奥沙利铂周围神经毒性模型大鼠行为学检测方法比较研究

摘要：目的：进行两种大鼠机械性痛觉敏感性测量方法、两种冷刺激缩足反应测量方法的比较研究。方法：雌性wistar大鼠，腹腔注射奥沙利铂4mg/kg，建立标准奥沙利铂周围神经毒性大鼠模型。检测机械和冷热温度刺激下大鼠行为学变化，并对不同行为学检测方法的特点进行比较分析。结果：模型组大鼠较正常组相比50%缩足阈明显降低（P<0.05）、出现痛觉过敏及痛觉超敏（P<0.05）、冷刺激诱发的缩足次数增多（P<0.05），二组大鼠对热痛刺激反应均无明显差异，与临床患者症状表现基本一致。结论：Von Frey纤维丝刺激检测中4g和15g方法可更好的模拟临床患者的痛觉过敏、超敏反应；up-down法客观量化的反应出大鼠缩足阈值下降的程度。冷温度刺激中，丙酮喷洒法可较直观的观察大鼠受到冷刺激后的反应。     

希罗达联合奥沙利铂治疗晚期贲门癌的临床研究

目的探讨希罗达联合奥沙利铂治疗晚期贲门癌的近期疗效及毒副反应。方法 45例患者均采用联合化疗方案,希罗达1000mg/(m2·d),分早晚2次,连服2周。奥沙利铂130mg/m2第1天静脉滴注,21d为1个周期,每个患者至少2周期的化疗。结果完全缓解(CR)2例,部分缓解(PR)24例,稳定(SD)12例,进展(PD)9例。有效率(CR+PR)57.8%。本组主要毒副反应为消化道反应,恶心、呕吐及腹泻;血液学毒性表现为白细胞减少、血小板减少及贫血;手足综合征也常见,另外还有感觉异常、疲劳等。结论希罗达联合奥沙利铂治疗晚期贲门癌疗效确切,毒副反应可以耐受。     

异甘草酸镁对奥沙利铂在人胃癌裸鼠模型中抗肿瘤作用的影响研究

目的:探讨异甘草酸镁对奥沙利铂在人胃癌裸鼠模型中抗肿瘤作用的影响。方法:建立人胃癌SGC-7901细胞裸鼠皮下移植瘤模型,并随机分为高、中、低剂量异甘草酸镁(Mg IG)联合奥沙利铂(L-OHP)组,单纯L-OHP组,单纯Mg IG组和葡萄糖对照组6组,连续尾静脉注射给药14 d,停药24 h后处死裸鼠,称取移植瘤质量,测量移植瘤体积,分别计算质量抑瘤率、体积抑瘤率,用TENEL法检测移植瘤组织的细胞凋亡率,并检测裸鼠肝功等指标。结果:高、中、低剂量Mg IG联合L-OHP组以及单纯L-OHP组的体积抑瘤率和质量抑瘤率均高于葡萄糖对照组,差异有统计学意义(P<0.05);各剂量Mg IG联合L-OHP组的抑瘤率高于单纯L-OHP组,且呈剂量依赖性,差异有统计学意义(P<0.05);与单纯L-OHP组相比,不同剂量Mg IG联合L-OHP组ALT和AST水平均较低,差异有统计学意义(P<0.01)。结论:异甘草酸镁对奥沙利铂的抗肿瘤作用具有协同作用,并能够潜在改善药物性肝损伤。     

雷替曲塞单药与联合奥沙利铂或伊立替康二线治疗晚期结直肠癌的临床对比观察

目的：探讨雷替曲塞单药与联合奥沙利铂或伊立替康方案二线治疗晚期结直肠癌的疗效和安全性。方法收集70例有明确病理诊断的晚期结直肠癌患者的临床资料,按化疗方案分为3组：A组（25例）：雷替曲塞2～3 mg／m2,静脉滴注,d1;B 组（22例）：奥沙利铂100～130 mg／m2,静脉滴注, d1,雷替曲塞剂量及用法同 A 组;C 组（23例）：伊立替康160～180 mg／m2,静脉滴注,d1,雷替曲塞剂量及用法同 A 组,均每3周重复,每2个周期评价疗效,最多治疗6个周期。结果70例患者均可评价疗效,A、B、C组有效率分别是4．0％（1／25）、31．8％（7／22）和21．7％（5／23）,3组疗效比较差异有统计学意义（P＜0．05）,其中A组有效率低于B、C组（P＜0．05）,B组与C组有效率比较差异无统计学意义（P＞0．05）;疾病控制率分别是52．0％（13／25）、77．2％（17／22）、73．9％（17／23）;中位无进展生存期分别是3．8个月、6．5个月、5个月;中位总生存期分别是9个月、13个月、11个月,3组比较差异均无统计学意义（P＞0．05）。最常见的毒性反应是粒细胞减少、转氨酶异常、消化道反应,以Ⅰ～Ⅱ级为主,粒细胞减少Ⅰ～Ⅱ级发生率分别为4．0％（1／25）、31．8％（7／22）、26．1％（6／23）,B、C组明显高于A组（P＜0．05）。转氨酶异常Ⅰ～Ⅱ级发生率分别为20．0％（5／25）、31．8％（7／22）、26．1％（6／23）,差异无统计学意义（P＞0．05）。腹泻Ⅰ～Ⅱ级发生率A组4．0％（1／25）、B组4．5％（1／22）低于C组34．8％（8／23）（P＜0．05）。结论雷替曲塞单药方案在晚期结直肠癌二线化疗中安全有效。雷替曲塞联合奥沙利铂或伊立替康方案疗效优于单药方案,毒性可耐受,值得临床推广应用。     

恒温在预防奥沙利铂引起的末梢神经毒性中的作用

目的 探讨恒温对预防奥沙利铂(L-OHP)化疗所致末梢神经毒性的临床效果研究。 方法 将60例使用L-OHP的患者,随机分为观察组与对照组各30例,对照组采用常规干预,观察组在常规干预基础上使用暖手宝进行恒温干预,观察4个化疗周期的末梢神经毒性程度。 结果 4个化疗周期间,观察组神经毒性症状程度均轻于对照组(Z=-2.924,P=0.003;Z=-2.360,P=0.018;Z=-3.008,P=0.003;Z=-2.133,P=0.033)。 结论 使用暖手宝可预防和减轻L-OHP化疗所致的周围神经毒性。     

Chemotherapy Alone for Patients With Stage II/III Rectal Cancer Undergoing Radical Surgery

Purpose.

The purpose of this prospective pilot study was to determine the efficacy of preoperative chemotherapy with six cycles of FOLFOX 6 (without radiation therapy) followed by radical surgery followed by six additional cycles of FOLFOX 6 for patients with stage II/III rectal cancer.

Patients and Methods.

From January 2010 to January 2014, patients with locally advanced rectal cancer who met the eligibility criteria were enrolled in this study. Patients received FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium i.v. over 2 hours on day 1, then bolus, and then continuous fluorouracil i.v. over 46 hours on days 1 and 2. Treatment was repeated every 14 days for 6 courses followed by radical surgery followed by additional 6 cycles of FOLFOX 6.

Results.

In total, 45 patients were enrolled in this study. In the preoperative re-evaluation, the overall response rate was 68.8% (clinical complete response was 4.4%, and the partial response was 64.4%). There were 14 cases (31.2%) of stable disease. No patients had progressive disease. Postoperatively, the pathologic complete response rate was 8 of 45 (17.8%; 95% confidence interval [CI]: 8.9%–28.9%). The median follow-up was 29 months (range 9–54 months). The actuarial 3-year overall survival and disease-free survival rates for all patients were 80.8% (standard error, 1.877; 95% CI: 69.3%–92.3%) and 67.9% (standard error, 2.319; 95% CI: 54.3%–81.5%), respectively.

Conclusion.

Neoadjuvant chemotherapy (FOLFOX) without radiotherapy is active and safe but cannot be considered a standard of care until the results of prospective randomized phase III trials are available.

Implications for Practice:

Neoadjuvant radiotherapy of rectal cancer represents the current standard of care. However, its use is also associated with short-term toxicity and long-term morbidity. With the increasing use of total mesorectal resection resulting in better local control and advances in systemic therapy for colorectal cancer, this study highlights the question of whether radiation is a necessary component of neoadjuvant therapy for all patients with rectal cancer or whether select patients could be spared the additional toxicities and inconvenience of radiotherapy. This study suggests that neoadjuvant FOLFOX without radiotherapy is active and safe, but it could not be considered a standard of care till now.     

培美曲塞联合铂类治疗难治性晚期乳腺癌疗效与安全性分析

目的:通过观察分析培美曲塞联合铂类药物治疗晚期乳腺癌的疗效及毒副反应,探寻难治性复发转移性乳腺癌的有效治疗方法。方法:选择60例晚期乳腺癌患者,根据体质不同予以培美曲塞联合顺铂或奥沙利铂方案化疗:培美曲塞500mg/m2,第1天;顺铂75mg/m2或奥沙利铂85mg/m2,第1天;每3周一疗程,每2个疗程进行1次疗效和安全性评价。结果:60例患者均可评价疗效,中位随访14个月,PR 22例,SD 20例,RR 36.7%,中位PFS 4.5个月(95%CI:3-11个月),中位OS 8.2个月(95%CI:7.5-12个月)。主要毒副反应为疲乏,其次为白细胞减少、胃肠道反应、末梢神经炎,但均较轻微。结论:培美曲塞联合铂类方案治疗复发转移性乳腺癌疗效值得肯定,毒副反应轻微,且无论联合顺铂或奥沙利铂生存率无明显差别,患者能够耐受。     

Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial

BackgroundThe oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC.MethodsIn this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4–10 and 18–24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety.ResultsMedian overall treatment duration with any study drug was 9.9 months (range 0.6–19.6); median treatment duration with regorafenib was 7.7 months (range 0.1–19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5 months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications.ConclusionRegorafenib + mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone.ClinicalTrials.gov identifier: NCT01289821.     

A Case of Liver Fibrosis with Splenomegaly after Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer

Previous studies reported that oxaliplatin is associated with sinusoidal obstruction syndrome. However few reports on oxaliplatin induced liver fibrosis are found in the literature. Furthermore pathogenesis of liver fibrosis is not well known. We report a case of 45-yr-old Korean man in whom liver fibrosis with splenomegaly developed after 12 cycles of oxaliplatin based adjuvant chemotherapy for colon cancer (T4N2M0). Thorough history taking and serological examination revealed no evidence of chronic liver disease. Restaging CT scans demonstrated a good response to chemotherapy. Five month after chemotherapy, he underwent right hepatectomy due to isolated metastatic lesion. The liver parenchyma showed diffuse sinusoidal dilatation and centrilobular vein fibrosis with necrosis without steatosis. We could conclude that splenomegaly was due to perisinusoidal liver fibrosis and liver cell necrosis induced portal hypertension by oxaliplatin. In addition, to investigate the pathogenesis of liver fibrosis, immunohistochemical stains such as CD31 and α-smooth muscle actin (α-SMA) were conducted with control group. The immunohistochemical stains for CD31 and α-SMA were positive along the sinusoidal space in the patient, while negative in the control group. Chemotherapy with oxaliplatin induces liver fibrosis which should be kept in mind as a serious complication.