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BMC Med. 2015 Dec 29;13:306. doi: 10.1186/s12916-015-0547-5.

A nested cohort study of 6,248 early breast cancer patients treated in neoadjuvant and adjuvant chemotherapy trials investigating the prognostic value of chemotherapy-related toxicities.

Abraham JE1,2,3,4, Hiller L5, Dorling L6, Vallier AL7,8, Dunn J9, Bowden S10, Ingle S11,12,13, Jones L14,15,16, Hardy R17,18,19, Twelves C20, Poole CJ21, Pharoah PD22, Caldas C23,24,25,26, Earl HM27,28,29.

Author information

1
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. ja344@medschl.cam.ac.uk.
2
NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. ja344@medschl.cam.ac.uk.
3
Strangeways Research Laboratory, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK. ja344@medschl.cam.ac.uk.
4
Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. ja344@medschl.cam.ac.uk.
5
Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. l.hiller@warwick.ac.uk.
6
Strangeways Research Laboratory, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK. ld429@medschl.cam.ac.uk.
7
Department of Oncology, Cambridge Cancer Trials Centre, Box 279 (S4), Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. anne-laure.vallier@addenbrookes.nhs.uk.
8
Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. anne-laure.vallier@addenbrookes.nhs.uk.
9
Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. j.a.dunn@warwick.ac.uk.
10
Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. s.j.bowden@bham.ac.uk.
11
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. susan.ingle@addenbrookes.nhs.uk.
12
NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. susan.ingle@addenbrookes.nhs.uk.
13
Department of Oncology, Cambridge Cancer Trials Centre, Box 279 (S4), Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. susan.ingle@addenbrookes.nhs.uk.
14
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. linda.jones@addenbrookes.nhs.uk.
15
NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. linda.jones@addenbrookes.nhs.uk.
16
Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. linda.jones@addenbrookes.nhs.uk.
17
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. richard.hardy@addenbrookes.nhs.uk.
18
NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. richard.hardy@addenbrookes.nhs.uk.
19
Department of Oncology, Cambridge Cancer Trials Centre, Box 279 (S4), Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. richard.hardy@addenbrookes.nhs.uk.
20
Level 4, Leeds Institute of Cancer and Pathology and Leeds Experimental Cancer Medical Centre, St James Institute of Oncology, Beckett Street, Leeds, LS9 7TF, UK. c.j.twelves@leeds.ac.uk.
21
Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. christopher.poole@warwick.ac.uk.
22
Strangeways Research Laboratory, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK. pp10001@medschl.cam.ac.uk.
23
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. carlos.caldas@cruk.cam.ac.uk.
24
NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. carlos.caldas@cruk.cam.ac.uk.
25
Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. carlos.caldas@cruk.cam.ac.uk.
26
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK. carlos.caldas@cruk.cam.ac.uk.
27
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Hills Road, Box 193, Cambridge, CB2 0QQ, UK. hme22@cam.ac.uk.
28
NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge, CB2 0QQ, UK. hme22@cam.ac.uk.
29
Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. hme22@cam.ac.uk.

Abstract

BACKGROUND:

The relationship between chemotherapy-related toxicities and prognosis is unclear. Previous studies have examined the association of myelosuppression parameters or neuropathy with survival and reported conflicting results. This study aims to investigate 13 common chemotherapy toxicities and their association with relapse-free survival and breast cancer-specific survival.

METHODS:

Chemotherapy-related toxicities were collected prospectively for 6,248 women with early-stage breast cancer from four randomised controlled trials (NEAT; BR9601; tAnGo; Neo-tAnGo). Cox proportional-hazards modelling was used to analyse the association between chemotherapy-related toxicities and both breast cancer-specific survival and relapse-free survival. Models included important prognostic factors and stratified by variables violating the proportional hazards assumption.

RESULTS:

Multivariable analysis identified severe neutropenia (grades ≥3) as an independent predictor of relapse-free survival (hazard ratio (HR) = 0.86; 95% confidence interval (CI), 0.76-0.97; P = 0.02). A similar trend was seen for breast cancer-specific survival (HR = 0.87; 95% CI, 0.75-1.01; P = 0.06). Normal/low BMI patients experienced more severe neutropenia (P = 0.008) than patients with higher BMI. Patients with fatigue (grades ≥3) showed a trend towards reduced survival (breast cancer-specific survival: HR = 1.17; 95% CI, 0.99-1.37; P = 0.06). In the NEAT/BR9601 sub-group analysis by treatment component, this effect was statistically significant (HR = 1.61; 95% CI, 1.13-2.30; P = 0.009).

CONCLUSIONS:

This large study shows a significant association between chemotherapy-induced neutropenia and increased survival. It also identifies a strong relationship between low/normal BMI and increased incidence of severe neutropenia. It provides evidence to support the development of neutropenia-adapted clinical trials to investigate optimal dose calculation and its impact on clinical outcome. This is important in populations where obesity may lead to sub-optimal chemotherapy doses.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00070278.

PMID:
26715442
PMCID:
PMC4693418
DOI:
10.1186/s12916-015-0547-5
[Indexed for MEDLINE]
Free PMC Article

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