Multicenter phase II trial of modified FOLFIRINOX in gemcitabine-refractory pancreatic cancer

Table 1 Baseline characteristics

Characteristics of the patients		n = 48	Percent
Age (yr)	median (IQR)	63.5 (57.5-69.0)
	40-49	4	8.3
	50-59	10	20.8
	60-69	25	52.1
	70-79	9	18.8
Sex	Male	23	47.9
	Female	25	52.1
ECOG-PS	0	22	45.8
	1	24	50
	2	2	4.2
Duration since diagnosis (mo)	median (IQR)	7.0 (3.0-12.0)
Location of pancreatic cancer	Head	18	37.5
	Body and tail	17	35.4
	Recurrence after resection	13	27.1
Number of metastatic site	0	10	20.8
	1	18	37.5
	2	14	29.2
	≥ 3	6	12.5
Metastatic sites (> 5%)	Liver	28	58.3
	Peritoneum	16	33.3
	Distant lymph node	8	16.7
	Lung	6	12.5
Level of CA 19-9	Normal	10	20.8
	> ULN	38	79.2
Prior GEM CTx	GEM monotherapy	6	12.5
	GEM + Erlotinib	38	79.2
	GEM + Capecitabine	2	4.2
	GEM + Cisplatin	1	2.1
	GEM + Nab-paclitaxel	1	2.1
Period of prior CTx (mo)	median (IQR)	4.1 (1.9-7.8)
Prior treatment other than CTx	Operation	13	27.1
	CCRT	6	12.5

IQR: Interquartile range; ECOG-PS: Eastern Cooperative Oncology Group-performance status; CA 19-9: Carbohydrate antigen 19-9; GEM: Gemcitabine; ULN: Upper limit of the normal range; CCRT: Concurrent chemo-radiotherapy; CTx: Chemotherapy.

Table 2 Tumor responses and survivals (intention-to-treat population)

	All (n = 48)	LAPC (n = 10)	MPC (n = 38)
Response, n (%)
CR	1 (2.1)	0 (0.0)	1 (2.6)
PR	8 (16.7)	0 (0.0)	8 (21.1)
SD	21 (43.8)	8 (80.0)	13 (34.2)
PD	7 (14.6)	1 (10.0)	6 (15.8)
Could not be evaluated	11 (22.9)	1 (10.0)	10 (26.3)
ORR	9 (18.8)	0 (0.0)	9 (23.7)
DCR	30 (62.5)	8 (80.0)	22 (57.9)
Survival, mo (95%CI)
Median PFS	5.8 (3.7-7.9)	8.8 (6.0-11.6)	5.4 (2.9-7.9)
Median OS (from 2nd-line CTx)	9.0 (6.4-11.6)	12.5 (4.9-20.1)	8.4 (5.4-11.4)
Median OS (from 1st-line CTx)	17.1 (10.6-23.6)	19.1 (13.8-24.4)	16.8 (8.8-24.8)

LAPC: Locally advanced pancreatic cancer; MPC: Metastatic pancreatic cancer; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; ORR: Objective response rate; DCR: Disease control rate; CI: Confidence interval; PFS: Progression-free survival; OS: Overall survival; CTx: Chemotherapy.

Table 3 Adverse events (≥ 5%)

N = 48	n (%)	Intensity according to the NCI-CTCAE v4.03
		Grade 1	Grade 2	Grade 3	Grade 4
Non-hematologic
Fatigue	11 (22.9)	3 (6.3)	0	8 (16.7)	-
Nausea and vomiting	32 (66.7)	17 (35.4)	15 (31.3)	0	0
Diarrhea	17 (35.4)	7 (14.6)	9 (18.8)	1 (2.1)	0
Constipation	8 (16.7)	4 (8.3)	4 (8.3)	0	0
Oral mucositis	15 (31.3)	4 (8.3)	10 (20.8)	1 (2.1)	0
Anorexia	10 (20.8)	9 (18.8)	0	1 (2.1)	0
Peripheral neuropathy	7 (14.6)	6 (12.5)	0	1 (2.1)	0
Biliary tract infection	3 (6.3)	0	0	3 (6.1)	0
Fever	10 (20.8)	1 (2.1)	9 (18.8)	0	0
Hematologic
Neutropenia	33 (68.8)	0	2 (4.2)	11 (22.9)	20 (41.7)
Thrombocytopenia	6 (12.5)	0	1 (2.1)	1 (2.1)	4 (8.3)
Febrile neutropenia	8 (16.7)	-	-	5 (10.4)	3 (6.3)

NCI: National Cancer Institute; CTCAE: Common Terminology Criteria for Adverse Events.

Table 4 Clinical trials of second-line treatment for gemcitabine pre-treated unresectable pancreatic cancer

Author (yr)	Type of study	Regimen	Patients, n	KPS ≥ 90 or ECOG ≤ 1, %	MPC, %	ORR, %	DCR, %	PFS/TTP, mo	OS, mo
Yoo et al[15] 2009	II	Modified FOLFOX	30	97	100	7	17	6.0 wk	14.9 wk
		Modified FOLFIRI.3	31	100	100	0	23	8.3 wk	16.6 wk
Novarino et al[14] 2009	II	Oxaliplatin/5-FU/LV	23	73.9	69.6	0	23.5	11.6 wk1	17.1 wk
Pelzer et al[5] 2011	III	BSC	23	52.2	69.6	0	NA	NA	2.3
		Oxaliplatin/5-FU/LV (OFF)	23	47.8	73.9	0	NA	NA	4.8 (P = 0.008)
Chung et al[23] 2013	II	FOLFOX4	44	NA	100	11.4	40.9	9.9 wk1	31.1 wk
Oettle et al[6] 2014	III	5-FU/LV (FF)	84	47.6	88.1	NA	NA	2	3.3
		Oxaliplatin/5-FU/LV (OFF)	84	53.9	88.2	NA	NA	2.9 (P = 0.019)	5.9 (P = 0.01)
Zaanan et al[17] 2014	Prospective cohort	FOLFOX2	27	44.4	100	0	36.4	1.7	4.3
Wang-Gillam et al[7] 2016	III	5-FU/LV	119	48	100	1	NA	1.5	4.2
		Nal-IRI/5-FU/LV	117	59	100	16	NA	3.1 (P < 0.001)	6.1 (P = 0.01)
		Nal-IRI	151	57	100	6	NA	2.7 (P = 0.1)	4.9 (P = 0.94)
Gill et al[24] 2016	III	Modified FOLFOX6	54	88.9	92.6	13.2	44.7	3.1	6.1
		Infusional 5FU/LV	54	94.3	94.4	8.5 (P = 0.36)	55.3	2.9 (P = 0.99)	9.9 (P = 0.02)
Present study	II	FOLFIRINOX with RIO	48 (MPC: 38)	95.8	79.2	18.8 (MPC: 23.7)	62.5 (MPC: 57.9)	5.8 (MPC: 5.4)	9 (MPC: 8.4)

¹Time to progression;

²First line therapy was GEM alone or FOLFIRI.3 alternating with GEM. KPS: Karnofsky Performance Scale; ECOG: Eastern Cooperative Oncology Group performance status; MPC: Metastatic pancreatic cancer; ORR: Objective response rate; DCR: Disease control rate; PFS: Progression-free survival; TTP: Time to progression; OS: Overall survival; 5-FU: 5-fluorouracil; LV: Leucovorin; NA: Not available; II: Phase II study; III: Phase III study; BSC: Best supportive care; Nal-IRI: Nanoliposomal irinotecan; RIO: Reduced dosage of irinotecan and oxaliplatin.

Table 5 Comparison with previous studies focused on FOLFIRINOX as a second-line therapy

Study characteristics			Patients characteristics				Treatment outcomes				Grade ≥ 3 AE (%)
Author (yr)	Type	Dose modification	Patients, n	Age, median (range)	ECOG	Cancer status (%)	ORR, %	DCR, %	PFS, mo	OS, mo	NP	Febrile NP	Fatigue	Nausea	Diarrhoea
Assaf et al[29] 2011	Retro	Standard	27	63 (45-83)	1-3	MPC (100)	18.5	62.9	3	8.5	56	3.7	NA	11	11
Lee et al[30] 2013	Retro	Standard	18	57 (44-68)	0-1	MPC (88.9)	27.8	55.6	2.8	8.4	38.9	11.1	NA	38.9	0
						LAPC (11.1)
Kobayashi et al[27] 2017	II	Irinotecan 56% or 67%	18	63 (46-68)	0-1	MPC (100)	22.2	61.1	2.8	9.8	66.7	5.6	NA	0	0
Present study	II	Irinotecan 67%	48	64 (40-79)	0-2	MPC (79.2)	All: 18.8	All: 62.5	All: 5.8	All: 9.0	64.6	16.7	16.7	0	2.1
		Oxaliplatin 71%				LAPC (20.8)	MPC: 23.7	MPC: 57.9	MPC: 5.4	MPC: 8.4
							LAPC: 0.0	LAPC: 80.0	LAPC: 8.8	LAPC: 12.5

AE: Adverse event; ECOG: Eastern Cooperative Oncology Group performance status; ORR: Objective response rate; DCR: Disease control rate; PFS: Progression-free survival; OS: Overall survival; NP: Neutropenia; WHO-PS,: World Health Organization performance status; II: Phase II study; Retro: Retrospective study; MPC: Metastatic pancreatic cancer; LAPC: Locally advanced pancreatic cancer; NA: Not available.