Prognostic Value of Lymph Node Ratios in Node Positive Rectal Cancer Treated with Preoperative Chemoradiation

cancer patients (Elder et al., 2007; Simunovic et al., 2009; Kotake et al., 2012). According to the guidelines for colorectal cancer from the AJCC/UICC, a minimum of twelve lymph nodes must be retrived and examined for accurate staging (Edge et al., 2010). Currently, to perform surgical staging of the colorectal cancer, the total number of resected lymph nodes will consider which might be varying substantially depending on the surgical situations (Shimomura et al., 2011). In addition to adequate surgical resection and precise pathologoic examination several factors influence the number of lymph nodes retrieved after curative resection. One of these factors is preoperative chemoradiation therapy which is now standard treatment for locally advanced rectal cancers patients. These neoadjuvant therapies result in a


Introduction
Lymph nodes involvement is an important factor that cancer patients (Elder et al., 2007;Simunovic et al., 2009;Kotake et al., 2012).According to the guidelines for colorectal cancer from the AJCC/UICC, a minimum of twelve lymph nodes must be retrived and examined for accurate staging (Edge et al., 2010).Currently, to perform surgical staging of the colorectal cancer, the total number of resected lymph nodes will consider which might be varying substantially depending on the surgical situations (Shimomura et al., 2011).In addition to adequate surgical resection and precise pathologoic examination several factors influence the number of lymph nodes retrieved after curative resection.One of these factors is preoperative chemoradiation therapy which is now standard treatment for locally advanced rectal cancers patients.These neoadjuvant therapies result in a lymph nodes (Wichmann et al., 2002;Baxter et al., 2005) are not infrequent among locally advanced rectal cancer patients who need an additional prognostic index for their adjuvant treatment decisions.

Prognostic Value of Lymph Node Ratios in Node Positive Rectal Cancer Treated with Preoperative Chemoradiation
Jamal Jafari Nadoshan 1 1 4

Abbas Alibakhshi 1 1
Recent studies showed LNR which means the ratio of involved to the total resected lymph nodes is a better prognosis predictor than pathological node (pN) and sometimes it has been found as an important predictive factor of mortality and recurrence (Rosenberg et al., 2008;2010;Ainsworth et al., 2010;Qiu et al., 2011;Tong et al., 2011).So the aim of the this study was to investigate the impact of LNR on prognosis,recurrence and survival of locally advanced rectal cancers patients in the presence of preoperative chemoradiation effect on the number of retrieved lymph nodes.

Materials and Methods
One hundred twenty eight cases of stage III rectal cancer undergoing a radical resection after preoperative chemoradiation over 11 years in Cancer Institute of Iran were included.Patients who had complete pathologic response after preoperative chemoradiation and patients who had no retrieved lymph node in proctectomy specimens were excluded.
All patients had undergone radical resection 4-6 weeks after neoadjuvant chemoradiation.During the study, the concurrent chemotherapy regime has changed of study to oral capecitabine 825mg/m twice daily as radiotherapy course included 45 GY in 25 fraction over 33 days.
Cancer research center of Cancer Institute of Iran approved this study on march 2011.No ethical consideration was applied to this study.
Recorded clinicopathologic features included age and gender of the patients,the tumours depths and differentiation, the number of harvested lymph nodes, the number of involved lymph nodes and the LNR.The (LNs) divided by the number of LNs retrieved.
concerning the mean and median in the sample.up was performed through tumor marker every two month at six month interval for the next three years.Chest xray and abdominal and pelvic ultrasonography was performed every six month and abdominal and pelvic computed tomography was performed annually.Colonoscopy was from the time of diagnosis until death, recurrence and histologically.Cause of death was registered for patients who died during follow-up.
The statistical analysis was made using statistical package for social science (SPSS Inc., Chicago, IL, USA,version 20).Survival curve was prepared by Kaplan-Meier analysis.Log-rank method and Cox multivariate analysis of prognostic factors.P value<0.05

Results
We studied 128 patients including 61 women (48%) and 67 men (52%).Patients had ages between 16 and 85 years with mean of 49 years.All patients had rectal adenocarcinoma and in 35 patients (27.3%) including 21 male and 14 female tumors was located in rectosigmoid junction.The tumors were well differentiated in 37%, medium differentiated in 40%, un-differentiated in 13% and mucinous in 10%.
Mean number of total examined lymph nodes was 10.3 ranging from 2 and 28.Mean number of involved lympn nodes was 5.8 ranging from 1 to 25.Only in 39 patients 12 or more than 12 lymph nodes were harvested and in 61 patients the number of harvested lymph nodes was 7-11.In the remaining 28 patients less than 7 lymph nodes patients received adjuvant chemotherapy.Mean duration of follow up was 39 months (range 1-156).
We found seven times higher risk of local recurrence among patients with LNR more than 0.2 compared with patients with LNR less than or equal to 0.2 (54 versus 4, was similar between two groups by LNR, while risk of death was 7 times higher among patients with LNR more than 0.2 compared with patients with LNR less than or To determine the effect of LNR on the prognosis, the than that of the group with a LNR greater than 0.2-69%  1.3(0.7-2.5)1.8(0.8-3.8)1.0(0.5-1.9)55+ vs. <35 1.2(0.6-2.4)1.4(0.6-3.1)1.1(0.5-2.3)Post-Operative Chemotherapy:

Discussion
In the current study we evaluate the prognostic impact of the LNR in patients with node positive rectal cancer who received preoperative chemoradiation therapy.Although nodal involvement is one of the most powerful prognostic factor in colorectal cancer, recently, the LNR these patients.In this study we found LNR as an accurate predictor of outcome of colorectal cancer patients who had inadequate number of harvested lymph nodes caused metastasis in our locally advanced rectal cancer patients.
Many studies (Nagtegaal et al., 2002;Wichmann et al., 2002;Baxter et al., 2005;Sermier et al., 2006;Rullier et al., 2008;Mekenkamp et al., 2009) have reported retrieved from patients with locally advanced rectal cancer who received preoperative chemoradiation, probably depletion (Marks et al., 2010).A study (Bakter et al., 2005) based on the surveillance, Epidemiology and End Result (SEER) registry showed that only 19% of patients with stage III rectal cancer had at least 12 retrieved lymph nodes after preoperative chemoradiation therapy.So LNR can improve the clinical decision for adjuvant treatment of these patients.
Previous study that evaluated the association between LNR and prognosis in patients with rectal cancer after preoperative chemoradiation reported various cutoff point for LNR chosen by various methods, but all of them found it as a powerful predictor of outcome and sometimes even more powerful than nodal status (Chin et al., 2009;Manilich et al., 2011;Tong et al., 2011).relationship between LNR s and survival rate in rectal cancer patients.The mean LNR was 0.34.LNR was an independent risk factor for local recurrence rate and disease free survival and overall survival in their study.
Similar to other studies, our study show the risk of local  2011) a total of 75 patients diagnosed as node positive after preoperative chemoradiation therapy followed by curative resection based on their median LNR which was 0.143.Patients with lower LNR had better overall survival.There was no difference between the survival rate of patients with higher LNR and also N2 patients.
In a study (Huh et al., 2010) on 514 colorectal cancer with proven lymph node metastasis patients were months, the 5-year overall survival rates of patients with LNR1, LNR2, LNR3, LNR4 were 79, 72, 62 and 55% respectively and the 5-year disease-free survival rates were 73, 67, 54 and 42% respectively.LNR remained evaluate prognostic effect of LNR in 154 node positive rectal cancer and found prognostic impact of LNR (<0.15, than 12 harvested lymph nodes as well as more than 12 harvested lymph nodes. Park et al. ( 2011) in a study on 186 stage III colorectal cancer patients had selected cutoff point of LNR as 0.07 Several studies (Peschaud et al., 2008;Kim et al., 2009;Priolli et al., 2009;Dekker et al., 2010;Rosenberg et al., 2010;Thomas et al., 2012) had chosen different cutoff points by different parameters such as quartiles, median value and arbitrary values.The cutoff points for LNR were proposed in many studies but the optimal level need to be determined.In our study the cutoff point was 0.2 according Rectal cancer patients according to metastatic lymph node ratio to mean and median of the sample , which is not approved as the optimal threshold for LNR.Also our study is a retrospective study with limited number of patients with a non uniform protocol for preoperative chemoradiation and also adjuvant chemotherapy.So the potential impact of LNR on outcome and prognosis of locally advanced rectal cancer patients treated by preoperative chemoradiation need to be investigated in large prospective studies with an optimal level of cutoff point.
In conclusion, LNR may help to determine the prognosis of colorectal cancers when the accurate staging in patients with fewer than 12 lymph nodes is not possible.
Figureure 1. Recurrence).Curve in stage III rectal cancer patients according Only in a study by shin on 190 rectal cancer patients LNR was not a predictive factor for local recurrence.Ceelen et al. (2010) reviewed 16 studies including 33,984 patients with stage III colon or rectal cancer conducted from 1975 to 2009.The prognostic value obtained by the LNR was superior to that of number of positive nodes.In seven studies, the total number of positive nodes was no longer an independent prognostic indicator when LNR was included in the regression model.In a study by Kang et al. ( Figureure 2. Metastases).Curve in stage III rectal cancer patients according