Editor(s): John Gibbs, M.D. Reviewers: Yuman Fong, M.D., David Nagorney, M.D., Mitchell C. Posner, M.D., Steven M. Strasberg, M.D., Jean-Nicholas Vauthey, M.D.

General reviews

Strasberg S, Belghiti J, Clavien PA, Gadzijev E, Garden JO, Lau W-Y, Makuuchi M, Strong RW. The Brisbane 2000 terminology of liver anatomy and resections. HPB 2000; 3: 333-339.

A lack of uniform terminology for liver resections has led to a confusing array of terms. The scientific committee of the International Hepato-pancreato-biliary association has created a rationale and anatomically correct nomenclature.

Vauthey JN. Liver imaging. A surgeon's perspective. Radiol Clin North Am 1998; 36: 445-457.

The broad spectrum of benign and malignant liver lesions is reviewed and the imaging strategy is outlined.

Weimann A, Ringe B, Klempnauer J, Lamesch P, Gratz KF, Prokop M, Maschek H, Tusch G, Pichlmayr R. Benign Liver Tumors: Differential diagnosis and indications for surgery. World J Surg 1997;21:983-991.

The clinical approach by a single center in the diagnosis and management of patients benign liver lesions is presented.

Jarnagin WR, Bodniewicz J, Dougherty E, Conlon K, Blumgart LH, Fong Y. A prospective analysis of staging laparoscopy in patients with primary and secondary hepatobiliary malignancies. J Gastrointest Surg 2000; 4: 34-43.

Laparoscopy identified 26 (67%) of 39 patients with unresectable disease. The yield of laparoscopy was greatest for detecting peritoneal metastases, additional hepatic tumors, and unsuspected advanced cirrhosis.

Hepatocellular Carcinoma - Overview

Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 1997; 26 (suppl 1): 34S-38S.

This article reviews our current understanding of Hepatitis C infection which has emerged as a significant risk factor in the development of hepatocellular carcinoma.

Nzeako UC, Goodman ZD, Ishak KG. Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients. Am J Clin Path 1996;105(1):65-75.

This review of 803 North American patients from the Armed Forces Institute of Pathology indicates worse prognosis for patients with cirrhosis. Interestingly, 43% of patients with hepatocellular carcinoma had no underlying liver cirrhosis.

Llovet JM, Bustamante J, Castells A, Vilana R, Del Carmen Ayuso M, Sala M, Bru C, Rodes J, Bruix J. Natural history of untreated nonsurgical hepatocellular carcinoma: Rationale for the design and evaluation therapeutic trials. Hepatology 1999;29(1):62-67.

A thorough evaluation of the natural history of untreated and unresected HCC in 102 patients. The heterogeneity of these patients is emphasized and factors, which correlate with survival, are identified. Recognition of the variability of natural history of HCC is essential for interpreting outcomes for any interventional therapy.

Torzilli G, Makuuchi M, Inoue K, Takayama T, Sakamoto Y, Sugawara Y, Kubota K, Zucchi A. No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncirrhotic patients: is there a way? A prospective analysis of our approach. Arch Surg 1999; 134: 984-992.

An algorithm for safe resection of hepatocellular carcinoma based on bilirubin, ascites, and indocyanine green retention rate at 15 minutes results in no 30-day mortality and 26% morbidity.

Surgical resection and transplantation

Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a western center. Ann Surg 1999;229(6):790-800.

A single center experience of hepatocellular carcinoma patients with cirrhosis and without cirrhosis. Of patients who underwent exploration 73% of noncirrhotics versus 62% of cirrhotics had curative resection. The lesion size was larger in the noncirrhotic group compared to the cirrhotic group (median size 10 cm vs. 6 cm). Fifty-seven of 100 patients with cirrhosis underwent lobectomy or greater.

Zhou XD, Tang ZY, Yang BH, Lin ZY, Ma ZC, Ye SL, Wu ZQ, Fan J, Qin LX, Zheng BH. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer 2001; 91: 1479-1486.

The implementation of screening programs in this high risk study population has resulted in the increased number of patients with small hepatocellular carcinoma less than 5 cm. Improved survival rates from increased resectability rates and decreased operative mortality have been observed. These authors have also employed reresection for intrahepatic recurrence and solitary pulmonary metastases to prolong survival.

Yamamoto J, Iwatsuki S, Kosuge T, Dvorchik I, Shimada K, Marsh JW, Yamasaki S, Starzl TE. Should hepatomas be treated with hepatic resection or transplantation? Cancer 1999;86(7):1151-1158.

The databases of the National Cancer center Hospital in Japan and the that of the university of Pittsburgh Medical center were combined to compare the outcome of hepatic resection (Hx) with orthotopic liver transplantation (OLTx). The early mortality rate was significantly lower in the Hx group while the overall survival between Hx and OLTx were similar. However, tumor-free survival following OLTx was significantly better in patients with HCC < 5 cm, unilobarly distributed tumors, and HCCs with either no or only microscopic vascular invasion.

Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique, and future prospects. Br J Surg 2001; 88: 165-175.

Percutaneous portal vein embolization to induce preoperatively determined small liver remnant hypertrophy has received recent interest. The technique, rationale and methods of volumetric measurement for portal vein embolization are reviewed.

Prognostic Factors/Recurrence

Bilimoria MM, Lauwers GY, Doherty DA, Nagorney DM, Belghiti J, Do KA, Regimbeau JM, Ellis LM, Curley SA, Ikai I, Yamaoka Y, Vauthey JN. International Cooperative Study group on hepatocellular carcinoma. Underlying liver disease, not tumor factors, predicts long-term survival after resection of hepatocellular carcinoma. Arch Surg 2001; 136: 528-535.

Death caused by hepatocellular carcinoma is rare beyond 5 years after resection in the absence of cirrhosis or fibrosis. The data suggests that chronic liver disease act as a field of cancerization contributing to new hepatocellular carcinoma.

Poon RTP, Fan ST, Ng IO, Wong J. Significance of resection margin in hepatectomy for hepatocellular carcinoma. A critical reappraisal. Ann Surg 2000; 231: 544-551.

A wide excision (> 1 cm) around the main hepatic tumor may not prevent intrahepatic recurrences. This study shows that underlying venous invasion or the presence of microsatellites typically results in narrow or positive microscopic margins following hepatic resection for hepatocellular carcinoma

Nonsurgical (Ablative approaches)

Curley SA, Izzo F, Ellis LM, Vauthey JN, Vallone P. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 2000; 232: 381-391.

Hepatic radiofrequency ablation has supplanted cryotherapy in many hepatic centers due to its ease of treatment application and low treatment associated mortality. In this study 110 patients with HCC undergo intraoperative (n = 31), laparoscopic (n = 3), or percutaneous (n = 76) RFA. Local tumor recurrence was observed in 4 patients (3.6%). Although 14 patients developed complications (12.7%), there were no treatment related deaths.

Adam R, Akpinar E, Johann M, Kunstlinger F, Majno P, Bismuth H. Place of cryosurgery in the treatment of malignant liver tumors. Ann Surg 1997;225(1), 39-50.

Cryosurgery with a focus on multimodality approaches combining cryotherapy with other therapeutic modalities is comprehensively reviewed.

Livragi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: Long-term results of percutaneous ethanol injection. Radiology 1995;197(1):101-108.

This is the largest series defining the indication, efficacy, and survival rates for percutaneous ethanol injection.

Neoadjuvant and Adjuvant

Venook AP, Warren RS. Regional chemotherapy approaches for primary and metastatic liver tumors. . Surg Oncol Clin N Am 1996;5(2):411-427.

An excellent review of the pharmacological basis for regional chemotherapy discussing the results of hepatic arterial infusion clinical trials and the rationale behind chemoembolization.

Paye F, Jagot P, Vilgrain V, Farges O, Borie D, Belghiti J. Preoperative chemoembolization of hepatocellular carcinoma. A comparative study. Arch Surg 1998;133:767-772.

Convincing evidence is lacking to support systematic preoperative chemoembolization prior to resection in patients with resectable hepatocellular carcinoma.

Lau WY, Leung TW, Ho SK, Chan M, Machin D, Lau J, Chan AT, Yeo W, Mok TS, Yu SC, Leung NW, Johnson PJ. Adjuvant intra-arterial iodine-131 labelled lipiodol for resectable hepatocellular carcinoma: A prospective randomized trial. Lancet 1999;353(9155):797-801.

In this study of adjuvant therapy after resection of hepatocellular carcinoma, patients were to either surgical resection alone or to post-operative, single dose, intra-arterial iodine-131 labeled lipiodol. The treated patients had a significantly increased disease-free survival without significant toxic effects.

Lau WY, Leung TWT, Lai B,Liew CT, Ho SKW, Yu SCH, Tang AMY. Preoperative systemic chemoimmunotherapy and sequential resection for unresectable hepatocellular carcinoma. Ann Surg 2001; 233: 236-241.

Twenty-seven of 150 patients (28%) with unresectable HCC who received systemic chemoimmunotherapy were found to have > 50% reduction in tumor volume. Fifteen patients with resectable disease following treatment underwent hepatic resection. After a median follow up of 27 months, 10 patients are reported to be disease free.

Biliary Tract Cancer - General Review

de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 1999; 341: 1368-1378.

An excellent contemporary review.

Nakeeb A, Pitt HA, Sohn TA, Coleman H, Abrams RA, Piantadosi S, Hruban RH, Lillemoe KD, Yeo CJ, Cameron JL. Cholangiocarinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 1996; 224: 463-473.

The 23-year experience by a large single institution of 294 patients with intraheptic, perihilar, and distal cholangiocarcinoma is reported.

Intrahepatic (peripheral) bile duct carcinoma

Weber SM, Jarnagin WR, Klimstra D, DeMatteo RP, Fong Y, Blumgart LH. Intrahepatic cholangiocarcinoma: Resectability, recurrence pattern, and outcomes. J Am Coll Surg 2001; 193: 384-391.

This single institutional study of 53 patients with intrahepatic cholangiocarcinoma who were deemed operable candidates revealed a resectability rate of 62%. The median survival for resected patients was 37.4 months versus 11.6 months. Factors predictive of poor survival following resection included vascular invasion, microscopic positive margin, or multiple tumors.

Casavilla FA, Marsh JW, Iwatsuki S, Todo S, Lee RG, Madariaga JR, Pinna A, Dvorchik I, Fung JJ, Starzl TE. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 1997; 185: 429-436.

Fifty-four patients with peripheral CCC underwent either hepatic resection (n = 34) or OLT (n = 20). Following operation actuarial patient and tumor free survival were similar. Factors that predicted poor outcome included positive margins, multiple tumors, and lymph node involvement.

Extrahepatic bile duct carcinoma

Jarnagin WR. Cholangiocarcinoma of the extrahepatic bile ducts. Semin Surg Oncol 2000; 19 156-176.

An excellent modern review of extrahepatic bile duct cancer.

Burke EC, Jarnagin WR, Hochwald SN, Pisters PW, Fong Y, Blumgart LH. Hilar cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 1998; 228: 385-394.

The experience with 90 patients with hilar cholangiocarcioma presenting at a single institution is reviewed. In one third of the patients, disease can be resected for cure with a long median survival.

Nimura Y, Hayakawa N, Kamiya J, Shionoya S. Hepatic segmentectomy with caudate lobe resection for bile duct carcinoma of the hepatic hilus. Wor J Surg 1990;14(4):535-544.

Landmark paper on curative resection for hilar cholangiocarcinoma. Forty-six of 66 patients underwent curative resection. Liver resection, including caudate lobectomy is recommended based on the demonstration of microscopic tumor involvement of the caudate lobe in 44 of 46 resections

Iwatsuki S, Todo S, Marsh JW, Madariaga JR, Lee RG, Dvorchik I, Fung JJ, Starzl TE. Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg 1998;187(4):358-364.

Partial or total hepatectomy with organ transplantation for hilar cholangiocarcinoma reveals complimentary long term survival benefits in selected patients. Future improvement in donor organ availability may expand treatment options.

Klempnauer J, Ridder GJ, von Wasielewski R, Werner M, Weimann A, Pichlmayr R. Resectional surgery of hilar cholangiocarcinoma: A multivariate analysis of prognostic factors. J Clin Oncol 1997;15(3);947-954.

Patients were treated surgically by bile duct resection alone, in combination with hepatectomy (partial or total), or combined with hepatic and vascular resection. Patients with convention bile duct resection alone or in combination with partial hepatic resection had improved survival compared to those who underwent total hepatectomy and orthotopic liver transplantation. The presence of lymph node metastases and residual disease adversely affected outcome.

Lee BH, Choe DH, Lee JH, Kim KH, Chin Sy. Metallic stents in malignant biliary obstruction: Prospective long-term clinical results. AJR 1997; 168: 741-745.

In patients with unresectable biliary tract malignancy, the placement of metallic stents can achieve favorable patency rates and offer adequate palliation

Pitt HA, Nakeeb A, Abrams RA, Coleman J, Piantadosi S, Yeo CJ, Lillemoe KD, Cameron JL. Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 1995; 221: 788-798.

Fifty patients who underwent surgical resection for perihilar cholangiocarcinoma received postoperative radiotherapy (n = 23) versus no radiotherapy (n = 27). Adjuvant radiation therapy failed to effect the length or quality of survival.

Gallbladder carcinoma

Box JC, Edge SB. Laparoscopic cholecystectomy and unsuspected gallbladder carcinoma. Sem Surg Oncol 1999; 16: 327-331.

A review of several management situations commonly encountered in patients with gallbladder cancer including 1) gallbladder cancer on final pathology 2) gallbladder cancer noted intraoperatively following laparoscopic removal

Fong Y, Jarnagin WR, Blumgart LH. Gallbladder cancer: Comparison of patients presenting initially for definitive operation with those presenting after non-curative intervention. Ann Surg 2000; 232:557-569

This study reports the results of treatment for 410 patients with gallbladder cancer over a 13 year period at a single Western referral center. Resectability, extent of liver involvement, and presence of nodal metastases were the most important determinants of outcome. Presentation after prior non-curative surgical exploration did not preclude radical resection or long-term survival.

Tsukada K, Kurosaki I, Uchida K, Shirai Y, Oohashi Y, Yokoyama N, Watanabe H, Hatakeyama K. Lymph node spread from carcinoma of the gallbladder. Cancer 1997;80(4):661-667.

The percentage of nodal disease increased according to T classification for pT1 (0%), pT2 (46%), pT3-4 (79%). These authors who advocate aggressive lymph node dissection report greater than 3-year survival in 5 of 28 patients with N2 disease.

Chijiiwa K, Nakano K, Ueda J, Noshiro H, Nagai E, Yamaguschi K, Tanaka M. Surgical treatment of patients with T2 gallbladder carcinoma invading the subserosal layer. J Am Coll Surg 2001;192: 600-607.

Positive prognostic factors for improved survival among patients with T2 gallbladder carcinoma include clear surgical margins after radical surgery, the absence of perineural invasion, or lymph node involvement.

Recent abstracts

Olschewski M, Lencioni R, Allgaier H, Cioni C, Deibert P, Frings H, Crocetti L, Laugenberger J, Zuber I, Paolicchi A, Blum HE, Bartolozzi C. A randomized comparison of radiofrequency thermal ablation and percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. Proceedings of the American Society of Clinical Oncology No. 500, 2001

102 patients with HCC less than 5 cm were treated with RFA (n =52) or PEI (n = 50). RFA were comparable to PEI with respect to safety and short-term survival. However, RFA was superior to PEI in local recurrence-free and event-free survival.

Lozano RD, Patt YZ, Ellis L, Hassan M, Chase J, Phan L, Vauthey J, Curley S, Abbruzzese J, Wolff R, Brown T. A phase II trial of a hepatic arterial infusion (HAI) of Platinol (CDDP), recombinant human interferon alpha-2b (rIFNa), Adriamycin (DOX), and 5-FU (PIAF) for the treatment of hepatocellular carcinoma (HCC). Proceedings of the American Society of Clinical Oncology No. 666, 2001

Of 17 patients treated with PIAF for HCC, 6 pts had a radiologic PR and 5 pts had stable disease. Four patients with radiologic PR underwent resection. Three had a histologic complete response and are reported disease free at a median of 2.5 years.

Roayaie S, Emre S, Fishbein T, Sheiner P, Miller C, Schwartz M. Long term results of liver transplantation and multimodal adjuvant therapy for the treatment of hepatocellular carcinoma larger than 5 cm. Proceeding of the Society of Surgical Oncology No 6, 2001

Eighty patients with unresectable HCC greater than 5 cm were enrolled in a protocol combining multimodal chemotherapy with liver transplantation. Patients underwent chemoembolization at the time of initial diagnosis. Doxorubicin was then given intraoperatively followed by 6 cycles postoperatively. 36 patients progressed while on the waiting list. Overall and disease free survival in the transplanted group was 44% and 48%, respectively.

Geschwind JH, Juluru K, Choti M, Thuluvath P, Huncharek M. Novel transcatheter arterial chemoembolization technique in the treatment of hepatocellular carcinoma: Effects on nontumorous liver tissue and impact on survival. Proceedings of the American Association for Cancer Research #3339, 2001.

A transcatheter arterial chemoembolization (TACE) protocol aimed at delivering the greatest amount of chemotherapy within tumor without occluding the hepatic artery feeding the tumor. Two separate injections consisting of a mixture of chemotherapeutic agents (cisplatin, doxorubicin, and mitomycin C) and lipiodol followed by a small amount of Ivalon particles was performed. Tumor markers and tumor viability assessed by imaging decreased in all patients. Mean survival rates were 88% and 72% at 1 and 3-year follow-up, respectively. The authors conclude that the TACE protocol prolonged survival and did not cause any appreciable damage to underlying liver tissue.

Arroyo G, Gallardo J, Rubio R, Orlandi L, Yanez M, Gamargo C, Ahumada M, Zarba J, Berlingeri G, Kowalzszyn R. Gemcitabine (Gem) in advanced biliary tract cancer (ABTC): Experience from Chile and Argentina in Phase II trials. Proceedings of the American Society of Clinical Oncology No. 626, 2001

42 patients with histologically proven ABTC received Gem 1000 mg/m2 in a 30 minute infusion weekly for 3 out of 4 weeks. At a median follow-up of 27 weeks, 42 pts were evaluable for toxicity and 39 pts for response. An overall response rate of 36% was observed (1 complete response, 13 partial response). Stable disease was observed in 11 patients. The regimen was well tolerated.

Doval DC, Sekkon JS, Fuloria J, Gupta SK, Vaid AK, Gupta S, Shukla VK. Gemcitabine and Cisplatin in chemotherapy-naïve, unresectable gallbladder cancer: a large multicenter phase II study. Proceedings of the American Society of Clinical Oncology No. 622, 2001

30 patients with unresectable gallbladder cancer received gemcitabine (1000 mg/m2) and cisplatin (70 mg/m2) on day 1 and gemcitabine (1000 mg/m2) alone on day 8 in a 21 day cycle. The median number of cycles received was 3.5. Of 26 evaluable patients, and overall response rate of 53% was observed (1 complete, 8 partial). 7 pts had stable disease.

Ongoing Clinical Trials - Hepatocellular

Phase II study of immunotherapy with Doxorubicin and protracted recombinant Interleukin-2 in patients with unresectable hepatocellular carcinoma (RPCI-RP-9814, NCI-G9901663)

A phase II trial of immunotherapy with Doxorubicin modulation to determine tumor response (objectively and immunologically), toxicity, and outcome in patients with unresectable hepatocellular carcinoma. Doxorubicin is administered intravenously (iv) over 3-5 minutes on day 1 and recombinant interleukin-2 iv continuously beginning on day 5 and continuing until day 57. Patients achieving partial or complete response regardless of immunologic response or stable disease with immunologic response are continued and treated until day 92.

Phase II study of Thalidomide in treating patients with unresectable hepatocellular carcinoma who are undergoing chemoembolization with Doxorubicin (199/15226; NYU-9937; NCI-99)

This phase II study investigates the feasibility and potential antiangiogenesis activity of Thalidomide following chemoembolization with Doxorubicin.

Phase I/II study of Doxorubicin adsorbed to magnetic targeted carriers in patients with recurrent or advanced hepatocellular carcinoma (FERX-MTC-DOX-001)

Doxorubicin adsorbed to a magnetic carrier is delivered intraarterially. A topically placed magnet over the liver retains increased drug level.

Phase I/II study of human alpha fetoprotein peptide immunization in HLA-A *0201 positive patients with hepatocellular carcinoma (UCLA-9905003; NCI-H00-0053)

HLA-A *0201 positive patients receive human alpha fetoprotein (hAFP) peptide immunization comprising hAFP (137-145), hAFP (158-166), and hAFP (542-550) intradermally into the proximal extremities or anterior trunk draining inguinal and axillary lymph nodes on days 0, 14, 28, and 42.

Ongoing Clinical Trials - Gallbladder and Biliary Tract

Phase II study of ONYX-015 in patients with primary hepatobiliary carcinomas (AECM-L970275; NCI-T98-0013)

Phase II study of intratumoral injection of a modified virus ONYX-015 in patients with primary liver or gallbladder cancer.

Phase II study of photodynamic therapy with porfimer sodium in patients with unresectable malignant bile duct obstruction (MSKCC-99015, NCI-G9901525)

The objective of this study is to determine the safety and efficacy of photodynamic therapy using porfimer sodium in patients with unresectable malignant bile duct obstruction. Patients receive porfimer sodium on day 1, followed by percutaneous or endoscopic laser light treatment on day 3. Patients achieving partial or complete response are treated to a maximum of 3 courses.

Phase I study of the radiosensitizer Gadolinium Texaphyrin with concurrent radiotherapy in patients with advanced biliary tree or pancreatic cancer (NYU-9955, NCI-G00-1908, ROCHE-NYU-9955)