Significance of serum tumor markers monitoring in carcinomas of unknown primary site

Abstract

Background/Aim. Unknown primary tumors represent a heterogeneous group of malignancies that are indicative of ominous prognosis. Cancer of unknown primary site (CUP) is defined as the lack of any detectable primary site after full evaluation, and accounts for approximately 3-5% of all newly diagnosed patients with malignancies. The aim of this report was to present the prognostic and predictive value of 8 serum tumor markers in this group of patients. Methods. The study involved 63 patients. On histological examination, all the patients were presented with metastatic tumors whose primary site (origin) could not be detected with noninvasive diagnostic techniques. Following the routine light microscopy, all histological findings were classified into one of the following three groups: plano-cellular carcinoma - 8 patients; adenocarcinoma - 33 patients; unclassifiable (undifferentiated) carcinoma - 22 patients. In all the cases we evaluated 8 serum tumor markers: alpha-fetoproteins (AFP), chronic gonadotrophin beta submit, human (beta-HCG), neuron specific enolase (NSE), marker of malignant ovarian tumors (CA 125), prostate-specific antigene (PSA), marker of malignant brest tumor (CA 15-3), marker of malignant pancreas tumor and gastrointestinal tumor (Ca 19-9), carcinoembryonic antigen (CEA) at the time of diagnosis. The patients on chemotherapy had the markers determined after the third and sixth chemocycle, i.e. at the time of illness progression observation, if present. The patients responding to chemotherapy with complete response (CR), partial response (PR) or stable disease (SD) had the markers determined after three-month periods until the time of relapse or progression. Chemotherapy was applied in 32 patients (20 females and 12 males), aged 29-70 years, who met the inclusion criteria. The following chemotherapy regimen was used: doxorubicin 50mg/m2 (day 1), cisplatin 60mg/m2 (day 1), and etoposide 120 mg/m2 (days 1-3). The period between two chemotherapy cycles was three weeks, and maximum five weeks in the case of prolonged hematological toxicity. Results. Most commonly elevated were NSE values (82.54%), while AFP values were least commonly elevated (11.11%). Average survival time was 17.89 months (95%CI 12.96; 22.83). The probability of 24 months' survival was 0.228. The group of 32 patients treated with chemotherapy had 12 (37.5%) fatal outcomes in the observed period (72 months). Average survival time was 26.6 months (95% CI 19.5; 33.7). Average tumor marker values before and after the chemotherapy were significantly lower for NSE and CA 125. Survival was significantly better in cases of NSE and CA 125 decrease of more than 20%. Conclusion. Increased values of serum tumor markers are very often in CUP. The tumors show nonspecific overexpression of tumor markers. The NSE and CA 125 levels show good correlation with response to the given chemotherapy. However, a routine evaluation of commonly used serum tumor markers has not been proven of any prognostic and predictive assistance.Uvod/Cilj. Tumori nepoznatog primarnog ishodista predstavljaju heterogenu grupu malignih tumora sa nepovoljnom prognozom. Kancer nepoznatog porekla (CUP) definise se kao odsustvo bilo kakvog primarnog tumora nakon kompletnog klinickog ispitivanja, a javlja se kod 3-5% svih bolesnika sa dijagnozom maligniteta. Cilj ovog ispitivanja bio je da se pokaze prognosticka i prediktivna vrednost 8 serumskih tumorskih markera u ovoj grupi bolesnika. Metode. U studiju je bilo ukljuceno 63 bolesnika kod kojih je histoloska analiza pokazala prisustvo metastatskog tumora cije se primarno ishodiste (poreklo) nije moglo dokazati neinvazivnim dijagnostickim tehnikama. Svi histoloski nalazi su na osnovu svetlosne mikroskopije klasifikovani u jednu od sledece tri grupe: planocelularni karcinomi - 8 bolesnika; adenokarcinomi - 33 bolesnika; nediferentovani karcinomi - 22 bolesnika. Kod svih bolesnika odredili smo nivo 8 serumskih tumorskih markera u trenutku postavljanja dijagnoze: Alfa-fetoprofein (AFP), humani horionski gonadotropin (beta-HCG), neuron specificna ekolaza (NSE), marker malignih tumora ovarijuma (CA 125), prostata specificni antigen (PSA), marker malignih tumora dojke (CA 15-3), marker malignih tumora pankreasa i gastrointestinalnog trakta (CA 19-9) i karcinoembrionalni antigen (CEA). Bolesnicima kojima je ordinirana hemioterapija markeri su odredjivani nakon treceg i sestog ciklusa hemioterapije, odnosno u trenutku registrovanja progresije bolesti, ukoliko je ova nastupila. Kod bolesnika ciji je odgovor na hemioterapiju procenjen kao kompletan odgovor (CR), parcijalni odgovor (PR) ili stabilna bolest (SD) markeri su odredjivani u tromesecnim intervalima do trenutka relapsa ili progresije. Hemioterapija je primenjena kod 32 bolesnika (20 zena i 12 muskaraca) starosti od 29-70 godina, koji su ispunjavali kriterijume za ukljucivanje. Primenjena je sledeca hemioterapijska sema: doksorubicin 50 mg/m2 (dan 1), cisplatin 60 mg/m2 (dan 1), etoposide 120 mg/m2 (dani 1-3). Interval izmedju hemioterapijskih ciklusa iznosio je 3 sedmice, a u slucaju protrahovane hematoloske toksicnosti najvise 5 sedmica. Rezultati. Najcesce bile su povisene vrednosti NSE (82,54%), a najredje AFP (11,11%). Prosecno vreme prezivljavanja iznosilo je 17,89 meseci (95% CI 12,96; 22,83). Verovatnoca da bolesnik prezivi 24 meseca iznosila je 0,228. Grupa od 32 bolesnika, koji su bili na hemioterapiji, u posmatranom periodu (72 meseca) imala je 12 (37,5%) letalnih ishoda. Prosecno vreme prezivljavanja bilo je 26,6 meseci (95% CI 19,5; 33,7). Srednje vrednosti tumorskih markera, pre i posle primenjene hemioterapije, bile su znacajno nize za NSE i CA 125. Prezivljavanje je bilo znacajno bolje u slucaju pada vrednosti nivoa NSE i CA 125 tokom terapije za vise od 20%. Zakljucak. Povisene vrednosti tumorskih markera u serumu vrlo su ceste u CUP sindromu. Ovi tumori pokazuju nespecificnu povecanu ekspresiju tumorskih markera. Nivo NSE i CA 125 pokazuje dobru korelaciju sa odgovorom na preduzetu hemioterapiju. Ne preporucuje se, medjutim, rutinska primena najcesce koriscenih serumskih tumorskih markera u svetlu prognosticke i prediktivne vrednosti.