Université François Rabelais de Tours, CHRU de Tours, France.
Br J Clin Pharmacol. 2010 Sep;70(3):367-75. doi: 10.1111/j.1365-2125.2010.03712.x.
Although treated using the same high-dose methotrexate (HD-MTX)-based multiagent chemotherapy, patients with primary central nervous system lymphoma (PCNSL) have significant differences in outcome. However, little information has been published about factors influencing outcome in PCNSL. As it is known that the pharmacokinetics of MTX vary considerably between subjects leading to different exposure in patients receiving the same dose, it is important to evaluate its role in response to chemotherapy.
This study is the first to evaluate the exposure-response relationship in patients treated with MBVP chemotherapy. We found that patients who were early non-responders to MBVP chemotherapy had poor survival, whatever the salvage regimen. Tumour response at early evaluation was not associated with MTX pharmacokinetics and increasing the dose would probably not improve results.
Although the standard treatment for primary central nervous system lymphoma (PCNSL) consists of three cycles of MBVP (methotrexate, BCNU, VP16, methylprednisolone) and radiotherapy, early failure of treatment may require modification of the treatment. However, our understanding of the outcome in such patients and of the factors involved in early failure of treatment is poor. In addition to known prognostic factors, we evaluated the influence of methotrexate (MTX) exposure on the response to MBVP chemotherapy in patients treated for PCNSL after the first two cycles.
We retrospectively analyzed all patients with PCNSL treated with the MBVP regimen over the previous 10 years. Clinical, personal data and known prognostic factors were studied. The parameters of MTX exposure were estimated using a population pharmacokinetic approach with NONMEM. Objective response (OR), overall survival (OS) and failure-free survival (FFS) were evaluated in all patients.
Thirty-seven patients were studied. We observed lower FFS and OS (0.49 years) in patients who were not able to receive the planned treatment (group 1, n=12) than in those who received three cycles (8.04 years) (group 2, n=25). Known prognostic factors were comparable in both groups, but mean dose of MTX and mean AUC tended to be lower in patients who failed prematurely or showed no response after two cycles.
We found that patients who were early non-responders to MBVP chemotherapy had poor survival, without major influence of MTX exposure. It is thus probably unlikely that increasing the dose of MTX would improve outcome.
尽管使用相同的大剂量甲氨蝶呤（HD-MTX）为基础的多药化疗治疗，但原发性中枢神经系统淋巴瘤（PCNSL）患者的预后存在显著差异。然而，关于影响 PCNSL 预后的因素，发表的信息很少。因为众所周知，MTX 在不同患者之间的药代动力学差异很大，导致接受相同剂量的患者的暴露情况不同，所以评估其对化疗反应的作用很重要。
本研究是首次评估接受 MBVP 化疗的患者的暴露-反应关系。我们发现，MBVP 化疗早期无反应的患者无论采用何种挽救方案，其生存预后均较差。早期评估时的肿瘤反应与 MTX 药代动力学无关，增加剂量可能不会改善结果。
尽管原发性中枢神经系统淋巴瘤（PCNSL）的标准治疗包括三个周期的 MBVP（甲氨蝶呤、卡氮芥、依托泊苷、甲基强的松龙）和放疗，但早期治疗失败可能需要修改治疗方案。然而，我们对这些患者的预后以及早期治疗失败相关因素的了解还很有限。除了已知的预后因素外，我们还评估了 MTX 暴露对 PCNSL 患者接受 MBVP 化疗前两个周期后反应的影响。
我们回顾性分析了过去 10 年接受 MBVP 方案治疗的所有 PCNSL 患者。研究了临床、个人资料和已知的预后因素。使用 NONMEM 进行群体药代动力学分析来估计 MTX 暴露的参数。对所有患者进行客观缓解（OR）、总生存（OS）和无失败生存（FFS）评估。
37 例患者接受了研究。与能够接受计划治疗的患者（第 1 组，n=12）相比，无法接受计划治疗的患者（第 2 组，n=25）的 FFS 和 OS 较低（0.49 年）。两组患者的已知预后因素相似，但在两个周期后出现早期无反应或无反应的患者中，MTX 的平均剂量和 AUC 均值均较低。
我们发现，MBVP 化疗早期无反应的患者预后较差，MTX 暴露的影响不大。因此，增加 MTX 剂量可能不会改善预后。
