Foods for special medical purposes are defined by the European Commission Directive 609/2013/EC as a category of dietary foods which should be used under medical supervision and are specially processed or formulated for the dietary management of patients that are in the impossibility to take, digest, absorb, metabolize or excrete ordinary foodstuffs, or certain nutrients contained therein or metabolites, or that have specific medically-determined nutrient requirements that cannot be satisfied by modifying the normal diet (37, 38). This category is currently under the Regulation N. 2016/128 of the European Commission and includes ONS, as well as enteral tube feeding formulas.
ONS are commercially available medical nutrition products in the form of ready-to-drink liquids, semi-solids, powders (with proteins, maltodextrins or lipids) or creams (for patients with dysphagia) that provide macronutrients and micronutrients required when normal food is insufficient to maintain or increase energy and intake (28). They are usually nutritionally complete mixtures for oral consumption and are most often recommended to supplement volitional food intake. If nutrient intake remains inadequate, a medical nutrition therapy can be administered by oral, enteral or parenteral route, depending on the functionality of the GI tract. The criteria for the escalation of nutritional measures in cancer patients include: a) inadequate food intake anticipated for more than 10 days due to surgery, CT or RT; b) food intake < 50% of the requirements for more than 1–2 weeks; c) anticipation that patient will not be able to eat and/or absorb the adequate amount of nutrients for a long period time, due to anticancer treatments; and d) the tumor itself impairs oral intake and food progression through the upper GI tract (39).
Various clinical trials are currently investigating the efficacy of perioperative enteral immunonutrition, i.e. ONS enriched in immunonutrients (arginine, glutamine, omega-3-fatty acids, ribonucleotides), and pre- and probiotics, with the aim of stimulating the host immune response, and improving control of the inflammatory response in cancer patients submitted to major surgery or CRT, as covered also by the most recent ESPEN guidelines (40, 41).
Advantages of medical nutrition intervention with ONS in cancer patients in the hemotherapy/radiotherapy/surgical setting
Literature data are increasingly supporting the effectiveness of nutritional therapy in cancer patients, with particular reference to hospital readmissions, hospital length of stay (LOS), response to anticancer treatments, and clinical outcomes. A retrospective cohort study recently analyzed the ONS utilization rate, hospital LOS and 30-day unscheduled hospital readmissions in an academic medical center hospital in United States and revealed that only 3.1% of malnourished patients received ONS, and that ONS users in oncology departments had 46.1% fewer readmissions than non-ONS counterparts; in addition, a shorter hospital LOS was observed when the interval between admission and ONS initiation was reduced (42).
A secondary analysis of the data from the Swiss prospective, randomized-controlled, multicenter trial EFFORT compared the outcomes of a protocol-guided individualized nutritional support (intervention group) to standard hospital food (control group) in 506 patients with a main admission diagnosis of cancer and characterized by a broad spectrum of cancer sites, treatment types and disease severities. Individualized nutritional support reduced the risk of mortality and improved functional and QoL outcomes in cancer patients with increased nutritional risk, further supporting the inclusion of nutritional care in cancer management guidelines (43). An improvement of nutritional status has been detected in pediatric cancer patients in the first 3 months of treatment, through the administration of ONS to subjects with a food intake < 75% of the recommended nutritional values for 3–5 consecutive days or through a nasoenteric tube when oral feeding was impossible, or when food intake was insufficient (oral intake < 60% of the recommendations) for 3–5 consecutive days (11). A double-blind, controlled trial evaluating the safety and tolerability of an oral targeted medical nutrition (TMN) supplement for the management of cachexia in patients with non-small-cell lung cancer revealed a trend for improved clinical outcomes and fewer adverse events with TMN vs. the comparator group (44).
In HNC, GI, and pancreatic cancer patients, the common anticancer treatments (i.e. surgery, RT, CT, or their combination) can often lead to consequences (e.g. dysphagia and xerostomia) that further complicate and challenge oral intake of food, with additional deleterious consequences on nutritional status (45).
However, a growing number of clinical studies is supporting ONS administration as an effective tool to limit cancer treatment consequences in those cancers. Preoperative nutrition intervention prior to upper GI cancer resection in 200 patients from Australia led to lower weight loss compared to those who did not follow the intervention and to lower hospital LOS in the group of patients who received ONS for > 2 weeks (46). A review of 29 trials, including studies on GI cancer patients, did not show a longer survival through the use of an adjuvant nutritional support, but revealed a significant benefit for a longer survival in a few selected subgroups of patients, depending on the tumor stage and compliance with nutritional support (47). Body weight loss was found lower in the ONS compared to the control group in a meta-analysis of randomized controlled trials involving GI cancer patients submitted to gastrectomy and/or chemotherapy. However, other anthropometric parameters did not differ significantly between the ONS and the control group (48). Kim et al. showed an increase in body weight, fat-free mass, skeletal muscle mass, body cell and fat mass in the ONS group vs. a decrease of those data in the control group in pancreatic and bile duct cancer patients receiving CT. Even the subjective global assessment and the fatigue scores were improved in the ONS group (49). A nutritional intervention in GI cancer patients undergoing perioperative CT should be aimed at preventing unintentional weight loss, thus reducing the risk of postoperative complications and sarcopenia, and improving the short-term survival (50). ONS administration for three months together with dietary advice in post-discharge patients at nutritional risk following colorectal cancer surgery reduced skeletal muscle loss and sarcopenia prevalence, as well as improved CT tolerance, compared to the group with dietary advice alone, thus underlying the importance of ONS treatment in post-discharge patients at nutritional risk (51). Despite these positive data, it should be noticed that the evidence for a positive influence of ONS on weight and nutritional status in patients undergoing surgery after CT for GI cancer should be supported by further research into optimal and customized nutrition support interventions and timing of interventions (52).
Nutritional counseling in combination with the administration of ONS from the start of RT in HNC patients and continuing for up to 3 months after its end showed better results versus nutritional counseling alone in terms of weight maintenance, with a smaller loss of body weight, increased protein-calorie intake, improved QoL and a better anticancer treatment tolerance. In addition, the use of ONS decreased the need for reduction or complete suspension of scheduled anticancer treatments (53). A cross-sectional study including 97 patients treated for oral and oropharyngeal cancer with a combination of surgery and CRT reported an immediate decrease of the QoL after the treatment and a 40.2% prevalence of malnutrition. However, malnutrition was prevented in a significant number of patients (72.5%) who were provided with ONS (54).
Also for lung cancer patients some studies have shown some improvements in weight maintenance, muscle function, and quality of life (22). ONS enriched with omega-3 fatty acids seemed to improve energy and protein intake, body composition and decreased fatigue, loss of appetite and neuropathy (55).
With reference to the immunonutrition described above, clinical data are increasingly emerging about its use in the oncologic setting and have shown that it is able to reduce overall infectious complications and hospital LOS in patients undergoing cancer surgery, but without affecting mortality (56). The meta-analysis of six randomized clinical trials enrolling patients affected by pancreatic cancer and undergoing surgical intervention revealed that immunonutrition significantly decreased the rate of infectious complications and the LOS by modulating the immune system, especially in the preoperative period (57). A single armed study with a historical control group including consecutive patients undergoing salvage surgery for recurrent HNC showed that preoperative immunonutrition was associated with a significant reduction in overall complications (35% vs. 58% in control group) and in hospital LOS (6 days vs. 17 days in control group) (58). The effectiveness of immunonutrition in addition to nutritional counseling in increasing the tolerance to CRT is now being tested vs. standard ONS in a pragmatic, bicentric, randomized, parallel-group, open label, controlled, pilot clinical trial enrolling HNC patients (59).
Benefits and advantages of an early nutritional intervention for cancer patients
Early identification of cancer patients at risk of malnutrition or who are malnourished is crucial in order to start a timely and adequate nutritional therapy. A seminal study including data from hundreds of patients in various hospital types showed that an early nutritional intervention reduced the average hospital LOS of 3.0 days versus a late nutritional intervention (60). With particular reference to cancer patients, a bicentric single-arm clinical trial enrolling 131 hypophagic, hospitalized cancer patients at nutritional risk and with contraindications for enteral nutrition revealed that an early 7-day supplemental parenteral nutrition resulted in improved body composition, handgrip strength and serum prealbumin levels, in the absence of any relevant clinical complications (61).
Wei et al. analyzed retrospectively the effect of early nutritional intervention on RT-induced oral mucositis and nutritional status in patients with HNC vs. enteral nutrition after restricted feeding. The authors reported an incidence of high-grade oral mucositis significantly lower in the early group vs. the late group (17.9% vs. 50%). Also, nutritional status assessments showed significantly weight and BMI losses in the latter group than in the former group at weeks 4 and 7 after RT. Moreover, fewer patients were malnourished in the early nutrition intervention group compared to the late intervention group (62).
These results are consistent with findings of another retrospective, exploratory study analyzing the electronic medical record data of patients with HNC undergoing CRT or RT. The patients that received a nutritional intervention since admission by a nutritional support team experienced a median weight loss of 3.3% vs. 7.3% in nonintervention group. In addition, grade 3 mucositis was observed in 25.0% of patients in the early nutritional intervention group vs. 70.0% in the nonintervention group. Finally, patients in the early nutritional intervention group were discharged earlier than those in the nonintervention group, with a median hospital LOS from the end of treatment of 12 days vs. 18 days (63).
New opportunities in the field of nutritional support are emerging from the application of artificial intelligence (AI). Machine learning (ML) is currently being tested on large electronic data sets as a tool to identify and grade malnutrition using large-scale data from cancer patients and could be helpful to speed up the diagnosis of malnutrition and implement a timely, individualized nutritional support in at-risk patients. In this setting, an observational, nationwide, multicenter cohort study that included 14134 cancer patients revealed the effectiveness of a ML-based algorithm to develop a fusion decision system that can be used to facilitate the identification and severity grading of malnutrition in patients with cancer (64). Research is also focusing on the application of AI in the imaging of sarcopenia, to improve its evaluation and prediction of outcomes (65). ML-based algorithms could represent a more flexible, automatic, and unified nutritional risk screening approach, with subsequent escalation of patients to nutrition groups as appropriate (66).