This study aimed to investigate the impact of underweight status on the prognosis of advanced-stage ovarian cancer. A total of 360 patients with stage III-IV epithelial ovarian cancer were enrolled and divided into three groups by body mass indexes (BMIs): underweight (BMI < 18.5 kg/m2); normal weight to overweight (18.5 kg/m2 BMI < 27.5 kg/m2); obesity (BMI ≥ 27.5 kg/m2). Progression-free survival (PFS), overall survival (OS), CA-125, and neutrophil to lymphocyte ratio (NLR) as a marker reflecting host inflammation and immunity were compared among the three groups according to the three treatment times: at diagnosis; after surgery; and after treatment. Only underweight status after treatment was associated with poor OS in comparison with normal weight to overweight or obesity (mean value, 44.9 versus 78.8 or 67.4 months;
Excessive bodyweight is an established risk factor for several types of cancer. In particular, epidemiologic data show that obesity defined as body mass index (BMI) ≥ 30 kg/m2 increases cancer risk and cancer-specific mortality [
However, the impact of underweight status on prognosis has not been adequately addressed. Although underweight status has been reported to be a high-risk factor for recurrence and death in patient with breast cancer [
Therefore, we investigated the impact of underweight status on prognosis in patients with advanced-stage ovarian cancer, depending on the time of measurement of BMI in relation to the treatment. Thus, we evaluated the relationship between underweight status and cancer progression, with related changes of systemic inflammation and immunity.
Clinicopathologic data for the current study were retrieved from a database of 360 patients registered in two tertiary medical centers (Seoul National University Hospital and Seoul National University Bundang Hospital) between 2000 and 2011. The current study was approved by the Institutional Review Board of Seoul National University Hospital. The patients’ medical records were reviewed retrospectively. Informed consent was not required since the current study was conducted by a retrospective review of medical records.
We included patients with the following inclusion criteria: those with epithelial ovarian cancer; those with advanced-stage disease, in particular, the International Federation of Gynecology and Obstetrics (FIGO) stage III-IV disease; those who underwent staging operation and taxane- and platinum-based chemotherapy; those with BMIs measured at three treatment points including “at diagnosis,” “after surgery,” and “after treatment.” We excluded patients with nonepithelial ovarian cancer, synchronous or metachronous cancer, and insufficient data for investigating the impact of BMI on survival.
BMIs at diagnosis, after surgery, and after treatment were defined as those measured at diagnosis, before the first administration of adjuvant chemotherapy, and after the last administration of adjuvant chemotherapy. Furthermore, all patients were classified into four groups based on the following BMI criteria suggested by the World Health Organization for the Asian population: underweight (BMI < 18.5 kg/m2); normal (18.5 kg/m2 ≤ BMI < 23.0 kg/m2); overweight (23.0 kg/m2 ≤ BMI < 27.5 kg/m2); and obesity (BMI ≥ 27.5 kg/m2) [
To evaluate the potential of cancer progression and related changes of systemic inflammation and immunity, serum CA-125 level and neutrophil to lymphocyte ratio (NLR) were investigated. NLR is known as a prognostic factor for recurrence and death in patients with ovarian cancer [
Clinicopathologic characteristics including age, grade, FIGO stage, histology, neoadjuvant chemotherapy, cycles of adjuvant chemotherapy, optimal debulking surgery, progression-free survival (PFS), and overall survival (OS) were collected. Patients treated with neoadjuvant chemotherapy received three cycles of taxane- and platinum-based chemotherapy before surgery, and optimal debulking surgery was considered when the size of residual tumor was less than 1 cm in the longest diameter. PFS was defined as the time that elapsed from the date after completion of the primary treatment to the date of clinically proven recurrence. OS was defined as the time that elapsed from the date of diagnosis to the date of cancer-related death or end of the study.
Kruskal-Wallis, Mann-Whitney
Clinicopathologic characteristics of all patients are depicted in Supplementary Table 1 (see Supplementary Material available online at
Among 360 patients, the following conditions were identified: underweight, normal, overweight, and obesity in 12 (3.3%), 162 (45.0%), 150 (41.7%), and 36 (10.0%) patients, respectively,
Underweight patients with advanced-stage ovarian cancer according to the treatment time.
After treatment, patients with hypertension were observed in 2 out of 29 underweight (6.9%), 20 out of 146 normal (13.7%), 19 out of 157 overweight (12.1%), and 13 out of 28 obesity (46.4%). The prevalence of hypertension significantly increased as the patient’s BMI after treatment increased toward obesity (
We compared PFS and OS among underweight, normal to overweight, and obesity patients, according to the treatment time. As a result, only patients with underweight status
Clinicopathologic factors affecting progression-free and overall survivals in all 360 patients with advanced-stage ovarian cancer.
Characteristics | Univariate | Multivariate | ||||
---|---|---|---|---|---|---|
HR | 95% CI |
|
Adjusted HR | 95% CI |
|
|
Progression-free survival | ||||||
≥53 years | 1.04 | 0.82–1.32 | 0.74 | — | — | — |
Stage IV disease | 1.27 | 0.95–1.69 | 0.11 | — | — | — |
Grade 3 disease | 1.11 | 0.80–1.53 | 0.53 | — | — | — |
Nonserous histology | 1.26 | 0.95–1.67 | 0.11 | — | — | — |
No neoadjuvant chemotherapy | 1.62 | 1.19–2.20 | <0.01 | 1.84 | 1.18–2.87 | <0.01 |
≤6 cycles of adjuvant chemotherapy | 1.03 | 0.81–1.32 | 0.81 | — | — | — |
Suboptimal debulking surgery | 1.54 | 1.21–1.96 | <0.01 | 1.71 | 1.22–2.39 | <0.01 |
Underweight after treatment | 1.25 | 0.80–1.93 | 0.33 | — | — | — |
Overall survival | ||||||
≥53 years | 1.12 | 0.79–1.58 | 0.52 | — | — | — |
Stage IV disease | 1.21 | 0.80–1.84 | 0.36 | — | — | — |
Grade 3 disease | 1.21 | 0.75–1.93 | 0.44 | — | — | — |
Nonserous histology | 1.58 | 1.07–2.33 | 0.02 | — | — | — |
No neoadjuvant chemotherapy | 1.65 | 1.08–2.54 | 0.02 | 1.88 | 1.28–2.77 | <0.01 |
≤6 cycles of adjuvant chemotherapy | 1.16 | 0.82–1.64 | 0.42 | — | — | — |
Suboptimal debulking surgery | 1.49 | 1.05–2.11 | 0.03 | 1.67 | 1.23–2.28 | <0.01 |
Underweight after treatment | 2.01 | 1.13–3.58 | 0.02 | 2.29 | 1.08–4.85 | 0.03 |
Kaplan-Meier analyses with the log-rank test for comparing progression-free survival and overall survival among patients with underweight, normal to overweight, and obesity with advanced-stage ovarian cancer: (a) at diagnosis; (b) after surgery; (c) after treatment.
Next, we compared CA-125 and NLR among underweight, normal to overweight, and obesity patients according to the treatment time (Table
Comparison of CA-125 and neutrophil to lymphocyte ratio (NLR) among underweight, normal to overweight, and obesity patients according to the treatment time.
BMI |
CA-125 |
NLR |
Confounding factors | |||
---|---|---|---|---|---|---|
Stage IV disease | Grade 3 disease | Nonserous histology | Suboptimal debulking | |||
At diagnosis | ||||||
Underweight | 185.5 | 8*,† | 1 (8.3)*,† | 3 (25.0)*,† | 4 (33.3)*,† | 2 (16.7)* |
Normal to overweight | 865* | 9*,‡ | 69 (22.3)*,‡ | 156 (50.3)*,‡ | 69 (22.3)*,‡ | 149 (48.1)*,† |
Obesity | 912.5* | 6.75†,‡ | 5 (13.9)†,‡ | 21 (58.3)†,‡ | 5 (13.9)†,‡ | 21 (58.3)† |
|
0.04 | 0.47 | 0.28 | 0.14 | 0.33 | 0.04 |
After surgery | ||||||
Underweight | 95.6*,† | 2.58*,† | 6 (18.8)*,† | 15 (46.9)*,† | 3 (9.4)*,† | 10 (32.2)*,† |
Normal to overweight | 190.0*,‡ | 2.67*,‡ | 65 (22.3)*,‡ | 146 (50)*,‡ | 67 (22.9)*,‡ | 143 (49)*,‡ |
Obesity | 87.5†,‡ | 3.14†,‡ | 5 (18.5)†,‡ | 16 (59.3)†,‡ | 5 (17.9)†,‡ | 16 (59.3)†,‡ |
|
0.78 | 0.23 | 0.83 | 0.60 | 0.29 | 0.08 |
After treatment | ||||||
Underweight | 8*,† | 2.15* | 5 (17.2)*,† | 13 (44.8)*,† | 6 (20.7)*,† | 10 (34.5)*,† |
Normal to overweight | 9*,‡ | 1.56*,† | 62 (20.7)*,‡ | 148 (50.7)*,‡ | 67 (22.4)*,‡ | 146 (48.8)*,‡ |
Obesity | 6.8†,‡ | 1.47† | 8 (28.6)†,‡ | 18 (66.7)†,‡ | 4 (14.3)†,‡ | 13 (46.4)†,‡ |
|
0.21 | 0.09 | 0.54 | 0.27 | 0.60 | 0.33 |
BMI: body mass index; *,†,‡no significant difference between two groups with the same symbol.
Furthermore, the rate of optimal debulking surgery was also different between underweight and obesity patient groups
On the other hand, underweight patients
Next, we compared clinicopathologic characteristics and prognosis according to the degree of weight loss, only in patients with underweight status
Furthermore, underweight patients with weight loss ≥10% showed poor PFS and OS in comparison with those with weight loss <10% (PFS, median value, 3.5 versus 16.8 months; OS, median value, 23.7 versus 58.1 months; Figure
Clinicopathologic factors affecting progression-free and overall survivals in 29 patients who showed underweight after treatment.
Characteristics | Univariate | Multivariate | ||||
---|---|---|---|---|---|---|
HR | 95% CI |
|
Adjusted HR | 95% CI |
|
|
Progression-free survival | ||||||
≥53 years | 1.91 | 0.79–4.63 | 0.15 | — | — | — |
Stage IV disease | 1.88 | 0.68–5.18 | 0.23 | 4.89 | 1.14–20.94 | 0.03 |
Grade 3 disease | 0.94 | 0.33–2.70 | 0.91 | — | — | — |
Nonserous histology | 2.99 | 1.13–7.90 | 0.03 | — | — | — |
No neoadjuvant chemotherapy | 1.54 | 0.51–4.64 | 0.45 | — | — | — |
≤6 cycles of adjuvant chemotherapy | 1.10 | 0.40–3.01 | 0.86 | — | — | — |
Suboptimal debulking surgery | 3.89 | 1.55–9.74 | <0.01 | 10.04 | 1.48–68.13 | 0.02 |
Weight loss ≥10% | 4.07 | 1.55–10.64 | <0.01 | 6.90 | 1.51–31.54 | 0.01 |
Overall survival | ||||||
≥53 years | 2.07 | 0.62–6.92 | 0.24 | — | — | — |
Stage IV disease | 1.92 | 0.40–9.25 | 0.42 | 11.9 | 1.00–141.1 | 0.05 |
Grade 3 disease | 0.77 | 0.17–3.47 | 0.73 | — | — | — |
Nonserous histology | 2.58 | 0.73–9.15 | 0.14 | — | — | — |
No neoadjuvant chemotherapy | 1.27 | 0.27–6.02 | 0.77 | — | — | — |
≤6 cycles of adjuvant chemotherapy | 3.84 | 0.78–18.91 | 0.10 | — | — | — |
Suboptimal debulking surgery | 2.64 | 0.88–7.91 | 0.08 | — | — | — |
Weight loss ≥10% | 12.81 | 2.54–64.65 | <0.01 | 15.27 | 1.42–164.5 | 0.02 |
Kaplan-Meier analyses with the log-rank test for comparing progression-free survival and overall survival between weight loss ≥10% and <10% in underweight patients after treatment.
In terms of the association between BMI and cancer risk and prognosis, most of the studies have focused mainly on the impact of obesity, because deleterious mechanisms related to obesity are expected to be unfavorable to cancer patients [
However, excessive weight loss can also be associated with poor prognosis, because it has similar features to cancer cachexia, a complex metabolic condition characterized by loss of skeletal muscle and body weight, developed in progressive disease [
Epidemiologically, the relationship between the risk of mortality and BMI is known to be U-shaped with the increased risk related to either cachexia showing very low BMI or obesity demonstrating very high BMI, whereas emerging data indicate that obesity is associated paradoxically with better prognosis in cancer patients [
However, underweight status can act as a poor prognostic factor in these patients. Theoretically, most patients with advanced-stage ovarian cancer should recover from their underweight status after treatment because the Warburg effect, that is, increased glucose uptake by tumors for glycolysis to generate ATP, is expected to reduce with the decrease of tumor burden after treatment [
To prove this hypothesis clinically, we investigated CA-125 as a tumor marker and NLR as a marker reflecting inflammation and immunity among underweight, normal weight to overweight, and obesity patients according to the treatment time. After treatment, although there were no differences of CA-125 among the three groups, underweight patients showed the highest NLR compared with normal weight to overweight and obesity patients, suggesting increased systemic inflammation (neutrophilia) and decreased immunity (lymphocytopenia) in these patients. This means that underweight status after treatment is a condition which increases the likelihood of cancer progression, and it can be considered as an early marker for poor prognosis in patients with advanced-stage ovarian cancer.
Chronic systemic inflammation is also known to be related to metabolic syndrome, which is in state of central obesity or excessive adiposity [
In terms of cancer cachexia, it was hard to assess exactly how many underweight patients after treatment were in cachectic state according to the retrospective analysis of medical records. To consider cancer patients to be in cachectic state, at least all three key features of cachexia should be presented as follows: weight loss >10%; systemic inflammation (C-reactive protein (CRP) > 10 mg/L); and reduced food intake (<1,500 kcal/day) [
Thus, we divided all underweight patients after treatment into two subgroups on the basis of weight loss by 10% from the bodyweight at diagnosis, considering the features of cancer cachexia. As a result, the risk of suboptimal surgery increased in underweight patients with weight loss ≥10% (63.6% versus 16.7%;
The current study is the first report demonstrating the impact of underweight status after treatment on prognosis of gynecologic cancer. However, there were some limitations. Firstly, we could not evaluate the impact of underweight status on prognosis of patients with early-stage ovarian cancer, because they showed good prognosis. Secondly, we measured only NLR as an indicator of host inflammation and immunity because other proinflammatory markers or cytokines were not included in the clinical setting. Thirdly, all patients in the current study were ethnically homogenous Asians, so the results may not be applicable to other ethnic groups.
In conclusion, we found that underweight status after treatment may be a poor prognostic factor in patients with advanced-stage ovarian cancer, and it is accompanied by increased tumor-induced inflammation and decreased immunity. Underweight status can act as an early marker to predict poor prognosis. In particular, paying attention to weight change is required during the treatment period, because more than half of underweight patients at diagnosis failed to gain weight and a weight loss ≥10% after treatment was associated with an increased risk of disease recurrence and mortality.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This research was supported by Grants (nos. 04-2012-0890, 03-2012-0170) from the Seoul National University Hospital Research Fund, the Priority Research Centers Program (no. 2009-0093820), Basic Science Research Program (2011-0025394), and World Class University (WCU) Program (no. R31-2008-000-10056-0) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology.