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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
Unfavourable cancer of unknown primary is the large majority of cases, where a metastatic adenocarcinoma or poorly differentiated carcinoma fits no recognised pattern and its origin cannot be found. Treatment has long been general-purpose platinum chemotherapy, but CUPISCO showed that matching drugs to the tumour's genetic faults after short chemotherapy holds the disease longer.
Most patients with cancer of unknown primary do not fit a favourable subset. They have adenocarcinoma or poorly differentiated carcinoma in the liver, lungs, bones or several sites at once, are often unwell at diagnosis, and survival is short; performance status and serum lactate dehydrogenase are the strongest predictors of survival. For thirty years treatment has been empirical: carboplatin with paclitaxel or gemcitabine with cisplatin, regimens chosen because they work across many cancers, with response rates around a third and median survival of about nine to twelve months in trial populations and shorter in the clinic. Randomised trials of classifier-directed site-specific chemotherapy (GEFCAPI 04, Lancet Oncology 2019, and a Japanese trial) did not improve on this, and PD-1 antibodies produced responses in about a fifth of patients in the NivoCUP trial (Annals of Oncology 2022) and the CUPISCO immunotherapy arm, leading to nivolumab's approval for CUP in Japan in 2021.
The CUPISCO trial (Lancet 2024) changed the framing. After three cycles of platinum-based induction chemotherapy, 636 patients with unfavourable CUP whose disease had not progressed were randomised to continue chemotherapy or to switch to molecularly guided therapy chosen by a tumour board from comprehensive genomic profiling, including targeted drugs for actionable alterations and atezolizumab for tumours with high mutational burden or without a target: progression-free survival rose from 4.4 to 6.1 months, a modest but real gain that established genomic profiling as part of the standard work-up. About a third of patients carry an actionable alteration (HER2, BRAF V600E, NTRK fusions, MSI or high tumour mutational burden, and others), and the ESMO 2023 guideline recommends profiling for all patients fit for treatment; circulating tumour DNA is an alternative when tissue is scarce. Trials now test targeted agents, immunotherapy combinations and antibody-drug conjugates with chemotherapy in first line, and DNA-methylation classifiers are being revisited as a route to site-specific immunotherapy choices. Early palliative care and honest discussion of prognosis are part of standard management.
| Setting | Approach | Guideline |
|---|---|---|
| Work-up | Exclude favourable subsets; comprehensive genomic profiling of tissue or plasma; assess performance status and lactate dehydrogenase. | not mapped |
| First line, fit patients | Platinum-based doublet (carboplatin-paclitaxel or gemcitabine-cisplatin) for three cycles, then continuation or a switch to molecularly guided therapy where an actionable alteration is found (CUPISCO). | not mapped |
| Actionable alterations | Tumour-agnostic therapies: pembrolizumab or nivolumab for MSI-high or high tumour mutational burden, NTRK inhibitors, BRAF and MEK inhibitors, HER2-directed therapy. | not mapped |
| Second line | Alternative chemotherapy, PD-1 antibody if not given (nivolumab approved in Japan), or trial entry; trials of antibody-drug conjugates and immunotherapy combinations. | not mapped |
| Poor performance status | Best supportive care with early palliative care involvement. | not mapped |