Intensified treatment in patients with local operable but oligometastatic pancreatic cancer - multimodal surgical treatment versus systemic chemotherapy alone: a randomized controlled trial [AIO-PAK-0219 METAPANC]

胰腺导管腺癌（PDAC）是最具侵袭性的癌症实体，最初出现在超过60%的转移患者中。在过去几年中，采用FOLFIRINOX方案（奥沙利铂、伊立替康、5-FU）的全身治疗已被证明是一种有效的治疗方法，可提高生存率，缓解率超过30%，肿瘤消退至完全缓解。然而，疾病复发或继发耐药不可避免地发生，导致总生存期仅约11个月。在转移性pdac组中，一个亚组患者表现为少转移性疾病，最多有三个肝转移，同步或异时发生，尽管没有一致的定义。与其他胃肠道癌症一样，这类患者可能存在潜在的治疗机会，包括手术。因此，虽然由于FOLFIRINOX的毒性，通常以降级的方式继续化疗是标准的治疗方法，但可以为患者提供原发癌和转移癌的手术切除。然而，到目前为止，手术与低转移患者的相关性尚不清楚，在欧洲，许多此类患者接受单独治疗。世界范围内既没有前瞻性数据，也没有对照随机临床试验的数据。在应用前瞻性随机iii期试验（METAPANC）中，将研究FOLFIRINOX诱导化疗后原发肿瘤手术切除与转移的相关性。只有在化疗至少4个月后肿瘤消退或病情稳定的患者才会被纳入。只有原发灶和转移灶能够得到治愈和完全切除的患者（实验组）将被随机分组。标准组包括4个月的化疗（FOLFIRINOX），随后是降糖化疗（标准治疗）。主要终点是总生存期。这项前瞻性随机试验伴随着一个转化研究项目，包括肿瘤组织的中心采样和分子特征、液体活检和放射组学方法。尽管PDAC的发病率越来越高，但符合试验条件的低转移患者数量很少，并将其定义为“罕见疾病”。因此，最大的德国医院（AIO/ACO研究）和荷兰胰腺癌组（DPCG）以及两个北欧中心（奥斯陆/NOR和赫尔辛基/FIN）将在该试验中招募患者。这三个国家的研究小组都对这项试验表达了浓厚的兴趣。我们设想在成功完成三期试验后，将手术切除纳入选定的低转移性PDAC患者的多模式治疗方案，从而改变实践结果。

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer entity and initially presents in more than 60% of the patients with metastasis. In the last years systemic therapy with the FOLFIRINOX protocol (Oxaliplatin, Irinotecan, 5-FU) has demonstrated as an effective therapy with increased survival and response rates above 30 % with tumor regression up to complete responses. However, recurrence of disease or secondary resistance inevitably occur leading to an overall survival of only approximately 11 months. In the group of metastasized PDACs a subgroup of patients presents with oligometastasized disease with a maximum of three liver metastases in a synchronous or metachronous fashion, though there is no consensus definition. As in other gastrointestinal cancers there might exist a potential curative window of opportunity for such patients including surgery. Thus, while continued chemotherapy usually in a de-escalated fashion due to toxicity of FOLFIRINOX is the standard of care, surgical resection of the primary cancer and the metastases may be offered to patients. However, the relevance of surgery in oligometastasized patients is unclear up to now and many patients in such context are treated individually in Europe. There exist neither prospective data nor data from controlled randomized clinical trials worldwide. In the applied prospective randomized phase-III trial (METAPANC) the relevance of surgical resection of the primary cancer and the metastases after induction chemotherapy with FOLFIRINOX will be investigated. Only patients with tumor regression or stable disease after at least 4 months of chemotherapy will be included. Only patients in whom a curative and complete resection of the primary and the metastases can be achieved (experimental arm) will be randomized. The standard arm consists of a 4-months chemotherapy (FOLFIRINOX) followed by a de-escalating chemotherapy (standard of care). The primary endpoint is overall survival. This prospective randomized trial is accompanied by a translational research program including the central sampling and molecular characterization of tumor tissue, liquid biopsy and radiomics approaches. Despite the increasing incidence of PDAC the number of oligometastatic patients eligible for this trial is small and defines it as ”rare disease“. Therefore, the largest German Hospitals (AIO/ACO Studie) and the Dutch Pancreatic Cancer Group (DPCG) as well as a two northern European centers (Oslo/NOR and Helsinki/FIN) will recruit patients in this trial. The study groups in the three countries have expressed their strong interest for this trial. We envision practice-changing results upon successful completion of the phase III trial with respect to the inclusion of surgical resection in multimodal regimens for selected patients with oligometastatic PDAC.