A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience

Abstract

Background: 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).

Materials and methods: 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.

Results: 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.

Conclusion: 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.

Implications for practice: 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.

Keywords: Cancer of unknown primary; Comprehensive genomic profiling; Diagnosis; Histology; Molecularly guided therapy; Next-generation sequencing.

Figure 1

CUPISCO (NCT03498521) study design. A phase II, randomized, open‐label, active‐controlled, multicenter trial to directly assess whether molecularly guided therapy (MGT), based on comprehensive genomic profiling, is superior to recommended systemic chemotherapy in patients with poor‐prognosis CUP who have achieved disease control after receiving three cycles of first‐line platinum‐doublet induction chemotherapy. Following induction therapy, patients are categorized as either category 1 patients, who achieved disease control (CR, PR, SD), or category 2 patients, who experienced disease progression. Category 1 patients will be randomized and category 2 patients will go directly to targeted therapy (as they progressed on chemotherapy), according to comprehensive genomic profiling and an MTB recommendation. The primary endpoint of the CUPISCO study is progression‐free survival in patients who achieved disease control after receiving three cycles of platinum‐doublet induction chemotherapy (category 1 patients). The primary comparison is between MGT (pooled) and standard chemotherapy. Abbreviations: CDx, companion diagnostic; CR, complete response; CUP, cancer of unknown primary; ECOG PS, Eastern Cooperative Oncology Group perfomance status; MSI, microsatellite instability; MTB, molecular tumor board; PD, progressive disease; PR, partial repsonse; SD, stable disease; TMB, tumor mutation burden.

Figure 2

Eligibility review lung algorithm for diagnostic workup in adenocarcinoma that are (A) CK7+ and TTF1− and (B) CK7+ and TTF1+. ^aSpecial cases re‐reviewed by the reference oncologist and/or radiologist. ^bIf imaging is incomplete or of an insufficient quality to comply with this algorithm, better quality and/or additional imaging may be requested by the eligibility review team for medical assessment. ^cNonspecific profile not excluding lung cancer; may be revisited at time of “other metastatic sites” consideration. ^dEscalation to referent experts is triggered by the eligibility review team. Note:  All cases may be escalated. Decisions may occur that deviate from the algorithm for case scenarios that were not previously encountered. ^eBrain, bone, liver, adrenal glands, and pleura are the most common sites of metastatic disease [32]. ^fAccepted markers for identification of differentiation toward adenocarcinoma are TTF1 and Napsin A, both of which are approximately 80% sensitive, although TTF1 is easier to assess as a nuclear stain [33]. ^gMay be one or more lung masses. Abbreviations: CK, cytokeratin; CUP, cancer of unknown primary; IHC, immunohistochemistry; max, maximum; NSCLC, non‐small cell lung cancer; TTF1, thyroid transcription factor 1.

Figure 3

Eligibility review intrahepatic cholangiocellular carcinoma (iCCC) algorithm for diagnostic workup. ^aPancreato‐biliary histology is compatible with CUP; however, iCCCs should be ruled out with help from referent radiologist. ^bMRI may be requested by the eligibility review team to provide more specific assessment of disease. ^cEscalation to referent experts is triggered by the eligibility review team. Abbreviations: CCC, cholangiocellular carcinoma; CK, cytokeratin; CUP, cancer of unknown primary; GI, gastrointestinal; IHC, immunohistochemistry; LN, lymph node.