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© 2003 American Society for Clinical Oncology Expanded Experience With an Intradermal Skin Test to Predict for the Presence or Absence of Carboplatin HypersensitivityFrom the Departments of Hematology/Medical Oncology and Gynecology/Obstetrics, the Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Maurie Markman, MD, Department of Hematology/Medical Oncology (R-35), the Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: markmam{at}ccf.org.
Purpose: Carboplatin-associated hypersensitivity is increasingly recognized as a potentially serious toxicity when this agent is administered for more than six total cycles.
Patients and Methods: Our group has used a predictive skin test in women with gynecologic cancers who have previously received more than six cumulative cycles of platinum-based chemotherapy. Thirty minutes before all subsequent carboplatin courses, a 0.02-mL aliquot from the solution prepared for treatment is injected intradermally. A positive test is considered to be a Results: From October 1998 through March 2003, 126 patients received a total of 717 carboplatin skin tests (median per patient, four tests; range, one to 54 tests). Of the 668 negative tests (93% of the total performed), 10 were associated with evidence of carboplatin hypersensitivity (1.5% false-negative rate; 95% CI, 0.6% to 2.4%), none of which were severe (eg, dyspnea, hypotension, cardiac/respiratory compromise). Of the 41 positive tests, the decision was made to not deliver the drug to 32 patients, although seven women ultimately underwent a future attempt at re-treatment with a platinum agent using a desensitization program. In seven episodes where patients received the carboplatin despite the finding of a positive test, six were associated with the development of symptoms of anaphylaxis (none severe). Conclusion: A negative carboplatin skin test seems to predict with reasonable reliability for the absence of a severe hypersensitivity reaction with the subsequent drug infusion. The implications of a positive test remain less certain, but limited experience with continued treatment suggests this approach must be undertaken with considerable caution.
CARBOPLATIN IS one of the most active and well-tolerated cytotoxic agents currently used in cancer management. The drug is a component of many state-of-the-art chemotherapy regimens, including its use in the management of advanced ovarian cancer.1–4 There are several particularly appealing features associated with the delivery of carboplatin. The agent is easy to administer (30-minute infusion) and is associated with a highly favorable side effect profile (eg, no hair loss, limited/no nausea or vomiting with appropriate antiemetic therapy). Unfortunately, in recent years, it has become increasingly appreciated that with prolonged use of carboplatin, there is a substantial risk for the development of clinically relevant hypersensitivity reactions.5–14 Of interest, these events essentially never occur until a patient has received multiple doses of platinum therapy (carboplatin or cisplatin). Apparently, it takes a relatively long time for a susceptible patient to develop hypersensitivity to the drugs, presumably owing to the presence of very small concentrations of metallic platinum present within the preparation.15–17 Although carboplatin hypersensitivity reactions can be mild in severity (eg, skin rash), more serious signs and symptoms (eg, hypotension, intense anxiety, dyspnea, cardiovascular collapse) may develop.11 Several management options have been proposed for patients who experience an anaphylactic episode, including discontinuation of further therapy with platinum agents, substitution of cisplatin for carboplatin, and re-treatment using a variety of desensitization strategies.11,12,14,18–20
Our group has previously reported preliminary results with an intradermal skin test designed to predict for the development of clinically relevant carboplatin sensitivity.21 Patients who have received more than six courses of platinum-based treatment have this test performed approximately 30 minutes before all subsequent treatments with carboplatin. The initial publication involving our experience with 47 patients suggested a negative skin test was an accurate predictor of the ability to safely deliver the carboplatin infusion. It was more difficult to determine the clinical significance of a positive result (eg, Over the past 4.5 years, we have extended our use of this skin-testing procedure to a total of 126 patients, all with gynecologic malignancies, who had previously received a minimum of six courses of platinum-based therapy, and we report here our expanded experience with this novel management strategy.
Patient Population Patients considered for entry onto the study were required to have received a minimum of six prior treatments with a platinum-based (cisplatin or carboplatin) chemotherapy regimen for a gynecologic malignancy. The skin-testing procedure (described below) was applied before all subsequent carboplatin-containing treatment regimens. Patients were permitted to receive either single-agent carboplatin or a carboplatin-based combination chemotherapy regimen. All individuals participating in the trial were required to sign an informed consent statement indicating that they understood the investigational nature of this predictive strategy.
Skin-Testing Procedure
A positive skin test was defined as that which resulted in a wheal of
Carboplatin Hypersensitivity Reactions The nurse who applied and interpreted the skin test would routinely record the results before initiating the actual carboplatin infusion. In this analysis, we examined the incidence and severity of observed hypersensitivity compared with the medical record documentation of the outcome of the skin-testing procedure.
From October 1998 through March 2003, a total of 126 patients received at least one course of carboplatin-based chemotherapy with preceding skin testing. Clinical characteristics of this patient population are outlined in Table 1  .
A total of 717 individual skin tests have been placed, with a median of four tests per patient (range, one to 54 tests). With one exception, there were no serious consequences associated with the skin-testing procedure itself, although several patients who developed a prominent local reaction also experienced brief but fairly intense pruritis at the intradermal testing site. All positive skin tests were noted to have developed within the initial 30-minute observation period. A single individual developed a 3-cm wheal and flare around the injection site that progressed over a few minutes to total body erythroderma. The patient complained of chills, chest discomfort, and mild dyspnea, but there were no other signs of severe anaphylaxis (eg, wheezing, intense anxiety, hypotension). After treatment with diphenhydramine and corticosteroids, the symptoms completely resolved. There were no further attempts to deliver a platinum agent to this patient. Of the 668 skin tests that were interpreted as being negative by the nursing staff (93.2% of total performed), on 10 occasions (in a total of seven patients), the patient subsequently developed signs of hypersensitivity (1.5% false-negative rate; 95% CI, 0.6% to 2.4%). Thus of the 87 patients in our series who were never recorded as having a positive skin test, seven (8% false-negative rate; 95% CI, 3% to 16%) experienced evidence of anaphylaxis during their course of carboplatin treatment. Of these 10 reactions, eight involved the development of facial flushing, a diffuse rash, or mild pruritis during the infusion, without more serious complications of anaphylaxis. Specifically, no patient experienced severe anxiety, dyspnea, hypotension, or other signs of respiratory or cardiac compromise. Two episodes of hypersensitivity in individuals with a negative skin test were characterized by facial flushing and the development of a rash several hours after the completion of the carboplatin infusion, which improved without further medical intervention.
A total of 41 tests (5.7% of the total performed) in 39 individuals were interpreted as being positive (as previously defined). On seven of these occasions (17% of positive tests), after discussion with the physician, the patient elected to proceed with the carboplatin infusions. In these seven situations, although the test was definitely interpreted as positive ( In the remaining 32 patients with a positive test, the planned carboplatin infusion was not administered. Seven (22%) of these patients subsequently elected to attempt to receive a platinum agent (cisplatin or carboplatin) using a formal desensitization program, of whom six were successful in receiving treatment with one of these drugs. Finally, a total of eight tests were interpreted as being borderline positive. In all of these cases, the carboplatin infusion was delivered without incident.
In this expanded single-institution experience with carboplatin skin testing involving 126 patients receiving more than six courses of platinum-based chemotherapy for a gynecologic malignancy, we confirmed the apparent clinical usefulness of the procedure to predict for the development of anaphylaxis to the agent. Specifically, of a total of 668 negative skin tests, there were only 10 occurrences (1.5% false-negative rate) of a hypersensitivity reaction occurring during the subsequently delivered carboplatin infusion. Further, although these reactions were disconcerting to the patient and staff, none of them were characterized as being severe (eg, severe anxiety, dyspnea, hypotension, or respiratory or cardiac compromise). Before our decision in October 1998 to use this skin-testing strategy, we had observed a 12% overall incidence of carboplatin hypersensitivity reactions among a total population of 205 gynecologic cancer patients who met the same criteria for treatment as that used in this skin-testing protocol.11 In addition, approximately one half of these reactions (6% of all patients receiving second-line carboplatin in our program) were at least of modest severity (eg, diffuse erythema, tachycardia, dyspnea, facial swelling, intense anxiety, hypertension, hypotension), with several episodes of severe respiratory and cardiac compromise being encountered. Thus although not definitively confirmed through the conduct of a randomized trial, the overall incidence of severe hypersensitivity reactions noted by our group in patients with a negative skin test would seem to represent a substantial reduction in the risk of observing this potentially serious toxicity of carboplatin.
What remains far less certain is the predictive value of a positive skin test, as for appropriate safety and ethical considerations, we did not routinely treat individuals who manifested a local reaction,20,22 as defined in our protocol (eg, In our series, patients with a borderline positive skin test were able to subsequently receive carboplatin without experiencing anaphylaxis. Although these data are reassuring regarding the clinical implications of a minor skin reaction, individuals in this setting should still be closely observed for the development of carboplatin hypersensitivity. Several women who demonstrated a positive skin test were able to subsequently be successfully treated with a platinum-based regimen using an aggressive desensitization program developed by our group.23 However, it remains uncertain whether an anaphylactic reaction would have developed in these individuals if given carboplatin in the absence of this complex method used to prevent a serious immunologic event. Although the process of skin testing used by our group is simple to apply and leads to a relatively rapid answer that can then be interpreted by the clinician, it does potentially result in the requirement to discard a solution of carboplatin previously prepared for drug delivery in an individual with a positive test. However, the solution can be used for another patient if this is done within 36 hours for premixed preparations stored at room temperature or within 5 days for premixed preparations that are refrigerated. This process may not be acceptable in smaller practice settings where there will be fewer opportunities to subsequently use the carboplatin within this relatively narrow time interval. An alternative strategy would be to make up a small volume of a carboplatin test solution, specifically for intradermal administration. After a negative test, the full solution can then be prepared. This approach may be reasonable in certain clinical settings, but it does add additional time and drug preparation costs for individual patients receiving this agent. It is important to emphasize that carboplatin hypersensitivity reactions are extremely uncommon during the initial courses of platinum treatment,11 so the issue of carboplatin skin testing is realistically only relevant in those situations where patients are receiving a second-line approach with the agent. With the recent interest in weekly carboplatin delivery, usually in association with the weekly administration of a taxane, it is reasonable to inquire whether the more frequent platinum dosing schedule will result in the earlier onset of a heightened risk of anaphylaxis.24–27 If subsequent experience demonstrates this to be a legitimate concern, then carboplatin skin testing may be an option to evaluate this risk in individual patients.28
The authors indicated no potential conflicts of interest.
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5. Planner RS, Weerasiri T, Timmins D, Grant P: Hypersensitivity reactions to carboplatin. J Natl Cancer Inst 83:1763–1764, 1991 6. Windom HH, McGuire WP III, Hamilton RG, et al: Anaphylaxis to carboplatin: A new platinum chemotherapeutic agent. J Allergy Clin Immunol 90:681–683, 1992[CrossRef][Medline] 7. Chang SM, Fryberger S, Crouse V, et al: Carboplatin hypersensitivity in children: A report of five patients with brain tumors. Cancer 75:1171–1175, 1995[CrossRef][Medline] 8. 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[CrossRef][Medline]
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11. Markman M, Kennedy A, Webster K, et al: Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 17:1141–1145, 1999 12. Rose PG, Fluellen L, Rodriguez M: Carboplatin hypersensitivity reactions in patients with ovarian and peritoneal carcinoma. Int J Gynecol Cancer 8:365–368, 1998[CrossRef]
13. 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 14. 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 82:550–558, 2001[CrossRef][Medline] 15. Cromwell O, Pepys J, Parish WE, et al: Specific IgE antibodies to platinum salts in sensitized workers. Clin Allergy 9:109–117, 1979[CrossRef][Medline] 16. Orbaek P: Allergy to the complex salts of platinum: A review of the literature and three case reports. Scand J Work Environ Health 8:141–145, 1982[Medline] 17. Freedman SO, Krupey J: Respiratory allergy caused by platinum salts. J Allergy 42:233–237, 1968[CrossRef] 18. 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[CrossRef][Medline] 19. Broome CB, Schiff RI, Friedman HS: Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions. Med Pediatr Oncol 26:105–110, 1996[CrossRef][Medline] 20. Dizon DS, Sabbatini PJ, Aghajanian C, et al: Analysis of patients with epithelial ovarian cancer or fallopian tube carcinoma retreated with cisplatin after the development of a carboplatin allergy. Gynecol Oncol 84:378–382, 2002[CrossRef][Medline]
21. Zanotti KM, Rybicki LA, Kennedy AW, et al: Carboplatin skin testing: A skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy. J Clin Oncol 19:3126–3129, 2001 22. Zweizig S, Roman LD, Muderspach LI: Death from anaphylaxis to cisplatin: A case report. Gynecol Oncol 53:121–122, 1994[CrossRef][Medline] 23. Markman M, Hsieh F, Zanotti K, et al: Initial experience with a novel desensitization strategy for carboplatin-associated hypersensitivity reactions. J Cancer Res Clin Oncol (in press) 24. Havrilesky LJ, Alvarez AA, Sayer RA, et al: Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer. Gynecol Oncol 88:51–57, 2003[CrossRef][Medline]
25. Loesch D, Robert N, Asmar L, et al: Phase II multicenter trial of a weekly paclitaxel and carboplatin regimen in patients with advanced breast cancer. J Clin Oncol 20:3857–3864, 2002 26. Wu CH, Yang CH, Lee JN, et al: Weekly and monthly regimens of paclitaxel and carboplatin in the management of advanced ovarian cancer: A preliminary report on side effects. Int J Gynecol Cancer 11:295–299, 2001[CrossRef][Medline] 27. Sehouli J, Stengel D, Elling D, et al: First-line chemotherapy with weekly paclitaxel and carboplatin for advanced ovarian cancer: A phase I study—The Ovarian Cancer Study Group of the Nordostdeutsche Gesellschaft fur Gynakologische Onkologie (NOGGO). Gynecol Oncol 85:321–326, 2002[CrossRef][Medline] 28. Yu DY, Dahl GVH, Shames RS, et al: Weekly dosing of carboplatin increases risk of allergy in children. J Pediatr Hematol Oncol 23:349–352, 2001[CrossRef][Medline] Submitted May 20, 2003; accepted October 2, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5-mm wheal, with a surrounding flare. 
