Carboplatin desensitization - simplified 4-step 2-bag method.

INTRODUCTION: Our cancer program adopted a method for carboplatin desensitization (4-step 2-bag method) that administers the same intensity of drug exposure with a simplified approach to product management in comparison to a published protocol (4-step 4-bag method). METHODS: The intensity of carboplatin administration for 1:1,000, 1:100, 1:10, and 1:1 dilutions and concomitant fluid administration were compared for the 4-step 2-bag (bags A, B) and 4-step 4-bag (bags 1, 2, 3, 4) methods. Pharmacy preparation of bags A and B is described. A succinct overview of the desensitization procedure is provided. Important considerations germane to pharmacy practice are presented. Chart review of patients who underwent carboplatin desensitization with the 4-step 2-bag method between 7/13/2021 and 11/22/2023 was performed to demonstrate institutional use. RESULTS: The 4-step 2-bag method delivers similar rates of drug intensity from start of desensitization to completion of the planned dose as the previously published 4-step 4-bag method. Accuracy of regimen-based dose administration is assured by infusion of bag B contents irrespective of infusion interruptions or rate changes necessitated by patient tolerance. Bag A provides the 1:1000 dilution in a pharmaceutically elegant manner using administration rates and volumes compatible with clinical practice. CONCLUSION: The 4-step 2-bag method for carboplatin desensitization administers controlled drug titration corresponding to 1:1000, 1:100, 1:10, and 1:1 dilutions for dose administration using two compounded admixture bags. Inaugural clinical use of the 4-step 2-bag method for carboplatin desensitization at our healthcare facility has proceeded with expected patient tolerance.

Cisplatin can be safely administered to ovarian cancer patients with hypersensitivity to carboplatin.

OBJECTIVE: Hypersensitivity reactions (HSR) are frequently reported in patients rechallenged with carboplatin for recurrent ovarian cancer (ROC) and represent a critical issue, since discontinuation of the platinum-based therapy could affect prognosis. Several strategies to allow platinum rechallenge have been described, with controversial outcomes. The aim of this study is to illustrate a 10-year experience with cisplatin in patients with a previous HSR to carboplatin or at risk for allergy. METHODS: A retrospective review of all patients with platinum sensitive ROC retreated with carboplatin was performed between January 2007 and May 2016 at the Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples. RESULTS: Among 183 patients, 49 (26.8%) presented HSR to carboplatin, mainly during second line therapy. Mean number of cycles before HSR was 8 (range 3-17). G2, G3 and G4 reaction were detected in 83%, 15% and 2% of patients, respectively. In a multivariate analysis including age, hystotype, BRCA status, previous known HSR, and combination drug administered, only the type of carboplatin-based doublet used as 2nd line therapy was found to significantly affect HSR development, with a protective effect of PLD (pegylated liposomal doxorubicin) (p = 0.014, OR = 0.027). Thirty seven patients (77%) with a previous HSR to carboplatin were rechallenged with cisplatin. Treatment was generally well tolerated. 5 patients (13.1%) experienced mild HSR to cisplatin, successfully managed in all cases. 14 patients were treated with cisplatin even without a carboplatin-related HSR due to other allergies. Among these, only one developed HSR (7.1%). CONCLUSIONS: Cisplatin rechallenge is a feasible approach in patients experiencing HSR to carboplatin to maintain the beneficial effect of platinum while reducing hypersensitivity-related risks.

Platinum desensitization in patients with carboplatin hypersensitivity: A single-institution retrospective study.

OBJECTIVES: The carboplatin desensitization (CD) protocol presented here allows patients with either a positive skin test or a prior hypersensitivity reaction (HSR) to safely, rapidly and effectively continue with carboplatin infusions. Newly described factors can identify patients at risk for developing adverse events during CD. METHODS: A retrospective review was performed on patients with gynecologic cancer who underwent CD between 2005 and 2014. The CD protocol uses a four-step dilution process over 3.5h. RESULTS: 129 patients underwent CD and completed a total of 788cycles. The desensitization protocol prevented HSRs in 96% (753 out of 788) of these cycles. Patients achieved an average of 6.1cycles (SD±4.55, range 0-23) with CD. The CD protocol allowed 73% (94 of 129) of the patients to undergo carboplatin infusion without reaction. Patients with moderate to life-threatening HSRs (grade 2 through 4) were 10.5years younger at initial CD than patients with grades 0 or 1 HSRs (52.3 vs. 63, P = 0.0307). One patient death occurred during her thirteenth desensitization cycle. The HSR in this case was complicated by pre-exisiting pulmonary hypertension. CONCLUSIONS: This is the largest study of its kind showing a safe, effective and rapid (3.5h) CD protocol. The majority of patients with a history of either carboplatin hypersensitivity reaction or a positive skin test completed the CD protocol without HSRs. Age was identified as a risk factor for HSR severity during CD. Age can be employed along with pre-load dependent cardiac conditions as a way to help risk stratify patients undergoing CD.

Drug-induced immune hemolytic anemia associated with anti-carboplatin and the first example of anti-paclitaxel.

BACKGROUND: Combined chemotherapy with carboplatin and paclitaxel is first-line treatment for lung and ovarian cancer. Drug-induced antibodies to carboplatin are rare but can cause severe, even fatal, hemolysis. Paclitaxel-induced immune hemolysis has not been reported. We describe a case of immune-mediated hemolysis associated with antibodies to carboplatin and paclitaxel in a woman with ovarian cancer who had received multiple chemotherapeutic agents over 7 years, including several courses of these two drugs. She required many transfusions. During a chemotherapy infusion the patient became hypotensive, was pale, and had rigors and red urine. The nadir hematocrit was 12.4%; peak bilirubin and lactate dehydrogenase were 16.3 mg/dL and 1188 units/L, respectively. STUDY DESIGN AND METHODS: Blood samples collected within hours after chemotherapy and 2 days later were tested for antibodies to carboplatin and paclitaxel. RESULTS: The direct antiglobulin test was positive with anti-IgG (3+) and anti-C3 (2+). The plasma collected shortly after chemotherapy agglutinated carboplatin-treated red blood cells (RBCs); untreated and paclitaxel-treated RBCs both reacted at the antiglobulin test most likely due to circulating carboplatin, paclitaxel, or both drugs. Serum collected 2 days later agglutinated (titer 2) and sensitized (titer 128) carboplatin-treated RBCs; untreated and paclitaxel-treated RBCs were nonreactive. An acid eluate reacted weakly in the presence of polyethylene glycol with carboplatin-treated RBCs. The serum reacted with untreated and enzyme-treated RBCs in the presence of soluble carboplatin and paclitaxel. CONCLUSION: Anti-carboplatin and the first example of anti-paclitaxel were detected in this patient's sample.

Risk-stratification protocol for carboplatin and oxaliplatin hypersensitivity: repeat skin testing to identify drug allergy.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum-based chemotherapies are increasingly being recognized. The authors developed a novel risk-stratification protocol that was used successfully in a small number of patients with carboplatin-induced HSRs. OBJECTIVE: To describe the utility of this protocol in a large number of patients with carboplatin- or oxaliplatin-induced HSRs. METHODS: A 5-year retrospective review of patients referred to Massachusetts General Hospital with carboplatin- or oxaliplatin-induced HSR was performed. Patients were managed using a risk-stratification protocol using 3 repeat skin tests (STs) with intervening desensitizations. If the repeat ST result remained negative 3 times, patients received subsequent infusions without desensitization. RESULTS: From 2008 to 2012, 142 patients (92 treated with carboplatin, 50 treated with oxaliplatin) completed 574 desensitizations. Most patients were women (84.5%, mean ± SD 58.1 ± 9.3 years). Patients with carboplatin-induced HSRs were classified as having positive (n = 32, 34.8%), negative (n = 38, 41.3%), or converted (n = 22, 23.9%) ST reactions when the initial negative ST reaction converted to positive at repeat ST. Of those with oxaliplatin-induced HSRs, 22 (44%) had positive, 25 (50%) had negative, and 3 (6%) had converted ST reactions. Of the patients with negative ST reactions, 17 with carboplatin-induced HSRs and 16 with oxaliplatin-induced HSRs safely completed 59 and 95 outpatient infusions, respectively, without desensitizations. For carboplatin and oxaliplatin, ST conversion was associated with an interval of at least 6 months from the HSR to the initial ST (carboplatin, P = .002; oxaliplatin, P = .045). CONCLUSION: This risk-stratification protocol for presumed carboplatin- and oxaliplatin-induced HSRs safely identifies false-negative ST reactions and nonallergic patients who can receive infusions without desensitizations. This leads to fewer unnecessary desensitizations and improved patient care.

Desensitization with oxaliplatin in patients intolerant of carboplatin desensitization.

INTRODUCTION: The tolerance and efficacy of oxaliplatin desensitization in patients who were intolerant of carboplatin desensitization were determined. MATERIALS AND METHODS: We retrospectively reviewed the Gynecologic Oncology patients who received carboplatin or oxaliplatin from December 2007 until August 2014. The number of treatments and number of patients of carboplatin standard infusions, carboplatin desensitizations, and oxaliplatin desensitizations were determined. RESULTS: Carboplatin infusions (2294) were administered to 281 patients. Twenty-eight (10%) of these patients developed carboplatin hypersensitivity and were treated with 205 carboplatin desensitizations. Nine (29%) patients were subsequently treated with 61 oxaliplatin desensitizations due to intolerance of carboplatin desensitization. Nine of the 10 patients tolerated this infusion well. Four of 9 evaluable patients had an objective response, 2 complete and 2 partial. CONCLUSIONS: Oxaliplatin desensitization seems well tolerated and effective in most patients who are intolerant of carboplatin desensitization.

Management of hypersensitivity reactions to Carboplatin and Paclitaxel in an outpatient oncology infusion center: a 5-year review.

BACKGROUND: A high incidence of hypersensitivity reactions (HSR) to carboplatin and Taxol is limiting the use of carboplatin and Taxol. OBJECTIVE: We conducted a 5-year study of all patients with HSR to carboplatin or Taxol to better understand the nature of infusion HSR and success or failure of management plans after the initial HSR. METHODS: We performed a retrospective chart review of all safety reports from the Massachusetts General Hospital outpatient chemotherapy infusion center between January 2006 and February 2011. All the patients with HSRs to carboplatin or Taxol were identified and included in the final analysis. We reviewed patient characteristics, clinical symptoms, timing, and treatment of the initial HSR, and determined if the patient was rechallenged despite an initial HSR. RESULTS: We identified 152 patients with HSR to carboplatin (n = 45) or Taxol (n = 107). Carboplatin HSR was less severe than Taxol HSR. When comparing the 2 groups, the patients with carboplatin HSRs more commonly described itchy palms and feet, generalized itch, and general urticaria and/or erythema, whereas patients with Taxol HSR more commonly described facial flushing, back pain, and chest or throat tightness (all P < .05). Among 40 patients with mild-to-moderate carboplatin HSRs, only 7 were rechallenged, and 100% tolerated rechallenge without desensitization. None of the patients with severe carboplatin HSRs (n = 5) were rechallenged. Most patients (75%) with Taxol HSRs were rechallenged, and 91% tolerated rechallenge without desensitization; the patients with a severe HSR to Taxol were less likely to be rechallenged. CONCLUSION: The clinical symptoms and timing of carboplatin HSR are distinct from Taxol HSR. Most patients with carboplatin HSR were not rechallenged, whereas most patients with Taxol HSR were successfully rechallenged.

Carboplatin-, oxaliplatin-, and cisplatin-specific IgE: cross-reactivity and value in the diagnosis of carboplatin and oxaliplatin allergy.

BACKGROUND: The diagnosis of hypersensitivity reactions (HSR) to platins is based on the characterization of the reaction and the results of skin testing. Platins can be irritants when used in skin testing; therefore, in vitro testing may offer an alternative diagnostic tool. OBJECTIVE: To evaluate sensitivity and specificity of platin specific IgE (sIgE) in patients with HSRs and in controls. METHODS: Twenty-four patients with immediate HSR to platins were included (carboplatin, 12; oxaliplatin, 12): 19 women and 5 men (mean age, 61 years). The control group included 17 patients exposed to platin and with no HSR. Skin testing was performed on 22 patients. Carboplatin sIgE and oxaliplatin sIgE were measured in 24 patients and 17 controls; carboplatin sIgE was measured in 21 patients. RESULTS: Skin test results were positive in 22 patients (carboplatin, 12/12; oxaliplatin, 10/12). Seven of 12 patients sensitive to carboplatin (59%) had positive carboplatin sIgE, 2 also had positive cisplatin sIgE, and all had negative oxaliplatin sIgE; 9 of 12 patients sensitive to oxaliplatin (75%) had positive sIgE to oxaliplatin, 8 of 12 (67%) also had positive carboplatin and cisplatin sIgE, to which they had not been exposed. All 5 carboplatin controls had negative sIgE; 3 oxaliplatin controls (25%) had positive carboplatin sIgE, and 2 had positive oxaliplatin sIgE. CONCLUSION: Carboplatin sIgE is very specific but less sensitive. In contrast, oxaliplatin sIgE had higher sensitivity but lower specificity. Analysis of our data suggests that oxaliplatin exposure was more immunogenic. This could be clinically relevant because patients sensitized to carboplatin may be able to tolerate oxaliplatin, but patients sensitized to oxaliplatin may be at risk when exposed to carboplatin and cisplatin.

Evaluation of basophil CD203c as a predictor of carboplatin-related hypersensitivity reaction in patients with gynecologic cancer.

The incidence of hypersensitivity reaction (HR) to carboplatin has been reported to increase after repeated use of the drug. However, a reliable ex vivo test to predict HR to carboplatin is not currently available. We evaluated the clinical usefulness of measuring basophil CD203c to predict carboplatin-related HR in this prospective case-control study conducted at Mie University Hospital between October 2009 and September 2010. Eleven patients had history of carboplatin-related HR within the past 3 years, and 19 had no history of HR after receiving more than 5 courses of carboplatin therapy. Six of these 19 patients developed carboplatin-related HR during the study period. The CD203c+ basophils (%) and the mean fluorescence intensity (MFI) were analyzed on a flow cytometer and compared between patients with and without HR. Changes in the CD203c expression on basophils before and after HR were also assessed in patients who developed HR during the study period. The median CD203c+ basophils (%) and ΔMFI after 30-min exposure to 50 µg/mL carboplatin were significantly higher in patients with HR (3.5% and ΔMFI 9.0) compared with those without (2.2% and ΔMFI 0.4) (p<0.05). In particular, these values were significantly higher in patients with grade 4 anaphylaxis (10.6% and ΔMFI 22.0). All five patients who developed grade 2-4 anaphylaxis during the study period had high CD203c+ basophils (%) and/or increased ΔMFI on the day before HR. The results suggest that basophil CD203c may be a promising biomarker for the prediction of severe carboplatin-related anaphylaxis.

An experimental biological test to diagnose hypersensitivity reactions to carboplatin: new horizons for an old problem.

Carboplatin, a second-generation platinum compound, is a chemotherapeutic drug effective in many types of cancers. Its use is limited by the development of systemic allergic reactions in up to 30% of the cancer patients. Therefore, it is very important to make a correct diagnosis of true carboplatin allergy, for the crucial clinical implications. In this regard, no biological test is actually available to detect specific immunoglobulin E in the sera of patients allergic to carboplatin. We evaluated a new experimental biological test in patients with suspected immunoglobulin E-mediated reactions to carboplatin. Three patients with suspected hypersensitivity reactions to carboplatin underwent skin tests with an undiluted aliquot (10 mg/ml) of carboplatin preparation planned for infusion. Total serum immunoglobulin E and specific immunoglobulin E to the two platinum salts carboplatin and cisplatin were determined with the ImmunoCAP system (Phadia AB, Uppsala, Sweden). We detected specific immunoglobulin E to carboplatin in all three patients, whereas specific immunoglobulin E to cisplatin was observed in one patient. The positivity of specific immunoglobulin E against carboplatin in these three patients is a new and encouraging observation for the development of a new important instrument that can help clinicians in their therapeutic decisions, after a hypersensitivity reaction to a platinum salt.

A protocol for risk stratification of patients with carboplatin-induced hypersensitivity reactions.

BACKGROUND: Management of patients with carboplatin-induced hypersensitivity reactions (HSR) has been complicated by high false-negative rates of carboplatin skin test (ST) results. These patients might be at risk for future carboplatin-induced HSRs. In this article we identify a strategy to improve risk stratification of patients with a history of carboplatin-induced HSRs by using a protocol that includes repeat skin testing and drug desensitization. OBJECTIVE: We sought to identify a management strategy for patients with a history of carboplatin-induced HSRs with negative carboplatin ST results. METHODS: From 2008-2010, patients with carboplatin-induced HSR underwent risk stratification per a protocol using 3 repeat STs with intervening drug desensitizations. RESULTS: Of the 44 patients with carboplatin-induced HSRs, 39 completed the protocol. Patients were classified as having positive ST results (n = 16), having negative ST results (n = 11), or ST converters when the ST result converted to positive after an initial negative result (n = 12). ST converters are more likely to have HSRs during subsequent desensitizations than patients with negative ST results (56.1% vs 4.5%, P < .001). ST converters had a significantly longer time interval between their initial HSR and initial ST evaluation compared with either patients with true-negative ST results (22.1 vs 6.0 months, P = .03) or patients with positive ST results (22.1 vs 1.8 months, P = .001). CONCLUSION: Our experience suggests that repeat STs are necessary for risk stratification in patients with a remote clinical history of HSR and an initial negative ST result because there is a significant rate of conversion to a positive ST result. ST converters have an increased risk of HSRs during subsequent carboplatin treatment.

Carboplatin hypersensitivity: does introduction of skin test and desensitization reliably predict and avoid the problem? A prospective single-center study.

BACKGROUND: Carboplatinum-based retreatment can be regarded as a standard option in the so-called platinum-sensitive ovarian cancer, but its use can be limited by the occurrence of sometimes severe hypersensitivity reactions (HSRs). This study analyzes the value of carboplatin skin testing and desensitization. PATIENTS AND METHODS: Between 2004 and 2006, all patients with carboplatin reinduction chemotherapy received an intradermal injection of 0.2 microL of carboplatin and saline as negative control before chemotherapy. Carboplatin was administered in the standard way if the test was negative. If positive, carboplatin was administered after an already published desensitization protocol. RESULTS: Fifty-four patients received retreatment with carboplatinum and were submitted to skin test. Seven patients (13%) had positive skin test, whereas 4 patients developed HSRs although they had negative skin test (8.5% false-negative rate). Skin test predicted HSRs in only 64% of the afflicted patients. Desensitization was performed in all patients with positive skin test, and 5 (71%) of 7 could receive 3 to 11 further carboplatinum courses. Repeated HSRs occurred in 2 of 7 patients despite desensitization; however, none of the HSRs after desensitization were severe. CONCLUSIONS: Skin test did not reliably predict carboplatinum-induced HSR, but desensitization was demonstrated to be a rather successful strategy. Taking the low predictive value into account, we started another prospective series of administering antiallergic medication to all patients with carboplatinum retreatment and offer desensitization if any HSR occurs.

Risk stratification for desensitization of patients with carboplatin hypersensitivity: clinical presentation and management.

BACKGROUND: Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for desensitization is uncertain. OBJECTIVES: To evaluate skin test (ST) reactivity to carboplatin in patients with recent and remote histories of carboplatin HSR and to review the relationship between skin test reactivity and tolerance of subsequent carboplatin desensitization. METHODS: Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 desensitizations to carboplatin. RESULTS: Carboplatin ST was positive in 25 of 38 patients (66%). Of patients with recent HSR (<3 months), 20 of 24 (83%) tested positive, whereas 5 of 14 (36%) with remote HSR (>9 months) tested positive (P < .01). Nineteen carboplatin ST+ and 11 ST- patients underwent desensitization to carboplatin. Seven ST+ patients (37%) had mild HSR during desensitization but completed the desensitization with additional treatment or protocol modification. ST- patients with a recent history of HSR (n = 3) tolerated a rapid protocol without HSR and remained ST- with repeated testing. Six of 8 ST- patients (75%) with remote HSR reacted during desensitization. The HSRs were more severe and often associated with an elevated tryptase level. Five of 7 patients retested became ST+ before the second desensitization. Carboplatin desensitization was successfully completed in 105 of 106 (99%) treatment courses. CONCLUSIONS: The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent desensitization. Initial ST- patients with a remote history of HSR are at high risk for conversion to ST+ and can develop more severe HSR.

Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents.

OBJECTIVES: To review clinical hypersensitivity reactions related to common cancer chemotherapy agents and to discuss potential management strategies. DATA SOURCES: PubMed searches were performed for articles published from 1970 to 2008 regarding hypersensitivity to cancer chemotherapy and related agents using the keywords hypersensitivity, allergy, chemotherapy, platinums, taxanes, asparaginase, epipodophyllotoxins, and procarbazine. Retrieved articles were surveyed for additional citations. STUDY SELECTION: Articles were reviewed for relevance to the subject matter, and the most pertinent articles were included in this review. RESULTS: Hypersensitivity reactions are commonly associated with the use of certain cancer chemotherapy drugs, including platinums, taxanes, asparaginase, procarbazine, and epipodophyllotoxins. Platinum agents (cisplatin, carboplatin, oxaliplatin) are associated with IgE-mediated hypersensitivity reactions, and skin testing may be indicated. Taxane (paclitaxel, docetaxel)-related reactions are generally non-IgE mediated, and premedication with corticosteroids and antihistamines is usually effective. Asparaginase has a high rate of hypersensitivity reactions that are likely IgE mediated or related to complement activation. Skin testing has been recommended but has not been validated for asparaginase. Procarbazine reactions can be IgE mediated but are also associated with a type III reaction manifested by pulmonary toxicity and cutaneous reactions. Hypersensitivity reactions related to epipodophyllotoxins may involve both immunologic and nonimmunologic factors that may be avoided with a slow infusion and premedication. CONCLUSION: With the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered. Knowledge of the presentations of these reactions and management options give the treating physician the means to make an informed decision of how best to proceed.

Diagnostic and predictive value of skin testing in platinum salt hypersensitivity.

BACKGROUND: Hypersensitivity reactions to platinum salts are potentially lethal adverse events in chemotherapy, and often require its discontinuation. Several preventive procedures have been proposed: premedication, desensitization regimens, or replacement with a different platinum salt. OBJECTIVE: We therefore assessed the value of skin tests with platinum salts. A positive result would confirm their responsibility in hypersensitivity reaction, whereas a negative result would identify candidates for continuation of therapy using a different platinum salt. METHODS: Patch tests, prick tests, and intradermal tests with cisplatin, carboplatin, and oxaliplatin were performed in 21 patients. RESULTS: Skin tests were positive in 14 of 21 cases. Prick tests were positive in 5 cases with the suspected platinum salt. Intradermal tests were positive in 12 of 19 cases, always when the hypersensitivity occurred less than 2 hours after infusion. Cross-reactions were observed in 4 cases. Delayed readings of skin tests at 24 hours and 48 hours were positive in 3 patients. Patch tests were negative in all the 21 patients tested. Replacement with another platinum salt was performed in 13 patients using one that gave a negative skin test. A relapse of symptoms occurred in 1 patient. CONCLUSION: Intradermal tests are particularly indicated for the diagnosis of immediate hypersensitivity reaction. Their good negative predictive value allows safe retreatment by detecting a potential cross-reaction. CLINICAL IMPLICATIONS: The frequency of cross-reactions among cisplatin, carboplatin, and oxaliplatin has not been clearly established. Skin tests allow different platinum salts to be given and avoid discontinuation of chemotherapy.