The treatment of CUP patients is guided by the results of the work-up described above. In addition, clinical knowledge of the metastatic pattern of tumors considered in the differential diagnosis and radiological features is crucial for classification (e.g., TTF-1-negative bronchial carcinoma vs. CUP or intrahepatic cholangiocellular carcinoma vs. CUP). When either clinical or molecular work-up suggests the origin of a primary tumor with a high probability, specific therapy according to the current guidelines of the respective tumor entity appears reasonable.

This subgroup is characterized by a favorable prognosis and includes:

Women with isolated axillary lymph node metastases (“breast-like CUP”).

Women with peritoneal carcinomatosis of a serous papillary adenocarcinoma (“ovary-like CUP”).

Squamous cell carcinoma of the head and neck with cervical or supraclavicular lymph node metastases (“head and neck-like CUP”).

Solitary metastasis or oligometastatic disease amenable to local therapy.

Adenocarcinomas with colorectal immunohistochemical marker profiles (“colon-like CUP”).

Carcinomas with renal cell carcinoma immunohistochemical marker profiles (“renal-like CUP”).

Men with osteoplastic osseous metastases and/or PSA elevation (“prostate-like CUP”).

For localized solitary metastases, as mentioned earlier, local therapy (resection or radiation plus/minus chemotherapy) should be considered.

For patients with unidentifiable CUPs, therapy selection should be based on performance status (PS) and LDH levels. Patients with an Eastern Cooperative Oncology Group (ECOG) PS ≤ 1 and normal LDH have a better prognosis (median overall survival of 12 months) compared to patients with elevated LDH and/or PS ≥ 2 (median overall survival of 4 months).

Platinum-based empirical chemotherapy (plus gemcitabine or taxanes) remains the first-line therapy for the majority of CUP patients, if no clinical trial is available. Doublet chemotherapy should be considered primarily in fit patients with normal LDH, while in all other cases, monotherapy or “best supportive care” is recommended.

In a meta-analysis that included 543 CUP patients with an unfavorable prognosis and compared 16 chemotherapy protocols, no advantage of a specific regimen was detected. It should be noted, however, that the confidence intervals were wide [13].

Evidence for the use of immunotherapy in CUP patients is still limited. In a phase II study 45 pretreated CUP patients were exposed to nivolumab. An overall survival of 15.9 months (95% CI 8.4–21.5 months) and a response rate of 22.9% were observed [14]. However, due to the heterogeneous and limited patient population, recommendations based on this study are limited.

Immunotherapy should be considered in CUP patients in the unfavorable prognostic group with mismatch repair deficiency/MSI‑H tumors in the second-line setting. First-line immunotherapy appears to be reasonable for the treatment of mismatch repair deficient/MSI‑H “colon-like” CUPs. Immunotherapy in the second-line setting is also an option for CUP patients in the unfavorable prognostic group with high PD-L1 expression or high tumor mutational burden (“TMB-high”).

Targeted therapy is recommended for NTRK fusion, ALK fusion, ROS‑1 fusion-positive, or EGFR-mutated CUPs. BRAF V600E-mutated CUPs should be treated with targeted therapy in the second-line setting (first-line in “NSCLC-like CUP”). After first-line therapy failure, targeted therapy based on the molecular profile (preferably discussed in a molecular tumor board) can also be considered.