Paclitaxel Hypersensitivity Research Articles

Oral premedication for the prevention of hypersensitivity reactions to paclitaxel

Premedication with dexamethasone, H1 and H2 receptor antagonists given intravenously prior to paclitaxel are highly successful in preventing life-threatening hypersensitivity reactions. We conducted a prospective study to assess the availability and safety of the administration of promethazine and dexamethasone per os in the premedication of paclitaxel hypersensitivity reactions. Of 180 eligible cancer patients, 100 patients received paclitaxel weekly and 80 patients, every 3 weeks. Patients received premedication with promethazine 25 mg per os, dexamethasone 2-20 mg per os and cimetidine 300 mg intravenously. One hundred patients in the weekly group received 940 cycles of paclitaxel. Hypersensitivity reactions occurred in one (1%) patient. There were no hypersensitivity reactions in 99% of patients. Eighty patients in the 3 weekly group received 464 cycles of paclitaxel. Hypersensitivity reactions occurred in (3) 4% of patients while 96% of patients had no hypersensitivity reactions. Two of these three patients had no further hypersensitivity reactions after receiving premedication intravenously. In the two groups 40 min/cycle reduction in treatment duration was observed. In conclusion, this study shows that drugs used for premedication prior to paclitaxel can be given orally. This strategy is feasible, gives excellent results in reducing hypersensitivity reactions and shortens the time of treatment for patients and treating staff.

Rapid inpatient and outpatient desensitization for carboplatin or paclitaxel hypersensitivity: A protocol effective in patients with gynecologic malignancies

5090 Background: The purpose of the study was to investigate the safety and efficacy of a rapid desensitization protocol used in the inpatient and outpatient settings for patients with hypersensitivity reactions (HR) to carboplatin or paclitaxel. Methods: The 3-solution, 12-step protocol combined gradual increases in the rate of infusion and concentration of the chemotherapy, infusing the target dose over 5.8 hours for inpatient and 3.8 hours for outpatient administration. Patients were premedicated with antihistamines without additional corticosteroids. Results: Between February 2000 and December 2004, 45 patients with history of ovarian (n=39), fallopian (n=3), endometrial (n=2), and peritoneal (n=1) cancer who had moderate to severe HR to either carboplatin or paclitaxel were evaluated. The 26 patients who reacted to carboplatin received a median of 8 courses before developing their initial HR while 16 of 19 patients with HR to paclitaxel reacted on their first exposure to the agent. 17 of 22 patients with HR to carboplatin had positive skin tests. All 45 patients successfully completed 195 planned courses of desensitization (88 courses of carboplatin and 107 of paclitaxel). After undergoing successful inpatient desensitization, 6 patients thus far have received 22 desensitizations in the outpatient setting without adverse reactions. Of 26 patients receiving carboplatin desensitization for recurrent cancer, 10 had a radiographic response (partial or complete response) and/or >50% drop of initial CA125 value, 11 had stable disease radiographically and/or CA125 response (<50% drop), 1 is still unevaluable for response, and 4 had progressive disease after 2 cycles of carboplatin. Conclusions: The rapid desensitization protocol has proven to be safe and effective in the inpatient and outpatient settings for patients with HR to either carboplatin or paclitaxel. This protocol has allowed appropriate patients to continue chemotherapy in the setting of moderate to severe HR, and the study warrants the incorporation of the protocol into standard clinical practice. No significant financial relationships to disclose.

Incidence and risk factors for paclitaxel hypersensitivity during ovarian cancer chemotherapy

Hypersensitivity reaction (HSR) is still a major concern during cancer chemotherapy with paclitaxel. In the present study, we investigated retrospectively the incidence of HSRs to paclitaxel and the risk factors in 105 patients (553 courses) who received adjuvant chemotherapy (paclitaxel and carboplatin) for ovarian cancer. Moderate to severe HSRs that led to cessation or discontinuation of the chemotherapy, including respiratory distress and hypotension, were observed in 14 patients (13.3%) and 16 courses (2.9%), regardless of the use of conventional premedication with glucocorticoid, and histamine H(1) and H(2) antagonists. The incidence of HSRs to paclitaxel in patients with ovarian cancer seemed to be considerably higher than those reported by other investigators in patients with other carcinomas such as non-small-cell lung cancer and breast cancer. Four risk factors were identified: (1) history of mild dermal reactions such as facial flushing and urticaria in previous courses, (2) presence of respiratory dysfunction, (3) obesity (body mass index >25), and (4) postmenopausal at the time of ovariectomy. The incidence of hypersensitivity increased linearly as the number of risk factors increased (r=0.992, P=0.008). It is likely that disappearance of the estrous cycle facilitates the occurrence of HSRs to paclitaxel.

Ovariectomy aggravates hypersensitivity reactions to paclitaxel in rats

Hypersensitivity reactions is still a matter of serious concern during chemotherapy with paclitaxel, particularly in patients with ovarian cancer. We recently reported that intravenous injection of paclitaxel causes acute lung injury characterized by vascular hyperpermeability, edema and respiratory dysfunction in rats. In the present study, we investigated the influence of ovariectomy on the paclitaxel- induced acute lung injury in rats. Ovariectomy worsened paclitaxel- induced acute lung injury, which was reversed by 17b-estradiol. The mRNA expression for endothelial nitric oxide synthase was reduced in lungs of ovariectomized rats. To determine the role for nitric oxide, we examined the effects of several agents that modulate nitric oxide concentration on the pulmonary response to paclitaxel. In ovary- intact rats, a nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester exaggerated paclitaxel- induced acute lung injury, while nitric oxide donors such as sodium nitroprusside and isosorbide dinitrate attenuated the lung injury. Sodium nitroprusside was also effective in alleviating the paclitaxel- induced acute lung injury in ovariectomized rats. These findings suggest that ovariectomy enhances the susceptibility to paclitaxel hypersensitivity, in which decrease in estrogen and subsequent reduction in nitric oxide synthesis may be involved.

Similarity and difference in the acute lung injury induced by a radiographic contrast medium and an anticancer agent paclitaxel in rats

Paclitaxel is one of the most frequently used anticancer agents but its use is sometimes limited because of the incidence of severe hypersensitivity reactions. The clinical symptoms of the reactions, including dyspnea and pulmonary edema, are similar to those induced by iodinated contrast medium during radiographic examination. Therefore, the premedication for the prophylaxis of hypersensitivity reactions to paclitaxel is carried out in accordance with that for radiographic contrast medium. In the present study, we compared the effects of paclitaxel and an iodinated radiocontrast medium ioxaglate on vascular permeability and pulmonary function in rats. Both paclitaxel (15 mg/kg) and ioxaglate (4 g iodine/kg) caused perivascular edema, plasma extravasation and decrease in arterial PaO 2. Dexamethasone inhibited plasma extravasation induced by the two compounds. In contrast, histamine H 1 and H 2 antagonists attenuated the effects of ioxaglate without inhibiting those of paclitaxel. On the other hand, a neurokinin NK 1 antagonist (LY303870: 0.5 mg/kg) significantly inhibited the pulmonary responses induced by paclitaxel but not by ioxaglate. Therefore, it is suggested that paclitaxel and ioxaglate cause similar acute lung injury but the mechanisms are different between the two compounds, in which histamine and substance P are involved in the pulmonary dysfunction induced by ioxaglate and paclitaxel, respectively. These findings also raise a possibility that more effective premedication is required for the prophylaxis of paclitaxel hypersensitivity.

Role of substance P in hypersensitivity reactions induced by paclitaxel, an anticancer agent

The role of substance P in adverse pulmonary reactions induced by an anticancer agent paclitaxel was investigated in rats and humans who undertook post-operative chemotherapy for ovarian cancer. In rats, paclitaxel caused a marked plasma extravasation and edema in lungs with a concomitant decrease in arterial partial oxygen pressure, which were reversed by an NK 1 antagonist LY303870. Substance P level in rat plasma and bronchoalveolar lavage fluid increased after paclitaxel injection. In 13 patients, plasma level of substance P but not histamine significantly ( P<0.05) increased during paclitaxel infusion. Therefore, substance P rather than histamine may be involved in paclitaxel hypersensitivity.

Pemirolast potently attenuates paclitaxel hypersensitivity reactions through inhibition of the release of sensory neuropeptides in rats

The effects of anti-allergic agents on the hypersensitivity reactions to paclitaxel, an anti-cancer agent, were examined in rats. Intravenous injection of paclitaxel (15 mg/kg) caused a marked extravasation of plasma protein in lungs and a transient decrease in arterial partial oxygen pressure ( PaO 2 ). The paclitaxel-induced protein extravasation was inhibited by low doses (0.1–1 mg/kg) of pemirolast or high doses (30–100 mg/kg) of cromoglycate. However, ketotifen was not effective. The decrease in PaO 2 induced by paclitaxel was also significantly reversed by pemirolast. On the other hand, the paclitaxel-induced plasma extravasation was not attenuated by a histamine H 1 blocker diphenhydramine or an H 2 blocker famotidine, but was significantly reduced by a neurokinin NK 1 antagonist LY303870 (0.5 mg/kg) and an NK 2 antagonist SR48968 (1 mg/kg). The concentrations of proteins and sensory peptides such as substance P, neurokinin A and calcitonin gene-related peptide but not histamine in the rat bronchoalveolar lavage fluid were elevated by paclitaxel injection. Both cromoglycate and pemirolast reduced the paclitaxel-induced rise in proteins and sensory peptides. Therefore, we demonstrated for the first time that sensory nerve peptides are involved in paclitaxel hypersensitivity and that an anti-allergic agent pemirolast attenuates the paclitaxel response by inhibiting the release of sensory nerve peptides.

Relationship between a history of systemic allergic reactions and risk of subsequent carboplatin hypersensitivity

Objective The establishment of clinical features identifying patients at a heightened risk for the development of carboplatin hypersensitivity may assist in the management of this important toxicity. Based on a previous report suggesting a history of “bee sting” allergy predicted for paclitaxel hypersensitivity, we attempted to determine if there was a relationship between a history of prior systemic allergic reactions and the subsequent development of carboplatin hypersensitivity. Patients and methods The medical records of all women treated in the Gynecologic Cancer Program of the Cleveland Clinic from June 1995 to May 2002 who received >6 cycles of platinum-based chemotherapy were retrospectively reviewed for a history of prior systemic hypersensitivity (e.g., medications, environmental exposure). The incidence of “positive” allergic histories was then examined in relation to the subsequent risk of patients developing either a documented carboplatin hypersensitivity reaction or a “positive” carboplatin skin test. Results The analysis included 174 patients (91 undergoing “carboplatin skin testing”) who received > 6 courses of carboplatin. Of 53 patients with no recorded history of systemic hypersensitivity treated prior to our routine use of carboplatin skin testing, 19% experienced an allergic reaction, in contrast to a 40% incidence of a documented carboplatin reaction in 30 patients with a recorded history of hypersensitivity to a medication or environmental exposure ( P < 0.05). For the 55 patients with no history of systemic hypersensitivity who underwent carboplatin skin-testing, 27% had a positive test result, in comparison to a 36% positive test rate in women with a previous history of a systemic hypersensitivity reaction recorded in the medical record ( P > 0.05). Conclusion This analysis suggests that patients with a prior history of systemic hypersensitivity to medications or environmental exposures may be at a heightened risk for experiencing allergic reactions to carboplatin.

Bee sting allergy may increase risk of paclitaxel hypersensitivity

Bee sting allergy may increase risk of paclitaxel hypersensitivity

Bee sting allergy may increase risk of paclitaxel hypersensitivity

Bee sting allergy may increase risk of paclitaxel hypersensitivity

Paclitaxel hypersensitivity reactions related to bee-sting allergy

Patients with a history of beesting allergy may have a higher risk of a hypersensitivity reaction with paclitaxel treatment. We suggest careful screening of patients for allergies.

Hypersensitivity Reactions in Ovarian Cancer Patients Receiving Paclitaxel

Objective: The aim of this study was to describe a rapid retreatment strategy in patients with paclitaxel hypersensitivity reactions.Methods: A retrospective review of all patients receiving standard 3-hour infusion paclitaxel-based chemotherapy after proper premedication at the Department of Gynecologic Oncology, University of Bari between 1995 and 1998, was performed. All patients who developed hypersensitivity reactions to paclitaxel were identified and their treatment course and outcome were reviewed. A review of the literature on this subject is also presented.Results: Eighty-six women were treated with 461 cycles of paclitaxel-based chemotherapy at our Unit. Twelve patients (14%) developed hypersensitivity reactions. All had received standard premedication consisting of corticosteroids and hystamine blockers. Hypersensitivity reactions consisted of isolated face flushes (3 patients), dyspnea and chest tightness (4 patients) or bronchospasm (5 patients). Eleven patients were rechallenged with the original paclitaxel solution starting at a slower rate after a second premedication with a double dosage of steroids. None of these patients had reactions in subsequent courses. Only one patient (the first of this series treated in February 1995), was retreated 5 days later under strict monitoring in intensive care unit.Conclusions: Retreatment with the original paclitaxel solution is safe in almost all patients with hypersensitivity reactions. The drug should be administered within the next 24 hours with a new premedication protocol.

Phase II study of paclitaxel in relapsed non-Hodgkin's lymphomas.

To assess the efficacy and toxicity of paclitaxel administered as a 96-hour infusion to patients with relapsed non-Hodgkin's lymphomas (NHLs). Eligible patients had relapsed NHL and measurable disease and were considered incurable. Paclitaxel was infused at a dose of 140 mg/m2 every 3 weeks. Premedications to prevent paclitaxel hypersensitivity reactions were not administered and no patients received corticosteroids. Expression of the multidrug resistance (mdr-1) gene was determined in tumor from 17 patients by mRNA quantitative polymerase chain reaction (PCR). Thirty-one patients received a total of 99 cycles of paclitaxel. Two patients were not assessable for response. The median age was 50 years, 71% had stage IV disease, and intermediate/high-grade histology was present in 65% of patients. Patients had received a median of three prior chemotherapy regimens, and 68% of patients had responded to the previous chemotherapy (chemotherapy-sensitive). Of 29 assessable patients, five (17%) achieved a partial response (PR). With a median potential follow-up time of 17 months, the median event-free and overall survival durations were 1.6 and 7.5 months, respectively. No correlation was found between response to paclitaxel and extent of prior treatment or response. The mdr-1 gene was easily detectable in 14 of 17 tumor biopsies, but was low in all but one sample. The most serious toxicity was grade 4 neutropenia, which occurred during 14% of cycles. Paclitaxel was well tolerated, but had a low response rate in patients with relapsed NHLs. There was no clear association between response to paclitaxel and extent of our response to prior treatment. Most patients had chemotherapy-sensitive disease, which suggests that the low response rate to paclitaxel was probably not due to general chemotherapy resistance. Paclitaxel provided good palliation in a minority of patients and is a reasonable agent to consider for use in patients who have failed to respond to standard chemotherapy.