Bruera Gemma, D'Andrilli Antonio, Simmaco Maurizio, Guadagni Stefano, Rendina Erino Angelo, 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 Aug 4;10:1155. doi: 10.3389/fonc.2020.01155. eCollection 2020.
Intensive oncological treatment integrated with resection of metastases raised the clinical outcome of metastatic colorectal cancer (MCRC). In clinical practice, complex evaluation of clinical (age, performance status, comorbidities), and biological (tumoral genotype, pharmacogenomic) parameters addresses tailored, personalized multidisciplinary treatment strategies. Patients with MCRC unsuitable for first-line intensive medical treatments are prevalent and showed worse clinical outcome. After progression to oxaliplatin-based chemotherapy, aflibercept/FOLFIRI significantly improved clinical outcome, even if no survival benefit was reported in adjuvant fast relapsers by aflibercept addition. The case reported a young-elderly (yE) patient with mutant colorectal cancer rapidly progressing to adjuvant chemotherapy, unfit owing to comorbidities, with multiple pharmacogenomic alterations, who gained long-term survival in clinical practice by multidisciplinary treatment strategy consisting of first-line and re-introduction of aflibercept-containing chemotherapy and two-stage lung metastasectomies. A 71-years-old yE patient, unfit for intensive oncological treatments owing to Cumulative Illness Rating Scale (CIRS) stage secondary, affected by c.35 G>T mutant colorectal cancer, rapidly progressing with lung metastases after adjuvant XelOx chemotherapy, reached long-term survival 66 months with no evidence of disease after first-line and re-introduction of tailored, modulated aflibercept (4 mg/kg) d1,15-irinotecan (120 mg/m) d1,15-5-fluorouracil (750 mg/m/day) dd1-4, 15-18; and secondary radical bilateral two-stage lung metastasectomies. Safety profile was characterized by limiting toxicity syndrome at multiple sites (LTS-ms), requiring 5-fluorouracil discontinuation and aflibercept reduction (2 mg/kg), because of G2 hand-foot syndrome (HFS) for >2 weeks, and G3 hypertension. Pharmacogenomic analyses revealed multiple alterations of fluoropyrimidine and irinotecan metabolism: severe deficiency of fluorouracil degradation rate (FUDR), single nucleotide polymorphisms of 28 variable number of tandem repeats (VNTR) 7R/7R homozygote, c.C3435T, c.C1236T, c.C667T homozygote, c.A166G, 28bp VNTR 2R/3R heterozygote. In clinical practice, a complex management evaluating clinical parameters and / genotype characterizing an individual patient with MCRC, particularly elderly and/or unfit owing to comorbidities, is required to properly address tailored, multidisciplinary medical and surgical treatment strategies, integrated with careful monitoring of superimposing toxicity syndromes, also related to pharmacogenomic alterations, to gain optimal activity, and long-term efficacy.
与转移灶切除术相结合的强化肿瘤治疗提高了转移性结直肠癌（MCRC）的临床疗效。在临床实践中，对临床（年龄、体能状态、合并症）和生物学（肿瘤基因型、药物基因组学）参数进行综合评估，以制定量身定制的个性化多学科治疗策略。不适合一线强化药物治疗的MCRC患者很常见，其临床疗效较差。在进展为基于奥沙利铂的化疗后，阿柏西普/ FOLFIRI显著改善了临床疗效，即使在辅助治疗中快速复发的患者中添加阿柏西普未报告生存获益。该病例报告了一名中老年（yE）患者，患有突变型结直肠癌，辅助化疗后迅速进展，因合并症不适合治疗，存在多种药物基因组学改变，通过由一线和重新引入含阿柏西普的化疗以及两阶段肺转移灶切除术组成的多学科治疗策略在临床实践中获得了长期生存。一名71岁的yE患者，因累积疾病分级量表（CIRS）二级而不适合强化肿瘤治疗，患有c.35 G>T突变型结直肠癌，辅助XelOx化疗后肺部转移迅速进展，在一线和重新引入量身定制的、调整后的阿柏西普（4 mg/kg）第1、15天 - 伊立替康（120 mg/m²）第1、15天 - 5-氟尿嘧啶（750 mg/m²/天）第1 - 4天、15 - 18天后，获得了66个月的长期生存且无疾病证据；随后进行了二期根治性双侧两阶段肺转移灶切除术。安全性特征为多部位限制性毒性综合征（LTS-ms），由于G2级手足综合征（HFS）持续超过2周以及G3级高血压，需要停用5-氟尿嘧啶并减少阿柏西普剂量（2 mg/kg）。药物基因组学分析显示氟嘧啶和伊立替康代谢存在多种改变：氟尿嘧啶降解率严重不足（FUDR）、28个可变串联重复序列（VNTR）7R/7R纯合子的单核苷酸多态性、c.C3435T、c.C1236T、c.C667T纯合子、c.A166G、28bp VNTR 2R/3R杂合子。在临床实践中，需要对MCRC个体患者，特别是因合并症而年老和/或不适合治疗的患者，进行综合管理，评估临床参数和/基因型，以正确制定量身定制的多学科药物和手术治疗策略，并仔细监测叠加的毒性综合征，这些综合征也与药物基因组学改变有关，以获得最佳活性和长期疗效。
