Medical Oncology Department, National Cancer Research Centre "Giovanni Paolo II", Via O. Flacco, 65, 70124, Bari, Italy.
Molecular Genetics Laboratory and Radiology, National Cancer Research Centre "Giovanni Paolo II", Via O. Flacco, 65, 70124, Bari, Italy.
BMC Cancer. 2018 May 10;18(1):552. doi: 10.1186/s12885-018-4479-2.
It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients.
A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21-81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m on days 1 and 2 and FM iv 100 mg/m on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients.
We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status.
This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed.
EUDRACT 2009-016487-36l ; date of registration 23 June 2010.
鉴于目前可用药物（包括抗 CTLA4/抗 PD1 免疫疗法和抗 BRAF/抗 MEK 抑制剂）的有效性，经常有人询问化疗在转移性黑色素瘤中是否仍能发挥作用。然而，只有大约一半的患者对这些药物有反应，并且大多数在 6-11 个月后进展。因此，仍然非常需要其他治疗选择。我们报告了第一个大的试验，即先用低剂量替莫唑胺（TMZ）作为化学调节剂来预先激活 O(6)-甲基鸟嘌呤 DNA-甲基转移酶（MGMT）的 DNA 修复作用，然后再用全剂量福莫司汀（FM）进行序贯治疗。主要终点是总反应率和安全性。我们还评估了特定的生物学参数，旨在将这些化疗方法针对选定的患者进行调整。
共纳入 69 例连续患者。主要特征包括中位年龄 60 岁（21-81 岁）和 M1c 期，74%的患者观察到该期，15%的患者有脑转移，42%的患者有高乳酸脱氢酶水平。采用以下方案：口服 TMZ 100mg/m 于第 1 和 2 天，FM iv 100mg/m 于第 2 天，TMZ 后 4 小时；进行了一项旨在分析 MGMT 甲基化状态和碱基切除修复（BER）基因表达的转化研究，纳入了 14 例患者。
我们报告的总反应率为 30.3%，包括 3 例完全缓解和 50.5%的疾病控制率。相关毒性发生率低，主要为血液学类型。尽管我们的人群预后非常差，但我们观察到 6 个月的无进展生存期和 10 个月的总生存期。与反应相关的一个非显著相关性与参与 BER 途径的三个基因（APE1、XRCC1 和 PARP1）的平均表达水平有关，而与 MGMT 甲基化状态无关。
对于不符合免疫或靶向治疗条件或先前治疗失败的患者，该方案可能是一种较好的选择。
EUDRACT 2009-016487-36l；注册日期 2010 年 6 月 23 日。
