Duffy A, Kortmansky J, Schwartz G K, Capanu M, Puleio S, Minsky B, Saltz L, Kelsen D P, O'Reilly E M
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Ann Oncol. 2008 Jan;19(1):86-91. doi: 10.1093/annonc/mdm441. Epub 2007 Sep 17.
To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival.
Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m(2)/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles.
Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months.
In combination with fixed dose gemcitabine at 40 mg/m(2) twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.
确定厄洛替尼与每周两次吉西他滨及放射治疗（RT）联合应用于局部晚期胰腺癌时的最大耐受剂量（MTD），评估该联合方案的安全性和毒性特征，并次要评估疗效、肿瘤进展时间和总生存期。
未接受过治疗的局部晚期胰腺癌患者接受每日厄洛替尼治疗，联合每周两次40mg/m²、持续30分钟的吉西他滨，以及在5.5周内每天180cGy、分28次给予的放射治疗，总量为5040cGy。厄洛替尼在连续队列中进行剂量递增（100mg、125mg）。确定MTD后，扩大队列以更好地明确毒性和初步疗效。所有患者均接受手术分期。放化疗后，患者在21天周期的第1天和第8天接受每周一次1000mg/m²的吉西他滨维持治疗，并每日服用厄洛替尼，共四个周期。
3例患者在剂量水平1（厄洛替尼100mg）接受治疗，未出现剂量限制性毒性。剂量水平2（厄洛替尼125mg）的6例患者中有2例出现剂量限制性毒性，即中性粒细胞减少和血小板减少，导致剂量延迟和肝酶升高。厄洛替尼与每周两次基于吉西他滨的放化疗联合应用时的MTD为每日100mg。另外11例患者在剂量水平1接受治疗。所有20例患者均可评估毒性。17例患者可评估疗效。部分缓解率为35%，53%病情稳定。所有患者的中位生存期为18.7个月。
与每周两次40mg/m²的固定剂量吉西他滨及每天180cGy的放射治疗联合应用时，厄洛替尼的MTD为每日100mg。在预后较差的癌症中，这是一种耐受性相对良好且具有生物活性的联合方案。
