Four categories which guide further evaluation

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1 Unknwn Primary Updated May 2017 by Di Maria Jiang (PGY-5 Medical Onclgy Resident, University f Trnt) Reviewed by Dr. Chistine Elser (Staff Medical Onclgist, University f Trnt) and Dr. Sct Dwden (Staff Medical Onclgist, University f Calgary) DISCLAIMER: The fllwing are study ntes cmpiled by the abve PGY-5 medical nclgy residents and reviewed by a staff medical nclgist. They reflect what we feel is relevant knwledge fr graduating medical nclgy residents preparing fr their final examinatin. The infrmatin has nt been surveyed r ratified by the Ryal Cllege. A) DEFINITION - A hetergeneus grup f metastatic cancers fr which a standardized wrk-up has failed t identify the site f rigin at the time f diagnsis B) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: 7 th -8 th mst cmmn malignancy in develped wrld; 3-5% f all malignancies (2% in US) Incidence and prevalence is decreasing ver time (prevalence decreased by 51% between 1973 and 2008 and the incidence decreased by 30%) - Mrtality: 4 th mst cmmn cause f cancer-related death - Lymph nde cnfined metastases median survival 6-9 mnths - Extrandal metastases median survival 2-4 mnths - Primary tumr fund in <30% f patients - In 20-50% f patients, primary nt fund in pstmrtem examinatin Fur categries which guide further evaluatin Adencarcinma 70% SCC 5% Neurendcrine carcinma 1% Prly differentiated tumrs 20-25% RISK FACTORS - Genetic: 2.8% familial and assciated with lung, kidney and clrectal cancers in families C) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - General cmplaints - Symptms related t site f metastatic disease - Multiple sites f invlvement >50% f patients - Cmmn sites: Liver Lungs Bnes Lymph ndes - Pattern f metastatic sites unreliable t determine primary site Favrable Prgnstic Subgrups - prly differentiated carcinma with midline distributin

2 - wmen with adencarcinma invlving nly axillary lymph ndes - SCC f cervical lymph ndes - Islated inguinal adenpathy - Prly differentiated neurendcrine carcinmas - Single, small and ptentially resectable tumr Unfavrable Prgnstic Features - male - pr PPS - high LDH - lw albumin - adencarcinma with metastases invlving multiple rgans - nn-papillary malignant ascites - peritneal metastases - multiple cerebral metastases - adencarcinma with multiple lung/pleural r bne lesins INVESTIGATIONS Fr all patients: - Physical Exam Head and neck, GU, rectal, pelvic, breast - Baseline bldwrk (CBC, electrlytes, LFT, Cr, calcium) - CT Chest/ Abdmen/ Pelvis - Mammgram - Urine cytlgy/ urinalysis - Cre bipsy Fr wmen with islated axillary lymph nde(s) - Breast MRI Squamus cell carcinma f the neck - PET CT Other investigatins if indicated: - Pelvis ultrasund - Tumr markers: PSA, AFP, HCG In certain situatins CEA, Ca125, Ca19-9 Invasive prcedures: - Nt recmmended fr initial wrkup - guided by clinical presentatin and initial wrk-up gastrscpy clnscpy fr liver metastases cystscpy fr retrperitneal lymph ndes and suspicius urine cytlgy triple endscpy fr islated neck lymph nde (laryngscpy, brnchscpy, upper endscpy) Nte: PET CT can be helpful t rule ut ther sites f metastases if there is a knwn single metastatic site and aggressive lcal treatment is being cnsidered Avid unnecessary tests and delays

3 Suspected metastatic malignancy Cmplete H/P, including breast, GU, pelvic, rectal exam Review f past bipsies r malignancies, remved lesins, spntaneusly regressing lesins and existing imaging studies CBC, lytes, LFTs, Cr, Ca CT c/a/p Hemccult Symptm-directed endscpy and fcused imaging Bipsy Cre needed bipsy and/r FNA f mst acceptable site Detailed pathlgy review Gene signature prfiling fr tissue f rigin nt recmmended fr standard management at this time (hwever, apprpriate tumur specific mutatins acceptable e.g. EGFR/ALK fr lung)

4 Wrkup fr Pssible Breast Primary - suspect when: adencarcinma with psitive axillary and mediastinal ndes adencarcinma in supraclavicular ndes, chest, peritneum, retrperitneum, liver, bne r brain - Mammgram - MRI and/r U/S f breast fr nn-diagnstic mammgram if histpathlgic evidence f breast cancer - MRI if mammgram nt adequate t assess extent f disease Dense breast tissue Psitive axillary ndes Evaluate chest wall - Cnsider NSCLC if mediastinal invlvement but wrkup negative fr breast primary Wrkup fr Pssible Germ Cell Primary - suspect when: adencarcinma f mediastinal ndes retrperitneal mass in male <65 years f age - Beta-hCG and AFP - Testicular U/S if elevated beta-hcg and AFP in male with mediastinal r retrperitneal mass - Cnsider NSCLC r varian germ cell if mediastinal invlvement but wrkup negative fr primary germ cell tumr Wrkup fr Pssible Ovarian Primary - suspect nn-germ cell varian when: mediastinal, inguinal, chest, peritneal r retrperitneal invlvement - CA 125 Wrkup fr Pssible Prstate Primary - PSA when: Male >40 years f age with adencarcinma r carcinma NOS Except if metastases limited t liver r brain Male with bne metastases r multiple sites f invlvement regardless f age Additinal Wrkup fr Adencarcinma r Carcinma Nt Otherwise Specified - CA 19-9 Peritneal disease r liver invlvement fr suspected pancreatic r biliary primary - AFP Liver invlvement - Urinary cytlgy fllwed by cystscpy Retrperitneal mass - Prctscpy fr rectal r anal cancer Male and females with Inguinal lymph nde invlvement - Endscpy Liver invlvement Nt rutinely fr malignant ascites Wrkup fr SCC - anal endscpy fr inguinal nde invlvement PATHOLOGY & MOLECULAR BIOLOGY - 5 majr subtypes (frm light micrscpy)

5 well t mderately differentiated adencarcinma (60%) prly differentiated adencarcinma r undifferentiated carcinma (29%) SCC (5%) Prly differentiated malignant neplasm (5%) Unable t be further classified by light micrscpy Neurendcrine tumrs (1%) - Immunhistchemistry predicts primary in 35-40% f patients impact n treatment chice and utcme nt clear ften valuable t direct further wrkup

6 Credit: NCCN Clinical Practice Guideline Occult Primary V Mlecular markers Cytgenetics relevant fr unknwn primary carcinmas/ neplasms: i12p germ cell tumrs (Ig) gene rearrangement lymphmas HPV/ p16 cervical cancer EBV genme naspharyngeal cancer t(15:19) midline carcinma (t[11;22] [q24;q12]) peripheral neurepithelial carcinma Oncgene verexpressin (testing fr mutatins/ verexpressin nt recmmended rutinely) C-myc Ras Her2 EGFR C-kit BCL-2 p53 Experimental ptins: - Gene Expressin Prfiling Ratinale: pattern f gene expressin may reflect genetic make-up f primary

7 Outcme data nt currently available t recmmend rutine use fr wrkup (NCCN) - Next Generatin Sequencing Ptential t identify actinable bimarkers utside f tissue specific markers Remains experimental D) TREATMENT - n specific regimen f chemtherapy is cnsidered standard f care - chice f regimen based n histlgic type f cancer - in general chemtherapy has limited efficacy and cnsiderable txicity in ccult primaries Adencarcinma First- Line Regimens - Carbplatin + Paclitaxel - Gemcitabine + Carbplatin - Gemcitabine + Irintecan respnse rates 25-45% Glfinpuls Cancer Treat Rev 2009: meta-analysis f 10 randmized trials, 683 patients, excluding favrable subset CUP. Cmpared platinum vs taxane vs bth vs neither n survival benefit with either platinum vs taxane vs bth n trials that cmpared systemic treatment t best supprtive care

8 Paclitaxel/carbplatin/etpside versus gemcitabine/irintecan in the first-line treatment f patients with carcinma f unknwn primary site: a randmized, phase III Sarah Cannn Onclgy Research Cnsrtium Trial Hainswrth JD et al. Cancer J. 2010;16(1):70. Regimen paclitaxel/carbplatin/etpside (PCE) versus gemcitabine/irintecan 4-6 cycles f each bth arms fllwed by single-agent gefitinib (median duratin 3 mnths) Primary Endpint 2 year survival Inclusin/Exclusin Criteria Inclusin: Untreated unknwn primary histlgically dcumented adencarcinma, prly differentiated andecarcinma, prly differentiated carcinma, r prly differentiated squamus carcinma Exclusin: Neurendcrine tumrs Wmen w/ adencarcinma islated t axillary LN Wmen w/ adencarcinma islated t peritneal invlvement Patients w/ resectable single metastasis Patients w/ squamus carcinma limited t cervical, supraclavicular r inguinal ndes Yung men with features f extragndal germ cell tumr Brain metastases unless cntrlled by previus surgical resectin r radiatin and nt requiring nging sterids Treatment fr anther cancer type within last 4 years Size (N) 198 patients in ttal but with slw accrual Target accrual was 320 Results 2 year survival PCE 15% Gemcitabine/Irintecan 18% Median Survival PCE 7.4 mnths Gemcitabine/Irintecan 8.5 mnths Median PFS PCE 3.3 mnths Gemcitabine/Irintecan 5.3 mnths Respnse Rate PCE 18% = Gemcitabine/Irintecan 18% Quality f Life: Txicity PCE Grade 3/4 Neutrpenia, thrmbcytpenia, anemia, febrile neutrpenia Gemcitabine/Irintecan Grade 3/4 Diarrhea Cnclusin PCE and gemcitabine/irintecan cmparable efficacy in the first-line Gemcitabine/irintecan preferable regimen due t favrable txicity prfile. Hwever, the mderate efficacy f bth regimens underscres the need fr nvel treatment appraches in this patient ppulatin. Other Cmments Shrt duratin f Gefitinib maintenance suggests little single-agent activity in this setting

9 Carb/Taxl 3 phase II trials Secnd Line: N standard f care clinical trials the best, treat as mst likely primary Hainswrth 2001: 39 patients treated with gemcitabine RR 8%, SD 25% Hainswrth Cancer 2005 phase II: n=40 CUP at least 1 previus chem regimen, treated with gemcitabine (1000 mg/m2) and irintecan (100mg/m2 D1 D8) q3w 10% ORR, 43% SD Median survival 4.5 mnths Treatment well tlerated Hainswrth Cancer 2010 phase II: n=48 CUP at least 1 previus chem regimen, treated with xaliplatin (130 mg/m2 D1) and capecitabine (1000 mg/m2 BID D1-14) q3w ORR 19%, 46% SD Median PFS 3.7m, OS 9.7 m Reasnably well tlerated Targeted Therapy Hainswrth JCO 2007: n=51 CUP previus chem r untreated, pr prgnstic clinical features received Bevacizumab (10mg/kg) and erltinib (150mg OD) q2w 10% partial respnse, 61% SD Median OS 7.4 mnths Well tlerated Hainswrth 2009: n=60 CUP, received carb/taxl + bev/erltib RR 53%, SD 28% OS 12.6m PFS 8m Getz 2013: n=46 CUP treated with carb/taxl/everlimus RR 34% OS 10.0 m PFS 4.1 m

10 Hainswrth 2015: n=89 CUP treated with carb/taxl +/- belinstat RR 45% vs 21% OS 12.4 vs 9.1 mnths PFS 5.4 vs 5.3 mnths