Cholangiocarcinoma (CCA)


For cholangiocarcinoma (CCA) patients, the possibility of a curative treatment remains in surgical procedures, however, less number of patients are amenable to tumor resection.1 Because CCA is typically diagnosed when the tumor has significantly advanced or when it is already unresectable, there is increased attention and focus in the development of non-surgical therapeutical approaches.2

Systemic Therapy

Gemcitabine and platinum are the most common first-line agents used for treating CCA patients with advanced or metastatic disease that do not respond to  locoregional treatment or suitable for surgical resection.1,3,4 The combination of gemcitabine and cisplatin results in greater efficacy than the use of gemcitabine alone.3 This treatment results, however, in a median overall survival lower than 1 year.1 The drugs are additionally capable of inducing severe side effects, including nausea and vomiting, which further supports the need to develop alternative treatments that can be used in the clinical practice.2 

The use of second-line chemotherapy in CCA treatment requires further investigational support as there is limited clinical information available. Most commonly used drugs are 5-fluorouracil and capecitabine.2 For patients that have failed to respond to gemcitabine-cisplatin combination in first-line treatment, the FOLFOX regimen (combination of folinic acid, oxaliplatin and 5-fluorouracil) may have a positive impact in treatment.5

Radiotherapy

The use of radiation to treat CCA is based on the application of high-energy rays or particles that are capable of targeting tumor cells.6 Technology development has promoted an increase in treatment efficacy and safety by allowing a more precise localization of the tumors to be treated.1 Radiotherapy can be used as a neoadjuvant therapy before surgery, as an adjuvant therapy after surgery, and as a main therapy in patients that present with advanced disease. Radiotherapy may also be part of the palliative care.6

The use of external beam radiation therapy (EBRT) in 3-dimensional conformal radiation therapy (3D-CRT) or in intensity-modulated radiation therapy (IMRT) allows x-rays to destroy tumor cells.1 In Stereotactic body radiotherapy (SBRT), charged proton or carbon particle beams are used instead of classical x-rays. The use of SBRT is important for applying high doses of ablative radiation with great precision and with a favorable dose-deposition profile. Effects on normal cells can be reduced with this treatment.1 

EBRT can be associated with chemotherapy after surgery benefiting patients that have undergone surgery with a lymph-node or resection-margin positive result.1 This radiation treatment may also help patients with localized intrahepatic tumors that cannot be resected.7,8 For extrahepatic tumors, the use of EBRT warrants additional studies.1

The use of EBRT for treating CCA is associated with several side effects that commonly subside after treatment. These side effects include skin damage of the treated area, nausea, vomiting, diarrhea, fatigue and affected blood cell counts.6

Brachytherapy may also be used in patients with localized disease, as first-line or in palliative treatment.1,6 In this internal radiation therapy, pellets of radioactive material are placed close to the tumor and there is reduced damage to the healthy tissues.6

Targeted Therapy

There is an acknowledged intratumoral and intertumoral heterogeneity in CCA disease that hampers the development of targeted effective therapies.1,2 Performing molecular profiling studies are aiding in visualizing the genomic and transcriptomic phenotypes subjacent to the different CCA subtypes.2 Different mutations between intrahepatic and extrahepatic tumors are evident, exposing distinct etiologies linked to the CCA tumors.1,2 

Pemigatinib (Pemazyre) and infigratinib (Truseltiq) are protein kinase inhibitors indicated for the treatment of CCA that express the abnormal form of the fibroblast growth factor receptor 2 (FGFR2) on the cell’s surface.9,10,11 These drugs block the receptor’s activity, reducing the growth and spread of the tumor cells.11

Other potential therapeutic targets in CCA patients, such as isocitrate dehydrogenase (IDH-1 and IDH-2) mutations are currently under study.1,2

Immunotherapy

The boosting of patients’ immune response to allow a better recognition and destruction of tumor cells are being explored as a potential therapy of CCA. There are, however, clinical and epidemiological factors, such as viral infections, influencing the efficacy of immunotherapy treatment.1 Different immune checkpoint inhibitors that bind to the programmed death-1 receptor (PD-1) and PD‐1 ligand (PD‐L1), namely, pembrolizumab, nivolumab, and durvalumab, are currently under study.1,2

Palliative Therapy

Palliative options can promote a decrease of symptoms that patients experience during the disease. Drugs for controlling pain and nausea can be prescribed. 

There are also several medical procedures that can offer relief of symptoms and improve quality of life. For example, a biliary stent or catheter can be placed in the bile ducts or a biliary bypass can be performed to alleviate a potential blocking caused by the tumor and drain bile into the small intestine. The stent placement can be combined with photodynamic therapy (PDT) in patients with unresectable tumors.12

References

1.Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma – evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018. Feb;15(2):95-111. doi:10.1038/nrclinonc.2017.157

2. Wang M, Chen Z, Guo P, Wang Y, Chen G. Therapy for advanced cholangiocarcinoma: current knowledge and future potential. J Cell Mol Med. 2021 Jan;25(2):618-628. doi:10.1111/jcmm.16151

3. Valle J, Wasan H, Palmer DH, et al. ABC-02 trial investigators. cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr;362(14):1273-81.doi:10.1056/NEJMoa0908721

4. Tsavaris N, Kosmas C, Gouveris P, et al.  Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs. 2004 Apr;22(2):193-8. doi:10.1023/B:DRUG.0000011797.09549.53

5. Lamarca A, Palmer DH, Wasan HS, et al. Advanced biliary cancer working group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021. May;22(5):690-701. doi:10.1016/S1470-2045(21)00027-9

6. Radiation therapy for bile duct cancer. American Cancer Society. Accessed on July 6, 2021.

7. Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2016. Feb;34(5):460-8. doi: 10.1200/JCO.2015.64.2710

8. Tao R, Krishnan S, Bhosale PR, Javle MM, Aloia TA, Shroff RT et al. Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol. 2016. Jan;34(3):219-26. doi:10.1200/JCO.2015.61.3778

9. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. US Food and Drug Administration. Accessed on July 6, 2021.

10. FDA grants accelerated approval to infigratinib for metastatic cholangiocarcinoma. US Food and Drug Administration. Accessed on July, 6, 2021.

11. Pemazyre. European medicines agency. Accessed on July 6, 2021.

12. Palliative therapy for bile duct cancer. American Cancer Society. Accessed on July 6, 2021.

Reviewed by Harshi Dhingra, MD, on 7/1/2021.

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