Identification of docetaxel, cisplatin, and 5-fluorouracil regimen hypersensitivity by In vitro T-cell activation assay

Hang Huong Ling; Chun-Bing Chen; Cheng-Hsu Wang; Yen-Min Huang

doi:10.4103/JCRP.JCRP_11_19

CASE REPORT

Year : 2019 | Volume : 6 | Issue : 4 | Page : 184-187

Identification of docetaxel, cisplatin, and 5-fluorouracil regimen hypersensitivity by In vitro T-cell activation assay

Hang Huong Ling¹, Chun-Bing Chen², Cheng-Hsu Wang¹, Yen-Min Huang¹
¹ Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Keelung and Chang Gung University College of Medicine, Taoyuan, Taiwan
² Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital at Keelung and Chang Gung University College of Medicine, Taoyuan, Taiwan

Date of Submission	05-Apr-2019
Date of Decision	08-May-2019
Date of Acceptance	15-May-2019
Date of Web Publication	22-Nov-2019

Correspondence Address:
Dr. Yen-Min Huang
Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Keelung, No. 200, Lane 208, Jijin 1^st Road, Keelung 20445
Taiwan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCRP.JCRP_11_19

Abstract

An in vitro T-cell activation assay measuring granulysin and granzyme B has been used to identify the drug hypersensitivity of common causative drugs, but not of chemotherapeutic drugs. Both granulysin and granzyme B are cytotoxic molecules involved in skin eruptions during drug hypersensitivity. Herein, we report the first clinical application of an in vitro T-cell activation assay to identify the causative agent in docetaxel, cisplatin, and 5-fluorouracil (5-FU)-related hypersensitivity in a patient with head-and-neck cancer. A significant increase in granulysin and granzyme B was observed for 5-FU rather than for docetaxel or cisplatin. Despite several limitations, we were still able to pinpoint 5-FU as the culprit drug in a chemotherapy combination without further drug rechallenge in our patient. In conclusion, an in vitro T-cell activation assay measuring granulysin and granzyme B can be a safe and alternative tool to determine the causative agent of hypersensitivity reactions in cancer patients who need combination chemotherapy.

Keywords: Docetaxel, cisplatin, and 5-fluorouracil, granulysin, granzyme B, hypersensitivity, in vitro T-cell activation assay

How to cite this article:
Ling HH, Chen CB, Wang CH, Huang YM. Identification of docetaxel, cisplatin, and 5-fluorouracil regimen hypersensitivity by In vitro T-cell activation assay. J Cancer Res Pract 2019;6:184-7

How to cite this URL:
Ling HH, Chen CB, Wang CH, Huang YM. Identification of docetaxel, cisplatin, and 5-fluorouracil regimen hypersensitivity by In vitro T-cell activation assay. J Cancer Res Pract [serial online] 2019 [cited 2020 Feb 22];6:184-7. Available from: http://www.ejcrp.org/text.asp?2019/6/4/184/271492

Introduction

The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) (TPF) is commonly used as induction chemotherapy for patients with locally advanced head-and-neck cancer. The adverse effects of this regimen include myelotoxicity, stomatitis, nausea, vomiting, diarrhea, and less frequently, hypersensitivity reactions. The incidence of all grades of skin rash or itchiness has been reported to be ~ 20% despite the use of premedications.^[1] Drug rechallenge is regarded to be the gold standard to determine the culprit drug in most circumstances; however, sometimes, it is not feasible owing to patient safety and ethical reasons.^[2] Several previous studies have reported the use of anin vitro T-cell activation assay measuring granulysin, granzyme B, or interferon-γ (IFN-γ) to identify the causative drug in patients with severe cutaneous adverse reactions (SCARs).^{[3],[4],[5],[6]} Herein, we report the first clinical application of anin vitro T-cell activation assay measuring granulysin and granzyme B to determine the culprit drug in TPF-related hypersensitivity in a patient with head-and-neck cancer.

Case Report

A 48-year-old Taiwanese male was diagnosed with squamous cell carcinoma of the left tonsil, cT2N2bM0, and Stage IV A (AJCC 7^th edition) in February 2017. He initially presented with the left neck Level III palpable, 5 cm × 4 cm, nontender mass which persisted for 1 month. Left tonsillectomy confirmed squamous cell carcinoma that was keratinizing and moderately differentiated. The results of immunohistochemistry staining for p16 were negative. 18-F fluorodeoxyglucose positron-emission tomography/computed tomography (CT) and head-and-neck CT revealed left tonsil cancer with left neck nodal metastasis, cT2N2bM0. A bone scan revealed no evidence of bony metastasis. He then started induction chemotherapy for the locally advanced disease, which consisted of docetaxel 75 mg/m² on day 1, cisplatin 75 mg/m² on day 1, and continuous infusion 5-FU 600 mg/m² on day 1 to 5.

One day after the completion of chemotherapy, he had a Grade 1 maculopapular rash over his face, Grade 3 oral mucositis, Grade 3 dysphagia, and Grade 3 hand-foot syndrome, according to the Common Terminology Criteria for Adverse Events version 4.0 (HHS/NHI/NCI, MD, USA). A physical examination revealed a maculopapular rash over his forehead and bilateral cheeks, multiple oral ulcers and blistering, and violaceous erythema plaques on his palms and soles [Figure 1]. No pustules or skin desquamation were observed. Laboratory tests revealed normal liver and renal function, with no leukocytosis or eosinophilia. The skin eruption progressed, and systemic corticosteroids were administered. Topical corticosteroids (i.e., clobetasol 0.05%), adequate pain control medications, and antihistamines were also prescribed. His symptoms resolved after 10 days of supportive treatment.

Figure 1: (a) Clinical features of Grade 1 maculopapular rash over the forehead and bilateral cheeks and Grade 3 oral mucositis. (b and c): Grade 3 hand-foot syndrome, erythema, and blistering of hands and feet interfering with normal activities after the first cycle of TPF chemotherapy

Click here to view

Due to the first episode of cutaneous adverse events involving the face and extremities immediately after finishing chemotherapy, the possibility of drug hypersensitivity was raised aside from hand-foot syndrome. We initially speculated that docetaxel was the causative drug based on the onset and timing of the dermatologic adverse events.^[7] Anin vitro T-cell activation test was performed to identify the culprit drug. We isolated peripheral blood mononuclear cells from the patient and cultured them with docetaxel, cisplatin, and 5-FU in RPMI-1640 medium (GIBCO Invitrogen, Life Technologies, Carlsbad, CA) supplemented with 10% human serum and IL-7 at 37°C in 5% CO₂ for 1 week.^[4],[5],[6] Dimethyl sulfoxide was used as the negative control, and phytohemagglutinin was used as the positive control. The levels of granulysin and granzyme B in the culture supernatants were measured by the enzyme-linked immunosorbent assay after 1 week. The sensitivities of this assay for granulysin and granzyme B were 1.56 ng/mL and 10 pg/mL, respectively.^[4],[8] Significant fold changes of granulysin (6.4-fold) and granzyme B (29.2-fold) were observed in 5-FU compared to those in cisplatin and docetaxel [Table 1]. Therefore, the assay preliminarily identified 5-FU as the culprit drug. We stopped induction chemotherapy and proceeded to definitive concurrent chemoradiotherapy (CCRT) in this patient. However, we did not resume cisplatin in the following CCRT after discussion with the patient. Alternative bioradiotherapy with cetuximab was initiated in mid-April. He underwent complete treatment without further adverse effects. The most recent head-and-neck CT in March 2018 revealed the maintenance of complete remission.

Table 1: Result of allergological investigation by in vitro T-cell activation assay

Click here to view

Discussion

Anin vitro T-cell activation assay measuring granulysin and granzyme B has been used to identify drug hypersensitivity in common causative drugs; however, hypersensitivity associated with chemotherapeutic drugs has not previously been reported.^[4],[5],[6] The traditional method of drug rechallenge is time-consuming and risky, as it may lead to the recurrence of SCARs and even fatal consequences.^[2] We used this assay because it can be performedin vitro is relatively safe and allows time for the patient to recover while awaiting the results.

Both granulysin and granzyme B are cytotoxic molecules involved in skin eruptions that are immunologically induced by drugs, particularly in SCARs.^[8],[9] Single granulysin or granzyme B assays may provide a sensitivity of 30%–50% for common causative drugs.^[3] Porebski et al. reported that a combination of granulysin, granzyme B, and IFN-γ assays may provide a sensitivity of 80% (confidence interval [CI]: 52%–96%) and specificity of 95% (CI: 80%–99%) for drug hypersensitivity.^[3] Although our patient demonstrated less severe cutaneous adverse events, the culprit drug was able to induce concomitantly significant fold changes in granulysin and granzyme B in the assay.

Platinum and taxanes are two common classes of chemotherapeutic agents that cause hypersensitivity reactions [Table 2]. Cisplatin hypersensitivity is mostly IgE-mediated and often occurs within minutes after infusion.^[10] Immediate hypersensitivity has also been observed with docetaxel; however, some patients may develop delayed skin reactions, occurring several days or up to 1 week after administration.^[7],[12] In comparison, few studies have investigated 5-FU hypersensitivity [Table 2].^{[14],[15],[16]} Dihydropyrimidine dehydrogenase (DPD) deficiency, which is associated with DPYD gene mutations, has been reported to increase 5-FU-related adverse events by incompetent 5-FU degradation.^[17] Different formulations, dosing, and route of administration of fluorouracil have been reported to result in diverse toxicities.^{[18],[19],[20]} Whether our patient with hypersensitivity to 5-FU had cross-hypersensitivity to other formulations such as capecitabine, tegafur, and TS-1 is unknown.

Table 2: Comparison of cisplatin, docetaxel, and 5-fluorouracil-related hypersensitivity

Click here to view

There are several limitations to this case report. First, few studies have reported on 5-FU-related hypersensitivity, and therefore, more cases are needed to confirm ourin vitro findings and to determine standardized cutoff values for hypersensitivity. Second, we lacked skin biopsies and skin patch tests for the second confirmation. In addition, we did not perform DPD deficiency tests in our patient. Nevertheless, thein vitro T-cell activation assay enabled the clinicians to avoid 5-FU and to select cisplatin or other efficacious drugs in the subsequent treatment of this patient. Our patient received cetuximab instead of cisplatin due to his preference.

Conclusion

We demonstrated a novel application of anin vitro T-cell activation assay which measured granulysin and granzyme B to pinpoint the culprit drug in a common chemotherapy combination in a patient with locally advanced head-and-neck cancer. Thisin vitro assay may provide clinicians with an alternative safe method to determine the causative agent of hypersensitivity in cancer patients who receive combination chemotherapy and possibly to resume other efficacious drugs.

Ethics approval and consent for publication

Local Institutional Review Board approval was obtained (No. 201801033B0). The patient provided informed consent for publication of this case.

Acknowledgment

We would like to thank Prof. Chung and his colleagues at the Drug Hypersensitivity Clinical and Research Center who provided assistance in the result of the article. We also thank all members of the Cancer Center of Chang Gung Memorial Hospital, Keelung, Taiwan, for their invaluable help.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.
2.	Aberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez J, et al. Drug provocation testing in the diagnosis of drug hypersensitivity reactions: General considerations. Allergy 2003;58:854-63.
3.	Porebski G, Pecaric-Petkovic T, Groux-Keller M, Bosak M, Kawabata TT, Pichler WJ. In vitro drug causality assessment in Stevens-Johnson syndrome – Alternatives for lymphocyte transformation test. Clin Exp Allergy 2013;43:1027-37.
4.	Chung WH, Pan RY, Chu MT, Chin SW, Huang YL, Wang WC, et al. Oxypurinol-specific T cells possess preferential TCR clonotypes and express granulysin in allopurinol-induced severe cutaneous adverse reactions. J Invest Dermatol 2015;135:2237-48.
5.	Lin CY, Wang CW, Hui CR, Chang YC, Yang CH, Cheng CY, et al. Delayed-type hypersensitivity reactions induced by proton pump inhibitors: A clinical andin vitro T-cell reactivity study. Allergy 2018;73:221-9.
6.	Lin YC, Sheu JN, Chung WH, Pan RY, Hung CJ, Cheng JJ, et al. Vancomycin-induced Stevens-Johnson syndrome in a boy under 2 years old: An early diagnosis by granulysin rapid test. Front Pediatr 2018;6:26.
7.	Picard M, Castells MC. Re-visiting hypersensitivity reactions to taxanes: A comprehensive review. Clin Rev Allergy Immunol 2015;49:177-91.
8.	Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008;14:1343-50.
9.	Chung WH, Wang CW, Dao RL. Severe cutaneous adverse drug reactions. J Dermatol 2016;43:758-66.
10.	Makrilia N, Syrigou E, Kaklamanos I, Manolopoulos L, Saif MW. Hypersensitivity reactions associated with platinum antineoplastic agents: A systematic review. Met Based Drugs 2010;2010. pii: 207084.
11.	Caiado J, Castells M. Presentation and diagnosis of hypersensitivity to platinum drugs. Curr Allergy Asthma Rep 2015;15:15.
12.	Picard M, Pur L, Caiado J, Giavina-Bianchi P, Galvão VR, Berlin ST, et al. Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions. J Allergy Clin Immunol 2016;137:1154-64.e12.
13.	Tham EH, Cheng YK, Tay MH, Alcasabas AP, Shek LP. Evaluation and management of hypersensitivity reactions to chemotherapy agents. Postgrad Med J 2015;91:145-50.
14.	Duley JA, Nethersell AB. Delayed hypersensitivity to 5-fluorouracil associated with reduced dihydropyrimidine dehydrogenase (DPD) activity. Adv Exp Med Biol 1998;431:147-50.
15.	Andou H, Itoh K, Tsuda T. A case of fluorouracil-induced pneumonitis. Nihon Kyobu Shikkan Gakkai Zasshi 1997;35:1080-3.
16.	Kounis NG, Koniari I, Patsouras N, Koutsogiannis N, Velissaris D, Soufras G, et al. Coronary vasospasm associated with 5-fluorouracil chemotherapy: Cardiac toxicity or cardiac hypersensitivity? Am J Emerg Med 2017;35:1769-71.
17.	Ezzeldin H, Diasio R. Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer 2004;4:181-9.
18.	Chionh F, Lau D, Yeung Y, Price T, Tebbutt N. Oral versus intravenous fluoropyrimidines for colorectal cancer. Cochrane Database Syst Rev 2017;7:CD008398.
19.	Demir S, Olgac M, Saglam S, Gelincik A, Colakoglu B, Buyukozturk S. Successful capecitabine desensitization for a delayed-type hypersensitivity reaction. J Investig Allergol Clin Immunol 2016;26:66-7.
20.	Tan CS, Lim R, Lim TC, Aw CW, Yeo SW, Lee SC. Toxic epidermal necrolysis associated with TS-1 in a patient with gastric cancer. Jpn J Clin Oncol 2011;41:666-8.