Cascinu Stefano, Berardi Rossana, Labianca Roberto, Siena Salvatore, Falcone Alfredo, Aitini Enrico, Barni Sandro, Di Costanzo Francesco, Dapretto Elisa, Tonini Giuseppe, Pierantoni Chiara, Artale Salvatore, Rota Silvia, Floriani Irene, Scartozzi Mario, Zaniboni Alberto
Polytechnic University of Marche-Riuniti Hospital Umberto I-GM Lancisi-G Salesi of Ancona, 60020 Ancona, Italy.
Lancet Oncol. 2008 Jan;9(1):39-44. doi: 10.1016/S1470-2045(07)70383-2.
Preclinical data have suggested a synergistic effect of cetuximab combined with gemcitabine and cisplatin and clinical data have shown a substantial improvement in response and survival when gemcitabine is combined with a platinum analogue compared with gemcitabine alone. The aim of this study was to assess the activity and feasibility of a combination of cetuximab with gemcitabine and cisplatin compared with use of gemcitabine and cisplatin alone for the treatment of advanced pancreatic cancer.
In a multicentre, randomised phase II trial, 84 patients with advanced pancreatic cancer were randomly assigned to either 250 mg/m2 cetuximab weekly, after a loading dose of 400 mg/m2, plus 1000 mg/m2 gemcitabine and 35 mg/m2 cisplatin on days 1 and 8 of a 21-day cycle or to the same chemotherapeutic regimen without cetuximab. The primary endpoint was objective response (defined as the proportion of patients whose best response was either partial response or complete response). Secondary endpoints included disease control (defined as the proportion of patients whose best response was either partial response, complete response, or stable disease), progression-free survival, and overall survival. All assessments of response at each site were done blindly by a local experienced radiologist who was not directly involved in the trial. Responses were measured according to an intention-to-treat analysis. This trial is registered with the Clinical Trial registry, number NCT00536614.
29 men and 13 women were randomly assigned to cetuximab plus gemcitabine and cisplatin (median age 61 years [range 38-78]) and 22 men and 20 women were randomly assigned to gemcitabine and cisplatin (median age 64 years [range 40-76]). Seven of 40 (17.5%) patients had an objective response in the cetuximab group (95% CI 7.3-32.8) and five of 41 (12.2%) patients had an objective response in the non-cetuximab group (95% CI 4.1-26.2). No significant difference was noted between the groups both for objective response (5.3% higher in the cetuximab group [95% CI -16.5 to 27.1]; chi2 test=0.360; p=0.549) or for disease control (3.5% higher in the non-cetuximab group [-34.0% to 27.0%]; 0.446; p=0.504). Overall median follow-up was 11.8 months (range 2.5-18.5). No significant differences between the groups were noted in median progression-free survival (hazard ratio 0.96, 95% CI 0.60-1.52, p=0.847) or in median overall survival (0.91, 0.54-1.55, p=0.739): median progression-free survival was 3.4 months (95% CI 2.4-5.1) in the cetuximab group and 4.2 months (2.6-5.4) in the non-cetuximab group; median overall survival was 7.5 months (5.1-8.8) and 7.8 months (5.3-15.0), respectively. 33 patients from both groups had at least one grade 3-4 toxic effect.
The addition of cetuximab to a combination of gemcitabine and cisplatin does not increase response or survival for patients with advanced pancreatic cancer. Although toxic effects were not increased by cetuximab, this combination should not be further assessed in phase III trials.
临床前数据提示西妥昔单抗联合吉西他滨和顺铂具有协同作用，临床数据显示，与单用吉西他滨相比，吉西他滨联合铂类类似物可显著提高缓解率并延长生存期。本研究旨在评估西妥昔单抗联合吉西他滨和顺铂与单用吉西他滨和顺铂治疗晚期胰腺癌相比的活性和可行性。
在一项多中心随机II期试验中，84例晚期胰腺癌患者被随机分为两组，一组在给予400mg/m²负荷剂量后，每周接受250mg/m²西妥昔单抗治疗，同时在21天周期的第1天和第8天接受1000mg/m²吉西他滨和35mg/m²顺铂治疗；另一组接受相同的化疗方案，但不使用西妥昔单抗。主要终点为客观缓解（定义为最佳缓解为部分缓解或完全缓解的患者比例）。次要终点包括疾病控制（定义为最佳缓解为部分缓解、完全缓解或疾病稳定的患者比例）、无进展生存期和总生存期。每个研究点的所有缓解评估均由未直接参与试验的当地经验丰富的放射科医生在盲态下进行。根据意向性分析来测量缓解情况。本试验已在临床试验注册中心注册，注册号为NCT00536614。
29例男性和13例女性被随机分配至西妥昔单抗联合吉西他滨和顺铂组（中位年龄61岁[范围38 - 78岁]），22例男性和20例女性被随机分配至吉西他滨和顺铂组（中位年龄64岁[范围40 - 76岁]）。西妥昔单抗组40例患者中有7例（17.5%）获得客观缓解（95%CI 7.3 - 32.8），非西妥昔单抗组41例患者中有5例（12.2%）获得客观缓解（95%CI 4.1 - 26.2）。两组间客观缓解率（西妥昔单抗组高5.3%[95%CI - 16.5至27.1]；χ²检验=0.360；p = 0.549）或疾病控制率（非西妥昔单抗组高3.5%[- 34.0%至27.0%]；χ²检验=0.446；p = 0.504）均未观察到显著差异。总体中位随访时间为11.8个月（范围2.5 - 18.5个月）。两组间中位无进展生存期（风险比0.96，95%CI 0.60 - 1.52，p = 0.847）或中位总生存期（风险比0.91，95%CI 0.54 - 1.55，p = 0.739）均未观察到显著差异：西妥昔单抗组中位无进展生存期为3.4个月（95%CI 2.4 - 5.1），非西妥昔单抗组为4.2个月（2.6 - 5.4）；中位总生存期分别为7.5个月（5.1 - 8.8）和7.8个月（5.3 - 15.0）。两组共有33例患者至少出现1次3 - 4级毒性反应。
对于晚期胰腺癌患者，在吉西他滨和顺铂的基础上加用西妥昔单抗并不能提高缓解率或延长生存期。虽然西妥昔单抗未增加毒性反应，但该联合方案不应在III期试验中进一步评估。
