Survival in Patients Treated with Definitive Chemo-Radiotherapy for Non-Metastatic Esophageal Cancer in North-West Iran

Esophageal cancer is one of the three most common cancers among Iranian people (Sadjadi et al., 2010). The five-year survival rate in the northern part of Iran is 13% (Ghadimi et al., 2011). DCRT as primary treatment modality is offered to esophageal cancer patients, as an alternative for patients considered medically unfit for surgery or having irresectable tumors (Smit et al., 2012). Although DCRT has not been compared directly with surgery in randomized trials, outcomes from published studies are similar to those seen in surgical trials in terms of survival and quality of life (Gwynne et al., 2011). Despite 45 years of the establishment of the regional center of RT, the effect of DCR in survival patients with esophageal cancer has been unknown. The purpose of the current study is to evaluate the effects of DCRT on survival of patients


Introduction
Esophageal cancer is one of the three most common cancers among Iranian people (Sadjadi et al., 2010).The five-year survival rate in the northern part of Iran is 13% (Ghadimi et al., 2011).DCRT as primary treatment modality is offered to esophageal cancer patients, as an alternative for patients considered medically unfit for surgery or having irresectable tumors (Smit et al., 2012).Although DCRT has not been compared directly with surgery in randomized trials, outcomes from published studies are similar to those seen in surgical trials in terms of survival and quality of life (Gwynne et al., 2011).Despite 45 years of the establishment of the regional center of RT, the effect of DCR in survival patients with esophageal cancer has been unknown.The purpose of the current study is to evaluate the effects of DCRT on survival of patients

Materials and Methods
This retrospective study was conducted in North-West of Iran from March of 2006 to March of 2011, included of 267 consecutive patients with locally advanced inoperable esophageal cancer.Clinical staging consisted of endoscopy, endoscopic ultrasound, barium swallow, computed tomography scan of the abdomen and thorax.Patients with metastatic diseases and those treated with palliative intent (radiation dose <30 Gy) have been excluded.Eligible inoperable patients were treated with DCRT or DRT alone.Clinicopathological variables and survival times were patient's medical records and collected by telephone contact.

Treatment protocol
Treatment protocol, consisting of either DCRT or DRT was begun immediately after diagnosis.RT was delivered by linear accelerator at 9 MV at 40 0 C Gy/min.The initial 44 Gy dose was administered using a conventional AP-PA.RT was delivered at 1.8-2 Gy/day for five consecutive days in a given week.Patients lay supine, with the tumor volume and surrounding nodes included within the RT field with longitudinal and lateral margins of 5 and 3 cm, respectively.The spinal cord dose was limited to 44 Gy.RT consisted of two course of Cisplatine (100 mg/m 2 per d) plus 5-FU (1000 mg/m 2 per day) for three consecutive days, beginning 1-5 week after concurrent with RT.Cisplatine was administered as a bolus over 30 min, simultaneously started with the 5-FU, with adequate hydration and anti-emetic drugs.

Statistical analysis
Descriptive analysis was done for demographic, pathology and clinical features.Results were expressed as means±standard deviation and percentage.The probability curves for survival were calculated according to the Kaplan-Meier Method and compared by the log-rank test.Multivariate analysis was carried out using the Cox proportional hazard model.P<0.05 was considered as statistically significant.The data were analyzed using by SPSS.v.16 software.

Univariate analysis
The median survival was 12.73±0.92(95%CI=10.92-14.54)months with 1, 3 and 5 year survival rates of 55%, 18% and 11%, respectively.As shown in Table 1, on univariate analysis for identifying potential prognostic factors related to age at diagnosis (p=0.015),N-stag (p=0.04),total dose of RT (p=0.001),Fraction (p<0.0001),Gap status(p=0.025),Chemotherapeutic regimens (P=0.027),5-Fu Mg/m 2 (P=0.004) and Comparing DCRT to DRT, There was a significant difference in survival between the two treatment groups (Figure 1).Fifty-eight of the 92 patients in the radiation-therapy group (63%)  died, as compared with 120 of the 175 patients in the combined-therapy group (68.6%).The median survival in the radiation-therapy group was 10.4 months, as compared with 13.9 months in the combined-therapy group (P=0.03 by the log-rank test).

Discussion
Esophageal cancer is the second and third most common malignancy in Iranian males and females, respectively (Sadjadi et al., 2010).The 5 years survival is reported to be only 12% East Azerbaijan province of Iran (Mirinezhad et al., 2012).Unfortunately, patients suffering from esophageal cancer often refer to medical care when it is unfit for or having irresectable tumors and so DCRT to treat them.In our study, the one, three and the five year survival rates were 55, 18 and 11%, respectively which are slightly lower as compared to those reported from other studies (Gwynne et al., 2011;Motoori et al., 2012;Semrau et al., 2012).This result could be explained by the fact that Iranian patients generally seek a medical advice with a delay and the diagnosis is made when the disease has reached an advanced stage (Ghadimi et al., 2011).This study revealed that, aging was one of the risk factors (P=0.02;OR=1.46 by the cox regression analysis) and again age was inversely associated with the survival rate (P=0.01), which is consistent with previous studies (Aghcheli et al., 2011;Ghadimi et al., 2011).We showed that nodal stage was an important prognostic factor; this was reported from another studies as well (P=0.04)(Gwynne et al., 2011;Semrau et al., 2012).Result in the current study did not show any statistical significance according to histology this is consistent with several prior studies (Gwynne et al., 2011;Semrau et al., 2012).There was no statistically significant difference in gender and tumors site of the upper, middle or lower esophagus this is consistent with other studies respectively (Byun et al., 2011;Semrau et al., 2012).Higher doses of radiation, was one of the Protective factors (P=0.005;OR=0.62 by the cox regression analysis) and was associated with a higher survival rate (P<0.001), as report by other study and may improve local control as well as survival (Byun et al., 2011;Gwynne et al., 2011;Semrau et al., 2012).We found a significant survival advantage for patients who received a combination of CT and RT as compared with RT alone (p=0.03), this is consistent with other report (Semrau et al., 2012).Results of our study were limited by the lack of recorded toxicity data in a standardized fashion.In conclusion, the survival rates of esophageal cancer treated with DCRT in North West of Iran is poor; therefore, early detection and improved treatment methods, with performed clinical trial study.