Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions.

BACKGROUND: The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. OBJECTIVE: We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. METHODS: Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. RESULTS: Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. CONCLUSIONS: Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions.

Phase II trial of GM-CSF in women with asymptomatic recurrent müllerian tumors.

OBJECTIVE: GM-CSF is a recombinant human cytokine, which promotes the proliferation and differentiation of granulocytes and monocytes, and is associated with anti-tumor activity. The primary objective was to define the median time to treatment termination (TTT) with women with relapsed ovarian cancer treated with single agent GM-CSF delivered subcutaneously (SC). PATIENTS AND METHODS: Open label phase II study in asymptomatic patients with recurrent müllerian malignancy without an indication for immediate systemic chemotherapy. In the first cohort of 35 women, GM-CSF 250 microg/m(2) was administered SC on days 1-14 of a 28-day cycle, the second cohort received continuous GM-CSF 150 microg/m(2) given with dose escalation. RESULTS: Seventy-two women were enrolled. Best overall response included one complete response, and 20 patients with stable disease (23%), 4 of whom had stable disease for >6 months. Median TTT was 78 days. Toxicity in both cohorts was generally mild; however, four patients experienced excessive toxicity and withdrew consent. In the first cohort, CA-125 dropped in 70% of women from their baseline on study value (median change -23%, range -48 to +116%) after 14 days of GM-CSF. The magnitude of CA-125 drop during the first 2 weeks of therapy also showed a positive inverse correlation with day 15 white cell count for the whole group (p=0.038). CONCLUSION: GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT is modest, a subset of women had prolonged stable disease.

Phase I trial of liposomal doxorubicin and ZD1839 in patients with refractory gynecological malignancies or metastatic breast cancer.

BACKGROUND: Pegylated liposomal doxorubicin has activity in both breast and ovarian cancer. Preclinical data noted that ZD1839 acts synergistically with chemotherapy. Given the lack of cross-resistance between these two agents, a phase I trial was initiated examining the safety and efficacy of the combination of liposomal doxorubicin and ZD1839 in patients with recurrent gynecologic or metastatic breast cancer. METHODS: Dose-limiting toxicity (DLT) was defined within the first two cycles of treatment. Escalating doses of liposomal doxorubicin were administered every 4 weeks with ZD1839. Pharmacokinetic analysis and correlative studies were performed. RESULTS: Thirty-five patients were enrolled in this study: six in each cohort. One DLT (febrile neutropenia) was observed in cohort 2. Dose level 3 was determined to be the maximum tolerated dose (MTD), and an additional ten patients were accrued. Serious adverse events (SAEs) included one patient with mental status changes believed secondary to disease progression and two central nervous system (CNS) bleeds believed to be unrelated to the combination of study agents. Toxicities were generally mild except for skin and gastrointestinal toxicity. No cardiac toxicity was observed. The best response to therapy included four partial responses and 20 patients with stable disease. CONCLUSIONS: Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer.

Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.

BACKGROUND: Hypersensitivity reactions (HSRs) to chemotherapeutic drugs, including mAbs, often require that the provoking medication be discontinued, thus raising a dilemma for the caregiver: further use could precipitate a severe, even fatal, allergic reaction on re-exposure, but alternative drugs might be poorly tolerated or much less effective compared with the preferred agent. OBJECTIVE: We have developed a standardized rapid desensitization protocol for achieving temporary tolerization to drug allergens. In this study we evaluate the safety and efficacy of this protocol. METHODS: Ninety-eight patients who had HSRs in response to treatment with carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, or rituximab received rapid desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records. RESULTS: Of the 413 desensitizations performed, 94% induced mild or no reactions. No life-threatening HSRs or deaths occurred during the procedure, and all patients received their full target dose. Most reactions occurred during the first desensitization. Reactions were most commonly reported at the last step of the protocol. Desensitizations through the intravenous and intraperitoneal routes were equally effective. CONCLUSIONS: Our standardized 12-step protocol for rapid drug desensitization is safe and effective and has been adopted as the standard of care at our institutions in treating patients with HSRs to chemotherapeutic drugs, including mAbs.

Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor.

BACKGROUND AND OBJECTIVES: Hypertension and proteinuria are common but poorly understood renal toxicities of vascular endothelial growth factor (VEGF) receptor signaling pathway inhibitors. In this phase II study of cediranib (AZD2171) for recurrent epithelial ovarian cancer, the time course and severity of BP changes and proteinuria were characterized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 46 women ages 41 to 77 years were treated with cediranib. 26% had baseline hypertension. Twice-daily BP was recorded. Urinalyses were performed every 2 weeks, and in some patients proteinuria was further quantified. RESULTS: 31 women (67%) developed hypertension by day 3; 87% by the end of the study. 43% developed grade > or =3 hypertension. Mean systolic BP increase over 3 days was 18 mmHg. Women above the mean age (> or =57 years) had a larger rise in systolic BP by day 3 (15.9 versus 7.0 mmHg). 14 women developed proteinuria. There was a dose response (45 versus 30 mg daily). Proteinuria also developed rapidly, with 7 of 14 women developing proteinuria within 2 weeks. Only 7 of 20 women who developed grade 3 hypertension developed proteinuria. CONCLUSIONS: Cediranib induced a rapid but variable rise in BP within 3 days of initiation in most patients. Proteinuria was common and also developed rapidly. The rapid development of hypertension suggests that acute inhibition of VEGF-dependent vasodilation might explain the BP rise with VEGF inhibitors. Clinicians must be vigilant in early detection and management of toxicities of this expanding drug class, especially in older patients.

Phase II study of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab as first-line chemotherapy for advanced mullerian tumors.

PURPOSE New strategies are needed to improve outcomes for patients with advanced ovarian cancer. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes vascular endothelial growth factor but is associated with GI perforations (GIPs) in patients with recurrent disease. PATIENTS AND METHODS An open-label, phase II clinical trial was conducted in newly diagnosed patients with stage > or = IC epithelial müllerian tumors. Patients received intravenous (IV) carboplatin (area under the curve = 5), paclitaxel (175 mg/m(2) IV), and bevacizumab (15 mg/kg IV) for six to eight cycles on day 1 every 21 days. Bevacizumab was omitted in the first cycle and continued as a single agent for 1 year. Results Sixty-two women participated in this study. Fifty-one patients (82%) were optimally surgically cytoreduced before treatment. The median age was 58 years (range, 18 to 77 years). Forty-five women (73%) had ovarian cancer, 10 (16%) had peritoneal cancer, four (6%) had fallopian tube cancers, and three (5%) had uterine papillary serous tumors. The majority of patients (90%) had stage III or IV disease. A median of 17 maintenance cycles (range, 0 to 25+ cycles) of bevacizumab (556 cycles) were administered with mild toxicity. Treatment was associated with two pulmonary embolisms and two GIPs, all occurring during the chemotherapy phase of treatment (364 total cycles). No grade 4 toxicities were seen during maintenance bevacizumab treatment. Radiographic responses were documented in 21 (75%) of 28 women with measurable disease (11 complete responses and 10 partial responses), with CA-125 responses in 76% of patients (11 complete responses, 21%; and 35 partial responses, 55%). The progression-free survival rate at 36 months was 58%. CONCLUSION The regimen of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab is feasible, safe, and worthy of future study in advanced ovarian cancer.