Chemotherapy for Biliary Tract Cancer in 2021

Takashi Sasaki; Tsuyoshi Takeda; Takeshi Okamoto; Masato Ozaka; Naoki Sasahira

doi:10.3390/jcm10143108

. 2021 Jul 14;10(14):3108. doi: 10.3390/jcm10143108

Chemotherapy for Biliary Tract Cancer in 2021

Takashi Sasaki ^1,^*, Tsuyoshi Takeda ¹, Takeshi Okamoto ¹, Masato Ozaka ¹, Naoki Sasahira ¹

Editor: Stanley W Ashley¹

PMCID: PMC8305063 PMID: 34300274

Abstract

Biliary tract cancer refers to a group of malignancies including cholangiocarcinoma, gallbladder cancer, and ampullary cancer. While surgical resection is considered the only curative treatment, postoperative recurrence can sometimes occur. Adjuvant chemotherapy is used to prolong prognosis in some cases. Many unresectable cases are also treated with chemotherapy. Therefore, systemic chemotherapy is widely introduced for the treatment of biliary tract cancer. Evidence on chemotherapy for biliary tract cancer is recently on the increase. Combination chemotherapy with gemcitabine and cisplatin is currently the standard of care for first-line chemotherapy in advanced cases. Recently, FOLFOX also demonstrated efficacy as a second-line treatment. In addition, efficacies of isocitrate dehydrogenase inhibitors and fibroblast growth factor receptor inhibitors have been shown. In the adjuvant setting, capecitabine monotherapy has become the standard of care in Western countries. In addition to conventional cytotoxic agents, molecular-targeted agents and immunotherapy have been evaluated in multiple clinical trials. Genetic testing is used to check for genetic alterations and molecular-targeted agents and immunotherapy are introduced based on tumor characteristics. In this article, we review the latest evidence of chemotherapy for biliary tract cancer.

Keywords: biliary tract cancer, cholangiocarcinoma, chemotherapy, cytotoxic agents, molecular targeted agents, immunotherapy, precision medicine, genetic testing

1. Introduction

Biliary tract cancer is a heterogeneous group of highly aggressive cancers including intrahepatic/perihilar/distal cholangiocarcinoma, gallbladder cancer, and ampullary cancer [1]. Biliary tract cancer is common in Japan, Southeast Asia, South America, and India [2,3]. Cholangiocarcinoma has been increasing worldwide, while the incidence of gallbladder cancer has been decreasing in recent years [4,5,6]. In Japan, the incidence and mortality of biliary tract cancer have plateaued over the last decade, with an annual incidence and mortality of approximately 22,000 and 18,000, respectively [7]. This cancer is still the sixth leading cause of cancer-related death. In Japan, more than 45% of new cases are diagnosed over the age of 80.

While surgical resection is considered the only curative treatment, postoperative recurrence can sometimes occur. Data from the biliary tract cancer registry in Japan revealed that five-year survival rates were 39.8% for gallbladder cancer, 24.2% for perihilar cholangiocarcinoma, 39.1% for distal cholangiocarcinoma, and 61.3% for ampullary cancer [8]. Adjuvant chemotherapy is sometimes introduced to achieve long-term survival for resected cases with poor prognostic factors. Many unresectable cases are also treated with chemotherapy. As surgery for biliary tract cancer is a highly invasive procedure, surgery may be avoided in potentially resectable cases due to old age or comorbidities. Therefore, systemic chemotherapy is widely introduced for the treatment of biliary tract cancer. Recently, evidence on chemotherapy for biliary tract cancer is on the increase. In addition to conventional cytotoxic agents, molecular-targeted agents and immunotherapy have widely been introduced in this field. Genetic testing is used to check for genetic alterations and molecular-targeted agents and immunotherapy are introduced based on tumor characteristics. Here, we review the latest evidence on chemotherapy for biliary tract cancer.

2. First-Line Chemotherapy for Advanced Biliary Tract Cancer

Standard chemotherapy for biliary tract cancer was not established until about 2000. Until then, chemotherapy for pancreatic cancer had been used as a reference. The efficacy of chemotherapy was confirmed in a randomized control study conducted before 2000 which compared chemotherapy to best supportive care in advanced pancreatic and biliary tract cancers [9]. Subsequently, a randomized controlled study comparing chemotherapy and best supportive care for unresectable gallbladder cancer was reported from India in 2010, confirming the usefulness of chemotherapy [10]. Between 2000 and 2010, gemcitabine and 5-fluorouracil were considered the key drugs for the treatment of advanced cases. A pooled analysis of clinical trials conducted between 1985 and 2006 identified gemcitabine, fluoropyrimidines, and cisplatin as the key active agents and concluded that gemcitabine combined with platinum compounds represented the provisional standard of chemotherapy for advanced biliary tract cancer [11].

The combination chemotherapy of gemcitabine and platinum compounds demonstrated good efficacy in advanced cases. A randomized phase II study (ABC-01) comparing the doublet of gemcitabine and cisplatin to gemcitabine alone was reported from the United Kingdom [12]. The doublet regimen was associated with improved tumor control and progression-free survival. Based on this result, the study was extended to a phase III study (ABC-02) to verify the prognostic effect of the combination chemotherapy relative to gemcitabine monotherapy [13]. Four hundred ten patients were randomized to receive either gemcitabine and cisplatin combination chemotherapy or gemcitabine alone. The primary endpoint was overall survival. The median overall survival was 11.7 months in the combination group and 8.1 months in the monotherapy group (hazard ratio, 0.64; p < 0.001). The median progression-free survivals of the combination and monotherapy groups were 8.0 months and 5.0 months, respectively (p < 0.001). The rate of tumor control among patients in the combination group was significantly increased (81.4% vs. 71.8%, p = 0.049). Although neutropenia occurred more frequently in the combination group, combination chemotherapy with gemcitabine and cisplatin was considered a feasible regimen for advanced biliary tract cancer. This combination chemotherapy was also evaluated in Japanese patients and similar efficacy was confirmed in a multicenter, randomized phase II study (BT-22) [14]. Treatment was repeated for up to 24 weeks in the ABC-02 study and up to 48 weeks in the BT-22 study. In a meta-analysis of these two studies, the efficacy of gemcitabine and cisplatin combination chemotherapy was confirmed in patients with good performance status (performance status of 0 or 1) and in patients with cholangiocarcinoma or gallbladder cancer [15]. On the other hand, the superiority of this combination chemotherapy was not shown in patients with poor performance status or ampullary cancer. The major grade 3/4 adverse events of gemcitabine and cisplatin combination chemotherapy were neutropenia and anemia. We also need to pay attention to renal dysfunction and hearing loss. Oxaliplatin is another platinum compound known to cause less renal damage and therefore does not require aggressive hydration, unlike cisplatin. Oxaliplatin is sometimes used as a substitute for cisplatin. However, the non-inferiority of gemcitabine and oxaliplatin combination chemotherapy, when compared to gemcitabine and cisplatin combination chemotherapy, has not been proven. One randomized controlled study comparing these two regimens was conducted in India [16]. A total of 243 patients with unresectable gallbladder cancer were randomly assigned to one of these two regimens. The median overall survivals of gemcitabine and oxaliplatin combination chemotherapy and gemcitabine and cisplatin combination chemotherapy were 9.0 months and 8.3 months, respectively (hazard ratio, 0.78; p = 0.057). Because the predetermined statistical threshold was not met, the study failed to prove non-inferiority. Moreover, this study was underpowered to determine the superiority of gemcitabine and oxaliplatin combination chemotherapy.

Several randomized controlled studies have been conducted in pursuit of treatment regimens that are superior to the standard treatment of gemcitabine and platinum compounds. Some involved combination chemotherapies which added a third drug to the doublet, while others involved a novel regimen. Table 1 summarizes previous randomized controlled studies on first-line chemotherapy for advanced biliary tract cancer. No additional benefits of epidermal growth factor receptor and vascular endothelial growth factor receptor inhibitors have been observed to date [17]. On the other hand, good results have been obtained with S-1, which is widely used in Japan [18,19].

Table 1.

Randomized controlled studies on first-line chemotherapy for advanced biliary tract cancer.

Authors	Year	Regimen	Phase	Result	N	RR	Median PFS	Median OS
Valle et al. [13]	2010	GemCis	3	Positive	204	26.1%	8.0 M	11.7 M
Valle et al. [13]	2010	GEM	3	Positive	206	15.5%	5.0 M	8.1 M
Sharma et al. [10]	2010	GEMOX	3	Positive	26	30.7%	8.5 M	9.5 M
		5FU + FA			28	14.3%	3.5 M	4.6 M
		BSC			27	0%	2.8 M	4.5 M
Lee et al. [17]	2012	GEMOX + Erlotinib	3	Negative	135	29.6%	5.8 M	9.5 M
Lee et al. [17]	2012	GEMOX	3	Negative	133	15.8%	4.2 M	9.5 M
Sharma et al. [16]	2019	GEMOX	3	Negative	119	25.2%	5.0 M	9.0 M
Sharma et al. [16]	2019	GemCis	3	Negative	124	23.4%	4.0 M	8.3 M
Morizane et al. [18]	2019	GEM + S-1	3	Positive	179	29.8%	6.8 M	15.1 M
Morizane et al. [18]	2019	GemCis	3	Positive	175	32.4%	5.8 M	13.4 M
Sakai et al. [19]	2018	GemCis + S-1	3	Positive	123	41.5%	7.4 M	13.5 M
Sakai et al. [19]	2018	GemCis	3	Positive	123	15.0%	5.5 M	12.6 M
Kim et al. [20]	2019	Cape + Oxaliplatin	3	Positive	108	15.7%	5.8 M	10.6 M
Kim et al. [20]	2019	GEMOX	3	Positive	114	24.6%	5.3 M	10.4 M
Phelip et al. [21]	2020	mFOLFIRINOX	2/3	Negative	94	25.0%	6.2 M	11.7 M
Phelip et al. [21]	2020	GemCis	2/3	Negative	96	19.4%	7.4 M	14.3 M
Kang et al. [22]	2012	S-1 + CDDP	rP2	Positive	47	23.8%	5.4 M	9.9 M
Kang et al. [22]	2012	GemCis	rP2	Positive	49	19.6%	5.7 M	10.1 M
Lee et al. [23]	2015	Cape + CDDP	rP2	Positive	44	27.3%	5.2 M	10.7 M
Lee et al. [23]	2015	GemCis	rP2	Positive	49	6.1%	3.6 M	8.6 M
Malka et al. [24]	2014	GEMOX + Cmab	rP2	Negative	76	23.1%	6.0 M	11.0 M
Malka et al. [24]	2014	GEMOX	rP2	Negative	74	29.0%	5.3 M	12.4 M
Chen et al. [25]	2015	GEMOX + Cmab	rP2	Negative	62	27.4%	6.7 M	10.6 M
Chen et al. [25]	2015	GEMOX	rP2	Negative	60	16.7%	4.1 M	9.8 M
Leone et al. [26]	2016	GEMOX + Pmab	rP2	Negative	45	24.4%	7.7 M	9.5 M
Leone et al. [26]	2016	GEMOX	rP2	Negative	44	18.2%	5.5 M	9.9 M
Vogel et al. [27]	2018	GemCis + Pmab	rP2	Negative	62	45.2%	6.5 M	12.8 M
Vogel et al. [27]	2018	GemCis	rP2	Negative	28	39.3%	8.3 M	20.1 M
Valle et al. [28]	2015	GemCis + Cediranib	rP2	Negative	62	44.1%	7.7 M	14.1 M
Valle et al. [28]	2015	GemCis	rP2	Negative	62	18.5%	7.4 M	11.9 M
Moehler et al. [29]	2014	GEM + Sorafenib	rP2	Negative	52	14.3%	3.0 M	8.4 M
Moehler et al. [29]	2014	GEM	rP2	Negative	50	10.0%	4.9 M	11.2 M
Santoro et al. [30]	2015	GEM + Vandetanib	rP2	Negative	58	19.3%	3.8 M	9.5 M
		GEM			56	13.5%	4.9 M	10.2 M
		Vandetanib			59	3.6%	3.5 M	7.6 M
Schnizari et al. [31]	2017	FOLFOX4	rP2	Positive	25	28.0%	5.2 M	13.0 M
Schnizari et al. [31]	2017	5FU + LV	rP2	Positive	23	21.7%	2.8 M	7.5 M
Markussen et al. [32]	2020	GEMOX + Cape	rP2	Negative	47	17.0%	5.7 M	8.7 M
Markussen et al. [32]	2020	GemCis	rP2	Negative	49	16.3%	7.3 M	12.0 M
dos Santos et al. [33]	2020	CPT-11 + CDDP	rP2	Positive	24	35%	5.3 M	11.9 M
dos Santos et al. [33]	2020	GemCis	rP2	Positive	23	31.8%	7.8 M	9.8 M

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N; number, RR; response rate, PFS; progression-free survival, OS; overall survival, M; months, rP2; randomized phase II study, GemCis; gemcitabine + cisplatin, GEM; gemcitabine, GEMOX; gemcitabine + oxaliplatin, 5FU; 5-fluorouracil, FA; folinic acid, BSC; best supportive care, CDDP; cisplatin, Cape; capecitabine, mFOLFIRINOX; modified FOLFIRINOX (5-fluorouracil + leucovorin + irinotecan + oxaliplatin), Cmab; cetuximab, Pmab; panitumumab; FOLFOX; 5-fluorouracil + leucovorin + oxaliplatin, LV; leucovorin, CPT-11; irinotecan.

S-1 is an oral fluoropyrimidine derivative used mainly in Asian countries. The combination of gemcitabine and S-1 was widely evaluated in phase II and randomized phase II studies in Japan [34,35,36,37]. Based on these results, a randomized phase III study comparing gemcitabine and S-1 combination chemotherapy with gemcitabine and cisplatin combination chemotherapy was conducted in Japan [18]. This study was conducted to evaluate the non-inferiority of gemcitabine and S-1 combination chemotherapy compared to gemcitabine and cisplatin combination chemotherapy. Patients with advanced biliary tract cancer were randomly assigned either gemcitabine and S-1 combination chemotherapy or gemcitabine and cisplatin combination chemotherapy. The primary endpoint was overall survival. The median overall survivals were 15.1 months and 13.4 months, respectively (hazard ratio 0.945, p = 0.046 for non-inferiority). Because the toxicities of gemcitabine and S-1 combination chemotherapy were deemed acceptable, this new doublet also became the standard of care for patients with advanced biliary tract cancer. The major grade 3/4 adverse event of gemcitabine and S-1 combination chemotherapy was neutropenia. We also need to pay attention to diarrhea, oral mucositis, maculopapular rash, and skin hyperpigmentation. S-1 was also evaluated as the triplet with gemcitabine and cisplatin. Based on the good result of a phase II study evaluating the efficacy of gemcitabine + cisplatin + S-1 combination chemotherapy [38], a phase III study was conducted to confirm the superiority of this triplet over gemcitabine and cisplatin combination chemotherapy in Japan [19]. Two hundred forty-six patients with advanced biliary tract cancer were randomized 1:1 to receive either the triplet or the doublet chemotherapy. The primary endpoint was overall survival. The median overall survivals of gemcitabine + cisplatin + S-1 combination chemotherapy and gemcitabine + cisplatin combination chemotherapy were 13.5 months and 12.6 months, respectively (hazard ratio 0.791, p = 0.046). This adverse event’s profile of the triplet chemotherapy was also acceptable. The major grade 3/4 adverse event of triplet chemotherapy was also neutropenia. This triplet is also needed to pay attention to diarrhea, stomatitis, and rash. Therefore, gemcitabine + cisplatin + S-1 combination chemotherapy is currently considered a standard regimen for advanced cases.

In summary, the global standard first-line chemotherapy for advanced biliary tract cancer is still gemcitabine and cisplatin combination chemotherapy. In Japan, gemcitabine + S-1 combination chemotherapy and gemcitabine + cisplatin + S-1 combination chemotherapy are also considered alternatives of gemcitabine + cisplatin combination chemotherapy in the first-line setting.

3. Second-Line Chemotherapy for Advanced Biliary Tract Cancer

The usefulness of second-line chemotherapy has been reported based on a systematic review and large retrospective studies, but standard treatment has not been established [39,40,41,42,43,44,45]. In Japan, S-1 is widely used as monotherapy in the clinical setting [46,47]. To establish the standard treatment of second-line chemotherapy, various treatments such as molecular-targeted agents and immunotherapy are being developed in addition to conventional cytotoxic agents [48]. Recently, several randomized phase II and phase III studies were reported, some of which showed positive results. Table 2 summarizes previous randomized controlled studies of second-line or third-line chemotherapy for advanced biliary tract cancer.

Table 2.

Randomized controlled studies on second-line or third-line chemotherapy for advanced biliary tract cancer.

Authors	Year	Regimen	Phase	Result	N	RR	Median PFS	Median OS
Abou-Alfa et al. [49]	2020	Ivosidenib	3	Positive	124	2.4%	2.7 M	10.8 M
Abou-Alfa et al. [49]	2020	BSC	3	Positive	61	0%	1.4 M	9.7 M
Lamarca et al. [50]	2021	FOLFOX	3	Positive	81	4.9%	4.0 M	6.2 M
Lamarca et al. [50]	2021	ASC	3	Positive	81	-	-	5.3 M
Jalve et al. [51]	2020	Cape + Varlitinib	2/3	Negative	64	9.4%	2.8 M	7.8 M
Jalve et al. [51]	2020	Cape	2/3	Negative	63	4.8%	2.8 M	7.5 M
Cereda et al. [52]	2016	Cape + MMC	rP2	Negative	29	3.4%	2.3 M	8.1 M
Cereda et al. [52]	2016	Cape	rP2	Negative	28	0%	2.1 M	9.5 M
Zheng et al. [53]	2018	Cape + Irinotecan	rP2	Positive	30	13.3%	3.7 M	10.1 M
Zheng et al. [53]	2018	Irinotecan	rP2	Positive	30	6.7%	2.4 M	7.3 M
Kim et al. [54]	2020	Trametinib	rP2	Negative	24	8.3%	1.4 M	4.3 M
Kim et al. [54]	2020	5FU + LV or Cape	rP2	Negative	20	10.0%	3.3 M	6.6 M
Demols et al. [55]	2020	Regorafenib	rP2	Positive	33	0%	3.0 M	5.3 M
Demols et al. [55]	2020	BSC	rP2	Positive	33	0%	1.5 M	5.1 M
Ueno et al. [56]	2021	S-1 + Resminostat	rP2	Negative	50	6.0%	2.9 M	7.8 M
Ueno et al. [56]	2021	S-1	rP2	Negative	51	9.8%	3.0 M	7.5 M
Ramaswamy et al. [57]	2021	Cape + Irinotecan	rP2	Negative	49	6.1%	2.3 M	5.2 M
Ramaswamy et al. [57]	2021	Irinotecan	rP2	Negative	49	0%	3.1 M	6.3 M
Yoo et al. [58]	2021	5FU + LV + nal-IRI	rP2	Positive	88	14.8%	7.1 M	8.6 M
Yoo et al. [58]	2021	5FU + LV	rP2	Positive	86	5.8%	1.4 M	5.5 M

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N; number, RR; response rate, PFS; progression-free survival, OS; overall survival, M; months, rP2; randomized phase 2 study, BSC; best supportive care, FOLFOX; 5-fluorouracil + leucovorin + oxaliplatin, ASC; active symptom control, Cape; capecitabine, MMC; mitomycin-C, 5FU; 5-fluorouracil, LV; leucovorin, nal-IRI; nano-liposomal irinotecan.

A phase III study (ABC-06) comparing FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) and active symptom control was conducted in the United Kingdom [50]. Patients with advanced biliary tract cancer treated previously with gemcitabine and cisplatin combination chemotherapy were included. Enrolled patients were randomized to receive either FOLFOX or active symptom control, which was the equivalent of best supportive care. Patients in the active symptom control group could receive FOLFOX after radiographic disease progression was confirmed. The primary endpoint was overall survival. The median overall survivals of FOLFOX and active symptom control groups were 6.2 months and 5.3 months, respectively (hazard ratio 0.69, p = 0.031). The benefit of FOLFOX was consistent across subgroups, including those with platinum sensitivity during first-line chemotherapy. The major grade 3/4 adverse events of FOLFOX were neutropenia, fatigue, and catheter-related infection. We also need to pay attention to peripheral neuropathy. This study was the first prospective phase III study that confirmed the benefit of chemotherapy after combination chemotherapy with gemcitabine and cisplatin. Another positive phase III study that showed the efficacy of second-line chemotherapy was the ClarIDHy study. This study was a global phase III study comparing ivosidenib and best supportive care. Ivosidenib is a first-in-class, oral, targeted, small-molecule inhibitor of mutant isocitrate dehydrogenase (IDH) 1 protein. IDH1 mutations occur in up to 20% of cholangiocarcinomas. Patients with advanced cholangiocarcinoma who had received 1–2 prior therapies were enrolled in this study. Patients were randomly assigned to either the ivosidenib group or the best supportive care group. The primary endpoint was progression-free survival. The median progression-free survivals of the ivosidenib and best supportive care groups were 2.7 months and 1.4 months, respectively (hazard ratio 0.37, p < 0.001). The major grade 3/4 adverse events of ivosidenib were reported as ascites. This study was the first prospective phase III study that demonstrated a clinical benefit in targeting a molecularly defined subgroup of cholangiocarcinoma and in evaluating genetic profiles of biliary tract cancer. In 2021, the result of a randomized phase II study (NIFTY) comparing 5-fluorouracil + leucovorin + nano-liposomal irinotecan and 5-fluorouracil + leucovorin was reported [58]. This triplet chemotherapy is now known as the NAPOLI regimen and is widely used for second-line chemotherapy in advanced pancreatic cancer. The additional benefit of nano-liposomal irinotecan was demonstrated in this study. Two other randomized phase II studies also showed positive results with capecitabine and irinotecan combination chemotherapy and with regorafenib monotherapy. However, the number of patients enrolled in these studies was relatively small. Therefore, further evaluation is required to establish more solid evidence on these two regimens.

Biliary tract cancers are a heterogeneous group of cancers with different genetic alteration profiles [59,60,61,62]. Potential clinically actionable alterations, defined as oncogenic driver alterations with matched therapeutic agents either under investigation or approved in other tumor types, were identified in 44.5% of patients, showing promise for precision medicine in this field [62]. Common genes implicated in biliary tract cancer tumorigenesis include IDH1, IDH2, fibroblast growth factor receptor (FGFR) 1, FGFR2, FGFR3, and human epidermal growth factor receptor (HER) 2. Encouraging results were seen in patients with identified mutational targets, especially in tumors harboring FGFR2 fusions, HER2, and IDH mutations. The efficacy of an IDH1 inhibitor (ivosidenib) was shown in a phase III study [49]. Several FGFR inhibitors have been evaluated in phase II studies [63,64,65,66]. FGFR2 rearrangements were reported in 7.4% and 3.6% of Japanese intrahepatic cholangiocarcinoma and perihilar cholangiocarcinoma patients, respectively [67]. Based on the results of a phase II study (FIGHT-202) [65], pemigatinib was approved in many countries for patients with FGFR2 fusion or rearrangement. The major grade 3/4 adverse events of pemigatinib were hypophosphatemia, arthralgia, stomatitis, hyponatremia, abdominal pain, and fatigue.

The efficacies of pembrolizumab for microsatellite instability (MSI)-high solid tumors [68] and neurotrophic tyrosine receptor kinase (NTRK) inhibitors (entrectinib and larotrectinib) for solid tumors with NTRK fusion have also been reported [69,70]. Only a few biliary tract cancer patients were included in these studies, owing to the rarity of these alterations. MSI-high biliary tract cancer was reported in 2.22% and 1.50% of Japanese cholangiocarcinoma and gallbladder cancer patients, respectively [71]. NTRK fusion positivity was reported in only 0.18% of biliary tract cancers [72]. The efficacy and safety of pembrolizumab were evaluated in KEYNOTE-028 and KEYNOTE-158 [73]. Pembrolizumab provides durable antitumor activity in 6–13% of patients with advanced biliary tract cancer regardless of programmed cell death 1 ligand 1 (PD-L1) expression and has manageable toxicity. Other immune checkpoint inhibitors were also evaluated in phase I or II studies involving both naïve and refractory advanced biliary tract cancer [74,75,76,77,78,79]. The results of these studies were promising, and further large-scale evaluation is underway. When using these immune checkpoint inhibitors, appropriate management of immune-related adverse events is required.

In summary, FOLFOX is becoming the standard second-line chemotherapy for refractory cases. The presence of IDH mutations, FGFR fusion/rearrangement and NTRK fusion, as well as MSI status, should be confirmed to consider treatment with relevant inhibitors or immune checkpoint inhibitors where applicable. It is also important to consider participation in clinical studies if molecular-targeted agents matched with identified gene alterations are available.

4. Adjuvant Chemotherapy for Resected Biliary Tract Cancer

While surgical resection is regarded as the only treatment with a chance of curing biliary tract cancer, postoperative recurrence can sometimes occur. However, standard adjuvant chemotherapy has not been established to date.

Several phase III studies have been reported on adjuvant chemotherapy for resected biliary tract cancer. The first phase III study evaluated the efficacy of adjuvant chemotherapy of 5-fluorouracil + mitomycin-C versus surgery alone in patients with resected pancreaticobiliary carcinoma [80]. Results indicated that gallbladder carcinoma patients who underwent noncurative resection may derive some benefit from systemic chemotherapy. However, alternative modalities must be developed for patients with carcinomas of the pancreas, bile duct, or ampulla of Vater. Several prospective phase III studies focused on adjuvant chemotherapy for biliary tract cancer were subsequently conducted, as summarized in Table 3.

Table 3.

Randomized controlled studies of adjuvant chemotherapy for resected biliary tract cancer.

Authors	Year	Biliary Site	Regimen	Phase	Result	N	Median RFS	Median OS
Neoptolemos et al. [81]	2012	EHCC, AC	5FU + FA	3	Marginal	143	23.0 M	38.9 M
			GEM			141	29.1 M	45.7 M
			Surgery alone			144	19.5 M	35.2 M
Ebata et al. [82]	2018	EHCC	GEM	3	Negative	117	36.0 M	62.3 M
Ebata et al. [82]	2018	EHCC	Surgery alone	3	Negative	108	39.9 M	63.8 M
Edeline et al. [83]	2019	ICC, EHCC, GBC	GEMOX	3	Negative	94	30.4 M	75.8 M
Edeline et al. [83]	2019	ICC, EHCC, GBC	Surgery alone	3	Negative	99	18.5 M	50.8 M
Primrose et al. [84]	2019	ICC, EHCC, GBC	Capecitabine	3	Marginal	223	24.4 M	51.1 M
Primrose et al. [84]	2019	ICC, EHCC, GBC	Surgery alone	3	Marginal	224	17.5 M	36.4 M

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N; number, RFS; recurrent-free survival, OS; overall survival, M; months, EHCC; extrahepatic cholangiocarcinoma, AC; ampullary cancer, ICC; intrahepatic cholangiocarcinoma, GBC; gallbladder cancer, 5FU; 5-fluorouracil, FA; folinic acid, GEM; gemcitabine, GEMOX; gemcitabine + oxaliplatin.

ESPAC-3 was a phase III study that evaluated the efficacy of adjuvant chemotherapy using 5-fluorouracil + folinic acid or gemcitabine monotherapy against surgery alone [81]. Patients with extrahepatic cholangiocarcinoma and ampullary cancer were enrolled in this study. This study did not show superiority of adjuvant chemotherapy over surgery alone based on an intention-to-treat analysis. However, sensitivity analysis adjusted for prognostic factors showed improved prognosis in both the adjuvant chemotherapy group and the gemcitabine monotherapy group compared to the surgery alone group. BCAT was a phase III study conducted to evaluate the efficacy of adjuvant chemotherapy using gemcitabine against surgery alone [82]. This Japanese study was limited to extrahepatic cholangiocarcinoma patients. Treatment outcomes of surgery alone were extremely good, and no additional benefits of gemcitabine were observed. PRODIGE 12-ACCORD 18 was a French phase III study that compared adjuvant gemcitabine and oxaliplatin combination chemotherapy with surgery alone [83]. All types of biliary tract cancer other than ampullary cancer were included. The efficacy of adjuvant combination chemotherapy was not demonstrated in this negative study. BILCAP was a British phase III study that compared adjuvant capecitabine and surgery alone [84]. While capecitabine monotherapy failed to show improvement based on an intention-to-treat analysis, significant improvement was demonstrated in a per-protocol analysis. The major grade 3/4 adverse events of capecitabine were hand-foot syndrome, diarrhea and fatigue. Because of this promising result, the American Society of Clinical Oncology guideline recommends adjuvant capecitabine monotherapy for resected biliary tract cancer [85].

In summary, capecitabine monotherapy of six months for adjuvant chemotherapy is considered standard treatment for resected biliary tract cancer in Western counties. Until prospective studies show otherwise, surgery alone remains the standard of care in Japan.

5. Ongoing Clinical Trials for Biliary Tract Cancer

Currently, effective chemotherapy for biliary tract cancer is extremely limited, and the development of new therapies is urgently needed. There are a large number of ongoing prospective studies for biliary tract cancer [86,87,88,89,90,91]. Based on promising early-phase study results, phase III studies are underway [92,93,94]. A list of major ongoing randomized controlled studies for biliary tract cancer is provided in Table 4. In addition to conventional treatments using cytotoxic agents, a wide variety of drugs such as molecular-targeted agents and immune checkpoint inhibitors are being investigated. Despite the low frequency of genetic alterations, precision medicine with molecular-targeted agents holds promise for selected patients. Umbrella and basket studies are increasingly being conducted, based on the need to build a mechanism to provide drugs suited to each genetic alteration regardless of tumor origin. The efficacy of immunotherapy combined with conventional treatment is also being investigated. In addition, a new large-scale trial for neoadjuvant chemotherapy is underway. Many new therapies that enhance the effectiveness of current regimens have been validated in late-phase clinical trials such as those listed in Table 4. On the other hand, many new drugs have been validated in other, slightly earlier phase clinical trials. It is hoped that such drugs will advance to late-phase clinical trials sooner. Like other cancers, it is also expected that molecular-targeted drugs and immunotherapy that matched cancer genetic characteristics, such as first-line FGFR inhibitors, can produce much better treatment than current standard treatments.

Table 4.

Major ongoing clinical studies for biliary tract cancer.

Regimen	N	Phase	Trial ID
First-line chemotherapy
NUC-1031 (Acelarin) + CDDP vs. GemCis (NuTide:121)	828	3	NCT04163900
GemCis + Pembrolizumab vs. GemCis (KEYNOTE-966)	788	3	NCT04003636
GemCis + Durvalumab vs. GemCis (TOPAZ-1)	757	3	NCT03875235
Pemigatinib vs. GemCis (FIGHT-302)	432	3	NCT03656536
GEMOX + KN035 vs. GEMOX (KN035-BTC)	390	3	NCT03478488
Infigratinib vs. GemCis (PROOF 301 trial)	384	3	NCT037773302
GemCis + nab-paclitaxel vs. GemCis (SWOG/S1815)	268	3	NCT03768414
Futibatinib vs. GemCis (FOENIX-CCA3)	216	3	NCT04093362
GemCis + Bintrafusp alfa vs. GemCis	512	2/3	NCT04066491
Second-line chemotherapy
TQB2450 + Anlotinib vs. Cape + Oxaliplatin or Cape + GEM	392	3	NCT04809142
Surufatinib vs. Cape	298	2/3	NCT03873532
Adjuvant chemotherapy
GemCis vs. Surgery alone or Cape (ACTICCA-1)	781	3	NCT02170090
GEM + Cape vs. Cape (AdBTC-1)	460	3	NCT03779035
S-1 vs. Surgery alone (ASCOT)	350	3	UMIN000011688
Neoadjuvant chemotherapy
Neoadjuvant & adjuvant GemCis vs. Adjuvant CTx (GAIN)	300	3	NCT03673072
Neoadjuvant GCS vs. Surgery first (NABICAT)	300	3	jRCTs031200388

Open in a new tab

CDDP; cisplatin, GemCis; gemcitabine + cisplatin, GEMOX; gemcitabine + oxaliplatin, Cape; capecitabine, GEM; gemcitabine, CTx; chemotherapy, GCS; gemcitabine + cisplatin + S-1.

6. Conclusions

Figure 1 shows the proposed treatment algorithm of chemotherapy for advanced biliary tract cancer in 2021. It is necessary to arrange this algorithm according to the medical situation in each country.

Proposed treatment algorithm of chemotherapy for advanced biliary tract cancer. GEM; gemcitabine, CDDP; cisplatin, FOLFOX; 5-fluorouracil + leucovorin + oxaliplatin, IDH; isocitrate dehydrogenase, FGFR; fibroblast growth factor receptor, MSI; microsatellite instability, NTRK; neurotrophic tyrosine receptor kinase.

Biliary tract cancer is considered a population with various genetic alterations. Genetic alterations are often measured before starting second- or third-line chemotherapy only in patients who are able to get enough tissue samples. If the effectiveness of molecular-targeted drugs and immunotherapy based on the characteristics of cancer is shown at first-line setting, it is thought that the trend of investigating genetic alterations from the time of diagnosis will accelerate in the future. In addition, to overcome the problem that biliary tract cancer is sometimes difficult to get enough tissue samples, there are great expectations for liquid biopsy in this field. Furthermore, there is an urgent need to develop more drugs that match genetic alterations and establish a system to deliver the drugs to the matched patients in clinical practice.

While evidence relating to chemotherapy for biliary tract cancer had been limited, numerous clinical studies have been conducted in the last decade and evidence is steadily accumulating. Many large-scale clinical studies are still underway, some of which may lead to improved treatment outcomes going forward.

Author Contributions

Writing—original draft preparation, T.S.; writing—review and editing, T.T., T.O., supervision, M.O., N.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

T.S. has received honoraria from Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Eisai Co., Ltd. T.T. has received honoraria from Taiho Pharmaceutical Co., Ltd. M.O. has received honoraria from Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Eisai Co., Ltd., AstraZeneca, ONO Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Novartis, MSD. N.S. has received research grants from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and has received honoraria Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd. The other author declares no conflicts of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1.Valle J.W., Kelley R.K., Nervi B., Oh D.Y., Zhu A.X. Biliary tract cancer. Lancet. 2021;397:428–444. doi: 10.1016/S0140-6736(21)00153-7. [DOI] [PubMed] [Google Scholar]
2.Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer Statistics, 2021. CA. Cancer J. Clin. 2021;71:7–33. doi: 10.3322/caac.21654. [DOI] [PubMed] [Google Scholar]
3.Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
4.Florio A.A., Ferlay J., Znaor A., Ruggieri D., Alvarez C.S., Laversanne M., Bray F., McGlynn K.A., Petrick J.L. Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012. Cancer. 2020;126:2666–2678. doi: 10.1002/cncr.32803. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Gad M.M., Saad A.M., Faisaluddin M., Gaman M.A., Ruhban I.A., Jazieh K.A., Al-Husseini M.J., Simons-Linares C.R. Epidemiology of Cholangiocarcinoma; United States Incidence and Mortality Trends. Clin. Res. Hepatol. Gastroenterol. 2020;44:885–893. doi: 10.1016/j.clinre.2020.03.024. [DOI] [PubMed] [Google Scholar]
6.Rawla P., Sunkara T., Thandra K.C., Barsouk A. Epidemiology of gallbladder cancer. Clin. Exp. Hepatol. 2019;5:93–102. doi: 10.5114/ceh.2019.85166. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Cancer Registry and Statistics Cancer Information Service, National Cancer Center, Japan (Vital Statistics of Japan) [(accessed on 1 June 2021)]; Available online: https://ganjoho.jp/reg_stat/statistics/dl/index.html.
8.Ishihara S., Horiguchi A., Miyakawa S., Endo I., Miyazaki M., Takada T. Biliary tract cancer registry in Japan from 2008 to 2013. J. Hepatobiliary Pancreat. Sci. 2016;23:149–157. doi: 10.1002/jhbp.314. [DOI] [PubMed] [Google Scholar]
9.Glimelius B., Hoffman K., Sjödén P.O., Jacobsson G., Sellström H., Enander L.K., Linné T., Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann. Oncol. 1996;7:593–600. doi: 10.1093/oxfordjournals.annonc.a010676. [DOI] [PubMed] [Google Scholar]
10.Sharma A., Dwary A.D., Mohanti B.K., Deo S.V., Pal S., Sreenivas V., Raina V., Shukla N.K., Thulkar S., Garg P., et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: A randomized controlled study. J. Clin. Oncol. 2010;28:4581–4586. doi: 10.1200/JCO.2010.29.3605. [DOI] [PubMed] [Google Scholar]
11.Eckel F., Schmid R.M. Chemotherapy in advanced biliary tract carcinoma: A pooled analysis of clinical trials. Br. J. Cancer. 2007;96:896–902. doi: 10.1038/sj.bjc.6603648. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Valle J.W., Wasan H., Johnson P., Jones E., Dixon L., Swindell R., Baka S., Maraveyas A., Corrie P., Falk S., et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: A mulitcentre randomized phase II study—The UK ABC-01 Study. Br. J. Cancer. 2009;101:621–627. doi: 10.1038/sj.bjc.6605211. [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Valle J., Wasan H., Palmer D.H., Cunningham D., Anthoney A., Maraveyas A., Madhusudan S., Iveson T., Hughes S., Pereira S.P., et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 2010;362:1273–1281. doi: 10.1056/NEJMoa0908721. [DOI] [PubMed] [Google Scholar]
14.Okusaka T., Nakachi K., Fukutomi A., Mizuno N., Ohkawa S., Funakoshi M., Nagino M., Kondo S., Nagaoka S., Funai J., 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;103:469–474. doi: 10.1038/sj.bjc.6605779. [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Valle J.W., Furuse J., Jitlal M., Beare S., Mizuno N., Wasan H., Bridgewater J., Okusaka T. Cisplatin and gemcitabine for advanced biliary tract cancer: A meta-analysis of two randomized trials. Ann. Oncol. 2014;25:391–398. doi: 10.1093/annonc/mdt540. [DOI] [PubMed] [Google Scholar]
16.Sharma A., Kalyan Mohanti B., Pal Chaudhary S., Sreenivas V., Kumar Sahoo R., Kumar Shukla N., Thulkar S., Pal S., Deo S.V., Pathy S., et al. Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in uresectable gallbladder cancer: Results of a phase III randomized controlled trial. Eur. J. Cancer. 2019;123:162–170. doi: 10.1016/j.ejca.2019.10.004. [DOI] [PubMed] [Google Scholar]
17.Lee J., Park S.H., Chang H.M., Kim J.S., Choi H.J., Lee M.A., Jang J.S., Jeung H.C., Kang J.H., Lee H.W., et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: A multicentre, open-label, randomized, phase 3 study. Lancet Oncol. 2012;13:181–188. doi: 10.1016/S1470-2045(11)70301-1. [DOI] [PubMed] [Google Scholar]
18.Morizane C., Okusaka T., Mizusawa J., Katayama H., Ueno M., Ikeda M., Ozaka M., Okano N., Sugimori K., Fukutomi A., et al. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: The FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann. Oncol. 2019;30:1950–1958. doi: 10.1093/annonc/mdz402. [DOI] [PubMed] [Google Scholar]
19.Sakai D., Kanai M., Kobayashi S., Eguchi H., Baba H., Seo S., Taketomi A., Takayama T., Yamaue H., Ishioka C., et al. Randomized phase III study of gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401-MITSUBA) Ann. Oncol. 2018;29(Suppl. 8):viii205–viii270. doi: 10.1093/annonc/mdy282. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Kim S.T., Kang J.H., Lee J., Lee H.W., Oh S.Y., Jang J.S., Lee M.A., Sohn B.S., Yoon S.Y., Choi H.J., et al. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: A multicenter, open-label, randomized, phase III, noninferiority trial. Ann. Oncol. 2019;30:788–795. doi: 10.1093/annonc/mdz058. [DOI] [PubMed] [Google Scholar]
21.Phelip J.M., Desrame J., Edeline J., Barbier E., Terrebonne E., Michel P., Perrier H., Dahan L., Bourgeois V., Khemissa Akouz F., et al. Modified FOLFIRINOX versus CISGEM first-line chemotherapy for locally advanced, non resectable and/or metastatic biliary tract cancer: Results of AMEBICA PRODIGE 38 Phase II trial. Ann. Oncol. 2020;31(Suppl. 4):S260–S273. doi: 10.1016/j.annonc.2020.08.030. [DOI] [Google Scholar]
22.Kang M.J., Lee J., Kim T.W., Lee S.S., Ahn S., Park D.H., Lee S.S., Seo D.W., Lee S.K., Kim M. Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract cancer. Acta Oncol. 2012;7:860–866. doi: 10.3109/0284186X.2012.682628. [DOI] [PubMed] [Google Scholar]
23.Lee J., Hong T.H., Lee I.S., You Y.K., Lee M.A. Comparison of the Efficacy between Gemcitabine-Cisplatin and Capecitabine-Cisplatin Combination Chemotherapy for Advanced Biliary Tract Cancer. Cancer Res. Treat. 2015;47:259–265. doi: 10.4143/crt.2013.230. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Malka D., Cervera P., Foulon S., Trarbach T., de la Fouchardière C., Boucher E., Fartoux L., Faivre S., Blanc J.F., Viret F., et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): A randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15:819–828. doi: 10.1016/S1470-2045(14)70212-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Chen J.S., Hsu C., Chiang N.J., Tsai C.S., Tsou H.H., Huang S.F., Bai L.Y., Chang I.C., Shiah H.S., Ho C.L., et al. A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. Ann. Oncol. 2015;26:943–949. doi: 10.1093/annonc/mdv035. [DOI] [PubMed] [Google Scholar]
26.Leone F., Marino D., Cereda S., Filippi R., Belli C., Spadi R., Nasti G., Montano M., Amatu A., Aprile G., et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti-BIL study) Cancer. 2016;122:574–581. doi: 10.1002/cncr.29778. [DOI] [PubMed] [Google Scholar]
27.Vogel A., Kasper S., Bitzer M., Block A., Sinn M., Schulze-Bergkamen H., Moehler M., Pfarr N., Endris V., Goeppert B., et al. PICCA study: Panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase II AIO study. Eur. J. Cancer. 2018;92:11–19. doi: 10.1016/j.ejca.2017.12.028. [DOI] [PubMed] [Google Scholar]
28.Valle J.W., Wasan H., Lopes A., Backen A.C., Palmer D.H., Morris K., Duggan M., Cunningham D., Anthoney D.A., Corrie P., et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): A randomised phase 2 trial. Lancet Oncol. 2015;16:967–978. doi: 10.1016/S1470-2045(15)00139-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Moehler M., Maderer A., Schimanski C., Kanzler S., Denzer U., Kolligs F.T., Ebert M.P., Distelrath A., Geissler M., Trojan J., et al. Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: A double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme. Eur. J. Cancer. 2014;50:3125–3135. doi: 10.1016/j.ejca.2014.09.013. [DOI] [PubMed] [Google Scholar]
30.Santoro A., Gebbia V., Pressiani T., Testa A., Personeni N., Arrivas Bajardi E., Foa P., Buonadonna A., Bencardino K., Barone C., et al. A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: The VanGogh study. Ann. Oncol. 2015;26:542–547. doi: 10.1093/annonc/mdu576. [DOI] [PubMed] [Google Scholar]
31.Schinzari G., Rossi E., Mambella G., Strippoli A., Cangiano R., Mutignani M., Basso M., Cassano A., Barone C. First-line Treatment of Advanced Biliary Ducts Carcinoma: A Randomized Phase II Study Evaluating 5-FU/LV Plus Oxaliplatin (Folfox 4) Versus 5-FU/LV (de Gramont Regimen) Anticancer Res. 2017;37:5193–5197. doi: 10.21873/anticanres.11942. [DOI] [PubMed] [Google Scholar]
32.Markussen A., Jensen L.H., Diness L.V., Larsen F.O. Treatment of Patients with Advanced Biliary Tract Cancer with Either Oxaliplatin, Gemcitabine, and Capecitabine or Cisplatin and Gemcitabine-A Randomized Phase II Trial. Cancers. 2020;12:1975. doi: 10.3390/cancers12071975. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.dos Santos L.V., Pinto G.S.F., Ferraz M.W.S., Bragagnoli A., Santos F., Haddad S., Barros A., Dias I.C.C., Lima J.P.S., Abdalla K.C. Cisplatin plus irinotecan versus cisplatin plus gemcitabine in the treatment of advanced or metastatic gallbladder or biliary tract cancer: Results of a randomized phase II trial ( NCT01859728)–The Gambit trial. J. Clin. Oncol. 2020;38(Suppl. 4):529. doi: 10.1200/JCO.2020.38.4_suppl.529. [DOI] [Google Scholar]
34.Sasaki T., Isayama H., Nakai Y., Ito Y., Kogure H., Togawa O., Toda N., Yasuda I., Hasebe O., Maetani I., et al. Multicenter, phase II study of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. Cancer Chemother. Pharmacol. 2010;65:1101–1107. doi: 10.1007/s00280-009-1115-5. [DOI] [PubMed] [Google Scholar]
35.Kanai M., Yoshimura K., Tsumura T., Asada M., Suzuki C., Niimi M., Matsumoto S., Nishimura T., Nitta T., Yasuchika K., et al. A multi-institution phase II study of gemcitabine/S-1 combination chemotherapy for patients with advanced biliary tract cancer. Cancer Chemother. Pharmacol. 2011;67:1429–1434. doi: 10.1007/s00280-010-1443-5. [DOI] [PubMed] [Google Scholar]
36.Sasaki T., Isayama H., Nakai Y., Ito Y., Yasuda I., Toda N., Kogure H., Hanada K., Maguchi H., Sasahira N., et al. A randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine monotherapy for advanced biliary tract cancer. Cancer Chemother. Pharmacol. 2013;71:973–979. doi: 10.1007/s00280-013-2090-4. [DOI] [PubMed] [Google Scholar]
37.Morizane C., Okusaka T., Mizusawa J., Takashima A., Ueno M., Ikeda M., Hamamoto Y., Ishii H., Boku N., Furuse J. Randomized phase II study of gemcitabine plus S-1 versus S-1 in advanced biliary tract cancer: A Japan Clinical Oncology Group trial (JCOG 0805) Cancer Sci. 2013;104:1211–1216. doi: 10.1111/cas.12218. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Kanai M., Hatano E., Kobayashi S., Fujiwara Y., Marubashi S., Miyamoto A., Shiomi H., Kubo S., Ikuta S., Yanagimoto H., et al. A multi-institution phase II study of gemcitabine/cisplatin/S-1 (GCS) combination chemotherapy for patients with advanced biliary tract cancer (KHBO 1002) Cancer Chemother. Pharmacol. 2015;75:293–300. doi: 10.1007/s00280-014-2648-9. [DOI] [PubMed] [Google Scholar]
39.Walter T., Horgan A.M., McNamara M., McKeever L., Min T., Hedley D., Serra S., Krzyzanowska M.K., Chen E., Mackay H., et al. Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: A large retrospective study. Eur. J. Cancer. 2013;49:329–335. doi: 10.1016/j.ejca.2012.08.003. [DOI] [PubMed] [Google Scholar]
40.Bridgewater J., Palmer D., Cunningham D., Iveson T., Gillmore R., Waters J., Harrison M., Wasan H., Corrie P., Valle J. Outcome of second-line chemotherapy for biliary tract cancer. Eur. J. Cancer. 2013;49:1511. doi: 10.1016/j.ejca.2012.11.024. [DOI] [PubMed] [Google Scholar]
41.Lamarca A., Hubner R.A., David Ryder W., Valle J.W. Second-line chemotherapy in advanced biliary cancer: A systematic review. Ann. Oncol. 2014;25:2328–2338. doi: 10.1093/annonc/mdu162. [DOI] [PubMed] [Google Scholar]
42.Brieau B., Dahan L., De Rycke Y., Boussaha T., Vasseur P., Tougeron D., Lecomte T., Coriat R., Bachet J.B., Claudez P., et al. Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Entérologues Oncologues. Cancer. 2015;121:3290–3297. doi: 10.1002/cncr.29471. [DOI] [PubMed] [Google Scholar]
43.Takahara N., Nakai Y., Isayama H., Sasaki T., Saito K., Oyama H., Kanai S., Suzuki T., Sato T., Hakuta R., et al. Second-line chemotherapy in patients with advanced or recurrent biliary tract cancer: A single center, retrospective analysis of 294 cases. Investig. New Drugs. 2018;36:1093–1102. doi: 10.1007/s10637-018-0670-1. [DOI] [PubMed] [Google Scholar]
44.Lowery M.A., Goff L.W., Keenan B.P., Jordan E., Wang R., Bocobo A.G., Chou J.F., O’Reilly E.M., Harding J.J., Kemeny N., et al. Second-line chemotherapy in advanced biliary cancers: A retrospective, multicenter analysis of outcomes. Cancer. 2019;125:4426–4434. doi: 10.1002/cncr.32463. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Zaidi A., Chandna N., Narasimhan G., Moser M., Haider K., Chalchal H., Shaw J., Ahmed S. Second-line Chemotherapy Prolongs Survival in Real World Patients with Advanced Biliary Tract and Gallbladder Cancers: A Multicenter Retrospective Population-based Cohort Study. Am. J. Clin. Oncol. 2021;44:93–98. doi: 10.1097/COC.0000000000000789. [DOI] [PubMed] [Google Scholar]
46.Sasaki T., Isayama H., Nakai Y., Mizuno S., Yamamoto K., Yagioka H., Yashima Y., Kawakubo K., Kogure H., Togawa O., et al. Multicenter phase II study of S-1 monotherapy as second-line chemotherapy for advanced biliary tract cancer refractory to gemcitabine. Investig. New Drugs. 2012;30:708–713. doi: 10.1007/s10637-010-9553-9. [DOI] [PubMed] [Google Scholar]
47.Suzuki E., Ikeda M., Okusaka T., Nakamori S., Ohkawa S., Nagakawa Y., Boku N., Yanagimoto H., Sato T., Furuse J. A multicenter phase II study of S-1 for gemcitabine-refractory biliary tract cancer. Cancer Chemother. Pharmacol. 2013;71:1141–1146. doi: 10.1007/s00280-013-2106-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Tella S.H., Kommalapati A., Borad M.J., Mahipal A. Second-line therapies in advanced biliary tract cancers. Lancet Oncol. 2020;21:e29–e41. doi: 10.1016/S1470-2045(19)30733-8. [DOI] [PubMed] [Google Scholar]
49.Abou-Alfa G.K., Macarulla T., Javle M.M., Kelley R.K., Lubner S.J., Adeva J., Cleary J.M., Catenacci D.V., Borad M.J., Bridgewater J., et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796–807. doi: 10.1016/S1470-2045(20)30157-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Lamarca A., Palmer D.H., Wasan H.S., Ross P.J., Ma Y.T., Arora A., Falk S., Gillmore R., Wadsley J., Patel K., et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): A phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22:690–701. doi: 10.1016/S1470-2045(21)00027-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
51.Jalve M.M., Oh D.Y., Ikeda M., Yong W.P., McIntyre N., Lindmark B., McHale M. Results from TreeTopp: A randomized phase II study of the efficacy and safety of varlitinib plus capecitabine versus placebo in second-line (2L) advanced or metastatic biliary tract cancer (BTC) J. Clin. Oncol. 2020;38(Suppl. 15):4597. [Google Scholar]
52.Cereda S., Milella M., Cordio S., Leone F., Aprile G., Galiano A., Mosconi S., Vasile E., Santini D., Belli C., et al. Capecitabine with/without mitomycin C: Results of a randomized phase II trial of second-line therapy in advanced biliary tract adenocarcinoma. Cancer Chemother. Pharmacol. 2016;77:109–114. doi: 10.1007/s00280-015-2919-0. [DOI] [PubMed] [Google Scholar]
53.Zheng Y., Tu X., Zhao P., Jiang W., Liu L., Tong Z., Zhang H., Yan C., Fang W., Wang W. A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin. Br. J. Cancer. 2018;119:291–295. doi: 10.1038/s41416-018-0138-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Kim R.D., McDonough S., El-Khoueiry A.B., Bekaii-Saab T.S., Stein S.M., Sahai V., Keogh G.P., Kim E.J., Baron A.D., Siegel A.B., et al. Randomised phase II trial (SWOG S1310) of single agent MEK inhibitor trametinib Versus 5-fluorouracil or capecitabine in refractory advanced biliary cancer. Eur. J. Cancer. 2020;130:219–227. doi: 10.1016/j.ejca.2020.01.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
55.Demols A., Borbath I., Van den Eynde M., Houbiers G., Peeters M., Marechal R., Delaunoit T., Goemine J.C., Laurent S., Holbrechts S., et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial. Ann. Oncol. 2020;31:1169–1177. doi: 10.1016/j.annonc.2020.05.018. [DOI] [PubMed] [Google Scholar]
56.Ramaswamy A., Ostwal V., Sharma A., Bhargava P., Srinivas S., Goel M., Patkar S., Mandavkar S., Jadhav P., Parulekar M., et al. Efficacy of Capecitabine Plus Irinotecan vs Irinotecan Monotherapy as Second-line Treatment in Patients With Advanced Gallbladder Cancer: A Multicenter Phase 2 Randomized Clinical Trial (GB-SELECT) JAMA Oncol. 2021;7:436–439. doi: 10.1001/jamaoncol.2020.6166. [DOI] [PMC free article] [PubMed] [Google Scholar]
57.Ueno M., Morizane C., Furukawa M., Sakai D., Komatsu Y., Nakai Y., Tsuda M., Ozaka M., Mizuno N., Muto M., et al. A randomized, double-blind, phase II study of oral histone deacetylase inhibitor resminostat plus S-1 versus placebo plus S-1 in biliary tract cancers previously treated with gemcitabine plus platinum-based chemotherapy. Cancer Med. 2021;10:2088–2099. doi: 10.1002/cam4.3813. [DOI] [PMC free article] [PubMed] [Google Scholar]
58.Yoo C., Kim K.P., Kim I., Kang M.J., Cheon J., Kang B.W., Ryu H., Jeong J.H., Lee J.S., Kim K.W., et al. Liposomal Irinotecan (nal-IRI) in combination with Fluorouracil (5-FU) and Leucovorin (LV) for Patients (pts) with Metastatic Biliary Tract Cancer (BTC) after Progression on Gemcitabine plus Cisplatin (GemCis): Multicenter Comparative Randomized Phase 2B study (NIFTY) J. Clin. Oncol. 2021;39(Suppl. 15):4006. [Google Scholar]
59.Nakamura H., Arai Y., Totoki Y., Shirota T., Elzawahry A., Kato M., Hama N., Hosoda F., Urushidate T., Ohashi S., et al. Genomic spectra of biliary tract cancer. Nat. Genet. 2015;47:1003–1010. doi: 10.1038/ng.3375. [DOI] [PubMed] [Google Scholar]
60.Valle J.W., Lamarca A., Goyal L., Barriuso J., Zhu A.X. New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov. 2017;7:943–962. doi: 10.1158/2159-8290.CD-17-0245. [DOI] [PMC free article] [PubMed] [Google Scholar]
61.Jusakul A., Cutcutache I., Yong C.H., Lim J.Q., Huang M.N., Padmanabhan N., Nellore V., Kongpetch S., Ng A.W.T., Ng L.M., et al. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov. 2017;7:1116–1135. doi: 10.1158/2159-8290.CD-17-0368. [DOI] [PMC free article] [PubMed] [Google Scholar]
62.Silverman I.M., Hollebecque A., Friboulet L., Owens S., Newton R.C., Zhen H., Féliz L., Zecchetto C., Melisi D., Burn T.C. Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib. Cancer Discov. 2021;11:326–339. doi: 10.1158/2159-8290.CD-20-0766. [DOI] [PubMed] [Google Scholar]
63.Javle M., Lowery M., Shroff R.T., Weiss K.H., Springfeld C., Borad M.J., Ramanathan R.K., Goyal L., Sadeghi S., Macarulla T., et al. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. J. Clin. Oncol. 2018;36:276–282. doi: 10.1200/JCO.2017.75.5009. [DOI] [PMC free article] [PubMed] [Google Scholar]
64.Mazzaferro V., El-Rayes B.F., Droz Dit Busset M., Cotsoglou C., Harris W.P., Damjanov N., Masi G., Rimassa L., Personeni N., Braiteh F., et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br. J. Cancer. 2019;120:165–171. doi: 10.1038/s41416-018-0334-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
65.Abou-Alfa G.K., Sahai V., Hollebecque A., Vaccaro G., Melisi D., Al-Rajabi R., Paulson A.S., Borad M.J., Gallinson D., Murphy A.G., et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671–685. doi: 10.1016/S1470-2045(20)30109-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
66.Goyal L., Meric-Bernstam F., Hollebecque A., Morizane C., Valle J.W., Karasic T.B., Abrams T.A., Kelley R.B., Cassier P., Furuse J., et al. Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrengements; Proceedings of the AACR Annual Meeting, Virtual Meeting; Philadelphia, PA, USA. 10–15 April/17–21 May 2021; Abstract CT-010. [Google Scholar]
67.Maruki Y., Morizane C., Arai Y., Ikeda M., Ueno M., Ioka T., Naganuma A., Furukawa M., Mizuno N., Uwagawa T., et al. Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: A prospective observational study (PRELUDE Study) J. Gastroenterol. 2021;56:250–260. doi: 10.1007/s00535-020-01735-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
68.Le D.T., Durham J.N., Smith K.N., Wang H., Bartlett B.R., Aulakh L.K., Lu S., Kemberling H., Wilt C., Luber B.S., et al. Mismatch repair deficiency predicts response of solid tumors of PD-1 blockade. Science. 2017;357:409–413. doi: 10.1126/science.aan6733. [DOI] [PMC free article] [PubMed] [Google Scholar]
69.Doebele R.C., Drilon A., Paz-Ares L., Siena S., Shaw A.T., Farago A.F., Blakely C.M., Seto T., Cho B.C., Tosi D., et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21:271–282. doi: 10.1016/S1470-2045(19)30691-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
70.Drilon A., Laetsch T.W., Kummar S., DuBois S.G., Lassen U.N., Demetri G.D., Natheson M., Doebele R.C., Fargo A.F., Pappo A.S., et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N. Engl. J. Med. 2018;378:731–739. doi: 10.1056/NEJMoa1714448. [DOI] [PMC free article] [PubMed] [Google Scholar]
71.Akagi K., Oki E., Taniguchi H., Nakatani K., Aoki D., Kuwata T., Yoshino T. The real-world data on microsatellite instability status in various unresectable or metastatic solid tumors. Cancer Sci. 2021;112:1105. doi: 10.1111/cas.14798. [DOI] [PMC free article] [PubMed] [Google Scholar]
72.Yoshino T., Pentheroudakis G., Mishima S., Overman M.J., Yeh K.H., Baba E., Naito Y., Calvo F., Saxena A., Chen L.T., et al. JSCO-ESMO-ASCO-JSMO-TOS: International expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions. Ann. Oncol. 2020;31:861–872. doi: 10.1016/j.annonc.2020.03.299. [DOI] [PubMed] [Google Scholar]
73.Piha-Paul S.A., Oh D.Y., Ueno M., Malka D., Chung H.C., Nagrial A., Kelley R.K., Ros W., Italiano A., Nakagawa K., et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies. Int. J. Cancer. 2020;147:2190–2198. doi: 10.1002/ijc.33013. [DOI] [PubMed] [Google Scholar]
74.Ueno M., Ikeda M., Morizane C., Kobayashi S., Ohno I., Kondo S., Okano N., Kimura K., Asada S., Namba Y., et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: A non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol. Hepatol. 2019;4:611–621. doi: 10.1016/S2468-1253(19)30086-X. [DOI] [PubMed] [Google Scholar]
75.Kim R.D., Chung V., Alese O.B., El-Rayes B.F., Li D., Al-Toubah T.E., Schell M.J., Zhou J.M., Mahipal A., Kim B.H., et al. A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer. JAMA Oncol. 2020;6:888–894. doi: 10.1001/jamaoncol.2020.0930. [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Feng K., Liu Y., Zhao Y., Yang Q., Dong L., Liu J., Li X., Zhao Z., Mei Q., Han W. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: Results from a phase II study. J. Immunother. Cancer. 2020;8:e000367. doi: 10.1136/jitc-2019-000367. [DOI] [PMC free article] [PubMed] [Google Scholar]
77.Klein O., Kee D., Nagrial A., Markman B., Underhill C., Michael M., Jackett L., Lum C., Behren A., Palmer J., et al. Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2020;6:1405–1409. doi: 10.1001/jamaoncol.2020.2814. [DOI] [PMC free article] [PubMed] [Google Scholar]
78.Chen X., Wu X., Wu H., Gu Y., Shao Y., Shao Q., Zhu F., Li X., Qian X., Hu J., et al. Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: A single-arm, open-label, phase II trial. J. Immunother. Cancer. 2020;8:e001240. doi: 10.1136/jitc-2020-001240. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Villanueva L., Lwin Z., Chung H.C., Gomez-Roca C.A., Longo F., Yanez E., Senellart H., Doherty M., Garcia-Corbacho J., Hendifar A.E., et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase 2 LEAP-005 study. J. Clin. Oncol. 2021;39(Suppl. 15):4080. doi: 10.1200/JCO.2021.39.15_suppl.4080. [DOI] [Google Scholar]
80.Takada T., Amano H., Yasuda H., Nimura Y., Matsushiro T., Kato H., Nagakawa T., Nakayama T., Study Group of Surgical Adjuvant Therapy for Carcinomas of the Pancreas and Biliary Tract Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95:1685–1695. doi: 10.1002/cncr.10831. [DOI] [PubMed] [Google Scholar]
81.Neoptolemos J.P., Moore M.J., Cox T.F., Valle J.W., Palmer D.H., McDonald A.C., Carter R., Tebbutt N.C., Dervenis C., Smith D., et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma. JAMA. 2012;308:147–156. doi: 10.1001/jama.2012.7352. [DOI] [PubMed] [Google Scholar]
82.Ebata T., Hirano S., Konishi M., Uesaka K., Tsuchiya Y., Ohtsuka M., Kaneoka Y., Yamamoto M., Ambo Y., Shimizu Y., et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br. J. Surg. 2018;105:192–202. doi: 10.1002/bjs.10776. [DOI] [PubMed] [Google Scholar]
83.Edeline J., Benabdelghani M., Bertaut A., Watelet J., Hammel P., Joly J.P., Boudjema K., Fartoux L., Bouhier-Leporrier K., Jouve J.L., et al. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J. Clin. Oncol. 2019;37:658–667. doi: 10.1200/JCO.18.00050. [DOI] [PubMed] [Google Scholar]
84.Primrose J.N., Fox R.P., Palmer D.H., Malik H.Z., Prasad R., Mirza D., Anthony A., Corrie P., Falk S., Finch-Jones M., et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): A randomized, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20:663–673. doi: 10.1016/S1470-2045(18)30915-X. [DOI] [PubMed] [Google Scholar]
85.Shroff R.T., Kennedy E.B., Bachini M., Bekaii-Saab T., Crane C., Edeline J., El-Khoueiry A., Feng M., Katz M.H.G., Primrose J., et al. Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline. J. Clin. Oncol. 2019;37:1015–1027. doi: 10.1200/JCO.18.02178. [DOI] [PubMed] [Google Scholar]
86.McNamara M.G., Goyal L., Doherty M., Springfeld C., Cosgrove D., Sjoquist K.M., Park J.O., Verdaguer H., Braconi C., Ross P.J., et al. NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121) Future Oncol. 2020;16:1069–1081. doi: 10.2217/fon-2020-0247. [DOI] [PubMed] [Google Scholar]
87.Bekaii-Saab T.S., Valle J.W., Van Cutsem E., Rimassa L., Furuse J., Ioka T., Melisi D., Macarulla T., Bridgewater J., Wasan H., et al. FIGHT-302: First-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol. 2020;16:2385–2399. doi: 10.2217/fon-2020-0429. [DOI] [PMC free article] [PubMed] [Google Scholar]
88.Makawita S., Abou-Alfa G.K., Roychowdhury S., Sadeghi S., Borbath I., Goyal L., Cohn A., Lamarca A., Oh D.Y., Macarulla T., et al. Infigratinib in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: The PROOF 301 trial. Future Oncol. 2020;16:2375–2384. doi: 10.2217/fon-2020-0299. [DOI] [PubMed] [Google Scholar]
89.Stein A., Arnold D., Bridgewater J., Goldstein D., Jensen L.H., Klümpen H.J., Lohse A.W., Nashan B., Primrose J., Schrum S., et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—A randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015;15:564. doi: 10.1186/s12885-015-1498-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
90.Nakachi K., Konishi M., Ikeda M., Mizusawa J., Eba J., Okusaka T., Ishii H., Fukuda H., Furuse J., Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT) Jpn. J. Clin. Oncol. 2018;48:392–395. doi: 10.1093/jjco/hyy004. [DOI] [PubMed] [Google Scholar]
91.Goetze T.O., Bechstein W.O., Bankstahl U.S., Keck T., Königsrainer A., Lang S.A., Pauligk C., Piso P., Vogel A., Al-Batran S.E. Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC)—A phase III study of the German registry of incidental gallbladder carcinoma platform (GR)- the AIO/ CALGP/ ACO- GAIN-trial. BMC Cancer. 2020;20:122. doi: 10.1186/s12885-020-6610-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
92.Shroff R.T., Javle M.M., Xiao L., Kaseb A.O., Varadhachary G.R., Wolff R.A., Raghav K.P.S., Iwasaki M., Masci P., Ramanathan R.K., et al. Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial. JAMA Oncol. 2019;5:824–830. doi: 10.1001/jamaoncol.2019.0270. [DOI] [PMC free article] [PubMed] [Google Scholar]
93.Yoo C., Oh D.Y., Choi H.J., Kudo M., Ueno M., Kondo S., Chen L.T., Osada M., Helwig C., Dussault I., et al. Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with pretreated biliary tract cancer. J. Immunother. Cancer. 2020;8:e000564. doi: 10.1136/jitc-2020-000564. [DOI] [PMC free article] [PubMed] [Google Scholar]
94.Boilève A., Hilmi M., Gougis P., Cohen R., Rousseau B., Blanc J.F., Ben Abdelghani M., Castanié H., Dahan L., Tougeron D., et al. Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Eur. J. Cancer. 2021;143:55–63. doi: 10.1016/j.ejca.2020.10.027. [DOI] [PubMed] [Google Scholar]

Associated Data

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Data Availability Statement

Not applicable.

[B1-jcm-10-03108] 1.Valle J.W., Kelley R.K., Nervi B., Oh D.Y., Zhu A.X. Biliary tract cancer. Lancet. 2021;397:428–444. doi: 10.1016/S0140-6736(21)00153-7. [DOI] [PubMed] [Google Scholar]

[B2-jcm-10-03108] 2.Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer Statistics, 2021. CA. Cancer J. Clin. 2021;71:7–33. doi: 10.3322/caac.21654. [DOI] [PubMed] [Google Scholar]

[B3-jcm-10-03108] 3.Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. Cancer J. Clin. 2021;71:209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]

[B4-jcm-10-03108] 4.Florio A.A., Ferlay J., Znaor A., Ruggieri D., Alvarez C.S., Laversanne M., Bray F., McGlynn K.A., Petrick J.L. Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012. Cancer. 2020;126:2666–2678. doi: 10.1002/cncr.32803. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B5-jcm-10-03108] 5.Gad M.M., Saad A.M., Faisaluddin M., Gaman M.A., Ruhban I.A., Jazieh K.A., Al-Husseini M.J., Simons-Linares C.R. Epidemiology of Cholangiocarcinoma; United States Incidence and Mortality Trends. Clin. Res. Hepatol. Gastroenterol. 2020;44:885–893. doi: 10.1016/j.clinre.2020.03.024. [DOI] [PubMed] [Google Scholar]

[B6-jcm-10-03108] 6.Rawla P., Sunkara T., Thandra K.C., Barsouk A. Epidemiology of gallbladder cancer. Clin. Exp. Hepatol. 2019;5:93–102. doi: 10.5114/ceh.2019.85166. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B7-jcm-10-03108] 7.Cancer Registry and Statistics Cancer Information Service, National Cancer Center, Japan (Vital Statistics of Japan) [(accessed on 1 June 2021)]; Available online: https://ganjoho.jp/reg_stat/statistics/dl/index.html.

[B8-jcm-10-03108] 8.Ishihara S., Horiguchi A., Miyakawa S., Endo I., Miyazaki M., Takada T. Biliary tract cancer registry in Japan from 2008 to 2013. J. Hepatobiliary Pancreat. Sci. 2016;23:149–157. doi: 10.1002/jhbp.314. [DOI] [PubMed] [Google Scholar]

[B9-jcm-10-03108] 9.Glimelius B., Hoffman K., Sjödén P.O., Jacobsson G., Sellström H., Enander L.K., Linné T., Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann. Oncol. 1996;7:593–600. doi: 10.1093/oxfordjournals.annonc.a010676. [DOI] [PubMed] [Google Scholar]

[B10-jcm-10-03108] 10.Sharma A., Dwary A.D., Mohanti B.K., Deo S.V., Pal S., Sreenivas V., Raina V., Shukla N.K., Thulkar S., Garg P., et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: A randomized controlled study. J. Clin. Oncol. 2010;28:4581–4586. doi: 10.1200/JCO.2010.29.3605. [DOI] [PubMed] [Google Scholar]

[B11-jcm-10-03108] 11.Eckel F., Schmid R.M. Chemotherapy in advanced biliary tract carcinoma: A pooled analysis of clinical trials. Br. J. Cancer. 2007;96:896–902. doi: 10.1038/sj.bjc.6603648. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B12-jcm-10-03108] 12.Valle J.W., Wasan H., Johnson P., Jones E., Dixon L., Swindell R., Baka S., Maraveyas A., Corrie P., Falk S., et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: A mulitcentre randomized phase II study—The UK ABC-01 Study. Br. J. Cancer. 2009;101:621–627. doi: 10.1038/sj.bjc.6605211. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B13-jcm-10-03108] 13.Valle J., Wasan H., Palmer D.H., Cunningham D., Anthoney A., Maraveyas A., Madhusudan S., Iveson T., Hughes S., Pereira S.P., et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 2010;362:1273–1281. doi: 10.1056/NEJMoa0908721. [DOI] [PubMed] [Google Scholar]

[B14-jcm-10-03108] 14.Okusaka T., Nakachi K., Fukutomi A., Mizuno N., Ohkawa S., Funakoshi M., Nagino M., Kondo S., Nagaoka S., Funai J., 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;103:469–474. doi: 10.1038/sj.bjc.6605779. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B15-jcm-10-03108] 15.Valle J.W., Furuse J., Jitlal M., Beare S., Mizuno N., Wasan H., Bridgewater J., Okusaka T. Cisplatin and gemcitabine for advanced biliary tract cancer: A meta-analysis of two randomized trials. Ann. Oncol. 2014;25:391–398. doi: 10.1093/annonc/mdt540. [DOI] [PubMed] [Google Scholar]

[B16-jcm-10-03108] 16.Sharma A., Kalyan Mohanti B., Pal Chaudhary S., Sreenivas V., Kumar Sahoo R., Kumar Shukla N., Thulkar S., Pal S., Deo S.V., Pathy S., et al. Modified gemcitabine and oxaliplatin or gemcitabine + cisplatin in uresectable gallbladder cancer: Results of a phase III randomized controlled trial. Eur. J. Cancer. 2019;123:162–170. doi: 10.1016/j.ejca.2019.10.004. [DOI] [PubMed] [Google Scholar]

[B17-jcm-10-03108] 17.Lee J., Park S.H., Chang H.M., Kim J.S., Choi H.J., Lee M.A., Jang J.S., Jeung H.C., Kang J.H., Lee H.W., et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: A multicentre, open-label, randomized, phase 3 study. Lancet Oncol. 2012;13:181–188. doi: 10.1016/S1470-2045(11)70301-1. [DOI] [PubMed] [Google Scholar]

[B18-jcm-10-03108] 18.Morizane C., Okusaka T., Mizusawa J., Katayama H., Ueno M., Ikeda M., Ozaka M., Okano N., Sugimori K., Fukutomi A., et al. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: The FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann. Oncol. 2019;30:1950–1958. doi: 10.1093/annonc/mdz402. [DOI] [PubMed] [Google Scholar]

[B19-jcm-10-03108] 19.Sakai D., Kanai M., Kobayashi S., Eguchi H., Baba H., Seo S., Taketomi A., Takayama T., Yamaue H., Ishioka C., et al. Randomized phase III study of gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401-MITSUBA) Ann. Oncol. 2018;29(Suppl. 8):viii205–viii270. doi: 10.1093/annonc/mdy282. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B20-jcm-10-03108] 20.Kim S.T., Kang J.H., Lee J., Lee H.W., Oh S.Y., Jang J.S., Lee M.A., Sohn B.S., Yoon S.Y., Choi H.J., et al. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: A multicenter, open-label, randomized, phase III, noninferiority trial. Ann. Oncol. 2019;30:788–795. doi: 10.1093/annonc/mdz058. [DOI] [PubMed] [Google Scholar]

[B21-jcm-10-03108] 21.Phelip J.M., Desrame J., Edeline J., Barbier E., Terrebonne E., Michel P., Perrier H., Dahan L., Bourgeois V., Khemissa Akouz F., et al. Modified FOLFIRINOX versus CISGEM first-line chemotherapy for locally advanced, non resectable and/or metastatic biliary tract cancer: Results of AMEBICA PRODIGE 38 Phase II trial. Ann. Oncol. 2020;31(Suppl. 4):S260–S273. doi: 10.1016/j.annonc.2020.08.030. [DOI] [Google Scholar]

[B22-jcm-10-03108] 22.Kang M.J., Lee J., Kim T.W., Lee S.S., Ahn S., Park D.H., Lee S.S., Seo D.W., Lee S.K., Kim M. Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract cancer. Acta Oncol. 2012;7:860–866. doi: 10.3109/0284186X.2012.682628. [DOI] [PubMed] [Google Scholar]

[B23-jcm-10-03108] 23.Lee J., Hong T.H., Lee I.S., You Y.K., Lee M.A. Comparison of the Efficacy between Gemcitabine-Cisplatin and Capecitabine-Cisplatin Combination Chemotherapy for Advanced Biliary Tract Cancer. Cancer Res. Treat. 2015;47:259–265. doi: 10.4143/crt.2013.230. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B24-jcm-10-03108] 24.Malka D., Cervera P., Foulon S., Trarbach T., de la Fouchardière C., Boucher E., Fartoux L., Faivre S., Blanc J.F., Viret F., et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): A randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15:819–828. doi: 10.1016/S1470-2045(14)70212-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B25-jcm-10-03108] 25.Chen J.S., Hsu C., Chiang N.J., Tsai C.S., Tsou H.H., Huang S.F., Bai L.Y., Chang I.C., Shiah H.S., Ho C.L., et al. A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. Ann. Oncol. 2015;26:943–949. doi: 10.1093/annonc/mdv035. [DOI] [PubMed] [Google Scholar]

[B26-jcm-10-03108] 26.Leone F., Marino D., Cereda S., Filippi R., Belli C., Spadi R., Nasti G., Montano M., Amatu A., Aprile G., et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti-BIL study) Cancer. 2016;122:574–581. doi: 10.1002/cncr.29778. [DOI] [PubMed] [Google Scholar]

[B27-jcm-10-03108] 27.Vogel A., Kasper S., Bitzer M., Block A., Sinn M., Schulze-Bergkamen H., Moehler M., Pfarr N., Endris V., Goeppert B., et al. PICCA study: Panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase II AIO study. Eur. J. Cancer. 2018;92:11–19. doi: 10.1016/j.ejca.2017.12.028. [DOI] [PubMed] [Google Scholar]

[B28-jcm-10-03108] 28.Valle J.W., Wasan H., Lopes A., Backen A.C., Palmer D.H., Morris K., Duggan M., Cunningham D., Anthoney D.A., Corrie P., et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): A randomised phase 2 trial. Lancet Oncol. 2015;16:967–978. doi: 10.1016/S1470-2045(15)00139-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B29-jcm-10-03108] 29.Moehler M., Maderer A., Schimanski C., Kanzler S., Denzer U., Kolligs F.T., Ebert M.P., Distelrath A., Geissler M., Trojan J., et al. Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: A double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme. Eur. J. Cancer. 2014;50:3125–3135. doi: 10.1016/j.ejca.2014.09.013. [DOI] [PubMed] [Google Scholar]

[B30-jcm-10-03108] 30.Santoro A., Gebbia V., Pressiani T., Testa A., Personeni N., Arrivas Bajardi E., Foa P., Buonadonna A., Bencardino K., Barone C., et al. A randomized, multicenter, phase II study of vandetanib monotherapy versus vandetanib in combination with gemcitabine versus gemcitabine plus placebo in subjects with advanced biliary tract cancer: The VanGogh study. Ann. Oncol. 2015;26:542–547. doi: 10.1093/annonc/mdu576. [DOI] [PubMed] [Google Scholar]

[B31-jcm-10-03108] 31.Schinzari G., Rossi E., Mambella G., Strippoli A., Cangiano R., Mutignani M., Basso M., Cassano A., Barone C. First-line Treatment of Advanced Biliary Ducts Carcinoma: A Randomized Phase II Study Evaluating 5-FU/LV Plus Oxaliplatin (Folfox 4) Versus 5-FU/LV (de Gramont Regimen) Anticancer Res. 2017;37:5193–5197. doi: 10.21873/anticanres.11942. [DOI] [PubMed] [Google Scholar]

[B32-jcm-10-03108] 32.Markussen A., Jensen L.H., Diness L.V., Larsen F.O. Treatment of Patients with Advanced Biliary Tract Cancer with Either Oxaliplatin, Gemcitabine, and Capecitabine or Cisplatin and Gemcitabine-A Randomized Phase II Trial. Cancers. 2020;12:1975. doi: 10.3390/cancers12071975. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B33-jcm-10-03108] 33.dos Santos L.V., Pinto G.S.F., Ferraz M.W.S., Bragagnoli A., Santos F., Haddad S., Barros A., Dias I.C.C., Lima J.P.S., Abdalla K.C. Cisplatin plus irinotecan versus cisplatin plus gemcitabine in the treatment of advanced or metastatic gallbladder or biliary tract cancer: Results of a randomized phase II trial ( NCT01859728)–The Gambit trial. J. Clin. Oncol. 2020;38(Suppl. 4):529. doi: 10.1200/JCO.2020.38.4_suppl.529. [DOI] [Google Scholar]

[B34-jcm-10-03108] 34.Sasaki T., Isayama H., Nakai Y., Ito Y., Kogure H., Togawa O., Toda N., Yasuda I., Hasebe O., Maetani I., et al. Multicenter, phase II study of gemcitabine and S-1 combination chemotherapy in patients with advanced biliary tract cancer. Cancer Chemother. Pharmacol. 2010;65:1101–1107. doi: 10.1007/s00280-009-1115-5. [DOI] [PubMed] [Google Scholar]

[B35-jcm-10-03108] 35.Kanai M., Yoshimura K., Tsumura T., Asada M., Suzuki C., Niimi M., Matsumoto S., Nishimura T., Nitta T., Yasuchika K., et al. A multi-institution phase II study of gemcitabine/S-1 combination chemotherapy for patients with advanced biliary tract cancer. Cancer Chemother. Pharmacol. 2011;67:1429–1434. doi: 10.1007/s00280-010-1443-5. [DOI] [PubMed] [Google Scholar]

[B36-jcm-10-03108] 36.Sasaki T., Isayama H., Nakai Y., Ito Y., Yasuda I., Toda N., Kogure H., Hanada K., Maguchi H., Sasahira N., et al. A randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine monotherapy for advanced biliary tract cancer. Cancer Chemother. Pharmacol. 2013;71:973–979. doi: 10.1007/s00280-013-2090-4. [DOI] [PubMed] [Google Scholar]

[B37-jcm-10-03108] 37.Morizane C., Okusaka T., Mizusawa J., Takashima A., Ueno M., Ikeda M., Hamamoto Y., Ishii H., Boku N., Furuse J. Randomized phase II study of gemcitabine plus S-1 versus S-1 in advanced biliary tract cancer: A Japan Clinical Oncology Group trial (JCOG 0805) Cancer Sci. 2013;104:1211–1216. doi: 10.1111/cas.12218. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B38-jcm-10-03108] 38.Kanai M., Hatano E., Kobayashi S., Fujiwara Y., Marubashi S., Miyamoto A., Shiomi H., Kubo S., Ikuta S., Yanagimoto H., et al. A multi-institution phase II study of gemcitabine/cisplatin/S-1 (GCS) combination chemotherapy for patients with advanced biliary tract cancer (KHBO 1002) Cancer Chemother. Pharmacol. 2015;75:293–300. doi: 10.1007/s00280-014-2648-9. [DOI] [PubMed] [Google Scholar]

[B39-jcm-10-03108] 39.Walter T., Horgan A.M., McNamara M., McKeever L., Min T., Hedley D., Serra S., Krzyzanowska M.K., Chen E., Mackay H., et al. Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: A large retrospective study. Eur. J. Cancer. 2013;49:329–335. doi: 10.1016/j.ejca.2012.08.003. [DOI] [PubMed] [Google Scholar]

[B40-jcm-10-03108] 40.Bridgewater J., Palmer D., Cunningham D., Iveson T., Gillmore R., Waters J., Harrison M., Wasan H., Corrie P., Valle J. Outcome of second-line chemotherapy for biliary tract cancer. Eur. J. Cancer. 2013;49:1511. doi: 10.1016/j.ejca.2012.11.024. [DOI] [PubMed] [Google Scholar]

[B41-jcm-10-03108] 41.Lamarca A., Hubner R.A., David Ryder W., Valle J.W. Second-line chemotherapy in advanced biliary cancer: A systematic review. Ann. Oncol. 2014;25:2328–2338. doi: 10.1093/annonc/mdu162. [DOI] [PubMed] [Google Scholar]

[B42-jcm-10-03108] 42.Brieau B., Dahan L., De Rycke Y., Boussaha T., Vasseur P., Tougeron D., Lecomte T., Coriat R., Bachet J.B., Claudez P., et al. Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Entérologues Oncologues. Cancer. 2015;121:3290–3297. doi: 10.1002/cncr.29471. [DOI] [PubMed] [Google Scholar]

[B43-jcm-10-03108] 43.Takahara N., Nakai Y., Isayama H., Sasaki T., Saito K., Oyama H., Kanai S., Suzuki T., Sato T., Hakuta R., et al. Second-line chemotherapy in patients with advanced or recurrent biliary tract cancer: A single center, retrospective analysis of 294 cases. Investig. New Drugs. 2018;36:1093–1102. doi: 10.1007/s10637-018-0670-1. [DOI] [PubMed] [Google Scholar]

[B44-jcm-10-03108] 44.Lowery M.A., Goff L.W., Keenan B.P., Jordan E., Wang R., Bocobo A.G., Chou J.F., O’Reilly E.M., Harding J.J., Kemeny N., et al. Second-line chemotherapy in advanced biliary cancers: A retrospective, multicenter analysis of outcomes. Cancer. 2019;125:4426–4434. doi: 10.1002/cncr.32463. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B45-jcm-10-03108] 45.Zaidi A., Chandna N., Narasimhan G., Moser M., Haider K., Chalchal H., Shaw J., Ahmed S. Second-line Chemotherapy Prolongs Survival in Real World Patients with Advanced Biliary Tract and Gallbladder Cancers: A Multicenter Retrospective Population-based Cohort Study. Am. J. Clin. Oncol. 2021;44:93–98. doi: 10.1097/COC.0000000000000789. [DOI] [PubMed] [Google Scholar]

[B46-jcm-10-03108] 46.Sasaki T., Isayama H., Nakai Y., Mizuno S., Yamamoto K., Yagioka H., Yashima Y., Kawakubo K., Kogure H., Togawa O., et al. Multicenter phase II study of S-1 monotherapy as second-line chemotherapy for advanced biliary tract cancer refractory to gemcitabine. Investig. New Drugs. 2012;30:708–713. doi: 10.1007/s10637-010-9553-9. [DOI] [PubMed] [Google Scholar]

[B47-jcm-10-03108] 47.Suzuki E., Ikeda M., Okusaka T., Nakamori S., Ohkawa S., Nagakawa Y., Boku N., Yanagimoto H., Sato T., Furuse J. A multicenter phase II study of S-1 for gemcitabine-refractory biliary tract cancer. Cancer Chemother. Pharmacol. 2013;71:1141–1146. doi: 10.1007/s00280-013-2106-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B48-jcm-10-03108] 48.Tella S.H., Kommalapati A., Borad M.J., Mahipal A. Second-line therapies in advanced biliary tract cancers. Lancet Oncol. 2020;21:e29–e41. doi: 10.1016/S1470-2045(19)30733-8. [DOI] [PubMed] [Google Scholar]

[B49-jcm-10-03108] 49.Abou-Alfa G.K., Macarulla T., Javle M.M., Kelley R.K., Lubner S.J., Adeva J., Cleary J.M., Catenacci D.V., Borad M.J., Bridgewater J., et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796–807. doi: 10.1016/S1470-2045(20)30157-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B50-jcm-10-03108] 50.Lamarca A., Palmer D.H., Wasan H.S., Ross P.J., Ma Y.T., Arora A., Falk S., Gillmore R., Wadsley J., Patel K., et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): A phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22:690–701. doi: 10.1016/S1470-2045(21)00027-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B51-jcm-10-03108] 51.Jalve M.M., Oh D.Y., Ikeda M., Yong W.P., McIntyre N., Lindmark B., McHale M. Results from TreeTopp: A randomized phase II study of the efficacy and safety of varlitinib plus capecitabine versus placebo in second-line (2L) advanced or metastatic biliary tract cancer (BTC) J. Clin. Oncol. 2020;38(Suppl. 15):4597. [Google Scholar]

[B52-jcm-10-03108] 52.Cereda S., Milella M., Cordio S., Leone F., Aprile G., Galiano A., Mosconi S., Vasile E., Santini D., Belli C., et al. Capecitabine with/without mitomycin C: Results of a randomized phase II trial of second-line therapy in advanced biliary tract adenocarcinoma. Cancer Chemother. Pharmacol. 2016;77:109–114. doi: 10.1007/s00280-015-2919-0. [DOI] [PubMed] [Google Scholar]

[B53-jcm-10-03108] 53.Zheng Y., Tu X., Zhao P., Jiang W., Liu L., Tong Z., Zhang H., Yan C., Fang W., Wang W. A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin. Br. J. Cancer. 2018;119:291–295. doi: 10.1038/s41416-018-0138-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B54-jcm-10-03108] 54.Kim R.D., McDonough S., El-Khoueiry A.B., Bekaii-Saab T.S., Stein S.M., Sahai V., Keogh G.P., Kim E.J., Baron A.D., Siegel A.B., et al. Randomised phase II trial (SWOG S1310) of single agent MEK inhibitor trametinib Versus 5-fluorouracil or capecitabine in refractory advanced biliary cancer. Eur. J. Cancer. 2020;130:219–227. doi: 10.1016/j.ejca.2020.01.026. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B55-jcm-10-03108] 55.Demols A., Borbath I., Van den Eynde M., Houbiers G., Peeters M., Marechal R., Delaunoit T., Goemine J.C., Laurent S., Holbrechts S., et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial. Ann. Oncol. 2020;31:1169–1177. doi: 10.1016/j.annonc.2020.05.018. [DOI] [PubMed] [Google Scholar]

[B56-jcm-10-03108] 56.Ramaswamy A., Ostwal V., Sharma A., Bhargava P., Srinivas S., Goel M., Patkar S., Mandavkar S., Jadhav P., Parulekar M., et al. Efficacy of Capecitabine Plus Irinotecan vs Irinotecan Monotherapy as Second-line Treatment in Patients With Advanced Gallbladder Cancer: A Multicenter Phase 2 Randomized Clinical Trial (GB-SELECT) JAMA Oncol. 2021;7:436–439. doi: 10.1001/jamaoncol.2020.6166. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B57-jcm-10-03108] 57.Ueno M., Morizane C., Furukawa M., Sakai D., Komatsu Y., Nakai Y., Tsuda M., Ozaka M., Mizuno N., Muto M., et al. A randomized, double-blind, phase II study of oral histone deacetylase inhibitor resminostat plus S-1 versus placebo plus S-1 in biliary tract cancers previously treated with gemcitabine plus platinum-based chemotherapy. Cancer Med. 2021;10:2088–2099. doi: 10.1002/cam4.3813. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B58-jcm-10-03108] 58.Yoo C., Kim K.P., Kim I., Kang M.J., Cheon J., Kang B.W., Ryu H., Jeong J.H., Lee J.S., Kim K.W., et al. Liposomal Irinotecan (nal-IRI) in combination with Fluorouracil (5-FU) and Leucovorin (LV) for Patients (pts) with Metastatic Biliary Tract Cancer (BTC) after Progression on Gemcitabine plus Cisplatin (GemCis): Multicenter Comparative Randomized Phase 2B study (NIFTY) J. Clin. Oncol. 2021;39(Suppl. 15):4006. [Google Scholar]

[B59-jcm-10-03108] 59.Nakamura H., Arai Y., Totoki Y., Shirota T., Elzawahry A., Kato M., Hama N., Hosoda F., Urushidate T., Ohashi S., et al. Genomic spectra of biliary tract cancer. Nat. Genet. 2015;47:1003–1010. doi: 10.1038/ng.3375. [DOI] [PubMed] [Google Scholar]

[B60-jcm-10-03108] 60.Valle J.W., Lamarca A., Goyal L., Barriuso J., Zhu A.X. New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov. 2017;7:943–962. doi: 10.1158/2159-8290.CD-17-0245. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B61-jcm-10-03108] 61.Jusakul A., Cutcutache I., Yong C.H., Lim J.Q., Huang M.N., Padmanabhan N., Nellore V., Kongpetch S., Ng A.W.T., Ng L.M., et al. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma. Cancer Discov. 2017;7:1116–1135. doi: 10.1158/2159-8290.CD-17-0368. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B62-jcm-10-03108] 62.Silverman I.M., Hollebecque A., Friboulet L., Owens S., Newton R.C., Zhen H., Féliz L., Zecchetto C., Melisi D., Burn T.C. Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib. Cancer Discov. 2021;11:326–339. doi: 10.1158/2159-8290.CD-20-0766. [DOI] [PubMed] [Google Scholar]

[B63-jcm-10-03108] 63.Javle M., Lowery M., Shroff R.T., Weiss K.H., Springfeld C., Borad M.J., Ramanathan R.K., Goyal L., Sadeghi S., Macarulla T., et al. Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma. J. Clin. Oncol. 2018;36:276–282. doi: 10.1200/JCO.2017.75.5009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B64-jcm-10-03108] 64.Mazzaferro V., El-Rayes B.F., Droz Dit Busset M., Cotsoglou C., Harris W.P., Damjanov N., Masi G., Rimassa L., Personeni N., Braiteh F., et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br. J. Cancer. 2019;120:165–171. doi: 10.1038/s41416-018-0334-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B65-jcm-10-03108] 65.Abou-Alfa G.K., Sahai V., Hollebecque A., Vaccaro G., Melisi D., Al-Rajabi R., Paulson A.S., Borad M.J., Gallinson D., Murphy A.G., et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671–685. doi: 10.1016/S1470-2045(20)30109-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B66-jcm-10-03108] 66.Goyal L., Meric-Bernstam F., Hollebecque A., Morizane C., Valle J.W., Karasic T.B., Abrams T.A., Kelley R.B., Cassier P., Furuse J., et al. Primary results of phase 2 FOENIX-CCA2: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrengements; Proceedings of the AACR Annual Meeting, Virtual Meeting; Philadelphia, PA, USA. 10–15 April/17–21 May 2021; Abstract CT-010. [Google Scholar]

[B67-jcm-10-03108] 67.Maruki Y., Morizane C., Arai Y., Ikeda M., Ueno M., Ioka T., Naganuma A., Furukawa M., Mizuno N., Uwagawa T., et al. Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: A prospective observational study (PRELUDE Study) J. Gastroenterol. 2021;56:250–260. doi: 10.1007/s00535-020-01735-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B68-jcm-10-03108] 68.Le D.T., Durham J.N., Smith K.N., Wang H., Bartlett B.R., Aulakh L.K., Lu S., Kemberling H., Wilt C., Luber B.S., et al. Mismatch repair deficiency predicts response of solid tumors of PD-1 blockade. Science. 2017;357:409–413. doi: 10.1126/science.aan6733. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B69-jcm-10-03108] 69.Doebele R.C., Drilon A., Paz-Ares L., Siena S., Shaw A.T., Farago A.F., Blakely C.M., Seto T., Cho B.C., Tosi D., et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21:271–282. doi: 10.1016/S1470-2045(19)30691-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B70-jcm-10-03108] 70.Drilon A., Laetsch T.W., Kummar S., DuBois S.G., Lassen U.N., Demetri G.D., Natheson M., Doebele R.C., Fargo A.F., Pappo A.S., et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N. Engl. J. Med. 2018;378:731–739. doi: 10.1056/NEJMoa1714448. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B71-jcm-10-03108] 71.Akagi K., Oki E., Taniguchi H., Nakatani K., Aoki D., Kuwata T., Yoshino T. The real-world data on microsatellite instability status in various unresectable or metastatic solid tumors. Cancer Sci. 2021;112:1105. doi: 10.1111/cas.14798. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B72-jcm-10-03108] 72.Yoshino T., Pentheroudakis G., Mishima S., Overman M.J., Yeh K.H., Baba E., Naito Y., Calvo F., Saxena A., Chen L.T., et al. JSCO-ESMO-ASCO-JSMO-TOS: International expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions. Ann. Oncol. 2020;31:861–872. doi: 10.1016/j.annonc.2020.03.299. [DOI] [PubMed] [Google Scholar]

[B73-jcm-10-03108] 73.Piha-Paul S.A., Oh D.Y., Ueno M., Malka D., Chung H.C., Nagrial A., Kelley R.K., Ros W., Italiano A., Nakagawa K., et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies. Int. J. Cancer. 2020;147:2190–2198. doi: 10.1002/ijc.33013. [DOI] [PubMed] [Google Scholar]

[B74-jcm-10-03108] 74.Ueno M., Ikeda M., Morizane C., Kobayashi S., Ohno I., Kondo S., Okano N., Kimura K., Asada S., Namba Y., et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: A non-randomised, multicentre, open-label, phase 1 study. Lancet Gastroenterol. Hepatol. 2019;4:611–621. doi: 10.1016/S2468-1253(19)30086-X. [DOI] [PubMed] [Google Scholar]

[B75-jcm-10-03108] 75.Kim R.D., Chung V., Alese O.B., El-Rayes B.F., Li D., Al-Toubah T.E., Schell M.J., Zhou J.M., Mahipal A., Kim B.H., et al. A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer. JAMA Oncol. 2020;6:888–894. doi: 10.1001/jamaoncol.2020.0930. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B76-jcm-10-03108] 76.Feng K., Liu Y., Zhao Y., Yang Q., Dong L., Liu J., Li X., Zhao Z., Mei Q., Han W. Efficacy and biomarker analysis of nivolumab plus gemcitabine and cisplatin in patients with unresectable or metastatic biliary tract cancers: Results from a phase II study. J. Immunother. Cancer. 2020;8:e000367. doi: 10.1136/jitc-2019-000367. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B77-jcm-10-03108] 77.Klein O., Kee D., Nagrial A., Markman B., Underhill C., Michael M., Jackett L., Lum C., Behren A., Palmer J., et al. Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2020;6:1405–1409. doi: 10.1001/jamaoncol.2020.2814. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B78-jcm-10-03108] 78.Chen X., Wu X., Wu H., Gu Y., Shao Y., Shao Q., Zhu F., Li X., Qian X., Hu J., et al. Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: A single-arm, open-label, phase II trial. J. Immunother. Cancer. 2020;8:e001240. doi: 10.1136/jitc-2020-001240. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B79-jcm-10-03108] 79.Villanueva L., Lwin Z., Chung H.C., Gomez-Roca C.A., Longo F., Yanez E., Senellart H., Doherty M., Garcia-Corbacho J., Hendifar A.E., et al. Lenvatinib plus pembrolizumab for patients with previously treated biliary tract cancers in the multicohort phase 2 LEAP-005 study. J. Clin. Oncol. 2021;39(Suppl. 15):4080. doi: 10.1200/JCO.2021.39.15_suppl.4080. [DOI] [Google Scholar]

[B80-jcm-10-03108] 80.Takada T., Amano H., Yasuda H., Nimura Y., Matsushiro T., Kato H., Nagakawa T., Nakayama T., Study Group of Surgical Adjuvant Therapy for Carcinomas of the Pancreas and Biliary Tract Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95:1685–1695. doi: 10.1002/cncr.10831. [DOI] [PubMed] [Google Scholar]

[B81-jcm-10-03108] 81.Neoptolemos J.P., Moore M.J., Cox T.F., Valle J.W., Palmer D.H., McDonald A.C., Carter R., Tebbutt N.C., Dervenis C., Smith D., et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma. JAMA. 2012;308:147–156. doi: 10.1001/jama.2012.7352. [DOI] [PubMed] [Google Scholar]

[B82-jcm-10-03108] 82.Ebata T., Hirano S., Konishi M., Uesaka K., Tsuchiya Y., Ohtsuka M., Kaneoka Y., Yamamoto M., Ambo Y., Shimizu Y., et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br. J. Surg. 2018;105:192–202. doi: 10.1002/bjs.10776. [DOI] [PubMed] [Google Scholar]

[B83-jcm-10-03108] 83.Edeline J., Benabdelghani M., Bertaut A., Watelet J., Hammel P., Joly J.P., Boudjema K., Fartoux L., Bouhier-Leporrier K., Jouve J.L., et al. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J. Clin. Oncol. 2019;37:658–667. doi: 10.1200/JCO.18.00050. [DOI] [PubMed] [Google Scholar]

[B84-jcm-10-03108] 84.Primrose J.N., Fox R.P., Palmer D.H., Malik H.Z., Prasad R., Mirza D., Anthony A., Corrie P., Falk S., Finch-Jones M., et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): A randomized, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20:663–673. doi: 10.1016/S1470-2045(18)30915-X. [DOI] [PubMed] [Google Scholar]

[B85-jcm-10-03108] 85.Shroff R.T., Kennedy E.B., Bachini M., Bekaii-Saab T., Crane C., Edeline J., El-Khoueiry A., Feng M., Katz M.H.G., Primrose J., et al. Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline. J. Clin. Oncol. 2019;37:1015–1027. doi: 10.1200/JCO.18.02178. [DOI] [PubMed] [Google Scholar]

[B86-jcm-10-03108] 86.McNamara M.G., Goyal L., Doherty M., Springfeld C., Cosgrove D., Sjoquist K.M., Park J.O., Verdaguer H., Braconi C., Ross P.J., et al. NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121) Future Oncol. 2020;16:1069–1081. doi: 10.2217/fon-2020-0247. [DOI] [PubMed] [Google Scholar]

[B87-jcm-10-03108] 87.Bekaii-Saab T.S., Valle J.W., Van Cutsem E., Rimassa L., Furuse J., Ioka T., Melisi D., Macarulla T., Bridgewater J., Wasan H., et al. FIGHT-302: First-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements. Future Oncol. 2020;16:2385–2399. doi: 10.2217/fon-2020-0429. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B88-jcm-10-03108] 88.Makawita S., Abou-Alfa G.K., Roychowdhury S., Sadeghi S., Borbath I., Goyal L., Cohn A., Lamarca A., Oh D.Y., Macarulla T., et al. Infigratinib in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: The PROOF 301 trial. Future Oncol. 2020;16:2375–2384. doi: 10.2217/fon-2020-0299. [DOI] [PubMed] [Google Scholar]

[B89-jcm-10-03108] 89.Stein A., Arnold D., Bridgewater J., Goldstein D., Jensen L.H., Klümpen H.J., Lohse A.W., Nashan B., Primrose J., Schrum S., et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—A randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015;15:564. doi: 10.1186/s12885-015-1498-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B90-jcm-10-03108] 90.Nakachi K., Konishi M., Ikeda M., Mizusawa J., Eba J., Okusaka T., Ishii H., Fukuda H., Furuse J., Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT) Jpn. J. Clin. Oncol. 2018;48:392–395. doi: 10.1093/jjco/hyy004. [DOI] [PubMed] [Google Scholar]

[B91-jcm-10-03108] 91.Goetze T.O., Bechstein W.O., Bankstahl U.S., Keck T., Königsrainer A., Lang S.A., Pauligk C., Piso P., Vogel A., Al-Batran S.E. Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC)—A phase III study of the German registry of incidental gallbladder carcinoma platform (GR)- the AIO/ CALGP/ ACO- GAIN-trial. BMC Cancer. 2020;20:122. doi: 10.1186/s12885-020-6610-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B92-jcm-10-03108] 92.Shroff R.T., Javle M.M., Xiao L., Kaseb A.O., Varadhachary G.R., Wolff R.A., Raghav K.P.S., Iwasaki M., Masci P., Ramanathan R.K., et al. Gemcitabine, Cisplatin, and nab-Paclitaxel for the Treatment of Advanced Biliary Tract Cancers: A Phase 2 Clinical Trial. JAMA Oncol. 2019;5:824–830. doi: 10.1001/jamaoncol.2019.0270. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B93-jcm-10-03108] 93.Yoo C., Oh D.Y., Choi H.J., Kudo M., Ueno M., Kondo S., Chen L.T., Osada M., Helwig C., Dussault I., et al. Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with pretreated biliary tract cancer. J. Immunother. Cancer. 2020;8:e000564. doi: 10.1136/jitc-2020-000564. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B94-jcm-10-03108] 94.Boilève A., Hilmi M., Gougis P., Cohen R., Rousseau B., Blanc J.F., Ben Abdelghani M., Castanié H., Dahan L., Tougeron D., et al. Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial. Eur. J. Cancer. 2021;143:55–63. doi: 10.1016/j.ejca.2020.10.027. [DOI] [PubMed] [Google Scholar]

PERMALINK

Chemotherapy for Biliary Tract Cancer in 2021

Takashi Sasaki

Tsuyoshi Takeda

Takeshi Okamoto

Masato Ozaka

Naoki Sasahira

Roles

Abstract

1. Introduction

2. First-Line Chemotherapy for Advanced Biliary Tract Cancer

Table 1.

3. Second-Line Chemotherapy for Advanced Biliary Tract Cancer

Table 2.

4. Adjuvant Chemotherapy for Resected Biliary Tract Cancer

Table 3.

5. Ongoing Clinical Trials for Biliary Tract Cancer

Table 4.

6. Conclusions

Figure 1.

Author Contributions

Funding

Informed Consent Statement

Data Availability Statement

Conflicts of Interest

Footnotes

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Chemotherapy for Biliary Tract Cancer in 2021

Takashi Sasaki

Tsuyoshi Takeda

Takeshi Okamoto

Masato Ozaka

Naoki Sasahira

Roles

Abstract

1. Introduction

2. First-Line Chemotherapy for Advanced Biliary Tract Cancer

Table 1.

3. Second-Line Chemotherapy for Advanced Biliary Tract Cancer

Table 2.

4. Adjuvant Chemotherapy for Resected Biliary Tract Cancer

Table 3.

5. Ongoing Clinical Trials for Biliary Tract Cancer

Table 4.

6. Conclusions

Figure 1.

Author Contributions

Funding

Informed Consent Statement

Data Availability Statement

Conflicts of Interest

Footnotes

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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