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Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Summary Background When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer... Full description

Journal Title: The Lancet Oncology 2011, Vol.12 (7), p.642-653
Main Author: Adams, Richard A, FRCP
Other Authors: Meade, Angela M, DPhil , Seymour, Matthew T, Prof , Wilson, Richard H, MD , Madi, Ayman, MRCP , Fisher, David, MSc , Kenny, Sarah L, MSc , Kay, Edward, BA , Hodgkinson, Elizabeth, BPharm , Pope, Malcolm , Rogers, Penny, BSc , Wasan, Harpreet, FRCP , Falk, Stephen, MD , Gollins, Simon, DPhil , Hickish, Tamas, MD , Bessell, Eric M, PhD , Propper, David, MD , Kennedy, M John, MD , Kaplan, Richard, Prof , Maughan, Timothy S, Prof
Format: Electronic Article Electronic Article
Language: English
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Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 1470-2045
Link: https://www.ncbi.nlm.nih.gov/pubmed/21641867
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title: Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial
format: Article
creator:
  • Adams, Richard A, FRCP
  • Meade, Angela M, DPhil
  • Seymour, Matthew T, Prof
  • Wilson, Richard H, MD
  • Madi, Ayman, MRCP
  • Fisher, David, MSc
  • Kenny, Sarah L, MSc
  • Kay, Edward, BA
  • Hodgkinson, Elizabeth, BPharm
  • Pope, Malcolm
  • Rogers, Penny, BSc
  • Wasan, Harpreet, FRCP
  • Falk, Stephen, MD
  • Gollins, Simon, DPhil
  • Hickish, Tamas, MD
  • Bessell, Eric M, PhD
  • Propper, David, MD
  • Kennedy, M John, MD
  • Kaplan, Richard, Prof
  • Maughan, Timothy S, Prof
subjects:
  • Aged
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents - administration & dosage
  • Antineoplastic Agents - therapeutic use
  • Clinical trials
  • Colorectal cancer
  • Colorectal Neoplasms - drug therapy
  • Disease Progression
  • Disease-Free Survival
  • Drug therapy
  • Drug Therapy, Combination
  • Fast track
  • Fast track — Articles
  • Female
  • Fluorouracil - administration & dosage
  • Fluorouracil - therapeutic use
  • Follow-Up Studies
  • Hematology, Oncology and Palliative Medicine
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Oncology
  • Organoplatinum Compounds - administration & dosage
  • Organoplatinum Compounds - therapeutic use
  • Quality of Life
  • Time Factors
ispartof: The Lancet Oncology, 2011, Vol.12 (7), p.642-653
description: Summary Background When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 1470-2045
fulltext: fulltext
issn:
  • 1470-2045
  • 1474-5488
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titleIntermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial
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creatorAdams, Richard A, FRCP ; Meade, Angela M, DPhil ; Seymour, Matthew T, Prof ; Wilson, Richard H, MD ; Madi, Ayman, MRCP ; Fisher, David, MSc ; Kenny, Sarah L, MSc ; Kay, Edward, BA ; Hodgkinson, Elizabeth, BPharm ; Pope, Malcolm ; Rogers, Penny, BSc ; Wasan, Harpreet, FRCP ; Falk, Stephen, MD ; Gollins, Simon, DPhil ; Hickish, Tamas, MD ; Bessell, Eric M, PhD ; Propper, David, MD ; Kennedy, M John, MD ; Kaplan, Richard, Prof ; Maughan, Timothy S, Prof
creatorcontribAdams, Richard A, FRCP ; Meade, Angela M, DPhil ; Seymour, Matthew T, Prof ; Wilson, Richard H, MD ; Madi, Ayman, MRCP ; Fisher, David, MSc ; Kenny, Sarah L, MSc ; Kay, Edward, BA ; Hodgkinson, Elizabeth, BPharm ; Pope, Malcolm ; Rogers, Penny, BSc ; Wasan, Harpreet, FRCP ; Falk, Stephen, MD ; Gollins, Simon, DPhil ; Hickish, Tamas, MD ; Bessell, Eric M, PhD ; Propper, David, MD ; Kennedy, M John, MD ; Kaplan, Richard, Prof ; Maughan, Timothy S, Prof ; on behalf of the MRC COIN Trial Investigators ; MRC COIN Trial Investigators
descriptionSummary Background When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand–foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding Cancer Research UK.
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languageeng
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subjectAged ; Antimetabolites, Antineoplastic ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - therapeutic use ; Clinical trials ; Colorectal cancer ; Colorectal Neoplasms - drug therapy ; Disease Progression ; Disease-Free Survival ; Drug therapy ; Drug Therapy, Combination ; Fast track ; Fast track — Articles ; Female ; Fluorouracil - administration & dosage ; Fluorouracil - therapeutic use ; Follow-Up Studies ; Hematology, Oncology and Palliative Medicine ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Oncology ; Organoplatinum Compounds - administration & dosage ; Organoplatinum Compounds - therapeutic use ; Quality of Life ; Time Factors
ispartofThe Lancet Oncology, 2011, Vol.12 (7), p.642-653
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1Meade, Angela M, DPhil
2Seymour, Matthew T, Prof
3Wilson, Richard H, MD
4Madi, Ayman, MRCP
5Fisher, David, MSc
6Kenny, Sarah L, MSc
7Kay, Edward, BA
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9Pope, Malcolm
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12Falk, Stephen, MD
13Gollins, Simon, DPhil
14Hickish, Tamas, MD
15Bessell, Eric M, PhD
16Propper, David, MD
17Kennedy, M John, MD
18Kaplan, Richard, Prof
19Maughan, Timothy S, Prof
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title
0Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial
1The Lancet Oncology
addtitleLancet Oncol
descriptionSummary Background When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand–foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding Cancer Research UK.
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1Antimetabolites, Antineoplastic
2Antineoplastic Agents - administration & dosage
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20Middle Aged
21Neoplasm Staging
22Oncology
23Organoplatinum Compounds - administration & dosage
24Organoplatinum Compounds - therapeutic use
25Quality of Life
26Time Factors
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titleIntermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial
authorAdams, Richard A, FRCP ; Meade, Angela M, DPhil ; Seymour, Matthew T, Prof ; Wilson, Richard H, MD ; Madi, Ayman, MRCP ; Fisher, David, MSc ; Kenny, Sarah L, MSc ; Kay, Edward, BA ; Hodgkinson, Elizabeth, BPharm ; Pope, Malcolm ; Rogers, Penny, BSc ; Wasan, Harpreet, FRCP ; Falk, Stephen, MD ; Gollins, Simon, DPhil ; Hickish, Tamas, MD ; Bessell, Eric M, PhD ; Propper, David, MD ; Kennedy, M John, MD ; Kaplan, Richard, Prof ; Maughan, Timothy S, Prof
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eissn1474-5488
codenLANCAO
abstractSummary Background When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4–26·1) in arm A and 14·4 months (8·0–24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008–1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0–28·1) in arm A and 18·0 months (12·1–29·3) in arm C (HR 1·087, 0·986–1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80–1·15, p=0·66), versus 1·54 (1·17–2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand–foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding Cancer Research UK.
copEngland
pubElsevier Ltd
pmid21641867
doi10.1016/S1470-2045(11)70102-4
oafree_for_read