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© 2000 American Society for Clinical Oncology Paclitaxel-Associated Hypersensitivity Reactions: Experience of the Gynecologic Oncology Program of the Cleveland Clinic Cancer CenterFrom the The Cleveland Clinic Taussig Cancer Center; and the Departments of Gynecology/Obstetrics and Hematology/Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Maurie Markman, MD, Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44105; email markmam{at}cesmtp.ccf.org
PURPOSE: : This study expands the existing limited data as to whether patients developing clinically significant paclitaxel-induced hypersensitivity reactions can continue to be treated with this important antineoplastic agent and how such retreatment might be undertaken. PATIENTS AND METHODS: More than 450 patients received paclitaxel, either as a single agent or in a combination regimen, for a female pelvic malignancy in the Gynecologic Oncology Program of the Cleveland Clinic Cancer Center from January 1995 through December 1998. RESULTS: Of the more than 450 patients, 44 (approximately 9%) developed at least one episode of a clinically relevant hypersensitivity reaction to the cytotoxic drug. All 43 individuals (plus an additional four patients referred to our center after having previously experienced a severe paclitaxel-associated hypersensitivity reaction at another institution) who were retreated with paclitaxel were ultimately able to receive the agent. Five patients required treatment with a standardized desensitization regimen, developed by our group, to successfully receive paclitaxel. DISCUSSION: On the basis of this large single-institution study of paclitaxel-associated hypersensitivity reactions, we conclude that with appropriate precautions essentially all individuals experiencing these reactions can be safely treated with this agent.
ONE OF THE RATHER unique and potentially serious toxicities of paclitaxel, an increasingly important agent in the management of malignant disease,1-3 is the development of hypersensitivity reactions.4,5 In the early development of this drug, extremely serious hypersensitivity reactions, including deaths, were documented.4-6 Clinical experience4,5 and the results of clinical trials1,4,5,7 have confirmed that a prophylactic regimen of dexamethasone plus a histamine-1 and histamine-2 receptor antagonist can successfully reduce the incidence and severity of paclitaxel-induced hypersensitivity reactions. Unfortunately, despite the use of prophylaxis, such reactions continue to occur and can be of considerable concern to patients, their families, the treating physician, and nursing staff.1,5 In clinical practice, a number of important issues must be considered in individuals who experience this distressing toxicity of paclitaxel. Is it safe to reinstitute paclitaxel in patients who experience a hypersensitivity reaction? How should this be done? Are there patients who cannot be successfully treated with paclitaxel if they develop a reaction? If so, how can they be identified? Is there a role for desensitization in patients developing severe hypersensitivity reactions? How should this procedure be conducted? In an effort to effectively deal with these highly clinically relevant concerns, the Gynecologic Oncology Program of The Cleveland Clinic Cancer Center developed a standardized therapeutic strategy for the reinstitution of paclitaxel in patients who experienced a hypersensitivity reaction to the agent. We report here the results of that strategy in more than 450 patients who received paclitaxel at our center for the treatment of a female pelvic malignancy from January 1995 through December 1998.
Prophylaxis for Paclitaxel-Associated Hypersensitivity Reactions All patients receiving paclitaxel in our program were treated, to prevent hypersensitivity reactions, with a prophylactic regimen, which consisted of dexamethasone (either 20 mg orally the night before treatment and the morning of treatment or 20 mg intravenously [IV] 30 minutes before paclitaxel delivery)8 plus diphenhydramine (50 mg) and famotidine (20 mg) IV 30 minutes before chemotherapy.4,5
Retreatment With Paclitaxel in Patients Experiencing Paclitaxel-Associated Hypersensitivity Reactions
Desensitization Protocol for Patients Experiencing a Second Hypersensitivity Reaction After the Reinstitution of Paclitaxel Patients who underwent this desensitization protocol were administered oral dexamethasone (20 mg) at bedtime, approximately 36 hours and 12 hours before the planned chemotherapy delivery. An additional 20 mg of dexamethasone was given orally the morning before coming to the clinic for treatment. Patients were then administered IV dexamethasone (20 mg), diphenhydramine (50 mg), and famotidine (20 mg) approximately 30 minutes before chemotherapy. The initial paclitaxel infusion for desensitization consisted of 2 mg of the agent diluted in 100 mL of normal saline delivered over 30 minutes (concentration approximately one thirtieth of a standard paclitaxel infusion). In the absence of the development of the signs or symptoms of a hypersensitivity reaction, 10 mg of paclitaxel was delivered in 100 mL of normal saline over the next 30 minutes. Again, if this infusion was completed without difficulty, the remainder of the paclitaxel was administered over 3 hours. If, despite the low concentration of paclitaxel used in this desensitization protocol, the patient experienced a hypersensitivity reaction, the paclitaxel infusion was stopped. Another dose of IV diphenhydramine (50 mg) and IV hydrocortisone were administered immediately. The paclitaxel infusion was reinitiated in approximately 30 minutes, after the symptoms had subsided. Patients who experienced another reaction at this point would have no further attempt at treatment with paclitaxel.
Patient Population From January 1995 through December 1998, more than 450 patients with a female pelvic malignancy were treated in the Gynecologic Oncology Program of The Cleveland Clinic Foundation with either single-agent paclitaxel or a paclitaxel-containing combination regimen (eg, cisplatin, carboplatin, or doxorubicin). All patients who received paclitaxel in our program during this time period are included in this analysis. It has been our group’s routine clinical practice for all women with female pelvic malignancies receiving paclitaxel in the outpatient setting to have the oncology nurse in extremely close proximity to the patient during the initial 5 minutes of the paclitaxel infusion. This is done to both decrease the time required to respond to the signs and/or symptoms of a hypersensitivity reaction (eg, immediate discontinuation of the infusion and rapid delivery of a second dose of diphenhydramine) and to minimize the severity of the toxic episode. Of the 450 patients, 44 (approximately 9% of the patient population) experienced a total of 71 episodes of clinically relevant paclitaxel-associated hypersensitivity reactions. The median age of these 44 women was 63 years (range, 31 to 84 years). Diagnoses included ovarian cancer (n = 33), endometrial cancer (n = 5), primary peritoneal carcinoma (n = 3), and cervix cancer (n = 3). All patients who developed a paclitaxel-associated hypersensitivity reaction were receiving the agent administered as a 3-hour infusion. We were unable to identify any unique patient characteristics that predicted for the development of a paclitaxel-associated hypersensitivity reaction, such as a prior history of allergy or concurrent medications. In addition, there was no difference in the incidence of hypersensitivity reactions in our patient population based on whether an individual received either oral or IV dexamethasone as part of the prophylaxis regimen. Thirty-four of the total reactions (48%) occurred during the initial course of paclitaxel, with 16 (23%), nine (13%), six (8%), and three (4%) reactions developing during courses 2, 3, 4, and 5, respectively. Seventy-seven percent of the 44 patients who developed a paclitaxel-associated hypersensitivity reaction experienced their first episode during their initial treatment with the agent, whereas eight individuals (18%) had their first reaction during course 2. Only two patients (5%) in our series experienced an initial reaction to paclitaxel after the second course of treatment with the drug. In this group of individuals, using the monitoring strategy noted above, less than 1% of women who received paclitaxel in our program developed a severe hypersensitivity reaction. The signs and symptoms of paclitaxel-associated hypersensitivity reactions in our patient population included at least one and usually several of the following manifestations of a hypersensitivity reaction: diffuse and intense erythroderma, pruritus, chest tightness, severe back pain, dyspnea, tachycardia, extreme anxiety, and the development of hypotension or hypertension. In all cases, the initial manifestations of the reaction occurred within the first 5 minutes of the infusion, with the vast majority of reactions developing within the first 1 to 2 minutes after treatment was initiated. (It should be noted that there will be a short delay from the start of the infusion until any drug reaches the patient because of the presence of saline in the plastic IV tubing.)
Retreatment With Paclitaxel In 65 instances (93%) of the 70 episodes where the paclitaxel infusion was reinitiated 30 minutes after an initial reaction, the patients were able to complete the infusion without the subsequent appearance of a second reaction. Five individuals did develop a second hypersensitivity reaction after the reinitiation of the paclitaxel infusion and subsequently received the desensitization protocol described above (Appendix 2). Four additional individuals sent to our group by other physicians after they had experienced a serious paclitaxel hypersensitivity reaction also underwent the desensitization procedure at our center. Eight of these nine patients completed the desensitization procedure without any evidence of a hypersensitivity reaction. One of the nine patients experienced a reaction during the initial desensitization infusion. However, after a 30-minute delay (as described in Appendix 2), the infusion was successfully reinitiated in this patient and she was able to complete treatment with the agent. Six of the nine patients at our center who underwent the desensitization protocol successfully received the agent during subsequent courses using our standard prophylaxis regimen (all IV medications 30 minutes before chemotherapy). Three patients elected to receive all further paclitaxel courses using the desensitization protocol, which was undertaken without incident.
To the best of our knowledge, this multiyear experience of a single large cancer program in evaluating and managing paclitaxel-associated hypersensitivity reactions is one of the most extensive reported in the oncologic literature. This analysis emphasizes several important clinically-relevant features of paclitaxel toxicity.4-6 First, although relatively uncommon (< 10% incidence in our series), hypersensitivity reactions can cause great distress to patients, family members observing the episode, and the doctors and nurses involved in the individual’s care. Second, essentially all patients experiencing a paclitaxel-associated hypersensitivity reaction can be successfully treated with this cytotoxic agent through the use of one of several management strategies, as clinically required.6,10 The decision to try to reinstitute paclitaxel should be based on the clinical importance of using this cytotoxic agent in a particular disease setting and not on a concern the drug will be excessively toxic if retreatment is attempted. In our opinion, it is relevant to emphasize the truly limited number of episodes of severe reactions (eg, significant hypotension or bronchospasm) encountered in this patient population during this 4-year time period, despite our treating more than 450 individuals with paclitaxel. We firmly believe our specific technique of paclitaxel delivery was directly responsible for this important clinical feature. In all patients who received paclitaxel in our program in the outpatient setting, the treating nurse remained within several feet of the patient during the initial 5 minutes of the infusion. With any sign or symptom of a hypersensitivity reaction (eg, chest discomfort, facial flushing, or sensation of extreme anxiety), the infusion was immediately discontinued, and another dose of diphenhydramine was administered. In our experience, because essentially all reactions to paclitaxel occur within this time frame, this short-term intensive monitoring should not impose an excessive burden on the nursing personnel. We can only speculate as to why it is possible to safely reinstitute therapy with paclitaxel after a short delay using the identical prophylactic regimen that had previously not prevented the development of a hypersensitivity reaction in an individual patient. However, it is reasonable to suggest that receptors on mast cells (or other immunologic cell types) responsible for the development of paclitaxel hypersensitivity reactions are blocked by the earlier infusion of the agent and are not accessible to react with the drug reinfused into the systemic compartment. This receptor blockade might occur either after the short-delay strategy or after a formal desensitization protocol (as described in Appendices 1 and 2). Although the desensitization protocol we used was successful in permitting the delivery of paclitaxel to the small number of patients who experienced a reaction with reinstitution of the agent after a short delay, it is possible the initial paclitaxel concentration used in this regimen (2 mg in 100 mL normal saline delivered over 30 minutes) is not optimal. Desensitization protocols in other areas of medicine (eg, iodine dye sensitivity) have used far lower initial concentrations of the offending agent (eg, > 100 to 1,000-fold dilution) in an attempt to achieve short-term immunologic blockade. In the rare individual unable to receive paclitaxel despite the maneuvers described by our group and others, it would not be unreasonable to attempt desensitization with an initial paclitaxel concentration substantially lower than that reported by our group. In summary, our large group experience with paclitaxel-associated hypersensitivity reactions has demonstrated that few, if any, patients developing such events cannot be successfully retreated with the drug if appropriate maneuvers are used to prevent a subsequent reaction.
1. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996
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Langer CJ, Ettinger DS: The burgeoning role of paclitaxel in advanced pulmonary malignancy. Oncologist 3:67-85, 1998
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Rowinsky EK, Donehower RC: Paclitaxel (Taxol). N Engl J Med 332:1004-1014, 1995 5. Weiss RB, Donehower RC, Wiernik PH, et al: Hypersensitivity reactions from Taxol. J Clin Oncol 8:1263-1268, 1990[Abstract]
6.
Peereboom DM, Donehower RC, Eisenhauer EA, et al: Successful re-treatment with Taxol after major hypersensitivity reactions. J Clin Oncol 11:885-890, 1993
7.
Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12:2654-2666, 1994
8.
Markman M, Kennedy A, Webster K, et al: Simplified regimen for the prevention of paclitaxel-associated hypersensitivity reactions. J Clin Oncol 15:3517, 1997 (letter) 9. Essayan DM, Kagey-Sobotka A, Colarusso PJ, et al: Successful parenteral desensitization to paclitaxel. J Allergy Clin Immunol 97:42-46, 1996[Medline] 10. Olson JK, Sood AK, Sorosky JI, et al: Taxol hypersensitivity: Rapid retreatment is safe and cost effective. Gynecol Oncol 68:25-28, 1998[Medline] Submitted March 1, 1999; accepted July 29, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
