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.

Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary peritoneal/fallopian tube cancers: A retrospective review.

OBJECTIVE: To describe the clinical outcome and tolerability of weekly ixabepilone (16-20mg/m(2) days 1, 8, 15 of a 28-day cycle)±biweekly bevacizumab (10mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. METHODS: A single-institution retrospective review was performed inclusive of all patients who received ≥2cycles from 01/2010 to 06/2014. Progression-free (PFS) and overall (OS) survival were determined using the Kaplan-Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. RESULTS: A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range:1-10) prior lines of chemotherapy. Patients completed a mean of 4.7±2.9cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, objective response rate (ORR) was 41.7% (12.5% complete, 29.2% partial); median duration of response or stabilization was 7months (range:2-30). Median PFS and OS were 5.2 and 9.6months, respectively. PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0months, p=0.01, HR 0.2, 95% CI 0.05-0.77; 9.6 versus 4.2months, p=0.02, HR 0.58, 95% CI 0.04-0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. CONCLUSIONS: Weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane-resistant endometrial and ovarian cancers. This combination warrants further prospective study in these populations.

An analysis of measured and estimated creatinine clearance rates in normal weight, overweight, and obese patients with gynecologic cancers.

STUDY OBJECTIVE: Different equations used to estimate creatinine clearance (Cl(cr)) in obese oncology patients can produce divergent estimated creatinine clearance values, which in turn can result in significantly different calculated carboplatin doses. Standardization of the calculation of creatinine clearance in patients of all body types is a desirable goal. The objective of our study was to examine the impact of increasing body mass index on the accuracy of creatinine clearance estimation methods and to determine the optimal equation for creatinine clearance estimation in the obese adult female cancer patient. DESIGN: Retrospective data analysis. PATIENTS: We compared the estimated creatinine clearance values produced by each of 11 equations to 24-hour creatinine clearance values measured in 119 adult female patients with gynecologic cancers grouped according to body composition. MEASUREMENTS AND MAIN RESULTS: We applied simple linear regression and Tukey mean-difference analysis to assess the relationship between estimated creatinine clearance values produced by these equations and measured creatinine clearance values for each patient. The relationship between measured creatinine clearance and estimated creatinine clearance produced by all equations displayed lower linear regression R (2) values and higher limits of agreement in obese patients than in nonobese groups. Agreement between measured and estimated creatinine clearance produced by the Cockcroft-Gault equation is sensitive to the particular weight parameter incorporated and is lowest using ideal weight or actual body weight. The Cockcroft-Gault equation incorporating an intermediate weight value reduced estimation bias. The Jelliffe equation produced the lowest R (2) values. CONCLUSION: Available model equations are less reliable for predicting creatinine clearance in obese female cancer patients (body mass index >30) than in nonobese patients. A measured glomerular filtration rate or creatinine clearance value is most accurate in obese female cancer patients. When using Cockcroft-Gault equation for estimation in this patient population, however, an intermediate weight value (adjusted or modified-adjusted) rather than ideal or actual body weight should be used.

Impact of carboplatin hypersensitivity and desensitization on patients with recurrent ovarian cancer.

PURPOSE: Hypersensitivity reactions (HSRs) to chemotherapy is an ongoing issue in cancer treatments. Strategies to induce tolerance and maximize chemotherapy efficacy include desensitization protocols. The precise impact of these protocols, however, in the long-term treatments remains unclear. We aim to compare overall survival (OS) in hypersensitive patients treated with carboplatin desensitization to patients without hypersensitivity reactions. We also sought to identify new risk factors for HSRs and reconfirm that the DNA repair enzyme, germline BRCA1/2 (gBRCA1/2), is a risk factor for hypersensitivity. EXPERIMENTAL DESIGN: Retrospective study in patients with ovarian cancer tested for gBRCA1/2 mutations who received more than six infusions of carboplatin from August 2005 to November 2016. Two-sided Fisher exact, Student's t test and Gehan-Breslow-Wilcoxon test were used for statistical analysis. Univariate and multivariate analyses were completed to identify independent predictors of survival. Statistical significance was set with a two-sided p value of 0.05. RESULTS: Ninety-one patients with gBRCA1/2 testing met inclusion. Forty patients (44%) were gBRCA1/2-deficient and 51 (56%) were gBRCA1/2-proficient. Patients with gBRCA1/2 deficiencies had a higher likelihood of developing carboplatin hypersensitivity, HR 6.433 (95% CI: 1.868-22.149). None of the patients with carboplatin hypersensitivity were given PARP inhibitors prior to the development of HSRs. The patients with recurrent advanced stage (III-IV) ovarian cancer had a higher likelihood of developing carboplatin hypersensitivity, HR 4.783 (1.008-22.689). Moreover, we found that hypersensitive patients who underwent carboplatin desensitization had a 48-month longer OS than patients without hypersensitivity to carboplatin not undergoing carboplatin desensitization (p = 0.0094). A subgroup analysis indicated that gBRCA1/2-proficient hypersensitive patients undergoing carboplatin desensitization had a 43-month longer OS than gBRCA1/2-proficient patients without HSRs (p = 0.034). CONCLUSIONS: We confirmed that gBRCA1/2 deficiency and advanced stage are independent risk factors for development of carboplatin hypersensitivity in ovarian cancer patients. Our study also shows improved OS in hypersensitive patients receiving CD compared to non-hypersensitive patients, independent of gBRCA1/2.

Development of a policy and procedure for accidental chemotherapy overdose.

A policy regarding rapid response to chemotherapy overdoses was developed by the authors in an attempt to minimize morbidity and mortality. The parameters of a chemotherapy overdose were defined to promote early recognition of an overdose incident. Resources needed to guide potential therapeutic interventions and required monitoring were developed. The policy defines the immediate actions to be taken in the event of a chemotherapy overdose. The availability of a chemotherapy overdose policy provides an enhanced level of safety for patients by ensuring that appropriate treatment is initiated without delay. The development of the policy was in response to the reporting of a tragic error at another institution. Healthcare providers must recognize and address potential areas of vulnerability to maximize patient safety.

Empiric carbapenem monotherapy in pediatric bone marrow transplant recipients.

OBJECTIVE: To determine which carbapenem (imipenem/cilastatin or meropenem) was the preferable empiric antibiotic monotherapy in pre-engrafted pediatric bone marrow transplant (BMT) patients in terms of patient tolerance, therapeutic efficacy, and cost. METHODS: We prospectively analyzed 16 pediatric BMT patients who received meropenem, and retrospectively analyzed 16 matched patients who had received imipenem/cilastatin for BMT procedures during the prior 2-year period. We evaluated the patients for evidence of bacterial infection, necessity for concurrent antibiotics, vomiting episodes, duration of concurrent total parenteral nutrition (TPN), and cost of therapy. RESULTS: We found no differences in the number of culture proven or clinically suspected breakthrough bacterial infections or the need for concurrent additional antibiotics between the groups. Our analysis found that patients who received meropenem experienced significantly less vomiting than those in the imipenem/cilastatin cohort. Our data showed both direct and indirect cost savings for the meropenem group. The statistical and clinical differences in the number of vomiting episodes between these groups impacted other aspects of patient care, antiemetic use, and TPN duration. CONCLUSIONS: By switching to meropenem, we reduced the cost of antiemetic therapy per patient treatment course, and also showed a trend toward reduced duration of TPN. We found that meropenem provided both clinical and fiscal advantages over imipenem/cilastatin as empiric antibiotic monotherapy in neutropenic pediatric BMT patients.