Opioid use during definitive chemoradiotherapy for esophageal cancer: A retrospective analysis

Opioid use during definitive chemoradiotherapy for esophageal cancer: A retrospective analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Opioid use during definitive chemoradiotherapy for esophageal cancer: A retrospective analysis kei takenaka, Yoshimi Fujishima, Katsumaro Kubo, Hiroki Kawaguchi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8165485/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Definitive chemoradiotherapy represents an alternative treatment option for esophageal cancer patients who are not considered candidates for resection or refuse surgery. Swallowing pain associated with chemoradiotherapy is a serious adverse event that disrupts patient quality of life; however, there are no comprehensive reports describing opioid management during chemoradiotherapy for esophageal cancer. We conducted a study to determine the proportion of patients who required opioids, the timing of opioid initiation, the amount and type of opioids used, and other factors for patients requiring opioids. Methods Data for esophageal cancer patients who had undergone definitive chemoradiotherapy from April 2013 to March 2023 were retrospectively examined using their medical records. Results A total of 141 patients (105 men and 36 women, mean age: 69.6 years old) were included in the analysis, of whom 68 (48.2%) required opioids during chemoradiotherapy, with a median maximum use of 41.25 mg/day and a median cumulative use of 420 mg oral morphine equivalent. Oral or transdermal opioids were administered in most cases, with the proportion of transdermal fentanyl increasing as pain increased. There was a bimodal distribution of opioid initiation with a peak on days 15 and 37 following the start of chemoradiotherapy, and a median on day 22.5. Significant factors associated with opioid use were younger age and concomitant esophageal mucositis, which required intravenous antibiotics. Conclusion Approximately half of the esophageal cancer patients who underwent definitive chemoradiotherapy required opioid pain control. Careful pain management is necessary for each patient. esophageal cancer definitive chemoradiotherapy opioid swallowing pain Figures Figure 1 Figure 2 Figure 3 Introduction For localized, resectable esophageal cancer patients, surgery represents the standard treatment; however, for those who are not considered candidates for resection or refuse surgery, definitive chemoradiotherapy (dCRT) is an alternative treatment option [1-5]. Following endoscopic resection for early esophageal cancer, dCRT may be performed if the margins are positive or undetermined or if residual tumor is present [6]. The most common acute adverse events of chemoradiotherapy include hematologic toxicity, esophagitis, and fatigue [7]; however, swallowing pain associated with chemoradiotherapy appears to be a serious adverse event that affects patient quality of life [8]. For chemoradiotherapy of esophageal cancer, it is important to predict when swallowing pain will occur and to provide adequate pain relief with opioids and other analgesics to complete treatment while maintaining quality of life and motivation for treatment. Although there are some reports on the use of opioids for chemoradiotherapy-induced pain in head and neck cancer [9, 10], to our knowledge, there are no reports on the timing or related factors of opioid use in esophageal cancer patients. Therefore, we determined the proportion of patients who required opioids among those who received dCRT for esophageal cancer at our hospital, the timing of opioid use, the amount and type of opioids used, and factors associated with patients who required opioids. Materials and Methods Patients Clinical data for esophageal cancer patients who had undergone dCRT from April 2013 to March 2023 were retrospectively extracted from their medical records. Inclusion criteria for dCRT were: esophageal primary tumor irradiated with a dose of 50 Gy or more in combination with chemotherapy. Exclusion criteria included: patients with recurrence, those in a palliative setting, treated with proton therapy, or treated with dCRT, but stopped before 50 Gy was reached because of adverse events. Data collection The duration of chemoradiotherapy was defined as the period from the beginning to the end of radiotherapy. The opioids included morphine, tramadol, hydromorphine, oxycodone, and fentanyl. Opioid use was determined as oral morphine equivalents for the maximum and cumulative doses during the chemoradiotherapy period. The analgesic potency ratio of oral morphine to oral tramadol, suppository morphine, oral hydromorphine, injection hydromorphine, oral oxycodone, injection oxycodone, sublingual fentanyl, and transdermal fentanyl was 0.2: 1.5: 5.0: 25: 1.5: 2.0: 30: 30, respectively. The background of the patients included age, gender, histopathology, clinical stage, site of primary tumor occupancy, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG)-performance status (PS), history of alcohol consumption, history of psychiatric disorders, and history of taking anxiolytic, antipsychotic, or sleeping pills (antipsychotic medication). Treatment-related factors included concomitant chemotherapy, radiation dose, whether prophylactic radiation was used, or whether intensity-modulated radiation therapy (IMRT) was used. Treatment-related adverse events included esophageal mucositis, which required intravenous antibiotics during chemoradiotherapy. Statistical analysis To compare the patient’s background, a t-test was used to compare continuous variables, and a chi-square test or Fisher’s exact test was used to compare categorical variables, with p < 0.05 considered statistically significant. Multivariate logistic regression analysis was performed for a related factor that showed a statistical trend (p < 0.25) for each univariate analysis. P value, odds ratio (OR), and 95% confidence interval (CI) of each factor are shown. All statistical analyses were performed using Microsoft Excel and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Results Patient background and clinical data Of the 331 esophageal cancer patients referred to the Department of Medical Oncology between April 2013 and March 2023, 223 were eligible for chemoradiotherapy. Of these, 144 were scheduled for dCRT, excluding 63 patients who received palliative chemoradiotherapy, 5 who received <50 Gy of the planned radiation dose, and 11 who received combined proton beam therapy. Of the 144 patients, 3 were discontinued before reaching a radiation dose of <50 Gy because of adverse events. Therefore, 141 patients were included in the analysis (Figure 1) . The mean age of the analyzed patients was 69.6 years (SD 8.9), with 105 (74.5%) males, 125 had squamous cell carcinoma, 3 had other types, and 13 had unknown histopathologic types. The clinical stage was I, II, III, and IV in 33, 22, 42, and 44 patients, respectively. The primary tumor location was cervical (n = 18), upper thoracic (n = 31), middle thoracic (n = 79), and lower thoracic and abdominal (n = 42), with the highest proportion of patients in the middle thoracic region (including duplicates). Forty-one (29.1%) patients were PS-0, and 99 patients were PS-1 or greater. The mean BMI was 20.8 kg/m 2 (SD 3.02), indicating a lean body type. Regarding alcohol consumption, 93 patients were current drinkers, 32 patients were ever drinkers, and 12 patients were never drinkers. Six patients had a history of psychiatric disorders (2 with dementia, 1 with depression, 1 with insomnia, 1 with alcohol dependence, and 1 with impaired decision-making), whereas 37 (26.2%) had taken antipsychotic, anxiolytic, or sleeping medications (Table 1) . Treatment delivery Of the 141 patients who received dCRT, 137 (97.2%) completed the planned radiotherapy. The majority of patients received 60 Gy (118/141 patients, 83.7%), and prophylactic irradiation was administered in many cases (124/140 patients). In addition, 73 patients were irradiated with IMRT ( Table 2 ). Chemotherapy included FP (700/70) [5-fluorouracil (5-FU) 700 mg/m 2 /day, days 1–4, days 29–32, cisplatin 70 mg/m 2 /day, days 1 and 29] for 100 patients, FP (1000/75) (5-FU 1,000 mg/m 2 /day, days 1–4, days 29–32, cisplatin 75 mg/m 2 /day days 1 and 29) for 6 patients, FOLFOX (5-FU bolus 400 mg/m 2 day 1, 5-FU 1,600 mg/m 2 /46 h continuous infusion, oxaliplatin 85 mg/m 2 /day, day 1, q2 weeks 3 courses) for 31 patients, 5-FU alone (5- FU 700 mg/m 2 /day, days 1–4, days 29–32) for 3 patients and TC (carboplatin and paclitaxel) for 1 patient. Adverse events during chemoradiotherapy included esophageal mucositis, which required intravenous antibiotics in 26 patients (18.4%) ( Table 2 ). For FP (700/70), 69 of 100 patients (69%) completed treatment without a dose reduction, 29 patients (29%) had a dose reduction, and 2 patients (2%) discontinued treatment during the course. In addition, 18 patients (18%) delayed the start of the second course for > 3 days beyond the scheduled date. The mean relative dose intensities (mRDI) for each drug were 94.6% (SD 10.5%) for 5-FU and 92.2% (SD 12.6%) for cisplatin. For FP (1000/75), 4 of 6 patients (66.7%) completed the study without dose reduction, 2 patients (33.3%) required dose reduction, and no patients discontinued treatment during the study. The mRDI for each drug was 95.0% (SD 12.3 %) for 5-FU and 96.7% (SD 5.16 %) for cisplatin. One patient (16.7%) began the second course > 3 days later than the scheduled date. FOLFOX was completed in 9 of 31 patients (29%) without dose reduction, 12 (38.7%) with dose reduction, and 10 (32.3%) discontinued treatment. The mRDI was 55.8% (SD 34.0%) for bolus 5-FU, 75.6% (SD 17.9%) for continuous infusion 5-FU, and 75.6% (SD 17.6%) for oxaliplatin. The start of the second course was delayed for > 2 days, and the beginning of the third course was delayed for > 2 days in 14 (45.2%) and 6 (28.6%) patients, respectively. The mRDI for 5-FU alone was 100% (SD 0.00%) (Table 3) . The percentage of patients who required opioids Of the 141 patients who received dCRT, a total of 68 patients (48.2%) required opioids during the chemoradiotherapy treatment period (Figure 1) . Timing of opioid initiation A bimodal distribution of opioid initiation was observed, with a peak on day 15 (6 patients) and day 37 (7 patients) following the start of chemoradiotherapy, and a median on day 22.5 (Figure 2) . Six patients were administered opioids at or shortly after the beginning of chemoradiotherapy (day 1–3). The reason was cancer pain in 4 patients, pain from scoliosis in 1 patient, and pain of unknown origin in 1 patient. For the 62 cases where opioids were initiated during the chemoradiotherapy, the reason for initiation were swallowing pain in 21 cases, sore throat in 14 cases, esophageal pain in 8 cases, pain in 4 cases, stomach pain in 1 case, esophagitis in 11 cases, and mucositis in 3 cases. Opioid use Opioid use was evaluated in 61 of 68 patients who required them, whereas 7 patients were excluded whose opioid use could not be accurately assessed because 5 were outpatients and 2 patients were discharged during the chemoradiotherapy period (Figure 1) . Maximum opioid use showed a median of 41.25 mg/day (range: 0.5 mg–170 mg/day) of oral morphine equivalent. The median cumulative opioid use was 420 mg (range: 0.5–4,110.25 mg) of oral morphine equivalent (Table 4) . The percentage of patients not using opioids 2 weeks after completing chemoradiotherapy was 11 (17.2%) out of 64 patients who were followed (Table 4) . Types of opioids used A total of 78 opioids (including concomitant use) were used in 68 patients at the time of their administration. Oral oxycodone was the most common opioid type prescribed in 28 patients representing 35.9% of total prescriptions, followed by transdermal fentanyl in 23 (29.5%), oral tramar in 12 (15.4%), oral morphine in 8 (10.3%), sublingual fentanyl in 5 (6.4%), oral hydromorphine in 1 (1.3%), and injectable oxycodone in 1 patient (1.3%) (Figure 3 a) . During the chemoradiotherapy period, 99 opioids (including concomitant use) were administered at the peak of opioid use in 61 patients who were followed. Transdermal fentanyl was the most common in 39 patients, representing 39.4% of total prescriptions, followed by oral oxycodone in 32 (32.3%), oral morphine in 10 (10.1%), oral tramar in 7 (7.1%), sublingual fentanyl in 6 (6.1%), oral hydromorphine in 2 (2.0%), injectable oxycodone in 1 (1.0%) , injectable hydromorphine in 1 (1.0%), and suppository morphine in 1 (1.0%) (Figure 3 b) . Opioids were administered as a single agent in 85.3% (58/68) of the patients, whereas 59% (36/61) of the patients were prescribed multiple opioids in combination at the peak of opioid use (Table 5) . Injectable opioids were administered to two patients throughout the chemoradiotherapy period. Background and treatment-related factors for patients requiring opioids In a univariable analysis comparing the opioid and nonopioid use groups, age was a significant predictive factor for opioid use (p = 0.000167). An ECOG-PS of 1 or higher and psychiatric disorders showed a trend as a predictive factor for opioid use (p = 0.1472 and p = 0.07766, respectively). Conversely, gender, histology, clinical stage (I/II vs. III/IV), tumor location (cervical, upper vs. middle, lower/abdominal), BMI, history of alcohol consumption, and antipsychotic medication were not significant factors (Table 1) . Univariate analysis was also conducted for treatment-related factors. Esophageal mucositis requiring intravenous antibiotics during the chemoradiotherapy period was a significant factor for opioid use (p = 0.00112). In contrast, concomitant chemotherapy (e.g., FP vs. FOLFOX, 5-FU alone, TC), radiation dose ≥ 60 Gy, prophylactic irradiation, and IMRT were not associated factors (Table 2) . Multivariate logistics regression analysis was conducted. Compared with patients aged 69 years or younger, those aged 70 years or older had a significant OR for opioid use of 0.362 (95% CI 0.17–0.77; p = 0.00835). Using a cutoff age of 70, which was close to the mean age of the total population (69.6 years old), patients < 70 years old were considered a significant predictor of opioid use. Esophageal mucositis requiring intravenous antibiotics also had a significant OR of 4.24 (95% CI 1.470–12.2; p = 0.00736). Esophageal mucositis requiring intravenous antibiotics was also a significant treatment-related factor for opioid use. No other significant factors were identified in the multivariate analysis (Table 6) . Discussion In this study, we examined the use of opioids for pain control during dCRT for esophageal cancer. Approximately half (48.2%) of the patients required opioids during dCRT, with a median maximum opioid use of 41.25 mg/day (range: 0.5 mg–170 mg/day) of oral morphine equivalent and a median cumulative use of 420 mg (range: 0.5–4,110.25 mg) of oral morphine equivalent. Oral or transdermal opioids were administered in most cases, with the proportion of transdermal opioids increasing concomitantly as pain increased. There was a bimodal distribution of opioid initiation with peaks on days 15 and 37 following the initiation of chemoradiotherapy, with a median on day 22.5. Significant factors associated with opioid use included younger age and concomitant esophageal mucositis, which required intravenous antibiotics. Previous studies have indicated that the percentage of patients requiring opioids for pain control was 73.3% and 83% and the maximum morphine-equivalent doses of opioids were 51 mg and 35 mg, respectively, for chemoradiotherapy of head and neck cancer [ 9 , 10 ]; however, opioid use tended to be slightly less frequent in esophageal cancer, likely because in chemoradiotherapy the latter, pain primarily stems from oral mucositis, causing significant discomfort in many patients [ 11 ]. Nevertheless, considering that maximal opioid use is not significantly different between esophageal and head and neck cancer, adequate opioid-based pain management is necessary during chemoradiotherapy for esophageal cancer. A phase II study evaluating the efficacy and safety of transdermal fentanyl in esophageal cancer patients with mucositis and a numeric rating scale of 4 or higher or grade 2 or higher undergoing chemoradiotherapy revealed good analgesia within 6–9 days of fentanyl use [ 12 ]. In the present study, oral opioid administration was most commonly used at initiation; however, the proportion of transdermal fentanyl increased as pain worsened. Pain caused by esophageal mucositis is primarily exacerbated by eating and drinking. Therefore, for cases in which pain became chronic or oral administration was difficult, transdermal fentanyl was considered a better option from the initiation of chemoradiotherapy. The timing of opioid initiation was bimodal between the middle and end of the chemoradiotherapy period, indicating the onset and peak of esophageal mucositis associated with chemoradiotherapy. With respect to background factors that require opioid use, opioid withdrawal has been reported in head and neck cancers. Kwon et al. reported a higher rate of alcohol dependence among patients with head and neck cancer who were unable to withdraw from opioids following chemoradiation therapy [ 13 ]. Zayed et al. reported oral cancer as the primary tumor, history of psychiatric illness, alcohol dependence or history of alcohol dependence, and opioid use before radiation therapy as risk factors for patients who required chronic opioid use for pain control following radiation therapy or chemoradiation for head and neck cancer [ 14 ]. Tuno et al. found the concomitant use of cetuximab as a risk factor for the long-term use of strong opioids in chemoradiotherapy for head and neck cancer [ 15 ]. In the present study, a history of psychiatric illness was not statistically significant with respect to opioid use; however, it tended to be higher in the group that required opioids in an univariable analysis. In esophageal cancer, patients with psychiatric illness are expected to have difficulty with opioid withdrawal, similar to those with head and neck cancer. Therefore, it may be necessary to use caution when administering opioids to patients with psychiatric illness, including the careful consideration of dosage. In the present study, the opioid use group was significantly younger compared with the nonopioid use group. The reason for this is unclear; however, there may have been bias, in which opioids were not actively prescribed to elderly patients because of potential side effects, such as drowsiness and constipation. Comorbid esophageal mucositis was clearly associated with the exacerbation of pain. A significantly higher percentage of patients in the present study who required opioids had comorbid esophageal mucositis that required intravenous antibiotics. Healthcare providers should consider the possibility of increased pain during the second to third weeks of chemotherapy when mucositis is expected to occur. There were several imitations to this study as follows: 1) this study was a retrospective analysis of clinical practice, and some of the items had missing values; 2) as the study focused on acute pain management during chemoradiotherapy, there was little information on opioid use after completing chemoradiotherapy. However, most patients were managed in an inpatient setting, and the amount and type of opioids used could be accurately determined while pain was controlled. Conclusion This is the first large study on opioid management during chemoradiotherapy for esophageal cancer. Half of the esophageal cancer patients who underwent dCRT required opioid pain control. Careful pain management is needed for these patients. Declarations Acknowledgements We would like to thank the patients and their families. We would also thank all staff in Kobe Minimally invasive Cancer Center. The part of this study was presented at the 2024 the Japanese Society of Medical Oncology Annal Meeting (Nagoya). Data availability statement The data collected during this study are not publicly available due to privacy and ethical restrictions, but de-identified data may be available from the corresponding author with approval of the institutional review board. Author contributions Study design: K.T., Y.F. Data Collection: K.T., Y.F., K.K., H.K., A.H., H.M. Data analysis: K.T., Y.F., K.K., H.K. Manuscript preparation: K.T. Manuscript review and revisions: all authors. Final approval of manuscript: all authors. Funding Sources There was no funding source for this report. Ethical declarations Conflict of interest The authors declare that they have no conflict of interest. Ethical approval This study was approved by the Institutional Review Board (approval No. 2023-09-04). References Kato K, Muro K, Minashi K et al (2011) Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for stage II–III esophageal squamous cell carcinoma: JCOG trial (JCOG9906). Int J Radiat Oncol Biol Phys 81(3):684–690. 10.1016/j.ijrobp.2010.06.033 Herskovic A, Martz K, al-Sarraf M et al (1992) Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326(24):1593–1598. 10.1056/NEJM199206113262403 Kato H, Sato A, Fukuda H et al (2009) A phase II trial of chemoradiotherapy for stage I esophageal squamous cell carcinoma: Japan Clinical Oncology Group Study (JCOG9708). Jpn J Clin Oncol 39(10):638–643. 10.1093/jjco/hyp069 Kato K, Ito Y, Nozaki I et al (2021) Parallel-group controlled trial of surgery versus chemoradiotherapy in patients with stage I esophageal squamous cell carcinoma. Gastroenterology 161:1878–1886. 10.1053/j.gastro.2021.08.007 Conroy T, Galais MP, Raoul JL et al (2014) Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 15(3):305–314. 10.1016/S1470-2045(14)70028-2 Nihei K, Minashi K, Yano T et al (2023) Final analysis of diagnostic endoscopic resection followed by selective chemoradiotherapy for stage I esophageal cancer: JCOG0508. Gastroenterology 164(2):296–299. 10.1053/j.gastro.2022.10.002 Mohammad NH, Hulshof MC, Bergman JJ et al (2014) Acute toxicity of definitive chemoradiation in patients with inoperable or unresectable esophageal carcinoma. BMC Cancer 14:56. 10.1186/1471-2407-14-56 Taniyama N, Nakajima Y, Ishikawa H et al (2010) Nursing care for radiation-induced esophagitis in patients with primary esophageal cancer and lung cancer treated with radiation therapy. Kitakanto Med J 60:105–110 Kawabata S, Nakamura Y, Matsushita N et al (2017) Using opioids to control pain due to mucosal damage after radiotherapy to treat head and neck cancer. Jpn J Pharm Palliat Care Sci 10:13–18 Zenda S, Matsuura K, Tachibana H et al (2011) Multicenter phase II study of an opioid-based pain control program for head and neck cancer patients receiving chemoradiotherapy. Radiother Oncol 101:410–414. 10.1016/j.radonc.2011.09.016 Sonis ST, Elting LS, Keefe D et al (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100(9 Suppl):1995–2025. 10.1002/cncr.20162 Xing SZ, Zhang Y (2015) Efficacy and safety of transdermal fentanyl for treatment of oral mucositis pain caused by chemoradiotherapy in patients with esophageal squamous cell carcinoma. Support Care Cancer 23:753–759. 10.1007/s00520-014-2419-5 Kwon JH, Hui D, Chisholm G et al (2013) Predictors of long-term opioid treatment among patients who receive chemoradiation for head and neck cancer. Oncologist 18(6):768–774. 10.1634/theoncologist.2013-0001 Zayed S, Lin C, Boldt RG et al (2021) Risk of chronic opioid use after radiation for head and neck cancer: a systematic review and meta-analysis. Adv Radiat Oncol 6:100583. 10.1016/j.adro.2020.09.023 Tuno T, Tokumaru J, Kojima M et al (2018) Survey of the period of tapering of a strong opioid analgesic for oral mucositis resulting from concomitant chemoradiotherapy for head and neck cancer after the end of treatment. Palliat Care Res 13(4):305–311. https://doi.org/10.2512/jspm.13.305 Tables Tables 1 to 6 are available in the Supplementary Files section. Supplementary Files IJCOTabletakenaka.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8165485","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":554904045,"identity":"4c88a953-bbb4-46fa-9e34-0a62ddc91441","order_by":0,"name":"kei takenaka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYFACNhCRwMDPQ6wGHpgWyR4UM4jRYnCGWC327McSHxfUpMkbnznAuuFHDUMev3wDAVt40g4bzziWY7jtbAPbzZ5jDMWSbQQdlt4mzcNWwbjtPP+324wNDIkbjhHSwv+8/TfPvwr7zf0MbGAt+wlqkUg7xszblpO4gbcBomUDwRC78SxZmrcvLXnGmQMgv0gkzjiWgF8Le3+a4Weeb8m2/T0JbDd+1Ngk9jcfIGANGpAgTfkoGAWjYBSMAuwAAH6XP2+dryn/AAAAAElFTkSuQmCC","orcid":"","institution":"Kobe Minimally invasive Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"kei","middleName":"","lastName":"takenaka","suffix":""},{"id":554904046,"identity":"cec81df2-54c4-4a1f-9a3d-5669fc870ab1","order_by":1,"name":"Yoshimi Fujishima","email":"","orcid":"","institution":"Kobe Minimally invasive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Yoshimi","middleName":"","lastName":"Fujishima","suffix":""},{"id":554904047,"identity":"89375846-a162-41fb-bb74-3d36a9131bb5","order_by":2,"name":"Katsumaro Kubo","email":"","orcid":"","institution":"Kobe Minimally invasive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Katsumaro","middleName":"","lastName":"Kubo","suffix":""},{"id":554904048,"identity":"ee9f3506-b1bb-46e5-a582-51d26296b767","order_by":3,"name":"Hiroki Kawaguchi","email":"","orcid":"","institution":"Kobe Minimally invasive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroki","middleName":"","lastName":"Kawaguchi","suffix":""},{"id":554904049,"identity":"53f1115e-496e-436c-8058-d1e658956043","order_by":4,"name":"Aya Harada","email":"","orcid":"","institution":"Kobe Minimally invasive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Aya","middleName":"","lastName":"Harada","suffix":""},{"id":554904050,"identity":"858d88f6-415a-4426-8b38-a42ffcc3522c","order_by":5,"name":"Hiroshi Mayahara","email":"","orcid":"","institution":"Kobe Minimally invasive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Mayahara","suffix":""}],"badges":[],"createdAt":"2025-11-20 14:10:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8165485/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8165485/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97893902,"identity":"1ef38539-573f-406d-aab8-66eb15d6339d","added_by":"auto","created_at":"2025-12-10 15:31:26","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":202832,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOFigtakenaka.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/c982efbec90a48b5c245def6.pdf"},{"id":97689753,"identity":"3f92b4a5-4d04-4ed4-a3e5-a1be871109e5","added_by":"auto","created_at":"2025-12-08 10:49:11","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7919,"visible":true,"origin":"","legend":"","description":"","filename":"ijcoIJCOD2501430.xml","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/d712f43f8e98d343b91990ce.xml"},{"id":97689750,"identity":"20f9bab8-1bb1-4eae-9c2a-1c6dae9115b2","added_by":"auto","created_at":"2025-12-08 10:49:11","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1023,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOD250143014998.go.xml","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/57b6fc3a050acd2da6bcbeb3.xml"},{"id":97689752,"identity":"81db5255-7f49-4182-9f23-c69456abb3f8","added_by":"auto","created_at":"2025-12-08 10:49:11","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":834,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOD2501430Import.xml","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/3e726223ade24feaa9f21e74.xml"},{"id":97689754,"identity":"878eb86b-8370-4e96-b011-47460aba874d","added_by":"auto","created_at":"2025-12-08 10:49:11","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54543,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOD25014300enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/d7dd8ca9a902be98ef2ddadb.xml"},{"id":97689758,"identity":"045f6b93-f24e-4bf7-aaf8-f4f3daa6acec","added_by":"auto","created_at":"2025-12-08 10:49:11","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":202832,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOFigtakenaka.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/be2bcf1c5c3f1a9dc713a6e1.pdf"},{"id":97892885,"identity":"9ce22509-5453-4255-bfd7-932ed52408ee","added_by":"auto","created_at":"2025-12-10 15:23:53","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":52110,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOD25014300structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/6c9e20c64fb8dd3e6543bcf4.xml"},{"id":97689757,"identity":"c981de89-4a26-4134-876a-e6e16b4e35f9","added_by":"auto","created_at":"2025-12-08 10:49:11","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60912,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/d85bd2105704a4322cb456b5.html"},{"id":97689746,"identity":"ebb9321a-d23d-44d7-99ec-0b908d5745bf","added_by":"auto","created_at":"2025-12-08 10:49:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":87039,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of patient selection\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/bcc262e8b28943ff0f0f3ded.png"},{"id":97894086,"identity":"4a5c9d71-5007-490a-98d9-d6b9745c5943","added_by":"auto","created_at":"2025-12-10 15:31:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":19910,"visible":true,"origin":"","legend":"\u003cp\u003eTiming of opioid initiation\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/1e2f5c478a78f3832dcfb9a7.png"},{"id":97892641,"identity":"c9554223-de1d-45ae-9277-ff6f908a3c46","added_by":"auto","created_at":"2025-12-10 15:16:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":89245,"visible":true,"origin":"","legend":"\u003cp\u003eThe number and proportion of opioids at initiation use (a) and maximum use (b) during chemoradiotherapy\u003c/p\u003e\n\u003cp\u003eThe percentage of each opioid on pie chart represents of its proportion of the total opioid number\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/a29e97f802035b9e1787be91.png"},{"id":100951915,"identity":"09660121-8596-4b44-a262-34fdde002d3e","added_by":"auto","created_at":"2026-01-23 07:11:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":702450,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/f661dcd9-37a0-4634-a1c3-37f38fa9da90.pdf"},{"id":97689748,"identity":"bb24409a-0587-4514-b307-193399ee7d85","added_by":"auto","created_at":"2025-12-08 10:49:11","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":94460,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOTabletakenaka.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8165485/v1/775e87bea704b6a86f730e1b.pdf"}],"financialInterests":"","formattedTitle":"Opioid use during definitive chemoradiotherapy for esophageal cancer: A retrospective analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFor localized, resectable esophageal cancer patients, surgery represents the standard treatment; however, for those who are not considered candidates for resection or refuse surgery, definitive chemoradiotherapy (dCRT) is an alternative treatment option [1-5]. Following endoscopic resection for early esophageal cancer, dCRT may be performed if the margins are positive or undetermined or if residual tumor is present [6]. The most common acute adverse events of chemoradiotherapy include hematologic toxicity, esophagitis, and fatigue [7]; however, swallowing pain associated with chemoradiotherapy appears to be a serious adverse event that affects patient quality of life [8]. For chemoradiotherapy of esophageal cancer, it is important to predict when swallowing pain will occur and to provide adequate pain relief with opioids and other analgesics to complete treatment while maintaining quality of life and motivation for treatment. Although there are some reports on the use of opioids for chemoradiotherapy-induced pain in head and neck cancer [9, 10], to our knowledge, there are no reports on the timing or related factors of opioid use in esophageal cancer patients. Therefore, we determined the proportion of patients who required opioids among those who received dCRT for esophageal cancer at our hospital, the timing of opioid use, the amount and type of opioids used, and factors associated with patients who required opioids.\u003c/p\u003e\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eClinical data for esophageal cancer patients who had undergone dCRT from April 2013 to March 2023 were retrospectively extracted from their medical records. Inclusion criteria for dCRT were: esophageal primary tumor irradiated with a dose of 50 Gy or more in combination with chemotherapy. Exclusion criteria included: patients with recurrence, those in a palliative setting, treated with proton therapy, or treated with dCRT, but stopped before 50 Gy was reached because of adverse events.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData collection\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe duration of chemoradiotherapy was defined as the period from the beginning to the end of radiotherapy. The opioids included morphine, tramadol, hydromorphine, oxycodone, and fentanyl. Opioid use was determined as oral morphine equivalents for the maximum and cumulative doses during the chemoradiotherapy period. The analgesic potency ratio of oral morphine to oral tramadol, suppository morphine, oral hydromorphine, injection hydromorphine, oral oxycodone, injection oxycodone, sublingual fentanyl, and transdermal fentanyl was 0.2: 1.5: 5.0: 25: 1.5: 2.0: 30: 30, respectively.\u003c/p\u003e\u003cp\u003eThe background of the patients included age, gender, histopathology, clinical stage, site of primary tumor occupancy, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG)-performance status (PS), history of alcohol consumption, history of psychiatric disorders, and history of taking anxiolytic, antipsychotic, or sleeping pills (antipsychotic medication). Treatment-related factors included concomitant chemotherapy, radiation dose, whether prophylactic radiation was used, or whether intensity-modulated radiation therapy (IMRT) was used. Treatment-related adverse events included esophageal mucositis, which required intravenous antibiotics during chemoradiotherapy.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTo compare the patient’s background, a t-test was used to compare continuous variables, and a chi-square test or Fisher’s exact test was used to compare categorical variables, with p \u0026lt; 0.05 considered statistically significant. Multivariate logistic regression analysis was performed for a related factor that showed a statistical trend (p \u0026lt; 0.25) for each univariate analysis. P value, odds ratio (OR), and 95% confidence interval (CI) of each factor are shown. All statistical analyses were performed using Microsoft Excel and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient background and clinical data\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eOf the 331 esophageal cancer patients referred to the Department of Medical Oncology between April 2013 and March 2023, 223 were eligible for chemoradiotherapy. Of these, 144 were scheduled for dCRT, excluding 63 patients who received palliative chemoradiotherapy, 5 who received \u0026lt;50 Gy of the planned radiation dose, and 11 who received combined proton beam therapy. Of the 144 patients, 3 were discontinued before reaching a radiation dose of \u0026lt;50 Gy because of adverse events. Therefore, 141 patients were included in the analysis \u003cstrong\u003e(Figure 1)\u003c/strong\u003e.\u003c/p\u003e\u003cp\u003eThe mean age of the analyzed patients was 69.6 years (SD 8.9), with 105 (74.5%) males, 125 had squamous cell carcinoma, 3 had other types, and 13 had unknown histopathologic types. The clinical stage was I, II, III, and IV in 33, 22, 42, and 44 patients, respectively. The primary tumor location was cervical (n = 18), upper thoracic (n = 31), middle thoracic (n = 79), and lower thoracic and abdominal (n = 42), with the highest proportion of patients in the middle thoracic region (including duplicates). Forty-one (29.1%) patients were PS-0, and 99 patients were PS-1 or greater. The mean BMI was 20.8 kg/m\u003csup\u003e2\u003c/sup\u003e (SD 3.02), indicating a lean body type. Regarding alcohol consumption, 93 patients were current drinkers, 32 patients were ever drinkers, and 12 patients were never drinkers. Six patients had a history of psychiatric disorders (2 with dementia, 1 with depression, 1 with insomnia, 1 with alcohol dependence, and 1 with impaired decision-making), whereas 37 (26.2%) had taken antipsychotic, anxiolytic, or sleeping medications \u003cstrong\u003e(Table 1)\u003c/strong\u003e.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTreatment delivery\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eOf the 141 patients who received dCRT, 137 (97.2%) completed the planned radiotherapy. The majority of patients received 60 Gy (118/141 patients, 83.7%), and prophylactic irradiation was administered in many cases (124/140 patients). In addition, 73 patients were irradiated with IMRT (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\u003cp\u003eChemotherapy included FP (700/70) [5-fluorouracil (5-FU) 700 mg/m\u003csup\u003e2\u003c/sup\u003e/day, days 1–4, days 29–32, cisplatin 70 mg/m\u003csup\u003e2\u003c/sup\u003e/day, days 1 and 29] for 100 patients, FP (1000/75) (5-FU 1,000 mg/m\u003csup\u003e2\u003c/sup\u003e/day, days 1–4, days 29–32, cisplatin 75 mg/m\u003csup\u003e2\u003c/sup\u003e/day days 1 and 29) for 6 patients, FOLFOX (5-FU bolus 400 mg/m\u003csup\u003e2\u003c/sup\u003e day 1, 5-FU 1,600 mg/m\u003csup\u003e2\u003c/sup\u003e/46 h continuous infusion, oxaliplatin 85 mg/m\u003csup\u003e2\u003c/sup\u003e/day, day 1, q2 weeks 3 courses) for 31 patients, 5-FU alone (5- FU 700 mg/m\u003csup\u003e2\u003c/sup\u003e/day, days 1–4, days 29–32) for 3 patients and TC (carboplatin and paclitaxel) for 1 patient. Adverse events during chemoradiotherapy included esophageal mucositis, which required intravenous antibiotics in 26 patients (18.4%) (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\u003cp\u003eFor FP (700/70), 69 of 100 patients (69%) completed treatment without a dose reduction, 29 patients (29%) had a dose reduction, and 2 patients (2%) discontinued treatment during the course. In addition, 18 patients (18%) delayed the start of the second course for \u003cu\u003e\u0026gt;\u003c/u\u003e3 days beyond the scheduled date. The mean relative dose intensities (mRDI) for each drug were 94.6% (SD 10.5%) for 5-FU and 92.2% (SD 12.6%) for cisplatin. For FP (1000/75), 4 of 6 patients (66.7%) completed the study without dose reduction, 2 patients (33.3%) required dose reduction, and no patients discontinued treatment during the study. The mRDI for each drug was 95.0% (SD 12.3 %) for 5-FU and 96.7% (SD 5.16 %) for cisplatin. One patient (16.7%) began the second course \u003cu\u003e\u0026gt;\u003c/u\u003e3 days later than the scheduled date. FOLFOX was completed in 9 of 31 patients (29%) without dose reduction, 12 (38.7%) with dose reduction, and 10 (32.3%) discontinued treatment. The mRDI was 55.8% (SD 34.0%) for bolus 5-FU, 75.6% (SD 17.9%) for continuous infusion 5-FU, and 75.6% (SD 17.6%) for oxaliplatin. The start of the second course was delayed for \u003cu\u003e\u0026gt;\u003c/u\u003e2 days, and the beginning of the third course was delayed for \u003cu\u003e\u0026gt;\u003c/u\u003e2 days in 14 (45.2%) and 6 (28.6%) patients, respectively. The mRDI for 5-FU alone was 100% (SD 0.00%) \u003cstrong\u003e(Table 3)\u003c/strong\u003e.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eThe percentage of patients who required opioids\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eOf the 141 patients who received dCRT, a total of 68 patients (48.2%) required opioids during the chemoradiotherapy treatment period \u003cstrong\u003e(Figure 1)\u003c/strong\u003e.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTiming of opioid initiation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA bimodal distribution of opioid initiation was observed, with a peak on day 15 (6 patients) and day 37 (7 patients) following the start of chemoradiotherapy, and a median on day 22.5 \u003cstrong\u003e(Figure 2)\u003c/strong\u003e. Six patients were administered opioids at or shortly after the beginning of chemoradiotherapy (day 1–3). The reason was cancer pain in 4 patients, pain from scoliosis in 1 patient, and pain of unknown origin in 1 patient. For the 62 cases where opioids were initiated during the chemoradiotherapy, the reason for initiation were swallowing pain in 21 cases, sore throat in 14 cases, esophageal pain in 8 cases, pain in 4 cases, stomach pain in 1 case, esophagitis in 11 cases, and mucositis in 3 cases.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOpioid use\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eOpioid use was evaluated in 61 of 68 patients who required them, whereas 7 patients were excluded whose opioid use could not be accurately assessed because 5 were outpatients and 2 patients were discharged during the chemoradiotherapy period \u003cstrong\u003e(Figure 1)\u003c/strong\u003e. Maximum opioid use showed a median of 41.25 mg/day (range: 0.5 mg–170 mg/day) of oral morphine equivalent. The median cumulative opioid use was 420 mg (range: 0.5–4,110.25 mg) of oral morphine equivalent \u003cstrong\u003e(Table 4)\u003c/strong\u003e. The percentage of patients not using opioids 2 weeks after completing chemoradiotherapy was 11 (17.2%) out of 64 patients who were followed \u003cstrong\u003e(Table 4)\u003c/strong\u003e.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTypes of opioids used\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA total of 78 opioids (including concomitant use) were used in 68 patients at the time of their administration. Oral oxycodone was the most common opioid type prescribed in 28 patients representing 35.9% of total prescriptions, followed by transdermal fentanyl in 23 (29.5%), oral tramar in 12 (15.4%), oral morphine in 8 (10.3%), sublingual fentanyl in 5 (6.4%), oral hydromorphine in 1 (1.3%), and injectable oxycodone in 1 patient (1.3%) \u003cstrong\u003e(Figure 3 a)\u003c/strong\u003e. During the chemoradiotherapy period, 99 opioids (including concomitant use) were administered at the peak of opioid use in 61 patients who were followed. Transdermal fentanyl was the most common in 39 patients, representing 39.4% of total prescriptions, followed by oral oxycodone in 32 (32.3%), oral morphine in 10 (10.1%), oral tramar in 7 (7.1%), sublingual fentanyl in 6 (6.1%), oral hydromorphine in 2 (2.0%), injectable oxycodone in 1 (1.0%) , injectable hydromorphine in 1 (1.0%), and suppository morphine in 1 (1.0%) \u003cstrong\u003e(Figure 3 b)\u003c/strong\u003e.\u003c/p\u003e\u003cp\u003eOpioids were administered as a single agent in 85.3% (58/68) of the patients, whereas 59% (36/61) of the patients were prescribed multiple opioids in combination at the peak of opioid use \u003cstrong\u003e(Table 5)\u003c/strong\u003e. Injectable opioids were administered to two patients throughout the chemoradiotherapy period.\u003c/p\u003e\n\u003ch3\u003eBackground and treatment-related factors for patients requiring opioids\u003c/h3\u003e\n\u003cp\u003eIn a univariable analysis comparing the opioid and nonopioid use groups, age was a significant predictive factor for opioid use (p\u0026thinsp;=\u0026thinsp;0.000167). An ECOG-PS of 1 or higher and psychiatric disorders showed a trend as a predictive factor for opioid use (p\u0026thinsp;=\u0026thinsp;0.1472 and p\u0026thinsp;=\u0026thinsp;0.07766, respectively). Conversely, gender, histology, clinical stage (I/II vs. III/IV), tumor location (cervical, upper vs. middle, lower/abdominal), BMI, history of alcohol consumption, and antipsychotic medication were not significant factors \u003cb\u003e(Table\u0026nbsp;1)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003eUnivariate analysis was also conducted for treatment-related factors. Esophageal mucositis requiring intravenous antibiotics during the chemoradiotherapy period was a significant factor for opioid use (p\u0026thinsp;=\u0026thinsp;0.00112). In contrast, concomitant chemotherapy (e.g., FP vs. FOLFOX, 5-FU alone, TC), radiation dose\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;60 Gy, prophylactic irradiation, and IMRT were not associated factors \u003cb\u003e(Table\u0026nbsp;2)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003eMultivariate logistics regression analysis was conducted. Compared with patients aged 69 years or younger, those aged 70 years or older had a significant OR for opioid use of 0.362 (95% CI 0.17\u0026ndash;0.77; p\u0026thinsp;=\u0026thinsp;0.00835). Using a cutoff age of 70, which was close to the mean age of the total population (69.6 years old), patients\u0026thinsp;\u0026lt;\u0026thinsp;70 years old were considered a significant predictor of opioid use. Esophageal mucositis requiring intravenous antibiotics also had a significant OR of 4.24 (95% CI 1.470\u0026ndash;12.2; p\u0026thinsp;=\u0026thinsp;0.00736). Esophageal mucositis requiring intravenous antibiotics was also a significant treatment-related factor for opioid use. No other significant factors were identified in the multivariate analysis \u003cb\u003e(Table\u0026nbsp;6)\u003c/b\u003e.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we examined the use of opioids for pain control during dCRT for esophageal cancer. Approximately half (48.2%) of the patients required opioids during dCRT, with a median maximum opioid use of 41.25 mg/day (range: 0.5 mg\u0026ndash;170 mg/day) of oral morphine equivalent and a median cumulative use of 420 mg (range: 0.5\u0026ndash;4,110.25 mg) of oral morphine equivalent. Oral or transdermal opioids were administered in most cases, with the proportion of transdermal opioids increasing concomitantly as pain increased. There was a bimodal distribution of opioid initiation with peaks on days 15 and 37 following the initiation of chemoradiotherapy, with a median on day 22.5. Significant factors associated with opioid use included younger age and concomitant esophageal mucositis, which required intravenous antibiotics.\u003c/p\u003e\u003cp\u003ePrevious studies have indicated that the percentage of patients requiring opioids for pain control was 73.3% and 83% and the maximum morphine-equivalent doses of opioids were 51 mg and 35 mg, respectively, for chemoradiotherapy of head and neck cancer [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]; however, opioid use tended to be slightly less frequent in esophageal cancer, likely because in chemoradiotherapy the latter, pain primarily stems from oral mucositis, causing significant discomfort in many patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Nevertheless, considering that maximal opioid use is not significantly different between esophageal and head and neck cancer, adequate opioid-based pain management is necessary during chemoradiotherapy for esophageal cancer.\u003c/p\u003e\u003cp\u003eA phase II study evaluating the efficacy and safety of transdermal fentanyl in esophageal cancer patients with mucositis and a numeric rating scale of 4 or higher or grade 2 or higher undergoing chemoradiotherapy revealed good analgesia within 6\u0026ndash;9 days of fentanyl use [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In the present study, oral opioid administration was most commonly used at initiation; however, the proportion of transdermal fentanyl increased as pain worsened. Pain caused by esophageal mucositis is primarily exacerbated by eating and drinking. Therefore, for cases in which pain became chronic or oral administration was difficult, transdermal fentanyl was considered a better option from the initiation of chemoradiotherapy. The timing of opioid initiation was bimodal between the middle and end of the chemoradiotherapy period, indicating the onset and peak of esophageal mucositis associated with chemoradiotherapy.\u003c/p\u003e\u003cp\u003eWith respect to background factors that require opioid use, opioid withdrawal has been reported in head and neck cancers. Kwon et al. reported a higher rate of alcohol dependence among patients with head and neck cancer who were unable to withdraw from opioids following chemoradiation therapy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Zayed et al. reported oral cancer as the primary tumor, history of psychiatric illness, alcohol dependence or history of alcohol dependence, and opioid use before radiation therapy as risk factors for patients who required chronic opioid use for pain control following radiation therapy or chemoradiation for head and neck cancer [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Tuno et al. found the concomitant use of cetuximab as a risk factor for the long-term use of strong opioids in chemoradiotherapy for head and neck cancer [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the present study, a history of psychiatric illness was not statistically significant with respect to opioid use; however, it tended to be higher in the group that required opioids in an univariable analysis. In esophageal cancer, patients with psychiatric illness are expected to have difficulty with opioid withdrawal, similar to those with head and neck cancer. Therefore, it may be necessary to use caution when administering opioids to patients with psychiatric illness, including the careful consideration of dosage.\u003c/p\u003e\u003cp\u003eIn the present study, the opioid use group was significantly younger compared with the nonopioid use group. The reason for this is unclear; however, there may have been bias, in which opioids were not actively prescribed to elderly patients because of potential side effects, such as drowsiness and constipation.\u003c/p\u003e\u003cp\u003eComorbid esophageal mucositis was clearly associated with the exacerbation of pain. A significantly higher percentage of patients in the present study who required opioids had comorbid esophageal mucositis that required intravenous antibiotics. Healthcare providers should consider the possibility of increased pain during the second to third weeks of chemotherapy when mucositis is expected to occur.\u003c/p\u003e\u003cp\u003eThere were several imitations to this study as follows: 1) this study was a retrospective analysis of clinical practice, and some of the items had missing values; 2) as the study focused on acute pain management during chemoradiotherapy, there was little information on opioid use after completing chemoradiotherapy. However, most patients were managed in an inpatient setting, and the amount and type of opioids used could be accurately determined while pain was controlled.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis is the first large study on opioid management during chemoradiotherapy for esophageal cancer. Half of the esophageal cancer patients who underwent dCRT required opioid pain control. Careful pain management is needed for these patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the patients and their families. We would also thank all staff in Kobe Minimally invasive Cancer Center.\u0026nbsp;The part of this study was presented at the 2024 the Japanese Society of Medical Oncology Annal Meeting (Nagoya).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data collected during this study are not publicly available due to privacy and ethical restrictions, but de-identified data may be available from the corresponding author with approval of the institutional review board.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudy design: K.T., Y.F. Data Collection: K.T., Y.F., K.K., H.K., A.H., H.M. Data analysis: K.T., Y.F., K.K., H.K. Manuscript preparation: K.T. Manuscript review and revisions: all authors. Final approval of manuscript: all authors.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no funding source for this report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board (approval No. 2023-09-04).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKato K, Muro K, Minashi K et al (2011) Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for stage II\u0026ndash;III esophageal squamous cell carcinoma: JCOG trial (JCOG9906). Int J Radiat Oncol Biol Phys 81(3):684\u0026ndash;690. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2010.06.033\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2010.06.033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHerskovic A, Martz K, al-Sarraf M et al (1992) Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326(24):1593\u0026ndash;1598. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJM199206113262403\u003c/span\u003e\u003cspan address=\"10.1056/NEJM199206113262403\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKato H, Sato A, Fukuda H et al (2009) A phase II trial of chemoradiotherapy for stage I esophageal squamous cell carcinoma: Japan Clinical Oncology Group Study (JCOG9708). Jpn J Clin Oncol 39(10):638\u0026ndash;643. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jjco/hyp069\u003c/span\u003e\u003cspan address=\"10.1093/jjco/hyp069\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKato K, Ito Y, Nozaki I et al (2021) Parallel-group controlled trial of surgery versus chemoradiotherapy in patients with stage I esophageal squamous cell carcinoma. Gastroenterology 161:1878\u0026ndash;1886. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.gastro.2021.08.007\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2021.08.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eConroy T, Galais MP, Raoul JL et al (2014) Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 15(3):305\u0026ndash;314. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1470-2045(14)70028-2\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(14)70028-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNihei K, Minashi K, Yano T et al (2023) Final analysis of diagnostic endoscopic resection followed by selective chemoradiotherapy for stage I esophageal cancer: JCOG0508. Gastroenterology 164(2):296\u0026ndash;299. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.gastro.2022.10.002\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2022.10.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMohammad NH, Hulshof MC, Bergman JJ et al (2014) Acute toxicity of definitive chemoradiation in patients with inoperable or unresectable esophageal carcinoma. BMC Cancer 14:56. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/1471-2407-14-56\u003c/span\u003e\u003cspan address=\"10.1186/1471-2407-14-56\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTaniyama N, Nakajima Y, Ishikawa H et al (2010) Nursing care for radiation-induced esophagitis in patients with primary esophageal cancer and lung cancer treated with radiation therapy. Kitakanto Med J 60:105\u0026ndash;110\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKawabata S, Nakamura Y, Matsushita N et al (2017) Using opioids to control pain due to mucosal damage after radiotherapy to treat head and neck cancer. Jpn J Pharm Palliat Care Sci 10:13\u0026ndash;18\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZenda S, Matsuura K, Tachibana H et al (2011) Multicenter phase II study of an opioid-based pain control program for head and neck cancer patients receiving chemoradiotherapy. Radiother Oncol 101:410\u0026ndash;414. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.radonc.2011.09.016\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2011.09.016\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSonis ST, Elting LS, Keefe D et al (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100(9 Suppl):1995\u0026ndash;2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cncr.20162\u003c/span\u003e\u003cspan address=\"10.1002/cncr.20162\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXing SZ, Zhang Y (2015) Efficacy and safety of transdermal fentanyl for treatment of oral mucositis pain caused by chemoradiotherapy in patients with esophageal squamous cell carcinoma. Support Care Cancer 23:753\u0026ndash;759. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00520-014-2419-5\u003c/span\u003e\u003cspan address=\"10.1007/s00520-014-2419-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKwon JH, Hui D, Chisholm G et al (2013) Predictors of long-term opioid treatment among patients who receive chemoradiation for head and neck cancer. Oncologist 18(6):768\u0026ndash;774. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1634/theoncologist.2013-0001\u003c/span\u003e\u003cspan address=\"10.1634/theoncologist.2013-0001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZayed S, Lin C, Boldt RG et al (2021) Risk of chronic opioid use after radiation for head and neck cancer: a systematic review and meta-analysis. Adv Radiat Oncol 6:100583. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.adro.2020.09.023\u003c/span\u003e\u003cspan address=\"10.1016/j.adro.2020.09.023\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTuno T, Tokumaru J, Kojima M et al (2018) Survey of the period of tapering of a strong opioid analgesic for oral mucositis resulting from concomitant chemoradiotherapy for head and neck cancer after the end of treatment. Palliat Care Res 13(4):305\u0026ndash;311. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2512/jspm.13.305\u003c/span\u003e\u003cspan address=\"10.2512/jspm.13.305\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 6 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"esophageal cancer, definitive chemoradiotherapy, opioid, swallowing pain","lastPublishedDoi":"10.21203/rs.3.rs-8165485/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8165485/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eDefinitive chemoradiotherapy represents an alternative treatment option for esophageal cancer patients who are not considered candidates for resection or refuse surgery. Swallowing pain associated with chemoradiotherapy is a serious adverse event that disrupts patient quality of life; however, there are no comprehensive reports describing opioid management during chemoradiotherapy for esophageal cancer. We conducted a study to determine the proportion of patients who required opioids, the timing of opioid initiation, the amount and type of opioids used, and other factors for patients requiring opioids.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eData for esophageal cancer patients who had undergone definitive chemoradiotherapy from April 2013 to March 2023 were retrospectively examined using their medical records.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 141 patients (105 men and 36 women, mean age: 69.6 years old) were included in the analysis, of whom 68 (48.2%) required opioids during chemoradiotherapy, with a median maximum use of 41.25 mg/day and a median cumulative use of 420 mg oral morphine equivalent. Oral or transdermal opioids were administered in most cases, with the proportion of transdermal fentanyl increasing as pain increased. There was a bimodal distribution of opioid initiation with a peak on days 15 and 37 following the start of chemoradiotherapy, and a median on day 22.5. Significant factors associated with opioid use were younger age and concomitant esophageal mucositis, which required intravenous antibiotics.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eApproximately half of the esophageal cancer patients who underwent definitive chemoradiotherapy required opioid pain control. Careful pain management is necessary for each patient.\u003c/p\u003e","manuscriptTitle":"Opioid use during definitive chemoradiotherapy for esophageal cancer: A retrospective analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-08 10:49:07","doi":"10.21203/rs.3.rs-8165485/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e489f91a-e4a6-43f6-b53d-296263472987","owner":[],"postedDate":"December 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-23T01:50:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-08 10:49:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8165485","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8165485","identity":"rs-8165485","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}