Bruera Gemma, Ricevuto Enrico
Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy.
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
Front Oncol. 2020 Feb 20;10:172. doi: 10.3389/fonc.2020.00172. eCollection 2020.
Cancer treatments induce symptoms/signs superimposing on individual patient's clinical status, determining heterogenous toxicity syndromes (TS). We reviewed intensive first line triplet chemotherapy-based regimens in metastatic gastro-intestinal cancers (mGI), based on FIr/FOx schedule, fluorouracil and weekly alternating irinotecan/oxaliplatin, to point out limiting TS (LTS) relevance. Metastatic colo-rectal (mCRC), pancreatic ductal adenocarcinoma (mPDAC), gastric carcinoma (mGC) patients were enrolled by careful decision-making including age, performance status (PS), and comorbidity status in real life phase II studies: FIr-B/FOx adding bevacizumab (B) overall, FIr-C/FOx-C adding cetuximab (C) in / wild-type mCRC; FIr/FOx in mPDAC; FD/FOx adding docetaxel (D) in mGC. Toxicity, individual LTS, LT alone (LTS-single site, LTS-ss) or associated to other limiting/G2 toxicities (LTS-multiple sites, LTS-ms) were evaluated, compared by chi-square test. In FIr-C/FOx-C, 5-fluorouracil/irinotecan pharmacogenomic biomarkers, 5-fluorouracil degradation rate (5-FUDR), SNPs were evaluated, related with LTS. FIr-B/FOx, FIr-C/FOx-C in mCRC, FIr/FOx in mPDAC, FD/FOx in mGC, showed activity, efficacy, toxicities similar to reported triplet regimens. LTS: mCRC FIr-B/FOx 44%, LTS-ms 24%, LTS-ss 20%, in young-elderly 46%, LTS-ms significantly increased vs. LTS-ss; FIr-C/FOx-C 65.5%, significantly increased LTS-ms vs. LTS-ss, in young-elderly 83%; mPDAC FIr/FOx 27.5%, mostly LTS-ms, in young-elderly 38.4% all LTS-ms; mGC FD/FOx 30%, all LTS-ms, in young-elderly 25%. Reduced FUDR, SNPs CYP3A4, UGT1A1, >1 positive pharmacogenomic biomarkers were prevalent in patients with gastrointestinal LTS. LTS is an innovative clinical parameter of toxicity burden, differential treatment-related TS in individual patient. LTS can evaluate pharmacogenomic biomarkers predictive relevance to select mGI patients fit for intensive treatments, at risk of limiting gastrointestinal toxicity. The trials were registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34, and Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009- 016793-32.
癌症治疗会引发叠加在个体患者临床状况之上的症状/体征，从而导致异质性毒性综合征（TS）。我们回顾了基于氟尿嘧啶/奥沙利铂（FIr/FOx）方案、氟尿嘧啶以及每周交替使用伊立替康/奥沙利铂的转移性胃肠道癌症（mGI）强化一线三联化疗方案，以指出限制性毒性综合征（LTS）的相关性。在真实世界的II期研究中，通过包括年龄、体能状态（PS）和合并症状态等在内的谨慎决策，纳入了转移性结直肠癌（mCRC）、胰腺导管腺癌（mPDAC）、胃癌（mGC）患者：总体上，FIr-B/FOx方案加用贝伐单抗（B）；在KRAS野生型mCRC中，FIr-C/FOx-C方案加用西妥昔单抗（C）；mPDAC采用FIr/FOx方案；mGC的FD/FOx方案加用多西他赛（D）。对毒性、个体LTS、单独的LTS（LTS-单部位，LTS-ss）或与其他限制性/G2毒性相关的LTS（LTS-多部位，LTS-ms）进行评估，并通过卡方检验进行比较。在FIr-C/FOx-C方案中，评估了5-氟尿嘧啶/伊立替康的药物基因组生物标志物、5-氟尿嘧啶降解率（5-FUDR）、单核苷酸多态性（SNPs），并将其与LTS相关联。mCRC中的FIr-B/FOx、FIr-C/FOx-C方案，mPDAC中的FIr/FOx方案，mGC中的FD/FOx方案，均显示出与已报道的三联化疗方案相似的活性、疗效和毒性。LTS情况如下：mCRC的FIr-B/FOx方案中为44%，LTS-ms为24%，LTS-ss为20%，在年轻和老年患者中为46%，LTS-ms较LTS-ss显著增加；FIr-C/FOx-C方案中为65.5%，LTS-ms较LTS-ss显著增加，在年轻和老年患者中为83%；mPDAC的FIr/FOx方案中为27.5%，大多为LTS-ms，在年轻和老年患者中为38.4%，均为LTS-ms；mGC的FD/FOx方案中为30%，均为LTS-ms，在年轻和老年患者中为25%。在胃肠道LTS患者中，降低的FUDR、CYP3A4和UGT1A1的SNPs以及超过1个阳性药物基因组生物标志物较为普遍。LTS是毒性负担的一个创新性临床参数，可区分个体患者中与治疗相关的TS。LTS能够评估药物基因组生物标志物的预测相关性，以选择适合强化治疗但有胃肠道毒性限制风险的mGI患者。这些试验已在意大利药品管理局（AIFA）的国家临床药物试验观察站（OsSC）注册，注册号分别为EudraCT 2007-004946-34和EudraCT 2009-016793-32。
