PROGNOSTIC FACTORS FOR SURVIVAL IN PATIENTS WITH METASTATIC COLORECTAL CANCER TREATED WITH FIRST- LINE CHEMOTHERAPY

https://www.journal-imab-bg.org J of IMAB. 2017 Apr-Jun;23(2) AN OPTIMIZED GC-MS METHOD FOR IDENTIFICATION OF COCAINE AND ITS MAJOR METABOLITES. Bonchev G. ................................................................... 1523 EVALUATION OF MAXILLARY BONE DIMENSIONS IN SPECIFIC AREAS FOR REMOVABLE DENTURES. Shopova D, Bozhkova T, Slavchev D, Muletarov S, Ivanova Z, Bozhikova E. ............................................................ 1527 PROGNOSTIC FACTORS FOR SURVIVAL IN PATIENTS WITH METASTATIC COLORECTAL CANCER TREATED WITH FIRSTLINE CHEMOTHERAPY Davidov D. .................................................................... 1532 DABIGATRAN AND DENTAL EXTRACTIONS Dinkova AS, AtanasovDT, Vladimirova-Kitova LG. .. 1536 CLINICAL CRITERIA FOR THE OUTCOME FORECAST OF ACUTE EXOGENOUS INTOXICATIONS WITH ORGANOPHOSPHORUS PESTICIDES Marinov P, Zlateva S, Ivanov D, Bonchev G, Sabeva Y, Georgiev K, Vazharov I. ............................................... 1541 COMPARISON OF DIAGNOSTIC CAPABILITIES OF ORTHOPANTOMOGRAPHY AND CONE BEAM COMPUTED TOMOGRAPHY IN DETERMINING THE TOPOGRAPHIC RELATIONSHIP BETWEEN IMPACTED MANDIBULAR THIRD MOLARS AND MANDIBULAR CHANNEL Kanazirska PG, Jordanov GY, Angelova IA, Bakardjiev AG. ....................................................................................... 1546 IMMUNOTOXICOLOGICAL ASPECTS OF BIOCOMPATIBILITY OF TITANIUM Lyapina M, Cekova M, Deliverska M, Galabov J, Kisselova A. ................................................................................... 1550 A CASE REPORT OF SARCOIDOSIS CUTIS LICHENOIDES Tsvetanova D, Yordanova IA, Pavlova V, Betova T, Gospodinov DK ............................................................ 1560 PSYCHOPATHOLOGICAL DYNAMICS OF A DISASTER VICTIM, REJECTING MENTAL HEALTH CARE – A CASE REPORT AND DISCUSSION Aleksandrov I, Yanev Y, Arnaoudova M, Dimitrov I, Stoyanov V. .................................................................................... 1564 HEALTH RECORDS AND INFORMATION TECHNOLOGY IN SUPPORT OF EXCHANGE OF HEALTH INFORMATION Deliversky J. ................................................................. 1567 VISCO-ELASTIC PROPERTIES OF SOFT RELINING MATERIALS – REVIEW Hristov I, Slavchev D, Zlatev S, Alexandrov S. .......... 1571 CONTENTS Journal of IMAB Annual Proceeding (Scientific Papers). 2017 Apr-Jun;23(2): http://dx.doi.org/10.5272/jimab.2017232 Journal of IMAB ISSN: 1312-773X https://www.journal-imab-bg.org


INTRODUCTION
Colorectal cancer (CRC) is the 3rd most commonly diagnosed and leading cause of cancer death in both sexes in the USA [1].There have been major advances in the chemotherapy treatment of metastatic CRC in the last 10 -15 years, involving the introduction of new cytotoxic and molecular targeted therapies.However, use of these newer treatments result in increased toxicities and are prohibitively expensive.Even though TNM staging system has been regarded as a standard staging system for colorectal cancer, there are still variations between patients who have the same stage; a set of patients will have minimal response and rapid dis-ease progression that culminates in death within a year of diagnosis [2].Many biomarkers have been studied as supplementary tools for further classification of the patients into the subgroups based on the current TNM staging system.It is increasingly recognized that variations within disease course and clinical outcome in colorectal cancer patients are influenced by not only oncological characteristics of the tumor itself but also host response factors [3].Hence, there is a need for accurate predictors of outcomes from treatment, in particular, in identifying those patients who are more likely to benefit.To understand this heterogeneity, some studies have evaluated molecular markers and clinical prognostic factors to predict treatment response.In a pooled analysis of source data from patients treated with first-line chemotherapy for metastatic CRC in 22 clinical trials, Koehne et al. divided patients into three prognostic groups (low, intermediate, and high risk) according to baseline factors: Eastern Cooperative Oncology Group performance status (ECOG PS), white blood count, alkaline phosphatase (ALP), and number of sites of metastatic disease [4].The low-risk patients had a median survival of 15 months, intermediate-risk patients had 11 months, and the high-risk patients had 6 months survival.Diaz et al. proved the applicability of Koehne's classification in a limited number of patients treated with irinotecan or oxaliplatin-based first-line chemotherapy [5].However, little is known about the inûuence of some haematological factors on prognosis.The aim of this study was to explore the prognostic significance for survival of certain clinical and pathological factors in patients with advanced or metastatic CRC treated with firstline chemotherapy.

PATIENTS AND METHODS
A retrospective study was conducted to investigate the possible prognostic factors for survival in metastatic CRC.We reviewed a cohort of 74 patients who had treated with chemotherapy for advanced or metastatic CRC between January 2002 and December 2011 in UMHAT-Dr.G. Stranski, Department of Medical Oncology.Patients had histologically confirmed CRC and were treated initially surgically with tumor resection when possible.All patients had clinical or biopsy evi-dence of advanced or metastatic disease with at least one measurable lesion.Assessment of extend of disease consisted of chest radiography, abdomen ultrasound and, if necessary, computer tomography of the thorax and abdomen was performed.Treatment schedule consisted of oxaliplatin or irinotecan based chemotherapy regimens.Oxaliplatin-based schedule means intravenous oxaliplatin 80 mg/m 2 on day 1, leucovorin 200 mg/m 2 intravenously on day 1 and 2 and 5-fluorouracil 400 mg/ m2 bolus followed by 5-fluorouracil 600 mg/m 2 as continued infusion, with repetition every two weeks.Irinotecan-based treatment means irinotecan 180 mg/m 2 day 1 intravenously, fluorouracil 450 mg/m 2 days 2-5 intravenously and leucovorin bolus 35 mg/m 2 day 2-5 intravenously, with repetition every 21 days.Both regimens were applied until disease progression or inappropriate toxicity.Detailed patient characteristics prior to initiation of first-line chemotherapy were acquired from hospital patient records.All patients were consecutive non-selected cases.Patients were not candidates for surgical treatment (either curative or palliative).
Different patient or tumor related factors were entered in the analysis based on characteristics identified by previous studies [6,7].Patient-related factors included age (≤60 years or >60 years), gender, World health organization (WHO) performance status, hemoglobin (Hb) level, total leukocyte count, platelet count, alkaline phosphatase (AP), lactate dehydrogenase (LDH).Anemia was defined as Hb <120 g/L in men and <110 g/L in women.Thrombocytosis was defined as a platelet count of > 400x10 9 /L.Elevated AP was defined higher than 280 UI/L.Elevated LDH was defined higher than 460 UI/L.Pathologic features was determined from the pathologist's reports.Parameter assessed included site of primary tumor (colon versus rectum), site of metastasis (liver versus others) and number of metastasis (single versus multiple).Follow-up information, including cause of death, was ascertained through a review of clinical notes.Overall survival (OS) calculated as time from start of treatment to death or last contact, was recorded and correlated with the above clinical, hematological and pathological parameters.The OS was estimated by the method of Kaplan and Meier [8].Variables were studied for influence on survival in a univariate analysis by using the log-rank test, and in a multivariate analysis using the Cox proportional hazard regression analysis [9].The results were considered statistically significant at the p< 0, 05 levels.
The median OS was 11 months (range 1-22) months.The following pre-treatment factors were identified as univariate predictors of poor survival (Table 2): number of metastatic sites>1, WHO performance status > 1, elevated platelet counts ≥400x10 9 /L, anemia with Hb level <120 g/L in men and <110 g/L in women.
No statistically significant differences were found for the following parameters: age, sex, site of primary tumor, AP level, LDH level, and leukocyte count.
Two factors were found to be significant in multivariate analysis.As shown in Table 3, the major unfavorable prognostic factors were multiple number of metastasis and performance status at presentation >1.

DISCUSSION
Over the last few years there has been an increased interest in clinical and molecular prognostic factors in stage IV mCRC.The reason for this is the recent advances in treatment options which have extended patient survival.
Our analysis included consecutive non-selected patients with advanced or mCRC treated in a single center and all patients were treated outside of clinical trials with palliative chemotherapy.Based on the univariate analysis, we distinguished four prognostic factors that influence survival: worsened PS, thrombocytosis, anemia and multiple site of metastasis.
Various studies on survival factors for advanced or mCRC have resulted in disparate results which probably depict differences in patient population and study design and hence make them difficult to evaluate.Nevertheless, in these studies performance status is established as a fundamental clinical prognostic factor in stage IV CRC [10,11].Worsening PS has been definitively associated with advanced disease and poor prognosis and this is confirmed in our analysis.The association between anemia and inferior survival capability has also been demonstrated by Kohne et al. previously in their multivariate analysis of 3,825 patients with mCRC treated with palliative chemotherapy in the setting of The main limitations of the present study are inherent to its retrospective nature and the relatively small number of patients.Prognostic factors that can risk stratify patients, predictive biomarkers that can help individualize treatment selection and predict a patient's response to therapy, facilitate the better understanding and treatment of the disease.Despite their adequate prognostic ability, none of the established prognostic models is 100% accurate.In consequence, the search for more accurate markers continues.Novel prognostic factors and more up-to-date models are urgently needed for patients with mCRC, especially in the era of targeted therapies.

CONCLUSIONS
This investigation confirm the potential role of some prognostic factors as survival, poor performance status, multiple sites of metastasis and thrombocytosis as predictive tools in metastatic CRC.Prognostic models should widely be used in the clinical practice to counsel patients, plan surveillance protocols, and select appropriate candidates for inclusion in adjuvant treatment protocols.Further improvements in our ability to predict CRC prognosis will rely on the integration of molecular and genetic markers in the currently established models.

Table 2 .
[12]lts of univariate survival analysis.Elevated level of platelets is observed as unfavorable prognostic factors in many solid tumors.Recently Baranyai Z. at al. reported thrombocytosis to be valuable predictive factor for poor prognosis in patients with mCRC[12].Our observations correlated with this report.The number of sites of metastases on presentation is reported to had no influence on overall survival from Assersohn et al. [13] Our findings do not confirm this result.

Table 3 .
Results of multivariate survival analysis.