Inadequate lymph node sampling as a risk factor in stage II colon cancer F. Zakaria and N. EL- Mashad Clinical Oncology Department. Faculty of Medicine, Tanta University Hospital, Tanta, Egypt Abstract Purpose: The aim of this study is to clarify the magnitude of the risk-to-benefit ratio with adjuvant therapy in high risk stage II colon cancer. Patients and Methods: 162 patients with pathologically documented stage II colon cancer were randomly distributed into two groups. The first group (80 patients) received Capecitabine for 6 cycles and the second group (82 patients) received FOLFOX4 for 6 cycles. All patients in both groups were assessed for disease-free survival (DFS) and overall survival (OS) as regards to chemotherapy regimen and high risk factors. Tolerability and safety were assessed for all study population in both groups. Results: Three-year DFS rates were 73% and 87% (Hazard ratio (HR)=2.051, 95%Cl(1.13-3.721), P-value= 0.018), 3-year OS rates were 87% and 93% (P-value=0.26); corresponding 5-year OS rates for patients with stage II disease were 34% and 93% (HR=2.555, 95%Cl(1.276-5.119), P-value=0.008) in the Capecitabine and Folfox4 groups, respectively. Statistical significant differences in 5-year DFS and OS with lymph node sampling > 12 lymph nodes in favor Folfox4 group (HR=0.172, 95%Cl(0.0080-0.370), P-value=<0.001) and (HR=0.087, 95%Cl(0.028-0.268), P-value=0.001) respectively. Multivariate analysis for all study population stated that the only significant risk factor was the inadequate lymph node sampling as regards to relapse (HR= 0.244, 95%CI (0.094-0.631), P-value=0.004) in stage II colon cancer. Diarrhea and peripheral sensory neuropathy (PSN) were the most pronounced side effects in FOLFOX4 treatment arm. Conclusion: This study has demonstrated that patients with microscopic disease do behave more like stage III colon cancer patients; our data suggest that we must analyze tumors at this level if at all possible and those patients with <12 lymph nodes resection should received adjuvant chemotherapy in favor of FOLFOX4 regimen with significant improvement in DFS which can be translated into an OS benefit. Introduction Treatment of node negative stage II (T3/ T4N0M0) colon cancer is controversial. While surgery to remove the tumor in the colon is universally accepted as initial treatment, the value of chemotherapy after that surgery to keep cancer from coming back is hard for patients and doctors to judge (1). Siegel R, et al, 2013, (2) showed that 25-40% of patients with stage II colon cancer experience recurrence after complete surgical Corresponding Author: Fatma Zakaria MD (fatmaz_555@ yahoo.com) and Nehal EL- Mashad MD (nehalelmashad@ yahoo.com), Clinical Oncology Department, Faculty of Medicine, Tanta University Hospital, Tanta, Egypt 46 removal of cancer. An effective therapy is needed to eliminate such micro metastases and improve cure rates of stage II colon cancer. The addition of oxaliplatin to weekly 5-FULV significantly improve disease free survival with stage III colon cancer. However, adjuvant chemotherapy with Oxaliplatin is controversial in stage II colon cancer (3). The key issue is to identify which subset of patients with stage II colon cancer are at increased risk for disease recurrence and stand to get the most benefit from adjuvant Oxaliplatin based chemotherapy regimen.
Patients and Methods This study was conducted at the Clinical Oncology Department, Tanta University from January 2006 to December 2011. Eligible patients were 21 to 74 years of age who have undergone complete resection of histologically proven stage II (T3/T4N0M0) colon cancer. Stage II patients classified as high risk for the purposes of an exploratory analysis had at least one of the following T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion, or inadequate Lymph nodes examined <12 lymph nodes. Prior chemotherapy, immunotherapy or radiotherapy was not permitted, and study treatment had to be started within 7 weeks of surgery. The study was approved by the ethics committee of faculty of medicine, Tanta University. Patients were randomly classified into two groups, Group I: Eighty patients received oral Capecitabine in dose 1250 mg/m2 twice daily 2 weeks on/one week off in 3-week cycles for 6 cycles & Group II: Eighty two patients received FolFox4 therapy (6 months), Oxaliplatin 85 mg/ m2 plus de Gramont régimen (bolus plus continuous infusion FU plus leucovorin) for 12 cycles every 2 weeks. Follow-up Patients were evaluated every 2 weeks during treatment, and then every 6 months for disease free survival (DFS) and overall survival (OS) as regards to treatment arms and risk factors, with minimum follow-up period of 2-year. Assessments were made for relapse, toxicity and death. Adverse events were graded according to the National Cancer Institute s Common Toxicity Criteria, Version 1. Statistical analysis Statistical presentation and analysis of the present study was conducted, using number and percentage for qualitative and tested by chisquare test. We used Kaplan-Meier and Cox regression for survival analysis by SPSS for Windows version 18.0 software package (SPSS Inc, Chicago, IL) where P-value < 0.05 was considered as statistically significant. 47 Results G. J. O. Issue 16, 2014 Patients and Treatment Between January 2006 to December 2011, 162 patients with stage II colon cancer were enrolled, 80 patients in Capecitabine treatment arm and 82 patients in Folfox4 treatment arm. In both groups, 46.75% and 37.80% of patients presented with age >60 years, 12% and 9.75% as Grade III, 16.25% and 82.93% as T4; for vascular invasion 35% and 36.59%, for evaluated lymph nodes less than 12 (25%) and 24 (39%) in Capecitabine and Folfox4 arms respectively (Table 1). Survival outcomes (OS & DFS) in all Patients After a median follow-up time of 43.2 months for overall survival, the probabilities of OS surviving at 3-years & 5-years rates were 87% and 93% (P-value=0.263) and 34% to 93% for Capecitabine and Folfox4 treatment arms respectively (HR=2.555, 95% CI(1.276-5.119), P<0.001). Overall, there were 6 deaths (7.3%) in Folfox4 group versus 12 deaths (15.0%) in Capecitabine group with insignificant p value=0.120. Also, there were 10 relapses (12.2%) in Folfox4 group and 20 relapses (25.0%) in Capecitabine group with significant p value=0.036. DFS probabilities (median follow-up, 33 months) for 3-years & 5-years rates were 73% and 87% and 18% and 87% for Capecitabine and Folfox4 treatment arms respectively (HR=2.051, 95%Cl(1.13-3.721), P=0.018). Subgroup analysis (Table 2) were performed to identify prognostic factors for DFS within stage II colon cancer relapsed patients in Capecitabine group showed that tumor size, number of evaluated lymph nodes, vascular invasion, performance status, clinical picture and CEA level showed significant statistical differences with p-value = < 0.001 for all factors. However, the potential benefit from Oxaliplatin based chemotherapy could not be excluded in any subgroup defined on the basis of prognostic factors at baseline, whereas a significant benefit from Oxaliplatin was confirmed in group of patients with vascular invasion and inadequate lymph node sampling (p-value 0.03&<0.001) respectively.
Lymph node sampling in stage II colon cancer, F. Zakaria, et. al. Table 1: Patients demographics and Baseline Characteristics 48
G. J. O. Issue 16, 2014 Fig. 1: Kaplan Meier estimates of overall survival by treatment arms In Multivariate Analysis (Table 3), the only remaining statistically significant prognostic factor for relapse was inadequate lymph node sampling (Odd ratio = 0.244, CI 95% (0.09-0.63), P=0.004). Five year DFS and OS with lymph node sampling < 12 and > 12 lymph nodes Interaction of number of lymph node sampling < 12 or > 12 lymph nodes evaluated with DFS and OS in both treatment groups were amazing with significant probabilities of surviving for > 12 lymph nodes evaluated at 3-years and 5-years (HR=0.172,95%Cl(0.0080-0.370),P=0.001)for DFS and (HR=0.087,95%Cl (0.028-0.268),P=0.001) for OS in favor of Folfox4 treatment arm (Fig.3-A,B,C,D). Safety The safety analysis, as originally for patients on treatment for all study population showed PSN Grade 2, 24.39% (20 patients) and Grade 3, 13.4% (11 patients) versus 15% (12 patients) and 0.0% for Folfox4 to Capecitabine groups respectively with significant p. value for Oxaliplatin group (p=0.001). The frequency of PSN among patients in the Folfox4 group declined during the follow-up period reaching 3.2 % after one year of treatment Table 4. Discussion On the basis of the disease-free survival (DFS) improvement offered by Oxaliplatin previously reported (1,3,4,5,6,,8), adjuvant Folfox4 49 Fig. 2. Kaplan-Meier estimates of disease- Free survival by treatment arms in both study groups should be considered after surgery for patients with stage II or III colon cancer, confirming the benefit of 3-years DFS already observed and demonstrating that the DFS benefit can translate into OS benefit. The clinical benefit of Folfox4 arm compared with Capecitabine arm in terms of 5-year OS and 5-year DFS reached statistical significance in favor Folfox4 arm in patients with stage II colon cancer with high risk features (HR=2.555,95%Cl(1.276-5.119),P=0.008) for OS and (HR=2.051,95%Cl(1.13-3.721), P value = <0.018) for DFS with 5-year DFS (18% vs 87%) and 5-year OS (34% vs 93%) for Capecitabine arm and Folfox4 arm respectively. Although chemotherapy after surgery is standard for patients with stage III colon cancer the role of adjuvant therapy for stage II colon cancer remains controversial (9). Recent publications (9,10,11) have demonstrated that for patients with stage II disease, FL improved survival at 5-year by 3.6% with a trend toward improved DFS at 5-year in patients with high risk stage II disease treated by Folfox4 arm. The traditional end point for clinical trials of adjuvant colon cancer end points (ACCENT) meta-analysis of adjuvant studies, which was carried out before the approval of oxaliplatin and irinotecan for advanced disease demonstrated that 3-year DFS was an excellent predictor of 5-year OS results (10) and could be an appropriate primary end point for adjuvant studies in colon cancer. These findings led to the approval by the U.S. Food and Drug administration of 3-year DFS as a primary end point of adjuvant colon cancer studies (12-15).
Lymph node sampling in stage II colon cancer, F. Zakaria, et. al. Table 2. Univariant analysis for different risk factors in both groups in patients showed recurrence event (Kaplan Meier) 50
G. J. O. Issue 16, 2014 Table 3. Multivariate analysis for all statistically significant risk parameters in all study population with stage II colon cancer. A literature based meta-analysis found no evidence of a statistically significant survival benefit of adjuvant chemotherapy for stage II colon cancer with curative resection, and so routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. However, there are groups of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, poorly differentiated histology or vascular invasion (16,17). In the present study, 40 patients (24.69%) presented with inadequate lymph node sampling (<12 evaluated lymph nodes) and 58 patients (35.8%) presented with vascular invasion in both study arms, Forty-nine patients (30.25%) with obstruction, eighty-one patients (50%) with T4 tumor, 18 patients (11.10%) with G III, 21 patients (12.96%) with peritoneal invasion and 45 patients (27.78%) with high CEA levels. The Univariate analysis as regards to DFS revealed significant statistical differences nearly in all risk factors in Capecitabine arm versus vascular invasion and inadequate lymph node sampling in Folfox4 arm, also, the multivariate analysis revealed inadequate lymph node sampling <12 lymph nodes as the only significant risk factor regarding DFS in the study population (HR = 0.244, 95%CI (0.09-0.63),P=0.004). Moreover, highly statistically significant improvement for 3-years and 5-years DFS and OS in favor Folfox4 arm within group of patients with lymph nodes sampling more than12 lymph nodes (HR=0.172,95%Cl(0.0080-0.370),P=<0.001) for DFS and (HR=0.087,95%Cl(0.028-0.268),P=<0.001) for OS. Levover TE, et al (2003), Cserni G, et al (2002), Miller EA, et al (2004) (18,19,20) reported that inadequate lymph node evaluation is associated with worse outcome in terms of tumor recurrence and patients survival, particularly in patients with stage II colorectal cancer. The basis for this association is not known, but it likely reflects inaccurate staging and resulting to lack of adjuvant therapy. In fact, some authors go as far as to suggest that patients deemed lymph node negative on the basis of a low number of retrieved lymph nodes should be considered as being at high risk of recurrence and thus as 51
Lymph node sampling in stage II colon cancer, F. Zakaria, et. al. (a) (b) Fig 3.A-B: Kaplan-Meier estimates of DFS by number of lymph nodes evaluated <12 or> 12 lymph nodes in both study groups (c) (d) Fig. 3.C-D: Kaplan-Meier estimates of OS of lymph nodes evaluated <12 or> 12 lymph nodes in both study groups being candidates for adjuvant therapy. Chang GJ, et al (2007) (21) reported that the number of nodes retrieved can drastically change the prognosis of the patient and it can eliminate the patient from the possibility of receiving adjuvant chemotherapy. Schippinger, et al, (2007) (22), reported in a multivariate analysis in evaluating prognostic parameters for tumor relapse and disease free survival, that the risk for tumor relapse was significantly lower in patients with more than 12 lymph nodes evaluated, p value= 0.01. Zolbec I, et al., (2008), Thomas, et al, (2008), Gray RG, (2010), Roth AD, et al, (2012) (23-26) have shown that there is a correlation between nodes retrieved and patients outcomes. Leila G, et al, (2013) (27) indicated that only less than a third of patients with colorectal cancer underwent adequate lymph nodes examination. Further investigations using careful pathologic reviewing of specimens with inadequate lymph node examined is suggested. The consistency of these findings indicates that most patients with colorectal cancer have inadequate lymph node evaluation, and as a result, patients with inadequately sampled nodes could be offered adjuvant chemotherapy. As regards to vascular invasion, Petersen VC, et al,(2009), York shire study (2007), Quah HM, et al, (2008) (28-30) reported that patients without vascular invasion showed significant statistical difference for 5- year survival. Betge J, et al, 52
G. J. O. Issue 16, 2014 Table 4. Treatment toxicities in both study groups according to National cancer Institute s common toxicity criteria, (NCICTC) version 1. (2012) (31) found that blood vessel invasion has been associated with poor outcome in colorectal cancer (CRC). The authors of this report evaluated venous and lymphatic invasion as potential prognostic indicators in patients with CRC focusing on Lymph node; negative patients venous and lymphatic invasion proved to be significant prognostic variables in unavailable and multivariable analysis. Extramural vascular involvement was of particular significance, when the analysis was restricted to patients with (AJCC-UICC) stage II disease venous invasion but not lymphatic invasion. For toxicity profile within the present study population, GIII diarrhea developed in 79 patients (96.34%) and GIII PSN developed in 11 patients (13.40%) were the most frequent adverse effects in Folfox4 arm. Compared with hand foot syndrome in Capecitabine arm, 67 patients (83.75%) developed GIII hand foot syndrome, as reported by Twelves C, et al, 53 (2005), Hyun-sook son, et al, (2009), Jung- A yun, et al, (2010) (32-34). André T, et al, (2004) (4), reported that GIII PSN was 12.4% during treatment decreasing to 1.1% after one year. André T, et al, (2009) (1) record among patients receiving oxaliplatin, the frequency of GIII PSN was 1.3% at 12 months after treatment and 0.7% at 48 months after treatment. With the exception of PSN, we have not identified any other long-term adverse effects of Folfox4 as reported by Grothey A, (2005) and Tournigand C, et al, (2006) (5,35). In conclusion, these results supported by recent and previous studies suggested that addition of oxaliplatin plus fluoropyrimidine therapy is useful after surgery for group of patients with high risk stage II colon cancer. However, this complex decision is not straight forward and requires integration of factual information, appreciation of the uncertainty of outcomes, and individual goals and values to
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