Impact of chemotherapy-induced neutropenia on survival in patients with breast, ovarian and cervical cancer: a systematic review

Abstract

Background: Recent advances in chemotherapy administration, including targeted therapies and dose-dense scheduling have led to an increased incidence of neutropenia. Chemotherapy-induced neutropenia has been shown to be associated with improved treatment outcomes in various solid tumor types. We looked to summarize the relationship between chemotherapy-induced neutropenia and survival in patients with breast, ovarian and cervical cancer and describe future directions of research. Methodology/Principle findings:A comprehensive PUBMED literature search was conducted using the key words "solid tumor", "breast cancer", "ovarian cancer", "cervical cancer", "endometrial cancer", in combination with "chemotherapy", "neutropenia", "survival", "disease recurrence" and "prognosis". The search was also guided through a review of the reference lists of original and review articles. Published papers included in the review met the following criteria: patients with breast, ovarian, endometrial or cervical cancer treated with chemotherapy; prospective and retrospective studies, both randomized and cohort designs, evaluating impact of neutropenia or leukopenia on disease outcome. Eleven studies met the inclusion criteria. Sample size ranged from 103-750 subjects. The majority of included studies were conducted in breast cancer patients (7 of 11). No studies related to endometrial cancer were identified. Outcome measures included overall survival, progression free survival and distant disease free survival. All studies were retrospective in nature. Of the 11 identified studies, 9 suggested that the occurrence of chemotherapy-induced neutropenia was associated with improvement in oncologic outcome.Conclusions/Significance: Evaluation of the impact of chemotherapy-induced neutropenia on outcomes in patients with breast, ovarian and cervical cancer is warranted utilizing prospectively collected data from patients enrolled in clinical trials.

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

“…Chia et al [ 35 ] comment that toxicity and clinical outcome may be more likely to correlate when the therapeutic agent targets the biological driver of the disease directly, for example, sunitinib-associated hypertension [ 36 ]. Although the mechanism behind the association between chemotherapy-induced neutropenia and clinical outcome is unclear, this study, in conjunction with previously published data [ 2 - 4 ], provides strong evidence that this association is real and clinically relevant.…”

“…Many studies in different tumour types have investigated the association between survival and measures of myelosuppression. Eskander et al [ 2 ] reviewed seven breast cancer studies with inter-study heterogeneity in trial design and varying toxicities, including leukocyte nadir, myelosuppression and neutropenia. The largest study [ 3 ] (n = 750), showed that patients with grade 2 or 3 neutropenia, on the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) scale, had a 10 % absolute survival advantage at 5 years compared to those with no neutropenia (multivariable P = 0.037).…”

Doxorubicin uptake in ascitic lymphoma model: resistance or curability is governed by tumor cell density and prolonged drug retention

“…It is clear that local intratumoral and systemic Dox effects are not always related. Clinical observations that hematologic toxicity is the best surrogate parameter for an adequate and curative dose [45,46] could not be confirmed in our findings. In our model tissue efflux of a temporarily retained Dox was consistently resulting in subsequent tumor relapse.…”

“…The parallels of cytotoxicity and myelosuppression indicate that the availability of Dox in a tumor microenvironment might be monitored by WBC and neutrophil counts [45,46]. However, its wide clinical implementation needs some further improvements.…”

Chemotherapy-induced neutropenia as a biomarker of survival in advanced ovarian carcinoma: An exploratory study of the Gynecologic Oncology Group

“…Because body surface area (BSA) dosing does not account for the complex processes of cytotoxic drug elimination, an unpredictable variation in effect may occur leading to easily recognized over-dosing as well as under-dosing, the latter resulting in significantly reduced anti-cancer effect. For this reason, some investigators advocate a "toxicity adjusted dose" in which drug-specific toxicity may be used as a biomarker for accurate dosing [4]. Because GOG-182 contains the largest number of primary advanced ovarian/peritoneal carcinoma that have been prospectively treated with the current standard chemotherapy regimen of carboplatin plus paclitaxel, we chose to use this study to test the hypothesis that chemotherapy-induced neutropenia may serve as a clinical biomarker for survival in this population.…”