The Oncologist, Vol. 9, No. 5, 546-549, September 2004; doi:10.1634/theoncologist.9-5-546
© 2004 AlphaMed Press
Hypersensitivity Reactions to Oxaliplatin and the Application of a Desensitization Protocol
David Gammona,
Pankaj Bhargavab,
Michael J. McCormickc
a Department of Pharmacy,
b Division of Hematology/Oncology, and
c Division of Pulmonary, Allergy and Critical Care Medicine, UMass Memorial Medical Center, Worcester, Massachusetts, USA
Correspondence:
David C. Gammon, BS.Ph., UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA. Telephone: 508-856-2915; Fax: 508-856-4141; e-mail: gammond{at}ummhc.org
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ABSTRACT
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Oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc.; New York, NY) is a third-generation platinum agent indicated for the treatment of colorectal cancer. Severe hypersensitivity reactions to oxaliplatin rarely occur; however, they do represent a threat to the small number of patients that are occasionally affected. We developed a desensitization protocol and successfully applied it to a patient with severe, grade 3, hypersensitivity to oxaliplatin. For patients who have mild sensitivity to oxaliplatin, slowing the run rate down and giving an antihistamine and/or a steroid usually suffice. Desensitization will help to provide the small number of patients who experience severe hypersensitivity reactions with the ability to further receive an effective therapy for their colorectal cancer. The desensitization protocol is described in detail.
Key Words. Chemotherapy • Hypersensitivity reactions • Oxaliplatin • Desensitization protocol
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INTRODUCTION
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Oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc.; New York, NY) is a third-generation platinum agent indicated for the second-line treatment of colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Results from the pivotal phase III clinical study, reported in 2002, showed that patients who received oxaliplatin plus 5-FU/LV, compared with those treated with 5-FU/LV alone, had a higher response rate, longer time to progression (5.6 months versus 2.6 months, respectively; p < 0.0001), and higher rate of relief from tumor-related symptoms (28% versus 15%, respectively; p < 0.002) [1]. These results led to U.S. Food and Drug Administration (FDA) approval of oxaliplatin for metastatic colorectal cancer. Oxaliplatin was generally well tolerated but resulted in higher rates of grade 3 and 4 neuropathies; toxicities did not result in a higher rate of treatment discontinuation [1, 2].
The oxaliplatin plus 5-FU/LV combination was recently shown to have clinical activity in the first-line treatment of advanced colorectal cancer. In an intergroup study that enrolled patients with stage IV colorectal cancer, patients who received oxaliplatin plus 5-FU/LV were compared with those receiving irinotecan (Campostar®; Pfizer Pharmaceuticals; New York, NY) plus 5-FU/LV; the former experienced a significantly longer median time to progression (7 months versus 6.9 months, respectively; p = 0.0014), greater response rate (45% versus 31%, respectively; p = 0.02), and longer overall survival (19.5 months versus 15 months, respectively; p = 0.002) [3]. In addition, fewer grade 3/4 toxicities were experienced in patients treated with oxaliplatin plus 5-FU/LV than in patients in the other treatment arm, with the exception of late paresthesias and neutropenia, which occurred with a higher incidence in oxaliplatin plus 5-FU/LV-treated patients. Results of that trial led to the recent approval of oxaliplatin in combination with 5-FU/LV for the treatment of first-line colorectal cancer by the FDA.
Oxaliplatin plus 5-FU/LV is also the first chemotherapeutic combination to demonstrate superiority over 5-FU/LV in adjuvant colorectal cancer. In a large phase III study that included patients with completely resected stage II/III colorectal cancer, patients who received oxaliplatin plus 5-FU/LV experienced a significantly greater 3-year disease-free survival rate than patients who received 5-FU/LV alone (78% versus 73%, respectively; p < 0.01) [4]. Furthermore, the risk of recurrence was 23% lower in patients treated with oxaliplatin plus 5-FU/LV. Overall, oxaliplatin plus 5-FU/LV was shown to be safe, although more patients in that treatment arm experienced neutropenia (<2% febrile neutropenia). More patients in the oxaliplatin plus 5-FU/LV treatment arm also experienced grade 3 paresthesias; however, the incidence was reduced to 1% at a 1-year follow-up.
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HYPERSENSITIVITY REACTIONS
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Despite the large number of chemotherapeutic agents used to treat cancer, hypersensitivity reactions tend to occur only in association with the use of a limited number of agents in a small number of patients. These agents include the taxanes paclitaxel (Taxol®; Bristol-Myers Squibb; Princeton, NJ) and docetaxel (Taxotere®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ); the platinum-containing compounds cisplatin (Platinol®; Bristol-Myers Squibb), carboplatin (Paraplatin®; Bristol-Myers Squibb), and oxaliplatin; the epipodophyllotoxins teniposide (Vumon®; Bristol-Myers Squibb) and etoposide (Etopophos®, VePesid®; Bristol-Myers Squibb); asparaginase (Elspar®; Merck & Company, Inc.; West Point, PA); procarbazine (Matulane®; Sigma Tau Pharmaceuticals, Inc.; Gaithersburg, MD); and, occasionally, doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH; Rubex®; Bristol-Meyers Squibb) and 6-mercaptopurine. A hypersensitivity reaction can occur either during (acute reaction) or following (delayed reaction) administration of a chemotherapeutic agent. Symptoms may include, but are not limited to, flushing, alterations in heart rate and blood pressure, dyspnea/bronchospasm, back pain, chest discomfort, fever, pruritis, erythema, nausea, and rash [5, 6]. The precise mechanisms responsible for hypersensitivity reactions are currently unknown. Some reactions may be caused by the nonimmune-mediated release of histamine or cytokines, as many patients can subsequently tolerate reexposure after premedication with antihistamines and steroids [6]. Multiple factors, including the route and rate of administration, previous exposure, form of the drug, whether it is given as a single agent or in combination, concomitant medications, concurrent autoimmune disease, and possibly disease state, can affect the hypersensitivity reaction rate to a given drug [6].
The platinum-containing agents cisplatin and carboplatin are most commonly used to treat gynecologic malignancies and adenocarcinoma of the lung. Platinum-containing agents are associated with hypersensitivity reactions, which have been reported to occur in 10% to 27% of patients treated with cisplatin or carboplatin [6]. The incidence of hypersensitivity reactions increases with multiple courses of the drugs and generally occurs after four to six courses [6, 7]. Symptoms of hypersensitivity reactions to platinum-containing agents, which usually occur within minutes of administration in patients with prior exposure, include facial edema, bronchospasm, hypotension, tachycardia, pruritis, and erythema [6]. In contrast to what occurs with taxanes, premedication with steroids and antihistamines may not prevent hypersensitivity reactions to platinum-containing agents [8]. Hypersensitivity reactions to platinum-containing compounds are thought to be mediated by IgE and/or the direct release of vasoactive substances [5]. The results of intradermal skin tests with carboplatin have been shown to be fairly reliable predictors of hypersensitivity reactions to the drug [6].
Only a small number of patients experienced hypersensitive reactions to oxaliplatin in clinical trials, and less than 1% experienced grade 3/4 reactions [7, 9, 10]. These hypersensitivity reactions were experienced after a median of seven (range 2–25) courses of oxaliplatin [7, 11, 12]. Most reactions were acute, occurring either during or shortly after infusion. Symptoms of hypersensitivity reactions to oxaliplatin in patients with colorectal cancer are similar in nature and severity to those reported with other platinum-containing agents and include facial flushing, erythema, pruritis, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema [7, 10–12]. Symptoms are generally mild; severe hypersensitivity reactions to oxaliplatin are rare [7, 11, 12]. A recent trial evaluating oxaliplatin for the second-line treatment of colorectal cancer reported a grade 3 hypersensitivity reaction necessitating treatment discontinuation in only one patient [2]. The type of hypersensitivity reaction was not further specified. The most recent trial investigating oxaliplatin for the first-line treatment of colorectal cancer did not report any hypersensitivity reactions [3]. When hypersensitivity reactions to oxaliplatin do occur, symptoms generally subside upon discontinuation of treatment and administration of steroids and antihistamines.
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MANAGEMENT OF HYPERSENSITIVITY REACTIONS
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Mild hypersensitivity reactions to oxaliplatin and other platinum compounds can be ameliorated in some patients through the use of steroids and antihistamines before administration of subsequent cycles [7]. However, premedication cannot prevent all hypersensitivity reactions, and mild reactions may escalate to severe reactions even when steroids and antihistamines are administered prior to oxaliplatin infusion. There are case reports in the literature describing patients who experienced hypersensitivity reactions during initial therapy with oxaliplatin and experienced similar and sometimes more severe symptoms during subsequent cycles despite receiving prophylactic steroids and antihistamines [7, 13]. In all cases of severe hypersensitivity to oxaliplatin, treatment had to be discontinued. In such cases, initiation of a desensitization protocol may allow the patient to continue treatment with oxaliplatin.
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DESENSITIZATION PROTOCOLS
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Desensitization protocols have been successfully used to manage hypersensitivity reactions to paclitaxel and platinum-containing compounds [5, 8]. Based on a carboplatin desensitization protocol developed by Windom et al. [14], Goldberg et al. [8] reported the success of a desensitization regimen in two patients that involved administration of increasing concentrations of carboplatin over a prolonged period of time. The dose of carboplatin was slowly titrated up so that the patients subsequently received infusions of 1/1,000, 1/100, and 1/10 of the total carboplatin dose; each infusion lasted from 90 minutes to 15 hours. The final infusion contained 90% of the total drug dose and was administered for 11–50 hours. In both patients, carboplatin intradermal skin tests, which were positive prior to the desensitization regimen, were negative at the same concentration of carboplatin following the regimen, indicating that desensitization had indeed occurred.
While some investigators have concluded that patients who develop severe hypersensitivity reactions to oxaliplatin are unlikely to tolerate further therapy [7], others have reported the successful implementation of oxaliplatin desensitization protocols based on the Goldberg et al. protocol [8, 11, 12, 15]. The specific details of the protocol used by Meyer et al. [11] are not available. The patient reported by Qureshi et al. [12] was premedicated with dexamethasone (Decadron®; Merck and Company, Inc.), famotidine (Pepcid®; Merck and Company, Inc.), and diphenhydramine (Benadryl®; Pfizer Pharmaceuticals) and was then given consecutive 90-minute infusions of 1/1,000, 1/100, and 1/10 of the total oxaliplatin dose. The final dose (90% of the total oxaliplatin dose) was infused over 6 hours. Subsequent cycles were administered over 6 hours with similar premedications and were well tolerated.
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AN OXALIPLATIN DESENSITIZATION PROTOCOL
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The desensitization protocol that was successfully used in the case study described below involves the following steps. Four serial dilutions (1:10,000, 1:1,000, 1:100, and 1:10) of the total oxaliplatin dose are each prepared in 100 ml dextrose 5% in water (D5W) (Table 1
). Starting with the lowest dose (bag 1), each dilution is infused over 60 minutes with careful monitoring of vital signs. A final infusion bag (bag 5), containing 90% of the total dose in 500 ml D5W, is then infused over 2 hours (Table 1).
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CASE STUDY
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The desensitization protocol described in this manuscript was first performed in a 50-year-old patient with a performance status of 0 and with metastatic colorectal cancer. The patient had previously received 12 courses of an investigational supply of oxaliplatin at a dose of 147 mg per cycle during the clinical trial without any allergic reactions. The regimen also included LV and 5-FU. Although the patient’s tumor responded to chemotherapy, she was removed from the study due to persistent neutropenia; the patient then received other chemotherapy regimens, all of which caused temporary regression of her cancer. During this time period, the patient received irinotecan as a single agent in doses ranging from 60–125 mg/m2. Approximately 18 months later, treatment with a combination of commercially available oxaliplatin at 100 mg/m2 and capecitabine (Xeloda®; Roche Laboratories, Inc.; Nutley, NJ) was started, and the patient experienced no problems during the first cycle. However, about 15 minutes after initiation of the second oxaliplatin infusion, the patient reported palpitations and flushing and was found to have a systolic blood pressure of 80 mmHg and pulse oxygenation of 84% on room air. The infusion was immediately stopped, and diphenhydramine and hydrocortisone were administered. The patient also developed a diffuse macular rash over her entire body as well as rigors, which were treated with meperidine (Demerol®; Sanofi-Synthelabo Inc.). These symptoms resolved within 90 minutes. For the next cycle, the patient was premedicated with oral dexamethasone starting 24 hours prior to chemotherapy, and she also received i.v. dexamethasone and diphenhydramine 30 minutes prior to treatment. In addition, the oxaliplatin infusion rate was reduced by 50%. Despite these measures, the patient experienced a similar hypersensitivity reaction approximately 20 minutes after starting the oxaliplatin infusion. Since the patient wanted to continue oxaliplatin treatment, a desensitization protocol adapted from the carboplatin regimens of Windom et al. [14] and Goldberg et al. [8] was developed (as described above).
The patient tolerated the desensitization regimen very well. Toward the end of the final 2-hour infusion, a faint macular rash with itching developed over the lower extremities. In subsequent cycles, the final infusion time was extended from 2 to 4 hours, and the patient was premedicated with hydrocortisone (100 mg i.v.) prior to desensitization. The patient was able to tolerate six cycles of treatment at 100 mg/m2, or a total dose of 173 mg, with the desensitization regimen and experienced no further reactions. The tumor regressed after three cycles but progressed after the sixth cycle, leading to discontinuation of treatment.
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CONCLUSION
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Hypersensitivity reactions to oxaliplatin are usually mild, and severe reactions are rare. When hypersensitivity reactions to oxaliplatin do occur, symptoms generally subside upon discontinuation of treatment. For patients who have mild sensitivity to oxaliplatin, slowing down the run rate and giving an antihistamine and/or a steroid will usually suffice. Implementation of the desensitization protocol described here may allow the small number of patients who do experience hypersensitivity reactions to oxaliplatin to continue to receive the drug and therefore continue to benefit from a very effective treatment option.
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ACKNOWLEDGMENT
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David Gammon, BS.Ph., is a member of the Sanofi-Synthelabo Pharmacy Advisory Board.
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REFERENCES
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- Rothenberg ML, Oza AM, Burger B et al. Final results of a phase III trial of 5-FU/leucovorin versus oxaliplatin versus the combination in patients with metastatic colorectal cancer following irinotecan, 5-FU, and leucovorin. Proc Am Soc Clin Oncol 2003;22:252.
- Rothenberg ML, Oza AM, Bigelow RH et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003;21:2059–2069.[Abstract/Free Full Text]
- Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23–30.[Abstract/Free Full Text]
- De Gramont A, Banzi M, Navarro M et al. Oxaliplatin/5-FU/LV in adjuvant colon cancer: results of the international randomized mosaic trial. Proc Am Soc Clin Oncol 2003;22:253.
- Robinson JB, Singh D, Bodurka-Bevers DC et al. Hypersensitivity reactions and the utility of oral and intravenous desensitization in patients with gynecologic malignancies. Gynecol Oncol 2001;82:550–558.[CrossRef][Medline]
- Shepherd GM. Hypersensitivity reactions to chemotherapeutic drugs. Clin Rev Allergy Immunol 2003;24:253–262.[Medline]
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- Goldberg A, Confino-Cohen R, Fishman A et al. A modified, prolonged desensitization protocol in carboplatin allergy. J Allergy Clin Immunol 1996;98:841–843.[CrossRef][Medline]
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- EloxatinTM (oxaliplatin for injection) [package insert]. New York: Sanofi-Synthelabo Inc., 2002.
- Meyer L, Zuberbier T, Worm M et al. Hypersensitivity reactions to oxaliplatin: cross-reactivity to carboplatin and the introduction of a desensitization schedule. J Clin Oncol 2002;20:1146–1147.[Free Full Text]
- Qureshi KM, Leichman C, Berdzik J et al. Incidence of hypersensitivity reactions to oxaliplatin (OXP) at Roswell Park Cancer Institute (RPCI) and protocol for desensitization. Proc Am Soc Clin Oncol 2003;22:789.
- Alliot C, Messouak D, Beets C et al. Severe anaphylactic reaction to oxaliplatin. Clin Oncol (R Coll Radiol) 2001;13:236.
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Received December 4, 2003;
accepted for publication May 21, 2004.
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Abstract
Introduction
