Abstract BackgroundAim Establishing prognostic factorsis very impor - PDF document

Abstract. Background/Aim: Establishing prognostic factorsis very important in the management of cancer patients. Ouraim was to evaluate the clinical significance of a panel oftumor markers, including CEA (Carcino EmbryonicAntigen), SCC (Squamous Cell Carcinoma Antigen), TPS(Tissue Polypeptide Specific Antigen) and CYFRA 21-1 inhead and neck cancer patients, for assessing treatmentresponse and prognosis of patients. Patients and Methods:We evaluated 312 blood samples from 143 head and neck 5519 Correspondence to: Prof. Vivian Barak, Head, ImmunologyLaboratory for Tumor Diagnosis, Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Tel: +97226776764, Fax: +972 26435308, e-mail: barakvivi@hadassah.org.il,barakvivi@gmail.comKey Words: Head and neck cancer, tumor markers, clinical utility. The Diagnostic and Prognostic Value of Tumor Markers (CEA, SCC, CYFRA 21-1, TPS) in Head and Neck Cancer PatientsVIVIAN BARAK, AMICHAY MEIROVITZ, VERA LEIBOVICI, JACOB RACHMUTTAMAR PERETZ, RON ELIASHARand MENACHEM GROSS 0250-7005/2015 $2.00+.40 panel of markers such as CEA combined with a cytokeratinmarker in various carcinomas, such as breast, ovary, bladder,studies, we evaluated in the present study a panel of tumormarkers including cytokeratins, as to their clinical value inPatients and MethodsThe aims of the present study were to investigate the clinical roleand significance of a panel of tumor markers: CEA, SCC, CYFRA21-1 and TPS in head and neck cancer patients, following variousPatients and methods. Serum (received after patients' bloodcentrifugation) levels of the tumor markers CEA, SCC, CYFRA 21-1,TPS were evaluated by conventional ELISA assays: TPS for thequantitative measurement of the M3 epitope of soluble fragments ofhuman cytokeratin 18 was purchased from IMMULITE SIEMENS,UK. For the other markers, CEA, SCC and CYFRA 21-1, ELISAkits were purchased from BRAHMS, Hennigsdorf 25, Germany.The following groups of 143 HNC patients (from them we received312 blood samples) were evaluated: larynx n=82, nasopharynxn=12, oral cavity n=33, parotid and other salivary glandmalignancies n=16. Of these patients, 120 were evaluated both priorto and after therapy (surgery, radiation, chemotherapy or combinedmodalities) and levels of the samples, as indicated in figures, weretreatment. Overall survival was estimated according to initial levelsof the tumor markers.software and incl

uded non parametric tests as Wilcoxon matched-pairs signed rank test, Mann-Whitney test and survival analysis(Kaplan Meyer method and the log rank test). A value less than0.05 was considered statistically significant. ResultsAll marker levels were higher in advanced disease (stages IIITPS was significant, 0.012, as shown in Figure 1. Thisfinding shows a good correlation between tumor mass andlevels of serum markers.Comparing serum tumor marker levels before andfollowing therapy, demonstrated higher levels of the markersdecreased levels post therapy (TPS, 0.03), as shown in Tumor marker levels (mean±SE) according to stage of disease in HNC patients. Figure 2. This finding shows an association of marker levelswith tumor mass, nodal status, activity of the disease,correlating to response to therapy.Patients with node positive disease had significantlyhigher TPS levels, compared to those with node negative0.02), as shown in Figure 3. The other threemarkers showed a similar trend, but did not reach statisticalsignificance. When correlated to irradiation therapy, onlySCC levels were significantly higher prior therapy thanfollowing irradiation therapy (0.05), as shown in Figure4. Rest of the markers showed a similar trend, however, withno statistical significance. We also compared marker levels in the subgroups of HNCpatients. TPS levels were significantly higher in the group ofParotid and other salivary gland patients (317+120) than inLarynx (76+10), Nasopharynx (66+13), and Oral cavitySimilarly, CYFRA 21-1 levels were also significantly higherin the Parotid and other salivary gland patients (15.211+9.93)cavity (1.49+0.23) patients (0.02). The other two markersdid not differ significantly between those groups of patients. A kinetic evaluation of an individual patient followed upevery 2 months with TPS, is shown in Figure 5. Thesignificant increases in TPS levels reflected earlier diseaserecurrence, shown later by a computed tomographic scan ofthis patient (see raw on the graph).Overall survival correlated best to TPS levels: of patientswith high TPS levels, 57% were alive after 2 years and 46%: Diagnostic and Prognostic Value of Tumor Markers in Head and Neck Cancer Patients 5521 Tumor markers levels (mean±SE) according to therapy in HNC patients. TPS levels (mean±SE) according to lymph nodes in HCN after 5 years, while of patients with low TPS levels, 90% ofthem were alive after 2 years and 75

% after 5y. The mostsensitive marker in the panel of tumor markers we tested,was the TPS.DiscussionTo achieve personalized treatment for cancer, markers fordetermining prognosis, predicting response to therapy andpredicting severe toxicity related to treatment, are urgentlyrequired and expected to increase survival, due to theirCEA has been evaluated for use as a prognostic parameterin patient outcomes. However, this marker is related mostlyto tumor mass and does not reflect proliferative activity. Incontrast, cytokeratin tumor markers reflect proliferativeactivity, which is one of the most important phenotypiccharacteristics of tumor aggressiveness and may thus bemore beneficial as a prognostic indicator. Cytokeratins are well recognized biomarkers in varioustypes of cancer, as we and others have demonstrated (6, 7).In Lung cancer, tumor markers including cytokeratins arerecommended for use in differential diagnosis, prognosis andtherapy monitoring, particularly of non-small cell lung cancer(NSCLC), as we and other colleagues have shown previously(8-17). Beyond lung cancer, there are an increasing numberof studies showing a remarkable sensitivity of cytokeratinmarkers, such as TPA and TPS, mostly in breast, as we havepreviously demonstrated (6, 19), but also in bladder, ovarian,and colorectal cancer (14-16). This might be explained by ahigher general cytokeratin release during cell death, thatcellular turnover in some situations (17).In our present study, only TPS levels were statisticallysignificant higher in advanced stage (stage III and IV)patients than in early stage (stage I and II) patients. TPS wasalso significantly higher in node positive patients, indicatinga significant correlation between the level of markers andtumor burden or proliferative activity of the patients. Wehave also previously shown in Breast Cancer the significanceof using TPS in addition to tumor mass markers as CEA andsuggesting earlier treatment and longer survival, similar tothe results in HNC patients of this study.In the present study we compared the tumor marker levelsin subgroups of HNC patients. TPS levels were significantlyhigher in patients with Parotid and other salivary glandnasopharynx and oral cavity. To our knowledge, this findingDuring recent years there have been many efforts toidentify new markers for HNC, using different methods,from HNC cell lines to proteomics (20-26). Thus, PLAU andIGFbp7 w

ere found significantly increased in HNC patientsrelative to controls (22). In addition, CD147 was suggestedto be a novel marker for the diagnosis of Oral Cancer. In arecent review, summarizing prognostic markers for HNCfrom the literature, the cytokine IL-6 was identified as themost significant predictor of patient's outcome (24).Additional markers for HNC were suggested as well, such asMMPs1,2 ,9 (26). Although these results are promising (22-26), a significant validation in a high number of patientsfollowed up adequately for a longer period is required, inSCC (in Squamous type Cancers), CEA, TPS and CYFRA21-1, are sensitive and useful tumor markers in HNCpatients. Higher levels of the markers were associated withactive disease, higher stages and node positive patients.Significant associations were demonstrated between responseto therapy, such as first surgery and radiation and decreasesin marker levels. Decreases in all 4 marker levels SCC levels (mean±SE) according to radiation therapy in HCN Kinetic evaluation of TPS levelsin a HNC patient. demonstrated positive therapy effects and a longer survival.Increases in TPS were the most sensitive predictors ofadvanced disease and poor prognosis, best correlated tooverall survival. Those results are in good concordance withour previous data on TPS and its significance in Breastcancer patients (27-30).We therefore suggest, introducinginto routine a panel of tumor markers including cytokeratins,for the useful follow up of HNC patients, assessment of theirresponse to therapy and early detection of recurrence for animproved survival.AcknowledgementsThe Authors appreciate and thank Mrs. Kalichman I and Dr NismanB for their technical assistance. They also thank Mr. AharonovichM for the statistical workup.References1 Siddiqui F and Gwede CK: Head and Neck Cancer in the elderly2 Atienza JA and Dasanu CA: Incidence of second primarycomprehensive review of literature. Curr Med Res Opin 3 Posner MR, Hershock DM, Blajman CR, Mickiewicz E,Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K,Ervin TJ, Murphy BA, Raez LE, Cohen RB, Spaulding M,Tishler RB, Roth B, Viroglio Rdel C, Venkatesan V, Romanov I,Agarwala S, Harter KW, Dugan M, Cmelak A, Markoe AM,Read PW, Steinbrenner L, Colevas AD, Norris CM Jr. andHaddad RI: Cisplatin and fluorouracil alone or with docetaxel inhead and neck cancer. N Engl J Med 4 Vermorken JB, Remenar E, van Herpen C, G Thier

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