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An emerging role for immuno-nutrition in patients undergoing radical cystectomy

Malnutrition is a potentially modifiable factor that is associated with considerable morbidity and is prevalent in patients with bladder cancer who are treated with radical cystectomy. Studies suggest a role for immuno-nutrition in optimizing patients’ nutritional status before undergoing this procedure, with the goal of improving patient outcomes.

Radical cystectomy is the standard of care for patients with clinically localized, muscle-invasive bladder cancer; however, it is associated with considerable risks such as infection, dehydration and sarcopenia. Malnutrition is a previously under-recognized cause of morbidity in this population and is estimated to occur in almost 22% of patients presenting for radical cystectomy1. The risks of postoperative complications in these patients are three times that of a patient who is well nourished (OR 3.3, 95% CI 1.3–8.0), with 74% of malnourished patients presenting with at >1 complication compared with only 47% in well-nourished patients2. Patients undergoing radical cystectomy are a unique population, who are particularly susceptible to nutritional deficiencies, owing to cancer-related cachexia, advanced age and the common use of chemotherapy in the neoadjuvant setting.

Complications associated with malnutrition are a consequence of impaired immunity, which results in poor wound healing and increased susceptibility to infections. Moreover, patients who undergo radical cystectomy exhibit catabolic states, leading to muscle tissue loss and net fat oxidation3. The catabolic effects of this operation have long-term implications, with more than one-third of lost protein stores not regained at 6 months postoperatively4. This situation translates into a clear effect on survival outcomes, as patients undergoing cystectomy with evidence of malnutrition have increased cancer-specific (49% versus 72%; P = 0.003) and overall (39% versus 70%; P = 0 .003) mortality compared with patients without malnutrition5. The detrimental effects of malnutrition also affect the economics of health care, as malnourished patients often require an increased duration of hospital stay and, consequently, increased hospital-incurred costs.

In an effort to mitigate the effect of malnutrition, scientific and clinical studies have focused on improving the nutritional status of patients undergoing radical cystectomy. In an approach termed ‘immuno-nutrition’, standard oral nutritional supplements are combined with immuno-nutrients (such as arginine, nucleotides and fatty acids) to improve patients’ immune responses, blunt the inflammatory process and support healing during the catabolic state observed in the peri-operative period.

Arginine is an immuno-nutrient that has garnered particular scientific interest. The basis of using arginine as an immuno-supplement is derived from its role in the immune pathway6,7. Arginine is a conditionally essential amino acid — that is, its synthesis can be limited under special pathophysiological conditions — and it is consumed by myeloid-derived suppressor cells (MDSCs) during episodes of physical injury. MDSCs rapidly expand after injury and differentiate into granulocytes, macrophages and dendritic cells. When arginine is depleted, MDSCs are unable to differentiate, which results in lymphocyte depletion and, consequently, a weak immune response and increased rates of infection7. Promising early data from animal studies have led to further investigation into the benefits of immuno-nutritional supplementation in the clinical setting.

In 2014, Bertrand and colleagues examined the clinical value of arginine-based immuno-nutrition on morbidity following radical cystectomy8. This prospective case–control study compared outcomes in 30 patients who received 7 days of immuno-nutrition (containing arginine, glutamine, fatty acids and nucleotides) with a historical, matched group of patients who did not receive immuno-nutrition. Patients were matched for age, gender, comorbidity scores, tumour stage, urinary diversion method and neoadjuvant chemotherapy status. Postoperative complication rates were significantly lower in the immuno-nutrition recipients than in the control group (40% versus 76.7%; P = 0.008), including significantly lower rates of infectious complications (23.3% versus 60%; P = 0.008) and postoperative ileus (6.6% versus 33.3%; P = 0.02). Furthermore, length of hospital stay was reduced by 3 days in the immuno-nutrition group (16.1 versus 19.1 days; P = 0.51).

A subsequent pilot randomized clinical trial investigated the effects of arginine-based immuno-nutrition on immune response and infection rates in patients who had undergone radical cystectomy9. In this study, Hamilton-Reeves and colleagues compared immune responses and complications between men consuming either a specialized immuno-nutritional (n = 14) or a conventional oral nutritional (n = 15) supplement before and after cystectomy. Following cystectomy, MDSC counts were significantly lower in the group receiving the specialized immuno-nutritional supplementation (P < 0.001), indicating an improved immune response to surgical stress. Moreover, the neutrophil:lymphocyte ratio was significantly lower in the immunonutrition group than in those receiving standard supplementation when measured 3 hours after the first incision (P = 0.039). This suggests that specialized immuno-nutrition consumption might positively modulate the acute immune response. Interestingly, participants receiving immuno-nutrition also had a 33% reduction in postoperative complication rates (95% CI 1–64; P = 0.060) and a 39% reduction in infection rates (95% CI 8–70; P = 0.027). This study demonstrated that a low-risk intervention can positively affect outcomes of radical cystectomy, supporting the role of immuno-nutrition in the peri-operative period.

A follow-up study by the same investigators examined the effects of perioperative specialized immuno-nutritional supplementation (containing arginine, nucleotides and fish oil) on the postoperative inflammatory response and muscle wasting after cystectomy6. This parallel, randomized, placebo-controlled pilot trial examined the T helper 1 (TH1)/TH2 cell balance, a measure of cell-mediated immunity and risk of infection, as well as IL-6, a marker of inflammatory response that also indicates risk of muscle wasting. The study showed that the immune response of patients who received immuno-nutrition was shifted toward a TH1 response, counteracting the TH1/TH2 imbalance that classically occurs following radical cystectomy and that is associated with weakened immunity and increased susceptibility to infection. Moreover, IL-6 elevation, which is associated with sarcopenia, was markedly attenuated in the immuno-nutrition group compared with the placebo group. These findings suggest a positive modulatory role of specialized immuno-nutritional supplementation on the differentiation of T helper cells at the time of surgery and a potential protective role against complications and postoperative cachexia.

These promising pilot study data have translated into a randomized phase III double-blind clinical trial, SWOG S1600 (NCT03757949), which is designed to evaluate the effect of a specialized immuno-nutritional supplement containing arginine, omega-3 fatty acids, dietary nucleotides and vitamin A on outcomes after radical cystectomy10. The study aims to enroll 200 patients with a primary end point of complication rates and secondary end points including infection rates, body composition changes assessed with dual-energy X-ray absorptiometry, readmission rates, quality-of-life outcomes, disease-free survival and overall survival. SWOG S1600 is currently recruiting patients and is expected to be completed in December 2023.

Immuno-nutrition has an important potential role in the peri-operative care pathway of patients undergoing radical cystectomy. Promising early research has demonstrated that this low-risk intervention could result in true benefit in a patient population who are at high risk of peri-operative morbidity; the results of upcoming trials are expected to further support this benefit.

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Correspondence to Siamak Daneshmand.

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Alsyouf, M., Djaladat, H. & Daneshmand, S. An emerging role for immuno-nutrition in patients undergoing radical cystectomy. Nat Rev Urol (2021). https://doi.org/10.1038/s41585-021-00529-2

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