Cancer Chemother Pharmacol (2014) 73:1021–1029 DOI 10.1007/s00280-014-2437-5
Original Article
Overcoming oxaliplatin hypersensitivity: different strategies are needed according to the severity and previous exposure Suh‑Young Lee · Hye‑Ryun Kang · Woo‑Jung Song · Kyung‑Hun Lee · Sae‑Won Han · Sang Heon Cho
Received: 21 May 2013 / Accepted: 5 March 2014 / Published online: 3 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose This study investigated the characteristics of oxaliplatin-related hypersensitivity reactions (HSR) and evaluated the efficacy of premedication and desensitization administration for controlling HSR in patients with gastrointestinal malignancy. Methods This retrospective study includes oxaliplatin hypersensitivity cases reported to our in-hospital, adverse drug reaction monitoring system between May 2008 and April 2012. We analyzed administration histories of oxaliplatin and premedication treatments, chemotherapy cycle and severity of the initial HSR, and prophylactic measures and their outcomes in subsequent chemotherapy cycles. Results One hundred and seventy-three patients showed hypersensitivity to oxaliplatin-based chemotherapy. Oxaliplatin HSR developed after mean chemotherapy cycle 6.3 ± 0.3. Specifically, while HSR occurred at cycle 7.6 ± 0.3 in the case of patients previously unexposed to oxaliplatin-containing chemotherapy, it occurred at cycle
2.6 ± 0.3 in previously exposed patients. Of the 173 patients who exhibited HSR, premedication was administered in 134 patients and 71.6 % of them succeeded in preventing HSR. Desensitization was attempted in 38 patients, including 20 patients in whom premedication administration was unsuccessful, and 89 % of desensitized patients successfully underwent oxaliplatin chemotherapy without HSR. As severity of HSR increased, the success rate by premedication decreased and the percentage of patients that underwent desensitization increased. Conclusions Attention should be paid to patients with any prior exposure to oxaliplatin, especially during early chemotherapy cycles. Given the high success rate of preventing HSR by desensitization administration and its apparent safety profile, we suggest that desensitization be considered as the first option for the treatment of grades 3 and 4 HSR cases.
S.-Y. Lee · H.-R. Kang · W.-J. Song · K.-H. Lee · S.-W. Han · S. H. Cho (*) Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea e-mail:
[email protected]
S.-Y. Lee · H.-R. Kang · W.-J. Song · S. H. Cho Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea
S.‑Y. Lee e-mail:
[email protected] H.‑R. Kang e-mail:
[email protected] W.‑J. Song e-mail:
[email protected] K.‑H. Lee e-mail:
[email protected]
S.-Y. Lee · H.-R. Kang · S. H. Cho Seoul National University Hospital Drug Safety Monitoring Center, Seoul, Korea S.-Y. Lee Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea K.-H. Lee · S.-W. Han Cancer Research Institute, Seoul National University, Seoul, Korea
S.‑W. Han e-mail:
[email protected]
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Keywords Oxaliplatin · Hypersensitivity · Premedication · Desensitization
Cancer Chemother Pharmacol (2014) 73:1021–1029
Materials and methods Study subjects
Abbreviations HSR Hypersensitivity reactions FOLFOX Folinic acid, fluorouracil, and oxaliplatin XELOX Capecitabine and oxaliplatin CTCAE Common Terminology Criteria for Adverse Events
Background Oxaliplatin, cisplatin, and carboplatin are categorized as platinum-containing chemotherapeutic agents. Such agents are reported to result in hypersensitivity reactions (HSR) [1]. Oxaliplatin, a third-generation, platinum-based agent, possesses a 1,2 diaminocyclohexane carrier and an oxalate ligand [2]. It is administered in combination with fluorouracil and leucovorin (FOLFOX regimen) for adjuvant chemotherapy in stage 3 colorectal cancer and for palliative chemotherapy in metastatic colorectal cancer, or with capecitabine (XELOX regimen) for metastatic gastric or colorectal cancer therapy [3]. Oxaliplatin is also used in locally developing colorectal carcinoma therapy and in pancreatic, gallbladder, and gynecologic cancer therapies [4, 5]. The most common adverse drug reaction of oxaliplatin is hematologic toxicity, which arises primarily as neutropenia. In addition, mild nausea, vomiting, and diarrhea can occur and are controllable with conservative management. Neurotoxicity is reported in 75 % of patients, but reversible in most cases [6]. Another important adverse effect of oxaliplatin is hypersensitivity. The frequency of hypersensitivity in patients undergoing oxaliplatin chemotherapy ranges between 12 and 15 % [7–9]. By extensive use of oxaliplatin for gastrointestinal cancer, the occurrence of oxaliplatin-related hypersensitivity increased during the last decade [10]. Reported indicators of oxaliplatin-induced hypersensitivity ranged from mild symptoms such as rash, erythema, itching, and fever to moderate-to-severe symptoms such as dyspnea, angioedema, and rarely shock and death [10]. Persistent HSR despite the use of premedication may result in discontinuation of oxaliplatin therapy. However, in most cases, the effectiveness of alternative anti-carcinogenic therapies is inferior to that of oxaliplatin. Therefore, it is crucial to appropriately manage HSR in patients using oxaliplatin. This study investigated characteristics of oxaliplatininduced HSR in patients with gastrointestinal malignancy and evaluated the efficacy of premedication and desensitization to manage oxaliplatin hypersensitivity.
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This was single-institutional retrospective cross-sectional study of 173 cases exhibiting HSR during oxaliplatin-based chemotherapy for gastrointestinal malignancy which were spontaneously reported by medical, nursing, and pharmacy staffs to the Drug Safety Monitoring Center in Seoul National University Hospital from May 2008 through April 2012. Oxaliplatin-containing chemotherapy regimens included FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and XELOX (capecitabine and oxaliplatin). We reviewed electronic medical records of reported cases and collected data on previous history of oxaliplatin administration, premedication status prior to the administration of chemotherapeutic agent. The severity of HSR and the cycle of chemotherapy when initial HSR appeared were also reviewed. If chemotherapy was continued after the initial HSR, we collected data on type of prophylactic treatment used and treatment results. This study was approved by the Institutional Review Board of Seoul National University Hospital and informed consent was waived. Assessment and management of oxaliplatin hypersensitivity Oxaliplatin‑containing chemotherapy Two regimens were used for oxaliplatin-containing chemotherapy. FOLFOX was given once every 2 weeks, administered at 85 mg/m2 of body surface area, followed by 200 mg/m2 of leucovorin and 1,000 mg/m2 of fluorouracil. In most cases, drugs were delivered in the following sequence, oxaliplatin, leucovorin, and fluorouracil. XELOX was given once every 3 weeks, administered at 130 mg/m2 body surface area, followed by daily 4,000 mg/ m2 of capecitabine for 2 weeks. Definition of hypersensitivity reactions In this study, oxaliplatin-induced hypersensitivity was defined as the occurrence of cutaneous symptoms (such as urticaria, rash, and angioedema), respiratory symptoms (such as dyspnea, bronchospasm, and laryngeal edema), gastrointestinal symptoms, neurological symptoms, or anaphylaxis subsequent to oxaliplatin administration. If HSR took place during the administration of oxaliplatin or prior to the administration of the next drug in the regimen’s sequence, oxaliplatin was diagnosed as the causative agent. If hypersensitivity occurred after the administration of subsequent drugs, oxaliplatin hypersensitivity was confirmed if there was a recurrence of symptoms despite eliminating other suspected drugs.
Cancer Chemother Pharmacol (2014) 73:1021–1029 Table 1 Grading of hypersensitivity reactions according to National Cancer Institute criteria (CTC v 3.0) Grade
Hypersensitivity reactions
1
Transient flushing or rash Drug fever
