eTable 1. Case series of unselected patients with CUP (in chronological order)*.

Reference	Study population	Results
Altman E, Cadman E: An analysis of 1539 patients with cancer of unknown primary site. Cancer 1986; 57: 120–4.	1539 patients from a single center (USA), timeframe 1922–1981	Median overall survival 5 months. Only 56% received therapy. 18% of cases not histologically confirmed. Patients with histological confirmation and who received therapy had a median survival of 7 months.
Alberts AS, Falkson G, Falkson HC, van der Merwe MP: Treatment and prognosis of metastatic carcinoma of unknown primary: analysis of 100 patients. Med Pediatr Oncol 1989; 17: 188–92.	100 patients from a single center (South Africa), timeframe 1977–1984	Median overall survival 124 days. Poor physical performance (ECOG score) was prognostically unfavorable.
Pavlidis N, Kalef-Ezra J, Briassoulis E, et al.: Evaluation of six tumor markers in patients with carcinoma of unknown primary. Med Pediatr Oncol 1994; 22: 162–7.	85 patients from three centers (Greece), timeframe 1986–1991	Aim was to study serum tumor markers. Median overall survival not stated, but the Kaplan–Meier curves provided showed it to be about 5 months. CA 19-9 and CA 15-3 levels correlated with number of metastases.
Abbruzzese JL, Abbruzzese MC, Hess KR, Raber MN, Lenzi R, Frost P: Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 1994; 12: 1272–80	657 patients from a single center (M. D. Anderson, USA), timeframe 1987–1992	Median overall survival 11 months. The patients studied appear to be a subgroup of the cases reported on again later by the same team of authors, see next row.
Hess KR, Abbruzzese MC, Lenzi R, Raber MN, Abbruzzese JL: Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res 1999; 5: 3403–10.	1000 patients from a single center (M. D. Anderson, USA), timeframe 1987–1994	Median overall survival 11 months. Two prognostic stratifications systems with 10 vs. 9 groups. Prognostically relevant parameters included number of organ systems involved, histological type (non-adenocarcinoma prognostically better, neuroendocrine carcinomas particularly good), and pattern of involvement (including adrenal metastases as particularly poor).
van de Wouw AJ, Janssen-Heijnen ML, Coebergh JW, Hillen HF: Epidemiology of unknown primary tumours; incidence and population- based survival of 1285 patients in Southeast Netherlands, 1984–1992. Eur J Cancer 2002; 38: 409–13.	1285 cases from cancer registry data (Netherlands, representing approx. 1 million inhabitants), timeframe 1984–1992	1024 histologically confirmed cases, 261 exclusively clinically diagnosed cases. Histologically confirmed cases: median age 66 years, median overall survival 11 weeks, 67% received only supportive therapy. Prognostically favorable: age <50 years, lymph node involvement.
Levi F, Te VC, Erler G, Randimbison L, La Vecchia C: Epidemiology of unknown primary tumours. Eur J Cancer 2002; 38: 1810–2.	699 cases from cancer registry data from two Swiss cantons (total number of inhabitants 786000), timeframe 1984–1993	543 histologically confirmed cases: median age 71 years, median overall survival 11 weeks. 156 exclusively clinically diagnosed cases: median age 79 years, median overall survival 6 weeks. Only prognostically more favorable histologically defined subgroup was squamous cell carcinomas with a median overall survival of 41 months.
Culine S, Kramar A, Saghatchian M, et al.: Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. J Clin Oncol 2002; 20: 4679–83.	150 patients from a single center (France), timeframe 1989–1999	Median overall survival 7.5 months. Establishing a prognostic model based on poor physical condition (ECOG score) and either presence of liver metastases or raised serum LDH (these two parameters correlated to each other) as unfavorable prognostic factors.
van de Wouw AJ, Jansen RL, Griffioen AW, Hillen HF: Clinical and immunohistochemical analysis of patients with unknown primary tumour. A search for prognostic factors in UPT. Anticancer Res 2004; 24: 297–301.	70 patients from a single center (Netherlands), timeframe 1990–1996	Median overall survival 12 weeks. Unfavorable prognostic factors: age ?60 years, ECOG score >1, number of organ systems involved >2, liver metastases, raised LDH.
Seve P, Ray-Coquard I, Trillet-Lenoir V, et al.: Low serum albumin levels and liver metastasis are powerful prognostic markers for survival in patients with carcinomas of unknown primary site. Cancer 2006; 107: 2698–705.	317 patients from a single center (Canada), timeframe 1998–2004	Median overall survival 104 days. Poor prognosis group defined by liver metastases or reduced serum albumin. ECOG score >1 also prognostically unfavorable.
Ponce Lorenzo J, Segura Huerta A, Diaz Beveridge R, et al.: Carcinoma of unknown primary site: development in a single institution of a prognostic model based on clinical and serum variables. Clinical Transl Oncol 2007; 9: 452–8.	100 patients from a single center (Spain), timeframe 2002–2006	Limited to main population of CUP by exclusion of subgroups with specific therapy options. Median overall survival 4.7 months. Unfavorable prognostic factors included ECOG score >1, number of organ systems involved >2, liver metastases.
Trivanovic D, Petkovic M, Stimac D: New prognostic index to predict survival in patients with cancer of unknown primary site with unfavourable prognosis. Clin Oncol 2009; 21: 43–8.	145 patients from two centers (Croatia), timeframe 2002–2007	Limited to main population of CUP by exclusion of subgroups with specific therapy options. Median overall survival 330 days. Unfavorable prognostic factors: ECOG score >1, liver metastases, raised LDH, anemia, higher age, QT prolongation.
Thöm I, Rogers C, Andritzky B, et al.: Single-center management of 136 patients with cancer of unknown primary site (CUP syndrome) over a period of 10 years. Onkologie 2009; 32: 741–6.	136 patients from a single center (Uniklinik Hamburg-Eppendorf), timeframe 1989–1998	Median overall survival 7.9 months. Prognostic parameters: patient?s general condition, sex (women had a better prognosis), mode of therapy (resection was best), Hübner prognostic group (based on tumor stage and patient?s general physical condition).
Fernandez-Cotarelo MJ, Guerra-Vales JM, Colina F, de la Cruz J: Prognostic factors in cancer of unknown primary site. Tumori 2010; 96: 111–6.	265 patients from a single center (Spain), timeframe 1999–2003	Median overall survival 2.5 months. Squamous cell carcinoma was prognostically favorable. Other prognostic factors: age, serum levels of albumin and alkaline phosphatase, treatment.
Petrakis D, Pentheroudakis G, Voulgaris E, Pavlidis N: Prognostication in cancer of unknown primary (CUP): development of a prognostic algorithm in 311 cases and review of the literature. Cancer treatment reviews 2013; 39: 701–8.	311 patients from a single center (Greece), timeframe 1988–2011	Median overall survival 8 months. Establishing a prognostic model based on poor physical condition (ECOG score), leukocytosis, and visceral metastases as unfavorable prognostic factors.

*Case series were collected through a combined approach that included searching a literature database (PubMed) using relevant search terms, and mining our own literature archive for relevant studies and relevant current publications for the literature they cited. All internationally published studies on CUP, in which patients were not selected with reference to age or suitability for treatment, and which investigated overall survival and clinically relevant patient characteristics (e.g., organ systems involved, tumor markers), are listed. Studies that were restricted to rarer subgroups were not included. However, studies that excluded rarer subgroups, but did investigate at least the most frequent subcategory (adenocarcinoma) are included. Some studies included patients without histological confirmation, whose diagnosis was made on an exclusively clinical basis; this is noted above individually for the relevant studies.