癌症病人於接受治療期間生物節律、癌症症狀、生活品質與存活期之關係

Relationships Among Circadian Rhythms, Cancer Symptoms, Quality of Life, and Survival in Cancer Patients During Active Treatment

張文蓓(Wen-Pei Chang)

指導教授 ： 林佳靜

臺北醫學大學/護理學院/護理學系碩士暨碩士在職專班/博士(2015年)

摘要

本研究以癌症病人之存活期作為主要之結果變項，除探討癌症病人於接受治療期間，其睡醒節律、疼痛、睡眠障礙對存活情形所造成的影響之現況外，更以肺癌病人為例，分析病人於接受治療期間其體內生物節律荷爾蒙濃度變化、睡醒節律變化、睡眠障礙、焦慮、憂鬱與疲憊症狀及生活品質之變化情形，並剖析肺癌病人於接受治療期間，上述之生物節律、癌症症狀及生活品質對其存活期之影響，並嘗試闡釋其影響機轉。總計四個主要子計畫，包括：
一、瞭解癌症病人在初接受癌症治療時，其疼痛與失眠影響存活情形之現況。
以回溯性世代追蹤設計，使用全民健康保險學術研究資料庫中之次級資料進行分析，擷取2004年第一次住院癌症病人，並計算出每日嗎啡類止痛藥物使用之劑量、並篩選出醫令中有無使用安眠藥物，串聯重大傷病證明明細檔中死亡日期至2004年至2007年止，以分析病人使用嗎啡類止痛藥物與安眠藥物對存活之影響。結果發現第一次因癌症住院之病人使用嗎啡類止痛藥物與安眠藥物與否，與其三年存活率極為相關；初診斷癌症之病人即有疼痛與或安眠問題存在，其存活時間會受到影響。
二、探討有癌痛之癌症病人於接受癌症治療時，其睡醒節律對存活情形之影響。
研究採長期追蹤，以2006年8月至2007年10月間，以癌症住院接受治療之疼痛病人為研究對象，後續存活情形追蹤至2013年7月31日。評估睡醒節律週期改變是否對存活率造成顯著影響。結果發現睡醒節律紊亂對正在接受治療的癌症疼痛住院病人存活有負向的影響，且睡醒節律為影響死亡的危險因子。尤其在身體功能狀態差的癌症疼痛病人，睡醒節律對存活情形之影響更為明顯。
三、比較接受不同治療癌症病人於治療期間，體內皮質醇濃度、褪黑激素濃度、睡醒節律、癌症症狀及生活品質之變化情形－以肺癌病人為例。
採前瞻縱貫性研究，並比較接受不同治療之肺癌病人於治療期間之體內皮質醇濃度、褪黑激素濃度、睡醒節律週期、症狀經驗（睡眠障礙、疲憊、焦慮及憂鬱）及生活品質之變化情形，由治療前追蹤至接受治療後第24週，共4次追蹤時間點。其中褪黑激素變化情形，於接受合併化學及放射線治療者與手術者較化學治療者變異係數低，但僅手術者褪黑激素變化情形與健康成人相同；接受口服標靶或口服化學治療藥物者比接受全身性化學治療藥物者生活品質佳，除疲憊、憂鬱與焦慮對生活品質有影響外，皮質醇斜率越平坦，生活品質也越差。
四、癌症病人接受治療期間，體內皮質醇濃度、褪黑激素濃度、睡醒節律、癌症症狀及生活品質與存活期之關係－以肺癌病人為例。
收案期間自2013年8月至2014年2月底，持續追蹤至2014年11月30日。以比較接受治療期間之肺癌死亡病人與肺癌存活者，此二族群其體內皮質醇濃度、褪黑激素濃度、睡醒節律週期、癌症症狀及生活品質變化與存活期之差異。發現肺癌死亡病人比存活病人顯著有更高比例之睡醒節律紊亂、睡眠問題、焦慮、憂鬱和重度疲憊問題，生活品質也較差。除此之外，存活病人皮質醇濃度平均值也顯著低於死亡者；且睡醒節律、褪黑激素平均濃度與存活期相關。
本研究於子計畫一使用全民健康保險學術研究資料庫之資料進行分析，以瞭解癌症病人在初接受癌症治療時，其疼痛與失眠影響存活情形之現況，此結果能提供醫療專業人員及醫事機構執行癌症病人疼痛與安眠的評估及處置之參考。而子計畫二採長期追蹤，以探討有癌痛之癌症病人於接受癌症治療時，其睡醒節律對存活情形之影響，此研究則具體證實睡醒節律與身體功能狀態與癌症病人死亡風險有相關性。子計畫三則以肺癌病人為例，經由比較接受不同治療之肺癌病人於治療期間，體內皮質醇濃度、褪黑激素濃度、睡醒節律、癌症症狀及生活品質之變化情形。此結果能能協助臨床醫護人員瞭解肺癌病人在接受治療期間，體內皮質醇濃度、褪黑激素濃度、睡醒節律、癌症症狀及生活品質之變化情形，藉此提醒臨床專業人員必需發展適合之護理措施，以進而改善肺癌病人之不適症狀及生活品質。此外，子計畫四則推估肺癌病人接受治療期間，體內生物節律與癌症症狀及生活品質及存活期之關係，藉此能提供臨床醫護人員規劃合宜之相關措施，以幫助肺癌病人的癌症症狀控制更具成效。
總合以上四個子計畫之結果，腫瘤本身與各種癌症治療方法經常會引發病人在治療過程中的困擾症狀，包括：疼痛、睡眠障礙、焦慮、憂鬱與疲憊等。這些症狀不僅彼此之間相互影響，這些症狀反過來也影響癌症治療的效果。經由本研究，顯示處於慢性壓力下之癌症病人，其體內生物節律荷爾蒙濃度和睡醒節律等之神經內分泌系統產生顯著變化，這些變化是上述症狀的深層原因之ㄧ，也是這些症狀可以影響癌症治療效果的可能機轉。本研究結果可提供臨床工作者將生物節律變化情形與症狀當作估計癌症病人生活品質與存活期之參考指標，也能據此發展出改善病人生活節律與症狀困擾的處置措施，可能有助病人之生活品質，或對延長其存活期也會有正面效益。

關鍵字

癌症 ； 治療 ； 生物節律 ； 癌症症狀 ； 生活品質 ； 存活期

並列摘要

The major resultant variant in this study is the survival of cancer patients. We had thoroughly investigaged the influences of the circadian rhythms, cancer symptoms, pain, insomnia during cancer treatments to their survival. Besides, we had used lung cancer as an example to further study the changes of circadian rhythm, levels of the circadian rhythm regulating hormone, insomnia, depression, fatigue, and quality of life during the cancer treatment periods. We had examined the magnitude of the influences of the circadian rhythm, cancer symptoms, and quality of life during treatment periods of lung cancer patients to their survival, and learnt the possible underlying mechanisms of these influences. There were four major sub-plans in this study:
1.To understand the influence of the pain and insomnia of cancer patients during the starting periods of their cancer treatments to their survivals. We had designed a retrospective cohort study and extracted the data from the National Health Insurance Research Database for analysis. We collected the data of the cancer in-patients who had admitted for their first-time cancer treatments in 2004. We calculated their daily used dosage of opioid analgesics, the usage or not of hypnotics, and then connected them to the dates of death between 2004 and 2007 to analyze the influence of the usage of opioid analgesics and/or hypnotics to their survivals. We had found that the cancer patients’usage of opioid analgesics and/or hypnotics during the first-time admission for cancer treatment was significantly correlated to their survivals. The pain and insomnia symptoms in the newly diagnosed cancer patients negatively affect their survivals. All the medical professionals and institutes related to cancer treatments can use our findings as important reference to evaluate and manage the pain and insomnia problem of their cancer patients. We believe that our findings contributing a lot to improve the cancer patients’qualities of life, even survivals.
2.To explore the influence of the circadian rhythm of cancer patients with pain during their cancer treatments to their survivals. We used a longitudinal follow-up study to include the inpatients admitted for cancer treatment from 2006 August to 2007 October as studying population. Their survivals were followed-up till July 31, 2013. Our aim was to know whether or not the change of their circadian rhythms had significant influence on their survivals. We found that the irregularities of the cancer in-patients’ circadian rhythms during cancer treatments did negatively influence their survivals, and the circadian rhythm was a risk factor of death. This effect was particularly prominent in the cancer patients with worse general fitness. All the medical professionals and institutes related to cancer treatments can use our findings for prognosis evaluation to better their treating plans for every patient.
3.Using lung cancer patient as example, comparing the change of the cortisone level, melatonin level, circadian rhythm, cancer symptoms, and quality of life during the treatment periods. We designed a prospective longitudinal study to compare the change of the cortisone level, melatonin level, circadian rhythm, cancer symptoms (sleep disturbance, fatigue, anxiety and depression), and quality of life during the treatment periods. We examined each cancer patients’levels in four separate times form immediate before the cancer treatment to the 24th week after the starting of the treatment. The results showed that the changes of melatonin levels were larger in the cancer patients undergone concurrent chemo-radiotherapy or surgical treatments than that in patients only undergone chemotherapies, which might be related to their disease stages. The patients took oral target therapies or chemotherapies had better quality of life than the patients underwent intra-venous systemic chemotherapy. Depression, anxiety, and fatigue influence the quality of life of patients, and we also found that the flatter the blood level slops of cortisone of the cancer patients, the worse their quality of life. These findings can help the medical professionals and institutes to develop patient-centered nursing care procedure according the cancer treatments the patients are undergoing to improve their quality of life.
4.The influence of the lung cancer patients’cortisone levels, melatonin levels, circadian rhythms, cancer symptoms, and qualities of life during the treatment periods to their survivals. We input the data of the patients admitted for lung cancer treatments form 2013 August to 2014 February and followed-up them to November 30th, 2014. Our aim was to compare the difference of the cortisone levels, melatonin levels, circadian rhythms, cancer symptoms, and qualities of life during the treatment periods in the survivors and the dead. The results revealed that the died lung cancer patients significantly had more irregulaity of circadian rhythm, sleep disturbance, anxitty, depression, fatigue, and quality of life than the survivors. Besides, the survivors’s mean cortisone levels were significantly lower than that of the dead. Furthermore, our results also showed that the circadian rhythm, and mean level of melatonin both can help predict the survival. The clinicians can use our study as a base to help improve their treatment plans for the lung cancer patients to promote their survival.

並列關鍵字

Cancer ； Treatment ； Circadian Rhythm ； Cancer Symptom ； Quality of Life ； Survival

參考文獻

Chen, M. L., Yu, C. T., & Yang, C. H. (2008). Sleep disturbances and quality of life in lung cancer patients undergoing chemotherapy. Lung Cancer, 62(3), 391-400. doi: 10.1016/j.lungcan.2008.03.016

行政院衛生署（2010，6月3日）．98年國人主要死因統計（以ICD-10編碼），2011年9月1日取自 http://www.doh.gov.tw/CHT2006/DM/DM2_p01.aspx?class_no=25&level_no=1&doc_no=76013

Abercrombie, H.C., Giese-Davis, J., Sephton, S., Epel, E. S., Turner-Cobb, J. M., & Spiegel, D. (2004). Flattened cortisol rhythms in metastatic breast cancer patients. Psychoneuroendocrinology. 29(8), 1082-1092.

Agarwal, M., Brahmanday, G., Chmielewski, G. W., Welsh, R. J., & Ravikrishnan, K. P. (2010). Age, tumor size, type of surgery, and gender predict survival in early stage (stage I and II) non-small cell lung cancer after surgical resection. Lung Cancer. 68(3), 398-402. doi:10.1016/j.lungcan.2009.08.008

Ancoli-Israel, S., Liu, L., Marler, M. R., Parker, B. A., Jones, V., Sadler, G. R. et al. (2006). Fatigue, sleep, and circadian rhythms prior to chemotherapy for breast cancer. Support Care Cancer, 14(3), 201-209. doi:10.1007/s00520-005-0861-0