Background
Colorectal cancer is one of the leading causes of cancer incidence and death worldwide [
1]. Although colorectal cancer mortality is declining in the developed countries, its incidence and mortality are increasing in other countries, including Korea, which are probably due to westernization of lifestyle [
2,
3].
Body mass index (BMI) of ≥ 30.0 kg/m
2 and 25.0–29.9 kg/m
2 are proposed by the World Health Organization (WHO) for classification of obesity and overweight, respectively [
4]. The prevalence of obesity using this definition is variable in different countries throughout the world [
5]. According to the definition, the prevalence of obesity is higher than 20 % in many countries in Western Europe and North America, whereas it is less than 10 % in Asian countries including Korea and Japan [
5]. Considerable efforts have been made to identify refined cut-offs of obesity for Asian countries in order to better reflect the health risk and provide appropriate action points [
6,
7]. In Korea, BMI cut-off of 25 kg/m
2 and 23.0–24.9 kg/m
2 is used for the definition of obesity and overweight, respectively [
8,
9].
While many epidemiology studies have shown that obesity increases the risk of developing colorectal cancer, there has been conflicting data on the prognostic impact of obesity in stage II and III colorectal cancer patients [
10‐
15]. Most of the previous studies were conducted in Caucasian population and to our knowledge no study has investigated the effect of obesity in Asian colorectal patients treated with adjuvant chemotherapy thus far. Considering the increase in the prevalence of colorectal cancer and obesity in some Asian countries and the difference in BMI distribution between Asian and Caucasian, there is an urgent need for data from Asian patients. In addition, very limited data regarding body weight change after colorectal cancer treatment and its impact on treatment outcome is available [
12]. Although body weight gain during the period of adjuvant chemotherapy is frequently observed in daily practice, its frequency and prognostic implication has not been studied in detail.
This study was undertaken to investigate how obesity and body weight change during chemotherapy influences prognosis in Korean colorectal cancer patients receiving adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy in order to provide preliminary answers to the above questions.
Discussion
In the present study, we have investigated the impact of obesity and body weight change during chemotherapy on the treatment outcome of Korean colorectal cancer patients receiving adjuvant FOLFOX chemotherapy. While obesity and colorectal cancer has become one of the major health problems in Asian countries including Korea, there has been paucity of data regarding obesity among Asian colorectal cancer patients [
19,
20]. To our knowledge this is the first Asian study to evaluate the prognostic role of body weight change during adjuvant chemotherapy treatment. We observed that baseline BMI is not associated with DFS, but body weight gain (≥ 5 kg) during the adjuvant chemotherapy has deleterious effect in overweight or obese patients (BMI ≥ 23.0 kg/m
2).
Although there has been some controversy in the prognostic role of obesity in stage II or III colorectal cancer patients, most data suggest negative prognostic role of obesity. From the result of Adjuvant Colon Cancer Endpoints (ACCENT) database, which is a pooled resource of over 20,000 colon cancer patients in adjuvant chemotherapy trials, obesity was associated with inferior outcome [
15]. The adverse prognostic effect was only observed in male patients, but there are inconsistent data regarding gender-related prognostic difference of obesity [
10,
14,
15].
However, these studies were all conducted in Western countries where BMI distribution is different form Asian population. In our study, 35.6 % of patients had BMI ≥ 25.0 kg/m
2 and only 2.9 % of patients had BMI ≥ 30 kg/m
2, which are similar to the incidence of Taiwanese and Japanese colorectal cancer patients (4.2 and 1.5 %, respectively) [
19,
20]. In contrast, 53.6 % of patients have BMI ≥ 25.0 kg/m
2 and 17.6 % have BMI ≥ 30 kg/m
2 in the ACCENT study population [
15]. Because of such a difference in BMI distribution between Asian and Caucasian population, we could not directly apply the findings from Western data to Asian colorectal cancer patients.
There are many studies evaluating the prognostic role of weight gain after cancer diagnosis in breast cancer patients [
21‐
23]. Weight gain after breast cancer diagnosis was associated with higher rates of recurrence and mortality [
21]. However, only one study has evaluated the prognostic role of weight change in stage III colon cancer patients [
12]. In contrast to breast cancer, there was no prognostic role of weight gain in stage III colon cancer patients in the Cancer and Leukemia Group B 89803 study which examined the addition of irinotecan to adjuvant 5-fluorouracil and leucovorin [
12]. In the present study, while there was no prognostic role of body weight change in the entire cohort, weight gain was a negative prognostic factor in overweight or obese patients. The discordant results may be attributable to differences in ethnicity, BMI distribution, chemotherapy regimen, and timing of body weight measurements. Meyerhardt and colleagues compared body weights measured at 4 months (in the middle of adjuvant chemotherapy) and 14 months after surgery (6 months after completion of chemotherapy) [
12]. As we measured body weight change during the adjuvant chemotherapy period (before surgery and at the last cycle of chemotherapy), body weight gain in the present study may reflect the direct influence of weight gain on chemotherapy sensitivity. Obesity leads to decreased level of circulating adiponectin and increased level of insulin-like growth factor 1 and leptin, which contribute to an increased risk of colorectal cancer [
24]. Moreover, there are data that tumor expression of leptin is associated with chemotherapy resistance [
25]. Therefore, it is tempting to speculate that body weight gain during the adjuvant chemotherapy period may have altered adipokine levels, which in turn contributed to chemotherapy resistance. Dynamic changes in adipokine levels might be more deleterious than the baseline BMI and the deleterious effect is potentiated in the higher BMI patients. However, because of limited number of patients, we could not evaluate effect size between weight gain and DFS. Future large prospective study is needed to confirm our result.
Adding expensive targeted agents such as cetuximab or bevacizumab to adjuvant chemotherapy have failed to decrease recurrence in stage III colon cancer patients [
26‐
29]. However, physical activity appears to reduce the risk of cancer recurrence and mortality in stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [
30]. In patients receiving adjuvant chemotherapy, life style modification may be a cost effective approach to improve treatment outcome. Future prospective study is needed to confirm whether life style interventions can improve the outcome. In the meantime, patients may be advised to maintain their body weight during adjuvant chemotherapy period.
There are several limitations in our study. This study was retrospectively designed that we lacked other important data of body habitus such as weight circumference, fat distribution and lifestyle factors including diet, physical activity and smoking that may have interaction with BMI and weight change. Moreover, we do not have body weight data during follow-up period after completion of chemotherapy. Therefore, it is essential to establish an Asian prospective colorectal cancer cohort to overcome these limitations and comprehensively study the impact of obesity and lifestyle factors on prognosis of Asian patients. Another limitation is the relatively small sample size that we could not perform more detailed analyses including sub-analysis according to patient sex. However, the patient cohort was homogenous that all patients received surgery at a high-volume center and received same adjuvant chemotherapy regimen. Lastly, we could not evaluate overall survival due to limited number of death events during the relatively short duration of follow-up, albeit the 3-year DFS has been demonstrated to have a good correlation with 5-year overall survival in colon cancer [
31].
Competing interests
The authors declare no conflict of interest.
Authors’ contributions
SWH and DWL were involved in study concept and design. SWH, DWL, YC, KHL, TYK, DYO, SAI, YJB, JWP, SBR, SYJ, GHK, KJP and TYK involved in data acquisition. Analysis and interpretation of data was done by SWH and DWL. Manuscript writing was made by SWH and DWL. Manuscript review and final approval was done by SWH, DWL, YC, KHL, TYK, DYO, SAI, YJB, JWP, SBR, SYJ, GHK, KJP and TYK.