Antitumoral Agent-Induced Constipation: A Systematic Review

Simple Summary Constipation is the third most common symptom in patients receiving cytotoxic chemotherapy, and it can impact their quality of life. There is no clear definition of constipation. Several factors may cause constipation in cancer patients, such as the direct effect of the tumor, comorbidities, polypharmacy, or antitumoral treatments. Being aware of its prevalence is crucial for all physicians and nurses who treat those patients to more precisely address the symptoms. A total of 22.07% of patients present constipation when they are under antitumoral treatments. The loss of enteric neurons following the administration of antitumoral treatments may cause constipation, but the etiology is not completely established. It is difficult to recommend specific treatments for antitumoral treatment-induced constipation without more knowledge of the specific cause. Narratives and scoping reviews recommend using laxatives as a treatment. Other studies show the benefits of acupuncture, moxibustion, osteopaths, and probiotics. In many countries, acupuncture and moxibustion are not available in the public system, and most healthcare professionals are not familiar with those methods. Thus, although laxatives may be used, more specific studies on the prevalence and etiology of and specific treatments for antitumoral treatment-induced constipation are needed. Abstract Background: Constipation is a common symptom in patients receiving antitumoral treatment. The mechanisms underlying antitumoral agent-induced constipation (ATAIC) are poorly defined. This systematic review aimed to analyze and synthesize the available information related to the prevalence, etiology, and treatment of ATAIC. Methods: A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines was conducted. The review included human studies written in English, French, or Spanish involving patients with cancer and containing information about the prevalence, etiology, and treatment of ATAIC. Results: A total of 73 articles were included. The reported prevalence ranged from 0.8% to 86.6%. Six studies reported an ATAIC prevalence of over 50%. The prevalence rates of constipation of grades 3 and 4 ranged between 0 and 11%. The importance of enteric neuronal integrity in gastrointestinal function was reported. The articles with the highest levels of evidence in relation to ATAIC treatment obtained in this systematic review studied treatments with acupuncture, sweet potato, osteopath, probiotics, and moxibustion. Conclusions: The prevalence of constipation in patients undergoing antitumoral treatment is very diverse. Studies specifically designed to report the prevalence of antineoplastic treatment-induced constipation are needed. The importance of enteric neuronal integrity in gastrointestinal function was described. Thus, neuroprotection could be an area of research for the treatment of chemotherapy-induced gastrointestinal disorders.


Introduction
Constipation is the third most common symptom in patients receiving cytotoxic chemotherapy.It ranges from 4.9 to 16% in outpatients receiving chemotherapy [1], and it is classified as severe in 5% and moderate in 11% of patients [2], with a great impact on the quality of life.Constipation may be a direct effect of the tumor [3], related to comorbidities [4], to collateral effects of the symptomatic treatment of cancer [5], or to its antitumoral treatment [2].
The mechanisms underlying antitumoral agent-induced constipation (ATAIC) are poorly defined [2].ATAIC has been linked to specific chemotherapeutic agents such as thalidomide, cisplatin, and vinca alkaloids that induce true ATAIC in up to 80-90% of patients [2,6].The invoked mechanism of ATAIC in this class of antitumoral agents is autonomic neuropathy [6] because of a direct effect of the alkaloid to the autonomic enteric neuronal system.Little is known about the mechanism of ATAIC related to other antitumoral agents.
Distinguishing true ATAIC from other causes of constipation is difficult, and it is a major issue hindering investigation [7].Given the scarcity of the literature concerning ATAIC, it is hard to accurately estimate its prevalence and severity among all chemotherapytreated persons with cancer.
In contrast to the high interest in addressing chemotherapy-induced nausea and vomiting [8], ATAIC has not received much attention in the literature, although there is clear evidence of the relation between common antitumoral agents and constipation [1].
In this context, this systematic review aimed to analyze and synthesize the available information related to the prevalence, etiology, and treatment of ATAIC.

Design and Data Sources
A systematic review was performed by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.This study project was registered at PROSPERO (registration #: CRD42023442306).
The search of the literature was conducted in the following databases: MEDLINE, PubMed, ISI Web of Science (ISI WoS), Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus.The search included all publications in these databases from inception to June 2023.

Eligibility Criteria
All types of human studies (written in English, French, or Spanish) involving patients with cancer were eligible for inclusion.Studies containing information about the prevalence, etiology, and treatment of ATAIC in patients with cancer and published as full-text articles were included.Protocols of studies were excluded.No other restrictions were placed on study design or assessment measures.Studies on pediatric populations, studies on animals, and studies relating to constipation secondary to antiemetic treatment related to cancer treatment were excluded.

Search Strategy and Study Selection
A search strategy was designed by combining MeSH terms and free text.Table 1 shows the search strategy for the MEDLINE database, which was adapted for the other databases.Articles identified in the search were separately screened and assessed independently for inclusion by two reviewers using Covidence software.(A.C.-B.and J.J.-T.reviewed all articles).The retrieved articles were sorted in three stages (by title, abstract, and full text) according to PRISMA guidelines [9] after removing duplicates.
Articles were excluded if they failed to meet the inclusion criteria; disagreements in this regard were separately solved by a third reviewer (JG-B).
Figure 1 illustrates the process of study selection and the reasons for exclusion.The retrieved articles were sorted in three stages (by title, abstract, and full text) according to PRISMA guidelines [9] after removing duplicates.
Articles were excluded if they failed to meet the inclusion criteria; disagreements in this regard were separately solved by a third reviewer (JG-B).
Figure 1 illustrates the process of study selection and the reasons for exclusion.

Data Extraction, Data Analysis, and Synthesis of Findings
All included articles were divided into subgroups according to the predetermined classification related to the aims of this review: prevalence, etiology, and treatment of ATAIC.Then, the studies were analyzed by topic.Data for each topic were extracted from the studies.
The characteristics of each article, including author, country, year of publication, study design, and main content(s), are available in Table 2 (prevalence), Table 3 (etiology), and Table 4 (treatment).
The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) [10] system was used to assess the certainty of the evidence of each outcome from the treatment results.The GRADE system includes five aspects: limitations, inconsistency, imprecision, indirectness, and publication bias.The certainty of the evidence was assessed as high, moderate, low, or very low by two independent reviewers (AC-B and JG-B) according to the GRADE approach.

The Characteristics of Included Studies
A total of 73 articles-which included information on 41,146 patients with cancerwere included in the review.From those 73 articles, 54 were included as they mentioned data about the prevalence of ATAIC, 6 were for their information relating to the etiology of ATAIC, and 17 were included as they mentioned pharmacological or non-pharmacological treatments to alleviate ATAIC.Three articles were used for both prevalence and treatment purposes [11-13].

Prevalence
The 54 studies mentioning aspects related to prevalence included information on 33,409 patients with cancer.The reported prevalence rate ranged from 0.8% to 86.6%, and the mean prevalence rate considering all studies was 22.07%.
The severity of constipation was reported in 13 of the 54 studies.The prevalence rates of constipation of grades 3 and 4 [19] ranged between 0 and 11%.

Etiology
Regarding the six studies mentioning aspects related to etiology, two were case reports [49,50], one was a randomized controlled trial [51], and three were narrative reviews [2,52,53].The total number of patients included was 145.One study focused on the treatment with 5-fluorouracil, one study used ipilimumab, study used vincristine, and in three studies, the antitumoral treatment was not specified.
The loss of enteric neurons following the administration of antitumoral treatments may cause constipation.
The main contents are available in Table 3.

Treatment
From the 17 studies mentioning aspects related to treatment, the number of patients included was 7786.From the type of cancers reviewed, five did not mention the location of the cancer [54][55][56][57][58], four mentioned treatments in patients with leukemia and lymphoma [6,27,59,60], three involved patients with breast cancer [12,61,62], two involved patients with multiple myeloma [11,63], two involved patients with lung cancer [18,64], and one involved patients with colorectal cancer [13].
The scoping review mentioned high-fiber diets, fluid intake exercises, and laxatives [56].
The retrospective studies reported the use of prophylactic laxatives and lubiprostone [27,60].
The case report explained the benefits of metoclopramide in a patient with ileus secondary to vincristine [6].
The main contents are explained in Table 4.

Discussion
Constipation is a feared and frequently reported symptom in patients with cancer treated with antitumoral agents.However, the results of this systematic review show the scarce knowledge of constipation related to the direct effects of antitumoral agents in the gastrointestinal tract that lead to constipation.
Pain has been the main symptom to address in cancer patients, but constipation is the third most common symptom in patients receiving cytotoxic chemotherapy [1], and it can impact the quality of life.There is no clear definition of constipation.Moreover, the characteristics of bowel function have been less assessed by physicians.Thus, historically, constipation is a symptom that has been less addressed.Patients may have a prior history of constipation before the cancer diagnosis, and it is crucial to analyze the causes of constipation.Constipation can appear at any moment of the cancer disease, but it is more severe as the illness becomes worse [65].General recommendations include the use of nonpharmacological approaches and laxatives.As laxatives, a combination of stool softeners and stimulants is usually needed [11,55].Laxatives can be administered while the patient is under a chemotherapy regimen.

Prevalence
Most of the studies that report the prevalence of constipation in this systematic review are not specifically designed to determine the prevalence of constipation and mention the prevalence of several symptoms.In addition, the definition of constipation is not even mentioned in most of them.As it appears in previous articles, some authors mention the need to improve the definition of constipation [66] as well as the need to consider other aspects that influence the presence of constipation in cancer patients.Thus, it is necessary to determine not only how often patients move their bowels, but also the characteristics of their stools as well as the side effects of laxatives or how much the quality of life is worsened when constipation appears [66].
Although most articles included in the study are in the period of 2007-2023, the search included all publications in databases from inception to June 2023.
The reported prevalence in this systematic review is very diverse and ranges from 0.8% to 86.6%.These results could be explained by the lack of a clear definition of ATAIC.The prevalence of constipation in patients with palliative care needs is also very diverse in the literature, ranging from 30 to 90% of patients [65].Other studies in advanced patients mention prevalence rates of 43% [67].It is noteworthy that only 13.1% of patients never described disturbed bowel function during their illness [66].
The prevalence of grades 3 and 4 of severity is much lower than the prevalence of grades 1 and 2. The maximum prevalence of high-severity constipation (grades 3 and 4) was 11% in a study using thalidomide, melphalan, prednisone, and bortezomib.
Gender, polypharmacy-not only opioids-and other medical conditions have been clearly described as factors related to constipation [67].Thus, to determine if constipation is more severe because of antitumoral treatments or due to other factors, studies should include the analysis of more variables, such as polypharmacy and chronic conditions.

Etiology
According to the results of this systematic review, the three main chemotherapeutic agents causing constipation are cisplatin, vinca alkaloids, and thalidomide.Thalidomide is currently less used than it was in the past.As far as cisplatin and vinca alkaloids are concerned, their effects on constipation could be related to the peripheral neurotoxicity of these treatments.
Only one of the studies mentioning aspects of etiology, a randomized clinical trial- [51], described that methanogenesis in patients with colorectal cancer under treatment with 5-fluorouracil had a positive association with constipation.The other studies mentioning aspects of etiology in this systematic review [2,49,50,52,53] only cited the importance of enteric neuronal integrity in gastrointestinal function.Thus, studies analyzing treatments involving neuroprotection could be designed as an initial step of personalized treatments for patients depending on the cause of constipation.
Currently, all patients follow the same general recommendations, such as the consumption of fiber or laxatives, without studying or considering each patient's enteric neuronal system.
Studies performed on mice-which were not included in this review as they did not meet the inclusion criteria-described the effects of 5-fluorouracil (5-FU) on the gastrointestinal tract [70].Those studies in mice show that 5-FU administered for 3 days increased gastrointestinal transit, induced acute intestinal inflammation, and reduced the proportion of neuronal nitric oxide synthase immunoreactive neurons.5-FU administered for 14 days induced a delayed gastrointestinal transit, the inhibition of colonic migrating motor complexes, increased short and fragmented contractions, and myenteric neuronal loss [70].
More studies have studied the link of chemotherapy and the enteric neuronal system in mice.Vera performed a study in which cisplatin-treated mice had an enteric neuronal loss that was associated with reduced colonic motor activity and a shorter gastrointestinal transit time [71].The authors concluded that chronic cisplatin treatment may induce an enteric neuropathy characterized by changes in myenteric neurons associated with marked gastrointestinal motor dysfunction.These promising studies in mice emphasize the importance of enteric neuronal integrity in gastrointestinal function and recommend more studies to be conducted on humans who receive those antineoplastic treatments.

Treatment
Seven out of the seventeen studies about the treatment of ATAIC have low or very low levels of evidence using the GRADE system [10].
Moreover, the treatments were not specifically focused on the etiology of this cause of constipation as it is not mentioned how the proposed treatment could benefit enteric neuropathy.This nonspecific approach of treating constipation without considering its etiology recalls how constipation is often treated.In this way, it reminds us of the situation of opioid-induced constipation, where the current guidelines still recommend laxatives as first-line therapy [72,73] instead of recommending the treatment with peripherally mu opioid receptor antagonists (PAMORAs).The use of PAMORAs could be the most reasonable approach focused on the mechanism of opioid-induced constipation.Some narrative reviews analyzed in this systematic review mentioned treatment with laxatives as a general recommendation for constipation instead of focusing on a more etiologic approach like the neuroprotection of the gut [55].
In 3 of these 17 studies related to treatment, vinca alkaloids were the antitumoral treatment used [6,27,60].Vinca alkaloids are also the antineoplastic treatments that appear the most in studies of constipation in children with cancer [74].From the rest of the 17 studies, 10 mention chemotherapy in general as a cause of constipation, and the others mention lenalidomide, thalidomide and bortezomib, vinca alkaloids, 5-fluorouracil epirrubicin, cyclophosphamide, and capecitabine plus oxaliplatin regimen.
The use of complementary and alternative medicines in cancer patients to cope with ATAIC has been studied [75].Toygar reported that 31.8% of patients knew about complementary and alternative medicine to cope with ATAIC [75].The most common method was phytotherapy (97.1%), and the most used herb was apricot (39.4%).Individuals' information sources on complementary and alternative medicine were mainly internet and social media instead of scientific sources or health professionals.Unfortunately, the study did not report the benefits of those treatments.
As far as acupuncture is concerned, studies in patients with opioid-induced constipation also reported benefits with acupuncture in a recent meta-analysis [76].
It should be considered that in many countries, acupuncture and moxibustion are not available in the public system, and most healthcare professionals are not familiar with those methods.Hence, although the results in this systematic review showed some effectiveness, most patients will not benefit from those treatments.Treatment with probiotics proved to be significatively effective in the treatment of constipation when compared to placebo (probiotics: 4% constipation; placebo: 28% constipation (p = 0.019)).High g: grams; PO: oral route; ml: milliliters; mg: milligrams; d: day; min: minutes; BSFS: the Bristol Stool Form Scale; CAS: Constipation Assessment Scale.GRADE Working Group grades of evidence.High quality: Further research is very unlikely to change our confidence in the estimate of effect.Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.Very low quality: We are very uncertain about the estimate.

Conclusions
The prevalence of constipation in patients undergoing antitumoral treatment is very diverse.It is important to emphasize the need to assess ATAIC in all cancer patients.Studies specifically designed to report the definition and prevalence of ATAIC are needed.
A specific pathophysiological approach to personalize the treatment of ATAIC is urgently needed.The importance of enteric neuronal integrity in gastrointestinal function has been described in basic research.Thus, future research should be focused on the effect of ATAIC on enteric neurons.Neuroprotection could be an area of research for the treatment of ATAIC.As far as treatment is concerned, research should be focused on the specific causes of constipation, avoiding general recommendations for all patients.Therefore, a more personalized approach will be performed if all patients are assessed in terms of their prevalence, their causes of constipation, and their specific treatments.Thus, although laxatives may be used, more specific studies on the prevalence and etiology of and specific treatments for antitumoral treatment-induced constipation are needed.

The Strengths and Limitations of This Study
To the best of our knowledge, this is the only systematic review of ATAIC in adults.It includes articles from four databases and does not exclude any articles for methodological reasons.
Important clinical issues regarding ATAIC such as prevalence, etiology, and treatment have been addressed in this systematic review to provide useful information for clinicians.
However, this study presents some limitations which should be recognized.First, there was a huge amount of methodological heterogeneity among the included studies that limited the strength of some of the final conclusions.
Second, studies mentioning etiology report hypotheses and do not report strong conclusions about the mechanism by which ATAIC occurs.
Finally, studies reporting treatment options are few and not oriented to the presumable cause of ATAIC.None of the studies related to treatment are focused on treatments that could enhance the neuroprotection of the gut.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram of study selection.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram of study selection.
* OR Tumor* OR Malign* Or Cancer* OR Neoplasms* OR Carcinoma* OR Oncol*
* OR Tumor* OR Malign* Or Cancer* OR Neoplasms* OR Carcinoma* OR Oncol*

Table 2 .
Studies related to prevalence of ATAIC.

Table 3 .
Studies related to the pathophysiology of ATAIC.

Table 4 .
Studies related to treatment of ATAIC.