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 / Библиотека им академика М.И. Перельмана / Книга_1260_Библиотеки_им_академика_М_И_Перельмана
.pdf
Oncological management of primary liver cancer 189
response rate and tumor control, but a benefit on overall
survival has not been clearly demonstrated [75]. The
combination of infusional 5-fluorouracil, leucovorin,
and oxaliplatin (FOLFOX) was recently evaluated in
Asian patients with HCC in a randomized trial compared
with doxorubicin [76]. At the time of final analysis,
there was a nonsignificant trend towards improved
overall survival in patients treated with FOLFOX compared with doxorubicin (6.4 versus 4.97 months,
P = 0.07). A post hoc analysis with longer follow-up later
found that the overall survival advantage with FOLFOX
was maintained. For patients with advanced HCC who
experience progressive disease on sorafenib or who are
intolerant of sorafenib, this study suggests that FOLFOX
may provide modest benefit.
stage HCC. Because HCCs are vascular tumors with
increased expression of VEGF and microvessel density,
inhibition of angiogenesis has been investigated as a potential therapeutic strategy [77]. Two randomized studies have
demonstrated improved overall survival in patients with
advanced HCC treated with sorafenib (Table 12.1). In the
phase III Sorafenib HCC Assessment Randomized Protocol
(SHARP) trial, 602 patients with ECOG PS 0–2andChild–
Pugh class A liver function were randomized to receive
sorafenib or a placebo [48]. Although the number of complete (0%) and partial responses (2%) to treatment was
low, sorafenib was associated with improved overall survival (median OS, 10.7 months versus 7.9 months,
P < 0.001). Furthermore, sorafenib was also associated
with a delay in TTP. Similar results were seen in the phase
III Asian-Pacific study of sorafenib versus placebo [78].
12.2.3.2 Molecularly targeted therapy
Until recently, no systemic therapies had been associated
with improved overall survival in patients with advanced-
Table 12.1 Results of selected randomized phase III clinical trials of molecularly targeted therapies for advanced HCC.
Agent Molecular target Line of
therapy
Sorafenib versus placebo [48] VEGFR, PDGFR, 1
FLT-3, RAF (0.45–0.74) 0.69 (0.55–0.87)
Sorafenib versus placebo [78] VEGFR, PDGFR, 1
FLT-3, RAF (0.42–0.79) 0.68 (0.50–0.93)
st
st
Other receptor tyrosine kinase inhibitors have been evaluatedinpatientswithadvancedHCCandcompareddirectly
against sorafenib (see Table 12.1). However, neither
ORR (%) TTP (months) Median OS
(months)
2 versus 1 5.5 versus 2.8; HR 0.58 10.7 versus 7.9; HR
3.3 versus 1.3 2.8 versus 1.4; HR 0.57 6.5 versus 4.2; HR
Brivanib versus placebo [138] VEGFR, FGFR 2
Ramucirumab versus VEGFR-2 2
placebo [83] 0.63 (0.52–0.75) 0.87 (0.72-1.05)
Brivanib versus sorafenib [80] VEGFR, FGFR 1
Sunitinib versus sorafenib [79] VEGFR, PDGFRα/β, 1
c-kit, FLT3, RET (0.96–1.31) 1.3 (1.13–1.50)
Linifanib versus sorafenib [81] VEGFR, PDGFR 1
Erlotinib + sorafenib versus EGFR 1
placebo + sorafenib [82] 1.14 (0.94–1.37) 0.93 (0.78–1.11)
Everolimus versus placebo [84] mTOR 2
EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; FLT-3, FMS-related tyrosine kinase 3; HR, hazard ratio;
mTOR, mammalian target of rapamycin; ORR, overall response rate (complete response or partial response as measured by Response Evaluation
Criteria in Solid Tumors [RECIST] or modified RECIST for HCC); OS, overall survival; PDGFR, platelet-derived growth factor receptor; PFS, progressionfree survival; RAF, Raf kinases; RET, glial cell line-derived neurotropic factor receptor (REarranged during Transfection); VEGFR, vascular endothelial
growth factor receptor.
nd
nd
st
st
st
st
nd
10 versus 2 4.2 versus 2.7; HR 0.56 9.4 versus 8.2; HR
(0.42–0.75) 0.89 (0.69–1.15)
7 versus 1 PFS: 2.8 versus 2.1; HR 9.2 versus 7.6; HR
12 versus 9 4.2 versus 4.1; HR 1.01 9.5 versus 9.9; HR
(0.88–1.16) 1.06 (0.93–1.22)
6.6 versus 6.1 4.1 versus 3.8, HR 1.13 7.9 versus 10.2; HR
13.0 versus 6.9 5.4 versus 4.0; HR 0.76 9.1 versus 9.8; HR
(0.64–0.90) 1.05 (0.90–1.22)
3.2 versus 4.0 mo; HR 9.5 versus 8.5; HR
2.2 versus 1.6 3.0 versus 2.6; HR 0.93 7.6 versus 7.3; HR
(0.75–1.15) 1.05 (0.86–1.27)
190 Chapter 12
sunitinib, brivanib, linifanibnor the combination of sorafenib
plus erlotinib have demonstrated superiority or noninferiority to sorafenib [79–82]. Additionally, no significant survival
advantage was observed in phase III trials of ramucirumab, a
monoclonal antibody that blocks activation of VEGFR-2, or
everolimus, an inhibitor of the mammalian target of rapamycin(mTOR), versus placeboand in patientswith advanced
HCC following first-line therapy with sorafenib [83,84].
KEY POINTS: HEPATOCELLULAR CARCINOMA
• Hepatocellular carcinoma arises in the setting of chronic liver disease and cirrhosis in over 80% of patients. This can adversely
affect overall survival, limit surgical options, and affect tolerance to systemic therapy.
• For patients with early-stage HCC, potentially curative treatment options exist.
– For patients without advanced cirrhosis, surgical resection is the preferred management.
– For patients with cirrhosis who are not candidates for resection, liver transplantation can be considered for patients
meeting transplant criteria.
– For patients with small HCCs who are poor surgical candidates because of impaired liver function or other serious medical
comorbidities, local ablative therapy can be considered.
– Neoadjuvant and adjuvant therapies have no proven bene fit and remain under investigation.
• For patients with intermediate-stage HCC, preserved liver function, and large or multifocal tumors without main portal vein
occlusion or extrahepatic metastases, hepatic artery embolization or radiation therapy can be considered.
• Cytotoxic chemotherapy has limited efficacy against HCC. Sorafenib has demonstrated an overall survival benefit for patients
with advanced HCC. Other molecularly targeted agents remain under investigation.
Other agents targeting different molecular pathways
involved in hepatocarcinogenesis, including hepatocyte
growth factor/c-MET (tivantinib, cabozantinib) and other
inhibitors of angiogenesis, remain under investigation
[85,86]. Furthermore, early promising results have been
demonstrated with the immune checkpoint inhibitor nivolumab, a monoclonal antibody that blocks the programmed
cell death 1 (PD-1) receptor on activated T cells [87].
12.3 Biliary tract cancers
Biliary tract cancers represent a heterogeneous group of
malignancies that include cholangiocarcinoma and
gallbladder carcinoma. Cholangiocarcinomas, primarily
adenocarcinoma, arise from the epithelium of the bile ducts
and are classified according to location as intrahepatic and
extrahepatic cholangiocarcinoma (Figure 12.2). Extrahepatic tumors can be further subclassified into hilar carcinomas, arising at or near the junction of the left and right
hepatic ducts, and distal cholangiocarcinoma. Approximately 60–70% of biliary tract cancers arise in the perihilar
region (Klatskin tumors). Extrahepatic and intrahepatic
cholangiocarcinomas occur in approximately 20–30% and
5–10% of patients, respectively [88]. Because most biliary
tract cancers present at an advanced stage, these cancers are
associated with a poor prognosis with five-year survival rates
less than 5–10% [89].
12.3.1 Resected, localized biliary tract
cancers: role of adjuvant therapy
Surgical resection represents the only potentially curative
treatment modality, but it is estimated that less than 35%
of patients are candidates for resection owing to extent of
local disease or presence of metastatic disease [90,91].
The five-year survival rates for patients with resected
biliary tract cancers are in the range of 30–50% [92].
Outcomes vary depending on location and stage of the
primary lesion. Distal cholangiocarcinomas have a
more favorable prognosis compared with perihilar
Figure 12.2 Anatomical classification of biliary tract cancers.
Source: Turaga [149]. Reproduced with permission of Springer.
Oncological management of primary liver cancer 191
cholangiocarcinoma [93]. Gallbladder carcinoma, in general, is the most aggressive of the biliary tract cancers and
is associated with the shortest median survival [94].
Multiple studies have demonstrated that the presence of
lymph node metastases in patients with cholangiocarcinoma is a poor prognostic factor [93,95–97]. Furthermore,
studies including patients with perihilar carcinoma and
distal cholangiocarcinoma have demonstrated survival differences related to total lymph node count among those
with pathologically node-negative disease [96,97]. This
observation has raised the possibility of a therapeutic benefit
for lymphadenectomy, but more likely reflects the effects of
accurate staging of disease. While lymph node dissection
itself may have little direct impact on survival, staging
information may influence decisions regarding postsurgical
treatment that potentially could affect outcome. Although
regional lymphadenectomy is performed routinely for carcinomas arising from extrahepatic bile ducts, indications for
lymph node dissection for intrahepatic cholangiocarcinoma
remain controversial [27,98]. Nonetheless, because lymph
node involvement is such an important prognostic factor,
lymphadenectomy should be considered to obtain a precise
stage of disease and to provide prognostic information that
could influence postoperative management.
Local recurrence in the liver is the most common
pattern for relapse following resection of biliary tract
cancers although there is a suggestion that gallbladder
cancer may also be associated with greater risk of distant
metastatic spread [90,94]. Because of the high rate of
recurrence, adjuvant chemotherapy and radiation have
been investigated as potential strategies to improve outcome. However, most of the studies investigating the
efficacy and tolerance of adjuvant therapy in this patient
population have been retrospective in nature and based
on small numbers of patients that include both
gallbladder and bile duct cancers arising from various
locations. Thus, the role of adjuvant therapy for resected
biliary tract cancers remains a controversial topic, and its
benefits have not been well defined.
12.3.1.1 Adjuvant chemotherapy
Although retrospective studies have suggested an advantage with adjuvant chemotherapy alone, randomized
studies have not demonstrated that chemotherapy can
improve survival following resection of cholangiocarcinoma. A multicenter randomized trial conducted in Japan
compared postoperative chemotherapy with mitomycin C
and 5-FU versus surgery alone in patients with resected
pancreaticobiliary malignancies. Among patients with
resected cholangiocarcinoma, five-year OS in patients
receiving chemotherapy (27%) was not significantly different to those undergoing surgery alone (24%) [99].
Furthermore, the European ESAPC-3 study randomized
patients with resected periampullary malignancies to
receiveadjuvant 5-FU with leucovorin versusgemcitabine
versus observation following surgery. Amongthe subsetof
patients with bile duct cancer, there was no improvement
in median survival associated with receipt of chemotherapy. The median survival rates of patients receiving
no chemotherapy, 5-FU/leucovorin, and gemcitabine
were 27, 18, and 20 months, respectively [100].
12.3.1.2 Adjuvant radiation therapy
Data have been mixed regarding the benefits of adjuvant
radiation therapy following complete resection of biliary
tract cancers. Some retrospective studies have demonstrated improved local control and survival among
patients with undergoing intraoperative and postoperative radiation therapy [101–103]. However, contrasting studies also suggest no improvement in outcome
and significant side-effects [104 – 106]. One subgroup of
patients who may benefit from postoperative radiation is
those with positive resection margins. In a retrospective
study of patients undergoing curative-intent surgery for
extrahepatic cholangiocarcinoma, those with microscopically positive resection margins who received adjuvant
radiation therapy had higher median disease-free survival rates than those who underwent surgery alone (21
months versus 10 months, respectively, P = 0.042) [107].
12.3.1.3 Adjuvant chemoradiation therapy
Several retrospective and phase II studies have suggested
benefit for postoperative chemoradiation therapy in
patients with completely or incompletely resected biliary
tract cancers. In a retrospective analysis of patients with
resected extrahepatic cholangiocarcinoma, similar survival was observed between patients with standard risk
disease (R0 resection, node-negative disease) and those
with high-risk disease (R1 resection, node-positive disease) who receivedadjuvantchemoradiation.The lack of a
survival difference between the two groups suggests that
patients at high risk for locoregional recurrence may
benefit from adjuvant chemoradiation following surgery [108]. Similarly, in another retrospective study of
patients with extrahepatic cholangiocarcioma undergoing
curative-intent resection, receipt of adjuvant chemoradiation therapy was associated with improved overall survival, disease-free survival, and locoregional control
192 Chapter 12
compared with surgical resection alone after controlling
for other prognostic factors [109]. A recent phase II study
provides prospective data regarding the benefitofadjuvant chemotherapy (capecitabine plus gemcitabine) followed by 5-FU-based chemoradiation after resection of
extrahepatic cholangiocarcinoma and gallbladder cancer.
Promising results were demonstrated: two-year OS, DFS,
and local recurrence rates were 65%, 52%, and 11%
respectively, among all 79 patients treated (54 with cholangiocarcinoma, 25 with gallbladder cancer) [110].
Among more recent retrospective studies that include
only patients with gallbladder carcinoma, adjuvant chemoradiation therapy following resection has been associated with improved survival after adjusting for other
predictors of survival [111,112]. Similarly, a model based
on treatment and outcome of patients with resected
gallbladder carcinoma included in the United States
National Cancer Institute SEER-Medicare database demonstrated the greatest benefit for adjuvant chemoradiation therapy among patients with node-positive disease
or with tumors staged as T2 or higher [113].
A recent meta-analysis has further examined the role of
adjuvant therapy in the treatment of biliary tract cancers [114]. The analysis was composed of trials of adjuvant
therapy for patients undergoing adjuvant chemotherapy,
radiotherapy, or both after curative-intent surgery for
gallbladder and bile duct cancers and included patients
who underwent surgery alone as a comparator group. In
the pooled data, there was a nonsignificant improvement
in OS with any adjuvant therapy compared with surgery
alone (odds ratio [OR] 0.74; 95% confidence interval [CI]
0.55–1.10;P = 0.06). A nonsignificant survival benefitwas
also observed when patients with gallbladder and bile duct
carcinomaswere analyzed independently. Those receiving
chemotherapy (OR 0.39; 95% CI 0.23–0.66; P < 0.001) or
chemoradiation therapy (OR 0.61; 95% CI 0.38–0.99;
P = 0.049) appeared to derive greater benefit than those
treated with radiation alone (OR 0.98; 95% CI 0.67–1.43;
P = 0.90). The greatest benefit was observed for adjuvant
therapy in patients with high-risk lymph node-positive
disease and those with incomplete R1 resections. These
data suggest that adjuvant chemotherapy or chemoradiation therapy may improve outcome in patients with
resected, high-risk gallbladder and bile duct cancers and
provide support for a common practice of administering
adjuvant therapy. However, prospective, randomized trials are necessary to further evaluate the benefit of postoperative therapy.
12.3.2 Locally advanced and metastatic
biliary tract cancers
12.3.2.1 Radiation and chemoradiation therapy
The majority of patients with cholangiocarcinoma present
with locally unresectable disease. There is limited experience with neoadjuvant therapy as a surgical conversion
strategy in the management of patients with initially unresectable, locally advanced disease. However, reports have
suggested a potential role for selected patients. In a retrospective report of 45 patients with resected extrahepatic
cholangiocarcinoma, 12 patients were treated with neoadjuvant therapy. Of these 12 patients, 10 had disease
deemed initially unresectable and two had potentially
resectable disease but received neoadjuvant chemoradiation therapy owing to physician preference. Supporting the
concept that neoadjuvant therapy can improve the ability to
resect initially unresectable disease, three of the 12 patients
who received neoadjuvant chemoradiation therapy had a
complete pathological response to treatment, and 11 of the
12 patients underwent an R0 resection [115]. Additionally,
in a series of patients with extrahepatic cholangiocarcinoma, three of nine patients who were treated with preoperative chemoradiation therapy had a pathological
complete response to therapy. Furthermore, all nine
patients who received chemoradiation therapy had negative margins at resection, compared with only half who did
not receive neoadjuvant therapy [116]. Although these
results are promising, particularly for patients with initially
unresectable disease, additional prospective studies are
needed to clarify the benefits of neoadjuvant therapy.
Although data are limited, radiation may also provide local control of disease for patients with unresectable, locally advanced disease. In a retrospective study
of patients with locally advanced extrahepatic cholangiocarcinoma who were treated with external beam
radiation thera py with concurrent chemotherapy and/
or brachytherapy, overall survival and local control
rates at one year were 59% and 90%, respectively. At
the time of death, the majority of patients had local
control of disease, suggesting that local effects of tumor
might be effectively controlled with r adiation therapy [117]. A more recent p hase II study demonstrated
high l ocal control rates with high-dose hypofractionated proton beam radiation therapy for locally
advanced, unresectable HCC and intrahepatic cholangiocarcinoma, supporting further investigation into
the role of radiation therapy for unresectable primary
liver cancers [64].
Oncological management of primary liver cancer 193
12.3.2.2 Hepatic artery-based therapy
Much of the data supporting the role of hepatic artery-based
therapy for primary liver cancers is derived from series also
including patients with HCC. Recent studies, however, have
examined the efficacy of hepatic artery embolization, particularly radioembolization, for localized, unresectable intrahepatic cholangiocarcinoma [118–122]. In a multiinstitutional series including 198 patients with intrahepatic
cholangiocarcinoma treated with chemoembolization,
bland embolization or yttrium-90 radioembolization, complete or partial radiographic responses were reported in 26%
of patients, while 62% had stable disease [123]. Median OS
was 13.2 months and did not vary according to type of
embolization technique. Randomized studies comparing the
various hepatic artery-based therapies to radiation or
chemotherapy are not yet available.
12.3.2.3 Chemotherapy
Systemic chemotherapy remains a cornerstone in the
palliative management of patients with unresectable
and metastatic biliary tract cancers. The combination of
5-FU, leucovorin, and etoposide has demonstrated an
overall survival benefit compared with best supportive
care in a randomized study of patients with advanced
biliary tract and pancreatic cancers (median OS, six
months versus 2.5 months) [124]. Furthermore, quality
of life measures improved more and deteriorated less often
in the patients receiving chemotherapy. Multiple phase II
studies have also demonstrated activity of chemotherapy
in the treatment of this disease. In a pooled analysis of 104
trials including 2810 patients with advanced biliary tract
cancer, superior tumor response and control rates were
observed in patients receiving chemotherapy regimens
containing gemcitabine and platinum [125].
The combination of gemcitabine and cisplatin has been
showntoimproveoverallsurvivalinpatientswithadvanced
biliary tract cancers. In the UK ABC-02 trial, patients with
advanced biliary tract cancers were randomized to receive
gemcitabine and cisplatin or gemcitabine alone. OS was
significantly improved in patients receiving combination
therapy compared with single-agent gemcitabine (11.7
months versus 8.1 months, P < 0.001) [126]. The rate of
tumor control, as defined by complete or partial responses
and stable disease, was also higher in patients receiving
gemcitabine and cisplatin (81.4% versus 71.8%,
P = 0.049). Similarly, a randomized phase II study reported
Table 12.2 Results of selected clinical trials of molecularly targeted therapies for advanced biliary tract cancers.
Agent/target Trial phase Line of
therapy
EGFR
Erlotinib [139]
Gemcitabine + oxaliplatin +/ erlotinib [140]
Gemcitabine + oxaliplatin +/ cetuximab [141]
Gemcitabine + oxaliplatin + capecitabine +
panitumumuab [142]
VEGF
Gemcitabine + oxaliplatin + bevacizumab [143]
Sorafenib [144]
Sorafenib [145]
Sunitinib [146]
HER2
Lapatinib [147] II 1
MEK
Selumetinib [148] II 2
EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; MEK, mitogen-activated protein kinase;
ORR, overall response rate; OS, overall survival; PFS, progression-free survival; VEGF, vascular endothelial growth factor.
II
III (randomized)
II (randomized)
II
II
II
II
II
1
1
1
1
1
Any
1
2
st/2nd
st
st
st
st
st
nd
st/2nd
nd
ORR (%) Median PFS
(months)
8
30 versus 16
(P = 0.005)
24 versus 23
33
40
2
0
8.9
0 1.8 5.2
12 3.7 9.8
2.6
5.8 versus 4.2; HR
0.80 (0.61–1.03)
6.1 versus 5.5
8.3
7.0
2.3
3
1.7
Median OS
(months)
7.5
9.5 versus 9.5; HR
0.93 (0.69–1.25)
11.0 versus 12.4
9.8
12.7
4.4
9
4.8
194 Chapter 12
by Okusaka et al. also showed improved outcome for patients
with advanced biliary tract cancers treated with the combination of gemcitabine and cisplatin compared with gemcitabine alone [127]. Although gemcitabine plus cisplatin has
been shown to be superior to gemcitabine alone, this combination has not been compared with other chemotherapy
combinations. Other regimens that have demonstrated
activity in advanced biliary tract cancers in phase II trials
have included gemcitabine and oxaliplatin [128–130], gemcitabine and fluoropyrimidine [131–133], and fluoropyrimidine and oxaliplatin [134].
Although chemotherapy has improved outcomes for
patients with advanced biliary tract cancers, prognosis for
KEY POINTS: BILIARY TRACT CANCERS
• Biliary tract cancers are a heterogeneous group of tumors composed of gallbladder carcinoma, intrahepatic, perihilar, and distal
cholangiocarcinoma. Most patients present at an advanced stage with unresectable disease.
• Surgical resection remains the only curative treatment modality.
• The role of adjuvant therapyfor completelyresected biliary tract cancersis controversial, and benefits have not been well defined.
– In R0 resected patients, external beam radiation has not shown survival benefit. However, adjuvant radiation may benefit
patients with positive resection margins.
– Adjuvant chemoradiation therapy may have benefit for patients with high-risk disease (lymph node and/or margin positive).
• There are limited data about the role of chemoradiation therapy for patients with locally advanced disease. In selected patients, it
may improve ability to resect initially unresectable tumors and improve local control. Radiation may also provide local control of
disease for patients with unresectable, locally advanced disease.
• Hepatic artery-based therapies are a promising strategy for patients with unresectable locally intrahepatic cholangiocarcinoma
and warrant prospective evaluation in comparison to other standards of care.
• Systemic chemotherapy with gemcitabine and cisplatin improves overall survival for patients with advanced biliary tract cancer.
Other combination chemotherapy regimens are active in the treatment of patients with metastatic disease.
patients remains poor. Targeted therapies directed against
signaling pathways in biliary tract cancers, including the
epidermal growth factor receptor (EGFR), angiogenesis, and
the mitogen-activated protein kinase (MEK) pathway, have
been investigated with early promising results (Table 12.2).
Recent studies have also identified genomic alterations in
cholangiocarcinoma and gallbladder cancer involving chromatin remodeling genes and the IDH1 and IDH2 genes that
encode metabolic enzymes [135]. Furthermore, alterations
in fibroblast growth factor receptor 2 (FGF2), including novel
gene fusions, have been identified [136,137]. These findings
have the potential to translate into new targets and improvements in therapy for patients with advanced disease.
12.4 Conclusion
Although the management of patients with primary liver
cancers remains challenging because of underlying liver
dysfunction, complex molecular biology, and heterogeneity of disease, recent progress in surgical and medical
therapy has improved the prognosis of patients with both
early and advanced disease. Future advances, including
those involving minimally invasive surgery, interventional radiology, and radiation techniques, have the
potential to further improve outcomes for patients with
early and intermediate-stage disease. Systemic chemotherapy can improve survival of patients with advanced
disease, and hopefully the identification of novel molecular targets and predictors of response will translate into
new therapeutic strategies. A multidisciplinary approach
is essential to optimizing patient outcome.
References
1 Torre LA, Bray F, Siegel RL, et al. Global cancer statistics,
2012. CA Cancer J Clin 2015; 65(2):87–108.
2 Siegel R, Miller K, Jemal A. Cance r statistics, 2014. CA
Cancer J Clin 2014; 64(1):9–29.
3 Bruix J, Sherman M. Management of hepatocellular carci-
noma. Hepatology 2005; 42(5):1208–1236.
4 Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma.
Lancet 2012; 379(9822):1245–1255.
5 Henderson JM, Sherman M, Tavill A, et al. AHPBA/AJCC
consensus conference on staging of hepatocellular carcinoma:
consensus statement. HPB (Oxford) 2003; 5(4):243–250.
Oncological management of primary liver cancer 195
6 Edge SB, Byrd D, Compton C, et al. AJCC Cancer Staging
Manual. New York: Springer, 2010.
7 Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular
carcinoma: the BCLC staging classification. Semin Liver
Dis 1999; 19(3):329–338.
8 A new prognostic system for hepatocellular carcinoma: a retro-
spective study of 435 patients: the Cancer of the Liver Italian
Program (CLIP) investigators. Hepatology 1998; 28(3):751–755.
9 Okuda K, Ohtsuki T, Obata H, et al. Natural history of
hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 1985; 56(4):918–928.
10 Kudo M, Chung H, Osaki Y. Prognostic staging system for
hepatocellular carcinoma (CLIP score): its value and limitations,
and a proposal for a new staging system, the Japan Integrated
Staging Score (JIS score). J Gastroenterol 2003; 38(3):207–215.
11 Leung TW, Tang A, Zee B, et al. Construction of the Chinese
University Prognostic Index for hepatocellular carcinoma
and comparison with the TNM staging system, the Okuda
staging system, and the Cancer of the Liver Italian Program
staging system: a study based on 926 patients. Cancer 2002;
94(6):1760–1769.
12 EASL–EORTC clinical practice guidelines: management of
hepatocellular carcinoma. J Hepatol 2012; 56(4):908–943.
13 Bruix J, Sherman M. Management of hepatocellular carci-
noma: an update. Hepatology 2011; 53(3):1020–1022.
14 Fong Y, Sun R, Jarnagin W, et al. An analysis of 412 cases of
hepatocellular carcinoma at a Western center. Ann Surg
1999; 229(6):790–799; discussion 799–800.
15 Nathan H, Schulick RD, Choti M, et al. Predictors of survival
after resection of early hepatocellular carcinoma. Ann Surg
2009; 249(5):799–805.
16 Chang CH, Chau G, Lui W, et al. Long-term results of hepatic
resection for hepatocellular carcinoma originating from the
noncirrhotic liver. Arch Surg 2004; 139(3):320–325; discussion 326.
17 Bruix J, Castells A, Bosch J, et al. Surgical resection of
hepatocellular carcinoma in cirrhotic patients: prognostic
value of preoperative portal pressure. Gastroenterology
1996; 111(4):1018–1022.
18 Rahbari NN, Mehrabi A, Mollberg N, et al. Hepatocellular
carcinoma: current management and perspectives for the
future. Ann Surg 2011; 253(3):453–469.
19 Pawlik TM, Poon R, Abdalla E, et al. Critical appraisal of the
clinical and pathologic predictors of survival after resection
of large hepatocellular carcinoma. Arch Surg 2005; 140
(5):450–457; discussion 457–458.
20 Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors
contributing to early and late phase intrahepatic recurrence
of hepatocellular carcinoma after hepatectomy. J Hepatol
38(2):200–207.
2003;
21 Cheung TT, Poon R, Yuen W, et al. Long-term survival
analysis of pure laparoscopic versus open hepatectomy for
hepatocellular carcinoma in patients with cirrhosis: a singlecenter experience. Ann Surg 2013; 257(3):506–511.
22 Zhou YM, Shao W, Zhao Y, et al. Meta-analysis of laparo-
scopic versus open resection for hepatocellular carcinoma.
Dig Dis Sci 2011; 56(7):1937–1943.
23 Roayaie S, Jibara G, Taouli B, et al. Resection of hepato-
cellular carcinoma with macroscopic vascular invasion. Ann
Surg Oncol 2013; 20(12):3754–3760.
24 Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple
tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology, 2008;
134(7):1908–1916.
25 Hasegawa K, Makuuchi M, Kokudo N, et al. Impact of histolog-
ically confirmed lymph node metastases on patient survival
after surgical resection for hepatocellular carcinoma: report of a
Japanese nationwide survey. Ann Surg 2014; 259(1):166–170.
26 Xiaohong S, Huikai L, Feng W, et al. Clinical significance of
lymph node metastasis in patients undergoing partial hepatectomy for hepatocellular carcinoma. World J Surg 2010;
34(5):1028–1033.
27 Ercolani G, Grazi GL, Ravaioli M, et al. The role of lympha-
denectomy for liver tumors: further considerations on the
appropriateness of treatment strategy. Ann Surg 2004; 239
(2):202–209.
28 MazzaferroV, RegaliaE, Doci R, et al. Liver transplantation for
the treatment of small hepatocellular carcinomas in patients
with cirrhosis. N Engl J Med 1996; 334(11):693–699.
29 Cho YK, Kim J, Kim M, etal. Systematic review of randomized
trials for hepatocellular carcinoma treated withpercutaneous
ablation therapies. Hepatology 2009; 49(2):453–459.
30 Lencioni RA, Allgaier H, Cioni D, et al. Small hepatocellular
carcinoma in cirrhosis: randomized comparison of radio–
frequency thermal ablation versus percutaneous ethanol
injection. Radiology 2003; 228(1):235–240.
31 Germani G, Pleguezuelo M, Gurusamy K, et al. Clinical
outcomes of radiofrequency ablation, percutaneous alcohol
and acetic acid injection for hepatocelullar carcinoma: a
meta-analysis. J Hepatol 2010; 52(3):380–388.
32 Huang J, Yan L, Cheng Z, et al. A randomized trial comparing
radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg 2010; 252(6):903–912.
33 Chen MS, Li J, Zheng Y, et al. A prospective randomized trial
comparing
hepatectomy for small hepatocellular carcinoma. Ann Surg
2006; 243(3):321–328.
34 Feng K, Yan J, Li X, et al. A randomized controlled trial of
radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol 2012; 57
(4):794–802.
35 Ni JY, Xu L, Sun H, et al. Percutaneous ablation therapy
versus surgical resection in the treatment for early-stage
hepatocellular carcinoma: a meta-analysis of 21, 494
patients. J Cancer Res Clin Oncol 2013; 139(12):2021–2033.
36 Llovet JM., Schwartz M, Mazzaferro V. Resection and liver
transplantation for hepatocellular carcinoma. Semin Liver
Dis 2005; 25(2):181–200.
percutaneous local ablative therapy and partial
196 Chapter 12
37 Portolani N, Coniglio A, Ghidoni S, et al. Early and late
recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg
2006; 243(2):229–235.
38 Poon RT, Fan S, Ng I, et al. Different risk factors and prognosis
for early and late intrahepatic recurrence after resection of
hepatocellular carcinoma. Cancer 2000; 89(3):500–507.
39 Meric F, Patt Y, Curley S, et al. Surgery after downstaging of
unresectable hepatic tumors with intra-arterial chemotherapy. Ann Surg Oncol 2000; 7(7):490–495.
40 Lee KT, Lu Y, Wang S, et al. The effect of preoperative
transarterialchemoembolization of resectable hepatocellular
carcinoma on clinical and economic outcomes. J Surg Oncol
2009; 99(6):343–350.
41 Wu CC, Ho Y, Ho W, et al. Preoperative transcatheter arterial
chemoembolization for resectable large hepatocellular carcinoma: a reappraisal. Br J Surg 1995. 82(1):122–126.
42 Sasaki A, Iwashita Y, Shibata K, et al. Preoperative trans-
catheter arterial chemoembolization reduces long-term survival rate after hepatic resection for resectable hepatocellular
carcinoma. Eur J Surg Oncol 2006; 32(7):773–779.
43 Kishi Y, Saiura A, Yamamoto J, et al. Preoperative trans-
arterial chemoembolization for hepatocellular carcinoma.
Hepatogastroenterology 2012; 59(119):2295–2299.
44 Yamamoto M, Arii S, Sugahara K, et al. Adjuvant oral
chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. Br J Surg 1996;
83(3):336–340.
45 Ono T, Yamanoi A, Nazmy El Assal O, et al. Adjuvant
chemotherapy after resection of hepatocellular carcinoma
causes deterioration of long-term prognosis in cirrhotic
patients: metaanalysis of three randomized controlled trials.
Cancer 2001; 91(12):2378–2385.
46 Wilhelm SM, Carter C, Tang L, et al. BAY 43 – 9006 exhibits
broad spectrum oral antitumor activity and targets the RAF/
MEK/ERK pathway and receptor tyrosine kinases involved
in tumor progression and angiogenesis. Cancer Res 2004; 64
(19):7099–7109.
47 Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/
ERK pathway, inhibits tumor angiogenesis, and induces
tumor cell apoptosis in hepatocellular carcinoma model
PLC/PRF/5. Cancer Res 2006; 66(24):11851–11858.
48 Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced
hepatocellular carcinoma. N Engl J Med 2008; 359(4):378–390.
49 Barbier L, Muscari F, Le Guellec S, et al. Liver resection after
downstaging hepatocellular carcinoma with sorafenib. Int J
Hepatol 2011; 2011: 791013.
50 Bruix J, Takayama T, Mazzaferro V, et al .Adjuvant
orafenib for hepatocellular carcinoma after resection or
s
ablation (STORM): a phase 3, randomised , double- blind,
placebo-controlled trial. Lancet Oncol 2015; 16 (13):
1344–54.
51 Llovet JM, Real MI, Montana X, et al. Arterial embolisation or
chemoembolisation versus symptomatic treatment in
patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359(9319):1734–1739.
52 Lo CM, Ngan H, Tso W, et al. Randomized controlled trial of
transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35(5):1164–1171.
53 Doffoel M, Bonnetain F, Bouche O, et al. Multicentre rand-
omised phase III trial comparing Tamoxifen alone or with
Transarterial Lipiodol Chemoembolisation for unresectable
hepatocellular carcinoma in cirrhotic patients (Federation
Francophone de Cancerologie Digestive 9402). Eur J Cancer
2008; 44(4):528– 538.
54 Groupe d’Etude et de Traitement du Carcinome Hepatocel-
lulaire. A comparison of lipiodol chemoembolization and
conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med 1995; 332(19):1256–1261.
55 Lammer J, Malagari K, Vogl T, et al. Prospective randomized
study of doxorubicin-eluting-bead embolization in the
treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010; 33(1):41–52.
56 Varela M, Real MI, Burrel M, et al. Chemoembolization of
hepatocellular carcinoma with drug eluting beads: efficacy
and doxorubicin pharmacokinetics. J Hepatol 2007; 46
(3):474–481.
57 Salem R, Lewandowski RJ, Mulcahy M, et al. Radioembo-
lization for hepatocellular carcinoma using Yttrium-90
microspheres: a comprehensive report of long-term outcomes. Gastroenterology 2010; 138(1):52–64.
58 Klein J, Dawson LA. Hepatocellular carcinoma radiation
therapy: review of evidence and future opportunities. Int
J Radiat Oncol Biol Phys 2013; 87(1):22–32.
59 Bujold A, Massey CA, Kim J, et al. Sequential phase I and II trials
of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 2013; 31(13):1631–1639.
60 Sansonno D, Lauletta G, Russi S, et al. Transarterial chemo-
embolization plus sorafenib: a sequential therapeutic scheme
for HCV-related intermediate-stage hepatocellular carcinoma:
a randomized clinical trial. Oncologist 2012; 17(3):359–366.
61 Kudo M, Imanaka K, Chida N, et al. Phase III study of
sorafenib after transarterial chemoembolisation in Japanese
and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011; 47(14):2117–2127.
62 Lencioni RA, Llovet JM, Han G, et al. Sorafenib or placebo in
combination with transarterial chemoembolization (TACE)
with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): phase II, randomized, double-blind SPACE trial. J Clin Oncol 2012; 30
(suppl 4): abstr. LBA154.
63 Wahl DR, Stenmark MH, Tao Y, et al. O
utcomes after stereotactic body radiotherapy or radiofrequency ablation for hepatocellular carcinoma. J Clin Oncol 2015 (epub ahead of print).
64 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
2015 (epub ahead of print).
65 Huang M, Liu G. The study of innate drug resistance of
human hepatocellular carcinoma Bel7402 cell line. Cancer
Lett 1999; 135(1):97–105.
Oncological management of primary liver cancer 197
66 Kato A, Miyazaki M, Ambiru S, et al. Multidrug resistance
gene (MDR-1) expression as a useful prognostic factor in
patients with human hepatocellular carcinoma after surgical
resection. J Surg Oncol 2001; 78(2):110–115.
67 Chenivesse X, Franco D, Brechot C. MDR1 (multidrug
resistance) gene expression in human primary liver cancer
and cirrhosis. J Hepatol 1993; 18(2):168–172.
68 Lai CL, Wu PC, Chan G, et al. Doxorubicin versus no anti-
tumor therapy in inoperable hepatocellular carcinoma. A
prospective randomized trial. Cancer 1988; 62(3):479–483.
69 Gish RG, Porta C, Lazar L, et al. Phase III randomized con-
trolled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or
doxorubicin. J Clin Oncol 2007; 25(21):3069–3075.
70 Fuchs CS, Clark JW, Ryan D, et al. A phase II trial of
gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 2002; 94(12):3186–3191.
71 Yang TS, Lin Y, Chen J, et al. Phase II study of gemcitabine in
patients with advanced hepatocellular carcinoma. Cancer
2000; 89(4):750– 756.
72 O’Reilly EM, Stuart K, Sanz-Altamira P, et al. A phase II study
of irinotecan in patients with advanced hepatocellular carcinoma. Cancer 2001; 91(1):101–105.
73 Chao Y, Chan W, Birkhofer M, et al. Phase II and pharmaco-
kinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer 1998; 78(1):34–39.
74 Patt YZ, Hassan M, Aguayo A, et al. Oral capecitabine for the
treatment of hepatocellular carcinoma, cholangiocarcinoma,
and gallbladder carcinoma. Cancer 2004; 101(3):578–586.
75 Yeo W, Mok T, Zee B, et al. A randomized phase III study of
doxorubicin versus cisplatin/interferon alpha02b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for
unresectable hepatocellular carcinoma. J Natl Cancer Inst
2005; 97(20):1532–1538.
76 Qin S, Bai Y, Lim H, et al. Randomized, multicenter, open-
label study of oxaliplatin plus fluorouracil/leucovorin versus
doxorubicin as palliative chemotherapy in patients with
advanced hepatocellular carcinoma from Asia. J Clin Oncol
2013; 31(28):3501–3508.
77 Semela D, Dufour JF. Angiogenesis and hepatocellular car-
cinoma. J Hepatol 2004; 41(5):864–880.
78 Cheng AL, Kang Y, Chen Z, et al. Efficacy and safety of
sorafenib in patients in the Asia-Pacific region with
advanced hepatocellular carcinoma: a phase III randomised,
double-blind, placebo-controlled trial. Lancet Oncol 2009;
10(1):25–34.
Cheng AL, Kang Y, Lin D, et al. Sunitinib versus sorafenib in
79
advanced hepatocellular cancer: results of a randomized
phase III trial. J Clin Oncol 2013; 31(32):4067–4075.
80 Johnson PJ, Qin S, Park J, et al. Brivanib versus sorafenib as
first-line therapy in patients with unresectable, advanced
hepatocellularcarcinoma: results from therandomizedphase
III BRISK-FL study. J Clin Oncol 2013; 31(28):3517–3524.
81 Cainap C, Qin S, Huang W, et al. Phase III trial of linifanib versus
sorafenib in patients with advanced hepatocellular carcinoma
(HCC). J Clin Oncol 2013; 30 (suppl 34); abstr. 249.
82 Zhu AX, Rosmorduc O, Evans T, et al. SEARCH: a phase III,
randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with hepatocellular carcinoma (HCC). Presented at the 37th Annual European
Society for Medical Oncology Congress, Vienna, Austria,
2012. Abstract 917.
83 Zhu AX, Park JO, Ryoo BY, et al. Ramucirumab versus placebo
as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib
(REACH): a randomised, double-blind, multicentre, phase 3
trial. Lancet Oncol 2015; 16(7):859–870.
84 Zhu AX, Kudo M, Assenat E, et al. Effect of everolimus on
survival in advanced hepatocellular carcinoma after failure
of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA
2014; 312(1):57– 67.
85 Finn RS. Emerging targeted strategies in advanced hepato-
cellular carcinoma. Semin Liver Dis 2013; 33 (suppl 1):S11–19.
86 Knox JJ, Cleary SP, Dawson LA. Localized and systemic
approaches to treating hepatocellular carcinoma. J Clin
Oncol 2015; 33(16):1835–1844.
87 El-Khoueiry AB, Melero I, Todd S, et al. Phase I/II safety and
antitumor activity of nivolumab in patients with advanced
hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol
2015; 33(suppl): abstr LBA101.
88 Nakeeb A, Pitt H, Sohn T, et al. Cholangiocarcinoma. A
spectrum of intrahepatic, perihilar, and distal tumors.
Ann Surg 1996; 224(4):463–473; discussion 473–475.
89 Shaib YH, Davila J, McGlynn K, et al. Rising incidence of
intrahepatic cholangiocarcinoma in the United States: a true
increase? J Hepatol 2004; 40(3):472–477.
90 Endo I, Gonen M, Yopp A, et al. Intrahepatic cholangiocarci-
noma: rising frequency, improved survival, and determinants
of outcome after resection. Ann Surg 2008; 248(1):84–96.
91 Wade TP, Prasad C, Virgo K, et al. Experience with distal bile
duct cancers in U.S. Veterans Affairs hospitals: 1987–1991. J
Surg Oncol 1997; 64(3):242–245.
92 Aljiffry M, Abdulelah A, Walsh M, et al. Evidence-based
approach to cholangiocarcinoma: a systematic review of the
literature. J Am Coll Surg 2009; 208(1):134–147.
current
93 DeOliveira ML, Cunningham S, Cameron J, et al. Cholan-
giocarcinoma: thirty-one-year experience with 564 patients
at a single institution. Ann Surg 2007; 245(5):755–762.
94 Jarnagin WR, Ruo L, Little S, et al. Patterns of initial disease
recurrence after resection of gallbladder carcinoma and hilar
cholangiocarcinoma: implications for adjuvant therapeutic
strategies. Cancer 2003; 98(8):1689–1700.
95 Kitagawa Y, Nagino M, Kamiya J, et al. Lymph node metas-
tasis from hilar cholangiocarcinoma: audit of 110 patients
who underwent regional and paraaortic node dissection.
Ann Surg 2001; 233(3):385–392.
96 Ito K, Ito H, Allen P, et al. Adequate lymph node assessment
for extrahepatic bile duct adenocarcinoma. Ann Surg 2010;
251(4):675–681.
97 Aoba T, Ebata T, Yokoyama Y, et al. Assessment of nodal
status for perihilar cholangiocarcinoma: location, number,
or ratio of involved nodes. Ann Surg 2013; 257(4):718–725.
198 Chapter 12
98 Adachi T, Eguchi S. Lymph node dissection for intrahepatic
cholangiocarcinoma: a critical review of the literature to
date. J Hepatobiliary Pancreat Sci 2014; 21(3):162–168.
99 Takada T, Amano H, Yasuda H, et al. Is postoperative adju-
vant chemotherapy useful for gallbladder carcinoma? A
phase III multicenter prospective randomized controlled
trial in patients with resected pancreaticobiliary carcinoma.
Cancer 2002; 95(8):1685–1695.
100 Neoptolemos JP, Moore M, Cox T, et al. Effect of adjuvant
chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected
periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 2012; 308(2):147–156.
101 Kraybill WG, Lee H, Picus J, et al. Multidisciplinary treatment
of biliary tract cancers. J Surg Oncol 1994; 55(4):239–245.
102 Todoroki T, Ohara K, Kawamoto T, et al. Benefits of adjuvant
radiotherapy after radical resection of locally advanced main
hepatic duct carcinoma. Int J Radiat Oncol Biol Phys 2000;
46(3):581–587.
103 Gerhards MF, van Gulik TM, Gonzalez Gonzalez D, et al.
Results of postoperative radiotherapy for resectable hilar
cholangiocarcinoma. World J Surg 2003; 27(2):173–179.
104 Pitt HA, Nakeeb A, Abrams R, et al. Perihilar cholangiocar-
cinoma. Postoperative radiotherapy does not improve survival. Ann Surg 1995; 221(6):788–797; discussion 797–798.
105 Gonzalez Gonzalez D, Gouma DJ, Rauws E, et al. Role of
radiotherapy, in particular intraluminal brachytherapy, in
the treatment of proximal bile duct carcinoma. Ann Oncol
1999; 10 (suppl 4):215–220.
106 Vern-Gross TZ, Shivnani A, Chen K, et al. Survival outcomes in
resected extrahepatic cholangiocarcinoma: effect of adjuvant
radiotherapy in a surveillance, epidemiology, and end results
analysis. Int J Radiat Oncol Biol Phys 2011; 81(1):189–198.
107 Gwak HK, Kim W, Kim H, et al. Extrahepatic bile ductcancers:
surgery alone versus surgery plus postoperative radiation
therapy. Int J Radiat Oncol Biol Phys 2010; 78(1):194–198.
108 Borghero Y, Crane CH, Szklaruk J, et al. Extrahepatic bile duct
adenocarcinoma: patients at high-risk for local recurrence
treated with surgery and adjuvant chemoradiation have an
equivalent overall survival to patients with standard-risk treated
with surgery alone. Ann Surg Oncol 2008; 15(11):3147–3156.
109 Kim TH, Han S, Park S, et al. Role of adjuvant chemo-
radiotherapy for resected extrahepatic biliary tract cancer.
Int J Radiat Oncol Biol Phys 2011; 81(5):e853–859.
110 Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809:
a phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine
in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol 2015; 33(24):2617–2622
.
111 Gold DG, Miller R, Haddock M, et al. Adjuvant therapy for
gallbladder carcinoma: the Mayo Clinic Experience. Int J
Radiat Oncol Biol Phys 2009; 75(1):150–155.
112 ChoSY,KimS,ParkS,et al. Adjuvant chemoradiation therapy
in gallbladder cancer. J Surg Oncol 2010; 102(1):87–93.
113 Wang SJ, Lemieux A, Kalpathy-Cramer J, et a l. Nomogram
for predict ing the be nefi t of adjuvant chemoradiotherapy
for resected gallbladder cancer. J Clin Oncol 2011;
29(35):4627–4632.
114 Horgan AM, Amir E, Walter T, et al. Adjuvant therapy in the
treatment of biliary tract cancer: a systematic review and
meta-analysis. J Clin Oncol 2012; 30(16):1934–1940.
115 Nelson JW, Ghafoori AP, Willett C, et al. Concurrent chemo-
radiotherapy in resected extrahepatic cholangiocarcinoma.
Int J Radiat Oncol Biol Phys 2009; 73(1):148–153.
116 McMasters KM, Tuttle T, Leach S, et al. Neoadjuvant chemo-
radiation for extrahepatic cholangiocarcinoma. Am J Surg
1997; 174(6):605–608; discussion 608–609.
117 Ghafoori AP, Nelson J, Willett C, et al. Radiotherapy in the
treatment of patients with unresectable extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys 2011; 81(3):654–659.
118 Gusani NJ, BalaaFK, Steel JL, et al.Treatment of unresectable
cholangiocarcinoma with gemcitabine-based transcatheter
arterial chemoembolization (TACE): a single-institution
experience. J Gastrointest Surg 2008; 12(1):129–137.
119 Vogl TJ, Naguib NN, Nour-Eldin NE, et al. Transarterial chemo-
embolization in the treatment of patients with unresectable
cholangiocarcinoma: results and prognostic factors governing
treatment success. Int J Cancer 2012; 131(3):733–740.
120 Saxena A, Bester L, Chua TC, et al. Yttrium-90 radiotherapy
for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg
Oncol 2010; 17(2):484–491.
121 Rafi S, Piduru SM, El-Rayes B, et al. Yttrium-90 radioembo-
lization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety
study. Cardiovasc Intervent Radiol 2013; 36(2):440–448.
122 Mouli S, Memon K, Baker T, et al. Yttrium-90 radioemboliza-
tion for intrahepatic cholangiocarcinoma: safety, response, and
survival analysis. J Vasc Interv Radiol 2013; 24(8):1227–1234.
123 Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy for
advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol 2013; 20(12):3779–3786.
Glimelius B, Hoffman K, Sjoden P, et al. Chemotherapy
124
improves survival and quality of life in advanced pancreatic
and biliary cancer. Ann Oncol 1996; 7(6):593–600.
125 Eckel F, Schmid RM. Chemotherapy in advanced biliary
tract carcinoma: a pooled analysis of clinical trials. Br J
Cancer 2007; 96(6):896–902.
126 Valle J, Wasan H, Palmer D, et al. Cisplatin plus gemcitabine
versus gemcitabine for biliary tract cancer. N Engl J Med
2010; 362(14):1273–1281.
127 Okusaka T, Nakachi K, Fukutomi A, et al. Gemcitabine alone
or in combination with cisplatin in patients with biliary tract
cancer: a comparative multicentre study in Japan. Br J
Cancer 2010; 103(4):469–474.
128 Andre T, Tournigand C, Rosmorduc O, et al. Gemcitabine
combined with oxaliplatin (GEMOX) in advanced biliary
tract adenocarcinoma: a GERCOR study. Ann Oncol 2004;
15(9):1339–1343.
129 Andre T, Reyes-Vidal JM, Fartoux L, et al. Gemcitabine and
oxaliplatin in advanced biliary tract carcinoma: a phase II
study. Br J Cancer 2008; 99(6):862–867.
Соседние файлы в папке Библиотека им академика М.И. Перельмана