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© 1999 American Society for Clinical Oncology Clinical Features of Hypersensitivity Reactions to CarboplatinFrom the Cleveland Clinic Cancer Center and Departments of Gynecology/Obstetrics and Hematology/Oncology, the Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Maurie Markman, MD, Department of Hematology/Medical Oncology, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; email markmam{at}cesmtp.ccf.org
PURPOSE: To characterize the clinical features of carboplatin-associated hypersensitivity reactions. PATIENTS: Patients with gynecologic malignancies treated at the Cleveland Clinic Foundation from June 1995 through July 1998 who experienced a carboplatin-associated hypersensitivity reaction were the subjects of this evaluation. RESULTS: Of the 205 patients treated with carboplatin during this time period, 24 (12%) developed a carboplatin hypersensitivity reaction. The median number of platinum (carboplatin plus cisplatin) courses for the first episode was eight (range, six to 21). Only three patients (13%) developed this toxicity during their initial chemotherapy regimen, with the remainder experiencing a reaction during their second (n = 15) or third (n = 6) carboplatin treatment program for recurrent disease. Thirteen patients (54%) developed at least moderately severe symptoms (diffuse erythroderma, tachycardia, chest tightness, wheezing, facial swelling, dyspnea, hypertension, or hypotension). In approximately one half of patients, the reaction developed after more than 50% of the carboplatin had been infused. Only one of three patients was successfully treated with the agent upon rechallenge. CONCLUSION: Carboplatin hypersensitivity reactions develop in patients who have been extensively pretreated with the agent. The clinical features are highly variable, but they are sufficiently different from those noted after the administration of paclitaxel that it should not be difficult to distinguish between reactions to the two agents. As carboplatin is increasingly used as initial and second-line chemotherapy of ovarian cancer and other malignancies, it can be anticipated that hypersensitivity reactions to the drug will become a more common and difficult clinical management issue.
OVER THE PAST decade, carboplatin has been demonstrated to be one of the most useful and well-tolerated cytotoxic agents available to the practicing oncologist. In patients with ovarian cancer, carboplatin is frequently used both as initial chemotherapy and in second-line or salvage settings.1 A particular appeal of carboplatin is its relative lack of nephrotoxicity and neurotoxicity, as well as the relatively low associated incidence of severe emesis, particularly in comparison to its parent compound, cisplatin. In addition, data from several trials have confirmed that it is possible to combine carboplatin with 3-hour infusional paclitaxel with an acceptable toxicity profile (particularly bone marrow suppression).2,3 This two-drug combination regimen permits outpatient management because it avoids the need for paclitaxel to be delivered over 24 hours, as is generally required when the agent is administered with cisplatin.4,5 As a result of the greater use of carboplatin in gynecologic malignancies, our group has recently noted an increased incidence of a relatively uncommon side effect of carboplatin: the development of carboplatin-associated hypersensitivity reactions.6-12 We thought it important to attempt to more fully characterize this toxicity of treatment in the gynecologic cancer patient population, to be able to more easily recognize its development, and to define appropriate management guidelines should this side effect of treatment be observed.
From July 1995 through August 1998, the Gynecologic Cancer Program of the Cleveland Clinic Foundation treated 205 patients with either single-agent carboplatin or a carboplatin-based combination chemotherapy regimen (generally delivered with paclitaxel).3 During this time period, we identified 24 patients (approximately 12% of our population receiving carboplatin; median age, 57 years; range, 35 to 72 years) who met reasonable criteria for a carboplatin-associated hypersensitivity reaction. These criteria included the following: (a) a reaction was observed minutes to several days after the administration of carboplatin; (b) after the initial hypersensitivity episode, symptoms of equivalent or greater severity developed after subsequent carboplatin treatments; (c) if other drugs (eg, paclitaxel) were administered before the reaction, carboplatin was believed to be the most likely cause of the event.
Perhaps the most striking feature of carboplatin-associated hypersensitivity reactions was the development of the initial episode after a significant number of courses of the drug had been administered to these patients without any evidence of an allergic reaction. This observation is consistent with previous reports in the medical literature regarding carboplatin6-10 and with the establishment of hypersensitivity reactions among individuals working with platinum metals in industry.13-15 A number of patients in our series received their initial chemotherapy with cisplatin, rather than carboplatin. As we were unable to observe any difference in the clinical characteristics of patients treated with carboplatin only or with cisplatin followed by carboplatin (eg, nature or severity of symptoms, total number of platinum courses before the development of a carboplatin reaction), we considered prior cisplatin courses in our calculation of the total number of "platinum treatments" before the onset of a carboplatin hypersensitivity reaction. The median number of platinum (carboplatin plus cisplatin) courses in our patient population for the observation of the first carboplatin hypersensitivity reaction was eight (range, six to 21) (Table 1). In fact, of the 24 patients in our series who experienced a hypersensitivity reaction to carboplatin, only three (13%) developed the side effect of treatment during their initial chemotherapy program (all during the final planned course), with the remaining 21 patients noted to have difficulty with the drug only after the initiation of second-line (n = 15) or third-line (n = 6) chemotherapy with the agent.
Prior chemotherapy in patients developing a carboplatin reaction in the second-line or third-line setting included cisplatin or carboplatin with either cyclophosphamide or paclitaxel. There were no differences in the characteristics of the hypersensitivity reactions observed on the basis of the specific drug combinations used in the first-line treatment setting. The severity of symptoms varied greatly. Several patients noted itching or erythema only, particularly of the palms and soles, or facial flushing, beginning shortly after the completion of therapy or up to 3 days after treatment. Other patients noted these symptoms during the chemotherapy infusion. Thirteen patients (54%) experienced a more severe reaction, including diffuse erythroderma, tachycardia, wheezing, facial swelling, chills, rigors, throat and chest tightness, dyspnea, emesis, and hypertension or hypotension. One patient's symptoms progressed to respiratory arrest, but she recovered completely. We were unable to identify any characteristics of our patient population that distinguished patients who experienced severe hypersensitivity reactions from those who developed more moderate symptoms (eg, rash and itching only). Of the 13 patients who developed a severe carboplatin hypersensitivity reaction, only five (38%) experienced the initial symptoms within the first several minutes after initiation of the drug infusion. In the remaining eight patients, at least one half of the treatment volume had been administered before the onset of symptoms (15 to 30 minutes after the infusion started). Overall, approximately one half of all patients exhibiting a carboplatin hypersensitivity reaction developed the initial symptoms within the first few minutes after drug delivery was started. In considering the time course for the development of the carboplatin-associated hypersensitivity reactions, it is important to note that all patients receiving this cytotoxic drug in our program also were treated with intravenous dexamethasone 20 mg approximately 30 minutes before chemotherapy delivery. This drug was used as a component of our standard prophylactic antiemetic regimen for carboplatin.16,17 In three patients, we attempted to administer another course of carboplatin approximately 1 month after the observed severe reaction. Patients were pretreated for several days with oral corticosteroids (dexamethasone), along with intravenous diphenhydramine 50 mg, given 30 minutes before the initiation of a slow infusion of carboplatin. In two of these patients, severe reactions developed despite the attempts at prophylaxis. There were no further attempts to administer carboplatin to these patients. In our patient population, efforts to further define individuals at risk for carboplatin hypersensitivity reactions were unsuccessful. There was no evidence that prior therapy with cisplatin, the use of single-agent carboplatin or the combination of carboplatin with paclitaxel, the administration of different carboplatin area-under-the concentration-time curve levels (we use a standard level of 5 or 6), or the length of the treatment-free interval between first-line, second-line, or third-line carboplatin delivery influenced the incidence or severity of reactions.
For several reasons, there has been limited discussion in the medical literature, in general, and the gynecologic oncology literature, in particular, regarding the topic of carboplatin-associated hypersensitivity reactions. First, until relatively recently, carboplatin was less commonly used in standard clinical practice than its parent compound, cisplatin. Second, as demonstrated in this report, hypersensitivity reactions to carboplatin generally do not develop until the patient has received multiple courses of treatment.6-10 Thus, if the use of carboplatin is limited to five or six courses during initial chemotherapy, or to only three to six courses in the salvage setting, the incidence of hypersensitivity reactions will probably be quite low. However, with more prolonged use (ie, > six courses), or with the administration of carboplatin both as a component of initial chemotherapy and in the second-line setting, the incidence of reactions is likely to be considerably greater. Third, it is possible that carboplatin hypersensitivity reactions are not always recognized. In fact, in our experience, the early signs can be fairly subtle and may include only a self-reported mild rash or itching that develops days after chemotherapy. Unfortunately, even in this retrospective analysis, we were unable to predict which patients would experience severe symptoms of a carboplatin hypersensitivity reaction on the basis of their development of mild symptoms with a previous course of treatment. In addition, it is likely that the severity and time course of carboplatin reactions have been significantly altered by the almost routine use of corticosteroids as a component of the "standard antiemetic" regimen for carboplatin administration, which also includes a serotonin S3 receptor antagonist.16,17 Patients may ascribe the signs and symptoms to something other than the chemotherapy when the development of symptoms occurs days after the treatment. Moreover, if a physician or nurse has not observed the rash, it is difficult to confirm the etiology or severity of the symptom complex. Finally, in patients treated with both carboplatin and paclitaxel, it is possible that reactions to carboplatin are being attributed mistakenly to the alternative agent. Although the overall incidence of paclitaxel-associated hypersensitivity reactions appears to be greater than that of carboplatin,18 there are several clinical features that strongly suggest that specific reactions are the result of treatment with the platinum agent rather than paclitaxel (Table 2).
First, in the patient in whom a reaction develops immediately, or shortly (15 to 30 minutes) after the initiation of the carboplatin infusion, there can be little question regarding the responsible agent. Second, it is well recognized that paclitaxel-associated hypersensitivity reactions most commonly occur within minutes of the initiation of the drug infusion during the first or second cycle of treatment with this cytotoxic agent.18 As previously discussed, carboplatin hypersensitivity reactions generally require multiple courses of prior exposure. Thus, in general, immediate hypersensitivity reactions observed during the initial treatment with carboplatin and paclitaxel will be caused by paclitaxel, whereas carboplatin should be considered a likely cause of this toxicity if it develops after more than five or six cycles of treatment. Third, at least in our experience, paclitaxel-associated hypersensitivity reactions are characterized by their remarkably consistent clinical course. The symptoms (eg, dyspnea, throat tightness, back pain) and signs (eg, diffuse erythema, wheezing, hypertension) will almost always develop within only a few minutes of the initiation of drug instillation and will rapidly subside with the discontinuation of the infusion. It is also possible in a large majority of patients to safely reinitiate the administration of paclitaxel (without the development of a second reaction) shortly after the signs and symptoms of the hypersensitivity reaction subside.19,20 In sharp contrast, carboplatin reactions follow a far more heterogeneous course. Although some events develop within minutes after initiation of the infusion, others are first noted near the completion of intravenous administration or several hours to days after the drug is delivered. In addition, in our patients experiencing the more serious reactions (eg, development of dyspnea, diffuse erythema), the symptoms completely subsided over a period of several hours, rather than minutes, despite the rapid administration of diphenhydramine and additional corticosteroids. A specific mechanism for carboplatin hypersensitivity reactions is suggested by the striking finding that almost 50% of all such episodes initially occurred during course 8 of platinum-based therapy. The patient has probably been sensitized during the initial regimen (generally six courses). However, the immune system may require additional stimulation during reintroduction of the drug (course 7) for a reaction to develop (course 8). On the basis of our experience with carboplatin-associated hypersensitivity reactions, we have developed a strategy to deal with these events when they occur. First, we attempt to determine whether a hypersensitivity reaction in an individual patient may be due to some other cause. This is particularly important because the initial signs and symptoms often occur a considerable length of time after the drug is administered. Second, if the episode is minor (eg, mild rash or itching), carboplatin is generally continued. If the reaction develops during the infusion or while the patient is still in the clinic, intravenous diphenhydramine 50 mg is administered. If the reaction occurs after the patient has returned home, she is advised to take the diphenhydramine orally (25 to 50 mg every 4 to 6 hours) if the symptoms persist. With future courses, the patient is advised to take this medication with the onset of any signs or symptoms suggestive of a hypersensitivity reaction. If there is no worsening of the allergic reactions with subsequent courses, carboplatin is continued (if clinically indicated). If the reaction is of greater severity (eg, diffuse erythema, development of dyspnea, wheezing), the decision to continue or discontinue treatment with carboplatin must balance the potential for serious toxicity with this approach versus the clinical utility of the cytotoxic drug in the individual patient. When the agent is being administered in the second-line ("salvage") setting in women with ovarian cancer, there are generally alternative drugs that reasonably can be used, rather than a platinum agent (eg, paclitaxel, topotecan, oral etoposide, or liposomal doxorubicin). In patients receiving initial chemotherapy for ovarian cancer, when long-term disease-free survival is a realistic goal, discontinuation of treatment with platinum is a major decision, as this class of drugs is the cornerstone of therapy for the malignancy. An attempt to "desensitize" the patient or provide maximum immunologic blockade (eg, several days of corticosteroids, prophylactic histamine receptor blockade), a strategy that has been used successfully in one of our patients, is probably justified in this specific clinical setting.21,22 However, in our experience, as a major portion of carboplatin hypersensitivity reactions develop after a considerable amount of carboplatin (> 50% of the planned dose) has already been administered to the patient, it is uncertain how successful desensitization will be for those who have developed severe reactions. On the basis of our experience, particular caution is advised in patients receiving their eighth course of carboplatin, or the second dose after reintroduction of the agent as second-line chemotherapy. The incidence of hypersensitivity reactions in our patient population during this single course of treatment is approximately 15%. It is also reasonable to inquire whether a patient documented to have a severe hypersensitivity reaction to carboplatin will also react if challenged, and treated, with cisplatin.6,23 Although we have no direct experience with this approach, the strategy may be worthy of at least one attempt in the rare situation of a patient who has received initial chemotherapy for ovarian cancer but would be unable to continue treatment with a platinum agent because of the development of a severe hypersensitivity reaction to carboplatin. Unfortunately, as the platinum itself is most likely to be responsible for the event,12,24 reactions to cisplatin would be anticipated in patients who have been previously sensitized to carboplatin. In summary, our experience over the past several years with carboplatin-associated hypersensitivity reactions has led us to conclude that this side effect of therapy is likely to become increasingly important as carboplatin-based regimens are used for initial and second-line therapy of ovarian cancer and other gynecologic malignancies. Although many patients experiencing this toxicity of treatment can continue to receive the cytotoxic agent with appropriate symptomatic management of, or prophylaxis for, the reactions, others will have to be switched to alternative therapeutic strategies.
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Bookman MA, McGuire WP III, Kilpatrick D, et al: Carboplatin and paclitaxel in ovarian carcinoma: A phase I study of the Gynecologic Oncology Group. J Clin Oncol 14:1895-1902, 1996 3. Markman M, Kennedy A, Webster K, et al: Carboplatin plus paclitaxel in the treatment of gynecologic malignancies: The Cleveland Clinic experience. Semin Oncol 24:26-29, 1997 (suppl 15) 4. Connelly E, Markman M, Kennedy A, et al: Paclitaxel delivered as a 3-hr infusion with cisplatin in patients with gynecologic cancers: Unexpected incidence of neurotoxicity. Gynecol Oncol 62:166-168, 1996[Medline] 5. Piccart MJ, Bertelsen K, Stuart G, et al: Is cisplatin-paclitaxel the standard in first-line treatment of advanced ovarian cancer? The EORTC-GCCG, NOCOVA, NCI-C and Scottish intergroup experience. Proc Am Soc Clin Oncol 16:352a, 1997 (abstr 1258) 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]
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Hendrick AM, Simmons D, Cantwell BMJ: Allergic reactions to carboplatin. Ann Oncol 3:239-240, 1992 8. Morgan JS, Adams M, Mason MD: Hypersensitivity reactions to carboplatin given to patients with relapsed ovarian carcinoma. Eur J Cancer 30A:1205-1206, 1994 9. 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[Medline]
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Planner RS, Weerasiri T, Timmins D, et al: Hypersensitivity reactions to carboplatin. J Natl Cancer Inst 83:1763-1764, 1991
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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 12. Shlebak AA, Clark PI, Green JA: Hypersensitivity and cross-reactivity to cisplatin and analogues. Chemother Pharmacol 35:349-351, 1995 13. 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] 14. Freedman SO, Krupey J: Respiratory allergy caused by platinum salts. J Allergy 42:233-237, 1968 15. Cromwell O, Pepys J, Parish WE, et al: Specific IgE anti-bodies to platinum salts in sensitized workers. Clin Allergy 9:109-117, 1979[Medline] 16. Markman M, Kennedy A, Webster K, et al: Control of carboplatin-induced emesis with a fixed low-dose of granisetron (0.5 mg) plus dexamethasone. Gynecol Oncol 60:435-437, 1996[Medline] 17. Markman M, Kennedy A, Webster K, et al: Low-dose intravenous ondansetron (8 mg) plus dexamethasone: An effective regimen for the control of carboplatin-induced emesis. J Cancer Res Clin Oncol 123:224-226, 1997[Medline] 18. Weiss RB, Donehower RC, Wiernik PH, et al: Hypersensitivity reactions from Taxol. J Clin Oncol 8:1263-1268, 1990[Abstract]
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Peereboom DM, Donehower RC, Eisenhauer EA, et al: Successful re-treatment with Taxol after major hypersensitivity reactions. J Clin Oncol 11:885-890, 1993 20. Markman M, Kennedy A, Webster K, et al: Experience with retreatment of gynecologic cancer patients experiencing paclitaxel-associated hypersensitivity reactions. Gynecol Oncol 64:307, 1997 21. Broome CB, Schiff RI, Friedman HS: Successful desensitization to carboplatin in patients with systemic hypersensitivity reactions. Med Pediatr Oncol 26:105-110, 1996[Medline] 22. 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] 23. Wiesenfeld M, Reinders E, Corder M, et al: Successful re-treatment with cis-dichlorodiammineplatinum(II) after apparent allergic reactions. Cancer Treat Rep 63:219-221, 1979[Medline] 24. Weiss RB: Hypersensitivity reactions to cancer chemotherapy. Semin Oncol 9:5-13, 1982[Medline] Submitted September 8, 1998; accepted December 22, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
