Morgan Robert J, Synold Timothy W, Xi Bixin, Lim Dean, Shibata Stephen, Margolin Kim, Schwarz Roderich E, Leong Lucille, Somlo George, Twardowski Przemyslaw, Yen Yun, Chow Warren, Tetef Merry, Lin Paul, Paz Benjamin, Koczywas Mariana, Wagman Lawrence, Chu David, Frankel Paul, Stalter Susan, Doroshow James H
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California, USA.
Clin Cancer Res. 2007 Feb 15;13(4):1232-7. doi: 10.1158/1078-0432.CCR-06-1735.
To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine.
Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m(2)) was administered into the peritoneal cavity in 2 L of warmed saline on days 1, 4, 8, and 12 of a 28-day cycle.
Thirty patients received 63 (median, 2; range, 0-6) courses. Tumors included ovary (14), uterus (2), colon (6), pancreas (3), and others (5). Dose-limiting toxicity included nausea, vomiting, diarrhea, dyspnea, fatal respiratory failure, and grade 3 elevation of alanine aminotransferase in three patients. Hematologic toxicity and pain were </=grade 2. Three patients had decreased or resolved ascites. Of 19 patients evaluable for response, 10 had stable disease (median, 3.5 courses) and 9 had progressive disease. The median peak peritoneal concentration was 1,116-fold (range, 456-1,886) higher than the peak plasma level. Plasma and peritoneal levels were undetectable within 8 to 12 h. At 120 mg/m(2), the median peritoneal area under the concentration versus time curve (AUC) was 82,612 ng/mL x h (range, 53,296-199,830) and the plasma AUC was 231 ng/mL x h (range, 47.6-259.5). The mean peritoneal advantage (AUC(peritoneal)/AUC(plasma)) was 847 (range, 356-1,385).
I.p. administration of gemcitabine is tolerated within the tested dosage range. Technical problems with the Porta-Cath device and i.p. therapy per se may have been exacerbated by the enrollment of many patients with a variety of advanced i.p. diseases. Given the significant increase in local dose intensity and the documented activity of this drug, this agent may be an excellent candidate for i.p. therapy in optimally debulked ovarian cancer, either alone or in combination.
确定腹腔注射吉西他滨的最大耐受剂量、毒性和药代动力学。
患者患有腹膜癌。在28天周期的第1、4、8和12天，将吉西他滨（40、80、120或160mg/m²）加入2L温热盐水中注入腹腔。
30例患者接受了63个疗程（中位数为2个疗程；范围为0 - 6个疗程）。肿瘤包括卵巢癌（14例）、子宫癌（2例）、结肠癌（6例）、胰腺癌（3例）和其他癌症（5例）。剂量限制性毒性包括恶心、呕吐、腹泻、呼吸困难、致命性呼吸衰竭，以及3例患者出现丙氨酸转氨酶3级升高。血液学毒性和疼痛≤2级。3例患者腹水减少或消失。在可评估疗效的19例患者中，10例病情稳定（中位数为3.5个疗程），9例病情进展。腹腔内药物浓度峰值中位数比血浆峰值高1116倍（范围为456 - 1886倍）。8至12小时内血浆和腹腔内药物浓度均检测不到。在120mg/m²剂量下，腹腔内浓度 - 时间曲线下面积（AUC）中位数为82612ng/mL·h（范围为53296 - 199830），血浆AUC为231ng/mL·h（范围为47.6 - 259.5）。腹腔内优势（AUC（腹腔）/AUC（血浆））均值为847（范围为356 - 1385）。
在测试的剂量范围内，腹腔注射吉西他滨是可耐受的。许多患有各种晚期腹腔疾病的患者入组，可能加剧了Porta - Cath装置和腹腔内治疗本身的技术问题。鉴于局部剂量强度显著增加以及该药物已证实的活性，该药物可能是最佳减瘤后的卵巢癌腹腔内治疗的理想选择，可单独使用或联合使用。
