Beyond first-line chemotherapy for advanced pancreatic cancer: An expanding array of therapeutic options?

Table 1 Clinical studies of second-line gemcitabine-containing regimens

Ref.	Regimen	Sample size	RR1	PFS/TTP (mo)	Med OS (mo)	1 yr survival
Kozuch et al[4], 2001	G-FLIP	34	24%	3.9	10.3	47%
Reni et al[6], 2008	PEFG	46	24%	5.0	8.3	26%
Demols et al[9], 2006	GEMOX	33	21%	4.2	6.0	NR
Fortune et al[76], 2009	GEMOX	17	24%	2.6	6.4	29%
Stathopoulos et al[77], 2006	Gem, Lipoplatin	24	8.3%	NR	4.0	NR
Tschoep et al[11], 2013	Gem, Cisplatin, RHT	23	4.3%	4.3	NR	NR
Morizane et al[12], 2012	Gem, S-1	40	18%	2.8	7.0	18%
Ernani et al[13], 2012	Gem, nab-Paclitaxel	10	20%	3.2	NR	NR

¹Intent-to-treat analysis. G-FLIP: Gemcitabine, 5-fluorouracil, leucovorin, cisplatin; PEFG: Cisplatin, epirubicin, 5-fluorouracil, gemcitabine; GEMOX: Gemcitabine, oxaliplatin; Gem: Gemcitabine; RHT: Regional hyperthermia; Nab-paclitaxel: Albumin-bound nanoparticle paclitaxel; NR: Not reported; PFS: progression free survival; OS: Overall survival; TTP: Time to progression.

Table 2 Clinical studies of second-line monotherapeutic regimens

Ref.	Regimen	Sample size	RR1	PFS/TTP (mo)	Med OS (mo)	1 yr survival
Jacobs et al[16], 2004	Rubitecan	198	11%	1.9	3.5	NR
Burris et al[15], 2005	Rubitecan	58	5.2%	2.0	3.1	9%
Yi et al[78], 2009	Irinotecan	33	9%	2.0	6.6	NR
Takahara et al[79], 2013	Irinotecan	56	3.6%	2.9	5.3	NR
Ko et al[17], 2013	Nanoliposomal irinotecan	40	7.5%	2.4	5.2	25%
Oettle et al[18], 2000	Paclitaxel	18	5.6%	NR	4.1	NR
Maeda et al[19], 2011	Paclitaxel	30	10%	NR	6.7	NR
Cereda et al[20], 2008	Docetaxel	10	0%	1.5	4.0	0%
Hosein et al[22], 2013	Nab-Paclitaxel	19	5%	1.7	7.3	37%
Boeck et al[24], 2007	Capecitabine	39	0%	2.3	7.6	NR
Bodoky et al[59], 2012	Capecitabine	38	7.9%	2.2	5.0	NR
Morizane et al[25], 2009	S-1	40	15%	2.0	4.5	14%
Todaka et al[26], 2010	S-1	52	3.8%	2.1	5.8	12%
Mizuno et al[28], 2013	S-1	67	6%	1.9	5.9	NR
Ioka et al[27], 2013	Best fluoropyrimidine2	40	10%	3.8	7.5	NR
Fukahori et al[80], 2012	Gemcitabine3	27	14%	2.6	8.0	NR
Androulakis et al[81], 2005	Oxaliplatin	18	0%	NR	3.5	NR
Boeck et al[82], 2007	Pemetrexed	52	3.8%	1.6	4.7	NR
Ulrich-Pur et al[48], 2003	Raltitrexed	19	0%	2.5	4.3	0%
Kindler et al[83], 2008	Arsenic trioxide	13	0%	1.6	3.8	0%

¹Intent-to-treat analysis;

²S-1 (67.5%), uracil-tegafur (20%), or 5-fluorouracil (12.5%);

³S-1 refractory disease. Nab-paclitaxel: Albumin-bound nanoparticle paclitaxel; NR: Not reported; PFS: Progression free survival; OS: Overall survival; TTP: Time to progression.

Table 3 Clinical studies of second-line cytotoxic combination regimens

Ref.	Regimen	Sample size	RR1	PFS/TTP (mo)	Med OS (mo)	1 yr survival
	Platinum based regimens
Tsavaris et al[29], 2005	FOLFOX	30	23%	5.1	5.8	NR
Mitry et al[84], 2006	FOLFOX	18	0%	0.9	1.3	NR
Gebbia et al[85], 2007	FOLFOX	42	14%	4	6.7	NR
Novarino et al[86], 2009	FOLFOX	23	0%	2.7	4.0	NR
Yoo et al[30], 2009	FOLFOX	30	6.7%	1.4	3.5	NR
Chung et al[31], 2013	FOLFOX	44	11%	2.3	7.3	NR
Berk et al[35], 2012	FOLFOX	46	17%	3.7	5.8	NR
Sancho et al[32], 2008	CapOx2	18	5.6%	3.9	5.8	NR
Xiong et al[33], 2008	CapOx	41	2.4%	2.3	5.4	21%
Gasent-Blesa et al[34], 2009	CapOx	15	6.7%	NR	5.3	NR
Berk et al[35], 2012	CapOx	39	18%	3.7	4.9	NR
Pelzer et al[87], 2009	OFF	37	5.4%	2.8	5.1	NR
Pelzer et al[37], 2011	OFF	23	0%	NR	4.8	NR
Pelzer et al[38], 2008	OFF	76	NR	3	6.1	NR
Assaf et al[40], 2011	FOLFIRINOX	27	19%	5.4	8.5	NR
Togawa et al[88], 2007	Cisplatin, S-1	17	29%	NR	10	32%
Kim et al[89], 2012	Cisplatin, S-1	11	0%	1.5	2.7	NR
Takahara et al[90], 2013	Oxaliplatin, S-1	30	10%	3.4	5.0	NR
Cantore et al[41], 2004	Oxaliplatin, irinotecan	30	10%	4.1	5.9	23%
Oh et al[42], 2010	Oxaliplatin, irinotecan	14	21%	1.4	4.1	7.1%
Reni et al[43], 2006	Oxaliplatin, raltitrexed	41	24%	1.8	5.2	12%
Mazzer et al[44], 2009	Oxaliplatin, pemetrexed	16	56%	3.3	NR	NR
	Non-platinum based regimens
Yoo et al[30], 2009	FOLFIRI	31	0%	1.9	3.9	NR
Gebbia et al[45], 2010	FOLFIRI	40	15%	3.7	6.0	0%
Cereda et al[91], 2010	FOLFIRI or XELIRI	34	0%	2.0	4.2	5.6%
Zaniboni et al[46], 2012	FOLFIRI	50	8%	3.2	5.0	NR
Neuzillet et al[47], 2012	FOLFIRI	63	7.9%	3.0	6.6	NR
Mizuno et al[28], 2013	S-1, irinotecan	60	18%	3.6	6.9	NR
Blaya et al[49], 2007	Capecitabine, docetaxel	24	13%	NR	NR	NR
Katopodis et al[50], 2011	Capecitabine, docetaxel	31	9.7%	2.4	6.4	15%
Kim et al[51], 2009	5-FU, paclitaxel	28	10%	2.5	7.6	NR
Lee et al[92], 2009	Conti-FAM3	31	12%	2.3	6.7	NR
Shi et al[93], 2012	Capecitabine, thalidomide	31	6.5%	2.7	6.1	NR
Saif et al[94], 2009	Capecitabine, PHY906	25	5.3%	NR	NR	NR
Ulrich-Pur et al[48], 2003	Irinotecan, raltitrexed	19	16%	4.0	6.5	NR
Reni et al[95], 2004	MDI	15	0%	1.7	6.1	0%
Cereda et al[96], 2011	Mitomycin, ifosfamide	21	4.8%	1.7	3.7	9.5%
Ko et al[52], 2008	Irinotecan, docetaxel	14	0%	1.2	4.5	21%

¹Intent-to-treat analysis;

²Pooled analysis of pancreatic (50%), biliary (22%), gallbladder (22%) and ampullary (6%) cancer;

³Pooled analysis of pancreatic (48%), biliary (35%) and gallbladder (16%) cancer. FOLFOX: Oxaliplatin, 5-fluorouracil, folinic acid, biweekly; CapOx: Capecitabine, oxaliplatin; OFF: Oxaliplatin, 5-fluorouracil, leucovorin, in 6-wk cycles; FOLFIRINOX: Oxaliplatin, leucovorin, 5-fluorouracil, irinotecan; FOLFIRI: 5-Fluorouracil, leucovorin, irinotecan; XELIRI: Capecitabine, irinotecan; 5-FU: 5-Fluorouracil; Conti-FAM: 5-Fluorouracil, doxorubicin, mitomycin-c; MDI: Mitomycin, docetaxel, irinotecan; NR: Not reported; PFS: Progression free survival; OS: Overall survival; TTP: Time to progression.

Table 4 Ongoing randomized phase II/III trials of refractory pancreatic cancer chemotherapy

Clinical trial	Design	Study arms	Goal enrollment	Primary measure	Previous therapy	Status
NCT00674973	Phase II	Erlotinib vs placebo	207	PFS, biomarkers	1 prior CT regimen	Active, not recruiting
NCT01074996	Phase II	S-1 vs S-1, leucovorin	96	OS	Gem-based	Recruiting
NCT01417000	Phase II	GVAX pancreas, cyclophosphamide, CRS-207 vs GVAX pancreas, cyclophosphamide	90	OS	≥ 1 prior CT regimen	Active, not recruiting
NCT01423604	Phase II	Capecitabine, ruxolitinib vs capecitabine, placebo	138	OS	Gem-based	Active, not recruiting
NCT01658943	Phase II	Selumetinib, MK2206 vs FOLFOX	133	OS, PFS	Gem-based	Recruiting
NCT01796782	Phase II	QYHJ granules vs Capecitabine	60	OS	Non-capecitabine containing CT	Active, not recruiting
NCT01121848	Phase III	Capecitabine or 5-FU, leucovorin vs XELOX or mFOLFOX-6	128	PFS	Gem-based	Active, not recruiting
NCT01494506	Phase III	MM-398 vs MM-398, 5-FU, leucovorin vs 5-FU, leucovorin	405	OS	Gem-based	Active, not recruiting
NCT01954992	Phase III	Glufosfamide vs 5-FU	480	OS	Gem-based	Recruiting
NCT01956812	Phase III	Gemcitabine, IMMU-107 vs Gemcitabine, placebo	440	OS	2 prior CT regimens, ≥ 1 Gem-based	Not yet open for recruitment

GVAX pancreas: Allogeneic pancreatic cancer cell vaccine, induces GM-CSF production; CRS-207: Attenuated listeria monocytogenes vaccine, induces immune response to mesothelin; MK2206: Akt inhibitor; FOLFOX: 5-Fluorouracil, leucovorin, oxaliplatin; QYHJ: Qingyihuaji formulation; 5-FU: 5-Fluorouracil; XELOX: Capecitabine, oxaliplatin; mFOLFOX-6: Modified schedule 5-fluorouracil, leucovorin, oxaliplatin; MM-398: Liposomal irinotecan; IMMU-07: Yttrium-90 radiolabeled humanized monoclonal antibody against mucin1 (CD227); PFS: Progression free survival; OS: Overall survival; CT: Chemotherapy; Gem-based: Gemcitabine-containing chemotherapy regimen.

Table 5 Clinical studies of second-line targeted therapies

Ref.	Regimen	Sample size	RR1	PFS/TTP (mo)	Med OS (mo)	1 yr survival
Ignatiadis et al[97], 2006	Gefitinib, docetaxel	26	0%	2.1	2.9	NR
Brell et al[98], 2009	Gefitinib, docetaxel	41	2.4%	1.8	4.5	0%
Kulke et al[55], 2007	Erlotinib, capecitabine	30	10%	3.4	6.5	26%
Tang et al[54], 2009	Erlotinib	50	0%	1.6	4.1	6 m = 39%3
Iyer et al[99], 2010	Erlotinib	18	0%	1.4	3.1	NR
Bodoky et al[59], 2012	Selumetinib	32	6.3%	2.1	5.4	NR
Ko et al[61], 2013	Selumetinib, erlotinib	46	0%	2.6	7.5	NR
Wolpin et al[62], 2009	Everolimus	33	0%	1.8	4.5	NR
Garrido-Laguna et al[63], 2010	Sirolimus	31	0%	NR	NR	6 m = 26%3
Javle et al[64], 2010	Everolimus, erlotinib	16	0%	1.6	2.9	NR
Javle et al[64], 2010	Temsirolimus	5	0%	0.6	1.5	NR
Dragovich et al[68], 2008	Vatalinib	65	NR%	6 m = 14%3	6 m = 31%3	NR
O’Reilly et al[69], 2010	Sunitinib	77	1.4%	1.3	3.7	NR
Ko et al[67], 2010	Bevacizumab, erlotinib	36	2.8%	1.3	3.4	6 m = 22%3
Astsaturov et al[100], 2011	Bevacizumab	16	0%	1.4	5.5	NR
Astsaturov et al[100], 2011	Bevacizumab, docetaxel	16	0%	1.6	4.2	NR
Milella et al[73], 2004	Celecoxib, 5-FU	17	12%	1.9	3.5	NR
Pino et al[74], 2009	Celecoxib, capecitabine2	35	8.6%	4.0	4.4	NR
Starling et al[101], 2012	Imatinib, gem, oxaliplatin	27	7.4%	4.6	5.6	28%
Carvajal et al[102], 2009	Flavopiridol, docetaxel	10	0%	1.9	4.2	0%
Nallapareddy et al[103], 2010	Sarcatinib	19	0%	1.6	2.5	NR

¹Intent-to-treat analysis;

²Pooled analysis of pancreatic (86%) and biliary (14%) cancer;

³6 m: 6 mo survival rate. 5-FU: 5-Fluorouracil; Gem: Gemcitabine; NR: Not reported; PFS: Progression free survival; OS: Overall survival; TTP: Time to progression.