Barbara Kulp

Clinical features of hypersensitivity reactions to carboplatin

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.

Carboplatin Skin Testing: A Skin-Testing Protocol for Predicting Hypersensitivity to Carboplatin Chemotherapy

PURPOSE A high incidence of moderate to severe hypersensitivity reactions (HRs) is noted in patients who have been treated with multiple courses of carboplatin. Presently, there is no reliable way to predict which patients may be at risk for this potentially severe adverse reaction. We developed a skin-test protocol to identify patients at high risk for HR to carboplatin chemotherapy. PATIENTS AND METHODS Patients undergoing more than seven courses of carboplatin received a 0.02-mL intradermal injection of an undiluted aliquot of their planned carboplatin infusion 1 hour before each course of the agent. A positive skin test was prospectively defined as that resulting in a wheel of at least 5 mm with a surrounding flare. We recently reported a 27% incidence of HRs in patients receiving more than seven courses of carboplatin. These patients served as historical controls for the current study. RESULTS Forty-seven patients with recurrent ovarian or primary peritoneal carcinoma receiving carboplatin were skin tested. Thirteen of 47 patients (28%) manifested a positive skin test at a median of nine total courses of carboplatin (range, eight to 17 courses). This rate of skin-test positivity was not significantly different from the incidence of documented HR reported in a historical control group (P =.89), suggesting comparable populations. A negative skin test accurately predicted the absence of HR in 166 of 168 courses of chemotherapy. Only two of 47 patients (4%) experienced a HR after a negative skin test. Thus, administering carboplatin only to patients with a negative skin test may result in a significant reduction in HRs relative to historical controls (P =.002). CONCLUSION An easily performed skin test appears to predict patients in whom carboplatin may be safely administered. Treatment modifications based on the results of skin testing may reduce the incidence of HRs in patients receiving repeated courses of carboplatin.

Paclitaxel-Associated Hypersensitivity Reactions: Experience of the Gynecologic Oncology Program of the Cleveland Clinic Cancer Center

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.

Expanded experience with an intradermal skin test to predict for the presence or absence of carboplatin hypersensitivity.

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 > or = 5-mm wheal, with a surrounding flare. 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.

Combination chemotherapy with carboplatin and docetaxel in the treatment of cancers of the ovary and fallopian tube and primary carcinoma of the peritoneum

PURPOSE Standard chemotherapy for advanced ovarian cancer currently includes a platinum agent (usually carboplatin) and paclitaxel. Because docetaxel is an active agent in platinum-resistant ovarian cancer, it is relevant to evaluate both the toxicity and efficacy of the combination of carboplatin and docetaxel in this clinical setting. PATIENTS AND METHODS The Gynecologic Oncology Program of the Cleveland Clinic Taussig Cancer Center conducted a phase II trial of carboplatin (area under the concentration-versus-time curve of 6) and docetaxel (60 mg/m(2)), delivered every 3 weeks for six courses, in patients with ovarian and fallopian tube cancers and primary carcinoma of the peritoneum who had either received no prior chemotherapy or had experienced a treatment-free interval of greater than 2 years before developing disease recurrence. RESULTS Fifty patients (median age, 57 years; range, 44 to 81 years) entered the trial (47 had had no prior chemotherapy). Our toxicity findings included the following: grade 4 neutropenia (64% of patients); hypersensitivity reactions (34%, none requiring discontinuation of therapy); peripheral neuropathy (6%). We had objective responses for 32 of 42 (81%) assessable patients. CONCLUSION The combination of carboplatin and docetaxel is highly active in ovarian cancer, with the major toxicity being bone marrow suppression. Hypersensitivity reactions are frequent but do not prevent continuation of treatment. With the dose and schedule employed in this trial, neurotoxicity is uncommon. Defining a role for this regimen in routine clinical practice will require the conduct of randomized controlled clinical trials.

Initial experience with a novel desensitization strategy for carboplatin-associated hypersensitivity reactions: carboplatin-hypersensitivity reactions.

PurposeCarboplatin hypersensitivity is an increasingly recognized toxicity in individuals receiving >6 cumulative courses of this important antineoplastic agent. We wished to determine if a novel multi-pronged approach to re-treating patients with a high risk for this potentially serious side effect could permit the safe delivery of this class of cytotoxic drugs.MethodsFive patients with gynecologic malignancies who had either experienced a documented carboplatin hypersensitivity reaction (n =4) or had a “positive” carboplatin skin test (n =1), received a multi-drug oral regimen administered over several days which was designed to block known mediators of anaphylaxis. Four of these individuals subsequently underwent treatment with either cisplatin or carboplatin employing a “dose escalation” desensitization schema.ResultsFour patients underwent successful treatment with either cisplatin or carboplatin (3, 4, 5, 6+ total additional courses) without any further evidence of hypersensitivity.ConclusionIn this preliminary report of a limited patient population, we have demonstrated the ability to safely deliver a platinum agent to individuals with either documented carboplatin hypersensitivity, or a high risk for this potentially serious toxicity of carboplatin. Further exploration of this novel management strategy in a larger group of patients is indicated.

An effective and more convenient drug regimen for prophylaxis against paclitaxel-associated hypersensitivity reactions.

Abstract“Standard” prophylaxis for paclitaxel-associated hypersensitivity reactions has included the systemic administration of H1 and H2 histamine antagonists, along with oral dexamethasone taken both the night prior to, and the morning of, each paclitaxel treatment. To improve patient convenience and compliance with steroid delivery, the Gynecologic Cancer Program of the Cleveland Clinic Foundation has treated patients with an all-intravenous prophylaxis regimen (diphenhydramine 50 mg, famotidine 20 mg, dexamethasone 20 mg) given 30 min prior to paclitaxel (without any earlier oral steroid dosing). To date, we have treated more than 200 patients who received all courses of paclitaxel with this simplified prophylactic regimen, of whom approximately 9% developed hypersensitivity reactions (major or minor). This incidence is comparable to our previously reported experience with hypersensitivity reactions in a similar number of patients receiving the standard prophylaxis (including oral dexamethasone) with their initial course of paclitaxel, and subsequent cycles employing this all-intravenous program. We conclude that this “modified” regimen for paclitaxel-associated hypersensitivity reactions (with all drugs administered approximately 30 min prior to the delivery of paclitaxel) is as effective as, and more convenient than, the standard regimen, and avoids delaying chemotherapy as a result of a patient failing to remember to take one or both oral steroid doses.

Neurotoxicity associated with a regimen of carboplatin (AUC 5-6) and paclitaxel (175 mg/m2 over 3 h) employed in the treatment of gynecologic malignancies

Abstract While the combination chemotherapy regimen of carboplatin (AUC 5–6) and paclitaxel (175 mg/m2 over 3 h) is widely employed in the treatment of ovarian cancer, there are limited data available in the oncologic literature regarding the neurotoxic potential of the program. We retrospectively reviewed the clinical course of 87 patients treated in the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center to address this important clinical issue. The overall incidence of peripheral neuropathy in this population was 25%, with 13% of women experiencing symptoms ≥grade 2 in severity. We conclude that while neurotoxicity is common following the use of this regimen, significant neurological dysfunction (≥grade 2) is relatively infrequent.

Paclitaxel administration to gynecologic cancer patients with major cardiac risk factors.

PURPOSE To examine the safety of administering paclitaxel to patients with preexisting significant cardiac risk factors. PATIENTS AND METHODS The medical records of gynecologic cancer patients with major cardiac risk factors who had been treated with paclitaxel (single-agent or combination regimen with cisplatin or carboplatin) at The Cleveland Clinic Foundation from 1993 through February 1998 were examined to determine the acute toxicity of therapy. RESULTS A total of 15 patients were found who met these criteria, of whom none were found to have suffered a worsening of cardiac function following treatment with paclitaxel. A single patient developed a severe paclitaxel-associated hypersensitivity reaction, but no cardiac sequela. CONCLUSION This series suggests that paclitaxel can be safely administered as a single agent or in a combination regimen with a platinum agent to some patients with significant cardiac risk factors, such as those associated with ischemic heart disease. However, since few patients had baseline severe conduction defects before paclitaxel treatment, the safety of this drug in this clinical setting remains to be determined.

Evidence that a treatment-free interval of less than 6 months does not equate with clinically defined platinum resistance in ovarian cancer or primary peritoneal carcinoma

Abstract The standard definition of platinum-resistant ovarian cancer or primary peritoneal carcinoma commonly includes patients whose disease initially responded to a platinum-based combination regimen, but recurred less than 6 months after the completion of primary therapy. Recent experience with several patients with these malignancies treated in the Gynecologic Cancer Program of the Cleveland Clinic Foundation, whose disease recurred within this period but who subsequently responded to platinum therapy, calls into question the validity and clinical relevance of this commonly employed definition, both for the conduct of phase 2 trials of new agents in ovarian cancer and primary peritoneal carcinoma, and for the standard management of women in this clinical setting.