Predictors of reduced relative dose intensity and its relationship to mortality in women receiving multi-agent chemotherapy for epithelial ovarian cancer

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Abstract

Objective

There is limited information concerning the role of relative dose intensity (RDI) on clinical outcomes in solid tumors. The objectives of our study were to evaluate the prognostic significance of RDI and predictors of reduced RDI in women with newly diagnosed advanced stage epithelial ovarian carcinoma (EOC) treated with platinum-based chemotherapy.

Methods

A multi-center retrospective study of women with FIGO stage III–IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy between 1995 and 2009 was conducted. Data were obtained to include the first four chemotherapy cycles administered. Outcomes included: (1) planned and delivered relative dose intensity (RDI), (2) progression-free (PFS) and overall (OS) survival. Survival estimates were based on Kaplan and Meier method, and multivariate analyses were based on logistic regression and Cox proportional hazards regression.

Results

Evaluable subjects included 325 women. With median follow-up of 34 months (range, 0.4–170), progression or recurrence was recorded in 241 (73.9%) and death in 179 (54.9%). In multivariate analysis, predictors of reduced planned RDI were: treatment off research protocols (odds ratio [OR] = 4.3; P < 0.001) and BSA > 2 m2 (OR = 6.14; P < 0.001); predictors of reduced delivered RDI were: BMI over 30 kg/m2 (OR = 2.35; P = 0.008) and use of carboplatin (OR = 2.71; P = 0.008). In multivariate analysis, the following factors were independently associated with OS: delivered RDI < 85% (hazard ratio [HR] = 1.71; P = 0.003) and elevated CA-125 at cycle 1 (HR = 2.29; P = 0.017).

Conclusion

In this retrospective analysis, reduced chemotherapy RDI for ovarian cancer was associated with lower OS, but not PFS, despite adjustment for established prognostic factors.

Highlights

► Relative dose intensity (RDI) is calculated as delivered dose intensity divided by a literature-derived standard dose intensity. ► In this retrospective analysis, RDI less than 85% of standard was associated with lower overall survival. ► Calculation and reporting of RDI in future prospective trials would be informative to further investigate these findings.

Introduction

Relative dose intensity (RDI), defined as the amount of a chemotherapeutic agent delivered compared to a standard dosing schedule over a specific time frame, has been implicated as a prognostic factor in several cancers. The relationship of response rates to RDI was introduced by Hryniuk and Bush, who observed a steep linear relationship between higher actual delivered chemotherapy RDI and improved response rates in metastatic breast cancer trials [1]. Strong evidence also exists in the lymphoma literature showing that RDI reductions are associated with lower survival [2]. In ovarian cancer, multiple trials have failed to demonstrate a survival advantage to escalating the dose intensity of primary chemotherapy [3], [4], [5], [6], [7], [8], [9], [10], [11]. However, only one prior study has specifically addressed the concept of RDI in ovarian cancer; Repetto et al. reported that RDI reductions had no impact on response rates or survival in patients with primary ovarian cancer after surgical management [12].

The aim of the current study was to evaluate factors predictive of (1) reduced RDI and (2) progression free survival (PFS) and overall survival (OS) in women with advanced stage epithelial ovarian carcinoma receiving their initial course of intravenous multi-agent chemotherapy following surgery.

Section snippets

Methods

This is a retrospective multi-center study of women who underwent primary surgical cytoreduction of International Federation of Gynecology and Obstetrics (FIGO) stage III–IV epithelial ovarian cancer at the University of North Carolina Hospitals (UNC) or Duke University Medical Center (DUMC) during the calendar years 1995 through 2009. Eligible patients were identified via ovarian tumor registries at both institutions. Institutional Review Board approval was obtained at each institution.

Results

Three hundred twenty five subjects met inclusion criteria, of whom 124 received primary treatment at UNC and 201 at DUMC. Table 2 shows the demographics. The median age at diagnosis was 60 years (range 24–84 years). One hundred eight patients (33.2%) had no comorbidities recorded, 187 (57.5%) had 1 or 2 comorbidities, and 30 (9.2%) had 3 or more comorbidities. More than two thirds of subjects (69.5%) had a BMI of less than 30 kg/m2 while 20.6% were obese or morbidly obese. Ninety percent (n = 291)

Discussion

While multiple previous studies have failed to identify an advantage to escalating the dose intensity of chemotherapy for ovarian cancer [3], [4], [5], [6], [7], [8], [9], [10], [11], the role of maintaining relative dose intensity in comparison to defined standard dosing regimens is not yet well defined. In this retrospective analysis of 325 women with advanced stage ovarian cancer, we found that maintenance of relative dose intensity of chemotherapy was associated with improved overall (OS),

Conflict of interest statement

Rabbie K. Hanna, Robin A. Laskey, Micael A. Lopez, Aaron Shafer, Laura J. Havrilesky, Robin A. Laskey, Linda Van Le, Marek S. Poniewierski, and Paola A. Gehrig, declare no conflict of interest. Gary H. Lyman, Angeles Alvarez Secord, and David C. Dale have received research funding from Amgen not related to the current study.

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