© Springer International Publishing Switzerland 2015
Leonard Berliner and Heinz U. Lemke (eds.)An Information Technology Framework for Predictive, Preventive and Personalised MedicineAdvances in Predictive, Preventive and Personalised Medicine810.1007/978-3-319-12166-6_77. Surgical Treatment for Hepatocellular Carcinoma
(1)
New York Methodist Hospital, Brooklyn, NY, USA
(2)
Weill Medical College of Cornell University, New York, USA
Abstract
The treatment of hepatocellular carcinoma (HCC) has undergone evolution and refinement over the past three decades. Changes in the understanding of HCC with respect to tumor size, number and location, underlying liver function and portal pressure, and hepatic anatomy, in combination with refinement of surgical techniques and technologies, have greatly influenced the approach to surgical management. Surgery is considered the mainstay of curative HCC treatment with resection and transplantation achieving the best outcomes in well-selected candidates (5-year survival of 60–80 %). Surgical resection of HCC, especially within the Milano/Mazzaferro criteria (i.e., solitary tumor ≤ 5 cm or up to three tumors all ≤ 3 cm) in patients with well-preserved liver function (Child-Pugh A and selectively B patients), offers the greatest chances for survival. Liver transplantation is considered the treatment of choice for patients with compromised liver function (Child-Pugh B/C). The clinical parameters identified in this Chapter will be used to generate Digital Patient Models (DPMs) to facilitate diagnosis, prognosis, and treatment selection, i.e. Model Guided Therapy (MGT). The following have been identified as key issues relating to Predictive, Preventive, and Personalized Medicine (PPPM) and surgical treatment for HCC: tumor characterization, such as size, number, and vascular invasion; the patientʼs clinical status, particularly the presence of cirrhosis, the degree of portal hypertension, and liver functional reserve; pre-operative management, such as patient selection for resection or transplantation, choice of donor, down-staging and bridging therapies; and, surgical techniques, including techniques to minimize blood loss and to ensure an adequate liver remnant.
Keywords
Personalized medicineHepatocellular carcinomaStagingTreatmentSurgeryHepatectomyLiver TransplantationDown-stagingBridging Therapy7.1 Introduction
The treatment of hepatocellular carcinoma (HCC) has undergone evolution and refinement over the past three decades. Changes in the understanding of HCC in the context of a wide variety of factors such as tumor size, number and location, underlying liver function and portal pressure, and hepatic anatomy, in combination with refinement of surgical techniques and technologies, have greatly influenced the approach to surgical management. Concerted efforts have been made to review and consolidate the worldwide experience in the management of HCC and recommendations for optimal treatment protocols, based on patient staging, have been made reflecting these findings [1–4].
Surgery is considered the mainstay of curative HCC treatment with resection and transplantation achieving the best outcomes in well-selected candidates (5-year survival of 60–80 %) [3]. In general, surgical resection of HCC, especially within the Milano/Mazzaferro criteria for liver transplantation (i.e., solitary tumor ≤ 5 cm or up to three tumors all ≤ 3 cm) in patients with well-preserved underlying liver function (Child-Pugh A and selectively B patients), offers the greatest chances for survival, while liver transplantation, in patients with compromised liver function (Child-Pugh B/C), is generally considered the treatment of choice. It is important to note that these recommendations are undergoing constant reassessment and revision. The application of specific techniques, such as radiofrequency ablation (reviewed in Chaps. 8 and 9) and the practice of reclassification of patients with well-compensated liver function, have, in some reports, suggested alternative treatment protocols. These issues relating to surgical management of HCC, and which emphasize the trend toward personalized medicine in HCC, will be discussed in this Chapter.
7.1.1 Surgical Resection
Surgical resection is the optimal treatment for HCC in non-cirrhotic patients (Child-Pugh A) in that it may be curative and because of the high reserve and regenerative capacity of a non-fibrotic liver [5]. Unfortunately, in Western countries only approximately 5 % of patients present with HCC without cirrhosis [6]. In Asian countries, approximately 40 % of patients will have HCC without cirrhosis due to the high incidence of hepatitis B virus (HBV) infection which predisposes patients to HCC in the absence of cirrhosis [6]. However, with careful patient selection and improved surgical techniques, peri-operative mortality rates in cirrhotic patients with HCC have been reported to be 2–3 % with a 5-year survival rate of approximately 60 % and blood transfusion requirements of less than 10 % [3]. Selection criteria for surgical resection has previously been based on the Child-Pugh class, however surgical outcomes have been improved when independent criteria, like serum bilirubin levels and presence of portal hypertension, are used to risk stratify operative candidates [7,8]. The Barcelona Clinic Liver Cancer (BCLC) criteria stratify patients for therapy in this fashion [1–3]. Patients with normal bilirubin levels and hepatic-portal vein gradient (HVPG) < 10 mm Hg have been reported to have a 5-year survival rate of < 70 %. This is in contrast to patients with hyperbilirubinemia and portal hypertension who have a < 30 % 5-year survival rate [7]. Surrogates of portal hypertension include esophageal varices and splenomegaly with platelet count < 100,000/mm3) [3].
The size and number of tumors, the presence of microsatellites, the presence of vascular invasion, and the width of resection margin have all been shown to have prognostic significance [3, 9–11]. Improved postoperative 5-year survival rates have been shown in patients with tumors < 5 cm in diameter (66 % for tumors < 2 cm, compared with 52 % for tumors 2–5 cm and 37 % for tumors > 5 cm) and with fewer numbers of tumor nodules (73 % with one tumor vs. 44 % with 3 or more tumors) [11]. The major contraindication to resection of HCC is the presence of extrahepatic disease, as HCC commonly spreads to lymph nodes, lungs, and bone [12].
Vascular invasion has been shown to play a major role in tumor recurrence and it is thought that recurrence often involves spread from the primary resected tumor, rather than metachronous tumor development [4, 13]. Microvascular invasion has been shown to be a significant factor affecting prognosis after surgical resection, especially with identification of invasion of a muscular vessel wall or of invasion more than 1 cm beyond the tumor edge as the two worst risk factors for prognosis [14]. Tumor resection margin also influences recurrence rate in that wider margins (2 cm vs. 1 cm) taken on solitary tumors have been shown to both decrease recurrence and improve survival [15].
Several treatments have been studied as adjuvant therapies to reduce recurrence after resection of HCC. This includes the use of interferon, chemotherapy, preoperative chemoembolization, internal radiation with 131I-labeled lipiodol, immune therapies with activated lymphocytes with interleukin-2 and retinoids, and vitamin K. At this time, the studies have not been sufficiently large or conclusive enough to support their use to improve postoperative survival [3,16].
Pre-operative portal vein embolization (PVE) of the branches supplying the portion of the liver to be resected (with the intention of increasing the residual liver volume if a major resection is envisioned) has been studied [17]. The average increase in the future liver remnant (FLR) following PVE is 9 % and 16 % in cirrhotic and normal liver, respectively [17] and PVE has been used to increase the volume of the FLR in all patients who undergo trisegmentectomy [12]. PVE has also been employed in those patients with chronic liver disease who are to undergo right hemihepatectomy or when the FLR is less than 40 % [12]. However, PVE is associated with a complication rate of 10–20 % and the occurrence of severe portal hypertension in 1 % of cirrhotic patients [18]. The overall effectiveness of PVE in the treatment of HCC in cirrhosis has not yet been properly tested in large controlled studies [3].
7.1.2 Surgical Resection Techniques
In addition to selecting patients with preserved liver function reserve, a variety of surgical techniques may be employed to minimize blood loss, which is highly associated with patient outcomes [3]. This includes pre-resection imaging planning, use of ultrasonic dissector, intermittent Pringle maneuver, low central venous pressure maintenance, and immediate post-operative management. These strategies have led to a decrease in blood transfusion from 80 to 90 % to less than 10 % in two decades [19].
The implementation of anatomic resections according to the Couinaud segments has ensured a surgical approach based on sound oncologic principles, although associated with modest decrease in early recurrence [3]. As described above, anatomic resections of 2 cm margins provide better survival outcome than narrow resection margins < 1 cm. However, it is important to maintain sufficient remnant liver volume to ensure adequate function.
Finally, laparoscopic video-assisted hepatic resection is being investigated as an alternative non-invasive approach aimed at preventing liver deterioration compared to open surgery [3].
7.1.3 Liver Transplantation
Liver transplantation is a curative option for patients with HCC, especially for those with underlying cirrhosis who may be poor candidates for surgical resection. Patients with a single lesion ≤ 5 cm, or up to 3 lesions each ≤ 3 cm in diameter, who meet the United Network for Organ Sharing (UNOS) criteria and those meeting extended criteria of University of California San Francisco (UCSF) which allows for a single lesion ≤ 6.5 cm or up to 4 lesions with none > 4.0 cm and a maximum combined tumor bulk of ≤ 8.0 cm have shown excellent 5-year survival rates of approximately 70 % [20–22]. However, the UCSF criteria have not been adopted by UNOS for liver transplantation in patients with HCC.
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