西妥昔单抗联合化疗治疗转移性结直肠癌的观察

目的 观察西妥昔单抗联合化疗方案治疗转移性结直肠癌的近期疗效及不良反应.方法 11例经病理组织学确诊的转移性结直肠癌患者,给予西妥昔单抗联合FOLFOX方案治疗,西妥昔单抗首次给予负荷剂量400 mg/m2,每周给予维持剂量为250 mg/m2.结果 全组11例患者中,完全缓解1例,部分缓解5例,稳定2例,进展3例,有效率54.5％ (6/11),疾病控制率为72.7％ (8/11),中位肿瘤进展时间为8.4个月.主要不良反应为痤疮样皮疹(9例)和腹泻(6例).5例合并肝转移患者中经治疗后1例转化为可切除病灶.患者耐受良好,无治疗相关死亡.结论 西妥昔单抗联合FOLFOX方案治疗转移性结直肠癌疗效较好,不良反应多可耐受.     

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.     

Phase II trial of edatrexate in patients with metastatic colorectal cancer

Summary Edatrexate is an analog of methotrexate whichin vitro demonstrated activity against human colon cancer xenografts grown in nude mice. In a phase II trial, 12 patients with metastatic colorectal cancer and no prior chemotherapy were treated with Edatrexate 80 mg/m²/week for an initial period of 8 weeks. No objective responses were observed. Edatrexate is inactive against colon cancer at the dose and schedule used in this trial.     

Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: Final results of a randomised, controlled, multicenter phase II study

Summary Background: Oxaliplatin-induced neurotoxicity is a growing, relevant clinical problem. In this study we evaluated the efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer. Methods: Chemotherapeutic treatment consisted of oxaliplatin 85 mg/m² given biweekly and weekly folinic acid 500 mg/m² followed by a 24-h infusion of 5-FU 2000 mg/m² (FUFOX). One cycle consisted of six consecutive weeks of treatment followed by two weeks of rest (=Treatment B). For Treatment A carbamazepine was added in a dosage for targeted plasma levels of 4–6 mg/L. Neurotoxicity was regularly assessed using a specific scale. Moreover, an evaluation of chronic sensory symptoms and a neurologic examination including tests for vibrational sense, strength and deep tendon reflexes were added creating a peripheral neuropathy (PNP) score. Results: The prospectively defined adequate number of patients needed to provide power for the primary outcome could not be achieved. 19 patients were assigned to Treatment A and 17 to Treatment B. At baseline, the distribution of all clinicopathologic variables was comparable between the two groups. Overall response rates were 16% and 24% and overall survival 15.1 months and 17.4 months for Treatment A and Treatment B, respectively. Between Treatment A and Treatment B there were no major differences when considering worst neurotoxicity during the study period (p=0.46). Grade 3/4 neurotoxicity occured in 4 patients with Treatment A vs. 6 patients with Treatment B. There were no major differences between both groups in each category of the PNP score. Conclusions: Based on the small number of patients and low statistical power of our study definite conclusions regarding efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer cannot be drawn.     

Open-label phase I trial of vandetanib in combination with mFOLFOX6 in patients with advanced colorectal cancer

Summary   Background: Vandetanib (ZACTIMA™) is a once-daily oral inhibitor of vascular endothelial growth factor, epidermal growth factor and RET receptor tyrosine kinases. The safety and tolerability of vandetanib plus mFOLFOX6 was investigated in patients with advanced colorectal cancer (CRC). Methods: Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of mFOLFOX6. Results: Seventeen patients received vandetanib 100 mg (n = 9) or 300 mg (n = 8) plus mFOLFOX6. The protocol definition of a tolerable dose (vandetanib-related dose-limiting toxicity [DLT] in less than two patients) was met in both dose cohorts, with one DLT of diarrhoea reported in each. Overall, the most common adverse events were diarrhoea, nausea and lethargy (all n = 11). There was no pharmacokinetic interaction between vandetanib and mFOLFOX6. Preliminary efficacy results included one complete response and three confirmed partial responses. Conclusions: In patients with advanced CRC, once-daily vandetanib (100 or 300 mg) with mFOLFOX6 was generally well tolerated.     

A phase II trial of gefitinib in combination with capecitabine and oxaliplatin as first-line chemotherapy in patients with advanced colorectal cancer

ABSTRACT

Objective: This study was designed as a multicentre phase II trial to assess the efficacy and safety of gefitinib in association with capecitabine and oxaliplatin in patients with untreated metastatic colorectal cancer.

Research design and methods: Patients with metastatic colorectal cancer that had received no prior chemotherapy for advanced disease were treated with oral gefitinib (250?mg daily) plus oral capecitabine (1000?mg/m² twice a day on Days 1–14) and intravenous oxaliplatin (120?mg/m² on Day 1 of each 3?week cycle).

Results: Thirty-five patients were enrolled. In the intention-to-treat analysis, 3 (8.6%) patients experienced a complete response (CR), 14 (40%) a partial response (PR) and 11 (31.4%) had stable disease (SD). The disease control rate (CR + PR + SD) was 80%, the median time to progression was 7.3 months (95%CI: 4.76–9.2) and the estimated median overall survival was 21.9 months (95% CI: 15.1–not reached). The most common grade 3 to 4 toxicities included diarrhoea (31%) and vomiting (5.7%).

Conclusions: The combination of capecitabine, oxaliplatin and gefitinib appears to have promising activity in chemotherapy-naïve metastatic colorectal cancer. A higher disease control rate and an increase in median overall survival were seen compared with previous reports with capecitabine and oxaliplatin in similar patient populations. The tolerability profile appears to be predictable and similar to capecitabine/oxaliplatin regimens.     

转移性结直肠癌3种一线化疗方案的药物经济学评价

目的：探讨转移性结直肠癌（mCRC）3种一线化疗方案的药物经济学效果及影响因素。方法：采用回顾性调查方法,纳入2012年1月1日-2015年10月30日期间符合纳入标准的mCRC患者,根据化疗方案不同分为FOLFOX组、CapeOx组和FOLFIRI组。以总住院费用为成本,无进展生存时间（PFS）为效果,对3种化疗方案进行成本-效果分析和敏感度分析,并评价化疗药物是否国产及医保支付对结果的影响。结果：共纳入678名患者,FOLFOX组（136例）、CapeOx组（392例）和FOLFIRI组（150例）间基本情况无统计学差异（P>0.05）,具有可比性。FOLFOX组、CapeOx组和FOLFIRI组PFS分别为154.15 d、156.16 d和165.84 d,不良反应各组间无统计学差异,总治疗费用分别为63 956.11元、73 826.06元和79 259.20元,成本-效果比分别为414.90、472.76和477.93。在FOLFOX方案的基础上,每增加一天PFS,FOLFIRI方案和CapeOx方案所追加的成本分别为57.86元和59.69元。敏感度分析结果与成本-效果分析一致。亚组分析表明,国产药物的效果略低于进口药物,成本均高于进口药物,成本-效果比低于进口药物,药物经济学效果好。3种方案患者自付费用成本-效果比FOLFOX方案 < CapeOx方案 < FOLFIRI方案,医保支付费用成本-效果比FOLFOX < FOLFIRI < CapeOx。结论：mCRC 3种一线化疗方案中,成本最低的为FOLFOX方案,效果最佳的为FOLFIRI方案,经济学效果最优为FOLFOX方案。     

Medical care consumption in a phase III trial comparing irinotecan with infusional 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer after 5-FU failure

We evaluated economic implications of treatment with irinotecan, following a RCT which demonstrated significantly increased survival at 1 year with irinotecan (45%) compared to infusional 5-fluorouracil (5-FU) (32%) in patients with metastatic colorectal cancer. Medical care consumption data were collected prospectively alongside the trial, with 256 patients followed for a median of 10 months. Follow-up was prolonged beyond treatment failure and medical care consumption was not protocol driven, enabling a realistic evaluation of economic implications. Medical care consumption associated with chemotherapy administration was lower with irinotecan as compared with infusional 5-FU. The cumulative number of days in hospital due to treatment toxicity and cancer complications, which is the key cost driver, was 14.4 (95% CI: 10.7-18.1) with irinotecan versus 17.5 (95% CI: 11.7-23.3) with infusional 5-FU. Thus, the survival benefit with second-line irinotecan compared to infusional 5-FU in patients with advanced colorectal cancer was achieved without increasing medical care consumption.     

结直肠癌伴发结肠息肉的临床分析

目的了解结直肠癌患者伴发结肠息肉的发生规律,探讨临床对结直肠癌伴发息肉的早期诊断及处理的策略。方法对67例结直肠癌患者的临床资料进行回顾性分析。结果 67例结直肠癌中有7例为复发性结直肠癌,于35例患者中检出息肉共95枚,其中22例有多发息肉;24例经组织病理活检,其中19例为腺瘤性息肉,1例出现癌变。结论结直肠癌伴发结肠息肉的比例较高,且多数为腺瘤性息肉,重视结直肠癌伴发息肉的处理是降低结直肠癌复发的重要措施。     

A phase II trial of pemetrexed in patients with metastatic renal cancer

Background. Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTA®) for the treatment of metastatic RCC. Patients and methods. Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0–2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600mg/m² as a 10min infusion every 3 weeks. Patients did not receive folic acid or vitamin B₁₂ supplementation. Results. Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2–25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5–27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. Conclusion. Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.     

伊立替康联合5-Fu/亚叶酸钙治疗FOLFOX化疗失败的晚期结直肠癌的疗效

目的评价我国晚期结直肠癌伊立替康联合5-Fu/亚叶酸钙(FOLFIRI方案)治疗FOLFOX化疗失败的临床疗效和毒副反应。方法 FOLFIRI方案二线治疗62例晚期结直肠癌。方法 :伊立替康180 mg/m2,第一天静脉滴注90 min;亚叶酸钙400 mg/m2,第一天滴注2 h;5-Fu 2.6g/m2,亚叶酸钙滴注结束后,立即持续泵入46 h。14 d为一周期,每3周期按RESIST标准评价疗效,所有患者至少接受3周期化疗,最多达12周期。结果 62例患者一共接受346个周期的化疗,所有患者均可评价疗效。部分缓解8例(12.9%),稳定32例(51.6%),总有效率为12.9%。无完全缓解病例。进展22例(35.5%),中位进展时间4.5个月。二线化疗后中位生存时间9.2个月。最常见的不良反应为非血液学毒性,Ⅲ级呕吐反应为6例(9.7%),Ⅲ~Ⅳ级迟发性腹泻为8例(12.9%),3例(4.8%)出现Ⅲ级乙酰胆碱能综合征,13例(20.9%)发生Ⅲ~Ⅳ级粒细胞减少,2例(3.2%)伴发热;无化疗相关性死亡病例。结论 FOLFIRI方案二线治疗FOLFOX化疗失败的晚期结直肠癌疗效确切,不良反应轻。     

Phase II trial and pharmacokinetic study of thalidomide in patients with metastatic colorectal cancer

Introduction. This study was designed to estimate the percentage of objective tumor responses, toxicity profile, and obtain additional information about the plasma pharmacokinetics of thalidomide in patients with refractory and progressing metastatic colorectal cancer. Study design. This phase II clinical trial was conducted according to the two-stage Simon method with the inclusion of consecutive patients. The study protocol was approved by the Institutional Review Board (IRB) of the Academic Hospital (HCPA) of the Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Patients and methods. Seventeen patients with previously treated, refractory progressive metastatic colorectal cancer were eligible. Six patients had prior radiotherapy. The patients had a median of one previous chemotherapy regimen. Patients were initially treated with 200mg/day of thalidomide with an increase in dose by 200mg/day every 2 weeks until a final daily dose of 800mg/day was achieved. Patients were evaluated every 8 weeks for response by radiographic criteria. Plasma pharmacokinetics studies were performed in four patients at 200mg level and in one patient at 600mg during the first 24h. Main outcome measures and results. A total of 17 patients were accrued, all of them being evaluable for toxicity and 14 for response. Thalidomide was well tolerated, with constipation, somnolence, dizziness, and dry mouth being the major toxicities. There were no objective response or stable disease. The median survival was 3.6 months. Single-agent thalidomide is a generally well-tolerated drug that showed no antitumor activity in patients with advanced pretreated metastatic colorectal cancer. Although thalidomide did not show antitumor activity in this patient population, future studies of this agent in patients at initial stages of the disease (when its antiangiogenic properties may be more relevant to disease progression) could be considered.     

腹腔镜辅助结直肠癌根治术治疗老年结直肠癌的效果分析

目的：分析腹腔镜辅助结直肠癌根治术治疗老年结直肠癌的临床效果。方法选择本院2012年3月~2014年3月收治的62例结直肠癌老年患者为研究对象,按照住院顺序随机分为对照组和观察组各31例,对照组患者行传统开腹直肠癌根治术,观察组患者采取腹腔镜辅助结直肠癌根治术,对两组手术情况、术中心肺功能及并发症情况进行比较。结果观察组手术时间、术中出血量、平均切口长度、术后排气时间及住院时间与对照组比较,差异有统计学意义(P<0.05);观察组患者术中射血分数(EF)、心脏指数(CI)、动脉血二氧化氮分压(PaCO2)、动脉血pH值及气道压力均明显高于对照组,差异有统计学意义(P<0.05);观察组并发症发生率为19.35%,对照组并发症发生率为45.16%,两组比较差异有统计学意义(P<0.05)。结论相比传统开腹手术,腹腔镜辅助结直肠癌根治术具有术中出血量少、术中心肺功能稳定、术后并发症少、恢复快等特点,值得在老年结直肠癌患者中进一步应用。     

81例老年肠癌患者的手术治疗分析与观察

目的 为进一步对做好老年肠癌患者的手术治疗工作提供科学依据.方法 针对性治疗与观察81例老年肠癌手术患者,采用回顾性方法研究分析临床资料.结果 本组81例患者均于入院确诊后12～72 h内手术,均获得根治切除术的手术治疗,手术时间平均(176.3±35.4)min,术中出血平均(142.6±13.1) ml,术后住院天数平均(10.1±3.4)d,术后出现切口感染2例,对出院患者进行随访6～12个月,有严重并发症出现的27例,本组总共出现死亡病例10例,死亡率为10.29%.结论 老年肠癌患者手术治疗是具有一定困难和风险的,只有熟练掌握老年肠癌手术治疗方法和相关技能,才能取得较好的手术效果.     

A phase II study of rebeccamycin analog NSC 655649 in patients with metastatic colorectal cancer

The analog, rebeccamycin tartrate salt (NSC 655649, Cancer Therapy Evaluation Program, National Cancer Institute) has broad preclinical anti-neoplastic activity. Preliminary data from phase I study demonstrated anti-tumor activity in colorectal carcinoma. This phase II trial evaluates its efficacy in patients with minimally treated metastatic colorectal cancer. Eligibility included Karnofsky performance status 70%, age 18 years and bidimensionally measurable disease. Thirteen patients were treated with NSC 655649 at 500mg/m² by central venous catheter once every 3 weeks by bolus injection. Thirty-four cycles (median [range] 2 [1–6]) of therapy were administered. Twelve patients are eligible for response assessment. No major objective responses were seen using the RECIST criteria; however stable disease was observed in three patients with mean duration of 15 weeks. The median time to progression was 8 weeks. There was no toxic death. Four patients received only one cycle of treatment, and three had disease progression. Toxicities were tolerable and hematologic toxicity was the most common. The median (range) granulocyte and platelet nadir counts were 2043/l (116–16,374/l) and 276×10³/l (5–769), respectively. Non-hematologic toxicities were moderate, including generalized weakness/fatigue, nausea/vomiting, diarrhea and anorexia. One patient required dose reduction; three patients required dose delays. NSC 655649 at this dose and schedule is inactive against advanced previously minimally treated metastatic colorectal cancer and further study of this drug as a single agent in this disease using an every three-week schedule is not warranted.     

A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil,and leucovorin for metastatic colorectal cancer

Summary  Tetrathiomolybdate (TM) is an oral copper chelator under development as an anti-angiogenic agent. We evaluated TM in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL). Serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 6 (IL-6), and IL-8 were measured to evaluate the anti-angiogenic effect. Twenty-four patients with metastatic colorectal cancer were treated. The combination with IFL was well tolerated and dose intensity of IFL was maintained during combination therapy with TM. By intention to treat analysis, the overall response rate (RR) was 25% (95% CI 9.8–46.7) and the median time to progression (TTP) was 5.6 months (95% CI 2.7–7.7). VEGF levels were correlated with TTP, as were changes in VEGF, IL-8, and IL-6. TM can be safely added to IFL without compromising dose intensity or diminishing the expected RR. Changes in serum VEGF, IL-8, and IL-6 after treatment may directly reflect changes in CRC tissue angiogenesis.