- Case report
- Open Access
Personalized prescription of tyrosine kinase inhibitors in unresectable metastatic cholangiocarcinoma
© The Author(s) 2018
- Received: 5 April 2018
- Accepted: 28 August 2018
- Published: 6 September 2018
Cholangiocarcinoma is an aggressive tumor with poor prognosis. Most of the cases are not available for surgery at the stage of the diagnosis and the best clinical practice chemotherapy results in about 12-month median survival. Several tyrosine kinase inhibitors (TKIs) are currently under investigation as an alternative treatment option for cholangiocarcinoma. Thus, the report of personalized selection of effective inhibitor and case outcome are of clinical interest.
Here we report a case of aggressive metastatic cholangiocarcinoma (MCC) in 72-year-old man, sequentially treated with two targeted chemotherapies. Initially disease quickly progressed during best clinical practice care (gemcitabine in combination with cisplatin or capecitabine), which was accompanied by significant decrease of life quality. Monotherapy with TKI sorafenib was prescribed to the patient, which resulted in stabilization of tumor growth and elimination of pain. The choice of the inhibitor was made based on high-throughput screening of gene expression in the patient’s tumor biopsy, utilized by Oncobox platform to build a personalized rating of potentially effective target therapies. However, time to progression after start of sorafenib administration did not exceed 6 months and the regimen was changed to monotherapy with Pazopanib, another TKI predicted to be effective for this patient according to the same molecular test. It resulted in disease progression according to RECIST with simultaneous elimination of sorafenib side effects such as rash and hand-foot syndrome. After 2 years from the diagnosis of MCC the patient was alive and physically active, which is substantially longer than median survival for standard therapy.
This case evidences that sequential personalized prescription of different TKIs may show promising efficacy in terms of survival and quality of life in MCC.
Cholangiocarcinoma (CCA) is a bile duct cancer that is mainly characterized by its late diagnosis and fatal outcome . CCA accounts about 3% of all gastrointestinal tumors and is second most common liver tumor after hepatocellular carcinoma . Overall 5-year survival rate is lower than 10% , while overall 1-year survival of patients at stage 4 is only 5% . Treatment options for CCA include surgery and chemotherapy, but only about 30% of patients are available for surgery .
Standard care chemotherapy treatment for CCA is Gemcitabine, which is administered alone or in combination with cytotoxic agents such as Cisplatin. The response rate ranges from 8 to 60%, depending on the cohort of patients . Nevertheless, these patients have a poor prognosis with a median survival of 6–12 months . Thus, there is a need for improvement of general CCA treatment options.
Currently there are several ongoing clinical trials utilizing different approaches for target therapy in CCA. Chimeric antigen receptor-modified T (CART) cell-based therapy was recently attempted in CCA . Authors reported 8.5- and 4.5-month partial response to CART-EGFR and CART-CD133 therapy respectively. Nevertheless, several associated side effects were discovered, from which epidermal damage was the most prominent. Indeed, so far CART showed limited efficiency in solid tumor and further studies are still required for successful clinical applications .
Results of published case reports and clinical trials for TKI usage in CCA
Number of patients
Duration of treatment
400 mg PO bid
4 months with later switch to oxaliplatin and gemcitabine; 6 month for the time of report
Transient disease stabilization; decrease of tumor markers CA 125, CA 19-9, CA 27.29
Maculopapular rash, hair thinning, grade 3 thrombocytopenia (disappeared after 1-week discontinuation), hypertension, facial rush
400 mg PO bid
2 years for the time of report
Stable disease with time-to-progression 5.7 month; decrease of tumor marker CA 19-9; decrease of bilirubin level and increase of liver synthesis parameters
Mild diarrhea, fatigue and skin toxicity; no dose reduction or interruption were made
400 mg PO bid; 7 days cessation after 1 year and dose reduction to 200 mg
4 years for the time of report
Stable disease; decrease of bilirubin level
Mild diarrhea, desquamation rush. Grade 1 hand-foot syndrome, mild thrombocytopenia (required 7 days cessation)
400 mg PO bid
1.8-month median duration
Median time to progression 5.6 month; median overall survival 5.7 month; disease control rate at 3 months 15.9%
Mild diarrhea, fatigue, hand-foot syndrome
400 mg PO bid
3.2-month median duration
Median time to progression 3.2 month; median overall survival 5.7 month; disease control rate at 3 months 73.3%
Skin rush in 5 patients grade 3 hand-foot syndrome in 1 patient
400 mg PO bid
2-month median duration
Disease control rate detected according suggested scheme 0%; median overall survival 9 month; median progression free survival 3 month
Grades 3 and 4 toxicities in 20 patients included: thrombosis/embolism, hypertension, fatigue, bilirubin evaluation, hand-foot syndrome
400 mg PO bid
From 1 to 12 months
Disease control rate at 3 months 32.6%; median overall survival 4.4 month; median progression free survival 2.3 month
Hand-foot syndrome, skin rush, diarrhea, fatigue and thrombocytopenia
Pazopanib 800 mg qd
Trametinib 2 mg qd
3-month median duration
Median overall survival 6.4 month; disease control rate detected according suggested scheme 75%; median progression free survival 3.6 month
Hypertension, fatigue, rash, diarrhea, nausea/vomiting, thrombocytopenia
In this report we describe a case of advanced metastatic CCA subsequently treated with TKI agents Sorafenib and Pazopanib, which resulted in 2-year survival period after initial diagnosis. Inhibitors were selected based on high throughput gene expression and molecular pathway activation analysis of the patient’s tumor biopsy, thus providing a personalized approach.
We profiled gene expression in formalin-fixed, paraffin-embedded (FFPE) patient’s tumor biopsy sample, obtained at the time of the first CCA diagnosis. Briefly total RNA was extracted using Ambion’s RecoverAll™ Total Nucleic Acid Isolation. Complete Whole Transcriptome Amplification WTA2 Kit (Sigma) was used for reverse transcription and library amplification. Hybridization was performed according to CustomArray ElectraSense™ Hybridization and Detection protocol. Hybridization efficiency was detected electrochemically using CustomArray ElectraSense™ Detection Kit and ElectraSense™ 4X2K/12K Reader.
Rating of target drugs provided by Oncobox test
The treatment regimen was next changed to Pazopanib, another TKI drug recommended based on the Oncobox rating. Sunitinib was not chosen because we attempted to eliminate the hand-foot syndrome, which occurred during Sorafenib administration. In the previous studies, Sunitinib treatment of CCA patients induced hand-foot syndrome in 43% of patients . On the other hand, recent clinical trial of Pazopanib in combination with Trametinib in CCA did not report hand-foot syndrome as a side effect . Pazopanib administration (800 mg daily) started since January 2017. The control MRI in July 2017 revealed progression in the lung nodes and 20% increase in sum of diameters of target lesions, which is a borderline between stabilization and progression according to RECIST (Fig. 2e). However, the change of treatment regimen resulted in elimination of Sorafenib side effects and general improvement of life quality. In addition, start of Pazopanib treatment coincided with a start of a trend towards decrease of serum GGT level (Fig. 3). As for October 2017 (2 years after initial diagnosis), the patient was alive and physically active, with Karnofsky scale 80%. Our patient passed away due to the liver failure in November 2017.
Our case report describes sequential use of TKI inhibitors Sorafenib and Pazopanib, which were selected based on personalized approach, for treating advanced CCA in patient who did not respond to standard therapy. Selected treatment improved patient life quality and survival period even though did not result in a response according to RECIST classification.
Available data on TKI usage in CCA patients underline that despite the potential benefit of such treatment not all patients respond equally. Therefore, it remains a clinical challenge to promptly identify potential responders. Selection of CCA patients, who may benefit from TKI treatment may be based on the molecular characteristics of tumor specimens.
Therefore, to support the usage of TKI in the current clinical case and select the most effective inhibitor we performed a molecular profile of patient tumor biopsy. Total RNA was extracted from FFPE tissue sample, obtained at the stage of the diagnosis, and gene expression was measured using microarray hybridization. Gene expression data was next used for calculating pathway activation scores and for building rating of target drugs using bioinformatical software Oncobox.
Performed analysis demonstrated that Ras and ERK signaling pathways were highly activated in the patient’s pathological tissue (Additional file 1: Table S1). These molecular pathways are implicated in various process linked with tumorigenesis such as cell proliferation, differentiation, survival and apoptosis . Ras pathway activates ERK pathway, but also is tightly connected with stress response, cell motility and cytoskeleton rearrangements . Normally both, ERK and Ras pathways are activated by binding of extracellular growth factors (like EGFR) to their receptor tyrosine kinases (RTKs). TKIs are capable of targeting RTKs, thus inhibiting cell proliferation and survival [30, 31].
Based on the observed molecular phenotype several TKIs were predicted to be effective in the current clinical case (Table 2). Considering both results of the bioinformatical analysis and available literature data on TKI efficiency in CCA, Sorafenib and then Pazopanib were prescribed to our patient. These drugs overlap in blocking FLT1, FLT4, KDR, C-Kit proto-oncogene and platelet derived growth factor receptor beta (PDGFRB). In addition, Pazopanib targets platelet derived growth factor receptor alpha (PDGFRA), while Sorafenib—B-Raf, C-Raf and ret proto-oncogenes, fibroblast growth factor receptor 1 (FGFR1) and FLT3. Both Pazopanib and Sorafenib are approved for treating advanced renal cell carcinoma (RCC); in addition, Sorafenib is approved for treatment of patients with unresectable hepatocellular carcinoma (HCC).
Thus, the performed analysis supported choice of treatment and predicted high chances of TKI efficiency for our patient. Even though the best clinical outcome across this case was progressive disease (according to RECIST), TKIs were beneficial for palliative care of metastatic CCA patient due to improvement of clinical parameters such as quality of life and survival. In addition, start of treatment with TKIs coincided with a trend towards decrease of serum GGT level.
The success of the most clinical trials of TKI in CCA was evaluated based on the time to progression or progression free survival and, therefore, disease progression was considered as an unsuccessful outcome and resulted in termination of treatment. In this case we report life quality improvement and prolonged survival with TKI therapy on the background of disease progression. This may point to the modest antitumor activity of TKIs in some patients, as also suggested by El-Khoueiry et al. . Such activity, even if not capable to trigger the response, could potentially be sufficient for slowing down disease progression and, thus, life quality improvement.
EP, MB, DA, AK, PS collected and interpreted patient data. EP and MB were involved in clinical management. MSu performed molecular analyses. MSu, MSe, AA, EA and EP wrote this manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Data deposition and access
Gene expression data derived from the patient’s tumor tissue were deposited at the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) under the Accession Number GSE107233.
Ethics approval and consent to participate
The patient provided consent for gene expression analysis of his sample and oral consent for the publication of this article. Gene expression profiling was approved by Institutional Review Board (IRB) at Clinical Center Vitamed, Moscow, Russia, according to the Declaration of Helsinki principles.
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- Bergquist A, von Seth E. Epidemiology of cholangiocarcinoma. Best Pract Res Clin Gastroenterol. 2015;29(2):221–32.View ArticlePubMedGoogle Scholar
- Rizvi S, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145(6):1215–29.View ArticlePubMedGoogle Scholar
- Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas. Gastroenterology. 2009;136(4):1134–44.View ArticlePubMedGoogle Scholar
- Yusoff AR, et al. Survival analysis of cholangiocarcinoma: a 10-year experience in Malaysia. World J Gastroenterol. 2012;18(5):458–65.View ArticlePubMedPubMed CentralGoogle Scholar
- Khan SA, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61(12):1657–69.View ArticlePubMedGoogle Scholar
- Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann Oncol. 2005;16(Suppl 2):93–6.View ArticleGoogle Scholar
- Valle J, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81.View ArticlePubMedGoogle Scholar
- Feng KC, et al. Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma. J Hematol Oncol. 2017;10(1):4.View ArticlePubMedPubMed CentralGoogle Scholar
- Castellarin M, et al. Driving cars to the clinic for solid tumors. Gene Ther. 2018;25:165–75.View ArticlePubMedGoogle Scholar
- Ahn DH, Bekaii-Saab T. Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications. J Gastrointest Oncol. 2017;8(2):293–301.View ArticlePubMedPubMed CentralGoogle Scholar
- Chakunta HR, et al. Cholangiocarcinoma: treatment with sorafenib extended life expectancy to greater than 4 years. J Gastrointest Oncol. 2013;4(4):E30–2.PubMedPubMed CentralGoogle Scholar
- Pinter M, et al. Sorafenib in unresectable intrahepatic cholangiocellular carcinoma: a case report. Wien Klin Wochenschr. 2011;123(1–2):61–4.View ArticlePubMedGoogle Scholar
- LaRocca RV, et al. Effective palliation of advanced cholangiocarcinoma with sorafenib: a two-patient case report. J Gastrointest Cancer. 2007;38(2–4):154–6.View ArticlePubMedGoogle Scholar
- Luo X, et al. Effectiveness and safety of sorafenib in the treatment of unresectable and advanced intrahepatic cholangiocarcinoma: a pilot study. Oncotarget. 2017;8(10):17246–57.View ArticlePubMedGoogle Scholar
- Pan TT, et al. A single-center experience of sorafenib monotherapy in patients with advanced intrahepatic cholangiocarcinoma. Oncol Lett. 2017;13(5):2957–64.View ArticlePubMedPubMed CentralGoogle Scholar
- El-Khoueiry AB, et al. SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs. 2012;30(4):1646–51.View ArticlePubMedGoogle Scholar
- Bengala C, et al. Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial. Br J Cancer. 2010;102(1):68–72.View ArticlePubMedGoogle Scholar
- Shroff RT, et al. The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Br J Cancer. 2017;116(11):1402–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Andersen JB, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology. 2012;142(4):1021–31.View ArticlePubMedGoogle Scholar
- Guo J, et al. Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma: asian versus non-Asian subgroup analysis of the COMPARZ trial. J Hematol Oncol. 2018;11(1):69.View ArticlePubMedPubMed CentralGoogle Scholar
- Yin X, et al. Elevation of serum gamma-glutamyltransferase as a predictor of aggressive tumor behaviors and unfavorable prognosis in patients with intrahepatic cholangiocarcinoma: analysis of a large monocenter study. Eur J Gastroenterol Hepatol. 2013;25(12):1408–14.View ArticlePubMedGoogle Scholar
- Zhang C, et al. Serum liver enzymes serve as prognostic factors in patients with intrahepatic cholangiocarcinoma. Onco Targets Ther. 2017;10:1441–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Buzdin AA, et al. Oncofinder, a new method for the analysis of intracellular signaling pathway activation using transcriptomic data. Front Genet. 2014;5:55.View ArticlePubMedPubMed CentralGoogle Scholar
- Artemov A, et al. A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation. Oncotarget. 2015;6(30):29347–56.View ArticlePubMedPubMed CentralGoogle Scholar
- Buzdin A, et al. Activation of intracellular signaling pathways as a new type of biomarkers for selection of target anticancer drugs. J Clin Oncol. 2017;35(15_suppl):e23142.Google Scholar
- Neuzillet C, et al. Sunitinib as second-line treatment in patients with advanced intrahepatic cholangiocarcinoma (SUN-CK phase II trial): safety, efficacy, and updated translational results. J Clin Oncol. 2015;33(3 suppl):343.View ArticleGoogle Scholar
- Shroff RT, et al. Pazopanib (P) and trametinib (T) in advanced cholangiocarcinoma (CC): a phase Ib study. J Clin Oncol. 2015;33(15 suppl):4072.Google Scholar
- Wada T, Penninger JM. Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 2004;23(16):2838–49.View ArticlePubMedGoogle Scholar
- Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170(1):17–33.View ArticlePubMedPubMed CentralGoogle Scholar
- Gollob JA, et al. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol. 2006;33(4):392–406.View ArticlePubMedGoogle Scholar
- Sonpavde G, Hutson TE. Pazopanib: a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007;9(2):115–9.View ArticlePubMedGoogle Scholar