多西他赛联合奥沙利铂和5-氟尿嘧啶方案治疗晚期胃癌41例

目的:观察多西他赛联合奥沙利铂和5-氟尿嘧啶(5-Fu)方案治疗晚期胃癌的近期疗效、毒副反应及生存状况。方法:收集2004-2010年我院41例晚期胃癌患者,多西他赛75 mg.m-2(d 1);奥沙利铂130 mg.m-2(d 2);5-Fu 400～500 mg.m-2.d-1,[d 2～d 5或持续泵入96 h(civ 96 h)],每21 d重复1次,至少2个周期。结果:总缓解率(ORR)为26.8%,疾病控制率(DCR)为78.0%。中位无进展生存期(PFS)为5.6个月(95%CI:3.52～7.6),中位总生存(OS)为12.3个月(95%CI:2.7～21.9)。1年生存率为46.3%(19/41);2年生存率为21.9%(9/41);3年生存率为7.3%(3/41)。常见的毒副反应为骨髓抑制(主要为白细胞及中性粒细胞减少)、胃肠道反应(恶心和呕吐)、腹泻和脱发等。结论:多西他赛联合奥沙利铂和5-FU方案治疗晚期胃癌疗效显著,毒副反应可耐受。化疗近期疗效是晚期胃癌PFS和OS的独立预后因素[危害比(HR):3.6;95%CI:1.8～7.3]。     

A phase II study of S-1 plus irinotecan and oxaliplatin in heavily-treated patients with metastatic colorectal cancer

Summary  Three-drug combination of fluoropyrimidine, irinotecan and oxaliplatin has shown survival benefits in patients with metastatic colorectal cancer (mCRC). Recently we performed a phase II study of a new 3-drug regimen, TIROX (S-1 plus irinotecan and oxaliplatin) to evaluate efficacy and safety in refractory mCRC patients. Patients with refractory to all of 3 drugs, age ≥18 years, PS 0–2, ≥1 measurable lesion(s) and adequate organ functions were eligible. S-1 was given 40 mg/m² twice a day on D1–14, oxaliplatin 85 mg/m² and irinotecan 150 mg/m² on D1 every 3 weeks. The primary endpoint was overall response rate (ORR). Between Mar 2007 and Nov 2007, 19 patients (of 18 planned) were enrolled; median age 50 years; M/F 12/7; PS 0/1/2 5/13/1; colon/rectum 11/8. By intent-to-treat analysis, ORR was 21.1% (95% CI, 8.7–43.7) and disease control rate was 52.6% (95% CI 31.5–72.8) with four PRs and six SDs. Median duration of disease control was 4.3 months (95% CI 1.7–6.9). Median PFS was 2.6 months (95% CI 2.2–2.9) and median OS was 9.8 months (95% CI 5.3–14.4) after median F/U of 15.4 months. G3/4 toxicities per pt included neutropenia (five, 26.3%), febrile neutropenia (two, 10.5%), thrombocytopenia (one, 5.3%), diarrhea (two, 10.5%) and fatigue (two, 10.5%). TIROX seemed to be feasible and efficacious for refractory mCRC patients, and could be an alternative for patients with good PS but no further treatment options.     

GS方案一线化疗后序贯替吉奥治疗晚期胰腺癌的临床观察

目的 比较晚期胰腺癌一线GS方案化疗后疾病得到控制者序贯替吉奥（S-1）单药治疗的疗效和对生存期的影响。方法 32例患者经一线GS（吉西他滨＋替吉奥）方案化疗4周期后,获得疾病控制的晚期胰腺癌患者,随机（1∶1）分为序贯S-1组（S-1组）和随访观察组（观察组）。每治疗2周期后评价疗效,观察无进展生存时间（PFS）、总生存时间（OS）及不良反应。结果 32例患者均可评价疗效。S-1组共接受93周期单药S-1化疗,S-1组和观察组中位PFS分别为7.0个月和5.2个月,中位OS分别为10.7个月和7.5个月,2组PFS和OS比较差异均有统计学意义（P〈0.05）。S-1组不良反应大多数表现为1～2级,3～4级仅有1例粒细胞减少及1例腹泻,2组之间差异无统计学意义（P〉0.05）。结论 晚期胰腺癌一线GS方案化疗后疾病得到控制者序贯S-1单药治疗安全有效,能显著延长患者的PFS及OS,且不良反应轻。     

Multicenter phase II study of S-1 monotherapy as second-line chemotherapy for advanced biliary tract cancer refractory to gemcitabine

Gemcitabine is widely used for the treatment of advanced biliary tract cancer (BTC) as first-line chemotherapy. However, there is no standard chemotherapy for patient with advanced BTC refractory to gemcitabine. We conducted a multicenter phase II study of S-1 monotherapy as second-line chemotherapy for patients with advanced BTC that were refractory to gemcitabine. S-1 was administered orally at a dose of 80 mg/m(2) for 28 days, followed by 14 days of rest. This regimen was repeated every 6 weeks. Tumor response was assessed every two cycles using the Response Evaluation Criteria in Solid Tumors version 1.0. Twenty-two patients were enrolled between March 2007 and January 2010, with 14 patients (64%) representing cases of recurrence after surgery. The overall response rate was 22.7%, and the overall disease control rate was 50.0%. The median overall survival time was 13.5 months (95% CI, 7.1-23.1 months) and the median time-to-progression was 5.4 months (95% CI, 2.6-17.2 months). Grade 3/4 toxicities included neutropenia (5%) and anemia (5%). The most common non-hematological toxicities were nausea (27%), anorexia (55%), and pigmentation (32%). In conclusion, S-1 monotherapy is feasible and moderately efficacious second-line chemotherapy for advanced BTC.     

吉西他滨联合奥沙利铂、地塞米松治疗非霍奇金淋巴瘤疗效观察

目的：观察吉西他滨联合奥沙利铂、地塞米松（GLD）方案治疗非霍奇金淋巴瘤（NHL）的有效性和安全性。方法回顾分析2011年1月—2014年9月诊治的35例 NHL 患者,给予吉西他滨1000 mg·m －2,d1,8,静脉滴注;奥沙利铂130 mg· m －2静脉滴注 d1,地塞米松20 mg·d －1,d1～4,静滴,每3周重复,2个周期评价疗效,治疗期间进行不良反应评估。结果35例 NHL 患者中,完全缓解（CR）7例,部分缓解（PR）11例,维持稳定（SD）4例,进展（PD）13例,客观有效率（ORR）为51．4％,疾病控制率（DCR）为62．9％;22例患者可评价无疾病进展期（PFS）,中位 PFS 为5个月（95％CI：0～17．7个月）,中位总生存期（OS）为9．5个月（95％CI：7．8～34．2个月）;主要不良反应为骨髓抑制,胃肠道反应、肝肾功能损害和神经毒性。结论GLD 方案对 NHL 有一定疗效,不良反应可耐受,是一个值得进一步研究的化疗方案。     

Phase II study of gemcitabine and cisplatin in chemonaive patients with advanced epithelial ovarian cancer

This phase II study evaluated the activity of gemcitabine (Gemzar) plus cisplatin (Platinol) as first-line treatment of advanced epithelial ovarian cancer. Forty-two chemonaive patients with advanced (stage III and IV) epithelial ovarian cancer received gemcitabine 1,250 mg/m(2) on days 1 and 8 and cisplatin 100 mg/m(2) on day 1, every 3 weeks, up to eight cycles. The median number of cycles completed was 5 (range 2-8). Of the 41 patients evaluable for tumor response, 20 had a partial response and nine had a complete response, for an overall clinical and pathologic response rate of 70.7% (95% CI 56.8-84.6%). Median overall survival for all 42 patients was 23.4 months (95% CI 15.9-29.9 months) and the median progression-free survival time was 10.4 months (95% CI 9.4-13.5 months). The combination was generally manageable. Hematologic toxicity (grade 3/4 neutropenia: 31.0/21.4%; grade 3/4 thrombocytopenia: 9.5/4.8%; grade 3/4 anemia: 11.9/0%) and nausea and vomiting (grade 3/4: 35.7/31.0%) were the most common toxicities. There was one toxic death (septic shock due to hematologic toxicity-induced infection). We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials with the addition of gemcitabine to first-line treatment appear warranted.     

Scheduled administration of low dose irinotecan before gemcitabine in the second line therapy of non-small cell lung cancer: a phase II study

We had previously demonstrated that low dose irinotecan (CPT-11) leads to increased accumulation of cells in S-phase and shows a therapeutic synergy with S-phase specific chemotherapy such as gemcitabine and 5-fluorouracil. In this phase II study, our objectives were to evaluate the tolerability and activity of low dose CPT-11 followed 24 h later by gemcitabine as second line therapy in patients with metastatic non-small cell lung cancer (NSCLC). CPT-11 (60 mg/m) was administered 24 h before gemcitabine (1000 mg/m) on days 1, 2, 8, and 9 every 3 weeks. Twenty-nine patients were evaluable for response. The median follow-up was 7.4 months. Partial response (PR) was seen in two (6.9, 95% confidence interval (CI): 0.009-0.228). PR and stable disease were seen in 22 patients (75.9, 95% CI: 0.564-0.897). The median survival time was 13.8 months (95% CI: 8.1-19.3). The median time to progression was 4.6 months (95% CI: 2.6-6.2). Thirty-eight patients were evaluable for toxicity. Neutropenia (grade 3 or 4) was observed in 27 patients (71%). Eight patients did not receive cycle 2 of therapy owing to prolonged neutropenia. No treatment-related deaths occurred. Scheduled administration of low dose CPT-11, 24 h before gemcitabine in the second line therapy of NSCLC yielded comparable disease control rates (PR and stable disease) when compared with other studies using the two chemotherapy drugs in the traditional sequence. However, this approach was associated with higher grade 3/4 neutropenia and is not recommended for further study in metastatic NSCLC.     

A phase II study of modified FOLFOX as first-line chemotherapy in advanced small bowel adenocarcinoma

This study aimed at assessing the efficacy and safety of biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX regimen) in patients with advanced small bowel adenocarcinoma (SBA). Thirty-three eligible patients with previously untreated SBA received 85 mg/m(2) of oxaliplatin intravenously over a 2-h period on day 1, together with 400 mg/m(2) of leucovorin over 2 h, followed by a 46-h infusion of 5-FU 2600 mg/m(2) every 2 weeks. All patients were evaluable for efficacy and toxicity. A median of nine cycles (range 3-18) was administered. The objective response rate was 48.5% [95% confidence interval (95% CI): 31-67%], with one complete response, 15 partial responses, 12 stable diseases, and five progressions. The median time to progression was 7.8 months (95% CI: 6.0-9.6) and the median overall survival was 15.2 months (95% CI: 11.0-19.4). Toxicity was fairly mild. Grade 3 toxicities included neutropenia (12.1%), thrombocytopenia (3.0%), nausea (6.1%), vomiting (3.0%), diarrhea (3.0%), peripheral neuropathy (9.1%), and fatigue (3.0%), and grade 4 toxicities occurred in none of the patients. The modified FOLFOX regimen is highly active and well tolerated as first-line chemotherapy for advanced SBA patients.     

Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies

Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II–III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson’s coefficient of determination (R ²). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R ²?=?0.81, 95% confidence interval [CI] 0.51–0.96). Six-month PFS was strongly correlated with 3-year PFS (R ²?=?0.89, 95% CI 0.62–0.96) in FL and was moderately correlated with 2-year OS (R ²?=?0.69, 95% CI 0.40–0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13%?±?1.2% increase in 2-year OS in DLBCL, a 23%?±?1.1% increase in 3-year PFS in FL, or a 6.7%?±?1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R ²?=?0.66 (95% CI 0.52–0.98) and R ²?=?0.69 (95% CI 0.22–0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.     

Efficacy of erlotinib in patients with advanced non-small cell lung cancer: a pooled analysis of randomized trials

Erlotinib is a potent reversible HER1/epidermal growth factor receptor tyrosine kinase inhibitor with single-agent activity in patients with non-small cell lung cancer. The aim of this study was to evaluate the efficacy of erlotinib for treating advanced non-small cell lung cancer by carrying out a pooled analysis of randomized controlled trials that compared erlotinib-based regimens with other agent-based regimens between January 1997 and 2011. Outcomes analyzed were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events. Fourteen trials including 7974 patients were identified. As first-line therapy was compared with chemotherapy, there was a similar ORR [OR: 0.33; 95% confidence interval (CI): 0.64-17.36; P=0.15], but decreased PFS [hazard ratio (HR): 1.55; 95% CI: 1.24-1.93; P<0.01] and OS (HR: 1.39; 95% CI: 0.99-1.94; P=0.05). As maintenance therapy was compared with placebo, erlotinib-based regimens significantly increased ORR (OR: 0.47; 95% CI: 0.31-0.70; P<0.01), prolonged PFS (HR: 0.71; 95% CI: 0.60-0.83; P<0.01), but did not improve OS (HR: 0.87; 95% CI: 0.68-1.11; P=0.22). As second/third-line therapy was compared with placebo, erlotinib-based regimens also significantly increased ORR (OR: 0.10; 95% CI: 0.02-0.41; P<0.01), prolonged PFS (HR: 0.61; 95% CI: 0.51-0.73; P<0.01), and improved OS (HR: 0.70; 95% CI: 0.58-0.84; P<0.01). However, as second/third-line therapy was compared with chemotherapy, the outcomes were similar between the two arms. When compared with PF299804, there was a decreased ORR (OR: 3.87; 95% CI: 1.27-11.81; P=0.02), and shortened PFS (HR: 0.58; 95% CI: 0.49-0.95; P=0.02). Meanwhile, erlotinib-based regimens showed no significant difference in adverse events, except for diarrhea, rash, and anemia. Erlotinib-based regimens significantly increased ORR and improved PFS as a first-line maintenance therapy or as a second/third-line therapy when compared with placebo.     

初诊伴髓外病变的多发性骨髓瘤患者的临床特征及预后分析 #br#

摘要：目的 分析初诊伴不同类型髓外病变（EMD）的多发性骨髓瘤（MM）患者临床特征及对预后的影响。方 法 回顾性分析本院收治资料完整的 99例初诊伴 EMD的 MM患者在性别、年龄、免疫球蛋白类型、DS分期、ISS分期 等临床特征上的异同,对不同髓外病变类型的患者进行生存及预后分析并探究不同治疗方案的预后意义。结果 伴骨旁髓外病变（bEMD,57例）与非骨旁髓外病变（sEMD,42例）的 MM患者之间临床特征差异无统计学意义（P＞ 0.05）。2种最多见髓外病变部位分别为肋骨（42.1%）及软组织（50.0%）。bEMD组和 sEMD组中位总生存期（OS,45 个月 vs. 15 个月）、中位无进展生存期（PFS,20 个月 vs.10 个月）差异均有统计学意义（P＜0.05）。年龄≥60 岁（HR= 2.333,95%CI：1.025～5.309,P＜0.05）、β2-MG≥2.7 mg/L（HR=4.361,95%CI：1.304～14.587,P＜0.05）及 TP53 突变 （HR=3.697,95%CI：1.015～13.469,P＜0.05）为影响 EMD患者 OS的独立预后因素。sEMD组含硼替佐米诱导化疗后 序贯 ASCT的患者中位 PFS（49个月vs. 9个月,P＜0.05）和中位 OS（79个月vs. 12个月,P＜0.05）与化疗后未行自体造 血干细胞移植患者相比具有统计学意义。结论 伴 sEMD的 MM患者预后较 bEMD差,含硼替佐米化疗序贯自体造 血干细胞移植有可能会延长伴 sEMD患者生存,改善预后。     

Safety and efficacy of single-day GemOx regimen in patients with pancreatobiliary cancer: a single institution experience

Background: GemOx (gemcitabine 1000 mg/m² >?100 min on day 1 and oxaliplatin 100 mg/m² on day 2 every 2 weeks) achieved a response rate of 26.8%, improved progression-free survival (PFS) but failed to demonstrate a benefit in overall survival (OS) compared with gemcitabine in pancreatic cancer. This regimen has regained attention after recent pooled- and meta-analysis suggested a survival benefit of gemcitabine–platinum doublets over gemcitabine. However, GemOx is associated with inconvenience to patients, early cumulative dose developing neuropathy and thrombocytopenia. In addition, fixed dose rate of gemcitabine showed no benefit >?30 min infusion schedule in the ECOG6201 study. Pharmacokinetic profiles of both drugs did not show statistically significant difference regardless of the order of administration.

Patients and methods: In order to create a more convenient and equally effective regimen, we conducted a retrospective study to evaluate the efficacy and safety of single-day modified GemOx (S-GemOx, gemcitabine 1000 mg/m² >?30 min and oxaliplatin 85 mg/m² >?2 h on day 1 every 2 weeks) in patients with pancreatic and biliary cancers.

Results: In all, 34 patients (median age 60 years, male/female: 17/17) received S-GemOx including locally advanced or metastatic pancreatic cancer (26) and biliary duct carcinoma (8). Median treatment was six cycles with duration of 12 weeks (range (r): 2 – 56). Median cumulative dose of oxaliplatin was 517.5 mg/m² (r: 85 – 2380). A total of 27 of 34 patients were evaluated for efficacy after initial staging: 1 (3.7%) complete response (CR), 4 (14.8%) partial response (PR), 18 (66.7%) stable disease and 4 (14.8%) progression of disease. Overall response rate (CR + PR) was 18.5%. Median PFS and OS were 7 and 11.6 months, respectively. All patients were assessed for toxicities. Grade 3/4 hematological toxicities include anemia (8%), neutropenia (11%), thrombocytopenia (5%), nausea/vomiting (3%), diarrhea (3%), hypersensitivity reaction (14%) and neuropathy (3%). No deaths occurred due to therapy.

Conclusions: S-GemOx regimen provides convenient schedule, toxicities appear to be comparable with GemOx. The incidence of neuropathy (3 vs 19.1%) and thrombocytopenia (5 vs 14%) are substantially lower compared with GemOx. Prospective studies of S-GemOx in a large patient population are warranted.     

Combination of gemcitabine and oxaliplatin in urothelial cancer patients with severe renal or cardiac comorbidities

Clinical trials in urothelial cancer exclude a large population of patients. An observational study evaluated the behavior of frail patients not eligible for cisplatin- or carboplatin-based regimens. Urothelial cancer patients requiring chemotherapy with either chronic renal failure (creatinine clearance <60 ml/min), and/or performance status (PS) > or =2 and/or cardiac dysfunction were prospectively observed. The treatment associated gemcitabine 1200 mg/m and oxaliplatin 85 mg/m, bimonthly (GO). Over 2 years, 31 of 45 (69%) patients with urothelial cancer requiring chemotherapy were not eligible for cisplatin- or carboplatin-based chemotherapy. Sixteen (52%) had a PS > or =2, 23 (74%) had creatinine clearance <60 ml/min, and 20 (65%) had an underlying cardiopathy. A total of 178 cycles of GO were administered (median 6 per patient, range 2-12). No aggravation of renal or cardiac status was noted. Acute grade 3 and 4 neutropenia and thrombocytopenia were observed in 16 and 13% of patients, respectively, with one febrile neutropenia. The median progression-free and overall survival values were 4.2 and 9.5 months, respectively. The majority of urothelial cancer patients have severe renal or cardiac comorbidities, and we conclude that in this subset of patients the combination of gemcitabine and oxaliplatin is well tolerated, and its clinical activity warrants further evaluation.     

Progression-free survival and time to progression as surrogate markers of overall survival in patients with advanced gastric cancer: analysis of 36 randomized trials

Progression-free survival (PFS) and time to progression (TTP) have been reported to correlate with overall survival (OS) in several types of cancers. To our knowledge, however, their use in the evaluation of new agents for AGC has not been investigated. We evaluated the potential of PFS and TTP to act as surrogates of OS in clinical trial settings. Randomized trials of systemic chemotherapy for advanced gastric cancer were identified by comprehensive electronic and manual search. Correlations between PFS/TTP and OS were evaluated. Thirty-six trials with a total of 83 treatment arms and 10,484 patients were selected for analysis. The nonparametric Spearman rank correlation coefficient (ρ) between median PFS/TTP and OS was 0.70 (95% CI, 0.59 to 0.82) and the correlation coefficient between hazard ratios in PFS/TTP and OS was 0.80 (95% CI, 0.68 to 0.92). Correlation tended to be higher in trials reporting PFS (ρ?=?0.85; 0.72-0.97) than in those reporting TTP (ρ?=?0.60; 0.24-0.97), trials in Non-Asian countries (ρ?=?0.80; 0.61-0.99) than Asia (ρ?=?0.67; 0.39-0.94), trials in patients with measurable lesions only (ρ?=?0.91; 0.77-1.00) than in those including non-measurable lesions (ρ?=?0.71; 0.50-0.93), albeit that none of these differences was significant. Our results indicate that improvements in PFS/TTP in advanced gastric cancer strongly correlate with improvements in OS. Further research is needed to clarify the surrogacy of PFS/TTP for OS or the role of PFS as the true end point in future randomized clinical trials of chemotherapy for AGC.     

Phase II trial of oxaliplatin combined with leucovorin and fluorouracil for recurrent/metastatic biliary tract carcinoma

Biliary tract carcinoma is often diagnosed at an advanced stage, and there is currently no established palliative standard of care. This phase II study investigated the efficacy and safety of combination chemotherapy of oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) in biliary tract carcinoma. Patients with unresectable or recurrent biliary tract carcinoma were enrolled, including pretreated and chemotherapy-naive patients. Treatment consisted of intravenous oxaliplatin (100 mg/m2, day 1) followed by leucovorin (100 mg/m2, day 1) and 5-FU (1000 mg/m2, days 1 and 2). Treatment was repeated every 3 weeks. The efficacy and safety of the treatment were determined. Twenty-eight patients were evaluable, and a total of 166 cycles were administered (median five cycles). One complete response (3.6%) and five partial responses (17.9%) were noted, with a response rate of 21.5% [95% confidence interval (CI): 6.2-36.7], according to Response Evaluation Criteria in Solid Tumors criteria. The median time to progression and overall survival was 3.5 months (95% CI: 2.7-4.3) and 10.0 months (95% CI: 7.2-12.8), respectively. The 1-year survival rate was 17.8%. Grade 3/4 neutropenia and thrombocytopenia were recorded in 18 and 4% of the patients, respectively. No treatment-related death was observed. Oxaliplatin in combination with leucovorin and 5-FU should be considered a feasible chemotherapy regimen for patients with recurrent/metastatic biliary tract carcinoma.     

吉西他滨联合奥沙利铂治疗复发和难治性弥漫性大B细胞淋巴瘤的疗效观察

目的 探讨GEMOX方案(吉西他滨联合奥沙利铂)治疗复发和难治性弥漫性大B细胞淋巴瘤(DLBCL)的近期疗效和不良反应.方法 27例复发和难治性DLBCL采用GEMOX方案治疗:吉西他滨(GEM) 1000 mg/m2静脉滴注,第1、8天;奥沙利铂(L-OHP)100 mg/m2静脉滴注,第2天.2组均21 d为1个周期,疗程不少于2个周期.观察疗效和不良反应,并随访疾病进展情况.结果 27例均能评价疗效(其中复发17例,难治10例),复发者总缓解率为64.7％(11/17),中位肿瘤进展时间(TTP)为7.5个月(95％ CI 6.8 ～8.2个月);难治者总缓解率为60.0％ (6/10),中位肿瘤进展时间为6.2个月(95％ CI 5.3～7.1个月).复发和难治患者总缓解率比较差异无统计学意义(P＞0.05),但中位肿瘤进展时间差异有统计学意义(P＜0.05);化疗不良反应程度较轻,主要不良反应为白细胞和血小板减少,但均为可逆,未出现因化疗毒性而死亡病例.结论 GEMOX方案是治疗复发和难治性DLBCL安全有效的可行性解救方案.     

Axitinib for the management of metastatic renal cell carcinoma

In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2–6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advancedRCCpreviously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable noncumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95%CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95%CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6).In the three studies, themost common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients.An observed association between diastolic blood pressure ≥90 mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second-line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm.     

Cord blood-derived cytokine-induced killer cells biotherapy combined with second-line chemotherapy in the treatment of advanced solid malignancies

This study investigated the efficacy of cord blood-derived cytokine-induced killer (CB-CIK) biotherapy combined with second-line chemotherapy in treating advanced solid malignancies after first-line chemotherapy failure. Forty patients with advanced solid malignancies after first-line chemotherapy failure were divided into two groups: CB-CIK cells transfusion plus second-line chemotherapy (CB-CIK+Chemotherapy) group and second-line chemotherapy alone (Chemotherapy) group. The ORR and DCR were 30% and 80% in CB-CIK + Chemotherapy group compared with 15% and 70% in Chemotherapy group (P = 0.451 for ORR and P = 0.716 for DCR) respectively. The time to progression and the median survival time were 3.45 months (95% CI 2.30-4.60 months) and 11.17 months (95% CI 9.05-13.28 months) in CB-CIK+Chemotherapy group compared with 2.03 months (95% CI 1.23-2.82 months) and 7.52 months (95% CI 5.97-9.06 months) in Chemotherapy group respectively. Compared with patients in Chemotherapy group, the patients in CB-CIK+Chemotherapy group had significantly longer PFS (P = 0.031) and overall survival (P = 0.048). In vitro studies further revealed that CB-CIK cells could overcome drug resistance in cisplatin-resistant lung adenocarcinoma cell line A549/CDDP through downregulating ABCG-2 and P-gp and induce cytotoxicity through the high level expression of CD3, CD56, FasL, and CD69. This could explain why CB-CIK could have synergistic effects with second-line chemotherapy shown in this clinical study. We concluded CB-CIK cells combined with second-line chemotherapy can significantly improve PFS and median survival compared with second-line chemotherapy alone in patients with advanced solid malignancies after first-line chemotherapy failure.     

Phase II study of gemcitabine plus cisplatin in metastatic breast cancer

Our objectives were to assess the efficacy and toxicity of gemcitabine plus cisplatin as first-line therapy in metastatic breast cancer (MBC). Patients with stage IV MBC and no prior chemotherapy for metastatic disease were treated with gemcitabine 1200 mg/m on days 1 and 8, and cisplatin 75 mg/m on day 1 every 21 days. Up to 6 cycles were given. A total of 46 patients with a median age of 49 years (range 24-77) and Karnofsky performance status of 80 or above were enrolled. In total, 238 cycles were administered. Of the 42 patients evaluable for response, seven (17%) achieved a complete response and 27 (64%) a partial response, for an overall response rate of 81% [95% confidence interval (CI) 69-93%]. Median time to progression was 14.9 months (95% CI 0-30.2 months). Median duration of response was 24.2 months (95% CI 11.2-37.3 months). The median survival was 27.9 months (95% CI 23.1-32.7 months), and the 1- and 2-year survival probabilities were 71.4 and 61.4%, respectively. All patients were evaluable for toxicity, and grade 3/4 WHO toxicities included neutropenia (41.3%), anemia (8.7%), thrombocytopenia (8.7%), alopecia (26.1%) and nausea/vomiting (32.6%). We conclude that gemcitabine plus cisplatin is a highly effective and safe first-line treatment for patients with MBC. The time to progression of 14.9 months compares favorably with other standard treatments (anthracyclines, taxanes). A randomized study is required to further investigate the role of this combination as first-line treatment for MBC.     

The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer

Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0–1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value?=?0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS?=?2–3) had worse survival as compared to patients with better performance status (PS?=?0–1, p?=?0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p?=?0.001). No statistical evidence of a survival difference was found between smokers and non-smokers in both treatment groups (p?=?0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance.