Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial.

MedStar author(s):
Citation: Lancet Oncology. 16(8):957-66, 2015 Aug.PMID: 26187751Institution: MedStar Washington Hospital CenterDepartment: Surgery/Colorectal SurgeryForm of publication: Journal ArticleMedline article type(s): Clinical Trial, Phase II | Journal Article | Multicenter Study | Research Support, N.I.H., ExtramuralSubject headings: *Adenocarcinoma/th [Therapy] | *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] | *Chemoradiotherapy, Adjuvant | *Neoadjuvant Therapy | *Rectal Neoplasms/th [Therapy] | Adenocarcinoma/pa [Pathology] | Adult | Aged | Aged, 80 and over | Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] | Canada | Chemoradiotherapy, Adjuvant/ae [Adverse Effects] | Disease Progression | Drug Administration Schedule | Female | Fluorouracil/ad [Administration & Dosage] | Humans | Infusions, Intravenous | Intention to Treat Analysis | Leucovorin/ad [Administration & Dosage] | Logistic Models | Male | Middle Aged | Multivariate Analysis | Neoadjuvant Therapy/ae [Adverse Effects] | Neoplasm Staging | Odds Ratio | Organoplatinum Compounds/ad [Administration & Dosage] | Rectal Neoplasms/pa [Pathology] | Remission Induction | Time Factors | Treatment Outcome | United StatesLocal holdings: Available online from MWHC library: 2001 - presentISSN:
  • 1470-2045
Name of journal: The Lancet. OncologyAbstract: BACKGROUND: Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response.FINDINGS: Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10-30) of 60 patients in group 1, 17 (25%, 16-37) of 67 in group 2, 20 (30%, 19-42) of 67 in group 3, and 25 (38%, 27-51) of 65 in group 4 achieved a pathological complete response (p=00036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 349, 95% CI 139-875; p=0011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients).FUNDING: National Institutes of Health National Cancer Institute.Copyright � 2015 Elsevier Ltd. All rights reserved.INTERPRETATION: Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to increase the proportion of patients eligible for less invasive treatment strategies; this strategy is being tested in phase 3 clinical trials.METHODS: We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II-III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m(2) per day by continuous infusion throughout radiotherapy, and 450 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 54 Gy). Patients in group 1 had total mesorectal excision 6-8 weeks after chemoradiation. Patients in groups 2-4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m(2) or 400 mg/m(2), according to the discretion of the treating investigator, oxaliplatin 85 mg/m(2) in a 2-h infusion, bolus fluorouracil 400 mg/m(2) on day 1, and a 46-h infusion of fluorouracil 2400 mg/m(2). The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816.All authors: Avila K, Cataldo PA, Chow OS, Coutsoftides T, Dietz DW, Fichera A, Garcia-Aguilar J, Herzig DO, Hunt SR, Kumar AS, Marcet JE, Oommen S, Patil S, Polite BN, Smith DD, Stamos MJ, Ternent CA, Timing of Rectal Cancer Response to Chemoradiation Consortium, Varma MGDigital Object Identifier: Date added to catalog: 2016-01-13
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article Available 26187751

Available online from MWHC library: 2001 - present

BACKGROUND: Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response.

FINDINGS: Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10-30) of 60 patients in group 1, 17 (25%, 16-37) of 67 in group 2, 20 (30%, 19-42) of 67 in group 3, and 25 (38%, 27-51) of 65 in group 4 achieved a pathological complete response (p=00036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 349, 95% CI 139-875; p=0011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients).

FUNDING: National Institutes of Health National Cancer Institute.Copyright � 2015 Elsevier Ltd. All rights reserved.

INTERPRETATION: Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to increase the proportion of patients eligible for less invasive treatment strategies; this strategy is being tested in phase 3 clinical trials.

METHODS: We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II-III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m(2) per day by continuous infusion throughout radiotherapy, and 450 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 54 Gy). Patients in group 1 had total mesorectal excision 6-8 weeks after chemoradiation. Patients in groups 2-4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m(2) or 400 mg/m(2), according to the discretion of the treating investigator, oxaliplatin 85 mg/m(2) in a 2-h infusion, bolus fluorouracil 400 mg/m(2) on day 1, and a 46-h infusion of fluorouracil 2400 mg/m(2). The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816.

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