甲氨蝶呤、顺铂、阿霉素和异环磷酰胺治疗ⅡB期肢体骨肉瘤的临床观察

目的 观察大剂量甲氨蝶呤（MTX）、顺铂（DDP）、阿霉素（ADM）和异环磷酰胺（IFO）4种药物两种不同组合方案治疗ⅡB期肢体骨肉瘤的疗效及毒副反应。方法 回顾性分析接受4种药物化疗方案的185例ⅡB期肢体骨肉瘤患者,其中93例接受意大利IOR-OS／N-5方案（MTX 8～12g／m²静滴6h,d₁;用药后12h亚叶酸钙解救12次,每次15mg;DDP 80～100mg／m²、ADM 60mg／m²静滴,d8;IFO 2.0g／m²静滴,d₂₁～d₂₅;美司那400mg每天IFO用后第0、4、8h静滴）,92例接受优化方案（除ADM由第8天静滴改为第21天与IFO联用外,其他同IOR-OS／N-5方案）。比较两种方案的疗效及毒副反应。结果 IOR-OS／N-5方案和优化方案组的保肢率分别为52.7％（49／93）和58.7％（54／92）。两组患者的3年复发率分别为14.0％、7.6％,3年转移率分别为47.3％、30.4％,差异均有统计学意义（P＜0.05）;两组患者的3年生存率分别为57.0％、75.0％,差异有统计学意义（P＜0.05）。两组患者的中位无病生存时间（DFS）分别为22.2个月（95％CI：16.2～28.2个月）和29.0个月（95％CI：23.8～34.3个月）,差异有统计学意义（P=0.024）;两组患者的中位总生存时间（OS）分别为32.2个月（95％CI：23.2～38.2个月）和36.1个月（95％CI：33.8～44.3个月）,差异有统计学意义（P=0.032）。两组患者的主要毒副反应为肝功能损害、骨髓抑制、恶心呕吐等。其中3、4级肝功能损害的发生率分别为35.2％、16.6％,3、4级白细胞减少的发生率分别为22.6％、30.2％。结论 将大剂量MTX、DDP、ADM和IFO这4种药物进行优化组合治疗骨肉瘤患者的耐受性好,疗效提高。     

TAC与TP方案治疗三阴性乳腺癌的临床观察

目的 比较新辅助化疗TAC与TP方案治疗三阴性乳腺癌（TNBC）的疗效和安全性。方法 102例三阴性乳腺癌患者均经病理组织学确诊,分为TAC组（52例）和TP组（50例）。TAC组：多西他赛75mg／m²或紫杉醇（紫杉醇脂质体）135mg／m² iv,d₁;吡柔比星40mg／m²或表柔比星75mg／m² iv,d₂;环磷酰胺600mg／m² iv,d₁。TP组：多西他赛75mg／m²或紫杉醇（紫杉醇脂质体）135mg／m² iv,d₁;顺铂30mg／m² iv,d₂～d₄。21天为1周期,化疗2～4个周期后行手术治疗。评价两组近期疗效和毒副反应。结果 TAC组获pCR 5例（9.6％）,PR 35例（67.3％）,SD 9例（17.3％）,RR为76.9％;TP组获pCR 4例（8.0％）,PR 32例（640％）,SD 5例（100％）,RR为72.0％,两组pCR率和RR差异均无统计学意义（P＞0.05）。102例患者中12例经2个周期化疗后肿瘤进展,其中TAC组3例,TP组9例。TAC组有2例发生房性前期收缩,TP组3例发生2级肾功能损伤。TAC组3～4级血液学毒性和脱发的发生率明显高于TP组,但TP组的3～4级胃肠道反应发生率高于TAC组。结论 TAC方案与TP方案在三阴性乳腺癌新辅助化疗中均具有一定疗效,不良反应尚可耐受。     

含多西他赛方案作为骨肉瘤二线化疗的疗效观察

目的 探讨含多西他赛方案二线治疗一线化疗失败的骨肉瘤肺转移患者的有效性和安全性。方法 收集2012年1月至2013年12月间我科收治的11例一线化疗失败的骨肉瘤肺转移患者,给予多西他赛（75 mg/m²,d₈）联合吉西他滨（675 mg/m²,d₁、d₈）／洛铂（30 mg/m²,d₂）方案二线化疗,21天为1周期,共化疗6个周期。采用RECIST标准10版评价疗效,NCI-CTC标准3.0版观察不良反应。结果 11例患者均完成化疗,可评价疗效。无完全缓解（CR）病例,部分缓解（PR）1例,疾病稳定（SD）4例,疾病进展（PD）6例;有效率（RR）为9.1％,疾病控制率（DCR）为45.5％。随访6～23个月, 3例死亡。中位无进展生存时间为10.5个月,中位生存时间为18.0个月,1年生存率为83.3％。主要不良反应为限制性骨髓抑制,化疗期间患者无明显肾功能异常及过敏反应,仅出现4级中性粒细胞及血小板减少1例。结论 含多西他赛方案二线治疗骨肉瘤肺转移,近期疗效满意,毒副反应可以耐受。     

洛铂或顺铂联合依托泊苷治疗广泛期小细胞肺癌的临床观察

目的 探讨依托泊苷联合洛铂化疗方案治疗小细胞肺癌（SCLC）的近期疗效、远期生存及毒副反应。方法 回顾性分析未经抗肿瘤治疗的广泛期SCLC患者85例,根据治疗方案分为两组,即依托泊苷+洛铂（EL）组42例和依托泊苷+顺铂（EP）组43例。EL组给予依托泊苷80 mg／m²,d₁～d₅,洛铂30 mg／m²,d₁;EP组给予依托泊苷80 mg／m²,d₁～d₅,顺铂25 mg／m²,d₁～d₃,21天为1周期。至少完成2个周期化疗以后评估疗效和毒副反应。 结果 EL组和EP组的有效率（RR）分别为59.5％和53.5％（P＞0.05）,疾病控制率（DCR）分别为80.9％和76.7％（P＞0.05）,但EL组的中位无进展生存时间（PFS）为6.5个月,高于EP组的4.5个月（P＜0.05）。EL组血小板减少的发生率高于EP组,恶心呕吐及肝肾功能损害的发生率均低于EP组（P＜0.05）。结论 同EP方案相比,EL方案可延长中位PFS,且消化道不良反应较轻,基本无肝肾毒性。     

奈达铂联合氟尿嘧啶诱导化疗加同步放化疗在局部晚期鼻咽癌的临床应用

目的 观察奈达铂联合氟尿嘧啶诱导化疗加同步放化疗治疗局部晚期鼻咽癌的疗效及安全性。方法70例局部晚期鼻咽癌患者随机分为试验组（35例）和对照组（35例）。试验组接受诱导化疗2个周期,化疗方案为奈达铂80mg／m²静滴,d1;氟尿嘧啶500 mg／m²静滴,d1～d5。21天为1周期。诱导化疗结束14天后进行同步放化疗,同步化疗采用奈达铂80mg／m²静滴,d1、d22、d43;放疗采用常规放疗,鼻咽部原发灶剂量为68～74 Gy,每次均为2 Gy,每周5次。对照组接受顺铂同步放化疗,同步化疗采用顺铂100 mg／m²静滴,d1、d22、d43;放疗方法同试验组。同步放化疗结束21天后进行辅助化疗2个周期,化疗方案为：顺铂80mg／m²静滴,d1;氟尿嘧啶500 mg／m2静滴,d1～d5。21天为1周期。结果 试验组35例患者中,1例因经济原因退出了研究,34例可评价疗效,对照组35例患者均可评价疗效。治疗结束3个月后试验组CR 30例,PR 4例,有效率达100.0％（完全缓解率为88.2％）;对照组CR 31例,PR 4例,有效率达100.0％（完全缓解率为88.6％）,两组比较差异无统计学意义（P＞0.05）。试验组、对照组2年生存率分别为94.1％和91.4％,两者比较差异无统计学意义（P＞0.05）。在诱导化疗期间,试验组的血液学不良反应主要为白细胞减少,发生率为70.6％,与对照组辅助化疗期间白细胞减少相比无明显差异。对照组在辅助化疗期间,恶心、呕吐的发生率要明显高于试验组在诱导化疗期间的发生率（P＜0.01）。在同步放化疗期间,试验组、对照组血小板减少的发生率分别为52.9％、14.3％,差异有统计学意义（P＜0.01）;对照组恶心、呕吐的发生率则高于试验组（P＜0.01）;两组患者口腔黏膜炎、放射性皮炎的发生率均达1000％。两组患者均无治疗相关性死亡。结论 奈达铂联合氟尿嘧啶诱导化疗加同步放化疗治疗局部晚期鼻咽癌的近期疗效较好,不良反应可以耐受,远期疗效有待进一步观察。     

紫杉醇、顺铂及卡培他滨联合放疗治疗晚期鼻咽癌的疗效观察

目的 探讨紫杉醇、顺铂及卡培他滨方案 （TPX）联合放疗治疗晚期鼻咽癌的疗效及安全性。方法 2002年2月至2007年9月收治57例Ⅲ、ⅣA期鼻咽癌患者,先予直线加速器常规放疗,鼻咽原发灶2Gy／f,每周5次,DT 70Gy,7周完成。放疗后2周,29例给予TPX方案化疗（紫杉醇175mg／m²静滴,d₁;顺铂 25mg／m²静滴,d₁～d₃;卡培他滨1.5g／m²口服,d₁～d₁₄,3周为1周期）;另28例给予TP方案化疗（紫杉醇175mg／m² 静滴,d₁;顺铂25mg／m²静滴,d₁～d₃,3周为1周期）。两组均化疗4周期。化疗完成后对两组的近期疗效和总生存期进行比较。结果 TPX组和TP组的总有效率（RR）分别为96.5％和92.9％（P＞0.05）;3年生存率分别为82.8％和57.1％（P＜0.05）;3年远处转移率分别为 24.1％和50.0％ （P＜0.05）;PTX组骨髓抑制、胃肠道反应、神经毒性及肝肾功损害等毒副反应与TP组相近（P＞0.05）,手足综合征高于TP组（P＜0.05）。结论 TPX方案较TP方案联合放疗能提高晚期鼻咽癌的生存率,减少远处转移,且化疗毒副反应可以耐受。     

雷替曲塞联合伊立替康2周方案对比FOLFIRI方案二线治疗晚期结直肠癌的疗效观察

目的 观察雷替曲塞联合伊立替康2周方案治疗转移性结直肠癌的有效性和安全性。方法 经病理组织学或细胞学确诊的50例晚期转移性结直肠癌患者分为试验组（n=25）和对照组（n=25）。试验组方案： 雷替曲塞 2.5mg／m² 静滴,d₁;伊立替康（CPT-11） 180mg／m² 静滴,d₁。对照组方案：CPT-11 180mg／m² 静滴90min,d₁;亚叶酸钙 400mg／m² 静滴,d₁;5-FU 400mg／m² 静滴,d₁;5-FU 2400mg／m² 持续静滴46～48 h,d₁、d₂。两方案均2周为1周期,每周期评价毒副反应,每3个周期评价疗效,直至疾病进展或毒性不能耐受,最多治疗12个周期。结果 试验组获CR 1例,PR 4例,SD 18例,PD 2例;对照组获PR 2例,SD 19例,PD 4例。两组有效率（RR）分别为20％和8％,疾病控制率（DCR）分别为92％和84％,差异均无统计学意义（P＞0.05）。试验组1、2级转氨酶升高的发生率为24％,高于对照组的4％（P＜0.05）;对照组1、2级中性粒细胞减少、口腔黏膜炎的发生率均高于试验组（48％ vs. 20％,32％ vs. 8％,P＜0.05）。结论 雷替曲塞联合伊立替康2周方案与FOLFIRI方案的近期疗效相当,但毒副反应更轻,可以作为转移性结直肠癌的有效姑息治疗方案。     

洛铂联合足叶乙甙或伊立替康治疗广泛期小细胞肺癌的临床观察

目的 观察洛铂联合足叶乙甙或伊立替康治疗广泛期小细胞肺癌（SCLC）的疗效和安全性。方法 收集经病理组织学确诊的初治或复治广泛期SCLC患者45例,其中接受LE方案（洛铂30mg／m²静滴,d₁;足叶乙甙 100mg／m²静滴,d₁～d₃,21天为1周期）25例,LI方案（洛铂30mg／m²静滴,d₁;伊立替康60mg／m²静滴,d₁、d₈、d₁₅,28天为1周期）20例。至少化疗2个周期后评价客观疗效和毒副反应。结果 45例患者均可评价疗效,获CR 2例,PR 24例,SD 15例,PD 4例,有效率（RR） 为57.8％。LE组的RR为48.0％（12／25）,LI组的RR为70.0％（14／20）,两组差异无统计学意义（P＞0.05）。LE组和LI组的中位总生存期分别为8.0个月和7.0个月。全组毒副反应主要为血液学毒性和胃肠道反应,其中3～4级血小板减少发生率为17.8％（8／45）,LI组较LE组高（30.0％ vs. 8.0％,P=0.002）。全组3～4级腹泻发生率为8.9％（4／45）,均发生于LI组且为复治患者。无治疗相关性死亡。结论 洛铂联合足叶乙甙或伊立替康治疗晚期SCLC疗效较好,毒副反应均可耐受,值得临床进一步研究。     

恶性肿瘤患者体表面积计算方法的比较

目的 探讨不同体重指数（BMI）的恶性肿瘤患者体表面积的计算方法。方法 对227例恶性肿瘤患者在住院当天、第2天和化疗前各测量1次空腹时的身高和实际体重,计算其平均值。按照不同BMI值（≤18.6kg／m²、18.6～23.9kg／m²、24～27.9kg／m²和≥28kg／m²）将患者分为消瘦组（17例）、正常体重组（107例）、超重组（82例）和肥胖组（21例）;计算各组患者的实际和理想体表面积,比较两者间差异。结果 正常体重组患者的实际和理想体表面积分别为1.590m²和1.584m²,差异无统计学意义（P＞0.05）;消瘦组患者的实际和理想体表面积分别为1.523m²和1.641m²（P＜0.05）;超重组患者的实际和理想体表面积分别为1.724m²和1.590m²（P＜0.05）;肥胖组患者的实际和理想体表面积分别为1.813m²和1.570m²（P＜0.05）。结论 不同BMI值患者的实际和理想体表面积有一定的差异,对于超重和肥胖的恶性肿瘤患者实施化疗建议根据理想体表面积计算化疗药物剂量,避免不必要的治疗风险。     

FOLFOX 4方案治疗中晚期原发性肝癌的临床研究

目的 观察评价FOLFOX 4方案系统化疗治疗国人中晚期原发性肝癌（PLC）的疗效和安全性。方法 2004年7月至2012年7月,共77例中晚期PLC患者接受FOLFOX 4方案的系统化疗,具体为：奥沙利铂（OXA） 85mg／m² 静滴,d₁;亚叶酸钙（LV） 200mg／m² 静滴2h,d₁、d₂; 氟尿嘧啶（5-FU） 400mg／m² 静推,继以600mg／m²持续静滴22h,d₁、d₂,每2周为1周期。按照RECIST 1.0 版标准每3个周期评价客观疗效,观察疾病进展时间（TTP） 和总生存期（OS）,并动态监测血清甲胎蛋白（AFP）的变化。毒副反应按照NCI-CTC 3.0标准观察和判定;神经系统毒性参照OXA专用神经病变分级标准评判。结果 全组患者中72例可评价疗效,获PR 3例, SD 37例,PD 32例,客观缓解率（RR）为4.2％,疾病控制率（DCR） 为55.6％,中位TTP为2.7个月,中位OS为6.1个月。AFP反应率为11.1％。分层分析显示,曾接受过系统治疗患者的化疗疗效并不劣于初治患者,但是有门脉侵犯或肝外转移患者的疗效和预后更差。常见的毒副反应为白细胞减少和轻度的周围神经毒性。结论 采用奥沙利铂为主的FOLFOX 4方案进行系统化疗,对于国人中晚期PLC患者具有良好的病情控制和生存获益,不良反应较轻,患者易于耐受,值得在临床上广泛应用。     

Phase I trial of gemcitabine and carboplatin in metastatic non-small-cell lung cancer: a Groupe Français de Pneumo-Cancérologie Study

BACKGROUND: The purpose of this study was to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the 21 days carboplatin plus gemcitabine regimen in previously untreated patients with stage IV non small-cell lung cancer (NSCLC). METHODS: At least three patients were entered at each dose level. The starting dose was carboplatin AUC 4 mg/ml per min (Area Under the Curve; Calvert formula) on day 1 and gemcitabine 750 mg/m(2) on days 1 and 8. Carboplatin was increased to AUC 5 (level 3, 4) then to AUC 6 (level 5-7). Gemcitabine was increased to 875 (level 2, 3), 1000 (level 4, 5), 1250 (level 6) and finally 1500 mg/m(2) (level 7). Twenty-nine patients were entered into this phase I study. RESULTS: At dose level 6, a DLT (grade 4 thrombocytopenia) was observed in one out of six patients. At dose level 7, no DLT was observed during the first course, so the MTD was not reached. During the second course, two out of four patients presented grade 4 thrombocytopenia. None of the five patients receiving two courses at level 6 presented a DLT, so this level was retained for further phase II studies. Of the 25 patients assessable for response, five achieved partial responses with a response rate of 20% (95% CI, 7 to 41%). The median survival time was 7 months and the 1-year survival rate was 24% (95% CI, 9 to 45%). CONCLUSION: The combination of carboplatin given on day 1 and gemcitabine given on days 1 and 8 every 3 weeks seems to be an acceptable regimen. The DLT consists exclusively of severe thrombocytopenia. Despite the MTD was not reached with carboplatin AUC 6 mg/ml per min and gemcitabine 1500 mg/m(2), the recommended dose for further phase II studies is carboplatin AUC 6 mg/ml per min and gemcitabine 1250 mg/m(2).     

Phase I trial of neoadjuvant preoperative chemotherapy with S-1 and irinotecan plus radiation in patients with locally advanced rectal cancer

PURPOSE: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with preoperative chemoradiotherapy with S-1 in patients with locally advanced rectal cancer. PATIENTS AND METHODS: We gave preoperative radiotherapy (total dose, 45 Gy) to 23 patients with locally advanced (T3/T4) rectal cancer. Concurrently, S-1 was given orally at a fixed dose of 80 mg/m2/day on Days 1-5, 8-12, 22-26, and 29-33, and irinotecan was given as a 90-min continuous i.v. infusion on Days 1, 8, 22, and 29. The dose of irinotecan was initially 40 mg/m2/day and gradually increased to determine the MTD and RD of this regimen. RESULTS: Among the 4 patients who received 90 mg/m2 irinotecan, 2 had Grade 4 neutropenia and 1 had Grade 3 diarrhea. Because dose-limiting toxicity (DLT) occurred in 3 of the 4 patients, 90 mg/m2 irinotecan was designated as the MTD. Consequently, 80 mg/m2 irinotecan was given to 7 additional patients, with no DLT, and this was considered the RD. Of the patients who received irinotecan at the RD or lower doses, 6 (31.6%) had a complete pathologic response (Grade 3) and 9 (47.4%) underwent sphincter-preserving surgery. CONCLUSIONS: With our new regimen, the MTD of irinotecan was 90 mg/m2, and the RD of irinotecan for Phase II studies was 80 mg/m2. Although our results are preliminary, this new neoadjuvant chemoradiotherapy was considered safe and active, meriting further investigation in Phase II studies.     

食管癌同期放化疗中奈达铂剂量递增临床Ⅰ期试验

[目的]探讨在食管癌同期放化疗中多西紫杉醇固定周剂量时奈达铂（NDP）的周最大耐受剂量（MTD）,并观察其不良反应。[方法]共入选20例初治食管鳞癌患者,采用三维适形放疗方法,DT：60～64Gy/30～32f,42～44d,同步化疗方案固定多西紫杉醇剂量20mg/w,共6w,NDP采用周剂量递增方法,起始剂量12mg/m2,递增剂量为6 mg/m2。剂量限制性毒性（DLT）定义为≥3级不良反应,出现DLT的前一剂量即为MTD。[结果]NDP 24mg/m2剂量水平时共有2例患者发生3～4级的DLT;NDP 18mg/m2、多西紫杉醇20mg即为MTD。主要不良反应为放射性食管炎、放射性肺炎、乏力和骨髓抑制。[结论]食管癌同步放化疗中固定多西紫杉醇20mg每周剂量时奈达铂每周最大耐受剂量为 18mg/m2。     

Phase I study of irinotecan and raltitrexed in patients with advanced gastrointestinal tract adenocarcinoma

To determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of irinotecan and raltitrexed given as sequential short infusions every 3 weeks, 33 patients with pretreated gastrointestinal adenocarcinoma (31 colorectal, 2 oesophagogastric) entered this open label dose-escalation study. For the first five dose levels patients received irinotecan 175-350 mg m(-2) followed by raltitrexed 2.6 mg m(-2). Level VI was irinotecan 350 mg m(-2) plus raltitrexed 3.0 mg m(-2), level VII was irinotecan 400 mg m(-2) plus raltitrexed 2.6 mg m(-2); 261 courses were administered. Only one patient at dose levels I-V experienced DLT. At level VI, 5/12 patients experienced DLT: one had grade 3 diarrhoea and lethargy, one had grade 4 diarrhoea and one had lethargy alone. Two others had lethargy caused by disease progression. There was no first-cycle neutropenia. At level VII, 3/6 patients experienced dose-limiting lethargy, one also had grade 3 diarrhoea. Dose intensity fell from over 90% for both drugs at level VI to 83% for irinotecan and 66% for raltitrexed at level VII. Lethargy was therefore the DLT, and level VII the MTD. Pharmacokinetic data showed no measurable drug interaction; 6/30 patients (20%) had objective responses. This combination is active with manageable toxicity. Recommended doses for further evaluation are irinotecan 350 mg m(-2) and raltitrexed 3.0 mg m(-2).     

局部晚期鼻咽癌洛铂单周方案同期放疗初探

目的 探讨局部晚期鼻咽癌洛铂单药单周方案同期放疗中洛铂最大耐受剂量(MTD)。方法 选择18例Ⅲ-ⅣA期鼻咽癌初治患者,采用根治性IMRT同时进行洛铂剂量递增试验。洛铂初始剂量10 mg/m²,组间递增剂量为5 mg/m²,每个剂量组至少3位受试者。如无剂量限制性毒性反应则进入下一剂量组直至MTD,定期评价疗效及不良反应。结果 10、15 mg/m²剂量组各3例,20、25 mg/m²剂量组6例。25mg/m²组出现2例剂量限制性毒性反应,因此MTD确定为20 mg/m²。患者治疗结束后3个月,鼻咽部肿瘤和颈部阳性淋巴结临床缓解率为100%。主要毒性反应为骨髓抑制。结论 洛铂单药周方案同期放化疗治疗局部晚期鼻咽癌的MTD为20mg/m²,该方案疗效可靠安全性较好,值得开展进一步临床研究。     

局部晚期鼻咽癌洛铂单周方案同期放疗初探

目的 探讨局部晚期鼻咽癌洛铂单药单周方案同期放疗中洛铂最大耐受剂量(MTD)。方法 选择18例Ⅲ-ⅣA期鼻咽癌初治患者,采用根治性IMRT同时进行洛铂剂量递增试验。洛铂初始剂量10 mg/m²,组间递增剂量为5 mg/m²,每个剂量组至少3位受试者。如无剂量限制性毒性反应则进入下一剂量组直至MTD,定期评价疗效及不良反应。结果 10、15 mg/m²剂量组各3例,20、25 mg/m²剂量组6例。25mg/m²组出现2例剂量限制性毒性反应,因此MTD确定为20 mg/m²。患者治疗结束后3个月,鼻咽部肿瘤和颈部阳性淋巴结临床缓解率为100%。主要毒性反应为骨髓抑制。结论 洛铂单药周方案同期放化疗治疗局部晚期鼻咽癌的MTD为20mg/m²,该方案疗效可靠安全性较好,值得开展进一步临床研究。     

Phase I study of MEN-10755, a new anthracycline in patients with solid tumours: a report from the European Organization for Research and Treatment of Cancer, Early Clinical Studies Group.

A phase I study was performed with MEN-10755, a novel anthracycline with promising preclinical antitumour activity, in patients with solid tumours to determine the maximum tolerated dose (MTD); the dose-limiting toxicities (DLTs); to document antitumour activity; and to propose a safe dose for phase II evaluation. MEN-10755 at a starting dose of 15 mg/m2/week was given by short intravenous infusion weekly for 3 weeks and cycles were repeated every 28 days. Twenty-four patients received 55 cycles. Doses of MEN-10755 were 15, 30, 40 and 45 mg/m2. At a dose of MEN-10755 45 mg/m2, treatment could not be given as planned due to neutropenia and one patient developed a decrease in cardiac function. This dose level was considered to be the MTD. Chemotherapy-naive patients could be treated with 40 mg/m2/week, and only one DLT (grade 4 neutropenia) was observed. At that dose, three of six chemotherapy pretreated patients developed a DLT during their first treatment cycle: one patient developed a grade 4 thrombocytopenia, one patient a grade 4 neutropenia and one patient developed a grade 3 acute hypersensitivity reaction resulting in discontinuation of treatment. At this dose level, one other patient did not receive treatment on day 15 as planned due to grade 3 neutropenia. No responses were observed. MEN-107555 at a dose of 30 mg/m2/week in pretreated patients and 40 mg/m2/week in chemotherapy-naive patients for three consecutive weeks followed by 1 week rest is recommended for phase II testing.     

A phase I and pharmacokinetic study of BAY59: a novel taxane

PURPOSE: To determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLT) and the pharmacokinetics of BAY59, a novel taxane given as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: Initially, 15 patients with previously treated (median of 4 prior chemotherapy regimens) refractory cancers, but with normal marrow, hepatic and renal function were treated with BAY59 at doses of 15, 30, 50, 75 and 100 mg/m2 using a standard dose escalation design. Subsequently, 11 patients were treated, 5 at 90 mg/m2 and 6 who had had prior oxaliplatin at 75 mg/m2. RESULTS: At 75 mg/m2, grade 4 neutropenia was noted in 2/6 patients, of whom 1 had grade 4 neutropenia lasting more than 5 days (DLT). At 100 mg/m2, 2/2 patients had febrile neutropenia, with 1 fatality. At 90 mg/m2, 2/5 patients had DLTs, including grade 3 neuropathy, severe lower extremity pain, dehydration and grade 4 neutropenia. The MTD was determined to be 75 mg/m2. A cohort of 6 patients, previously exposed to oxaliplatin, were enrolled at the MTD to evaluate the incidence of neurotoxicity. While DLTs (grade 3 arthralgia, grade 4 neutropenia) were noted in 3/6 patients, there was no increase in the incidence of neurotoxicity. There were no responses. Pharmacokinetics of BAY59 was linear over the doses studied, with a median terminal half-life of 21 h. CONCLUSIONS: The recommended phase II dose for BAY59 is 75 mg/m2.     

Paclitaxel, epirubicin and cyclophosphamide combination in first-line treatment of metastatic breast cancer: a dose escalation study

The purpose of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of combined paclitaxel, epirubicin and cyclophosphamide in patients with metastatic breast cancer. The dose of paclitaxel was planned to be escalated from 150 to 225 mg/m(2)in 25 mg/m(2) steps, while the doses of epirubicin and cyclophosphamide were fixed at 50 and 500 mg/m(2), respectively. Because of DLT, the dose of paclitaxel was maintained at 200 mg/m(2) and the dose of epirubicin was increased to 90 mg/m(2). The MTD was reached at a dose of paclitaxel and epirubicin of 200 and 75 mg/m(2), respectively. DLT were mainly febrile neutropenia and grade 4 neutropenia lasting for > or =7 days. Among the 35 evaluable patients, there were 2 (6%) complete responses and 19 (53%) partial responses for an overall response rate of 59% [95% confidence interval (CI): 41-74%]. The triplet paclitaxel/epirubicin/cyclophosphamide is an effective and well-tolerated combination worthy of further investigation in the treatment of patients with metastatic breast cancer.