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PURPOSE: Several allelic variants of the gene DPYD encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine. METHODS: The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record–based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period. RESULTS: At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non–fluoropyrimidine-based regimen was accomplished in 96%. CONCLUSION: Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it. [ABSTRACT FROM AUTHOR]

Purpose: Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile. Methods: We searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies. Results: Rates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (≤1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks. Conclusions: PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays. [ABSTRACT FROM AUTHOR]

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. 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. 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. Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy with autologous stem cell support for the treatment of breast cancer can have a profound effect on patients' quality of life (QOL).  This article reviews findings from studies assessing QOL before, during, and after high-dose chemotherapy.  The impact of high-dose therapy on overall QOL and specific aspects of QOL including physical functioning, symptoms, psychosocial/emotional and cognitive functioning, sexual functioning, and role functioning is considered.  High-dose chemotherapy with stem cell transplant results in largely transient impairment of overall QOL and physical functioning, with subsequent improvement to baseline or better over time. Despite these encouraging global QOL findings, many patients continue to suffer considerable symptoms and concerns attributable to their transplant long after completion of the therapy.  Additional research in this area is needed to optimize QOL for patients receiving high-dose chemotherapy. [ABSTRACT FROM AUTHOR]

Introduction: A preliminary analysis of our double high-dose chemotherapy with stem cell rescue (HD-SCR) clinical trial for breast cancer, and preclinical cross-resistant studies, suggested that melphalan (M) adversely affected response to subsequent chemotherapy, i.e., that the sequence of alkylating agents (AAs) might affect response. We, therefore, constructed and examined preclinical models to determine whether prior exposure to M, in fact, adversely affected response to other therapy.Purpose: The purpose of the study was to determine whether the sequence of AAs, specifically the prior use of M, adversely affected response to subsequent treatment.Methods: The methods employed were the following: (1) Human tumor cell lines rendered resistant by in vitro sequential exposure to five different AAs were developed. The resistant cell lines were examined for cross-resistance to alkylating and other agents. (2) In vivo studies in the p388 mouse leukemia for resistance and cross-resistance among the AAs. (3) In vivo studies of the effect of sequence of AAs on response in mice bearing EMT6 breast cancer. (4) The double transplant model was developed in the mouse and the sequence of high-dose AAs was studied. (5) Biochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) studies of the various resistant tumor cell lines.Results: (1) The in vitro human tumor cells resistant to M were cross-resistant in 57% of tests to other AAs. In contrast, resistance for other AAs crossed to other agents in only 10 to 20% of tests. (2) The in vivo studies of p388 indicated that resistance to M commonly crossed to other AAs and many non-AAs. (3) The results for the mouse breast cancer (EMT6) studies of the sequence of AAs again indicated that M employed first markedly reduced responsiveness to subsequent treatment, particularly with AAs. (4) The double transplant model: again, M first markedly reduced response to other agents. (5) The in vitro resistant human tumor cell lines, particularly the breast cancer cell line MCF7, were found to contain high concentrations of glutathione S1 transferase gamma, which is consistent with that mechanism being responsible for resistance.Conclusion: The sequence of alkylating agent treatment may substantially influence response. Melphalan, particularly, produces resistance that commonly crosses to the other AAs. Mechanistic studies indicate significant changes in glutathione S1 transferase, a known mechanism for broadly based resistance to AAs. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and feasibility of concurrent radiation therapy and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide (AC). Methods and Materials: After definitive breast surgery and AC chemotherapy, 40 patients with operable Stage II or III breast cancer received protocol-based treatment with concurrent paclitaxel and radiation therapy. Paclitaxel was evaluated on 2 schedules, with treatment given either weekly × 12 weeks (60 mg/m2), or every 3 weeks × 4 cycles (135–175 mg/m2). Radiation fields and schedules were determined by the patient’s surgery and pathology. The tolerability of concurrent therapy was evaluated in cohorts of 8 patients as a phase I study. Results: Weekly paclitaxel treatment at 60 mg/m2 per week with concurrent radiation led to dose-limiting toxicity in 4 of 16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and CT-based radiotherapy simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135–175 mg/m2. However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2 of 24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule. Conclusions: Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible after adjuvant AC chemotherapy for early-stage breast cancer. Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury. [Copyright &y& Elsevier]