Systemic therapy for unresectable, mixed hepatocellular-cholangiocarcinoma: treatment of a rare malignancy
Original Article

Systemic therapy for unresectable, mixed hepatocellular-cholangiocarcinoma: treatment of a rare malignancy

Jane E. Rogers1, Ryan M. Bolonesi2, Asif Rashid3, Khaled M. Elsayes4, Mohamed G. Elbanan4, Lindsey Law5, Ahmed Kaseb5, Rachna T. Shroff5

1Pharmacy Clinical Programs, U.T. M.D. Anderson Cancer Center, Houston, TX 77030, USA; 2Medical Science Liaison, Octapharma USA Inc., New York, USA; 3Department of Pathology, 4Department of Diagnostic Radiology, 5Department of Gastrointestinal Medical Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX 77030, USA

Contributions: (I) Conception and design: All authors; (II) Administrative support: RT Shroff, A Kaseb; (III) Provision of study materials or patients: JE Rogers, RM Bolonesi, A Rashid, KM Elsayes, MG Elbanan, L Law; (IV) Collection and assembly of data: JE Rogers, RM Bolonesi, L Law, A Kaseb, RT Shroff; (V) Data analysis and interpretation: JE Rogers, RM Bolonesi, A Kaseb, RT Shroff; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Jane E. Rogers, Pharm. D, BCOP. Pharmacy Clinical Programs, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Email:

Background: Combined hepatocellular-cholangiocarcinoma (HCC-CC) has a reported incidence of less than 5% of primary hepatic malignancies. The treatment approach to this malignancy is undefined. Our objective of this case series is to provide some insight into chemotherapy and/or targeted therapy in this setting.

Methods: Pathologic and radiographic review confirmed seven combined HCC-CC patients during a 5-year time frame [2009–2014]. Data points were demographics, chemotherapy and/or targeted therapy given in the first and second-line setting, localized treatment if given, first radiographic result, progression-free survival (PFS), and overall survival (OS).

Results: Seven patients were identified. Front-line treatment showed a median PFS of 3.4 months. Total median OS was 8.3 months. Regimens given included gemcitabine alone +/− bevacizumab, gemcitabine + platinum (GP) +/− bevacizumab, and sorafenib. Front-line treatment with these regimens showed progressive disease in 71% (5 patients) on first radiographic scan with all patients who received sorafenib front-line progressing at that restaging. Disease-control (complete response + partial response + stable disease) was seen in 29% of patients (2 patients) with 1 patient receiving GP and 1 patient receiving gemcitabine + bevacizumab. Of note, 2 patients that received GP +/− bevacizumab in the second-line setting had disease control on first radiographic scan.

Conclusions: Our retrospective review speaks to the rarity of this malignancy and challenges that are associated with its diagnosis and treatment. GP +/− bevacizumab showed disease control in first or second-line treatment in 3 patients. Treatment with this regimen in this rare malignancy subgroup warrants further investigation.

Keywords: Carcinoma; hepatocellular; cholangiocarcinoma (CC); antineoplastic agents

Submitted Dec 14, 2016. Accepted for publication Feb 10, 2017.

doi: 10.21037/jgo.2017.03.03


Combined hepatocellular-cholangiocarcinoma (HCC-CC) represents a small percentage (0.4–4.7%) of primary hepatic malignancies (1-3). Given the rarity of this disease, there are no clear treatment guidelines for advanced HCC-CC. The World Health Organization defines this malignancy as a tumor unequivocally admixed with both hepatocellular and CC (3). Surgical resection is the mainstay curative option; however, higher recurrence rates and shorter disease-free survival in HCC-CC have been reported compared to each separate malignancy (2,4-6). Liver transplantation appears to have poorer survival for combined HCC-CC in relation to HCC alone, although results are conflicting (2,7,8). Systemic therapy experience is limited to small case reports with regimens including sorafenib, doxorubicin + cisplatin, gemcitabine + cisplatin, fluorouracil monotherapy, and fluorouracil + oxaliplatin (9,10). With our case series, we aim to add to the existing knowledge with our institutional experience.


Our hepatobiliary database was reviewed during a 5-year time frame [2009–2014] for patients treated as mixed HCC-CC based on patient presentation, radiologic review, and multidisciplinary discussion. Of the 27 patients initially identified, seven were found to be independently confirmed by radiographic review as mixed HCC-CC and pathologically confirmed independently as either having a mixed HCC-CC diagnosis or having adenocarcinoma with both HCC and CC features. Pathologic features of these seven cases are listed in detail in Table 1. Similar to other reports, immunohistochemical (IHC) features identified for HCC were hepatocyte paraffin 1 monoclonal antibody (HepPar-1), polyclonal carcinoembryonic antigen (pCEA), and CD10 with CC features of cytokeratin 7 (CK7), cytokeratin 19 (CK19), MOC31 (1,2).

Table 1
Table 1 Pathology
Full table

Data collection points included baseline demographics (age, gender, race, birth geographic region), relevant medical history such as hepatitis B or C (HBV or HCV) or cirrhosis, diagnosis date, carbohydrate antigen 19-9 (CA19-9) at baseline; alpha-fetoprotein (AFP) at baseline; first-line therapy, localized therapy if utilized, second-line therapy, progression date, and death date or last follow-up. Outcomes reported were disease control rate first scan result on first-line or second-line treatment, progression-free survival (PFS), and overall survival (OS). Response was determined at first radiographic reimaging and was classified as disease-control (complete response + partial response + stable disease) or progression. Progression included patients who discontinued therapy due to toxicity. PFS was defined from the start of therapy to radiographic progression/toxicity withdraw or last follow-up, and OS was defined from the diagnosis date to date of death or last follow-up. Descriptive statistics were used with continuous variables described using median or mean, and range with categorical data summarized using frequencies and percentages.


Individual patient details and outcomes are summarized in Tables 2 and 3, respectively. Mean age was 53-year-old (range, 34–64 years) with most (57%) patients being female. A total of 57% had HBV or HCV with 42% having cirrhosis. When reported, CA19-9 and AFP were elevated at baseline in most cases. Regimens used in first-line were sorafenib (3 patients), gemcitabine + bevacizumab (2 patients), gemcitabine alone (1 patient), and gemcitabine plus cisplatin (1 patient). Seventy-one percent had progressive disease at first reimaging. Disease control was seen in two patients; one patient received gemcitabine plus platinum and one patient received gemcitabine + bevacizumab. All first-line sorafenib patients progressed at first radiographic evaluation. Front-line treatment only showed a median PFS of 3.4 months (range, 2.3–7 months).

Table 2
Table 2 Demographics
Full table
Table 3
Table 3 First and second-line treatment
Full table

Three patients went on to receive second-line therapy after progression and showed a median PFS of 6.5 months (range, 3.5–8.5 months). Regimens given second-line were gemcitabine + oxaliplatin (1 patient), gemcitabine + oxaliplatin + bevacizumab (1 patient), and fluorouracil + leucovorin + irinotecan (FOLFIRI) (1 patient). The two patients who receive gemcitabine + oxaliplatin with or without bevacizumab had disease control on first-scan. The patient that received FOLFIRI in the second-line had progression on first-scan. Of note, all patients who received a platinum (cisplatin or oxaliplatin) in combination with gemcitabine during their disease showed disease control with this regimen regardless of timing of therapy. These three patients had an impressive median OS of 17.5 months. The median OS of the entire cohort was 8.3 months (range, 3.3–32.8 months). Of note, our patient that had a prolonged survival (32.8 months) received localized intensity-modulated radiation therapy (IMRT) after first-line disease control with gemcitabine + cisplatin.


Our case review confirms the rarity of combined HCC-CC and the issues that surround its diagnosis with only 7 out of 27 patients having both radiographic and pathologically confirmation after initial multidisciplinary review. Baseline clinical characteristics for combined HCC-CC have been conflicting and appear dependent on the geographic location (1,2). Our case series showed overlapping characteristics for both individual malignancies: elevation in CA19-9, AFP, cirrhosis, and hepatitis history; however our limited size and diverse patient geographic distribution makes it difficult to determine which are more prominent for this mixed tumor type.

Similar to the poor outcomes seen in HCC-CC with surgical resection and transplantation, systemic therapy appears to only minimally impact survival (1,2,5-8). Our case series demonstrates a median PFS of 3.4 months with front-line therapy and a median OS of 8.3 months. Sorafenib, FDA approved for front-line treatment of advanced HCC, has a median PFS and OS of 5.5 and 10.7 months, respectively (11). Additionally, in CC, gemcitabine plus cisplatin in the front-line setting has a median PFS of 8 months and median OS of 11.7 months based on the phase III ABC-02 study (12). Our case series indicated poorer outcomes when HCC-CC was treated similarly to these two separate malignancies.

Rare malignancies such as HCC-CC often rely on case reports, anecdotal experience, and extrapolating from more common malignancies in order to provide a guide for rational treatment decision-making. Although our case series carries limitations, gemcitabine + platinum (GP) with or without bevacizumab showed disease control in all patients (3 patients) that received this treatment in the first or second-line setting. Patients with advanced combined HCC-CC disease that are deemed unresectable need viable treatment options. Our small case series suggests a regimen that may have efficacy in this difficult disease and warrants further investigation.




Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The study was approved by Institutional Review Board of U.T. M.D. Anderson Cancer Center (PA11-1209) and a waiver of consent was granted due to patients lost to follow-up, no longer at the institution, or expired.


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Cite this article as: Rogers JE, Bolonesi RM, Rashid A, Elsayes KM, Elbanan MG, Law L, Kaseb A, Shroff RT. Systemic therapy for unresectable, mixed hepatocellular-cholangiocarcinoma: treatment of a rare malignancy. J Gastrointest Oncol 2017;8(2):347-351. doi: 10.21037/jgo.2017.03.03