Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland.
Clinical Cooperation Unit Molecular Haematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Oncologist. 2021 May;26(5):e769-e779. doi: 10.1002/onco.13744. Epub 2021 Mar 25.
CUPISCO is an ongoing randomized phase II trial (NCT03498521) comparing molecularly guided therapy versus platinum-based chemotherapy in patients newly diagnosed with "unfavorable" cancer of unknown primary (CUP).
Patients with an unfavorable CUP diagnosis, as defined by the European Society of Medical Oncology (ESMO), and available cancer tissue for molecular sequencing are generally eligible. Potential patients with CUP entering screening undergo a review involving reference histopathology and clinical work-up by a central eligibility review team (ERT). Patients with "favorable" CUP, a strongly suspected primary site of origin, lack of tissue, or unmet inclusion criteria are excluded.
As of April 30, 2020, 628 patients had entered screening and 346 (55.1%) were screen failed. Screen fails were due to technical reasons (n = 89), failure to meet inclusion and exclusion criteria not directly related to CUP diagnosis (n = 89), and other reasons (n = 33). A total of 124 (35.8%) patients were excluded because unfavorable adeno- or poorly differentiated CUP could not be confirmed by the ERT. These cases were classified into three groups ineligible because of (a) histologic subtype, such as squamous and neuroendocrine, or favorable CUP; (b) evidence of a possible primary tumor; or (c) noncarcinoma histology.
Experience with CUPISCO has highlighted challenges with standardized screening in an international clinical trial and the difficulties in diagnosing unfavorable CUP. Reconfirmation of unfavorable CUP by an ERT in a clinical trial can result in many reasons for screen failures. By sharing this experience, we aim to foster understanding of diagnostic challenges and improve diagnostic pathology and clinical CUP algorithms.
A high unmet need exists for improved treatment of cancer of unknown primary (CUP); however, study in a trial setting is faced with the significant challenge of definitively distinguishing CUP from other cancer types. This article reports the authors' experience of this challenge so far in the ongoing CUPISCO trial, which compares treatments guided by patients' unique genetic signatures versus standard chemotherapy. The data presented will aid future decision-making regarding diagnosing true CUP cases; this will have far-reaching implications in the design, execution, and interpretation of not only CUPISCO but also future clinical studies aiming to find much-needed treatment strategies.
CUPISCO 是一项正在进行的随机二期临床试验（NCT03498521），比较了分子指导治疗与新诊断为“不利”不明原发癌（CUP）的铂类化疗患者。
一般符合以下条件的患者可入组：欧洲肿瘤内科学会（ESMO）定义的不利 CUP 诊断，以及有可供分子测序的癌症组织。进入筛选的潜在 CUP 患者接受了参考组织病理学和中央资格审查小组（ERT）进行的临床检查。具有“有利”CUP、强烈怀疑原发部位起源、缺乏组织或不符合纳入标准的患者被排除在外。
截至 2020 年 4 月 30 日，已有 628 名患者进入筛选，其中 346 名（55.1%）筛选失败。筛选失败的原因是技术原因（n=89）、未直接与 CUP 诊断相关的纳入和排除标准不达标（n=89）和其他原因（n=33）。共有 124 名（35.8%）患者因 ERT 无法确认不利的腺或低分化 CUP 而被排除。这些病例分为三组，因（a）组织学亚型，如鳞状细胞癌和神经内分泌癌，或有利的 CUP；（b）可能存在原发性肿瘤的证据；或（c）非癌组织学而不符合条件。
CUPISCO 的经验突出了在国际临床试验中进行标准化筛选所面临的挑战，以及诊断不利 CUP 的困难。ERT 对不利 CUP 的临床验证可能会导致筛选失败的多种原因。通过分享这一经验，我们旨在提高对诊断挑战的认识，并改善诊断病理学和临床 CUP 算法。
癌症未知原发灶（CUP）的治疗需求未得到满足；然而，在试验环境中进行研究面临着一个重大挑战，即明确区分 CUP 与其他癌症类型。本文报道了在正在进行的 CUPISCO 试验中作者迄今为止面临的这一挑战，该试验比较了基于患者独特基因特征指导的治疗与标准化疗。所提供的数据将有助于未来对真正的 CUP 病例进行诊断决策；这将对 CUPISCO 乃至未来旨在寻找急需治疗策略的临床试验的设计、执行和解释产生深远影响。
