Oligomeric Enteral Nutrition in Undernutrition, due to Oncology Treatment-Related Diarrhea. Systematic Review and Proposal of An Algorithm of Action

Oncology treatment-related diarrhea and malnutrition appear together in oncological patients because of the disease itself, or the treatments that are administered for it. Therefore it is essential to carry out a nutritional treatment. Enteral nutrition formulas, containing peptides and medium chain triglycerides, can facilitate absorption in cases of malabsorption. There are few references to the use of enteral nutrition in the clinical society guidelines of patient management with oncology treatment-related diarrhea (OTRD). A bibliographic review of the studies with oligomeric enteral nutrition in OTRD found only nine studies with chemotherapy (all with the same oligomeric formula in which oral mucositis improves, while the rest of the outcomes show different results), and eight studies with radiotherapy (with different products and very heterogeneous results). We hereby present our action algorithm to supplement the diet of OTRD patients with an oligomeric enteral nutrition formula. The first step is the nutritional assessment, followed by the assessment of the functional capacity of the patient’s intestine. With these two aspects evaluated, the therapeutic possibilities available vary in degrees of complexity: These will range from the usual dietary recommendations, to supplementation with oral oligomeric enteral nutrition, along with complete enteral nutrition with oligomeric formula, and up to potentially total parenteral nutrition.


Introduction
In the recent years there have been substantial advances in molecularly-targeted therapies for the treatment of patients with cancer. However, chemotherapy and radiotherapy are continuously used alone, combined, or utilized even before surgery. Chemo-radiotherapy causes and even exacerbates a symptom that worsens the nutritional status of our patients, which symptom is caused by digestive toxicity, such as nausea, vomiting, mucositis and diarrhea.
Diarrhea and malnutrition appear together in the oncological patient as a consequence of the disease itself, or because of the administered treatments. Chemotherapy and radiotherapy cause different undesirable effects on the gastrointestinal tract mucosa, like inflammation, edema, ulceration and atrophy. The increase in mucosal permeability, combined with immunosuppression, predisposes the patient to bacterial translocations, septicemia and ischemia [1].
In general, all guidelines recommend that an early intervention should be performed when the patient initiates oncological treatment to prevent the progression of the severity of diarrhea. The treatment to be performed will depend upon the degree of the severity of the diarrhea, as well as the presence of other risk factors: Fever, vomiting, neutropenia, frank bleeding in the stool, moderate/severe abdominal pain, and dehydration. Patients with mild diarrhea and without risk factors can be treated on an outpatient basis with oral antidiarrheal and pharmacological measures, while those with severe diarrhea and/or risk factors will need in-patient treatment.
It is striking that most of the treatments that appear in the guidelines are focused upon diarrhea, but very few consider the adequate nutritional support to avoid malnutrition. Diarrhea is associated with loss of water and electrolytes, but also with nutrient malabsorption. Oncological patients are susceptible to a high risk of malnutrition due to cancer anorexia-cachexia syndrome, the oncological treatment toxicity, cancer-associated digestive dysfunction, psychological factors, etc. The appear-ance of diarrhea in these types of patient substantially worsens their quality of life [10,14].
Nutritional counseling and oral nutritional supplements should be used to increase dietary intake and to prevent oncology-therapy-associated weight loss and interruption of cancer therapy [42]. ESPEN expert group recommendations for action against cancer-related malnutrition press the point that patients with cancer are at particularly high risk for malnutrition, both because of the disease and its treatments. Furthermore, the deaths of 10-20% of patients with cancer can be attributed to malnutrition, rather than to the malignancy itself. Nutrition counselling by a health care professional is regarded as the first line of nutrition therapy [15]. Ravasco et al. [43] observe that nutritional therapy provided an early and timely individualized nutritional counseling, and that education has a sustained effect upon outcomes, nutritional intake and status, late radiotherapy toxicity, quality of life and prognosis.
Certain guidelines recommend the use of some type of enteral nutrition treatment [19,22,23,27,33,36,39,41]. The majority refers to the contribution of glutamine [19,36,39,41], probiotics [30,39] and omega 3 fatty acids [36,41], although the recent ESMO Clinical Practice Guidelines [41] indicate that more studies are required to advise its use. With regard to the contribution of nutritional supplements, some only indicate that products with high osmolality should be avoided [20,34], others that these supplements should only be used in severe degrees of diarrhea [23] or in severe malnutrition [33], but only two guides refer to the use of oligomeric formulas [22,27].
It has been suggested that an oligomeric diet might be protective to the intestinal mucosa when administered to patients with diarrhea associated with oncotherapy. Polymeric enteral nutrition is the usual type of formula used in patients who need nutritional enteral support, but some patients could need alternative formulas because of severe diarrhea. Choice of oligomeric enteral formula may be important to improve nutrients' absorption and to achieve the goal of the successful completion of scheduled nutrition and a smooth transition to the normal diet [44].
The polymeric enteral formula contains nitrogen in the form of whole proteins and needs the gastrointestinal tract digestion process. On the other hand, the nitrogen sources of oligomeric enteral formula are hydrolyzed proteins (oligopeptides of varying lengths, dipeptides and tripeptides).
These peptides of oligomeric enteral formulas have specific uptake transport mechanisms and are thought to be absorbed more efficiently than whole proteins. Given impaired digestive function in cancer patients with diarrhea associated with systemic treatment, oligomeric enteral formulas place less burden on the digestive system and are absorbed better, and thus are thought to be more favorable options compared with polymeric formulas [18].
Data from convincing animal experiments and human preclinical studies report reduced pancreatic or biliary stimulation with oligomeric formula diet, compared to a regular or polymeric diet [45]. Protein is provided as free amino acids or peptides, which reduces the requirement for enzymatic hydrolysis before absorption, and reduces the risk of presenting an 'antigenic' load. The provision of fats as medium chain triacylglycerol allows their absorption directly into portal blood without the need for enzymatic hydrolysis and emulsification by bile salts. Thus, oligomeric formulae can be valuable therapies in Crohn's disease [46], and help maintain gut integrity by delivering a readily-available source of nutrients directly to the gastrointestinal mucosa. Moreover, oligomeric enteral nutrition was shown to reduce the mucosal production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in patients with Crohn's disease, and dietary histidine ameliorates murine colitis by an inhibition of pro-inflammatory cytokine production in macrophages [47].
Mucosal injury is a common oncological treatments side effect, resulting in symptoms of stomatitis and diarrhea. The mucosal injury causes impaired absorption and eating disorder in addition to pain associated with the bleeding and ulceration, resulting in increased healthcare costs and an impaired quality of life [48].
Oligomeric enteral nutrition formulas could help to maintain mucosal integrity in the gastrointestinal tract, thereby resulting in maintained nutrient absorption. The pathogenic mechanism underlying gastrointestinal mucosal injury caused by anticancer therapies involves damage in the DNAs of normal mucosal epithelial cells and fibroblast cells, resulting in suppressed cell growth and tissue repair. Kawashima et al. [49] investigated the effects of oral supplementation with oligomeric enteral nutrition diet on mucin in 5-fluorouracil-induced intestinal mucositis. The results of their studies show that the length of the intestinal tract, dry weight and villus height were reduced by 5-fluorouracil administration. Those animals receiving an oligomeric enteral nutrition diet showed an improvement in digestive and absorptive function. The authors conclude that oligomeric enteral nutrition has the ability to improve the intestinal tract defense function mainly exerted through small intestinal mucin, indicating the possibility of relieving gastrointestinal mucosal injury caused as an adverse effect of anticancer drugs.
Supported by these studies, we infer that the use of nutritional supplements with oligomeric formulas in patients with OTRD who present malnutrition could be very useful. Prior to the design of a performance algorithm, we consider it would be necessary to carry out a literature review on the use of oligomeric enteral nutrition formulas in patients with OTRD.

Review on the Use of Oligomeric Enteral Nutrition Formulas in Malnourish Patients with OTRD
The mechanisms involved in the chemotherapy-associated diarrhea are not well explained, and they vary according to the type of chemotherapy used, being more common after the administration of topoisomerase inhibitors (irinotecan, the highest risk), methotrexate at high doses, fluoropyrimadines (5-fluorouracil, capecitabine) or taxanes as docetaxel. It has been postulated that it could be due to the damage of the intestinal crypts, or changes in the intestinal microflora, with an alteration of the transport of fluids in the colon and a lower absorption of water. In addition, mucositis induced by chemotherapy produces a malabsorption of nutrients that contribute to osmotic diarrhea. Most of the literature is based upon clinical observations in which the number and consistency of bowel movements are collected, as well as whether or not they are accompanied by blood, mucus and pain. On the other hand, irradiation on the cells of the intestinal mucosa causes a loss of mucosal surface, with the loss of intestinal permeability, motility and absorption of nutrients. It also facilitates the translocation of the intestinal microflora, the appearance of ulcers, necrosis, mucous membrane bleeding and even more serious complications, such as intestinal fistula.
The most characteristic clinical manifestation is diarrhea [50]. Lees clear are the mechanisms of TKI-induced and immunotherapy-induced diarrhea, since it has not been widely studied yet, but most of the hypotheses link this toxicity to mechanisms that are shared with chemotherapy-induced diarrhea [7].
An oligomeric enteral nutrition diet can be a nutritional treatment of choice in the patient with OTRD for its easy absorption, inhibition of pro-inflammatory cytokine production and maintenance of mucosal integrity. There are very few published reviews on the efficacy of enteral peptide nutrition in patients with diarrhea associated with oncotherapy. We found a Cochrane review in patients with radiotherapy, but the researcher was not able to perform meta-analysis due to the lack of studies [51].
Given the limited published evidence, we consider that a bibliographic review on the subject was necessary prior to the preparation of the nutritional support algorithm in patients with OTRD.
For this review, we researched on-line databases PUBMED, MEDLINE, EMBASE and the Cochrane library up to March 2019, using the following terms: ((Chemotherapy) or (radiotherapy)) and ((oral mucositis) or (diarrhea) or (peptide diet) or (elemental diet) or (oligomeric diet)) in order to collect potentially relevant articles. Animal, not clinical, trials and non-adult studies were excluded. Retrieved articles were reviewed for relevance, duplicates were discarded, and the full text of all potentially relevant articles was classified and assessed for inclusion using predetermined criteria. Only clinical trials about oligomeric elemental or peptide enteral nutrition were screened. Reference lists of all of the included articles were reviewed for additional possibly relevant citations. Further details about the literature search process are provided in Figure 1. Relevant studies were identified [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68], and their results are summarized in Tables 2 and 3. Regarding the studies with oligomeric diets in oncological patients under treatment with radiotherapy [52][53][54][55][56][57][58][59] (Table 2), 998 patients were collected (476 in the intervention groups and 522 in the control groups). The three oldest studies [52][53][54] were conducted with Vivonex ® without significant differences in the response to stool characteristics, or in the amount of weight lost. The next two studies to appear [55,56] were performed with Vital HNR ® , detecting an improvement in the severity and duration of diarrhea in the group that took the enteral nutrition product. Subsequently, another study with 677 patients [57] shows a significant reduction in intestinal toxicity, the suppression of radiotherapy and weight improvement with an undefined elemental diet. But this is a study that is only a conference abstract, and does not define the type of oligomeric enteral nutrition used. The last study that we found which compares oligomeric diet with habitual    During the treatment cycle (4 weeks).
Elental ® (Ajinomoto Pharmaceutical) (80 g/ 300 kcal amino-acid-rich, fat free, elemental diet) Examine the preventive effects of OD on oral mucositis and sarcopenia progression during chemo (chemoradio) therapy for esophageal cancer OD tended to reduce the incidence of oral mucositis (Arm 1, 23.5% and Arm 2, 12.5%), but there was no statistically significant difference. The average body mass index and body fat mass decreased significantly in both groups. Lean body mass was reduced in Arm 1, but was increased in Arm; the relative change of lean body mass after the treatment was significant between Arm 1 and Arm 2 (p = 0.007). The incidence of diarrhea was greater in Arm 2 than in Arm 1 (31.3 and 11.8%, respectively), and was grade 2 or less.
Single institution, small patient number Most of the patients who consumed OD suffered from a lower degree of mucositis compared to control group. OD was associated with a significantly improved rate of completion of chemoradiation (no interruption). There was no significant difference between OD group and control group in terms of mean change of body weight or total protein and albumin levels in blood serum before and after chemoradiation. There was a significant difference between the Elental ® group and the control group in mean change of C-reactive protein levels in blood serum; however, there was no significant difference in mean change of body weight and total protein level in blood serum before and after chemoradiation. Diarrhea were no determinated.

Single institution. Retrospective
Single institution, Whether an oral OD prevents chemotherapy associated oral mucositis and body weight loss.
The incidence of oral mucositis was significantly lower in the treatment group (9.1 %) than in the control group (27.3%). The median body weight loss in the treatment group was significantly smaller than that in the control group (p = 0.015). The treatment group was significantly associated with high cumulative S-1 continuation rates (log-rank p = 0.047). No differences in diarrhea between groups.
Single-institutional study with a small sample size OD: Oligomeric diet.
Regarding the studies with oligomeric diets in oncological patients under treatment with radiotherapy [52][53][54][55][56][57][58][59] (Table 2), 998 patients were collected (476 in the intervention groups and 522 in the control groups). The three oldest studies [52][53][54] were conducted with Vivonex ® without significant differences in the response to stool characteristics, or in the amount of weight lost. The next two studies to appear [55,56] were performed with Vital HNR ® , detecting an improvement in the severity and duration of diarrhea in the group that took the enteral nutrition product. Subsequently, another study with 677 patients [57] shows a significant reduction in intestinal toxicity, the suppression of radiotherapy and weight improvement with an undefined elemental diet. But this is a study that is only a conference abstract, and does not define the type of oligomeric enteral nutrition used. The last study that we found which compares oligomeric diet with habitual diet is that of McGough et al. [58] that uses EO28 ® . It does not find improvement in gastrointestinal symptoms or nutritional status, because only 24% of patients take the product. Finally Feng Shao et al. [59] compares an oligomeric diet (Peptisorb ® ) with or without microorganisms and fish oil, with an improvement in abdominal pain, bloating and diarrhea.
Regarding chemotherapy-induced intestinal mucositis [60][61][62][63][64][65][66][67][68] (Table 3), all the studies we have found used the same oligomeric formula of enteral nutrition (Elental ® ). In total there are 345 patients, of whom 203 were treated with this oligomeric enteral nutrition, and the rest are controls without enteral nutrition. In summary, the main objective of the studies is the effect of this type of oral nutritional supplement on oral mucositis in patients with chemotherapy. In all of the studies [60][61][62][63][64][65][66][67][68] oral mucositis improves, while the rest of the outcomes show different results. Only one study observes improvement in controls on body weight [68], while two others do not find differences [64,67], although in another they find improvement in lean body mass [60]. With regards to the response of diarrhea to this supplementation, the majority of studies do not find differences compared to the control group [62,65,66,68]. Despite these poor results, some authors note that hospitalization time decreases [62], and there are fewer cases in which chemotherapy should be stopped due to its side effects [64,67].
The results of the studies that we have reviewed are very heterogeneous, both in the type of patients, as well as the type of cancer to be treated, in the chemotherapy/radiotherapy dose and in the enteral nutrition formula used, thus the difficulty to draw conclusions. It is not known what proportion of normal diet should be replaced by oligomeric formula to confer the most benefit. In addition to the proportion determination, it is likely that the formulation of the oligomeric diet is important. Similarly, the proportion of fat derived from medium chain triglycerides is likely to be impactful, as this will influence the degree of pancreatic and biliary secretions, both of which may exacerbate damage to the intestinal mucosa [45].
Although oligomeric enteral nutrition formulas have not shown homogeneous efficacy in all studies, we do not have effective pharmacological treatments for these patients [69,70]. At present, the recombinant keratinocyte growth factor-1, palifermin, is thought to be a promising agent for the management of oral mucositis associated with cancer treatment. Regardless of its usefulness in decreasing oral mucositis, the safety of this growth factor in cancer patients remains unclear, and it is expensive compared to other types of therapies for oral mucositis [71]. Compared to other treatment options available for intestinal mucositis in cancer patients, oligomeric enteral nutrition could be an attractive agent, because it is neither costly, nor a growth factor treatment, such as palifermin. Furthermore, no side effects of enteral nutrition have been reported thus far. However, only a few published reports are available on the efficacy of oligomeric enteral nutrition for the treatment of chemo-radiotherapy-induced intestinal mucositis (Tables 2 and 3).
Harada et al. [67] show that administration of an oligomeric enteral formula was associated with a suppressed expression of protein C reactive. According to in vitro data from the same group, this oligomeric enteral formula could successfully downregulate the expression of inflammatory cytokines in the immortalized human keratinocyte cell line HaCaT [72]. In this way, it might suppress protein C reactive expression via the downregulation of inflammatory cytokines. Harada et al. also showed previously that this oligomeric enteral formula can treat mucositis and dermatitis by accelerating mucosal and skin recovery through FGF2 induction and reepithelization in vivo [73].
The Tanaka group have studied and measured the intestinal mucosal integrity on the basis of plasma diamine oxidase activity. In a recent study they found that the integrity of the intestinal mucosa tends to be maintained in the enteral oligomeric nutrition group [66]. Previous studies have shown that amino acids themselves can protect the mucosa and have anti-inflammatory effects [74]. Furthermore, the administration of an oligomeric enteral nutrition during chemotherapy has been reported to have the potential prevent mucositis [61,63]. In these studies authors group observe that body weight is maintained in the intervention group, in front of weight loss in a control group.
It could be explained, because oligomeric enteral nutrition with Glutamine may have maintained gastrointestinal mucosal integrity, and in this way, maintain nutrient absorption. Furthermore, amino acids may be more suitable than proteins to provide nutrients, as proteins require digestion. Fijlstra et al. [75] observe that enteral administration of amino acid mixtures enable normal amino acid absorption in patients with mucositis.
Enteral oligomeric nutrition could offer mechanisms of protection of the intestinal mucosa. It might increase and stabilize the intestinal bacterial microbiota [76]. In addition, enteral oligomeric nutrition contains amino acids instead of whole protein. These amino acids could have less antigenic power, and thus have less pro-inflammatory effect for the intestinal mucosa [48]. Therefore, this type of oligomeric enteral nutrition, in addition to providing the necessary nutrients in a malnourished patient, could have a non-negligible, anti-inflammatory effect.
However, in the clinical practice guidelines of the different scientific societies, there are dietary recommendations for the nutritional treatment of OTRD, and in some cases these recommend the use of oligomeric enteral nutrition [22,27], but do not offer protocols of action with oral enteral nutrition.
Based on these nutritional recommendations of the scientific societies and the publications reviewed with oligomeric enteral nutrition formulas, we propose a protocol of action before the appearance of OTRD.

Nutritional Support Algorithm in Patients with OTRD
A direct effect of OTRD is that malabsorption and therefore the risk of malnutrition in these patients is very high. An oligomeric enteral nutrition diet can be the nutritional treatment of choice in patients with OTRD for its easy absorption. Enteral oligomeric nutrition may also have anti-inflammatory effects, change the microbiota, and also lower antigenic effects that protect the oro-intestinal mucosa [67,68]. Its main effect, however, is to maintain the nutritional status of the patient, and to better withstand oncological treatment.
The algorithm of action that we propose covers two aspects: On the one hand, the nutritional assessment of the patient with regard to its nutrient reserve, and on the other hand, the intestinal capacity to absorb nutrients ( Figure 2). The first step in the algorithm we propose is the nutritional assessment of the OTRD oncologic patient. These patients display a high risk of malnutrition, suffering from cancer cachexia, and under aggressive oncological treatment they present OTRD, a side effect causing malabsorption [10]. There are multiple nutritional assessment tests specific to the patient with cancer [15], the majority resulting in a handful of indicators such as: Non-volitional weight loss, low body mass index or reduced muscle mass, reduced food intake or assimilation, and inflammation or disease burden. These criteria have been gathered in a recent consensus by the Global Leadership Initiative on Malnutrition (GLIM), composed by representatives of several of the leading global clinical nutrition societies, and are those that we recommend [77].
anti-inflammatory effects, change the microbiota, and also lower antigenic effects that protect the oro-intestinal mucosa [67,68]. Its main effect, however, is to maintain the nutritional status of the patient, and to better withstand oncological treatment.
The algorithm of action that we propose covers two aspects: On the one hand, the nutritional assessment of the patient with regard to its nutrient reserve, and on the other hand, the intestinal capacity to absorb nutrients. (Figure 2) The first step in the algorithm we propose is the nutritional assessment of the OTRD oncologic patient. These patients display a high risk of malnutrition, suffering from cancer cachexia , and under aggressive oncological treatment they present OTRD, a side effect causing malabsorption [10]. There are multiple nutritional assessment tests specific to the patient with cancer [15], the majority resulting in a handful of indicators such as: Non-volitional weight loss, low body mass index or reduced muscle mass, reduced food intake or assimilation, and inflammation or disease burden. These criteria have been gathered in a recent consensus by the Global Leadership Initiative on Malnutrition (GLIM), composed by representatives of several of the leading global clinical nutrition societies, and are those that we recommend [77].
The second step is the assessment of the functional capacity of the patient's intestine. In this step, the presence of OTRD would indicate the intestinal inability to absorb nutrients and the loss of fluids and electrolytes.
With these two aspects evaluated, we could encounter a case within the most advantageous diagnosis of a well-nourished patient without diarrhea, in which only regular dietary measures to prevent the risk of malnutrition would be necessary. On the opposite side of the spectrum, we would find a patient with severe malnutrition and diarrhea, where a nutritional treatment using exclusive enteral nutrition with an oligomeric formula would be required. Thus, the therapeutic possibilities will vary from less to more complexes, depending upon the patient's initial nutritional situation and the existence of OTRD. These courses of treatment will range from the usual dietary The second step is the assessment of the functional capacity of the patient's intestine. In this step, the presence of OTRD would indicate the intestinal inability to absorb nutrients and the loss of fluids and electrolytes.
With these two aspects evaluated, we could encounter a case within the most advantageous diagnosis of a well-nourished patient without diarrhea, in which only regular dietary measures to prevent the risk of malnutrition would be necessary. On the opposite side of the spectrum, we would find a patient with severe malnutrition and diarrhea, where a nutritional treatment using exclusive enteral nutrition with an oligomeric formula would be required. Thus, the therapeutic possibilities will vary from less to more complexes, depending upon the patient's initial nutritional situation and the existence of OTRD. These courses of treatment will range from the usual dietary recommendations, to supplementation with oral oligomeric enteral nutrition, complete enteral nutrition with oligomeric formula and then to finally total parenteral nutrition.
After an initial evaluation and nutritional therapy, a reassessment after 5-7 days of the nutritional treatment effectiveness, both OTRD responses and nutritional parameters, is recommended. Consequently, if symptoms do not subside, or the patient continues to deteriorate, it is recommended to move to the next therapeutic step.

Conclusions
Oncology therapies cause frequently digestive toxicity, such as nausea, vomiting, mucositis and diarrhea. OTRD and malnutrition tend to manifest together in the oncological patient as a consequence of the disease itself, or because of the treatments that are administered. Regardless of the cause of the OTRD, it is essential to carry out a nutritional treatment that facilitates absorption, reduces waste and digestive symptoms, and contributes to the prevention of malnutrition, which is so frequent in the oncological population. Formulas containing peptides and medium chain triglycerides can facilitate absorption in case of, e.g., malabsorption or short bowel syndrome. Standard OTRD management guidelines are widely published. Most of the treatments that appear in the guidelines are focused upon the treatment of OTRD, but very few consider the adequate nutritional support in order to prevent malnutrition. Some guidelines recommend the use of oligomeric enteral nutrition, but do not offer any protocols of action with oral enteral nutrition. The results of the studies that we have reviewed are very heterogeneous, so it is very difficult to draw conclusions. Nevertheless, we consider that the use of nutritional supplements with oligomeric formulas in patients with OTRD who present malnutrition could be very useful. Because enteral oligomeric nutrition could offer protective mechanisms for the intestinal mucosa, we propose a protocol of action before the appearance of OTRD.
Although this review is based mainly upon studies focused on chemotherapy and radiotherapy, we think that our conclusions and recommendations would most likely be widely applied to the management of malnutrition associated to new anticancer agents, despite the paucity of data about their management.