Abstract
Background
Obesity increases risk for colorectal cancer (CRC) development and historically has been connected to poor outcomes. The obesity paradox describes recent data showing that obesity may be protective in some diseases. This study examined the association between obesity and overall survival (OS) in stage IV CRC, evaluating factors that may contribute to disease course.
Methods
This was a single-institution, retrospective study of patients with stage IV CRC who underwent resection, chemotherapy, and/or radiation. Patients were grouped by body mass index (BMI) at diagnosis, as normal weight (NW), overweight, or obese. Cox regression models were used to estimate the effects of patient, disease, and treatment characteristics on OS.
Results
320 patients with stage IV CRC were identified, including 108 NW, 109 overweight, and 103 obese patients. No statistically significant differences were found in age, sex, race, primary tumor site, KRAS/BRAF mutational status, tumor stage, or treatment modality between groups. Obese patients more frequently had higher node-positive disease. Duration of chemotherapy significantly differed by BMI (median duration: NW = 6.5 months, overweight = 6.2, and obese = 11.7, p = 0.04). Chemotherapy adverse event scores and reasons for chemotherapy cessation did not differ by BMI group. On multivariable analysis, NW and overweight patients were at increased risk of death compared to obese patients (NW: HR 1.95, 95% CI 1.39–2.73; overweight: HR 1.43, 95% CI 1.03–1.99).
Conclusions
Obesity at diagnosis is associated with improved OS in stage IV CRC. Patients with obesity underwent a longer duration of chemotherapy and experienced greater decreases in BMI during this period.
Keywords: Colorectal cancer, Metastatic colorectal cancer, Obesity, Chemotherapy, BMI
Background
The overall mortality of stage IV colorectal cancer (CRC) has improved since the mid-1990s [1, 2]. Nevertheless, CRC remains one of the most commonly diagnosed cancers in the United States, and its incidence appears to be increasing in individuals under the age of 50 [3]. The reasons for the rising incidence of CRC in younger adults is thought to be due in part to changes in modifiable risk factors, such as decreased activity and increased obesity [4].
Obesity, defined as a body mass index (BMI) ≥ 30.0, has been associated with a 1.3 times increased risk of developing CRC [5, 6]. Proposed mechanisms for this association include metabolic and hormonal alterations, such as hyperinsulinemia, increased leptin levels [7], and obesity-associated inflammation [8]. Higher BMI has also been linked to worse prognosis and shorter survival in certain subgroups of patients with CRC, with shorter disease-free and overall survival in patients with BMI > 35 [9, 10]. These findings have led to clinical recommendations and guidelines regarding weight loss and maintenance of normal weight (NW) in cancer survivors [11].
However, recent studies have called into question the assumption that BMI is a negative prognostic factor in CRC. Some studies have found no association between BMI and CRC recurrence or death [12], while others have found a U- or J-shaped association between BMI and CRC survival, suggesting being underweight or extremely obese was associated with worse prognosis, while being overweight was a positive prognostic indicator [12, 13]. This protective effect of higher BMI in cancer and other disease processes has been termed the “obesity paradox” [14]. This has been shown in multiple, but not all studies on multiple cancers, looking at the effect of obesity on survival [14, 15].
Although the obesity paradox is becoming more recognized, the biological mechanisms for the obesity paradox remain unknown. Therefore, this study sought to determine the association between BMI, survival outcomes, and chemotherapy duration in patients with stage IV CRC undergoing treatment with surgical resection, chemotherapy, and/or radiation. We hypothesized that obese CRC patients would tolerate chemotherapy longer, ultimately resulting in extended survival.
Methods
This was a single institution, retrospective analysis of patients presenting with stage IV CRC between January 2006 and April 2016. Clinicopathologic and follow-up data were prospectively gathered in the institution’s cancer registry under an Institutional Review Board-approved protocol. BMI was calculated from weight measured and recorded by a medical assistant and patient-reported height in their electronic medical records. Treatment details were obtained from patients’ electronic medical records.
Patients included in this study had normal or higher BMI, diagnosis of stage IV colon or rectal cancer, and underwent treatment for their disease with surgery, chemotherapy, and/or radiation. BMI groups are based on categories defined by the World Health Organization: NW (18.5 – <25.0), overweight (25.0 – <30.0), and obese (≥ 30.0). Chemotherapy adverse events were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). The most severe chemotherapy-related adverse event was selected for each patient. Additional data were collected on demographics, disease stage per American Joint Committee on Cancer (AJCC) Cancer Staging System, locations of metastases, treatment type and treatment duration.
Chi-squared or Fisher’s exact tests (where appropriate) were used to compare categorical variables, and Kruskal Wallis tests were used to compare continuous variables between BMI categories. Time was calculated from diagnosis to death due to any cause, and patients still alive were censored at last follow-up. Overall survival probabilities were estimated and plotted using the Kaplan-Meier method. Cox regression models assessed the effects of clinicopathologic and treatment variables on overall survival (OS). Estimated effects of predictors are reported as hazard ratios (HR) with 95% confidence intervals (CI). All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC).
Results
320 patients with stage IV CRC with a median age at diagnosis of 59 years (range 23–89) were stratified by BMI group for analysis (Table 1). In this cohort, 144 (45.0%) were female and 285 (94.4%) patients were white. Most (208 patients; 65.0%) had a colon primary tumor, and most presented with high tumor (T) stages – T3 (61.0%) or T4 (33.8%) – and node (N)-positive disease – N1 (35.4%) or N2 (42.7%). The liver was the most common site of metastasis (77.8%), although lung (14.7%) and peritoneal (24.4%) metastases were also common. Most patients underwent surgical resection of their primary tumor and/or metastases (63.4%). Most patients were treated with chemotherapy (89.4%). Most patients (81.7%) received multi-agent chemotherapy regimen (e.g., 5-Fluorouracil/Leucovorin + Oxaliplatin [FOLFOX] or 5-Fluorouracil/Leucovorin + Irinotecan [FOLFIRI]) and about half of them (48.8%) received targeted therapies (e.g., bevacizumab, panitumumab and cetuximab) at some point during their treatment course. At a median follow-up of 18.7 months, median OS was 20.9 months. There were no statistically significant differences between BMI groups with regards to age, sex, race, primary tumor site, T stage, KRAS/BRAF mutational status, multi-agent chemotherapy received, or targeted therapy received. However, obese patients were more likely to have N2 disease and less likely to have N0 disease compared to their overweight and NW counterparts (N2 disease in 60.6% obese vs. 39.1% overweight vs. 27.4% NW patients; N0 disease in 12.1% obese vs. 20.3% overweight vs. 33.9% NW patients; p < 0.01).
Table 1.
Characteristics of patients with stage IV colorectal cancer who underwent treatment
| Covariate | Level/Statistic | Total N = 320 |
Normal weight N = 108 |
Overweight N = 109 |
Obese N = 103 |
P-value |
|---|---|---|---|---|---|---|
| Sex (%) | Female | 144 (45.0%) | 54 (50.0%) | 39 (35.8%) | 51 (49.5%) | 0.06 |
| Male | 176 (55.0%) | 54 (50.0%) | 70 (64.2%) | 52 (50.5%) | ||
| Age at diagnosis, years | Median (Range) | 59 (23–89) | 56 (23–89) | 61 (23–88) | 59 (26–85) | 0.21 |
| Race (%) | Black | 12 (4.0%) | 6 (6.0%) | 3 (2.9%) | 3 (3.0%) | 0.75 |
| Hispanic | 4 (1.3%) | 2 (2.0%) | 1 (1.0%) | 1 (1.0%) | ||
| Native American | 1 (0.3%) | 1 (1.0%) | 0 (0%) | 0 (0%) | ||
| White | 285 (94.4%) | 91 (91.0%) | 99 (96.1%) | 95 (96.0%) | ||
| Missing | 18 | 8 | 6 | 4 | ||
| Primary tumor site (%) | Colon | 208 (65.0%) | 67 (62.0%) | 70 (64.2%) | 71 (68.9%) | 0.56 |
| Rectum | 112 (35.0%) | 41 (38.0%) | 39 (35.8%) | 32 (31.1%) | ||
| Tumor (T) stage (%) | T0 | 2 (1.0%) | 0 (0%) | 2 (3.1%) | 0 (0%) | 0.34 |
| T1 | 1 (0.5%) | 0 (0%) | 1 (1.5%) | 0 (0%) | ||
| T2 | 7 (3.6%) | 2 (3.2%) | 2 (3.1%) | 3 (4.4%) | ||
| T3 | 119 (61.0%) | 33 (53.2%) | 41 (63.1%) | 45 (66.2%) | ||
| T4 | 66 (33.8%) | 27 (43.5%) | 19 (29.2%) | 20 (29.4%) | ||
| Missing | 125 | 46 | 44 | 35 | ||
| Nodal (N) stage (%) | N0 | 42 (21.9%) | 21 (33.9%) | 13 (20.3%) | 8 (12.1%) | < 0.01 |
| N1 | 68 (35.4%) | 24 (38.7%) | 26 (40.6%) | 18 (27.3%) | ||
| N2 | 82 (42.7%) | 17 (27.4%) | 25 (39.1%) | 40 (60.6%) | ||
| Missing | 128 | 46 | 45 | 37 | ||
| KRAS/BRAF mutated (%) | No | 80 (61%) | 26 (63%) | 27 (63%) | 27 (56%) | 0.74 |
| Yes | 52 (39%) | 15 (37%) | 16 (37%) | 21 (44%) | ||
| Missing | 188 | 67 | 66 | 55 | ||
| Chemotherapy – multi-agent regimen used (%) | No | 55 (18%) | 21 (21%) | 20 (20%) | 14 (14%) | 0.42 |
| Yes | 246 (82%) | 80 (79%) | 81 (80%) | 85 (86%) | ||
| Missing | 19 | 7 | 8 | 4 | ||
| Chemotherapy – targeted therapy used (%) | No | 154 (51%) | 51 (50%) | 53 (52%) | 50 (50%) | 0.95 |
| Yes | 147 (49%) | 50 (50%) | 48 (48%) | 49 (50%) | ||
| Missing | 19 | 7 | 8 | 4 |
All patients were M1 stage. BMI categories are defined as normal weight (BMI 18.5-<25.0), overweight (BMI 25.0-<30.0), and obese (BMI ≥ 30.0). Bold p-value indicates statistical significance (P < 0.05)
BMI Body mass index
Median OS for NW, overweight, and obese patients was 18.2, 22.3, and 24.0 months, respectively (Fig. 1). On univariable analysis, younger age, primary tumor of the rectum, undergoing surgery of the primary tumor and/or metastases, and receipt of chemotherapy were associated with improved OS (Table 2). In contrast, BMI group was not associated with differences in OS (p = 0.15). However, after adjusting for the effects of age, diabetes, primary tumor site, surgery, and receipt of chemotherapy, NW and overweight patients were at 1.95- and 1.43-times increased risk of death, respectively, compared to obese patients (Table 3).
Fig. 1.
Kaplan-Meier survival curves demonstrating OS stratified by BMI group of patients with stage IV colorectal cancer who received treatment. BMI categories are defined as normal weight (BMI 18.5-<25.0), overweight (BMI 25.0-<30.0), and obese (BMI ≥ 30.0) BMI – body mass index, OS – overall survival
Table 2.
Univariable survival analysis of patients with stage IV colorectal cancer who received treatment
| Covariate | Overall Survival | |||||
|---|---|---|---|---|---|---|
| Level | N | Hazard Ratio | 95% CI | P-value | ||
| Sex | Female | 144 | 1.02 | 0.80 | 1.32 | 0.86 |
| Male | 176 | Ref | - | - | ||
| BMI category | Normal | 108 | 1.33 | 0.97 | 1.81 | 0.15 |
| Overweight | 109 | 1.06 | 0.77 | 1.45 | ||
| Obese | 103 | Ref | - | - | ||
| Age at diagnosis (per year) | 320 | 1.02 | 1.01 | 1.03 | < 0.01 | |
| Diabetes | Yes | 47 | 1.36 | 0.97 | 1.90 | 0.08 |
| No | 273 | Ref | - | - | ||
| Liver metastasis | Yes | 249 | 1.10 | 0.81 | 1.49 | 0.54 |
| No | 71 | Ref | - | - | ||
| Lung metastasis | Yes | 47 | 1.04 | 0.72 | 1.49 | 0.85 |
| No | 273 | Ref | - | - | ||
| Peritoneal metastasis | Yes | 78 | 0.92 | 0.68 | 1.23 | 0.56 |
| No | 242 | Ref | - | - | ||
| Primary site | Colon | 208 | 1.32 | 1.01 | 1.72 | 0.04 |
| Rectum | 112 | Ref | - | - | ||
| Surgery of primary and/or metastasis | Yes | 203 | 0.41 | 0.32 | 0.54 | < 0.01 |
| No | 123 | Ref | - | - | ||
| Chemotherapy | Yes | 286 | 0.33 | 0.23 | 0.47 | < 0.01 |
| No | 34 | Ref | - | - | ||
| Radiation | Yes | 52 | 0.75 | 0.52 | 1.07 | 0.11 |
| No | 268 | Ref | - | - | ||
BMI categories are defined as normal weight (BMI 18.5-<25.0), overweight (BMI 25.0-<30.0), and obese (BMI ≥ 30.0). Bold p-value indicates statistical significance (P < 0.05)
BMI Body mass index, CI Confidence interval
Table 3.
Multivariable survival analysis of patients with stage IV colorectal cancer who received treatment
| Covariate | Overall Survival | |||||
|---|---|---|---|---|---|---|
| Level | N | Hazard Ratio | 95% CI | P-value | ||
| BMI category | Normal | 108 | 1.95 | 1.39 | 2.73 | < 0.01 |
| Overweight | 109 | 1.43 | 1.03 | 1.99 | ||
| Obese | 103 | Ref | - | - | ||
| Age at diagnosis (per year) | 320 | 1.01 | 1.00 | 1.02 | 0.11 | |
| Diabetes | Yes | 47 | 1.60 | 1.12 | 2.29 | < 0.01 |
| No | 273 | Ref | - | - | ||
| Primary site | Colon | 208 | 1.78 | 1.34 | 2.37 | < 0.01 |
| Rectum | 112 | Ref | - | - | ||
| Surgery of primary and/or metastasis | Yes | 203 | 0.30 | 0.22 | 0.40 | < 0.01 |
| No | 117 | Ref | - | - | ||
| Chemotherapy | Yes | 286 | 0.24 | 0.16 | 0.36 | < 0.01 |
| No | 34 | Ref | - | - | ||
BMI categories are defined as normal weight (BMI 18.5-<25.0), overweight (BMI 25.0-<30.0), and obese (BMI ≥ 30.0). Bold p-value indicates statistical significance (P < 0.05)
BMI Body mass index, CI Confidence interval
BMI groups were compared by treatments received and treatment complications (Table 4). BMI groups did not have statistically significant differences in rates of surgery (63.1% of obese vs. 65.1% of overweight vs. 62.0% of NW patients, p = 0.89) or chemotherapy (87.4% of obese vs. 90.8% of overweight vs. 89.8% of NW patients, p = 0.71). Among patients who received chemotherapy, duration of chemotherapy differed by BMI group, with obese patients undergoing significantly longer durations of chemotherapy than either NW or overweight people (median chemotherapy duration: 11.7 months in obese vs. 6.2 months in overweight vs. 6.5 months in NW patients, p = 0.04).
Table 4.
Comparison of treatment characteristics between obese, overweight, and normal weight patients with stage IV colorectal cancer who received treatment
| Covariate | Level | Total N = 320 |
Normal N = 108 |
Overweight N = 109 |
Obese N = 103 |
P-value |
|---|---|---|---|---|---|---|
| Surgery of primary and/or metastasis | No | 117 (36.6%) | 41 (38.0%) | 38 (34.9%) | 38 (36.9%) | 0.89 |
| Yes | 203 (63.4%) | 67 (62.0%) | 71 (65.1%) | 65 (63.1%) | ||
| Duration chemotherapy, months | Median (Range) |
7.4 (0–88.9.9) |
6.5 (0.0–47.3.0.3) |
6.2 (0.0–32.8.0.8) |
11.7 (0.0–88.9.0.9) |
0.04 |
| Missing | 102 | 41 | 32 | 29 | ||
| Change in BMI after chemotherapy (kg/m2) | Median (Range) |
−1.4 (−14.0-9.6) |
−0.7 (−7.2-9.6) |
−1.2 (−8.1-6.3) |
−2.9 (−14.0-6.9) |
< 0.01 |
| Missing | 31 | 15 | 9 | 7 | ||
| Relative change in BMI after chemotherapy | Median (Range) |
−5.1% (−44.1%−51.7%) |
−3.1% (−33.3%−51.7%) |
−4.4% (−29.5%−22.4%) |
−7.7% (−44.1%−19.1%) |
0.07 |
| Missing | 31 | 15 | 9 | 7 | ||
| Chemotherapy | No | 34 (10.6%) | 11 (10.2%) | 10 (9.2%) | 13 (12.6%) | 0.71 |
| Yes | 286 (89.4%) | 97 (89.8%) | 99 (90.8%) | 90 (87.4%) | ||
| Chemotherapy adverse event score | 0 | 48 (18.8%) | 19 (22.9%) | 14 (15.6%) | 15 (18.1%) | 0.72 |
| 1 | 75 (29.3%) | 24 (28.9%) | 28 (31.1%) | 23 (27.7%) | ||
| 2 | 83 (32.4%) | 29 (34.9%) | 29 (32.2%) | 25 (30.1%) | ||
| 3 | 41 (16.0%) | 9 (10.8%) | 14 (15.6%) | 18 (21.7%) | ||
| 4 | 8 (3.1%) | 2 (2.4%) | 4 (4.4%) | 2 (2.4%) | ||
| 5 | 1 (0.4%) | 0 (0%) | 1 (1.1%) | 0 (0%) | ||
| Missing | 30 | 14 | 9 | 7 | ||
| Reason for chemo cessation* | Lost to follow-up | 59 (23.7%) | 23 (28.0%) | 15 (16.9%) | 21 (26.9%) | 0.61 |
| No evidence of disease | 20 (8.0%) | 5 (6.1%) | 10 (11.2%) | 5 (6.4%) | ||
| Not tolerated | 30 (12.0%) | 8 (9.8%) | 13 (14.6%) | 9 (11.5%) | ||
| Progression | 108 (43.4%) | 37 (45.1%) | 40 (44.9%) | 31 (39.7%) | ||
| Transfer of care | 32 (12.9%) | 9 (11.0%) | 11 (12.4%) | 12 (15.4%) | ||
| Missing | 31 | 15 | 9 | 7 |
BMI categories are defined as normal weight (BMI 18.5-<25.0), overweight (BMI 25.0-<30.0), and obese (BMI ≥ 30.0). Bold p-value indicates statistical significance (P < 0.05)
BMI Body mass index
*6 patients still receiving chemotherapy
To evaluate whether weight changes in response to chemotherapy were similar between BMI groups, changes of BMI before and after undergoing chemotherapy in patients from different BMI groups were compared. Changes in BMI were different between BMI groups (median change in BMI: −2.9 in obese vs. −1.2 overweight vs. −0.7 in NW patients, p < 0.01), although a statistically significant association was not evidenced when considering relative change in BMI after completion of chemotherapy. Chemotherapy-associated side effects and reasons for chemotherapy cessation were then compared by BMI group. Adverse events due to chemotherapy were graded by NCI CTCAE, and there were no significant differences in the severity of chemotherapy-associated adverse events between BMI groups (p = 0.72). Reasons for cessation were coded as progression of disease, intolerance of side effects, loss to follow-up, transfer of care, or no evidence of disease. The BMI groups did not statistically significantly differ regarding reasons for cessation of chemotherapy (p = 0.61).
Discussion
In this study, patients with obesity had a significantly decreased risk of mortality after diagnosis of stage IV CRC and receipt of treatment compared to overweight and NW patients, after accounting for age, diabetes, primary site, surgery, and chemotherapy. NW patients had the highest risk of death, with almost twice the risk of death compared to obese patients. Patients with obesity were more likely to undergo longer durations of chemotherapy and were able to sustain larger losses in absolute BMI after chemotherapy compared to NW and overweight patients. In this cohort, obese patients were not at increased risk of more severe chemotherapy-associated adverse events and obese patients were not more likely to cite side effects as the reason for stopping chemotherapy. These data suggest there may be an obesity paradox in stage IV CRC and that higher BMI may be associated with decreased risk of mortality after diagnosis with stage IV CRC and duration of treatment.
The obesity paradox has been studied in a variety of chronic diseases, such as cardiovascular disease [16, 17], chronic kidney disease [18], and some cancers [19]. For CRC, the data regarding the prognostic impact of BMI have been mixed. A meta-analysis of patients with CRC found that overweight patients have decreased mortality compared to NW patients (HR 0.79, 95% CI 0.71–0.88), although the authors also found no association between BMI and all-cause mortality in their own prospective cohort [12]. In a study of patients with CRC liver metastases undergoing liver resection, after adjustment for cofounders, obesity was an independent predictor of improved OS (HR 0.31, 95% CI 0.10–0.91) [20]. A U-shaped association between BMI and morality has been found in certain subpopulations of patients with non-metastatic CRC, where high-normal and overweight patients have improved survival compared to underweight and obese patients [13].
Theories explaining the obesity paradox hypothesize that excess adiposity may confer physiologic advantages in times of stress. For example, excess adipose tissue may provide improved nutritive reserves that allow patients to withstand the cachectic effects of chronic disease and treatment [17, 21]. Nutritional habits such as plant-based diet has been evaluated for its effect on survival in metastatic CRC with some suggestion that this diet may help, but the study was not stratified by BMI [21]. Therefore, the interplay between nutritional status and BMI needs to be better characterized. Other theories suggest patients with higher BMI may receive more optimal treatment [22] or obesity-related tumors may have more favorable biology. It should be noted that BMI is one anthropometric measure of adiposity and is not sufficiently granular to reflect muscle mass, body fat percentage, or distribution of adiposity. Additional anthropomorphic measurements, such as visceral fat/psoas muscle ratio and body roundness index, have been posited as more descriptive measurements of adiposity and sarcopenia. Although prior studies have demonstrated higher visceral fat/psoas muscle ratio is associated with worse prognosis in some subsets of patients with CRC, additional studies are needed in to delineate the impact of visceral adiposity and sarcopenia on outcomes in patients with metastatic CRC [23]. Visceral adiposity is thought to correlate more with changes in insulin resistance and levels of insulin growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) which is proposed to stimulate tumor growth and prevent apoptosis [24].
Despite the limitations of BMI as a measurement, the findings of this study suggest that the theory of physiologic advantage may have some validity, as patients in the three BMI groups did not differ significantly with regards to clinicopathologic factors, such as KRAS/BRAF mutation, or treatment modalities, such as receipt of chemotherapy and types of chemotherapy regimen. In fact, obese patients were more likely to be node-positive and nevertheless had improved OS. Although causation cannot be established in this study, obese patients were more likely to undergo longer durations of chemotherapy with larger losses of absolute BMI compared to NW and overweight patients. Obese patients were not found to experience more severe chemotherapy side effects and were not more likely to stop chemotherapy due to side effects.
Limitations of this study include its retrospective and single-institution design. There was a higher rate of missing information for some of the studied variables, particularly for T and N stage since over one-third of patients did not undergo surgical resection of their primary tumor. This study also cannot eliminate bias due to illness-related weight loss at presentation, although there were no differences in baseline clinicopathologic factors between the BMI groups. The lack of detailed longitudinal weight and BMI data including pre-illness, pre- and post-chemotherapy after each regimen received throughout the treatment course of many patients significantly limits the analysis and interpretation. Despite these limitations, our study provides real-world data to demonstrate that patients with obesity receive treatment for longer periods.
Further research is needed to elucidate the mechanism by which higher BMI appears to be associated with longer chemotherapy duration and improved survival in stage IV CRC. Although a randomized controlled trial investigating the impact of BMI on mortality in colorectal cancer is not feasible, longitudinal studies following weight, development of CRC, and prognosis may be possible. Investigation of the change in BMI throughout treatment may also be warranted, as well as studies investigating the impact of nutritional status or more specific anthropomorphic measurements on CRC outcomes.
Acknowledgements
This work was supported by the Holden Comprehensive Cancer Center through funds from the National Cancer Institute of the National Institutes of Health under award number P30 CA086862 for supporting the Biostatistics Core. CGT was supported by National Institutes of Health T32 CA148062.
Abbreviations
- CRC
colorectal cancer
- BMI
Body Mass Index
- OS
Overall survival
- NW
normal weight
- NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
- HR
Hazard Ratios
- CI
Confidence Intervals
Authors’ contributions
CT was involved in conceptualization of the project, data collection and evaluation, writing a significant portion of the manuscript. CD was a significant author and editor of the manuscript. BJ collected data and assisted in writing the manuscript. SM performed the data analysis. EEHF, ACS, MEM were all involved in data collection. DJB was involved in data review and manuscript editing. EET reviewed and edited the manuscript. CHFC was involved in project conceptualization, data evaluation and manuscript editing.
Funding
This work was supported by the Holden Comprehensive Cancer Center through funds from the National Cancer Institute of the National Institutes of Health under award number P30 CA086862 for supporting the Biostatistics Core. CGT was supported by National Institutes of Health T32 CA148062.
Data availability
Due to the small sample size and risk of identification, study data have not been deposited publicly.
Declarations
Ethics approval and consent to participate
Patient data were prospectively gathered in the institution’s cancer registry under a protocol approved by the University of Iowa Institutional Review Board. Patients with cancer receiving care at the University of Iowa Health Care were registered in the institutional Cancer Registry. The research herein was conducted in adherence to the Declaration of Helsinki under a protocol with a waiver of consent approved by the University of Iowa Institutional Review Board (IRB #201903702), with appropriate protections of patient privacy.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Catherine G. Tran and Carine Dornbush contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Due to the small sample size and risk of identification, study data have not been deposited publicly.