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Few studies have examined care processes within providers' and institutions' control that expedite or delay care. The authors investigated the timeliness of breast cancer care at a comprehensive cancer center, focusing on factors influencing the time from initial consultation to first definitive surgery (FDS). The care of 1,461 women with breast cancer who underwent surgery at Dana-Farber/Brigham and Women's Cancer Center from 2011 to 2013 was studied. The interval between consultation and FDS was calculated to identify variation in timeliness of care based on procedure, provider, and patients' sociodemographic characteristics. Targets of 14 days for lumpectomy and mastectomy and 28 days from mastectomy with immediate reconstruction were set and used to define delay. Mean days between consultation and FDS was 21.6 (range 1-175, sd 15.8) for lumpectomy, 36.7 (5-230, 29.1) for mastectomy, and 37.5 (7-111, 16) for mastectomy with reconstruction. Patients under 40 were less likely to be delayed (OR = 0.56, 95 % CI = 0.33-0.94, p = 0.03). Patients undergoing mastectomy alone (OR = 2.64, 95 % CI = 1.80-3.89, p < 0.0001) and mastectomy with immediate reconstruction (OR = 1.34 95 % CI = 1.00-1.79, p = 0.05) were more likely to be delayed when compared to lumpectomy. Substantial variation in surgical timeliness was identified. This study provides insight into targets for improvement including better coordination with plastic surgery and streamlining pre-operative testing. Cancer centers may consider investing in efforts to measure and improve the timeliness of cancer care. [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]

The last 2–3 years have brought significant changes to both the adjuvant and palliative treatment of breast cancer. The addition of paclitaxel to the adjuvant setting has brought the largest increase in benefit from adjuvant therapy since the initial CMF trials in the 1970s. Changes in the schedule of administration of the taxanes in the palliative setting have substantially diminished the toxicity without an apparent compromise in the efficacy of these important agents. The combination of chemotherapy and Herceptin in the first line treatment of metastatic breast cancer has resulted in enhancement of survival of women with advanced disease. In only a few short years, the future for women diagnosed with breast cancer has come to look substantially brighter. [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]