Clinical benefit of COX-2 inhibitors in the adjuvant chemotherapy of advanced non-small cell lung cancer: A systematic review and meta-analysis

Table 1 Characteristics of each individual study

Trials or Ref.	Year	Phase	Study period	Country	Sample (I/C)	Age (I/C)	Male (female) (I/C)	Histology (I/C) (AC, SCC, Other)	Extent of disease, Stage	ECOG PS or Karnofsky score	Treatment Line	Interventions	Control	Follow-up in mo
Lilenbaum et al[22]	2006	II	Feb 2002 to Sept 2003	United States	133 (67/66)	62.7 (37-84)/63.5 (41-78)	40 (27)/40 (26)	NA, NA, NA	ШB, IV	ECOG 0-1	Second	Celecoxib 400 mg po bid + DTX 35 mg/m2 or GEM 1000 mg/m2 + CPT-11 60-100 mg/m2 ivgtt day 1 and day 8, q3w	DTX 35 mg/m2 or GEM 1000 mg/m2 + CPT-11 60-100 mg/m2 ivgtt day 1 and day 8, q3w	NA
GECO[23]	2007	Ш	Jan 2003 to May 2005	Italy	400 (149/251)	61.5 (29-71)/59.0 (37-70)	120 (29)/202 (49)	68/134, 47/53, 34/64	ШB, IV	ECOG 0-1	First	Rofecoxib 50 mg po qd + GEM 1200 mg/m2 in 30-min or PCI GEM 1200 mg/m2 over 120-min iv infusions days 1 and 8 + DDP 80 mg/m2 ivgtt qd day 1, q3w	GEM 1200 mg/m2 in 30-min or PCI GEM 1200 mg/m2 over 120-min iv infusions days 1 and 8 + DDP 80 mg/m2 ivgtt qd day 1, q3w	22
Zhou et al[29]	2007	II	June 2004 to June 2005	China	65 (32/33)	57.0 (45-77)/55.5 (40-76)	24 (8)/24 (9)	17/19, 9/8, 5/3	ШB, IV	ECOG 0-2	First	Celecoxib 400 mg po bid days 1-12 + NVB 25 mg/m2 iv qd day 1 and 8 + DDP 75 mg/m2 ivgtt qd days 1 and 2, q3w	NVB 25 mg/m2 iv qd days 1 and 8 + DDP 75 mg/m2 ivgtt qd days 1 and 2, q3w	NA
Xiong et al[28]	2008	II	Jan 2003 to Jan 2006	China	60 (30/30)	56.4/58.3	16 (14)/17 (13)	16/17, 10/10, 4/3	ШB, IV	ECOG 0-2	First	Celecoxib 400 mg po bid + NVB 25 mg/m2 iv qd days 1 and 8 + DDP 70 mg/m2 ivgtt qd days 1-3, q3w	NVB 25 mg/m2 iv qd days 1 and 8 + DDP 70 mg/m2 ivgtt qd days 1-3, q3w	NA
CYCLUS[24]	2011	Ш	May 2003 to May 2006	Sweden	316 (158/158)	66 (38-85)/65 (37-85)	73 (85)/87 (71)	77/94, 38/27, 43/36	ШB, IV	ECOG 0-2	First	Celecoxib 400 mg po bid + GEM or NVB + CBP or DDP, ivgtt q3w1	Placebo + GEM or NVB + CBP or DDP, ivgtt q3w	36
NVALT-4[25]	2011	Ш	July 2003 to Dec 2007	Netherlands	561 (281/280)	62 (40-84)/61 (33-84)	184 (97)/171 (109)	138/132, 44/57, 99/91	ШB, IV	ECOG 0-2	First	Celecoxib 400 mg po bid + DTX 75 mg/m2 ivgtt qd day 1 + CBP ivgtt qd day 1, q3w2	Placebo + DTX 75 mg/m2 ivgtt qd day 1 + CBP ivgtt qd day 1, q3w	NA
Liu et al[30]	2012	NA	Jan 2006 to May 2011	China	46 (24/22)	62 (49-75)/64 (52-76)	14 (10)/15 (7)	15/14, 9/8, 0/0	ШB, IV	Karnofsky ≥ 70	First	Celecoxib 400 mg po bid days 1-5 + DTX 75 mg/m2 ivgtt qd day 1 + DDP 100 mg/m2 ivgtt qd day 1, q3w	DTX 75 mg/m2 ivgtt qd day 1 + DDP 100 mg/m2 ivgtt qd day 1, q3w	NA
Sörenson et al[32]	2013	Ш	May 2006 to May 2009	Sweden	107 (52/55)	65 (37-84)	50/57	65, 16, 26	ШB, IV	NA	First	Celecoxib at a dose of 400 mg bid + carboplatin plus gemcitabine/vinorelbine	Carboplatin + gemcitabine/ vinorelbine	5
Gitlitz et al[33]	2014	II	NA	United States	120 (78/42)	63 (35-81)/65 (36-84)	78 (42)/42 (25)	45/24, 21/11, 12/7	ШB, IV	ECOG 0-2	Second	Apricoxib (400 mg/d) + erlotinib (150 mg/d) on 21-d cycles	Placebo + erlotinib (150 mg/d) on 21-d cycles	NA
0822-GCC[26]	2015	II	NA	United States	72 (36/36)	62/66	20 (16)/20 (16)	24/25, 8/6, 4/5	ШB, IV	ECOG 0-2	Second	Apricoxib 400 mg po qd + DTX 75 mg/m2 or PET 500 mg/m2, q3w	Placebo 400 mg po qd DTX 75 mg/m2 or PET 500 mg/m2, q3w	NA
Teng et al[31]	2015	II	Aug 2009 to May 2012	China	81 (41/40)	57.7 (28-72)/57.3 (33-76)	30 (11)/26 (14)	28/26, 13/14, 0/0	ШB, IV	ECOG 0-1	First	Celecoxib 200 mg po bid + NVB 25 mg/m2 ivgtt days 1 and 8 + DDP 70 mg/m2 ivgtt qd day 1, q4w	NVB 25 mg/m2 ivgtt days 1 and 8 + DDP 70 mg/m2 ivgtt qd day 1, q4w	NA
CALGB-30801[27]	2017	Ш	Nov 2013 to Jan 2016	United States	312 (154/158)	64 (38-83)/64 (36-89)	82 (72)/87 (71)	NA, 44/43, NA	ШB, IV	ECOG 0-2	First	Celecoxib 400 mg po bid + CBP + PET 500 mg/m2 day 1, q3w for nonsquamous or Celecoxib 400 mg po bid + CBP day 1 + GEM 1000 mg/m2 day 1 and day 8, q3w for squamous	Placebo + CBP + PET 500 mg/m2 day 1, q3w for nonsquamous or placebo + CBP day 1 + GEM 1000 mg/m2 day 1 and day 8, q3w for squamous	31

¹The dose of chemotherapeutic agents was not mentioned in the trial. ²The dose of carboplatin was not mentioned in the trial. AC: Adenocarcinoma; I/C: Interventions/Control; Bid: Twice daily; CBP: Carboplatin; CR: Complete response; d: Day; DDP: Cisplatin; DTX: Docetaxel; iv: Intravenously; ECOG PS: Eastern Cooperative Oncology Group performance status; GEM: Gemcitabine; ivgtt: Intravenous drip; PCI: Prolonged constant infusion; NA: Not applicable; NVB: Vinorelbine; PET: Pemetrexed; OS: Overall survival; PFS: Progression free survival; Po: Orally; PR: Partial response; SCC: Squamous cell carcinoma; q: Every; w: Weeks.

Table 2 The risk of bias in the included studies

Trial or Ref.	Year	Randomization methods	Stratification factors	Double blind	Follow-up	Intent to treat
Lilenbaum et al[26]	2006	Centralized	ECOG PS, age, sex, disease stage, response to treatment	No	NA	Yes
GECO[23]	2007	Centralized	Treatment, gender, PS, disease stage, tumor histology, center (three categories according to size)	No	Median follow-up of 22 mo of alive patients (range 0-40)	Yes
Zhou et al[29]	2007	Envelopes	Types	No	NA	No: 4 of 65 excluded from analysis
Xiong et al[28]	2008	Random number table	Disease stage, COX-2 expression	No	NA	Yes
CYCLUS[24]	2011	Minimization	ECOG PS, sex, stage, smoking status	Yes	After randomization, the follow-up time ranged from 0 to 36 mo	Yes
NVALT-4[25]	2011	Centralized	PS, extent of disease, use of salicylic acid, histology, COX-2 expression, treatment	No	NA	Yes
Liu et al[30]	2012	Mechanical sampling method	Stage	No	NA	Yes
Sörenson et al[32]	2013	Minimization	ECOG PS, sex, stage, smoking status	Yes	After randomization, the follow-up time ranged from 0 to 36 mo	Yes
Gitlitz et al[33]	2014	NA	ECOG PS, sex, age	Yes	The median follow-up time was 30 mo	Yes
0822-GCC[26]	2015	Centralized	ECOG PS, sex, stage, race	Yes	NA	Yes
Teng et al[31]	2015	NA	Serum DKK-1 levels	No	NA	Yes
CALGB-30801[27]	2017	Stratified random permuted-blocks procedure	Sex, histology and chemotherapy, smoking status, stage, age group, PS	Yes	The median follow-up time was 31 mo	Yes

ECOG: Eastern Cooperative Oncology Group; PS: Performance status; COX-2: Cydooxygenase-2; NA: Not available.

Table 3 Subgroup analyses of the toxicities of COX-2 inhibitor

Toxicity	RCT, n	RR (95%CI)	P value for between groups	Toxicity	RCT, n	RR (95%CI)	P value for between groups
Leucopenia	8	1.20 (1.03, 1.40)	0.020	Diarrhea	3	1.31 (0.64, 2.71)	0.460
COX-2 inhibitor type				COX-2 inhibitor type
Celecoxib	6	1.26 (1.07, 1.49)	0.280	Celecoxib	2	1.24 (0.59, 2.62)	0.940
Rofecoxib	1	0.80 (0.43, 1.50)		Rofecoxib	1	3.05 (0.13, 74.1)
Apricoxib	1	0.92 (0.47, 1.80)		Apricoxib	1	2.69 (0.33, 22.3)
Treatment line				Treatment line
First-line	6	1.20 (1.02, 1.42)	0.900	First-line	2	0.91 (0.40, 2.07)	0.080
Second-line	2	1.19 (0.76, 1.87)		Second-line	2	4.10 (0.95, 17.60)
Phase				Phase
II	4	1.14 (0.77, 1.69)	0.720	II	2	4.10 (0.95, 17.60)	0.080
III	4	1.21 (1.03, 1.44)		III	2	0.91 (0.40, 2.07)
Thrombocytopenia	8	1.33 (1.05, 1.68)	0.017	Gastric ulcer	2	1.00 (0.25, 3.97)	0.997
COX-2 inhibitor type				COX-2 inhibitor type
Celecoxib	6	1.40 (1.08, 1.81)	0.560	Celecoxib	2	1.00 (0.25, 3.97)	NA
Rofecoxib	1	1.02 (0.59, 1.76)		Rofecoxib	NA	NA
Apricoxib	1	3.00 (0.13, 71.30)		Apricoxib	NA	NA
Treatment line				Treatment line
First-line	6	1.24 (0.97, 1.58)	0.090	First-line	2	1.00 (0.25, 3.97)	NA
Second-line	2	2.66 (1.14, 6.17)		Second-line	NA	NA
Phase				Phase
II	4	2.69 (1.19, 6.07)	0.070	II	2	1.00 (0.25, 3.97)	NA
III	4	1.23 (0.96, 1.56)		III	NA	NA
Anemia	5	1.32 (0.75, 2.33)	0.343	Asthenia	7	0.84 (0.56, 1.28)	0.426
COX-2 inhibitor type				COX-2 inhibitor type
Celecoxib	3	2.76 (0.96, 7.97)	0.110	Celecoxib	5	0.94 (0.60, 1.48)	0.590
Rofecoxib	1	0.80 (0.38, 1.69)		Rofecoxib	1	0.51 (0.16, 1.64)
Apricoxib	2	3.14 (0.51, 19.50)		Apricoxib	2	0.94 (0.20, 4.44)
Treatment line				Treatment line
First-line	3	1.07 (0.56, 2.05)	0.140	First-line	5	0.92 (0.60, 1.42)	0.560
Second-line	3	2.91 (0.89, 9.98)		Second-line	3	0.53 (0.15, 1.88)
Phase				Phase
II	4	3.03 (1.00, 9.24)	0.100	II	4	0.75 (0.28, 2.02)	0.900
III	2	1.01 (0.52, 1.97)		III	3	0.86 (0.54, 1.39)
Nausea	7	0.85 (0.53, 1.36)	0.507	Cardiotoxicity	5	2.39 (1.06, 5.42)	0.037
COX-2 inhibitor type				COX-2 inhibitor type
Celecoxib	5	0.87 (0.50, 1.51)	0.960	Celecoxib	3	1.55 (0.53, 4.50)	0.540
Rofecoxib	1	0.76 (0.27, 2.13)		Rofecoxib	1	4.58 (1.01, 20.70)
Apricoxib	2	1.00 (0.15, 6.72)		Apricoxib	1	3.00 (0.13, 71.30)
Treatment line				Treatment line
First-line	6	0.84 (0.52, 1.37)	0.860	First-line	4	2.35 (1.01, 5.49)	0.880
Second-line	2	1.00 (0.15, 6.72)		Second-line	1	3.00 (0.13, 71.30)
Phase				Phase
II	4	1.44 (0.58, 3.59)	0.400	II	1	3.00 (0.13, 71.30)	0.880
III	3	0.67 (0.36, 1.25)		III	4	2.35 (1.01, 5.49)
Neurotoxicity	4	1.02 (0.23, 4.45)	0.977
COX-2 inhibitor type
Celecoxib	3	1.02 (0.18, 5.83)	0.100
Rofecoxib	1	1.02 (0.06, 16.07)
Apricoxib	NA	NA
Treatment line
First-line	4	1.02 (0.23, 4.45)	1.000
Second-line	NA	NA
Phase
II	2	3.09 (0.13, 73.20)	0.420
III	2	0.68 (0.11, 4.04)

RCT: Randomized controlled trial; RR: Relative risk; CI: Confidence interval; NA: Not applicable.