CASE REPORT

A 66-year-old male with a history of type 2 diabetes (diagnosed in the 1990s), coronary artery disease status post coronary artery bypass grafting times four vessels in 2015, hypertension, hyperlipidemia, and gastroesophageal reflux disease presented with diarrhea and respiratory distress in the fall of 2020. He was severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—positive and diagnosed with coronavirus disease 2019 (COVID-19).

During evaluation, a computerized tomography (CT) scan was performed and noted to have a 1.8 by 1.6 cm enhancing lesion in the head of the pancreas, as well as another 6-mm enhancing nodule in the pancreas. Fatty infiltration of the pancreas was also noted. A biopsy was performed and was consistent with a neuroendocrine tumor.

In terms of nutrition history, he reported poor oral intake with a 45-lb (20.5 kg) weight loss over the last 2 months. The body mass index (BMI) was 32 kg/m2. He reported recurrent nausea, early satiety, and ongoing diarrhea. His reported dietary intake was the following: Breakfast: toast with jam or cereal with milk; Morning snack: occasional cookie with milk; Lunch: half of a sandwich; Evening meal: some form of protein, such as chicken, with rice; Snack: ice-cream, which has recently been added for weight gain; and Beverages: milk, water, and diet soda.

He then met with a surgeon and a recommendation was made to move ahead with a total pancreatectomy.

DISCUSSION

This case presentation and panel discussion took place during the virtual course, Comprehensive Nutritional Therapy: Tactical Approaches in 2021 (Part 1, March 19, 2021; Part 2, March 20, 2021), which was organized by the American Society for Parenteral and Enteral Nutrition (ASPEN) Physician Engagement Committee and preceded the ASPEN 2021 Nutrition Science & Practice Conference. The moderator for this session was Manpreet Mundi, MD; and the panelists were Alessandro Laviano, MD; Robert G. Martindale, MD, PhD; and Teresa Zimmers, PhD.

Assessment of nutrition status

Dr Mundi: How do we assess his nutrition status in the setting of obesity?

Dr Laviano: This case really reflects the average cancer patient we are now seeing in North America and Europe because the majority of patients with cancer that we are evaluating are either overweight or obese. Because of this, we are no longer using BMI as a marker of malnutrition and instead are focusing more on the changes in body weight, which in this patient was ∼45 lbs (20.5 kg) in the last 2 months. Additionally, we are focusing more importantly on the presence of nutrition alarm symptoms. In this situation, he reported nausea as well as diarrhea, and thus he had a number of symptoms that place him at risk for developing malnutrition.

Recently, ASPEN and European Society for Clinical Nutrition and Metabolism (ESPEN) developed recommendations for the diagnosis of malnutrition that are referred to as the Global Leadership Initiative on Malnutrition (GLIM) criteria.1 These criteria utilize pathogenic/etiologic (reduced food intake or assimilation and inflammation or disease burden) and phenotypic (nonvolitional weight loss, low BMI, and reduced muscle mass) characteristics to diagnose malnutrition. In this situation, he has a reduction in appetite, nausea, decreased food intake, decreased weight, and probably fatigue when combined with his cancer diagnosis, so he would meet the GLIM criteria for malnutrition even at his current BMI, which exceeds 30 kg/m2. So, to me, this is a typical patient with cancer who has sufficient etiologic and phenotypic characteristics to meet the diagnosis of malnutrition. Now, whether he is cachectic, we can discuss later on. 2

Dr Mundi: In addition to focusing on GLIM criteria for malnutrition, would adding other metrics, such as bioimpedance or CT scan measurement of lean mass, be helpful?

Dr Laviano: Certainly, in many cases in which the CT scan or other imaging is not available, then we can base the diagnosis on the known or available phenotypic and etiologic characteristics. However, as is common in patients with cancer, such as this gentleman, we do have a CT scan and often serial CT scans available of the abdomen. This gives us the opportunity to not only confirm the diagnosis of malnutrition and cachexia, but also to actually measure the quantity of muscle mass he has lost. So, I would recommend, when available, utilizing the slice of the CT scan encompassing the third lumbar vertebrae to measure and quantify the degree of muscle mass present.

Of course, sometimes we are also trying to obtain other laboratory and biochemical parameters that can aid in the diagnosis of malnutrition. For example, inflammatory markers such as C-reactive protein or the neutrophil-to-lymphocyte ratio, which has also been used by oncologists to predict the outcome for patients, can provide valuable etiologic information to aid in the diagnosis of malnutrition.

In this case, based on the history and exam findings, we know the patient is malnourished. However, by combining that history with additional information such as quantity of muscle mass and possibly quality of muscle mass with the presence of inflammation, we can provide a more precise profiling of the nutrition status. This allows you to then decide which of the abnormal characteristics do you focus your intervention on. If the patient has a high inflammatory response, that could be your target to address through nutrition intervention.

Impact of COVID-19 on cachexia and malnutrition 3

Dr Mundi: In this situation, he was diagnosed with a neuroendocrine tumor, which we do not often see present with cachexia and such a degree of weight loss. Certainly, COVID-19 may have played a role in his development of malnutrition. However, could you discuss the impact of malignancy from a nutrition standpoint and what are some of the changes we expect with the development of cancer cachexia?

Dr Zimmers: This patient is quite interesting from the standpoint of understanding cachexia. COVID-19 likely played a tremendous role in the phenotype of this patient. There is a recent article by Anker et al2 published in the Journal of Cachexia, Sarcopenia, and Muscle that evaluated three different studies that reported on weight loss and cachexia in 589 patients with COVID-19. They noted that the frequency of ≥5% weight loss was 37% (range 29%–52%) with associated features that were very much like cancer cachexia.

Now, only a small minority of these patients would actually meet the definition of malnourished or underweight by BMI alone. But the majority had all of the features of chronic inflammation, including change in body composition that is probably due to the effects of the virus itself inducing systemic inflammation in a very similar manner to cancer. So, I imagine that the impact of COVID-19 on top of the cancer is really quite profound in this setting.

This discussion also reveals a gap in our knowledge base regarding pancreatic neuroendocrine tumors and cachexia. The vast majority of pancreatic cancer research in the context of cachexia has focused on pancreatic adenocarcinoma, whereas virtually nothing has been done in the space of neuroendocrine tumors. It is possible that these tumors do not cause cachexia, or it is possible that no one has really looked carefully in that setting. So, I think that is an interesting opportunity.

Prehabilitation for surgery

Dr Martindale: To me, this gentleman meets several criteria for being high risk for surgical intervention, including his significant weight loss, significant inflammation in the setting of COVID-19, and cancer, even though it is a neuroendocrine tumor. In this setting, we should make every effort to preserve or improve his lean body mass through resistance exercise as well as higher dietary protein for as much time as we have prior to surgery.

Additionally, 5 days prior to surgery he should be provided immune-modulating formulas as there is plethora of data to support benefit through use in the preoperative setting. Adiamah et al3 recently published a meta-analysis in the Annals of Surgery that evaluated 16 studies reporting on 1387 patients undergoing surgery for gastrointestinal (GI) cancers, including colorectal cancer, pancreatic surgery, and gastric cancer. The study formula contained ω-3 fatty acids, arginine, and nucleotides and was provided for 5 days prior to surgery. They found that the immune-modulating formula reduced infectious complications and length of hospital stay when compared with the control formula.

In terms of the impact of or to the gut microbiota, we know that surgery itself is a major insult to the microbiota. There is also relative ischemia as we lose blood flow to the GI tract, resulting in loss of integrity of the brush border. I think there are emerging data indicating that we should support the microbiota in the surgical setting, whether it be colorectal surgery or any major upper GI tract surgery. Many groups are now using prebiotics or probiotics in the preoperative setting. We at Oregon Health & Science University routinely give probiotics as part of our bowel prep for colorectal surgery.

So, the best approach to prepare for surgery would be to utilize probiotics as well as immune-modulating nutrition for 5 days prior to surgery. Additionally, as soon as we know the diagnosis and surgery is scheduled, we have to start focusing on ensuring adequate protein intake as well as enhancing resistance training for as long as we can prior to surgery. 5

Dr Mundi: In this situation, we have a gentleman with significant weight loss in the setting of pancreatic cancer and COVID-19. He also has a large upcoming surgery. What are some of the parameters/criteria that you would use for him to proceed with that surgery?

Dr Laviano: This is a great point in that this patient is at high risk of developing complications. We have to balance the potential negative effects of delaying surgery with the positive effect caused by improvement in nutrition status and this should be a discussion among the surgeon, nutrition experts (including his dietitian), and the patient prior to surgery.

This case with COVID-19 is also highlighting a major outcome that is not discussed as often as it needs to be: that of deferred care. In Europe and in the US, during the pandemic, we are seeing significant underdiagnosis of many diseases such as cancer.4 In the Netherlands for example, there was a significant reduction in the diagnosis of cancer for many months. This did not occur because there really were no cases of malignancy; instead, patients were scared to go to the hospital and undergo examination.

But back to our patient and what is the best option for him. We should start with a clear assessment of the risks as well as the benefits of delaying surgery from a surgical point of view, nutrition point of view, and oncological point of view. Personally, I would wait at least 5–7, even perhaps 10 days, to implement some form of prehabilitation to mitigate the negative effects of malnutrition. 6

Dr Mundi: If I could build upon the prehabilitation concept? We previously discussed adequate protein, adequate nutrition, resistance training, prebiotics, and immune-modulating nutrition. What else can we do to prepare this patient, especially in such an inflammatory state? Do we consider fish oil or specialized proresolving mediators (SPMs) or other agents prior to surgery?

Dr Martindale: The data from animal models would support the use of SPMs in this situation. However, we do not have sufficient human trials to support this decision. I tend to be a firm believer in the concept that resolution of inflammation after surgery is key because we are going to cause a tremendous amount of inflammation at the site. And because we know that SPMs enhance resolution of that inflammation, to me, there is no reason to not use them. We are seeing some tremendous work being done with SPMs and ω-3 fatty acids in COVID-19 to enhance resolution of inflammation, which can often be chronic and last much longer than just the viral activity.5, 6 COVID-19 is a catabolic illness that is occurring on top of another catabolic disease: his pancreatic cancer. So he is at very high risk, and I would do everything to give him the best opportunity to heal. 7

Dr Zimmers: As we are discussing his upcoming surgery, is there a role for assessing his pancreatic enzyme function and addressing that preoperatively to optimize nutrition even in the setting of a neuroendocrine tumor?

Dr Laviano: That is a very good point that you have raised. Danai et al7 published a manuscript in Nature that revealed that a significant contributor to the development of malnutrition and cachexia in patients with pancreatic cancer was secondary to altered exocrine function or reduction in the digestion and subsequent absorption of nutrition due to lack of pancreatic enzymes. Although this study focused on pancreatic adenocarcinoma and not neuroendocrine tumors, I think this is a fantastic point of discussion that you have raised.

So, if I may support the concept of prehabilitation that we are discussing? I think that the perioperative period is a fantastic window of opportunity to modulate the metabolism of the patient and influence not only early postoperative complications but long-term survival of the patient. We have to use this opportunity to not only improve recovery from surgery, but to increase the susceptibility of the patient to take advantage of adjuvant therapy if he were to receive 4–6 weeks of adjuvant therapy.

Postsurgical nutrition optimization 8

Dr Mundi: Excellent point indeed. To provide an update, many components of the prehabilitation that you have mentioned were carried out for our patient. His weight was stabilized, and he received immune-modulating therapy prior to surgery. He then underwent exploratory laparotomy, total pancreatectomy with hepaticojejunostomy, gastrojejunostomy, total duodenectomy, splenectomy, radical retroperitoneal/abdominal lymphadenectomy, and feeding jejunostomy (J)-tube placement. The surgeons did try and create a pancreaticojejunostomy and preserve some component of the pancreas, but could not. An intraoperative ultrasound revealed near complete atrophy of the pancreas with essentially no pancreatic parenchyma and no visible ducts. Our patient underwent total pancreatectomy, and a feeding J-tube was placed. How would we manage this patient's nutrition both immediately after surgery and in the next few days?

Dr Laviano: If the surgical procedure was not complicated by a leak or anastomotic dehiscence, then the patient should start to be fed quite early on, preferably the first day after surgery with enteral nutrition. In Europe, there is a lot of interest in the Enhanced Recovery After Surgery (ERAS) program. One of the core tenants of this program is to start feeding, especially oral intake, quite soon after surgery to speed up the recovery phase. So, I would support that our patient should be started with enteral feeding on the first postoperative day. His feedings should be progressively increased and transitioned from enteral nutrition to oral feedings as soon as tolerated not only to reduce complications but to actually accelerate the functional recovery of the patient.

Dr Martindale: To add to what Dr Laviano has mentioned, this gentleman has now had a total pancreatectomy and that adds multiple layers of complexity as we discuss providing nutrition. As we start nutrition, we will need to be careful with his glucose control and monitor and treat that closely. With the loss of his pancreas, we have lost insulin-producing beta cells, so he is at risk for hyperglycemia. We have also lost glucagon-producing alpha cells, thus putting him at high risk for developing hypoglycemia because glucagon is one of our key counterregulatory enzymes. Even though hyperglycemia is associated with complications, hypoglycemia can be lethal. So, we have to be very careful because he is high risk for developing labile diabetes.

Additionally, his atrophic pancreatic gland may have arisen because of the lesion in the head of the pancreas blocking the pancreatic duct. So, if on imaging there is any evidence of ductal obstruction, we should provide preoperative pancreatic enzymes. We should continue those now postoperatively as he expands his intake. Overall, in terms of nutrition, we want to start early, but progress slowly with careful monitoring of glycemic control and absorption of nutrients we are providing. 9

Dr Mundi: Both of you have mentioned that enteral nutrition should be started early. Would you start with a standard polymeric formula or, keeping in mind his total pancreatectomy, would you use a specialized formula such as peptide-based diet with or without pancreatic enzymes?

Dr Laviano: In terms enteral nutrition, our hospital protocol recommends starting with a standard polymeric formula because at this point, we do not have robust evidence for specialized formulas such as diabetes specific formulas that can mitigate hyperglycemia.

Dr Martindale: I would add that we give immune-modulating formulas postoperatively as well. For one, we have immune-modulating formulas available that are concentrated (1.5 kcal/ml), not too hyperosmolar, and provide a significant portion of protein as peptides. Additionally, many of the protocols that evaluated immune-modulating formulas provided the formulas both preoperatively and postoperatively in patients at high risk of malnutrition. They noted that in individuals who were well nourished prior to surgery, there was only benefit in providing immune-modulating formulas prior to surgery. In those who were malnourished like our patient, there was benefit in providing metabolic-modulating formula both before and after surgery.8 This case is made more problematic by the total pancreatectomy, essentially taking out all of the pancreatic proteases and lipase. When starting enteral nutrition, it will be essential to add pancreatic enzymes to cover the loss of exocrine pancreas enzymes. Another benefit of the immune and metabolic formula in this case is the large amount of medium chain triglycerides (MCT) oil, which does not require exocrine pancreatic enzymes for absorption directly into the portal circulation. 10

Dr Mundi: There is also a question from the audience regarding the use of parenteral nutrition in this setting. As you are starting enteral nutrition and titrating up, do you provide supplemental parenteral nutrition? How aggressive should we be with nutrition, especially parenteral nutrition, in this setting?

Dr Laviano: The protocol we have in our hospitals here in Italy is that you start with enteral nutrition and try to progress to a goal. If you are not able to reach goal feedings within 72–96 h, then you start supplementing with parenteral nutrition. So, we only supplement with parenteral nutrition if we are not able to reach goal feedings with enteral nutrition in 3–4 days.

Dr Martindale: I agree 100%. I think the days of trying to get to goal feedings very early are gone. We have good clinical trial data showing that giving full energy in the first couple of days after a major catabolic event may be detrimental. Data from over seven prospective trials found that there is no advantage in reaching goal energy early. So, I would recommend that we start low and slowly ramp up the nutrition, giving time for his mitochondria and the patient to adapt to the catabolic stress after surgery so that he is able to better tolerate the macronutrients.

Post-hospitalization optimization of nutrition 11

Dr Mundi: We are running out of time; however, I will share how his clinical course played out. During hospitalization, he was started on enteral feeds at 10 ml/h and slowly titrated up. However, he could not advance beyond 20 ml/h because of significant abdominal pain. He did require parenteral nutrition for 7 days postoperatively. He was slowly able to transition to oral intake, and prior to discharge, his 3-day average energy intake was 1660 calories and 85 g of protein. So, let's finish by discussing management of his nutrition post-discharge. Cancer is becoming a chronic disease, and that has significant implications for nutrition optimization. So, when would we see him back for follow-up? What measurements would you obtain to follow him nutritionally? Are there any other ways to optimize his nutrition for long-term success that we have not discussed?

Dr Laviano: I completely agree with you in that, in 2021, cancer is becoming a chronic disease with many patients having a long clinical journey. So far, for this patient we have just focused on a very short catabolic crisis, but he will need longstanding nutrition support that goes beyond the post-surgical period through chemotherapy, through radiotherapy, and beyond.

And, if we are not able to provide adequate nutrition support, it will have a negative impact on the next catabolic phases. In this situation, if we are not able to provide nutrition support after surgery, he may not be able to complete adjuvant therapy. In January of this year, Clinical Nutrition published the results of two prospective randomized control trials along with an editorial regarding the use of oral nutrition supplements, also emphasizing that patients who are nutritionally depleted are less likely to tolerate neoadjuvant and adjuvant treatment.9 So, it is important for us to realize that patients need nutrition support, not only during the small period of catabolic crisis, but throughout the clinical journey.

Dr Zimmers: Certainly; the data are quite strong for ensuring that there is adequate protein intake. The data surrounding ω-3 fatty acids are less clear but could promote resolution of inflammation and preservation of muscle mass.

Dr Martindale: In terms of immune-modulating nutrition and their long-term use, we do not have sufficient data to comment. The protocols regarding immune-modulating nutrition typically provide it for 7–10 days post- operatively at the most. Where we have the most opportunity is to evaluate prolonged use in certain populations, such as this patient who is going to be catabolic for quite some time with recent COVID-19 and has a difficult clinical course ahead of him.

Dr Laviano: We are hoping to publish some of the work we have done in patients who have gastric cancer who are receiving supplementation with immune-modulating nutrition prior to surgery that revealed a reduction in the inflammatory microenvironment. Inflammatory tumor microenvironment is one of the major determinants of outcome in this cohort. So at least from an anatomical standpoint, we can hypothesize that modulating the inflammatory response through immune enhancing nutrition can modify the tumor microenvironment and perhaps impact long-term outcomes for these patients.

Dr Martindale: I fully agree—similar theoretical benefits can also be noted with SPMs, perhaps through potentiation of macrophages cleaning up the cellular damage. There are some data regarding patients with head and neck cancer and the use of arginine supporting improved outcomes. So, I think there is a lot of potential here for immune-modulating nutrition and cancer that has not been fully explored yet.

Dr Mundi: Well, that was a tremendous discussion, and I knew with the panelists we had that this was going to be a treat. I thoroughly enjoyed this discussion and want to thank the panelists for participating.

Key points

With the growing prevalence of obesity, in place of using BMI as a marker of malnutrition, the focus should be to utilize pathogenic/etiologic and phenotypic characteristics along with body composition data and nutrition alarm symptoms when available.

Key components of prehabilitation for surgery include a focus on preserving/improving lean mass through increased activity and resistance training, optimization of nutrition through screening, nutrition support and use of immune-modulating formulas, and preoperative prophylaxis against thrombosis, infection, nausea, and vomiting. Emerging data also indicate that support for microbiota and use of fish oil or SPMs may be important as well; however, additional clinical trials are needed.

Postoperative nutrition optimization after total pancreatectomy consists of gradually initiating nutrition early with aggressive glycemic control, early mobilization, and continuation of immune-modulating nutrition. (Supplemental) parenteral nutrition should be considered if not able to reach goal feedings, whether orally or enterally, in 3–4 days.

CONFLICT OF INTERESTS

ManpreetMundi has research grants from Fresenius Kabi, Nestlé, VectivBio, and Real Food Blends. Alessandro Laviano has a research grant from Fresenius Kabi. Manpreet Mundi is on the advisory board of Fresenius Kabi and Baxter. Jeffrey I. Mechanick received honoraria for lectures and program development by Abbott Nutrition. Jayshil J. Patel is a consultant for Baxter. Alessandro Laviano received honoraria for lectures sponsored by Abbott, Baxter, B. Braun, Fresenius Kabi, Nestlé Health Science, and Nutricia and is a member of the Scientific Advisory Board of Nutricia Oncology and Smartfish. Robert Martindale is on advisory boards for Nestlé and Fresenius Kabi and has received honoraria for program development for Baxter. Teresa A. Zimmers is a consultant for Pfizer and Immuneering and is on scientific advisory boards for Emmyon and PeleOs.

AUTHOR CONTRIBUTIONS

Manpreet Mundi, Jeffrey I. Mechanick, and Jayshil J. Patel contributed to the conception of the manuscript. Manpreet Mundi drafted the manuscript. Jeffrey I. Mechanick, Jayshil J. Patel, Alessandro Laviano, Robert Martindale, and Teresa A. Zimmers critically revised the manuscript. All authors agree to be accountable for all aspects of work, ensuring integrity and accuracy.