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Meta-Analysis
. 2017 Jul 28;7(7):CD008398.
doi: 10.1002/14651858.CD008398.pub2.

Oral versus intravenous fluoropyrimidines for colorectal cancer

Fiona Chionh  1 , David Lau, Yvonne Yeung, Timothy Price, Niall Tebbutt
Affiliations
Meta-Analysis

Oral versus intravenous fluoropyrimidines for colorectal cancer

Fiona Chionh et al. Cochrane Database Syst Rev. .

Abstract

Background: Patients prefer oral to intravenous (IV) palliative chemotherapy, provided that oral therapy is not less effective. We compared the efficacy and safety of oral and IV fluoropyrimidines for treatment of colorectal cancer (CRC).

Objectives: To compare the effects of oral and IV fluoropyrimidine chemotherapy in patients treated with curative or palliative intent for CRC.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 5), along with OVID MEDLINE, OVID Embase, and Web of Science databases, in June 2016. We also searched five clinical trials registers, several conference proceedings, and reference lists from study reports and systematic reviews. We contacted pharmaceutical companies to identify additional studies.

Selection criteria: We included randomised controlled trials (RCTs) comparing oral and IV fluoropyrimidine chemotherapy in patients treated with curative or palliative intent for CRC.

Data collection and analysis: Three review authors extracted data and assessed risk of bias independently. We assessed the seven domains in the Cochrane 'Risk of bias' tool and three additional domains: schedules of outcome assessment and/or follow-up; use of intention-to-treat analysis; and baseline comparability of treatment arms.

Main results: We included nine RCTs (total of 10,918 participants) that examined treatment with curative intent for CRC with neoadjuvant and/or adjuvant chemotherapy. We included 35 RCTs (total of 12,592 participants) that examined treatment with palliative intent for inoperable advanced or metastatic CRC with chemotherapy (31 first-line studies, two second-line studies, and two studies of first- or second-line chemotherapy). All studies included male and female participants, and no studies included participants younger than 18 years of age. Patients treated with curative intent for CRC with neoadjuvant and/or adjuvant chemotherapy • Disease-free survival (DFS): DFS did not differ between participants treated with oral versus IV fluoropyrimidines (hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.87 to 1.00; seven studies, 8903 participants; moderate-quality evidence).• Overall survival (OS): OS did not differ between participants treated with oral versus IV fluoropyrimidines (HR 0.92, 95% CI 0.84 to 1.00; seven studies, 8902 participants analysed; high-quality evidence).• Grade ≥ 3 adverse events (AEs): Participants treated with oral fluoropyrimidines experienced less grade ≥ 3 neutropenia/granulocytopenia (odds ratio (OR) 0.14, 95% CI 0.11 to 0.16; seven studies, 8087 participants; moderate-quality evidence), stomatitis (OR 0.21, 95% CI 0.14 to 0.30; five studies, 4212 participants; low-quality evidence), and any grade ≥ 3 AEs (OR 0.82, 95% CI 0.74 to 0.90; five studies, 7741 participants; low-quality evidence). There was more grade ≥ 3 hand foot syndrome (OR 4.59, 95% CI 2.97 to 7.10; five studies, 5731 participants; low-quality evidence) in patients treated with oral fluoropyrimidines. There were no differences between participants treated with oral versus IV fluoropyrimidines in occurrence of grade ≥ 3 diarrhoea (OR 1.12, 95% CI 0.99 to 1.25; nine studies, 9551 participants; very low-quality evidence), febrile neutropenia (OR 0.59, 95% CI 0.18 to 1.90; four studies, 2925 participants; low-quality evidence), vomiting (OR 1.05, 95% CI 0.83 to 1.34; eight studies, 9385 participants; low-quality evidence), nausea (OR 1.21, 95% CI 0.97 to 1.51; seven studies, 9233 participants; low-quality evidence), mucositis (OR 0.64, 95% CI 0.25 to 1.62; four studies, 2233 participants; very low-quality evidence), and hyperbilirubinaemia (OR 1.67, 95% CI 0.52 to 5.38; three studies, 2757 participants; very low-quality evidence). Patients treated with palliative intent for inoperable advanced or metastatic CRC with chemotherapy • Progression-free survival (PFS): Overall, PFS was inferior in participants treated with oral versus IV fluoropyrimidines (HR 1.06, 95% CI 1.02 to 1.11; 23 studies, 9927 participants; moderate-quality evidence). Whilst PFS was worse in participants treated with oral compared with IV fluoropyrimidines when UFT/Ftorafur or eniluracil with oral 5-fluorouracil (5-FU) was used, PFS did not differ between individuals treated with oral versus IV fluoropyrimidines when capecitabine, doxifluridine, or S-1 was used.• OS: Overall, OS did not differ between participants treated with oral versus IV fluoropyrimidines (HR 1.02, 95% CI 0.99 to 1.05; 29 studies, 12,079 participants; high-quality evidence). OS was inferior in participants treated with oral versus IV fluoropyrimidines when eniluracil with oral 5-fluorouracil (5-FU) was used.• Time to progression (TTP): TTP was inferior in participants treated with oral versus IV fluoropyrimidines (HR 1.07, 95% CI 1.01 to 1.14; six studies, 1970 participants; moderate-quality evidence).• Objective response rate (ORR): ORR did not differ between participants treated with oral versus IV fluoropyrimidines (OR 0.98, 95% CI 0.90 to 1.06; 32 studies, 11,115 participants; moderate-quality evidence).• Grade ≥ 3 AEs: Participants treated with oral fluoropyrimidines experienced less grade ≥ 3 neutropenia/granulocytopenia (OR 0.17, 95% CI 0.15 to 0.18; 29 studies, 11,794 participants; low-quality evidence), febrile neutropenia (OR 0.27, 95% CI 0.21 to 0.36; 19 studies, 9407 participants; moderate-quality evidence), stomatitis (OR 0.26, 95% CI 0.20 to 0.33; 21 studies, 8718 participants; low-quality evidence), mucositis (OR 0.17, 95% CI 0.12 to 0.24; 12 studies, 4962 participants; low-quality evidence), and any grade ≥ 3 AEs (OR 0.83, 95% CI 0.74 to 0.94; 14 studies, 5436 participants; low-quality evidence). There was more grade ≥ 3 diarrhoea (OR 1.66, 95% CI 1.50 to 1.84; 30 studies, 11,997 participants; low-quality evidence) and hand foot syndrome (OR 3.92, 95% CI 2.84 to 5.43; 18 studies, 6481 participants; moderate-quality evidence) in the oral fluoropyrimidine arm. There were no differences between oral and IV fluoropyrimidine arms in terms of grade ≥ 3 vomiting (OR 1.18, 95% CI 1.00 to 1.40; 23 studies, 9528 participants; low-quality evidence), nausea (OR 1.16, 95% CI 0.99 to 1.36; 25 studies, 9796 participants; low-quality evidence), and hyperbilirubinaemia (OR 1.62, 95% CI 0.99 to 2.64; nine studies, 2699 participants; low-quality evidence).

Authors' conclusions: Results of this review should provide confidence that treatment for CRC with most of the oral fluoropyrimidines commonly used in current clinical practice is similarly efficacious to treatment with IV fluoropyrimidines. Treatment with eniluracil with oral 5-FU was associated with inferior PFS and OS among participants treated with palliative intent for CRC, and eniluracil is no longer being developed. Oral and IV fluoropyrimidines have different patterns of side effects; future research may focus on determining the basis for these differences.

PubMed Disclaimer

Conflict of interest statement

FC has been provided with honorarium from Roche to speak at a non‐promotional educational meeting. DL has received an educational grant from Roche. TP is on advisory boards for Roche and Amgen. NT is on advisory boards for Roche, Amgen and Bayer.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.1 1 In this graph, the risk of bias for each domain was calculated using the worst assessment documented for that domain in the contributing studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.1 1 In this summary, the risk of bias for each domain was scored using the worst assessment documented for that domain in the study.
4
4
Forest plot of disease‐free survival.
5
5
Forest plot of comparison: 4 Progression‐free survival with, outcome: 4.4 Progression‐free survival with subgroup analysis ‐ oral fluoropyrimidine backbone.
6
6
Funnel plot of progression‐free survival.
1.1
1.1. Analysis
Comparison 1 Disease‐free survival, Outcome 1 Disease‐free survival.
1.2
1.2. Analysis
Comparison 1 Disease‐free survival, Outcome 2 Disease‐free survival with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.
1.3
1.3. Analysis
Comparison 1 Disease‐free survival, Outcome 3 Disease‐free survival with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
1.4
1.4. Analysis
Comparison 1 Disease‐free survival, Outcome 4 Disease‐free survival with subgroup analysis ‐ Oral fluoropyrimidine backbone.
2.1
2.1. Analysis
Comparison 2 Overall survival (curative intent studies), Outcome 1 Overall survival (curative intent studies).
2.2
2.2. Analysis
Comparison 2 Overall survival (curative intent studies), Outcome 2 Overall survival (curative intent studies) with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.
2.3
2.3. Analysis
Comparison 2 Overall survival (curative intent studies), Outcome 3 Overall survival (curative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
2.4
2.4. Analysis
Comparison 2 Overall survival (curative intent studies), Outcome 4 Overall survival (curative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
3.1
3.1. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 1 Grade ≥ 3 diarrhoea (curative intent studies).
3.2
3.2. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 2 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.
3.3
3.3. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 3 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
3.4
3.4. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 4 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
3.5
3.5. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 5 Grade ≥ 3 hand foot syndrome (curative intent studies).
3.6
3.6. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 6 Grade ≥ 3 neutropenia/granulocytopenia (curative intent studies).
3.7
3.7. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 7 Grade ≥ 3 febrile neutropenia (curative intent studies).
3.8
3.8. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 8 Grade ≥ 3 vomiting (curative intent studies).
3.9
3.9. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 9 Grade ≥ 3 nausea (curative intent studies).
3.10
3.10. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 10 Grade ≥ 3 stomatitis (curative intent studies).
3.11
3.11. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 11 Grade ≥ 3 mucositis (curative intent studies).
3.12
3.12. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 12 Grade ≥ 3 hyperbilirubinaemia (curative intent studies).
3.13
3.13. Analysis
Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 13 Any grade ≥ 3 adverse events (curative intent studies).
4.1
4.1. Analysis
Comparison 4 Progression‐free survival, Outcome 1 Progression‐free survival.
4.2
4.2. Analysis
Comparison 4 Progression‐free survival, Outcome 2 Progression‐free survival with subgroup analysis ‐ Single‐agent vs combination therapy.
4.3
4.3. Analysis
Comparison 4 Progression‐free survival, Outcome 3 Progression‐free survival with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
4.4
4.4. Analysis
Comparison 4 Progression‐free survival, Outcome 4 Progression‐free survival with subgroup analysis ‐ Oral fluoropyrimidine backbone.
4.5
4.5. Analysis
Comparison 4 Progression‐free survival, Outcome 5 Progression‐free survival for combination therapy with subgroup analysis ‐ Oxaliplatin‐based vs irinotecan‐based.
4.6
4.6. Analysis
Comparison 4 Progression‐free survival, Outcome 6 Progression‐free survival for combination therapy with subgroup analysis ‐ with Bev vs no Bev.
5.1
5.1. Analysis
Comparison 5 Overall survival (palliative intent studies), Outcome 1 Overall survival (palliative intent studies).
5.2
5.2. Analysis
Comparison 5 Overall survival (palliative intent studies), Outcome 2 Overall survival (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.
5.3
5.3. Analysis
Comparison 5 Overall survival (palliative intent studies), Outcome 3 Overall survival (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
5.4
5.4. Analysis
Comparison 5 Overall survival (palliative intent studies), Outcome 4 Overall survival (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
5.5
5.5. Analysis
Comparison 5 Overall survival (palliative intent studies), Outcome 5 Overall survival (palliative intent studies) for combination therapy with subgroup analysis ‐ Oxaliplatin‐based vs irinotecan‐based.
6.1
6.1. Analysis
Comparison 6 Time to progression, Outcome 1 Time to progression.
7.1
7.1. Analysis
Comparison 7 Objective response rate, Outcome 1 ORR.
8.1
8.1. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 1 Grade ≥ 3 diarrhoea (palliative intent studies).
8.2
8.2. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 2 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.
8.3
8.3. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 3 Grade ≥ 3 diarrhea (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
8.4
8.4. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 4 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
8.5
8.5. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 5 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis for combination therapy ‐ Oxaliplatin‐based vs irinotecan‐based.
8.6
8.6. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 6 Grade ≥ 3 hand foot syndrome (palliative intent studies).
8.7
8.7. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 7 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.
8.8
8.8. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 8 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
8.9
8.9. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 9 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
8.10
8.10. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 10 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis for combination therapy ‐ Oxaliplatin‐based vs irinotecan‐based.
8.11
8.11. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 11 Grade ≥ 3 neutropenia/granulocytopenia (palliative intent studies).
8.12
8.12. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 12 Grade ≥ 3 febrile neutropenia (palliative intent studies).
8.13
8.13. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 13 Grade ≥ 3 vomiting (palliative intent studies).
8.14
8.14. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 14 Grade ≥ 3 nausea (palliative intent studies).
8.15
8.15. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 15 Grade ≥ 3 stomatitis (palliative intent studies).
8.16
8.16. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 16 Grade ≥ 3 mucositis (palliative intent studies).
8.17
8.17. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 17 Grade ≥ 3 hyperbilirubinaemia (palliative intent studies).
8.18
8.18. Analysis
Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 18 Any grade ≥ 3 adverse events (palliative intent studies).
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Hoff 2001 {published data only (unpublished sought but not used)}
    1. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, Kuperminc M, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first‐line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. Journal of Clinical Oncology 2001;19(8):2282‐92. - PubMed
    1. Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, et al. Oral capecitabine vs intravenous 5‐fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. British Journal of Cancer 2004;90(6):1190‐7. - PMC - PubMed
Hofheinz 2012 {published and unpublished data}
    1. Hofheinz RD, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non‐inferiority, phase 3 trial. Lancet Oncology 2012;13(6):579‐88. - PubMed
Kato 2012 {published and unpublished data}
    1. Gamoh M, Andoh H, Yamaguchi T, Maeda S, Sasaki Y, Suzuki T, et al. A randomized pilot study comparing safety and efficacy of irinotecan plus S‐1 plus bevacizumab (IRIS1BV) and modified FOLFIRI plus BV (mFOLFIRI+BV) in patients (pts) with metastatic colorectal cancer (MCRC): The result of T‐core0702. Annals of Oncology 2011;22(Suppl 9):ix49‐ix50, abstr 109.
    1. Kato S, Andoh H, Gamoh M, Yamaguchi T, Murakawa Y, Sasaki Y, et al. A randomized pilot study comparing safety and efficacy of irinotecan plus S‐1 (IRIS) plus bevacizumab (BV) and modified (m) FOLFIRI plus BV in patients (pts) with metastatic colorectal cancer (mCRC): first report of T‐CORE0702. Journal of Clinical Oncology 2011;4(Suppl):abstr 496.
    1. Kato S, Andoh H, Gamoh M, Yamaguchi T, Murakawa Y, Shimodaira H, et al. Safety verification trials of mFOLFIRI and sequential IRIS + bevacizumab as first‐ or second‐line therapies for metastatic colorectal cancer in Japanese patients. Oncology 2012;83:101‐7. - PubMed
Kim 2001a {published data only (unpublished sought but not used)}
    1. Kim NK, Lee KY, Park JK, Yun SH, Roh JK, Min JS. Prospective Randomized Trials Comparing Intravenous 5‐Fluorouracil and Oral Doxifluridine as a Postoperative Adjuvant Treatment for Advanced Rectal Cancer [Korean]. Journal of the Korean Surgical Society 2001;60(2):195‐9. - PubMed
    1. Min JS, Kim NK, Park JK, Yun SH, Noh JK. A prospective randomized trial comparing intravenous 5‐fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer. Annals of Surgical Oncology 2000;7(9):674‐9. - PubMed
Kohne 2008 {published data only (unpublished sought but not used)}
    1. Kohne CH, Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, et al. Irinotecan combined with infusional 5‐fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first‐line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Annals of Oncology 2008;19(5):920‐6. - PubMed
Lembersky 2006 {published data only (unpublished sought but not used)}
    1. Lembersky BC, Wieand HS, Petrelli NJ, O'Connell MJ, Colangelo LH, Smith RE, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project protocol C‐06. Journal of Clinical Oncology 2006;24(13):2059‐64. - PubMed
Martoni 2006 {published data only (unpublished sought but not used)}
    1. Martoni AA, Pinto C, Fabio F, Lelli G, Llimpe FLR, Gentile AL, et al. Capecitabine plus oxaliplatin (xelox) versus protracted 5‐fluorouracil venous infusion plus oxaliplatin (pvifox) as first‐line treatment in advanced colorectal cancer: a GOAM phase II randomised study (FOCA trial). European Journal of Cancer 2006;42(18):3161‐8. - PubMed
Mei 2014 {published data only}
    1. Mei Z, Yanhua Z, Weiyan G, Hongxia H, Lige Y, Tiandong K. Clinical observation of S‐1 plus oxaliplatin in the treatment of locally advanced or metastatic colorectal cancer [Chinese]. Cancer Research and Clinic 2014;26(12):820‐2.
Nogue 2005 {published data only (unpublished sought but not used)}
    1. Nogue M, Salud A, Batiste‐Alentorn E, Saigi E, Losa F, Cirera L, et al. Randomised study of tegafur and oral leucovorin versus intravenous 5‐fluorouracil and leucovorin in patients with advanced colorectal cancer. European Journal of Cancer 2005;41(15):2241‐9. - PubMed
    1. Salud A, Saigi E, Batiste‐Alentorn E, Losa F, Cirera L, Mendez M, et al. Randomized phase IV trial of oral tegafur and low dose leucovorin versus intravenous 5‐fluorouracil and leucovorin in the treatment of advanced colorectal cancer (ACC): final results. Journal of Clinical Oncology 2004;22(14S):abstr 3547.
Pectasides 2012 {published and unpublished data}
    1. Pectasides D, Papaxoinis G, Kalogeras K, Eleftheraki A, Xanthakis I, Makatsoris T, et al. XELIRI‐‐bevacizumab versus FOLFIRI‐bevacizumab as first‐line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis. BMC Cancer 2012;12(1):271. - PMC - PubMed
Pectasides 2015 {published data only (unpublished sought but not used)}
    1. Maniadakis N, Fragoulakis V, Pectasides D, Fountzilas G. XELOX versus FOLFOX6 as an adjuvant treatment in colorectal cancer: an economic analysis. Current Medical Research and Opinion 2009;25(3):797‐805. - PubMed
    1. Pectasides D, Karavasilis V, Papaxoinis G, Gourgioti G, Makatsoris T, Raptou G, et al. Randomized phase III clinical trial comparing the combination of capecitabine and oxaliplatin (CAPOX) with the combination of 5‐fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) as adjuvant therapy in patients with operated high‐risk stage II or stage III colorectal cancer. BMC Cancer 2015;15:384. - PMC - PubMed
    1. Pectasides DG, Papaxoinis G, Xanthakis I, Kouvatseas G, Kotoula V, Xiros N, et al. Randomized phase III trial of FOLFOX versus XELOX as adjuvant chemotherapy in patients with early‐stage colorectal adenocarcinoma. Journal of Clinical Oncology 2014;32(5s):abstr 3617.
Porschen 2007 {published data only (unpublished sought but not used)}
    1. Arkenau HT, Arnold D, Cassidy J, Diaz‐Rubio E, Douillard JY, Hochster H, et al. Efficacy of oxaliplatin plus capecitabine or infusional fluorouracil/leucovorin in patients with metastatic colorectal cancer: a pooled analysis of randomized trials. Journal of Clinical Oncology 2008;26(36):5910‐7. - PubMed
    1. Porschen R, Arkenau HT, Kubicka S, Greil R, Seufferlein T, Freier W, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. Journal of Clinical Oncology 2007;25(27):4217‐23. - PubMed
Rothenberg 2008 {published data only (unpublished sought but not used)}
    1. Rothenberg M, Navarro M, Butts C, Bang Y, Cox J, Goel R, et al. Phase III trial of capecitabine + oxaliplatin (XELOX) vs. 5‐fluorouracil (5‐FU), leucovorin (LV), and oxaliplatin (FOLFOX4) as 2nd‐line treatment for patients with metastatic colorectal cancer (MCRC). Journal of Clinical Oncology 2007;25(18S):abstr 4031.
    1. Rothenberg ML, Cox JV, Butts C, Navarro M, Bang YJ, Goel R, et al. Capecitabine plus oxaliplatin (XELOX) versus 5‐fluorouracil/folinic acid plus oxaliplatin (FOLFOX‐4) as second‐line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Annals of Oncology 2008;19(10):1720‐6. - PubMed
Schilsky 2002a {published and unpublished data}
    1. Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, et al. Randomized, open‐label, phase III study of a 28‐day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first‐line therapy in patients with metastatic/advanced colorectal cancer. Journal of Clinical Oncology 2002;20(6):1519‐26. - PubMed
Seymour 2011 {published data only (unpublished sought but not used)}
    1. Seymour MT, Thompson LC, Wasan HS, Middleton G, Brewster AE, Shepherd SF, et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open‐label, randomised factorial trial. Lancet 2011;377(9779):1749‐59. - PMC - PubMed
Shigeta 2016 {published and unpublished data}
    1. Hasegawa H, Endo T, Ochiai D, Uchida H, Okabayashi T, Imai S, et al. A randomized Phase II study of tegafur/uracil (UFT), oral leucovorin and irinotecan, combination therapy (TEGAFIRI)+bevacizumab versus FOLFIRI+bevacizumab for the first‐line treatment of patients with metastatic colorectal cancer. European Journal of Cancer 2013;49 (Suppl 2):S557, abstr 2390.
    1. Shigeta K, Hasegawa H, Okabayashi K, Tsuruta M, Ishii Y, Endo T, et al. Randomized phase II trial of TEGAFIRI (tegafur/uracil, oral leucovorin, irinotecan) compared with FOLFIRI (folinic acid,5‐fluorouracil, irinotecan) in patients with unresectable/recurrent colorectal cancer. International Journal of Cancer 2016;139(4):946‐54. - PubMed
Shimada 2014 {published data only (unpublished sought but not used)}
    1. Shimada Y, Hamaguchi T, Mizusawa J, Saito N, Kanemitsu Y, Takiguchi N, et al. Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: Final results of JCOG0205. European Journal of Cancer 2014;50(13):2231‐2240. - PubMed
    1. Shimada Y, Hamaguchi T, Moriya Y, Saito N, Kanemitsu Y, Takiguchi N, et al. Randomized phase III study of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients (pts) with stage III colon cancer (CC): final results of Japan Clinical Oncology Group study (JCOG0205). Journal of Clinical Oncology 2012;30(Suppl):abstr 3524.
Silvestris 2010 {published data only (unpublished sought but not used)}
    1. Silvestris N, Maiello E, Vita F, Cinieri S, Santini D, Russo A, et al. Update on capecitabine alone and in combination regimens in colorectal cancer patients. Cancer Treatment Reviews 2010;36(Suppl 3):S46‐55. - PubMed
Souglakos 2012 {published and unpublished data}
    1. Souglakos J, Ziras N, Kakolyris S, Boukovinas I, Kentepozidis N, Makrantonakis P, et al. Randomised phase‐II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5‐fluorouracil, irinotecan) plus bevacizumab as first‐line treatment of patients with unresectable/metastatic colorectal cancer (mCRC). British Journal of Cancer 2012;106(3):453‐9. - PMC - PubMed
Twelves 2012 {published and unpublished data}
    1. Scheithauer W, McKendrick J, Begbie S, Borner M, Burns WI, Burris HA, et al. Oral capecitabine as an alternative to i.v. 5‐fluorouracil‐based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Annals of Oncology 2003;14(12):1735‐43. - PubMed
    1. Twelves C, Scheithauer W, McKendrick J, Seitz JF, Hazel G, Wong A, et al. Capecitabine versus 5‐fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X‐ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Annals of Oncology 2012;23(5):1190‐7. - PubMed
    1. Twelves C, Wong A, Nowacki MP, Abt M, Burris H, 3rd, Carrato A, et al. Capecitabine as adjuvant treatment for stage III colon cancer. New England Journal of Medicine 2005;352(26):2696‐704. - PubMed
Van Cutsem 2001a {published and unpublished data}
    1. Cutsem E, Sorensen J, Cassidy J, Daniel F, Harper P, Bailey N, et al. International phase III study of oral eniluracil (EU) plus 5‐fluorouracil (5‐FU) versus intravenous (IV) 5‐FU plus leucovorin (LV) in the treatment of advanced colorectal cancer (ACC). Journal of Clinical Oncology, Proceedings of American Society of Clinical Oncology 2001;20:abstr 522.
Van Cutsem 2001b {published data only (unpublished sought but not used)}
    1. Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, et al. Oral capecitabine vs intravenous 5‐fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. British Journal of Cancer 2004;90(6):1190‐7. - PMC - PubMed
    1. Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. Journal of Clinical Oncology 2001;19(21):4097‐106. - PubMed
Yamada 2013 {published and unpublished data}
    1. Matsumoto H, Yamada Y, Takahari D, Baba H, Yoshida K, Komatsu Y, et al. The SOFT study: A randomized phase III trial of S‐1/oxaliplatin (SOX)plus bevacizumab versus 5‐FU/l‐LV/oxaliplatin (mFOLFOX6) plus bevacizumab in patients with metastatic colorectal cancer [SOFT Study Group]. European Journal of Cancer 2013;49(Suppl 2):S486, abstr 2167.
    1. Takahari D, Yamada Y, Matsumoto H, Baba H, Yoshida K, Nakamura M, et al. A randomized phase III trial of S‐1/oxaliplatin (SOX) plus bevacizumab versus 5‐FU/l‐LV/oxaliplatin (mFOLFOX6) plus bevacizumab in patients with metastatic colorectal cancer: the SOFT study. Journal of Clinical Oncology 2013;15(suppl):abstr 3519.
    1. Yamada Y, Takahari D, Matsumoto H, Baba H, Nakamura M, Yoshida K, et al. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S‐1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open‐label, non‐inferiority, randomised phase 3 trial. Lancet Oncology 2013;14:1278‐86. - PubMed
Yamazaki 2015 {published and unpublished data}
    1. Ojima H, Yamakazi K, Kuwano H, Otsuji T, Kato T, Shimada K, et al. Randomized Phase II study of S‐1, oral leucovorin, and oxaliplatin combination therapy (SOL) versus mFOLFOX6 in patients with untreated metastatic colorectal cancer (mCRC). European Journal of Cancer 2011;47(Suppl 1):427, abstr 6118.
    1. Otsuji T, Yamazaki K, Ojima H, Kuwano H, Kato T, Shimada K, et al. Updated survival results of the randomized phase II study of S‐1, oral leucovorin, and oxaliplatin combination therapy (SOL) versus mFOLFOX6 in patients with untreated metastatic colorectal cancer (mCRC). Journal of Clinical Oncology 2012;30(Suppl 4):abstr 586.
    1. Yamazaki K, Kuwano H, Ojima H, Otsuji T, Kato T, Shimada K, et al. A randomized phase II study of combination therapy with S‐1, oral leucovorin, and oxaliplatin (SOL) and mFOLFOX6 in patients with previously untreated metastatic colorectal cancer. Cancer Chemotherapy and Pharmacology 2015;75(3):569‐77. - PubMed
Yasui 2015 {published and unpublished data}
    1. Baba H, Muro K, Yasui H, Shimada Y, Tsuji A, Sameshima S, et al. Updated results of the FIRIS study: A phase II/III trial of 5‐FU/l‐leucovorin/irinotecan (FOLFIRI) versus irinotecan/S‐1 (IRIS) as second‐line chemotherapy for metastatic colorectal cancer (mCRC). Journal of Clinical Oncology 2011;29(Suppl):abstr 3562. - PubMed
    1. Muro K, Boku N, Shimada Y, Tsuji A, Sameshima S, Baba H, et al. Irinotecan plus S‐1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second‐line chemotherapy for metastatic colorectal cancer: a randomised phase 2/3 non‐inferiority study (FIRIS study). Lancet Oncology 2010;11(9):853‐60. - PubMed
    1. Yasui H, Muro K, Shimada Y, Tsuji A, Sameshima S, Baba H, et al. A phase 3 non‑inferiority study of 5‑FU/l‑leucovorin/irinotecan(FOLFIRI) versus irinotecan/S‑1 (IRIS) as second‑line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. Journal of Cancer Research and Clinical Oncology 2015;141:153‐60. - PMC - PubMed
Yu 2005 {published data only (unpublished sought but not used)}
    1. Yu B‐M, Wu W‐Q. Irinotecan combined with fluoropyrimidine in treatment for advanced/metastatic colorectal carcinoma. Chung‐Hua Wai Ko Tsa Chih [Chinese Journal of Surgery] 2005;43(9):557‐60. - PubMed

References to studies excluded from this review

Ansfield 1977 {published data only}
    1. Ansfield F, Klotz J, Nealon T, Ramirez G, Minton J, Hill G, et al. A phase III study comparing the clinical utility of four regimens of 5‐fluorouracil: a preliminary report. Cancer 1977;39(1):34‐40. - PubMed
Bajetta 1997 {published data only}
    1. Bajetta E, Bartolomeo M, Somma L, Vecchio M, Artale S, Zunino F, et al. Doxifluridine in colorectal cancer patients resistant to 5‐fluorouracil (5‐FU) containing regimens. European Journal of Cancer Part A 1997;33(4):687‐90. - PubMed
Bedikian 1983 {published data only}
    1. Bedikian AY, Stroehlein J, Korinek J, Karlin D, Bodey GP. A comparative study of oral tegafur and intravenous 5‐fluorouracil in patients with metastatic colorectal cancer. American Journal of Clinical Oncology 1983;6(2):181‐6. - PubMed
Bjerkeset 1986 {published data only}
    1. Bjerkeset T, Fjosne HE. Comparison of oral ftorafur and intravenous 5‐fluorouracil in patients with advanced cancer of the stomach, colon or rectum. Oncology 1986;43(4):212‐5. - PubMed
Borner 2002 {published data only}
    1. Borner MM, Schoffski P, Wit R, Caponigro F, Comella G, Sulkes A, et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. European Journal of Cancer 2002;38(3):349‐58. - PubMed
Douglass 1978 {published data only}
    1. Douglass HO, Jr, Lavin PT, Woll J, Conroy JF, Carbone P. Chemotherapy of advanced measurable colon and rectal carcinoma with oral 5‐fluorouracil, alone or in combination with cyclophosphamide or 6‐thioguanine, with intravenous 5‐fluorouracil or beta‐2'‐deoxythioguanosine or with oral 3(4‐methyl‐cyclohexyl)‐1(2‐chlorethyl)‐1‐nitrosourea: a Phase II‐III study of the Eastern Cooperative Oncology Group (EST 4273). Cancer 1978;42(6):2538‐45. - PubMed
Fan 2005 {published data only}
    1. Fan L, Liu W‐C, Zhang Y‐J, Ren J, Pan B‐R, Liu D‐H, et al. Oral xeloda plus bi‐platinu two‐way combined chemotherapy in treatment of advanced gastrointestinal malignancies. World Journal of Gastroenterology 2005;11(28):4300‐4. - PMC - PubMed
Hahn 1975 {published data only}
    1. Hahn RG, Moertel CG, Schutt AJ, Bruckner HW. A double‐blind comparison of intensive course 5‐flourouracil by oral vs. intravenous route in the treatment of colorectal carcinoma. Cancer 1975;35(4):1031‐5. - PubMed
Hennig 2008 {published data only}
    1. Hennig IM, Naik JD, Brown S, Szubert A, Anthoney DA, Jackson DP, et al. Severe sequence‐specific toxicity when capecitabine is given after Fluorouracil and leucovorin. Journal of Clinical Oncology 2008;26(20):3411‐7. - PubMed
Kim 2001b {published data only (unpublished sought but not used)}
    1. Kim NK, Min JS, Park JK, Yun SH, Sung JS, Jung HC, et al. Intravenous 5‐fluorouracil versus oral doxifluridine as preoperative concurrent chemoradiation for locally advanced rectal cancer: prospective randomized trials. Japanese Journal of Clinical Oncology 2001;31(1):25‐9. - PubMed
Lima 2005 {published data only}
    1. Lima APR, Giglio A. Randomized crossover trial of intravenous 5‐FU versus oral UFT both modulated by leucovorin: a one‐centre experience. European Journal of Cancer Care 2005;14(2):151‐4. - PubMed
Maetani 1993 {published data only}
    1. Maetani S. Multicenter clinical trial of UFT with FT for patients with colorectal cancer. Therapeutic Research 1993;14(6):226‐32.
Munoz 2008 {published data only (unpublished sought but not used)}
    1. Munoz Llarena A, Salud Salvia A, García Girón C, Murias Rosales A, Burillo M, Arizcun Sánchez‐Morate A, et al. Randomized phase III trial, with irinotecan and capecitabine (XELIRI) versus irinotecan, 5FU and folinic acid (Saltz regimen) in first‐line treatment on metastatic colorectal cancer patients (CRC). ASCO 2008 Gastrointestinal Cancers Symposium. 2008:abstr 379.
NCT00070122 {published and unpublished data}
    1. NCT00070122. Combination chemotherapy and bevacizumab in treating patients with locally recurrent colorectal cancer. http://clinicaltrials.gov/ct2/show/NCT00070122 (accessed 8 June 2016).
NCT01193452 {published and unpublished data}
    1. NCT01193452. S‐1/leucovorin (SL) versus sLV5FU2 as the first‐line treatment for elderly patients with colorectal cancer. http://clinicaltrials.gov/ct2/show/NCT01193452 (accessed 8 June 2016).
NCT01196260 {published data only}
    1. NCT01196260. Combination chemotherapy treatments in patients with colorectal cancer stage II and III. http://clinicaltrials.gov/ct2/show/NCT01196260 (accessed 8 June 2016).
NCT01279681 {published data only}
    1. NCT01279681. Randomized phase III trial of mFOLFOX7 or XELOX plus bevacizumab versus 5‐fluorouracil/leucovorin or capecitabine plus bevacizumab as first‐line treatment in elderly patients with metastatic colorectal cancer. http://clinicaltrials.gov/ct2/show/NCT01279681 (accessed 8 June 2016).
NCT01736904 {published data only (unpublished sought but not used)}
    1. NCT01736904. wXELIRI versus FOLFIRI regimen in the treatment of advanced colorectal cancer patients. http://clinicaltrials.gov/ct2/show/NCT01736904 (accessed 8 June 2016).
Pfeiffer 2006 {published data only}
    1. Pfeiffer P, Mortensen JP, Bjerregaard B, Eckhoff L, Schonnemann K, Sandberg E, et al. Patient preference for oral or intravenous chemotherapy: A randomised cross‐over trial comparing capecitabine and Nordic fluorouracil/leucovorin in patients with colorectal cancer. European Journal of Cancer 2006;42(16):2738‐43. - PubMed
Queißer 1979 {published data only}
    1. Queißer W, Schaefer J, Arnold H, Drings P, Geldmacher J, Hartwich G, et al. A prospective multi‐centre study of the response of metastatic gastrointestinal tumours [Prospektive kontrollierte studie bei metastasierten gastrointestinalen tumoren: vergleich zwischen 5‐fluorouracil ‐ carmustin und ftorafur ‐ carmustin]. Deutsche Medizinische Wochenschrift 1979;104(35):1231‐6. - PubMed
Revazishvili 2008 {published data only (unpublished sought but not used)}
    1. Revazishvili P, Shavdia M, Chvamichva R, Shavidia N. Oral ftorafur in treatment of advanced colorectal cancer. Annals of Oncology 2008;19(Suppl 8):viii147, abstr 437.
Sizer 2006 {published data only (unpublished sought but not used)}
    1. Sizer B, Makris A, Barone C, Mainwaring P, Eggleton P. QoL and resource use analysis of tegafur‐uracil/LV or 5‐FU/LV in first‐line metastatic colorectal cancer (mCRC): final results of a multicenter phase II study. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I 2006;24(18S):abstr 3631.
Skof 2009 {published data only (unpublished sought but not used)}
    1. Skof E, Rebersek M, Hlebanja Z, Ocvirk J. Capecitabine plus Irinotecan (XELIRI regimen) compared to 5‐FU/LV plus Irinotecan (FOLFIRI regimen) as neoadjuvant treatment for patients with unresectable liver‐only metastases of metastatic colorectal cancer: a randomised prospective phase II trial. BMC Cancer 2009;9:120. - PMC - PubMed
Tournigand 2012 {published data only}
    1. Tournigand C, Samson B, Scheithauer W, Lledo G, Viret F, Andre T, et al. Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first‐line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial. Abstract No: LBA3500, Presenter: Christophe Tournigand, MD, PhD. 2012 ASCO Annual Meeting, Gastrointestinal (Colorectal) Cancer Track‐ Oral Abstract Session. Available from: http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_ses... (accessed 26 September 2012).
    1. Tournigand C, Samson B, Scheithauer W, Lledo G, Viret F, Andre T, et al. Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first‐line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial. Journal of Clinical Oncology 2012;30(Suppl):abstr LBA3500.
Twelves 2006 {published data only}
    1. Twelves C, Gollins S, Grieve R, Samuel L. A randomised cross‐over trial comparing patient preference for oral capecitabine and 5‐fluorouracil/leucovorin regimens in patients with advanced colorectal cancer. Annals of Oncology 2006;17(2):239‐45. - PubMed

References to ongoing studies

Barsukov 2015 {published data only}
    1. Barsukov Y, Perevoshikov A, Kuzmichev D, Mammadli Z, Polynovskiy A. Combined treatment of resectable distal rectal cancer with different fluoropyrimidines. European Journal of Surgical Oncology 2012;38(9):832, abstr 324.
GOIM 2802 {unpublished data only}
    1. GOIM 2802. Bevacizumab + FOLFOX4 or XELOX2 as first‐line treatment in colorectal cancer. Randomized phase II study. https://www.clinicaltrialsregister.eu/ctr‐search/trial/2010‐022091‐31/IT (accessed 29 August 2016).
Joarder 2012 {published data only}
    1. Joarder R, Basu A, Choudhury KB, Dasgupta C, Dasgupta P, Ghosh K. Neoadjuvant chemoradiation with oral capecitabine versus intravenous 5‐fluorouracil and leucovorin in locally advanced carcinoma rectum – a randomized trial: an interim report. Journal of Cancer Research and Therapeutics 2012;8(Suppl 3):S159.
Muro 2016 {published data only}
    1. Muro K, Kim TW, Park YS, Uetake H, Nishina T, Nozawa H, et al. A multinational, randomized, phase III trial of XELIRI (+bevacizumab) versus FOLFIRI (+bevacizumab) as the second‐line chemotherapy for metastatic colorectal cancer: Asian XELIRI project (AXEPT). Journal of Clinical Oncology 2016;34(Suppl 4S):abstr TPS780. - PMC - PubMed
NCT02280070 {published data only}
    1. NCT02280070. RP II study of SOX vs mFOLFOX6 in patients with resectable rectal cancer (KSCC1301). https://clinicaltrials.gov/ct2/show/record/NCT02280070 (accessed 27 June 2016).

Additional references

Allegra 2011
    1. Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C‐08. Journal of Clinical Oncology 2011;29(1):11‐6. - PMC - PubMed
André 2009
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