bryostatin-1 and Esophageal-Neoplasms

We sought to determine the response rate and toxicity profile of sequential paclitaxel and bryostatin-1, a novel, selective inhibitor of protein kinase C, in patients with advanced esophageal cancer.. Patients with advanced esophageal and gastroesophageal junction cancer were enrolled. All gave informed consent. They were initially treated with paclitaxel 90 mg/m(2) intravenously on Day 1 and bryostatin-1 50 microg/m2 on Day 2 weekly for three consecutive weeks out of four. Because of severe myalgias, dosing was reduced to paclitaxel 80 mg/m2 with bryostatin-1 40 microg/m2 and then to paclitaxel 80 mg/m2 with bryostatin-1 25 microg/m2.. Twenty-four patients were enrolled, with 22 assessable for response. The partial response rate was 27%. 10 patients treated with bryostatin-1 40-50 microg/m2 had a response rate of 40 versus 17% at bryostatin-1 25 microg/m2 (p-value = 0.3). Median time-to-progression was 3.7 months and median survival was 8.3 months. Grade 3/4 myalgias were seen in 50% of patients. Myalgias appeared to be related to bryostatin-1 dose. Because of toxicity, the trial was closed prior to full accrual.. Despite potential anti-tumor activity of this combination in patients with advanced esophageal cancer, further development is not warranted, given the severe toxicity, especially myalgias, that were seen.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Carcinoma, Squamous Cell; Disease Progression; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Paclitaxel

Accurate response assessment is essential for evaluating new cancer treatments. We evaluated the impact of Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria and tumor shape on response assessment in patients with metastatic esophageal cancer.. In 19 patients with metastatic esophageal cancer in a phase II trial of bryostatin-1 and paclitaxel, response was retrospectively assessed for 89 lesions with RECIST and WHO criteria on baseline and serial follow-up CT scans. The eccentricity factor (EF) was introduced for measuring the degree to which tumor shape diverges from a perfect sphere [EF = radical1-(LPD/MD)(2), where LPD is the largest perpendicular diameter and MD is the maximal diameter].. The disagreement rate in best overall response categorization between RECIST (unidimensional) and WHO (bidimensional) criteria was 26.3%. Change in eccentricity was significantly greater (P < 0.01) for patients with disagreement (mean 0.31, range 0-0.91). When the short axis was used for unidimensional lymph node measurement, disagreement between WHO and RECIST lessened.. Response assessment by WHO and RECIST differs substantially. Greater change in eccentricity is associated with greater discordance between WHO and RECIST. The discordance between WHO and RECIST may impact on how effective a therapy is judged to be.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Esophageal Neoplasms; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Macrolides; Male; Middle Aged; Neoplasm Staging; Neoplasms; Paclitaxel; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome

Protein Kinase C (PKC), involved in transmembrane signaling of cell surface receptors, promotes carcinogenesis and tumor progression. Bryostatin-1 competes with PKC for phorbol esters (tumor promoters), thus inhibiting tumor progression. Bryostatin-1 also increases cytotoxicity of paclitaxel in a sequential fashion. We studied sequential paclitaxel and bryostatin-1 in patients with untreated, advanced gastric adenocarcinoma.. Patients with histologic proof of gastric or gastroesophageal junction adenocarcinoma with advanced, measurable cancers were eligible. Patients were required to have near normal organ function and ECOG performance status of 0 or 1. All patients gave an informed consent. Patients received paclitaxel 80 mg/m2 in 2 h intravenously on day 1 and bryostatin-1 40 mcg/m2 in 1 h intravenously on day 2 each week for 3 consecutive weeks out of 4. Primary objective was to assess the objective response rate.. In a multi-center setting, 37 patients were enrolled and 35 were assessable for response. A confirmed partial response rate was 29%. The median time-to-progression was 4.25 months and the median survival time was 8 months. Grade 3 cumulative myalgias occurred in 55% of patients. Twelve patients discontinued therapy due to myalgias, including 6 patients who had not progressed after achieving a partial response. Other toxic effects were uncommon.. Sequential paclitaxel plus bryostatin-1 resulted in a superior response rate than would be expected of paclitaxel alone in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Further development of this combination is warranted once an effective method to ameliorate or prevent myalgias can be established.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bryostatins; Disease Progression; Dose-Response Relationship, Drug; Esophageal Neoplasms; Esophagogastric Junction; Female; Humans; Macrolides; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Survival Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Biotechnology; Bryostatins; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Design; Esophageal Neoplasms; European Union; Humans; Lactones; Macrolides; Paclitaxel; United States