2011

Hellenic Society of Medical Oncology

Consensus Meeting on Hepatobiliary and Pancreatic Cancer

A. Athanasiadis, V. Barbounis, S. Delis, C. Dervenis, N. Diamantopoulos, C. Emmanouilidis, N. Giannakou, E. Hatzitheoklitos, M. Konstantoulakis, N. Mathou, G. Nasioulas, P. Papakostas, K. Paraskeva, E. Samantas, G. Sotiropoulos, J. Souglakos, L.Thanos, C. Triantopoulou, K. Tiniakou, L. Vini

Suggestions, Opinions and Recommendations for the Diagnosis, Management, Treatment and Surveillance of Hepatobiliary and Pancreatic Cancer

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LEGAL DISCLAIMER

HeSMO considers adherence to these guidelines to be voluntary. The ultimate determination regarding their application is to be made by the physician in light of each patient’s individual circumstances. In view of the consultory and non-binding nature, these guidelines cannot form the basis for legal action or litigation for compliance or absence of compliance in the clinical practice setting but can only be considered as general guidelines based on best available evidence for assistance in decision-making. Any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. HESMO makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way. In addition, these guidelines describe evaluations and administration of therapies in clinical practice; they cannot be assumed to apply to interventions performed in the context of clinical trials, given that such clinical studies are designed to test innovative management strategies in a disease for which better treatment is sorely needed. However, by reviewing and synthesizing the latest literature, this practice guideline serves to identify questions for further research and the settings in which investigational therapy should be considered.

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Evidence Level and Recommendation Grade

Level of Evidence

I Evidence from at least one large randomized control trial of good methodological quality (low potential for bias) or meta-analyses of well- conducted RCTs without heterogeneity

II Small RCTs or large RCTs with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity

III Prospective cohort studies

IV Retrospective cohort studies or case-control studies

V Studies without control group, case reports, experts opinions

Strength of Recommendation

A Strong evidence for efficacy with a substantial clinical benefit, strongly recommended

B Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended

C Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, etc.) optional

D Moderate evidence against efficacy or for adverse outcome, generally not recommended

E Strong evidence against efficacy or for adverse outcome, never recommended

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Contents LEGAL DISCLAIMER ...... 2

1. HEPATOCELLULAR CARCINOMA ...... 7

1.1. MOLECULAR BASIS AND GENETICS: PREDICTIVE AND PROGNOSTIC MARKERS ...... 7

1.2 CLINICAL PRESENTATION AND DIAGNOSIS ...... 9

1.3 HISTOPATHOLOGICAL FEATURES ...... 12

1.3.1 Tumor biopsy versus noninvasive imaging methods ...... 12

1.3.2 Histopathological criteria for small (≤ 20 mm) HCC diagnosis ...... 12

1.3.3 Histological grading of HCC ...... 14

1.3.4 Microvascular invasion ...... 14

1.3.5 Fibrolamellar Carcinoma ...... 14

1.3.6 Immunophenotype of HCC ...... 15

1.4 RISK FACTORS, POPULATION SCREENING AND SURVEILLANCE 16

1.4.1 Surveillance tests ...... 17

1.5 Imaging ...... 19

1.6 RESECTABLE CARCINOMA ...... 21

1.6.1 Preoperative Assessment ...... 21

1.6.2 Resection ...... 23

1.7 LIVER TRANSPLANTATION ...... 25

1.8 PATHOLOGY REPORT ...... 26

1.8.1 Macroscopical examination ...... 26

1.8.2 Histopathology ...... 26

1.8.3 HCC Staging ...... 27

1.9 MULTICENTRIC VS METASTATIC HCC ...... 27 Final document Page 4

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1.10 LOCOREGIONAL THERAPY ...... 29

1.10.1 Ablation ...... 29

1.10.2 Percutaneous Ethanol Injection ...... 29

1.10.3 Radiofrequency Ablation (RFA) After PEI ...... 29

1.10.4 RFA ...... 30

1.10.5 Cryoablation ...... 30

1.10.6 Microwave Ablation ...... 30

1.10.7 Laser Ablation ...... 31

1.10.8 TACE ...... 32

1.10.9 Yttrium ...... 33

1.11 ROLE OF RADIOTHERAPY IN NON-RESECTABLE DISEASE ...... 33

1.12 SYSTEMIC THERAPY ...... 34

2. CHOLANGIOCARCINOMA ...... 37

2.1 GALLBLADDER CANCER ...... 37

2.1.1 Introduction ...... 37

2.1.2 Mass on Imaging ...... 37

2.1.3 Management ...... 39

2.1.3.5 Treatmen of advanced disease ...... 43

2.2 INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA .. 45

2.2.1 Classification ...... 45

2.2.2 Imaging ...... 46

2.2.3 Pathology Report ...... 48

2.2.4 Surgery ...... 51

2.2.4.2 Extrahepatic cholangiocarcinoma ...... 52

2.2.5 Adjuvant Therapy ...... 53

2.2.6 Treatment of Locally Advanced and Metastatic Cholangiocarcinoma ...... 54

2.2.7 Palliative Approaches ...... 57

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3. PANCREATIC CANCER ...... 62

3.1 GENERAL CONSIDERATIONS ...... 62

3.2 MOLECULAR BASICS AND GENETICS: PREDICTIVE AND PROGNOSTIC MARKERS ...... 63

3.2.1 Molecular basics ...... 63

3.2.2 Genetic Predisposition ...... 63

3.2.3 Predictive and Prognostic Markers ...... 64

3.3 HISTOPATHOLOGICAL FEATURES ...... 64

3.4 DIAGNOSIS, ALARMING SYMPTOMS AND SIGNS ...... 66

3.4.1 Alarming Symptoms and Signs ...... 66

3.4.2 Diagnosis ...... 66

3.4.3 Tumor-Associated Antigens ...... 66

3.4.5 Biopsy...... 67

3.5 STAGING ...... 68

3.5.1 Imaging ...... 68

3.5.2 Pathology Report ...... 69

3.5.3 Prognostic Factors ...... 71

3.6 MANAGEMENT ...... 73

3.6.1 Surgery ...... 73

3.6.2 Adjuvant treatment of resected pancreatic cancer ...... 78

3.6.3 Management of Unresectable Pancreatic Cancer ...... 79

3.6.4 Role of radiotherapy ...... 82

4. REFERENCES ...... 87

5. APPENDICES ...... 118

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1. HEPATOCELLULAR CARCINOMA

1.1. Molecular Basis and Genetics: Predictive and Prognostic Markers Carcinogenesis of hepatocellular carcinoma (HCC) is a multistep process that requires several genetic alterations. During a long pre-neoplastic period irreversible structural modifications in genes and chromosomes, as well as epigenetic alterations, contribute to the development of the malignant hepatocyte phenotype. As a result, HCC may present a variety of genetic and epigenetic changes and may be classified in several molecular subtypes. Several pathways have been implicated in the carcinogenic process in HCC and some of them are extensively studied.

Several chromosomal aberrations have been reported (amplification of 1q, 8q, 6p, and 17q or loss of 8p, 16q, 4q, 17p, and 13q), some of which (i.e. loss of 4q) have been correlated with more aggressive phenotype (1). Unfortunately, no clear genetic associations and conclusions could be drawn since the majority of the studies include a limited number of samples without incorporation of validation or control groups.

There is growing evidence implicating the Wnt developmental pathway in HCC pathogenesis. Increased expression and nuclear accumulation of -catenin has been observed in up to 62% of HCC and has been correlated with poorer prognosis and higher rate of tumor recurrence (2). Furthermore, -catenin mutations were demonstrated in 26-41% of the cases and associated with aflatoxin exposure and HCV infection (3;4). In addition, mutations of other genes involved in Wnt pathway such as the axis inhibition protein 1 (Axin1) and in lower frequency of Axin2 have been reported in HCC (5). Of course these data are limited to provide conclusive evidence that aberrant activation of the Wnt pathway is responsible for the initiation of carcinogenesis in HCC as has been demonstrated in other solid tumors (typically colorectal cancer).

A large number of studies suggest that p53 tumor suppressor gene plays a crucial role in malignant transformation in HCC. Mutations of p53 vary in different geographic areas, presumably due to differences in both etiological

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agents and host susceptibility. In areas with high exposure to aflatoxin B1 (AFB1) a point mutation at the third position of codon 249 is the predominant type of p53 mutation. The same mutation has been detected in non-tumorous liver reflecting the AFB1 exposure in a dose-dependent manner, indicating that this is an early mutational event in liver carcinogenesis (6). This finding provides the rational for analysis of serum for the codon 249ser mutation as a biomarker for AFB1 exposure and early detection of HCC, but this must be proven in prospective studies.

Alterations in several other pathways, such as overexpression of TGF- (7), inactivation of Rb (8), or Met overexpression (9) have been reported in HCC. The exact role of these pathways and their significance in HCC remains rather unknown.

More compelling data were obtained with the use of novel technologies for high scale genomic analysis. An early genomic study classified HCC tumors in two subclasses with different prognosis based on the expression signature of genes related with cell proliferation, anti-apoptotic signals, ubiquitination and SUMOylation (Small Ubiquitin-like Modifier, SUMO) (10). Data from a recent gene expression profiling study suggested existence of distinct categories of HCC with different prognosis due to different molecular genetics, providing evidence that the transformation process is driven by different mechanisms depending on the etiological factors (11). Since all large-scale gene expression profiles studies have been conducted in a limited number of samples again no definitive conclusion could be drawn. In general, the most valuable information derived from microarray experiments is that HCC is a genetically diverse disease, which could be divided in several subclasses.

Finally, aberrant expression of several microRNAs has been implicated in HCC carcinogenesis, and miRNA expression signatures correlated with disease course and prognosis of patients with HCC. For example, a 20-miRNA signature was correlated with venous invasion and disease free and overall survival (12), while upregulation of mir-221 and mir-21 was associated with reduced apoptosis and increased angiogenesis (13). Similarly to gene

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expression profiling, miRNAs expression signatures may be used for sub- classification of HCC leading to elucidation of the pathogenetic mechanisms in the carcinogenic process.

Despite the aforementioned data, mechanistic studies regarding the implication of specific pathways (gene or protein) to each particular step of malignant transformation are still missing. The adaptation of new research strategies and the incorporation of new molecular technologies may expand our knowledge on molecular biology of HCC offering the opportunity of rationally designed targeted therapies.

Recommendations  There is no validated biomarker that could be used as prognostic biomarker in the daily clinical practice.  There is no available marker for the prediction of the effect of treatment for HCC.

1.2 Clinical Presentation and Diagnosis

HCC is often an asymptomatic disease with no physical signs at presentation, except for those related to an underlying chronic liver disease and/or cirrhosis. A palpable and tender mass in the upper abdomen or a hepatic arterial bruit might be found in more advanced cases. HCC could be suspected in patients with previously compensated cirrhosis with a rapid deterioration of liver function, a new onset or refractory ascites, variceal bleeding, appearance of encephalopathy an acute intra-abdominal bleeding, jaundice, weight loss and fever. Occasionally, paraneoplastic syndromes can occur, such as hypercholesterolemia, erythrocytosis, hypercalcemia and hypoglycemia.

The diagnosis of HCC is based on imaging, biopsy and alpha-fetoprotein (AFP) serology. It is widely accepted that AFP is insufficiently sensitive or specific for use as a diagnostic tool as it can be elevated in intrahepatic cholangiocarcinoma (ICC) and sometimes in liver metastases from colorectal cancer so its use is no longer unanimously recommended. Nevertheless, high levels of AFP >200 ng/mL, (various

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer cut-offs of that level have been reported) in association with a typical imaging modality might be highly suggestive of HCC (14;15).

HCC can be diagnosed radiologically with a contrast-enhanced study (dynamic CT- scan or MR) providing typical specific imaging features exist (16) (17) (18). Contrast-enhanced ultrasonography (CEUS) is not widely available and positron emission tomography (PET/CT) is considered to be inadequate. To correctly document the existence of HCC, a 3-phase study is required (arterial, venous, and delayed phases). The presence of arterial uptake followed by “washout” in the venous and delayed phases is highly specific for HCC (19) (20) (21) (22).

The current recommendations for the diagnosis of HCC are presented in Figure 1 (23;24). When a hepatic lesion is smaller than 1 cm on initial imaging, no further, detailed investigation is initially required, because most of these lesions will end up to be cirrhotic nodules. In this scenario, the imaging technique that first documented the presence of the nodule is repeated at 3-month intervals, and if changes are noted, patients could be further investigated accordingly. If a lesion above 1 cm in diameter is found on US, further imaging with a multidetector CT scanner or dynamic MRI should be applied. Contrast enhanced ultrasound is considered to be less specific. If the appearances are typical for HCC, in arterial and venous phases, on either CT scan or MRI, the diagnosis of HCC is confirmed, and no further action, invasive or noninvasive, is required. A second imaging study (CT scan or MRI) should be performed, if the US imaging findings are not typical for HCC and if the appearance is then typical the diagnosis is confirmed. Otherwise, the suspected lesion should be biopsied. As performance and quality of the imaging study is so critical for the non-invasive diagnosis of HCC, it should ideally be performed in diagnostic centers with expertise, according to strict performance imaging protocols.

As mentioned above, a biopsy confirmation is not necessarily required for the diagnosis of HCC, if typical imaging features are present. However, the above recommendations apply only to nodules identified in patients with liver cirrhosis. In patients without cirrhosis or known liver disease, biopsy should be strongly considered to confirm the diagnosis of HCC.

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Recommendations

 In patients with cirrhosis or known liver disease if a lesion smaller than 1cm is recognized on ultrasound surveillance, follow up should be offered with ultrasound at 3-6 months intervals (LoE III; GoR B). If there has been no change over a period of up to 2 years, routine surveillance can be continued (LoE III; GoR B).  In patients with cirrhosis or known liver disease if a lesion larger than 1 cm is found on ultrasound surveillance, further investigation with either 3-phase multidetector CT scan or dynamic contrast enhanced MR should be done. If the imaging appearances are typical of HCC, the diagnosis of HCC is definite and no further test is required. If the imaging findings are atypical of HCC, a second contrast enhanced study should be performed, or the lesion should be biopsied (LoE II; GoR B).  In patients without chronic liver disease biopsy of the lesion should be strongly considered (LoE II; GoR A).

Figure 1: Algorithm of investigation of small nodules found on screening in patients at risk for HCC.

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1.3 HISTOPATHOLOGICAL FEATURES

1.3.1 Tumor biopsy versus noninvasive imaging methods

According to international guidelines for HCC diagnosis, described in more details above, biopsy is not required in tumors >10 mm in a cirrhotic liver if CT or MRI show a typical vascular pattern. However, the false positive rate of HCC diagnosis with noninvasive imaging techniques varies between 0%-33%. For lesions <10 mm, noninvasive imaging techniques are not accurate and cannot be used for treatment decisions.

The 2011 American Association for the Study of Liver Disease (AASLD) guidelines reported that 52%-56% of patients with lesions 10-20 mm will need liver biopsy. The specificity and sensitivity of liver biopsy in diagnosing HCC with an 18-20-gauge needle are 100% and 86%-93%, respectively. Tumor biopsy results are less reliable for tumors ≤ 10 mm. The risk of needle track seeding in a recent meta-analysis was 2.7% with a 17-month median time between biopsy and seeding (25). About 2 to 11% of biopsy specimens may be inadequate for histological diagnosis (26).

1.3.2 Histopathological criteria for small (≤ 20 mm) HCC diagnosis

HCC arising in cirrhosis is usually preceded by the appearance of non-malignant precancerous lesions such as large regenerative nodules (LRN), low grade dysplastic nodules (LGDN) and high grade dysplastic nodules (HGDN). In non- cirrhotic liver, the evolution of hepatocellular neoplasia in humans has not as yet been clarified (27).

International guidelines for HCC diagnosis have restricted the use of biopsy to liver nodules with atypical vascular pattern on CT or MRI (10-15% of cases). In a background of cirrhosis, these are often small (<20 mm), iso/hypovascular, well differentiated hepatocellular lesions posing a diagnostic challenge between HGDN and well differentiated HCC. Biopsy provides both architectural and cytological information as well as material for subsequent biomarker studies, therefore it is considered superior to fine needle aspiration

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as reported by an International Consensus Group for Hepatocellular Neoplasia in 2009 (28;29).

Early HCC are small (≤ 20 mm), vaguely nodular tumors with indistinct margins and well differentiated histology with a few portal tracts present, varying numbers of unpaired arteries, pseudoglandular pattern and, frequently, diffuse fatty change. Microscopic vascular invasion (MVI) is not seen. Stromal invasion into portal tracts/septa is a very useful diagnostic feature in favor of malignancy when differentiating from a HGDN and it may be confirmed by absence of ductular reaction highlighted by immunostains for biliary keratins 7 or 19 (28). Immunostaining for glypican 3, heat shock protein 70, and glutamine synthetase helps in the differential diagnosis from HGDN since positivity for two of these markers confirms HCC (27;29;30).

Progressed HCC (a HCC form of distinctly nodular type) may develop from pre-existing dysplastic nodule or from an early HCC and, characteristically, has distinct margins and a fibrous capsule. It may be small (< 20 mm), usually well to moderately differentiated, rarely steatotic, without portal tracts but with well-developed unpaired arteries and not uncommon MVI. Progressed HCC may take the gross and radiological appearance of “nodule-in-nodule” (27;29).

It should be underlined that not all primary carcinomas arising in a cirrhotic liver are HCC. Similarly, the early concept that only two types of primary liver carcinoma exist, HCC and cholangiocarcinoma, is not valid anymore. For example, primary liver carcinomas of mixed or uncertain origin, such as combined hepatocellular-cholangiocarcinomas (some may have stem cell features) and carcinosarcomas, are now recognized and can only be diagnosed by careful histopathological examination (30).

In a non-cirrhotic liver, the main differential diagnostic challenge lies between HCC, because of its wide spectrum of differentiation and histological patterns, and the intrahepatic cholangiocarcinoma or secondary liver metastases (29).

Correct classification and subtyping of HCC using morphological and immunophenotypical criteria is important not only for diagnosis but also for

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providing tissue biomarker information permitting, hopefully in the near future, a personalized approach to HCC treatment.

1.3.3 Histological grading of HCC

Histological grading such as the Edmondson & Steiner’s since 1954 (grades I- IV) and the Armed Forces Institute of Pathology (AFIP) (grades 1-4) classification (31), was based on progressive nuclear and cytological features, while the most recent WHO classification (30) is based on tumor differentiation (well, moderate, poor, undifferentiated). Histological grade has been recommended to be reported in resected specimens of HCC; however, its clinical significance and usefulness on an individual basis is not evident. In liver biopsies of HCC, grading should not be commented on unless the tumor is of high grade (poorly differentiated). Data on the prognostic significance of histological grading are contradictory.

1.3.4 Microvascular invasion

Microvascular invasion (MVI) is an independent risk factor for recurrence and a marker of poor prognosis following liver resection/transplantation for HCC. Conventional imaging methods are ineffective for detecting MVI and no established biomarkers for predicting MVI are currently available. Histological examination of the resected specimen is the most accurate method for detecting MVI. However, MVI may be suspected in large tumors (>3 cm), with grossly nodular pattern and extranodular growth, in the confluent multinodular type, as well as in poorly differentiated (high grade) HCC, based on the pre- treatment liver biopsy (32).

1.3.5 Fibrolamellar Carcinoma

Fibrolamellar carcinoma is a rare, special histological type of HCC arising in non-cirrhotic liver of children and young adults. Fibrolamellar carcinoma is associated with a better prognosis than classical HCC occurring in cirrhotic livers but similar to that of HCC of non-cirrhotic livers (30).

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1.3.6 Immunophenotype of HCC

A new subtype of progressed HCC, has been recently proposed which is recognized by the presence of tumor cells (>5%) expressing stem/hepatic progenitor cell (HPC) markers such as cytokeratin 19, epithelial cell adhesion molecule (EpCAM), CD133 and others. It is still unknown whether the CK19 immunophenotype represents a true stem/HPC origin or dedifferentiation of mature hepatocytes (29). This subtype behaves more aggressively than the classic progressed HCC not expressing stem/HPC markers and shows higher recurrence rate following resection, resistance to chemotherapy and radiotherapy, and increased frequency of metastasis (29;30).

Recommendations

 Core biopsies of small liver lesions (<20 mm) should be evaluated by expert pathologists. In 10-20mm tumors arising in a background of chronic liver disease, core liver biopsy is superior to fine needle aspiration cytology (FNAC) for HCC diagnosis.  True stromal invasion is an important diagnostic criterion favoring HCC and it is further documented by absence of ductular reaction highlighted by immunostains for keratins 7 or 19. Histopathological diagnosis of HCC is reinforced by positive immunostains (2 out of 3) for glypican 3, heat shock protein 70, and glutamine synthetase (LOE IV; GOR B).  Histological examination of the resected specimen is currently the most accurate method for detecting microvascular invasion (LOE I; GOR A).  Fibrolamellar carcinomas are special types of HCC occurring in children and young adults that have better prognosis than HCC arising in cirrhotic liver but similar to HCC of non-cirrhotic livers (LOE I; GOR A).

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1.4 Risk Factors, Population Screening and Surveillance Population screening for HCC refers to the application of diagnostic tests in patients at risk, while surveillance refers to the repeated application of screening tests. The level of risk for HCC determines the adoption or not of screening, the choice of the screening test, the surveillance interval and the management strategy in case of abnormal results. Surveillance for HCC has become widely accepted, despite inadequate evidence of benefit. The results of a single randomized controlled trial of surveillance versus no surveillance have shown the existence of a survival benefit, when a strategy of 6-monthly surveillance with alpha fetoprotein (AFP) and ultrasound has been applied (33).

The level of risk for HCC is related to the incidence of HCC. According to this, the decision is made for a patient to enter into a surveillance program. Surveillance for HCC can generally be recommended for certain at-risk groups. It is widely known that HCC detected after the onset of symptoms has a dismal prognosis (5-year survival, 0%-10%). In contrast, small HCC’s when still asymptomatic, can be often treated successfully (34;35).

Risk factors for HCC are usually the same as for liver cirrhosis. As such, it has been estimated that in a 60-80% of confirmed HCC there is also evidence of underlying liver cirrhosis. According to this, HCC surveillance is strongly recommended to Asian male hepatitis B virus (HBV) carriers over age 40, Asian female HBV carriers over age 50, HBV carriers with family history of HCC, African/North American blacks with hepatitis B, cirrhotic HBV carriers, hepatitis C-related cirrhosis, stage 4 primary biliary cirrhosis, genetic hemochromatosis and cirrhosis, alpha 1-antitrypsin deficiency with cirrhosis, and cirrhosis of other etiologies. (Table 1)

On the other hand, the surveillance benefit is uncertain for the following groups of patients: HBV carriers younger than 40 (males) or 50 (females), hepatitis C and stage 3 fibrosis and non-cirrhotic nonalcoholic fatty liver disease (NAFLD) (23). Recent data suggested that the incidence of HCC in patients with autoimmune hepatitis related cirrhosis is not adequately high to warrant surveillance for this particular group of patients (36).

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In Caucasian HBV carriers with no cirrhosis and inactive hepatitis, as determined by normal ALT values and low HBV DNA concentration, the incidence of HCC is too low to make surveillance worthwhile (37). However, even to low risk groups, there are additional risk factors that have to be taken into account including older age, persistence of viral replication, co-infection with hepatitis C virus or human immunodeficiency virus (HIV), or the presence of other liver diseases. Nevertheless, even in the absence of cirrhosis, adult Caucasian patients with active hepatitis B disease are likely at risk for HCC and should be screened. Additionally, patients with HBV-related cirrhosis who clear the hepatitis virus spontaneously or after treatment (hepatitis B and C) are likely at a reduced risk of developing HCC, but this statement needs confirmation in clinical studies. Therefore, there are no specific recommendations for these groups of patients and they should continue to undergo surveillance.

1.4.1 Surveillance tests There are two categories of screening tests; serological and radiological. With regards to AFP, as a serological test, receiver operating curve (ROC) analysis suggests that a cut-off value of 20 ng/mL is considered the best acceptable balance between sensitivity and specificity. However, at this level the sensitivity is only 60%, making it inadequately sensitive for general use. If a higher cut-off is applied a progressively smaller proportion of HCC’s will be identified. Therefore, AFP is considered to be an inadequate screening test for HCC (38;39). Other serological tests that have been used, as the Des- gamma carboxyprothrombin (DCP), the ratio of glycosylated AFP to total AFP, alpha fucosidase, glypican 3 and heat shock protein (HSP)-70 cannot be recommended as screening tests, according to existing data.

As a radiological test, ultrasonography (US) has been widely proved to be a useful screening test for HCC surveillance. Ultrasound has a reported sensitivity between 65% and 80% and specificity greater than 90% when used as a screening test. Though its performance characteristics are not ideal, US is superior to any of the serological tests available (40;41).

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The use of CT scanning, as a screening test for HCC, has been reported. However, the performance characteristics of CT scanning have been mainly developed in diagnostic/staging studies and are unknown in HCC surveillance.

The combined use of AFP and ultrasound, which is frequently used in clinical practice, increases detection rates, but also increases false-positive rates. AFP-only surveillance had a 5.0% false positive rate, ultrasound alone had a 2.9% false positive rate, but in combination the false positive rate was estimated to be 7.5% (42).

The ideal surveillance interval is not yet clearly defined. Based on tumor doubling times, surveillance interval of 6-12 months has been proposed. A positive randomized control trial by Zhang et al, mentioned above (33), used a 6-month surveillance interval. However, results of a retrospective study in patients screened at 6 or 12 monthly intervals showed similar survival outcome (43). On the contrary, a more recent retrospective study showed that 6-month surveillance interval is superior to 12-month for the detection of early HCC and patient survival (44). More frequent surveillance interval, every 3 months, does not seem to improve detection of small HCCs when compared to 6-month interval according to another recent retrospective study (45).

Recommendations

 Surveillance programs are recommended for patients at high risk for developing HCC (LOE I; SOR A). The at-risk groups for whom surveillance is recommended are summarized in Table 1.  Ultrasound alone is the best available test for HCC surveillance (LOE II; SOR A).  The recommended surveillance interval is every 6 months (LOE II; SOR B).



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Table 1: Groups for whom HCC is recommended or in whom the risk of HCC is increased (modified from Bruix et al).

Surveillance recommended Surveillance benefit uncertain Asian male hepatitis B carriers over age 40 Hepatitis B carriers younger than 40 (males) or 50 (females) Asian female hepatitis B carriers over age 50 Hepatitis C and stage 3 fibrosis

Hepatitis B carrier with family history of Non-cirrhotic NAFLD HCC

African/North American Blacks with hepatitis B cirrhotic hepatitis B carriers

Hepatitis C cirrhosis

Stage 4 primary biliary cirrhosis

Genetic hemochromatosis and cirrhosis

Alpha 1-antitrypsin deficiency and cirrhosis

Cirrhosis of other etiology

1.5 Imaging

A focal lesion in the liver of a patient with known cirrhosis is highly likely to be HCC. Initial assessment should be done by multi detector computed tomography (MDCT) of the liver using appropriate imaging protocol (local spread) and MDCT of the lungs (to rule out metastases). Magnetic resonance imaging (MRI) with contrast enhancement may increase the accuracy of lesion characterization (46).

A suspicious lesion on US generally requires additional imaging studies to confirm the stage of the tumor, while sensitivity for detection of small nodules may be low. The addition of arterial phase imaging to CT scanning increases the number of tumor nodules detected, but in nodular cirrhotic livers the sensitivity to detect HCC is low. The overall sensitivity of MRI is similar to that of triphasic CT scan, but in patients with nodular cirrhotic livers MRI has better sensitivity and specificity (47).

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Staging should include chest CT scan and CT scan (alternatively MRI) of the abdomen. CT is highly accurate in the staging of HCC as the number of lesions, segmental anatomy, regional adenopathy, vascular tumor invasion, and metastases can be easily detected. Distinction between bland thrombus and tumor thrombus is not always feasible, but early enhancement within the thrombus is indicative of tumor origin (48). CT scan of the chest and bone scintigraphy need to be additionally performed in transplant candidates.

For estimation of respectability, accurate measurement of the adequate future liver remnant (FLR) should be done using CT volumetry techniques, while the possibility of major vascular invasion should be investigated by MDCT angiography (49). CT volume measurement technique may also predict the prognosis of unresectable HCC patients after TACE (50).

Preliminary results showed that contrast-enhanced intraoperative ultrasonography (CEIOUS) could provide information not obtainable with conventional IOUS during surgery for hepatocellular carcinoma (HCC). CEIOUS increases the accuracy of IOUS and affects the surgical radicalness (51).

The imaging techniques most commonly used for assessing tumor response include CT and MRI. Imaging modalities and imaging criteria vary according to the opted treatment (surgical resection and transplantation or nonsurgical treatments such as transarterial chemoembolization, radiofrequency ablation, and molecular targeted therapy). Efficacy of nonsurgical treatments for malignancy is usually evaluated by the Response Evaluation Criteria In Solid Tumors (RECIST). These criteria, based on tumor size and shrinkage, are often inappropriate in HCCs. The response criteria should take into account tumor necrosis induced by treatment. Tumor necrosis is estimated by a disappearance of hypervascularization on contrast-enhanced imaging. New tools such as functional imaging (perfusion imaging, diffusion-weighted MR imaging) could be of major importance (52).

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Recommendations

 Characterization of malignant liver lesions in a cirrhotic liver should be performed with contrast-enhanced MRI (gadolinium) (LOE III; SOR B).  In a non-cirrhotic liver characterization of malignant liver lesions may be performed with either contrast-enhanced MRI (gadolinium) or dynamic multidetector CT (LOE III; SOR B).  For resectability estimation MDCT angiography and CT volumetry are strongly recommended (LOE III; SOR B).  Functional imaging techniques (perfusion CT, diffusion MRI) could be important in the evaluation of tumor response to treatment (LOE III; SOR C).

1.6 Resectable Carcinoma

1.6.1 Preoperative Assessment

Preoperative assessment of liver function is of paramount importance in the selection of patients undergoing different therapeutic modalities. The Child- Turcotte-Pugh (CTP) score is the most common measure to evaluate liver function preoperatively based on clinical and laboratory criteria. There are 3 grades of liver dysfunction, CTP class A, B and C). Classes B and C have been associated with poor prognosis after resection (53). Nevertheless, CTP score for class A has proven insufficient to evaluate the operative risk. This Group is fairly heterogenous and CTP score is inaccurate to differentiate low from high risk individuals. In addition this classification does not indicate how much liver parenchyma can be removed without postoperative liver insufficiency (54).

In Asia different liver function tests are employed such as the indocyanine green (ICG), monoethylglycinexylidide (MEGX) and galactose elimination capacity (GEC). ICG, the most commonly used, is based on the clearance of the dye from the liver. ICG is entirely removed by the liver and excreted

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unaffected to the bile and does not undergo enterohepatic recirculation. Elimination is considered to be impaired when 15% or more of the dye remains (Retention Rate) within the plasma 15 minutes following administration of the dye. A safe major hepatic resection can be performed in cirrhotics with an ICG clearance between 10-15% (55). Selection of the ideal candidates involves an adequate assessment of the liver functional reserve and tumor extension (56). However, selection of patients without portal hypertension as defined by hepatic venous pressure gradient (HVPG) <10mmHg, ICG15 <20%, absence of esophageal varices, splenomegaly and/or low platelet count (<100.000/mm) leads to a resectability rate of less than 20%.

CT volumetry is required as a surrogate marker of liver function, and several studies have documented a strong correlation of Residual liver volume and post- resection mortality. Portal vein embolization (PVE) is recommended in cirrhotic patients if future liver remnant (FLR) is less than 40% (57). With ICG–R15 values below 20% PVE is recommended for FLR between 40 and 60%.

LiMAx breathing test combined with CT volumetry is also suggested to assess function of the FLR. This volume–function analysis, although helpful preoperatively, needs to be evaluated in randomized trials.

The Model for End-Stage Liver Disease (MELD) score is also important as a single test to estimate liver function in Child A patients. Many studies have revealed an association between MELD score and postoperative mortality and morbidity. In particular, MELD >9 is considered a relative contraindication for major liver resection while MELD >11 is an absolute contraindication for any segmental resection due to the high mortality rate (58). Portal hypertension itself is not a contraindication to resection in patients with HCC and cirrhosis if the MELD score is low (59).

In all patients, a pre-procedural physical examination and screening blood tests, including measurements of prothrombin internationalized normalized ratio (INR), partial thromboplastin time (PTT) and platelet count should be performed.

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Based on a thorough preoperative work-up, surgery is recommended if technically feasible with negative margins and low postoperative dysfunction rate.

Recommendations

 CTP score is recommended for assessing liver function preoperatively (LOE II; SOR B).  ICG–R15 may be used as a complementary method to risk estimation (LOE III; SOR B).  If major resection is planned, CT volumetry and MELD score are supplementary preoperatively to assess morbidity (LOE III; SOR B).  Portal hypertension and/or PLTs<100.000 is a relative contraindication to resection, depending on the type of the resection (LOE II; SOR B).  Multifocality, extrahepatic disease, major vascular invasion are contraindications for resection for the majority of the patients (LOE III; SOR B).  Hepatic resection is indicated for patients with adequate liver function, tumor without major vascular invasion and adequate liver remnant.  PVE should be used to increase FLR.  Resection margins > 2cm and anatomic resections benefit patients in terms of oncological outcome.  Surgeon’s experience determines the technique and the method (open or laparoscopic) of resection.

1.6.2 Resection

Liver resection is the primary and potentially curative treatment in well- selected patients with HCC. Resection provides 5-year survival over 50% but with recurrence rate at 5 years exceeding 70%. CTP score is the primary index for preoperative surgical risk evaluation of patients considered for hepatic resection. The ratio of the FLR/ total liver volume is crucial in the preoperative surgical planning. The ratio must be at last 20% in patients without cirrhosis and at least 30-40% in patients with a Child–Pugh score A. If the FLR/ total liver volume ratio is below recommended values, pre-operative

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portal vein embolization (PVE) should be considered to achieve liver hypertrophy. Furthermore tumor characteristics especially size, macro- or microscopic vascular invasion and multifocal disease should be estimated. Generally hepatic resection as a potentially curative option should be considered for patients with adequate liver function (Child A without portal hypertension), solitary mass without major vascular invasion and adequate liver remnant (60;61).

Various transection techniques have been described but it seems that only the surgeon’s experience and the tumor location should determine the optional method. Patient undergoing hepatectomy seem to benefit from a resection margin of 2 cm, whereas anatomic resections should be intended if not contraindicated by the patient’s liver function. Anterior approach technique seems beneficial in patients with a HCC at least 5 cm. Different techniques in order to achieve optimal vascular control during hepatectomy have been advocated, but it seems that hepatic resections without major vascular occlusion can be safe when adhering to the guidelines of modern liver surgery or when using total hepatic vascular exclusion for lesions infiltrating the major hepatic veins or those adjacent to the cavohepatic junction. Finally, laparoscopic resection is indicated in the hands of experienced surgeons for tumors 5 cm or less located in the peripheral segments of the liver.

Recommendations

 The choice of treatment is driven by the cancer stage, the resources available, and the level of practitioner expertise. Most recommendations for staging-guided treatment rely on the findings of retrospective studies.

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1.7 Liver Transplantation

Orthotopic liver transplantation (OLT) is the best available curative treatment for patients with HCC and cirrhosis in the absence of metastases or macroscopic vascular invasion. Selection criteria for transplantation include the so-called Milano criteria (single tumor of up to 5 cm, or up to 3 tumors sized each 3 cm or less in diameter, with no evidence of macrovascular invasion or extra hepatic disease) or the expanded criteria adopted by the University of California San Francisco (UCSF) (solitary tumor of up to 6.5 cm or 3 tumors or less with diameters of up to 4.5 cm and a maximum total tumor size of 8 cm). Selection based on the Milano criteria resulted in a 4-year overall survival rate of 75% and a recurrence- free survival rate of 83%, whereas based on the UCSF resulted in survival rates varying from 38% to 93%.

Living donor liver transplantation (LDLT) has been associated with higher recurrence rates possibly due to proliferative stimuli of the regenerating liver graft. The MELD score serves as a measure of pre-transplant mortality. Salvage transplantation (ST) refers to liver resection as a primary therapy, considering OLT for tumor recurrence or deterioration in liver function. ST does not increase the operative risk and offers a chance of long term survival when HCC recurrence is limited (62).

OLT can achieve long term results in cases of primary resection and poor histologic features (such as satellites or microvascular injection). Tissue analysis and micro-arrays are important in the management algorithm. On an intention-to-treat basis liver resection is superior to transplantation in the Milan Criteria group with low MELD score although more data is required. Treatment before liver transplantation can be offered as bridge or down staging therapy and includes radiofrequency ablation (RFA), conformal radiation therapy, trans arterial chemoembolization (TACE), sorafenib, percutaneous ethanol injection (PEI) and hepatic resection for downstaging (63). While controversy over quite a few issues regarding liver transplantation in HCC was mounting over the last decades, an international consensus

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer meeting was held at Zurich in 2011 and produced specific guidelines and recommendations for HCC patients eligible for LOT (64). Appendix I

Recommendations

 OLT is the best available curative treatment of HCC on cirrhosis without metastases or vascular invasion.  The Milan and UCSF criteria are recommended for selection of HCC patients for OLT.  ST offers a reasonable method to treat following HCC recurrence with good histologic features.  Bridging or down staging therapies before liver transplantation can be administered although more data is required.  Incorporating tumor biology into selection criteria is of paramount importance though Milan criteria are surrogate marker of HCC aggressiveness.

1.8 Pathology Report

An adequate pathology report of HCC resection specimens should include the following essential data (65;66):

1.8.1 Macroscopical examination . Specimen: type (lobectomy, segmentectomy, hepatectomy), weight and dimensions. . Tumor(s): number and dimensions, distance from surgical margin(s), macroscopic vascular invasion, presence of satellite nodules. . Additional evaluation: liver capsule and adjacent tissues, non-tumorous liver parenchyma, gall bladder, number and location of lymph nodes.

1.8.2 Histopathology . Tumor type, histological pattern and histological differentiation (grades I-IV or grades 1-4) (30;31;67). . Multinodular disease: differentiation between multicentric and metastatic disease (if feasible).

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. Comments on: surgical resection margins, vascular and perineural invasion, presence of fibrous capsule and satellite nodules, invasion of liver capsule, liver hilum, visceral peritoneum, or adjacent organs, lymph node metastases, lesions related to preoperative treatment/tumor ablation (percentage of necrotic tumor). . Non-tumorous liver parenchyma: underlying chronic liver disease (etiology, grading and staging as appropriate), presence of dysplastic foci, small or large cell change in cirrhotic nodules or biliary intraepithelial neoplasia. . pTNM classification - SNOMED or ICD O Codes (68;69).

1.8.3 HCC Staging Staging systems other than TNM that incorporate features related to the nature of underlying hepatic disease, liver function, patient performance status and/or size and number of nodules are increasingly being used for assessing patient prognosis in clinical trials and in therapeutic management. Of these, the Barcelona Clinic Liver Cancer Staging Classification (BCLC) has the widest international consensus (70;71), [Figure 2]. Nevertheless, despite the TNM staging system’s inferior prognostic ability, it has been used almost exclusively for patients undergoing liver resection (72).

1.9 Multicentric vs metastatic HCC

In the case of multinodular HCC, it is clinically very important to differentiate multicentric origin from intrahepatic metastasis. Multicentric HCC has usually a more indolent behavior with late recurrence, while metastatic HCC is more aggressive and might show early recurrence. The most accurate method to address this issue is tumor allelotyping, but this is still investigational and has not yet entered clinical practice. Currently, macroscopic (also assessed by imaging) and histological criteria are used for this distinction (65).

Recommendations

 For accurate pathological staging of HCC, the pathology report for surgical specimens should include detailed macroscopical

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(number & dimension of tumor(s), vascular invasion, presence of satellite nodules, extension to adjacent tissues/organs, number and location of lymph nodes) and histological (vascular invasion, invasion of liver capsule, hilum or adjacent tissues, lymph node metastases) data (LOE I; SOR A).  In multinodular HCC, the most accurate method for the distinction of multicentric origin from intrahepatic metastasis is tumor allelotyping. This method has not as yet entered clinical practice, therefore, macroscopic (also assessed by imaging) and histological criteria should be routinely used (LOE III; SOR B).  The Barcelona Clinic Liver Cancer Staging Classification (BCLC) should be used for therapeutic decisions and clinical trials entry for all patients with HCC (LOE II; SOR B).  pTNM classification should be used for pathological staging of HCC and included in the pathology report of surgical specimens (LOE I; SOR A).  Combination of the prognostic information from BCLC and TNM staging may be used for evaluating the outcome of surgically-treated patients with HCC (LOE II; SOR B).

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1.10 Locoregional Therapy

1.10.1 Ablation There are several potentially curative or palliative approaches to the treatment of hepatocellular carcinoma (73;74).

For patients presenting with early-stage HCC, with some preserved liver function (falling within class A or B of the Child–Pugh system), and a solitary HCC nodule measuring < 5 cm in diameter or no more than three nodules, each measuring < 3 cm in diameter, the choice of therapy is dictated by the severity of the liver dysfunction, the extent of portal hypertension, and the patient's performance status with respect to coexisting conditions. Surgical resection should be first considered for patients with solitary tumors and no portal hypertension. Otherwise, the most appropriate treatment for patients with early-stage HCC is liver transplantation. Local ablation is a safe and effective therapy for patients who cannot undergo resection or as a palliative treatment approach before transplantation (71;75;76).

Patients with mild cancer-related symptoms, vascular invasion, or extrahepatic spread are considered to have advanced-stage disease and are not suitable candidates for radical therapies.

1.10.2 Percutaneous Ethanol Injection Percutaneous ethanol injection (PEI) was introduced into clinical practice in the 1980s, being the first percutaneous treatment for HCC (77). With this technique, 95% ethanol is injected directly into the tumor, using US or CT guidance. Ethanol induces local tumor necrosis as a result of cellular dehydration, protein denaturation, and chemical occlusion of tumor vessels.

1.10.3 Radiofrequency Ablation (RFA) After PEI While PEI proved to be a valuable treatment for preferably small HCC lesions, several randomized controlled trials indicate that its effectiveness in small HCCs is outrun by RFA with respect to overall survival, cancer-free survival rates, local recurrence, and tumor response (78;79).

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1.10.4 RFA RFA is a safe and effective technique for the treatment of early stage HCC (80-82). Predictors of complete ablation (or complete response) are small size (diameter ≤3 cm) tumors and well-differentiated and non-infiltrative HCCs. Several studies have reported complete ablation rates of 80–100% in HCCs ≤3 cm, 50–80% in HCCs 3–5 cm, and 25% in HCCs >5 cm (83-85).

Developments in technology, such as powerful generators or bipolar multiprobe arrays, and in technical maneuvers have allowed treatment of even larger tumors (86).

Needle biopsy before treatment, poor differentiation degree of the tumor, subcapsular lesions, patients treated in multiple sessions, and lesions requiring more than one electrode placement were identified as risk factors for less successful outcome (87).

1.10.5 Cryoablation An advantage of this technique is that it can be applied for larger tumors up to 8 cm, whereas most of the other tumor ablative techniques are successful only for small tumors (88). However, this technique has fallen out of favor for the treatment of HCC, primarily because of the complication rate described as high as 40.7% and the risk of “cryoshock”, a life-threatening condition resulting in multiorgan failure, severe coagulopathy and disseminated intravascular coagulation following cryoablation, which has been described at a rate of 1%.

1.10.6 Microwave Ablation Microwave ablation (MWA) is performed mostly in small HCCs. They concluded that there is a significantly higher probability of long-term survival after MWA treatment for patients with a single tumor of 4.0 cm or less and Child-Pugh class A cirrhosis (89). MWA has been compared to other ablative techniques in several studies. Seki et al. retrospectively compared MWA to PEI for small HCCs (≤2 cm). They concluded that MWA may be superior to PEI for the local control of moderately or poorly differentiated small HCCs (90). The only randomized study comparing MWA and RFA showed that both

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer techniques had equivalent therapeutic effects, complication rates, and rates of residual foci of untreated disease. However, RFA offers the advantage of tumor ablation being achieved in fewer sessions (91).

1.10.7 Laser Ablation A single-probe insertion can only create a small volume of ablation, so often multiple optical fibers have to be placed for treatment of larger lesions (>5 cm), which may be technically cumbersome and result in prolonged treatment times. Selection criteria for laser-induced interstitial thermotherapy (LITT) are broadly similar to those of other ablative techniques. Ideally, lesions should be < 3 cm in diameter and located deep within the liver parenchyma. Arienti et al. performed a multicenter study on 353 patients treated with LITT aiming to investigate safety and complications, and reported that LITT is a safe treatment with major complication rate of only 1.5% (0.8% deaths) and minor complication rate of 6.2%. He also stated that complete response was achieved in 60%, regardless of tumor size, and in 81% in lesions ≤3 cm HCCs (92). Tumor seeding after treatment has not been reported. There is one randomized trial in which LITT is compared to RFA for treatment of early stage HCC (nodule or three nodules ≤3 cm each).

Recommendations

. Ablation methods should be used in patients when resection is not possible (LOE II; SOR B). . Best results are seen with small, uninodular tumors of 3 cm or less (LOE III; SOR B). . Repeated procedures are often needed to obtain complete tumor ablation, especially for larger lesions (LOE III; SOR B). . RFA may be a safe and effective bridge to liver transplantation over a waiting period of six months (LOE III; SOR B). . MWA provides higher probability of long-term survival for patients with a single tumor less than 4.0 cm and Child-Pugh class A cirrhosis (LOE III; SOR C). . For most tumor ablative techniques, increasing tumor diameter decreases the likelihood of complete ablation. Combination of local ablation and intra-arterial therapies may help overcome shortcomings of monotherapy Final document Page 31

Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer treatment for larger tumors (LOE III; SOR C).

1.10.8 TACE Transarterial chemoembolization (TACE) has been established as the standard of care for nonsurgical patients presenting with large or multinodular noninvasive tumor isolated to the liver and with preserved liver function (93). TACE is also used in patients with early-stage HCC when curative therapies – including liver transplantation, hepatic resection, and image-guided ablation – are precluded, as well as in the setting of combination strategies including transcatheter and percutaneous treatments (94-97).

A meta-analysis of randomized, controlled trials assessing the use of arterial embolization, chemoembolization, or both as primary palliative treatment for hepatocellular carcinoma showed that these procedures were associated with an improved 2-year survival rate as compared with conservative treatment (98). TACE is also used as a neoadjuvant therapy or as a means of downstaging a patient's condition before liver transplantation, but whether these approaches provide a survival benefit is unclear. A postembolization syndrome of fever and abdominal pain related to hepatic ischemia occurs in up to 50% of patients treated with TACE. Embolization should not be performed without the use of a chemotherapeutic agent; there are few data to guide the choice of the chemotherapeutic agent or the retreatment schedule, which in practice ranges from 2 to 5 sessions. The ideal TACE scheme should allow maximum and sustained concentration of the chemotherapeutic drug within the tumor, with minimal systemic exposure, combined with calibrated tumor vessel obstruction (99). While conventional TACE with administration of an anticancer-in-oil emulsion followed by embolic agents has been the most popular technique, the introduction of embolic, drug-eluting beads has provided an attractive alternative to Lipiodol-based regimens (95). In recent randomized, controlled trials, the use of a drug-eluting bead that releases the drug in a controlled fashion during TACE has been shown to be associated with a reduction in both hepatic and systemic side effects and with an increase in local tumor response (95).

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1.10.9 Yttrium Radioembolization with yttrium-90 microspheres has recently been used as palliative treatment for patients with Child–Pugh class A cirrhosis and intermediate-stage hepatocellular carcinoma. It has also been used for the downstaging of unresectable HCC to potentially curative treatments, like surgical resection, percutaneous ablation, and even bridging to liver transplantation (100). Although several studies have provided useful data, there is a need for further investigation of this therapy and randomized trials.

1.11 Role of Radiotherapy in Non-Resectable Disease

Technological advances related to planning and delivery of external beam radiotherapy (RT) allow nowadays focal administration of high dose radiation to HCC tumors while sparing surrounding liver tissue. There is growing evidence supporting the value of 3D conformal or stereotactic body RT for patients with unresectable disease.

Experience from 3D conformal RT to doses between 40Gy and 60Gy in several studies is encouraging. The objective response rate ranges from 30% to 56%, the median survival from 10 to 15 months, the 1-year survival from 50% to 90% and the 5-year survival from 9% to 25%. A variety of fractionation schemes and doses have been used with a tendency for improved local control with higher doses (101).

Radiotherapy has been also used in combination with TACE in various schemes, more frequently in patients with portal vein and inferior vena cava tumor thrombus. Response rates ranged from 25% to 80%, 2-year survival from 10% to 55% and 5-year survival from 9% to 19%. The combined approach showed some advantages over reserving RT as salvage therapy. Reduction of tumor volume after TACE may allow less uninvolved liver to be irradiated permitting the use of higher doses with less toxicity (102).

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Stereotactic body radiation therapy has been recently used in phase I studies mostly in patients with Child–Pugh’s A or B with 1-3 lesions with a cumulative diameter of less than 6cm. Preliminary results suggested SBRT as a feasible and well tolerated non-invasive therapy in properly selected patients. Local control and disease stabilization was observed in over 90% of HCC patients and the 1 and 2-year survival reported as high as 75% and 60% respectively (103).

Recommendations

. Radiotherapy might be an option in patients with unresectable disease not suitable for liver transplantation and those with local disease who are not operable due to performance status or comorbidity. It should be noted there are limited data to support the use of radiotherapy in these patients (LOE IV; SOR C).

1.12 SYSTEMIC THERAPY

The majority of patients with HCC have unresectable or metastatic disease at presentation, with poor prognosis. The therapeutic options in advanced disease are limited due to marginal, if any, efficacy of conventional cytotoxic chemotherapy. HCC is a chemotherapy resistant tumor due partly to the expression of multidrug resistance 1 (MDR-1) gene. Moreover most patients have limited tolerance, when full doses of poly-chemotherapy are administered due to underlying liver cirrhosis, which farther limits the feasibility and the efficacy of systemic chemotherapy. Cytotoxic chemotherapy produces low response rates and no survival benefit.

Today the knowledge of the underlying molecular mechanisms of carcinogenesis in HCC has expanded the therapeutic approaches by the introduction of the targeted therapy option. HCC is a heterogeneous disease with dysfunction of various signaling pathways such as Ras/Raf/MEK/ERK, PI3k/Akt/mTOR, Wnt/β-Catenin or Hedgehog pathway (104).

The altered signaling pathways result in proliferation and angiogenesis disorders reflected in the high levels of circulating molecules such as the

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and the overexpression of receptors such as the one of the epidermal growth factor (EGFR).

The oral multikinase inhibitor sorafenib was the first agent to demonstrate a statistically significant improvement of overall survival in Child–Pugh liver function class A patients with advanced HCC, though the added clinical benefit was only 3 months (105). Nevertheless, this is the first agent that has ever showed a substantive benefit in a phase III randomized study.

Selected patients with Child-Pugh class B could also benefit from the treatment with sorafenib.

Recommendations

 HCC patients should be encouraged to be enrolled in clinical trials.  HCC patients with advanced, inoperable or metastatic disease and Child-Pugh class A liver function should be treated with sorafenib (LOE I; SOR A).  Selected HCC patients with advanced, inoperable or metastatic disease and Child-Pugh class B liver function could benefit if treated with sorafenib (LOE IV; SOR C).

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Figure 2. The BCLC staging system for HCC (M: metastasis classification. N: node classification. PS: performance status. RFA: radiofrequency ablation. TACE: transarterial chemoembolization)

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2. CHOLANGIOCARCINOMA

2.1 Gallbladder Cancer

2.1.1 Introduction Gallbladder cancer (GBC) is an uncommon (incidence of about 5000 new cases/year in the United States), but highly fatal malignancy. In early stages GBC is usually asymptomatic and diagnosed incidentally on imaging or on pathological specimens post cholecystectomy. In advanced disease constitutional symptoms or jaundice may occur. Unfortunately only about 10- 20% of patients present with tumor confined to the gallbladder wall, whereas 40-60% of patients have lesions that perforate the gallbladder wall and invade adjacent organs and 30% of patients have metastatic disease. Survival for patients with GBC is correlated with the stage of the disease. The 5-year survival rate in early stages is approximately 40% and in locoregional disease 15%. In advanced and metastatic disease the prognosis is very poor.

2.1.2 Mass on Imaging In cases of suspected gallbladder disease, ultrasonography (US) is often the first imaging technique because of its relatively low cost and widespread availability (106). Although US has a relatively high sensitivity for the detection of tumor at advanced stages, it’s accuracy is low in case of early and small lesions and furthermore is unreliable for staging. Therefore, CT and, increasingly, MRI are more widely used for further characterization of suspicious and potentially malignant gallbladder lesions and for staging (107;108).

Gallbladder carcinoma may appear, at any of these imaging techniques, as a mass completely occupying or replacing the gallbladder lumen, as a focal or diffuse asymmetric gallbladder wall thickening or as an intraluminal polypoid lesion. MDCT is now widely available and has a reported accuracy of up to 84% in determining local extent or the T stage of primary gallbladder carcinoma (109) and 85% in predicting resectability through its ability to

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer delineate hepatic and vascular invasion, lymphadenopathy, and distant metastases (110). MDCT is commonly performed as unenhanced and iodinated contrast-enhanced studies during the hepatic arterial and portal venous phases, from which multiplanar and 3D volume-rendered reconstruction images may be generated to provide a vascular road map, as well as coronal oblique images, which are useful for surgical planning.

The all-in-one protocol supplementing MRI with MR cholangio-pancreatography (MRCP) and contrast-enhanced arterial and portal phase 3D angiography (MR angiography) may be up to 100% sensitive for bile duct and vascular invasion, but sensitivity falls to 56% for lymph node metastases (111).

PET/CT has a promising role in the detection of unsuspected metastases, which may alter staging and therapy (112). To date, prospective studies that directly compare CT, MRI, and PET/CT in their ability to diagnose and stage gallbladder carcinoma have not been performed (113).

Because small hepatic, peritoneal, and omental tumor implants can be missed at preoperative imaging, thorough laparoscopic or open exploration could precede aggressive surgery, either at the same or at an earlier operation (114). After resection imaging should be recommended every six months at least the first 2 years. There are no data to support aggressive surveillance. There should be a patient/physician discussion regarding appropriate follow- up schedules concerning imaging (61).

In patients with disseminated disease or medical contraindications to surgery, imaging-guided percutaneous biopsy for tissue confirmation can be performed before palliative therapy.

Recommendations

 US should not be recommended for early gallbladder cancer diagnosis or staging (LOE III; SOR C).  MDCT combined with CT angiography is the preferred initial technique for the diagnosis, staging and resectability estimation of gallbladder cancer (LOE II; SOR B).

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 MRI combined with MRCP and MRA could be used alternatively in cases of biliary ducts dilatation or when MDCT is contraindicated (LOE II; SOR B).  There are no data to support the use of PET-CT preoperatively.

2.1.3 Management

2.1.3.1 Surgery Upon identifying a suspicious gallbladder mass on imaging or development of jaundice, some essential principles have to be considered regarding preoperative workup, respectability and surgical details as following (61):  Pre-op workup o CT/MRI upper abdomen o Chest imaging o Liver function test o Assessment of hepatic reserves o Consider staging laparoscopy  Assessment of resectability o Patients with liver or distant metastasis, nodal metastases beyond the porta hepatis and extensive involvement of the porta hepatis causing jaundice or vascular involvement should be considered as having unresectable disease.  Surgery o Surgery aims to R0 resection o Extended cholecystectomy (limited liver resection with at least 2 cm clear margin) o Lymphadenectomy of the hepatoduodenal ligament o Major liver resections and bile duct resection when necessary to achieve R0 resection

Laparoscopic cholecystectomy (LC) is the treatment of choice and can be safely performed for cholecystolithiasis due to technical improvements. However, LC is not acceptable in gallbladder carcinoma because of the high

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer risk of dissemination. The dissection plane on the liver side is within the subserosal layer. Therefore, if the lesion has extended beyond the muscular layer positive resection margins may result. Even in whole layer cholecystectomy with liver bed exposure, remnant cancer cells may occur (115).

In case of incidental diagnosis: In contrast to advanced GB cancer which is often diagnosed by imaging prior to surgery, early GB cancer invading the mucosa or muscularis propria is usually diagnosed incidentally only in pathology specimens(116). In GB cancer invading the subserosal layer, high rates of vascular and perineural invasion with positive lymph nodes (40%) are observed. Although no RCT concerning re-resection exists, there are retrospective studies supported the concept of radical resection (hepatectomy and lymphadenectomy) in patients with subserosal invasion of the GB wall (117). If the cystic stump is free of tumor, extrahepatic bile duct resection is not necessary for adequate margins. Bile duct resection is required in cases of cystic duct invasion, jaundice and hepatoduodenal invasion.

For stage Tis or T1a tumors, LC is sufficient. Patients with T1b tumors should undergo liver-bed resection and lymphadenectomy, and patients with >pT2 tumors should undergo systematic liver resection with lymphadenectomy (114). Even when incidental GBC diagnosed with LC is advanced, adequate additional surgery may improve outcome (118).

Many port-site recurrences (PSR) have been reported after LC, but the incidence of wound recurrence is not higher than after open cholecystectomy. Additional port-site excision is recommended after radical re-resection, but the effectiveness of such measure is debated.

2.1.3.2 Pathology Report Essential data to be included in the pathology report for cholecystectomy specimens with gallbladder carcinoma (GBC) are (119): Macroscopical examination . Specimen: type (laparoscopic/open cholecystectomy), dimensions of gallbladder, intact/open, content, lymph nodes (location, number, size).

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. Tumor: location, dimensions, gross appearance (grossly apparent/inapparent, diffuse/scirrhous, polypoid, papillary, ulcerated), gross extent of tumor spread. Histopathology . Tumor type according to WHO 2010 (120): adenocarcinoma (biliary type, intestinal type, gastric foveolar type, clear cell, mucinous, signet ring cell, cribriform, hepatoid), adenosquamous carcinoma, carcinosarcoma, squamous cell carcinoma, intracystic papillary neoplasm with an associated invasive carcinoma, mucinous cystic neoplasm with an associated invasive carcinoma, undifferentiated carcinoma (121) . Histological differentiation (well, moderate, poor) . Extent of local tumor spread . Comments on: tumor border, lymphocytic reaction, vascular and perineural spread, lymph node metastases, surgical excision margins . pTNM classification (68;69)- ICD-O Codes

Recommendations

 For accurate pathological reporting of gallbladder carcinoma the pathology report should include detailed macroscopical (tumor location, morphology and dimensions, number and location of lymph nodes) and histological (type, differentiation, vascular invasion, depth of invasion, evaluation of resection margins, lymph node metastases) data (LOE I; SOR A).  pTNM classification should be used for pathological staging of gallbladder carcinoma and included in the pathology report (LOE I; SOR A).

2.1.3.3 Adjuvant Treatment Radiotherapy and Chemoradiotherapy Following resection, there is often need for adjuvant therapy to reduce the high risk of recurrence. In contrast to patients who have margin-positive resections, in whom locoregional recurrences predominate, the pattern of disease recurrence following complete resection of GBC is distant plus local. Thus, locoregional (RT) and systemic (chemotherapy) adjuvant treatments have been tried.

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Due to the low incidence of GBC, most trials evaluating the adjuvant role of chemotherapy or radiotherapy administered either alone or concurrently, represent single institution phase 2 trials. Disadvantages of most of these trials are the lack of randomization, lack of homogeneity as often combine gallbladder cancers with cholangiocarcinoma, and the small numbers of patients enrolled, making it difficult to draw definitive conclusions.

Postoperative external beam radiation therapy (RT) administered alone or concurrently with chemotherapy can diminish local recurrence rates, but the lack of randomized trials makes it difficult to conclude whether treatment has any impact on survival. Nevertheless, survival advantage have been implied in many retrospective series in which either radiation alone or chemoradiotherapy (with 5-FU usually used as radiosensitizer) was administered. In most cases, the authors concluded that the patients who underwent RT survived longer than those who did not (122;123), even though this conclusion has been disputed by others (124).

One group of investigators attempted to construct a prediction model for estimating the survival benefit of adjuvant RT based on data in 4180 patients with resected GBC who were reported to the National Cancer Institute’s (NCI) Surveillance, Epidemiology and End Results (SEER) database between 1988 and 2003 (123). In multivariate analysis, older age, male sex, nonpapillary histology and no adjuvant RT were significant predictors of worse overall survival. The authors concluded that patients with ≥ T2, node-positive disease derived the greatest benefit from RT.

In another retrospective study of 2,325 patients who had undergone surgery for GBC, again data obtained from the SEER database, median survival was 14 months versus 8 months in the groups receiving adjuvant chemoradiation or not respectively (p<0.0001). The survival benefit of adjuvant chemoradiation was even more pronounced (16 vs 5 months, p<0.0001) when they only considered the group of patients with positive regional lymph nodes (125).

Most of the experience of chemoradiation in biliary tract cancer involved concurrent chemoradiation with 5-FU. More recently, chemoradiation using

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer capecitabine as the chemotherapy component has been tested. The experience of concurrent chemoradiation with gemcitabine is limited and therefore not recommended.

2.1.3.4 Adjuvant Chemotherapy There are very few studies evaluating the use of adjuvant chemotherapy alone in patients with biliary tract cancer. Thus, there are limited data to define a standard regimen or definitive clinical benefit of adjuvant chemotherapy.

Retrospective analyses of patients with GBC cancer showed no clear benefit of adjuvant chemotherapy (126).

A phase 3 trial from Japan comparing surgery with and without postoperative chemotherapy with 5-FU and mitomycin-c showed a benefit from adjuvant chemotherapy (127). Among 112 patients with GBC the 5-year survival rate was significantly higher in patients who received adjuvant chemotherapy (26% vs 14% p=0.0367). Similarly, the 5-year DFS was 20.3% in the chemotherapy group compared to 11.6% in the control group (p=0.0210). When the patients stratified according to the type of surgery, the benefit of chemotherapy was statistically significant among those undergoing a non-curative (9% vs. 0%, P=0.02) but not curative resection (46% vs. 31%, P=0.15).

Due to very limited data on use chemotherapy in the adjuvant setting, recommendations for fluoropyrimidine-based or gemcitabine-based chemotherapy represent an extrapolation from studies of patients with advanced disease.

Recommendations

 Fluoropyrimidine-based chemoradiation should be considered after resection for all patients except for T1N0M0 GBC (LOE II; SOR C).  Fluoropyrimidine or gemcitabine-based adjuvant chemotherapy. (LOE II; SOR C).

2.1.3.5 Treatmen of advanced disease The prognosis of advanced GBC is very poor. For patients with locoregional disease, chemoradiotherapy is an appropriate option, although RCTs are

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer lacking. Similar to cholangiocarcinoma, most institutions utilize infusional 5-FU during external beam radiation. Systemic chemotherapy has provided short term benefit in the treatment of metastatic or advanced GBC. Most published trials are small phase 2 and heterogeneous (consisting of both GBC and cholangiocarcinoma).

There are only limited data evaluating the impact of chemotherapy on survival. The only randomized trial available compared chemotherapy (GEMOX) versus best supportive care in patients with advanced GBC and showed a significant increase in overall survival in the GEMOX group (9.5 vs 4.5 months) (128).

A large number of chemotherapy combinations have been tested in phase 2 trials in the treatment of advanced GBC and cholangiocarcinoma and demonstrated some activity. Examples include gemcitabine and cisplatin (129), gemcitabine and capecitabine (130), gemcitabine and oxaliplatin (131) capecitabine and oxaliplatin (132) and capecitabine and cisplatin (133).

A recent pooled analysis of 104 phase 2 trials of patients with advanced biliary tract cancers showed that the combination of gemcitabine plus cisplatin is associated with the greatest benefit (134). Additional support for gemcitabine and cisplatin combination comes from a recent randomized phase 3 trial (ABC-02 trial) enrolled patients with advanced GBC and cholangiocarcinoma, demonstrated that the combination of gemcitabine and cisplatin is superior to gemcitabine alone in terms of response and overall survival (11.7 vs. 5 months, HR 0.63; p<0.001) (129).

Recommendations

 Gemcitabine plus cisplatin combination chemotherapy is the preferred first-line treatment in advanced GBC (LOE I; SOR A).  Other gemcitabine-based chemotherapy have showed potential benefit in advanced GBC (LOE II; SOR A).  Other fluoropyrimidine or capecitabine-based chemotherapy have showed potential benefit in advanced GBC (LOE IIl; SOR A).  GBC patients should be encouraged to participate in clinical trials.

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 Fluoropyrimidine chemoradiation for locally advanced GBC disease is an acceptable option (LOE IIl; SOR C).

2.2 Intrahepatic and Extrahepatic Cholangiocarcinoma

2.2.1 Classification Cholangiocarcinomas are tumors arising from the bile ducts. They are classified as extrahepatic tumors (87-92%) or intrahepatic tumors (8-13%). Extrahepatic tumors are divided into proximal, middle, and distal ductal tumors. Tumors located at the confluence of the right and left hepatic ducts with the proximal common hepatic duct are called Klatskin tumors (135). Bismuth classification is used for perihilar cholangiocarcinomas (136).

Intrahepatic Intrahepatic tumors arise from the small ducts and are often diffuse and multicentric; satellite nodules may occur in about 65% of patients.

Solitary, well-demarcated tumors are difficult to differentiate from primary hepatocellular carcinomas (HCCs). The diffuse sclerosing or scirrhous types are densely fibrotic and have annular long strictures. They are generally confined to the proximal ducts.

Intrahepatic tumors have a special predilection for perineural spread. Infiltration of adjacent liver occurs in 23% of cases, and peritoneal seeding occurs in 9%. Lymphatic spread is common and occurs in the cystic and common bile duct (CBD) nodes in about 15% of intrahepatic tumors.

Extrahepatic Usually they are tumors of the nodular variety also called the papillary type. The tumors are nodular on the intraluminal and extraluminal surfaces, and they form irregular strictures. They are most common in the distal duct and in the periampullary region.

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Extrahepatic tumors also spread to the cystic and common bile duct (CBD) nodes (32%), to the celiac nodes in about 16% of cases and to the peripancreatic and superior mesenteric nodes. Hematogenous spread to the liver, peritoneum, or lung is extremely rare.

2.2.2 Imaging The preferred initial investigation in a patient with jaundice or right upper quadrant pain is ultrasonography (US). Biliary ductal dilatation is easily demonstrated by US, but the tumor mass is seldom localized by this imaging modality (137). CT may easily demonstrate atumor which is nodular and mass-like, but tumors of the diffuse sclerosing variety are difficult to detect (138;139). MDCT angiography techniques are required to assess the vascular supply, a possible vascular infiltration and importantly the potential for resectability (140).

Compared with the other imaging techniques, endoscopic retrograde cholangiopancreatography (ERCP) offers a more definitive investigation that can depict a periampullary tumor or any bile duct strictures. However, with the advent of magnetic resonance cholangiopancreatography (MRCP), effortless demonstration of stricture-causing tumors is possible (141). The disadvantages of MRCP are its inability to distend the duct and the equivocal findings due to long segments and minimal narrowing in diffuse sclerosing tumors. MRI is also very important for the diagnosis and differential diagnosis of intrahepatic cholangiocarcinoma while MR angiography has shown promising results in the estimation of vascular invasion (142). ERCP and percutaneous transhepatic cholangiography (PTC) should be reserved in cases where an interventional therapeutic procedure is needed (stent placement, drainage) or for bile sampling for cytology (143). The role of endoscopic and intraductal US in the management of these tumors is yet to be defined (144). EUS-guided fine-needle aspiration (FNA) of suspected hilar cholangiocarcinoma has an established role in potentially operable patients with negative brush cytology or equivocal imaging findings (145).

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Determination of the preferred examination is complex in the presence of a predisposing condition such as primary sclerosing cholangitis (PSC). Some findings have demonstrated the potential role of PET/CT, which improves the depiction of cholangiocarcinoma superimposed on PSC (146). Furthermore, PET/CT is particularly valuable in detecting unsuspected distant metastases which are not diagnosed by standard imaging. Thus, PET/CT staging has an important impact on selection of adequate therapy (147).

Criteria for assessing unresectability by imaging

Imaging is of great importance in the decision-making process at multidisciplinary meetings while determining resectability.

The major determinants of resectability are the following: a.the extent of tumor within the biliary tree, b. the amount of hepatic parenchyma involved, c. vascular invasion, d. hepatic lobar atrophy, e. metastatic disease.

Determination of resectability is most challenging in patients with Klatskin tumors. About half of patients with Klatskin tumors determined to be resectable preoperatively have unresectable disease intraoperatively.

The radiological criteria defining unresectability in patients with hilar tumors and local tumor invasion are the following (148): a. Bilateral hepatic duct involvement up to secondary biliary radicles, b. Encasement or occlusion of the main portal vein, c. Unilateral tumor extension to secondary biliary radicles with contralateral portal vein or hepatic artery encasement or occlusion, d. Hepatic lobar atrophy with contralateral portal vein or hepatic artery encasement or occlusion, e. Hepatic lobar atrophy with contralateral tumor extension to secondary biliary radicles, f. Insufficient predicted hepatic reserve following extended hepatectomy.

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In case of metastatic disease radiological criteria defining unresectability are: a. Lymph node metastases beyond the hepatoduodenal ligament (N2 lymph nodes) (peripancreatic, periduodenal, periportal, celiac, or superior mesenteric lymph nodes) b. Distant metastases

Recommendations

 The preferred initial investigation in a patient with jaundice or right upper quadrant pain is ultrasonography (US) [LOE II; SOR B].  MRI with MRCP and MRA are the optimal initial investigations for suspected cholangiocarcinoma (LOE II; SOR B).  MDCT does not usually define the extent of hilar or extrahepatic cholangiocarcinoma (LOE II; SOR B).  ERCP and PTC are reserved for stent insertion for palliative purposes in unresectable tumors and for bile sampling when cytology is needed for diagnosis (LOE I; SOR A).  ERCP, when available, is usually favoured above PTC. There is no clear evidence that PTC should generally be favoured over ERCP on the basis of the level of obstruction. However, PTC may be the modality of choice depending on local expertise and anatomical considerations (LOE III; SOR C).  EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma could be used in potentially operable patients with negative brush cytology or equivocal imaging findings (LOE II; SOR B).

2.2.3 Pathology Report Cholangiocarcinomas are malignant tumors that derive from epithelial cells (cholangiocytes) lining the small intrahepatic bile ducts and bile ductules (ICC), or large hilar and extrahepatic bile ducts (ECC). The risk factors, pathogenesis, morphology, treatment, and prognosis of ICC are different from

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ECC (149;150). According to TNM classification (68;69) and WHO 2010 classification (120), ECC are further divided into perihilar (carcinomas of the right, left and common bile ducts i.e. proximal to the origin of the cystic duct, also known as Klatskin tumors) and distal bile duct (distal to the origin of cystic bile duct) types. Two types of precursor lesions are proposed to precede the development and progression of cholangiocarcinoma: biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasms (IPN) (120;151).

Intrahepatic cholangiocarcinoma (ICC) Essential data to be included in the pathology report for surgical specimens of ICC are (152;153):

Macroscopical examination

. Dimensions and weight of resection specimen, recognition of hepatic lobes or segments included, gross description of extrahepatic bile ducts (if included), gross description of gallbladder (if included), lymph nodes (location, number, size) . Tumor: dimensions, distance from nearest hepatic and bile duct surgical resection margin, gross appearance (mass forming type, periductal infiltrating, intraductal growth), presence of satellite nodules, vascular invasion or intrahepatic metastasis. . Additional evaluation: liver capsule and adjacent tissues, gross appearance of non-tumorous liver parenchyma

Histopathology

. Tumor type or histological variant (adenocarcinoma, adenosquamous and squamous carcinoma, mucinous carcinoma, signet ring cell carcinoma, clear cell carcinoma, mucoepidermoid carcinoma, lymphoepithelioma-like carcinoma, and sarcomatous ICC) (according to WHO 2010)(151), histological differentiation (well, moderate, poor).

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. Comments on: surgical resection margins and distance of tumor from surgical resection margins (if <1 cm), vascular and perineural invasion, invasion of liver capsule, liver hilum, visceral peritoneum, or adjacent organs, lymph node metastases. . Non-tumorous liver parenchyma: underlying chronic liver disease (grading and staging according to etiology), presence of biliary intraepithelial neoplasia, other liver lesions. . pTNM classification (which is similar to HCC) (68;69) – ICD-O Codes.

Extrahepatic cholangiocarcinoma (ECC) Essential data to be included in the pathology report for surgical specimens of ECC are (152;153):

Macroscopical examination . Recognition of anatomical structures included in the specimen and dimensions. If hepatic lobe or segment is included, then its weight should also be recorded. Evaluation of bile duct, vascular and hepatic (if relevant) surgical excision margins and extent to adjacent tissues. Lymph nodes (location, number, size) . Tumor: dimensions, gross morphology (polypoid/papillary, nodular, scirrhous constricting, and diffusely infiltrating) . Additional evaluation: gallbladder dimensions, gross appearance of non- tumorous liver parenchyma (if included in the specimen)

Histopathology . Tumor type (according to WHO 2010: adenocarcinoma of biliary or gastric foveolar or intestinal type, adenosquamous carcinoma, carcinosarcoma, clear cell adenocarcinoma, squamous cell carcinoma) and histological differentiation (well, moderate, poor)(120).

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. Comments on: local tumor extent (depth of invasion, extension to adjacent organs), surgical resection margins and distance of tumor from these, presence of biliary intraepithelial neoplasia, vascular and perineural invasion, lymph node metastases . pTNM classification – ICD-O Codes (68;69)

Recommendations

 For accurate pathological reporting of cholangiocarcinoma the pathology report should include detailed macroscopical and histological details (LOE I; SOR A).  pTNM classification should be used for pathological staging of intrahepatic and extrahepatic cholangiocarcinoma and included in the pathology report (LOE I; SOR A).

2.2.4 Surgery Surgery represents the only potentially curative treatment modality in patients with both intra- and extrahepatic cholangiocarcinoma (154;155). Important prognostic and clinical factors are the timing to surgery, preoperative development of jaundice, quality of liver parenchyma (absence of steatosis, fibrosis or cirrhosis), the presumed volume of the remnant liver after resection and the presence of loco-regional lymph node metastasis. Achievement of resection with tumor-free margins (R0-resection) is paramount for long-term survival in cases of cholangiocarcinoma (156-165).

2.2.4.1 Intrahepatic cholangiocarcinoma Except in cases of primary sclerosing cholangitis, intrahepatic cholangiocarcinoma usually arises in non-cirrhotic livers. This characteristic makes its identification difficult, and diagnosis usually coincides with the development of symptoms. Most patients present with large, locally advanced, or metastatic tumors. In recent years, increasing evidence suggests that the prognosis after radical surgical therapy may not be as dismal as previously assumed with

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer postoperative 3-year and 5-year survival being as high as 60% and 44% in some series (156;157;159-161;164;165). In selected cases, surgical therapy could be considered for intrahepatic recurrence in the absence of extrahepatic tumor disease (166;167).

Recommendations

 Extended liver resections are justified in the case of intrahepatic cholangiocarcinoma in the noncirrhotic liver (LOE III; SOR B).  Radical resections with tumor-free margins (R0 resection) favour long-term survival (LOE II; SOR A).  Tumor size provides no prognostic information (LOE IV; SOR B).  Tumor multifocality and vascular invasion adversely affect overall survival (LOE II; SOR C).  Lymphadenectomy of the loco-regional lymph nodes should be considered because up to 1/3 of patients may have N1 status (LOE III; SOR B).  N1 status is a poor prognostic factor for overall survival (LOE II; SOR B).  The efficacy and safety of neo-adjuvant radio-chemotherapy protocols have to be examined in prospective, multicentric studies (LOE V; SOR C).

2.2.4.2 Extrahepatic cholangiocarcinoma The ability to achieve complete resection is often limited by the locally advanced nature of the tumor at presentation. Surgical management of hilar cholangiocarcinoma was primarily palliative with generally poor outcomes in earlier decades. Early reports of resection of hilar cholangiocarcinoma typically involved resection of the biliary tree with hepaticojejunostomy (168). In the last 20 years, surgical management of hilar cholangiocarcinoma has evolved due to improvements in preoperative imaging and an enhanced appreciation of tumor growth characteristics (160;163;169;170). This evolution, that involved an expansion from simple resection of the extrahepatic biliary tree with hepaticojejunostomy to extrahepatic biliary tree resection combined with anatomical liver resections, preoperative portal vein embolization up to right trisectionectomy in the no-touch technique with portal vein reconstruction (158;162;171;172). However, the resectability rate

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer remains highly variable, ranging between 28% and 95% and curative resection rates ranging between 14% and 95%, respectively (158). Liver transplantation can be considered for selected cases as a part of a multidisciplinary approach (173;174).

Recommendations

 A meticulous preoperative work-up optimizes resectability rates (LOE III; SOR A).  Preoperative jaundice release increases the post-resectional regeneration capacity of the liver and enhances the operative results (LOE III; SOR A).  Complete resection with tumor-free margins (R0 resection) remains the most effective and only potentially curative therapy for extrahepatic cholangiocarcinoma (LOE III; SOR B).  Major hepatic resection increases the possibility of R0 resection (LOE IV; SOR C).  Vascular invasion and loco-regional lymph node metastasis are poor prognostic factors for long-term survival (LOE IV; SOR C).  The efficacy and safety of neo-adjuvant radio-chemotherapy protocols have to be examined in prospective, multicentric studies (LOE V; GOR C).  Liver transplantation could be considered for selected cases as a part of a multidisciplinary approach, combined with neo-adjuvant radio- chemotherapy and staging laparotomy (LOE II; SOR B).

2.2.5 Adjuvant Therapy

The benefit of adjuvant therapy remains controversial. Most experts agree that there is some benefit for patients with positive resection margins and for node positive disease. The most commonly used regimens are fluoropyrimidine- based chemoradiotherapy followed by fluoropyrimidine, and fluoropyrimidine or gemcitabine adjuvant chemotherapy. For patients with positive margins a wider resection or ablation (for intrahepatic tumors) is also recommended (61;175-180).

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Recommendations

Extrahepatic Cholangiocarcinoma  For patients with resected, margin-negative extrahepatic cholangiocarcinoma (R0) and negative regional nodes observation or fluoropyrimidine chemoradiation or fluoropyrimidine or gemcitabine chemotherapy are acceptable options (LOE II; SOR C).  For patients with positive resection margins (R1, R2), carcinoma in situ at margin or positive regional lymph nodes, fluoropyrimidine- based chemoradiotherapy (LOE II; GOR A) followed by additional fluoropyrimidine or gemcitabine chemotherapy or fluoropyrimidine based or gemcitabine based chemotherapy for positive regional lymph nodes are acceptable (LOE II; SOR C).

Intrahepatic Cholangiocarcinoma  For patients with no residual local disease, no adjuvant therapy is recommended (LOE II; SOR A).  For patients with microscopic margins (R1) or residual local disease (R2), options include resection by an experienced hepatobiliary surgeon (LOE II; SOR C), ablation or fluoropyrimidine chemoradiation (LOE II; SOR C) or fluoropyrimidine-based or gemcitabine-based chemotherapy regimen (LOE II; SOR C).

2.2.6 Treatment of Locally Advanced and Metastatic Cholangiocarcinoma Locally advanced and unresectable cholangiocarcinoma can practically be divided into three groups of patients: a) patients with R1-R2 resection, with microscopic or macroscopic residual disease after complete surgical removal effort, b) unresectable disease at diagnosis and c) local relapse after initial surgery. There is a small chance of cure for the first group of patients, with appropriate adjuvant treatment. For the second and third group of patients therapeutic interventions are mainly of palliative nature, in order to relieve pain, jaundice and itching and with the probability of a small increase in overall survival. There are several predictive survival models and the main predictive factors are performance status of the patient , the existence of Final document Page 54

Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer metastatic disease and the site of the disease, as intrahepatic cholangiocarcinoma carries the worst prognosis (181-184).

In case of R1-R2 resection of extrahepatic cholangiocarcinoma, adjuvant chemoradiotherapy with fluoropyrimidine (5FU or capecitabine) is recommended. Radiotherapy can be either the classic conformal or stereotactic or a combination of external radiotherapy with brachytherapy. After the completion of chemoradiotherapy, gemcitabine based adjuvant chemotherapy can also be used. In the case of intrahepatic cholangiocarcinoma with R1-R2 resection, a more radical surgery can be attempted or else ablation can be used with radiofrequency, microwaves or cryotherapy. Finally, chemoradiotherapy as described in extrahepatic disease can be used, with the exception of brachytherapy (185;186).

In case of unresectable disease or local recurrence, treatment options are modified. In ECC, stent placement is recommended and if possible the use of photodynamic therapy may also be beneficial. Alternative options are chemoradiotherapy, brachytherapy, palliative chemotherapy or supportive care. In unresectable ICC, ablation with or without embolization (using a chemotherapeutic drug or an isotope) can be offered. Alternative options alsoinclude chemoradiotherapy, palliative chemotherapy or supportive care. In very few cases, cholangiocarcinoma may become resectable after initial treatment (downsizing). Finally, in very well selected cases and in the context of clinical trials liver transplantation may be part of a broad therapeutic plan. We should also accept that for patients with poor performance status the wiser option is best supportive care given the dismal prognosis(173;187).

In metastatic disease, our choices are more limited and survival is almost always less than a year. Supportive care is very important for these patients (188-190). Various chemotherapeutic regimens can improve the quality of life and probably overall survival. Drugs that have showed efficacy are fluoropyrimidines (5FU, capecitabine), gemcitabine, cisplatin and oxaliplatin in various combinations (129;191;192). The combination of gemcitabine-cisplatin has proven superior to monotherapy with gemcitabine and is currently

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer considered the standard of care (129). There has been, however, no comparison to other active combinations, as the combination of gemcitabine- capecitabine (GemCap) or the combination gemcitabine-oxaliplatin (GEMOX), which may be as effective as gemcitabine-cisplatin (130-132;134).

As far as targeted therapy is concerned, some interesting results from a small phase II trial with the combination of GEMOX-bevacizumab (193). or the combination of bevacizumab-erlotinib were announced few years ago and showed promising activity as first or second line treatment in patients with good performance status. In any case, standard first-line regimen for good performance status patients is still considered the combination of gemcitabine-cisplatin. Comparison of this regimen with other active combinations or with the addition of targeted agents is much awaited.

In patients with poor performance status, monotherapy with gemcitabine or a fluoropyrimidine is an acceptable alternative, as well as supportive care only. In patients with good performance status second line treatment can also be considered. The combination of bevacizumab and erlotinib showed promising activity, but can not be still recommended (194). Finally, it is very important to include patients with cholangiocarcinoma in large multicentric trials, in order to find the most effective treatment for this rare disease (61;176;194).

Recommendations

 For locally advanced intrahepatic cholangiocarcinoma with R1- R2 resection options include: a) a more radical surgery (LOE II; SOR A), b) ablation (radiofrequency, microwaves, cryotherapy), (LOE III; SOR C), c) chemoradiotherapy (LOE II; SOR C).  For locally advanced extrahepatic cholangiocarcinoma with R1- R2 resection, chemoradiotherapy with fluoropyrimidine is usually used (with or without adjuvant gemcitabine-based chemotherapy) (LOE II; SOR C).  For locally advanced unresectable intrahepatic cholangiocarcinoma, options include: a) ablation, b) embolization (with a chemotherapeutic drug or an isotope) (LOE IV; SOR C), c)

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer chemoradiotherapy (LOE II; SOR C), d) chemotherapy (LOE III; SOR C) or e) best supportive care (LOE II, SOR A). For selected patients with tumors of hepatic duct bifurcation (Klatskin tumor), liver transplantation in the context of a clinical trial can be used (LOE IV; SOR C).  For locally advanced unresectable extrahepatic cholangiocarcinoma, a stent placement (LOE II; SOR C), combined with photodynamic therapy (LOE III; SOR C) is a valid option. Alternatively, chemoradiotherapy (LOE II; SOR A), chemotherapy (LOE III; SOR C) or supportive care (LOE II; SOR A) can be used, depending on the situation.  For metastatic disease, supportive care is the most important component of a comprehensive treatment plan. For first-line treatment, the combination of cisplatin and gemcitabine is considered the standard of care (LOE I; SOR A). For poor performance status patients, monotherapy with gemcitabine or a fluoropyrimidine (LOE II; SOR C) or alternatively best supportive care only are recommended. For second line treatment, a clinical trial or best supportive care are best options.  Participation of patients with cholangiocarcinoma in clinical trials is paramount in order to improve current treatments and develop new options in this rare disease.

2.2.7 Palliative Approaches

2.2.7.1 Palliative Stenting. Proximal malignant strictures ERCP with stent insertion is the first-line choice for palliation in patients with inoperable CCA. Successful biliary drainage by endoscopic stenting can be achieved in more than 90% of patients with low procedure related morbidity and mortality (195;196).

Several randomized trials comparing surgical by-pass to endoscopic stenting in patients with unresectable malignancies showed similar success rates for biliary decompression and overall survival, but lower morbidity and 30-day mortality for the ERCP patients (195-197). ERCP could also reduced the cost, shortened the hospital stay and improved the quality of life as compared to

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer surgery (198;199). Percutaneous transhepatic (PTC) stent insertion showed to be less successful and cause more complications compared to ERCP, therefore it should be reserved for patients with duodenal obstruction or failed ERCP (200).

Both plastic and self- expandable metal stents (SEMS) have been used for endoscopic biliary drainage. Several comparative studies have shown that SEMS provide longer patency and reduce the need for reintervention for stent occlusion compared with plastic stents in patients with malignant distal common bile duct obstruction. In a systemic review and meta-analyses, the median time to stent occlusion ranged from 111 to 273 days for metal stents versus 62 to 165 days for plastic stents. The median patient survival ranged from 99 to 175 days, suggesting that many patients die long before stent occlusion occurs (201). No significant difference was seen between the metal and plastic stents in terms of technical success, therapeutic success, 30-day mortality, or complications.

The prolonged patency of metal stents is offset by their significantly higher cost as compared to the plastic stents. Cost effective analysis suggested that initial metal stenting is the most cost effective approach in patients who survived more than 6 months (202).

Therefore, predicting the prognosis of a patient before ERCP may allow selection of patients most likely to benefit from initial SEMS insertion. Two prospective studies concluded that tumor size and presence of liver metastases were independent prognostic factors for shorter survival (202;203).

Covered SEMS does not seem to have prolonged patency compared with uncovered SEMS (204).

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2.2.7.2 Endoscopic Stenting for Hilar Cholangiocarcinoma (HCCA) Palliation of patients with hilar strictures involving the bifurcation or its branches) poses technical difficulties, especially in advanced lesions (Bismuth type III and IV).

The risk of cholangitis after contrast injection into undrained biliary ducts is well known, and may be as high as 40%, depending on the complexity of the lesion, and the completeness of drainage (205). Successful initial drainage, regardless of the procedure, is the most important factor in determining clinical outcome (206).

In patients with Bismuth type I hilar strictures, a single biliary stent is sufficient to palliate jaundice, since the two lobes communicate with each other. In patients with more advanced tumors, relief of jaundice generally requires drainage of 1/4 to 1/3 of a healthy liver or proportionally more in those with underlying dysfunction (205).

Many studies have reported good results with unilateral drainage using a single stent in about 80% of patients with type II and III Bismuth tumors (207- 210). No difference in efficacy has been shown between single stent placement in the left or right system (211). Other authors have reported increased survival in patients with drainage of both obstructed lobes (212).

Still, the amount of the liver that need to be drained remains as an unresolved issue.

In hilar tumors, self-expanding metallic stents (SEMS) have been demonstrated to be more cost-effective and require less subsequent interventions than plastic (polyethylene) ones (213). Uncovered SEMS, offer the advantage of draining side branches because of the open mesh of SEMS and in many cases a single unilateral SEMS is efficient. However, the deployment of multiple SEMS can be significantly more challenging than that of multiple plastic stents.

At present, the modern approach to HCCA is to use some kind of a cross- sectional imaging study, such as MRCP or liver CT, before ERCP to map the

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer malignancy and target drainage (214;215). Using selective MRCP or CT- targeted drainage of malignant hilar biliary obstruction enables the endoscopist to choose the optimal bile ducts for stenting, avoiding thus atrophied hepatic segments and minimizing the risk of postprocedural cholangitis.

Over the course of the disease, re-intervention will be needed in about one third of cases.

Uncovered or partially covered SMES are not removable, therefore in cases of occlusion further stents need to be inserted through the previously placed stents, which of course can be technically difficult and may even require transhepatic interventions.

2.2.7.3 Percutaneous Drainage in HCCA The percutaneous approach (PTC) is more invasive than the endoscopic approach with ERCP, for it requires percutaneous tube placement and a longer hospital stay. PTC is indicated when MRCP suggests that ERCP will probably fail to accomplish biliary drainage, or in cases that ERCP had already failed, particularly in patients with Bismuth types III and IV.

A retrospective comparison between the endoscopic and percutaneous implantation of SEMS for Bismuth types III and IV stenosis, demonstrated a significantly higher success rate for PTC. There was no significant difference in terms of the incidence of cholangitis, overall complications, procedure related mortality, and stent patency. Survival was significantly longer in those with successful drainage independent of the type of intervention (216).

In cases with difficult anatomy, PTC can be combined with ERCP in a rendezvous maneuver, in which a guidewire is inserted transhepatically and grasped endoscopically with a basket or a snare, and further endoscopic approach is feasible, without the need of further transhepatic interventions.

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2.2.7.4 Preoperative stenting prior to potentially curative surgery for cancer Pre-surgical biliary drainage has been used in an attempt to reduce morbidity and mortality in patients with pancreatico-biliary malignancy, who are going to undergo a curative resection. It has been proposed that reduction in serum bilirubin level may reduce postoperative bleeding complications. Furthermore, temporary plastic stent insertion provides relief of jaundice while patients are waiting in a long surgical list.

However, preoperative biliary drainage remained a subject of debate. Answer to this question was recently provided by a large prospective randomized controlled trial, which compared endoscopic preoperative biliary drainage using 10F plastic stents followed by surgery 4 to 6 weeks later to surgery alone within 1 week of diagnosis, in patients with malignant distal biliary obstruction. This RCT found no benefit from the preoperative drainage and demonstrated that preoperative biliary drainage increased the overall complication rate (217). Both the complication rate of the initial ERCPs and the need for re-intervention were high as stent occlusion accounted for 15 of the 27 patients who suffered cholangitis.

Recommendations

 In patients with inoperable CCA, ERCP with stent insertion is the first-line drainage procedure for jaundice palliation (LOE I; SOR A).  Self Expandable Metal Endoprosthesis (SMES) offers advantages over plastic endoprostheses, in terms of stent patency and number of reinterventions in exchange of a higher cost (LOE I; SOR A).  In patients with CCA who are going for a potentially curative surgery, preoperative ERCP is not indicated unless there is cholangitis or significant delay in surgery and the patient has intense pruritis (LOE I; SOR A).  ERCP is recommended as the first-line drainage procedure of palliation of jaundice in patients with inoperable tumors of Bismuth types I and III (LOE I; SOR A).

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 PTC is the second choice drainage procedure when ERCP had failed; in intrahepatic advanced CCA (Bismuth types III and IV) PTC might be the first approach (LOE II; SOR B).  In patients with suspected hilar or intrahepatic CCA, preoperative CT or MRCP is strongly recommended to plan the strategy for drainage and to avoid injecting dye into ducts that cannot be drained (LOE II; SOR B).  The need of complete biliary drainage in patients with Bismuth type II to IV stenoses remains controversial. A single stent seems to be appropriate in most cases, provided that undrained segments have not been opacified by contrast (LOE II; SOR B).  Prophylactic antibiotics are mandatory before any intervention for hilar obstruction, because of the high risk of cholangitis, especially in cases of incomplete drainage (LOE II; SOR B).

3. PANCREATIC CANCER

3.1 General Considerations

Pancreatic cancer is an uncommon malignancy characterized by an aggressive growth behavior and an extremely poor prognosis. Though not very common, pancreatic cancer represents the 4th to 5th leading cause of cancer-related deaths in Western countries, with a 5-year survival rate of 5% and a 1-year mortality rate roughly equal its incidence rate (218),(219). Despite recent diagnostic and therapeutic advances, pancreatic adenocarcinoma (PDAC) prognosis has not really improved. The majority of patients with pancreatic cancer present initially with metastatic disease, and only 15-20% of them are determined to be surgical candidates. At present, there is no effective screening test for pancreatic cancer.

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3.2 Molecular Basics and Genetics: Predictive and Prognostic Markers

3.2.1 Molecular basics Genetic alterations in pancreatic cancer have been described from many decades ago. Malignant pancreatic transformation involves alterations in multiple oncogenes and tumor – suppressor genes that are involved in a variety of signaling pathways. K-RAS gene mutations are found in up to 95% (60-95%) of PDAC and therefore represent the most common mutation for this cancer (219). Recent studies based on high throughput sequencing approaches describe numerous original regions prone to frequent large genetic alterations during carcinogenesis. One hundred and forty four minimal regions (identified in 119 independent loci) are subjected to such changes and play a potential role in tumor progression, with loci encoding for p16INK4A, TP53, MYC, K-RAS to be the most significant.

Over 130 microRNAs are documented as deregulated in PDAC and pancreatic cancer cell lines but few data exist on the precise mechanisms of such alteration (220).

3.2.2 Genetic Predisposition True familial pancreatic cancer is rare. However some patients are at greater risk of developing a pancreatic cancer. The risk of pancreatic cancer is increased significantly (18-fold) in families with an affected first-degree relative. Pancreatic cancer is associated with several genetic syndromes, including hereditary pancreatitis syndrome, hereditary non polyposis colorectal cancer (HNPCC), hereditary atypical multiple mole melanoma syndrome, hereditary BRCA2-related breast and ovarian cancer and Peutz-Jeghers syndrome.

However, when predominantly pancreatic cancer is seen, the most common known causes are mutations in the PALB2 and BRACA2 genes, both also associated with breast cancer (221).

Mutations in PALB2 and BRACA2 are inherited in an autosomal dominant pattern. When assessing hereditary cancer risk, a patient’s personal and

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer family history is collected to investigate the risk for hereditary pancreatic cancer. If predominantly pancreatic cancer is seen, genetic testing for PALB2 and BRACA2 may be appropriate (222).

3.2.3 Predictive and Prognostic Markers Prognostic and predictive markers for pancreatic cancer could play a role to improve treatment by identifying patients who may or may not require a given therapy, and determining those most likely to benefit from a therapy. Despite the progress in research, none of the many “independent” molecular markers reported till now, has yet become established in routine clinical practice. None the less, the most adverse prognostic markers seem to be the loss of SMAD4 expression and SMAD4 mutations, the down-regulation of E-cadherine and the VEGF expression (223). There is preliminary evidence about the role of new promising prognostic and predictive biomarkers, such as the presence of circulating tumor cells, Genome-wide single nucleotide polymorphisms (SNPs), alterations of the Cytidine Deaminase (CDA) and markers of the EGFR pathway and especially, the K-ras mutations in exon 2, but all these markers need to be properly validated (224).

3.3 Histopathological Features

The pancreas is a multifunctional organ consisting of an exocrine component, made of lobular units of acini and of pancreatic ducts and an endocrine component, made of endocrine cells, clustered in the Langerhan’s islets.

The classification of the pancreatic neoplasms is based on: 1) the gross appearance of the tumor (solid, cystic or intraductal) and 2) the line(s) of cellular differentiation of the neoplastic cells (ductal, acinar or endocrine). Clinical findings (age and sex of the patients), location of the neoplasm (head or tail), presenting symptoms and radiographic features, can aid in the diagnosis of pancreatic neoplasms. The most common cellular differentiation is ductal and the less common is neuroendocrine and acinar (225).

According to WHO (2010) classification, the pancreatic tumors are classified as benign, premalignant and malignant.

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Pancreatic Ductal adenocarcinoma (PDA) is the most common pancreatic tumor accounting >85% of all pancreatic tumors. Less commonly accounted entities are intraductal papillary mucinous neoplasms (3-5%), neuroendocrine neoplasms (3-4%), serous cystadenomas (1-2%), mucinous cystic neoplasms (1-2%), acinar cell carcinomas (1-2%), solid-pseudopapillary neoplasms (1- 2%) and pancreatoblastomas (<1%). These entities include some of the most treatable pancreatic neoplasms, so their proper recognition is very important.

Most PDAs arise in the head of pancreas and are macroscopically firm, sclerotic and poorly defined masses, with mean diameter 2.5- 3.5 cm. They usually invade the common bile duct and/or the main pancreatic duct and extend into peripancreatic or retroperitoneal adipose tissue. Microscopically, most DAs are composed of well – to moderate developed glandular and duct-like structures, which infiltrate haphazardly the pancreatic parenchyma, associated with a desmoplastic stroma. They can be graded in a 3-tiered system, based in assessment of glandular differentiation, mucin production, number of mitosis (per 10HPF) and nuclear features. Perineural invasion, seen in ~90% of the cases, is a common mechanism for extrapancreatic extension and for lymph node metastasis. Venous invasion is seen in ~50% of the cases.

The most common precursor lesions of PDAs are pancreatic intraepithelial neoplasias (PanINs) and less frequently, mucinous cystic tumors (MCTs) and intraductal papillary mucinous neoplasias (IPMNs).

PanINs are microscopic lesions affecting small pancreatic ducts and are categorized into four groups, PanIN-1A, PanIN-1B, PanIN-2 and PanIN-3, based on the degree of cellular atypia (226).

MCT are true cystic neoplasms, without communication with the ductal system and are lining by columnar, mucin-producing epithelium, supported by an ovarian-type stroma. IPMNs are intraductal neoplasms composed of tall columnar, mucin- containing cells, forming papillary structures. MCTs and IPMNs are classified as adenomas, borderline (low-grade malignant) and carcinomas, non-invasive or invasive, based on the degree of cellular atypia

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer and or stromal invasion. Carcinomas arising in MCTs and in IPMNs behave usually better than ordinary PDAs.

3.4 Diagnosis, Alarming Symptoms and Signs

3.4.1 Alarming Symptoms and Signs Pancreatic cancer does not usually cause definite symptoms until survival is severely compromised. The presenting symptoms of this disease can include weight loss, jaundice, floating stools, pain, dyspepsia, nausea, and depression; however, no early warning signs of pancreatic cancer have been established (227).

Sudden onset of adult type 2 diabetes in patients 50 years or older may be linked to a new diagnosis of pancreatic cancer. Patients with long-standing diabetes may also develop pancreatic cancer. Thus, pancreatic carcinoma should be considered in diabetic patients with unusual manifestation, such as abdominal symptoms and continuous weight loss (228). Acute pancreatitis may also be the first signal of a pancreatic neoplasia, especially in the elderly patients when no obvious cause such as gallstones or alcohol abuse can be recognised (229). Occasionally, pancreatic cancer may be presented and diagnosed after the development of migratory thrombophlebitis (230).

3.4.2 Diagnosis All patients, for whom there is clinical suspicion of pancreatic cancer or evidence of a dilated duct (stricture), should undergo initial evaluation by dynamic-phase helical or spiral CT performed according to a defined pancreatic protocol. Subsequent decisions regarding diagnostic management and respectability should involve multidisciplinary consultation, with reference to appropriate radiographic studies to evaluate the extent of the disease (231).

3.4.3 Tumor-Associated Antigens Many tumor-associated antigens have been studied in connection with pancreatic adenocarcinoma. CA19-9 is commonly expressed and shed in pancreatic and hepatobiliary disease as well as in many solid malignancies, thus is not tumor- specific. However, the degree of increase in CA19-9 levels

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer may be useful in differentiating pancreatic adenocarcinoma from inflammatory conditions of the pancreas and for treatment monitoring. Preoperative measurement of CA19-9 levels should be performed after biliary decompression is complete and bilirubin is normal (232).

3.4.4 Differential Diagnosis Chronic pancreatitis and other benign conditions (e.g. autoimmune pancreatitis) are included in the differential diagnosis of patients suspected of having pancreatic cancer. Increased level of serum IgG4 is the most sensitive and specific laboratory indicator for autoimmune pancreatitis (233).

3.4.5 Biopsy Pathological proof of malignancy is mandatory in unresectable cases or when preoperative treatment is planned. For patients expected to undergo surgery with radical intent, a previous biopsy is not necessary, and even preoperative percutaneous sampling should be avoided. In the presence of metastatic lesions they can be biopsied under ultrasound or CT guidance (231).

Recommendations

 Genetic testing for PALB2 and BRACA2 is appropriate for persons with predominantly pancreatic cancer (LOE III; SOR C).  Standardized – according to WHO – and correct histological classification of the pancreatic neoplasms has significant prognostic and therapeutic implications (LOE I; SOR A).  No single serum tumor-marker is optimal for screening asymptomatic patients (LOE II; SOR D).  A multidisciplinary approach to the diagnosis of pancreatic cancer is recommended (LOE I; SOR A).

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3.5 STAGING 3.5.1 Imaging Multidetector computed tomography (MDCT) scanning is generally accepted to be the first line of investigation in a patient with suspected pancreatic cancer (234). A dedicated protocol involves thin sections, three phases of contrast enhancement, and 3D-CT angiographic techniques providing an assessment of vascular invasion by the tumor (235). Advanced post processing angiographic techniques can also allow prediction of difficulties that may occur during surgery. In the estimation of unresectability, CT shows a positive predictive value of 100%, meaning that if a tumor seems unresectable on CT, no further imaging is required.

For the estimation of infiltrated lymph nodes, CT presents very low sensitivity, while for local extension CT, MRI and EUS seem equal showing 96-100% specificity and positive predictive value (236). Very small peritoneal implants sometimes cannot be seen even with the use of thin-section MDCT, therefore only laparoscopy can definitely exclude peritoneal dissemination.

MDCT permits the detection of very small hepatic lesions (<5mm) that are sometimes difficult to characterize. MRI is more helpful than CT in differentiating metastases from other hepatic masses, but still very small hepatic metastases on liver surface may be missed by both methods and can only be found during surgery with the use of intraoperative US (237).

If the patient is clinically jaundiced and biliary ductal dilatation is demonstrated on ultrasonographic (US) examination, endoscopic retrograde cholangiopancreatography (ERCP) is the investigation of choice with the potential of a drainage procedure and stent insertion.

Ultrasound is often the first test performed in symptomatic patients. US is used for diagnosis rather than staging, although liver metastasis and ascites may be seen (238). Significant technical improvements in US have occurred while the use of contrast enhanced techniques has increased the accuracy of the method. It may be used for problem solving in thin patients specifically in the case of complex cystic lesions (239).

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Magnetic resonance imaging (MRI) has improved considerably in recent years, and it continues to evolve (240). Studies comparing CT and MRI found that detection and assessment of resectability to be similar with both modalities (241). MRI has some disadvantages as it takes longer, costs more, is more complex, and is limited by artifacts. The current role of MRI is probably problem-solving. That is, if the mass is not demonstrable on a CT or US imaging, MRI could be used to evaluate a small lesion of the pancreas causing obstructive jaundice. MRI is also helpful in evaluating and characterizing liver lesions in patients with pancreatic cancer. Limitations for MRI are considered the small peripancreatic lymph nodes, the early tumor infiltration of the vessels and the fact that it does not allow a definitive exclusion of liver micrometastases as well as peritoneal carcinomatosis (242).

In the detection and staging of small tumors, endoscopic US (EUS) can be a reliable test when it is performed by experienced physicians. EUS requires special endoscopic skills and expertise, and it is less readily available worldwide (243). Previous studies have demonstrated a higher sensitivity and specificity with EUS than with other modalities, but these results probably reflect the use of suboptimal CT and MRI techniques. There is evidence suggesting that EUS is similar to CT in diagnosis and staging of pancreatic cancer.

EUS-guided fine-needle aspiration (FNA) is safe and effective, especially for pancreatic head masses. EUS-guided FNA has sensitivity and specificity similar to that of CT-guided FNA cytology (FNAC) but it is generally preferred for pancreatic head and body masses.

In general, TNM is best assessed by MDCT but all imaging methods tend to understage pancreatic cancer. The percentage of overstaging is relatively low, the lowest being that of EUS.

3.5.2 Pathology Report Pathology reports must include the minimum data set required for the microscopic characteristic of the tumors and clinically useful information. Although there is no uniform consensus for the gross pathological

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer examination of the pancreatoduodenectomy specimens, there is a general agreement for using standardized protocols, including multicolor staining of the circumferential soft tissue margins (the anterior surface, the medial surface facing the superior mesenteric vein, the surface flanking the superior mesenteric artery and the posterior surface) and serial perpendicular sectioning for evaluation of their clearance, as well as extensive tissue sampling for evaluation of the cancer origin and for reporting the number and location of lymph nodes (244).

The pathology cancer synoptic reports (protocols) from the College of American Pathologists (CAP) are most commonly used for reporting the results from the pathological analysis of surgical specimens. The design of these protocols was based on the AJCC/UICC TNM staging system and in compliance with the Commission of Cancer of the American College of Surgeons.

For pancreatic tumors, two protocols have been developed, one for tumors of the exocrine pancreas and one for tumors of the endocrine pancreas (245;246). Both protocols include checklists for: (1) type of surgical specimen(s), (2) type of surgical procedure, (3) tumor site (4) tumor size (in greatest diameter), (5) histologic type, (6) microscopic tumor extension, (7) status of resection margins, (8) lymphovascular invasion, (9) perineural invasion, (10) pathologic staging (pTNM), (11) additional pathologic findings, (12) ancillary studies and (13) clinical history. Additional information for exocrine tumors include: (14) histologic grade (for ductal adenocarcinoma) and (15) treatment effects (for carcinomas treated with neoadjuvant therapy) and for endocrine tumors: (14) tumor focality, (15) World Health Organization Classification, (16) functional type, (17) mitotic activity and (18) tumor necrosis. The staging system for pancreatic exocrine cancer continues to evolve. Knowledge of the extent of the disease is necessary in order to communicate a uniform definition of the disease and also essential for a better comparison of the different therapeutic strategies and approaches to pancreatic carcinoma. The most commonly used system for staging of the pancreatic cancer is the TNM classification of the American Joint Committee

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer on Cancer (AJCC) (247). Because only a few patients with pancreatic cancer will eventually undergo surgical resection of the pancreas (and adjacent lymph nodes), a single TNM classification is applied for both clinical and pathologic staging.

Pathologic staging (pTNM) depends on pathologic documentation of the anatomic extend of the disease, whether or not the primary tumor has been completely removed. If a biopsied tumor is not resected for any reason, and the highest T and N categories can be confirmed microscopically, we accept that the criteria for pathologic classification and staging have been satisfied even without complete removal of the primary cancer.

In the latest 7th edition of the AJCC staging, two major changes were made: (a) The Mx category no longer exists for all tumors. There is no pathologic M0 category and the clinical M0 (or M1) must be used to complete stage groups, and (b) neuroendocrine tumors and carcinoid tumors of the pancreas have been now included in the TNM staging system. The committee decided that all pancreatic neuroendocrine tumors, irrespective of been classified as benign or malignant, should be staged by the exocrine cancer staging system, and that inclusion of these tumors in the staging system will improve data collection and subsequent identification of their potential. No changes have been made in the T and N categories. APPENDIX II

3.5.3 Prognostic Factors Recent validation or concordance between AJCC stage and overall survival has been provided through evaluation of 121,713 patients with pancreatic adenocarcinoma induced in the National Cancer Database (including surgical and non- surgical cases), (248), and of 3851 patients with resected neuroendocrine tumors (249).

For resectable pancreatic adenocarcinoma, metastatic disease in regional lymph nodes, poorly differentiated histology and increased size of the primary tumor have been associated with decreased survival (250). Perineural invasion and lymphovascular invasion have been also associated with poor prognosis (251). The significance of the status of resection margins remains debatable.

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Although not included in the TNM staging system, the status of resection margins is considered to be prognostically significant for recurrence and survival in the TNM manual.

In Europe and the UK, many pathologists use a definition of “negative margin” based on a 1 mm clearance. Recently, a margin clearance more than 1.5 mm has proven to be a significant prognostic factor for survival, equivalent to margins of a greater distance (252).

Concerning endocrine tumors of the pancreas, the prognosis primarily depends on the functional subtype, the completeness of the surgical resection and the anatomic extend of the disease (253).

Recommendations

 MDCT (pancreatic protocol) is nowadays the method of choice in the evaluation of pancreatic cancer (LOE I; SOR A).  MRI is considered as a problem solving technique in equivocal or difficult cases and for the differential diagnosis between pancreatic cancer vs chronic pancreatitis (LOE II; SOR B).  EUS should be used when CT or MRI fail to depict the mass in cases of strong clinical or laboratory suspicion (LOE III; SOR C).  EUS-guided FNA should be performed in unresectable cases or in cases of uncertain imaging findings in high-risk candidates for surgery (LOE II; SOR B).  There are no data to support the use of PET-CT preoperatively.  Standardized protocols for the gross pathological examination and pathology cancer synoptic reports of the pancreatoduodenectomy specimens must be used in order to provide relevant clinical information (LOE I; SOR A).  AJCC/UICC TNM staging system must be used for clinical and pathological staging of all pancreatic tumors (LOE I; SOR A).

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 The post-resection prognosis of a patient with pancreatic carcinoma is primarily determined by the anatomic extent of disease as defined by the TNM stage groupings.  For resectable pancreatic adenocarcinoma, metastatic disease in regional lymph nodes, poorly differentiated histology, increased size of the primary tumor, and perineural and/or lymphovascular invasion have been associated with poor prognosis.  For endocrine tumors of the pancreas, the prognosis is primarily depended on the functional subtype, the completeness of the surgical resection and the anatomic extend of the disease.  For resectable pancreatic adenocarcinoma, the prognostic value of the minimal clearance of the resection margin(s) involvement has to be verified.

3.6 MANAGEMENT 3.6.1 Surgery Surgical resection when possible offers a significantly improved prognosis, with a median survival after resection of 14–20 months and poses the patient's only hope for cure with a 5-year survival rate up to 25% (254-256). This is supported by studies showing a distinct advantage of potentially curative (R0) versus palliative (R1/R2) surgery (257;258).

Tumors considered localized and resectable should demonstrate the following: no distant metastases, no radiographic evidence of SMV abutment, distortion, tumor thrombus, or venous encasement and clear fat planes around the celiac axis, hepatic artery, and SMA. Radiographic findings of tumor abutment on the portal vein or SMV with venous deformity and limited encasement of the mesenteric v. and portal v. represent the extent of venous involvement that would categorize a tumor as borderline resectable. Encasement of a short segment of the hepatic a., without evidence of tumor extension to the celiac axis and/or tumor abutment of the SMA involving < 180 degrees of the artery circumference suggests a borderline arterial involvement. Figures 3 & 4

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Figure 3. The circumferential resection margins in pancreatoduodenectomy specimens consist of the anteriior surface, the medial surfacce facing the superior mesenteric vein (SMV), the surface flanking the superiior mesenteric artery (SMA), and the posterior surface.

Figure 4. Slicing of the specimen in an axial plane. This techniquue produces a large number of specimen slicess, provides good views of the tumor and its relationships to the key anatomical structures and the entire circumferential margin, and assists in the achievement of a high lymph node yieeld.

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Unresectable tumors include those with distant metastases, nodal metastasis beyond the field of resection, SMA or celiac encasement greater than 180 degrees, unreconstructable SMV/portal occlusion, or aortic invasion, or encasement, as summarized in the National Comprehensive Cancer Network (NCCN) Clinical Guidelines for pancreatic adenocarcinoma (version 1.2012, www.nccn.org).

Over the last 3 decades, pancreatic surgeons have attempted to push the limits of resection in patients with advanced disease with an aim to completely remove the tumor (259-263) by performing extended resections. This includes extended lymphadenectomies, vascular resections, multiorgan resections, metastasectomies and even removal of tumor recurrence.

Extended lymphadenectomy was developed as a result of the observation that lymph nodes of the para-aortic region were frequently positive for pancreatic cancer metastases. Some retrospective studies from Japan in the 1980s showed a survival benefit for extended lymphadenectomy in pancreatoduodenectomy. However, three RCTs, a meta-analysis, as well as a large Japanese RCT published in abstract form, showed no increase in survival rates for the extended procedure but a trend toward increased morbidity (264-267). Thus, extended lymphadenectomy cannot be recommended, and should only be considered when patients are included in a RCT.

Pancreatic carcinoma frequently infiltrates the portal vein or the superior mesenteric vein; pancreatectomy combined with portal vein resection represents a potentially curative treatment in these cases but is still a controversial procedure. The current literature suggests that portal vein/superior mesenteric vein resection combined with pancreatectomy is a safe and feasible procedure that increases the number of patients who undergo curative resection and, therefore, provides important survival benefits to selected groups of patients (268). Reports of arterial resections and reconstruction have been reported for pancreatic tumors (269-273). While

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer venous resection and reconstruction has been performed in many series, the resistance to arterial resections (hepatic artery or celiac trunk) is strong, because data on the benefit of arterial resection are limited, and therefore it should only be conducted in the context of adequately powered RCTs (274).

The presence of distant metastases in patients with pancreatic cancer has generally been considered an indicator of terminal disease. However, there have been a number of reports (case reports and even some large series) highlighting attempts from surgical resection of distant metastases (liver, peritoneum) (275;276). In 2008, Michalski et al (277) reviewed the available literature on liver resections for pancreatic ductal adenocarcinoma, which included the results from 3 case reports and 21 studies (the largest had 11 patients undergoing liver resection). They concluded that while such resections were technically feasible in selected patients, the actual benefit could be determined only from larger randomized controlled trials.

In an attempt to obtain complete removal of pancreatic cancer, surgeons have resorted to en bloc resections entailing removal of adjacent viscera/vessels that are grossly infiltrated by tumor. From the limited data available, it can be concluded these resections are technically feasible, when performed in high volume centers with the necessary expertise, and associated with improved survival as compared to no resection, comparable to standard resections for lesions not involving adjacent organs (278).

Recurrence of pancreatic ductal adenocarcinoma occurs in up to 80% of pancreatic cancer patients within 2 years from their curative resection. Recurrences occur because, in most cases, occult (local and/or distant) micrometastases are present at the time of the initial resection. Resection for recurrent pancreatic cancer does not seem to substantially prolong overall survival. However, there might be a subgroup of patients that benefits from these procedures, and this has to be analyzed in randomized controlled trials (279).

At the time of diagnosis, approximately 80% of patients are found to have an unresectable tumor, because of local spread or metastatic disease. Therefore,

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer most patients will undergo palliative treatment, which is aimed at the improvement of the quality of life and the prevention of symptoms. About 15- 25% of patients suffer from gastric outlet obstruction at the time of diagnosis and another 15-20% will develop later. There is still some controversy on the use of routine gastro-intestinal bypass for PC diagnosed as unresectable at the time of exploratory laparoscopy or laparotomy. During the last decades, the development of interventional radiology and endoscopy has allowed palliation of obstructive jaundice by the insertion of percutaneous or endoluminal stents with minimal morbidity and mortality. The double bypass procedure (biliary-enteric, gastro-enteric) is the preferable method in patients without metastases or major arterial infiltration and a life expectancy > 6 months (280), otherwise endoscopic biliary stenting is the treatment of choice for unresectable PC with obstructive jaundice (281).

Surgical resection (R0) is the only potentially curative technique for managing pancreatic cancer. Despite the progress in surgical treatment, the overall prognosis following resection remains unsatisfactory to date. It is hoped that progress in multimodality treatment and modern therapies, resulting from both clinical and advanced basic research, can improve the prognosis of this malignancy in the near future.

Recommendations

 Decisions about diagnostic management and respectability should involve multidisciplinary consultation with reference to appropriate imaging studies to evaluate the extent of disease (LOE II; SOR B).  Diagnostic staging laparoscopy to rule out occult metastases is used selectively in patients who are at higher risk for disseminated disease (borderline resectable disease, markedly elevated CA 19-9, large primary tumors or large regional lymph nodes) (LOE II; SOR B).  Tumors considered localized and resectable should demonstrate the following: no distant metastases, no radiographic evidence of SMV

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer and portal vein abutment, distortion, tumor thrombus, or venous encasement (LOE II; SOR B).  Borderline resectable tumors are those with venous involvement of the SMV/portal vein, encasement of the SMV/portal vein but without encasement of the nearby arteries, tumor abutment of the SMA not to exceed greater than 180 degrees of the circumference of the vessel wall (LOE II; SOR B).  Surgical resection (R0) is the only potentially curative technique for managing pancreatic cancer (LOE II; SOR B).  The more complex resections should only be undertaken in high volume specialized centers of pancreatic surgery after a careful assessment of the risk/benefit ratio in the individual patient (LOE I; SOR A).  The double bypass procedure (biliary-enteric, gastro-enteric) is the preferable method in patients without metastases or major arterial infiltration and a life expectancy > 6 months, otherwise endoscopic biliary stenting is the treatment of choice for unresectable PC with obstructive jaundice (LOE II; SOR B).

3.6.2 Adjuvant treatment of resected pancreatic cancer After pancreatic resection the 5 year survival is usually <20%, posing the need for postoperative treatment. The use of postoperative chemoradiation (CRT) is supported by several studies but refuted by others. The first RCT showing benefit from adjuvant CRT was the GIST trial that suggested an increase of median survival from 11 to 18 months by the addition of 40 cGy and 5-FU (282). Similar results were seen in the EORTC study (17 vs 12 months) (177). The role of adjuvant therapy was also explored by the European Study Group for Pancreatic Cancer 1 study (ESPAC-1), which compared controls (surgery alone) to patients receiving post-operatively either 5-FU chemotherapy or chemoradiation (sequential or concurrent) (283). The group receiving adjuvant chemotherapy had a 5-year survival of 20%, compared to 10% of the combination treatment and to 8% for the control group. The study has influenced practice in Europe, whereas in the USA, adjuvant chemoradiation is still the preferred option.

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The emergence of gemcitabine as an active drug altered the design of subsequent studies. In 2007, the German-Austrian CONKO-1 study demonstrated that adjuvant gemcitabine for 6 months, after R0 or R1 resection, increased the median PFS from 6.9 months, in untreated patients, to 13.9 months, although the benefit in overall survival was less clear (22 vs 20 months) (284). This study established the dominant place of adjuvant gemcitabine in pancreatic cancer. Furthermore, a study from the Radiation Therapy Oncology Group (RTOG) tested the role of adjuvant chemoradiation (5040 cGy concurrent with continuous infusion 5FU) followed by adjuvant chemotherapy with either 5FU or gemcitabine. The study showed that the gemcitabine group had a trend to superior 3-year survival (20.5 months vs 16.9 months, HR 0.82, p=0.09) (285).

Recommendations

 Adjuvant chemotherapy with gemcitabine for 6 months should be offered (LOE I; SOR A).  Chemoradiation is a valid treatment option, especially in patients with positive margins (LOE I; SOR B).  Chemoradiation followed by gemcitabine is a valid treatment option, especially in patients with positive margins (LOE I; SOR B).

3.6.3 Management of Unresectable Pancreatic Cancer

3.6.3.1 Palliation

Gastroduodenal decompression According to several studies, gastric outlet obstruction may occur in 4-20% of unresectable PDA. Prophylactic gastric bypass is not currently recommended in patients found unresectable during the attempted resection. This is mainly due to the successful use of expanding duodenal stents. Laparoscopic gastric bypass is less morbid and can be considered.

Biliary decompression Biliary obstruction is common with head of pancreas tumors. In the past, staging laparotomy with biliary bypass was performed for such unresectable

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer patients. This procedure is largely replaced by more accurate staging due to advanced imaging and endoscopic or transdermal biliary stenting. Randomized studies and meta-analyses have shown that surgical stenting offers no better relief that endoscopic stenting, and is additionally associated with higher perioperative complications. Controversy may exist regarding the type of stent used, plastic vs metallic. Expandable metallic stents provide wider lumen and less reocclusion rate but they are more expensive. There seems to be no increase of biliary sepsis, especially in patients receiving chemotherapy, as initially feared. Therefore, the choice of the stent should be individualized taking into consideration the goal of treatment and the life expectancy of a patient, preferably in the context of multidisciplinary approach.

Pain control The majority of patients develop at some stage clinically important pain, which the clinician should be aware and prepared to manage. Pain can be the primary morbidity and the major cause of quality of life deterioration in such patients. Involvement of the celiac plexus and retroperitoneal structures can be the main source of pain. Most patients can be controlled with opioids, usually at increasing doses as tumor progresses. Relief can also be achieved by palliative radiation to the pancreatic/retroperitoneal mass. Celiac plexus neurolysis using alcohol injection is a highly successful procedure, obviating the need or deducing the requirements of opioids, thus averting related toxicity. Intractable pain requires more invasive approaches and should be approached by multidisciplinary specialized teams. In general, pain relief should be the outmost goal of the palliation, without consideration to physical or psychological dependency or sedation.

Recommendations

 Gastric outlet obstruction is best treated by duodenal stents. Routine surgical gastric bypass is not recommended (LOE II; SOR A).  Biliary obstruction is best treated by endoscopic stents (LOE II; SOR A).

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 Pain relief is achieved by liberal use of opiates, celiac plexus neurolysis, palliative radiation, or referral to pain control teams (LOE III; SOR A).

3.6.3.2 Chemotherapy for metastatic disease In the last decade, gemcitabine has replaced 5-FU and mitomycin-C as the backbone of treatment for advanced pancreatic cancer although the response rates, as well as overall survival, are low. A 6-month course is considered a standard approach although only a fraction of the patients remain progression-free during this time period. Combination of gemcitabine with other chemotherapeutic agents has largely failed to improve overall survival, albeit there may be occasionally benefit in the PFS. In particular, combinations of gemcitabine with platinums are intriguing, and such combinations are supported by meta-analysis. There is no clear preferred platinum compound to be used, as they are deemed of similar activity in pancreatic cancer. Apart from platinum agents, a UK study showed that the combination of gemcitabine with capecitabine provides modest survival benefit, contradicting prior studies using fluoropyrimidines (286). Interestingly, a study by the National Cancer Institute (NCI) of Canada showed a very modest survival advantage of the combination of gemcitabine with erlotinib, an EGFR-Tyrosine Kinase Inhibitor (287). A statistically significant (but not clinically important) overall survival advantage of nearly 3 weeks has led to its regulatory approval.

In 2011, a comparative study of the combination of irinotecan–oxaliplatin– Leucovorin/5-Fluorouracil (FOLFIRINOX) was reported to be significantly superior in terms of overall survival (10.5 vs 6.9 months, HR 0.61, p=0.0008) and response (28% vs 11%) to gemcitabine monotherapy (288). The remarkable findings of this study challenges the prevailing nihilism regarding the treatment of metastatic disease and resulted in the incorporation of this aggressive but toxic regimen in the acceptable treatment options, particularly for fit patients, if regulatory impediments can be overcome. A further therapeutic option in advanced pancreatic cancer has been recently provided after the announcement of the results of the phase III study of gemcitabine with or without nab-paclitaxel (MPACT study). This trial suggested that the

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer addition of nab-paclitaxel is associated with improvement of the response rate the time to treatment failure (TTF) and also of the overall survival by 1.8 months (8.5 versus 6.7, HR=0.72, p=0.00015) (289).

There is no established second line treatment for progressing patients. In general, alternative drug approaches could be tried (i.e. 5-FU based treatment if gemcitabine was initially used). A combination of oxaliplatin with fluoropyrimidine (FOLFOX) has shown survival advantage (290). Taxanes, as nab-paclitaxel, have also shown activity in second line setting and could be used in combination with other agents in selected patients (291;292).

Patients under treatment should be followed by routine clinical evaluations, serial tumor marker (CA 19-9) measurements and imaging as needed, taking into consideration the limited scope of the systemic treatment.

Recommendations  Gemcitabine monotherapy is an acceptable monotherapy treatment (LOE I; SOR A).  Gemcitabine-erlotinib combination is an acceptable treatment (LOE I; SOR B).  FOLFIRINOX is an acceptable first-line treatment, in selected fit patients (LOE I; SOR B).  Gemcitabine/NabPaclitaxel may provide a further first-line option, upon regulatory approval (LOE I; SOR B).  Combination of gemcitabine with platinum compounds or capecitabine can be considered (LOE III; SOR B).  Second line treatment could be administered based on alternative potentially active drugs (LOE III; SOR B).

3.6.4 Role of radiotherapy

3.6.4.1 Adjuvant treatment in resectable disease There is no uniform consensus on what constitutes “standard” adjuvant therapy for pancreatic cancer. This controversy derives from several studies,

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer each fraught with its own limitations. Standards of care also vary somewhat on the geography. Chemoradiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America, based on the small Gastrointestinal Tumor Study Group trial and large case series analyses from John Hopkins and the Mayo Clinic. By contrast, chemotherapy alone is widely recommended in Europe on the basis of the aforementioned ESPAC-1 and CONKO-001 trials. In 1985, the GITSG trial was the first to report a survival benefit (median OS 20 months versus 11 months and 5-year OS 18% versus 8%) in patients who received bolus 5-FU with radiation treatment postoperatively (282). However, the results of almost all studies cannot be considered definitively conclusive, mainly because of the small numbers of patients (underpowering the GITSG and the EORTC), the radiation regimen used (split course) and, most importantly, the lack of quality control of radiation treatment. A recent randomized phase II study, showed that adjuvant gemcitabine followed by gemcitabine-based 3D conformally planned radiotherapy to 50Gy is feasible and slightly more toxic than gemcitabine alone (285;293). However, the study design was not appropriate to reveal any survival benefits and in addition, the potential effect of chemoRT on local recurrence could possibly be underestimated because this study included only patients with R0 resection. It is likely that achieving local control is relatively more important in patients with R1 resection. A meta-analysis of 6 trials involving 875 patients showed that chemotherapy improved median and 5- year survival while chemoRT offered no significant survival benefit (294). A subsequent subgroup analysis estimated that chemoRT was more effective for patients with positive margins (295).

3.6.4.2 Neo-adjuvant treatment in resectable or borderline resectable disease

The theoretical advantages of neoadjuvant chemoradiotherapy in patients with respectable pancreatic cancer include the potential to downsize tumors and increase the likelihood of margin-free resection, the potential to select for surgery those patients with a more stable disease or disease that is more sensitive to therapy, and the treatment of micrometastases at an earlier stage. A retrospective review from the MD Anderson Cancer Center suggested that

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer approximately 25% of patients are found to have progressive disease after chemoradiation. Some small phase II studies reported that only 45-75% of patients were actually submitted to surgical resection after induction chemoradiation, claiming therefore that patients who experience disease progression suffer from an extremely aggressive tumor which cannot be cured by extensive surgery (296;297). There is also some evidence that preoperative chemoradiotherapy increases the chance of margin-negative resection with a trend to improved disease-free survival (298). Overall, reported median and 2-year OS figures in these small series do not appear to represent a remarkable improvement when compared to those patients submitted to immediate surgery.

The use of neoadjuvant therapy in borderline resectable disease is a highly debated topic. No randomized phase III trials have compared this approach to standard surgery. Retrospective reviews and some small phase II studies have reported that between 20 and 35% of borderline respectable patients who completed neoadjuvant chemoradiotherapy had R0 resections. In a recently published study, capecitabine-based chemoradiotherapy, given preoperatively in patients with borderline resectable tumors, was reported to be well-tolerated and effective with 46% of the patients achieving a R0 resection (299).

3.6.4.3 Treatment of locally advanced non-resectable disease Chemoradiation is a conventional option for the management of patients with locally advanced unresectable pancreatic cancer and good performance status. The role of chemoradiation was initially defined in the trial conducted by GITSG, which showed a 2-fold increase in median survival (42.2 versus 22.9 weeks) achieved with 5-FU and split-course radiotherapy compared to radiation alone. Although there are no randomized studies, there is some evidence to suggest that concurrent gemcitabine and radiation can yield similar outcomes to 5-FU based chemoradiation. The choice between upfront chemoradiation versus induction chemotherapy followed by consolidation chemoradiation should be based on disease characteristics. For patients presenting with uncontrolled pain or obstructive symptoms, it might be

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer preferable to start with chemoradiation. Initial treatment with chemotherapy might facilitate systemic disease control and also might be a useful strategy for selecting patients who are more likely to benefit from subsequent chemoradiotherapy. The GERCOR study showed that the addition of radiotherapy after 5-FU or gemcitabine chemotherapy for 3 months improved median and overall survival of those patients who had no evidence of progression on chemotherapy (300). This approach is currently being evaluated in an ongoing phase III trial. A qualitative systematic review including two meta-analyses, 13 randomized trials and 6 non-randomized studies reported that chemoradiotherapy increases overall survival when compared with best supportive care or with radiotherapy but is more toxic. Chemoradiotherapy is not superior to chemotherapy alone in terms of survival while induction chemotherapy before chemoradiotherapy improves survival (301).

3.6.4.4 Radiotherapy for recurrent disease For patients experiencing local or locoregional recurrence following resection, chemoradiotherapy could be considered if not previously administered, especially for those with good performance status whose recurrence occurred more than 6 months after initial treatment.

3.6.4.5 Radiotherapy for symptom palliation A significant subset of patients with pancreatic cancer will require substantial palliative interventions to manage symptoms such as biliary obstruction, gastric outlet obstruction and cancer-related pain. Most patients with locally advanced or metastatic pancreatic cancer experience severe abdominal and back pain mainly due to infiltration of retroperitoneal nerves. Radiotherapy to doses of 30-40Gy in 2.5-3.0Gy per fraction can achieve pain relief in 50-70% of patients with no severe toxicity (302).

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Recommendations

 Gemcitabine or fluoropyrimidine-based chemoradiotherapy with additional gemcitabine or 5-fluoruracil chemotherapy is an option for adjuvant treatment following resection of pancreatic cancer, especially for patients with tumors of the pancreatic head, large (>3cm) T3 tumors and for patients with R1 resection (LOE II; SOR B).  Following CT simulation and 3-D conformal planning, postoperative radiotherapy should be administered to a dose of 45Gy in 1.8-2.0Gy per fraction, with high energy photons to the tumor bed, surgical anastomoses and adjacent lymph nodes, followed by a 5-10Gy boost to the tumor bed.  Neoadjuvant chemoradiotherapy for resectable pancreatic cancer is not routinely recommended, except on a clinical trial (LOE III; SOR B).  Neoadjuvant chemoradiotherapy is an option for borderline resectable pancreatic cancer (LOE II; SOR B).  Chemotherapy followed by chemoradiotherapy is an option for patients with locally advanced pancreatic cancer with good performance status (LOE III; SOR B).  Chemotherapy or best supportive care is recommended for patients with poor performance status (LOE III; SOR B).

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Suggestions, Opinions & Recommendations for December 7-9, 2011 Hepatobiliary and Pancreatic Cancer pancreatic adenocarcinoma beneficial? A meta-analysis of an unanswered question. J Gastrointest Surg 2006 May;10(5):689-97. (296) Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008 Jul 20;26(21):3496-502. (297) Talamonti MS, Small W, Jr., Mulcahy MF, Wayne JD, Attaluri V, Colletti LM, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol 2006 Feb;13(2):150-8. (298) Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, et al. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. J Gastrointest Surg 2001 Mar;5(2):121-30. (299) Stokes JB, Nolan NJ, Stelow EB, Walters DM, Weiss GR, de Lange EE, et al. Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer. Ann Surg Oncol 2011 Mar;18(3):619-27. (300) Huguet F, Andre T, Hammel P, Artru P, Balosso J, Selle F, et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 2007 Jan 20;25(3):326-31. (301) Huguet F, Girard N, Guerche CS, Hennequin C, Mornex F, Azria D. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 2009 May 1;27(13):2269-77. (302) Morganti AG, Trodella L, Valentini V, Barbi S, Macchia G, Mantini G, et al. Pain relief with short-term irradiation in locally advanced carcinoma of the pancreas. J Palliat Care 2003;19(4):258-62.

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5. APPENDICES

APPENDIX I

Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report, Zyrich Level of Strength of

evidence recommendation

Assessment of candidates with HCC for liver transplantation 1. When considering treatment options for patients with HCC, the BCLC staging system is the preferred staging 2b (P) Strong system to assess the prognosis of patients with HCC.

2. The TNM system (7th ed.) including pathological examination of the explanted liver, should be used for 2b (P) Strong determining prognosis after transplantation with the addition of assessment of microvascular invasion.

3. Either dynamic CT or dynamic MRI with the presence of arterial enhancement followed by washout on portal venous or delayed imaging is the best non-invasive test to make a 1b (D) Strong diagnosis in cirrhotic patients suspected of having HCC and for preoperative staging.

4. Extrahepatic staging should include CT of the chest, and 3b (D) Strong CT or MRI of the abdomen and pelvis.

5. Tumour biopsy is not required in cirrhotic patients considered for liver transplantation who have high-quality 1b (D) Weak dynamic CT or MRI findings typical for HCC and a lesion larger than 1 cm according to current AASLD guidelines.

6. For patients with lesions smaller or equal to 10 mm, non- invasive imaging does not allow an accurate diagnosis and should not be used to make a decision for or against 1b (D) Strong transplantation.

Criteria for listing candidates with HCC in cirrhotic livers for DDLT

7. Liver transplantation should be reserved for HCC patients who have a predicted 5-year survival comparable to non- NA Weak HCC patients.

8. Preoperative assessment of the size of the largest tumor 2a (P) Strong' or total diameter of tumors should be the main consideration

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Level of Strength of

evidence recommendation

in selecting patients with HCC for liver transplantation.

9. The Milan criteria are currently the benchmark for the selection of HCC patients for liver transplantation, and the 2a (P) Strong basis for comparison with other suggested criteria.

10. A modest expansion of the number of potential candidates may be considered on the basis of several 3b (P) Weak studies showing comparable survival for patients outside the Milan criteria.

11. Patients with worse prognosis may be considered for liver transplantation outside the Milan criteria if the NA Weak dynamics of the waiting list allow it without undue prejudice to other recipients with a better prognosis.

12. α-fetoprotein concentrations add prognostic information in HCC patients and may be used for making decisions 2b (P) Weak regarding transplantation in combination with imaging criteria.

13. Biomarkers other than α-fetoprotein cannot yet be used for clinical decision making regarding liver transplantation 2b (P) Strong for HCC

14. Indication for liver transplantation in HCC should not rely on microvascular invasion because it cannot be reliably 2b (P) Strong detected prior to transplantation.

Criteria for HCC candidates with non-cirrhotic livers

15. The Milan criteria and its modifications are not applicable to patients with HCC developing in a non-cirrhotic liver. Such patients with non-resectable HCC and absence 4 (P) Weak of macrovascular invasion and extrahepatic spread may be considered as appropriate candidates for liver transplantation.

16. Patients with HCC in non-cirrhotic liver who were treated by resection, and have intrahepatic recurrence of HCC and 4 (P) Weak no evidence of lymph node or macrovascular invasion, may be considered for salvage transplantation.

Role of downstaging

17. Transplantation may be considered after successful 5 (P) Weak downstaging.

18. Liver transplantation after successful downstaging 5 (P) Strong should achieve a 5-year survival comparable to that of HCC

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Level of Strength of

evidence recommendation

patients who meet the criteria for liver transplantation without requiring downstaging.

19. Criteria for successful downstaging should include tumor 4 (P) Strong size and number of viable tumors.

20. α-fetoprotein concentrations before and after 4 (P) Weak downstaging may add additional information.

21. Based on existing evidence, no recommendation can be made for preferring a specific locoregional therapy for NA None downstaging over others.

Managing patients on the waiting list

22. Periodic waiting-list monitoring should be performed by imaging (dynamic CT, dynamic MRI, or contrast-enhanced 5 (P) Strong ultrasonography) and α-fetoprotein measurements.

23. Based on current absence of evidence, no recommendation can be made on bridging therapy in NA None patients with UNOS T1 (≤2 cm) HCC.

24. In patients with UNOS T2 (one nodule 2–5 cm or three or more nodules each ≤3 cm) HCC (Milan criteria) and a 4 (P) Weak likely waiting time longer than 6 months, locoregional therapy may be appropriate.

25. No recommendation can be made for preferring any NA None type of locoregional therapy to others.

26. Patients found to have progressed beyond criteria acceptable for listing for liver transplantation should be 5 (P) Strong placed on hold and considered for downstaging.

27. Patients with progressive disease in whom locoregional intervention is not considered appropriate, or is ineffective, 5 (P) Strong should be removed from the waiting list.

Role of LDLT

28. LDLT is acceptable for HCC patients who have an expected 5-year survival similar to comparably staged patients receiving a deceased donor liver. In LDLT, careful NA Weak attention should be given to psychosocial considerations regarding both donor and recipient.

29. LDLT must be restricted to centers of excellence in liver NA Strong surgery and liver transplantation to minimize donor risk and

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maximize recipient outcome.

30. In patients following LDLT for HCC within the accepted regional criteria for DDLT, retransplantation for graft failure 5 (P) Weak is justified.

31. In patients following LDLT for HCC outside the accepted regional criteria for DDLT, retransplantation for graft failure 5 (P) Strong using a deceased donor organ is not recommended.

Post-transplant management

32. Post-transplant monitoring may include 6–12 monthly contrast-enhanced CT or MRI imaging and α-fetoprotein 5 (P) Weak measurements.

33. There is currently insufficient evidence from clinical trials to base a recommendation for choosing the type or dose of NA None immunosuppression therapy to influence the incidence of HCC recurrence or its prognosis.

34. Based on current evidence, no recommendation can be made on the use of mTOR inhibitors solely to reduce the NA None risk of HCC recurrence outside clinical trials.

35. The current evidence does not justify the routine use of adjuvant antitumor therapy after liver transplantation for NA Weak HCC outside of a controlled clinical trial.

36. HCC recurrence after liver transplantation may be treated by surgery for resectable lesions or by locoregional 4 (P) Weak therapy or systemic therapy (including sorafenib) for unresectable lesions.

37. Liver retransplantation is not appropriate treatment for NA Strong recurrent HCC.

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APPENDIX II Pancreatic Cancer - TNM staging

Primary tumor (T)

TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: In situ carcinoma* T1: Tumor limited to the pancreas, 2cm or less in greatest dimension T2: Tumor limited to the pancreas, more than 2cm in greatest dimension T3: Tumor extends beyond the pancreas but without involvement of the celiac axis T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor). * This also includes the PanIn III classification

Regional lymph nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis Regional lymph nodes are different in respect to the location of the primary tumor

Distant metastasis (M) M0: No distant metastasis M1: Distant metastasis At present, positive peritoneal cytology is considered M1 disease

AJCC stage groupings Stage 0: Tis, N0, M0 Stage IA: T1, N0, M0 Stage IB: T2, N0, M0 Stage IIA: T3, N0, M0 Stage IIB: T1, N1, M0 / T2, N1, M0 / T3, N1, M0 Stage III: T4, Any N, M0 Stage IV: Any T, Any N, M1

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