Table of Contents  

Zopf: Diagnosis and systemic therapy for hepatobiliary cancer


Liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), is the second most common cause of cancer-related death, and its incidence rate is increasing.1 In the last decade, knowledge and understanding of liver cancer has improved, and in recent years new laboratory technologies have identified several molecular abnormalities that could enable more accurate classification of the disease and, thus, better treatment. The discovery of the TP53 hotspot mutation led to a change in tumour classification and, since then, by combining conventional clinical criteria with molecular data has had a significant effect on treatment decisions.2,3

The development of ultrasound, computerized tomography (CT) and magnetic resonance imaging (MRI) has been instrumental in the earlier diagnosis and accurate staging of liver cancer, which affords advanced treatment options. Currently, several treatment options targeting pro-cancer molecular pathways are available and have proven survival benefit. Depending on the individual, further potentially curative options, such as resection of tumours, are available, and palliative therapies are applied in those with advanced cancer.4

This review presents and summarizes the available data on diagnostic approaches to hepatobiliary cancer, and the conservative medical therapy options.

Diagnosis of hepatocellular carcinoma and cholangiocarcinoma

Identification of HCC and the differentiation of HCC from CC are highly relevant as proper staging strongly influences the therapeutic procedures available. Moreover, risk factors for both tumour entities broadly overlap, and in some cases intrahepatic CC is difficult to distinguish from HCC using established imaging methods. Imaging in HCC and CC is based on contrast-enhanced dynamic imaging methods such as contrast-enhanced ultrasound (CEUS), CT and MRI. Some special types that include liver cancers of mixed differentiation (HCC/CC) may be picked up on biopsy.

Diagnosis of hepatocellular carcinoma

Liver cancer can be diagnosed by imaging or biopsy. Patients at high risk of HCC show a specific imaging pattern (CT or MRI) of nodules > 10 mm in their cirrhotic livers. These nodules are identified by intense uptake of contrast agent during the arterial phase, followed by contrast washout in the venous or delayed phases.510 As HCCs mostly contain arterial blood, they appear brighter during the arterial phase than the surrounding liver, which contains both arterial and venous blood. During the venous phase, HCC appears less bright because it contains contrast-free arterial blood, whereas the surrounding liver parenchyma contains venous blood containing the contrast agent. This typical dynamic contrast pattern identifies HCC with limited levels of sensitivity, but with specificity near to 100%;10 for CEUS, the specificity values are not as high.11,12 In the absence of this typical appearance, a biopsy is needed to detect HCC.

Immunohistochemical analysis of glypican 3, heat shock protein 70, clathrin heavy chain and glutamine synthetase can be used to confirm HCC diagnosis, but these examinations do not replace the expertise of a pathologist.1315

As radiological analysis detects HCC with high levels of specificity, biopsies are no longer necessary for many patients.

To characterize lesions identified by surveillance, an algorithm has been developed and validated.5,7,9 Lesions that are < 10 mm in size are less likely to be HCC and require a short-interval follow-up, commonly every 3 months for at least 2 years. Lesions > 10 mm are suspected to be HCC. If CT or MRI shows typical characteristics of HCC, no further investigation is needed. If the features are atypical for HCC, a biopsy can be performed. However, a negative biopsy does not exclude HCC because it is difficult to differentiate between early-stage HCC and dysplastic nodules. In complicated diagnostic cases of liver cancer, sampling errors also have to be considered, and a second biopsy should be taken.16

A special feature of the HCC is the staging system. The most commonly used staging classification is the Barcelona Clinic Liver Cancer (BCLC) system, which has been widely validated.1720 This system determines cancer stage and patient prognosis based on tumour burden, severity of liver disease and the patient’s performance status. BCLC 0 or BCLC A describes very early and early-stage HCC with a solitary lesion, or up to three nodules < 3 cm without macrovascular invasion or extrahepatic spread; liver function is preserved. Patients in these early stages can benefit from potentially curative treatment options such as resection, ablation or transplantation.

Barcelona Clinic Liver Cancer B includes patients with intermediate-stage HCC without symptoms but large, multifocal tumours without macrovascular invasion or extrahepatic spread. If liver function is not compromised, these patients may be candidates for transarterial chemoembolization (TACE). However, patients with large but solitary HCC > 5 cm without macrovascular invasion are assigned to stage BCLC A.20,21 These patients might benefit from tumour resection.1719

Stage BCLC C includes patients with advanced-stage HCC presenting with tumours that have spread beyond the liver and/or vascular invasion and/or mild cancer-related symptoms [Eastern Cooperative Oncology Group (ECOG) grades 1 and 2]. In these cases, a systemic therapy is the only treatment option, as described later in this review. Patients with BCLC D have end-stage disease with poor liver function (Child–Pugh class C) and are not candidates for transplantation and/or have marked cancer-related symptoms (ECOG > 2). The prognosis of this group is poor and these patients require supportive care. Measurements of α-fetoprotein (AFP) will not affect treatment strategy and might be useful only in clinical trials.1720

Diagnosis of cholangiocarcinoma

Cholangiocarcinoma is divided into three subtypes, based on its anatomical location: intrahepatic cholangiocarcinoma (iCC), peripheral cholangiocarcinoma (pCC) and ductal cholangiocarcinoma (dCC) (outside the liver).

Intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is further divided, based on phenotype, into mass-forming, periductal infiltrating and intraductal growth types.22 The clinical symptoms of iCC are non-specific, and include abdominal pain, cachexia, fatigue, night sweats and malaise.23 iCC frequently presents as an intrahepatic mass on imaging modalities such as CT and MRI. The use of contrast enhancement improves the sensitivity of imaging-based detection of iCC. These tumours typically have progressive uptake of contrast agents during the venous phase, in contrast to HCC.24 CT and MRI are interchangeable in the evaluation of tumour size and detection of satellite lesions; however, CT is better for assessment of vascular encasement, identification of extrahepatic metastasis and determination of resectability.25,26

The tumour marker carbohydrate antigen 19-9 (CA 19-9) can aid in the diagnosis, but it detects iCC with only 62% sensitivity and 63% specificity.27 Moreover, increased levels of CA 19-9 can be found in cholestasis due to choledocholithiasis or bacterial cholangitis. Nevertheless, very high CA 19-9 levels (> 1000 U/ml) have been associated with metastatic iCC, so this marker might be used in staging rather than diagnosis.28 A definitive diagnosis of iCC requires biopsy of the mass.

The treatment of choice for iCC is surgical resection if the patients have potentially resectable tumours and are appropriate surgical candidates. Liver transplantation as a curative option for iCC is very controversial because the recurrence rate within 5 years after transplantation is 70%. However, patients with very small iCCs < 2 cm in the context of liver cirrhosis do well undergoing liver transplantation. In patients with non-resectable iCC, locoregional therapies, such as TACE and radiofrequency ablation, are therapeutic options.29 For advanced-stage iCC, systemic chemotherapy, as discussed later, is the standard of care.30

Peripheral cholangiocarcinoma

Peripheral cholangiocarcinoma can present with exophytic or intraductal macroscopic growth patterns. The exophytic or mass-forming type can be of a nodular or periductal (the most common subtype) structure.31 As in iCC cases, patients with pCC can show only non-specific symptoms; however, they often present with symptoms of biliary obstruction with jaundice and, less commonly, cholangitis.25 In addition, hypertrophy of the unaffected lobe can be observed (hypertrophy–atrophy complex).23 Laboratory parameters affected by pCC are parameters of cholestasis, such as alkaline phosphatase and bilirubin, but they do not provide specific information. For unknown reasons, serum CA19-9 levels are less specific in the diagnosis of pCC than of iCC. To exclude immunoglobulin G4 (IgG4)-associated disease of the bile ducts, which can present in a similar clinical manner, IgG4 levels should be measured.23

Imaging for pCC can be performed with MRI, CT, magnetic resonance cholangiopancreatography, endoscopic cholangiography (ERC), endoscopic cholangioscopy and endoscopic ultrasound. Of these methods, MRI plus magnetic resonance cholangiopancreatography is the preferred imaging modality because it has a high accuracy, up to 95% in the assessment of resectability and tumour extent.23 Additionally, endoscopic ultrasound can be helpful in evaluation of the presence of regional lymphadenopathy, and fine-needle biopsy can aid in detecting omental metastasis. However, fine-needle biopsy should not be performed on the primary tumour to avoid dissemination of the tumour.32 ERC is a diagnostic and a therapeutic approach. It can be used to assess and sample the biliary system via brush cytology or biopsy, and can be therapeutically applied for dilatation and stent placement in case of biliary obstruction.

The Bismuth–Corlette classification is based on the anatomical location of CC and describes the expansion along the biliary tree.23 If possible, resection or transplantation is chosen in a curative approach. For patients who are not candidates for surgical therapy, systemic chemotherapy is recommended, as described later.

Ductal cholangiocarcinoma

The precursor lesions of dCC are intraductal papillary neoplasm and biliary intraepithelial neoplasia.33 The clinical complaints are similar to pCC, with painless jaundice and elevation of cholestasis parameters in the laboratory analysis. dCCs are grouped as extrahepatic CCs, although they are similar to pCC with respect to their pathogenesis and therapeutic options. Therefore, the diagnostic methods and the therapeutic approaches for dCC are generally identical to those for pCC.

Systemic therapy of hepatocellular carcinoma

In HCC, conventional systemic chemotherapy shows no significant survival advantages. Several phase III trials testing doxorubicin monotherapy, PIAF regimen (cisplatin, interferon α-2b, doxorubicin and fluorouracil) or FOLFOX4 regimen (fluorouracil, leucovorin and oxaliplatin) had no beneficial effect in the treatment of HCC and presented in some instances with significant toxicity.3436 Also, with anti-oestrogen therapies and vitamin D derivates, randomized studies failed.16

In 2007, a phase III Study of Sorafenib in Patients with Advanced Hepatocellular Carcinoma (SHARP) trial demonstrated survival benefits for the multi-protein kinase inhibitor sorafenib versus placebo [10.7 months vs. 7.9 months, hazard ratio (HR) 0.69], which was a breakthrough in therapy for HCC.37 A similar beneficial outcome was observed in another phase III trial in Asian patients mostly with hepatitis B-related HCC, which was conducted at the same time.38 Sorafenib is recommended in patients with good liver function (Child–Pugh A) and advanced tumour burden (BCLC C), or with tumours at intermediate stage (BCLC B) progressing on locoregional therapies. Treatment is associated with manageable side effects such as diarrhoea, hand–foot skin reactions, fatigue and/or hypertension. Unfortunately, no predictive biomarkers of responsiveness to sorafenib exist. The antitumour effect of sorafenib results from targeting cancer cells and their microenvironment by blocking up to 40 multi-protein kinases, including angiogenic [e.g. vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor beta (PDGFRB)] and proliferative drivers (e.g. RAF1, BRAF and KIT).

Several phase II trials have failed in challenging sorafenib in first-line or placebo in second-line regimens. These therapies include sunitinib (multi-targeted tyrosine kinase inhibitor of VEGFR and PDGFR, and KIT), brivanib [selective dual inhibitor of VEGFR and fibroblast growth factor receptor (FGFR) tyrosine kinases], ramucirumab (VEGFR2 inhibitor), linifanib (VEGFR and PDGFR inhibitor), erlotinib [epidermal growth factor receptor (EGFR) inhibitor] and everolimus (mechanistic target of rapamycin inhibitor). The reasons for these negative results include marginal anti-tumoral potency, liver toxicity, flaws in trial design and lack of biomarker-based enrichment.39 These negative trials underline the stable benefits of sorafenib in first-line therapy. It is estimated that only half of the patients progressing to sorafenib will be considered for second-line therapies. Their median survival is 7–8 months.

Recently, a phase III trial comparing regorafenib, another multi-kinase inhibitor targeting similar kinases to sorafenib, with placebo in patients intolerant of sorafenib or progressing under sorafenib treatment, demonstrated a survival benefit (10.6 months vs. 7.8 months, HR 0.62).40 Improved survival was reported in all subgroups. These results suggest that regorafenib is a potent anticancer agent with a substantial clinical benefit and it will be adopted by clinical guidelines as the standard of care for patients destined for second-line therapy. The prevalence of toxicity (fatigue, hand–foot syndrome, hypertension) was higher than reported for sorafenib. Adverse events leading to treatment discontinuation were observed in 10% of cases.

With only two drugs as effective systemic treatments for this prevalent tumour entity, the need for novel therapies is high. Most of the substances currently under investigation in phase II trials are immune checkpoint inhibitors, MET inhibitors and anti-angiogenic agents. The following sections describe the substances in detail.

Immune checkpoint inhibitors

Several inhibitory pathways in the immune system are connected to modulate the duration and amplitude of immune responses. Immune checkpoint inhibitors have shown substantial activity in patients with advanced solid malignant tumour entities, such as non-small-cell lung cancer and melanoma. A pilot study with the CTLA-4 monoclonal antibody tremelimumab presented a median survival of 8.2 months in patients with advanced HCC.41 However, PD-1-specific inhibitory antibodies (nivolumab and pembrolizumab) seem to be better tolerated than anti-CTLA agents. A recent phase I–II trial with nivolumab in patients with advanced HCC has demonstrated long-term rates of up to 16% objective responses.42 Ongoing phase III trials are further investigating nivolumab (NCT02576509) and pembrolizumab (NCT02702401) in first- and second-line settings.

MET inhibitors

It is assumed that the MET signalling pathway is activated in only 50% of patients with advanced HCC. The tubulin inhibitor tivantinib has been shown to increase time to progression in a randomized, placebo-controlled phase II trial in a subgroup of patients with advanced HCC and high expression of MET.43 These findings have initiated two biomarker-enriched phase III trials investigating the efficacy of tivantinib in second-line therapy (NCT01755767, NCT02029157). There are several studies providing evidence that the mechanism of action of tivantinib is related to microtubule dynamics independently of MET. Another drug, cabozantinib, inhibits both MET and VEGFR2. It is currently under investigation in a phase III study in the second-line setting (NCT01908426).

Anti-angiogenic agents

Novel drugs enhancing and/or mimicking the mechanism of action of sorafenib and regorafenib are currently under investigation. The multi-kinase inhibitor lenvatinib, blocking VEGFR1–3, platelet-derived growth factor receptor alpha, FGFR1–4, RET and KIT, has been tested in a phase II trial. Thirty seven per cent of the patients with intermediate and advanced HCC showed partial response according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) and a median overall survival of 18.7 months.44 These results are being investigated in comparison with sorafenib in an ongoing phase III trial (NCT01761266). Moreover, two selective VEGFR2 inhibitors (ramucirumab and apatinib) are being evaluated in the second-line setting. Ramucirumab is being investigated in patients with an AFP level > 400 ng/ml based on subgroup analysis data (NCT02435433) and apatinib is undergoing investigation for all candidates (NCT02329860).

Systemic therapy of cholangiocarcinoma

Many patients with CC present with non-resectable intra- and extrahepatic metastases or advanced tumour stage at diagnosis.4548 The median survival of untreated patients with non-resectable CC is only about 3–6 months.49 Therefore, most patients are undergoing palliative systemic chemotherapy.

Adjuvant setting

The role of adjuvant chemotherapy or chemoradiation after complete resection is not definite yet. Unfortunately, local recurrence, especially of extrahepatic CC, is common. Thus, European (European Society for Medical Oncology) and US (National Comprehensive Cancer Network) guidelines mention adjuvant therapy as an option.50 In case of R0 resection without lymph node involvement, the mentioned guidelines recommend adjuvant chemotherapy with gemcitabine or 5-fluorouracil (5-FU). Patients with R1 resection or positive lymph nodes could be treated with chemoradiotherapy. A recent phase III trial investigated sequential chemotherapy with gemcitabine and capecitabine for 12 weeks followed by chemoradiotherapy, and showed promising results.51 Currently, the role of adjuvant chemotherapy is undergoing further evaluation in phase III trials [Capecitabine or Observation After Surgery in Treating Patients with Biliary Tract Cancer (BILCAP) (NCT00363584), Gemcitabine Hydrochloride and Oxaliplatin or Observation in Treating Patients with Biliary Tract Cancer that has Been Removed by Surgery (PRODIGE-12) (NCT01313377), Adjuvant Chemotherapy with Gemcitabine and Cisplatin Compared to Observation After Curative Intent Resection of Biliary Tract Cancer (ACTICCA-1) (NCT02170090)] in European countries.

Palliative chemotherapy

Systemic chemotherapy using a combination of 5-FU and leucovorin, with or without etoposide, has been shown to improve survival.52 Phase II studies with 5-FU have demonstrated response rates from 10% to 34%.53,54 On the other hand, the combination of 5-FU, capecitabine and platinum (cisplatin/oxaliplatin) has not improved response rates significantly.5559 Recently, various chemotherapeutic drugs have been investigated; response to gemcitabine monotherapy ranged between 17% and 36%.60,61 Gemcitabine in combination with capecitabine induced a response in 25% of patients,6266 and a dual approach with oxaliplatin and gemcitabine resulted in a response rate of 50%.6769 Since 2010, combination therapy with gemcitabine and cisplatin has been recommended as standard first-line chemotherapy for non-resectable CC.30 In the ABC-02 trial median survival was significantly longer in the combination therapy group than in the gemcitabine monotherapy group (11.7 months vs. 8.1 months).30 However, patients with reduced renal function can also be treated with oxaliplatin. In elderly patients or patients with impaired ECOG performance status, monotherapy with gemcitabine is usually recommended.

Second-line chemotherapy

There are currently no data providing clear evidence of any benefit of second-line chemotherapies. Median survival in a Japanese phase II trial as well as in the larger ABC-02 phase III trial with gemcitabine and cisplatin was 11.7 and 11.2 months, respectively.70 Interestingly, in the Japanese trial, 75% of patients received a second-line therapy, compared with only 15% of patients in the ABC-02 trial. A systematic review analysed data from more than 750 patients with CC. The median progression-free survival (PFS) and overall survival (OS) were 3.2 and 7.2 months, respectively, with second-line therapies. The response rate and rate of tumour control were low, at 7.7% and 48%, respectively.71 A large retrospective analysis compared various second-line regimens with best supportive care and showed a survival benefit of such regimens.72

Investigational targets and drugs

Several trials of dendritic cell-based vaccines, peptide-based vaccines and antibodies have been initiated. Immunotherapeutic approaches can be divided into passive and active therapies.7394 Passive immunotherapies include EGFR and VEGFR antibodies. EGFR expression is observed in iCC, but overexpression of EGFR occurs in only 5–32% of patients. KRAS mutations are detected less often in CC than in other other cancer entities.73,74 In one study, the EGFR antibody cetuximab in combination with gemcitabine and oxaliplatin (GEMOX) was associated with a response rate of 63%.75 Another trial failed to demonstrate any beneficial effect of cetuximab and GEMOX.76 It is possible that KRAS mutations are responsible for resistance to EGFR antibodies. An Asian phase II study did not demonstrate a benefit of EGFR antibody therapy in KRAS wildtype.77 Combination therapy with GEMOX and the tyrosine kinase inhibitor erlotinib had no effect in patients with CC.78 Erlotinib was also investigated in a dual approach with bevacizumab, a VEGFR antibody with a tolerable toxicity profile, and a response rate of 12% was reported.79 In this study the PFS was 4.4 months and the OS 9.9 months.79 In contrast with HCC, the multi-kinase inhibitor sorafenib alone as well as in combination with erlotinib or gemcitabine did not demonstrate any significant antitumour effect on CC.8085 Another tyrosine kinase inhibitor, cediranib, which was investigated in combination with gemcitabine and cisplatin in a phase II trial, did not demonstrate an advantage over gemcitabine and cisplatin.86 Nevertheless, the multi-kinase inhibitor sunitinib showed a PFS of 1.7 months with a response rate of 8.9% in second-line therapy.87 The multi-targeted kinase inhibitor vandetanib targeting EGFR and VEGFR, in combination with gemcitabine, resulted in no survival benefit.88 Recently, a response rate of 12% was achieved with the MEK1/2 inhibitor selumetinib, with PFS of 3.7 months and OS of 9.8 months.89 The oral pro-drug of 5-FU (S1) in combination with gemcitabine and cisplatin produced a response rate of 20%, but this is not different from the response rates to monotherapies.90,91

The combination of the c-MET inhibitor tivantinib with gemcitabine was associated with only low response rates,92 and in combination with cabozantinib, another c-MET inhibitor, resulted in no objective response in CC.93

As an active immunotherapeutic approach, checkpoint inhibitors could be an effective treatment option, because PD-L1 is expressed in the majority of iCC and is associated with decreased survival.94 However, the role of checkpoint inhibitors in the treatment of CC has not been investigated fully until now. Therefore, immunotherapeutic approaches for CC are not yet included into standard of care.



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