1. Introduction It is not too rare 3-5% year of newly diagnosed malignant tumours 4° most common cause of cancer- related death in both sex.

2. Background The most important breakthrough in the management of CUP is the identification of clinicopathologic subgroups to choose specific treatment protocols 20% of patients, the similarity of clinical presentation to those of known primary cancer at a similar stage as resulted in the identification of patients with favourable clinical and pathological future

3. Background 80% of pts have an ufavourable outcome future Identification of reliable prognostic factors are currently investigated in many trials

4. Background Favourable risk (20%) Unfavourable risk (80%)

5. Favourable groups Poorly differentiated carcinoma with midline nodal distribution Women with papillary adenocarcinoma of peritoneal cavity Poorly differentiated neuroendocrine carcinomas Women with adenocarcinoma involving only axillary lymph nodes

6. Favourable groups Squamous cell carcinoma involving cervical lymph nodes Men with blastic bone metastatic lesions from an adenocarcinoma with elevated serum prostate-specific antigen Isolated inguinal lymphadenopathy from squamous carcinoma Patients with a single small metastasis

7. Favourable highlights Tailored treatment as applied in metastatic tumours of known primary Similar prognosis and clinical course High response rates to treatments Observations of the metachronous appearance of the primary tumor

8. Favourable Treatable Subset of Patients with Cancer of Unknown Primary Site SubsetHistology Special diagnostic Tests Treatment Women, isolated axillary adenopathy Adenocarcinoma, PDC ER/PR/HER2 stains, MR breast Treat as stage II breast cancer Women, peritoneal carcinomatosis Adenocarcinoma, PDC Serum CA 125Treat as stage III ovarian cancer Man, blastic bone metastasisAdenocarcinomaSerum, tumor PSATreat as metastatic prostate cancer Single metastasisAdenocarcinoma, PDC PET scanDefinitive local therapy+- chemotherapy Young man, extragonadal GCT features PDCSerum HCG, AFPTreat as poor prognosis germ cell tumor Isolated cervical nodesSquamousENT exam, PET scanTreat as locally advanced head/neck cancer Isolated inguinal nodesSquamous Definitive local therapy +- chemotherapy Neuroendocrine TumorsWell and Poor differentiated Ocrteoscan,Chromogran ine Octreotide Analogs, Chemotherapy

9. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective? Pts with predominantly nodal disease Burden Female patients had predominantly peritoneal malignant deposits of papillary serous adenocarcinomatous or undifferentiated carcinomatous histology

10. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of CUP: Active, but how effective? Pts characteristics SUBSET

11. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective? Univariate analysis

12. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective? Multivariate analysis

13. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective? OS CR Non CR

14. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective? OS and TTP in months

15. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective? Response to chemotherapy

16. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective? Conclusion Highly predictive positive factors: N° of metastatic sites (1-3 Vs 4 or more) High serum CA125 Normal serum CA 19-9 Complete response status was not included in the prognostic factor analysis, although its achievement predicted superior outcome

17. PENTHEROUDAKIS et Al: Acta Oncologica, 2005 Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective? Conclusion No prognostic significance In patient management with platinum-based regimens, sex, performance status,histological grade, and peritoneal or nodal disease group Trend for statistical significance for female sex and peritoneal disease

18. G. R. Varadhachary, et Al: Lancet Oncol 2008 Favourable Carcinoma of unknown primary with a colon-cancer profile changing paradigm and emerging definitions CUP in association with a colon-cancer profile (CCP-CUP) is an example of an emerging, specific CUP subset that seems to benefit from a tailored approach CCP-CUP is identified by CK20 and CDX2- positive and CK7-negative immunohistochemistry CCP-CUP derive substantial benefit from the use of specific treatments developed for colon cancer Larger clinical trials are warranted to more definitely test this finding

19. G. R. Varadhachary, et Al: Lancet Oncol 2008 Favourable Carcinoma of unknown primary with a colon-cancer profile changing paradigm and emerging definitions

20. G. R. Varadhachary, et Al: JCO 2008 Favourable Molecular Profiling of CUP Correlation With Clinical Evaluation

21. G. R. Varadhachary, et Al: JCO 2008 Favourable Molecular Profiling of CUP Correlation With Clinical Evaluation

22. Unfavourable groups Adenocarcinoma metastatic to the liver or other organs Malignant ascites from a nonpapillary adenocarcinoma Multiple cerebral metastases from an adenocarcinoma or squamous carcinoma Multiple lung/pleural metastases from an adenocarcinoma Multiple metastatic bone disease from an adenocarcinoma

23. Unfavourable highlights Regression or dormancy of the primary Development of early Aggressive biology Systemic metastases Resistance to the therapy

24. Unfavourable highlights Despite of biomolecular knowledge, this remain an eterogeneous group of pathology Majority (80%) of pts with CUP had unfavourable outcome features Identification of reliable prognostic indicators remain a challenge Many studies with multivariate analysis have try to discover prognostic factors, but without an international consensus

25. Prognostic Factors in CUP Adverse Prognostic Variables AutorN° ptsUnivariateMultivariateResults Kambhu62Poor performance statusVisceral metastases below the diaphragm 30% of Response Rate Visceral metastases below the diaphragm Hainsworth220Tumor location outside retroperitoneal and peripheral 138 pts-63% Response Rate, 58 pts-26% had complete response, 10-year survival 16% lymph nodes No. of metastatic sites Abnormal serum CEA levelsPositive smoking history Abnormal serum LDH levelsOlder age Positive smoking history Abbruzzese657Male sex Adenocarcinoma histologic type No. of metastatic sites Lung, Liver, Bone, Pleura,Brain metastases Liver metastases Van der Gaast 79Poor performance status Good-prognosis WHO- 0 and alkaline phosphatase 4 years. Intermediate-prognosis WHO 0 or = 1.25 N. median survival 10 months Poor-prognosis WHO>=1 and an alkaline phosphatase level > or = 1.25 N. median survival 4 months Adenocarcinoma histologic type Serum alkaline phosphatase Bone, Liver metastases Serum alkaline phosphatase Serum AST

26. Prognostic Factors in CUP Prognostic Variables AutorN° ptsPrognostic Variables Results Lortholary311Male sex PS 1 Adenocarcinoma No. of metastatic sites 1 adenocarcinoma: 164 cases; squamous cell carcinoma: 90 cases; neuro-endocrine tumor: 10 cases; and others: 20 cases primary carcinoma was found in only 6% of the cases Median survival 9 months Culine150PS 1 Elevated LDH levels 3 subgroups of patients with median survivals of 10.8, 6.0, and 2.4 months; Good-risk and poor-risk patients were identified, with median survivals of 11.7 months and 3.9 months, 1-year survival rates were 53% and 23%, respectively Seve317PS 1 Liver metastases High comorbidity score Lymphopenia Elevated LDH serum levels Low serum albumin levels good-risk patients median survivals of 371 days poor-risk patients median survivals 103 days Lenzi337Male sex Age 64 years No. of metastatic sites 2 977 pts with CUP; PDC patients enjoyed better survival than PDA; The long median survival and chemotherapy responsiveness of UPC patients with PDC and PDA could not be confirmed Hess10001 or 2 metastatic organ sites, nonadenocarcinoma, histology, NO liver, bone, adrenal, or pleural metastases Median survival of the 10 subgroups ranged from 40 months (95% confidence interval, 22–66 months), High risk group median survival 5 months

27. Kenneth R. Hess et Al: Clinical Cancer Research 1999 Classification and Regression Tree Analysis of 1000 Consecutive Patients with Unknown Primary Carcinoma 1000 pts segregated into 10 groups with similar clinical features and survival Unfavourable

28. Kenneth R. Hess et Al: Clinical Cancer Research 1999 Classification and Regression Tree Analysis of 1000 Consecutive Patients with Unknown Primary Carcinoma

29. Kenneth R. Hess et Al: Clinical Cancer Research 1999 Classification and Regression Tree Analysis of 1000 Consecutive Patients with Unknown Primary Carcinoma OS

30. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With Carcinomas of an Unknown Primary Site Identification of subsets of patients with clinical and pathologic features requiring specific guidelines that may translate into prolonged survival Unfortunately, the majority of CUP (85%) do not fall into one of these favorable subsets The benefit of chemotherapy over best supportive care is still unknown The optimal chemotherapy remains to be determined

31. S Culine et Al: JCO, 2002 Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With CUP 150 pts CUP excluding favourable subset Results were validated in an independent set of pts Unfavourable

32. S Culine et Al: JCO, 2002 Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With CUP Unfavourable Pts characteristics

33. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With CUP Univariate analysis for survival

34. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With CUP

35. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With CUP

36. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With Carcinomas of an Unknown Primary Site Univariate analysis for survival

37. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With Carcinomas of an Unknown Primary Site

38. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With Carcinomas of an Unknown Primary Site Prognostic Model

39. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With Carcinomas of an Unknown Primary Site OS in Reference Population

40. S Culine et Al: JCO, 2002 Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With Carcinomas of an Unknown Primary Site OS in Validation Population

41. P. Seve et Al: Cancer, march 2006 The Influence of Comorbidities, Age, and Performance Status on the Prognosis and Treatment of Patients with Metastatic Carcinomas of Unknown Primary Site OS evaluated at cancer center NOT evaluated at cancer center

42. P. Seve et Al: Cancer, march 2006 The Influence of Comorbidities, Age, and Performance Status on the Prognosis and Treatment of Patients with Metastatic Carcinomas of Unknown Primary Site

43. P. Seve et Al: Cancer, September 2006 Unfavourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site

44. P. Seve et Al: Cancer, September 2006 Unfavourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site

45. P. Seve et Al: Cancer, September 2006 Unfavourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site

46. P. Seve et Al: Cancer, September 2006 Unfavourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site Multivariate Analisys Of OS

47. P. Seve et Al: Cancer, September 2006 Unfavourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site Prognostic Model Good No liver Metastases Poor Liver Metastases and Low albumin or Low albumin 61 39 371 122 12 108 Prognostic Group Prognostic variable Survival,% Survival (months) N° pts 1yr Median

48. P. Seve et Al: Cancer, September 2006 Favourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site OS In Reference pts Good risk Poor risk

49. P. Seve et Al: Cancer, September 2006 Favourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site Good risk Poor risk OS In Independent pts

50. M. Kodaira, et Al: Annals of Oncology 2009 Bone metastasis and poor performance status are prognostic factors for survival of CUP in patients treated with systematic chemotherapy Pts characteristics

51. M. Kodaira, et Al: Annals of Oncology 2009 Treatments Results Bone metastasis and poor performance status are prognostic factors for survival of CUP in patients treated with systematic chemotherapy

52. M. Kodaira, et Al: Annals of Oncology 2009 Bone metastasis and poor performance status are prognostic factors for survival of CUP in patients treated with systematic chemotherapy Univariate e Multivariate analisys

53. M. Kodaira, et Al: Annals of Oncology 2009 Bone metastasis and poor performance status are prognostic factors for survival of CUP in patients treated with systematic chemotherapy Prognostic Model

54. But the chemotherapy regimens influences the outcome of CUP?

55. D. E. Saad, et Al: Oncology/Hematology 2000 Prognostic stratification in UPC: a role for assessing the value of conventional-dose and high-dose chemotherapy for CUP

56. D. E. Saad, et Al: Oncology/Hematology 2000 Prognostic stratification in UPC: a role for assessing the value of conventional-dose and high-dose chemotherapy for CUP

57. D. E. Saad, et Al: Oncology/Hematology 2000 Prognostic stratification in UPC: a role for assessing the value of conventional-dose and high-dose chemotherapy for CUP No chemotherapy regimen can be considered standard in the treatment of CUP without features of the extragonadal germ cell syndrome or of the other favorable subgroups Trials performed to date had only active treatments in their arms, and therefore no definitive conclusions can be drawn regarding the superiority of active therapy versus best supportive care

58. V. Golfinopoulos, et Al: Cancer Treatment Reviews 2009 Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple- treatments meta-analysis Data sources: PubMed and the Cochrane Library Central Registry of Controlled Trials Randomized controlled trials comparing No favourable subset Regimens are divided in : platinum, taxane, both, or neither; non-platinum/non-taxane. No type of chemotherapy has been solidly proven to prolong survival in patients with CUP

59. V. Golfinopoulos, et Al: Cancer Treatment Reviews 2009 Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple- treatments meta-analysis

60. V. Golfinopoulos, et Al: Cancer Treatment Reviews 2009 Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple- treatments meta-analysis CONCLUSION No trials compared systemic treatment to best supportive care All arms referred to chemotherapy Multiple-treatments meta-analysis showed no significant benefit Point estimates of hazard ratios favored platinum, taxane, or both (hazard ratios 0.69, 0.66, and 0.81, respectively, as compared with monotherapy with an agent other than platinum or taxane)

61. Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: A systematic literature review Pentheroudakis, et Al: Cancer Treatment Reviews 2009

62. Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: A systematic literature review Pentheroudakis, et Al: Cancer Treatment Reviews 2009

63. Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: A systematic literature review Pentheroudakis, et Al: Cancer Treatment Reviews 2009

64. Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: A systematic literature review Pentheroudakis, et Al: Cancer Treatment Reviews 2009 Chemotherapy activity and pts Outcome in CUP and Metastatic tumors of KNOWN primary

65. CONCLUSION Despite advances in molecular immunohistochemistry and imaging technology, the diagnosis and therapy of CUP remains a challenge Major advance in the field over the last decade was made by identifying the clinicopathological subsets of CUP patients with a more favourable prognosis.

66. CONCLUSION This allowed for tailoring of the therapeutic strategy towards more intensive modalities for good risk groups Patients with midline nodal metastases as well as women with non-mucinous peritoneal carcinomatosis are thought to have entities equivalent to extragonadal germ cell cancer and ovarian cancer may respond to systemic platinum- based chemotherapy and occasionally enjoy long- term survival

67. CONCLUSION Most patients received platinum based chemotherapy, commonly coupled with a taxane. Response rate 50%, among the highest reported to date, reproduced by a few authors using platinum- taxane regimens No prospective studies or meta-analysis of prognostic factors for CUP have been published