Clinical outcomes for previously treated patients with advanced biliary tract cancer: a meta-analysis

Figures & data

Table 1. PICOST eligibility criteria for the systematic review.

Criteria	Inclusion criteria	Exclusion criteria
Population	Adults (≥18 years) with advanced (unresectable and/or metastatic) biliary adenocarcinoma, including intrahepatic or extrahepatic cholangiocarcinoma and gallbladder cancer • Previously treated for advanced disease • Performance status of 0–1 (or equivalent) • Recurrent disease when stage not specified	Populations consisting exclusively of patients with one of the following characteristics: • Ampulla of Vater cancer • Previously treated with anti-PD1/PD-L1 agents • Performance status of ≥2 (or equivalent) • Stage I or II disease • Central nervous system metastasis
Interventions/comparators	Any pharmacologic treatment licensed by the US FDA or European Medicines Agency for any indication, including off-label treatments	NA
Outcomes	Efficacy outcomes: • Objective response rate (and numbers of patients with complete response or partial response when available) • Median overall survival • Median progression-free survival Safety outcomes: • Any-cause and treatment-related adverse events • Any-cause and treatment-related grade 3–5 adverse events • Any-cause and treatment-related serious adverse events • Discontinuation due to adverse events • Deaths due to adverse events Patient-reported outcomes (e.g., EQ-5D, EORTC QLQ-C30)	NA
Study design	• Randomized controlled trials • Nonrandomized trials • Single-arm trials	• Animal or in vitro studies • Case reports/series • Editorials, commentaries, letters, reviews • Pharmacokinetics or pharmacodynamics studies
Time	From 2000 onward	NA
Language	English	NA

EORTC QLQ-C30: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire; EQ-5D: EuroQol-5 Dimension; NA: Not applicable.

Figure 1. PRISMA flow diagram.

Flow diagram depicting the study search and selection processes.

Table 2. General characteristics of studies included in the systematic review.

Trial	Study design	Country	Trial arm	Treatment	n	Ref.
Bengala et al. (2010)	Single-arm	NR	1	Sorafenib	26	[33]
Sasaki et al. (2011)	Single-arm	Japan	1	Gemcitabine + cisplatin	20	[34]
Rohrberg et al. (2012)	Single-arm	Denmark	1	Erlotinib + bevacizumab	16	[35]
Sasaki et al. (2012)	Single-arm	Japan	1	S-1	22	[36]
Yi et al. (2012)	Single-arm	Multinational	1	Sunitinib	56	[37]
Sinn et al. (2013)	Single-arm	Germany	1	Oxaliplatin + natrium folinate + 5-fluorouracil	6	[38]
Suzuki et al. (2013)	Single-arm	Japan	1	S-1	40	[39]
Hwang et al. (2015)	Single-arm	South Korea	1	mFOLFOX3 (oxaliplatin + 5-fluorouracil + leucovorin)	30	[40]
Cereda et al. (2016)	RCT	Italy	1	Capecitabine	26	[41]
			2	Capecitabine + mitomycin	29
Goyal et al. (2017)	Single-arm	USA	1	Cabozantinib	19	[42]
Kobayashi et al. (2017)	Single-arm	Japan	1	Gemcitabine + S-1	41	[43]
Shroff et al. (2017)	Single-arm	USA	1	Pazopanib + trametinib	25	[44]
Arkenau et al. (2018)	Single-arm	Multinational	1	Pembrolizumab + ramucirumab	26	[45]
Ikeda et al. (2018)	Single-arm	Japan	1	Trametinib	20	[46]
Javle et al. (2018)	Single-arm	Multinational	1	Infigratinib	61	[47]
Larsen et al. (2018)	Single arm	Denmark	1	Gemcitabine + irinotecan + bevacizumab + capecitabine	48	[48]
Matsuyama et al. (2018)	Single-arm	Japan	1	Gemcitabine + cisplatin	27	[49]
Zheng et al. (2018)	RCT	China	1	XELIRI (irinotecan + capecitabine)	30	[50]
			2	Irinotecan	30
Kim et al. (2019)	Single-arm	South Korea	1	Binimetinib + capecitabine	34	[51]
Kim et al. (2019)	Single-arm	South Korea	1	XELOX (capecitabine + oxaliplatin)	50	[52]
Park et al. (2019)	Single-arm	Multinational	1	Erdafitinib	17	[53]
Sun et al. (2019)	Single-arm	USA	1	Regorafenib	43	[54]
Belkouz et al. (2020)	Single-arm	Netherlands	1	FOLFIRINOX (fluorouracil + leucovorin + irinotecan + oxaliplatin)	30	[55]
Chakrabarti et al. (2020)	Single-arm	USA	1	Trifluridine/tipiracil	27	[56]
Demols et al. (2020)	RCT	Belgium	1	Regorafenib	33	[57]
			2	Placebo	33
Kim et al. (2020)	Single-arm	USA	1	Nivolumab	54	[26]
Kim et al. (2020)	Single-arm	USA	1	Regorafenib	39	[25]
Klein et al. (2020)	Single-arm	Australia	1	Nivolumab + ipilimumab	33	[58]
Piha-Paul et al. (2020)	Single-arm	Multinational	1	Pembrolizumab	24	[59]
Piha-Paul et al. (2020)	Single-arm	Multinational	1	Pembrolizumab	104	[59]
Ueno et al. (2020)	Single-arm	Japan	1	Lenvatinib	26	[60]
Choi et al. (2021)	RCT	South Korea	1	mFOLFOX (oxaliplatin + 5-fluorouracil)	59	[61]
			2	mFOLFIRI (irinotecan + 5-fluorouracil)	59
Lamarca et al. (2021)	RCT	UK	1	Active symptom control	81	[62]
			2	Active symptom control + mFOLFOX	81
Ma et al. (2021)	Single-arm	USA	1	Paclitaxel injection concentrate for nano-dispersion	20	[63]
Okano et al. (2021)	Single-arm	Japan	1	Axitinib	19	[64]
Ramaswamy et al. (2021)	RCT	India	1	CAPIRI (capecitabine + irinotecan)	49	[65]
			2	Irinotecan	49
Villaneuva et al. (2021)	Nonrandomized trial	Multinational	1	Pembrolizumab + lenvatinib	31	[66]
Woodford et al. (2021)	Single arm	Australia	1	Capecitabine + nab-paclitaxel	10	[67]
Yoo et al. (2021)	RCT	South Korea	1	Liposomal irinotecan + flurouracil + leucovorin	88	[68]
			2	Flurouracil + leucovorin	86

Note: N represents the reported total number of patients who received at least one dose of treatment.

NR: Not reported; RCT: Randomized controlled trial.

Figure 2. Funnel plot for the assessment of publication bias.

A funnel plot of the 34 trial arms included in the meta-analysis of objective response rate was symmetrical. An accompanying Egger’s test showed no evidence of publication bias (intercept: 0.43; 95% CI: -1.57 to 2.44; p = 0.67).

Figure 3. Meta-analysis of objective response rate.

‘Responders’ denotes the number of patients with an objective response (complete response + partial response). ‘Total’ denotes the number of patients who received at least one dose of treatment.

OR: Objective response.

Figure 4. Meta-analysis of overall survival.

Grey lines represent Kaplan–Meier estimates of overall survival for each trial arm. Black squares represent the end of follow-up for each trial. The thick black line represents the random effects pooled overall survival estimate with 95% CI (dashed lines). The p-value was derived from Cochran’s Q test of heterogeneity (I² test statistic).

Table 3. Summary of pooled Kaplan–Meier estimates of overall survival and progression-free survival.

	OS	PFS
Number of studies	22	20
Number of arms	26	24
Number (%) of OS events	899 (84.3)	892 (90.5)
Person-months^†	8404.9	4187.8
Event rate per 100 person-months	10.7	21.3
Median survival (months)^‡	6.6	3.2
95% CI for median OS^‡	(5.9–7.1)	(2.8–3.8)
OS rate at 6 months, %^‡ (95% CI)	54.1 (49.6–59.0)	25.8 (20.3–32.7)
OS rate at 12 months, %^‡ (95% CI)	24.8 (20.7–29.6)	7.0 (4.5–10.8)
OS rate at 18 months, %^‡ (95% CI)	8.4 (5.7–12.4)	1.3 (0.6–2.9)
OS rate at 24 months, %^‡ (95% CI)	2.4 (1.3–4.4)	0.1 (0.0–0.6)
OS rate at 30 months, %^‡ (95% CI)	0.4 (0.1–1.2)	0.0 (0.0–0.3)
OS rate at 36 months, %^‡ (95% CI)	0.1 (0.0–0.4)	–
OS rate at 42 months, %^‡ (95% CI)	0.0 (0.0–0.1)	–
OS rate at 48 months, %^‡ (95% CI)	0.0 (0.0–0.0)	–

† Calculated as the total time-at-risk (in months) for all patients across all trials.

‡ Estimates derived from the random effects pooled survival curve using methodology from Combescure et al. [32].

KM: Kaplan–Meier; OS: Overall survival; PFS: Progression-free survival.

Figure 5. Meta-analysis of progression-free survival.

Grey lines represent Kaplan–Meier estimates of progression-free survival for each trial arm. Black squares represent the end of follow-up for each trial. The thick black line represents the random effects pooled progression-free survival estimate with 95% CI (dashed lines). The p-value was derived from Cochran’s Q test of heterogeneity (I² test statistic).

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