ROK study-C (Rainbow of KIBOU study-colorectum): a colorectal cancer survivor cohort study on food, nutrition, physical activity, psychosocial factors and its influences on colorectal cancer recurrence, survival and quality of life in Japan

Self-administrated questionnaires collect information on demographics (education, marital status, number of children, living situation, income, occupation and social activities), height, body weight, history of body weight, smoking history, history of medication including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), developmental history, family health history, and for women, menopausal status, menstrual and reproductive history and hormone use.

Although the etiological role of diet such as alcoholic beverages, red meat processed meat in CRC has been recognized [9], much less is known the association between diet and CRC prognosis. In a few study accessed the relationship between diet or nutrition and CRC prognosis, it was shown that the risk of recurrence or death increases with ‘Western diet’ (meals high in meats, fats, refinded grains, and desserts) [14], and the risk is lowered in people with high blood vitamin D concentrations [15]. However there is insufficient evidence to confirm these findings [11]. Therefore, in ROK Study-C, we measured participants’ food intake including meat and vegetables, nutrients such as vitamins, and dietary patterns, and investigated the relationship between these factors and prognosis. In this study, a food frequency questionnaire (FFQ) is used to assess the average intake of 147 food and beverage items over the previous year [16]. For most food items, participants were asked about consumption frequency and their usual portion size. The validity and reproducibility of the FFQ had already been established as reasonable [17‐19].

In addition to diet and exercise, many patients are interested in and actively practice CAM. This includes the use of oral and topical agents and health-promoting methods such as acupuncture, moxibustion, and yoga, which differ from health insurance-supported practice. Although approximately 50% of cancer patients utilize CAM in Japan [20], there is insufficient evidence regarding its survival efficacy [7, 21]. The use of CAM is assessed with a self-administrated questionnaire based on previous studies. Participants are asked at each survey point about the use (including before diagnosis), total length of use, frequency, cost, and duration, reasons for starting and withdrawing from each CAM [13].

Low levels of physical activity is a convincing risk factor for CRC [9]. Further in relation to the prognosis of CRC, the level of physical activity is one of the most promising factors for improving prognosis [11, 12, 22]. In addition, the increase in the amount of physical activity is also important in terms of improving the QOL of cancer patients and preventing other cancers and cardiovascular diseases [12], so it may lead to reduce all-cause mortality of CRC survivors.

In ROK Study-C, a self-administrated questionnaire previously validated during the JPHC Study is used to assess physical activity [23]. Prior to surgery, participants are asked about their typical level of physical activity during the year prior to diagnosis and again 1 year and 5 years after surgery.

Since obesity is also a convincing risk factor for CRC [9], to prevent overweight may improve the prognosis of CRC survivors. Previous studies have shown a relationship between higher body mass index (BMI) and body fatness before or at the time of diagnosis and a higher all-cause mortality or CRC recurrence or CRC-specific mortality, however, results were not consistent [11].

While BMI is not a valid measure for fat distribution or body composition, research using other markers such as waist and hip circumference and computed tomography (CT) scan [24, 25].

In ROK Study-C, in addition to BMI, data are collected via CT-images for the assessment of body composition. CT-images are retrieved from medical records of all participants as shown in Fig. 2.

Participants were also asked about meals and taste preferences, bathing, sleeping, dental health, and use of the Internet.

CRC survivors experience many psychosocial challenges and concerns during not only pre-operative but also post-operative period. Psychosocial issues reported in CRC survivors include depression, anxiety, disturbance in body image, avoiding coping, hopelessness and stress related to physical and psychosocial changes [26‐33]. There is a lack of research exploring the relationship between these psychosocial problems and CRC prognosis. Some previous studies have reported an association between hopelessness, coping style, and recurrence, whereas others have found no association, and consistent and reliable results have not been obtained [33].

In ROK Study-C, psychosocial problems are assessed at each survey point. The Japanese version of Hospital Anxiety and Depression Scale (HADS) is used to measure the level of depression and anxiety [34]. To assess the stress, a self-administrated questionnaire based on previous studies and interviews of cancer survivors is used. Participants are asked the existence and degree of 14 stressful conditions from cancer [13].

Our goal of supporting cancer survivors is not absence of psychosocially illness but presence of psychosocially wellness. So ROK Study-C focuses on well-beings of CRC survivors. In recent years, conceptions of psychosocial well-being such as ‘ikigai’ (‘something that makes one’s life seem worth living’, described in detail below), ‘hope’ (not ‘hopeless’ but ‘hope’) [35, 36], ‘posttraumatic growth (PTG) and benefit finding (BF),’ and social support are beginning to be noticed in relation to adaptation to adverse circumstances such as illness and improvement of QOL.

Ikigai, in Japanese, is used to describe a concept closer to ‘a purpose in life’, ‘a reason to live’ or ‘something that makes one’ life seem worth living’, and includes various factors such as family, hobbies/enjoyment, connection with friends/community, social participation, etc. [37]. Having ikigai only enriches life, but also draws attention to health outcomes. In Japanese studies, having ikigai demonstrated lower risk of psychosocial problems such as depression and lower mortality from all cause, cerebrovascular diseases and ischemic heart disease [38‐42]. However, the associations between cancer mortality or incidence and ikigai were inconsistent [41‐44]. Though there is no term fully comparable in English, the concept of ikigai is becoming understood around the world. In ROK Study-C, a self-administrated questionnaire based on previous studies and interviews of cancer survivors is used to assess ikigai [13, 38]. Participants are asked the existence of 7 items of ikigai and space is available to report the ikigai that are not specified on the questionnaire.

Hope is one of the most commonly used indicators of subjective well-being. Hope is one of the essential elements of life that forms the basis of life in every stage of peoples’ lives, including cancer survivors [35, 36]. Hope helps people find meaning in struggle and maintain a will to endure even in adversity, and is thought to be related to adaptability and coping strategies to adapt to difficulty [35, 36, 45, 46]. A high level of hope plays an important role in maintaining one’s physical condition in cancer patients as well, and has been shown to be strongly associated with adaptation to cancer [47, 48]. However, few longitudinal studies have examined the association between hope and prognosis in CRC survivors. To evaluate the level of hope, we employ the Japanese version of Herth Hope Index (HHI) [49].

Exposure to stressful and traumatic events can have severe and chronic psychological consequences. Researches on adversities have long been focused on the negative influence of these events on changes in peoples’ lives [50‐52]. These theories have made a great contribution to understanding the difficulties of people in times of adverse life events. However, in the past 20 years, from the criticism of emphasizing only negative influences, researches have also aimed to consider the positive impact of adversities. Many studies focused on positive psychology have reported positive changes such as posttraumatic growth (PTG) and benefit finding (BF) in people who have experienced various traumatic events such as disease, disaster, bereavement, crime, etc. [53‐56]. Such positive changes are products brought about in the process of adaptation to an adversity and can also be a coping strategy for adaptation. Thus, they play important role in the cognitive adaptation theory to adversity, and expect to reconstruct lives of people in adversities. A few studies have found that PTG and BF were experienced relatively large proportion of CRC survivors [57‐59], however, prevalence of PTG and BF in long-term CRC survivor, factors that develop positive changes, and the association between positive changes and CRC prognosis have not been sufficiently examined. In this study, a self-administrated questionnaire based on previous studies and interviews of cancer survivors is used to assess PTG and BF [13, 38].

In ROK Study-C, psychosocial well-beings are assessed at each survey point.

Biomarkers from blood samples will be investigated for the association with prognosis and treatment effect. The following is the list of candidate substances to be measured: endogenous hormones (estrone, estradiol, sex-hormone binding globulin, androgen, etc.), insulin and insulin-like growth factor (C-peptide, IGF-1, IGFBP-3, IGFBP-1, etc.), adipocytokines (adiponectin, leptin, etc.), markers of inflammation (C-reactive protein, etc.), nutrients (isoflavones, folate, 25-hydroxyvitamin D, etc.), and other substances (markers of oxidative stress, etc.). Germline mutations will be used for the association with prognosis and toxicity of drugs. The following is the list of candidates genes to be assessed: genetic polymorphisms of hormone synthesized and metabolized genes, hormone receptor genes, genes related to insulin-like growth factor, genes related to one-carbon metabolism, vitamin D receptor genes, genes related to oxidative stress, and genes related to the metabolism of therapeutic agents. Tissue biomarkers will be used for sub-classification by molecular subtype to investigate the exposure-tumor subtype interaction.

Follow-up in the daily practice of NCC Hospital is based on the Japanese guidelines [60], as shown in Fig. 2. In cases involving hospital transfers or deaths, inquiries will make with the receiving hospital or be linked with data contained in the cancer registry.

A number of instruments are used in ROK Study-C to measure various dimension of QOL at each survey points. The MOS 36-item Short Form Survey (SF-36) [61] is used as a comprehensive QOL. Cancer-related QOL is assessed by the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) [62] and Colorectal cancer 29 (CR-29) [63]. Wexner’s Scale [64], an index of postoperative anal function is used to evaluate bowel movement function. International prostate score (I-PSS) [65] and overactive bladder symptom score (OABSS) [66, 67] are used to evaluate urinary function.

For sexual function in men, a 15-item version of the International Index Erectile Function (IIEF) [68] score is used. For women, the Female Sexual Function Index (FSFI) [69] is used. The FSFI was developed as an evaluation scale for multidimensional and objective measurement of female sexual function, and it has been translated into approximately 30 languages and is widely used. Although the original version of the FSFI contains questions regarding participants’ condition over the past month, the Japanese version considered the frequency of sexual intercourse in Japan and this period was changed to the past 3 months, and the validity of this change was validated [70].

The Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0, Japan Clinical Oncology Group/Japanese Society of Clinical Oncology (JCOG/JSCO) version is used to evaluate adverse events, and the evaluation will be carried out in accordance with NCC Hospital postoperative treatment guidelines.