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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Multimodality treatment for hepatocellular carcinoma

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Liver Cancer Institute & Zhongshan Hospital, Shanghai Medical University, Shanghai, China

Hepatocellular carcinoma (HCC), a fatal malignancy endemic in sub-Saharian Africa and southeast Asia, remains a great challenge, particularly in treatment aspect. Fortunately, the prognosis of HCC has been gradually altered based on the advances of hepatic surgery, early detection, medical imaging, regional cancer therapies and multimodality combination treatment. In the United States, the 5-year relative survival rates in the periods of 1974–76, 1980–82 and 1986–93 were 4%, 4% and 6% in white, being 1%, 2% and 4% in black respectively (Landis et al. 1998).

General consideration of HCC

The incidence rate of HCC ranked third in developing countries (Parkin et al. 1993). In China, HCC has become the second cancer killer since 1990s. The etiological factors of HCC include viral hepatitis B and C; chemical carcinogens, such as aflatoxin; in rural area of China where HCC is endemic, HCC mortality correlated with contamination of drinking water, microcystin found in such water proved to be promotor of hepatocarcinogenesis; others, such as alcohol, smoking, genetics, etc.

HCC is hypervascular in the majority. Arterioportal shunt is frequently found in large tumor. Tumor thrombi are also common in portal and hepatic veins, which lead to intrahepatic and distant metastases. Most of the HCC associated with cirrhosis, posthepatitic cirrhosis accounted for the majority.

Alpha fetoprotein (AFP) is the best tumor marker for HCC. Abnormal serum AFP is found in 60–70% of HCC patients in the Far East. Serum HBV and HCV markers are important diagnostic aid for HCC. Ultrasonography (US) is of value to detect 1 cm HCC. Computed tomography (CT), spiral CT, Lipiodol-CT, magnetic resonance imaging (MRI) also provide important information's. Arteriography remains useful despite invasive. For differential diagnosis, secondary liver cancer, hemangioma, adenoma, inflammatory pseudotumor, focal nodular hyperplasia and adenomatous hyperplasia are common diseases to be excluded.

Staging of HCC

The TNM classification (1997) for liver is summarized: T1 – Solitary, ≤ 2 cm, without vascular invasion. T2 – Solitary, ≤ 2 cm, with vascular invasion; multiple, one lobe, ≤ 2 cm, without vascular invasion; solitary, > 2 cm, without vascular invasion. T3 – Solitary, > 2 cm, with vascular invasion; multiple, one lobe, ≤ 2 cm, with vascular invasion; multiple, one lobe, > 2 cm, with or without vascular invasion. T4 – Multiple, more than one lobe; invasion of major branch of portal or hepatic veins; perforation of visceral peritoneum. N1 – Regional lymph node metastasis. M1 – Distant metastasis.

Stage grouping: Stage I – T1, N0, M0. Stage II – T2, N0, M0. Stage IIIA – T3, N0, M0. Stage IIIB – T1, N1, M0; T2, N1, M0; T3, N1, M0. Stage IVA – T4, Any N, M0. Stage IVB – Any T, Any N, M1.

The T, N, and M categories are based on physical examination, imaging, and/or surgical exploration.

Okuda proposed a staging system in 1985, which includes: (a) Tumor size: > 50% (+), < 50% (-). (b) Ascites: (+) and (-). (c) Albumin: < 3 g/dl (+) and > 3 g/dl (-). (d) Bilirubin: > 3 mg/dl (+) and < 3 mg/dl (-). Stage I: all (-). Stage II: 1 or 2 (+). Stage III: 3 or 4 (+). For coexisted cirrhosis, ChildPugh classification is universally accepted.

Evolution of HCC treatment

In late 19th century, irregular hepatic resection has been the earliest treatment modality for HCC. In the 1950s, hepatic lobectomy was first employed for treatment of large HCC and achieved curable outcome in some patients; hepatic artery ligation (HAL) and cannulation with infusion (HAI) were advocated; chemotherapy and radiotherapy were also started in this period. In the 1960s, Starzl performed the first liver transplantation, although the value in treatment of HCC was confirmed until 1990s. In the 1970s, the application of AFP serosurvey resulted in detection of small (≤ 5 cm) and resectable HCCs, the 5-year survival after resection was double to that of large HCC resection. In the 1980s, re-resection for subclinical recurrent HCC resulted in further prolong survival; cytoreduction and sequential resection for initially unresectable HCC has become feasible based on the rapid progress of regional cancer therapies, such as transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI), as well as multimodality combination therapy. In the 1990s, prevention of recurrence has become a new target; studies of metastasis on the molecular level, has provided new clues for the control of recurrence and metastasis (1–3).

The 5-year survival rates of different treatment modalities were 40.8% for resection and 8.0% for TAE I TACE (Arii et al. 1996, nationwide survey in Japan); 31% for resection and 32% for liver transplantation (Michel et al. 1997, collective data in France); 68% for liver transplantation, 44% for resection, 36% for PEI and 22% for TACE (Colella et al. 1998); 64.9% for small HCC resection (n = 735) and 37.4% for large HCC resection (n = 1050) (1).

Selection of treatment modality

Tumor status, liver function and general condition are three major determinants for selection of treatment modalities. TNM classification includes tumor size, number of tumor nodules, involvement, vascular invasion, invasion of major branch of portal or hepatic veins, regional lymph node metastasis, and distant metastasis. T1, T2 and part of T3 are candidates for surgery, part of T3 and T4 are indicated for TACE. Liver function can be divided into compensated and noncompensated (high bilirubin, reversed albumin/globulin ratio, prolonged prothrombin time, etc). Child A with localized HCC is good for surgery, TACE can be considered with multiple HCC in Child A and part of Child B, conservative treatment is the choice for Child C. General condition includes age, cardiac and pulmonary function, coexisted diseases, etc.

For small HCC (≤ 5 cm) with child A or compensated liver function, resection is the first choice, limited resection is suggested in a cirrhotic liver. For patient contraindicates to resection, regional cancer therapies, such as cryosurgery, microwave ablation, ethanol injection can be chosen. Patient with small HCC and Child B cirrhosis, PEI or superselective TACE can be considered. However, patient with Child C or noncompensated liver function, only conservative treatment is indicated.

For localized large HCC (> 5 cm) with Child A or compensated liver function, resection is the best choice. For unresectable localized HCC, cytoreduction and sequential resection is a good approach. Hepatic artery cannulation combined with ligation is effective for cytoreduction. Regional radiotherapy can be added.

For multiple HCC, TACE is the best. TACE can still be tried in individual patients who had tumor thrombus in the main portal vein when collateral circulation is good and liver function acceptable. For HCC with Child C cirrhosis, only symptomatic treatment is indicated.

Implication of multimodality combination treatment for HCC

Although surgical resection provides the best outcome, unfortunately, unresectable HCC accounted for around 90%. Therefore, studies on effective approach to improve prognosis of unresectable HCC and further prolong survival of patients after resection are needed. To this end, multimodality treatment will probably be a hope. Broadly speaking, multimodality treatment includes: (a) a multidisciplinary approach including surgery, regional cancer therapies, radiotherapy, drug therapy, biotherapy, etc.; (b) a combination of different treatment modalities; (c) sequential use of different treatment modality; or (d) repeated use of the same treatment modality. Of different modes of combination, multi modality treatment with resection provides potential cure of the disease, has attracted more attention. It has been observed that the 5-year survival of inpatients has increased from 4.8% in 1958–70, 12.2% in 1971–83, to 50.5% in 1984–96, which might be a result of decreasing mean tumor diameter (11.7, 10.5 and 9.5 cm, respectively) and increasing use of multimodality treatment (1). This chapter will mainly discuss combination of regional cancer therapies and followed by resection, resection followed by preventive treatment, and combined/sequential use of 2–3 regional cancer therapies for unresectable HCC.

HAL combined with HAI and followed by resection

For patient with unresectable large but localized HCC and Child A cirrhosis, a combination of HAL and HAI is effective for cytoreduction, and sequential resection following marked shrinkage of tumor is feasible in around 20% of patients. The unresectability is mainly due to right lobe tumor with a small left cirrhotic liver, which can not tolerate the major hepatic resection; or a large HCC closed to major intrahepatic vessels or ducts, which makes resection difficult. It has been demonstrated that the combination of HAL and HAI was more effective for cytoreduction than that of HAL or HAI each alone (Zhou et al. 1991). A catheter with implantable injection port is inserted through the right gastric epiploic artery to the hepatic artery, the opening of the catheter is adjusted at the right or left hepatic artery according to the location of the tumor, The accurate positioning of the catheter is verified by injection of methylene blue. Hepatic artery ligation is then made but maintain the patency of the inserted catheter. Postoperative chemoembolization is given once a month using chemotherapeutic agents and Lipiodol. Cisplatin, adriamycin (or epirubicin), 5-fluorouracil or flurodeoxyuridine and mitomycin C are agents commonly use, and two or three of these agents are selected. Regional radiotherapy, intraarterial radioimmunotherapy or 131I-labeled Lipiodol can also be added. After a median of 5 months, adequate reduction of tumor size is achieved to meet the criteria of sequential resection. Indication for sequential resection including marked shrinkage of tumor by 50% in diameter, albumin and globulin ratio has returned to normal, and medical imaging indicates that resection is technically feasible. Limited resection is the choice for sequential resection. Residual cancer was found in the majority of surgical specimens indicating the necessity of sequential resection. The 5-year survival of sequential resection was around 40–60% (4).

TACE and followed by resection

In patients with unresectable large but localized HCC and coexisted with Child A or part of Child B cirrhosis, TACE is a nonsurgical approach for cytoreduction when uptake of Lipiodol in the tumor is adequate. TACE was therefore useful to improve resectability of unresectable HCC (Majno et al. 1997). TACE using similar agents as mentioned above, with interval of 2–3 months and a total of 2–4 courses which takes around 6 months, is hopeful for a small proportion of patients to receive sequential resection (5). For this group of patients, 5-year survival of patients with sequential resection (30–50%) was much higher than that without sequential resection (7–15%) (being 59.0% vs. 13.7%, Chen et al. 1996), although a prospective trial is needed.

Resection followed by TACE and other treatment

The 5-year recurrent rate after curative resection of HCC was as high as 60–70%, being 40–50% for small HCC resection. Besides multicentric origin of HCC, spreading of the original lesion is the main cause of recurrence in the liver. Efforts have been made for prevention of recurrence. Preoperative TACE for resectable HCC is not advocated (Wu et al. 1995, Harada et al. 1996, Uchida et al. 1996), however some authors observed improving survival (Di Cardo et al. 1998). It was the opinion that preoperative TACE might benefit patients with tumor > 8 cm, but not 2–8 cm (Lu et al. 1999). Postoperative TACE claimed to prolong survival (Takenaka et al. 1995). One or two course of TACE is suggested with interval around 5 months after curative resection, which seems helpful to control undetectable residual HCC after a “curative resection”. Postoperative adjuvant arterial infusion chemotherapy also claimed effective (Nakashima et al. 1996), however, prospective trials failed to demonstrate the effectiveness (Ono et al. 1997, Lai et al. 1998). A randomized trial failed to demonstrate the additional benefit of LAK/IL-2 after HCC resection (Kawata et al. 1995). Multi modal therapy including hepatectomy, TACE and PEI also claimed to improve survival of stage IVa HCC (Harada et al. 1996). Interestingly, a randomized trial revealed that oral polyprenoic acid prevents second primary HCC after surgical resection (6). More and more paper reported that IFN may prevent HCC (7). Therefore, IFN might be used after curative resection.

Multimodality treatment of recurrent HCC

Re-resection was proved the best for treatment of subclinical recurrence with 1–2 small nodules (8). AFP and ultrasonography monitoring after curative HCC resection, in an interval of 2–3 months, is of value to detect small recurrent HCC. The 5-year survival after re-resection was around 30–40%, and being 40–60% calculated from the first resection, which was better than that of TACE (Jeng et al. 1992, Lee et al. 1995, Poon et al. 1999). Re-resection is also indicated in patient with solitary lung metastasis, particularly when the recurrent lesion appears few years after the initial liver resection, and the 5-year survival was even better than that of re-resection in the liver. PEI is currently treatment of choice for patient contraindicates to surgery. Repeated PEI is needed for a better result, and the 5-year survival was next to that of re-resection. Patient with multiple recurrent HCC nodules in the liver, repeated TACE in an interval of 2–3 months is the treatment choice, the 5-year survival was better than that of conservative treatment. PEI combined with TACE was claimed superior to that of TACE alone (Ishii et al. 1996).

TACE, PEI and their combination

For patient with unresectable HCC, TACE is indicated for large or multifocal HCC (TNM Stage II, IIIA, part of IIIB and part of IVA) with Child A or part of Child B cirrhosis. Agents commonly used are similar to that of HAI mentioned above. The procedure is repeated in an interval of 1–3 months depend on the uptake of Lipiodol as well as recovery of liver function and general status. Uptake of Lipiodol in the tumor correlated well to the response of TACE (Stefanini et al. 1995). Inadequate control of tumor, down staging of ChildPugh classification with the increasing TACE courses, and risk of enhance lung metastasis are demerits of TACE treatment. The 5-year survival after TACE ranged from 7–20%, superselective TACE yields better result. Prognostic factors include Lipiodol uptake, number of HCC nodule, thrombus in the portal vein, etc. However, a randomized trial indicated that TACE does not improve the survival of patients with advanced HCC (Bruix et al. 1998).

PEI is indicated for unresectable small HCC, the 5-year survival was 32% in a series with 105 patients (Lencioni et al. 1995). It is important to repeat the procedure for around 10 times in an interval of about 3–7 days, and try to cover the entire HCC nodule. The coagulation effect prevents further infiltration of ethanol to the peripheral area, therefore, PEI is inadequate to cover the entire tumor nodule in one injection. Acetic acid (15–50%) is an alternative to ethanol, the 5-year survival up to 49% has been reported in small HCC (≤ 3 cm) (Ohnishi et al. 1996). Percutaneous microwave therapy is a new approach as regional cancer therapy for HCC.

A combination of TACE and PEI was currently proved to be effective treatment for large HCC (> 3 cm) with 5-year survival of 35–47% (9), and better than that of TACE/PEI each alone (Allgaier et al. 1998). For small HCC, 5-year survival of TACE combined with PEI was 42.0%, being 63.6% in resection group (Tateishi et al. 1997).

Other treatment modalities

Cryosurgery yielded 26.9% of 5-year survival, the addition of HAL/HAI improved survival further (Zhou et al. 1998). Radiotherapy has been one of the treatment choice for unresectable HCC since 1950s (Ariel 1956). Recently, TACE has surpassed radiotherapy to be the first choice of treatment for unresectable HCC. Factors that favor better response including larger dosage of irradiation, smaller tumor size, etc. Other internal radiotherapy, such as radioimmunotherapy using 131I-antiferritin, 131Ianti HCC monoclonal antibody, 131Ianti AFP, etc. have been tried. A prospective trial revealed that in terms of survival, 131I-Lipiodol and TACE were equally effective (Raoul et al. 1997). 90Y-microsphere or 32P-microsphere has also been reported. For chemotherapy, intrahepatic arterial infusion is effective in most of the patients, whereas intravenous administration is disappointed. Randomized trial failed to demonstrate the effect of Tamoxifen in the treatment of advanced HCC (Riestra et al. 1998). Biotherapy will of implication in control of residual cancer. Instead of the old biological response modifiers, Interferon-α (IFN), Interleukin-2 (IL-2), LAK/IL-2, etc. are preparations that currently used. Prospective trials claimed that combined locoregional immunochemotherapy using IFN/IL-2 improved survival of unresectable HCC (10), and Octreotide increased median survival from 4 months to 13 months in advanced HCC (Kouroumalis et al. 1998).

Conclusion

Multimodality combination treatment using HAL plus HAI or repeated TACE and followed by sequential resection yielded 40–60% of 5-year survival in a small part of patients with unresectable but localized HCC. TACE combined with PEI was superior to that of each alone. All of these indicate a significant potential of studies on multimodality treatment, particularly the development of novel regional cancer therapies as well as better combination modes.

However, prospective randomized trials are important for final evaluation. Analysis of factors influencing prognosis of multimodality treatment indicated that biological characteristics and coexisted hepatitis and cirrhosis are important aspects, therefore, invasiveness of HCC and coexisted Child C cirrhosis remain major targets to be studied.

References

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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6903

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