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© 2001 American Society for Clinical Oncology Carboplatin Skin Testing: A Skin-Testing Protocol for Predicting Hypersensitivity to Carboplatin ChemotherapyFrom The Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Kristine Zanotti, MD, The Cleveland Clinic Foundation, 9500 Euclid Ave, Desk A81, Cleveland, OH 44012; email: zanottk{at}.ccf.org
PURPOSE: A high incidence of moderate to severe hypersensitivity reactions (HRs) is noted in patients who have been treated with multiple courses of carboplatin. Presently, there is no reliable way to predict which patients may be at risk for this potentially severe adverse reaction. We developed a skin-test protocol to identify patients at high risk for HR to carboplatin chemotherapy. PATIENTS AND METHODS: Patients undergoing more than seven courses of carboplatin received a 0.02-mL intradermal injection of an undiluted aliquot of their planned carboplatin infusion 1 hour before each course of the agent. A positive skin test was prospectively defined as that resulting in a wheel of at least 5 mm with a surrounding flare. We recently reported a 27% incidence of HRs in patients receiving more than seven courses of carboplatin. These patients served as historical controls for the current study. RESULTS: Forty-seven patients with recurrent ovarian or primary peritoneal carcinoma receiving carboplatin were skin tested. Thirteen of 47 patients (28%) manifested a positive skin test at a median of nine total courses of carboplatin (range, eight to 17 courses). This rate of skin-test positivity was not significantly different from the incidence of documented HR reported in a historical control group (P = .89), suggesting comparable populations. A negative skin test accurately predicted the absence of HR in 166 of 168 courses of chemotherapy. Only two of 47 patients (4%) experienced a HR after a negative skin test. Thus, administering carboplatin only to patients with a negative skin test may result in a significant reduction in HRs relative to historical controls (P = .002). CONCLUSION: An easily performed skin test appears to predict patients in whom carboplatin may be safely administered. Treatment modifications based on the results of skin testing may reduce the incidence of HRs in patients receiving repeated courses of carboplatin.
OVER THE PAST decade, carboplatin has been demonstrated to be one of the most useful and well-tolerated cytotoxic agents available for a wide variety of malignancies. Its clinical efficacy in ovarian and primary peritoneal carcinoma are well described,1,2 and it is now considered a standard first-line agent for these diseases. In addition, patients who recur after initial treatment with carboplatin often respond to it a second time.3 Carboplatin’s low rate of toxicity and outpatient administration enable patients to maintain a reasonable quality of life while receiving the agent and also make it an increasingly preferred agent for the palliative treatment of recurrent disease. However, as a result of its extended use, an increased incidence of carboplatin-associated hypersensitivity reactions (HRs) has been observed.4-6 We previously reviewed the incidence and clinical manifestations of HRs in patients undergoing carboplatin chemotherapy in the Gynecologic Cancer Program of the Cleveland Clinic Foundation and found a dramatic increase in the rate of HR in patients receiving an extended number of courses of the drug.4 Although a 1% incidence of HR was documented in patients receiving less than six courses of the agent, this rate increased to 27% in patients receiving more than seven courses of the drug. The median number of platinum courses for the first allergic reaction was eight. When these reactions occur, greater than 50% of patients develop at least moderately severe symptoms, including diffuse erythroderma, tachycardia, angina, wheezing, edema, facial swelling, dyspnea, hypertension, or hypotension.4 The potential for even more severe consequences is evident in a growing number of reports that describe life-threatening reactions (respiratory arrest, anaphylaxis, and seizure) and even death as a result of allergic reactions to carboplatin.4,6-10 Presently there is no reliable way to predict which patients may be at risk for this significant adverse reaction, limiting enthusiasm for the extended use of carboplatin. It is important to develop strategies that would permit oncologists to identify patients who may be at risk for developing an allergy to this agent. Skin testing has been useful in evaluating allergy to other medications, such as penicillin.11 The specific objective of this study was to assess the ability of carboplatin skin testing to prospectively identify patients at risk for allergic reaction to carboplatin.
Patients This study was approved by the institutional review board at The Cleveland Clinic Foundation. All patients undergoing more than seven courses of chemotherapy with carboplatin for a gynecologic malignancy at our institution between October 1998 and August 2000 were approached for participation in this study.
Skin-Test Protocol Thirty minutes after the administration of the skin test, chemotherapy pretreatment was delivered. All patients received dexamethasone (20 mg), diphenhydramine (50 mg), famotidine (20 mg), and granisetron (0.5 mg) as pretreatment 30 minutes before carboplatin infusion. Carboplatin was then administered over 30 minutes. Skin tests were read 5, 15, and 30 minutes after administration (before the administration of chemotherapy premedication) and 15, 30, and 60 minutes after initiation of carboplatin infusion. A positive skin test was defined as that which resulted in a wheel of at least 5 mm in diameter, with a surrounding flare. Because case reports of skin testing after carboplatin hypersensitivity reaction has occurred correlate well with sensitization to carboplatin,6,13-15 we felt that offering patients with a positive skin test an adjustment in their planned carboplatin infusion was ethically justified. Patients with a positive skin test were, therefore, offered the following several options: (1) to infuse carboplatin as planned, (2) to discontinue carboplatin in favor of another agent, or (3) to withhold carboplatin and treat at a later date after attempting desensitization. The desensitization protocol consisted of the oral administration of 20 mg of dexamethasone for 4 days before chemotherapy. Chemotherapy premedication was then administered according as stated above followed by a slow dose escalation of carboplatin (1/1000 of full dose over 30 minutes, followed by 1/100 of full dose over 15 minutes, followed by 1/10 of full dose over 15 minutes, followed by the remaining dose over 30 minutes). If at any point during the dose escalation allergic signs or symptoms were noted, carboplatin infusion was discontinued.
Allergic Reaction Defined
Statistical Analysis
Forty-seven patients participated in this study. Thirty-three patients had ovarian carcinoma, and 14 patients had primary peritoneal carcinoma. All patients were receiving carboplatin for relapsed disease after treatment with a platinum agent in the initial setting. Patients received a mean of four courses (range, one to 14 courses) during this study period and a mean of 11 courses (range, seven to 21 courses) of carboplatin in total. Seven patients had also previously received cisplatin. A total of 181 skin tests were administered; the results of the skin tests are listed in Tables 1 and 2. There were 168 negative skin tests. A negative skin test accurately predicted the absence of HR in 166 of 168 courses of chemotherapy, yielding a negative predictive value of 99% for an individual skin test (95% confidence interval, 96% to 100%). Only 4% (two of 47) patients experienced an allergic reaction after a negative skin test, and both of these were considered mild. With this skin-test protocol, administering carboplatin only to patients with a negative skin test may result in a significantly lower incidence of allergic reaction relative to the historical control group (4% v 27%, P = .002).
All positive skin tests became so within 30 minutes of skin test administration and no patient experienced hypersensitivity reaction as a result of the skin test itself. The median course number for the appearance of a positive skin test was nine (range, eight to 17 courses), which was comparable with the median course number for the first allergic reaction seen in the historical control group. Thirteen (28%) of 47 patients had a positive skin test, which was not different from the 27% rate of HR seen in historical controls (P = .89). Four of these 13 patients opted to proceed with their planned carboplatin infusion, despite their positive skin test: three experienced HR (true-positive), and one did not (false-positive). The three HRs experienced by patients with a positive skin test who elected to proceed with carboplatin infusion were considered mild to moderate in severity. The skin tests for the remaining nine patients could not be directly evaluated because these patients elected not to receive their planned carboplatin infusion after their positive skin test. Of the nine patients with a positive skin test who did not proceed with their planned carboplatin infusion, five elected subsequent treatment after attempting a desensitization protocol. Despite extended high-dose steroid pretreatment, three of these five patients ultimately experienced an allergic reaction. HRs in these three patients were considered mild to moderate in severity.
The existence of hypersensitivity to platinum compounds is well established among refinery workers inhaling complex salts of platinum.16-18 After prolonged exposure to these agents, a small number of workers develop rhinitis, conjunctivitis, asthma, urticaria, and contact dermatitis. For several reasons, these clinical manifestations have been regarded as a type 1 hypersensitivity, rather than a toxic or irritant effect of the agent. Like an allergic reaction, there is a period of platinum salt exposure before symptoms develop. Interestingly, a rather prolonged exposure (1 to 2 years) before sensitization is characteristic of platinum hypersensitivity in these workers. Once sensitized, patients experience recurrent HR with subsequent exposure to the compound. Demonstration of passive transfer of skin reactivity by serum of the sensitive refinery workers is further evidence for an antibody mediated type 1 hypersensitivity mechanism.17 Platinum-specific immunoglobin E has also been demonstrated by radioallergosorbent test in sensitized workers.19 Allergic reactions have also been reported in patients receiving these platinum-containing chemotherapeutic agents.6,16,20-24 These reports describe adverse reactions to carboplatin that suggest a type 1 hypersensitivity mechanism similar to that seen in refinery workers. Like platinum allergy in persons working with the industrial salts, patients appear to become sensitized only after prolonged exposure to carboplatin. Often, patients in this setting are receiving palliative treatment for recurrent disease. A number of case studies describe the use of skin testing in individuals sensitized by platinum compounds. Typical wheel and flare responses to intradermal injections of commercially available carboplatin preparations occurred in five of seven patients who had previously demonstrated allergy to carboplatin.6,13-15 A reasonable negative predictive value is also suggested in two reports which describe nonreaction to skin testing in carboplatin-exposed, but nonsensitized, individuals.6,15 Although these reports of carboplatin skin testing seem promising, there is currently no data on the use of skin testing as a tool to prospectively identify patients who may be at risk for a hypersensitivity reaction. We evaluated a skin-testing protocol for identifying patients who may be at risk for hypersensitivity reaction to carboplatin chemotherapy. The skin test is easily administered and does not seem to, by itself, induce HR. Because of the dramatic increase in the observed rate of HR in patients receiving an extended number of courses of carboplatin, skin testing need only be applied to patients receiving more than seven courses of the agent. The accuracy of a negative skin test was confirmed in this study. A negative skin test predicted the absence of a HR in 166 of 168 courses of chemotherapy. Of significance, the two allergic reactions not predicted by the skin test were considered quite mild. With this skin-test protocol, administering carboplatin only to patients with a negative skin test has the potential to significantly reduce the incidence of allergic reaction nearly seven-fold and possibly eliminate the occurrence of severe reactions altogether. Although the predictive value of a positive skin test could not be ascertained directly, several lines of evidence suggest a reasonably low false-positive rate. First, the 28% rate of skin-test positivity was not significantly different from that of allergic reactions seen in our historical control group. Second, the median course number for a positive skin test was nine, which was similar to the median course number for the first episode of HR in the historical controls (median course number = eight). Lastly, in addition to the three true-positive skin tests in the study, three of five patients with a positive skin test who later elected to attempt desensitization ultimately experienced an allergic reaction, despite prolonged high-dose steroid pretreatment. This suggests prior sensitization at the time of the initial skin test. Thus, patients demonstrating a positive skin test seem to have a high probability of being sensitized to carboplatin. In summary, the occurrence of HRs to carboplatin has become more problematic as a result of the expanding clinical applications of the agent. At a minimum, these reactions are uncomfortable and alarming to the patient and, at worst, they may be fatal. The skin-test protocol adds little complexity to the outpatient chemotherapy routine and represents a strategy to allow oncologists to identify patients who may be at risk for an allergic reaction. This study provides evidence that treatment modifications based on the results of skin testing have the potential to significantly reduce the incidence of hypersensitivity reaction to carboplatin and improve the therapeutic ratio associated with the extended use of this drug. Based on these data, it is reasonable to administer carboplatin to all patients with a negative skin test. For patients with a positive skin test, one must carefully weigh both the risks and benefits of continuation of carboplatin therapy. As the majority of individuals receiving an extended number of courses of the agent are being treated in a palliative setting for recurrent disease, the risks of attempting further treatment with carboplatin in potentially sensitized individuals may outweigh the benefits of continued therapy with carboplatin. For patients receiving potentially curative or significantly effective palliative therapy with carboplatin, however, continuation of the agent may be highly desirable. Although desensitization has not proven to be entirely reliable, one may elect to cautiously continue carboplatin therapy using a desensitization protocol.5,8,13,14 Participating patients must understand that, although successful in many cases, recurrent reactions may be severe, and death from anaphylaxis has been reported in one patient undergoing a trial of desensitization.10
1. Rozenweig M, Martin A, Beltansody M, et al: Randomized trial of carboplatin versus cisplatin in advanced ovarian cancer, in Bunn PA, Ozols RF, Canetta R, et al (eds): Carboplatin: Current Perspectives and Future Directions. Philadelphia, PA: WB Saunders, 1990 pp 195-203 2. Steis RG, Urba WJ, VanderMolen LA, et al: Ten-year follow-up of patients receiving cisplatin, doxorubicin, and cyclophosphamide chemotherapy for advanced epithelial ovarian carcinoma. J Clin Oncol 7: 223-228, 1989[Abstract] 3. Gore ME, Fryatt I, Wiltshaw E, et al: Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 36: 207-211, 1990[Medline]
4.
Markman M, Kennedy A, Webster K, et al: Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 17: 1141-1145, 1999 5. Rose PG, Fusco N, Fluellen L, et al: Carboplatin hypersensitivity reactions in patients with ovarian and peritoneal carcinoma. Int J Gynecol Cancer 8: 365-368, 1998 6. Weidmann B, Mulleneisen N, Bojko P, et al: Hypersensitivity reactions to carboplatin: Report of two patients, review of the literature, and discussion of diagnostic procedures and management. Cancer 73: 2218-2222, 1994[Medline] 7. Chang SM, Fryberger S, Crouse V, et al: Carboplatin hypersensitivity in children. Cancer 75: 1171-1175, 1995[Medline] 8. Kook H, Kim KM, Choi SH, et al: Life-threatening carboplatin hypersensitivity during conditioning for autologous PBSC transplantation: Successful rechallenge after desensitization. Bone Marrow Transplant 21: 727-729, 1998[Medline] 9. Sood AK, Gelder MS, Huang SW, et al: Anaphylaxis to carboplatin following multiple previous uncomplicated courses. Gynecol Oncol 57: 131-132, 1995[Medline] 10. Zweizig SM, Roman LD, Muderspach LI: Death from anaphylaxis to cisplatin: A case report. Gynecol Oncol 5: 121-122, 1994
11.
deShazo RD, Kemp SF: Allergic reactions to drugs and biologic agents. JAMA 278: 1895-1906, 1997 12. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748-1756, 1989[Abstract] 13. Broome CB, Schiff RI, Friedman HS: Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions. Med Pediatr Oncol 26: 105-110, 1996[Medline] 14. Goldberg A, Confino-Cohen R, Fishman A, et al: A modified, prolonged desensitization protocol in carboplatin allergy. J Allergy Clin Immunol 98: 841-843, 1996[Medline] 15. Windom HH, McGuire WP, Hamilton RG, et al: Anaphylaxis to carboplatin: A new platinum chemotherapeutic agent. J Allergy Clin Immunol 90: 681-683, 1992[Medline] 16. Cleare MJ, Highes EG, Jacoby B, et al: Immediate (type I) allergic responses to platinum compounds. Clin Allergy 6: 183-195, 1976[Medline] 17. Freedman SO, Krupey J: Respiratory allergy caused by platinum salts. J Allergy 42: 233-237, 1968 18. Ørbaek P: Allergy to the complex salts of platinum: A review of the literature and three case reports. Sand J Work Environ Health 8: 141-145, 1982 19. Cromwell O, Pepys J, Parish WE, et al: Specific IgE antibodies to platinum salts in sensitized workers. Clin Allergy 9: 109-117, 1979[Medline]
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Hendrick AM, Simmons D, Cantwell BMJ: Allergic reactions to carboplatin. Ann Oncol 3: 239-240, 1992 21. Morgan JS, Adams M, Mason MD: Hypersensitivity reactions to carboplatin given to patients with relapsed ovarian carcinoma. Eur J Cancer 30A: 1205-1206, 1994
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Saunders MP, Denton CP, O’Brien MER, et al: Hypersensitivity reactions to cisplatin and carboplatin: A report on six cases. Ann Oncol 3: 574-576, 1992 23. Shlebak AA, Clark PI, Green JA: Hypersensitivity and cross-reactivity to cisplatin and analogues. Cancer Chemother Pharmacol 35: 349-351, 1995[Medline] 24. Tonkin KS, Rubin P, Levin L: Carboplatin hypersensitivity: Case reports and review of the literature. Eur J Cancer 29A: 1356-1357, 1993 Submitted September 18, 2000; accepted March 16, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. The negative predictive value of a skin test was calculated along with the corresponding 95% confidence interval. Positive predictive value could not be calculated because treatment modifications occurred in patients with a positive skin test. 
