PURPOSE Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline BRCA1/2 or PALB2 (g BRCA/PALB2+) mutation. Phase IB data from a trial that used cisplatin, gemcitabine, and veliparib treatment demonstrated a high response rate (RR), disease control rate (DCR), and overall survival (OS) in this population. We designed an open-label, randomized, multicenter, two-arm phase II trial to investigate cisplatin and gemcitabine with or without veliparib in g BRCA/PALB2+ PDAC. PATIENTS AND METHODS Eligible patients had untreated g BRCA/PALB2+ PDAC with measurable stage III to IV disease and Eastern Cooperative Oncology Group performance status of 0 to 1. Treatment for patients in arm A consisted of cisplatin 25 mg/m2 and gemcitabine 600 mg/m2 intravenously on days 3 and 10; treatment for patients in arm B was the same as that for patients in arm A, and arm A also received veliparib 80 mg orally twice per day on days 1 to 12 cycled every 3 weeks. The primary end point was RRs of arm A and arm B evaluated separately using a Simon two-stage design. Secondary end points were progression-free survival, DCR, OS, safety, and correlative analyses. RESULTS Fifty patients were evaluated by modified intention-to-treat analysis. The RR for arm A was 74.1% and 65.2% for arm B ( P = .55); both arms exceeded the prespecified activity threshold. DCR was 100% for arm A and 78.3% for arm B ( P = .02). Median progression-free survival was 10.1 months for arm A (95% CI, 6.7 to 11.5 months) and 9.7 months for arm B (95% CI, 4.2 to 13.6 months; P = .73). Median OS for arm A was 15.5 months (95% CI, 12.2 to 24.3 months) and 16.4 months for arm B (95% CI, 11.7 to 23.4 months; P = .6). Two-year OS rate for the entire cohort was 30.6% (95% CI, 17.8% to 44.4%), and 3-year OS rate was 17.8% (95% CI, 8.1% to 30.7%). Grade 3 to 4 hematologic toxicities for arm A versus arm B were 13 (48%) versus seven (30%) for neutropenia, 15 (55%) versus two (9%) for thrombocytopenia, and 14 (52%) versus eight (35%) for anemia. CONCLUSION Cisplatin and gemcitabine is an effective regimen in advanced g BRCA/PALB2+ PDAC. Concurrent veliparib did not improve RR. These data establish cisplatin and gemcitabine as a standard approach in g BRCA/ PALB2+ PDAC.
Anthracyclines are powerful anticancer agents and among the most important tools in the chemotherapy armamentarium of medical oncologists. They are approved for use in the treatment of a broad variety of solid and hematologic neoplasms. However, the usefulness of these agents, particularly doxorubicin, the most widely used anthracycline, is limited by considerable toxicity, especially damage to the cardiac muscle, which is cumulative and mostly irreversible, restricting extended use of this drug. In the last 30 years, extensive research with a variety of drug-delivery systems has attempted to overcome this limitation, with clinical success mostly confined to liposome formulations. Liposomal doxorubicin, and particularly pegylated liposomal doxorubicin, has shown significant pharmacologic advantages and an added clinical value over doxorubicin. Here, we review the mechanisms of action and toxicity of doxorubicin, and ways to reduce toxicity, with a focus on liposome-based drug-delivery systems.
Lithium treatment in pregnancy is associated with a higher rate of cardiovascular anomalies. Women who are treated with lithium during organogenesis should undergo fetal echocardiography and level-2 ultrasound.
Bevacizumab treatment is associated with an increased risk of hypertension (HTN), a potential marker for effectiveness. We aimed to assess whether grades 2-3 HTN during bevacizumab treatment was associated with increased overall survival (OS) or progression-free survival (PFS). One hundred and eighty-one patients with metastatic colorectal cancer (CRC), who were treated in our Department from January 2009-February 2011 were included. Bevacizumab was administered jointly with standard first- or second-line chemotherapy protocols. Blood pressure was measured before each treatment. HTN was graded using common toxicity criteria. There were 181 CRC patients. Grades 2-3 HTN developed in 81 patients (44.75 %) but not in 100 patients (55.25 %); no patient developed grades 4-5 HTN. Median follow-up was 15.2 months. HTN was associated with better OS in HTN-positive versus HTN-negative patients (median not reached vs. 36.8 months, p = 0.029) and better PFS (29.9 vs. 17.2 months, p = 0.024, respectively). Bevacizumab-related HTN may represent a biomarker for clinical benefit in metastatic colorectal cancer patients.
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