and INR < 1.5 Blood products may be required. 2 - Antibiotics should be given 1hour prior to the procedure- eg 750mgs Cefuroxamine iv. No post-procedure antibiotics are required unless there is a specific indication. 3 - Fluids only 3-4 hrs pre-procedure. 4 - Sedation/ analgesia advised for procedure. Technique: 1 - Preliminary hepatic angiography to (a) assess the hepatic arterial anatomy and (b) to assess the patency of the portal vein + branches. ie Coeliac axis and SMA studies with selective studies where necessary to establish the optimal site for catheter placement. (Fig 3, 4). Various catheters are used for the initial angiography and subsequent selective catheterisation eg Cordis sidewinders, mesenteric catheters and Cobra catheters. The hub of the Cordis catheter can be non-lipiodol- friendly and will disintegrate if Lipiodol is introduced directly through it. Exchange to a Cobra is advised for direct injection. Alternatively, having placed the Cordis in a stable site, a microcatheter eg Terumo Progreat, can be used for final selection of the intrahepatic branches. Fig 3 - Coeliac injection - Left hepatic artery arising from left gastric artery. Fig 4 - Catheter advanced beyond LGA origin for chemoembolisation 5

6 2 - Chemoembolisation can be performed where there is lobar portal vein branch ( Fig 5,6 ) occlusion/tumour but it is not advocated in the presence of main portal vein occlusion. (For HEPONE trial - see protocol) Thrombus in the portal vein in the presence of HCC, is generally due to tumour thrombus. 3 - Where there is evidence of a hepatic artery- portal vein communication, ( Fig 7) this can be embolised with coils or spongostan etc prior to the delivery of the mixture. Where there is a hepatic artery to hepatic vein communication seen during angiography, the chemoembolic mixture will pass through this to the lungs. The communication may be initially embolised with spongostan or coils prior to introducing the mixture. 4 - Selectively catheterise the hepatic arterial branches feeding the tumour and deliver chemoembolic mixture to these vessels ( Fig 8) mgs Adriamycin is provided by Pharmacy in a 10cc volume. This is mixed with 10ccs Lipiodol using 2 x 20 cc luerlock syringes and a 3- way tap- at least 5 mixes advocated. It is recommended that the Adriamycin is not exposed to air. Always wear protective glasses to avoid eye splashes. Double gloving is also recommended. The mixture should be introduced slowly to avoid reflux of the material and continuous screening used to ensure none of the mixture is inadvertently introduced into a vessel other than that selected. 6 - Small and avascular tumors- slow injection: Large tumours with large blood supply may merit an additional 5 ccs Lipiodol and the introduction of a particulate material eg Contour in order to slow the blood flow to the tumour and aid in dwell time of the chemoembolic mixture within the tumour. 7 - Not all HCCs are hypervascular and a slow injection is required to encourage as much of the mixture as possible into the lesion. Where the Lipiodol is not seen to be retained well, there is likely to be a poor response to treatment. 8 - Where there is bilobar disease, consideration should be given to treating the disease in separate sessions. 9 - Particulate material used should be of greater size than 300 microns in order to avoid damage to small bile duct arterioles with resultant bile duct necrosis. 6

7 Fig 5 - Diffuse infiltrative HCC right lobe of liver Fig 6 - Right lobar portal branch occluded by thrombus-same patient Fig 7 - Arterio-portal shunting: Chemoembolisation inappropriate here. Fig 8 - Good selective arterial position for delivery of chemoembolic mixture. With thanks to Drs John Rose and Simon Olliff for their help with the HEPONE protocol 7

8 10 - Avoid introduction of the mixture into non-tumour-bearing liver to avoid liver damage Avoid introduction of mixture into the cystic artery as this may lead to gallbladder infarction ( Fig 9,10) Although this can lead to right upper quadrant pain masked by the tumour embolisation, it rarely requires cholecystectomy. However damage to bile duct arteries may lead to the development of arterio-biliary fistulae Avoid introducing the mixture into the left gastric artery where the left hepatic arises from this vessel Avoid introduction of mixture into extrahepatic arterial branches The procedure should be tempered according to the individual patient situation eg (a) a young patient with patent portal venous branches should be treated aggressively with delivery of the chemoembolic mixture + Contour where the anatomy allows. (b) An older patient with severe background liver disease should have the tumour treated as selectively as possible incurring as little damage to non-tumour-bearing liver as possible. (c) Patients with pedunculated or encapsulated lesions can be treated aggressively. These patients will have the best response. Fig 9 - Two months post chemoembolisation. Fig 10 - gallbladder infarction 8

9 Post- procedure The Chemoembolisation syndrome: Following arterial chemoembolisation it is very common to develop elevated transaminases and elevation of body temperature. Transaminase rise may be in the range of several fold the upper limit of normal to many times the ULN. Temperature changes are often fluctuating and can reach more than 39 o C. Typically the temperature swings over a period of 3-5 days before returning to normal. Persistent temperature beyond this should raise suspicion of abscess formation within the liver. The changes in transaminases and body temperature are referred to as the chemoemblisation syndrome. Early after chemoembolisation development of this syndrome used to be considered evidence that the procedure was effective and the changes observed were ascribed to tumour necrosis. While it is possible that temperature changes may indeed be secondary to necrosis it has been demonstrated that changes in transaminases are more likely to reflect collateral damage to normal hepatocytes. In a multivariate analysis neither transaminase rise nor temperature elevation were associated with improved outcome indeed patients with temperature rise did somewhat worse than patients in whom this symptom was absent. Response to treatment: 1 - If the AFP is elevated at the outset, it will be useful as a gauge of response. Reduction of the AFP following chemoembolisation correlates with CT assessment of response but does not correlate overall with survival. 2 - CT follow-up at 8weeks is recommended. CT response is the most accurate means of assessing the effectiveness of this treatment modality. Survival was assessed in patients with HCC based on their CT response 8 weeks after the first treatment with chemoembolisation. There was a clear survival benefit in patients who were shown to have a reduction in tumour volume indeed some of these patients went on to have a curative procedure either resection (Fig 11,12) or transplantation. (Table 2). 9

10 Table 2 - Tumour response Fig 11 - CT pre-treatment. Disease Assessment Measureable disease 10 Fig 12 - CT Post-treatment Assessment, Staging and Response Tables. Surface area approximation- multiply the longest diameter by the greatest perpendicular diameter. Multiple lesions for a single organ site- the sum of the diameters of all measured lesions. Unmeasureable disease - extension into adjacent structures/nodes.

11 Tumour response (WHO criteria ) Measureable disease COMPLETE RESPONSE - CR - The disappearance of all known disease, determined by 2 observations not less than 4 weeks apart. PARTIAL RESPONSE - PR - 50% or more decrease in total tumour size of the lesions which have been measured to determine the effect of therapy by 2 observations not less than 4 weeks apart. In addition there can be no appearance of new lesions or progression of any lesion. NO CHANGE - NC - a 50% decrease in total tumour size cannot be established nor has a 25% increase in size of one or more measureable lesions been demonstrated. PROGRESSIVE DISEASE - PD - a 25% increase in size of one or more measureable lesions, or the appearance of new lesions. Unmeasureable disease CR - Complete response- Complete disappearance of all known disease for at least 4 weeks. PR - Partial response- Estimated decrease in tumour size of 50% or more for at least 4 weeks. NC - No change- no significant change for at least 4 weeks. This includes stable disease, estimated decrease of less than 50% and lesions with estimated increase of less than 25%. PD - Progressive disease- appearance of any new lesion not previously identified or an estimated increase of 25% or more in existent lesions. 11

12 Repeat chemoembolisation - a case of diminishing returns? There is frequently confusion amongst clinicians regarding whether to repeat chemoembolisation in patients with HCC based on the reported response to their first treatment. The literature does not provide any clear answers on this issue. Looking at the data from The Royal Infirmary, Edinburgh it is clear that as a cohort the likelihood of disease progression increases after repeated embolisations. This may be partly due to occlusion of the hepatic artery making drug delivery more difficult in repeated treatments or may represent inherent resistance to this treatment modality in some tumours. When responses are analysed on a more specific basis it becomes clear that patients who progress after the first chemoembolisation are extremely unlikely to respond on subsequent treatments. Based on these response patterns, a recommendation has been made that repeat chemoembolisation be reserved for patients who have either static disease or tumour reduction. Table 3 - % of tumour response as assessed by CT scan following repeated transarterial chemoembolisation. Not assessable indicates that the patient was unable to attend for repeat scanning. 12

13 Table 4 - Treatment and subsequent response based on response to first chemoembolisation. References: 1991 Transcatheter hepatic arterial therapy for symptomatic malignancy JR Coll Surg Edin Dec ; 36(6): Guthrie CM, Leahy AL, Redhead DN, Garden OJ Chemoembolisation for hepatocellular carcinoma. Madhavan KK, Garden OJ, Crosbie JL, Redhead DN Br J Surg Vol 83 Suppl 1 Poster Cytolysis following chemoembolisation for hepatocellular carcinoma. Letter BJS Aug; 86(8) Wigmore SJ, Madhavan KK, Redhead DN, Garden OJ Limited benefit of hepatic artery chemoembolisation in management of colorectal hepatic metastases. Adib R, Wigmore SJ, Redhead DN, Currie EJ, Parks RW, Madhavan KK, Garden OJ. Augis Abstract 13

14 2003 Postchemoembolisation syndrome- tumour necrosis or hepatocyte injury? Br J Cancer Oct 20:89(8): Wigmore SJ, Redhead DN, Thomson BN, Currie EJ, Parks RW, Madhavan KK, Garden OJ Predicting survival in patients with liver cancer considered for transarterial chemoembolization. Wigmore SJ, Redhead DN, Thomson BN, Parks,RW,Garden OJ Eur J Surg Oncol. Feb;30(1):41-5. Embolic materials for Chemoembolisation The embolisation particles used are: CONTOUR microns in size. Made by Boston Scientific Cork Ltd, Cork Business & Technology Park, Model Farm Road, Cork Ireland. REF No Order from Boston Scientific. This product is made in various sizes. It is important to use the size stated ( microns or larger-) in the liver as particles of smaller size can obliterate very fine arteries supplying the bile ducts. This can lead to bile duct necrosis. Hence the use of particles > 355 microns. Lipiodol Ultrafluid is made by Guerbet. It is iodised oil fluid injection BP. It is supplied in a packet of 5 x 10mls ampoules. Recommended up to 15ccs per procedure. The Guerbet Laboratories are at Shenley Pavilions, Chalk Dell Drive, Shenley Wood, Milton Keynes, Buckinghamshire. MK 5 6LB UK. Spongostan - absorbable gelatin sponge. Provided in a sheet of 7cms x 5cms x1cm. Needs to be cut with sterile scissors into small, injectable pieces. Johnson& Johnson Medical Ltd, The Braccans, London Road, Bracknell, Berkshire RG 12 2AJ. Trufill - PVA - polyvinyl alcohol. Particles of various dimensions in suspension- recommend particles > 355 microns. Supplied by Johnson & Johnson Co. The Braccans, London Road, Bracknell, Berkshire RG 12 2AJ. 14

15 Publisher Edinburgh Univesity Press Office Editorial and Production Director Klavs Zarins Publication Date October 2004

16 Contact details: Mr. S. J. Wigmore University Department of Surgery Royal Infirmary of Edinburgh Tel: Dr. D. Redhead Dept of Clinical Radiology Royal Infirmary of Edinburgh Tel: