Abstract

Introduction Paclitaxel can cause peripheral neuropathy in up to 60% of patients. Chemotherapy-induced peripheral neuropathy (CIPN) compromises quality of life and often leads to dose reduction or discontinuation of lifesaving chemotherapy. Preclinical models have suggested the possible neuroprotective effect of progesterone through remyelination and other mechanisms.

Objectives  The aim of this study was to evaluate the incidence of CIPN for different menopausal status.

Materials and Methods  We evaluated the effect of menopausal status, as a surrogate for circulating progesterone levels, on the risk of developing paclitaxel-induced peripheral neuropathy, in an audit of breast cancer patients. Data on CIPN (by clinical history and examination) and other variables were collected from the case charts of patients who had received paclitaxel-based chemotherapy for breast cancer at our institution.

Results  Five hundred and fifty women were treated with either neoadjuvant or adjuvant paclitaxel in this period. Of these, 262 (47.6%) women were premenopausal, 49 (8.9%) were perimenopausal, and 239 (43.5%) were postmenopausal at the time of diagnosis. Forty-five (8.1%) women had pre-existing diabetes mellitus. Two hundred and fifty-six (82.31%) developed chemotherapy-induced amenorrhea (CIA).

CIPN was seen in 32.7% of women who continued to be premenopausal after receiving chemotherapy and 62.3% of postmenopausal women. Thirty-five (77.8%) out of forty-five diabetic women developed CIPN. On a multivariate logistic regression model, pre-existing diabetes mellitus (risk ratio [RR] = 2.64, 95%-confidence interval [CI]: 1.26–5.52, p = 0.009), postmenopausal (RR = 2.84, 95%-CI = 1.48–5.45, p = 0.002), and CIA status (RR = 2.17, 95%-CI = 1.14–4.12, p = 0.018) were significantly associated with the development of CIPN. Number of cycles did not appear to have an impact (p= 0.819).

Conclusions  Postmenopausal status was independently associated with higher incidence of CIPN. One of the possible mechanisms could be lower circulating progesterone levels in these patients. A randomized controlled trial (CTRI/2015/11/006381) is ongoing to test this hypothesis.

Introduction

Breast cancer is the most common cancer among women worldwide, and also the leading cause of cancer death in over 100 countries.[1] [2] Management of breast cancer involves multimodality treatment and taxanes have moved into first-line therapy with disease free and overall survival benefits.[3]

The antineoplastic activity of paclitaxel is accompanied by potentially debilitating side effects such as a peripheral neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of several first-line chemotherapeutic agents[4]. CIPN is a schedule and dose-dependent cumulative toxicity with dose being the most important risk factor for developing CIPN.[4] [5] [6] Other causal factors are prior/concomitant administration of platinum compounds or vinca alkaloids, age, pre-existing neuropathy of other causes, while common among them is diabetes.[7] [8] [9] [10] The most widely accepted mechanism of paclitaxel-induced neuropathy is a “dying back” process starting from the distal nerve endings and eventually resulting in a disturbed cytoplasmic flow in the affected neurons.[4] [11] [12] Injury of neuronal and nonneuronal cells within the peripheral nervous system, macrophage activation in both the dorsal root ganglion and peripheral nerve, and microglial activation within the spinal cord are other plausible mechanisms behind taxane-induced neuropathy.[13] Various pharmacological and nonpharmacological agents have been tested for the management of CIPN. A systematic review investigating 18 agents, such as amifostine (WR-2721), glutamine, vitamin E, recombinant human leukemia inhibitory factor (AM424), acetyl-l-carnitine, among others, found that there are no agents that have shown consistent, clinically meaningful benefits for CIPN prevention.[14]

Progesterone has been evaluated for a neuroprotective effect in animal models of Alzheimer's disease, stroke, and traumatic brain injury via genomic and nongenomic pathways[15] but never evaluated for its possible role in preventing CIPN. We propound that progesterone with its neurotropic effect would be protective against clinically manifest peripheral neuropathy. In this audit, we evaluated the effect of menopausal status as a surrogate for circulating progesterone levels on the risk of developing taxane-induced peripheral neuropathy and therefore its potential use in its prevention of CIPN.

Materials and Methods

Study Design

At a tertiary cancer center in Mumbai, we conducted a retrospective audit of data collected on 550 women on follow-up treated with taxanes for breast cancer. In 2013, data was recorded of incidence of CIPN among women presenting to the follow-up clinic and had received taxane-based chemotherapy for nonmetastatic breast cancer. We performed a retrospective audit of that cross-sectional cohort.

Study Population

The inclusion criteria were all women who presented in that month to the follow-up clinic, having been treated at our institute for nonmetastatic breast cancer and having received taxane-based chemotherapy. Women were in varying stages of 2 to 4 years of follow-up from adjuvant therapy.

Objectives

The primary aim of the audit was to evaluate if there was any difference in the incidence of CIPN in our patient cohort by menopausal status. The secondary aims were to evaluate any other factors that play a role in the same.

Study Groups

Treatment-related details and clinician reports documenting CIPN were obtained from the hospital case records. Clinical information such as data on CIPN (by clinical history including CIPN while on chemotherapy and sensory neuropathy examination if available), menstrual history, and other variables were also collected from patient's records seen in the follow-up outpatient department. Women were considered pre/perimenopausal if their last menstrual period was within the previous 1 year. We have reviewed the data as premenopausal and postmenopausal at presentation prior to chemotherapy. We have reclassified patients based on surrogate markers for circulating progesterone into three groups:

1. Those patients who continued to have menstrual cycles post-chemotherapy completion as premenopausal (a surrogate for sustained cyclical presence of progesterone).

2. Those patients who achieved chemotherapy-induced amenorrhea (CIA) after a few chemotherapy cycles (surrogate for presence of progesterone levels for few cycles).

3. Those patients who were postmenopausal prior to chemotherapy (no or negligible circulating progesterone).

Neuropathy (sensory) was evaluated on a score of 1 to 4 using the National Cancer Instiutue -Common Toxicity Criteria (NCI-CTC) 2.0 version (4) for adverse events.

Statistical Analysis

Descriptive statistics were used to summarize baseline characteristics and treatment timelines. Univariate and multivariate cox regression analysis was used to evaluate factors affecting CIPN. For descriptive analysis and cox estimates, IBM SPSS Statistics for Windows, Version 21.0, IBM Corp, Armonk, New York, United States, was used.

Ethics Approval

The study (Project no: 900774) was approved by the institutional ethics committee on February 18, 2021 and a waiver of consent was granted as it was a retrospective audit of data collected in the clinic. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with Helsinki Declaration of 1964, as revised in 2013.

Results

We evaluated women who were seen in the breast follow-up clinic. Of the 550, median age was 48 years (range: 22–77 years); 490 women were less than 60 years of age, whereas 60 women were above the age of 60. Two hundred and sixty-two (47.6%) women were premenopausal, 49 (8.9%) were perimenopausal, and 239 (43.5%) were postmenopausal. Two hundred and fifty-six (82.31%) women gave history of having developed CIA. Of the 262 premenopausal women, 52 (19.8%) and 3/49 (6.1%) perimenopausal women did not develop CIA or resumed their menstrual cycle while on treatment ([Table 1]). Forty-five out of 550 (8.1%) women were diabetics on treatment prior to starting treatment for breast cancer. Paclitaxel-based chemotherapy was administered either in the neoadjuvant or the adjuvant setting. Dosing schedules were either weekly, biweekly (dose dense with granulocyte colony stimulating factor [GCSF] support), or triweekly ([Table 2]).

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