Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain

Sun Kyung Baek; Sang Won Shin; Su-Jin Koh; Jung Han Kim; Hyo Jung Kim; Byoung Yong Shim; Seok Yun Kang; Sang Byung Bae; Hwan Jung Yun; Sun Jin Sym; Hye Sook Han; Ha Yeong Gil

doi:10.1371/journal.pone.0252781

. 2021 Aug 17;16(8):e0252781. doi: 10.1371/journal.pone.0252781

Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain

Sun Kyung Baek ¹, Sang Won Shin ^2,^*, Su-Jin Koh ³, Jung Han Kim ⁴, Hyo Jung Kim ⁵, Byoung Yong Shim ⁶, Seok Yun Kang ⁷, Sang Byung Bae ⁸, Hwan Jung Yun ⁹, Sun Jin Sym ¹⁰, Hye Sook Han ¹¹, Ha Yeong Gil ¹²

Editor: Ahmed Negida¹³

¹Internal Medicine, Kyung Hee University Medical Center, Seoul, South Korea

²Internal Medicine, Korea University College of Medicine, Seoul, South Korea

³Department of Hematology-Oncology, Ulsan University Hospital, Ulsan University College of Medicine, Ulsan, South Korea

⁴Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University College of Medicine, Seoul, South Korea

⁵Internal Medicine, Hallym University Sacred Heart Hospital Anyang, Anyang, South Korea

⁶Internal Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea

⁷Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, South Korea

⁸Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, South Korea

⁹Internal Medicine, Chungnam National University College of Medicine, Daejeon, South Korea

¹⁰Internal Medicine, Gachon University Gil Medical Center, Incheon, South Korea

¹¹Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, South Korea

¹²Medical Affairs, Internal Medicine, Pfizer Pharmaceuticals Korea Ltd., Seoul, South Korea

¹³Zagazig University, EGYPT

Competing Interests: We declare that the authors have no other competing interests. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

^✉

* E-mail: shinsw@kumc.or.kr

Roles

Sun Kyung Baek: Data curation, Investigation, Writing – original draft

Sang Won Shin: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Supervision, Writing – original draft, Writing – review & editing

Su-Jin Koh: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Jung Han Kim: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Hyo Jung Kim: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Byoung Yong Shim: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Seok Yun Kang: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Sang Byung Bae: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Hwan Jung Yun: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Sun Jin Sym: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Hye Sook Han: Data curation, Investigation, Methodology, Resources, Supervision, Visualization, Writing – review & editing

Ha Yeong Gil: Formal analysis, Writing – review & editing

Ahmed Negida: Editor

PMCID: PMC8370612 PMID: 34403429

Abstract

Purpose

Evaluation of symptoms and signs for the management of neuropathic cancer pain (NCP) is challenging. This study aimed to identify clinical predictors of NCP and symptoms and signs most relevant of those in Korean patients.

Methods

This nationwide, descriptive, cross-sectional, multicenter, observational study included 2,003 cancer patients aged ≥20 years who reported a visual analog scale (VAS) score ≥1 for pain and provided informed consent for participation. The Douleur Neuropathic (DN4) questionnaire (score ≥4) was used to determine symptoms and signs as well as the presence of NCP.

Results

The prevalence of NCP was associated with age <65 years [OR, 1.57; 95% CI, 1.270–1.934], disease duration >6 months (OR, 1.57; 95% CI, 1.232–2.012), stage IV cancer (OR, 0.75; 95% CI, 0.593–0.955), history of chemotherapy (OR, 1.74; 95% CI, 1.225–2.472), and moderate-to-severe cancer pain (OR, 2.05; 95% CI, 1.671–2.524) after multivariate analysis. The most common descriptive symptoms of NCP were tingling, electric shock, and pins and needles. For NCP patients in the presence or absence of the clinical predictors, pins and needles (p = 0.001) and painful cold (p<0.001) symptoms were significantly frequent in patients with moderate-to-severe pain. Tingling, numbness, and touch hypoesthesia (p = 0.022, 0.033, 0.024, respectively) were more frequent in those with longer cancer duration and hyperesthesia (p = 0.024) was more frequent in young patients.

Conclusion

Age <65 years, disease duration >6 months, stage IV cancer, history of chemotherapy, and moderate-to-severe cancer pain, were identified as predictors of NCP. Some symptoms and signs of NCP were associated with these predictors. Further studies are warranted on the pathogenesis and management of NCP with respect to the symptoms and signs, and factors associated with pain severity in Korean patients.

Introduction

One of the most fearful symptoms of cancer is pain. Chronic cancer pain is defined as chronic pain caused by the primary cancer itself, metastasis or its treatment [1]. Despite a plethora of guidelines and recommendations, cancer pain is frequently under-treated with more than 50% of patients with cancer describing the intensity of cancer pain as moderate or severe [2]. One of the barriers to pain control is inadequate pain assessment which, ideally, should consider the intensity and underlying etiology and mechanism [3]. While nociceptive pain is sensitive to opioids, the responsiveness of neuropathic pain to opioids is weak [4]. This is particularly important for neuropathic cancer pain (NCP) as a combination of non-opioid analgesic drugs with conventional opioid analgesia is required for the optimal management of NCP [5].

The International Association for the Study of Pain (IASP) classification of chronic pain for International Classification of Diseases (ICD-11) identifies specific codes for chronic NCP (neuropathic pain caused by a tumor), as well as neuropathic pain caused by a primary tumor or metastases damaging or injuring the peripheral or central nervous system [6]. Neuropathic pain affects up to 40% of cancer patients and is associated with increased pain intensity and decreased quality of life (QOL) [7–9]. Previously, we also reported the incidence rate of NCP in cancer patients in Korea and the relevance that NCP deteriorates patients’ QOL [10]. For clinicians, the identification of NCP is dependent on the careful evaluation of the symptoms and signs. However, in daily clinical practice, identifying NCP can be difficult or sometimes easily neglected due to the nature of symptoms and NCP may be considered to be non-cancer associated pain [11,12]. To overcome this problem and to assist in the early detection of NCP, the present study evaluated clinical predictors of NCP and descriptive symptoms and signs associated with NCP among cancer patients in Korea.

Materials and methods

Data collection

This nationwide, cross-sectional, descriptive, non-interventional, multicenter study was conducted from February 2013 to March 2014 in 28 hospitals in Korea, including 21 tertiary referral hospitals, 5 secondary referral hospitals, and 2 municipal general hospitals. Inclusion criteria were as follows: age ≥20 years, diagnosis of cancer, cancer pain with a visual analog scale (VAS) score ≥1, and the ability to understand and sign the informed consent form. Patients with pain not associated with cancer were excluded at the discretion of the attending physician. Patients’ demographic and clinical characteristics (age, sex, cancer duration, cancer stage, and comorbidities related to NCP) and their treatment history (radiotherapy, chemotherapy, and surgery) were collected from medical records. Questionnaires and case report forms were collected, and study data were analyzed. The study (study ID: KCSG PC13-02) was approved by the central institutional review board (IRB) of the Korean Cancer Study Group (KCSG). After central approval, institutional approval was obtained from the institutions of the participating investigators. All procedures were, therefore, performed in accordance with the ethical standards of the institutional and/or national research committee and within the guidelines of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Pain assessment

All patients were evaluated by physicians, who determined the presence of cancer pain using the VAS and the presence of NCP using the Douleur Neuropathic (DN4) questionnaire during patients’ regular visits. We defined a VAS score ≥1 as cancer pain. The DN4 questionnaire includes seven pain descriptors, namely, burning painful cold, electric shocks, tingling, pins and needles, numbness, and itching, along with three additional symptoms, namely, hypoesthesia to touch, hypoesthesia to pinpricks, and allodynia to a paintbrush. The former seven descriptors were assessed via patient interviews, while the latter three were assessed via standardized clinical examinations. We defined a DN4 score ≥4 as NCP.

Statistical analysis

Patients were categorized into NCP (DN4 score ≥4) and non-NCP (DN4 score <4) groups. In the univariable analysis, patients’ demographic and clinical characteristics were compared between the NCP and non-NCP groups using Student’s t-tests for continuous variables and chi-square tests for categorical variables. To identify independent predictors of NCP, multivariable logistic regression analysis was used; the multivariable model included patients’ demographic characteristics (age and gender) and variables with a p-value of <0.1 in the univariable analysis.

Differences in symptoms reported by patients through the DN4 questionnaire were analyzed between the NCP and non-NCP groups using logistic regression models. In both univariable and age- and sex-adjusted multivariable analysis, the non-NCP group was the designated reference group. The distribution of clinical predictors in the NCP group was analyzed using chi-square tests.

All reported p-values were two-tailed, and a p-value of <0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics 20.0 (IBM Corporation, NY, USA).

Results

Baseline characteristics of the patients and clinical predictors of NCP

A total of 2,003 patients participated in this study, and NCP was present in 722 (36.0%) of these patients. According to univariable analysis, using Student’s t-tests for continuous variables and chi-square tests for categorical variables, the proportion of NCP was higher among patients aged <65 years compared to those aged ≥65 years (p<0.001), in patients with cancer duration ≥6 months compared to <6 months (p = 0.001), and in patients with stage I–III cancer compared to those with stage IV cancer (p = 0.021). There were 494 patients with comorbidities (309 patients with diabetes, 44 patients with liver cirrhosis, 43 patients with traumatic injury, 41 with herpes zoster) and the proportion of patients with comorbidities was not significantly different between the two groups (p = 0.133). Regarding treatment history, the proportion of patients with NCP was higher among patients with a history of chemotherapy (p<0.001) and among patients with a history of cancer surgery (p = 0.003). Finally, the proportion of patients with NCP was higher among patients with moderate-to-severe pain (VAS score ≥4) compared to those with mild pain (VAS score <4; p<0.001; Table 1).

Table 1. Comparison of the characteristics between the NCP and non-NCP groups (N = 2,003).

N (%)	Total N = 2,003	NCP N = 722 (%)	Non-NCP N = 1,281 (%)	P-value
Gender				0.281
Male	1,089	381 (35.0)	708 (65.0)
Female	914	341 (37.3)	573 (62.7)
Age (years), mean±SD	60.9±11.3	59.5±10.7	61.7±11.5	<0.001
<65	1,213	489 (40.3)	724 (59.7)	0.001
≥65	790	233 (29.5)	557 (70.5)
Cancer duration (months), mean±SD	26.3±37.1	30.1±42.1	24.1±33.7	0.001
<6	545	143 (26.2)	402(73.8)	0.001
≥6	1,458	579 (39.7)	879(60.3)
Cancer stage				0.021
Stage I–III	399	163 (40.9)	236 (59.1)
Stage IV	1,428	494 (34.6)	951 (66.6)
Comorbidities				0.133
None	1,509	530 (35.1)	979 (64.9)
Present	494	192 (38.9)	302 (61.1)
Radiotherapy				0.310
Never received	1,401	515 (36.8)	886 (63.2)
Received	602	207 (34.4)	395 (65.6)
Chemotherapy				<0.001
Never received	250	54 (21.6)	196 (78.4)
Received^†	1,751	668 (38.1)	1,083 (61.9)
Cancer surgery				0.003
Did not undergo	1,204	403 (33.5)	801 (66.5)
Underwent	799	319 (39.9)	480 (60.1)
Pain VAS score, mean±SD	4.4±2.3	4.9±2.3	4.1±2.0	<0.001
<4 (mild pain)	830	225 (27.1)	605(72.9)	<0.001
≥4 (moderate-to-severe pain)	1,173	497 (42.4)	676 (57.6)

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χ² test, Student’s t-tests for continuous variables and chi-square tests for categorical variables.

NCP: Neuropathic cancer pain; SD: Standard deviation; VAS: Visual analog scale.

Multivariable logistic regression analysis revealed that age <65 years compared to age ≥65 years [odds ratio (OR), 1.57; 95% confidence interval (CI), 1.27–1.93], cancer duration of >6 months compared to that of <6 months (OR, 1.57; 95% CI, 1.23–2.01), stage IV cancer compared to stage I–III cancer (OR, 0.75; 95% CI, 0.59–0.96), a previous or current history of chemotherapy (OR, 1.74; 95% CI, 1.23–2.47), and moderate-to-severe pain (VAS score ≥4; OR, 2.05; 95% CI, 1.67–2.52) were significant clinical predictors of NCP (Table 2).

Table 2. Clinical predictors of patients with NCP (N = 2,003).

Predictors (Reference)	Adjusted OR	95% CI	P-value
Female (Male)	1.036	0.849–1.265	0.729
Age <65 years (≥65 years)	1.567	1.270–1.934	<0.001
Cancer duration ≥6 months (<6 months)	1.574	1.232–2.012	<0.001
Cancer stage IV (I-III)	0.752	0.593–0.955	0.019
Chemotherapy, done (Never done)	1.740	1.225–2.472	0.002
Surgery, done (Never done)	1.127	0.917–1.386	0.256
Pain VAS score, Moderate/Severe (Mild)	2.054	1.671–2.524	<0.001

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Logistic regression analysis, variables with p-value<0.1 from the univariable analysis were included.

CI: Confidence interval; NCP: Neuropathic cancer pain; OR: Odds ratio; VAS: Visual analog scale.

Frequency of the descriptive symptoms and signs of NCP

Overall, the most common neuropathic symptom was tingling (N = 1,114, 55.6%), followed by electric shocks (N = 1,069, 53.4%) and pins and needles (N = 844, 42.1%). Among the groups categorized on the basis of the DN4 questionnaire score, commonly experienced symptoms were tingling (NCP; N = 638 vs non-NCP; N = 476), electric shocks (NCP; N = 632 vs non-NCP; N = 437), and pins and needles (NCP; N = 471 vs non-NCP; N = 373). An increased OR was noted for all symptoms and signs described in the DN4 questionnaire, indicating the increased incidence of these symptoms in NCP patients in both univariable and multivariable models. Prick hypoesthesia (OR, 36.95; 95% CI, 20.88–65.38) and touch hypoesthesia (OR, 20.56; 95% CI, 15.79–26.78) were associated with increased odds of being present in the NCP group by chi-square tests (Table 3).

Table 3. Differences in selecting symptom items of the DN4 questionnaire between the NCP (N = 722) and non-NCP (N = 1,281) groups.

DN4 Symptom items	Total	NCP	Non-NCP	Univariable	Multivariable^*
DN4 Symptom items	N = 2,003(%)	N = 722 (%)	N = 1,281 (%)	Crude OR (95% CI)	Adjusted OR (95% CI)	Pseudo R²^**
Burning	312 (15.6)	198 (63.5)	114 (36.5)	3.87 (3.01–4.98)	3.86 (3.00–4.97)	0.088
Painful Cold	450 (22.5)	345 (76.7)	105 (23.3)	10.25 (8.00–13.13)	10.51 (8.18–13.48)	0.265
Electric shocks	1,069 (53.4)	632 (59.1)	437 (40.9)	13.56 (10.57–17.40)	13.35 (10.40–17.14)	0.348
Tingling	1,114 (55.6)	638 (57.3)	476 (42.7)	12.85 (9.96–16.56)	12.69 (9.84–16.37)	0.330
Pins and Needles	844 (42.1)	471 (55.8)	373 (44.2)	4.57 (3.76–5.55)	4.53 (3.72–5.51)	0.168
Numbness	512 (25.6)	398 (77.7)	114 (22.3)	12.58 (9.87–16.02)	12.57 (9.86–16.03)	0.318
Itching	328 (16.4)	220 (67.1)	108 (32.9)	4.76 (3.70–6.13)	4.64 (3.60–5.98)	0.111
Touch hypoesthesia	524 (26.2)	436 (83.2)	88 (16.8)	20.67 (15.89–26.88)	20.56 (15.79–26.78)	0.405
Prick hypoesthesia	213 (10.6)	200 (93.9)	13 (6.1)	37.37 (21.13–66.09)	36.95 (20.88–65.38)	0.233
Hyperesthesia	238 (11.9)	189 (79.4)	49 (20.6)	8.92 (6.41–12.40)	8.75 (6.29–12.19)	0.147

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Chi-square tests, all statistically significant, P<0.001.

*Age- and sex-adjusted

**Negelkerke R².

CI: Confidence interval; NCP: Neuropathic cancer pain; OR: Odds ratio.

Clinical symptoms and signs of NCP according to each predictor

The prevalence of the clinical predictors (age <65 years, cancer duration ≥6 months, stage I–III cancer, history of chemotherapy, VAS score for pain ≥4) was assessed among the patients in the NCP group for each of the clinical symptoms and signs (Table 4). Among NCP patients with hyperesthesia, the proportion of patients aged <65 years (74.6%) was significantly higher than that of patients aged ≥65 years (25.4%) (p = 0.024). The proportion of patients with cancer duration of ≥6 months was significantly higher among NCP patients presenting with tingling (81.5%), numbness (83.2%), or touch hypoesthesia (83.0%) (p = 0.022, 0.033, 0.024, respectively). NCP patients with painful cold and pins and needles were more likely to have moderate-to-severe pain (p<0.001, p = 0.001, respectively). There were no significant differences between patients with early-stage cancer (stage I–III) and those with later-stage cancer (stage IV) or between patients with a history of chemotherapy and those without a history of chemotherapy (Table 4).

Table 4. Characteristics of neuropathic pain only in NCP patients in the presence or absence of the clinical predictors of NCP^†.

Total	Age (years) (N = 722)			Cancer duration (months) (N = 722)			Cancer stage (N = 657)			Chemotherapy (N = 722)			Pain VAS (N = 722)
Total	<65 (N = 489)	≥65 (N = 233)	P-value	≥6 (N = 579)	<6 (N = 143)	P-value	I–III (N = 163)	IV (N = 494)	P-value	Yes (N = 668)	No (N = 54)	P-value	≥4 (N = 497)	<4 (N = 225)	P-value
Burning	128 (64.6)	70 (35.4)	0.317	156 (78.8)	42 (21.2)	0.633	41 (22.3)	143 (77.7)	0.404	180 (90.9)	18 (9.1)	0.393	146 (73.7)	52 (26.3)	0.097
Painful cold	229 (66.4)	116 (33.6)	0.507	272 (78.8)	73 (21.2)	0.436	74 (23.7)	238 (76.3)	0.599	318 (92.2)	27 (7.8)	0.844	266 (77.1)	79 (22.9)	<0.001
Electric shocks	420 (66.5)	212 (33.5)	0.069	510 (80.7)	122 (19.3)	0.450	143 (25.0)	430 (75.0)	0.927	587 (92.9)	45 (7.1)	0.449	439 (69.5)	193 (30.5)	0.401
Tingling	437 (68.5)	201 (31.5)	0.276	520 (81.5)	118 (18.5)	0.022	146 (25.0)	438 (75.0)	0.861	591 (92.6)	47 (7.4)	0.924	439 (68.8)	199 (31.2)	1.000
Pins and needles	314 (66.7)	157 (33.3)	0.452	373 (79.2)	98 (20.8)	0.409	108 (24.9)	325 (75.1)	0.989	432 (91.7)	39 (8.3)	0.331	345 (73.2)	126 (26.8)	0.001
Numbness	271 (68.1)	127 (31.9)	0.88	331 (83.2)	67 (16.8)	0.033	95 (26.2)	268 (73.8)	0.420	367 (92.2)	31 (7.8)	0.835	275 (69.1)	123 (30.9)	0.932
Itching	154 (70.0)	66 (30.0)	0.437	176 (80.0)	44 (20.0)	1.000	55 (26.6)	152 (73.4)	0.541	206 (93.6)	14 (6.4)	0.548	147 (66.8)	73 (33.2)	0.492
Touch hypoesthesia	299 (68.6)	137 (31.4)	0.602	362 (83.0)	74 (17.0)	0.024	102 (25.6)	296 (74.4)	0.610	409 (93.8)	27 (6.2)	0.139	291 (66.7)	145 (33.3)	0.156
Prick hypoesthesia	136 (68.0)	64 (32.0)	0.994	166 (83.0)	34 (17.0)	0.286	52 (28.0)	134 (72.0)	0.283	187 (93.5)	13 (6.5)	0.645	138 (69.0)	62 (31.0)	1.000
Hyperesthesia	141 (74.6)	48 (25.4)	0.024	155 (82.0)	34 (18.0)	0.533	37 (22.3)	129 (77.7)	0.444	173 (91.5)	16 (8.5)	0.661	135 (71.4)	54 (28.6)	0.421

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χ² test

^†Multiple-choice response.

NCP: Neuropathic cancer pain; VAS: Visual analog scale.

Discussion

In the present study, we analyzed data from a nationwide cancer pain survey in Korea, focusing on predictors of NCP and the clinical significance of patient-reported symptoms and signs most relevant for these predictors in Korean patients. Our study identified five clinical predictors of NCP: age <65 years, a past or current history of chemotherapy, cancer duration of ≥6 months, moderate-to-severe pain (VAS score ≥4), and early-stage cancer (stage I–III). Bulls et al. reported that older adults (aged ≥65 years) with gynecologic cancer are at higher risk for NCP [13]. Other studies have also reported a higher prevalence of neuropathy in older patients [14,15]. In the present study, 20% of the older (≥65 years) and 7% of the younger (<65 years) age groups had not received chemotherapy (S1 Table). Older patients are less likely to receive chemotherapy, which can explain the increased association of NCP with the younger age group in our study. A recent study reported that the predictors of NCP were associated with the location of neural invasion, a longer disease duration, a higher pain intensity, recent surgery or chemotherapy, the use of one or more adjuvant analgesics, and the presence of an episodic incident or breakthrough pain [16]. This was similar to our study, where NCP was found to be associated with chemotherapy, moderate-to-severe pain and longer duration of cancer.

However, in our study, surgery had a significant association with NCP in univariate, but not in multivariate, analysis. There were 399 patients with stage I, II, or III cancer and 799 patients underwent surgery. About half of the patients who underwent surgery had palliative surgery rather than curative surgery on the primary tumor, which may explain the difference from the previous report. Additionally, we enrolled various cancer patients in this study. Gastrointestinal cancer was the most common (49% of patients), followed by respiratory cancer (24%), skin, bone, and connective cancer (14%), hematologic malignancy (14%), genitourinary cancer (13%), breast cancer (11%), and head and neck cancer (9%) [10]. Since approximately half of the patients registered in this study had gastrointestinal cancer, it indicates that there are fewer patients who have undergone chronic pain-related surgeries, such as mastectomy or thoracotomy [17]. Moreover, less invasive surgical techniques might result in less postsurgical pain. Lumpectomy might result in more pain than a modified radical mastectomy [18].

Early neuropathic symptoms and signs of platinum analog-treated patients include loss of ankle jerks and decreased vibratory sensibility in the toes associated with numbness, tingling or paresthesias in finger and toes and prolonged treatment may worsen those symptoms. Pin and temperature sensation, joint position and light touch perception are less severely affected [19,20]. In our study, the most frequently reported symptoms were tingling, electric shock, and pins and needles, and these symptoms were most frequently reported by both NCP and non-NCP groups. It is possible for neuropathic pain to begin with common symptoms such as tingling, pins and needles and electric shocks. A Spanish prospective study, conducted over 1 month, that recruited 366 patients with cancer, aged ≥18 years, diagnosed with NCP (DN4 ≥4), and with moderate-to-severe pain (VAS ≥4), reported that the most common symptoms were tingling (79.8%), pins and needles (76.2%) and electric shocks (72.4%) [21]. This showed a similar distribution of descriptive symptoms as the NCP group in the present study. In contrast, an Indian study reported that a pricking type of pain was the most characteristic feature (47.8%), followed by shooting pain (38.3%), in patients with NCP [22]. These differences in descriptive symptoms might be associated with differences in study design, ethnicity, or expressive language used to express patients’ pain. The symptoms and signs of highest relevance to NCP were prick hypoesthesia and touch hypoesthesia. Further studies to clarify symptom definitions and to elucidate the pathogenesis of NCP are needed for its effective management.

The evaluation of pain begins with a patient interview regarding the symptoms. Currently, there is no gold standard method for the diagnosis of neuropathic pain. In daily practice, screening questionnaires are suitable for identifying potential patients with neuropathic pain. For cancer patients, these questionnaires are preferred over imaging studies such as electroneuromyography or magnetic resonance imaging. A screening tool for neuropathic pain could alert physicians about the possibility of NCP. Medical oncologists generally use three screening tools for neuropathic pain, namely pain DETECT [23], the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) [24], and the DN4 questionnaire [25]. Among these, only LANSS and the DN4 questionnaire feature items related to sensory examination. The LANSS was more specific, although less sensitive, than the DN4. The DN4 questionnaire is more sensitive than LANSS, regardless of the pain severity [26].

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, dose-dependent complication of anticancer drugs, including platinum, taxanes, epothilones, vinca alkaloids, and newer agents such as bortezomib [27]. In our study, of the 722 patients with NCP, 93% had a history of chemotherapy. Although anticancer chemotherapeutics can intensify painful peripheral neuropathy, there was no significant difference in the symptomatology of NCP between patients with and without a history of chemotherapy. However, some symptoms and signs were related to specific predictors. Hyperesthesia was more frequent in patients aged <65 years than in those aged ≥65 years. Tingling and touch hypoesthesia were more frequent in patients with longer cancer duration (≥6 months). And painful cold and pins and needles were associated with moderate and severe cancer pain. To our knowledge, this study is very meaningful as it analyzed each of the symptoms and signs based on the predictors of NCP. These finding could help physicians in the early diagnosis and management of NCP.

This study has some limitations. First, the cross-sectional design limits our knowledge of various pre-referral treatments and their degree of consistency with standard guidelines. Second, the origin of cancer, stage of cancer, and anticancer treatment differed among the enrolled patients. There is controversy over the association of status or site of cancer with NCP [14,28], rather, whether NCP is associated with neurological involvement secondary to the disease or its treatment. Third, we did not differentiate dominant or neuropathic components from mixed type with nociceptive and neuropathic pain. As we searched for the frequency and risk factors of NCP in all patients with cancer pain through cross-sectional studies, we were not able to study the cause of NCP. This is required through other studies in the future. Fourth, the patients’ narratives, including their interpretation of pain, may be governed by their culture and language [29]. Finally, we defined that patients had cancer pain if they complained of cancer pain (NRS ≥1), regardless of treatment. Patients with pain more than VAS 3 were usually considered for treatment in clinical practice. There might be limits to the application of treatment in clinical practice. However, this study is helpful in identifying patients who are expected to have NCP in advance and for monitoring their symptoms and signs by risk factors.

In conclusion, the results of this nationwide cross-sectional study in Korea have shown predictors of NCP and the identification of symptoms and signs associated with NCP. To the best of our knowledge, this is the first study that has analyzed each descriptive symptom and sign based on the predictors of NCP, as obtained by the DN4 questionnaire. More studies to substantiate the characteristics of NCP could help in its early detection, correct diagnosis and efficient management.

Supporting information

S1 Table. Comparison of patients receiving/not receiving chemotherapy and age <65 or ≥65 years.

(DOCX)

Click here for additional data file.^{(25.8KB, docx)}

Acknowledgments

On behalf of the Korean Cancer Study Group (KCSG), we thank the investigators who participated in this study: So Yeon Oh, Dae Sik Hong, Kyung Hee Lee, So Young Yoon, Jung Lim Lee, Hyun Chang, Keon Uk Park, Young Seon Hong, Sung Rok Kim, Na Ri Lee, Jeanno Park, Sang Cheul Oh, Seung-Sei Lee, Dae Ro Choi, Jooseop Chung, In Sil Choi, and Joung Soon Jang. In addition, we appreciate the assistance in statistical analysis provided by Sook Jung Hyun, Professor of Health Administration, Department of Management & Administration, Baekseok Arts University. Editorial assistance was provided by David P. Figgitt PhD, ISMPP CMPP^™, Content Ed Net, with funding from Viatris.

Data Availability

Data underlying the study cannot be made publicly available due to ethical restrictions on personal data imposed by the central IRB of Korean Cancer study group and the IRB committees of the hospitals involved in the study. The participants in the study did not consent to the public sharing of their data. To access the data, Interested researchers may contact kcsg@kcsg.org for more information.

Funding Statement

We confirm that this study was sponsored by Pfizer Pharmaceuticals Korea Ltd. Ha Yeong Gil, the employee of Pfizer Pharmaceuticals Korea Ltd., contributed in the study design, data analysis, decision to publish, or preparation of the manuscript.

References

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PLoS One. doi: 10.1371/journal.pone.0252781.r001

Decision Letter 0

Ahmed Negida

5 Feb 2021

PONE-D-20-33583

Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain

PLOS ONE

Dear Dr. Shin,

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Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Yes

**********

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: The manuscript by Baek et al. aims to identify new predictors of NCP in Korean population of cancer patients by using the DN4. Although authors identified some signs and symptoms associated with NCP, the main objective and output are not enough empathised leaving in the reader a feeling of non-understanding the relevance of the results.

Overall, this is an interesting attempt, but there are some points to address:

1) Line 72: authors mentioned that the prevalence of NCP is 20-30% in cancer patients, worldwide? In Korea? Please specify.

2) Line 81: according to authors, few studies have reported how patients described the influence of their symptoms, however, no reference is provided. I would appreciate to see the references.

3) Patients aged >20 years are included in the present study. However, results only show the comparison between <65 and > 65. Could authors explain the reason for this selection? Have the authors performed any previous analysis to define this age categories?

4) In order to facilitate the comprehensive interpretation of the results, I would appreciate the authors to mention which statistical method has been used for each analysis in the results section, including figures and tables, as it is only mentioned in “Statistical analysis”.

5) Concerning the Figure 1: please consider that P values less than 0.001 are summarized with three asterisks (***) not two (**).

There is not Title nor footnotes in Figure 1.

6) Please add a reference in line 203 that confirms that the presence of comorbidities is higher in the elderly.

7) Reference 9 in line 206 does not correspond to the sentence as it mentions the results of the current manuscript. Please check.

8) In the discussion, authors explain that the longer duration and higher intensity of the treatment received in the younger patients could explain the results. However, there is no information about the treatment dose or the treatment duration in the sample analysed. Therefore, I would recommend showing this information in a table or to elaborate another explanation for the result found.

9) If, as mentioned in the discussion, DN4 may have limitations when used in patients with severe pain, why authors have decided to use this questionnaire to evaluate their participants if more than 50% presented moderate to severe pain? Are they sure that this is the appropriate tool for this study? Please justify.

10) Has been data provided or deposited to a public repository? If not, more detailed information should be added to the statistics (behind means, medians…).

Reviewer #2: Manuscript Number: PONE-D-20-33583

Title: Significance of descriptive symptoms and signs and clinical parameters as predictors

of neuropathic cancer pain

Summary

I appreciate the opportunity to review this interesting report. This is a nationwide cross-sectional study in Korea that have shown predictors of NCP and the identification of symptoms and signs associated with NCP.

Major Strengths

This is an interesting article that first describe symptoms and signs based on the predictors of NCP, as obtained by the DN4 questionnaire using nationwide data.

Major Weakness

Please describe more specific sources and methods of selection of participants. (Ex, hospital type, department, visit number…)

The authors indicate that the inclusion criteria were cancer pain with VAS ≥ 1. I think the VAS 1 is not suitable. Is there any reason?

In my opinion, the diagnosis of NCP is more complex one. Especially in the cancer pain population, in which nociceptive and neuropathic components frequently co-exist. How did the authors differentiate NCP with mixed type pain?

In the discussion, page 18, line 266-267, is there any reference? As I know, NCP may occur directly as in tumor-associated neural compression.

According to the previous report, surgery is one of predictor of NCP. Please discuss more about the predictor of NCP.

Minor Comments

According to the STROBE guideline, the title represents “Indicate the study’s design”.

Reviewer #3: Authors have presented an analysis of signs and symptoms of cancer pain in a large sample size. The topic is surely interesting and useful for clinicians in order to improve diagnosis of cancer pain. Authors (as they stated in the background) have already published part of the data in a previous paper and some data seem the same. Please control accurately it.

The major concern regarding the manuscript is the selection of the patients: it seems that a VAS>1 could lead to wrong results (even though we have no any informations about drugs that patients took).

I would suggest to consider only patients with pain more than 3 (as usually considered in literature), eventually stratifying the population in mild (VAS 4-6) and severe (VAS 7-10) pain. This stratification could be more reliable to clinical practice and could be more helpful for a clear analysis of the samples size.

I have also some concerns about the statistical analysis and the data presentation. It should be better to evaluate if there are differences in percentages of patients among the same group (NCP and no NCP). As presented, it seems that authors have evaluated differences between NCP and no NCP for the single variable. This analysis could be misunderstanding also considering also the huge heterogeneity of the sample size. Please discuss it

Can we have some data about use of analgesic drugs and eventually differences in type of drugs used and pain relief obtained in the two groups?it could be helpful to understand if a better analysis of the signs and symptoms could improve the effectiveness of treatment.

Finally it should be necessary to revise English and revise several typos.

Reviewer #4: Thanks for opportunity of reviewing this article. This is an interesting study, but there are several limitations with NCP predictor.

Method

1.In method section, explanation of study design and definition is lacking.

2.What are the criteria for determining NCP and Non-NCP? The criteria for diagnosis are unclear.

3.P6 L 105 “A VAS score ≥1 was indicative of cancer pain.” Do you have a reference? Is this the standard set by the authors? Are they defined by the authors?

Result

Table 1

1.Comorbidity is also an important factor in determining cancer pain. For example, the case of patient with severe DM, the sensitivity of pain decreases and pain patterns may be different due to DM neuropathy. Could you add details about Comorbidity?

2.The type of cancer is also an important factor. If you can, add it.

3.The type of cancer is also an important factor. If you can, add it.

Cancer patients often use narcotic analgesics, which can also lead to hyperalgesia if prolonged exposure to analgesics. Add the presence or absence of narcotic pain killers.

4.P8 L139, Table 1

The standard for dividing the VAS score is set to 4, do you have any reference?

Discussion

In the discussion section, the discussion is too long, and the content of the sentence is in conflict. Need to clean up.

1. What is the clinical meaning of this investigation result?

2. P15 199-206, I cannot understand your explanation

3. According to your results, chemotherapy is also a risk factor for NCP. Old age receives less chemotherapy than young age, so why have more NCP in old age? Does cancer pain decrease in young age receiving toxic agent chemotherapy?This section conflicts with your results and needs clarification. In addition, check the reference again.

4. P16 L217-239 Combine in one paragraph.

Delete "Failure of identifying NCP leads to unsatisfactory pain management in Asian countries where physician–patient communication tends to be reserved or of short duration"(??)

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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PLoS One. 2021 Aug 17;16(8):e0252781. doi: 10.1371/journal.pone.0252781.r002

Author response to Decision Letter 0

13 Apr 2021

29 March, 2021

Dear Editor-in-Chief, PLOS ONE

We deeply appreciate your insightful comments on our manuscript entitled, “Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain”. Your comments were really helpful for revising our manuscript. We totally agree with the comments of the reviewers and have revised our manuscript according to reviewers’ comments. All relevant data are within the manuscript, and the changes and responses to specific comments are shown below. We hope that these changes will satisfy the editors and reviewers.

Also, we confirm that this study was sponsored by Pfizer Pharmaceuticals Korea Ltd. Ha Yeong Gil, the employee of Pfizer Pharmaceuticals Korea Ltd., contributed in the study design, data analysis, decision to publish, or preparation of the manuscript. We declare that the authors have no other competing interests. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Thank you again for providing important comments on our work. We hope you can consider this paper for publication in PLOS ONE.

Sincerely,

Sang Won Shin, MD, PhD.

Medical Oncology, Department of Internal Medicine

Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

73, Inchon-ro, Seongbuk-gu, Seoul, 136-705, Republic of Korea

Tel:+82-2-920-5350, Fax: +82-2-920-6951

E-mail: shinsw@kumc.or.kr

Response to the Referee

29 March, 2021

Thank you very much for your comments regarding our manuscript. We answered your comments with point-by-point descriptions and changed the manuscript accordingly.

Response: We would like to thank you for the careful comments. Based on the reviewer’s suggestion, we revised our paper, again. The revised words and sentences are red colored.

Overall, this is an interesting attempt, but there are some points to address:

1) Line 72: authors mentioned that the prevalence of NCP is 20-30% in cancer patients, worldwide? In Korea? Please specify.

Response: We would like to thank you for the careful comments. As you advised, the references have been reinforced and the sentence was modified as follows.

“Neuropathic pain affects up to 40% of cancer patients and is associated with increased pain intensity and decreased quality of life (QOL) [7-9]. Previously, we also reported the incidence rate of NCP in cancer patients in Korea and the relevance that NCP deteriorates patients’ QOL [10].” (line 77-82)

Added references:

[8] Bennett MI, Rayment C, Hjermstad M, et al. (2012) Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain 153: 359-365.

[9] Rayment C, Hjermstad MJ, Aass N, et al. (2013) Neuropathic cancer pain: prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative-Computerised Symptom Assessment study. Palliat Med 27: 714-721.

2) Line 81: according to authors, few studies have reported how patients described the influence of their symptoms, however, no reference is provided. I would appreciate to see the references.

Response: We would like to thank you for the careful comments. We have excluded the sentence because it seems to cause confusion.

Response: Thank you for the helpful comments. More than half of new cancer cases are diagnosed in adults over the age of 65 years. Older cancer patients are at high risk for chemotherapy-related toxicities including NCP. Bulls et al evaluated the longitudinal change in patients with NCP in older (>65) and younger (<65) patients. So, we compared patients based on age 65 years. We have added the article of Bulls et al as a reference.

“Our study identified five clinical predictors of NCP: age <65 years, a past or current history of chemotherapy, cancer duration of ≥6 months, moderate-to-severe pain (VAS score ≥4), and early-stage cancer (stage I–III). Bulls et al. reported that older adults (aged ≥65 year) with gynecologic cancer are at higher risk for NCP [13].” (line 217-220)

Added reference:

[13] Bulls HW, Hoogland AI, Kennedy B, et al. (2019) A longitudinal examination of associations between age and chemotherapy-induced peripheral neuropathy in patients with gynecologic cancer. Gynecol Oncol 152: 310-315.

Response: We would like to thank you for the careful comments. As you advised, we have added a sentence about statistical analysis in the results section, including figures and tables.

“According to univariable analysis, using Student’s t-tests for continuous variables and chi-square tests for categorical variables, the proportion of NCP was higher among patients aged <65 years compared to those aged ≥65 years (p<0.001), in patients with cancer duration ≥6 months compared to <6 months (p=0.001), and in patients with stage I–III cancer compared to those with stage IV cancer (p=0.021).” (line 143-147)

“Prick hypoesthesia (OR, 36.95; 95% CI, 20.88–65.38) and touch hypoesthesia (OR, 20.56; 95% CI, 15.79–26.78) were associated with increased odds of being present in the NCP group by chi-square tests (Table 3).” (line 186-188)

Table 1: “χ2 test, Student’s t-tests for continuous variables and chi-square tests for categorical variables” (line 159-160)

Table 2: “Logistic regression analysis, variables with p-value<0.1 from the univariable analysis were included.” (line 172-173)

Table 3: “Chi-square tests, all statistically significant” (line 190)

5) Concerning the Figure 1: please consider that P values less than 0.001 are summarized with three asterisks (***) not two (**). There is not Title nor footnotes in Figure 1.

Response: Thank you for your helpful comments. We have converted Figure 1 to Table 2 to explain the Results more easily.

Table 2. Clinical predictors of patients with NCP (N=2,003)

Predictors(Reference) Adjusted OR 95% - CI P-value

Female (Male) 1.036 0.849 - 1.265 0.729

Age <65 years (≥65 years) 1.567 1.270 - 1.934 <0.001

Cancer duration≥6 months (<6 months) 1.574 1.232 - 2.012 <0.001

Cancer stage IV (I-III) 0.752 0.593 - 0.955 0.019

Chemotherapy, done (Never done) 1.740 1.225 - 2.472 0.002

Surgery, done (Never done) 1.127 0.917 - 1.386 0.256

Pain VAS score, Moderate/Severe (Mild) 2.054 1.671 - 2.524 <0.001

Logistic regression analysis, variables with p-value<0.1 from the univariable analysis were included.

CI: confidence interval; NCP: neuropathic cancer pain; OR: odds ratio; VAS: visual analog scale

6) Please add a reference in line 203 that confirms that the presence of comorbidities is higher in the elderly.

Response: We would like to thank you for the careful comments. We excluded the sentence while revising the Discussion section.

7) Reference 9 in line 206 does not correspond to the sentence as it mentions the results of the current manuscript. Please check.

Response: We would like to thank you for the careful comments. We removed the reference which did not correspond to the sentence.

Response: We would like to thank you for the careful comments. We added Supplementary Table1 and revised the sentence.

“In the present study, 20% of the older (≥65 years) and 7% of the younger (<65 years) age groups had not received chemotherapy (S1 Table). Older patients are less likely to receive chemotherapy, which can explain the increased association of NCP with the younger age group in our study.” (line 228-232)

S1 Table. Comparison of patients receiving/not receiving chemotherapy and age <65 or ≥65 years

Chemotherapy Non-chemotherapy Total P-value

Age <65 years 1,123 (92.6) 90 (7.4) 1,213 (60.6) <0.001

Age ≥65 years 630 (79.7) 160 (20.3) 790 (39.4)

Response: We would like to thank you for the careful comments. Unfortunately, the quote seems to have been wrong. Perez C et al reported the LANSS is considerably more specific than the DN4 if pain is severe and intermittent, not moderate and severe. We removed the sentence.

10) Has been data provided or deposited to a public repository? If not, more detailed information should be added to the statistics (behind means, medians…).

Response: We would like to thank you for the careful comments. We have added information about mean and standard deviations in Table 1. All relevant data are within the paper.

Table 1. Comparison of the characteristics between the NCP and non-NCP groups (N=2,003)

N(%) Total

N=2,003 NCP

N=722 (%) Non-NCP

N=1,281 (%) P-value

Gender 0.281

Male 1,089 381 (35.0) 708 (65.0)

Female 914 341 (37.3) 573 (62.7)

Age (years), mean�SD 60.9±11.3 59.5±10.7 61.7±11.5 <0.001

<65 1,213 489 (40.3) 724 (59.7) 0.001

≥65 790 233 (29.5) 557 (70.5)

Cancer duration (months), mean�SD 26.3±37.1 30.1±42.1 24.1±33.7 0.001

<6 545 143 (26.2) 402(73.8) 0.001

≥6 1,458 579 (39.7) 879(60.3)

Cancer stage 0.021

Stage I–III 399 163 (40.9) 236 (59.1)

Stage IV 1,428 494 (34.6) 951 (66.6)

Comorbidities 0.133

None 1,509 530 (35.1) 979 (64.9)

Present 494 192 (38.9) 302 (61.1)

Radiotherapy 0.310

Never received 1,401 515 (36.8) 886 (63.2)

Received 602 207 (34.4) 395 (65.6)

Chemotherapy <0.001

Never received 250 54 (21.6) 196 (78.4)

Received† 1,751 668 (38.1) 1,083 (61.9)

Cancer surgery 0.003

Did not undergo 1,204 403 (33.5) 801 (66.5)

Underwent 799 319 (39.9) 480 (60.1)

Pain VAS score, mean�SD 4.4±2.3 4.9±2.3 4.1±2.0 <0.001

<4 (mild pain) 830 225 (27.1) 605(72.9) <0.001

≥4 (moderate-to-severe pain) 1,173 497 (42.4) 676 (57.6)

χ2 test, Student’s t-tests for continuous variables and chi-square tests for categorical variables

NCP: neuropathic cancer pain; SD: standard deviation; VAS: visual analog scale

Reviewer #2: Manuscript Number: PONE-D-20-33583

Title: Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain

Summary

Major Strengths

This is an interesting article that first describe symptoms and signs based on the predictors of NCP, as obtained by the DN4 questionnaire using nationwide data.

Major Weakness

Please describe more specific sources and methods of selection of participants. (Ex, hospital type, department, visit number…)

Response: We would like to thank you for the careful comments. We have added the requested information about hospitals.

“This nationwide, cross-sectional, descriptive, non-interventional, multicenter study was conducted from February 2013 to March 2014 in 28 hospitals in Korea, including 21 tertiary referral hospitals, 5 secondary referral hospitals, and 2 municipal general hospitals.” (line 96-99)

The authors indicate that the inclusion criteria were cancer pain with VAS ≥ 1. I think the VAS 1 is not suitable. Is there any reason?

Response: We totally agree that the diagnosis of NCP is more complex. We thought your opinion was very important. However, we were sorry that we did not differentiate NCP with mixed type pain or explore the cause of NCP. We have added this concern as a limitation.

In the discussion, page 18, line 266-267, is there any reference? As I know, NCP may occur directly as in tumor-associated neural compression.

Response: We would like to thank you for the careful comments. We agree with your opinion, have revised the sentence, and added the reference.

“There is controversy over the association of status or site of cancer with NCP [14, 28], rather, whether NCP is associated with neurological involvement secondary to the disease or its treatment.” (line 307-309)

Added references:

[14] Lewis MA, Zhao F, Jones D, et al. Neuropathic Symptoms and Their Risk Factors in Medical Oncology Outpatients With Colorectal vs. Breast, Lung, or Prostate Cancer: Results From a Prospective Multicenter Study. J Pain Symptom Manage. 2015;49(6):1016-24.

[28] Oosterling A, te Boveldt N, Verhagen C, et al. (2016) Neuropathic Pain Components in Patients with Cancer: Prevalence, Treatment, and Interference with Daily Activities. Pain Pract 16: 413-421.

According to the previous report, surgery is one of predictor of NCP. Please discuss more about the predictor of NCP.

Response: We would like to thank you for the careful comments. We have added one paragraph about your comments.

“However, in our study, surgery had a significant association with NCP in univariate, but not in multivariate, analysis. There were 399 patients with stage I, II, or III cancer and 799 patients underwent surgery. About half of the patients who underwent surgery had palliative surgery rather than curative surgery on the primary tumor, which may explain the difference from the previous report. Additionally, we enrolled various cancer patients in this study. Gastrointestinal cancer was the most common (49% of patients), followed by respiratory cancer (24%), skin, bone, and connective cancer (14%), hematologic malignancy (14%), genitourinary cancer (13%), breast cancer (11%), and head and neck cancer (9%) [10]. Since approximately half of the patients registered in this study had gastrointestinal cancer, it indicates that there are fewer patients who have undergone chronic pain-related surgeries, such as mastectomy or thoracotomy [17]. Moreover, less invasive surgical techniques might result in less postsurgical pain. Lumpectomy might result in more pain than a modified radical mastectomy [18].” (line 241-254)

Minor Comments

According to the STROBE guideline, the title represents “Indicate the study’s design”.

Response: We totally agree with you. However, our research is a cross-sectional study that shows the frequency and risk factors of NCP in patients with cancer pain, and is limited by enrolling patients with VAS 1 or higher, regardless of treatment. We have included this in the limitations section.

“Third, we did not differentiate dominant or neuropathic components from mixed type with nociceptive and neuropathic pain. As we searched for the frequency and risk factors of NCP in all patients with cancer pain through cross-sectional studies, we were not able to study the cause of NCP. This is required through other studies in the future. Fourth, the patients’ narratives, including their interpretation of pain, may be governed by their culture and language [29]. Finally, we defined that patients had cancer pain if they complained of cancer pain (NRS≥1) regardless of treatment. Patients with pain more than VAS 3 were usually considered for treatment in clinical practice. There might be limits to the application of treatment in clinical practice. However, this study is helpful in identifying patients who are expected to have NCP in advance and for monitoring their symptoms and signs by risk factors.” (line 310-325)

Response: We would like to thank you for the careful comments. However, we were sorry that we analyzed a difference between the risk factors of NCP and the descriptive symptoms (with or without NCP) in patients with cancer pain, which makes it difficult to see differences in the same group.

Can we have some data about use of analgesic drugs and eventually differences in type of drugs used and pain relief obtained in the two groups? it could be helpful to understand if a better analysis of the signs and symptoms could improve the effectiveness of treatment.

Response: We would like to thank you for the careful comments. Previously, we published a study on the association of NCP and QOL in the same patients, and a part relating to treatment was included in that paper (Oh SY, Shin SW, Koh SJ, Bae SB, Chang H, et al. Multicenter, cross-sectional observational study of the impact of neuropathic pain on quality of life in cancer patients. Support Care Cancer. 2017;25:3759-67). In this study, we presented the results that were not included in the previous study. The contents of treatment were reported in previous study. It is as follows (blue color) for your reference.

More than half of the patients (n= 1,173, 58.6%) had had moderate to severe pain (VAS≥4), implying that cancer pain was not adequately managed. Pharmacologic management for pain was as follows: 1,313 patients received opioids (65.6%), 748 received non-opioid analgesics (37.3%), 464 received anticonvulsants (23.2%), 134 received antidepressants (6.7%), 91 received corticosteroids (4.5%), 68 received benzodiazepines (3.4%), and 16 received phenothiazines (0.8%) (permitted overlap).

Finally it should be necessary to revise English and revise several typos.

Response: We would like to thank you for the careful comments. We have revised the English throughout the manuscript.

Reviewer #4: Thanks for opportunity of reviewing this article. This is an interesting study, but there are several limitations with NCP predictor.

Method

1. In method section, explanation of study design and definition is lacking.

2. What are the criteria for determining NCP and Non-NCP? The criteria for diagnosis are unclear.

3. P6 L 105 “A VAS score ≥1 was indicative of cancer pain.” Do you have a reference? Is this the standard set by the authors? Are they defined by the authors?

Response: We would like to thank you for the careful comments. We added the definition of cancer pain and NCP.

“We defined a VAS score ≥1 as cancer pain.” (line 115)

“We defined a DN4 score ≥4 as NCP.” (line 120-121)

Result

Table 1

2. The type of cancer is also an important factor. If you can, add it.

3. The type of cancer is also an important factor. If you can, add it.

Cancer patients often use narcotic analgesics, which can also lead to hyperalgesia if prolonged exposure to analgesics. Add the presence or absence of narcotic pain killers.

Response: We would like to thank you for the careful comments. Previously, we published a study on the association of NCP and QOL in the same patients, and a part relating to treatment was included in that paper (Oh SY, Shin SW, Koh SJ, Bae SB, Chang H, et al. Multicenter, cross-sectional observational study of the impact of neuropathic pain on quality of life in cancer patients. Support Care Cancer. 2017;25:3759-67). In this study, we presented results that were not included in previous study. Comorbidity and treatment were included in the previous report. We have briefly included comorbidity in the Results section and the type of cancer in the Discussion section. However, we were sorry that we could not include narcotic analgesics. For your reference, the contents of the previous paper on treatment are described below (blue color)

Results section:

“There were 494 patients with comorbidities (309 patients with diabetes, 44 patients with liver cirrhosis, 43 patients with traumatic injury, 41 with herpes zoster) and the proportion of patients with comorbidities was not significantly different between the two group (p=0.133).” (line 147-150)

Discussion section:

4. P8 L139, Table 1

The standard for dividing the VAS score is set to 4, do you have any reference?

Response: We would like to thank you for the careful comments. We divided patients based on VAS 4 because patients with VAS 4 or more need treatment. There is likely a controversy. We have added that as a limitation.

“Finally, we defined that patients had cancer pain if they complained of cancer pain (NRS≥1), regardless of treatment. Patients with pain more than VAS 3 were usually considered for treatment in clinical practice. There might be limits to the application of treatment in clinical practice. However, this study is helpful in identifying patients who are expected to have NCP in advance and for monitoring their symptoms and signs by risk factors.” (line 320-325)

Discussion

In the discussion section, the discussion is too long, and the content of the sentence is in conflict. Need to clean up.

1. What is the clinical meaning of this investigation result?

2. P15 199-206, I cannot understand your explanation

3. According to your results, chemotherapy is also a risk factor for NCP. Old age receives less chemotherapy than young age, so why have more NCP in old age? Does cancer pain decrease in young age receiving toxic agent chemotherapy? This section conflicts with your results and needs clarification. In addition, check the reference again.

Response: We would like to thank you for the careful comments. We cleaned up the Discussion section, deleted the sentence, and revised the paragraph. Our study identified age <65 years as risk factors, not old age. We would like to explain the reason that older patients are less likely to receive chemotherapy.

“In the present study, we analyzed data from a nationwide cancer pain survey in Korea, focusing on predictors of NCP and the clinical significance of patient-reported symptoms and signs most relevant for these predictors in Korean patients. Our study identified five clinical predictors of NCP: age <65 years, a past or current history of chemotherapy, cancer duration of ≥6 months, moderate-to-severe pain (VAS score ≥4), and early-stage cancer (stage I–III). Bulls et al. reported that older adults (≥65 years) with gynecologic cancer are at higher risk for NCP [13]. Other studies have also reported a higher prevalence of neuropathy in older patients [14,15]. In the present study, 20% of the older (≥65 years) and 7% of the younger (<65 years) age groups had not received chemotherapy (Supplementary Table 1). Older patients are less likely to receive chemotherapy, which can explain the increased association of NCP with the younger age group in our study. A recent study reported that the predictors of NCP were associated with the location of neural invasion, a longer disease duration, a higher pain intensity, recent surgery or chemotherapy, the use of one or more adjuvant analgesics, and the presence of an episodic incident or breakthrough pain [16]. This was similar to our study, where NCP was found to be associated with chemotherapy moderate-to-severe pain and longer duration of cancer.” (line 213--240)

4. P16 L217-239 Combine in one paragraph.

Delete "Failure of identifying NCP leads to unsatisfactory pain management in Asian countries where physician–patient communication tends to be reserved or of short duration"(??)

Response: We would like to thank you for the careful comments. As you advised, we revised the manuscript as follows.

“Early neuropathic symptoms and signs of platinum analog-treated patients include loss of ankle jerks and decreased vibratory sensibility in the toes associated with numbness, tingling or paresthesias in finger and toes and prolonged treatment may worsen those symptoms. Pin and temperature sensation, joint position and light touch perception are less severely affected [19, 20]. In our study, the most frequently reported symptoms were tingling, electric shock, and pins and needles, and these symptoms were most frequently reported by both NCP and non-NCP groups. It is possible for neuropathic pain to begin with common symptoms such as tingling, pins and needles and electric shocks. A Spanish prospective study, conducted over 1 month, that recruited 366 patients with cancer, aged ≥18 years, diagnosed with NCP (DN4 ≥4), and with moderate-to-severe pain (VAS ≥4), reported that the most common symptoms were tingling (79.8%), pins and needles (76.2%) and electric shocks (72.4%) [21]. This showed a similar distribution of descriptive symptoms as the NCP group in the present study. In contrast, an Indian study reported that a pricking type of pain was the most characteristic feature (47.8%), followed by shooting pain (38.3%), in patients with NCP [22]. These differences in descriptive symptoms might be associated with differences in study design, ethnicity, or expressive language used to express patients’ pain. The symptoms and signs of highest relevance to NCP were prick hypoesthesia and touch hypoesthesia. Further studies to clarify symptom definitions and to elucidate the pathogenesis of NCP are needed for its effective management.” (line 255-273)

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PLoS One. doi: 10.1371/journal.pone.0252781.r003

Decision Letter 1

Ahmed Negida

24 May 2021

Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain

PONE-D-20-33583R1

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PLoS One. doi: 10.1371/journal.pone.0252781.r004

Acceptance letter

Ahmed Negida

5 Aug 2021

PONE-D-20-33583R1

Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain

Dear Dr. Shin:

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Supplementary Materials

S1 Table. Comparison of patients receiving/not receiving chemotherapy and age <65 or ≥65 years.

(DOCX)

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Data Availability Statement

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PERMALINK

Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain

Sun Kyung Baek

Sang Won Shin

Su-Jin Koh

Jung Han Kim

Hyo Jung Kim

Byoung Yong Shim

Seok Yun Kang

Sang Byung Bae

Hwan Jung Yun

Sun Jin Sym

Hye Sook Han

Ha Yeong Gil

Roles

Abstract

Purpose

Methods

Results

Conclusion

Introduction

Materials and methods

Data collection

Pain assessment

Statistical analysis

Results

Baseline characteristics of the patients and clinical predictors of NCP

Table 1. Comparison of the characteristics between the NCP and non-NCP groups (N = 2,003).

Table 2. Clinical predictors of patients with NCP (N = 2,003).

Frequency of the descriptive symptoms and signs of NCP

Table 3. Differences in selecting symptom items of the DN4 questionnaire between the NCP (N = 722) and non-NCP (N = 1,281) groups.

Clinical symptoms and signs of NCP according to each predictor

Table 4. Characteristics of neuropathic pain only in NCP patients in the presence or absence of the clinical predictors of NCP†.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Ahmed Negida

Roles

Author response to Decision Letter 0

Decision Letter 1

Ahmed Negida

Roles

Acceptance letter

Ahmed Negida

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Table 4. Characteristics of neuropathic pain only in NCP patients in the presence or absence of the clinical predictors of NCP^†.