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    MCO 2011 - Slide 34 - N. Pavlidis - Spotlight session - Cancer of unknown primary MCO 2011 - Slide 34 - N. Pavlidis - Spotlight session - Cancer of unknown primary Presentation Transcript

    • C ANCER OF U NKNOWN P RIMARY S ITE PROFESSOR OF MEDICAL ONCOLOGY MEDICAL SCHOOL, UNIVERSITY OF IOANNINA GREECE ESO Masterclass, April 2011 N ICHOLAS P AVLIDIS
    • CANCER OF UNKNOWN PRIMARY ( CUP ) 1) DEFINITION 2) EPIDEMIOLOGY 3) PATHOLOGY 4) NATURAL HISTORY 5) DIAGNOSTIC APPROACH 6) TREATMENT
    • I S T HERE A D EFINITION FOR C ANCER O F U NKNOWN P RIMARY O RIGIN ?
    • T HE D EFINITION All patients presented with histologically confirmed metastatic carcinoma in whom a complete medical history, careful physical examination, chest x-ray, full blood count, stool occult blood testing and urinalysis did not identify the primary site. In 1970’s
      • Histologically confirmed metastatic cancer
      • Detailed medical history
      • Complete physical examination (plus pelvic and rectal exam)
      • Chest radiography
      • Full blood count
      • Biochemistry
      • Urinalysis
      • Stool occult blood testing
      • Histopathology review and use of immunohistochemistry
      • Computed tomography of chest, abdomen and pelvis
      • Mammography or MRI (in certain cases).
      • PET – scan (in certain cases).
      C LINICAL AND L ABORATORY D ATA R EQUIRED T O D EFINE A P ATIENT AS H AVING A C UP
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    • W HAT IS THE I NCIDENCE OF C ANCER OF U NKNOWN P RIMARY S ITE ?
    • EPIDEMIOLOGY OF CANCER OF UNKNOWN PRIMARY Geographical area Source Frequency (%) Period USA SEER 2.3 1973-1987 Australia New South Wales Registry 4.2 1970-1990 Netherlands Eindhoven Cancer Registry 4.0 1984-1992 Finland IARC 2.5 - Germany - 7.8 1968-1984 Russia - 3.6 - Switzerland Local registries 2.3 1984-1993 Japan IARC 3.0 -
    • DON’T FORGET THAT
      • CUP represents the 7 th – 8 th most frequent type of cancer and the 4 th commonest cause of cancer death.
      • It is considered to be more common than non-Hodgkin’s lymphoma
    • THE N ATURAL H ISTORY OF C ANCER OF U NKNOWN P RIMARY S ITE
    • FUNDAMENTAL CHARACTERISTICS
      • Early dissemination
      • Clinical absence of primary at presentation
      • Aggressiveness
      • Unpredictable metastatic pattern
    • UNPREDICTABLE METASTATIC PATTERN
      • Refers to the differences in the incidence of metastatic sites at diagnosis between known and unknown primary carcinomas
      • E x a m p l e
      • Pancreatic cancer presenting as CUP has 4-fold higher incidence to affect bones, and 30% incidence to appear with lung metastases.
    • C ancer of U nknown P rimary Site : One or more Diseases ?
    • H I S T O L O G Y I N C I D E N C E A d e n o c a r c i n o m a Well to moderately differentiated Poorly or undifferentiated   S q u a m o u s c e l l c a r c i n o m a   U n d i f f e r e n t i a t e d ne o p l a s m s Not specified carcinoma Neuroendocrine tumors Lymphomas Germ cell tumors Melanomas Sarcomas Embryonal malignancies   HISTOLOGICAL CLASSIFICATION 50 % 35 % 10 % 5 %
    • CLINICOPATHOLOGICAL ENTITIES OF CUP O R G A N H I S T O L O G Y Liver (mainly) and/or other organs AdenoCa M or P diff Lymph nodes Mediastinal – Retroperitoneal (midline distribution) U or P diff Ca Axillary AdenoCa W to P diff Cervical SCC Ca Inguinal U Ca, SCC, mixed SCC / adenoCa W = well, M = moderately, P = poorly, U = undifferentiated
    • W = well, M = moderately, P = poorly, U = undifferentiated Lungs Pulmonary metastases Pleural effusion AdenoCa various diff AdenoCa M or P diff Peritoneal cavity Peritoneal adenocarcinomatosis in females Malignant ascites of other unknown origin Papillary or serous adenoCa ( ± psammoma bodies ) Mucin adenoCa M or P diff ( ± signet ring cells )
    • W = well, M = moderately, P = poorly, U = undifferentiated Bones (solitary or multiple) AdenoCa of various diff Brain (solitary of multiple) AdenoCa of various diff or squamous cell Ca Neuroendocrine tumors P diff Ca with neuroendocrine features (mainly), low-grade neuroendocrine Ca, small cell anaplastic Ca Melanoma U neoplasm with melanoma features.
    • WHAT IS THE OPTIMAL INVESTIGATIONAL DIAGNOSTIC APPROACH FOR THE IDENTIFICATION OF THE PRIMARY TUMOR ?
    • HOW DO WE SEARCH FOR THE PRIMARY ? By IMAGING By ENDOSCOPY By HISTOPATHOLOGY Immunohisto-chemistry Advanced Molecular Technology CT- scans MRIs PET- scans Mammography Ultrasonography Conventional Radiology ENT panendoscopy Bronchoscopy Colonoscopy Proctoscopy Colposcopy
    • By HISTOPATHOLOGY
    • STEPS OF IMMUNOHISTOCHEMICAL DIAGNOSTIC APPROACH FOR CUP
      • Carcinoma AE 1/3 pancytokeratin
      • Lymphoma Common leucocyte antigen (CLA)
      • Melanoma S100, HMB45
      • Sarcoma S100, Vimentin
      STEP 1 (Detects broad type of cancer)
      • Adenocarcinoma CK 7/20, PSA
      • Germ cell tumour PLAP, OCT4, AFP, HCG
      • Hepatocellular Carcinoma Hepar 1, canalicular pCEA/CD10/CD13
      • Renal cell carcinoma RCC, CD10
      • Thyroid carcinoma TTF1, thyroglobulin
      • Neuroendocrine carcinoma Chromogranin, synaptophysin, PGP 9.5, CD56
      • Squamous carcinoma CK 5/6, p63
      STEP 2 (Detects subtype of carcinoma)
      • Prostate PSA, PAP
      • Lung TTF1
      • Breast GCDFP-15, mammaglobulin, ER
      • Colon CD X 2, CK 20
      • Pancreas/Biliary CD X 2, CK 20, CK7
      • Ovary ER, Ca 125, mesothelin
      STEP 3 (Detects origin of an adenocarcinoma)
    • C YTOKERATINS (CKS)
      • Monoclonal antibodies against cytokeratin polypeptides CK7 and CK20
    • CK7 CK20 CK7 + CK20 + CK7 + CK20 - CK7 - CK20 + CK7 - CK20 - Urothelial tumors Ovarian mucinous adenocarcinoma Pancreatic adenocarcinoma Cholangiocarcinoma Lung adenocarcinoma Breast carcinoma Thyroid carcinoma Endometrial carcinoma Cervical carcinoma Salivary gland carcinoma Cholangiocarcinoma Pancreatic carcinoma Colorectal Carcinoma Merkel cell carcinoma Hepatocellular carcinoma Renal cell carcinoma Prostate carcinoma Squamous cell & small cell lung carcinoma Head & neck carcinoma
    • MOLECULAR ANALYSIS [Microarray Platforms] > 80% accuracy
    • Gene expression profiling A s s a y s Assay Platform Tissue No. of Tumor types Number of genes Accuracy in known tumors (%) Veridex RT-PCR mRNA FFPE 6 and ”other” 10 76 Pathwork Diagnostics Tissue of Origin test cDNA microarray Frozen/ FFPE 15 1500 89 Rosetta Genomics MiReview met RT-PCR miRNA FFPE 22 48 miRNAs 86 bioTheranostics CancerType ID RT-PCR mRNA FFPE 39 (including subtypes) 92 86
    • By IMAGING
      • Imaging Study
      • Chest X-ray
      • Barium studies
      • CT-scans
      • Mammography
      • MRI (breast)
      • FDG-PET SCAN
      • Diagnostic Value
      • Prerequisite test
      • Useless
      • 40% accuracy / Guidance to biopsy
      • Low sensitivity
      • 60% accuracy
      • 43% accuracy / more sensitive for occult H+N and Lung Ca
      IMAGING STUDIES IN CUP
    • By ENDOSCOPY
    • ENDOSCOPY
      • Should always be symptoms - or sings oriented investigational procedures
      • ENT panendoscopy : in cervical node involvement
      • Bronchoscopy : in radiographic indications or symptoms
      • Colonoscopy : in relevant symptoms and signs
      • Proctoscopy : in inguinal node involvement
      • Colposcopy : in inguinal node involvement
    • SERUM TUMOR MARKERS
      • Routine evaluation of current commonly used markers have
      • not been proven of any prognostic or diagnostic assistance
      • A non – specific multiple overexpression of the adenocarcinoma
      • markers (CEA, CA 125, CA 15-3, CA 19-9) has been observed in
      • the majority of CUP patients.
      • Worthwhile to request :
      • PSA in men with bone metastatic adenocarcinoma
      • Β- HCG & AFP in men with an undifferentiated tumor
      • AFP in patients with hepatic tumors
      • CA 125 women with papillary adenocarcinoma of peritoneal cavity.
      • CA 15-3 women with adenocarcinoma involving only axillary lymph nodes .
    • HOW OFTEN CAN THE PRIMARY TUMOR BE INDENTIFIED ?
    • IDENTIFICATION OF PRIMARY SITE BY EXTENSIVE ROUTINE DIAGNOSTIC WORK - UP
      • The antemortem frequency of detection of primary site by imaging, endoscopy or immunohistochemistry studies remains around 30%.
      Pavlidis et al, Eur J Cancer 39: 1990-2005, 2003
    •  
    • IDENTIFICATION OF PRIMARY SITE AT AUTOPSY FROM ALL PUBLISHED SERIES
      • Years of Publications : 1944 - 2000
      No of Autopsies : 884 Primary Site Found : 73 % (644 / 884) Genital system 7 % Stomach 6 % Bladder / ureter 0.01 % Breast 0.007 % Other 10 % Lung 27 % Pancreas 24 % Liver/bile duct 8 % Kidney /adrenals 8 % Bowel 7 % Primary Sites Identified :
    • IDENTIFICATION OF PRIMARY SITE BY GENETIC PROFILING (MICROARRAYS) FROM ALL PUBLISHED CUP SERIES
      • Years of Publications : 2005- 2007
      No of Samples : > 500 (cDNA) Biological Assignment of Primaries (Accuracy) : 50 – 87 % Primary Sites Identified : Liver/bile duct 8 % Kidney / adrenals 6 % Bladder / ureter 5 % Stomach 3 % Other 18 % Breast 15 % Pancreas 12.5 % Bowel 12 % Lung 11.5 % Genital system 9 %
    • WHAT IS THE OPTIMAL THERAPEUTIC APPROACH OF CANCER OF UNKNOWN PRIMARY ?
    • Overall comparative results of chemotherapy in CUP patients. A review of all phase II non –randomized studies 5-FU / Anthracycline combinations Platinum based combinations Platinum / taxane –based combinations No articles 12 28 18 Years 1964 - 1993 1983 - 2009 1997 - 2010 No patients 738 1238 1317 Response Rate % (mean ) 16.8 33.5 39.5 Mean Survival (months) 6.7 8.4 11.4
    • DO WE HAVE EFFECTIVE DRUGS FOR CANCER OF UNKNOWN PRIMARY OR WE JUST HAVE RESPONSIVE SUBSETS OF PATIENTS ?
    • DIAGNOSTIC AND THERAPEUTIC MANAGEMENT OF CANCER OF AN UNKNOWN PRIMARY N. Pavlidis, E. Briasoulis, J. Hainsworth, E.A. Greco 39 : 1990 – 2005, 2003
    • WHAT IS CANCER OF UNKNOWN PRIMARY ? Lung-hidden CUP Pancreas-hidden CUP Liver-hidden CUP Prostate-hidden CUP Breast-hidden CUP Colon-hidden CUP Kidney-hidden CUP Gastric-hidden CUP
    • FAVOURABLE OR GOOD PROGNOSIS SUBSETS UNFAVOURABLE OR POOR PROGNOSIS SUBSETS CUP
    • THE FAVOURABLE SUBSETS OR GOOD PROGNOSIS SUBSETS
    • 1.  Poorly differentiated carcinoma with midline distribution (extragonadal germ cell syndrome). F a v o u r a b l e S u b s e t s 2. Women with papillary adenocarcinoma of peritoneal cavity. 3.   Women with adenocarcinoma involving only axillary lymph nodes. 4.   Squamous cell carcinoma involving cervical lymph nodes 5. Poorly differentiated neuroendocrine carcinomas. 6. Men with blastic bone metastases and elevated PSA (adenocarcinoma). 7. Isolated inguinal adenopathy (squamous carcinoma). 8. Patients with a single , small, potentially resectable tumor.
    • CHARACTERISTICS OF PATIENTS WITH POORLY DIFFERENTIATED CUP GENDER / AGE : Men / < 50 yrs TUMOR INVOLVEMENT : Mediastinum Retroperitoneum Lungs Lymph nodes TUMOR MARKERS : Elevated serum levels of β -HGC or AFP CLINICAL EVOLUTION : Rapid tumor growth RESPONSE TO Rx : Favourable response to Cisplatin - based chemotherapy. RR 50% (CRs: 15-25%) SURVIVAL : Median : 13 months 15% long – term survivors
    • Cancer of Unknown Primary Patients with Midline Nodal Distribution: midway between poor and favourable prognosis ? Pentheroudakis G, Stoyianni A, Pavlidis N. N : 64 patients ORR (to platinum ) : 48% (CRs : 11%) Survival : 12 mos 2-yr Survival : 18% Cancer Treatment Reviews (37:120-126,2011) Literature Review = N 714 pts , ORR : 35 – 65 % , Survival (median) : 12 mos
    • PERITONEAL CARCINOMATOSIS IN FEMALES Incidence 10 % of invasive serous ovarian Ca, 10% of CUP patients Mean Age ( yrs ) 60 ( 25 – 80 ) Clinical Picture Abdominal distension, pelvic masses, ascites T H E N A T U R A L H I S T O R Y Surgical Picture Abdominal masses, peritoneal disease, ascites, with normal ovaries Histology Papillary serous carcinoma ( ± psammoma bodies ) Serum CA-125 Often abnormal or markedly elevated.
    • WOMEN WITH PAPILLARY ADENOCARCINOMA OF PERITONEAL CAVILY ( Peritoneal Adenocarcinomatosis ) Treatment :
      • As FIGO III ovarian cancer.
      • Surgical cytoreduction.
      • Platinum – based chemotherapy.
      Response Rate : 40 – 60 % (CR : 30 %) Survival : Median : 16 months Long – term survival : 5-yr: 10 %
    • Serous Papillary Peritoneal Carcinoma: Unknown primary tumour, ovarian cancer counterpart or a distinct entity? A systematic review Years : 1980 – 2008 (25 studies) N o Pts : SPPCs 579 SOCs 1408 SPPC = Serous Papillary Peritoneal Carcinoma SOC = Serous Ovarian Carcinoma G. Pentheroudakis, N. Pavlidis Crit Rev Oncol Hematol 75: 27-42, 2010 SPPCs SOCs ORR 71% 70% OS (median) 24,4 mos 29 mos
    • ISOLATED AXILLARY NODAL METASTASES FROM AN OCCULT PRIMARY BREAST CANCER
    • Years : 1975 – 2006 (24 studies) N : 689 patients Mean Age : 52 yr Menopause status : Postmenopausal 66% Premenopausal 34% Histology : Ductal adenocarcinoma 83%, ER/PR 40 - 50/%, HER2 31% Nodal status : N1 : 48% > N1 : 52% Simultaneous distant mets : 2%
      • Mastectomy / axillary dissection : 59 %
      • Primary breast irradiation : 26 %
      • Observation : 15 %
      • Logoregional recurrence rate : 25 % (mostly in observation cases)
      • 5-yr Survival : 72 % (similar to stage II-III breast cancer)
      • No survival difference between conservative management (breast preservation + RT) and mastectomy
      Treatment and Outcome
    • TREATMENT RECOMMENDATIONS AXILLARY LYMPH NODE S u r g i c a l B i o p s y Other Neoplasm Compatible with Breast Cancer +ve for Breast Cancer Complete Axillary Dissection ± BC Surgery + Radiotherapy Standard treatment -ve for Breast Cancer Chemotherapy or hormonotherapy depending on age and menopausal status Mammogram U/S MRI Type III level of evidence
    • SQUAMOUS CELL CANCER INVOLVING CERVICAL LYMPH NODES Survival :
      • 5-year survival 35–50% .
      • Documented long term disease – free survivors.
      Treatment :
      • As locally advanced head-neck cancer.
      • Surgery alone is inferior except pN1 neck disease with no extracapsular extension.
      • Radiation : both sides of neck and mucosa (entire pharyngeal axis and larynx).
      • Chemotherapy remains undefined (despite encouraging results with Platinum-based).
    • POORLY DIFFERENTIATED NEUROENDOCRINE CARCINOMAS S u r v i v a l : Median : 14.5 months 3-yr : 24% T r e a t m e n t : Platinum – based or paclitaxel / carboplatin – based chemotherapy R e s p o n s e : 50 – 70% ( CR : 25% )
    • Neuroendocrine carcinoma of unknown primary : A systematic review of the literature and a comparative study with other neuroendocrine tumours. Stoyianni A, Pentheroudakis G, Pavlidis N. Years : 1988 - 2010 No Papers : 39 No Patients : 515 N Patients treated : 174 (34 %) (Platinum –based) RR : 55 % (21% CRs) Median Survival : 15.5 mos (11.6 – 40) Long –term Survivors : 13% Cancer Treatment Reviews (2011, in press)
    • OTHER FAVOURABLE CUP SUBSETS
      • Men with adenocarcinoma blastic bone metastases (and elevated PSA)
      • Rx = Treat as metastatic prostate cancer
      • Isolated inguinal lymphadenopathy from squamous cell carcinoma
      • Rx = Dissection ± radiotherapy
      • Single metastatic site
      • Rx = Dissection ± radiotherapy
    • THE UNFAVOURABLE SUBSETS OR POOR PROGNOSIS SUBSETS
    • U N F A V O U R A B L E S U B S E T S
      • Adenocarcinoma metastatic to the liver or other organs
      • Non-papillary malignant ascites (adenocarcinoma)
      • Multiple cerebral metastases (adeno or squamous Ca)
      • Multiple lung/pleural metastases (adenocarcinoma)
      • Multiple metastatic bone disease (adenocarcinoma)
    • Greco F, Pavlidis N. Semin Oncol, 2009
    • THE SUBSET OF ADENOCARCINOMA METASTATIC TO THE LIVER
    • HISTOLOGIC SPECTRUM OF LIVER METASTASES Histology Mousseau et al [Bull Cancer 1991] Ayoub et al [JCO 1998] Hogan et al [Clin Radiol 2002] Poussel et al [Gastr Clin Biol 2005] Lazaridis et al [Cancer Treat Rev 2008] Total (N= 91) (N=365) (N=88) (N=118) (N=49) (N=711) Adenocarcinoma 78% 61% 79.5% 58% 69% 69% Undifferentiated 12% 27% 3.5% 20% 24% 20% Neuroendocrine - 9% 9% 14% 6% 9% Squamous 6% 2% 4.5% 4% 0% 4% Others 4% 1% 3.5% 4% - 3%
    • OVERALL RESULTS OF CHEMOTHERAPY IN CUP PATIENTS WITH LIVER METASTASES
      • N o of trials : 5 (1991, 1998, 2002, 2005, 2008)
      • N o of patients : 711
      • Response rate : < 20%
      • Median survival : 5.5 months
      Bull Cancer 1991, J Clin Oncol 1998, Clin Radiol 2002, Gastroent Clin Biol 2005, Cancer Treat Rev 2008
    • HOW SHOULD WE TREAT PATIENTS WITH UNFAVOURABLE CUP?
      • Patients with relatively young age and good P.S. could offer a chance of platinum - based chemotherapy
      • Alternatively, best supportive care should be recommended.
      ESMO, Clinical Recommendations 2008
    • PHASE II TRIAL OF BEVACIZUMAB AND ERLOTINIB IN CUP [J Clin Oncol 2007]
      • 47 eligible patients
      • Bevacizumab 10 mg/kg i.v. q 2 wks
      • Erlotinib 150 mg p.o. daily
      • ORR : 5 ( 10 % ) had PR
      • 29 ( 61 % ) had SD
      • Survival : median : 7.4 mos
      • 1-year : 33%
    • SECOND - LINE CHEMOTHERAPY IN CUP PATIENTS (a) From dignosis, (b) From start of 2 nd line CX REGIMENS N ORR (%) MEDIAN SURVIVAL (months) Gemcitabine 39 8 - Fluorouracile Leukovorin 25 0 9 a Docetaxel Gemcitabine 15 28 8 b Gemcitabine Irinotecan 40 10 4.5 Capecitabine Oxaliplatin 25 13 3.9
      • DOES THE IDENTIFICATION OF PRIMARY SITE BY MOLECULAR PROFILING IMPROVE PATIENTS’ OUTCOME ?
      ? WHAT IS THE EVIDENCE TODAY ?
    • Lancet Oncology 6: 596-99, 2008
      • Survival : CR/PR = 15,5 months
      • SD = 14,0 months
      CLINICOPATHOLOGICAL CHARACTERISTICS OF PATIENTS WITH GENE PROFILE DIAGNOSIS OF COLON CANCER J Clin Oncol 26:4442 – 48, 2008 SURVIVAL DATA 23 patients
    • A Phase II Study of Treatment Based on Molecular Profiling Diagnosis for Patients with CUP JD Hainsworth, www.clinicaltrials.gov Empiric CUP Treatment CUP after conventional work-up Specific Diagnosis No Specific Diagnosis Site-specific Treatment Gene expression profiling
    • Treatment of CUP Directed by Molecular Profiling Diagnosis: A Prospective, Phase II Trial
      • N : 110 patients
      • Assay : Cancer TYPE ID – assay (bioTheranostics, Inc), a 92 gene RT-PCR assay
      • Prediction of Primary : 89%
      Hainsworth J, et al, ASCO 2010
    • FEASIBILITY OF MOLECULAR PROFILING - RESULTS IN PATIENTS ENROLLED N o of Patients (%) Total patients enrolled 110 Pts who received assay-directed therapy 66 (60%) Pts did not receive assay-directed therapy due to various reasons 44 (40%)
    • RESULTS OF ASSAY – DIRECTED THERAPY Diagnosis No of Patients Evaluated Objective Response (%) Stable disease > 6 months Pancreatic 10 2 ( 20%) 5 ( 50%) Colorectal 8 2 ( 25%) 4 ( 50%) Urinary bladder 8 4 ( 50%) 2 ( 25%) Non-small cell lung 4 4 (100%) 0 Ovarian 4 4 (100%) 0 Breast 3 3 (100%) 0 Gallbladder 3 1 ( 3%) 2 ( 67%) Liver 3 0 3 (100%) Renal cell 3 0 2 ( 67%) Skin (squamous) 3 1 ( 33%) 0 Carcinoid - intestine 2 0 1 ( 50%)
    • IRINOTECAN-CONTAINING REGIMENS IN CUP 1-yr Reference N Regimen ORR Med. Survival ASCO 2002 80 Cisplatin/Gemcitab vs Cisplatin/ IRINO 42 % vs 25 % 22% vs 23% JCO 2003 80 Cisplatin/Gemcitab vs Cisplatin/ IRINO 55 % vs 38 % 8 mos vs 6 mos Oncologist 2004 132 Taxol/Carbo/VP-16  IRINO 30 % 9.1 mos Cancer Chem Pharm 2007 47 Oxaliplatin/ IRINO 13 % 9.5 mos
    • COMPARATIVE ACTIVITY OF CHEMOTHERAPY BETWEEN PTS WITH METASTATIC BREAST OR COLORECTAL CANCER & CUP PTS Pentheroudakis et al, Cancer Treat Rev, 2008 CX = Chemotherapy, A= Anthracycline, T= Taxane Metastatic Breast Cancer 5 (R) 2802 A-based T-based 41% 22 months CUP and A-based CX 10 (II+R) 679 A-based 29% 7 months N Studies N Pts Rx ORR OS (median) Metastatic Colorectal Cancer 7 (R) 2978 FU-based Oxal-based Irin-based 39% 19 months CUP and Colorectal Type of CX 8 (II + R) 673 FU-based Oxal–based Irin - based 14% 5.5 months
    • QUESTION Do we have evidence that site-specific treatment offers better response rates and better survival to poor prognosis CUP patients ? ANSWER
      • Poor evidence
      • Anecdotal data
      • Randomized studies are lacking
      • Solid proof is waranted
    • STEPS IN DIAGNOSTIC AND THERAPEUTIC MANAGEMENT STEP I   SEARCH FOR PRIMARY SITE Complete Medical History and Physical Examination Basic Laboratory Work-up and/or Specific Tests STEP II RULE-OUT POTENTIALLY TREATABLE OR CURABLE TUMORS (Immunohistochemistry or other studies) i.e. Breast Cancer Germ-cell Tumors Prostate Cancer Ewing Sarcoma Lymphomas PNET Tumors STEP III CHARACTERIZE THE SPECIFIC CLINICOPA THOLOGICAL ENTITY TREAT THE PATIENT FAVOURABLE SUBSETS [ With “Curative ” Intent ] UNFAVOURABLE SUBSETS [ With “Palliative” Intent ] DIAGNOSIS OF METASTATIC CARCINOMA (by histopathology)
    • clinical practice guidelines Annals of Oncology 21 , 2010 Cancers of unknown primary site : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up N. Pavlidis, E. Briasoulis & G. Pentheroudakis On behalf of the ESMO Guidelines Working Group
    • CARCINOMA OF UNKNOWN PRIMARY
      • A HUMAN MODEL FOR
      • METASTATIC DISEASE
    • CANCER OF UNKNOWN PRIMARY SITE Hidden Lung Ca Hidden Colon Ca Hidden Renal Ca Hidden Prostate Ca Hidden Liver Ca Hidden Breast Ca Hidden Ovary Ca Hidden Head/Neck Ca Hidden Germ Cell Ca Hidden Neuroendocrine Ca IMAGING CT, MRI, PET PATHOLOGY Immunohistochemistry Molecular THE ENTIRE ONCOLOGY IN A SINGLE DISEASE
    • T hank you