Longitudinal Associations of Chemotherapy-Induced Symptom Clusters with Healthcare Utilization and Mortality among Patients with Gastrointestinal Cancers

Longitudinal Associations of Chemotherapy-Induced Symptom Clusters with Healthcare Utilization and Mortality among Patients with Gastrointestinal Cancers | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Longitudinal Associations of Chemotherapy-Induced Symptom Clusters with Healthcare Utilization and Mortality among Patients with Gastrointestinal Cancers View ORCID Profile Chengbo Zeng , Nneka N. Ufere , Patricia C. Dykes , Shumenghui Zhai , Yu-Jen Chen , Jiancheng Ye , Maria O. Edelen , Andrea L. Pusic , Jason B. Liu , Kelsey S. Lau-Min , Kelly M. Kenzik doi: https://doi.org/10.1101/2025.10.08.25337569 Chengbo Zeng 1 Patient Reported Outcomes, Value and Experience (PROVE) Center, Department of Surgery, Brigham and Women’s Hospital , Boston, MA, USA 2 Harvard Medical School , Boston, MA, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Chengbo Zeng For correspondence: czeng8{at}bwh.harvard.edu Nneka N. Ufere 2 Harvard Medical School , Boston, MA, USA 3 Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital , Boston, MA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Patricia C. Dykes 2 Harvard Medical School , Boston, MA, USA 4 Department of Medicine, Brigham and Women’s Hospital , Boston, MA, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shumenghui Zhai 5 School of Nursing, Pacific Lutheran University , Tacoma, WA, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yu-Jen Chen 6 Center for Surgery and Public Health, Department of Surgery, Brigham and Women’s Hospital , Boston, MA, USA MPH Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jiancheng Ye 7 Weill Cornell Medicine, Cornell University , New York, NY, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maria O. Edelen 1 Patient Reported Outcomes, Value and Experience (PROVE) Center, Department of Surgery, Brigham and Women’s Hospital , Boston, MA, USA 2 Harvard Medical School , Boston, MA, USA 8 RAND Corporation , Boston, MA, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrea L. Pusic 1 Patient Reported Outcomes, Value and Experience (PROVE) Center, Department of Surgery, Brigham and Women’s Hospital , Boston, MA, USA 2 Harvard Medical School , Boston, MA, USA 9 Division of Plastic and Reconstructive Surgery, Department of Surgery, Brigham and Women’s Hospital , Boston, MA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jason B. Liu 1 Patient Reported Outcomes, Value and Experience (PROVE) Center, Department of Surgery, Brigham and Women’s Hospital , Boston, MA, USA 10 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kelsey S. Lau-Min 2 Harvard Medical School , Boston, MA, USA 11 Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital , Boston, MA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kelly M. Kenzik 1 Patient Reported Outcomes, Value and Experience (PROVE) Center, Department of Surgery, Brigham and Women’s Hospital , Boston, MA, USA 2 Harvard Medical School , Boston, MA, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Background Chemotherapy (CTX) induced neurological and gastrointestinal (GI) symptom clusters are common, but their longitudinal associations with healthcare utilization and mortality remain unclear. Patients and Methods We conducted a retrospective study of 973 GI cancer patients in the Mass General Brigham Health System from 2019 to 2024. Patient-reported symptoms, including constipation, decreased appetite, diarrhea, dyspnea, fatigue, fever, insomnia, nausea, paresthesia, pain, rash, and vomiting, were routinely collected at CTX initiation, days 30, 60, or 90. Primary outcomes were all-cause urgent care visits, emergency department (ED) visits, and death within one year of CTX. Neurological cluster was defined by the presence of fatigue, insomnia, paresthesia, and pain. GI cluster included constipation, decreased appetite, diarrhea, nausea, and vomiting. Time-to-event analysis was used to predict each outcome based on changes in neurological and GI clusters over the first 90 days of CTX. We also examined whether findings varied by age group, comorbidity level, time since diagnosis, cancer stage, and type. Results Over time, the burden of neurological symptoms was significantly higher than that of GI symptoms. Higher neurological burden was associated with an increased risk of urgent care visits (Adjusted HR: 1.27 [95% CI: 0.97–1.67]), but not ED visits or death, with stronger associations among older adults and those without comorbidities. In contrast, higher GI burden was associated with greater risks of ED visits (Adjusted HR: 1.10 [95% CI: 1.02–1.19]) and death (Adjusted HR: 1.08 [95% CI: 0.94–1.24]), but not urgent care visits, with stronger effects among older adults, patients with comorbidities, and those with advanced cancers. Conclusions Neurological and GI clusters were common among patients with GI cancers receiving CTX. Their short-term changes exhibited differential associations with long-term healthcare utilization and mortality. Background Chemotherapy (CTX), a central component of treatment for gastrointestinal (GI) cancers can lead to severe symptoms, which contribute to increased healthcare utilization and higher mortality. 1 , 2 – 8 Existing studies have examined the associations between individual symptoms and overall symptom burden and these outcomes. 9 – 11 Yet, symptoms often co-occur and form distinct clusters, such as “nausea-vomiting” and “fatigue-insomnia.” 12 – 15 A symptom cluster may share a common underlying mechanism or arise from a primary symptom that triggers secondary ones. 12 , 16 – 18 As a result, different symptom clusters may have varying associations with clinical outcomes. Neurological and GI symptoms are two major CTX-induced clusters. 5 , 8 , 19 Commonly administered CTX agents for GI cancers, such as 5-FU, oxaliplatin, irinotecan, and paclitaxel, cause significant toxicities affecting the nervous and digestive systems. 11 , 20 – 23 These agents form the backbone of widely used regimens for GI cancers, including FLOT, FOLFOX, and FOLFIRI, which may amplify the toxicities of individual agents and result in a broad spectrum of symptoms involving both neurological damage and GI side effects. 9 – 11 , 20 – 32 Individual symptoms within a cluster may change during CTX, leading to varying burdens of neurological and GI clusters. Currently, their longitudinal associations with healthcare utilization and mortality remain unclear. Evidence is lacking on whether their short-term changes are associated with long-term healthcare utilization and mortality, and which cluster has a stronger impact. This knowledge, if found, could help clinicians to prioritize symptom management, alleviate adverse side effects, and ultimately improve cancer care. We sought to analyze the burden of GI and neurological clusters over time and examine their associations with one-year healthcare utilization and mortality among patients receiving CTX for GI cancers. Specifically, we aimed to address three research questions: (1) What are the most prevalent co-occurring symptoms within each cluster during the first 90 days of CTX? (2) Are the short-term changes in the burden of these two clusters associated with the risks of one-year healthcare utilization and mortality? and (3) Are these associations, if present, consistent across prognostic groups? Methods Study design, setting, and data resource This was a retrospective cohort study using electronic medical records (EHR) and patient-reported symptom data routinely collected during the care of GI cancer patients within the Mass General Brigham (MGB) Health System. Symptom assessment is part of the MGB PROMs Program, details of which had been described in prior research. 33 – 36 The Patient-Reported Outcome (PRO) version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE ® ) was used to assess symptoms. Patients with a scheduled appointment were asked to complete symptom assessments one week before their visit, using either the EHR’s patient portal or on tablets provided at the clinic for those who did not complete them beforehand. The reported scores were made available to clinicians and patients to support treatment planning and clinical decision-making. Study population Between 01/2019 and 01/2024, we identified adult patients who met the following criteria: (1) had a diagnosis of all-stage colorectal, esophageal, hepatobiliary, pancreatic, or gastric cancers based on ICD-10 codes ( Supplemental Table S1 ) , (2) initiated any cytotoxic chemotherapy to GI cancers, as determined by treatment regimens and their department specialties in the EHR, and (3) completed at least two symptom assessments within 15 days of CTX initiation (i.e., the start of a new CTX episode), or at 30-, 60-, or 90- days post-initiation. Outcomes of interest We examined all-cause healthcare utilization and death within one year of CTX initiation. Healthcare utilization outcomes included (1) urgent care visits, (2) emergency department (ED) visits, and (3) hospital admissions. Urgent care and ED visits were identified based on department specialties. Our primary outcomes were (1) urgent care visits, (2) ED visits, and (3) death, with focuses on their incidence and time to first occurrence. In secondary analyses, we modeled the incidence rate of hospital admissions, given that about 95% of patients were hospitalized at least once within one year of CTX initiation. Symptom assessment using PRO-CTCAE The PRO-CTCAE evaluated the presence, frequency, severity, and interference of the 12 most common CTX-related symptoms: constipation, decreased appetite, diarrhea, dyspnea, fatigue, fever, insomnia, nausea, paresthesia, pain, rash, and vomiting. 7 , 24 – 26 , 37 , 38 Each symptom was assigned a composite score ranging from 0 to 3, with a score of 1 or higher indicating the presence of a symptom. 39 , 40 Based on existing evidence 9 – 11 , the neurological cluster was defined as the number of any fatigue, insomnia, paresthesia, and pain, resulting in a total score ranging from 0 to 4. The GI cluster included constipation, decreased appetite, diarrhea, nausea, and vomiting, yielding a total score ranging from 0 to 5. 11 , 20 – 23 Demographic and clinical characteristics Demographic characteristics included age, sex, race/ethnicity, level of education, employment status, and insurance type. Clinical characteristics included cancer site, months since diagnosis, cancer stage, concurrent use of immunotherapy, radiation therapy, and targeted therapy during CTX (all coded as Yes/No), Charlson comorbidity index (CCI), and receipt of specific CTX agents. Statistical analysis We calculated symptom prevalence across four time points. For each symptom, we calculated the prevalence of co-occurring symptoms. Particularly, we were interested in the prevalence of any neurological and GI symptoms, as well as their co-occurring symptoms. We then summarized the most common symptom combinations within each cluster. Finally, we calculated the burdens of neurological and GI clusters over time. We calculated the incidences of urgent care visits, ED visits, and death within one-year of CTX initiation for the overall population and stratified by age group( 2 months), cancer stage(≤III or IV), and cancer site(pancreatic cancer or others), as these are important prognostic factors. 41 – 43 Time-to-event analysis was used to predict each outcome based on changes in neurological and GI clusters over the first 90 days of CTX. For urgent care and ED visits, we used propensity score weighting to account for immortal time bias introduced by death. We further explored whether the associations were consistent across different prognostic subgroups. We adjusted covariates including age, race, fever, dyspnea, cancer sites, cancer stages, concurrent target therapy, immunotherapy, radiation therapy, time since diagnosis, and comorbidity burden, all of which were associated with healthcare utilization and death. 41 – 43 We reported hazard ratios (HR) with 95% confidence intervals (CI). Secondary analyses were conducted to examine the associations between the burden of symptom clusters within 90 days of CTX and the incidence rate of one-year hospital admission using negative binomial regression. Multiple imputation with 50 replicates was used to handle missing symptom data in all regression analyses. 44 Ethics Review This study was approved by the Dana-Farber/Harvard Cancer Center (DF/HCC) Institutional Review Board (No. 25-048). Results Overview Among the 973 patients, more than half were older adults(53%), males(56.7%), White(86.6%), and non-Hispanic(90.5%)( Table 1 ; Figure 1 ). The most common cancer sites were colorectal(39.8%) and pancreatic(27.8%). About 32% of patients had stage IV cancers. Download figure Open in new tab Figure 1. Inclusion and exclusion flowchart for patients with gastrointestinal cancers completed at least two symptom monitoring within the Mass General Brigham Health System, 2019-2024 *: any colorectal, esophagus, liver and bile duct, pancreatic, and stomach cancers View this table: View inline View popup Table 1. Demographic and clinical characteristics of patients with gastrointestinal cancers receiving chemotherapy, 2019-2024 (N=973) Symptom prevalence and co-occurrence At CTX initiation, the most prevalent symptoms were fatigue(72.8%), pain(67.9%), and insomnia(61.1%)( Table 2 ). The most common GI symptoms were decreased appetite(54.7%), diarrhea(50.1%), and constipation(41.5%). More than 75% of patients reported at least two neurological symptoms. Among patients with fatigue, 78.8% experienced pain, and 72.3% reported insomnia( Figure 2 ;Table S3 ), making “fatigue-insomnia-pain” the most common combination(32%, 188/594; Table S4 ). Over 57.5% of patients had at least two GI symptoms. Among those with decreased appetite, 60.1% had nausea, 59.1% had diarrhea, and 53.7% had constipation( Figure 2 ;Table S3 ), with the most common GI symptom combination being “constipation-decreased appetite-diarrhea-nausea”(16%, 72/450; Table S4 ). Table S2 presents symptom prevalence while Table S3 and Figures S1a - S1c present the corresponding co-occurring symptoms, from days 30 to 90. Over time, “fatigue-insomnia-paresthesia-pain” and “decreased appetite-diarrhea-nausea” were the two most common combinations. Download figure Open in new tab Figure 2. Co-occurring percentages among 12 symptoms in patients with gastrointestinal cancers at chemotherapy initiation (N = 783) Notes : 783 out of 973 patients completed symptom monitoring at chemotherapy initiation. View this table: View inline View popup Table 2. Baseline symptom prevalence of patients with gastrointestinal cancers receiving chemotherapy, 2019-2024 (N = 783) Burden of neurological and GI clusters over time Both neurological and GI clusters followed similar patterns over time, showing an increase from days 0 to 30 followed by a gradual decline( Figure 3 ). Throughout the first 90 days of CTX, the burden of the neurological cluster was consistently higher than that of the GI cluster. Download figure Open in new tab Figure 3. Burden of the neurological and gastrointestinal symptom clusters over time Notes: CTX: Chemotherapy; NEURO: Neurological symptoms (i.e., fatigue, insomnia, paresthesia, and pain); GI: Gastrointestinal symptoms (i.e., constipation, decreased appetite, diarrhea, nausea, and vomiting). Across the four time points, the sample sizes were patients who completed symptom monitoring. Healthcare utilization and changes in the burden of neurological and GI clusters The one-year incidence of urgent care and ED visits were 8.6%(95%CI: 6.9–10.4%) and 53.3%(95%CI: 50.2–56.5%), respectively. A higher incidence of urgent care visits was found among patients with comorbidities, compared to those without( Figure 4a ;Table S5 ). Higher incidences of ED visits were found among patients with comorbidities, stage IV cancers, and pancreatic cancer( Figure 4b ;Table S5 ). Among patients with urgent care and/or ED visits, there were no significant differences in time to healthcare utilization across levels of burden of neurological and GI clusters at CTX initiation. However, we observed a clear, though non-significant, trend indicating that patients with a higher burden of neurological symptoms at CTX initiation had shorter intervals to their first urgent care visit ( Table S6 ). Similarly, patients with a higher burden of GI symptoms at CTX initiation experienced shorter intervals to their first ED visit. Download figure Open in new tab Download figure Open in new tab Figure 4. Incidence of outcomes of interests for the overall cohort or stratified by patient subgroups (N=973). Notes: CCI: Charlson comorbidity index; mos: Month The incidence rate of admission was 22.65(95%CI: 21.52–23.84%) per 100 person years, with higher rates found among recently diagnosed patients and those without pancreatic cancer( Figure 4c ;Table S5 ). Urgent care visits Time to event analyses found that an increased burden of neurological symptoms from CTX initiation to day 90 post-initiation was associated with a higher risk of urgent care visits(HR: 1.27[95%CI: 0.97–1.67]; Figure 5a ) but not ED visits. Subgroup analyses showed similar trends, with marginally or statistically significant associations observed among older adults(HR: 1.36[95%CI: 0.97–1.90]) and patients without comorbidities(HR: 1.34[95%CI: 1.00–1.80]). Download figure Open in new tab Download figure Open in new tab Download figure Open in new tab Download figure Open in new tab Figure 5. Longitudinal associations of neurological (NEURO) and gastrointestinal (GI) symptom clusters and outcomes of interests (N=973). Notes: we adjusted for age, race, cancer sites, cancer stages, fever, dyspnea, concurrent target therapy, concurrent immunotherapy, concurrent radiation therapy, duration after diagnosis, and comorbidities. NEURO: Neurological symptoms (i.e., fatigue, insomnia, paresthesia, and pain); GI: Gastrointestinal symptoms (i.e., constipation, decreased appetite, diarrhea, nausea, and vomiting). Emergency department visits Conversely, an increased burden of GI symptoms from CTX initiation to day 90 post-initiation was associated with a higher risk of ED visits(HR: 1.10[95%CI: 1.02–1.19]; Figure 5b ) but not urgent care visits. Subgroup analyses showed generally consistent trends, with significant associations found among older adults, patients with comorbidities, stage IV cancers, and those with pancreatic cancer. Hospital admissions More than 95% of the patients were hospitalized within 90 days of CTX initiation. The incidence rate of hospital admissions was 22.7(95%CI: 21.5–23.8) per 100 person-years, with significant differences across time since diagnosis and cancer site( Table S5 ). Secondary analyses found that only progression of the GI cluster from CTX initiation to day 90 was significantly associated with the incidence rate of admission(incidence rate ratio [IRR]: 1.09[95%CI: 1.02–1.17]; Figure 5c ), with relatively stronger associations observed among older adults(IRR: 1.12[95%CI: 1.02–1.21) and patients with comorbidities(IRR: 1.20[95%CI: 1.07–1.34]). Death and changes in the burden of neurological and GI clusters The one-year incidence of death was 20.8%(95%CI: 18.2–23.3%). Higher incidences of death were found among older adults, patients with comorbidities, diagnosis more than two months, stage IV cancers, and those with pancreatic cancer( Figure 4c ;Table S5 ). There were no significant differences in time to death across levels of burden of neurological and GI clusters at CTX initiation. However, we observed a trend, though non-significant, indicating that patients with a higher burden of GI symptoms at CTX initiation had shorter intervals to death ( Table S6 ). Although not statistically significant, longitudinal regression analysis revealed that the risk of death was positively associated with an increase in GI cluster burden(HR: 1.08[95%CI: 0.94–1.24]; Figure 5d ) but not with the neurological cluster from CTX initiation to day 90 post-initiation. Subgroup analyses revealed suggestive but non-significant associations between the change in GI symptom burden and death among older adults, patients with stage IV cancers, and in those without pancreatic cancer. Discussions Neurological and GI symptoms were confirmed as two prevalent clusters within the first 90 days of CTX initiation. Although the burden of neurological cluster remained higher than that of GI cluster over time, its progression was only associated with an increased risk of one-year urgent care visits, with stronger associations found among older adults and patients without comorbidities. In contrast, progression of the GI cluster was associated with higher risks of one-year ED visits and admission, with stronger effects among older adults and patients with comorbidities. Our findings reinforce the notion that symptoms often co-occur during CTX. 5 , 7 , 8 , 19 , 45 We defined clusters by the presence of neurological and GI symptoms, as any symptoms detected during CTX should be managed promptly and appropriately to prevent unintended consequences, such as dose reductions and premature treatment discontinuation. The neurological and GI clusters were conceptualized based on commonly used CTX agents, their mechanisms of toxicity, and the corresponding side effects. 9 – 11 , 20 – 32 Each cluster had consistently prevalent combinations over time, such as “fatigue-insomnia-paresthesia-pain” and “decreased appetite-diarrhea-nausea”. Neurological and GI clusters showed distinct associations with healthcare utilization. Only the neurological cluster showed a positive association with the risk of urgent care visits. Neurological symptoms are often chronic in nature 46 – 48 and may not require emergency-level care, making them more appropriately managed in urgent care centers. The stronger associations found among older adults and/or patients without comorbidities suggest that older patients with lower disease burden may be more likely to visit urgent care centers for managing neurological symptoms. In contrast, GI symptoms tend to be more acute and potentially life-threatening, 49 , 50 often requiring timely medical intervention. This may explain their stronger associations with ED visits and hospital admissions. The stronger effects observed among older adults and patients with comorbidities highlight that, in patients with higher disease burden, managing GI symptoms timely is critical to preventing further deterioration, reducing unplanned ED visits, and even preventing frequent admission. The GI cluster showed a borderline positive association with mortality, with stronger effects found among older adults, patients with stage IV cancers, and those without pancreatic cancer. No significant association was found between the neurological cluster and mortality. These findings reinforced that GI symptoms and their consequences, such as dehydration and electrolyte imbalance, are generally more acute than neurological symptoms and need timely management. 51 , 52 Progressive GI symptoms may increase the risk of death, particularly among older adults with advanced cancers. The borderline association may be attributable to the relatively low incidence of one-year mortality and the small difference in GI symptom burden within the first 90 days of CTX between patients who died and those who survived. Implications Our findings have important implications for enhancing the assessment and management on neurological and GI symptoms to reduce healthcare utilization and mortality. The evidence of co-occurring symptoms underscores the need to raise awareness of these two clusters among both clinicians and patients, enabling more thorough symptom assessments. When clinicians and patients understand which symptoms tend to co-occur, they can better anticipate and explore other potential symptoms when a primary symptom is identified. 12 , 17 , 18 This may uncover symptoms that might otherwise be missed. Moreover, given that GI symptoms may be life-threatening, particularly among older adults with a high disease burden and/or advanced cancers, frequent monitoring of the full range of GI symptoms in high-risk populations may enable earlier interventions and improve treatment outcomes. Symptom co-occurrence also presents opportunities for more cost-effective interventions. For example, by targeting the underlying mechanism for a specific cluster, clinicians may be able to manage multiple symptoms collectively. 12 , 18 , 53 – 55 Understanding the cascade of symptoms within a cluster and targeting the primary one may also help prevent the development of secondary symptoms. 12 , 17 , 18 , 53 , 56 Finally, the distinct associations of neurological and GI symptoms with healthcare utilization suggested that they may require different levels of care. Chronic neurological symptoms, which may require ongoing care, may be more appropriate for urgent care triage, while acute GI symptoms may necessitate ED evaluation and timely management. Strengths Our study utilized a real-world cohort within an integrated health system that has a standardized, well-established PROMs program. We examined whether short-term changes of neurological and GI clusters were associated with long-term healthcare utilization and death, with a rigorous study design to minimize attrition bias and immortal time bias inherent in observational EHR data. We also explored whether these associations were consistent across various prognostic subgroups. These methodological approaches strengthen the internal validity of our findings and support the generation of high-quality evidence with meaningful clinical relevance for routine cancer care. Limitations Although the PRO-CTCAE captured the 12 most common CTX-related symptoms, other symptoms, such as dizziness, heartburn, and bloating, were not included. Additionally, a small number of patients may have received urgent or emergency care outside the MGB system, which could not be captured in this study and may have led to an underestimation of healthcare utilization. What is more, the low incidence of urgent care visits and the small sample sizes of patients with pancreatic cancer or comorbidities may have limited our ability to detect statistical significance. Finally, given that our study was conducted in the Boston metropolitan area, caution is needed when generalizing our findings to other regions of the country. Conclusions Neurological and GI clusters were common among patients with GI cancers receiving CTX. Their progression within the first 90 days from CTX initiation exhibited differential associations with one-year healthcare utilization and death. Statement and Declarations Competing interests No other conflicts of interest were reported. Consent for publication This is a secondary data analysis based on de-identified electronic medical records. Therefore, no patient consent is needed. Data availability statement Individual patient data will not be shared. Ethical approval statement and consent to participate This study was approved by the Dana-Farber/Harvard Cancer Center (DF/HCC) Institutional Review Board (IRB protocol number: 25-048). This study involves secondary data analysis and does not require patient consent. Funding No funding resource related to this study. Supplemental Materials View this table: View inline View popup Download powerpoint Table S1. Cancer types and ICD-10 codes View this table: View inline View popup Download powerpoint Table S2. Symptom prevalence of patients with gastrointestinal cancers receiving chemotherapy, 2019-2024 View this table: View inline View popup Table S3. Co-occurring symptoms in patients with GI cancers across the four time points of chemotherapy View this table: View inline View popup Download powerpoint Table S4. Prevalent combination of neurological and gastrointestinal symptom clusters over time View this table: View inline View popup Download powerpoint Table S5. Incidences of one-year urgent care visits, ED visits, death, and admission for the overall population and stratified by age groups, degrees of comorbidity, and cancer sites (N=973) View this table: View inline View popup Download powerpoint Table S6. Time to first event of one-year urgent care visits, ED visits, and death across burdens of neurological and GI symptom clusters at CTX initiation Download figure Open in new tab Figure S1. Co-occurring percentages among 12 symptoms in patients with gastrointestinal cancers at days 30, 60 and 90 of chemotherapy initiation (N = 973) Acknowledgments The authors thank the clinicians and program staff for their support on the successful implementation of patient-reported outcome measure collection at the gastrointestinal cancer clinics. We appreciate Mariem Ahmed for helping with manuscript preparation. Footnotes We added an academic degree to a coauthor. References 1. ↵ U.S. Cancer Statistics Working Group . 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