World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Original Article

Volume 15, Number 6, December 2024, pages 902-921

The Prevalence of 5-Fluorouracil and Capecitabine Cardiotoxicity: A Systematic Review and Meta-Analysis

↓ Figure 2. The evaluation of the risk of bias in randomized control trials using the Cochrane Risk-of-Bias tool 2.0 (RoB 2.0).

↓ Figure 3. The evaluation of the risk of bias in non-randomized studies using The Risk Of Bias In Non-randomized Studies (ROBINs).

↓ Figure 4. Forest plot of cardiotoxicity in patients receiving 5-FU monotherapy. 5-FU: 5-fluorouracil.

↓ **Table 1.** Characteristics of the Included Studies
No.	Author, year	Region	Study design	Sample size	No. of participants^a	Study duration (months)	Age (years)	Male (N, %)	Comorbidity	Cancer type	Prior CMT
^aDetails of the dosage regimen for each arm are shown in Supplementary Materials 3 and 4 (www.wjon.org). 5-FU: 5-fluorouracil; CMT: chemotherapy; LV: leucovorin; N/A: not applicable; PLD: pegylated liposomal doxorubicin; RT: radiotherapy; UFT: uracil/ftorafur.
1	Alberto et al, 1988 [27]	Switzerland	Randomized trial	52	27	25	-	10.1	61.5 ± 2.12	27, 51.92%	N/A	Colon or rectum cancer	None
2	Ansari et al, 2017 [28]	Australia and New Zealand	Randomized controlled trial	322	161	161	-	3	62.75 ± 10.05	235, 72.98%	N/A	Rectal cancer	N/A
3	Bajetta et al, 1993 [29]	Italy	Prospective randomized Trial	222	110	112	-	16.75	61.34 ± 9.18	123, 55.41%	N/A	Advanced colorectal cancer	None
4	Barutca et al, 2004 [30]	Turkey	Prospective study	28	28	-	-	15 days	67.51 ± 10.44	17, 61%	N/A	Colorectal cancer, gastrointestinal system cancers	N/A
5	Becouarn et al, 1995 [31]	France	Prospective study	86	86	-	-	52	61.81 ± 8.79	42, 48.84%	N/A	Advanced colorectal cancer	Palliative chemotherapy (8.14%)
6	Berenberg et al, 1995 [32]	United States	Phase II clinical study	76	76	-	-	5	N/A	N/A	N/A	Advanced gastric cancer	None
7	Bonnetain et al, 2005 [33]	France	Randomized phase II trial	134	45	89	-	6	63.26 ± 7.73	110, 82.09%	N/A	Metastatic gastric cancer	N/A
8	Breton et al, 2021 [34]	France	Pooled analysis	2,190	1,068	395	727	3.6	66.8 ± 2.33	654, 61.2%	N/A	Metastatic colorectal cancer	N/A
9	Brucher et al, 2004 [35]	Germany	Prospective study	76	76	-	-	64.8	54 ± 6.48	59, 77.6%	N/A	Esophageal squamous cell carcinoma	N/A
10	Cascinu et al, 2003 [36]	Italy	Randomized controlled trial	183	91	92	-	48	61.84 ± 8.58	100, 54.64%	N/A	Stage III colon cancer	N/A
11	Cashin et al, 2016 [37]	Sweden	Randomized controlled trial	48	24	24	-	78	60±10.61	24, 50%	N/A	Colorectal peritoneal metastases	N/A
12	Ceyhan et al, 2005 [38]	Turkey	Prospective study	37	37	-	-	N/A	60	26, 70.27%	N/A	Colorectal cancer, gastric cancer, breast cancer, metastatic lung carcinoid, nasopharyngeal carcinoma	N/A
13	Citron et al, 1992 [39]	United States	Prospective study	86	86	-	-	6	61.26 ± 9.41	65, 76%	N/A	Non-small cell lung cancer	N/A
14	Cunningham et al, 2009 [40]	United Kingdom	Randomized controlled trial	725	363	362	-	48	61.2 ± 8.89	126, 17.38%	N/A	Metastatic colorectal cancer	N/A
15	Daniele et al, 2003 [41]	Italy	Prospective study	34	34	-	-	3.9	76.33 ± 3.59	23, 67.65%	Cardiovascular (55.88%), respiratory (32.35%), gastrointestinal/hepatobiliary (17.65%), genitourinary (17.65%), osteoarticular (14.71%), diabetes (17.65%), endocrinologic (5.88%)	Stage IV colorectal cancer	Previous adjuvant chemotherapy (11.76%)
16	de Forni et al, 1992 [8]	France	Prospective study	367	65	302	-	N/A	55.25 ± 12.40	230, 62.67%	N/A	Head and neck cancer, breast cancer, colon/rectum cancer, esophagus cancer, cervix cancer	N/A
17	Dencausse et al, 2002 [42]	Germany	Prospective randomized study	155	105	50	-	60	62.58 ± 10.03	108, 69.68%	N/A	Colon cancer	N/A
18	Dencausse et al, 2001 [43]	Germany	Prospective study	21	21	-	-	6.75	60.69 ± 3.27	14, 66.67%	N/A	Rectal cancer	N/A
19	Ducreux et al, 2002 [44]	France	Randomized trial	207	103	104	-	36	59.95 ± 9.05	134, 64.73%	N/A	Metastatic or locally advanced adenocarcinoma of the pancreas	None
20	Ducreux et al, 2004 [45]	France	Randomized controlled trial	63	15	17	31	N/A	55.63 ± 11.58	42, 66.67%	N/A	Advanced pancreatic carcinoma	N/A
21	Ducreux et al, 2005 [46]	Belgium	Randomized phase II trial	57	29	28	-	8	59.96	31, 54.39%	N/A	Locally advanced or metastatic biliary tract cancer	None
22	Dyhl-Polk et al, 2021 [47]	Denmark	Prospective study	108	108	-	-	N/A	65.15 ± 9.11	59, 54.6%	Ischemic heart disease (0.9%), previous stroke (7.4%), heart failure (0.9%), atrial fibrillation (4.6%), other heart disease (2.7%), hypertension (32.4%), hypercholesterolemia (67.6%), diabetes mellitus (5.6%)	Colorectal or anal cancer	N/A
23	Francini et al, 1994 [48]	Italy	Randomized controlled trial	239	118	121	-	54	56.76	126, 52.72%	N/A	Surgically resected colon cancer	N/A
24	Garufi et al, 1997 [49]	Italy	Phase I study	34	34	-	-	9	55.34 ± 12.19	19, 55.88%	N/A	Metastatic adenocarcinoma of the colon or rectum	Prior chemotherapy (13/34)
25	Gradishar et al, 1991 [50]	United States	Retrospective review	244	34	210	-	N/A	N/A	N/A	N/A	Gastric cancer, Head and neck cancer	N/A
26	Granito et al, 2015 [51]	Italy	Retrospective study	26	26	-	-	31	65.48 ± 7.07	23, 88.46%	Mild ascites (30.76%), absent ascites (69.23%)	Hepatocellular carcinoma	N/A
27	Haas et al, 1995 [52]	USA	Phase II study	37	37	-	-	N/A	61.24 ± 9.19	24, 64.86%	One patient had a myocardial infarction four years before presenting colon cancer. He was maintained on stable doses of nitrates and a calcium channel blocker.	Metastatic adenocarcinoma of the colon or rectum	Adjuvant CMT 2, adjuvant CMT/RT 1, adjuvant immunotherapy/CMT 2, advanced CMT 2, immunotherapy 3, immunotherapy/RT 1, RT 5, none 22
28	Harbeck et al, 2017 [53]	Germany	Randomized controlled trial	210	105	105	-	N/A	61.82 ± 10.96	0	N/A	Metastatic breast cancer	Prior PLD (37%), capecitabine (36%)
29	Hartung et al, 1996 [54]	Germany	Retrospective study	92	55	37		13	Median 59.7	55, 59.78%	N/A	Colon cancer, rectal cancer	N/A
30	Hartung et al, 2001 [55]	Germany	Phase II clinical study	51	51	-	-	20.2	58.35 ± 11.77	38, 74.51%	N/A	Metastatic colorectal cancer	N/A
31	Highley et al, 2009 [56]	United Kingdom	Phase II study	46	46	-	-	6	68.09 ± 2.49	33, 71.74%	N/A	Transitional cell carcinoma of the urinary tract	None
32	Hoff et al, 2001 [57]	United States, Canada, Brazil, Mexico	Phase III randomized controlled study	605	303	302	-	13.3	63.05 ± 10.98	378, 62.48%	N/A	Advanced or metastatic colorectal cancer	Adjuvant 5-FU (36.3%)
33	Jack et al, 1995 [58]	Southeast Scotland	Randomized controlled trial	332	167	165	-	Median follow-up of 15 years	53.97 ± 8.34	0	N/A	Breast cancer	N/A
34	Jager et al, 1995 [59]	Germany	Prospective study	69	69	-	-	N/A	55.98 ± 8.67	50, 72.46%	N/A	Advanced colorectal and rectal carcinoma	N/A
35	Jegannathen et al, 2011 [60]	United Kingdom	Phase II clinical study	50	50	-	-	N/A	55.35 ± 8.47	40, 80%	N/A	Head and neck cancer	N/A
36	Jensen et al, 2006 [25]	Denmark	Prospective study	668	362	92	214	N/A	N/A	N/A	Hypercholesterolemia, diabetes, hypertension, cerebral ischemia	Colorectal cancer, gastric cancer	N/A
37	Kerr et al, 1995 [61]	United Kingdom	Phase I clinical trial	43	43	-	-	N/A	56 ± 9.38	28, 65.12%	N/A	Colorectal cancer	N/A
38	Khan et al, 2012 [62]	Pakistan	Retrospective study	301	18	283	-	N/A	47.13 ± 10.99	75, 24.92%	N/A	N/A	N/A
39	Kim et al, 2003 [63]	Korea	Prospective study	122	53	69	-	N/A	55.98 ± 11.16	70, 57.38%	N/A	Adenocarcinoma of the colon (colon cancer)	N/A
40	Klausner et al, 1987 [64]	Israel	Prospective study	30	30	-	-	19	51.03 ± 11.03	20, 66.67%	N/A	Metastatic malignant melanoma	None
41	Kohne et al, 2005 [65]	Europe	Phase III prospective, multicenter, randomized, non-blinded	427	213	214	-	27.6	60.25 ± 9.24	268, 62.32%	N/A	Metastatic colorectal cancer	N/A
42	Kok et al, 1996 [66]	The Netherlands	Prospective study	29	29	-	-	24 weeks or until progression.	59.39 ± 8.14	25, 86.21%	N/A	Metastatic adenocarcinoma of the esophagus or esophagogastric junction area.	None
43	Kolaric et al, 1986 [67]	Slovenia	Controlled phase III clinical study	115	56	59	-	N/A	51.89 ± 8.34	71, 61.74%	N/A	Gastric cancer, rectosigmoid cancer	N/A
44	Kosmas et al, 2008 [68]	Greece	Prospective study	644	397	193	54	N/A	65.91 ± 2.26	N/A	Hyperlipidemia, obesity, chronic obstructive pulmonary disease	Colorectal cancer, head and neck cancer, breast cancer	N/A
45	Kuzel et al, 1993 [69]	USA	Phase II study	22	22	-	-	1	68.29 ± 6.55	22, 100%	N/A	Metastatic prostate carcinomas refractory to hormonal therapy	None
46	Kwakman et al, 2017 [70]	United Kingdom	Retrospective study	2,461 event	397	2,064	-	N/A	N/A	N/A	N/A	Colorectal cancer	N/A
47	Labianca et al, 1982 [26]	Italy	Retrospective study	1,083	480	603	-	N/A	N/A	N/A	Ischemic heart disease	Gastric cancer, breast cancer	N/A
48	Labianca et al, 1988 [71]	Italy	Randomized trial	54	28	26	-	22	55.48 ± 9.53	33, 61%	N/A	Advanced colorectal cancer	None
49	Leichman et al, 2005 [72]	United States	Retrospective study	690	340	350	-	13	60.78 ± 11.38	407, 57%	N/A	Metastatic or recurrent colorectal cancer	Previous adjuvant CMT or immunotherapy (or both) was allowed as long as ≥ 1 year had elapsed since discontinuation of therapy. No previous chemotherapy for advanced disease was permitted.
50	Lestuzzi et al, 2014 [15]	Italy and Germany	Prospective study	231	49	182	-	9	57.5	148, 64.07%	Obesity (9.09%), diabetes mellitus (12.12%), hypertension (33.33%), dyslipidemia (23.81%), coronary artery disease (3.46%), active smoker (40.69%), former smoker (23.38%)	Colorectal cancer, breast cancer, head and neck cancer, gastric or bowel cancer	N/A
51	Mayer et al, 2021 [73]	Unites States	Phase III randomized controlled study	308	160	148	-	58	51.85 ± 9.00	0	N/A	Breast cancer	Prior neoadjuvant taxane 160/160, prior RT 122/160, prior neoadjuvant anthracycline 136/160
52	Meydan et al, 2005 [74]	Turkey	Prospective study	231	163	68	-	N/A	57 ± 18.47	138, 59.74%	Coronary artery disease, hypertension, diabetes mellitus	Colorectal cancer, gastric cancer, pancreas and gallbladder, breast cancer, neuroendocrine, head and neck cancer	N/A
53	Naredi et al, 2003 [75]	Sweden	Prospective randomized study	39	21	18	-	46	64.38 ± 8.74	27, 69.23%	N/A	Metastasis colorectal cancer	N/A
54	Ngan et al, 2001 [76]	Australia and New Zealand	Prospective study	82	82	-	-	12	58.74 ± 12.36	55, 67.07%	N/A	Localized adenocarcinoma of the rectum	N/A
55	Nobile et al, 1985 [77]	Italy	Phase II clinical study	38	38	-	-	N/A	60.59 ± 8.43	20, 52.63%	N/A	Advanced colorectal cancer	7/38 had failed prior 5-FU treatment.
56	Oman et al, 2005 [78]	Sweden	Phase I/II clinical trial	68	68	-	-	3.9	62.07 ± 11.23	29, 42.65 %	N/A	Non-resectable pancreas cancer	N/A
57	Poorter et al, 1995 [79]	The Netherlands	Prospective study	30	30	-	-	22	54.69 ± 10.54	12, 40%	N/A	Metastatic gastrointestinal cancer	N/A
58	Primrose et al, 2019 [80]	United Kingdom	Randomized controlled trial	447	223	224	-	N/A	62.92 ± 2.48	224, 50.11%	N/A	Biliary tract cancer	N/A
59	Regazzoni et al, 1996 [81]	Switzerland	Retrospective study	106	106	-	-	N/A	56 ± 10.32	N/A	N/A	Breast cancer	81% had previously received anthracyclines
60	Rosso et al, 1994 [82]	Italy	Prospective study	79	79	-	-	28.75	61.34 ± 7.46	50, 63.29%	N/A	Advanced colorectal carcinoma	N/A
61	Schober et al, 1993 [83]	Germany	Prospective study	390	250	89	51	N/A	52 ± 13.85	260, 66.67%	Hypertension, diabetes, hyperlipidemia, history of coronary or peripheral artery disease	Gastric cancer, colorectal cancer	Pretreatment with etoposide, adriamycin, and cisplatin 1/390
62	Schuster et al, 1991 [84]	Germany	Randomized controlled trial	61	30	31	-	24	56.29 ± 9.29	39, 63.93%	N/A	Advanced colorectal carcinoma	None
63	Smorenburg et al, 2014 [85]	The Netherland	Randomized controlled trial	78	38	40	-	39	75.07 ± 4.36	0	N/A	Metastatic breast cancer	Previous adjuvant CMT with anthracyclines was allowed, considering a cumulative dose of < 240 mg/m² of doxorubicin or < 450 mg/m² of epirubicin and completion for at least 12 months
64	Stockler et al, 2011 [86]	Australia, New Zealand	Randomized controlled study	323	214	109	-	39.6	59.67	0	N/A	Advanced breast cancer	N/A
65	Terzoli et al, 2004 [87]	Italy	Prospective study	80	80	-	-	14	60.24 ± 9.34	46, 57.50%	N/A	Advanced colorectal cancer	Adjuvant CMT 13/80
66	Tsavaris et al, 1990 [88]	Greece	Prospective study	74	74	-	-	7.4	61	46, 62.16%	N/A	Advanced colorectal cancer	RT 16/74, 5-FU with or without mitomycin C 17/74
67	Tsavaris et al, 2005 [89]	Greece	Prospective study	522	333	189	-	N/A	62.04 ± 2.31	N/A	Hyperlipidemia, obesity, chronic obstructive pulmonary disease	Head and neck cancer, colorectal cancer	None
68	Tsuchida et al, 2005 [90]	Japan	Retrospective study	14	14	-	-	27	64.11 ± 9.08	12, 86%	N/A	Recurrence of esophageal squamous cell carcinoma	Cisplatin (50 - 80 mg/m²) for 1 day and 5-FU (500 - 800 mg/m²) for 5 days (eight patients)
69	Urba et al, 1992 [91]	United states	Prospective study	24	24	-	-	12.5	61.04 ± 9.25	20, 83%	One patient died of a myocardial infarction with the risk factors of mild hypertension and mild obesity.	Resectable adenocarcinoma of the esophagus	None
70	Van Cutsem et al, 2001 [92]	Europe, Australia, New Zealand, Taiwan and Israel	Phase III randomized controlled study	602	301	301	-	N/A	63.60 ± 9.59	343, 56.98%	N/A	Colorectal cancer	Capecitabine 56/301, 5-FU 41/301
71	Van Erning et al, 2016 [93]	The Netherland	Retrospective study	357	164	193	-	N/A	74.53	109, 58.60%	None	Stage III colon cancer	N/A
72	Van Groeningen et al, 1989 [94]	The Netherlands	Prospective study	22	22	-	-	6	59.46 ± 12.57	8, 36.36%	N/A	Advanced colorectal cancer	Prior hepatic intra-arterial 3/22, IV 5-aza-2’-deoxycytidine 1/22, IV cisplatin and hepatic intra-arterial 5-FU 1/22
73	Wang et al, 1998 [95]	Taiwan	Prospective study	41	41	-	-	18.4	59.92 ± 7.62	33, 80.48%	N/A	Advanced colorectal cancer	N/A
74	Weh et al, 1994 [96]	Germany	Prospective study	57	57	-	-	41	56.27 ± 9.38	36, 63.16%	N/A	Metastatic colorectal carcinoma	N/A
75	Wenzel et al, 2002 [97]	Austria	Prospective study	26	26	N/A	-	25	58.9 ± 7.32	19, 73.08%	N/A	Metastatic renal cell carcinoma	N/A
76	Yang et al, 1999 [98]	Taiwan	Prospective study	36	36	-	-	9	57.68 ± 10.64	21, 58.33%	N/A	Colorectal cancer	5-FU/levamisole (4/36), 5-FU/LV (17/36)
77	Yang et al, 2001 [99]	Taiwan	Phase II clinical study	26	26	-	-	N/A	55.48 ± 12.62	18, 69.23%	N/A	Advanced colorectal cancer	None
78	Yang et al, 2002 [100]	Taiwan	Prospective study	51	26	25	-	N/A	59 ± 10.22	29, 56.9%	N/A	Metastatic colorectal cancer	Oral UFT 300 mg/m²/day plus LV 90 mg/day
79	Ychou et al, 2003 [101]	France	Prospective study	53	53	-	-	38	65.05 ± 9.05	25, 47.17%	N/A	Metastatic colorectal cancer	Prior CMT 16/53, 30.19%
80	Yilmaz et al, 2007 [102]	Turkey	Prospective study	27	27	-	-	24 h	51.60 ± 12.77	15, 55.56%	Diabetes, hypertension	Colorectal cancer, gastric cancer, liver cancer, distal esophagus cancer	N/A

↓ Table 1. Characteristics of the Included Studies

No.

Author, year

Region

Study design

Sample size

No. of participants^a

Study duration (months)

Age (years)

Male (N, %)

Comorbidity

Cancer type

Prior CMT

Arm A

Arm B

Arm C

^aDetails of the dosage regimen for each arm are shown in Supplementary Materials 3 and 4 (www.wjon.org). 5-FU: 5-fluorouracil; CMT: chemotherapy; LV: leucovorin; N/A: not applicable; PLD: pegylated liposomal doxorubicin; RT: radiotherapy; UFT: uracil/ftorafur.

Alberto et al, 1988 [27]

Switzerland

Randomized trial

10.1

61.5 ± 2.12

27, 51.92%

N/A

Colon or rectum cancer

None

Ansari et al, 2017 [28]

Australia and New Zealand

Randomized controlled trial

322

161

62.75 ± 10.05

235, 72.98%

N/A

Rectal cancer

N/A

Bajetta et al, 1993 [29]

Italy

Prospective randomized Trial

222

110

112

16.75

61.34 ± 9.18

123, 55.41%

N/A

Advanced colorectal cancer

None

Barutca et al, 2004 [30]

Turkey

Prospective study

15 days

67.51 ± 10.44

17, 61%

N/A

Colorectal cancer, gastrointestinal system cancers

N/A

Becouarn et al, 1995 [31]

France

Prospective study

61.81 ± 8.79

42, 48.84%

N/A

Advanced colorectal cancer

Palliative chemotherapy (8.14%)

Berenberg et al, 1995 [32]

United States

Phase II clinical study

N/A

Advanced gastric cancer

None

Bonnetain et al, 2005 [33]

France

Randomized phase II trial

134

63.26 ± 7.73

110, 82.09%

N/A

Metastatic gastric cancer

N/A

Breton et al, 2021 [34]

France

Pooled analysis

2,190

1,068

395

727

3.6

66.8 ± 2.33

654, 61.2%

N/A

Metastatic colorectal cancer

N/A

Brucher et al, 2004 [35]

Germany

Prospective study

64.8

54 ± 6.48

59, 77.6%

N/A

Esophageal squamous cell carcinoma

N/A

Cascinu et al, 2003 [36]

Italy

Randomized controlled trial

183

61.84 ± 8.58

100, 54.64%

N/A

Stage III colon cancer

N/A

Cashin et al, 2016 [37]

Sweden

Randomized controlled trial

60±10.61

24, 50%

N/A

Colorectal peritoneal metastases

N/A

Ceyhan et al, 2005 [38]

Turkey

Prospective study

N/A

26, 70.27%

N/A

Colorectal cancer, gastric cancer, breast cancer, metastatic lung carcinoid, nasopharyngeal carcinoma

N/A

Citron et al, 1992 [39]

United States

Prospective study

61.26 ± 9.41

65, 76%

N/A

Non-small cell lung cancer

N/A

Cunningham et al, 2009 [40]

United Kingdom

Randomized controlled trial

725

363

362

61.2 ± 8.89

126, 17.38%

N/A

Metastatic colorectal cancer

N/A

Daniele et al, 2003 [41]

Italy

Prospective study

3.9

76.33 ± 3.59

23, 67.65%

Cardiovascular (55.88%), respiratory (32.35%), gastrointestinal/hepatobiliary (17.65%), genitourinary (17.65%), osteoarticular (14.71%), diabetes (17.65%), endocrinologic (5.88%)

Stage IV colorectal cancer

Previous adjuvant chemotherapy (11.76%)

de Forni et al, 1992 [8]

France

Prospective study

367

302

N/A

55.25 ± 12.40

230, 62.67%

N/A

Head and neck cancer, breast cancer, colon/rectum cancer, esophagus cancer, cervix cancer

N/A

Dencausse et al, 2002 [42]

Germany

Prospective randomized study

155

105

62.58 ± 10.03

108, 69.68%

N/A

Colon cancer

N/A

Dencausse et al, 2001 [43]

Germany

Prospective study

6.75

60.69 ± 3.27

14, 66.67%

N/A

Rectal cancer

N/A

Ducreux et al, 2002 [44]

France

Randomized trial

207

103

104

59.95 ± 9.05

134, 64.73%

N/A

Metastatic or locally advanced adenocarcinoma of the pancreas

None

Ducreux et al, 2004 [45]

France

Randomized controlled trial

N/A

55.63 ± 11.58

42, 66.67%

N/A

Advanced pancreatic carcinoma

N/A

Ducreux et al, 2005 [46]

Belgium

Randomized phase II trial

59.96

31, 54.39%

N/A

Locally advanced or metastatic biliary tract cancer

None

Dyhl-Polk et al, 2021 [47]

Denmark

Prospective study

108

N/A

65.15 ± 9.11

59, 54.6%

Ischemic heart disease (0.9%), previous stroke (7.4%), heart failure (0.9%), atrial fibrillation (4.6%), other heart disease (2.7%), hypertension (32.4%), hypercholesterolemia (67.6%), diabetes mellitus (5.6%)

Colorectal or anal cancer

N/A

Francini et al, 1994 [48]

Italy

Randomized controlled trial

239

118

121

56.76

126, 52.72%

N/A

Surgically resected colon cancer

N/A

Garufi et al, 1997 [49]

Italy

Phase I study

55.34 ± 12.19

19, 55.88%

N/A

Metastatic adenocarcinoma of the colon or rectum

Prior chemotherapy (13/34)

Gradishar et al, 1991 [50]

United States

Retrospective review

244

210

N/A

Gastric cancer, Head and neck cancer

N/A

Granito et al, 2015 [51]

Italy

Retrospective study

65.48 ± 7.07

23, 88.46%

Mild ascites (30.76%), absent ascites (69.23%)

Hepatocellular carcinoma

N/A

Haas et al, 1995 [52]

USA

Phase II study

N/A

61.24 ± 9.19

24, 64.86%

One patient had a myocardial infarction four years before presenting colon cancer. He was maintained on stable doses of nitrates and a calcium channel blocker.

Metastatic adenocarcinoma of the colon or rectum

Adjuvant CMT 2, adjuvant CMT/RT 1, adjuvant immunotherapy/CMT 2, advanced CMT 2, immunotherapy 3, immunotherapy/RT 1, RT 5, none 22

Harbeck et al, 2017 [53]

Germany

Randomized controlled trial

210

105

N/A

61.82 ± 10.96

N/A

Metastatic breast cancer

Prior PLD (37%), capecitabine (36%)

Hartung et al, 1996 [54]

Germany

Retrospective study

Median 59.7

55, 59.78%

N/A

Colon cancer, rectal cancer

N/A

Hartung et al, 2001 [55]

Germany

Phase II clinical study

20.2

58.35 ± 11.77

38, 74.51%

N/A

Metastatic colorectal cancer

N/A

Highley et al, 2009 [56]

United Kingdom

Phase II study

68.09 ± 2.49

33, 71.74%

N/A

Transitional cell carcinoma of the urinary tract

None

Hoff et al, 2001 [57]

United States, Canada, Brazil, Mexico

Phase III randomized controlled study

605

303

302

13.3

63.05 ± 10.98

378, 62.48%

N/A

Advanced or metastatic colorectal cancer

Adjuvant 5-FU (36.3%)

Jack et al, 1995 [58]

Southeast Scotland

Randomized controlled trial

332

167

165

Median follow-up of 15 years

53.97 ± 8.34

N/A

Breast cancer

N/A

Jager et al, 1995 [59]

Germany

Prospective study

N/A

55.98 ± 8.67

50, 72.46%

N/A

Advanced colorectal and rectal carcinoma

N/A

Jegannathen et al, 2011 [60]

United Kingdom

Phase II clinical study

N/A

55.35 ± 8.47

40, 80%

N/A

Head and neck cancer

N/A

Jensen et al, 2006 [25]

Denmark

Prospective study

668

362

214

N/A

Hypercholesterolemia, diabetes, hypertension, cerebral ischemia

Colorectal cancer, gastric cancer

N/A

Kerr et al, 1995 [61]

United Kingdom

Phase I clinical trial

N/A

56 ± 9.38

28, 65.12%

N/A

Colorectal cancer

N/A

Khan et al, 2012 [62]

Pakistan

Retrospective study

301

283

N/A

47.13 ± 10.99

75, 24.92%

N/A

Kim et al, 2003 [63]

Korea

Prospective study

122

N/A

55.98 ± 11.16

70, 57.38%

N/A

Adenocarcinoma of the colon (colon cancer)

N/A

Klausner et al, 1987 [64]

Israel

Prospective study

51.03 ± 11.03

20, 66.67%

N/A

Metastatic malignant melanoma

None

Kohne et al, 2005 [65]

Europe

Phase III prospective, multicenter, randomized, non-blinded

427

213

214

27.6

60.25 ± 9.24

268, 62.32%

N/A

Metastatic colorectal cancer

N/A

Kok et al, 1996 [66]

The Netherlands

Prospective study

24 weeks or until progression.

59.39 ± 8.14

25, 86.21%

N/A

Metastatic adenocarcinoma of the esophagus or esophagogastric junction area.

None

Kolaric et al, 1986 [67]

Slovenia

Controlled phase III clinical study

115

N/A

51.89 ± 8.34

71, 61.74%

N/A

Gastric cancer, rectosigmoid cancer

N/A

Kosmas et al, 2008 [68]

Greece

Prospective study

644

397

193

N/A

65.91 ± 2.26

N/A

Hyperlipidemia, obesity, chronic obstructive pulmonary disease

Colorectal cancer, head and neck cancer, breast cancer

N/A

Kuzel et al, 1993 [69]

USA

Phase II study

68.29 ± 6.55

22, 100%

N/A

Metastatic prostate carcinomas refractory to hormonal therapy

None

Kwakman et al, 2017 [70]

United Kingdom

Retrospective study

2,461 event

397

2,064

N/A

Colorectal cancer

N/A

Labianca et al, 1982 [26]

Italy

Retrospective study

1,083

480

603

N/A

Ischemic heart disease

Gastric cancer, breast cancer

N/A

Labianca et al, 1988 [71]

Italy

Randomized trial

55.48 ± 9.53

33, 61%

N/A

Advanced colorectal cancer

None

Leichman et al, 2005 [72]

United States

Retrospective study

690

340

350

60.78 ± 11.38

407, 57%

N/A

Metastatic or recurrent colorectal cancer

Previous adjuvant CMT or immunotherapy (or both) was allowed as long as ≥ 1 year had elapsed since discontinuation of therapy. No previous chemotherapy for advanced disease was permitted.

Lestuzzi et al, 2014 [15]

Italy and Germany

Prospective study

231

182

57.5

148, 64.07%

Obesity (9.09%), diabetes mellitus (12.12%), hypertension (33.33%), dyslipidemia (23.81%), coronary artery disease (3.46%), active smoker (40.69%), former smoker (23.38%)

Colorectal cancer, breast cancer, head and neck cancer, gastric or bowel cancer

N/A

Mayer et al, 2021 [73]

Unites States

Phase III randomized controlled study

308

160

148

51.85 ± 9.00

N/A

Breast cancer

Prior neoadjuvant taxane 160/160, prior RT 122/160, prior neoadjuvant anthracycline 136/160

Meydan et al, 2005 [74]

Turkey

Prospective study

231

163

N/A

57 ± 18.47

138, 59.74%

Coronary artery disease, hypertension, diabetes mellitus

Colorectal cancer, gastric cancer, pancreas and gallbladder, breast cancer, neuroendocrine, head and neck cancer

N/A

Naredi et al, 2003 [75]

Sweden

Prospective randomized study

64.38 ± 8.74

27, 69.23%

N/A

Metastasis colorectal cancer

N/A

Ngan et al, 2001 [76]

Australia and New Zealand

Prospective study

58.74 ± 12.36

55, 67.07%

N/A

Localized adenocarcinoma of the rectum

N/A

Nobile et al, 1985 [77]

Italy

Phase II clinical study

N/A

60.59 ± 8.43

20, 52.63%

N/A

Advanced colorectal cancer

7/38 had failed prior 5-FU treatment.

Oman et al, 2005 [78]

Sweden

Phase I/II clinical trial

3.9

62.07 ± 11.23

29, 42.65 %

N/A

Non-resectable pancreas cancer

N/A

Poorter et al, 1995 [79]

The Netherlands

Prospective study

54.69 ± 10.54

12, 40%

N/A

Metastatic gastrointestinal cancer

N/A

Primrose et al, 2019 [80]

United Kingdom

Randomized controlled trial

447

223

224

N/A

62.92 ± 2.48

224, 50.11%

N/A

Biliary tract cancer

N/A

Regazzoni et al, 1996 [81]

Switzerland

Retrospective study

106

N/A

56 ± 10.32

N/A

Breast cancer

81% had previously received anthracyclines

Rosso et al, 1994 [82]

Italy

Prospective study

28.75

61.34 ± 7.46

50, 63.29%

N/A

Advanced colorectal carcinoma

N/A

Schober et al, 1993 [83]

Germany

Prospective study

390

250

N/A

52 ± 13.85

260, 66.67%

Hypertension, diabetes, hyperlipidemia, history of coronary or peripheral artery disease

Gastric cancer, colorectal cancer

Pretreatment with etoposide, adriamycin, and cisplatin 1/390

Schuster et al, 1991 [84]

Germany

Randomized controlled trial

56.29 ± 9.29

39, 63.93%

N/A

Advanced colorectal carcinoma

None

Smorenburg et al, 2014 [85]

The Netherland

Randomized controlled trial

75.07 ± 4.36

N/A

Metastatic breast cancer

Previous adjuvant CMT with anthracyclines was allowed, considering a cumulative dose of < 240 mg/m² of doxorubicin or < 450 mg/m² of epirubicin and completion for at least 12 months

Stockler et al, 2011 [86]

Australia, New Zealand

Randomized controlled study

323

214

109

39.6

59.67

N/A

Advanced breast cancer

N/A

Terzoli et al, 2004 [87]

Italy

Prospective study

60.24 ± 9.34

46, 57.50%

N/A

Advanced colorectal cancer

Adjuvant CMT 13/80

Tsavaris et al, 1990 [88]

Greece

Prospective study

7.4

46, 62.16%

N/A

Advanced colorectal cancer

RT 16/74, 5-FU with or without mitomycin C 17/74

Tsavaris et al, 2005 [89]

Greece

Prospective study

522

333

189

N/A

62.04 ± 2.31

N/A

Hyperlipidemia, obesity, chronic obstructive pulmonary disease

Head and neck cancer, colorectal cancer

None

Tsuchida et al, 2005 [90]

Japan

Retrospective study

64.11 ± 9.08

12, 86%

N/A

Recurrence of esophageal squamous cell carcinoma

Cisplatin (50 - 80 mg/m²) for 1 day and 5-FU (500 - 800 mg/m²) for 5 days (eight patients)

Urba et al, 1992 [91]

United states

Prospective study

12.5

61.04 ± 9.25

20, 83%

One patient died of a myocardial infarction with the risk factors of mild hypertension and mild obesity.

Resectable adenocarcinoma of the esophagus

None

Van Cutsem et al, 2001 [92]

Europe, Australia, New Zealand, Taiwan and Israel

Phase III randomized controlled study

602

301

N/A

63.60 ± 9.59

343, 56.98%

N/A

Colorectal cancer

Capecitabine 56/301, 5-FU 41/301

Van Erning et al, 2016 [93]

The Netherland

Retrospective study

357

164

193

N/A

74.53

109, 58.60%

None

Stage III colon cancer

N/A

Van Groeningen et al, 1989 [94]

The Netherlands

Prospective study

59.46 ± 12.57

8, 36.36%

N/A

Advanced colorectal cancer

Prior hepatic intra-arterial 3/22, IV 5-aza-2’-deoxycytidine 1/22, IV cisplatin and hepatic intra-arterial 5-FU 1/22

Wang et al, 1998 [95]

Taiwan

Prospective study

18.4

59.92 ± 7.62

33, 80.48%

N/A

Advanced colorectal cancer

N/A

Weh et al, 1994 [96]

Germany

Prospective study

56.27 ± 9.38

36, 63.16%

N/A

Metastatic colorectal carcinoma

N/A

Wenzel et al, 2002 [97]

Austria

Prospective study

N/A

58.9 ± 7.32

19, 73.08%

N/A

Metastatic renal cell carcinoma

N/A

Yang et al, 1999 [98]

Taiwan

Prospective study

57.68 ± 10.64

21, 58.33%

N/A

Colorectal cancer

5-FU/levamisole (4/36), 5-FU/LV (17/36)

Yang et al, 2001 [99]

Taiwan

Phase II clinical study

N/A

55.48 ± 12.62

18, 69.23%

N/A

Advanced colorectal cancer

None

Yang et al, 2002 [100]

Taiwan

Prospective study

N/A

59 ± 10.22

29, 56.9%

N/A

Metastatic colorectal cancer

Oral UFT 300 mg/m²/day plus LV 90 mg/day

Ychou et al, 2003 [101]

France

Prospective study

65.05 ± 9.05

25, 47.17%

N/A

Metastatic colorectal cancer

Prior CMT 16/53, 30.19%

Yilmaz et al, 2007 [102]

Turkey

Prospective study

24 h

51.60 ± 12.77

15, 55.56%

Diabetes, hypertension

Colorectal cancer, gastric cancer, liver cancer, distal esophagus cancer

N/A