Current status and dilemma of second-line treatment in advanced pancreatic cancer: is there a silver lining?

Figures & data

Figure 1 PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) flow diagram of study selection.

Table 1 Randomized controlled trials evaluating second-line chemotherapy in gemcitabine-refractory advanced pancreatic cancer

Study	Treatment	No of patients	Median age	ECOG 0–1 (%)/KPS 90–100 (%)	Metastatic disease (%)	Response rate	Median response duration	Median PFS	Median OS
Ioka et al^Citation47	S-1 + irinotecan S-1	60 67	62 65	100 100	100 100	ORR 18.3% ORR 6.0%	TTF 2.1 months TTF 1.8 months	3.5 months 1.9 months	6.8 months 5.8 months
Ueno et al^Citation45	SL S-1	69 71	65 64	100 100	NR NR	ORR 27.5% ORR 19.7%	TTF 3.7 months TTF 2.4 months	3.8 months 2.7 months	6.3 months 6.1 months
Gill et al^Citation12	mFOLFOX6 FU/LV	54 54	65 67	88.9 94.4	92.6 94.4	CR 0%; PR 13.2%; SD 44.7% CR 0%; PR 8.5%; SD 55.3%	TTP 2.2 months TTP 3.8 months	3.1 months 2.9 months	6.1 months 9.9 months
Wang-Gillam et al^Citation11	Nanoliposomal irinotecan plus FU/LV Nanoliposomal irinotecan FF	117 151 149	63 65 63	59 57 51	100 100 100	ORR 16% ORR 6% ORR 1%	TTF 2.3 months TTF 1.7 months TTF 1.4 months	3.1 months 2.7 months 1.6 months	6.1 months 4.9 months 4.2 months
Ohkawa et al^Citation46	S-1 + oxaliplatin S-1	136 132	65 63.5	100 100	100 100	ORR 20.9% ORR 11.5%	NR NR	3.0 months 2.8 months	7.4 months 6.9 months
Oettle et al^Citation10	OFF FF	76 84	62 61	53.9 47.6	88.2 88.1	CR 1.3% CR 1.2%	TTP 2.9 months TTP 2.0 months	2.9 months 2.0 months	5.9 months 3.3 months
Ge et al^Citation44	SL S-1	45 47	NR NR	NR NR	100 100	NR NR	NR NR	3.0 months 1.9 months	6.3 months 5.5 months
Pelzer et al^Citation13 (terminated)	OFF BSC	23 23	60 61	47.8 52.2	73.9 69.6	CR 0%; PR 0% CR 0%; PR 0%	NR NR	NR NR	4.82 months 2.30 months
Ciuleanu et al^Citation14	Glufosfamide BSC	148 155	58 57	40 44	100 100	CR 0%; PR 2.1%; SD 31% CR 0%; PR 0.7%; SD 19%	NR NR	46 days 43 days	105 days 84 days
Yoo et al^Citation27	mFOLFIRI.3 mFOLFOX	31 30	55 55	100 97	NR NR	PR 0%; SD 23%; PD 68% PR 7%; SD 10%; PD 70%	NR NR	8.3 weeks 6.0 weeks	16.6 weeks 14.9 weeks
Ulrich-Pur et al^Citation35	Raltitrexed plus irinotecan Raltitrexed	19 19	63 60	21 21	100 100	PR 16%; SD 32% PR 0%; SD 37%	RD 14 weeks RD 11 weeks	4.0 months 2.5 months	6.5 months 4.3 months

Notes: FU/LV = leucovorin 400 mg/m² on Day 1, fluorouracil 400 mg/m² bolus on Day 1, followed by fluorouracil 2,400 mg/m² continuous infusion for 46 hours every 14 days. mFOLFOX6 = FU/LV plus oxaliplatin 85 mg/m² on Day 1 every 14 days. FF = intravenous folinic acid 200 mg/m² and continuous infusion of fluorouracil 2,000 mg/m² over 24 hours on days 1, 8, 15, and 22 of a 6-week cycle. OFF = FF plus oxaliplatin 85 mg/m² on days 8 and 22. mFOLFIRI.3 = irinotecan 70 mg/m² on Day 1, leucovorin 400 mg/m² on Day 1, fluorouracil 2,000 mg/m² over 46 hours from Day 1, followed by irinotecan 70 mg/m² every 2 weeks. mFOLFOX = oxaliplatin 85 mg/m² on Day 1, leucovorin 400 mg/m² on Day 1, followed by fluorouracil 2,000 mg/m² over 46 hours every 2 weeks.

Abbreviations: BSC, best supportive care; CR, complete response; ECOG, Eastern Oncology Cooperative Group; KPS, Karnofsky performance status; NR, not reported; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; S-1, tegafur/gimeracil/oteracil; SL, S-1 plus leucovorin; TTF, time to treatment failure; TTP, time to progression.

Table 2 Single-armed phase II clinical trials evaluating second-line single-agent chemotherapy in advanced pancreatic cancer

Study	Treatment	No of patients*	ECOG 0–1 (%)/KPS 90–100 (%)	Metastatic disease (%)	Response rate	Median survival
Hosein et al^Citation22	Nab-paclitaxel 100 mg/m^2 on days 1, 8, and 15 of a 28-day cycle	19	79	95	CR 0%; PR 5%; SD 32%	OS 7.3 months; PFS 1.7 months
Ko et al^Citation20	Nanoliposomal irinotecan 120 mg/m^2 every 3 weeks	40	60	100	PR 7.5%; SD 42.5%; PD 25.0%	OS 5.2 months; PFS 2.4 months
Sudo et al^Citation18	S-1 40 mg/m^2 orally, twice a day for 4 weeks on a 6-week cycle	21	71.4	95	PR 9.5%; SD 43%	OS 6.3 months; PFS 4.1 months
Yi et al^Citation19	Irinotecan 150 mg/m^2 every 2 weeks	33	94	100	PR 9%; SD 39%	OS 6.6 months; PFS 2.0 months
Morizane et al^Citation17	S-1 40 mg/m^2 orally, twice a day for 4 weeks on a 6-week cycle	40	90	100	CR 0%; PR 15%; SD 43%; PD 38%	OS 4.5 months; PFS 2.0 months
Boeck et al^Citation21	Capecitabine 1,250 mg/m^2 orally, twice a day for 2 weeks on a 3-week cycle	39	51	97	PR 0; SD 39%; PD 31%	OS 7.6 months
Boeck et al^Citation16	Pemetrexed 500 mg/m^2 every 3 weeks	52	94.2	88.5	PR 3.8%; SD 19.2%; PD 59.6%	OS 20 weeks
Androulakis et al^Citation15	Oxaliplatin 130 mg/m^2 every 3 weeks	18	72	72	CR 0%; PR 0%; SD 16.7%	OS 3.5 months

Notes:

* All patients were previously treated with first-line gemcitabine monotherapy or gemcitabine-based combination therapy.

Abbreviations: CR, complete response; ECOG, Eastern Oncology Cooperative Group; KPS, Karnofsky performance status; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; S-1, tegafur/gimeracil/oteracil.

Table 3 Single-armed phase II clinical trials evaluating second-line combination chemotherapy in advanced pancreatic cancer

Study	Treatment	No of patients*	ECOG 0–1 (%)/KPS 90–100 (%)	Metastatic disease (%)	Response rate	Median response duration	Median survival
Ettrich et al^Citation32	Docetaxel 75 mg/m^2 on Day 1 + oxaliplatin 80 mg/m^2 on Day 2 on a 21-day cycle	44	69.7	81.8	CR 0%; PR 15.9%; SD 31.8%; PD 52.3%	NR	OS 10.1 months; PFS 1.82 months
Braghiroli et al^Citation49	Metformin 850 mg orally, three times a day plus paclitaxel 80 mg/m^2 weekly for 3 weeks on a 4-week cycle	20	60	100	SD 31.6%	TTP 44 days	OS 4.3 months; PFS 1.5 months
Soares et al^Citation43	Docetaxel 30 mg/m^2 on days 1 and 8 plus capecitabine 800 mg/m^2 orally, twice a day on days 1–14 on a 21-day cycle	42	74	100	CR 0%; PR 14.3%; SD 59.5%; PD 26.2%	TTF 3.0 months	OS 5.3 months; PFS 3.7 months
El-Hadaad and Wahba^Citation26	Oxaliplatin 85 mg/m^2 on days 1 and 15, leucovorin 20 mg/m^2 and 5-FU 500 mg/m^2 on days 1, 8, and 15 every 3 weeks	30	83.3	20	PR 6.7%; SD 20%; PD 40%	RD 13 weeks	OS 22 weeks
Kim et al^Citation33	S-1 40–60 mg orally, twice a day on days 1–14 plus cisplatin 60 mg/m^2 on Day 1 on a 21-day cycle	11	81.8	81.8	CR 0%; PR 0%; SD 9.1%	TTP 44 days	OS 81 days
Zaniboni et al^Citation38	Irinotecan 180 mg/m^2 on Day 1, leucovorin 200 mg/m^2 on days 1 and 2, 5-FU 400 mg/m^2 bolus on days 1 and 2, and 5-FU 600 mg/m^2 continuous infusion for 22 hours on days 1 and 2 every 2 weeks	50	100	74	PR 8%; SD 28%; PD 52%	NR	OS 5.0 months; PFS 3.2 months
Katopodis et al^Citation42	Capecitabine 800 mg/m^2 orally, twice a day on days 1–14 plus docetaxel 75 mg/m^2 on Day 1 on a 21-day cycle	31	93.6	96.8	PR 9.7%; SD 22.6%; PD 67.6%	TTP 2.37 months	OS 6.3 months; PFS 2.4 months
Cereda et al^Citation48	Mitomycin 8 mg/m^2 on Day 1 plus ifosfamide 2,500 mg/m^2 and mesna 3,000 mg/m^2 on days 1–3 on a 28-day cycle	20	60	100	PR 5%; SD 10%; PD 85%	NR	OS 3.7 months; PFS 1.7 months
Pelzer et al^Citation23	Oxaliplatin 85 mg/m^2 on days 8 and 22, folinic acid 500 mg/m^2 and 5-FU 2,600 mg/m^2 on days 1, 8, 15, and 22 every 6 weeks	37	NR	100	CR 2.7%; PR 2.7%; SD 43.2%; PD 51%	TTP 12 weeks	OS 22 weeks
Novarino et al^Citation25	Oxaliplatin 40 mg/m^2, 5-FU 500 mg/m^2, and leucovorin 250 mg/m^2 weekly for 3 weeks on a 4-week cycle	23	74	69.5	ORR 0%; SD 23.5%; PD 76.5%	TTP 11.6 weeks	OS 17.1 weeks
Kim et al^Citation41	5-FU 1,000 mg/m^2 on days 1–3 plus paclitaxel 175 mg/m^2 on Day 1 on a 28-day cycle	28	46.4	93	PR 10%; SD 20%; PD 70%	TTP 2.5 months	OS 7.5 months
Xiong et al^Citation28	Oxaliplatin 130 mg/m^2 on Day 1 plus capecitabine 1,000 mg/m^2 orally, twice a day on days 1–14 every 3 weeks	39	71.4	95	PR 2.6%; SD 26%	NR	OS 23 weeks; PFS 9.9 weeks
Ko et al^Citation37 (unacceptable toxicity)	Docetaxel 65 mg/m^2 plus irinotecan 160 mg/m^2 every 3 weeks	14	93	100	PR 0%; SD 21.4%; PD 64.3%	TTF 36 days; TTP 49 days	OS 134 days
Reni et al^Citation30	Raltitrexed 3 mg/m^2 plus oxaliplatin 130 mg/m^2 every 3 weeks	41	61	100	PR 24%; SD 27%; PD 37%	NR	OS 5.2 months; PFS 1.8 months
Stathopoulos et al^Citation34	Gemcitabine 1,000 mg/m^2 on days 1 and 15 plus lipoplatin 25–125 mg/m^2 on days 1 and 15 on a 28-day cycle	24	50	79.2	CR 0%; PR 8.3%; SD 58.3%	NR	OS 4 months
Demols et al^Citation31	Gemcitabine 1,000 mg/m^2 on Day 1 plus oxaliplatin 100 mg/m^2 on Day 2 every 2 weeks	33	87.9	65	PR 22.6%; SD 38.7%; PD 38.7%	TTP 4.2 months	OS 6 months
Tsavaris et al^Citation24	Oxaliplatin 50 mg/m^2, leucovorin 50 mg/m^2, and 5-FU 500 mg/m^2 weekly	30	NR	97	PR 23.3%; SD 30.0%; PD 46.7%	RD 22 weeks; TTP 22 weeks	OS 25 weeks
Cantore et al^Citation29	Oxaliplatin 60 mg/m^2 on days 1 and 15 plus irinotecan 60 mg/m^2 on days 1, 8, and 15 on a 28-day cycle	30	30	100	PR 10%; SD 23%; PD 33%	TTP 4.1 months	OS 5.9 months
Reni et al^Citation36	Mitomycin 6 mg/m^2 on Day 1 plus docetaxel and irinotecan on days 2 and 8 with escalating doses every 4 weeks	15	27	100	CR 0%; PR 0%; SD 23%; PD 77%	TTP 1.7 months	OS 6.1 months
Rothenberg et al^Citation40	Eniluracil 50 mg orally on days 1–7 plus 5-FU 20 mg/m^2 orally on days 2–6 on a 28-day cycle	48	77	100	PR 2%	NR	OS 3.4 months

Notes:

* All patients were previously treated with first-line gemcitabine monotherapy or gemcitabine-based combination therapy.

Abbreviations: CR, complete response; ECOG, Eastern Oncology Cooperative Group; KPS, Karnofsky performance status; NR, not reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RD, response duration; SD, stable disease; S-1, tegafur/gimeracil/oteracil; TTF, time to treatment failure; TTP, time to progression; 5-FU, 5-fluorouracil.

Table 4 Targeted agents tested in advanced pancreatic cancer in the second-line setting

Study	Study design	Treatment	No of patients*	ECOG 0–1 (%)/KPS 90–100 (%)	Metastatic disease (%)	Response rate	Median PFS	Median OS
Chung et al^Citation64	Randomized phase II	Selumetinib plus MK-2206 mFOLFOX	58 62	100 100	74 63	PR 1.7%; SD 20.7% PR 6.5%; SD 22.6%	1.9 months 2.0 months	3.9 months 6.7 months
Ko et al^Citation53	Single-arm phase II	Selumetinib plus erlotinib	46	100	96	SD 41%	1.9 months	7.3 months
Hurwitz et al^Citation65	Randomized phase II	Ruxolitinib plus capecitabine Capecitabine	64 63	46.9 42.9	100 100	CR 1.6%; PR 6.3%; SD 32.8%; PD 37.5% CR 0%; PR 1.6%; SD 34.9%; PD 33.3%	1.7 months 1.5 months	4.5 months 4.3 months
Wu et al^Citation58	Single-arm phase II	Lapatinib plus capecitabine	17	88	100	CR 0%; PR 0%; SD 35.3%; PD 35.3%	2.6 months	5.2 months
Dragovich et al^Citation62	Single-arm phase II	Vatalanib	65	95	92	PR 3.1%; SD 27.7%; PD 52.3%	2 months	NR
Renouf et al^Citation51	Single-arm phase II	Erlotinib	49	80.4	88.2	SD 32%	NR	3.78 months
Bodoky et al^Citation63	Randomized phase II	Selumetinib Capecitabine	32 38	NR NR	100 100	PR 5%; SD 32%; PD 61% PR 9%; SD 28%; PD 63%	2.1 months 2.2 months	5.4 months 5.0 months
Arcaroli et al^Citation68	Single-arm phase II	Saracatinib	19	100	100	CR 0%; PR 0%; SD 10.5%; PD 89.5%	1.6 months	2.5 months
Astsaturov et al^Citation60	Randomized phase II	Bevacizumab Bevacizumab plus docetaxel	16 16	100 100	100 100	PD 87.5% PD 81.25%	43 days 48 days	165 days 125 days
Ramanathan et al^Citation72	Randomized phase II	PX-12 (54 mg/m^2) PX-12 (128 mg/m^2)	9 7	60 57	NR	SD 22.2%; PD 77.8% PD 100%	0.9 months 0.6 months	3.2 months for all
Javle et al^Citation55	Single-arm phase II	Everolimus plus erlotinib	15	100	100	PD 93.75%	49 days	87 days
Chawla et al^Citation71	Phase I/II	Rexin-G (dose 1) Rexin-G (dose 2)	6 7	100 100	100 100	PR 11.1%; SD 88.9%	3 months 7.65 months	4.3 months 9.2 months
Ko et al^Citation54	Single-arm phase II	Bevacizumab plus erlotinib	36	100	100	PR 2.8%; SD 19%	NR	102 days
O’Reilly et al^Citation61	Single-arm phase II	Sunitinib	77	88.3	100	CR 0%; PR 1.4%; SD 20.3%; PD 54%	1.31 months	3.68 months
Brell et al^Citation57	Single-arm phase II	Gefitinib plus docetaxel	41	92.7	NR	PR 2%; SD 46%; PD 37%	1.8 months	4.5 months
Wolpin et al^Citation67	Single-arm phase II	Everolimus	33	100	100	CR 0%; PR 0%; SD 21%; PD 67%	1.8 months	4.5 months
Pino et al^Citation70	Single-arm phase II	Capecitabine plus celecoxib	35	74	94	PR 9%; SD 29%; PD 65.7%	17 weeks	19 weeks
Carvajal et al^Citation69	Single-arm phase II	Flavopiridol plus docetaxel	10	NR	100	SD 33%; PD 67%	NR	4.2 months
Kulke et al^Citation52	Single-arm phase II	Capecitabine plus erlotinib	30	100	100	PR 10%	3.4 months	6.5 months
Ignatiadis et al^Citation56	Single-arm phase II	Gefitinib plus docetaxel	26	92.3	NR	SD 19.2%; PD 65.3%	NR	2.9 months

Notes:

* All patients were previously treated with first-line gemcitabine monotherapy or gemcitabine-based combination therapy.

Abbreviations: CR, complete response; ECOG, Eastern Oncology Cooperative Group; KPS, Karnofsky performance status; NR, not reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; PX-12, inhibitor of Thioredoxin-1; SD, stable disease.

Figure 2 The treatment outcome trends over time plotted against the year of the studies including overall survival (A), progression-free survival (B), and response rate (C).

Table 5 Selected ongoing phase II or III clinical trials in patients with pretreated advanced pancreatic cancer

Clinical trial identifier	Type of study	Regimen	No of patients	Primary endpoint
NCT2726854	Phase II	Apatinib	30	PFS, ORR
NCT2967770	Randomized phase II	MTT vs SOC	58	PFS
NCT2558868	Randomized phase II	Oxaliplatin + irinotecan vs irinotecan	80	OS
NCT2195180	Randomized phase II	ERY-ASP + GEM/FOLFOX4 vs GEM/FOLFOX4	141	PFS
NCT2677038	Phase II	Olaparib	24	ORR
NCT2042378	Phase II	Rucaparib	19	ORR
NCT2890355	Randomized phase II	Veliparib + mFOLFIRI vs FOLFIRI	143	OS
NCT1954992	Randomized phase III	Glufosfamide vs 5-FU	480	OS
NCT2923921	Randomized phase III	AM0010 + FOLFOX vs FOLFOX	566	OS
NCT1834235	Randomized phase II	NPC-1C + GEM + ABX vs GEM + ABX	81	OS, safety, and tolerability
NCT2362048	Randomized phase II	ACP-196 vs ACP-196 + pembrolizumab	73	Treatment emergent adverse events

Abbreviations: MTT, molecularly tailored therapy; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; SOC, standard of care; 5-FU, 5-fluorouracil; GEM, gemcitabine; ERY-ASP, L-asparaginase encapsulated in erythrocytes; NPC-1C, ensituximab; ABX, nano albumin bound-paclitaxel; ACP-196, acalabrutinib; FOLFOX, folinic acid + fluorouracil + oxaliplatin; FOLFIRI, folinic acid + fluorouracil + irinotecan.

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