Ann Surg Oncol DOI 10.1245/s10434-014-3807-2

ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY

Does Obesity Affect Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Disseminated Mucinous Appendiceal Neoplasms? Patricio M. Polanco, MD, Alvaro I. Sanchez, MD, MS, Lekshmi Ramalingam, MD, Heather Jones, MPA-C, Amer Zureikat, MD, Matthew Holtzman, MD, Steven Ahrendt, MD, James Pingpank, MD, Herbert J. Zeh, MD, David L. Bartlett, MD, and Haroon A. Choudry, MD Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA

ABSTRACT Background. Obesity has been described as a risk factor for surgical complications and may play a prominent role in the progression, recurrence, and survival rates of various cancers. Our objective was to investigate the impact of being overweight or obese on perioperative and oncologic outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) from mucinous appendiceal neoplasms (MAN). Methods. From a prospectively maintained database (2001–2010) of CRS/HIPEC for PC from MAN, we evaluated the body mass index (BMI) of patients, categorizing them into normal weight (NW \ 25 kg/m2), overweight (OW = 25 to 29.9 kg/m2), and obese (OB C 30 kg/m2). We compared the perioperative and oncologic outcomes among groups. Results. Of the 282 patients in the database, 234 had BMI data available, and 81, 79, and 74 patients were categorized as NW, OW, and OB, respectively. Although there was a trend toward increased risk of overall complications, wound infections, deep vein thrombosis, respiratory and renal complications, and anastomotic leaks in the OW and OB groups, these differences only achieved statistical significance for renal (p = 0.03) and pulmonary

This paper was presented and awarded First Place at the poster session of the Eighth International Symposium of the Regional Cancer Therapies, Indian Wells, CA, Feb 16–18, 2013. Ó Society of Surgical Oncology 2014 First Received: 5 April 2013 P. M. Polanco, MD e-mail: [email protected]

(p = 0.02) complications in the OW and OB groups, respectively. The 5-year survival rate for NW, OW, and OB patients was 63.9, 48, and 54.4 %, respectively (p = 0.63). The median time to progression was 21.1 (NW), 21.7 (OW), and 23.9 (OB) months (p = 0.83). Conclusions. OW and OB patients may have an increased risk of renal and pulmonary complications, respectively. Obesity has no major impact on perioperative mortality and long-term oncologic outcomes in patients undergoing CRS/ HIPEC for MAN.

Mucinous appendiceal neoplasms (MAN) are a heterogeneous group of tumors ranging from noninvasive adenomas to invasive adenocarcinomas that often lead to peritoneal dissemination of mucinous ascites and tumor deposits. If peritoneal carcinomatosis (PC) due to MAN is left untreated, progression of disease with small bowel obstruction and death from starvation is expected. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) is considered the standard of care for PC from MAN, demonstrating improved survival with this aggressive approach.1–4 This specialized procedure usually involves long operative times, multivisceral resections, and the potential for significant perioperative complications. At our cancer referral center, we observed that a large number of patients undergoing CRS/HIPEC for MAN were overweight or obese. It is well known that obesity is a growing epidemic in the United States. Data from the National Health and Nutrition Examination Survey reported that more than 33 % of adults in the United States are obese (BMI [ 30 kg/m2) and more than 64 % are overweight (BMI [ 25 kg/m2).5 Considering this major epidemiologic trend, it is relevant to evaluate the impact of

P. M. Polanco MD et al.

obesity on perioperative aspects and long-term oncologic outcomes of surgery. Previous studies have reported increased perioperative complications and mortality in obese patients undergoing abdominal surgeries.6,7 Moreover, there is an increasing interest on the link between obesity and cancer.8 Recent reports suggest that obesity can play a prominent role in the progression, recurrence, and survival rates of various cancers including breast, colorectal, and pancreatic cancer among others.8 Although there is little data available, some authors have suggested that hormonal, inflammatory, and metabolic mediators triggered by obesity activate pathways that lead to DNA damage and cancer initiation or progression.9 The primary objective of our study was to investigate the impact of being overweight or obese on perioperative morbidity, mortality, and long-term oncologic outcomes after CRS/HIPEC in patients with PC from MAN. MATERIALS AND METHODS From a prospective maintained database, we identified 282 consecutive patients with PC from MAN who underwent CRS/HIPEC between May 2001 and July 2010. The study was approved by the University of Pittsburgh institutional review board, and all procedures were performed by surgeons with extensive experience in regional therapies. All the patients were subjected to a standardized institutional protocol for HIPEC that was initiated after CRS using the closed technique and a roller-pump heat exchanger perfusion machine (Thermo Chem HT-100, ThermaSolutions, Melbourne, FL) that allowed adequate saline flow ([800 ml/min) and a target intraperitoneal tissue temperature of 42 °C.10,11 Most patients received mitomycin C with 30 mg added to the perfusate initially for 60 min followed by an additional 10 mg of mitomycin C added for a further 40 min. Deidentified patient information for the study included age at surgery, gender, race/ethnicity, ASA score, and preoperative body mass index (BMI; kg/m2). Patients were categorized into normal weight (NW; BMI \ 25 kg/m2), overweight (OW; BMI = 25–29 kg/m2), and obese (OB; BMI [ 30 kg/m2). Information obtained from the institutional database included intraoperative simplified peritoneal carcinomatosis index (SPCI) tumor grade, operative time, number of visceral anastomoses, estimated blood loss (EBL), completeness of cytoreduction13 (defined as CC-0, no visible residual disease; CC-1, residual tumors B2.5 mm; CC-2, residual tumors 2.5 mm to 2.5 cm; CC-3, residual tumors C2.5 cm), length of hospital stay (hospital-LOS), and intensive care unit length of stay (ICU-LOS).12,13 Outcome measures included perioperative complications according to the Clavien–Dindo classification and oncologic

outcomes of overall survival and time to disease progression.14 Statistical Analysis All variables were analyzed descriptively and compared among BMI categories. Continuous variables were summarized as mean ± standard deviation (SD) and median with interquartile range (IQR), and they were compared using parametric (1-way analysis of variance) or nonparametric (Kruskal–Wallis) test according to their distribution. Categorical variables were summarized as absolute and relative frequencies and were compared using Chi squared or Fisher exact tests depending on their group size. Values of p \ .05 were used to indicate statistical significance. The associations of BMI and complications were analyzed using unadjusted logistic regressions. Initially, the analyses were performed for BMI as a continuous variable to assess the odds of complications per increasing BMI. Secondly, the analyses were performed for BMI as categories to compare the odds of complications among normal weight, overweight, and obese patients. Unadjusted Cox regressions for proportional hazards were used to analyze associations of BMI and oncological outcomes. Initially, the analyses were performed for BMI as a continuous variable to assess the hazard of survival and time to disease progression per increasing BMI. Secondly, survival time and time to disease progression among BMI categories were estimated using the Kaplan–Meier method, and comparisons among normal weight, overweight, and obese patients were performed using log-rank tests. Unadjusted Cox regressions were performed to assess hazard of survival and time to disease progression among BMI categories. Analyses were performed in Stata (version 12) software. Findings for logistic regressions were presented as odds ratios (OR) with 95 % confidence intervals (95 % CI). Findings for Cox regressions were presented as hazard ratios (HR) with 95 % CI. Overall survival was calculated from the date of surgery to the date of death or to the date of their last follow-up. Time to disease progression was calculated from the date of surgery to the date of tumor recurrence or to the date of their last follow-up. RESULTS During the 10-year study period, 282 patients underwent CRS/HIPEC for PC from MAN. Of these, 234 patients had documented BMI data at the time of treatment and were suitable for analysis; 81 (34.6 %), 79 (33.8 %), and 74 (31.6 %) patients were categorized as NW, OW, and OB, respectively. The mean age for the entire group was

Impact of Obesity on CRS/HIPEC TABLE 1 Patient characteristics by BMI categories BMI categories

p value

Normal weight (n = 81)

Overweight (n = 79)

Obese (n = 74)

Mean (SD)

52.3 (10.6)

56.5 (11.7)

54.1 (12.0)

Median (IQR)

52.7 (46.9–59.1)

57.7 (48.1–65.7)

54.0 (46.6–59.2)

49 (60.4 %)

30 (37.9 %)

34 (45.9 %)

Age

Female

0.064

Race White

74 (91.3 %)

62 (91.1 %)

69 (93.2 %)

African American Asian

1 (1.2 %) 2 (2.4 %)

3 (3.8 %) 0 (0.0 %)

1 (1.3 %) 0 (0.0 %)

Hispanic

1 (1.2 %)

1 (1.2 %)

0 (0.0 %)

Other

3 (3.7 %)

3 (3.8 %)

4 (5.4 %)

ASA score

(n = 59)

(n = 51)

(n = 56)

1–2

10 (16.9 %)

12 (23.5 %)

9 (16.1 %)

3–4

49 (83.1 %)

39 (76.5 %)

47 (83.9 %)

Mean (SD)

13.5 (5.1)

12.5 (5.0)

12.1 (4.9)

Median (IQR)

13 (9–18)

13 (9–16)

13 (9-15)

Low

55 (67.9 %)

48 (60.7 %)

47 (63.5 %)

High

25 (30.9 %)

31 (39.2 %)

26 (35.1 %)

463.0 (149.6)

517.2 (171.9)

482.3 (186.9)

479 (353–575)

506 (417–620)

467.5 (374.5–553.5)

1625.3 (2248.9)

1471.8 (1532.6)

1190.6 (1186.6)

Simplified peritoneal carcinomatosis index (SPCI)

0.573

Operating room time in minutes Median (IQR) Estimated blood loss in ml Mean (SD) Median (IQR)

0.561

0.132

Grade

Mean (SD)

0.015 0.549

0.150

0.499 812.5 (450–2200)

1000 (500–2000)

800 (350–1500)

Complete resection (CC-0/1)

63 (77.7 %)

67 (84.8 %)

60 (81.0 %)

0.501

Number of anastomosis

(n = 80)

(n = 78)

(n = 72)

0.080

0

33 (41.2 %)

23 (29.5 %)

35 (48.6 %)

1–2

43 (53.8 %)

50 (64.1 %)

30 (41.7 %)

C3

4 (5 %)

5 (6.4 %)

7 (9.7 %)

Mean (SD)

13.7 (7.6)

15.9 (10.3)

13.3 (7.7)

Median (IQR)

12 (9-15)

12 (10–18)

11 (9–14)

(n = 67)

(n = 69)

(n = 70)

Length of hospital stay in days

ICU length of stay in days

0.220

Mean (SD)

3.0 (1.6)

4.1 (3.1)

3.3 (3.7)

Median (IQR)

3 (2–4)

3 (2–6)

2 (2–4)

0.070

Overall morbidity

46 (56.7 %)

51 (64.5 %)

52 (70.2 %)

0.215

Morbidity grade 3–4 60-days mortality

16 (19.7 %) 0 (0.0 %)

24 (30.3 %) 1 (1.27 %)

20 (27.0 %) 1 (1.35 %)

0.290 0.545

Patients were categorized as normal weight if BMI \ 25 kg/m2, overweight if BMI = 25–29 kg/m2, and obese if BMI C 30 kg/m2 BMI body mass index, SD standard deviation, IQR interquartile range, ICU intensive care unit

54.3 years. Majority of the patients were male (51.7 %) and white (91.9 %). The demographics by weight categories are summarized in Table 1. The OW and OB groups include a larger proportion of male patients with 62 and

54 %, respectively, in comparison with 39.5 % in the NW group (p = 0.02). ASA score was categorized in 2 groups (1–2 and 3–4) and revealed no distinction between BMI groups (p = 0.562).

P. M. Polanco MD et al. TABLE 2 Logistic regressions for the associations of BMI with complications

Any complication

BMI as continuous OR (95 % CI)

Overweight vs normal weight OR (95 % CI)

Obese vs normal weight OR (95 % CI)

1.02 (0.97–1.07)

1.38 (0.73–2.62)

1.79 (0.92–3.49)

Anastomotic leak

1.07 (0.97–1.17)

4.32 (0.47–39.5)

4.57 (0.49–41.8)

Cardiac

0.95 (0.88–1.01)

1.03 (0.44–2.38)

0.81 (0.33–1.99)

DVT

1.04 (0.96–1.14)

3.25 (0.63–16.6)

2.29 (0.40–12.9)

Pulmonary

1.05 (1.01–1.11)a

2.03 (0.97–4.24)

Renal

1.07 (1.01–1.14)

Wound infection

1.04 (0.98–1.09)

a

3.28 (1.12–9.06)

2.38 (1.14–4.97)a a

2.38 (0.77–7.33)

1.32 (0.59–2.98)

2.07 (0.95–4.51)

Unadjusted logistic regressions were performed separately for any complication, anastomotic leak, cardiac, deep venous thrombosis, pulmonary complication, renal complication, and wound infection. Initially, regressions were used to assess the odds of complications per increasing BMI. Secondly, regressions were used to compare the odds of complications in overweight and obese patients compared to normal weight patients BMI body mass index, OR odds ratio, 95 % CI 95 % confidence interval, DVT deep venous thrombosis a

Indicates statistical significance at p \ .05

The mean preoperative SPCI for the overall group was 12.8 and was similar among NW, OW, and OB patients being 13.5, 12.5, and 12.1, respectively (p = 0.13). There was no significant difference in operative time, EBL, number of visceral anastomoses, and rates of complete cytoreduction (CC-0/1) among the groups. Of the 234 patients, 150 (64.1 %) had low-grade tumors and 82 (35 %) had high-grade tumors, with 2 patients having unspecified histology grading (0.9 %). Table 1 depicts comparisons among groups, showing no statistically significant disparity regarding histologic grading (p = 0.57). Hospital-LOS and the ICU-LOS were 14.3 and 3.5 days for the entire group, respectively, with no significant difference between groups (p = 0.22) as shown in Table 1. The overall morbidity rate for NW, OW, and OB subjects was 56.8, 64.6, and 70.3 %, respectively, demonstrating a trend toward increased rate of complications as BMI increased, without achieving statistical significance (p = 0.22). Grade 3/4 morbidity, according to Clavien–Dindo classification, occurred in 19.7, 30.4, and 27.0 % of NW, OW, and OB patients, respectively (p = 0.21). Only 2 patients in the overall cohort (0.85 %) died in the 60-day postoperative period, 1 in the OW and 1 in the OB group. Unadjusted logistic regression analysis revealed that increments of BMI as a continuous variable (Table 2) was associated with a trend toward increasing overall complications, wound infections, deep vein thrombosis, respiratory and renal complications, and anastomotic leaks, but was only statistically significant for renal (OR 1.07; 95 % CI 1.01–1.14; p = 0.03) and pulmonary complications (OR 1.05; 95 % CI 1.01–1.11, p = 0.02). Unadjusted regression analysis of BMI categories showed a trend toward increased odds ratio of most complications when OW and OB patients were compared with NW patients

TABLE 3 Cox regressions for the proportional hazard for the association of BMI with survival and time to disease progression BMI as continuous HR (95 % CI) Death during follow-up

Overweight vs normal weight HR (95 % CI)

Obese vs normal weight HR (95 % CI)

1.01 (0.97–1.06) 1.29 (0.71–2.33) 1.00 (0.52–1.90)

Time to 1.01 (0.98–1.05) 1.12 (0.72–1.75) 0.99 (0.63–1.55) disease progression Unadjusted Cox regressions were performed separately for survival and time to disease progression. Initially, regressions were used to assess the hazards of survival and time to disease progression per increasing BMI. Secondly, regressions were used to compare the hazards in overweight and obese patients compared with normal weight patients BMI body mass index, HR hazard ratio, 95 % CI 95 % confidence interval

(Table 2). This increased risk only reached statistical significance for renal complications for the OW group (OR 3.28; 95 % CI 1.12–9.60; p = 0.02) and pulmonary complications for the OB group (OR 2.38; 95 %CI 1.14–4.97; p = 0.03). Unadjusted Cox regression analysis revealed that BMI was not associated with increased risk of death or disease progression during follow-up (Table 3). Pulmonary complications occurred in 71 patients, most commonly including pleural effusions and respiratory failure in 26 (36.6 %) and 15 (20 %) patients, respectively. Of the latter patients, 4 needed reintubation, with 1 requiring a tracheostomy. Of the 37 patients with renal complications, 25 (67.6 %) had urinary tract infections and 6 (16.2 %) had acute renal failure, with 1 requiring hemodialysis. As shown in Fig. 1a, b, Kaplan–Meier analysis did not reveal statistical differences among BMI groups in overall

Impact of Obesity on CRS/HIPEC

A Survival

Probability 1.00

Normal weight Over weight Obese

0.75

0.50

0.25

Log-rank test s p-value = 0.627

0.00 0

20

40

60

80

100

Time in months

B

Time to progression

Probability 1.00

Normal weight Over weight Obese

0.75

Log-rank test s p-value = 0.831 0.50

0.25

0.00

0

20

40

60

80

100

Time in months

FIG. 1 a Kaplan–Meier survival curves for overall survival (OS) for each category of BMI. The 5-year survival rate for NW, OW, and OB patients was 63.3, 48.01, and 54.4 %, respectively (p = .627). b Kaplan–Meier curves for time to progression (TTP) for each category of BMI. The median time to progression was 21.07 (NW), 21.7 (OW), and 23.9 (OB) months (p = .831)

survival or time to progression. The 5-year survival rate for NW, OW, and OB was 63.3, 48.01, and 54.4 %, respectively (p = 0.63). The median time to progression was 21.07 (NW), 21.7(OW), and 23.9(OB) months (p = 0.83). DISCUSSION The impact of obesity on perioperative morbidity and long-term oncologic outcomes after aggressive surgical therapy is of considerable importance in light of the prevailing obesity epidemic and growing evidence implicating obesity with increased surgical complications and cancer initiation/progression.8,9 Our institutional data support the national epidemiologic trend with close to two-thirds of patients (65.4 %) undergoing CRS/HIPEC for MAN being classified as overweight or obese.

The management of MAN with PC has radically changed over the last 2 decades. Historically, surgeons would only perform serial palliative debulking procedures to alleviate mass effect and obstructive symptoms.15,16 During the 1990s Sugarbaker introduced the concept of radical curative CRS to remove macroscopic tumor deposits combined with perioperative intraperitoneal chemotherapy (PIC) to treat residual microscopic disease. With CRS plus intraperitoneal chemotherapy, long-term survival has improved significantly as reported by several retrospective series.17–19 Consequently, and despite the lack of randomized controlled trials, CRS followed by PIC has become the accepted standard of care for the treatment of PC of appendiceal origin.4,20 However, this radical surgical approach to achieve complete disease clearance often involves extensive multivisceral resections, prolonged operative times, increased blood loss, and several visceral anastomoses that have been described as predictors of perioperative morbidity.21–23 The morbidity rate of CRS/HIPEC reported by other institutions ranges from 7 to 68 %, with an average of 37.5 % according to a recent meta-analysis by McBride et al.,3 In our series, the overall morbidity rate was 63.7 %, with Clavien–Dindo grade 3/4 morbidity accounting for 25.6 % of complications. This relatively high incidence of postoperative morbidity may be explained by the aggressive surgical approach needed to achieve a high rate of complete cytoreduction (81.2 %) in our patients with a high preoperative SPCI. Based on National Surgical Quality Improvement database from the American College of Surgeons (ACS-NSQIP), Causey et al. recently reported on the association of obesity with surgical complications after major abdominal surgery for Crohn’s disease.6 He found an increased rate of morbidity from 22 to 32 % in obese versus normal weight patients. In contrast, Mullen et al.,24 in an earlier series using ACS-NSQIP data as well, showed that obesity was not a risk factor for perioperative complications or mortality except for a higher rate of wound complications. These studies were limited by the accuracy of the databases and also by the inability to classify the severity of the complications. In our series, comparison between groups showed a clear trend of increasing complications with increasing BMI. Also, while severe morbidity (Clavien–Dindo 3/4) was only present in 19.7 % of patients with NW, it was almost 1.5 times higher in the OW and OB groups, reaching 30.4 and 27 %, respectively. However, this clinically relevant difference did not attain statistical significance, probably related to the small sample size in our study. No significant differences were found between the groups regarding tumor burden (SPCI) or histologic classification. Notably, ASA score, a measure of preoperative physical status, was similar across BMI categories. Also, the extent of surgery denoted by the

P. M. Polanco MD et al.

operative time, EBL, number of visceral anastomoses, and completeness of cytoreduction was comparable between groups. In our study, there was a trend toward increased number of anastomoses in the overweight group compared with the normal weight and obese groups. In addition, there was a trend toward increased anastomotic leaks in the unadjusted logistic regression analysis when overweight versus normal weight patients were compared (Table 2). As depicted in Table 2, increasing BMI was associated with a trend toward increased postoperative morbidity, except for cardiac events; however, statistical significance was only achieved for renal and respiratory complications. For each unit increment in BMI, the risk of renal and pulmonary complications increased by 7 and 5 %, respectively. These findings were also confirmed when logistic regression was used to compare the odds ratio for complications between groups. OW and OB patients had at least a 2-fold and 3-fold increased risk of renal and pulmonary complications, respectively, when compared with NW patients. Mortality was minimal in our series with only 2 deaths among the entire group of 234 patients. Obesity is now an accepted risk factor for several gastrointestinal malignancies including colorectal cancer.25,26 Moreover, it may have an impact on long-term outcomes and recurrence of colon cancer as described by Dignam et al.,27 who found that a BMI greater than 35.0 kg/m2 at diagnosis was associated with an increased risk for recurrence and death from colon cancer. There is currently no available data in the literature about a relationship between obesity and MAN. In our study, overall survival and time to progression did not seem to be affected by increasing BMI when Kaplan–Meier analysis was used to compare oncologic outcomes among NW, OW, and OB groups. In a similar study, Votanopoulos and colleagues did not demonstrate increased postoperative morbidity or mortality after CRS/HIPEC in obese (BMI C 30 kg/m2) patients with peritoneal surface disease from colon or appendiceal cancers. However, a subset of severely obese patients (BMI C 35 kg/m2) did have higher readmission rates after 30 days, more frequent surgical/radiologic interventions for postoperative complications, and worse overall survival in patients with disseminated low-grade appendiceal disease.28 A smaller series of patients reported recently by McPartland et al. also evaluated the effect of elevated BMI on perioperative and oncologic outcomes after CRS/HIPEC for peritoneal malignancies. They found no major differences in outcomes when compared across BMI categories, except for an increased rate of deep vein thrombosis in the overweight category.29 Our data are limited by the retrospective nature of the analysis of a prospectively maintained database, including some missing data points. In addition, the small number of events or complications in the comparison analysis among

subgroups limited the ability to detect significant differences and to perform multivariate analysis. In summary, we conclude that two-thirds of patients with PC from MAN undergoing CRS/HIPEC are either OW or OB. OW and OB patients demonstrated a trend toward higher rates of severe postoperative complications (Clavien–Dindo grade 3/4), with statistical significance achieved for renal complications in OW patients and pulmonary complications in obese patients. However, BMI had no impact on perioperative mortality, overall survival, or time to progression. Our data suggest that the potential impact of BMI on perioperative morbidity is an essential component of preoperative discussions with patients and for operative planning; however, it should not preclude CRS/HIPEC in PC for MAN since it has no effect on longterm oncologic outcomes. DISCLOSURE

None.

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Does obesity affect outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for disseminated mucinous appendiceal neoplasms?

Obesity has been described as a risk factor for surgical complications and may play a prominent role in the progression, recurrence, and survival rate...
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