THE EFFECT OF PRETREATMENT NEUTROPHIL/LEUCOCYTE RATIO ON SURVIVAL IN PATIENTS WITH LOCALLY ADVANCED ESOPHAGEAL CANCER RECEIVING CHEMORADIOTHERAPY

Transcription

1 Acta Medica Mediterranea, 2017, 33: 905 THE EFFECT OF PRETREATMENT NEUTROPHIL/LEUCOCYTE RATIO ON SURVIVAL IN PATIENTS WITH LOCALLY ADVANCED ESOPHAGEAL CANCER RECEIVING CHEMORADIOTHERAPY FERYAL KARACA 1, ÇIĞDEM USUL AFŞAR 2, NECAT ALMALI 3, SENEM KARABULUT 4, MEHMET KARABULUT 5, SIDDIK KESKIN 6, SERKAN AKBULUT 7 1 Adana Numune Education and Research Hospital, Department of Radiation Oncology - 2 Acibadem Bakirkoy Hospital, Department of Medical Oncology- 3 Van YüzüncüYil University Medical Faculty, Department of General Surgery - 4 Bakirkoy Dr Sadi Konuk Education and Research Hospital, Clinic of Medical Oncology - 5 Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Department of General Surgery - 6 Van YüzüncüYıl University Medical Faculty, Department of Biostatistics - 7 Adana Numune Education and Research Hospital, Department of General Surgery ABSTRACT Introduction: Esophageal cancer (EC) is a highly lethal malignancy. The majority of esophageal cancers are squamous cell or adenocarcinomas. Although the incidence of squamous cell carcinoma (SCC) is decreasing in the United States, the incidence of adenocarcinoma arising out of Barrett's esophagus is rising dramatically, although less so in the last few years. Treatment in locally advanced EC (LA-EC) must be multidisciplinary. There are only few factors which affects the prognosis. Our aim was to investigate the prognostic and predictive roles of pretreatment neutrophil/leucocyte (neu/leu) ratios in LA-EC patients receiving chemoradiotherapy (CRT). Materials and methods: Sixty patients with non-metastatic EC (youngest 31 years old) who applied to our hospital between 2011 and 2015 were included in this study. Neu/leu ratios were calculated before CRT and after CRT. The Kaplan-Meier method was used for estimating the survival function from lifetime data. In addition, Cox regression model was also used to explore the relationship between the survival of a patient and several explanatory variables. Results: There was statistical significance between neu/leu ratio before CRT and OS (p= 0.047). One unit increase in neu/leu ratio, increases the probability of being alive times (1/0.367). There was statistical significance between neu/leu ratio before CRT and progression-free survival (PFS) (p= 0.046). One unit increase in neu/leu ratio, increases the probability of no relapse (1/0.281) times. This means that the patients with higher neu/leu ratio before CRT have a lower risk of relapse. Discussion and conclusion: Multimodal therapeutic strategies combining chemotherapy, radiation therapy and surgery have been shown to be feasible and to have a positive impact on outcomes by decreasing the risk of locoregional recurrence and often by increasing overall survival. The overall survival (OS) and disease-free survival (DFS) of patients is too short in patients with LA-EC. Our study shows that patients with LA-EC who had higher pretreatment neu/leu ratios have better OS and PFS. Keywords: esophageal cancer, survival, chemotherapy, radiotherapy, neutrophil. DOI: / _2017_6_144 Received November 30, 2016; Accepted May 20, 2017 Introduction Esophageal cancer (EC) is a life-threatening malignancy with a rather poor prognosis. Each year new cases in the average are reported, and 406,800 mortalities related to EC are reported annually (1-4). In the highest-risk area, stretching from Northern Iran through the central Asian republics to North-Central China, 90% of cases are squamous cell carcinomas (SCC) (5,6). Major risk factors in these areas are not well understood, but are thought to include poor nutritional status, low intake of fruits and vegetables, and drinking beverages at high temperatures. In contrast, in low-risk areas such as the United States and several Western countries, smoking and excessive alcohol consumption account for about 90% of the total cases of esophageal SCC (7). More than half of the patients are nonresectable at the time of diagnosis. Esophagectomy

2 906 Feryal Karaca, Çiğdem Usul Afşar et Al is the gold standard treatment in resectable EC. Only 35% of patients have the chance for curative surgery at the initial diagnosis (1-4). Prognosis is poor in patients treated only with esophagectomy who were not treated with additional therapies (8). Significant changes have occurred in the survey done with curative surgery techniques developed in addition to the standard curative surgical approaches and supportive care possibilities (9). In some studies carried out on EC, approaches targeting improvement of quality of life have been suggested local operation following CRT or CRT following operation. It has been proven that complete resection was possible in patients who were operated after neoadjuvant CRT (10). These studies have been carried out both on cases with adenocarcinoma and SCCs, and clinicians are in agreement that CRT improves the 5- year survival in both groups. However, different opinions have emerged between clinicians on effects of postoperative treatment. Together with this, it is known that neoadjuvant treatments can have some adverse preoperative effects (11,12). The lymph node invasion in patients is a poor prognostic factor, and patients with N2 or worser grades have poor prognostic characteristics (2). The two- and five-year overall survival (OS) and disease-free survival (DFS) are related to nodal involvement (3). Curative surgery is the primary treatment in early stage EC; however, treatment in LA-EC must be multidisciplinary (4). In our study, it was attempted to observe whether or not there are any differences in survival of patients with EC according to their pretreatment neu/leu ratios. Materialsand methods Sixty patients with non-metastatic EC (youngest 31 years old) who applied to our hospital between 2011 and 2015 were included in this study. After abdominal and thoracic computed tomography (CT) scans of the patients, further imaging methods were used in some patients for staging. Staging of 34 (56.6%) patients were made with CT and magnetic resonance imaging (MRI), while the same was made with CT followed by positron emission tomography (PET-CT) in 26 (43.4%) patients. Clinical stages of 48 (80 %) patients who received definitive CRT were T2-T3-T4, N2, M0, while the clinical stages of 12 (20%) patients who received CRT after surgery were T2-T3, N1, M0. Treatment protocol was decided for all the patients following the diagnosis with biopsy based on the clinical stage. Definitive CRT was administered to patients with locally advanced cancer at the time of diagnosis and who were not good candidates of surgery. Complete blood count (CBC) was done before CRT and at control to all patients. Neu/leu ratio was calculated before CRT and after CRT. Decision for surgery was made with preoperative staging for all the patients taken to surgery. Detailed physical examinations were performed on the patients followed by liver and renal function tests. Barium esophagogram, abdominal ultrasound, abdominal and thoracic CT was taken from every patient, and further imaging methods were performed when required. In addition to the trans-thoracic esophagectomy, thoracic and abdominal lymph node dissections were performed on 12 patients when surgery was possible. For the supra-carinal tumors, cervical lymphadenectomy was performed, and anastomosis was performed with cervical approach. Cardiac toxicity, pulmonary complications, necrosis, bleeding, mediastinitis, thoracic abscess, abdominal or thoracic infections, or thromboembolism were seen in none of our patients, and none of our patients underwent re-surgery. Increases of morbidity or mortality were not seen in any of the 12 patients taken under strict follow-up in the postoperative period. Staging of the patients were made according to the TNM classification of International Union Against Cancer TNM, 7 th Edition (13). All of the patients had R0 resection. Patients were evaluated by a multidisciplinary team, and were included in curative treatment protocols based on their clinical stages at the time of the diagnosis. Chemotherapy Cisplatin 75 mg/m 2 intravenous (IV) on day 1, fluorouracil mg/m2 IV continuous infusion over 24 hours daily on days 1-4, cycled every 28 days for 2-4 cycles for 2 cycles with radiation, followed by 2 cycles without radiation or cisplatin 30mg/m 2 IV on day 1, capecitabine 800 mg/m 2 PO BID on days1-5, weekly for 5 weeks or paclitaxel 50 mg/m 2 IV on day 1, carboplatin AUC 2 IV on day 1, weekly for 5 weeks were used as CRT protocols. Radiotherapy (RT) CT scans were taken in the first time for all patients in supine position with their hands under their heads. For upper- and mid-section esophageal

3 The effect of pretreatment neutrophil/leucocyte ratio on survival in patients with locally tumors, neck and whole thoracic CT was taken with 5-mm slices. For the lower thoracic esophageal tumors, CT was taken with 5-mm slices so as to include the abdomen together with the thorax. Gross tumor volume (GTV), clinical target volume (CTV), planning target volume (PTV) and organs under risk were determined. Esophageal tumor was taken as the basis for GTV. CTV was drawn by placing a 5-mm margin over and under GTV. PTV was drawn with a 1-mm margin on CTV by considering the daily set-up errors and movements of organs. Cervical and thoracic lymph nodes for upper and medium mediastinal esophagus tumors and celiac lymph nodes for lower thoracic esophagus tumors were drawn separately when drawing GTV and CTV. Adjuvant 45 Gy external RT was administered to patients who had undergone operation, and 50,4 Gy external RT was administered to patients who had received definitive CRT. No toxicity that would require the termination or interruption of RT was seen during the RT except for grade 2 esophagitis in 48 (80%) patients and grade 2 esophagitis in 12 (20%) patients. All patients were supported with supplemental enteral feeding solutions throughout their treatments. Follow-up of Patients Patients were followed-up for a period of 4 years starting from diagnosis. No delayed toxicity related to the treatment was seen in the controls in the post-treatment period; furthermore, we had no cases with secondary malignancies. OS and DFS periods were calculated for the patients. Mortality and morbidity in patients were followed postoperatively. All the treated patients were seen in control visits every three months within the first 2 years. Control visits were made every 6 months in the following three years; and then patients without complaints were controlled annually. In the control visits, physical examination was performed and whole blood test, tumor marker (CEA), and renal and liver function tests were carried out. Neck CT, thoracic CT and lower/upper abdominal CT studies were performed every 3 months for the first 2 years. PET-CT study was performed on patients with suspicious lesions in their CTs to re-staging, and the treatment protocol was re-arranged accordingly. During the follow-ups, patients were classified as local relapse, locoregional metastasis and distant organ metastasis. Local recurrences, lymph node metastasis and distant organ metastasis were searched for in follow-ups. Local recurrences were found in the followups in 15 (25%) of patients, near metastases were found together with local recurrence in 21 (35%) patients, and near and distant metastases were found together with local recurrence in 9 (15%) patients. Palliative surgery was performed on 22 (36.6%) patients, palliative chemotherapy was administered to 41 (68.3%) and palliative RT was administered to 3 (5%) of patients. Grade 2 esophagitis was seen in 21 (35%) of patients during the additional treatments, and grade 3 esophagitis was seen in 28 (46.6%) of the patients; treatment was interrupted untill the symptoms of patients were improved. Statistical Analysis Descriptive statistics for the studied variables (characteristics) were presented as mean, standard deviation, minimum and maximum values. Survival analysis was performed to determine the median survival time for the groups. The Kaplan Meier method was used for estimating the survival function from lifetime data. In addition, Cox regression model was also used to explore the relationship between the survival of a patient and several explanatory variables. Statistical significance level was considered as 5% and Statistical Package for the Social Sciences (SPSS) (version 17) statistical program was used for all statistical computations. Results Sixty patients in total who were diagnosed with EC were included in this study; general characteristics of these patients are summarized in Table 1. Twenty-three females (38.3%) and 37 (61.7%) males were included in this study. Of the patients included in the study, 12 (20 %) had upper (cervical) EC, 33 (55%) had thoracic EC, and 15 (25%) had lower EC. Pathologically, 21 (35%) patients had squamous-cell cancer and 39 (65%) had adenocarcinoma. Two of the patients (3.3%) were determined as stage 1, 17 (38.3%) as stage 2, and 41 (68.4%) were determined as stage 3. Treatment protocols administered to patients are summarized in Table 2. Following their initial curative treatments, patients were evaluated for local recurrence, near metastasis and distant metastasis. The entire portion of the group was administered palliative therapy. Local recurrence occurred in 28 (46.6%) of the patients. Near metastasis occurred in 38 (63.3%) of

4 908 Feryal Karaca, Çiğdem Usul Afşar et Al Total 60 (%100) Female 23 (%38,3) Male 37 (% 61,7) Age Median 62 Range Location of tumor Cervical esophagus 12 (% 20) Thoracic esophagus 33 (% 55) Lower esophagus 15 (%25) Pathology Squamous-cell carcinoma 21 (% 35) Adenocarcinoma 39 (%65) Tumor Grade High Grade 41 (% 68,3) Medium Grade 13 (%21,6) Low Grade 6 (%10,1) near metastasis and distant metastasis were present in 15 (25%) patients. Depending on the performance status of the patients, palliative surgery was performed on 32 (53. %) patients, palliative chemotherapy was administered to 42 (70%) patients, and palliative RT was administered to 6 (10%) patients. Metastatic status of the patients and treatment protocols administered are shown in Table 3. Chemotherapy Regimen Cisplatin+5 FU 60 (%100) Number of patients operated 12 (%20) Operation Type Transthoracic Esophagectomy 12 (%100) Nodal Dissection 12 (%100) R0 Resection 10 (%83,3) R1 Resection 2(%16.7) Number of patients with definitive therapy 48 (%80) Radiotherapy Tumor Diameter T1 0 (%0) Adjuvant Definitive 45 Gy (180cGy/day) 50,4 Gy (180cGy/day) T2 12 (%20) T3 23 (%38,3) T4 25 (%41,7) Lymph Nodes N0 48 (%63,4) N1 22 (%36,6) N2 0 (%0) N3 0 (%0) Number of patients with positive surgical margins 2 (% 16,6) Lympho-vascular invasion 10 (% 83,3) Metastasis No 60 (%100) Stage Stage 1 2 (%3,3) Stage 2 17 (%28,3) Stage 3 41 (%68,4) Stage 4 0 (%0) Table 1: General Characteristics of Patients. the patients. Distant metastasis occurred in 13 (21.6%) of the patients. Number of patients with local recurrences and near metastases was 20 (33.3%). Near and distant metastases were present together in 11 (18.3%) patients. Local recurrence, CT-base 3D Conformal 60 (%100) Follow-up time 4 years Table 2: Treatment Types. 5 FU: 5 fluorouracile; CT: computed tomography; 3D: threedimensional Metastasis after treatment Local recurrence 28 (%46,6) Near metastasis 38(% 63,3) Distant metastasis 13 (%21,6) Local recurrence + near metastasis 20 (%33,3) Near metastasis +distant metastasis 11 (%18,3) Local recurrence +near metastasis +distant metastasis 15 (%25) Palliative surgery 32 (%53,3) Palliative chemotherapy 42 (%70) Chemotherapy administered Cisplatin+5 FU Palliative radiotherapy 6 (%10) Table 3: Locations of metastases and palliative treatments received by patients. 5 FU: 5 fluorouracile There was no statistical significance between age, gender and OS but there was statistical significance between neu/leu ratio before CRT and OS (p= 0.047) (Table 4).

5 The effect of pretreatment neutrophil/leucocyte ratio on survival in patients with locally Although there was no statistical significance, the probability of death was higher (1.224 times) among women (Table 4). Neu/leu ratio before CRT had 5% effect on survival time which was statistically significant. One unit increase in neu/leu ratio, increases the probability of being alive times (1/0.367) (Table 4). There was statistical significance between neu/leu ratio before CRT and PFS (p= 0.046) (Table 5). One unit increase in neu/leu ratio, increases the probability of no relapse (1/0.281) times. This means that the patients with higher neu/leu ratio before CRT have a lower risk of relapse (Table 5). Discussion B SE Wald df p OR Variables in the Equation B SE Wald df p Exp(B) In our single-center study, we included 60 patients, out of which 48 were operated and 12 were not operated. CRT was administered to the entire cohort. DFS of the patients was found as 172 days as the mean, and 141 days as the median. The mean OS of the patients was 318 days, and the median was 283 days. When divided according to sex, the mean value for females was 144,6 days, and the mean value for males was 172,2 days. It was found that operated patients had a mean survival period of 159,4 days, while patients not operated had a mean survival period of 242,8 days. A common and general treatment approach has not been indicated for EC currently. The meta analysis of Cavallin and colleagues has shown that 95,0% CI for OR Lower 95,0% CI for Exp(B) Lower Upper Neu/leu before CRT -1,002 0,505 3,941 1,047,367 1,011 7,317 Gender,202,389,271 1,603 1,224,571 2,624 Age -,020,015 1,664 1,197,981,952 1,010 Table 4: Overall survival according to age, gender and neu/leu ratio before CRT. Neu/leu: neutrophil/leucocyte; CRT: chemoradiotherapy; CI: confidence interval; OR: odds ratio Upper Neu/leu before CRT -1,271 0,637 3,983 1,046 0, ,423 Gender 0,067 0,323 0,043 1,836 1,069 0,568 2,013 Age 0,004 0,011 0,127 1,721 1,004 0,982 1,027 Table 5: Progression free survival (PFS) according to age, gender and neu/leu ratio before CRT Neu/leu: neutrophil/leucocyte; CRT: chemoradiotherapy; CI: confidence interval; OR: odds ratio patients with good histopathology respond well to adjuvant therapies of EC; while patients with poor histopathology respond poorly to EC treatments (14). In our study, 68.4 % of the patients were stage 3 and were locally advanced. Histopathological findings were high-grade in 68.3 % of our patients. In our study we carried out as a single-center study, only 42 (68.4%) patients were stage 3, and the remaining 2 (3.3%) patients were stage 1, and 17 (28.3%) patients were stage 2. Because of this, the numbers for survival analyses were not adequate when the patients were divided as early and late stages, they were considered within the same group. Our patients did not give full response to treatments because their tumors were locally advanced and with higher grades, and they had poor prognosis. Her-2 over-expression is important for treatment in patients with gastroesophageal esophagus tumors (15). Tumors in this part of the esophagus are classified as intestinal-cell cancers, and are considered as cancers with good or medium differentiation (16). All these markers show the clinicopathology in the EC and determine the optimal treatment regimen. Cisplatin and 5-fluorouracile (FU) regimen was administered to all the patients with local recurrence and metastases. Cisplatin+5-FU regimen is the most commonly used and the most effective treatment modality in EC. Particularly, the use of cisplatin as a sinle agent is a commonly used treatment as regards its effectiveness (17). Palliative RT is recommended for patients with EC with local recurrence, pain and bleeding after curative treatment. Palliative RT was administered to our 6 (10%) patients. Patients tolerated RT in palliative dosages well. When patients who received definitive CRT (50 Gy) and patients who received only RT (64 Gy) were compared, the median survival times were found as 14 months versus 9 months. The group that definitive CRT was administered survived longer. We also administered definitive CRT to our patients in whom operation was not possible. It is possible to administer three dimensional conventional RT and intensity-modulated RT (IMRT) in EC that had shown early clinical signs. However, the entire portion of our patients was treated with conformal RT. Hematologic toxicity related to treatment was not seen.

6 910 Feryal Karaca, Çiğdem Usul Afşar et Al Only a portion of patients with LA-EC can be operated, because most of these patients are considered as inoperable at the time of diagnosis. Definitive CRT administration is foreseen for such patients in many studies. In the NT study, patients were divided into two groups and received different RT dosages. Two hundred and eighteen patients were included in this study, out of which 85% were SCC and 15% were adenocarcinoma with clinical T1-T4, NO-N1, M0 stages. RT in the highest dosage (64.8 Gy) and the standard 50.4 Gy were administered to the patients. Cisplatin+5-FU chemotherapy was administered concurrently to all patients. No significant differences were seen between the median survival times (13 months vs. 18 months). Our study and NT have shown that 50.4 Gy RT will suffice for patients who had received definitive CRT (cisplatin+5-fu) (18). The OS and DFS of patients are too short in patients with LA-EC. In our study, we showed that the patients with higher neu/leu ratio before CRT had better OS and PFS. The response given to cancer and inflammation effects the survival of patients. In literature, there is evidence that C-reactive protein was a negative factor for the survival of LA-EC patients (19,20). In another study, hypoalbuminemia was a negative factor on survival in patients who had esophagectomy. Hypoalbuminemia can be a prognostic and predictive factor in patients treated with CRT (21,22). To our knowledge, our study is the first one which shows that patients with LA-EC and who had higher pretreatment neu/leu ratios have better OS and PFS. Conclusion EC is a rather frequent cancer in the Eastern Anatolia Region of Turkey. Local people consume their foods and drinks very hot. Drinking tea with a method unique for the region (by keeping a lump of sugar in the mouth) also causes erosion in the esophagus. In this single-center study, we attempted to show that EC had a very aggressive course when diagnosed at locally advanced stages. Treatment methods for LA-EC must be developed urgently and a consensus must be reached. Patients diagnosed with EC must be treated with a multidisciplinary approach. Specialists in general surgery, gastroenterology, medical oncology, radiation oncology, radiology and pathology must play their roles together in the treatment of EC. Perhaps genetic researches will also be required in the upcoming years. In our single-center study, it was seen that our data were parallel with the international data. In this aggressive tumor, the advancements related to tumor biology, in which attempts were being made for the last four decades, have provided increase in the survival of the EC. EC is an aggressive neoplasm without genetic instability and with rather dynamic characteristics. We showed the importance of neu/leu ratio before CRT on survival. Immunology and immunotherapies are the new area of interest for cancer patients. More detailed researches are required for EC and immunologic response. References 1) Enzinger PC, Mayer RJ. Esophageal Cancer. N Engl J Med 2003; 349: ) Yeh HL, Hsu CP, Lin JC, Jan JS, Lin JF, Chang CF. A retrospective study of postoperative chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. Formos J Surg 2012; 45: ) Xu Y, Chen Q, Yu X, Zhou X, Zheng X, Mao W. Factors influencing the risk of recurrence in patients with esophageal carcinoma treated with surgery: a single institution analysis consisting of 1002 cases. Oncol Lett 2013; 5: ) Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 2007; 8: ) Gholipour C, Shalchi RA, Abbasi M. A histopathological study of esophageal cancer on the western side of the Caspian littoral from 1994 to Dis Esophagus 2008; 21: ) Tran GD, Sun XD, Abnet CC, et al. Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int J Cancer 2005; 113: ) Engel LS, Chow WH, Vaughan TL, et al. Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst 2003; 95: ) Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Long-termresults of a randomized trial of surgery with or without preoperativechemotherapy in esophageal cancer. J Clin Oncol 2009; 27: ) Khushalani N. Cancer of the esophagus and stomach. Mayo Clin Proc 2008; 83: ) Courrech SE, Aleman BM, Boot H, van Velthuysen ML, van Tinteren H, van Sandick JW. Systematic review of the benefits and risks of neoadjuvant chemoradiation for oesophageal cancer. Br J Surg 2010; 97: ) Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an

7 The effect of pretreatment neutrophil/leucocyte ratio on survival in patients with locally FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011; 29: ) Kelsen DP, Winter KA, Gunderson LL, et al. Longterm results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol 2007; 25: ) Sobin LH, Gospodarowicz MK, Wittekind C, eds. UICC TNM Classification of Malignant Tumors. 7th ed. New York, NY: Wiley-Blackwell; ) Cavallin F, Scarpa M, Alfieri R, Cagol M, Castoro C. The Role of Surgery in Patients With a Complete Clinical Response After Chemoradiation for Esophageal Cancer. Ann Surg 2014, doi: /sla ) Huang L, Lu Q, Han Y, Li Z, Zhang Z, Li X. ABCG2/V-ATPase was associated with the drug resistance and tumor metastasis of esophageal squamous cancer cells. Diagn Pathol 2012; 7: ) Shan L, Ying J, Lu N. HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population. Diagn Pathol 2013; 8: ) Leichman L, Berry BT. Experience with cisplatin in treatment regimens for esophageal cancer. Semin Oncol 1991; 18: ) Conroy T, Galais M-P, Raoul J-L, et al. Definitive chemoradyotherapywith FOLFOX versus fluorourasil and cisplatin patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised phase 2/3 trial. Lancet Oncol 2014; 15: ) Nozoe T, Saeki H and Sugimachi K. Significance of pre-operative elevation of serum C-reactive protein as an indicator of prognosis in esophageal carcinoma. Am J Surg 2001; 182: ) Zingg U, Forberger J, Rajcic B, Langton C, Jamieson GG.Association of C-reactive protein levels and longterm survival after neoadjuvant therapy and esophagectomy for esophageal cancer. J Gastrointest Surg 2010; 14: ) Wang CY, Hsieh MJ, Chiu YC, Li SH, Huang HW, Fang FM, et al. Higher serum C-reactive protein concentration and hypoalbuminemia are poor prognostic indicators in patients with esophageal cancer undergoing radiotherapy. Radiother Oncol 2009; 92: ) Di Fiore F, Lecleire S, Pop D, Rigal O, Hamidou H, Paillot B, et al. Baseline nutritional status is predictive of response to treatment and survival in patients treated by definitive chemoradiotherapy for a locally advanced esophageal cancer. Am J Gastroenterol 2007; 102: Corresponding author CIGDEM USUL AFSAR, MD, Assoc. Prof Acibadem Bakirkoy Hospital Department of Medical Oncology Istanbul (Turkey)