Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / @xirurgi_2025 / @xirurgi_2025 - 436 - файл
.pdf
416 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
Figure 7 Perihilar cholangiocarcinoma treatment algorithm.
Approach to Resection
Type of Resection
For small or peripheral tumors, an anatomical or non-anatomical/parenchymal sparing approach can be used; anatomical
resections result in improved survival and lower recurrence
rates (Si et al. 2019). Most patients have advanced disease at
diagnosis and require a hemi-hepatectomy or extended hepatectomy (de Jong et al. 2011; Endo et al. 2008). Involvement of
the biliary tree with biliary obstruction occurs occasionally
requiring en-bloc resection and reconstruction (Endo et al.
2008; Mazzaferro et al. 2020). Preoperative biliary drainage
again may be required (Cillo et al. 2019; Mazzaferro et al. 2020).
Resection and reconstruction of the inferior biliary vena cava
or portal vein may be performed in selected patients to achieve
an R0 resection, with comparable outcomes (Alikhanov et al.
2021; Conci et al. 2020).
Margins
Although an R0 resection is ideal, there is conflicting evidence
about its role as a predictor for survival and long-term recurrence (Farges et al. 2011; Murakami et al. 2011; Ribero et al.
2012). Lymph node status appears a more important prognostic marker (Hewitt et al. 2022; Lauterio et al., 2021). Notably,
in a multicenter study of 212 patients, those with nodal metastases had similar outcomes irrespective of R1 or R0 resection
status, while those without nodal metastases, R1 status was the
strongest predictor of poor outcome (Farges et al. 2011).
Future Liver Remnant
The future liver remnant volume required to avoid postoperative liver failure is similar in intrahepatic cholangiocarcinoma
to other liver tumors (25% with normal liver function)
(Mazzaferro et al. 2020). However, iCCA commonly arises in
patients with chronic liver disease, where a cut-off of 40% is
generally acceptable (Mazzaferro et al. 2020). To increase the
safety of extended liver resection with inadequate future liver
remnant, limited data suggests portal vein embolization may be
used albeit with a less predictable response in chronic liver disease (Glantzounis et al. 2017). The ALPPS procedure has been
used for locally advanced iCCA with encouraging rates of R0
resection and long-term survival (Bednarsch et al. 2019; J. Li
et al. 2020a) but with higher morbidity and mortality thereby
limiting its use (Serenari et al. 2016).
Lymphadenectomy
Lymph node metastases occur in up to 30–40% of iCCA when
lymphadenectomy is performed (de Jong et al. 2011). Although
lymph node positivity is an important prognostic factor after liver
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 417
https://t.me/medicina_free
resection (Clark et al. 2011), therapeutic porta hepatitis lymphadenectomy does not improve overall survival (Shimada et al. 2009).
The NCCN guidelines recommend lymphadenectomy with a
minimum yield of six nodes for iCCA (NCCN 2021). This is
likely to become more important with nodal staging being important role in stratification for adjuvant therapy (Mazzaferro et al.
2020).
Minimally Invasive Surgery
A minimally invasive approach to liver resection for iCCA may
be possible with equivalent overall survival and lymph node
yield and results with improved short-term outcomes in
selected cases (W. Lee et al. 2016; Ratti et al. 2016); overall in
most situations however it is not appropriate. A robotic
approach may address some of these limitations and a study of
34 iCCA resections (15 robotic, 19 open), equivalent oncological outcomes were achieved (Shapera et al. 2022).
Outcomes after Resection
Long-term outcomes after resection for iCCA remain poor.
Meta-analysis has demonstrated a median survival of 28
months with 5-year overall survival of 30% (Table 4) (Mavros
et al. 2014). Important prognostic factors include tumor size,
the presence of multifocal disease, lymph node metastases, and
vascular invasion (Mavros et al. 2014). Multifocal disease
outcomes appear equivalent between surgery and transarterial
chemoembolization or hepatic artery infusional therapy
(Wright et al. 2018).
Re-resection
The liver is the commonest site of recurrence within two years
of resection (83%) but recurrence occurring after two years is
usually extrahepatic (61%) (Doussot et al. 2016). The prognosis
is generally poor in the setting of recurrence, however, some
patients with liver-only recurrence may be suitable for re-resec-
tion (Spolverato et al. 2016). In a multicenter study of 400
patients with recurrent iCCA, resection of recurrent liver-only
disease improved median survival (26.7 months) compared to
intra-arterial therapy (9.6 months) or standard chemotherapy
(16.8 months) (Spolverato et al. 2016).
Liver Transplantation
Historically, liver transplantation has been contraindicated for
iCCA due to poor outcomes and post-transplant survival (1-year
survival < 50%) (Goldstein et al. 1993; Pichlmayr et al. 1995).
However, recent studies have demonstrated better survival in
patients found to have iCCA or combined hepatocellular-chol-
angiocarcinoma in the explant when originally transplanted for
hepatocellular carcinoma (Facciuto et al. 2015; Sapisochin et al.
2016; Sotiropoulos et al. 2008; Vilchez et al. 2016). These results
Table 4 Selected outcomes after liver resection for intra-hepatic cholangiocarcinoma.
Article, country Study period Number of patients Morbidity <90 days Mortality <90 days 5-year survival
Spolverato et al. (2015)
Multinational
Li et al. (2011)
China
Ali et al. (2013)
USA
Tabrizian et al. (2015)
USA
Bektas et al. (2015)
Germany
Luo et al. (2014)
China
Kim et al. (2015)
Korea
Si et al. (2019)
China
1990–2013
Multi-center
2001–2008
Single-center
1997–2011
Single-center
1995–2011
Single-center
1995–2010
Single-center
2007–2011
Single-center
1995–2012
Single-center
2006–2010
Single-center
584 - - 22%
115 35% 2% 17%
121 43% 1% Vascular resection 44%
No vascular resection: 23%
82 - 1% 40%
221 30% 5% 36% 3 year-survival
1333 12% 1% 17%
215 30% 1% Lymph node dissection: 30%
Non-lymph node dissection: 43%
702 26% 4.4% Anatomical resection: 36%
Non-anatomical resection: 25%
418 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
combined with success with hilar cholangiocarcinoma using the
Mayo Clinic Protocol have reintroduced liver transplantation as
a treatment for cholangiocarcinoma in two ways.
Liver transplant for iCCA may be considered in the following
situations: (1) in patients with early disease and cirrhosis; a
multi-center study of 48 patients with a single tumor ≤2cm had
a 5-year survival of 65% (Sapisochin et al. 2016). This is being
studied in a prospective multi-center trial (Mazzaferro et al.
2020). (2) Unresectable i-CCA due to local invasion and location, may be suitable for liver transplantation following neoadjuvant chemotherapy (Lunsford et al. 2018; McMillan et al.
2022). In a series of 18 patients over 12 years, liver transplantation was used to treat patients with locally advanced/unresectable iCCA that demonstrated stability for 6 months on
neoadjuvant chemotherapy (McMillan et al. 2022). The authors
reported a 1-, 3- and 5-year overall survival of 100%, 71% and
57% respectively (McMillan et al. 2022); validation with multicentre clinical trials is required.
Key Take Home Messages
1 Surgery is the only curative treatment for intrahepatic cholangiocar-
cinoma.
2 Liver resection should aim for an R0 resection and include a lymphad-
enectomy for nodal staging.
3 Portal vein embolization or ALPPS can be used to improve the safety
of liver resection in patients with inadequate future liver remnant.
4 A minimally invasive approach may be appropriate in selected
patients.
5 Liver transplantation remains experimental but can be considered as
part of a clinical trial.
6 A treatment algorithm for perihilar cholangiocarinoma is outlined in
Figure 8.
Figure 8 Intrahepatic cholangiocarcinoma treatment algorithm.
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 419
https://t.me/medicina_free
Areas for Further Research
1 Optimized chemotherapy regimens
Improved targeted and Immunotherapy regimens
2
3
Predictive biomarkers
Trusted Websites for Further Reading
https://www.mayoclinic.org/diseases-conditions/cholangio
carcinoma/symptoms-causes/syc-20352408
https://www.cancer.gov/pediatric-adult-rare-tumor/rare-
tumors/rare-digestive-system-tumors/cholangiocarcinoma
References
Abbas, S. and Sandroussi, C. (2013). Systematic review and meta-analysis
of the role of vascular resection in the treatment of hilar
cholangiocarcinoma. HPB (Oxford) 15 (7): 492–503. doi: 10.1111/j.1477-
2574.2012.00616.x.
Acher, A.W., Weber, S.M., and Pawlik, T.M. (2021). Liver transplantation for
perihilar cholangiocarcinoma: patient selection and outcomes. Expert
Rev Gastroenterol Hepatol 15 (5): 555–566. doi: 10.1080/17474124.2021.
1890584.
Al Mahjoub, A., Menahem, B., Fohlen, A. et al. (2017). Preoperative biliary
drainage in patients with resectable perihilar cholangiocarcinoma: is
percutaneous transhepatic biliary drainage safer and more effective than
endoscopic biliary drainage? A meta-analysis. J Vasc Interv Radiol 28 (4):
576–582. doi: 10.1016/j.jvir.2016.12.1218.
Ali, S.M., Clark, C.J., Zaydfudim, V.M. et al. (2013). Role of major vascular
resection in patients with intrahepatic cholangiocarcinoma. Ann Surg
Oncol 20 (6): 2023–2028. doi: 10.1245/s10434-012-2808-2.
Alikhanov, R., Dudareva, A., Trigo, M.A., and Serrablo, A. (2021). Vascular
resection for intrahepatic cholangiocarcinoma: current considerations. J
Clin Med 10 (17). doi: 10.3390/jcm10173829.
Aloia, T.A., Charnsangavej, C., Faria, S. et al. (2007). High-resolution
computed tomography accurately predicts resectability in hilar
cholangiocarcinoma. Am J Surg 193 (6): 702–706. doi: 10.1016/j.
amjsurg.2006.10.024.
Amin, M.B., Edge, S.B., Greene, F.L. (eds.) (2017). AJCC Cancer Staging
Manual, (Vol. 1024). New York: Springer.
Aoba, T., Ebata, T., Yokoyama, Y. et al. (2013). Assessment of nodal status
for perihilar cholangiocarcinoma: location, number, or ratio of involved
nodes. Ann Surg 257 (4): 718–725. doi: 10.1097/SLA.0b013e3182822277.
Bednarsch, J., Czigany, Z., Lurje, I. et al. (2019). The role of ALPPS in
intrahepatic cholangiocarcinoma. Langenbecks Arch Surg 404 (7): 885–
894. doi: 10.1007/s00423-019-01838-2.
Bektas, H., Yeyrek, C., Kleine, M. et al. (2015). Surgical treatment for
intrahepatic cholangiocarcinoma in Europe: a single center experience.
J Hepatobiliary Pancreat Sci 22 (2): 131–137. doi: 10.1002/jhbp.158.
Blechacz, B., Komuta, M., and Roskams, T. et al. (2011). Clinical diagnosis
and staging of cholangiocarcinoma, Nat Rev Gastroenterol Hepatol, 8 (9):
512-522. doi: 10.1038/nrgastro.2011.131.
Bridgewater, J., Galle, P.R., Khan, S.A. et al. (2014). Guidelines for the
diagnosis and management of intrahepatic cholangiocarcinoma. J
Hepatol 60 (6): 1268–1289. doi: 10.1016/j.jhep.2014.01.021.
Cillo, U., Fondevila, C., Donadon, M. et al. (2019). Surgery for cholangiocarci-
noma. Liver Int 39 (Suppl 1): 143–155. doi: 10.1111/liv.14089.
Clark, C.J., Wood-Wentz, C.M., Reid-Lombardo, K.M. et al. (2011).
Lymphadenectomy in the staging and treatment of intrahepatic
cholangiocarcinoma: a population-based study using the National
Cancer Institute SEER database. HPB (Oxford) 13 (9): 612–620. doi:
10.1111/j.1477-2574.2011.00340.x.
Conci, S., Vigano, L., Ercolani, G. et al. (2020). Outcomes of vascular
resection associated with curative intent hepatectomy for intrahepatic
cholangiocarcinoma. Eur J Surg Oncol 46 (9): 1727–1733. doi: 10.1016/j.
ejso.2020.04.007.
Corvera, C.U., Blumgart, L.H., Akhurst, T. et al. (2008). 18F-fluorodeoxyglucose
positron emission tomography influences management decisions in
patients with biliary cancer. J Am Coll Surg 206 (1): 57–65. doi: 10.1016/j.
jamcollsurg.2007.07.002.
Darwish Murad, S., Kim, W.R., Harnois, D.M. et al. (2012). Efficacy of
neoadjuvant chemoradiation, followed by liver transplantation, for
perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 143 (1):
88–98 e83; quiz e14. doi: 10.1053/j.gastro.2012.04.008.
de Jong, M.C., Marques, H., Clary, B.M. et al. (2012). The impact of portal
vein resection on outcomes for hilar cholangiocarcinoma: a multiinstitutional analysis of 305 cases. Cancer 118 (19): 4737–4747. doi:
10.1002/cncr.27492.
de Jong, M.C., Nathan, H., Sotiropoulos, G.C. et al. (2011). Intrahepatic
cholangiocarcinoma: an international multi-institutional analysis of
prognostic factors and lymph node assessment. J Clin Oncol 29 (23):
3140–3145. doi: 10.1200/JCO.2011.35.6519.
DeOliveira, M.L., Cunningham, S.C., Cameron, J.L. et al. (2007).
Cholangiocarcinoma: thirty-one-year experience with 564 patients at a
single institution. Ann Surg 245 (5): 755–762. doi: 10.1097/01.sla.
0000251366.62632.d3.
Doussot, A., Gonen, M., Wiggers, J.K. et al. (2016). Recurrence patterns and
disease-free survival after resection of intrahepatic cholangiocarcinoma:
preoperative and postoperative prognostic models. J Am Coll Surg 223
(3): 493–505 e492. doi: 10.1016/j.jamcollsurg.2016.05.019.
Ebata, T., Yokoyama, Y., Igami, T. et al. (2012). Portal vein embolization
before extended hepatectomy for biliary cancer: current technique and
review of 494 consecutive embolizations. Dig Surg 29 (1): 23–29. doi:
10.1159/000335718.
Endo, I., Gonen, M., Yopp, A.C. et al. (2008). Intrahepatic cholangiocarcinoma:
rising frequency, improved survival, and determinants of outcome after
resection. Ann Surg 248 (1): 84–96. doi: 10.1097/SLA.0b013e318176c4d3.
Ethun, C.G., Lopez-Aguiar, A.G., Anderson, D.J. et al. (2018). Transplantation
versus resection for hilar cholangiocarcinoma: an argument for shifting
treatment paradigms for resectable disease. Ann Surg 267 (5): 797–805.
doi: 10.1097/SLA.0000000000002574.
Facciuto, M.E., Singh, M.K., Lubezky, N. et al. (2015). Tumors with
intrahepatic bile duct differentiation in cirrhosis: implications on
outcomes after liver transplantation. Transplantation 99 (1): 151–157.
doi: 10.1097/TP.0000000000000286.
Farges, O., Fuks, D., Boleslawski, E. et al. (2011). Influence of surgical
margins on outcome in patients with intrahepatic cholangiocarcinoma:
a multicenter study by the AFC-IHCC-2009 study group. Ann Surg 254
(5): 824–829; discussion 830. doi: 10.1097/SLA.0b013e318236c21d.
Farges, O., Regimbeau, J.M., Fuks, D. et al. (2013). Multicentre European
study of preoperative biliary drainage for hilar cholangiocarcinoma.
Br J Surg 100 (2): 274–283. doi: 10.1002/bjs.8950.
Ferrero, A., Lo Tesoriere, R., Vigano, L. et al. (2009). Preoperative biliary
drainage increases infectious complications after hepatectomy for
420 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
proximal bile duct tumor obstruction. World J Surg 33 (2): 318–325. doi:
10.1007/s00268-008-9830-3.
Franken, L.C., Olthof, P.B., Erdmann, J.I. et al. (2021). Short- and long-
term outcomes after hemihepatectomy for perihilar cholangiocarcinoma:
does left or right side matter? Hepatobiliary Surg Nutr 10 (2): 154–162.
doi: 10.21037/hbsn-19-948.
Furusawa, N., Kobayashi, A., Yokoyama, T. et al. (2014). Surgical treatment
of 144 cases of hilar cholangiocarcinoma without liver-related mortality.
World J Surg 38 (5): 1164–1176. doi: 10.1007/s00268-013-2394-x.
Glantzounis, G.K., Tokidis, E., Basourakos, S.P. et al. (2017). The role of
portal vein embolization in the surgical management of primary
hepatobiliary cancers. A systematic review. Eur J Surg Oncol 43 (1): 32–
41. doi: 10.1016/j.ejso.2016.05.026.
Goldstein, R.M., Stone, M., Tillery, G.W. et al. (1993). Is liver transplantation
indicated for cholangiocarcinoma? Am J Surg 166 (6): 768–771;
discussion 771-762. doi: 10.1016/s0002-9610(05)80696-8.
Hameed, A., Pang, T., Chiou, J. et al. (2016). Percutaneous vs. endoscopic
pre-operative biliary drainage in hilar cholangiocarcinoma - a systematic
review and meta-analysis. HPB (Oxford) 18 (5): 400–410. doi: 10.1016/j.
hpb.2016.03.002.
Heimbach, J.K., Gores, G.J., Haddock, M.G. et al. (2004). Liver
transplantation for unresectable perihilar cholangiocarcinoma. Semin
Liver Dis 24 (2): 201–207. doi: 10.1055/s-2004-828896.
Hewitt, D.B., Brown, Z.J., and Pawlik, T.M. (2022). Surgical management of
intrahepatic cholangiocarcinoma. Expert Rev Anticancer Ther 22 (1):
27–38. doi: 10.1080/14737140.2022.1999809.
Hochwald, S.N., Burke, E.C., Jarnagin, W.R. et al. (1999). Association of
preoperative biliary stenting with increased postoperative infectious
complications in proximal cholangiocarcinoma. Arch Surg 134 (3): 261–
266. doi: 10.1001/archsurg.134.3.261.
Hu, H.J., Wu, Z.R., Jin, Y.W. et al. (2019). Minimally invasive surgery for
hilar cholangiocarcinoma: state of art and future perspectives. ANZ J
Surg 89 (5): 476–480. doi: 10.1111/ans.14765.
Iacono, C., Ruzzenente, A., Campagnaro, T. et al. (2013). Role of
preoperative biliary drainage in jaundiced patients who are candidates
for pancreatoduodenectomy or hepatic resection: highlights and
drawbacks. Ann Surg 257 (2): 191–204.
Jarnagin, W.R., Fong, Y., DeMatteo, R.P. et al. (2001). Staging, resectability, and
outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234 (4):
507–517; discussion 517-509. doi: 10.1097/00000658-200110000-00010.
Kato, T., Tsukamoto, E., Kuge, Y. et al. (2002). Clinical role of (18)
F-FDGPET for initial staging of patients with extrahepatic bile duct
cancer. Eur J Nucl Med Mol Imaging 29 (8): 1047–1054. doi: 10.1007/
s00259-002-0852-z.
Kennedy, T.J., Yopp, A., Qin, Y. et al. (2009). Role of preoperative biliary
drainage of liver remnant prior to extended liver resection for hilar
cholangiocarcinoma. HPB (Oxford) 11 (5): 445–451. doi: 10.1111/j.1477-
2574.2009.00090.x.
Kim, D.H., Choi, D.W., Choi, S.H. et al. (2015). Is there a role for systematic
hepatic pedicle lymphadenectomy in intrahepatic cholangiocarcinoma?
A review of 17 years of experience in a tertiary institution. Surgery 157
(4): 666–675. doi: 10.1016/j.surg.2014.11.006.
Kimmings, A.N., van Deventer, S.J., Obertop, H. et al. (1995). Inflammatory
and immunologic effects of obstructive jaundice: pathogenesis and
treatment. J Am Coll Surg 181 (6): 567–581.
Kluge, R., Schmidt, F., Caca, K. et al. (2001). Positron emission
tomography with [(18)F]fluoro-2-deoxy-D-glucose for diagnosis and
staging of bile duct cancer. Hepatology 33 (5): 1029–1035. doi:
10.1053/jhep.2001.23912.
Krähenbühl, L., Schäfer, M., and Krähenbühl, S. (1998). Reversibility of
hepatic mitochondrial damage in rats with long-term cholestasis. J
Hepatol 28 (6): 1000–1007.
Lauterio, A., De Carlis, R., Centonze, L. et al. (2021). Current surgical
management of peri-hilar and intra-hepatic cholangiocarcinoma.
Cancers (Basel) 13 (15).
Lee, H.Y., Kim, S.H., Lee, J.M. et al. (2006). Preoperative assessment of
resectability of hepatic hilar cholangiocarcinoma: combined CT and
cholangiography with revised criteria. Radiology 239 (1): 113–121. doi:
10.1148/radiol.2383050419.
Lee, W., Park, J.H., Kim, J.Y. et al. (2016). Comparison of perioperative and
oncologic outcomes between open and laparoscopic liver resection for
intrahepatic cholangiocarcinoma. Surg Endosc 30 (11): 4835–4840. doi:
10.1007/s00464-016-4817-x.
Li, J., Moustafa, M., Linecker, M. et al. (2020a). ALPPS for locally advanced
intrahepatic cholangiocarcinoma: did aggressive surgery lead to the
oncological benefit? An international multi-center study. Ann Surg
Oncol 27 (5): 1372–1384. doi: 10.1245/s10434-019-08192-z.
Li, J., Tan, X., Zhang, X. et al. (2020b). Robotic radical surgery for hilar
cholangiocarcinoma: a single-centre case series. Int J Med Robot 16 (2):
e2076. doi: 10.1002/rcs.2076.
Li, Y.M., Bie, Z.X., Guo, R.Q. et al. (2022). Effect of hepatic artery resection
and reconstruction on the prognosis of patients with advanced hilar
cholangiocarcinoma. World J Gastrointest Oncol 14 (4): 887–896. doi:
10.4251/wjgo.v14.i4.887.
Li, Y.Y., Li, H., Lv, P. et al. (2011). Prognostic value of cirrhosis for
intrahepatic cholangiocarcinoma after surgical treatment. J Gastrointest
Surg 15 (4): 608–613. doi: 10.1007/s11605-011-1419-8.
Liang, L., Li, C., Wang, M.-D. et al. (2021). The value of lymphadenectomy
in surgical resection of perihilar cholangiocarcinoma: a systematic
review and meta-analysis. Int J Clin Oncol 26 (9): 1575–1586. doi:
10.1007/s10147-021-01967-z.
Lim, J.H., Choi, G.H., Choi, S.H. et al. (2013). Liver resection for Bismuth
type I and Type II hilar cholangiocarcinoma. World J Surg 37 (4): 829–
837. doi: 10.1007/s00268-013-1909-9.
Lopera, J.E., Soto, J.A., and Munera, F. (2001). Malignant hilar and perihilar
biliary obstruction: use of MR cholangiography to define the extent of
biliary ductal involvement and plan percutaneous interventions.
Radiology 220 (1): 90–96. doi: 10.1148/radiology.220.1.r01jl3990.
Lunsford, K.E., Javle, M., Heyne, K. et al. (2018). Liver transplantation for
locally advanced intrahepatic cholangiocarcinoma treated with
neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol
Hepatol 3 (5): 337–348.
Luo, X., Yuan, L., Wang, Y. et al. (2014). Survival outcomes and prognostic
factors of surgical therapy for all potentially resectable intrahepatic
cholangiocarcinoma: a large single-center cohort study. J Gastrointest
Surg 18 (3): 562–572. doi: 10.1007/s11605-013-2447-3.
Mantel, H.T., Westerkamp, A.C., Sieders, E. et al. (2016). Intraoperative frozen
section analysis of the proximal bile ducts in hilar cholangiocarcinoma is of
limited value. Cancer Med 5 (7): 1373–1380. doi: 10.1002/cam4.693.
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 421
https://t.me/medicina_free
Masselli, G., Manfredi, R., Vecchioli, A., and Gualdi, G. (2008). MR
imaging and MR cholangiopancreatography in the preoperative
evaluation of hilar cholangiocarcinoma: correlation with surgical and
pathologic findings. Eur Radiol 18 (10): 2213–2221. doi: 10.1007/
s00330-008-1004-z.
Mavros, M.N., Economopoulos, K.P., Alexiou, V.G., and Pawlik, T.M.
(2014). Treatment and Prognosis for Patients With Intrahepatic
Cholangiocarcinoma: systematic Review and Meta-analysis. JAMA Surg
149 (6): 565–574. doi: 10.1001/jamasurg.2013.5137.
Mazzaferro, V., Gorgen, A., Roayaie, S. et al. (2020). Liver resection and
transplantation for intrahepatic cholangiocarcinoma. J Hepatol 72 (2):
364–377. doi: 10.1016/j.jhep.2019.11.020.
McMillan, R.R., Javle, M., Kodali, S. et al. (2022). Survival following liver
transplantation for locally advanced, unresectable intrahepatic
cholangiocarcinoma. Am J Transplant 22 (3): 823–832. doi: 10.1111/
ajt.16906.
Murakami, Y., Uemura, K., Sudo, T. et al. (2011). Prognostic factors after
surgical resection for intrahepatic, hilar, and distal cholangiocarcinoma.
Ann Surg Oncol 18 (3): 651–658. doi: 10.1245/s10434-010-1325-4.
Nagino, M., Ebata, T., and Mizuno, T. (2021). Oncological superiority of
right-sided hepatectomy over left-sided hepatectomy as surgery for
perihilar cholangiocarcinoma: truth or biased view? Ann Surg 274 (1):
31–32. doi: 10.1097/sla.0000000000004534.
Nagino, M., Ebata, T., Yokoyama, Y. et al. (2013). Evolution of surgical
treatment for perihilar cholangiocarcinoma: a single-center 34-year
review of 574 consecutive resections. Ann Surg 258 (1): 129–140. doi:
10.1097/SLA.0b013e3182708b57.
NCCN. (2021). NCCN guidelines version 4.2021 hepatobiliary cancers. In:
National Cancer Care Network.
Neuhaus, P., Jonas, S., Bechstein, W.O. et al. (1999). Extended resections for
hilar cholangiocarcinoma. Ann Surg 230 (6): 808–818; discussion 819.
doi: 10.1097/00000658-199912000-00010.
Neuhaus, P., Thelen, A., Jonas, S. et al. (2012). Oncological superiority of
hilar en bloc resection for the treatment of hilar cholangiocarcinoma.
Ann Surg Oncol 19 (5): 1602–1608. doi: 10.1245/s10434-011-2077-5.
Nimura, Y., Hayakawa, N., Kamiya, J. et al. (1990). Hepatic segmentectomy
with caudate lobe resection for bile duct carcinoma of the hepatic hilus.
World J Surg 14 (4): 535–543; discussion 544. doi: 10.1007/bf01658686.
Olthof, P.B., Coelen, R.J.S., Wiggers, J.K. et al. (2017). High mortality after
ALPPS for perihilar cholangiocarcinoma: case-control analysis
including the first series from the international ALPPS registry. HPB
(Oxford) 19 (5): 381–387. doi: 10.1016/j.hpb.2016.10.008.
Pichlmayr, R., Weimann, A., Oldhafer, K.J. et al. (1995). Role of liver
transplantation in the treatment of unresectable liver cancer. World J
Surg 19 (6): 807–813. doi: 10.1007/bf00299775.
Ratti, F., Cipriani, F., Ariotti, R. et al. (2016). Safety and feasibility of
laparoscopic liver resection with associated lymphadenectomy for
intrahepatic cholangiocarcinoma: a propensity score-based casematched analysis from a single institution. Surg Endosc 30 (5): 1999–
2010. doi: 10.1007/s00464-015-4430-4.
Ratti, F., Fiorentini, G., Cipriani, F. et al. (2020a). Perihilar cholangiocarcinoma:
are we ready to step towards minimally invasiveness? Updates Surg 72 (2):
423–433. doi: 10.1007/s13304-020-00752-3.
Ratti, F., Fiorentini, G., Cipriani, F. et al. (2020b). Technical insights on
laparoscopic left and right hepatectomy for perihilar cholangiocarcinoma.
Ann Surg Oncol 27 (13): 5191–5192. doi: 10.1245/s10434-020-08647-8.
Ribero, D., Pinna, A.D., Guglielmi, A. et al., … Italian Intrahepatic
Cholangiocarcinoma Study, G. (2012). Surgical approach for long-term
survival of patients with intrahepatic cholangiocarcinoma: a multiinstitutional analysis of 434 patients. Arch Surg, 147(12), 1107–1113.
doi: 10.1001/archsurg.2012.1962.
Ribero, D., Zimmitti, G., Aloia, T.A. et al. (2016). Preoperative cholangitis
and future liver remnant volume determine the risk of liver failure in
patients undergoing resection for hilar cholangiocarcinoma. J Am Coll
Surg 223 (1): 87–97. doi: 10.1016/j.jamcollsurg.2016.01.060.
Rimola, J., Forner, A., Reig, M. et al. (2009). Cholangiocarcinoma in
cirrhosis: absence of contrast washout in delayed phases by magnetic
resonance imaging avoids misdiagnosis of hepatocellular carcinoma.
Hepatology 50 (3): 791–798. doi: 10.1002/hep.23071.
Rosen, C.B., Heimbach, J.K., and Gores, G.J. (2010). Liver transplantation
for cholangiocarcinoma. Transpl Int 23 (7): 692–697. doi:
10.1111/j.1432-2277.2010.01108.x.
Sakamoto, E., Nimura, Y., Hayakawa, N. et al. (1998). The pattern of
infiltration at the proximal border of hilar bile duct carcinoma: a
histologic analysis of 62 resected cases. Ann Surg 227 (3): 405–411. doi:
10.1097/00000658-199803000-00013.
Sapisochin, G., Facciuto, M., Rubbia-Brandt, L. et al., i, C. C. A. I. C..
(2016). Liver transplantation for “very early” intrahepatic
cholangiocarcinoma: international retrospective study supporting a
prospective assessment. Hepatology 64 (4): 1178–1188. doi: 10.1002/
hep.28744.
Schnitzbauer, A.A., Lang, S.A., Goessmann, H. et al. (2012). Right portal
vein ligation combined with in situ splitting induces rapid left lateral liver
lobe hypertrophy enabling 2-staged extended right hepatic resection in
small-for-size settings. Ann Surg 255 (3): 405–414. doi: 10.1097/
SLA.0b013e31824856f5.
Serenari, M., Zanello, M., Schadde, E. et al. (2016). Importance of primary
indication and liver function between stages: results of a multicenter
Italian audit of ALPPS 2012-2014. HPB (Oxford) 18 (5): 419–427. doi:
10.1016/j.hpb.2016.02.003.
Shapera, E.A., Ross, S., Syblis, C. et al. (2022). Analysis of oncological
outcomes after robotic liver resection for intrahepatic cholangiocarcinoma.
Am Surg 31348221093933. doi: 10.1177/00031348221093933.
Shimada, K., Sano, T., Nara, S. et al. (2009). Therapeutic value of lymph
node dissection during hepatectomy in patients with intrahepatic
cholangiocellular carcinoma with negative lymph node involvement.
Surgery 145 (4): 411–416. doi: 10.1016/j.surg.2008.11.010.
Si, A., Li, J., Yang, Z. et al. (2019). Impact of anatomical versus non-
anatomical liver resection on short- and long-term outcomes for patients
with intrahepatic cholangiocarcinoma. Ann Surg Oncol 26 (6): 1841–
1850. doi: 10.1245/s10434-019-07260-8.
Sotiropoulos, G.C., Kaiser, G.M., Lang, H. et al. (2008). Liver transplantation
as a primary indication for intrahepatic cholangiocarcinoma: a singlecenter experience. Transplant Proc 40 (9): 3194–3195. doi: 10.1016/j.
transproceed.2008.08.053.
Spolverato, G., Kim, Y., Alexandrescu, S. et al. (2016). Management and
outcomes of patients with recurrent intrahepatic cholangiocarcinoma
following previous curative-intent surgical resection. Ann Surg Oncol 23
(1): 235–243. doi: 10.1245/s10434-015-4642-9.
Spolverato, G., Vitale, A., Cucchetti, A. et al. (2015). Can hepatic resection
provide a long-term cure for patients with intrahepatic cholangiocarcinoma?
Cancer 121 (22): 3998–4006. doi: 10.1002/cncr.29619.
422 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
Su, C.H., Tsay, S.H., Wu, C.C. et al. (1996). Factors influencing postoperative
morbidity, mortality, and survival after resection for hilar
cholangiocarcinoma. Ann Surg 223 (4): 384–394.
Tabrizian, P., Jibara, G., Hechtman, J.F. et al. (2015). Outcomes following
resection of intrahepatic cholangiocarcinoma. HPB (Oxford) 17 (4):
344–351. doi: 10.1111/hpb.12359.
Tan, E.K., Rosen, C.B., Heimbach, J.K. et al. (2020). Living donor liver
transplantation for perihilar cholangiocarcinoma: outcomes and
complications. J Am Coll Surg 231 (1): 98–110. doi: 10.1016/j.
jamcollsurg.2019.12.037.
Tang, Z., Yang, Y., Zhao, Z. et al. (2018). The clinicopathological factors
associated with prognosis of patients with resectable perihilar
cholangiocarcinoma: a systematic review and meta-analysis. Medicine
(Baltimore) 97 (34): e11999. doi: 10.1097/MD.0000000000011999.
Tillich, M., Mischinger, H.J., Preisegger, K.H. et al. (1998). Multiphasic
helical CT in diagnosis and staging of hilar cholangiocarcinoma. AJR
Am J Roentgenol 171 (3): 651–658. doi: 10.2214/ajr.171.3.9725291.
Tran, T.B., Ethun, C.G., Pawlik, T.M. et al. (2019). Actual 5-year survivors
after surgical resection of hilar cholangiocarcinoma. Ann Surg Oncol 26
(2): 611–618. doi: 10.1245/s10434-018-7075-4.
Van Beers, B.E. (2008). Diagnosis of cholangiocarcinoma. HPB (Oxford) 10
(2): 87–93. doi: 10.1080/13651820801992716.
van der Gaag, N.A., Rauws, E.A., van Eijck, C.H. et al. (2010). Preoperative
biliary drainage for cancer of the head of the pancreas. N Engl J Med 362
(2): 129–137. doi: 10.1056/NEJMoa0903230.
Vilchez, V., Shah, M.B., Daily, M.F. et al. (2016). Long-term outcome of
patients undergoing liver transplantation for mixed hepatocellular
carcinoma and cholangiocarcinoma: an analysis of the UNOS database.
HPB (Oxford) 18 (1): 29–34. doi: 10.1016/j.hpb.2015.10.001.
Vilgrain, V. (2008). Staging cholangiocarcinoma by imaging studies. HPB
(Oxford) 10 (2): 106–109. doi: 10.1080/13651820801992617.
Vogl, T.J., Schwarz, W.O., Heller, M. et al. (2006). Staging of Klatskin tumours
(hilar cholangiocarcinomas): comparison of MR cholangiography, MR
imaging, and endoscopic retrograde cholangiography. Eur Radiol 16 (10):
2317–2325. doi: 10.1007/s00330-005-0139-4.
Wang, L., Lin, N., Xin, F. et al. (2019). A systematic review of the comparison
of the incidence of seeding metastasis between endoscopic biliary
drainage and percutaneous transhepatic biliary drainage for resectable
malignant biliary obstruction. World J Surg Oncol 17 (1): 116. doi:
10.1186/s12957-019-1656-y.
Wright, G.P., Perkins, S., Jones, H. et al. (2018). Surgical resection does not
improve survival in multifocal intrahepatic cholangiocarcinoma: a
comparison of surgical resection with intra-arterial therapies. Ann Surg
Oncol 25 (1): 83–90. doi: 10.1245/s10434-017-6110-1.
Xiang, S., Lau, W.Y., and Chen, X.P. (2015). Hilar cholangiocarcinoma:
controversies on the extent of surgical resection aiming at cure. Int J
Colorectal Dis 30 (2): 159–171. doi: 10.1007/s00384-014-2063-z.
Yu, W., Gu, Z., Shi, S. et al. (2014). Effect evaluation of vascular resection
for patients with hilar cholangiocarcinoma: original data and metaanalysis. Cell Biochem Biophys 69 (3): 509–516. doi: 10.1007/
s12013-014-9825-7.
Zaborowski, A., Heneghan, H.M., Fiore, B. et al. (2020). Neoadjuvant
chemoradiotherapy and liver transplantation for unresectable hilar
cholangiocarcinoma: the Irish experience of the mayo protocol.
Transplantation 104 (10): 2097–2104. doi: 10.1097/TP.0000000000003114.
Chemotherapy
Joanna Lee & Katrin Sjoquist
Adjuvant Therapy
Outcomes remain poor for operable cholangiocarcinoma even
with complete curative intent resections. Current evidence supports a role for adjuvant fluoropyrimidine based chemotherapy
in appropriately selected patients, with some caveats.
Prospective phase III chemotherapy trials have been largely
negative, with only two suggesting a benefit with oral fluoropyrimidines. The role of adjuvant (chemo) radiotherapy is also
debated (see radiation section of chapter). Guidelines vary by
institution but nevertheless, it is generally agreed that patients
with R1 resections or lymph node involvement should be considered for adjuvant therapy (Shroff et al. 2019; Valle et al.
2016).
The only phase III trial to report a statistically significant
survival benefit is the JCOG 1202/ASCOT trial which
randomized 440 patients with R0 or R1 resection of biliary
tract cancers to observation, or 6 months of the fluoropyrimidine S-1. 3-year overall survival (OS) was longer in the adjuvant S-1 group at 77.1% (95% CI 70.9–82.1%) compared to
surgery alone 67.6% (95% CI 61.0–73.3%; Hazard Ratio (HR)
0.694 95% CI 0.514–0.935). Three-year relapse free survival
(RFS) was also improved in the S-1 group 62.4% (95% CI 55.6–
68.4%) compared to 50.9% (95% CI 44.1–57.2%; HR 0.797,
95% CI 0.613–1.035). The most common grade 3–4 adverse
event was cholangitis in 7.2% (Ikeda et al. 2022). This study was
performed on an Asian population, and results have not been
reproducible in other populations.
Capecitabine is another oral fluoropyrimidine with potential
adjuvant activity. The phase III BILCAP trial recruited 447
patients with macroscopically complete resection of cholangiocarcinoma randomized to 6 months of oral capecitabine 1250
mg/m2, or observation. BILCAP failed to reach its primary
endpoint of improved OS in the ITT population, but did demonstrated a benefit for capecitabine in a per protocol analysis
(adjusted HR 0.75, 95% CI 0.58–0.97). 32% of patients discontinued capecitabine due to toxicity, most commonly hand-foot
syndrome. There was also one case of grade four coronary
event (Primrose et al. 2019).
To date no phase III trial has demonstrated a benefit to adju-
vant intravenous chemotherapy compared to observation. For
example, the PRODIGE-12 trial randomized 194 patients with
R0/R1 resection of localized cholangiocarcinoma to 12 cycles
of gemcitabine and oxaliplatin, or observation. There was a statistically insignificant difference in median RFS (30.4 months
vs 18.5 months) and OS (75.8 vs 50.8 months) in favor of
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 423
https://t.me/medicina_free
chemotherapy No subgroup with clear benefit was identified
(Edeline et al. 2019). Similarly, ESPAC-3 evaluated the role of
adjuvant single agent gemcitabine or 5-fluoruracil/folinic acid
in resected (R0 or R1) periampullary adenocarcinoma
including 96 (22%) patients with localized intrapancreatic
cholangiocarcinoma. There was no improvement in OS with
chemotherapy for the whole population in unadjusted analyses.
The median OS for the biliary subgroup was 27.2 months (95%
CI, 15.4–31.9), 18.3 months (95% CI, 12.9–28.7), and 19.5
months (95% CI, 16.2–36.1) for the observation, 5-fluororuacil, and gemcitabine groups respectively (Neoptolemos et al.
2012). It should be noted that this trial was not powered to
detect a difference in survival for the cholangiocarcinoma
subgroup.
Two trials examining newer systemic treatments are ongoing.
The phase III ACTICCA-01 trial initially compared adjuvant
gemcitabine and cisplatin, to observation for resected cholangiocarcinoma and gallbladder carcinomas. Following the
BILCAP results, the control arm was amended to capecitabine
and a sub-study was included to address the question of adjuvant chemoradiotherapy (see radiation section). The phase II
ACCORD trial evaluates adjuvant immunotherapy (camrelizumab (anti PD-1)) combined with capecitabine chemoradiation, compared with observation for patients with high-risk
resectable extrahepatic cholangiocarcinoma and gallbladder
cancer. High-risk is defined as R1 resection or R0 resection
with T2-4 or N1 pathology.
There is some data to support adjuvant systemic therapy for
resected cholangiocarcinoma, but room for improvement; new
approaches and trials are warranted. Given the poor outcomes
with resection alone it is recommended that risks and benefits
of adjuvant chemotherapy should be discussed for all suitable
patients.
Adjuvant Chemoradiotherapy
See radiotherapy section.
Neoadjuvant Treatment
Neoadjuvant therapy is not standard practice in the treatment
of cholangiocarcinoma. There is a lack of strong prospective
trial data, and most evidence is from retrospective series. Most
neoadjuvant studies for unresectable extrahepatic cholangiocarcinoma used combined chemoradiotherapy with reports of
pathological response and successful R0 resection. This will be
discussed in more detail in the radiotherapy section of this
chapter.
A meta-analysis identified two single center studies in which
patients with intrahepatic cholangiocarcinoma received neoadjuvant chemotherapy (Rizzo and Brandi 2021). In one prospective study, 8 of 22 patients with unresectable cholangiocarcinoma
or gallbladder carcinoma received neoadjuvant gemcitabine. 4
achieved R0 and 4 R1 resection with a group median survival of
19.3 months compared to 7.5 months for those treated with
chemotherapy alone (p = 0.032) (Kato et al. 2013). In a retrospective study of 74 patients with unresectable intrahepatic
cholangiocarcinoma, 39 patients received neoadjuvant chemotherapy (mostly gemcitabine doublet). Median survival was
comparable to patients with upfront resectable disease without
chemotherapy:24.1 months compared to 25.7 months (HR
1.23, 95% CI 0.77 to 1.97). In contrast, patients with unresectable disease treated with chemotherapy alone had a shorter
median survival of 7.8 months (HR 3.80, 95% CI 2.29 to 6.30)
(Le Roy et al. 2017).
Prospective trials looking at neoadjuvant systemic therapy
are in progress, including the phase II DEBATE trial assessing
the effect of neoadjuvant cisplatin and gemcitabine with or
without durvalumab (ClinicalTrials.gov 2020) and a phase II
trial of triplet chemotherapy with gemcitabine cisplatin and
nab-paclitaxel (ClinicalTrials.gov 2022).
First Line Treatment of Unresectable or
Metastatic Disease
Chemotherapy remains the standard of care for unresectable or
metastatic cholangiocarcinoma despite relatively poor outcomes. The standard regimen is gemcitabine-based doublet,
often with cisplatin or oxaliplatin. Gemcitabine combined with
nab-paclitaxel or capecitabine has also shown some activity.
These combinations have not been directly compared in a trial
setting.
Chemotherapy
The strongest evidence for first line gemcitabine and cisplatin
comes from the randomized phase III ABC-02 trial which
compared gemcitabine + cisplatin, to gemcitabine. Median OS
was 3.6 months greater with the doublet (HR 0.64 95%CI 0.52–
0.80, p <0.001). Tumor control rate was greater in the
combination arm at 81.4% compared to 71.8% for gemcitabine
(P = 0.049). HR for death was in favor of combination for both
intrahepatic and extrahepatic CCA subgroups. Grade 3–4 neutropenia was more common in patients receiving combination
(25.3% vs 16.6%) but there were no increased infections.
The phase II GERCOR trial of GEMOX in advanced biliary
tract cancer included 33 untreated patients including 16 with
intrahepatic and 4 with extrahepatic cholangiocarcinoma.
Overall response rate (ORR) was 36% and median OS for the
first-line cohort was 15.4 months. Most common grade 3–4
toxicities were myelosuppression, and peripheral sensory neuropathy (André et al. 2004).
A phase II trial of gemcitabine and nab-paclitaxel in 74
patients with advanced or metastatic cholangiocarcinoma
424 3 HEPATOBILIARY AND PANCREAS CANCER
https://t.me/medicina_free
demonstrated an ORR of 30%, median PFS of 7.7 months, and
median OS of 12.4 months (95% CI 9.2–15.9). The 6-month
PFS of 61% observed in this trial however did not meet the prespecified threshold of 70% (Sahai et al. 2018). Moreover, 82%
experienced a grade 3 or higher adverse events.
Fluoropyrimidine based regimens such as capecitabine with
oxaliplatin (CAPOX) or infusional 5-FU with oxaliplatin
(FOLFOX) should be considered for patients with biliary obstruction. A South Korean phase III randomized study comparing
CAPOX to GEMOX demonstrated non-inferiority of CAPOX in
an Asian population based on 6-month PFS with a pre-specified
non-inferiority margin of 15%. Out of 222 randomized patients,
116 had a biliary primary. Median OS was similar for the ITT
population; 10.4 months for CAPOX and 10.6 months for
GEMOX, and 6-month PFS of 45% and 47% respectively. The HR
for death in the cholangiocarcinoma subgroup was 1.034 (95% CI
0.691–1.584). There was no significant difference in the rates of
grade 3–4 adverse events (Kim et al. 2019).
Triplet combinations are not widely used due to toxicity and
lack of evidence. No OS nor PFS benefit was demonstrated for
FOLFORINOX compared to gemcitabine and cisplatin in the
phase II PRODIGE 38 AMEBICA trial (Phelip et al. 2022).
Gemcitabine, cisplatin, and nab-paclitaxel combination has
been explored in a single arm phase II study of 45 cholangiocarcinoma patients. The median OS was not reached for the intrahepatic group (95% CI 13.6-NE), and was 13.2 months (95% CI
1.8-NE) for the extrahepatic group. This combination is yet to
be evaluated in a prospective phase III trial (Shroff et al. 2019).
Adding immunotherapy to chemotherapy may confer longer
term disease control in patients with advanced cholangiocarcinoma. The phase III TOPAZ-1 trial randomized 685 patients
with untreated unresectable, recurrent (> 6 months since adjuvant therapy) or metastatic biliary tract cancers to gemcitabine
and cisplatin with either durvalumab or placebo. Preliminary
results showed a small improvement in median OS (12.8
months vs 11.5 months; HR 0.8 95% CI 0.66–0.97), with benefits across all disease locations and PD-L1 expression. Rates of
grade 3–4 adverse events were similar: 62.7% with durvalumab
and 64.9% for placebo (Oh et al. 2020). However, the modest
survival benefit needs to be weighed against the potential cost
of treatment.
Single agent chemotherapy is an option for patients with
poorer performance status, however response rates and survival
outcomes are generally inferior to doublet regimens, as outlined in Table 5.
Non-Cytotoxic Systemic Therapy
A few trials have demonstrated activity of immunotherapy and
targeted therapy in pretreated cholangiocarcinoma, but it is not
yet known whether these drugs (excluding durvalumab) will be
active in the first-line setting. The FIGHT-302 and PROOF301 trials are comparing FGFR inhibitors pemigatinib and infigratinib against gemcitabine and cisplatin in the first line
setting; results are pending (Bekaii-Saab et al. 2020; Makawita
et al. 2020).
Table 5 Table of studies of including patients treated with first-line single agent chemotherapy in patients with metastatic cholangiocarcinoma.
Regimen Study Dose and schedule N
2
Leucovorin
Modulated
Fluorouracil
Gemcitabine Penz et al. 2001 (Penz et al. 2001) 2 weekly gemcitabine 2200 mg/m2 32* 22 11.5 (range 3.0–24.0)
Capecitabine Patt et al. 2004 (Patt et al. 2004) Capecitabine 1000 mg/m2 BD days
* Includes gallbladder carcinoma
^ Excludes gallbladder carcinoma
Choi et al. 2000 (Choi et al. 2000) FU 375 mg/m
days 1 to 5 every 3–4 weeks.
Chen et al. 1998 (Chen et al. 1998) 2600MG/M2 5-FU + 150MG LV OVER
24 HOURS. WEEKLY FOR 6 WEEKS.
Okusaka et al. 2010 (Okusaka et al.
2010)
Novarino et al. 2013 (Novarino
et al. 2013)
Valle et al. 2010 (Valle et al. 2010) Gemcitabine 1000 mg/m2 on days
Sasaki et al. 2013 (Sasaki et al.
2013)
gemcitabine 1000
1, 8 and 15 of a 28-day cycle
Gemcitabine 1250 mg/m2 days 1
and 8 of 21 day cycle
1, 8, 15 of 28 day cycle
Gemcitabine 100 mg/m2 on days
1, 8, 15 of 28 day cycle
1–14 of 21 day cycle.
+ LV 25 mg/m2 on
mg m−2 on days
28* 32 6 (Range 1–16)
19* 33 7
42* 11.9 ^8.0 (95% CI 6.1–16.0)
18* 0 8.3 months (95% CU
206* ^11.6 8.1 months (95% CI,
18^ 5.6 15.0
18^ 6 8.1 (95% CI 7.4–8.9)
Response
rate (%) Median OS (months)
4.7–12.9)
7.1 to 8.7)
21 MANAGEMENT OF INTRAHEPATIC AND EXTRAHEPATIC CHOLANGIOCARCINOMA 425
https://t.me/medicina_free
Second Line Treatment and Beyond
Chemotherapy
Patients who progress on first-line treatment are generally
limited to alternative chemotherapy regimens or trial referral
provided they remain well. 5-Fluorouracil based regimens can
be used for patients who have previously received gemcitabinebased regimens and vice versa, but the potential survival gains
are small and may come at the expense of quality of life.
FOLFOX6, and 5-FU with liposomal irinotecan have been
evaluated in second line trials, however the data for many other
regimens have been extrapolated from first-line studies.
The ABC-06 phase III open label trial randomized 162
patients with advanced biliary tract cancer and ECOG of 0 or 1
to modified FOLFOX6 and active symptom control, or active
symptom control alone following radiological progression on
cisplatin and gemcitabine combination. There was only a modest improvement in median OS for the chemotherapy arm: 6.2
months (95% CI 5.4–7.6) compared to 5.3 months (95% CI
44.1–5.8). However, there was improved OS for the FOLFOX6
group 50.6% (95% CI 39.3–60.9) at 6 months compared to
35.5% (95% CI 25.2–46) for active symptom control, and 25.9%
at 12 months compared to 11.4% suggesting a subset of patients
may survive longer with chemotherapy. However the rates of
grade 3–5 adverse events was higher with FOLFOX (69% v
52%), and there were three chemotherapy-related deaths
(Lamarca et al. 2021). FOLFOX6 therefore represents a standard of care option for second line therapy in suitable patients
with preserved performance status.
The randomized phase 2b NIFTY trial compared liposomal
irinotecan, fluorouracil, and leucovorin combination to fluorouracil and leucovorin in patients who had progressed on gemcitabine and cisplatin. This trial reported an improved PFS of
7.1 months for the intervention arm compared to 1.4 months
(HR 0.56, 95% CI 0.39–0.81), and OS of 8.6 months compared
to 5.5 months (HR 0.68 95% CI 0.48–0.98). However, this was
likely skewed by the results of the gallbladder subgroup.HR for
OS for the gallbladder group was 0.29 (95% CI 0.14–0.58) compared to 0.86 (95% CI 0.50–1.48) for intrahepatic, and 1.06
(95% CI 0.53–2.16) for the extrahepatic subgroup. Serious
adverse events were reported in 42% of patients in the irinotecan arm compared to 24%, and fatal adverse events were identified in 6% compared to 1% for the control arm (Yoo et al. 2021).
Patients who have not had gemcitabine in the first-line setting
may be treated with GEMOX which was shown in the phase II
GERCOR trial to have activity in patients who had prior chemotherapy. A response rate of 22%, PFS of 3.9 months, and OS of
7.6 months was reported, however patients with gallbladder carcinoma represented 33% of this group (André et al. 2004).
Addition of bevacizumab to FOLFIRI or GEMOX has been
evaluated in small cohorts but is not recommended due to paucity of data (Guion-Dusserre et al. 2015; Zhu et al. 2010).
Similarly regorafenib was found to have no survival benefit
compared to placebo (Demols et al. 2020).
Non-Cytotoxic Systemic Therapy
Molecular analyses of cholangiocarcinoma have shown that this
is a diverse group of cancers rich in-molecular aberrations, many
with prognostic and predictive implications. The frequencies of
these mutations vary widely based on anatomical, pathological,
and geographical distribution (Churi et al. 2014; Nakamura et al.
2015; Lowery et al. 2018; Zou et al. 2014; Javle et al. 2016) (see
Figure 9). There is a growing body of evidence that the use of
matching therapeutic agents can confer improved response rates
and longer survival compared to standard cytotoxic therapy. In
the MOSCATO-01 trial 34 of 43 patients with previously treated
advanced biliary tract cancer underwent genetic sequencing, with
31 found to have at least one molecular aberration. 18 of these
patients were able to undergo treatment with a corresponding
drug with an objective response rate of 33% and disease control
rate of 88%, and a median PFS of 5.2 months (95% CI, 1.7–15.9)
(Verlingue et al. 2017). Microsatellite instability is uncommon in
cholangiocarcinoma with a prevalence of 2–5% but is significant
as it can predict for response to checkpoint inhibitor immunotherapy (Bonneville et al. 2017; Piha-Paul et al. 2020).
Common Intrahepatic Mutations
11%
15%
15%
TP53 KRAS IDH1 ARID1A FGFR2
30%
19%
Common Extrahepatic Mutations
18%
22%
27%
TP53 KRAS IDH1 SMAD4 ERBB2
Figure 9 Pie chart of common mutations in intrahepatic and
extrahepatic cholangiocarcinoma based on larger molecular profiling
studies (Churi et al. 2014; Nakamura et al. 2015; Lowery et al. 2018; Zou
et al. 2014). N.B: some of these mutations are not mutually exclusive.
40%
33%
Соседние файлы в папке @xirurgi_2025