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Hepatocellular carcinoma: Gardening strategies and bridges to transplantation
LIVER TRANSPLANTATION WORLDWIDE Hepatocellular Carcinoma: Gardening Strategies and Bridges to Transplantation Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Llovet JM, Mas X, Aponte JJ, Fuster J, Navasa M, Christensen E, Rodes J, Bruix J. Gut 2002;50:123-128. (Reprinted with permission from Gut.) Abstract Background: Survival after liver transplantation for early hepatocellular carcinoma (HCC) is worsened by the increasing dropout rate while waiting for a donor. Aims: To assess the cost effectiveness of adjuvant therapy while waiting for liver transplantation in HCC patients. Method: Using a Markov model, a hypothetical cohort of cirrhotic patients with early HCC was considered for: (1) adjuvant treatment-resection was limited to Child-Pugh’s A patients with single tumours, and percutaneous treatment was considered for ChildPugh’s A and B patients with single tumours unsuitable for resection or with up to three nodules < 3 cm; and (2) standard management. Length of waiting time ranged from six to 24 months. Results: Surgical resection increased the transplantation rate (>10%) and provided gains in life expectancy of 4.8-6.1 months with an acceptable cost ($40,000/ year of life gained) for waiting lists > or ⴝ 1 year whereas it was not cost effective ($74,000/life of year gained) for shorter waiting times or high dropout rate scenarios. Percutaneous treatment increased life expectancy by 5.2-6.7 months with a marginal cost of approximately $20,000/year of life gained in all cases, remaining cost effective for all waiting times. Conclusions: Adjuvant therapies for HCC while waiting for liver transplantation provide moderate gains in life expectancy and are cost effective for waiting lists of one year or more. For shorter waiting times, only percutaneous treatment confers a relevant survival advantage. (Gut 2002;50:123-128.)
Comments Cancer often is a systemic disease, and hepatocellular cancer (HCC) is no different. This lesson was learned early in orthotopic liver transplantation (OLT), when patients undergoing OLT for advanced HCC developed recurrent disease in the allograft.1 The new liver, a fresh garden full of HCC adhesion sites, trophic and growth factors, was rapidly seeded with viable cancer cells present in the blood or micrometastases causing recurrent lesions with death. Obviously, what is needed to make OLT more successful for HCC is systemic therapy directed at the micrometastases, the seeds of the parent weed. This approach has been hindered by ineffective systemic
therapy for HCC. The lack of available cadaveric livers also has stifled systematic studies to address this issue. The advent of live donor transplantation may or may not alleviate this issue and help advance therapy for HCC. HCC and patient selection. Given the lack of therapies and reliable methods for detecting micrometastases, the transplant community has used surrogate markers for their presence. These endpoints include tumor size, multicentricity, and vascular invasion. These criteria have been established by outcome-based studies and the current limits established by those pushing the envelope.2,3 Because of increasing waiting time duration, most United States transplant centers direct therapy at the primary tumor(s) within the liver to prevent tumor progression and development of biologically/clinically important micrometastases. Such therapies are defined as bridging the patient to OLT. This approach is based on gardening principles, clipping the weeds before they flower and seed. The clinical transplant team has a plethora of neoadjuvant therapies in their tool shed to treat the primary tumor including percutaneous ethanol injection, chemoembolization, and radiofrequency ablation, but in the garden analogy, the best weed killer is not yet known. What tool is most effective and cost effective? Bridging the HCC patient to liver transplantation. Decision making in medicine may be based on tradition, empiric data, mechanisms of disease, socioeconomic costs, and beliefs, or a complex interplay enmeshing these issues. In the absence of hard data, decision analysis increasingly is being used to point to the correct therapeutic protocol. This is the approach recently reported in Gut and authored by Llovet et al,4 highly regarded HCC and hepatology investigators. They suggest that neoadjuvant therapies for HCC patients administered while the patients are waiting for liver transplantation provide gains in life expectancy and are cost effective. However, the investigators limited their decision analysis to percutaneous ethanol injection therapy (PEIT). The rationale was not obvious but related to concerns regarding peritoneal seeding with radiofrequency ablation and the lack of data with chemoembolization. Should PEIT, therefore, become the neoadjuvant therapy of choice? The answer is an emphatic no. Chemoembolization (CE) and radiofrequency ablation (RFA) still should remain in the practitioner’s tool shed. Many centers, including ours, use CE effectively as a bridge to OLT.5 Indeed, chemoembolization is the only therapy that has had a demon-
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strated survival advantage shown in a randomized controlled trial.6 In data yet to be published, our dropout rate for patients receiving CE while awaiting OLT is only 9%, far below the rate of 23% used in this decision analysis for untreated patients. Likewise, radiofrequency continues to show promise as an antitumor therapy, although concerns remain regarding its association with needle track seeding; however, this concern is limited primarily to surface lesions.7 Thus, we believe the tool shed should remain full, and CE, RFA, and PEIT should all remain viable approaches to bridging HCC patients to OLT. However, we emphasize that systemic therapy directed at the micrometastases would be more logical, and such studies should be encouraged despite the current organ shortage. Gregory J. Gores, MD Transplant Center Mayo Clinic Rochester, MN
References 1. Pichlmayr R, Weimann A, Ringe B. Indications for liver transplantation in hepatobiliary malignancy. Hepatology 1994;20: 33S-40S. 2. Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: Diagnosis and treatment. Gastroenterology 2002;122:1609-1619. 3. Jonas S, Bechstein WO, Steinmuller T, Herrmann M, Radke C, Berg T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080-1086. 4. Llovet JM, Mas X, Aponte JJ, Fuster J, Navasa M, Christensen E, et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50:123-128. 5. Harnois DM, Steers J, Andrews JC, Rubin JC, Pitot HC, Burgart L, et al. Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma. Liver Transpl Surg 1999;5:192-199. 6. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet 2002;359:1734-1739. 7. Llovet JM, Vilana R, Bru C, Bianchi L, Salmeron JM, Boix L, et al. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001; 33:1124-1129.
Comments Cancer often is a systemic disease, and hepatocellular cancer (HCC) is no different. This lesson was learned early in orthotopic liver transplantation (OLT), when patients undergoing OLT for advanced HCC developed recurrent disease in the allograft.1 The new liver, a fresh garden full of HCC adhesion sites, trophic and growth factors, was rapidly seeded with viable cancer cells present in the blood or micrometastases causing recurrent lesions with death. Obviously, what is needed to make OLT more successful for HCC is systemic therapy directed at the micrometastases, the seeds of the parent weed. This approach has been hindered by ineffective systemic
therapy for HCC. The lack of available cadaveric livers also has stifled systematic studies to address this issue. The advent of live donor transplantation may or may not alleviate this issue and help advance therapy for HCC. HCC and patient selection. Given the lack of therapies and reliable methods for detecting micrometastases, the transplant community has used surrogate markers for their presence. These endpoints include tumor size, multicentricity, and vascular invasion. These criteria have been established by outcome-based studies and the current limits established by those pushing the envelope.2,3 Because of increasing waiting time duration, most United States transplant centers direct therapy at the primary tumor(s) within the liver to prevent tumor progression and development of biologically/clinically important micrometastases. Such therapies are defined as bridging the patient to OLT. This approach is based on gardening principles, clipping the weeds before they flower and seed. The clinical transplant team has a plethora of neoadjuvant therapies in their tool shed to treat the primary tumor including percutaneous ethanol injection, chemoembolization, and radiofrequency ablation, but in the garden analogy, the best weed killer is not yet known. What tool is most effective and cost effective? Bridging the HCC patient to liver transplantation. Decision making in medicine may be based on tradition, empiric data, mechanisms of disease, socioeconomic costs, and beliefs, or a complex interplay enmeshing these issues. In the absence of hard data, decision analysis increasingly is being used to point to the correct therapeutic protocol. This is the approach recently reported in Gut and authored by Llovet et al,4 highly regarded HCC and hepatology investigators. They suggest that neoadjuvant therapies for HCC patients administered while the patients are waiting for liver transplantation provide gains in life expectancy and are cost effective. However, the investigators limited their decision analysis to percutaneous ethanol injection therapy (PEIT). The rationale was not obvious but related to concerns regarding peritoneal seeding with radiofrequency ablation and the lack of data with chemoembolization. Should PEIT, therefore, become the neoadjuvant therapy of choice? The answer is an emphatic no. Chemoembolization (CE) and radiofrequency ablation (RFA) still should remain in the practitioner’s tool shed. Many centers, including ours, use CE effectively as a bridge to OLT.5 Indeed, chemoembolization is the only therapy that has had a demon-
Liver Transplantation, Vol 9, No 2 (February), 2003: pp 199-200
199
200
Liver Transplantation Worldwide
strated survival advantage shown in a randomized controlled trial.6 In data yet to be published, our dropout rate for patients receiving CE while awaiting OLT is only 9%, far below the rate of 23% used in this decision analysis for untreated patients. Likewise, radiofrequency continues to show promise as an antitumor therapy, although concerns remain regarding its association with needle track seeding; however, this concern is limited primarily to surface lesions.7 Thus, we believe the tool shed should remain full, and CE, RFA, and PEIT should all remain viable approaches to bridging HCC patients to OLT. However, we emphasize that systemic therapy directed at the micrometastases would be more logical, and such studies should be encouraged despite the current organ shortage. Gregory J. Gores, MD Transplant Center Mayo Clinic Rochester, MN
References 1. Pichlmayr R, Weimann A, Ringe B. Indications for liver transplantation in hepatobiliary malignancy. Hepatology 1994;20: 33S-40S. 2. Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma: Diagnosis and treatment. Gastroenterology 2002;122:1609-1619. 3. Jonas S, Bechstein WO, Steinmuller T, Herrmann M, Radke C, Berg T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 2001;33:1080-1086. 4. Llovet JM, Mas X, Aponte JJ, Fuster J, Navasa M, Christensen E, et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002;50:123-128. 5. Harnois DM, Steers J, Andrews JC, Rubin JC, Pitot HC, Burgart L, et al. Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma. Liver Transpl Surg 1999;5:192-199. 6. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet 2002;359:1734-1739. 7. Llovet JM, Vilana R, Bru C, Bianchi L, Salmeron JM, Boix L, et al. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001; 33:1124-1129.