1. What Factors Predict Outcome At Relapse After Previous Esophagectomy And Adjuvant Therapy in High-Risk Esophageal Cancer? Edward Yu 1, Patricia Tai 5, Richard Malthaner 3, Larry Stitt 4, George Rodrigues 1, Rashid Dar 1, Brian Yaremko 1, Jawaid Younus 2, Michael Sanatani 2, Mark Vincent 2, Brian Dingle 2, Dalilah Fortin 3, Richard Inculet 3 Department of Oncology, Divisions of Radiation Oncology 1 /Medical Oncology 2, Surgical Oncology 3, Biostatistics 4, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada Department of Radiation Oncology 5, Allan Blair Cancer Center, Regina, Saskatchewan, Canada Introduction: Management of patients who have disease relapse after completion of surgery and adjuvant chemo-radiation (CRT) is controversial. Some oncologists would advocate intensive therapeutic intervention due to promising experience on treatment for recurrence disease while others would recommend palliative support due to the concerns for poor patient outcome post disease recurrence. In Addition, it is not clear if patient outcome is improved post adjuvant CRT when patients at risk have resection margin involvement and if time interval to recurrence can affect patient survival post relapse. The present study was conducted to determine what factors will affect patient outcome at relapse after previous surgery and adjuvant CRT in high-risk esophageal cancer patients This clinical information may be useful in providing appropriate guidance for oncologists to manage esophageal cancer patients after disease relapse. Method and Materials : Data were analyzed for patients at London Regional Cancer Program (LRCP) from 1989 – 1999 with diagnosis of “high-risk” resected esophageal cancer. High-risk pathological findings were defined as T3 or T4 disease and/or regional nodal (N1) involvement. Adjuvant therapy consisted of chemotherapy followed by concurrent CRT Chemotherapy consisted of 4 cycles of either ECF (epirubicin 50mg/m 2 continuous infusion for 21 days and cisplatinum 60mg/m 2 day 1 and q21 days), with epirubicin omitted during the concurrent phase with RT, or 4 cycles of CF (cisplatinum 100mg/m 2 day 1 and q 21 days) and 5 fluorouracil 1000mg/m 2 days 1-4 continuous infusion and q21 days). Total RT dose ranged from 45-60 Gy at 1.8-2.0 Gy fractions at discretion of the treating radiation oncologist. In general, 45-50 Gy was used for microscopic disease while higher doses up to 60 Gy were reserved for patients with margin involvement or residual disease. Relapse was defined as disease recurrence at local, regional or distant sites as the first event in the follow up. Local relapse was defined as recurrence at or immediately adjacent to the anastomotic site. Thirteen patients had positive resection margin while 9 (70%) had positive radial margin and 4 (30%) had positive proximal resection margin. Relapse patient cohort follow-up ranged from 1.3-100 months with a median of 30.5 mos. All 46 patients with relapse died of disease. The median post recurrence OS rates were 5.8 mos with 12 mos, 24 mos and 36 mos at 20%, 10% and 5% respectively. Distant relapses were 45% and bone, liver, lung and brain were the common sites. Of the prognostic factors including age gender, pathological stage, histology, resection margins status, relapse patterns and time interval for recurrence only resection margin status and time interval for recurrence were significant in univariate (P=0.008, and P=0.002), and multivariate (P=0.027, and P=0.003) analysis, respectively. Patients with late relapse (>12 mos) had a median post recurrence OS rate of 8.4 mos vs early relapse ( 12 mos vs 4.1 mos for <12 mos was significant (P=0.01, Log- rank). Relapse patients with negative resection margin had a median post-recurrence OS rate of 5.8 mos compared to 2.6 mos with positive resection margins (P=0.006,Log- rank)(Figure2). The median post recurrence CSS rates for negative and positive resection margins were 6.1 mos and 2.7 mos (P=0.01, Log-rank), respectively. Patients who had positive resection margins and relapsed 12 mos and/or negative resection margins) of 6.0 mos (P=0.003, Log-rank) (Figure 3). The median post recurrence CSS rates for positive resection margins and <12 mos compared to others were 1.7 mos and 8.1 mos (P=0.006, Log-rank), respectively. Conclusion: Our result demonstrated that positive surgical resection margins and a short time interval to relapse of < 12 mos are independent variables and have negative impact on patient outcome. Identification of these prognostic factors should aid physicians to deliver appropriate care particularly for those with poor outcome. Figure 2 The Effect of Resection Margin Status on Post-Recurrence Overall Survival Figure 3 The Effect of both Time of Relapse and Resection Margin Status on Post-Recurrence Overall Survival ( P= 0.003, Log-rank) (P=0.006, Log-rank) (P= 0.007, Log-rank) Table 1 Patient Demographics AgeMedian 61 yearsRange (37-82 years) GenderMale Female 42(91%) 4(8%) Pathological stageT1 T2 T3 T4 N0 N1 1(2%) 9(20%) 33(74%) 2(4%) 44(96%) HistologyAdenocarcinoma Squamous 31(67%) 15(33%) Resection margin status Negative Positive 33(72%) 13(28%) Regional relapse was recurrent at the mediastinum and/or peri-esophageal region excluding local relapse. Distant relapse was tumor recurrence at the distant site, i.e. brain, liver, and lung. Univariate logistic regression analysis was used for prognostic factors including age, gender, pathological stage, histology, resection margins status, relapse, time interval for recurrence. A subsequence multivariate comparison and to obtain odds ratio estimates was performed. Post recurrence cause-specific survival (CSS) was defined as the interval between the date of first disease recurrence and the death or last follow-up with death due to cancer being defined as an event. Post recurrence overall survival (OS) was defined as the interval between the date of first disease recurrence and the death or last follow-up being defined as an event. Survival estimates were obtained using Kaplan-Meier methodology. Survival comparisons were performed using Log-rank statistics. Reference 1. Yu et al., Radiotherp & Oncol 73 (2), 2004. Results: We have previously reported a cohort of 69 patients with high-risk esophageal cancer post esophagectomy and CRT (1). At the time of analysis, 12(13%) patients were alive, 54(83%) were dead, and 3(4%) lost follow up. There were 46 (67%) patients who had disease relapse. Median time for relapse post adjuvant treatment was 28 months (range: 0.1 to 40 months). The patient demographics of this relapse group were shown in Table 1: median age of 61 years (range: 37-82 years), with 42 (91%) male, 44 (96%) node-positive at diagnosis, 31 (67%) adenocarcinoma. Surgery was either trans-hiatal (86%) or trans-thoracic (14%) with 33 (72%) negative resection margin. Figure 1 The Effect of Time of Relapse on Post-Recurrence Overall Survival