A multi-center phase II study of oxaliplatin, irinotecan, and capecitabine in advanced gastric/gastroesophageal junction carcinoma.
ABSTRACT There is no standard first-line therapy for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma and the prognosis remains poor. Our institution conducted a phase I study of oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule. The regimen was tolerated; pharmacodynamic studies revealed no drug interactions, and there was one confirmed response in a gastric cancer patient. We performed a phase II trial in advanced gastric and GEJ adenocarcinoma to determine response rate and response duration.
This was a multi-center single treatment arm study involving six sites. Only prior adjuvant therapy was allowed. Patients had ECOG performance status of 0-2, adequate organ function, and were able to tolerate oral medications. All patients received oxaliplatin 60 mg/m(2) intravenously (IV) and irinotecan 50 mg/m(2) IV weekly times 4 weeks with a 2-week rest period. Capecitabine 450 mg bid orally was received on days 1 through 5 every week for 4 weeks, followed by a 2-week rest. Patients were assessed for response after the first two cycles; response duration, overall survival, and adverse events were also recorded. We estimated an improvement in historical response rate by 30% would have clinical meaning.
A total of 39 patients were accrued and all were assessed for toxicity; 30 patients were evaluable for response. The median age was 57.8 years (31-79 years) and 74% were male. Two patients had a complete response, with nine patients achieving a partial response. The total response rate was 28%, with nine patients not evaluable for response. The median response duration was noted at 5.97 months and median overall survival was 8.98 months. There were no grade 5 treatment related events, with all deaths secondary to disease progression. Only five grade 4 events occurred (neutropenia, hyperkalemia, hypokalemia (2), thrombosis/embolism) without grade 4 diarrhea or sensory neuropathy.
Oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule does induce responses in advanced gastric and GEJ adenocarcinoma. However, the total response rate is modest and not an improvement over other regimens.
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ABSTRACT: Introduction: Fluoropyrimidine therapy has been a mainstay in the treatment of cancers of the esophagus and stomach for nearly half of a century in the form of intravenous 5-fluorouracil. Capecitabine , an oral fluoropyrimidine precursor, was first approved in 2001 for the treatment of metastatic colon cancer and may be used interchangeably with parenteral 5-FU in the treatment of upper gastrointestinal (GI) cancers. Areas covered: In this article, mechanisms of action and synergy with other systemic therapies and radiation are reviewed. A summary of the most important clinical trial results shaping the use of capecitabine in the treatment of cancers of the esophagus and stomach is offered, along with an update of upcoming areas of interest using this agent in these disease types. Expert opinion: Improvements in understanding molecular mechanisms of disease, defining distinct disease subtypes based on histology, genetic background and levels of protein expression as well as signaling pathways may start to clarify the reasons underlying heterogeneous clinical behaviors and different outcomes between patients with seemingly similar tumor types. Capecitabine ushered in the era of oral chemotherapy, providing ease of administration with comparable if not superior efficacy to its older parental counterpart. The best way to fully exploit its potential in gastroesophageal cancers is being actively studied worldwide at all stages of disease management.Expert Opinion on Investigational Drugs 10/2013; · 4.74 Impact Factor
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ABSTRACT: The association between venous thromboembolism and chemotherapy for esophagogastric cancer is well known in patients treated with palliative intent. Whether this risk extends to the neoadjuvant and perioperative setting is unclear. A retrospective interrogation of databases of patients receiving perioperative chemotherapy for potentially curative intent at the Leicester (2006-2011) and Nottingham (2004-2011) esophagogastric cancer centers was performed. Thromboembolic events were diagnosed in 48 of 384 patients (12.5%), 21 (5.5%) at presentation, 12 (3%) during neoadjuvant chemotherapy, and 15 (3.9%) in the postoperative period. There were no deaths from thromboembolic disease. By site these comprised catheter-related axillary vein thrombosis in 7 patients, deep venous thrombosis in 12 patients, and pulmonary embolism in 29 patients. Twenty-five of the 29 pulmonary emboli were incidental findings on staging computed tomography imaging. Combination chemotherapy with epirubicin, cisplatin, and capecitabine appeared to carry the greatest risk for the development of thromboembolism. Seven of the 12 patients (58%) who developed thromboembolism during neoadjuvant chemotherapy did not proceed to surgery because of deterioration in performance status. Preoperative thromboembolic disease resulted in a significant increase in the interval between chemotherapy and surgery, but did not influence either length of hospital stay or survival. Venous thromboembolism will develop in 12.5% of patients treated with potentially curative intent. This adverse event can occur at any time during the patient journey. In contrast to the commonly held view, this did not translate into a poorer prognosis.Diseases of the Esophagus 05/2013; · 1.64 Impact Factor
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ABSTRACT: MEDICATION SAFETY Overlooked Renal Dosage Adjustments A retrospective analysis of 647 patients at hospital discharge com-pared required renal dosage adjust-ments to dosage actually prescribed. This study was conducted at VieCuri Medical Centre in Venlo, Netherlands. Patient demographics and renal function data were col-lected, and dosage adjustment needs were assessed via the pharmacy-supported discharge counseling ser-vice. The incidence of inappropriate dosing based on renal function was measured at hospital discharge. Thirty-seven percent of patients evaluated during the study period (237/647) had a creatinine clear-ance less than 51 mL/min/1.73 m 2 ; dosage adjustment was warranted in 23.9% (411/1,718) of prescrip-tions. When dosage adjustment should have been performed, more than 40% of prescriptions (169/411; 41.1%) were inappropri-ate for renal function (9.8% of pre-scriptions overall; 169/1,718). Fur-thermore, 60.4% (102/169) of inappropriate prescriptions pos-sessed the potential for moderate or severe clinical consequences, as evaluated by a panel of two clinical pharmacologists and one nephrolo-gist. Study authors also noted a lack of standardized dosing guidelines for agents requiring renal dosage adjustment. The authors also sug-gested that augmenting medication systems by adding dynamic renal dosing alerts would improve moni-toring. Summary: A comparison of suggested renal dosing and actual dosing at hospital discharge revealed that appropriate prescribing may be overlooked. van Dijk EA, Drabbe NRG, Kruijtbosch M, De Smet PAGM. Drug dosage adjust-ments according to renal function at hos-pital discharge. Ann Pharmacother. 2006;40:1254-1260.Hospital pharmacy 12/1122; 41.