J Cancer Res Clin Oncol (2004) 130: 25–28DOI 10.1007/s00432-003-0501-3 Maurie Markman Æ Fred Hsieh Æ Kristine ZanottiKenneth Webster Æ Gertrude PetersonBarbara Kulp Æ Ann Spicel Æ Jerome Belinson Initial experience with a novel desensitization strategyfor carboplatin-associated hypersensitivity reactions:carboplatin-hypersensitivity reactions Received: 17 June 2003 / Accepted: 28 August 2003 / Published online: 15 October 2003Ó Springer-Verlag 2003 Abstract Purpose: Carboplatin hypersensitivity is anincreasingly recognized toxicity in individuals receiving >6 cumulative courses of this important antineoplastic agent. We wished to determine if a novel multi-pronged Considerable retrospective data have documented the approach to re-treating patients with a high risk for this clinical utility of platinum agents when employed as potentially serious side effect could permit the safe second-line treatment of recurrent ovarian cancer delivery of this class of cytotoxic drugs. Methods: Five (Markman and Bookman 2000; Gershenson et al. 1989; patients with gynecologic malignancies who had either Hoskins et al. 1991; Gore et al. 1990; Markman et al.
experienced a documented carboplatin hypersensitivity 1991). Objective response rates ranging from 20–70% reaction (n =4) or had a ‘‘positive’’ carboplatin skin test have been reported in this clinical setting, based on the (n =1), received a multi-drug oral regimen administered length of the ‘‘treatment-free interval’’ from the com- over several days which was designed to block known pletion of primary chemotherapy (Hoskins et al. 1991; mediators of anaphylaxis. Four of these individuals Gore et al. 1990; Markman et al. 1991). Due to its more subsequently underwent treatment with either cisplatin favorable toxicity profile, carboplatin is generally the or carboplatin employing a ‘‘dose escalation’’ desensiti- preferred platinum drug in this clinical setting (Mark- zation schema. Results: Four patients underwent suc- man and Bookman 2000; Markman et al. 1997).
cessful treatment with either cisplatin or carboplatin Unfortunately, it is now well-recognized that patients (3, 4, 5, 6+ total additional courses) without any further receiving carboplatin as second-line treatment of ovar- evidence of hypersensitivity. Conclusion: In this pre- ian cancer have at least a modest risk for experiencing liminary report of a limited patient population, we have hypersensitivity reactions (Markman et al. 1999; Dizon demonstrated the ability to safely deliver a platinum et al. 2002; Robinson et al. 2001; Rose et al. 1998; agent to individuals with either documented carboplatin Chang et al. 1995; Weidmann et al. 1994; Hendrick et al.
hypersensitivity, or a high risk for this potentially seri- 1992; Morgan et al. 1994). The symptoms associated ous toxicity of carboplatin. Further exploration of this with this process range from a minor rash to diffuse novel management strategy in a larger group of patients erythroderma, severe anxiety, dyspnea, tachycardia, hypotension, and (in very rare cases) death. (Markmanet al. 1999; Dizon et al. 2002; Robinson et al. 2001; Rose Keywords Carboplatin Æ Hypersensitivity reactions Æ et al. 1998; Chang et al. 1995; Weidmann et al. 1994; Hendrick et al. 1992; Morgan et al. 1994; Zweizig et al.
Several management approaches have been proposed to deal with this relatively uncommon, but potentiallyserious, complication of carboplatin treatment. Theseinclude avoidance of further administration of the drug M. Markman (&) Æ F. Hsieh Æ K. Zanotti Æ K. Webster following documentation of hypersensitivity, delivery of G. Peterson Æ B. Kulp Æ A. Spicel Æ J. BelinsonDepartments of Hematology, Medical Oncology, the agent by an extended infusion schedule, and use of a Gynecology/Obstetrics, and Pulmonary/Critical Care Medicine, variety of ‘‘desensitization schema’’ (Markman et al.
The Cleveland Clinic Foundation, 9500 Euclid Avenue, 1999; Dizon et al. 2002; Robinson et al. 2001; Rose et al.
1998; Chang et al. 1995; Weidmann et al. 1994; Hend- E-mail: [email protected].: +1-216-445-6888 rick et al. 1992; Goldberg et al. 1996; Broome et al.
Development of an effective strategy to prevent fu- (Zanotti et al. 2001), where an attempt was made to ture platinum-associated hypersensitivity reactions in deliver further platinum treatment employing this individuals experiencing such an event requires consid- eration of the substantial clinical heterogeneity of thesymptom-complex, both in presentation and severity(Markman et al. 1999). In some patients the signs of hypersensitivity develop immediately upon initiation ofthe drug infusion, similar to the almost universal pattern observed with paclitaxel anaphylaxis (Markman et al.
The ‘‘desensitization’’ protocol consisted of a number of elements 2000). However, in others, the reaction begins when one- designed to reduce the risk for the subsequent development of a half or more of the treatment volume has been instilled.
serious hypersensitivity reaction, including: Finally, in a subset of patients, minor rashes may be 1. Substitution of cisplatin for carboplatin: previous anecdotal noted several days after therapy (Markman et al. 1999).
reports have suggested that patients documented to have Further, while reactions can be quite mild in severity, experienced hypersensitivity to carboplatin may be successfully events of far greater consequence can occur.
treated with cisplatin (Dizon et al. 2002; Weidmann et al.
This unpredictable pattern suggests multiple immu- 1994; Hendrick et al. 1992). [It was planned that if a patient nological and non-immunological mechanisms may be was able to be treated with cisplatin without developing areaction, but systemic side effects were found to be unac- involved in different patients experiencing carboplatin- ceptable (e.g., emesis), subsequent treatment with carboplatin, associated hypersensitivity reactions (Cromwell et al.
employing an identical protocol as described below, would be 1979; Orbaek 1982; Freedman and Krupey 1968; Zan- otti and Markman 2001). As a result, it is not surprising 2. Delivery of cisplatin (or carboplatin) at escalating concentra- tions: a standard management strategy designed to prevent that prevention of this process has met with variable serious immediate-type hypersensitivity reactions in patients reported success (Markman et al. 1999; Dizon et al.
known to be highly allergic to a medication includes drug 2002; Robinson et al. 2001; Rose et al. 1998; Chang et al.
administration at progressively higher concentrations, beginning 1995; Weidmann et al. 1994; Hendrick et al. 1992; with extremely dilute solutions (Table 1). [Our group, and oth-ers, had previously shown this strategy to be potentially useful in Morgan et al. 1994; Zweizig et al. 1994; Goldberg et al.
a subset of individuals experiencing severe paclitaxel-associated anaphylaxis (Markman et al. 2000; Essayan et al.1996)].
We have recently developed a novel ‘‘desensitization 3. Administration of several pharmaceutical agents prior to each strategy’’ which attempts to block multiple biological platinum treatment, each designed to block different immuno- pathways potentially involved in the evolution of the logical pathways potentially involved in the clinical symptoms ofhypersensitivity: these included: (a) corticosteroids (prednisone); (b) H-2 receptor [famotidine (Pepcid)] and H-1 (diphenhydra- hypersensitivity. In this report we describe the outcome mine) blockade; (c) 5-lipoxygenase inhibition [zileuton (Zyflo)]; of five patients who either had previously experienced a (d) cysteinyl leukotriene receptor-1 antagonism [montelukast sodium (Singulair)]; (e) COX 1 and COX 2 inhibition (indom-ethecin); and (f) an oral beta-agonist [albuterol sulfate (Vol- developed a ‘‘strongly positive’’ carboplatin skin test max)]. The drug administration schedule and doses employedare outlined in Table 2.
4. Cisplatin/carboplatin skin testing: immediately prior to infusing the first dilution of cisplatin/carboplatin an intradermal skin test ‘‘desensitization procedure’’. Each solution was administered in was performed [0.02 ml cisplatin or carboplatin removed from 50 ml of normal saline (1st 30 min; 2nd 15 min; 3rd 15 min; final the solution (‘‘undiluted’’) which had been prepared for treat- 30 min) with the next higher concentration delivered immediately ment]. If a ‘‘positive test’’ (at least 5 mm wheel with a sur- following successful completion of the preceding infusion. The rounding flare) was observed, the planned platinum treatment ‘‘dilutions’’ were made from the solution prepared for drug would not be given (Zanotti et al. 2001).
administration. (With cisplatin, the final concentration of drug wasadministered with 25 grams of mannitol) All patients being considered for treatment with this program who had previously experienced a carboplatin hypersensitivity reaction, or who had developed a ‘‘positive’’ carboplatin skin test, were extensively counseled regarding the potential for the devel- opment of a serious anaphylactic reaction resulting from additional platinum, despite the precautions to be employed to prevent such an event. Further, alternative non-platinum-based managementoptions were discussed in detail.
Table 2 Multi-drug regimen employed to prevent generation of mediators of anaphylaxis 6 h·3 doses beginning the day (10 a.m.; 4 p.m.; 10 p.m.) prior to chemotherapy Montelukast sodium (Singulair) 10 mg PO QD HS For 1 day (10 a.m.; 4 p.m.; 10 p.m.) prior to chemotherapy For 1 day (10 a.m.; 10 p.m.) prior to chemotherapy only a corticosteroid) designed to prevent an immuno- To date, a total of five patients (median age 58 years)with ovarian cancer cared for in the Gynecologic Cancer program of the Cleveland Clinic have undergone anattempt In this preliminary report of a small group of women employing this ‘‘desensitization procedure’’.
with documented carboplatin-associated hypersensitiv- All five women had previously been treated with ity, or a high risk for development of such an event carboplatin during primary therapy without experienc- based on a ‘‘strongly positive’’ carboplatin-skin test, we ing hypersensitivity. In three patients there was evidence have shown that use of a novel multi-pronged manage- of a both a biological and clinical response to second- ment approach has permitted the safe administration of line treatment with carboplatin when the allergic reac- While it is unknown if alternative, and perhaps less Four of these women had documented carboplatin- complex, strategies might have produced similar favor- associated anaphylaxis, while one had a markedly ‘‘po- able results, it is the belief of our group that the potential sitive’’ carboplatin skin-test prior to employing the severity of carboplatin hypersensitivity in this setting ‘‘desensitization program’’ (Zanotti et al. 2001). In two warrants major efforts to prevent reactions if this class of patients evidence of carboplatin-hypersensitivity initially agents is ever to be administered again. In this regard it led to therapy with other cytotoxic agents before is important to recognize that several deaths have been attempting re-treatment with a platinum drug.
documented in individuals with known platinum- All patients were informed of the potential serious hypersensitivity who were retreated with platinum risk associated with re-treatment with a platinum agents (Zweizig et al. 1994; Dizon et al. 2002). Further, agent, prior to proceding with the ‘‘desensitization of eight patients with either documented carboplatin hypersensitivity reactions or a ‘‘positive’’ skin test our Two patients had the dose of oral prednisone reduced group has attempted to re-treat over the last several from 150 mg (50 mg TID), the day immediately prior years with a less rigorous ‘‘desensitization protocol’’ to chemotherapy, to 50 mg, due to excessive anxiety, (e.g., several days of high dose steroids followed by a ‘‘dose escalation’’ desensitization schema), five subse- Four of the five patients were able to successfully quently experienced an anaphylactic reaction (Markman receive treatment with platinum-based chemotherapy (two patients continued with cisplatin, two switched to It remains unknown which biological pathway is carboplatin) employing the ‘‘desensitization program’’ most likely to be implicated in the signs and symptoms outlined in Table 2 (total additional platinum-cycles of carboplatin-associated anaphylaxis. As previously delivered: 3, 4, 5, 6+). One patient developed a ‘‘posi- noted, the heterogeneity of the observed reactions argues tive’’ skin test immediately prior to the first test dose of for the conclusion that the pathophysiology of hyper- platinum, despite the extensive pre-treatment regimen, sensitivity to platinum agents is quite complex. Thus, in and further attempts to employ a platinum agent were this clinical setting, attempting to interfere with as many known immunological and non-immunological path- The clinical course of one of the five patients included ways of anaphylaxis as possible would appear to be the in this report is particularly noteworthy. The patient The regimen employed in this patient population in- reaction in the fall of 1999 (erythematous pruritic rash cluded modification of the platinum species (substitution on the legs, arms, face, neck). At that time an unsuc- of cisplatin or carboplatin), general immunosuppression cessful attempt was make to treat her with a similar, and interference with both basophil and eosinophil but not identical ‘‘desensitization program’’ to that activation (prednisone); attempts to prevent mast cell described in this report (4 days of oral prednisone, degranulation (escalating concentrations of cisplatin/ followed by regimen of escalating concentrations of carboplatin; oral beta-agonist therapy), interference carboplatin). The patient developed a diffuse rash when with H-1 (famotidine) and H-2 (diphenhydramine) the final solution was being infused, and she was sub- receptors, prevention of the formation, and inhibition of sequently treated with several non-platinum based the activity of cysteinyl leukotrienes (montelukast so- cytotoxic regimens. With recent disease progression, the dium, zileuton) and prevention of the formation of patient elected to try this modified ‘‘desensitization proinflammatory prostaglandins (indomethicin).
program’’. To date, she has received a total of six cycles While the outcome of treatment for the individuals of cisplatin employing this procedure, and has achieved included in this preliminary report appears promising, major symptomatic benefit from the agent. In addition the number of patients managed in this manner is quite to the use of cisplatin, rather than carboplatin, with this limited and the overall success of this novel strategy more recent attempt at ‘‘desensitization’’ the regimen remains to be defined. As a result, we have initiated a employs multiple pharmacologic agents (rather than formal study to more critically evaluate the role of this program in those patients with either documented car- Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, boplatin hypersensitivity or a ‘‘positive’’ carboplatin Rubin S, Jones W, Almadrones L, Lewis JL Jr. (1991) Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9:389–393 Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Bel- inson J (1997) Continued chemosensitivity to cisplatin/car- boplatin in ovarian carcinoma despite treatment with multipleprior platinum-based regimens. Gynecol Oncol 65:434–436 Markman M, Kennedy A, Webster K, Elson P, Peterson G, Kulp Broome CB, Schiff RI, Friedman HS (1996) Successful desensiti- B, Belinson J (1999) Clinical features of hypersensitivity reac- zation to carboplatin in patients with systemic hypersensitivity tions to carboplatin. J Clin Oncol 17:1141–1145 reactions. Med Pediatr Oncol 26:105–110 Markman M, Bookman MA (2000) Second-line treatment of Chang SM, Fryberger S, Crouse V, Tilford D, Prados MD (1995) Carboplatin hypersensitivity in children. A report of five Markman M, Kennedy A, Webster K, Kulp B, Peterson G, Bel- patients with brain tumors. Cancer 75:1171–1175 inson J (2000) Paclitaxel-associated hypersensitivity reactions: Cromwell O, Pepys J, Parish WE, Hughes EG (1979) Specific IgE experience of the Gynecologic Oncology Program of the antibodies to platinum salts in sensitized workers. Clin Allergy Cleveland Clinic Cancer Center. J Clin Oncol 18:102–105 Morgan JS, Adams M, Mason MD (1994) Hypersensitivity reac- Dizon DS, Sabbatini PJ, Aghajanian C, Hensley ML, Spriggs DR tions to carboplatin given to patients with relapsed ovarian (2002) Analysis of patients with epithelial ovarian cancer or fallopian tube carcinoma retreated with cisplatin after the Orbaek P (1982) Allergy to the complex salts of platinum. A review development of a carboplatin allergy. Gynecol Oncol 84:378– of the literature and three case reports. Scand J Work Environ Essayan DM, Kagey-Sobotka A, Colarusso PJ, Lichtenstein LM, Robinson JB, Singh D, Bodurka-Bevers DC, Wharton JT, Ger- Ozols RF, King ED (1996) Successful parenteral desensitization shenson DM, Wolf JK (2001) Hypersensitivity reactions and to paclitaxel. J Allergy Clin Immunol 97:42–46 the utility of oral and intravenous desensitization in patients Freedman SO, Krupey J (1968) Respiratory allergy caused by with gynecologic malignancies. Gynecol Oncol 82:550–558 Rose PG, Fusco N, Fluellen L, Rodriguez M (1998) Carboplatin Gershenson DM, Kavanagh JJ, Copeland LJ, Stringer CA, Morris hypersensitivity reactions in patients with ovarian and perito- M, Wharton JT (1989) Re-treatment of patients with recurrent neal carcinoma. Int J Gynecol Cancer 8:365–368 epithelial ovarian cancer with cisplatin-based chemotherapy.
Weidmann B, Mulleneisen N, Bojko P, Niederle N (1994) Hyper- sensitivity reactions to carboplatin. Report of two patients, Goldberg A, Confino-Cohen R, Fishman A, Beyth Y, Altaras M review of the literature, and discussion of diagnostic procedures (1996) A modified, prolonged desensitization protocol in carboplatin allergy. J Allergy Clin Immunol 98:841–843 Zanotti KM, Markman M (2001) Prevention and management of Gore ME, Fryatt I, Wiltshaw E, Dawson T (1990) Treatment of antineoplastic-induced hypersensitivity reactions. Drug Safety relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Zanotti KM, Rybicki LA, Kennedy AW, Belinson JL, Webster KD, Kulp B, Peterson G, Markman M (2001) Carboplatin skin Hendrick AM, Simmons D, Cantwell BMJ (1992) Allergic reac- testing: a skin-testing protocol for predicting hypersensitivity to tions to carboplatin. Ann Oncol 3:239–240 carboplatin chemotherapy. J Clin Oncol 19:3126–3129 Hoskins PJ, OÕReilly SE, Swenerton KD (1991) The Ôfailure free Zweizig S, Roman LD, Muderspach LI (1994) Death from ana- intervalÕ defines the likelihood of resistance to carboplatin in phylaxis to cisplatin: a case report. Gynecol Oncol 53:121–122 patients with advanced epithelial ovarian cancer previouslytreated with cisplatin: relevance to therapy and new drugtesting. Int J Gynecol Cancer 1:205–208

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