Risk factors and pharmacotherapy for chemotherapy-induced peripheral neuropathy in paclitaxel-treated female cancer survivors: A retrospective study in Japan.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse reaction in cancer patients treated with several cytotoxic anticancer agents including paclitaxel. Duloxetine, an antidepressant known as a serotonin-noradrenalin reuptake inhibitor, is the only agent that has moderate evidence for the use to treat painful CIPN. The present retrospective cohort study aimed to analyze risk factors for paclitaxel-induced peripheral neuropathy (PIPN), and investigate ongoing prescription drug use for PIPN in Japan. Female breast and gynecologic cancer patients who underwent paclitaxel-based chemotherapy at a single center in Japan between January 2016 and December 2019 were enrolled in this study. Patients' information obtained from electronic medical records were statistically analyzed to test possible risk factors on PIPN diagnosis. Patients' age, total paclitaxel dose, the history of female hormone-related diseases, hypertension and body mass index (BMI), but not additional platinum agents, were significantly associated with increased PIPN diagnosis. Drugs prescribed for PIPN included duloxetine, pregabalin, mecobalamin and Goshajinkigan, a polyherbal medicine, regardless of poor evidence for their effectiveness against CIPN, and were greatly different between breast and gynecologic cancer patients diagnosed with PIPN at the departments of Surgery and Gynecology, respectively. Thus, older age, greater total paclitaxel dose, the history of estrogen-related diseases, hypertension and BMI are considered risk factors for PIPN in paclitaxel-based chemotherapy of female cancer patients. It appears an urgent need to establish a guideline of evidence-based pharmacotherapy for PIPN.

Introduction

Cancer chemotherapy with anti-cancer drugs, such as taxanes, platinum-containing agents, vinca alkaloids and proteasome-inhibiting agents including bortezomib, often causes chemotherapy-induced peripheral neuropathy (CIPN), a potentially dose-limiting adverse reaction, which impairs patients’ quality of life [1-4]. The pathogenesis of CIPN still remains largely unclear, although preclinical studies have suggested possible involvement of oxidative stress, various humoral factors, and altered function or expression of ion channels and receptors in the development or maintenance of CIPN [5]. The detailed molecular mechanisms underlying CIPN appear to vary with types of chemotherapeutic agents, e.g. resident and infiltrating macrophages play a critical role in the CIPN following administration of paclitaxel, a microtubule-stabilizing agent, but not oxaliplatin, a platinum agent [6-9]. Clinically, paclitaxel is widely used to treat breast and gynecologic (ovarian, fallopian tube, endometrial) cancers in females, leading to CIPN with high frequency [4, 10]. Among platinum agents capable of causing CIPN [4, 11], carboplatin is often included in the paclitaxel-based, front-line regimens, whereas the incidence of CIPN following paclitaxel and carboplatin combination treatment is similar to or less than that following paclitaxel alone [12-15]. Our clinical and preclinical studies have shown that 57 years of age or older and endocrine therapy were significantly associated with severer PIPN at a private hospital in Izumi city, Japan, and that ovariectomy aggravated PIPN in laboratory animals, an effect reversed by estrogen supplementation [16].

According to the updated American Society of Clinical Oncology (ASCO) guidelines, no agents are available for prevention of CIPN, and duloxetine is the only agent that has appropriate evidence to support its use for treatment of established painful CIPN [17], although its effectiveness on taxane-induced painful CIPN is controversial [18]. The moderate usefulness of duloxetine for treatment of CIPN in cancer patients treated with various cytotoxic chemotherapeutics including paclitaxel has also been supported by clinical trials in Japan [19, 20]. Nonetheless, apart from opioids and non-steroidal anti-inflammatory drugs (NSAIDs) that are often used to treat cancer pain, vitamin B12, pregabalin and Goshajinkigan, a Chinese polyherbal medicine, in addition to duloxetine, are commonly prescribed for treatment of CIPN in Japan [21], although there is poor evidence for their effectiveness against CIPN [17, 22–24].

In the present study, we retrospectively analyzed the association of various factors including older age, cumulative dose of paclitaxel and addition of platinum agents with PIPN diagnosis in female breast or gynecologic cancer survivors who underwent paclitaxel-based chemotherapy at Kindai University Hospital in Osakasayama city, Japan, and examined current trends in prescription drug use to treat PIPN.

Methods

Study design, setting and patient data collection

This was a single-center, retrospective cohort study using data obtained from electronic medical records of female patients who were diagnosed with breast cancer or gynecologic (ovarian, fallopian tube or endometrial) cancer and underwent paclitaxel-based chemotherapy at Kindai University Hospital in Osakasayama City, Japan, between 1st January, 2016, and 31st December, 2019. The collected patient information included age, body surface area (BSA), body mass index (BMI), metastasis at initial diagnosis, treatment history, ongoing diseases, such as diabetes, hyperlipidemia and hypertension, medical history of non-cancer, female hormone-related diseases (defined as diseases the pathogenesis of which involves altered levels of estrogens) including ovarian cyst, uterine fibroid and endometriosis, typical diseases associated with estrogens [25-27]. Information concerning the diagnosis of PIPN was also collected retrospectively from the medical record. At the departments of Surgery (breast cancer) and Gynecology (gynecologic cancers), Kindai University Hospital, PIPN was routinely diagnosed by physicians or by nurses or pharmacists under a physician’s direction according to CTCAE version 5.0. In treatment history, we also checked prescription of duloxetine, pregabalin, mecobalamine (vitamin B12) and Goshajinkigan, a polyherbal medicine, which are often used for treatment of painful peripheral neuropathy including CIPN in Japan, after the onset of paclitaxel treatment.

Ethics approval

This study was approved by Ethics Committees of Kindai University, Faculty of Medicine (approval number 31–222, January 21, 2020) and Faculty of Pharmacy (approval number 20–156, April 22, 2020), which waved the requirement of informed consent, owing to the retrospective nature of this study and approved the use of an opt-out strategy concerning patient consent. Namely, patients were included in the research unless they requested to be excluded, and our clinical study information was communicated to the patients through the institutional website. All data/samples were fully anonymized before the authors accessed them, and any members of our research team named in the author list did not have direct access to patient identification when analyzing the data from patients’ information.

Inclusion and exclusion criteria

Inclusion criteria were two or more administrations of paclitaxel, no history of paclitaxel treatment prior to the observation period, no participation in a clinical trial, no prior use of oxaliplatin (by far the highly neurotoxic platinum agent and not used for treatment of breast or gynecologic cancers) or vinca alkaloids, no use of nanoparticle albumin-bound (nab)-paclitaxel, no preexisting neuropathy-like symptoms including numbness, no prescription of duloxetine, pregabalin, mecobalamine or Goshajinkigan before the onset of paclitaxel treatment. Of 431 female patients with beast or gynecological cancer who underwent paclitaxel-based chemotherapy, 148 who did not meet the inclusion criteria were excluded and the residual 283 were enrolled in this study.

Statistical analysis

The total dose of paclitaxel and age are shown using box-and-whisker plots, and their differences between breast cancer patients and gynecologic cancer patients were statistically analyzed by Mann-Whitney’s U test. The association of various factors with PIPN diagnosis was analyzing by Fisher’s exact test in a dichotomous manner. Continuous variables were divided into two categories using median splits. Age and total dose of paclitaxel were also categorized into two groups using optimal cutoff values determined from the receiver operating characteristic (ROC) curves. Multivariate logistic regression analysis was conducted to test the association of age, total dose of paclitaxel and addition of platinum agents with PIPN diagnosis, showing odds ratios with 95% confidence intervals (CIs). Kaplan-Meier curves were generated to visualize the time-related increase in PIPN diagnosis in two separate groups, and their differences between the two were analyzed by the log-rank test. Hazard ratios with 95% CIs were also calculated using a Cox proportional hazard regression model. A p value less than 0.05 was considered statistically significant. We used EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (version 3.6.3, R Foundation for Statistical Computing, Vienna, Austria), which was a modified version of R commander (version 2.6–2), as described elsewhere [28].

Results

Characteristics of patients enrolled in the present study

In this study, 283 patients including 162 breast and 121 gynecologic cancer survivors who met inclusion criteria (S1 Fig) were enrolled for statistical analysis (Table 1). Of the paclitaxel-treated breast cancer survivors, 138 and 24 received weekly paclitaxel and dose-dense paclitaxel, respectively, while 115 of the paclitaxel-treated gynecologic cancer patients received tri-weekly paclitaxel (S1 Table). It is to be noted that nobody of the 162 paclitaxel-treated breast cancer patients received additional administration of platinum agents, while all of 121 paclitaxel-treated gynecologic cancer patients received platinum agents including carboplatin (n = 120) and cisplatin (n = 1) (Table 1; S1 Table). The total dose of paclitaxel was significantly greater in gynecologic cancer patients than in breast cancer patients (S2 Fig). There was no significant difference of age between breast and gynecologic cancer patients (S2 Fig).

Table 1

Clinical characteristics of female cancer patients enrolled in this study.

	n	n/nTotal (%)
Cancer type
Breast cancer	162	57.2
Gynecologic cancer	121	42.8
Addition of platinum agents
No	162	57.2
Yes	121	42.8
Diagnosis of PIPN
No	45	15.9
Yes	238	84.1

The total number of the enrolled patients was 283.

Association of various factors with diagnosis of PIPN in female cancer survivors who underwent paclitaxel-based chemotherapy

Fisher’s exact test indicated significant association of Age ≥ 58 and total paclitaxel dose ≥ 944.9 (medians), but not cancer types or additional administration of platinum agents, with PIPN diagnosis in female cancer survivors, which was supported by multivariate logistic regression analysis [Odds ratios for age and total paclitaxel dose over the medians, 2.03 (95% CI, 1.03–4.00; p = 0.040) and 2.83 (95% CI, 1.35–5.91; p = 0.00575), respectively] (Table 2). The optimal cutoff values of age and total dose of paclitaxel in analysis of their association with PIPN diagnosis were 55 years of age and 924.8 mg/m2, respectively, as estimated by ROC analysis (Table 2). Interestingly, medical history of female hormone-related diseases, hypertension and BMI ≥ 21.8 (median), but not surgery, metastasis, diabetes hyperlipidemia or BSA ≥ 1.526 m2 (median) were significantly associated with PIPN diagnosis, as evaluated by Fisher’s exact test (Table 2).

Table 2

Association of various factors with diagnosis of PIPN in female cancer patients.

	Diagnosis of PIPN
	%		Multivariate
Factor	(Yes/Yes+No)	p	Odds ratio (95% CI)	p
Cancer type
Breast cancer	84.6 (137/162)
Gynecologic cancer	83.5 (101/121)	0.870
Age (Median: 58)
< 58	79.6 (109/137)		Reference
≥ 58	88.4 (129/146)	0.0511	2.03 (1.03–4.00)	0.040
Age (Optimal cutoff value: 55)
< 55	77.8 (91/117)
≥ 55	88.6 (147/166)	0.0202
Total dose of PCT (Median: 944.9)
< 944.9 mg/m2	78.0 (110/141)		Reference
≥ 944.9 mg/m2	90.1 (128/142)	0.00575	2.83 (1.35–5.91)	0.00575
Total dose of PCT (Optimal cutoff value: 924.8)
< 924.8 mg/m2	74.6 (85/114)
≥ 924.8 mg/m2	90.5 (153/169)	0.000439
Addition of platinum agents
No	84.6 (137/162)		Reference
Yes	83.5 (101/121)	0.870	0.669 (0.331–1.35)	0.261
Surgery
No	86.7 (13/15)
Yes	84.0 (225/268)	1.00
Metastasis
No	86.7 (117/135)
Yes	81.8 (121/148)	0.329
Medical history of female hormone-related diseases
No	82.0 (205/250)
Yes	100 (33/33)	0.00403
Diabetes
No	83.3 (224/269)
Yes	100 (14/14)	0.137
Hyperlipidemia
No	84.0 (226/269)
Yes	85.7 (12/14)	1.00
Hypertension
No	81.8 (189/231)
Yes	94.2 (49/52)	0.0338
BSA (Median: 1.526)
< 1.526	82.3 (116/141)
≥ 1.526	85.9 (122/142)	0.421
BMI (Median: 21.8)
< 21.8	78.2 (111/142)
≥ 21.8	90.1 (127/141)	0.00878

The association between various factors and PIPN diagnosis was analyzed in a dichotomous manner, where continuous variables were divided into two categories using medians. The optimal cutoff values for patients’ age and total dose of paclitaxel (PCT) were also determined from the receiver operating characteristic (ROC) curves, and used for categorization. BSA, body surface area; BMI, body mass index. Effect of each factor on PIPN diagnosis was analyzed by Fisher’s exact test. Further, effects of age, total dose of PCT and addition of platinum agents on PIPN diagnosis were evaluated by multivariate logistic regression analysis. CI, confidence interval.

Kaplan-Meier curves show time-related increase in PIPN diagnosis (Fig 1). The log-rank test indicated significant impact of age ≥ 58 (median) and ≥ 55 (optimal cut-off value) years on PIPN diagnosis (p = 0.0103 and 0.0153, respectively), and the Cox proportional hazard model provided hazard ratios, 1.398 (95%CI, 1.082–1.805) and 1.383 (95%CI, 1.064–1.799), respectively (Fig 2A). On the other hand, total paclitaxel dose, regardless using medians or optimal cut-off values for categorization, or additional platinum agents had no significant impact on PIPN diagnosis (Fig 2B and 2C).

Fig 1

Kaplan-Meier curves for the time-related increase in PIPN diagnosis in female cancer patients treated with paclitaxel (PCT), and their association with older age (a), greater total paclitaxel dose (b) and additional administration of platinum agents (c). Medians were 58 years of age (a, left) and 944.9 mg/m2 of total paclitaxel dose (b, left), and optimal cutoff values estimated by ROC analysis were 55 (a, right) and 924.8 (b, right), respectively. Statistical significance between two groups was analyzed by a log-rank test. Hazard ratios (HRs) with 95% CIs were calculated using a Cox proportional hazard regression model.

Fig 2

Prescription drug use for PIPN in female cancer patients who were diagnosed with PIPN at the departments of Surgery and Gynecology.

Of 283 enrolled female cancer patients, 238 including 137 breast and 101 gynecologic cancer patients were diagnosed with PIPN at the departments of Surgery and Gynecology, respectively. Data show the prescription rate of each drug among patients diagnosed with PIPN.

Pharmacotherapy to treat PIPN in female cancer survivors who underwent paclitaxel-based chemotherapy

Of 283 enrolled patients, 124 (43.8%) received prescription of one or more of duloxetine, pregabalin, mecobalamin and Goshajinkigan (Table 3), well-known medicines used for treatment of peripheral neuropathy in Japan [21]. It is noteworthy that 4 patients received duloxetine, pregabalin or mecobalamin without PIPN diagnosis (Table 3). Of 238 cancer patients with PIPN diagnosis (see Table 1), 20–30% received pregabalin, mecobalamin or Goshajinkigan, while only 14% received duloxetine (Fig 2). Interestingly, the prescription rates of duloxetine, mecobalamin and Goshajinkigan were greater in gynecologic cancer patients diagnosed with PIPN at Gynecology department than in breast cancer patients diagnosed with PIPN at Surgery department, while the prescription rate of pregabalin was rather greater in the latter patients than in the former (Fig 2).

Table 3

Pharmacotherapy to treat PIPN in female cancer patients.

		PIPN
Medication	n	Yes	No
Duloxetine	34	33	1
Pregabalin	66	65	1
Mecobalamin	64	62	2
Gosyajinkigan	55	55	0

Of 283 enrolled female cancer patients, 124 received prescription of one or more of duloxetine, pregabalin, mecobalamin and Goshajinkigan for treatment of PIPN.

Discussion

Our retrospective cohort study showed that older age and increased total paclitaxel dose were associated with increases in PIPN diagnosis in female breast and gynecologic cancer patients, in agreement with the previous reports [16, 29–31]. Our study also identified the significant impact of the medical history of female hormone-related diseases, hypertension and BMI on PIPN development. On the other hand, additional administration of platinum agents, such as carboplatin and cisplatin (120 and 1 cases, respectively) was not associated with increased PIPN diagnosis, as reported previously [12-16].

Our recent preclinical study demonstrated that ovariectomy dramatically aggravated the development of PIPN in an estrogen-reversible manner in mice, suggesting that estrogen protects against PIPN development [16] and supporting clinical evidence for the impact of older age on the increased incidence or severity of PIPN in the present and previous studies [16, 29–31]. Thus, the present study ascertains that the estrogen decline, particularly in postmenopausal cancer patients, is a risk factor of PIPN. Taken together, the present results indicating the association of the history of estrogen-related diseases including ovarian cyst, uterine endometriosis and leiomyomas with PIPN development might suggest the critical role of estrogens in the pathophysiology of PIPN. Particularly, it has been reported that endometriosis induces somatic pain or allodynia/hyperalgesia containing inflammatory and neuropathic components, in addition to visceral pain [32, 33]. Further clinical and preclinical studies are necessary to clarify the molecular mechanisms underlying the involvement of the altered estrogen levels in PIPN.

The present study identified significant association of hypertension and increased BMI with PIPN diagnosis (see Table 2). Interestingly, there is clinical evidence for the association between hypertension and CIPN in cisplatin-treated patients [34]. Whether hypertension itself or pharmacotherapy for hypertension is associated with CIPN/PIPN is still open to question.

It is to be noted that all of paclitaxel-treated gynecologic cancer patients received platinum agents, while nobody of paclitaxel-treated breast cancer patients was treated with platinum agents in the present study, thereby providing a potential bias. It is also noteworthy that the total paclitaxel dose was slightly but significantly greater in gynecologic cancer patients than in breast cancer patients (see S2 Fig).

As described in the previous report from survey of the management of CIPN in Japan [21], the present study ascertained that many of female cancer patients with PIPN were prescribed with pregabalin, mecobalamin or Goshajinkigan (see Table 3) in spite of poor evidence for their effectiveness against CIPN [17, 22–24], while relatively few patients with PIPN received duloxetine, the only medicine that has moderate evidence for the use to treat the established CIPN [17] (see Table 3 and Fig 2). Goshajinkigan, a polyherbal medicine that legally requires a prescription to be dispensed in Japan, contains fixed proportions of 10 crude herbal extracts, i.e. achyranthes root, rehmannia root, dioscorea, rhizome, cornus fruit, alisma rhizome, plantago seed moutan bark, pariah sclerotium, aconite root and cinnamon bark [35]. Goshajinkigan is widely used for treatment of diabetic neuropathy, and appears to have limited effectiveness on CIPN [22, 35, 36]. Surprisingly, there were great differences in drugs prescribed to treat PIPN at the departments of Surgery for breast cancer patients and of Gynecology for gynecologic cancer patients. This might simply reflect different preference of physicians belonging to different departments, but is still open to question. Pharmacists may be able to contribute to the improvement of treatment of CIPN/PIPN in female cancer survivors undergoing chemotherapy through identifying high-risk patients and making appropriate evidence-based recommendations.

There are several limitations of this study. This is a single-center retrospective study that had a relatively small sample size. As did all other observational studies, the present study possibly had unmeasured confounding factors, which could lead to biased effect estimates. In addition, as mentioned above, no breast cancer patients had additional platinum agents, while all gynecologic cancer patients received administration of carboplatin or cisplatin. Therefore, we could not exactly discriminate the effects of additional platinum agents and differences of cancer types or medical care departments on PIPN incidence. Despite these limitations, we argue that this study is useful to ascertain risk factors for the development and progression of PIPN and to highlight currently ongoing prescription drug use for PIPN in Japan.

Conclusions

In paclitaxel-treated female breast and gynecologic cancer patients, older age and increased total paclitaxel dose were significantly associated with the incidence of PIPN, and the history of female hormone-related disease, hypertension and BMI also had significant impact on PIPN development. On the other hand, additional administration of platinum agents had no significant impact on PIPN diagnosis. Our study also highlighted the current trends of prescription drugs used for treatment of PIPN, which included duloxetine, pregabalin, mecobalamin and Goshajinkigan, regardless of the limited scientific evidence for their effectiveness against CIPN. Together, older age, greater total paclitaxel dose, medical history of female hormone-related diseases, hypertension and BMI should be considered risk factors for PIPN development in paclitaxel-based chemotherapy of female cancer patients. Thus, there is an urgent need to establish a guideline of evidence-based pharmacotherapy for PIPN available for cancer patients undergoing chemotherapy at different departments.

Diagram of patient selection.

PCT, paclitaxel. *Two patients had both ovarian and fallopian tube cancers.

(PDF)

Click here for additional data file.

Comparison of total dose of paclitaxel (PCT) and age between breast and gynecologic cancer patients.

The top graphs show box-and-whisker plots. Statistical significance was analyzed by Mann-Whitney’s U test.

(PDF)

Click here for additional data file.

(PDF)

Click here for additional data file.

Chemotherapy regimens used in female breast and gynecologic cancer patients treated with paclitaxel at Kindai University Hospital.

PCT, paclitaxel; ddPCT, dose-dense paclitaxel; wPCT, weekly paclitaxel; HP, trastuzumab + pertuzumab; BEV, bevacizumab; HER, trastuzumab; ddTC, dose-dense paclitaxel + carboplatin; TP, paclitaxel + cisplatin; tri-weekly TC, tri-weekly paclitaxel + carboplatin; wTC, weekly paclitaxel + carboplatin.

(PDF)

Click here for additional data file.

21 Oct 2021

PONE-D-21-29568Association between risk factors and pharmacotherapy of chemotherapy-induced peripheral neuropathy in paclitaxel-treated female cancer survivors: A retrospective study in JapanPLOS ONE

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Reviewer #1: Hiramoto et al. conducted a retrospective chart review to identify predictors of paclitaxel-induced peripheral neuropathy. They find some associations that are pretty well established including age and paclitaxel dose. They also find some interesting findings, particularly the hormone-related diseases association that connects to their prior work on estrogen levels. The major concern is that several of the analyses with the downstream endpoints of duloxetine or other neuropathy-agent use should not be conducted because they are highly confounded with the primary analysis of PIPN. Pending resolution of the following suggestions this manuscript could be acceptable for publication.

Major:

-The methods must explain how “diagnosis of PIPN” was defined. Who diagnosed this? Was it based on clinician prospective evaluation or retrospective collection from the medical record? Were PIPN assessments mandated? Was

a patient-reported questionnaire used? Etc.

-The association of clinical factors with prescription of duloxetine or other agents for PIPN diagnosis is not worth analyzing or reporting. The decision to prescribe these agents is substantially confounded by the PIPN diagnosis, which was already directly analyzed for association with these clinical variables. These entire analyses should be removed. Instead, you should just report the descriptive statistics of which drugs were prescribed for PIPN (currently in table 1) and perhaps analyze the association of PIPN diagnosis (however defined) with PIPN treatment. The abstract needs to be rewritten after removing these unnecessary analyses.

-The “time-related increases” section could be merged with the previous sections as this is just an alternative analysis method to answer the same questions. Again, this should not be done for duloxetine and other agents since these are indirect associations mediated by PIPN. Just analyze the association with PIPN and merge into the previous section.

Minor:

-Line 48: duloxetine is only for painful CIPN, not sensory or motor. It was also effective only for platinum-induced, not taxane-induced, painful CIPN in the JAMA trial (Smith et al., https://pubmed.ncbi.nlm.nih.gov/23549581/) (albeit in an unplanned secondary analysis). This should be corrected throughout, including the last sentence of the conclusion (which should not definitively recommend duloxetine for all PIPN) and abstract.

-Line 94: why did you exclude oxaliplatin and then conduct analyses of the other platinums?

-Line 109: The optimal cutoff method is very problematic as it allows for any possible association to be detected. Why was this used instead of median? Or a continuous variable using logistic regression?

-Figure 1: The objective of this study is not to explore differences between breast and gynecologic cancer in terms of age or paclitaxel dose. This is not a sufficiently informative figure to include in the main manuscript. It can be moved to supplement.

-Table 2: Please replace columns 1, 2, and 3 with one column that reports the % (#s) for yes (for example, row 1 would read: breast cancer, 84.6% (136/162)).

-Line 72: Please further define “female hormone-related diseases” since this is an important variable in your analysis. Was there a complete list of diseases that would have qualified? Or that did qualify?

-Line 282: You do not have any data on CIPN severity and cannot conclude that platinums enhance severity and not incidence from your data. Also delete lines 342-344 for the same reason and because this analysis should be removed.

-Lines 284-290: It would be worthwhile to mention that “female hormone-related diseases” were associated with PIPN within this paragraph since it also fits with this hypothesis (currently lines 319-322). I think more should be made of this finding in the context of your work.

-Lines 314-319: It is confusing that the discussion goes through risk factors, then treatment strategies, and then goes back to risk factors. Please move this content up to before the treatment strategies paragraph.

Optional/typographical:

-Table 1: Replace “operation” with “surgery”

Reviewer #2: Overall a well designed, conducted, and interesting article. I offer the following comments before it is accepted for publication:

1. I'm not familiar with the herbal medicine goshajinkigan. The article looks at patients prescribed the medicine, but is it possible for patients to be taking it without a prescription (e.g. over-the-counter, given that is herbal). If so, how do you know other patients were not taking it which would skew the results?

2. Inclusion criteria (line 94) says: no dministration of oxaliplatin or vinca alkaloids. Presumably this means "no prior use of" the drugs as there are patients included it the analysis who were given a platinum. Suggest slight rewording to make it clear.

3. Line 128. The study included only 283 patients, so why does the data in the results (lines 128-129) give numbers for patients also excluded from the study. How is that information relevant? Suggest this is changed so only discusses patients included in the study

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Reviewer #1: Yes: Dan Hertz

Reviewer #2: No

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30 Nov 2021

Responses to Reviewer #1

We thank the reviewer #1 for understanding significance of our study and providing important opinions useful to improve our manuscript.

R1-1) The methods must explain how “diagnosis of PIPN” was defined. Who diagnosed this? Was it based on clinician prospective evaluation or retrospective collection from the medical record? Were PIPN assessments mandated? Was a patient-reported questionnaire used? Etc.

This is a very important opinion that we should consider. Information concerning the diagnosis of PIPN was collected retrospectively from the medical record. At the departments of Surgery (breast cancer patients) and Gynecology (gynecologic cancers patients, Kindai University Hospital, PIPN was routinely diagnosed by physicians or by nurses or pharmacists under a physician’s direction according to CTCAE version 5.0. These comments have been described in the ‘Methods’ section (Lines 75-79).

R1-2) The association of clinical factors with prescription of duloxetine or other agents for PIPN diagnosis is not worth analyzing or reporting. The decision to prescribe these agents is substantially confounded by the PIPN diagnosis, which was already directly analyzed for association with these clinical variables. These entire analyses should be removed. Instead, you should just report the descriptive statistics of which drugs were prescribed for PIPN (currently in table 1) and perhaps analyze the association of PIPN diagnosis (however defined) with PIPN treatment. The abstract needs to be rewritten after removing these unnecessary analyses.

We thank Reviewer #1 for providing kind advices. To address the reviewer’s requests, we have made a lot of revisions in the text, tables and figures, as follows.

R1-2-1: According to the reviewer’s suggestions, original Tables 3 and 4 showing the association of clinical factors with prescription of duloxetine or other agents for PIPN have been withdrawn, and the related sentences in the text including Abstract have been deleted (Lines 11-14, 18-21, 56-60, 115, 120, 122, 141, 165-179, 197-209, 227, 228-230, 232-233, 237, 248, 251, 254, 256, 282, 289-293, 296-299).

R1-2-2: The description concerning ‘Drugs prescribed to treat PIPN’ in original Table 1 has been deleted. Alternatively, descriptive statistics of drugs for PIPN in association with PIPN diagnosis have been shown in new Table 3 and new Fig. 2. The related explanations and modifications have been made in the text including Abstract (Lines 14-18, 20-21, 60, 144-150, 197-221, 259, 262-271, 293-296, 299-301).

R1-2-3: Considering the above revisions in response to the reviewer, the title of our manuscript has been altered to “Risk factors and pharmacotherapy for chemotherapy-induced peripheral neuropathy in paclitaxel-treated female cancer survivors: A retrospective study in Japan” (Page 1).

R1-3) The “time-related increases” section could be merged with the previous sections as this is just an alternative analysis method to answer the same questions. Again, this should not be done for duloxetine and other agents since these are indirect associations mediated by PIPN. Just analyze the association with PIPN and merge into the previous section.

As suggested by Reviewer #1, the “time-related increases” section has been merged with the “Association of various factors with diagnosis of PIPN in female cancer survivors who underwent paclitaxel-based chemotherapy” section. The data of the analysis of the time-related correlations between prescription drug use for PIPN treatment and factors including age, paclitaxel dose or platinum addition have been deleted from original Fig 2 (now, new Fig 1). The related parts of the text have been modified (Lines 179-194).

R1-4) Line 48: duloxetine is only for painful CIPN, not sensory or motor. It was also effective only for platinum-induced, not taxane-induced, painful CIPN in the JAMA trial (Smith et al., https://pubmed.ncbi.nlm.nih.gov/23549581/) (albeit in an unplanned secondary analysis). This should be corrected throughout, including the last sentence of the conclusion (which should not definitively recommend duloxetine for all PIPN) and abstract.

I thank Reviewer #1 for suggesting an important point. The JAMA trial paper by Smith et al. has been cited and mentioned in Introduction (Lines 47-48), and the sentences indicating definitive recommendation of duloxetine for PIPN treatment in the text including Abstract and Conclusions have been modified (Lines 5, 20-21, 47-50,293-296, 299-301).

R1-5) Line 94: why did you exclude oxaliplatin and then conduct analyses of the other platinums?

The original sentence “-----no administration of oxaliplatin-----” was not clear, and altered to “-----no prior use of oxaliplatin” (Lines 101-103). In the present study, a few subjects had the history of the use of oxaliplatin for treatment of cancers other than breast and gynecologic cancers. Among different platinum agents, oxaliplatin most frequently causes severe CIPN. We thus considered that the prior use of oxaliplatin might affect the development of CIPN in breast and gynecologic cancer patients treated with paclitaxel and/or the other platinum agents including carboplatin. We then decided to exclude patients who had the history of oxaliplatin use. Considering the reviewer’s comment, we incorporated additional brief explanation into the text (Lines 101-103).

R1-6) Line 109: The optimal cutoff method is very problematic as it allows for any possible association to be detected. Why was this used instead of median? Or a continuous variable using logistic regression?

I thank Reviewer #1 for giving an opinion. Considering the reviewer’s opinion, we used a median split, in addition to the optimal cut-off values, for categorization in new Table 2 and new Fig 1, though the cut-off values determined by ROC analysis are useful when certain values other than medians have specific meanings (e.g. menopausal age in this study). The related parts of the text have been modified (Lines 116-118, 155-162, 168-177, 179-185, 187-194).

R1-7) Figure 1: The objective of this study is not to explore differences between breast and gynecologic cancer in terms of age or paclitaxel dose. This is not a sufficiently informative figure to include in the main manuscript. It can be moved to supplement.

As suggested by Reviewer #1, original Fig 1 has been altered to a supplementary figure, S2 Fig. The related parts of the text have been modified (Lines 142-144).

R1-8) Table 2: Please replace columns 1, 2, and 3 with one column that reports the % (#s) for yes (for example, row 1 would read: breast cancer, 84.6% (136/162)).

New Table 2 has been modified as suggested by Reviewer #1 (Lines 168-177).

R1-9) Line 72: Please further define “female hormone-related diseases” since this is an important variable in your analysis. Was there a complete list of diseases that would have qualified? Or that did qualify?

In the present study, “female hormone-related diseases” were defined as diseases the pathogenesis of which involves altered levels of estrogens, and included ovarian cyst, uterine endometriosis and leiomyomas, typical diseases associated with estrogens (Int J Mol Sci. 2020, 21 (8), 2815; Biomec Res Int. 2021, 2021, 6660087; Reprod Sci. 2016, 23 (2), 163-175). This has been explained in the text (Lines 73-75).

R1-10) Line 282: You do not have any data on CIPN severity and cannot conclude that platinums enhance severity and not incidence from your data. Also delete lines 342-344 for the same reason and because this analysis should be removed.

Considering Reviewer #1’s opinions, description about CIPN severity has been removed, as explained above.

R1-11) Lines 284-290: It would be worthwhile to mention that “female hormone-related diseases” were associated with PIPN within this paragraph since it also fits with this hypothesis (currently lines 319-322). I think more should be made of this finding in the context of your work.

As suggested by Reviewer #1, comments and discussions concerning the association between the history of female hormone-related diseases and PIPN, citing related papers, have been incorporated into Para 1 in Discussion, (Lines 228-230, 239-246).

R1-12) Lines 314-319: It is confusing that the discussion goes through risk factors, then treatment strategies, and then goes back to risk factors. Please move this content up to before the treatment strategies paragraph.

According to Reviewer #1, description about the association between risk factors and prescription drug use for PIPN has been removed, as explained above. Alternatively, come discussion about the trends and of prescription drug use for treatment of PIPN (Lines 262-271).

R1-13) Table 1: Replace “operation” with “surgery”

As suggested by Reviewer #1, ‘operation’ has been replaced with ‘surgery’ in new Table 2 (Lines 169-170).

Responses to Reviewer #2

We thank Reviewer #2 for considering that our manuscript is interesting, and for providing important suggestions.

R2-1) I'm not familiar with the herbal medicine goshajinkigan. The article looks at patients prescribed the medicine, but is it possible for patients to be taking it without a prescription (e.g. over-the-counter, given that is herbal). If so, how do you know other patients were not taking it which would skew the results?

This is an important comment that we have to address. Goshajinkigan, a polyherbal medicine that legally requires a prescription to be dispensed in Japan, contains fixed proportions of 10 crude herbal extracts, i.e. achyranthes root, rehmannia root, dioscorea, rhizome, cornus fruit, alisma rhizome, plantago seed moutan bark, pariah sclerotium, aconite root and cinnamon bark (Kono et al., 2013, Cancer Chemother Pharmacol 72, 1283). Goshajinkigan is widely used for treatment of diabetic neuropathy, and appears to have limited effectiveness on CIPN (Kono et al., 2013, Cancer Chemother Pharmacol 72, 1283; Hashino et al., 2018, Int J Clin Oncol 23, 434; Kuriyama et al., 2018, Support Care Cancer 23, 1843). In the present study, we could retrospectively collect information of Goshajinkigan use from medical records. Considering the reviewer’s comment, more explanation of Goshajinkigan has been incorporated into the text (Lines 262-267).

R2-2) Inclusion criteria (line 94) says: no administration of oxaliplatin or vinca alkaloids. Presumably this means "no prior use of" the drugs as there are patients included it the analysis who were given a platinum. Suggest slight rewording to make it clear.

We thank Reviewer #2 for making an important comment. As the reviewer suggests, we have intended to mean “no prior use of”, and modified the text (Lines 101-103).

R2-3) Line 128. The study included only 283 patients, so why does the data in the results (lines 128-129) give numbers for patients also excluded from the study. How is that information relevant? Suggest this is changed so only discusses patients included in the study.

The description of the results in the original manuscript might not be clear. Considering the reviewer’s comment, we have simply described “In this study, 283 patients including 162 breast and 121 gynecologic cancer survivors who met inclusion criteria (S1 Fig) were enrolled for statistical analysis (Table 1)” in the revised manuscript (Lines 134-135).

Submitted filename: Responses.docx

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3 Dec 2021

Risk factors and pharmacotherapy for chemotherapy-induced peripheral neuropathy in paclitaxel-treated female cancer survivors: A retrospective study in Japan

PONE-D-21-29568R1

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21 Dec 2021

PONE-D-21-29568R1

Risk factors and pharmacotherapy for chemotherapy-induced peripheral neuropathy in paclitaxel-treated female cancer survivors: A retrospective study in Japan

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