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Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial

Summary Background Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal ca... Full description

Journal Title: Lancet 2011, Vol.377 (9779), p.1749-1759
Main Author: Seymour, Matthew T, Prof
Other Authors: Thompson, Lindsay C, MSc , Wasan, Harpreet S, Prof , Middleton, Gary, MD , Brewster, Alison E, MD , Shepherd, Stephen F, MD , O'Mahony, M Sinead, MBBS , Maughan, Timothy S, Prof , Parmar, Mahesh, Prof , Langley, Ruth E, PhD
Format: Electronic Article Electronic Article
Language: English
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Quelle: Alma/SFX Local Collection
Publisher: Kidlington: Elsevier Ltd
ID: ISSN: 0140-6736
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title: Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial
format: Article
creator:
  • Seymour, Matthew T, Prof
  • Thompson, Lindsay C, MSc
  • Wasan, Harpreet S, Prof
  • Middleton, Gary, MD
  • Brewster, Alison E, MD
  • Shepherd, Stephen F, MD
  • O'Mahony, M Sinead, MBBS
  • Maughan, Timothy S, Prof
  • Parmar, Mahesh, Prof
  • Langley, Ruth E, PhD
subjects:
  • Adenocarcinoma - drug therapy
  • Adenocarcinoma - mortality
  • Adenocarcinoma - pathology
  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols - adverse effects
  • Antineoplastic Combined Chemotherapy Protocols - therapeutic use
  • Articles
  • Biological and medical sciences
  • Cancer
  • Capecitabine
  • Care and treatment
  • Chemotherapy
  • Clinical trials
  • Colorectal cancer
  • colorectal carcinoma
  • Colorectal Neoplasms - drug therapy
  • Colorectal Neoplasms - mortality
  • Colorectal Neoplasms - pathology
  • councils
  • Deoxycytidine - administration & dosage
  • Deoxycytidine - adverse effects
  • Deoxycytidine - analogs & derivatives
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug therapy
  • elderly
  • Female
  • Fluorouracil - administration & dosage
  • Fluorouracil - adverse effects
  • Fluorouracil - analogs & derivatives
  • Frail Elderly
  • Frailty
  • Gastroenterology. Liver. Pancreas. Abdomen
  • General aspects
  • Health aspects
  • Humans
  • Infusions, Intravenous
  • Internal Medicine
  • Male
  • Medical sciences
  • Middle Aged
  • Organoplatinum Compounds - administration & dosage
  • Organoplatinum Compounds - adverse effects
  • Quality of Life
  • Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
  • survival
  • Toxicity
  • Tumors
  • United Kingdom
ispartof: Lancet, 2011, Vol.377 (9779), p.1749-1759
description: Summary Background Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. Methods We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. Findings 459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3–7·5] vs 4·5 months [2·8–6·4]; hazard ratio 0·84, 95% CI 0·69–1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14–1·52), less widespread disease (1·51, 1·05–2·19), and use of oxaliplatin (0·57, 0·39–0·82) were predictive of better OTU. Interpretation FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and el
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
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titleChemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial
sourceAlma/SFX Local Collection
creatorSeymour, Matthew T, Prof ; Thompson, Lindsay C, MSc ; Wasan, Harpreet S, Prof ; Middleton, Gary, MD ; Brewster, Alison E, MD ; Shepherd, Stephen F, MD ; O'Mahony, M Sinead, MBBS ; Maughan, Timothy S, Prof ; Parmar, Mahesh, Prof ; Langley, Ruth E, PhD
creatorcontribSeymour, Matthew T, Prof ; Thompson, Lindsay C, MSc ; Wasan, Harpreet S, Prof ; Middleton, Gary, MD ; Brewster, Alison E, MD ; Shepherd, Stephen F, MD ; O'Mahony, M Sinead, MBBS ; Maughan, Timothy S, Prof ; Parmar, Mahesh, Prof ; Langley, Ruth E, PhD ; on behalf of the FOCUS2 Investigators ; the National Cancer Research Institute Colorectal Cancer Clinical Studies Group ; National Cancer Research Institute Colorectal Cancer Clinical Studies Group ; FOCUS2 Investigators
descriptionSummary Background Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. Methods We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. Findings 459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3–7·5] vs 4·5 months [2·8–6·4]; hazard ratio 0·84, 95% CI 0·69–1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14–1·52), less widespread disease (1·51, 1·05–2·19), and use of oxaliplatin (0·57, 0·39–0·82) were predictive of better OTU. Interpretation FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. Funding Cancer Research UK and the Medical Research Council.
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0ISSN: 0140-6736
1EISSN: 1474-547X
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3PMID: 21570111
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languageeng
publisherKidlington: Elsevier Ltd
subjectAdenocarcinoma - drug therapy ; Adenocarcinoma - mortality ; Adenocarcinoma - pathology ; Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Articles ; Biological and medical sciences ; Cancer ; Capecitabine ; Care and treatment ; Chemotherapy ; Clinical trials ; Colorectal cancer ; colorectal carcinoma ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - mortality ; Colorectal Neoplasms - pathology ; councils ; Deoxycytidine - administration & dosage ; Deoxycytidine - adverse effects ; Deoxycytidine - analogs & derivatives ; Disease-Free Survival ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug therapy ; elderly ; Female ; Fluorouracil - administration & dosage ; Fluorouracil - adverse effects ; Fluorouracil - analogs & derivatives ; Frail Elderly ; Frailty ; Gastroenterology. Liver. Pancreas. Abdomen ; General aspects ; Health aspects ; Humans ; Infusions, Intravenous ; Internal Medicine ; Male ; Medical sciences ; Middle Aged ; Organoplatinum Compounds - administration & dosage ; Organoplatinum Compounds - adverse effects ; Quality of Life ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; survival ; Toxicity ; Tumors ; United Kingdom
ispartofLancet, 2011, Vol.377 (9779), p.1749-1759
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0Elsevier Ltd
12011 Elsevier Ltd
22015 INIST-CNRS
3Copyright © 2011 Elsevier Ltd. All rights reserved.
4COPYRIGHT 2011 Elsevier B.V.
5Copyright Elsevier Limited May 21-May 27, 2011
62011 Elsevier Ltd. All rights reserved. 2011 Elsevier Ltd
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0Seymour, Matthew T, Prof
1Thompson, Lindsay C, MSc
2Wasan, Harpreet S, Prof
3Middleton, Gary, MD
4Brewster, Alison E, MD
5Shepherd, Stephen F, MD
6O'Mahony, M Sinead, MBBS
7Maughan, Timothy S, Prof
8Parmar, Mahesh, Prof
9Langley, Ruth E, PhD
10on behalf of the FOCUS2 Investigators
11the National Cancer Research Institute Colorectal Cancer Clinical Studies Group
12National Cancer Research Institute Colorectal Cancer Clinical Studies Group
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title
0Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial
1Lancet
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descriptionSummary Background Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. Methods We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. Findings 459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3–7·5] vs 4·5 months [2·8–6·4]; hazard ratio 0·84, 95% CI 0·69–1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14–1·52), less widespread disease (1·51, 1·05–2·19), and use of oxaliplatin (0·57, 0·39–0·82) were predictive of better OTU. Interpretation FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. Funding Cancer Research UK and the Medical Research Council.
subject
0Adenocarcinoma - drug therapy
1Adenocarcinoma - mortality
2Adenocarcinoma - pathology
3Administration, Oral
4Adult
5Aged
6Aged, 80 and over
7Antineoplastic Combined Chemotherapy Protocols - adverse effects
8Antineoplastic Combined Chemotherapy Protocols - therapeutic use
9Articles
10Biological and medical sciences
11Cancer
12Capecitabine
13Care and treatment
14Chemotherapy
15Clinical trials
16Colorectal cancer
17colorectal carcinoma
18Colorectal Neoplasms - drug therapy
19Colorectal Neoplasms - mortality
20Colorectal Neoplasms - pathology
21councils
22Deoxycytidine - administration & dosage
23Deoxycytidine - adverse effects
24Deoxycytidine - analogs & derivatives
25Disease-Free Survival
26Dose-Response Relationship, Drug
27Drug Administration Schedule
28Drug therapy
29elderly
30Female
31Fluorouracil - administration & dosage
32Fluorouracil - adverse effects
33Fluorouracil - analogs & derivatives
34Frail Elderly
35Frailty
36Gastroenterology. Liver. Pancreas. Abdomen
37General aspects
38Health aspects
39Humans
40Infusions, Intravenous
41Internal Medicine
42Male
43Medical sciences
44Middle Aged
45Organoplatinum Compounds - administration & dosage
46Organoplatinum Compounds - adverse effects
47Quality of Life
48Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
49survival
50Toxicity
51Tumors
52United Kingdom
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titleChemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial
authorSeymour, Matthew T, Prof ; Thompson, Lindsay C, MSc ; Wasan, Harpreet S, Prof ; Middleton, Gary, MD ; Brewster, Alison E, MD ; Shepherd, Stephen F, MD ; O'Mahony, M Sinead, MBBS ; Maughan, Timothy S, Prof ; Parmar, Mahesh, Prof ; Langley, Ruth E, PhD
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7Antineoplastic Combined Chemotherapy Protocols - adverse effects
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11Cancer
12Capecitabine
13Care and treatment
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15Clinical trials
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17colorectal carcinoma
18Colorectal Neoplasms - drug therapy
19Colorectal Neoplasms - mortality
20Colorectal Neoplasms - pathology
21councils
22Deoxycytidine - administration & dosage
23Deoxycytidine - adverse effects
24Deoxycytidine - analogs & derivatives
25Disease-Free Survival
26Dose-Response Relationship, Drug
27Drug Administration Schedule
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29elderly
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32Fluorouracil - adverse effects
33Fluorouracil - analogs & derivatives
34Frail Elderly
35Frailty
36Gastroenterology. Liver. Pancreas. Abdomen
37General aspects
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39Humans
40Infusions, Intravenous
41Internal Medicine
42Male
43Medical sciences
44Middle Aged
45Organoplatinum Compounds - administration & dosage
46Organoplatinum Compounds - adverse effects
47Quality of Life
48Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
49survival
50Toxicity
51Tumors
52United Kingdom
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jtitleLancet
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Seymour, Matthew T, Prof
1Thompson, Lindsay C, MSc
2Wasan, Harpreet S, Prof
3Middleton, Gary, MD
4Brewster, Alison E, MD
5Shepherd, Stephen F, MD
6O'Mahony, M Sinead, MBBS
7Maughan, Timothy S, Prof
8Parmar, Mahesh, Prof
9Langley, Ruth E, PhD
aucorp
0on behalf of the FOCUS2 Investigators
1the National Cancer Research Institute Colorectal Cancer Clinical Studies Group
2National Cancer Research Institute Colorectal Cancer Clinical Studies Group
3FOCUS2 Investigators
formatjournal
genrearticle
ristypeJOUR
atitleChemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial
jtitleLancet
addtitleLancet
date2011
risdate2011
volume377
issue9779
spage1749
epage1759
pages1749-1759
issn0140-6736
eissn1474-547X
codenLANCAO
notesFOCUS2 Investigators listed at end of paper
abstractSummary Background Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. Methods We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. Findings 459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3–7·5] vs 4·5 months [2·8–6·4]; hazard ratio 0·84, 95% CI 0·69–1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14–1·52), less widespread disease (1·51, 1·05–2·19), and use of oxaliplatin (0·57, 0·39–0·82) were predictive of better OTU. Interpretation FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. Funding Cancer Research UK and the Medical Research Council.
copKidlington
pubElsevier Ltd
pmid21570111
doi10.1016/S0140-6736(11)60399-1
oafree_for_read