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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.

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.

SUBMITTER: Abraham JE

PROVIDER: S-EPMC4693418 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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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 Jean E JE Hiller Louise L Dorling Leila L Vallier Anne-Laure AL Dunn Janet J Bowden Sarah S Ingle Susan S Jones Linda L Hardy Richard R Twelves Christopher C Poole Christopher J CJ Pharoah Paul D P PD Caldas Carlos C Earl Helena M HM

BMC medicine 20151229

<h4>Background</h4>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.<h4>Methods</h4>Chemotherapy-related toxicities were collected prospectively for 6,248 women with early-stag ...[more]

PMID: 26715442

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Project description:ImportanceDespite existing evidence of a benefit associated with cisplatin-based adjuvant chemotherapy (AC) after radical cystectomy (RC) for chemotherapy-naive patients with pT3/T4 and/or pN+ urothelial carcinoma of the bladder (UCB), to our knowledge, no studies have addressed the effectiveness of AC in those who received neoadjuvant chemotherapy (NAC) before surgery.ObjectiveTo assess the comparative effectiveness of AC vs observation for patients with pT3/T4 and/or pN+ UCB previously treated with NAC and RC.Design, setting, and participantsThis observational cohort study used the National Cancer Data Base (January 1, 2006, through December 31, 2012) to identify individuals who received NAC and RC followed by AC or observation for pT3/T4 and/or pN+ UCB.Main outcomes and measuresAfter multiple imputation was used to handle missing data, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier and Cox proportional hazards regression analyses were performed with a 6-month conditional landmark to compare overall survival (OS) among patients who received NAC and RC followed by AC vs observation. In addition, exploratory analyses were conducted to examine the heterogeneity of the treatment effect according to age (continuous), sex (female vs male), Charlson comorbidity index (?1 vs 0), pT/N stage (pT3/T4N0 vs pTanyN+), and surgical margin status (positive vs negative) by testing interaction terms within the IPTW-adjusted Cox proportional hazards regression model.ResultsOf the 788 patients with pT3/T4 and/or pN+ UCB (mean [SD] age, 65.3 [9.4] years; 603 [76.5%] male and 185 [23.5%] female), 184 (23.4%) received NAC and RC followed by AC and 604 (76.6%) received NAC and RC followed by observation. The 6-month conditional landmark, IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for NAC and RC followed by AC (29.9 months; interquartile range, 15.1-85.4 months) vs NAC and RC followed by observation (24.2 months; interquartile range, 12.9-58.9 months) (P?=?.046). The 5-year IPTW-adjusted rates of OS were 36.8% for NAC and RC followed by AC vs 24.7% for NAC and RC followed by observation. In the IPTW-adjusted Cox proportional hazards regression analysis, NAC and RC followed by AC was associated with a significant OS benefit (hazard ratio, 0.78; 95% CI, 0.61-0.99; P?=?.046). Interaction term analyses indicated that the OS benefit of NAC and RC followed by AC decreased significantly with age (hazard ratio, 0.97; 95% CI, 0.95-0.99; P?=?.02), whereas no significant interaction was observed with sex (P?=?.82), Charlson comorbidity index (P?=?.51), pT/N stage (P?=?.95), and surgical margin status (P?=?.29).Conclusions and relevanceThis study found that AC after NAC and RC may be associated with an OS benefit for patients with pT3/T4 and/or pN+ UCB. The present findings should be considered as preliminary evidence to conduct a randomized clinical trial to address this association.

Dataset Information

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.

Publications

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.

Similar Datasets

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