Abstract

METHODS

Adiposity measures

Patients with a pretreatment CT scan archived at Moffitt were included in this study (n = 99). Radiologic measures of adiposity were obtained from routine diagnostic CT scans using a Siemens CT Leonardo digital workstation (Siemens Medical Solutions). Visceral and subcutaneous fat areas (VFA and SFA, respectively) were measured from a single axial slice at the L4–L5 interver-tebral space.^27,28 The CT attenuation level was set between −190 to −30 Hounsfield units, regions of adipose tissue were delineated, and areas of total, VFA, and SFA were calculated (Fig. 1A–D). Linear perinephric fat thickness (PNF) is defined as the shortest distance (in mm) between the kidney and abdominal wall at the level of the renal vein (Fig. 1E).²⁹ The VFA to SFA ratio (V/S) was calculated to provide a single measure of abdominal fat, as published previously.^27,30 Elevated V/S indicated higher visceral fat compared with subcutaneous fat, and a threshold was set at V/S = 0.4 to define visceral obesity.³¹ Quantitative CT adiposity measurements have been validated in colon cancer, with a measurement error rate of 0.5%.^28,32 Height and weight recorded before surgery were used to calculate BMI (weight in kg divided by height in m²).

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Figure 1

Radiological measurement of visceral (VFA) and subcutaneous fat area (SFA) and linear perinephric fat thickness (PNF). Measurement of VFA (A, C) and SFA (B, D) by CT analysis software for 2 representative patients (A, B, and C, D). Visceral fat to subcutaneous fat ratio (V/S) differences observed for patient with (A) high VFA vs (D) high SFA. Patient in (A) and (B) is viscerally obese, with a V/S of 1.55 but a body mass index (BMI) of 27. Patient in (C) and (D) is obese when defined by BMI (BMI = 37), but is not viscerally obese (V/S = 0.23). (E) PNF measurement taken at level of the left renal vein.

RESULTS

Adiposity and rectal cancer outcomes

After resection, 5-year OS rate was 83.84% and DFS rate was 74.75%. Twenty-six patients had recurrent disease or died during follow-up. Figure 2 presents Kaplan-Meier estimates of DFS and OS time by obesity measures (BMI, V/S, and PNF). Disease-free survival and OS did not differ by obesity when defined by BMI (Fig. 2A). Viscerally obese patients (V/S ≥0.4) had shorter DFS (p = 0.02, Fig. 2B) and a higher number of documented recurrences (22 vs 4) than patients that were not viscerally obese. A trend toward worse OS was observed among those with V/S ≥0.4 (Fig. 2B; p = 0.14). Perinephric fat thickness higher than the median (12 mm) was associated with worse OS (p = 0.047) but not DFS (Fig. 2C; p = 0.18).

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Figure 2

Kaplan-Meier estimates of disease-free and overall survival by obesity measures, defined by (A) body mass index (BMI) (≥30), (B) visceral to subcutaneous fat area ratio (V/S) (≥0.4), or (C) perinephric fat thickness (PNF) (>12.2 mm).

Table 4 presents the associations among BMI, V/S, and PNF and rectal cancer outcomes. In crude analysis, patients with elevated V/S had a significantly elevated risk of shorter DFS (HR = 3.50; 95% CI, 1.21 –10.17). When adjusted for grade and pathologic response to treatment (a highly correlated measure of clinical response with additional clinical accuracy), the association became marginally significant (AHR = 2.5; 95% CI, 0.9–7.5; p = 0.09). In the stratified analysis, patients with well to moderately differentiated tumors and high visceral obesity (V/S ≥0.4) were more likely to have shorter DFS (AHR = 4.99; 95% CI, 1.2–21.6), after adjusting for response to treatment. Figure 3 presents the survival probability when combining treatment response and visceral adiposity. Patients with partial/no pathological response to neoadjuvant therapy with high visceral adiposity had the poorest DFS compared with patients with compete pathological response or those with partial/no response and low V/S (p = 0.02). Results were unchanged in multivariate models when controlling for comorbid conditions (eg, diabetes, hypertension, and hypercholesterolemia) or age (data not shown). There were no differences in DFS or OS by BMI, overall or among patients with well to moderately differentiated tumors. Increasing PNF appeared to be associated with worse OS in unadjusted models (HR = 1.06; 95% CI, 1.01 – 1.11), but significance was not maintained when adjusting for grade and treatment response (AHR = 1.04; 95% CI, 0.99–1.09; Table 4) or stratified by grade (AHR = 1.05; 95% CI, 0.99–1.11).

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Figure 3

Probability of (A) disease-free and (B) overall survival by response to neoadjuvant therapy and visceral to subcutaneous fat area ratio (V/S). (A) Patients with partial/no response (PR/NR) to neoadjuvant therapy with high V/S had the poorest disease-free survival compared with patients with compete response (CR) or those with partial/no response (PR/NR) that had low V/S (p = 0.03). (B) Similarly, PR/NR patients with high V/S appeared to have the poorest overall survival compared with others, but the differences among groups were not statistically significant (p = 0.32).

Table 4

Multivariate Cox Regression Modeling: Adiposity Variable and Rectal Cancer Outcomes

	Disease-free survival				Overall survival
	Crude HR	Adjusted HR*	95% CI	p Value	Crude HR	Adjusted HR	95% CI	p Value
Overall (n = 96)
BMI
<30	1.00	1.00	Ref	0.36	1.00	1.00	Ref	0.31
≥30	1.51	1.52	0.63–3.67		1.77	1.77	0.59–5.32
V/S
<0.4	1.00	1.00	Ref	0.09	1.00	1.00	Ref	0.28
≥0.4	3.50	2.53	0.85–7.49		2.64	2.03	0.57–7.20
PNF, mm	1.03	1.01	0.97–1.06	0.52	1.06	1.04	0.99–1.09	0.16
Well-moderately differentiated tumors (n = 90)
BMI
<30	1.00	1.00	Ref	0.16	1.00	1.00	Ref	0.23
≥30	1.75	1.97	0.76–5.10		1.98	2.09	0.64–6.86
V/S
<0.4	1.00	1.00	Ref	0.03	1.00	1.00	Ref	0.17
≥0.4	5.45	4.99	1.15–21.63		3.14	2.89	0.64–13.10
PNF, mm	1.03	1.03	0.99–1.07	0.22	1.05	1.05	0.99–1.11	0.09

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^*Adjusted for grade (poorly differentiated vs well differentiated/moderate) and pathologic response (none/partial vs complete).

BMI, body mass index; HR, hazard ratio; PNF, perinephric fat thickness; SFA, subcutaneous fat area; VFA, visceral fat area; V/S, visceral fat to subcutaneous fat ratio.

DISCUSSION

This is the first report to apply multiple quantitative visceral fat measurements (ie, SFA, VFA, and PNF) in addition to BMI to examine the associations between obesity and nonmetastatic rectal cancer patient outcomes after neoadjuvant chemoradiation treatment. We evaluated 2 quantitative measures of visceral adiposity, V/S, and the thickness of the PNF. Interestingly, in our set of rectal cancer patients, 62% of patients met criteria for obesity by V/S and only 41% of patients had BMI ≥30. The 2 different quantitative measures of visceral adiposity (V/S and PNF) were strongly associated with key preoperative metabolic comorbidities, and BMI was not. Our study suggests that elevated visceral adiposity is associated with an increased risk of recurrence, which was most evident among patients with well to moderately differentiated tumors and those with incomplete pathological response to neoadjuvant chemoradiation treatment. Given the disparity in reported data about obesity and CRC outcomes, this report helps to elucidate the relationship between rectal cancer outcomes and obesity.

The correlations between visceral adiposity and metabolic abnormalities among rectal cancer patients observed in this study are consistent with what has been shown among patients with cardiovascular disease and visceral fat.³¹ Balentine and colleagues have shown that quantitative measures of visceral obesity, such as VFA and SFA, were superior to BMI in correlating with comorbid conditions associated with obesity, such as diabetes and hypertension.²⁸ Similarly, we observed that both high V/S and PNF had significant associations with the conditions that contribute to metabolic syndrome, including diabetes, hypertension, and hypercholesterolemia, and BMI did not. Males were more likely to be viscerally obese by V/S in our study. This is consistent with the observation that central obesity, although a less precise surrogate measure of visceral adiposity, is more common in males.³²

A unique contribution of this study is that visceral obesity was studied in the select population of patients with rectal cancer that underwent neoadjuvant therapy. There have been few studies evaluating adiposity and rectal cancer outcomes.^3,9,18,34 Meyerhardt and colleagues reported that among male patients with rectal cancer, increased BMI was associated with an increased risk of local recurrence (HR =1.61; 95% CI, 1.00–2.59); andnoassociations were found among women or for OS in either sex.⁹ However, conclusions remain inconsistent with other conflicting studies reporting no difference or superior outcomes among obese rectal cancer patients.^3,18,34 Similarly, this study found no significant associations with obesity defined by BMI and rectal cancer survival.

Our findings of elevated risk of shorter DFS with visceral adiposity (eg, V/S) are consistent with findings reported within the few studies that have examined radiologic measures of adiposity. Using similar measures to those reported here, Moon and colleagues demonstrated that CRC patients with high V/S had a significantly worse DFS compared with patients with a low V/S (AHR = 1.98; 95% CI, 1.02–3.87), and BMI had no influence on outcomes.²⁷ Kang and colleagues, who defined visceral adiposity by VFA alone (obesity VFA >130), reported a trend toward worse DFS among viscerally obese rectal cancer patients (3-year DFS of 82.5% vs 74.4%, respectively), but these differences were not statistically significant.³⁴ In addition, among metastatic colon cancer patients, higher VFA independently predicted poorer outcomes in patients treated with targeted bevaci-zumab therapy, but not standard chemotherapy treatment.³⁵ The associations between PNF and OS in univariate models are consistent with the poorer outcomes observed with elevated PNF in hepatobiliary,²⁹ pancreatic,³⁶ and prostate³⁷ cancers. Notably, very few studies have examined whether obesity is an independent prognostic factor in multivariable models, as thoroughly conducted in this study. In addition, we found that a higher V/S among patients with well to moderately differentiated tumors were associated with worse DFS. We identified a high-risk group of patients with the combination of an incomplete pathological response to neoadjuvant therapy and high visceral adiposity who had far worse DFS compared with patients with complete pathological response or those with incomplete response that had low V/S. These findings suggest that after controlling for tumor grade and response to treatment (strong prognostic factors),³⁸ visceral obesity has a detrimental effect on outcomes for patients with rectal cancer. A larger study using radiologic measures of visceral adiposity is needed to confirm our findings.

The fundamental biological basis for the association between adiposity and CRC outcomes remains largely unelucidated. Adipose tissue, which was historically considered merely an energy storage depot, is now increasingly recognized as a complex secretory organ that produces pro- and anti-inflammatory adipokines (eg, adiponectin, leptin, and resistin) and cytokines (eg, tumor necrosis factor–α, interleukin-6, interleukin-1, and monocyte chemoattractant protein-1)^23,39 that can play a role locally, peripherally, or centrally in a variety of physiological processes.²³ Visceral adipose tissue has been associated with a greater degree of obesity-related metabolic derangements than subcutaneous fat,^21–23 which is the rationale behind evaluating V/S.^27,31 These metabolic derangements include insulin resistance, aberrant insulin-like growth factor–axis signaling, ⁴⁰ alterations in adipokine levels and low-level chronic inflammation,²⁴ all of which have been associated with increase cell growth, tumor proliferation, and progression.^23,41 Given the intimate association and proximity of visceral adipose tissue to rectal cancers, it is biologically plausible that visceral adiposity in endocrine and/or paracrine fashion can promote poor outcomes among patients with rectal cancer.

It could be postulated that survival differences in rectal cancer attributed to visceral obesity might be a result of the technical challenges associated with operations on obese patients as opposed to normal-weight individuals. In particular, pelvic dissection with optimal total mesorectal excision can be particularly difficult in viscerally obese patients. Although obesity (BMI) has been associated with worse short-term and perioperative outcomes; oncologic parameters among obese patients with rectal cancer are similar to those in nonobese patients.³,^18,42,43 In fact, a recent series of almost 600 patients with rectal cancer reported no difference in 5-year DFS or OS in obese vs nonobese patients undergoing radical resection.¹⁸ In this current study, there were no differences in radial margin status or number of lymph nodes removed between obese and nonobese patients. We are confident that the differences observed in DFS and OS by visceral obesity (V/S or PNF) are not explained by the technical differences in surgical procedures. It could also be hypothesized that visceral adiposity can impact response to neoadjuvant chemoradiation, as evidenced by our observation of less T down-staging in viscerally obese patients. The current dosing of adjuvant and neoadjuvant therapy is often based on standard parameters such as body surface area and BMI and can potentially be better formulated with consideration of more precise measures of visceral adiposity.⁶ Finally, we observed that visceral obesity was more associated with pre-existing metabolic abnormalities than BMI, emphasizing the physiologic relevance of visceral obesity and supporting its link with cancer outcomes. It is possible that the accurate determination of visceral obesity can represent a surrogate for the multifactorial influence of surgical and medical treatment delivery and biology that underlie potentially worse outcomes in patients with rectal cancer.

There are limitations of this study. Body mass index and V/S were obtained at the time of diagnosis from medical records, which might not reflect changes in BMI that occurred before diagnosis. Weight loss is a major symptom of advanced disease; however, it is not widely prevalent among stage II and III patients and should not have impacted the results of this study. In addition, we had a relatively small sample size that limited our power to detect or rule out (eg, BMI) significant associations in some analyses and inhibited stratified analyses by factors such as sex. However, unlike previous studies that have reported on radiologically determined adiposity, this study includes a homogeneous population of nonmetastatic rectal cancer patients that were all treated with neoadjuvant chemoradiation followed by radical resection (low anterior or abdominoperineal resection). Although small, this study was strengthened by the focus on a homogeneous patient population that reduced the possibility of outcomes differences due to stage or treatment differences. A larger sample size in future studies will help to confirm our findings. Finally, the study population was primarily non-Hispanic white patients and does not provide information on minority populations. We comprehensively analyzed the association between adiposity measures and comorbid conditions as well as outcomes using systematic statistical analyses. Overall, we have demonstrated that there is a significant relationship between visceral adiposity and oncologic outcomes (eg, survival), including superior DFS with lower V/S. Even when subject to multivariate analysis, V/S but not BMI was a predictor of DFS among this group of rectal cancer patients.

CONCLUSIONS

Given the epidemic of obesity in the United States and performance-based health care reform, more studies are needed to precisely delineate the relationship between obesity and cancer. It is becoming increasingly apparent that BMI alone is inadequate as a consistent prognostic indicator. As the focus on outcomes and comparative effectiveness research increases, the development of accurate and reliable risk and prognosis stratification strategies are clearly necessary to better guide patient treatment decisions, such as the use of behavioral interventions and more aggressive or accurately dosed adjuvant therapy regimens. Radiologic visceral fat quantification with its use of existing diagnostic imaging might ultimately represent an easily performed and more cost-effective, precise, and reproducible instrument of clinical prognostication. Although it remains unclear which of these quantitative measures, such as V/S or PNF, is the most optimal measure, our study represents an important proof of concept that visceral adiposity is an important determinant of outcomes in patients with rectal cancer undergoing neoadjuvant chemoradiation and radical resection. Additional studies that elucidate the physiologic and biologic mechanisms (eg, endocrine/adipokine activity of adipose tissue, hyperinsulinemia, insulin-like growth factor signaling) mediating the adiposity–CRC link are also clearly needed. The incorporation of quantitative measures of visceral obesity and corresponding correlative molecular studies into prospective oncologic therapeutic and epidemiologic studies is warranted.

Acknowledgment

Abbreviations and Acronyms

Footnotes

REFERENCES