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IFALD FORMULA
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In a 2020 study of neonates diagnosed with IFALD, switching to 100% fish oil (Omegaven, Fresenius Kabi) reversed the liver disease in 11 of 15 infants (J Clin Med 2020;9[11]:3393).
However, a meta-analysis from 2016 did not find fish oil containing SMOFlipid to have a strong protective effect against IFALD compared with 100% soybean oil, despite a sevenfold reduction in phytosterols (J Pediatr Gastroenterol Nutr 2016;62[5]:776-792). Similarly, a Cochrane Review did not find any lipid emulsions with or without fish oil to provide better protection against PNALD (Cochrane Database Syst Rev 2019;6:CD013163).
Even with a better understanding of the limitations of soybean oil, the choice of lipid emulsion for patients coming into the neonatal ICU isn’t always straightforward. Drs. Cohran and Gura said they continue to use soybean oil for their patients. Dr. Cohran prefers a composite lipid emulsion, one made of multiple lipid types such as soybean oil, olive oil, MCT (or medium-chain triglycerides) oil and fish oil. She uses soybean oil in low amounts and carefully monitors total and direct bilirubin. When bilirubin reaches 2 mg/dL, an indication of IFALD, she switches patients to Omegaven.
Dr. Gura said each lipid source has its limitations and its place in treating unique patient cases. A soybean oil such as Nutralipid or Intralipid has a long history of use, is efficient in terms of required fatty acids and is well tolerated for a short duration of therapy, she noted.
Beyond lipids, experts said prioritizing enteral nutrition in neonates and oral feeding in adults is crucial. In infants, feeding enterally helps the remaining intestine adapt and improves patient safety and the likelihood they can transition from parenteral nutrition (PN) entirely. With “[adult] oral intake, the liver gets first pass at those nutrients,” Ms. Matarese said. In contrast, with PN, the liver typically is last for nutrient delivery. Oral feeding in adults also stimulates enteral hepatic circulation, villus height and crypt depth, she said.
“If there is any way I can rehabilitate the remnant bowel, I think it offers the best potential for health and improved quality of life,” Ms. Matarese stressed.
Team Effort Best for Care
Transitioning from PN requires a team of experts. In addition to gastroenterologists, surgeons and neonatologists, pharmacists and dietitians are necessary to ensure patients are receiving the appropriate formula based on their intestinal anatomy. The pharmacists and dietitians are also integral for assessing the TPN to ensure patients receive the appropriate vitamins and minerals, especially in the current time of shortages, and that enteral nutrition is formulated for a patient’s unique anatomy and limitations. As an example, if a patient lacks their distal small bowel, they’re likely to have a vitamin B12 deficiency and also absorb fat-soluble vitamins poorly, Dr. Cohran said. If patients are missing their proximal small intestine, they are more susceptible to iron deficiency.
Pharmacists and dietitians are also essential as teams work with healthcare companies to access products and reconcile PN recipes, Dr. Cohran said. This collaboration is likely to be one reason that patients who receive treatment at a specialized center have better outcomes. There’s a bigger opportunity for out-of-the-box and holistic thinking with a multidisciplinary team, Dr. Gura said. Dr. Cohran has patients who travel more than five hours to be seen by her team in Chicago.
But “everybody can’t jump on a plane to fly to Boston, Cincinnati or Chicago,” Dr. Cohran said.
If a provider is trying to support a patient who has IFALD but is not located near a major center, getting in touch with a large center can be critical, Dr. Gura said, as is diving into the rapidly evolving literature on IFALD. It may be useful to ask nearby professionals such as pharmacists, dietitians, social workers or neonatologists to help. At first, a gastroenterologist may need to mentor a pharmacist because most don’t receive formal training in this area, Dr. Gura said. However, it will become a very useful partnership quickly, she said.
All three experts said there is a way to see patients return to a more normal life, to see children safe to swim and rough-house with their siblings, Dr. Cohran said. “What drives me is tapering children from PN and allowing them to live their best life.”
Lifestyle Changes Improve Pediatric NAFLD
By Kate O’Rourke
Pharmacists often are relied on by their physician colleagues for their medication management expertise. But their worth on the care team also hinges on the ability to recommend non-pharmacologic therapy when appropriate.
A new study of pediatric patients with nonalcoholic fatty liver disease (NAFLD) suggests that may indeed be the best approach.
The study—results of which were presented at the 2021 Liver Meeting (abstract 45) and published in Clinical Gastroenterology and Hepatology (2021 Dec 4. doi:10.1016/j.cgh.2021.11.039)—found that an intensive multidisciplinary lifestyle management program resulted in significant weight loss and reduced steatosis and fibrosis in pediatric patients with NAFLD.
The results are an encouraging development, given the prevalence of the disease, noted investigator Sander Lefere, MD, PhD, a postdoctoral researcher in the Department of Gastroenterology and Hepatology at Ghent University, in Belgium. Secondary to increasing rates of obesity in children and adolescents, pediatric NAFLD is now the most common pediatric liver disease worldwide (J Pediatr 2016;172:9–13), he noted.
The prospective study included children and adolescents with NAFLD admitted for severe obesity at a tertiary center, the Zeepreventorium De Haan, in Belgium, between July 2019 and January 2021, who were placed on an intensive lifestyle regimen composed of caloric restriction, physical activity, education and psychosocial support in a residential multidisciplinary setting.
To assess liver steatosis and fibrosis, the researchers performed liver ultrasonography and transient elastography with controlled attenuation parameter (CAP) and liver stiffness measurement at baseline and after six and 12 months. Fibrosis was defined as a liver stiffness measurement of at least 7 kPa for F2 fibrosis, at least 9 kPa for F3 and at least 11 kPa for F4; CAP values of at least 248 dB/m were considered elevated.
The median age of the 204 patients was 14.0 years, and the median body mass index z score was 2.8. NAFLD was found on ultrasound in 71.1% of patients, whereas 68.6% had CAP values measuring at least 248 dB/m. In the cohort, 32.8% of patients had at least F2 fibrosis, including 10.3% with transient elastography measurements of at least 9 kPa.
After six months, median weight loss was 16% in the 167 patients who were evaluated. Liver steatosis and fibrosis also were markedly improved, with regression and resolution of fibrosis occurring in 73.1% and 61.5% of patients who had fibrosis at baseline, respectively.
Resolution of steatosis occurred in 47.1% of patients with steatosis at baseline, the investigators reported. Fasting serum alanine aminotransferase (ALT) levels and for insulin resistance decreased significantly over the one-year period (P<0.001).
“To our knowledge, this is the largest study to date to investigate the efficacy of a structured weight loss program on improving NAFLD in children and adolescents with severe obesity (aged 8-18 years). Our findings are strengthened by the use of transient elastography for the diagnosis and follow-up of liver fibrosis in the study population,” Dr. Lefere said, noting that previous studies that have investigated the efficacy of lifestyle intervention for pediatric NAFLD have relied on serum ALT levels or liver ultrasound, which are suboptimal and do not provide data on liver fibrosis, the key outcome marker in these patients.
“Based on our results, prompt careful hepatic examination of children and adolescents with severe obesity is warranted, as well as timely referral to weight loss programs,” Dr. Lefere said. “These data further support the importance of the development and evaluation of alternative and effective weight loss programs for NAFLD in the outpatient setting.”
16% Median weight loss 47.1%
Liver steatosis resolution 61.5%
Comprehensive Liver fibrosis Approach Is Needed
resolution Ali Mencin, MD, the director of the Pediatric Fatty Liver Clinic and Pediatric Endoscopy at Columbia Doctors Children’s Health, in New York City, said the study demonstrates the importance of healthy lifestyle in improving liver injury in NAFLD. “Previous studies have shown that weight loss through diet and exercise or bariatric surgery result in improvements in ALT and liver histology. However, most patients struggle with adhering to a healthy lifestyle recommendation.
“The degree of NAFLD improvement in Dr. Lefere’s study can likely be attributed to the intervention— intensive lifestyle changes in a residential setting with education and psychosocial support,” Dr. Mencin said. “This highlights the need for a more comprehensive approach to lifestyle management beyond standardof-care counseling to achieve improved outcomes in NAFLD. Unfortunately, few patients have access to such programs.”
Dr. Mencin said it would be interesting to know “the specifics of the intervention in this study and more details about their success in reducing BMI.” Drs. Lefere and Mencin reported no relevant financial disclosures. Dr. Cohran reported financial relationships with Abbott Nutrition, Nutricia and Takeda. Dr. Gura reported financial relationships with Alcresta, Fresenius Kabi, Lexicomp, NorthSea Therapeutics and Otsuka Pharmaceutical Factory. Dr. Matarese reported no relevant financial disclosures.
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No Game Changer in Rectal Cancer?
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study’s primary end points were overall response rate to PD-1 blockade with or without chemoradiation, and pathologic complete response or clinical complete response rate at 12 months after PD-1 blockade with or without chemoradiation.
All patients had dMMR and BRAF V600E wild-type tumors, and the mean tumor mutational burden was 67, explained lead study author Andrea Cercek, MD, the head of the colorectal cancer section and codirector of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center, in New York City. Most patients enrolled had big bulky tumors, 94% had node-positive disease and approximately half had Lynch syndrome, he added.
At the meeting, Dr. Cercek called the findings “unprecedented” and “thrilling.”
“We’ve now treated a total of 14 patients, and 100% have had a clinical complete response to dostarlimab alone,” Dr. Cercek said. “No patients have required chemotherapy, radiation or surgery. There have been no disease recurrences observed, though longer followup is certainly required to establish the durability of this treatment.”
“It’s been one of the first studies ever to really show a complete response, especially in rectal cancer, which is difficult to treat,” Dr. Holle said. Although the results were intriguing, it was done “in a very small number of patients at one institution. It looked at the response rate, which is important, but there hasn’t been enough time to see if dostarlimab improves survival in these patients.”
Patients and healthcare providers have the same goal: to see patients live a long, cancer-free life. “Right now, we don’t know if that is going to be the case with this drug because it is early in the course of the disease for these patients,” Dr. Holle explained. “Although they had a complete response, we don’t know if that will be a durable response.”
Although the median follow-up is only 6.8 months, Dr. Cercek said at the ASCO meeting that four patients have been followed nearly two years, and only four have received less than six months of the required treatment—very small numbers. The study does suggest, however, that giving immunotherapy in the neoadjuvant setting could be a viable and effective option, and in this case meant that patients did not need neoadjuvant radiation and then surgery, Dr. Holle said. “In rectal cancer that is locally advanced, the goal is to shrink all of the tumor as much as possible, so that you can remove everything with surgery,” she explained.
In conventional rectal cancer treatment, neoadjuvant cancer therapy typically takes six months before the surgery. That means a six-month complete response has not even taken the patients beyond the neoadjuvant period. “So, we don’t know if this actually increased survival longer than normal treatment,” Dr. Holle said. “The normal treatment is about six months, then you have surgery, and you follow patients very closely for five years. If they’re completely free of disease, we consider them cured.”
The hope is that by that time, the patient will live the remainder of his or her life without rectal cancer, because most patients will have a recurrence within five years if it is going to recur, she added.
Genetic Mutations a Limiting Factor
Another caveat is the patient population. This study is only relevant to a small number of patients with rectal cancer. To understand why this is, it’s important to know how dostarlimab works, which goes back to understanding the biology behind it.
The body contains mismatch repair (MMR) genes that are involved in correcting mistakes or mutations made when DNA is copied in cells. Some people, however, have a deficiency in MMR (dMMR), which makes it easier for cells that have many DNA mutations to proliferate, leading to the growth of cancer.
The body has several checkpoints within the immune system to kill cancer cells, including programmed death 1 (PD-1), a protein found on T cells. PD ligand 1 (PD-L1) is often found on cancer cells or other immune cells invading the tumor. When PD-1 binds to PDL-1, it prevents the T cells from killing cancer cells. So, PD-1 inhibitors such as dostarlimab prevent PD-1 from binding to PDL-1 and enables the immune system to effectively kill the cancer cells. Patients with dMMR tend to respond to checkpoint inhibitors due to the high number of DNA mutations, which are thought to stimulate immune responses, such as those from checkpoint inhibitors.
Only about 5% to 10% of rectal cancer patients have a dMMR mutation.
Results Not Yet Practice-Changing
The study results were meaningful and promising, but require more study before they will change practice, according to Kimmie Ng, MD, MPH, who was invited to comment during the ASCO session. “The 100% clinical complete response rate is unprecedented in rectal cancer, and the potential to decrease morbidity by eliminating pelvic radiation and surgery for our patients is huge,” said Dr. Ng, an associate professor of medicine at Harvard Medical School and the co-director of the Colon and Rectal Cancer Center at Dana-Farber Cancer Institute, both in Boston.
Dr. Ng called neoadjuvant dostarlimab a “promising new treatment for patients with stage II to III dMMR rectal cancer,” but also reiterated the need for longer follow-up as well as additional patients. “These findings are clinically meaningful and scientifically plausible, but more data are needed before they become practice-changing,” Dr. Ng concluded.
The single-arm phase 2 study will ultimately enroll 30 patients with newly diagnosed clinical stage II and III, mismatch repair–deficient (dMMR) rectal cancer.
—Lisa Holle, PharmD, BCOP
—Andrea Cercek, MD
Video Exclusive
Lisa Holle, PharmD, discusses how to put the NEJM study results into perspective when talking with rectal cancer patients. Visit pharmacypracticnews.com and click on the multimedia tab.
Dr. Cercek reported a financial relationship with Bayer, GlaxoSmithKline, Incyte, Janssen, Merck, Regenix and Seattle Genetics Dr. Ng reported a financial relationship with for Bayer, Bicara Therapeutics, BiomX, GlaxoSmithKline, Redesign Health, Seattle Genetics, and X-Biotix Therapeutics. Dr. Holle reported no relevant financial disclosures.
