High-dose dexamethasone and prolonged infusion time prevent oxaliplatin-related hypersensitivity reactions in patients with metastatic colorectal cancer

High-dose dexamethasone and prolonged infusion time prevent oxaliplatin-related hypersensitivity reactions in patients with metastatic colorectal cancer | 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 High-dose dexamethasone and prolonged infusion time prevent oxaliplatin-related hypersensitivity reactions in patients with metastatic colorectal cancer Koichiro Yoshino, Hiroki Osumi, Akira Ooki, Shohei Udagawa, Mikako Tamba, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7362787/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Oxaliplatin (OXA), a key cytotoxic agent used in the treatment of gastrointestinal cancers, is frequently discontinued due to hypersensitivity reactions (HSRs). We developed a protocol to mitigate HSRs and assessed its clinical efficacy. Methods We retrospectively analyzed HSRs in patients with metastatic colorectal cancer (mCRC) who were treated with OXA-containing regimens between 2005 and 2019. We evaluated the clinical utility of our HSR prevention protocol in patients who experienced grade 1–3 HSRs following OXA-based chemotherapy. The protocol involved increasing dexamethasone to 16.5 mg/body and extending the OXA infusion time from 2 to 4 hours. Results Among 205 patients, 105 (51.2%) experienced grade 1, 95 (46.3%) grade 2, and 5 (2.4%) grade 3 HSRs. Most patients (87.8%) received either the FOLFOX4 or modified FOLFOX6 regimen. Patients underwent a median of 11 OXA cycles before their initial HSR. OXA was successfully reintroduced in 108 patients (52.7%) using the HSR prevention protocol. The median OXA-free interval was 23 days and the median progression-free survival after reintroduction was 6.4 months (95% confidence interval [CI]: 4.6–8.2). Reasons for discontinuation included a second HSR in 97 patients (47.3%), disease progression in 74 (36.1%), and chemotherapy-induced peripheral neuropathy (CIPN) in 15 (7.3%). Forty-six patients (22.4%) experienced an HSR during the initial prevention protocol. Only six patients (2.9%) experienced grade 3 HSRs and no grade 4 or 5 events were observed. Conclusion High-dose dexamethasone and prolonged infusion time may enable OXA reintroduction, providing an alternative to permanent discontinuation in mCRC patients with prior HSRs. Registry number: 2024-GB-073 (retrospectively registered). oxaliplatin hypersensitivity reaction prevention protocol metastatic colorectal cancer Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide, accounting for approximately 900,000 deaths annually. It also represents about 10% of all diagnosed cancers and cancer-related deaths globally. CRC is the second most common cancer in women and the third in men [ 1 ]. Although the prognosis for patients with metastatic colorectal cancer (mCRC) remains poor, it has improved in recent years due to advances in diagnostic techniques and treatment approaches, including surgery and chemotherapy. Oxaliplatin (OXA) is a third-generation platinum-based cytotoxic agent. Similar to other platinum-based agents, such as cisplatin (CDDP) and carboplatin (CBDCA), OXA exerts its antitumor activity by inhibiting DNA synthesis through cross-linking with DNA bases [ 2 ]. Structurally, OXA differs from other platinum compounds in that it contains a 1,2-diaminocyclohexane group as its carrier ligand and an oxalate group as its leaving group [ 2 ]. OXA demonstrates strong antitumor activity against CRC cell lines and is considered a key drug in CRC treatment. Compared with CDDP, OXA is less nephrotoxic and less myelotoxic than CBDCA [ 3 ]. It is one of the standard therapies for postoperative adjuvant chemotherapy and first-line cytotoxic chemotherapy for mCRC [ 4 ], as recommended by several international guidelines for CRC treatment [ 5 – 7 ]. In Japan, OXA is also indicated for the treatment of metastatic pancreatic [ 8 ], gastric [ 9 – 12 ], small bowel [ 13 ], and esophageal cancers [ 14 , 15 ]. The most common adverse events associated with OXA include hypersensitivity reactions (HSRs), chemotherapy-induced peripheral neuropathy (CIPN) [ 16 ], myelosuppression, and gastrointestinal symptoms. HSRs to platinum compounds are a well-recognized phenomenon [ 17 ]. As early as the 1950s, literature reported that exposure to platinum salts induced bronchial asthma in platinum refinery workers [ 18 ]. These reactions were first described for CDDP [ 19 , 20 ], with similar reactions also reported for CBDCA [ 21 , 22 ]. This type of toxicity has been sporadically noted in clinical trials evaluating the efficacy of OXA in chemotherapy and has been described in several case reports. Systematic reviews have shown prevalence rates of 10–18.9% for OXA, 5–20% for CDDP, and 1–44% for CBDCA. Allergic reactions are frequently cited as a reason for switching chemotherapy regimens [ 23 ]. The main symptoms of HSRs include facial and palmar flushing, pruritus and other cutaneous manifestations, respiratory symptoms such as dyspnea, gastrointestinal symptoms such as nausea and vomiting, and potentially life-threatening circulatory disturbances. Life-threatening reactions are reported to occur in approximately 1% of cases [ 23 – 25 ]. Severe HSRs requiring discontinuation of OXA may limit treatment options and reduce overall survival (OS). Identifying risk factors for HSRs is important for predicting patient risk; however, some reports suggest that these reactions are unpredictable due to the variability in onset patterns and symptom presentation [ 26 ]. Reported risk factors include the number of OXA courses [ 27 ], cumulative OXA dose [ 28 ], oxaliplatin-free interval (OFI) [ 29 ], history of allergies, and female sex [ 30 ]. With appropriate supportive care to mitigate HSRs, OXA can be administered for longer durations, potentially improving survival outcomes. Several protocols to prevent HSRs have been reported, with rechallenge success rates ranging from 28.6–89% [ 27 , 28 , 31 – 34 ]. These protocols commonly involve increasing corticosteroid doses or extending the infusion duration. Reported corticosteroid regimens include methylprednisolone at 1 mg/kg [ 32 ] [ 34 ] or 120 mg [ 33 ], hydrocortisone at 500 mg [ 31 ], and dexamethasone at 20 mg [ 27 , 28 ]. Extended infusion durations include increasing the administration time from 2 to 6 hours [ 31 ], or gradually escalating the infusion rate to complete administration within 4 to 6 hours [ 28 ] [ 33 ] [ 34 ]. However, such protocols are often unsuitable for outpatient settings due to complex administration procedures and prolonged infusion times. Based on previous reports and our clinical experience, we developed an HSR prevention protocol for OXA. This study aimed to evaluate the efficacy and safety of this protocol in patients with mCRC who experienced OXA-induced HSRs. Patients and Methods This single-institution retrospective study evaluated the efficacy and safety of a HSR prevention protocol in patients who experienced OXA-induced HSRs. The primary endpoint was the incidence of all grades of OXA-induced HSRs. Secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. We retrospectively enrolled patients with mCRC who were treated with OXA-containing chemotherapy regimens and developed OXA-induced HSRs between 2005 and 2019 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research in Tokyo, Japan. OXA-containing chemotherapy regimens included FOLFOX-based (leucovorin, fluorouracil, and OXA) and CapeOX-based (capecitabine and OXA) regimens. Ethics Statement This study was approved by the Institutional Review Board of the Japanese Foundation for Cancer Research, Tokyo, Japan (registry number 2024-GB-073). The study protocol was posted on the hospital website, and participants were given the opportunity to opt out; therefore, additional informed consent was not required. All procedures were conducted in accordance with the principles of the Declaration of Helsinki. HSR prevention protocol The HSR prevention protocol included increasing the doses of dexamethasone to 16.5 mg/body, chlorpheniramine to 5 mg/body, and famotidine to 20 mg/body, and extending the OXA infusion time from 2 to 4 hours (Fig. 1 ). For the FOLFOX-based regimen, premedication consisted of chlorpheniramine 5 mg/body and famotidine 20 mg/body administered over 5 minutes, followed by palonosetron 0.75 mg/body and dexamethasone 16.5 mg/body administered over 15 minutes. OXA (85 mg/m²), dissolved in 250 mL of 5% dextrose, was administered over 4 hours. After completion of OXA administration, leucovorin (200 mg/m²) was administered over 2 hours, followed by a rapid intravenous (IV) bolus of fluorouracil (400 mg/m²) and a continuous IV infusion of fluorouracil (2,400 mg/m²) over 46 hours. For the CapeOX-based regimen, premedication included chlorpheniramine 5 mg/body and famotidine 20 mg/body administered over 5 minutes, followed by palonosetron 0.75 mg/body and dexamethasone 16.5 mg/body administered over 15 minutes. OXA (130 mg/m²), dissolved in 500 mL of 5% dextrose, was administered over 4 hours. Capecitabine was administered at 2,000 mg/m²/day, beginning on the evening of the day of OXA administration. Data collection Patient characteristics—including age, sex, body surface area (BSA), KRAS status, primary tumor site, and metastatic sites—number of OXA courses until HSR onset, cumulative OXA dose, OFI, initial HSR grade, treatment outcomes of the HSR prevention protocol, safety, and factors contributing to the protocol’s success—were assessed. The cumulative OXA dose was calculated as the sum of the product of the number of doses and the dose reduction rate. This may differ from the actual dose administered due to fractional adjustments or other clinical factors. HSR grades were recorded in electronic medical records and assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Under CTCAE v4.0, the applicable system organ class is “immune system disorders,” and the corresponding preferred term is “allergic reaction.” Statistical analysis PFS was defined as the time from protocol initiation to the first objective evidence of disease progression or death from any cause. OS was defined as the time from initiation of the HSR prevention protocol to the date of death. PFS and OS were estimated using the Kaplan–Meier method. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were defined according to the Response Evaluation Criteria in Solid Tumors, version 1.1. OFI was defined as the number of days from the onset of the initial HSR to the day the HSR prevention protocol regimen was administered. Logistic regression analysis was used to identify factors associated with allergic reactions. Variables with p-values < 0.05 were considered statistically significant. All statistical analyses were performed using EZR software version 1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is based on R and R Commander [ 35 ]. Results Patient characteristics A total of 205 patients were enrolled between August 2005 and January 2021 (Table 1). The median age was 60 years (range: 27–80), and 109 patients (53.2%) were female. Seventy-six patients (37.6%) had a history of drug and/or food allergies. Eastern Cooperative Oncology Group performance status scores were 0 in 153 patients (74.6%), 1 in 50 patients (24.4%), and 2 in 2 patients (1.0%). Additionally, 180 patients (87.8%) received FOLFOX-based chemotherapy, while 25 patients (12.2%) received CapeOX-based chemotherapy. Most patients received OXA as either first-line (n = 140, 68.3%) or second-line (n = 41, 20.0%) treatment for mCRC. There were no significant differences in baseline characteristics between the successful and unsuccessful rechallenge groups. Details of the initial HSR The median number of OXA cycles before HSR onset was 11 (range: 2–47) (Fig. 2 ). The median cumulative OXA dose was 1,439 mg/m² (range: 233–6,100), and the median dose per BSA was 884 mg/m² (range: 170–3,407). The median OFI was 23 days (range: 13–890). Grade 1 HSRs were the most frequent, occurring in 105 patients (51.2%), followed by grade 2 HSRs in 95 patients (46.3%) and grade 3 HSRs in 5 patients (2.4%) (Fig. 3 a). Erythema occurred in 148 patients (72.2%), pruritus in 107 (52.2%), nausea and vomiting in 20 (9.8%), chills in 19 (9.3%), dyspnea in 14 (6.8%), decreased oxygen saturation in 13 (6.3%), fever in 11 (5.4%), abnormal blood pressure in 9 (4.4%), and pharyngeal discomfort in 5 (2.4%) (Fig. 3 a). Details of the second HSR A total of 205 patients received the HSR prevention protocol, among whom 97 (47.3%) experienced a second HSR. Forty-seven patients (22.9%) experienced an HSR on the same day the prevention protocol regimen was administered. The median time to the second HSR was 14 days (range: 0–910). Grade 1 HSRs occurred in 44 patients (45.4%), grade 2 in 47 (48.4%), and grade 3 in 6 (6.2%). No grade 4 or 5 HSRs were reported (Fig. 3 b). Erythema occurred in 69 patients (71.1%), pruritus in 41 (42.3%), nausea and vomiting in 4 (4.1%), chills in 11 (11.3%), dyspnea in 8 (8.2%), decreased oxygen saturation in 15 (15.5%), fever in 12 (12.4%), abnormal blood pressure in 2 (2.0%), and pharyngeal discomfort in 2 (2.0%) (Fig. 3 b). The proportion of patients experiencing chills, fever, and decreased oxygen saturation increased compared with the initial HSR. Reasons for discontinuing the HSR prevention protocol Among the patients who discontinued treatment, 44 (21.5%) experienced grade 1 HSRs, 47 (22.9%) experienced grade 2, and 6 (2.9%) experienced grade 3. In addition, 74 patients (36.1%) discontinued due to disease progression, and 15 (7.3%) due to CIPN (Table 2). Fifty-four patients discontinued at the start of the protocol, of whom 46 experienced an HSR (Fig. 4 ). The median number of protocol cycles was 3 (range: 1–40). Logistic regression analysis for risk factors of second HSR Univariate logistic regression analysis showed that receiving the CapeOX-based regimen (odds ratio: 0.39; 95% confidence interval [CI]: 0.16–0.98; p = 0.04) and having an OFI ≥ 15 days (odds ratio: 3.44; 95% CI: 1.22–9.71; p = 0.02) were associated with the incidence of a second hypersensitivity reaction (HSR). These factors remained independently significant in multivariate analysis: CapeOX-based regimen (odds ratio: 0.33; 95% CI: 0.13–0.84; p = 0.02) and OFI ≥ 15 days (odds ratio: 3.96; 95% CI: 1.39–11.3; p = 0.01) (Table 3). Efficacy of the HSR prevention protocol A total of 108 patients (52.4%) were successfully rechallenged with OXA using the HSR prevention protocol. The ORR was 54.2%, comprising CR in 0.5%, PR in 53.7%, SD in 42.9%, and PD in 2.9%. The DCR was 97.1%. The median PFS was 6.4 months (95% CI: 4.8–8.2) and the median OS was 22.7 months (95% CI: 20.0–26.9) (Fig. 5 ). Discussion In this study, we evaluated the efficacy and safety of a hypersensitivity reaction prevention protocol combining high-dose dexamethasone (16.5 mg/body) and prolonged infusion time (4 hours) in 205 patients with metastatic colorectal cancer who experienced grade 1–3 oxaliplatin-induced hypersensitivity reactions. Our results demonstrated that 108 patients (52.7%) were successfully rechallenged with oxaliplatin, achieving a median progression-free survival of 6.4 months and median overall survival of 22.7 months. Importantly, only 6 patients (2.9%) experienced grade 3 second hypersensitivity reactions, with no grade 4 or higher severe reactions observed. Furthermore, we identified CapeOX-based regimen as a protective factor, while oxaliplatin-free interval ≥ 15 days was identified as a risk factor for second hypersensitivity reactions. These findings provide a practical alternative to permanent oxaliplatin discontinuation due to hypersensitivity reactions. To the best of our knowledge, this is the largest study to evaluate the safety and efficacy of an HSR prevention protocol in patients with mCRC who experienced grade 1–3 HSR after receiving OXA-based chemotherapy. The mechanisms underlying OXA-induced HSRs remain incompletely understood. These reactions are thought to primarily involve type I hypersensitivity, also referred to as immediate hypersensitivity, which occurs within minutes of exposure [ 36 ]. This response is triggered by immunoglobulin E (IgE) antibodies that bind to the surface of mast cells and basophils. Upon re-exposure to the antigen, the IgE antibodies cross-link, leading to the release of intracellular granules (degranulation) [ 36 ]. These granules release large quantities of inflammatory mediators—such as histamine, serotonin, and heparin—causing rapid vasodilation and increased vascular permeability. The resulting plasma leakage from blood vessels can lead to hypotension, urticaria, and edema [ 36 ]. In this study, 108 patients (52.4%) were successfully rechallenged with OXA using the HSR prevention protocol. Previous reports have indicated that increasing the doses of dexamethasone and antihistamines from the sixth cycle of modified FOLFOX6 treatment significantly reduced the incidence of OXA-related HSRs [ 27 ]. While this strategy appears promising in suppressing OXA-related HSRs, increasing the dose of prophylactic agents such as corticosteroids for all patients may pose risks due to the potential for severe adverse effects. Other reports have also shown that lowering the infusion rate and using premedication with corticosteroids and histamine receptor antagonists can enable successful re-administration of platinum agents. In a recent retrospective study by O'Ceabhaill et al., 777 patients with relapsed ovarian, fallopian tube, or primary peritoneal cancer were retreated with carboplatin [ 37 ]. The data indicated that gradually increasing the infusion duration to 3 hours during carboplatin rechallenge, combined with appropriate premedication, may reduce the incidence of HSRs compared with the standard 30-minute infusion [ 37 ]. Another study reported that continuous 6-hour infusion of OXA may reduce the risk of hypersensitivity. In one trial, only 1 of 100 patients (1%) treated with OXA as a 6-hour infusion added to chronomodulated 5-fluorouracil (5-FU) and folinic acid experienced an HSR as part of first-line therapy for advanced colorectal cancer [ 38 ]. Furthermore, no HSRs were observed in 151 patients who received 1,087 courses of constant-rate OXA infusion and in 491 patients who received 3,106 courses of chronomodulated OXA infusion [ 38 ]. Notably, five patients who developed HSRs during 2-hour infusions of OXA did not experience symptoms when re-exposed to 6-hour infusions. The mechanism underlying this effect remains unclear; however, it is hypothesized that prolonged infusion reduces the drug’s maximum plasma concentration. In addition to the role of premedication, a rechallenge protocol involving prolonged OXA infusion for prophylaxis has been reported. According to Maindrault-Goebel et al., the duration of OXA infusion was extended from 2 to 6 hours in five patients who had developed laryngospasm in response to OXA, and no recurrence of symptoms was observed [ 40 ]. Although the precise mechanism by which prolonged OXA infusion suppresses HSRs is unknown, it is assumed that slower administration may lower peak plasma levels. In this study, the use of fluoropyrimidines—particularly 5-FU more than capecitabine—and an OFI longer than 15 days were identified as risk factors for a second HSR. Two previous reports investigated HSRs in CapeOX-based regimens [ 28 , 41 ]; however, neither study found CapeOX to be a statistically significant risk factor. It is possible that HSRs were less likely to occur due to the lower number of treatment cycles compared with FOLFOX-based regimens. Additionally, although OFI has been discussed in the context of stop-and-go strategies [ 29 , 42 , 43 ], it has rarely been evaluated in the setting of HSR prevention protocols. Based on the results of our study, we recommend the following treatment strategies for OXA-related HSRs: If grade 1 or 2 HSRs occur—excluding those with dyspnea—OXA-containing chemotherapy may be continued using a rechallenge protocol [ 31 ]. However, in cases of grade 2 or 3 HSRs involving cardiovascular or respiratory symptoms, the decision to continue or discontinue OXA-containing treatment should be made with caution [ 31 ]. If subsequent chemotherapies, such as irinotecan or anti-epidermal growth factor receptor antibodies, remain active options, we recommend switching to these agents or administering continuous infusion of 5-FU/leucovorin without OXA [ 31 ]. Particular caution should be exercised regarding the duration of OXA reintroduction in stop-and-go strategies [ 44 ], as prolonged reintroduction intervals may increase the risk of a second HSR. Maintaining uninterrupted use of key drugs, when possible, may contribute to prolonged overall survival. Therefore, minimizing adverse effects is essential to achieving successful chemotherapy outcomes, and a comprehensive understanding of each drug’s safety and efficacy profile is required. The accuracy of adverse event monitoring should be enhanced through a multidisciplinary approach involving physicians, nurses, and pharmacists. Ongoing monitoring of side effects supports early detection and prevention, preserves quality of life, and contributes to improved treatment efficacy. When these two factors are present, caution and careful consideration are required when re-administering OXA due to the possibility of HSR. This study has several limitations. Although it was retrospective in design, the sample size was relatively small, and definitive conclusions could not be drawn. Nevertheless, the findings may still be valuable in informing everyday clinical practice. In conclusion, the success rate of OXA reintroduction using the HSR prevention protocol was comparable to those reported in previous studies addressing manageable adverse events. This protocol offers a viable alternative to the permanent discontinuation of OXA in patients who develop HSRs. Declarations Ethics Approval This study was approved by the ethics review board of the Cancer Institute Hospital of the Japanese Foundation of Cancer Research (registry number 2024-GB-073) and was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Conflict of Interest The authors declare no conflicts of interest. Funding This work has not received external funding. Author Contributions Conception and design: KY, HO, and ES; acquisition of data: KY; analysis and interpretation of data: KY, HO, and ES; writing, review, and/or revision of the manuscript: all authors; administrative, technical, or material support: KY, HO, and ES; study supervision: ES. Acknowledgements The authors thank Ms. Yuki Horiike, Ms. Hitomi Hannan, and Ms. Yukie Naito for managing the data. Data Availability The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71(3):209–249 Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7(8):573–584 Misset JL (1998) Oxaliplatin in practice. 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Oncology 79(1–2):136–143 Shen Y, Li C, Liu W, Mao W, Qian H, Wang H et al (2018) Clinical Analysis of Hypersensitivity Reactions to Oxaliplatin Among Colorectal Cancer Patients. Oncol Res 26(5):801–807 Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M et al (2006) OPTIMOX1: A Randomized Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal Cancer—A GERCOR Study. J Clin Oncol 24(3):394–400 Jimenez-Rodriguez T-W, de las Vecillas L, Labella M, Lynch D-M, Besz KM, Marquis K et al (2024) Differential presentation of hypersensitivity reactions to carboplatin and oxaliplatin: Phenotypes, endotypes, and management with desensitization. Allergy 79(3):679–689 Tables Tables are available in the Supplementary Files section. Supplementary Files TablesofOHPallergyregimen.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revisions 04 Nov, 2025 Reviewers agreed at journal 09 Oct, 2025 Reviewers invited by journal 09 Oct, 2025 Editor assigned by journal 21 Aug, 2025 First submitted to journal 13 Aug, 2025 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-7362787","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":527067541,"identity":"06c96f03-8b14-4e12-a7c8-3dfb55d14b48","order_by":0,"name":"Koichiro Yoshino","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIie2SsUoEMRCGJyzEJhDLWRbyDAOBA+EeZhchleCBzZWRA6+5B7jHEATrXQLarPoCItpcL9teYaJGrsjdWgrmq/6Q+ZKZEIBM5g+CwGwB9LX4DBK61+/N9pdKaR2NKKESouKhtqBkaaRcLi6H2exFAZ46H56V7hwb5jA9B/aQvKYS3aJa04UGNMaHjZ60rih7MCcWHuuUorC5KgTVjcWziQ+uuW2f7piFMFCf7HBX0UNQbqzjB5VqR6EqKNcwopQrP4tXNBcbExSNYRZLhvieWfB++TaIba3kkX8xsXVKrh17t/MpSUy/2A/8OB6JodC3xLE/aPiPEo+UNobViJLJZDL/hA8/IVnukUVk7QAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-9877-9336","institution":"Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":true,"prefix":"","firstName":"Koichiro","middleName":"","lastName":"Yoshino","suffix":""},{"id":527067542,"identity":"26c26c4f-2521-4b94-8f45-5d9bef12285b","order_by":1,"name":"Hiroki Osumi","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Hiroki","middleName":"","lastName":"Osumi","suffix":""},{"id":527067543,"identity":"8b9197a4-1ef7-45bb-8d4d-3fa630f085ef","order_by":2,"name":"Akira Ooki","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Akira","middleName":"","lastName":"Ooki","suffix":""},{"id":527067544,"identity":"2dea1cb6-c624-4fd5-9de3-6eefb4bf5d10","order_by":3,"name":"Shohei Udagawa","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foudation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Shohei","middleName":"","lastName":"Udagawa","suffix":""},{"id":527067545,"identity":"556feb23-26c6-49c9-93b8-ffdb55a9a866","order_by":4,"name":"Mikako Tamba","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foudation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Mikako","middleName":"","lastName":"Tamba","suffix":""},{"id":527067546,"identity":"37efebc7-d59d-4f32-acf2-b825a072588f","order_by":5,"name":"Shota Fukuoka","email":"","orcid":"","institution":"Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Shota","middleName":"","lastName":"Fukuoka","suffix":""},{"id":527067547,"identity":"300183fc-65fa-44a7-8d0f-db916a944617","order_by":6,"name":"Takeru Wakatsuki","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Takeru","middleName":"","lastName":"Wakatsuki","suffix":""},{"id":527067548,"identity":"05e253e1-8283-4b4b-b4cf-de8053bea1d7","order_by":7,"name":"Mariko Ogura","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Mariko","middleName":"","lastName":"Ogura","suffix":""},{"id":527067549,"identity":"96bf032f-cf71-4a4d-b2b6-773edaa058de","order_by":8,"name":"Keisho Chin","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Keisho","middleName":"","lastName":"Chin","suffix":""},{"id":527067550,"identity":"f80c3b04-f946-41fc-9e1d-9929f2ec8467","order_by":9,"name":"Kensei Yamaguchi","email":"","orcid":"","institution":"The Cancer Institute Hospital of Japanase Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Kensei","middleName":"","lastName":"Yamaguchi","suffix":""},{"id":527067551,"identity":"282b1dcc-df1e-4dc7-be2a-43a85e4a9bfd","order_by":10,"name":"Eiji Shinozaki","email":"","orcid":"https://orcid.org/0000-0002-7448-5894","institution":"The Cancer Institute Hospital of Japanese Foundation for Cancer Research","correspondingAuthor":false,"prefix":"","firstName":"Eiji","middleName":"","lastName":"Shinozaki","suffix":""}],"badges":[],"createdAt":"2025-08-13 08:47:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7362787/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7362787/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94236643,"identity":"1c0b0cbd-590a-4884-91c0-8edaf04a346a","added_by":"auto","created_at":"2025-10-24 02:15:27","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":11562,"visible":true,"origin":"","legend":"","description":"","filename":"ijcoIJCOD2500976.xml","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/f454d8880cc9b117f62b3eb8.xml"},{"id":94236642,"identity":"05cce09a-bd74-4dcc-adae-141da1dff7b8","added_by":"auto","created_at":"2025-10-24 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02:15:27","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":101758,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOD25009760structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/c3af2dcc8cc9bac136ef8bcc.xml"},{"id":94236645,"identity":"3b450abd-7354-4052-93d9-8803bfff7f81","added_by":"auto","created_at":"2025-10-24 02:15:27","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":112755,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/b906b1bb66782f82bd32e508.html"},{"id":94236633,"identity":"4ee8d762-21c7-40d4-b412-413289929cfe","added_by":"auto","created_at":"2025-10-24 02:15:26","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":101673,"visible":true,"origin":"","legend":"\u003cp\u003eHypersensitivity prevention protocol\u003c/p\u003e\n\u003cp\u003eThe difference between the HSR prevention protocol and the usual regimen is that dexamethasone is increased from 6.6 mg to 16.5 mg/body, and the duration of OXA administration is extended from 2 to 4 hours. Abbreviations HSR, hypersensitivity reaction; OXA, oxaliplatin.\u003c/p\u003e","description":"","filename":"Slide1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/79582eb9bee0e55fe914c7d8.jpg"},{"id":94236635,"identity":"5e008b9d-f820-4e10-8f86-5e467853da99","added_by":"auto","created_at":"2025-10-24 02:15:26","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":88797,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of courses and patients until HSR occurred\u003c/p\u003e\n\u003cp\u003eThe numbers of OXA administrations and patients who experienced HSR from the start of treatment were recorded. Abbreviations HSR, hypersensitivity reaction; OXA, oxaliplatin.\u003c/p\u003e","description":"","filename":"Slide2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/3b1f0e964bfad7f9db1b4140.jpg"},{"id":94236638,"identity":"30094c6c-d581-4049-8003-460b163a45e8","added_by":"auto","created_at":"2025-10-24 02:15:26","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":82737,"visible":true,"origin":"","legend":"\u003cp\u003eDetails of the initial and second HSR\u003c/p\u003e\n\u003cp\u003eThe pie chart shows the HSR grade, number of patients, and percentage. The bar graph shows HSR symptoms according to grade. Grade 3 symptoms related to circulatory and respiratory dynamics are common, and these symptoms increase with the second HSR. a. A total of 205 patients underwent initial HSR with OXA-based chemotherapy. b. A total of 97 patients with HSR were included in the HSR prevention protocol. Abbreviations HSR, hypersensitivity reaction; OXA, oxaliplatin.\u003c/p\u003e","description":"","filename":"Slide3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/01431a176d9654d9b7445009.jpg"},{"id":94236637,"identity":"61f0d53f-f971-4175-aa86-917ccca2e795","added_by":"auto","created_at":"2025-10-24 02:15:26","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":97927,"visible":true,"origin":"","legend":"\u003cp\u003eReasons for discontinuing the HSR prevention protocol\u003c/p\u003e\n\u003cp\u003eReasons for discontinuing HSR prevention protocols at frequency. A lower frequency resulted in a higher HSR percentage, whereas a higher frequency resulted in a higher PD percentage. Abbreviations HSR, hypersensitivity reaction; PD, progression disease.\u003c/p\u003e","description":"","filename":"Slide4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/05fa9a70475bbff98c6ac651.jpg"},{"id":94236639,"identity":"31962442-fe01-4dcf-9ef1-fce4b9948407","added_by":"auto","created_at":"2025-10-24 02:15:26","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":61898,"visible":true,"origin":"","legend":"\u003cp\u003ePFS and best response in patients with metastatic colorectal cancer receiving HSR prevention protocol\u003c/p\u003e\n\u003cp\u003eA total of 205 patients underwent the HSR prevention protocol. The median PFS was 6.4 months (95% CI 4.6-8.2 months). The median OS was 22.7 months (95% CI 20-26.9 months). The ORR was 53.7% (CR, 0.5%; PR, 53.2%; SD, 42.9%; and PD, 2.9%, not evaluable 0.5%), and the DCR was 96.6%. Abbreviations HSR, hypersensitivity reaction; PFS, progression-free survival; OS, overall survival; ORR, overall response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progression disease, DCR, disease control ratio.\u003c/p\u003e","description":"","filename":"Slide5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/8c23a32f3813876fe9760808.jpg"},{"id":94237341,"identity":"5d31ce8c-6a14-44f1-a0fd-66546a1813a6","added_by":"auto","created_at":"2025-10-24 02:23:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1050620,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/93d70b3f-2a01-483e-a72c-eabb4435ea79.pdf"},{"id":94236636,"identity":"48e6d975-8775-453d-886a-a9d5748b4ba9","added_by":"auto","created_at":"2025-10-24 02:15:26","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16217,"visible":true,"origin":"","legend":"","description":"","filename":"TablesofOHPallergyregimen.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7362787/v1/f9d516d1d20205c932dbcbd5.xlsx"}],"financialInterests":"","formattedTitle":"High-dose dexamethasone and prolonged infusion time prevent oxaliplatin-related hypersensitivity reactions in patients with metastatic colorectal cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide, accounting for approximately 900,000 deaths annually. It also represents about 10% of all diagnosed cancers and cancer-related deaths globally. CRC is the second most common cancer in women and the third in men [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although the prognosis for patients with metastatic colorectal cancer (mCRC) remains poor, it has improved in recent years due to advances in diagnostic techniques and treatment approaches, including surgery and chemotherapy.\u003c/p\u003e\u003cp\u003eOxaliplatin (OXA) is a third-generation platinum-based cytotoxic agent. Similar to other platinum-based agents, such as cisplatin (CDDP) and carboplatin (CBDCA), OXA exerts its antitumor activity by inhibiting DNA synthesis through cross-linking with DNA bases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Structurally, OXA differs from other platinum compounds in that it contains a 1,2-diaminocyclohexane group as its carrier ligand and an oxalate group as its leaving group [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. OXA demonstrates strong antitumor activity against CRC cell lines and is considered a key drug in CRC treatment. Compared with CDDP, OXA is less nephrotoxic and less myelotoxic than CBDCA [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It is one of the standard therapies for postoperative adjuvant chemotherapy and first-line cytotoxic chemotherapy for mCRC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], as recommended by several international guidelines for CRC treatment [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In Japan, OXA is also indicated for the treatment of metastatic pancreatic [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], gastric [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], small bowel [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and esophageal cancers [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe most common adverse events associated with OXA include hypersensitivity reactions (HSRs), chemotherapy-induced peripheral neuropathy (CIPN) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], myelosuppression, and gastrointestinal symptoms. HSRs to platinum compounds are a well-recognized phenomenon [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. As early as the 1950s, literature reported that exposure to platinum salts induced bronchial asthma in platinum refinery workers [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. These reactions were first described for CDDP [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], with similar reactions also reported for CBDCA [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. This type of toxicity has been sporadically noted in clinical trials evaluating the efficacy of OXA in chemotherapy and has been described in several case reports. Systematic reviews have shown prevalence rates of 10\u0026ndash;18.9% for OXA, 5\u0026ndash;20% for CDDP, and 1\u0026ndash;44% for CBDCA. Allergic reactions are frequently cited as a reason for switching chemotherapy regimens [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe main symptoms of HSRs include facial and palmar flushing, pruritus and other cutaneous manifestations, respiratory symptoms such as dyspnea, gastrointestinal symptoms such as nausea and vomiting, and potentially life-threatening circulatory disturbances. Life-threatening reactions are reported to occur in approximately 1% of cases [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Severe HSRs requiring discontinuation of OXA may limit treatment options and reduce overall survival (OS).\u003c/p\u003e\u003cp\u003eIdentifying risk factors for HSRs is important for predicting patient risk; however, some reports suggest that these reactions are unpredictable due to the variability in onset patterns and symptom presentation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Reported risk factors include the number of OXA courses [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], cumulative OXA dose [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], oxaliplatin-free interval (OFI) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], history of allergies, and female sex [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. With appropriate supportive care to mitigate HSRs, OXA can be administered for longer durations, potentially improving survival outcomes.\u003c/p\u003e\u003cp\u003eSeveral protocols to prevent HSRs have been reported, with rechallenge success rates ranging from 28.6\u0026ndash;89% [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. These protocols commonly involve increasing corticosteroid doses or extending the infusion duration. Reported corticosteroid regimens include methylprednisolone at 1 mg/kg [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] or 120 mg [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], hydrocortisone at 500 mg [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and dexamethasone at 20 mg [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Extended infusion durations include increasing the administration time from 2 to 6 hours [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], or gradually escalating the infusion rate to complete administration within 4 to 6 hours [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, such protocols are often unsuitable for outpatient settings due to complex administration procedures and prolonged infusion times.\u003c/p\u003e\u003cp\u003eBased on previous reports and our clinical experience, we developed an HSR prevention protocol for OXA. This study aimed to evaluate the efficacy and safety of this protocol in patients with mCRC who experienced OXA-induced HSRs.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eThis single-institution retrospective study evaluated the efficacy and safety of a HSR prevention protocol in patients who experienced OXA-induced HSRs. The primary endpoint was the incidence of all grades of OXA-induced HSRs. Secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. We retrospectively enrolled patients with mCRC who were treated with OXA-containing chemotherapy regimens and developed OXA-induced HSRs between 2005 and 2019 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research in Tokyo, Japan. OXA-containing chemotherapy regimens included FOLFOX-based (leucovorin, fluorouracil, and OXA) and CapeOX-based (capecitabine and OXA) regimens.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eEthics Statement\u003c/h2\u003e\u003cp\u003e This study was approved by the Institutional Review Board of the Japanese Foundation for Cancer Research, Tokyo, Japan (registry number 2024-GB-073). The study protocol was posted on the hospital website, and participants were given the opportunity to opt out; therefore, additional informed consent was not required. All procedures were conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eHSR prevention protocol\u003c/h3\u003e\n\u003cp\u003eThe HSR prevention protocol included increasing the doses of dexamethasone to 16.5 mg/body, chlorpheniramine to 5 mg/body, and famotidine to 20 mg/body, and extending the OXA infusion time from 2 to 4 hours (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For the FOLFOX-based regimen, premedication consisted of chlorpheniramine 5 mg/body and famotidine 20 mg/body administered over 5 minutes, followed by palonosetron 0.75 mg/body and dexamethasone 16.5 mg/body administered over 15 minutes. OXA (85 mg/m\u0026sup2;), dissolved in 250 mL of 5% dextrose, was administered over 4 hours. After completion of OXA administration, leucovorin (200 mg/m\u0026sup2;) was administered over 2 hours, followed by a rapid intravenous (IV) bolus of fluorouracil (400 mg/m\u0026sup2;) and a continuous IV infusion of fluorouracil (2,400 mg/m\u0026sup2;) over 46 hours. For the CapeOX-based regimen, premedication included chlorpheniramine 5 mg/body and famotidine 20 mg/body administered over 5 minutes, followed by palonosetron 0.75 mg/body and dexamethasone 16.5 mg/body administered over 15 minutes. OXA (130 mg/m\u0026sup2;), dissolved in 500 mL of 5% dextrose, was administered over 4 hours. Capecitabine was administered at 2,000 mg/m\u0026sup2;/day, beginning on the evening of the day of OXA administration.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003ePatient characteristics\u0026mdash;including age, sex, body surface area (BSA), \u003cem\u003eKRAS\u003c/em\u003e status, primary tumor site, and metastatic sites\u0026mdash;number of OXA courses until HSR onset, cumulative OXA dose, OFI, initial HSR grade, treatment outcomes of the HSR prevention protocol, safety, and factors contributing to the protocol\u0026rsquo;s success\u0026mdash;were assessed. The cumulative OXA dose was calculated as the sum of the product of the number of doses and the dose reduction rate. This may differ from the actual dose administered due to fractional adjustments or other clinical factors. HSR grades were recorded in electronic medical records and assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Under CTCAE v4.0, the applicable system organ class is \u0026ldquo;immune system disorders,\u0026rdquo; and the corresponding preferred term is \u0026ldquo;allergic reaction.\u0026rdquo;\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003ePFS was defined as the time from protocol initiation to the first objective evidence of disease progression or death from any cause. OS was defined as the time from initiation of the HSR prevention protocol to the date of death. PFS and OS were estimated using the Kaplan\u0026ndash;Meier method. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were defined according to the Response Evaluation Criteria in Solid Tumors, version 1.1. OFI was defined as the number of days from the onset of the initial HSR to the day the HSR prevention protocol regimen was administered. Logistic regression analysis was used to identify factors associated with allergic reactions. Variables with p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. All statistical analyses were performed using EZR software version 1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is based on R and R Commander [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003ePatient characteristics\u003c/h2\u003e\u003cp\u003eA total of 205 patients were enrolled between August 2005 and January 2021 (Table\u0026nbsp;1). The median age was 60 years (range: 27\u0026ndash;80), and 109 patients (53.2%) were female. Seventy-six patients (37.6%) had a history of drug and/or food allergies. Eastern Cooperative Oncology Group performance status scores were 0 in 153 patients (74.6%), 1 in 50 patients (24.4%), and 2 in 2 patients (1.0%). Additionally, 180 patients (87.8%) received FOLFOX-based chemotherapy, while 25 patients (12.2%) received CapeOX-based chemotherapy. Most patients received OXA as either first-line (n\u0026thinsp;=\u0026thinsp;140, 68.3%) or second-line (n\u0026thinsp;=\u0026thinsp;41, 20.0%) treatment for mCRC. There were no significant differences in baseline characteristics between the successful and unsuccessful rechallenge groups.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDetails of the initial HSR\u003c/h3\u003e\n\u003cp\u003eThe median number of OXA cycles before HSR onset was 11 (range: 2\u0026ndash;47) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median cumulative OXA dose was 1,439 mg/m\u0026sup2; (range: 233\u0026ndash;6,100), and the median dose per BSA was 884 mg/m\u0026sup2; (range: 170\u0026ndash;3,407). The median OFI was 23 days (range: 13\u0026ndash;890). Grade 1 HSRs were the most frequent, occurring in 105 patients (51.2%), followed by grade 2 HSRs in 95 patients (46.3%) and grade 3 HSRs in 5 patients (2.4%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). Erythema occurred in 148 patients (72.2%), pruritus in 107 (52.2%), nausea and vomiting in 20 (9.8%), chills in 19 (9.3%), dyspnea in 14 (6.8%), decreased oxygen saturation in 13 (6.3%), fever in 11 (5.4%), abnormal blood pressure in 9 (4.4%), and pharyngeal discomfort in 5 (2.4%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eDetails of the second HSR\u003c/h3\u003e\n\u003cp\u003eA total of 205 patients received the HSR prevention protocol, among whom 97 (47.3%) experienced a second HSR. Forty-seven patients (22.9%) experienced an HSR on the same day the prevention protocol regimen was administered. The median time to the second HSR was 14 days (range: 0\u0026ndash;910). Grade 1 HSRs occurred in 44 patients (45.4%), grade 2 in 47 (48.4%), and grade 3 in 6 (6.2%). No grade 4 or 5 HSRs were reported (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). Erythema occurred in 69 patients (71.1%), pruritus in 41 (42.3%), nausea and vomiting in 4 (4.1%), chills in 11 (11.3%), dyspnea in 8 (8.2%), decreased oxygen saturation in 15 (15.5%), fever in 12 (12.4%), abnormal blood pressure in 2 (2.0%), and pharyngeal discomfort in 2 (2.0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). The proportion of patients experiencing chills, fever, and decreased oxygen saturation increased compared with the initial HSR.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eReasons for discontinuing the HSR prevention protocol\u003c/h2\u003e\u003cp\u003eAmong the patients who discontinued treatment, 44 (21.5%) experienced grade 1 HSRs, 47 (22.9%) experienced grade 2, and 6 (2.9%) experienced grade 3. In addition, 74 patients (36.1%) discontinued due to disease progression, and 15 (7.3%) due to CIPN (Table\u0026nbsp;2). Fifty-four patients discontinued at the start of the protocol, of whom 46 experienced an HSR (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The median number of protocol cycles was 3 (range: 1\u0026ndash;40).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eLogistic regression analysis for risk factors of second HSR\u003c/h2\u003e\u003cp\u003eUnivariate logistic regression analysis showed that receiving the CapeOX-based regimen (odds ratio: 0.39; 95% confidence interval [CI]: 0.16\u0026ndash;0.98; p\u0026thinsp;=\u0026thinsp;0.04) and having an OFI\u0026thinsp;\u0026ge;\u0026thinsp;15 days (odds ratio: 3.44; 95% CI: 1.22\u0026ndash;9.71; p\u0026thinsp;=\u0026thinsp;0.02) were associated with the incidence of a second hypersensitivity reaction (HSR). These factors remained independently significant in multivariate analysis: CapeOX-based regimen (odds ratio: 0.33; 95% CI: 0.13\u0026ndash;0.84; p\u0026thinsp;=\u0026thinsp;0.02) and OFI\u0026thinsp;\u0026ge;\u0026thinsp;15 days (odds ratio: 3.96; 95% CI: 1.39\u0026ndash;11.3; p\u0026thinsp;=\u0026thinsp;0.01) (Table\u0026nbsp;3).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eEfficacy of the HSR prevention protocol\u003c/h2\u003e\u003cp\u003eA total of 108 patients (52.4%) were successfully rechallenged with OXA using the HSR prevention protocol. The ORR was 54.2%, comprising CR in 0.5%, PR in 53.7%, SD in 42.9%, and PD in 2.9%. The DCR was 97.1%. The median PFS was 6.4 months (95% CI: 4.8\u0026ndash;8.2) and the median OS was 22.7 months (95% CI: 20.0\u0026ndash;26.9) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we evaluated the efficacy and safety of a hypersensitivity reaction prevention protocol combining high-dose dexamethasone (16.5 mg/body) and prolonged infusion time (4 hours) in 205 patients with metastatic colorectal cancer who experienced grade 1\u0026ndash;3 oxaliplatin-induced hypersensitivity reactions. Our results demonstrated that 108 patients (52.7%) were successfully rechallenged with oxaliplatin, achieving a median progression-free survival of 6.4 months and median overall survival of 22.7 months. Importantly, only 6 patients (2.9%) experienced grade 3 second hypersensitivity reactions, with no grade 4 or higher severe reactions observed. Furthermore, we identified CapeOX-based regimen as a protective factor, while oxaliplatin-free interval\u0026thinsp;\u0026ge;\u0026thinsp;15 days was identified as a risk factor for second hypersensitivity reactions. These findings provide a practical alternative to permanent oxaliplatin discontinuation due to hypersensitivity reactions.\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, this is the largest study to evaluate the safety and efficacy of an HSR prevention protocol in patients with mCRC who experienced grade 1\u0026ndash;3 HSR after receiving OXA-based chemotherapy.\u003c/p\u003e\u003cp\u003eThe mechanisms underlying OXA-induced HSRs remain incompletely understood. These reactions are thought to primarily involve type I hypersensitivity, also referred to as immediate hypersensitivity, which occurs within minutes of exposure [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. This response is triggered by immunoglobulin E (IgE) antibodies that bind to the surface of mast cells and basophils. Upon re-exposure to the antigen, the IgE antibodies cross-link, leading to the release of intracellular granules (degranulation) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. These granules release large quantities of inflammatory mediators\u0026mdash;such as histamine, serotonin, and heparin\u0026mdash;causing rapid vasodilation and increased vascular permeability. The resulting plasma leakage from blood vessels can lead to hypotension, urticaria, and edema [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, 108 patients (52.4%) were successfully rechallenged with OXA using the HSR prevention protocol. Previous reports have indicated that increasing the doses of dexamethasone and antihistamines from the sixth cycle of modified FOLFOX6 treatment significantly reduced the incidence of OXA-related HSRs [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. While this strategy appears promising in suppressing OXA-related HSRs, increasing the dose of prophylactic agents such as corticosteroids for all patients may pose risks due to the potential for severe adverse effects.\u003c/p\u003e\u003cp\u003eOther reports have also shown that lowering the infusion rate and using premedication with corticosteroids and histamine receptor antagonists can enable successful re-administration of platinum agents. In a recent retrospective study by O'Ceabhaill et al., 777 patients with relapsed ovarian, fallopian tube, or primary peritoneal cancer were retreated with carboplatin [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The data indicated that gradually increasing the infusion duration to 3 hours during carboplatin rechallenge, combined with appropriate premedication, may reduce the incidence of HSRs compared with the standard 30-minute infusion [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Another study reported that continuous 6-hour infusion of OXA may reduce the risk of hypersensitivity. In one trial, only 1 of 100 patients (1%) treated with OXA as a 6-hour infusion added to chronomodulated 5-fluorouracil (5-FU) and folinic acid experienced an HSR as part of first-line therapy for advanced colorectal cancer [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Furthermore, no HSRs were observed in 151 patients who received 1,087 courses of constant-rate OXA infusion and in 491 patients who received 3,106 courses of chronomodulated OXA infusion [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Notably, five patients who developed HSRs during 2-hour infusions of OXA did not experience symptoms when re-exposed to 6-hour infusions.\u003c/p\u003e\u003cp\u003eThe mechanism underlying this effect remains unclear; however, it is hypothesized that prolonged infusion reduces the drug\u0026rsquo;s maximum plasma concentration. In addition to the role of premedication, a rechallenge protocol involving prolonged OXA infusion for prophylaxis has been reported. According to Maindrault-Goebel et al., the duration of OXA infusion was extended from 2 to 6 hours in five patients who had developed laryngospasm in response to OXA, and no recurrence of symptoms was observed [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Although the precise mechanism by which prolonged OXA infusion suppresses HSRs is unknown, it is assumed that slower administration may lower peak plasma levels.\u003c/p\u003e\u003cp\u003eIn this study, the use of fluoropyrimidines\u0026mdash;particularly 5-FU more than capecitabine\u0026mdash;and an OFI longer than 15 days were identified as risk factors for a second HSR. Two previous reports investigated HSRs in CapeOX-based regimens [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]; however, neither study found CapeOX to be a statistically significant risk factor. It is possible that HSRs were less likely to occur due to the lower number of treatment cycles compared with FOLFOX-based regimens. Additionally, although OFI has been discussed in the context of stop-and-go strategies [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e], it has rarely been evaluated in the setting of HSR prevention protocols.\u003c/p\u003e\u003cp\u003eBased on the results of our study, we recommend the following treatment strategies for OXA-related HSRs: If grade 1 or 2 HSRs occur\u0026mdash;excluding those with dyspnea\u0026mdash;OXA-containing chemotherapy may be continued using a rechallenge protocol [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. However, in cases of grade 2 or 3 HSRs involving cardiovascular or respiratory symptoms, the decision to continue or discontinue OXA-containing treatment should be made with caution [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. If subsequent chemotherapies, such as irinotecan or anti-epidermal growth factor receptor antibodies, remain active options, we recommend switching to these agents or administering continuous infusion of 5-FU/leucovorin without OXA [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Particular caution should be exercised regarding the duration of OXA reintroduction in stop-and-go strategies [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], as prolonged reintroduction intervals may increase the risk of a second HSR.\u003c/p\u003e\u003cp\u003eMaintaining uninterrupted use of key drugs, when possible, may contribute to prolonged overall survival. Therefore, minimizing adverse effects is essential to achieving successful chemotherapy outcomes, and a comprehensive understanding of each drug\u0026rsquo;s safety and efficacy profile is required. The accuracy of adverse event monitoring should be enhanced through a multidisciplinary approach involving physicians, nurses, and pharmacists. Ongoing monitoring of side effects supports early detection and prevention, preserves quality of life, and contributes to improved treatment efficacy. When these two factors are present, caution and careful consideration are required when re-administering OXA due to the possibility of HSR.\u003c/p\u003e\u003cp\u003eThis study has several limitations. Although it was retrospective in design, the sample size was relatively small, and definitive conclusions could not be drawn. Nevertheless, the findings may still be valuable in informing everyday clinical practice.\u003c/p\u003e\u003cp\u003eIn conclusion, the success rate of OXA reintroduction using the HSR prevention protocol was comparable to those reported in previous studies addressing manageable adverse events. This protocol offers a viable alternative to the permanent discontinuation of OXA in patients who develop HSRs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the ethics review board of the Cancer Institute Hospital of the Japanese Foundation of Cancer Research (registry number 2024-GB-073) and was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003ch2\u003eConflict of Interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work has not received external funding.\u003c/p\u003e\n\u003ch2\u003eAuthor Contributions\u003c/h2\u003e\n\u003cp\u003eConception and design: KY, HO, and ES; acquisition of data: KY; analysis and interpretation of data: KY, HO, and ES; writing, review, and/or revision of the manuscript: all authors; administrative, technical, or material support: KY, HO, and ES; study supervision: ES.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThe authors thank Ms. Yuki Horiike, Ms. Hitomi Hannan, and Ms. Yukie Naito for managing the data.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71(3):209\u0026ndash;249\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7(8):573\u0026ndash;584\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMisset JL (1998) Oxaliplatin in practice. Br J Cancer 77(Suppl 4):4\u0026ndash;7\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCervantes A, Adam R, Rosell\u0026oacute; S, Arnold D, Normanno N, Ta\u0026iuml;eb J et al (2023) Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 34(1):10\u0026ndash;32\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMorris VK, Kennedy EB, Baxter NN, Benson AB 3rd, Cercek A, Cho M et al (2023) Treatment of Metastatic Colorectal Cancer: ASCO Guideline. 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Crit Rev Oncol Hematol 82(1):51\u0026ndash;77\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrandi G, Pantaleo MA, Galli C, Falcone A, Antonuzzo A, Mordenti P et al (2003) Hypersensitivity reactions related to oxaliplatin (OHP). Br J Cancer 89(3):477\u0026ndash;481\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHunter DMR, Perry KMA (1945) Asthma caused by the complex salts of platinum. Br J Ind Med 2(2):92\u0026ndash;98\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCleare MJ, Hughes EG, Jacoby B, Pepys J (1976) Immediate (type I) allergic responses to platinum compounds. Clin Allergy 6(2):183\u0026ndash;195\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShlebak AA, Clark PI, Green JA (1995) Hypersensitivity and cross-reactivity to cisplatin and analogues. 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Oncology 76(4):231\u0026ndash;238\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMori Y, Nishimura T, Kitano T, Yoshimura K-i, Matsumoto S, Kanai M et al (2010) Oxaliplatin-Free Interval as a Risk Factor for Hypersensitivity Reaction among Colorectal Cancer Patients Treated with FOLFOX. Oncology 79(1\u0026ndash;2):136\u0026ndash;143\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShen Y, Li C, Liu W, Mao W, Qian H, Wang H et al (2018) Clinical Analysis of Hypersensitivity Reactions to Oxaliplatin Among Colorectal Cancer Patients. Oncol Res 26(5):801\u0026ndash;807\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M et al (2006) OPTIMOX1: A Randomized Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal Cancer\u0026mdash;A GERCOR Study. 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Allergy 79(3):679\u0026ndash;689\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"oxaliplatin, hypersensitivity reaction, prevention protocol, metastatic colorectal cancer","lastPublishedDoi":"10.21203/rs.3.rs-7362787/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7362787/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOxaliplatin (OXA), a key cytotoxic agent used in the treatment of gastrointestinal cancers, is frequently discontinued due to hypersensitivity reactions (HSRs). We developed a protocol to mitigate HSRs and assessed its clinical efficacy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively analyzed HSRs in patients with metastatic colorectal cancer (mCRC) who were treated with OXA-containing regimens between 2005 and 2019. We evaluated the clinical utility of our HSR prevention protocol in patients who experienced grade 1–3 HSRs following OXA-based chemotherapy. The protocol involved increasing dexamethasone to 16.5 mg/body and extending the OXA infusion time from 2 to 4 hours.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 205 patients, 105 (51.2%) experienced grade 1, 95 (46.3%) grade 2, and 5 (2.4%) grade 3 HSRs. Most patients (87.8%) received either the FOLFOX4 or modified FOLFOX6 regimen. Patients underwent a median of 11 OXA cycles before their initial HSR. OXA was successfully reintroduced in 108 patients (52.7%) using the HSR prevention protocol. The median OXA-free interval was 23 days and the median progression-free survival after reintroduction was 6.4 months (95% confidence interval [CI]: 4.6–8.2). Reasons for discontinuation included a second HSR in 97 patients (47.3%), disease progression in 74 (36.1%), and chemotherapy-induced peripheral neuropathy (CIPN) in 15 (7.3%). Forty-six patients (22.4%) experienced an HSR during the initial prevention protocol. Only six patients (2.9%) experienced grade 3 HSRs and no grade 4 or 5 events were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHigh-dose dexamethasone and prolonged infusion time may enable OXA reintroduction, providing an alternative to permanent discontinuation in mCRC patients with prior HSRs.\u003c/p\u003e\n\u003cp\u003eRegistry number: 2024-GB-073 (retrospectively registered).\u003c/p\u003e","manuscriptTitle":"High-dose dexamethasone and prolonged infusion time prevent oxaliplatin-related hypersensitivity reactions in patients with metastatic colorectal cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-24 02:15:21","doi":"10.21203/rs.3.rs-7362787/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2025-11-04T05:02:13+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-10-09T22:44:28+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-09T11:21:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-21T13:41:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-08-13T04:35:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e6d2d8f2-bb93-4fbc-b2da-eb6a6c23f279","owner":[],"postedDate":"October 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-03T14:41:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-24 02:15:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7362787","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7362787","identity":"rs-7362787","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}