Association between circadian rhythms and chemotherapy-induced peripheral neuropathy in breast cancer patients = 유방암 환자의 일주기리듬과 항암화학요법유발 말초신경병증의 연관성

다국어 초록 (Multilingual Abstract)

Background and Aim
Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent adverse effect of chemotherapy. Recent research has indicated a potential association between the circadian rhythm and CIPN. The objective of this study was to investigate the circadian rhythm of breast cancer patients before chemotherapy and its association with CIPN.

Methods
In this prospective observational study, 39 participants diagnosed with breast cancer were enrolled. Their biological rhythms were evaluated by measuring their serum cortisol levels during a 24-hour period of overnight hospitalization. Behavioral rhythm was evaluated using actigraphy and sleep diaries to assess rest-activity rhythm and sleep-wake rhythm. The circadian variables of each rhythm were calculated using Cosinor and nonparametric analysis, and sleep phase variables were measured with sleep analysis. Phase angle difference (PAD) of cortisol acrophase and sleep end time was also measured to assess circadian misalignment. CIPN was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN20 (EORTC QLQ-CIPN20) at before chemotherapy (T0), third and seventh cycles of chemotherapy (C3 and C7, respectively), one-month post-chemotherapy (T1) and nine-month post-chemotherapy (T2). The circadian and sleep phase variables were grouped according to their median value, and the group and time effect was examined.

Results
The linear mixed effects model for circadian variables of serum cortisol, actigraphy, and sleep phase variables revealed no significant association with CIPN. When circadian misalignment was assessed based on the PAD, the lower PAD group exhibited a significant advancement of cortisol acrophase in the lower PAD group relative to the higher PAD group (p<0.001). Furthermore, the EORTC QLQ-CIPN20 global score and sensory scale score of the lower PAD group at T1 were found to be significantly higher in comparison to the higher PAD group, with mean differences of 18.61 ± 5.21 (p<0.001) and 28.68 ± 7.46 (p<0.001), respectively.

Conclusion
The present study is the inaugural research to evaluate the association between the circadian rhythm and CIPN based on objective measurement of biological and behavioral rhythms and their circadian misalignment in breast cancer patients. Findings from the present study suggest that individuals with lower pulse amplitude (PAD), whose behavioral rhythm is delayed in relation to their biological rhythm, exhibit a heightened susceptibility to CIPN compared to those with higher PAD. Further research with a larger sample size is required to gain a comprehensive insight into the mechanisms by which circadian misalignment affects CIPN.

국문 초록 (Abstract)

연구배경
항암화학요법유발 말초신경병증(chemotherapy-induced peripheral neuropathy, CIPN)은 암환자들이 흔히 경험하는 항암 부작용이다. 최근 CIPN과 일주기리듬과의 관련성이 제시되었으나, 객관적인 일주기리듬 평가를 기반으로 수행한 연구는 부족하다. 본 연구는 항암화학요법 시행 전 유방암 환자의 일주기리듬을 객관적으로 평가하고, CIPN과의 관련성을 분석하고자 하였다.

연구방법
본 연구는 전향적 관찰연구로 시행하였으며, 39명의 유방암 환자를 대상으로 일주기리듬과 CIPN을 평가하였다. 생물학적 일주기리듬은 1박 2일간 입원을 통해 혈중 코티솔 농도를 측정하여 분석하였다. 행동학적 일주기리듬은 액티그래피와 수면일지를 이용하여 활동-휴식 리듬과 수면-각성 주기를 평가하였다. 각 일주기리듬 변수는 Cosinor 분석과 nonparametric 분석을 이용하여 계산하였다. 또한 코티솔 정점시간과 수면 종료시간의 위상각 차이(phase angle difference, PAD)를 측정하여 일주기리듬 엇갈림(circadian misalignment)를 평가하였다. CIPN은 the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN20 (EORTC QLQ-CIPN20)를 사용하여 항암화학요법 시행 전(T0), 3번째 및 7번째 투약일(C3, C7), 항암화학요법 종료 1개월 및 9개월(T1, T2) 시점에 평가하였다. 각 일주기리듬 지표는 중앙값으로 범주화하여, CIPN에 대한 그룹 및 시점 효과를 분석하였다.

연구결과
선형혼합모형을 이용한 통계분석 결과, 개별 일주기리듬의 일주기 지표와 시점의 CIPN에 대한 효과는 유의하지 않았다. 반면, 일주기리듬 엇갈림을 의미하는 PAD 그룹의 특성을 분석하였을 때, lower PAD 그룹은 higher PAD 그룹에 비하여 코티솔 정점시간이 이른 것으로 나타났다(p<0.001). 또한 T1 시점에서 lower PAD 그룹의 EORTC QLQ-CIPN20의 종합점수와 감각신경 점수는 higher PAD에 비해 높은 것으로 나타났으며, 그룹간 차이는 각각 18.61 ± 5.21점 (p<0.001)과 28.68 ± 7.46점 (p<0.001)으로 나타났다.

결론
본 연구는 유방암 환자에서 일주기리듬과 일주기리듬 엇갈림을 객관적으로 측정하고, CIPN과의 관련성을 밝힌 최초의 연구이다. 본 연구 결과는 생물학적 리듬에 비해 행동학적 리듬이 지연된 lower PAD 그룹이 higher PAD 그룹에 비하여 CIPN에 보다 취약함을 시사한다. 추후 일주기리듬 엇갈림이 CIPN에 영향을 미치는 기전을 밝히기 위하여 보다 많은 참여자를 기반으로 한 연구가 필요하다.

목차 (Table of Contents)

• 1. Introduction 1
• 1.1 The necessity for research into CIPN 1
• 1.2 Circadian rhythms and CIPN 4
• 1.3 Circadian characteristics of cancer patients 5
• 1.4 The assessment of circadian rhythms 8
• 1.5 Research hypothesis 12
• 2. Methods 15
• 2.1 Study design 15
• 2.1.1 Study participants 15
• 2.1.2 Calculation of sample size and power analysis 17
• 2.1.3 Study timeline 18
• 2.2 Assessment of CIPN 20
• 2.3 Assessment of circadian rhythm 21
• 2.3.1 Serum cortisol concentration 21
• 2.3.2 Actigraphy protocol 23
• 2.3.3 Sleep diary 24
• 2.4 Calculation of circadian variables 25
• 2.4.1 Data preprocessing process 25
• 2.4.2 Cosinor analysis 27
• 2.4.3 Nonparametric analysis 28
• 2.4.4 Area under the curve 29
• 2.4.5 Sleep analysis 29
• 2.4.6 Circadian misalignment 30
• 2.5 Assessment of psychobehavioral characteristics 32
• 2.5.1 Morningness-Eveningness Questionnaire (MEQ) 32
• 2.5.2 Munich Chronotype Questionnaire (MCTQ) 32
• 2.5.3 Hospital Anxiety and Depression Scale (HADS) 33
• 2.5.4 Pittsburgh Sleep Quality Index (PSQI) 34
• 2.6 Statistical analysis 34
• 3. Results 37
• 3.1 Study participant recruitment 37
• 3.2 Association between serum cortisol rhythm and CIPN 42
• 3.2.1 Baseline characteristics of the participants 42
• 3.2.2 Circadian and sleep characteristics according to circadian variables of serum cortisol 45
• 3.2.3 CIPN according to circadian variables of serum cortisol 48
• 3.3 Association between actigraphic rhythm and CIPN 50
• 3.3.1 Baseline characteristics of the participants 50
• 3.3.2 Circadian and sleep characteristics according to circadian variables of actigraphy 55
• 3.3.3 CIPN according to circadian variables of actigraphy 57
• 3.4 Association between sleep phase and CIPN 61
• 3.4.1 Baseline characteristics of the participants 61
• 3.4.2 Circadian and sleep characteristics according to sleep phase 61
• 3.4.3 CIPN according to circadian variables of sleep phase 66
• 3.5 Association between PAD of cortisol acrophase and sleep end time and CIPN 68
• 3.5.1 Baseline characteristics of the participants 68
• 3.5.2 Circadian and sleep characteristics according to PAD 68
• 3.5.3 CIPN according to PAD 72
• 4. Discussion 77
• References 87
• Abstract in Korean 96