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Phase II, parallel-design study of preoperative combined modality therapy and the matrix metalloprotease (mmp) inhibitor prinomastat in patients with esophageal adenocarcinoma
Purpose: This randomized phase II, parallel-design study evaluated preoperative combined modality therapy and the matrix metalloprotease (MMP) inhibitor prinomastat in patients with resectable adenocarcinoma of the esophagus that were stage II or greater. The objectives of the trial were to determine pathologic complete response rate (pCR), overall response rate, progression-free survival, pattern of disease relapse, and two-year and overall Survival.
Patients and Methods: Preoperative staging included computed tomography, endoscopic ultrasound, and, when feasible, laparoscopy. Eligible patients were randomized to preoperative prinomastat or placebo. plus continuous infusion 5-FU, cisplatin, paclitaxel, and Concurrent radiotherapy. Esophagectomy was performed on day 71. Adjuvant paclitaxel and prinomastat were available to all Study patients.
Results: Between August 2000 and June 2001, 15 of a planned 78 patients were randomized into the trial. One patient after randomization withdrew consent. Fourteen patients, 7 in each arm. completed preoperative treatment and Surgery. pCR was achieved in 5 patients: 1/7 prinomastat and Q 7 placebo. Disease improvement was achieved in 7 patients; 5/7 prinomastat and 2/7 placebo. At a median follow-up of 28 months, 7 patients (2 prinomastat, 5 placebo) are alive with no evidence of disease. The primary prinomastat related toxicity was moderate to severe musculoskeletal toxicity interfering with daily function. This toxicity was managed with treatment rest, dose reduction, or discontinuation. Five patients (3 prinomastat and 2 placebo) had life-threatening thrombo-embolic events, which led to early evaluation of safety and efficacy, and subsequent termination of the Study.
Conclusion: All patients, regardless of treatment arm, were able to successfully undergo neoadjuvant combined modality therapy and esophagectomy. However, early closure of the study due to unexpected thrombo-embolic events precluded any conclusions regarding clinical activity of prinomastat in locally advanced esophageal cancer patients
Breaking and entering into the CNS: clues from solid tumor and nonmalignant models with relevance to hematopoietic malignancies
Various malignancies invade the CNS sanctuary site, accounting for the vast majority of CNS neoplastic foci and contributing to significant morbidity as well as mortality. The blood–brain barrier (BBB) exhibits considerable impermeability to chemotherapeutic agents, severely limiting therapeutic options available for patients developing metastatic CNS involvement, accounting for poor outcomes. The mechanisms by which malignant cells breach the highly exclusive BBB and subsequently survive in this unique anatomical site remain poorly understood, with most of the current knowledge stemming from non-malignant and solid malignancy models. While solid and hematologic malignancies may face different challenges once within the CNS (e.g., solid tumor parenchymal metastasis compared to masses/nodules/leptomeningeal disease in hematologic malignancies), commonality exists in the process of migrating across the BBB from the circulation. Specifically considering this last point, this review aims to survey the current mechanistic knowledge regarding malignant migration across the BBB, necessarily emphasizing the better studied solid tumor and nonmalignant models with the intention of highlighting both the current knowledge gap and additional work required to effectively consider how hematopoietic malignancies breach the CNS