PREOPERATIVE IMMUNONUTRITION FOR PATIENTS WHO UNDERGO PRIMARY CYTOREDUCTIVE SURGERY FOR OVARIAN CANCER

Abstract

Objective:

The role of preoperative immunonutrition interventions for patients with gynecologic malignancies has not been well-studied.

Methods:

We performed a prospective observational study to assess the feasibility of a preoperative immunonutrition supplementation plan for patients with advanced ovarian cancer who underwent primary cytoreductive surgery between August 2019 and November 2022. Patients were encouraged to drink the provided immunonutrition supplement at each meal for up to 7 days prior to surgery. Patients completed standardized daily intake surveys as well as laboratory tests and weight measurements throughout the study.

Results:

A total of 29 patients were enrolled, 17 of whom met inclusion criteria. Participants demonstrated a median weight gain of 3.8 kg over the study period, with high compliance, consuming an average of 2.2 Ensure^® Surgery Immunonutrition Shakes daily. On the day of surgery, 16 of 17 patients (94%) found the supplement satisfying, and 12 (71%) reported feeling better prepared for surgery. The median length of postoperative hospital stay was 8 days (interquartile range, 6–9), and the median length from day of surgery to start of chemotherapy was 36 days (interquartile range, 35–40). Preoperative laboratory assessments showed significant increases in neutrophils (+4.27 cells/μL, p<0.001), C-reactive protein (+23.03 mg/L, p<0.001), interleukin 6 (+160.22 pg/mL, p<0.001), and interleukin 10 (+4.62 pg/mL, p=0.279).

Conclusions:

Implementing a preoperative immunonutrition supplementation program among patients with advanced ovarian cancer who undergo primary cytoreductive surgery is feasible, and future studies are warranted to confirm whether such a program could benefit patient outcomes.

Introduction

Malnutrition secondary to cancer is a state of deficiency or imbalance of nutrients due to undernutrition, causing adverse effects in bodily functions or form.[1] Malnutrition can lead to a deficiency in energy and protein and a decrease in fat-free mass, resulting in adverse clinical outcomes.[2, 3] More than 50% of patients with gynecologic cancer present with at least mild malnutrition at diagnosis.[4–6] Patients with newly diagnosed ovarian cancer are especially vulnerable as they commonly experience bloating, abdominal pain, difficulty eating, and early satiety, which can affect dietary habits and lead to poor nutritional status.[7] Among patients with gynecologic cancers, poor nutritional status has been linked to higher risk of suboptimal surgery, surgical complications, and decreased survival, especially in older patients.[8, 9] Patients with newly diagnosed ovarian cancer who undergo primary cytoreduction followed by adjuvant chemotherapy are frequently interested in preoperative interventions to maximize treatment results.[10] The period from diagnosis to primary surgery is an opportune time to administer interventions to improve nutrition. As such, the National Comprehensive Cancer Network recommends evaluation of nutritional status during the baseline workup for patients with newly diagnosed ovarian cancer prior to cytoreductive surgery.[10]

As more information has become evident that the immune system is critical in the fight against cancer, this has given rise to the emerging field of immunonutrition. Immunonutrition with newly developed formulas aims to modulate the body’s inflammatory response in the perioperative period and could aid in improving immune status, decreasing treatment toxicity, and improving patient outcomes.[11] Patients who undergo surgery for gastrointestinal malignancies and receive classic perioperative enteral nutrition supplementation or immunonutrition experience fewer surgical site infections, decreased length of hospital stay, and fewer complications.[12, 13] Decreased hospital costs are also observed with use of perioperative immunonutrition.[14] Little is known about the role of nutrition interventions for patients with ovarian cancer, and evidence is limited on what is feasible and should be considered successful regarding the implementation and clinical uptake of a nutrition program for these patients.

This feasibility study investigated the role of preoperative nutrition instruction and immunonutrition supplementation in patients with ovarian cancer preparing for primary cytoreductive surgery. We aimed to better understand the relation of a preoperative nutrition program with patient-reported outcomes and immunomodulation.

Methods

Study Design

This multi-institutional (Memorial Sloan Kettering Cancer Center, NY; Baptist Health Miami Cancer Institute, FL), prospective observational study occurred from October 2019 to November 2022, and assessed the feasibility of a preoperative immunonutrition supplementation plan. The intervention included a standardized instructional encounter, designed by the clinical nutrition service at a tertiary care institution, that addressed the importance of perioperative nutrition, diet and calorie recommendations, and introduced the nutritional supplement selected by the clinical nutrition service, the Ensure^® Surgery Immunonutrition Shake. This 330-calorie shake is commercially available and consistent with immunonutrition formulas as well as dosing studied previously.[15] Ensure^® Surgery shakes contain 18g of protein, 4.2g of arginine, and 1.1g of omega-3 fatty acids.[15]

After obtaining informed consent and confirming eligibility, participants received 21 bottles of the shake and were instructed to drink one bottle 3 times per day for 7 days prior to primary cytoreductive surgery. Seven days was chosen based on prior studies,[13] because the concept of a 1-week program is easy to grasp, and we hypothesized that this is a realistic goal for patients prior to surgery. The last day of the intervention occurred either 1 or 2 days before surgery, depending on the patient’s need for mechanical bowel preparation.

The primary outcome was the feasibility of implementing a preoperative immunonutrition program for patients who undergo primary cytoreductive surgery for ovarian cancer. This protocol aimed to establish the feasibility of addressing nutritional concerns during the relatively short period between diagnosis and primary surgery.

Assessments/Evaluation Plan

At time of inclusion, patients completed a ‘Pre-Study Nutrition Intake Form’, assessing the number of meals per day and the type and amount of food ingested (Appendix 1). For the next 7 days, patients completed a ‘Daily Supplement/Food Intake Form’, which assessed the number of meals per day, the type and amount of food ingested, and symptoms experienced during the intervention. This form featured a Bristol Stool Chart to assess bowel movements (Appendix 2). On the day of surgery, patients completed a ‘Day of Surgery Intake Form’, assessing the patient’s satisfaction with the supplement, ease with instructed consumption, and perception of surgery preparation (Appendix 3). Additional assessments included weight and body mass index (BMI; kg/m²); laboratory measures (complete blood count, C-reactive protein, tumor necrosis factor-alpha, interleukin 10, and interleukin 6) obtained during presurgical testing, on the day of surgery, and postoperatively within 7 days after surgery; and a postoperative chart evaluation including time of admission and time to chemotherapy initiation (Table 1).

Table 1:

Study assessments and evaluation forms completed by patients, with time of completion, per study protocol.

	Time of Completion
Assessment/Evaluation	Screening and Consent	Presurgical Testing	During Nutrition Supplementation	Preoperative - Day of Surgery	Postoperative - Within 7 days After Surgery
Complete blood count		X		X	X
C-reactive protein		X		X	X
Tumor necrosis factor-α		X		X	X
Interleukin 6		X		X	X
Weight	X			X	X
Body mass index	X			X	X
Pre-Study Nutrition Intake Form*	X
Daily Supplement/Food Intake Form with Bowel Function Assessment*			X
Day of Surgery Intake Form*				X

^*These forms can be found in the Supplementary Material (Appendix 1–3).

Inclusion/Exclusion Criteria

Inclusion criteria included suspected ovarian, fallopian tube or primary peritoneal cancer, scheduled primary cytoreduction, and a sufficient preoperative window to administer the intervention. Exclusion criteria included receipt of neoadjuvant chemotherapy, surgery scheduled <8 days from the initial visit, no scheduled exploratory laparotomy, diagnosed diabetes mellitus, and allergy to the shake.

Statistical Analysis

The primary endpoint was the rate of patient participation in the immunonutrition program. Each question on the three assessment forms was analyzed separately. Counts and percentages were reported for categorical variables. Descriptive statistics including median and interquartile range (IQR) and mean and standard deviation (SD), and differences in measurements at different time points, were calculated for weight, BMI, and laboratory values. Time point #1 (baseline) was defined as the time of inclusion in the study, time point #2 was defined as the time period between the initial measurement 7 days prior to surgery up to the day prior to surgery, and time point #3 was defined as the day of surgery. Wilcoxon signed rank test was applied to test for changes between different time points for continuous variables. Time of admission and time to chemotherapy initiation were summarized descriptively. Two-sided p-values were calculated. All analyses were performed using R 4.2.2 (https://www.R-project.org/).

In accordance with the journal’s guidelines, we will provide our data for independent analysis by a selected team by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.

Results

Twenty-nine patients were enrolled, and 17 were evaluable and included in analysis (Figure 1); 12 patients were excluded, 9 underwent neoadjuvant chemotherapy, and 3 had non-ovarian histology. Among the 17 patients, median age was 65 years (range, 43–81), median time from consent until day of surgery was 11 days (IQR, 8–12), median length of hospital stay following surgery was 8 days (IQR, 6–9), and median time from day of surgery to adjuvant chemotherapy initiation was 36 days (IQR, 35–40). Median weight at baseline was 65.2 kg (IQR, 58.6–77.1), time point #2 was 67.8 kg (IQR, 57.7–77.8), and time point #3 was 69.0 kg (IQR, 58.6–76.9) (baseline vs time point #3, p=0.345). Median weight change from baseline to time point #2 was −0.9 kg, from time point #2 to postoperative examination was 1.1 kg, and from baseline to postoperative examination was 0.4 kg (Figure 2A). Median BMI at baseline was 27.1 kg/m² (IQR, 22.9–32.0), time point #2 was 27.5 kg/m² (IQR, 22.9–31.2), and time point #3 was 28.4 kg/m² (IQR, 24.1–31.1) (baseline vs time point #3, p=0.889). Median BMI change from baseline to time point #2 was −0.2 kg/m², from time point #2 to postoperative examination was 0.4 kg/m², and from baseline to postoperative examination was 0.2 kg/m² (Figure 2B).

Figure 1:

Consort diagram of patients enrolled and included in the study.

Figure 2:

(A) Boxplots of patient weight measurements at the 3 different time periods throughout the study; (B) boxplots of patient body mass index measurements at the 3 different time periods throughout the study. The initial measurement (time point #1) was performed at the time of enrollment onto the study; measurement #2 (time point #2) was performed in the time period between the initial measurement 7 days prior to surgery up to the day prior to surgery; and the final measurement (time point #3) was performed on the day of surgery.

Preoperative laboratory assessments at baseline, time point #2, and time point #3, respectively, were as follows: mean absolute neutrophil levels were 5.06 cells/μL (SD, 1.37), 6.04 cells/μL (SD, 2.18), and 9.33 cells/μL (SD, 2.84), respectively, for a total mean increase of 4.27 cells/μL (p<0.001); mean C-reactive protein levels were 4.19 mg/L (SD, 7.5), 3.82 mg/L (SD, 4.31), and 27.22 mg/L (SD, 26.88), respectively, for a total mean increase of 23.03 mg/L (p<0.001); mean tumor necrosis factor-alpha levels were 9.79 pg/mL (SD, 3.35), 8.04 pg/mL (SD, 3.69), and 8.11 pg/mL (SD, 3.76), respectively, for a total mean decrease of 0.58 pg/mL (p= 0.454); mean interleukin 10 levels were 9.43 pg/mL (SD, 1.34), 9.79 pg/mL (SD, 1.89), and 14.08 pg/mL (SD, 14.61), respectively, for a total mean increase of 4.62 pg/mL (p=0.279); and mean interleukin 6 levels were 9.09 pg/mL (SD, 7.26), 46.02 pg/mL (SD, 128.57), and 169.26 pg/mL (SD, 218.62), respectively, for a total mean increase of 160.22 pg/mL (p<0.001) (Figures 3A–E).

Figure 3:

Bar graphs of mean laboratory values of (A) absolute neutrophils, (B) C-reactive protein, (C) tumor necrosis factor-α, (D) interleukin 10, and (E) interleukin 6 stratified by time of measurement with 95% confidence intervals. The initial measurement (time point #1) was performed at the time of enrollment onto the study; measurement #2 (time point #2) was performed in the time period between the initial measurement 7 days prior to surgery up to the day prior to surgery; and the final measurement (time point #3) was performed on the day of surgery.

On the ‘Pre-Study Nutrition Intake Form’, no patients reported daily nausea or vomiting, and 3 (18%) reported difficulty eating and drinking daily. Patients reported a median intake of 3 meals (range, 2–5) and 3 snacks (range, 1–5) per day, consisting of median servings of 2 grains/starches, 2 vegetables, 2 dairy, 2 fruits, 2 proteins, and 2 oils/fats/sweets. Three patients (18%) were using nutrition supplements. All 17 patients either agreed or strongly agreed they would be able to finish at least 1 shake each day, and 10 (59%) believed they would be able to finish at least 3 shakes.

On day #1 of the program, 5 of 17 patients (29%) completed one shake, 4 (24%) completed two, and 8 (47%) completed three. Fourteen patients (82%) reported no issues completing the shakes and 3 (18%) reported an unpleasant taste while drinking the shake. Four patients (24%) reported increased satiety upon finishing day #1, 1 (6%) reported diarrhea, and 1 (6%) reported constipation. Among 50 bowel movements, the most common stool consistency reported on the Bristol Stool Chart was Type 4 (n=10, 20%), followed by Type 6 (n=9, 18%) and Type 2 (n=8, 16%).

On day #4, 5 patients (29%) completed one shake, 2 (12%) completed two, and 10 (59%) completed three. One patient (6%) reported improved appetite, 5 (29%) reported a pleasant taste, 3 (18%) reported an unpleasant taste, and 9 (53%) were neutral regarding taste. One patient (6%) reported improved energy, 1 (6%) reported increased nausea, and 3 (18%) reported increased satiety. Among 55 bowel movements, the most common stool consistencies reported were Type 6 (n=11, 20%) and Type 4 (n=10, 18%).

On day #7, 6 patients (35%) completed one shake, 3 (18%) completed two, 8 (47%) completed three. Three patients (18%) reported a pleasant taste, 3 (18%) reported an unpleasant taste, and 11 (65%) were neutral regarding taste. No patients reported nausea, and 4 (24%) reported increased satiety. Among 58 bowel movements, the most common stool consistency was Type 6 (n=12, 21%), followed by Type 2 (n=8, 14%), Type 3 (n=8, 14%), Type 4 (n=8, 14%), and Type 5 (n=8, 14%).

Patients completed an average of 2.19 shakes per day, ranging from 2.06 on day #6 to 2.47 on day #3 (Figure 4).

Figure 4:

Bar chart demonstrating frequency of patients finishing 0, 1, 2, or 3 Ensure^® Surgery Immunonutrition Shakes stratified by day of the standardized nutrition program.

On the ‘Day of Surgery Intake Form’, 12 patients (71%) either agreed or strongly agreed, “participating in the study helped to better control their surgery preparation.” Sixteen patients (94%) reported the “supplement was satisfying;” 15 (88%) reported they “could easily drink at least one supplement each day;” 10 (59%) reported they “could easily drink all three supplements each day;” and 12 (71%) reported they felt “better prepared for surgery after the study.”

Discussion

Summary of Main Results

Our findings suggest a standardized preoperative immunonutrition program is feasible for patients who undergo primary cytoreduction for ovarian cancer. The preoperative period demonstrated efficiency as an opportune time to complete an immunonutrition program, with a median interval of 11 days from consent to surgery. Patients exhibited modest increases in weight and BMI throughout the intervention; however, many patients with newly diagnosed ovarian cancer have rapidly accumulating ascites, which may have accounted for these observations. Patients consumed the supplement while maintaining a healthy diet, suggesting feasibility and a potential for nutritional benefit in a group who noted difficulty tolerating oral intake. High adherence to the immunonutrition program was noted, with an average consumption of 2.2 shakes per day. Patients felt an increased sense of readiness for surgery. During the stressful time of a cancer diagnosis, an increased sense of control alone may have incalculable benefit.

Results in the Context of Published Literature

We noted a modulation of hematologic cytokines and immunocytokines including interleukin 6, interleukin 10, absolute neutrophils, C-reactive protein, and tumor necrosis factor-alpha; although, the extent to which the supplement contributed to these changes is unclear. Ovarian cancer produces immune suppression factors that target effective immune system surveillance, giving cancer cells an advantage in the balance between continued proliferation and evasion versus leukocyte-mediated apoptosis.[16] Interleukin 6 is regarded as a proinflammatory cytokine mediator with effects on inflammation, immune response, and hematopoiesis.[17, 18] Interleukin 6 levels are commonly overexpressed in the tumor microenvironment, promoting tumorigenesis by regulating signaling pathways, including apoptosis, proliferation, angiogenesis, metabolism, and metastasis.[19] Conversely, interleukin 10 is an essential cytokine for T-helper cell function, T-cell immune surveillance, and suppression of cancer-associated inflammation.[20–22] Interleukin 10 is emerging as a key cytokine in the battle of the host against cancer given its immune surveillance and pathogenic anti-inflammatory properties.[22] Interleukin 10 secretion in the ovarian cancer microenvironment may enable more effective translation of potential immunotherapies into the clinical setting.[23, 24] As the importance of modulating immune response is elucidated, particularly during the time of surgery, the role of immunoregulatory supplements will become clearer.

Like interleukin 6, C-reactive protein and tumor necrosis factor-alpha are innate immune proteins involved in proinflammatory responses and serve a contradictory role in cancer proliferation. Although tumor necrosis factor has been linked to tumor angiogenesis, invasion, and metastasis, various studies indicate it exhibits an antioncogenic effect in mouse models.[25, 26] Given its cytotoxic and immunomodulatory effects on malignant tumors, tumor necrosis factor has been targeted as a chemotherapeutic drug but has been limited by adverse events.[26] C-reactive protein is an acute-phase reactant protein involved in tissue fibroblast formation and complement activation [16]. The proliferative versus protective role of C-reactive protein on cancer progression or remission is undefined. The alteration of systemic interleukin 6/interleukin 10 ratios as well as C-reactive protein and tumor necrosis factor-alpha levels from immunonutrition versus the tumor microenvironment has not been studied and warrants further investigation on possible benefits to oncologic outcomes.

Ensure^® Surgery shakes contain 18g of protein, 4.2g of arginine, and 1.1g of omega-3 fatty acids.[15] Arginine is an essential amino acid involved in various metabolic processes, while omega-3 fatty acids are long-chain polyunsaturated essential fatty acids that reduce inflammation and improve blood flow.[27] Arginine depletion following surgery has been linked to immune dysfunction, leading to an increased risk of postoperative infections.[28] A 2011 meta-analysis of 35 gastrointestinal malignancy studies found arginine-supplemented diets were associated with a 41% reduction in overall infectious complications and decreased length of hospital stay.[29] A study of 200 patients with colorectal cancer found those who received preoperative oral arginine and omega-3 fatty acid supplementation had significantly better immune response, gut oxygenation, and microperfusion than controls.[30] These findings may help to explain the favorable length of hospital stay seen amongst our cohort.

The National Comprehensive Cancer Network recommends evaluation of nutritional status during the baseline workup for patients with newly diagnosed ovarian cancer prior to cytoreductive surgery.[10] Preoperative nutritional status is assessed in various ways (eg, weight, BMI, anthropometrics, serum protein, serum albumin, transferrin, lymphocyte count).[31] Nutritional and immunological status before surgery can impact incidence of postoperative complications and overall survival outcomes in patients with newly diagnosed malignancies.[32] A 2016 retrospective study found prognostic nutritional index levels <45 were associated with shorter progression-free and overall survivals (hazard ratio, 1.75, p<0.001) in 344 patients with newly diagnosed ovarian cancer.[33] Likewise, a 2011 retrospective study of 300 patients with newly diagnosed gynecologic cancer found that decreased albumin levels and BMI were associated with increased occurrence of postoperative complications, hospital readmissions, reoperations, intensive care unit admissions, and cancer recurrences (p<0.01).[34] Our results suggest an immunonutrition program prior to cytoreductive surgery may improve nutritional metrics (eg, BMI, albumin levels), and therefore improve postoperative and disease outcomes in ovarian cancer.

Strengths and Weaknesses

This study explores preoperative immunonutrition supplements that have not been studied in patients with ovarian cancer. The prospective, multi-institutional design enhances the generalizability and applicability of our findings across diverse clinical settings. The high adherence rate and patient-reported satisfaction with the program support its feasibility and acceptability in a short preoperative period. We assessed clinical outcomes and patient perceptions, offering a holistic view of the intervention’s impact. The limited sample size and exclusion of 12 patients from analysis may limit the generalizability of findings. Without a control group, it is not possible to establish causality or directly compare the effects of the intervention to standard preoperative care. Additionally, patient exercise and activity was not evaluated in the study but could have affected weight change and other variables; this will be an important factor to evaluate in future studies. Finally, the true clinical impact of perioperative immunonutrition on cancer survival outcomes cannot be determined due to lack of long-term data.

Implications for Practice and Future Research

Our findings provide preliminary evidence for the role of structured nutritional interventions in improving surgical preparedness and recovery among patients with ovarian cancer who undergo primary cytoreductive surgery. Future randomized controlled trials with extended follow-up are needed to confirm clinical benefit.

Conclusions

This study demonstrated the feasibility of implementing a preoperative immunonutrition program for patients who undergo cytoreductive surgery for ovarian, fallopian tube, or primary peritoneal cancer. The intervention was well tolerated, had high rates of patient adherence and satisfaction, and led to measurable improvements in surgical preparedness.

KEY MESSAGES.

What is already known on this topic – Patients with newly diagnosed ovarian cancer who undergo primary cytoreductive surgery followed by adjuvant chemotherapy are frequently interested in preoperative interventions to maximize the results of their treatment; however, the role of preoperative immunonutrition interventions for these patients has not been well-studied.

What this study adds – Our findings suggest preoperative immunonutrition supplementation is well-tolerated and feasible in the short window before surgery for patients who undergo primary cytoreductive surgery for ovarian cancer. Patients consumed an average of 2.2 shakes daily and reported an increased sense of readiness for their procedure.

How this study might affect research, practice or policy – Our findings provide preliminary evidence for the role of structured preoperative immunonutritional interventions in improving surgical preparedness and recovery, and establish a foundation for future randomized controlled trials to confirm whether these interventions could benefit patient outcomes.