Estabilishment of treatment for CDDP-refractory ovarian carcinoma

在晚期卵巢恶性肿瘤中，卵巢透明细胞腺癌(OCCA)较常见的浆液性囊腺癌预后较差，主要原因是OCCA对以顺铂为基础的化疗敏感性较差。OCCA的发病率最近一直在上升，约占所有卵巢癌的20%以上。我们用从口腔鳞癌患者建立的两种细胞系HAC-2和KK进行体外药敏试验，结果表明：0.5 ng/ml的SN-38(CPT-11的活性形式)、8.1 ng/ml的MMC、10.7 ng/ml的DOX、110.0 ng/ml的依托泊苷对OCCA的生长抑制率为50%。HAc-2细胞移植到裸鼠体内的肿瘤生长抑制实验显示…此外，MMC是最有效的药物，其次是DOX、CPT-11、依托泊苷和CDDP。此外，在该模型中，CPT-11和MMC在与单一药物相同的剂量强度下显示出最高的抗肿瘤活性。在此基础上，我们设计了CPT-11与MMC的组合方案：CPT-11,140 mg/m^2加入500ml生理盐水中，在第1、14、28天输注4小时以上；MMC，7 mg/m^2，在第1、14、28天。疗程每4周重复一次。该方案至少给患者2个疗程。25例单纯OCCA患者共60个疗程中，6个疗程出现3级腹泻。其他中毒迹象也是可以接受的。完全应答(CRS)5例，部分应答(PR)8例，无变化(NCS)9例，进展性疾病(PD)3例，总应答率为52%(95%可信区间：32.4%~71.6%)。与12名无反应者相比，13名有反应者的生存期显著延长(化疗开始后的中位生存期：22个月对7个月，p&lt；0.001)。HATHUS，本方案首次证明了在单纯OCCA患者中有显著的活性。较少

Among advanced ovarian malignancies, clear cell adenocarcinoma of the ovary (OCCA) has worse prognosis compared with the more commom serous cystadenocarcinoma, mainly because of poor sensitivity of OCCA to CDDP-based chemotherapy^1. Indeed, there has been no one patient with pure OCCA showing an appreciable response to chemotherapy. OCCA has recently been increasing in prevalence and has occupied approximately more than 20% of all ovarian cancer. Thus, there is an urgent need to find an effective chemotherapeutic regimen for OCCA.We conducted in vitro chemosensitivity test assessing anti-tumor activities of various agents against OCCA using two cell lines, HAC-2 and KK,established from patients with OCCA.The results showed that 50% growth inhibition was obtained by 0.5ng/ml of SN-38 (active form of CPT-11), 8.1ng/ml of MMC,10.7ng/ml of DOX,110.0ng/ml of etoposide, and 130ng/ml of CDDP.In vivo tumor growth inhibitory test using HAC-2 cells transplanted into BALB/C nude mice demonstrated … More that MMC was the most potent agent, followed by DOX,CPT-11, etoposide, and CDDP.Moreover, a combination of CPT-11 and MMC at the same dose intensity as that of a single agent exhibited by far the highest anti-tumor activity in this model. The same results were obtained in other OCCA cell lines.Based on the above results, we designed a combination of CPT-11 and MMC.Protocol was as follows ; CPT-11,140mg/m^2 in 500ml of saline infused over 4 hours on day 1,14, and 28 ; and MMC,7mg/m^2 bolus on day 1,14, and 28. The course was repeated every 4 weeks. At least 2 courses of this regimen were given to patients. Among total 60 courses for consecutive 25 patients with pure OCCA,grade 3 diarrhea was observed in 6 courses. Other toxic signs were acceptable. The responses were 5 complete responses (CRs), 8 partial responses (PRs), 9 no changes (NCs), and 3progressive diseases (PDs), with overall response rate being 52% (95% Confidence interval : 32.4% -71.6%). Thirteen responders showed a significantly longer survival compared with 12 non-responders (median survival after the start of chemotheraphy : 22 months vs 7months, p < 0.001 for Log-rank test).HAThus, the present protocol is the first to demonstrate a significant activity in patients with pure OCCA. Less