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Korean J Gastroenterol  <  Volume 82(6); 2023 <  Articles

Korean J Gastroenterol 2023; 82(6): 288-294  https://doi.org/10.4166/kjg.2023.114
Leucovorin-induced Hypersensitivity Reaction in a Patient with Metastatic Colorectal Cancer Treated with Cetuximab Plus FOLFOX Chemotherapy: A Case Report
Minna Kim1*, Dong Hyun Kim1*, Jong Yoon Lee1 , Young-Hee Nam2, Jong Hoon Lee1
Division of Gastroenterology, Department of Internal Medicine, Dong-A University College of Medicine1; Division of Allergy and Clinical Immunology, Department of Internal Medicine, Dong-A University College of Medicine2, Busan, Korea
Correspondence to: Jong Yoon Lee, Division of Gastroenterology, Department of Internal Medicine, Dong-A University College of Medicine, 32 Daesingongwon-ro, Seo-gu, Busan 49201, Korea. Tel: +82-51-240-5042, Fax: +82-51-242-5852, E-mail: ljyhateo@gmail.com, ORCID: https://orcid.org/0000-0002-6542-8062

*These authors are contributed equally to this work.
Received: September 18, 2023; Revised: November 6, 2023; Accepted: November 11, 2023; Published online: December 25, 2023.
© The Korean Journal of Gastroenterology. All rights reserved.

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The FOLFOX regimen (combination of leucovorin, 5-fluorouracil, and oxaliplatin) is the first-line treatment for high-risk stage 2 and 3 colorectal cancer patients. While hypersensitivity reactions (HSRs) caused by oxaliplatin are commonly reported, HSRs due to leucovorin have been infrequently reported. This report aims to investigate the clinical presentation, diagnosis, and management of leucovorin induced HSRs. A 60-year-old female developed generalized edema, dyspnea, and facial redness during cetuximab plus FOLFOX chemotherapy administered for management of metastatic colorectal cancer. Because HSRs induced by oxaliplatin are commonly reported, we initially presumed an oxaliplatin-induced HSR. However, despite undergoing oxaliplatin desensitization, HSRs persisted, and they were still observed when leucovorin was administered without oxaliplatin. The patient was diagnosed with leucovorin-induced HSR and underwent leucovorin desensitization. However, the reactions recurred within 30 minutes of the initiating the desensitization. Considering unsuccessful leucovorin desensitization, leucovorin was excluded. The patient received cetuximab and oxaliplatin chemotherapy without leucovorin to date without any adverse effects. While leucovorin-induced HSRs are infrequently reported, they should still be regarded as potential adverse effects.
Keywords: Colorectal cancer; Leucovorin; Hypersensitivity
INTRODUCTION

The FOLFOX regimen (combination of leucovorin, 5-fluorouracil [5-FU], and oxaliplatin) is considered first-line therapy for high-risk patients with colorectal cancer (CRC) stages 2 and 3.1 Combination of target agents such as bevacizumab or cetuximab with FOLFOX is preferred for management of metastatic CRC (mCRC).2 However, adverse reactions such as hematological and gastrointestinal tract toxicity, neuropathy, and hypersensitivity reactions (HSRs) to oxaliplatin have been reported.3 In contrast to oxaliplatin-induced HSRs (incidence rate of approximately 12%), only a few cases of leucovorin-induced HSRs have been reported.4-7 Moreover, the FOLFOX regimen includes concurrent administration of leucovorin and oxaliplatin. Therefore, leucovorin-induced HSRs may be misattributed to those caused by oxaliplatin.8 However, despite the rarity of leucovorin HSRs, there have been reports of HSRs caused by leucovorin. In one case report, a patient with rectal cancer and hepatic metastasis was started on palliative therapy with 5-FU and leucovorin. Immediately after leucovorin administration, the patient developed diffuse urticaria and dyspnea. The skin tests were positive for leucovorin and negative for folic acid, and the patient continued chemotherapy treatment with 5-FU alone without experiencing side effects.5 In another case report, a patient with stage IV KRAS-mutated cecal adenocarcinoma with ovarian metastases underwent complete resection of the primary tumor and metastases. Postoperative FOLFOX chemotherapy was initiated. However, during the 10th cycle of chemotherapy, the patient experienced lower back pain and fever. This was initially attributed to the side effects of oxaliplatin, and the patient continued 5-FU and leucovorin without oxaliplatin for the remaining chemotherapy cycles. However, HSRs continued within 10 minutes of leucovorin administration. In this case, a skin prick test (SPT) conducted eight weeks after the occurrence of the 1st episode and was negative for folic acid.6

We report a case of HSRs observed during cetuximab and FOLFOX combination therapy administered to a patient with mCRC. Initially, we suspected that the HSR was due to oxaliplatin, but ultimately, it was diagnosed as an HSR caused by leucovorin.

CASE REPORT

Prior to the initiation of the study, informed consent was obtained from the patient, allowing the patient to make an explicit and voluntary decision.

A 60-year-old female with no relevant medical history or known drug allergies was diagnosed with stage IIIB sigmoid colon cancer in April 2020. The patient underwent laparoscopic low anterior resection and initiated adjuvant FOLFOX chemotherapy between May and October 2020. One year after completing chemotherapy, multiple lung metastases were detected based on positron emission tomography computed tomography. Genetic analysis revealed epidermal growth factor receptor mutation but no mutations in the KRAS, NRAS, and BRAF genes. The patient received cetuximab plus FOLFOX chemotherapy from November 2021 and achieved disease stabilization after completion of 18 chemotherapy cycles, and we decided to continue cetuximab and FOLFOX combination therapy. The sequence of cetuximab plus FOLFOX chemotherapy was as follows: cetuximab administration, followed by the simultaneous administration of oxaliplatin and leucovorin, and finally the administration of 5-FU. The patient received intravenous dexamethasone (5 mg) and chlorpheniramine (4 mg) before initiation of each chemotherapy cycle to minimize potential chemotherapy induced adverse effects and successfully completed 18 chemotherapy cycles without any adverse effects.

The 19th chemotherapy cycle was initiated in November 2022. No medications that could interact with leucovorin were administered, and laboratory tests did not reveal any abnormal findings. The patient received leucovorin and oxaliplatin following cetuximab administration; however, she developed facial flushing and pruritus on the trunk within 30 minutes. Her blood pressure (BP) was 90/50 mmHg, heart rate (HR) was 101 beats per min (bpm), and peripheral capillary oxygen saturation (SpO2) was 89%. Laboratory test results showed a serum tryptase level of 11.4 μg/L (normal <11 μg/L) within 4 hours of symptom onset. Chemotherapy was discontinued, and the patient’s symptoms improved after the administration of oxygen and fluids. The patient was referred for an allergy consultation and oxaliplatin desensitization was scheduled for the next treatment cycle based on the clinical suspicion that oxaliplatin was the causative drug.

The patient was admitted for the 19th chemotherapy cycle two weeks later, and after receiving cetuximab, oxaliplatin desensitization was performed. No abnormal reactions were observed after she received cetuximab and oxaliplatin, and we administered leucovorin, which however led to facial flushing and dyspnea 20 minutes after the administration of this drug. The patient’s vital signs were as follows: BP 96/60 mmHg, HR 103 bpm, and SpO2 100%. The patient’s symptoms improved following an intravenous injection of chlorpheniramine (4 mg/mL).

On December 19, 2022, the patient was admitted to the hospital for 20th chemotherapy cycle and underwent oxaliplatin desensitization following cetuximab injection. During this cycle, the patient was closely monitored for any adverse effects over an extended period. After confirming her condition was stable over several hours, the patient received leucovorin. However, the patient developed dyspnea and urticaria within 5 min of drug administration, and her BP was 100/64 mmHg, HR was 90 bpm, and SpO2 was 95%. Her symptoms improved after the administration of oxygen, fluids, and an intravenous injection of chlorpheniramine (4 mg). Despite the absence of adverse effects over several hours after oxaliplatin desensitization, we could not completely exclude the possibility of delayed oxaliplatin-induced HSR. To conclusively establish the causal association between the patient’s symptoms and the administered medication, we first administered leucovorin, followed by oxaliplatin desensitization.

The patient was admitted in February 2023 for the 21st chemotherapy cycle and was successfully administered cetuximab. Following leucovorin administration, she developed facial redness 20 minutes later with BP of 100/68 mmHg, HR 86 bpm, and SpO2 of 97%. After the administration of intravenous dexamethasone (5 mg), the patient’s symptoms improved, and subsequently, both the oxaliplatin desensitization and administration of 5-FU was successfully completed in sequence. Based on the fact that the patient developed the same HSR as before when leucovorin was administered alone, we diagnosed leucovorin-induced HSR. In this cycle, the symptoms were milder when leucovorin was administered alone compared to when it was administered with oxaliplatin. Therefore, we decided to continue the chemotherapy treatment in the following order: cetuximab, leucovorin, oxaliplatin desensitization, and 5-FU.

On February 27, 2023, the patient was admitted for the 22nd cycle of chemotherapy treatment. After successfully administering cetuximab without any adverse effects, leucovorin was subsequently administered. However, within 30 minutes, the patient experienced dyspnea and redness of the trunk (Fig. 1), with a BP of 100/60 mmHg and SpO2 of 95%. The patient’s symptoms improved after the intravenous administration of chlorpheniramine (4 mg), and subsequently, the administration of other chemotherapy agents was successfully completed without any adverse effects. After consultation with the allergist, the causative drug was suspected to be leucovorin because the same HSR occurred within 30 minutes of administering leucovorin without oxaliplatin.

Figure 1. Red rash papules on the trunk appeared after administrating leucovorin within 30 minutes.

Leucovorin desensitization was planned for the next cycle. On March 30, 2023, the patient was admitted for the 23rd chemotherapy cycle and was successfully administered cetuximab without any complications. Leucovorin (5.2 mg) was mixed with 500 mL of 5% dextrose and was administered at a rate of 2 mL/hour, with the infusion rate gradually increased at 15-minute intervals. We aimed to gradually administer leucovorin, commencing from 5.2 mg, without any adverse reactions and subsequently increasing the dose 10-fold to eventually administer a total dose of 520 mg. Table 1 illustrates the leucovorin desensitization protocol. The severity of HSRs was determined based on the Common Terminology Criteria for Adverse Events system.9 Leucovorin was diluted to a ratio of 1:100 and administered at a rate of 2 mL/hour; after 15 minutes, the patient did not report any adverse reactions, so the infusion rate was increased to 5 mL/hour. However, following the rate increase, the patient experienced facial redness, dyspnea. The patient’s SpO2 dropped to 88%, BP was 96/64 mmHg, and HR was 74 bpm. Leucovorin administration was stopped, and the patient’s symptoms improved after receiving intravenous chlorpheniramine (4 mg) and oxygen supplementation. Table 2 summarizes the patient’s general clinical data.

Table 1 . The Leucovorin Desensitization Protocol Used in 23rd Cycle of Chemotherapy

1. Dexamethasone 5 mg and chlorpheniramine 4 mg were administered intravenously before the chemotherapy treatment.
2. Desensitization protocol using a total dose of 520 mg of leucovorin
Total dose520 mgSolution concentrationTotal dose in each solution
Solution A520 mL0.01 mg/mL5.2 mg
Solution B520 mL0.10 mg/mL52 mg
Solution C520 mL1.00 mg/mL520 mg
StepSolutionRate (mL/hr)Time (min)
1A215
2A515
3A1015
4A2015
5B515
6B1015
7B2015
8B4015
9C1015
10C2015
11C4015
12C7515
3. If the patient experiences hypersensitivity reaction at any point, discontinue infusion and administer 4 mg of chlorpheniramine and 5 mg of hydrocortisone intravenously. Intramuscular injection of 0.3 mg/mL of epinephrine can be given based on the severity of the symptom.


Table 2 . Summary of Hypersensitivity Reactions Occurring in the Patient

CycleSituation at the time of symptom onsetHypersensitivity reactionsGrade
19th cycle (failed)30 minutes after the start of oxaliplatin and leucovorin infusionFacial flushing, pruritus on the trunk, hypotension, SpO2 89%4
19th cycle (retry)20 minutes after the initiation of leucovorin infusionFacial flushing, dyspnea2
20th cycle5 minutes after the initiation of leucovorin infusionDyspnea, urticaria2
21st cycle20 minutes after the start of leucovorin infusion without the previous administration of oxaliplatinFacial flushing2
22nd cycle30 minutes after the start of leucovorin infusionRedness on the trunk, dyspnea2
23rd cycle15 minutes after the start of leucovorin infusion in a 1:100 diluted doseFacial flushing, dyspnea4

SpO2, peripheral capillary oxygen saturation.



Despite attempts to achieve leucovorin desensitization, the patient continued to experience a severe reaction and was anxious regarding continuation of chemotherapy. Therefore, for the 24th chemotherapy cycle on May 2, 2023, leucovorin was excluded and only administered only cetuximab and oxaliplatin. The patient successfully completed the administration of cetuximab and oxaliplatin without any adverse effects, and to date, the patient has received two additional cycles of cetuximab and oxaliplatin chemotherapy.

DISCUSSION

Following an increase in the number of patients who benefit from chemotherapy, FOLFOX is widely being used in clinical practice, which has led to an increase in the prevalence of associated adverse effects.10,11 While adverse effects of oxaliplatin are commonly reported, those associated with leucovorin are rare.12 Here, we discuss the clinical manifestation of HSRs attributed to leucovorin, the diagnostic process for our patient in comparison with other case reports, and the management approach.

Leucovorin-induced HSRs can manifest with a variety of symptoms, ranging from mild symptoms such as pruritus and urticaria to more severe manifestations including anaphylaxis.13,14 These reactions can manifest either shortly after the first leucovorin infusion or, as in our case, after several cycles of chemotherapy. There have been reported cases of HSRs attributed to leucovorin (Table 3). Of the 13 cases, four experienced HSRs after the first leucovorin infusion,5,8 and in one case, HSR occurred on the 7th administration of leucovorin.14 In the other case reports, HSRs were reported to occur after 10 or more administrations of leucovorin.6-8,12,13 The pathophysiology and mechanisms underlying HSR remain unclear; however, immediate-type HSRs secondary to oxaliplatin use are attributable to immunoglobulin (Ig)E-mediated type I hypersensitivity.15 In one case report, there was an increase in serum tryptase levels and a positive intradermal skin test (IDT) to leucovorin.6 Also, specific IgE antibodies were detected in patients who experienced HSR after leucovorin administration, suggesting that leucovorin-induced HSR is mediated by IgE allergic reactions.16 As in our case, HSRs can occur after several injections. On the other hand, HSRs have also occurred during the first administration of leucovorin in instances where individuals have consumed foods or vitamins containing folate.6 In this case, additional tests such as IDT or SPT were not conducted. However, typical HSRs, such as flushing, rash, and dyspnea, occurred and the serum tryptase level was elevated within 30 minutes after leucovorin administration, and the symptoms occurred after the patient received several additional cycles of chemotherapy. Therefore, our patient was also presumed to have experienced HSRs mediated by IgE.

Table 3 . List of Cases Reported on Hypersensitivity Reactions Induced by Leucovorin

Author (yr)Age, sexThe type of cancer and the chemotherapy regimen prior to the HSRChemotherapy regimen, cycle, and clinical events in which HSRs to LV first occurredDiagnosis test results for of HSR due to LV
Benchalal et al.14 (2002)80, MStage III colon cancer, 6 cycles of 5-FU and LVRegimen: FOLFIRI
1st cycle: rash
2nd cycle: rash, hypotension
Clinical diagnosis:
No more reactions occurred after LV was excluded
Vermeulen et al.5 (2003), 1st case57, MMetastatic rectal cancerRegimen: 5-FU and LV
1st cycle: diffuse urticaria and dyspnea
SPT: positive for LV
IDT: positive for LV
Vermeulen et al.5 (2003), 2nd case59, MMetastatic colon cancerRegimen: FOLFOX
1st cycle: diffuse urticaria
2nd cycle: diffuse urticaria
SPT: negative for LV
IDT: positive for LV
Clinical diagnosis:
Successful oral desensitization
Damaske et al.12 (2012)53, MStage IV colon cancer, 12 cycles of
FOLFOX 6-bevacizumab, 12 cycles of
FOLFIRI-bevacizumab, 12 cycles of
FOLFOX 6-bevacizumab
Regimen: FOLFOX 6-bevacizumab
13th cycle: flushing, pruritus, wheals
15th cycle: aggravated hives, pruritus
18th cycle (LV dose reduction was done): redness, pain, headache, facial flushing
19th cycle (OX dose reduction was done): pruritus, headache, elevated blood pressure, chest tightness, hotness, extreme diaphoresis
20th cycle (OX was discontinued): flushing, headache, general pain, low back spasm and pain, diaphoretic
Clinical diagnosis: No more reactions occurred after LV was excluded
Ureña-Tavera et al.8 (2015), 1st case65, MStage IV gastric adenomaRegimen: FOLFOX
1st cycle: facial erythema and general urticaria
SPT, IDT: negative to LV
DPT: positive to LV
Tryptase: normal
Ureña-Tavera et al.8 (2015), 2nd case66, FStage IV colon adenocarcinoma, 17 cycles of FOLFOXRegimen: FOLFOX
18th cycle: genital and scalp itching, rhinoconjunctivitis, general malaise
SPT, IDT: negative to LV
DPT: positive to LV
Tryptase: normal
Ureña-Tavera et al.8 (2015), 3rd case52, FStage IV rectal adenocarcinoma, 18 cycles of FOLFOXRegimen: FOLFOX
19th cycle: intense chilling
SPT, IDT: negative to LV
DPT: positive to LV
Tryptase: normal
Ureña-Tavera et al.8 (2015), 4th case73, MStage IV colon adenocarcinomaRegimen: FOLFIRI
1st cycle: facial erythema, urticaria, and eyelid angioedema
SPT, IDT: negative to LV
DPT: positive to LV
Tryptase: normal
Ureña-Tavera et al.8 (2015), 5th case80, MStage IV colon adenocarcinoma, 10 cycles of FOLFOX, 7 cycles of FOLFIRIRegimen: FOLFIRI
8th cycle: dyspnea, chest pain, oxygen desaturation (85%), and facial erythema
SPT, IDT: negative to LV
DPT: positive to LV
Tryptase: normal
Florit-Sureda et al.7 (2016)56, MStage III sigmoid colon cancer, 12 cycles of FOLFOX, 9 cycles of FOLFOX6Regimen: FOLFOX 6
10th cycle: heating sense, erythema, oedema, pruritus, abdominal pain
11th cycle: erythema, pruritus, dyspnea
12th cycle (OX was excluded): facial redness, pruritus, dyspnea
Clinical diagnosis: No more reactions occurred after LV was excluded
Gudimetla et al.13 (2019)62, FStage IV adenocarcinoma of the sigmoid colon, 3 months of mFOLFOX 6, 8 cycles of mFOLFOX 6-bevacizumabRegimen: mFOLFOX 6 with bevacizumab
9th cycle: numbness
10th cycle (OX was excluded): numbness
11th cycle (LV dose reduction was done): numbness
Clinical diagnosis: No more reactions occurred after the change of the regimen (LV was excluded)
Apraxine et al.6 (2022), 1st case72, MStage IV colon cancer,
1st line therapy (FOLFOX-panitumumab), Maintenance therapy (capecitabine), 2nd line therapy (capecitabine, irinotecan, bevacizumab), FOLFIRI-bevacizumab, And 3 cycles of FOLFOX-panitumumab
Regimen: FOLFOX-panitumumab
4th cycle: Lower back muscle pain
5th cycle: Fever, facial edema
6th cycle: Facial and chest erythema with chills
7th cycle: Diffuse erythema with labial edema and tachycardia
Serum tryptase: elevated IDT: positive for LV
Apraxine et al.6 (2022), 2nd case45, FStage IV colon cancer, 9 cycles of FOLFOXRegimen: FOLFOX
10th cycle: Lower back muscle pain
11th cycle (only 5-FU and LV was administered): Lower back muscle pain and shivering
Regimen: FOLFIRI-bevacizumab after 6 months due to metastatic relapse
1st cycle: shivering, skin mottling, tachycardia, and cyanosis
Clinical diagnosis: No more reactions occurred after LV was excluded

HSR, hypersensitivity reaction; LV, leucovorin; 5-FU, 5-fluorouracile; FOLFIRI, folic acid, 5-FU, irinotecan; SPT, skin prick test; IDT, intradermal test; FOLFOX, FA, 5-FU, oxaliplatin; OX, oxaliplatin; DPT, drug provocation test; mFOLFOX, modified FOLFOX.



Treatment with antihistamines, antiemetics, and corticosteroids used as premedication and a slow infusion rate are usually sufficient in patients with mild hypersensitivity reactions.17 However, desensitization can be a safe and effective approach to manage IgE-mediated drug reactions in patients who develop severe HSRs.18-20 A study has reported urticaria, headache, and elevated BP following bevacizumab plus FOLFOX chemotherapy in a patient with stage IV colon cancer.12 The patient was diagnosed with leucovorin-induced HSR, and oxaliplatin monotherapy was used owing to failed leucovorin desensitization. We also attempted leucovorin desensitization in our patient; however, chemotherapy excluding leucovorin was continued owing to failure of desensitization.

We attributed the initial HSR to oxaliplatin, considering that oxaliplatin-induced HSRs are more common. However, the causal association between the administered drug and symptoms was unclear. We switched the order of administration of leucovorin and oxaliplatin desensitization to confirm the role of leucovorin in HSR and diagnosed leucovorin-induced HSR and attempted leucovorin desensitization, which unfortunately was unsuccessful. Considering the unsuccessful desensitization, leucovorin was excluded, and the patient has received cetuximab and oxaliplatin chemotherapy without leucovorin to date, without any adverse effects.

Oxaliplatin-induced HSRs occur more frequently than those caused by leucovorin. Furthermore, accurate diagnosis of leucovorin-induced HSRs is challenging owing to concurrent administration of oxaliplatin and leucovorin in chemotherapeutic regimens. Although leucovorin-induced HSRs are rare, they should be considered potential adverse effects, and close monitoring is important. Further research is warranted to investigate the mechanisms, diagnosis, and management of leucovorin-induced HSRs.

ACKNOWLEDGEMENTS

I would like to extend my deep gratitude to all those who provided support and assistance throughout the completion of this paper.

Financial support

None.

Conflict of interest

None.

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