PMID- 28752564 OWN - NLM STAT- MEDLINE DCOM- 20170912 LR - 20220329 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 7 IP - 7 DP - 2017 Jul 28 TI - Oral versus intravenous fluoropyrimidines for colorectal cancer. PG - CD008398 LID - 10.1002/14651858.CD008398.pub2 [doi] LID - CD008398 AB - 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. FAU - Chionh, Fiona AU - Chionh F AD - Olivia Newton-John Cancer Research Institute, Level 5, Olivia Newton-John Cancer Wellness & Research Centre, Austin Hospital, 145-163 Studley Rd, Heidelberg, Victoria, Australia, 3084. FAU - Lau, David AU - Lau D FAU - Yeung, Yvonne AU - Yeung Y FAU - Price, Timothy AU - Price T FAU - Tebbutt, Niall AU - Tebbutt N LA - eng PT - Journal Article PT - Meta-Analysis PT - Review PT - Systematic Review DEP - 20170728 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Antineoplastic Agents) RN - 0 (Organoplatinum Compounds) RN - 0 (Pyridines) RN - 0 (Pyrimidines) RN - 0 (oxiplatin) RN - 039LU44I5M (Floxuridine) RN - 1548R74NSZ (Tegafur) RN - 2E2W0W5XIU (eniluracil) RN - 56HH86ZVCT (Uracil) RN - 6804DJ8Z9U (Capecitabine) RN - 7673326042 (Irinotecan) RN - U3P01618RT (Fluorouracil) RN - V1JK16Y2JP (doxifluridine) RN - XT3Z54Z28A (Camptothecin) SB - IM UOF - doi: 10.1002/14651858.CD008398 MH - Administration, Oral MH - Adult MH - Antineoplastic Agents/*administration & dosage/adverse effects MH - Camptothecin/administration & dosage/analogs & derivatives MH - Capecitabine/administration & dosage MH - Chemotherapy, Adjuvant MH - Colorectal Neoplasms/*drug therapy/mortality/pathology MH - Disease-Free Survival MH - Female MH - Floxuridine/administration & dosage MH - Fluorouracil/administration & dosage MH - Humans MH - Injections, Intravenous MH - Irinotecan MH - Male MH - Neoadjuvant Therapy MH - Organoplatinum Compounds/administration & dosage MH - Palliative Care MH - Pyridines/administration & dosage MH - Pyrimidines/*administration & dosage MH - Randomized Controlled Trials as Topic MH - Tegafur/administration & dosage MH - Uracil/administration & dosage/analogs & derivatives PMC - PMC6483122 COIS- 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. EDAT- 2017/07/29 06:00 MHDA- 2017/09/13 06:00 PMCR- 2018/07/28 CRDT- 2017/07/29 06:00 PHST- 2017/07/29 06:00 [pubmed] PHST- 2017/09/13 06:00 [medline] PHST- 2017/07/29 06:00 [entrez] PHST- 2018/07/28 00:00 [pmc-release] AID - CD008398.pub2 [pii] AID - 10.1002/14651858.CD008398.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2017 Jul 28;7(7):CD008398. doi: 10.1002/14651858.CD008398.pub2.