Final Results of NRG Oncology RTOG 0246: An Organ-Preserving Selective Resection Strategy in Esophageal Cancer Patients Treated with Definitive Chemoradiation.

INTRODUCTION: The impact of selective surgical resection for patients with esophageal cancer treated with definitive chemoradiation has not been clearly evaluated long-term. METHODS: NRG (National Surgical Adjuvant Breast and Bowel Project, Radiation Therapy Oncology Group, Gynecologic Oncology Group) Oncology Radiation Therapy Oncology Group 0246 was a multi-institutional, single-arm, open-label, nonrandomized phase II study that enrolled 43 patients from September 2003 to March 2008 with clinical stage T1-4N0-1M0 squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction from 19 sites. Patients received induction chemotherapy with fluorouracil (650 mg/m2/d), cisplatin (15 mg/m2/d), and paclitaxel (200 mg/m2/d) for two cycles followed by concurrent chemoradiation consisting of 50.4 Gy of radiation (1.8 Gy per fraction) and daily fluorouracil (300 mg/m2/d) with cisplatin (15 mg/m2/d) over the first 5 days. After definitive chemoradiation, patients were evaluated for residual disease. Selective esophagectomy was considered only for patients with residual disease after chemoradiation (clinical incomplete response) or recurrent disease on surveillance. RESULTS: This report looks at the long-term outcome of this selective surgical strategy. With a median follow-up of 8.1 years (minimum to maximum for 12 alive patients 7.2-9.8 years), the estimated 5- and 7-year survival rates are 36.6% (95% confidence interval [CI]: 22.3-51.0) and 31.7% (95% CI: 18.3-46.0). Clinical complete response was achieved in 15 patients (37%), with 5- and 7-yearr survival rates of 53.3% (95% CI: 26.3-74.4) and 46.7% (95% CI: 21.2-68.7). Esophageal resection was not required in 20 of 41 patients (49%) on this trial. CONCLUSIONS: The long-term results of NRG Oncology Radiation Therapy Oncology Group 0246 demonstrate promising efficacy of a selective surgical resection strategy and suggest the need for larger randomized studies to further evaluate this organ-preserving approach.

A Phase II study of a paclitaxel-based chemoradiation regimen with selective surgical salvage for resectable locoregionally advanced esophageal cancer: initial reporting of RTOG 0246.

PURPOSE: The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites. METHODS AND MATERIALS: The study was designed to detect an improvement in 1-year survival from 60% to 77.5% (α = 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU) (650 mg/mg(2)/day), cisplatin (15 mg/mg(2)/day), and paclitaxel (200 mg/mg(2)/day) for two cycles, followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg(2)/day) with cisplatin (15 mg/mg(2)/day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal cancer who did not have systemic disease. RESULTS: Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to March 2006. Forty-one patients were eligible for analysis. Clinical stage was ≥T3 in 31 patients (76%) and N1 in 29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+ nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%. CONCLUSIONS: In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival rate (77.5%) was not achieved (1 year, 71%; 95% confidence interval< 54%-82%).

Proposed modification of nodal status in AJCC esophageal cancer staging system.

BACKGROUND: The current American Joint Committee on Cancer (AJCC) esophageal cancer staging for nodal status is difficult to interpret and is based solely on lymph node location relative to the primary tumor's esophageal location. Recent reports suggest that the number of lymph nodes involved is also an important factor. We reviewed our esophageal experience to propose an improved nodal staging system. METHODS: In all, 1,027 patients with resected esophageal cancer from 1970 to 2005 were reviewed. Lymph nodes stations were assigned according to AJCC criteria. Overall survival was assessed by Kaplan-Meier analysis. The impact of location, number of involved lymph nodes, and use of preoperative chemotherapy or radiation therapy, or both, was assessed. RESULTS: Nonregional nodal involvement (n = 17) was associated with decreased survival compared with regional (n = 441) or celiac nodal (n = 73) involvement (3-year: 0% versus 24% and 23%; p < 0.001). The number of involved lymph nodes was strongly associated with survival (3-year: 0 nodes = 63%, 1 to 3 nodes = 31%, more than 3 nodes = 13%; p < 0.001), and multivariable Cox proportional-hazards analysis suggested that the location and number of involved lymph nodes were independent predictors of survival (p < 0.001). We propose a modified nodal staging system that designates celiac nodes as regional and includes number of involved nodes: pN0, no nodes (3 years = 63%, n = 496); pN1-regional, 1 to 3 nodes (3 years = 32%, n = 292); pN2-regional, more than 3 nodes (3 years = 14%, n = 222); pN3-nonregional node (3 years = 0%, n = 17 [p < 0.0001]). This modified nodal staging system better predicts survival than the current AJCC nodal staging system in which survival for pN1 (3 years = 24%) and pM1a (3 years = 23%) do not differ (p = 0.67). The use of induction before surgical resection did not alter the predictive effect of the new nodal staging system. CONCLUSIONS: Modification of the AJCC nodal classification system to incorporate the number of involved lymph nodes with regional and nonregional node location simplifies and better predicts long-term survival than does the current AJCC nodal system.

Comparison of CT methods for determining the fat content of the liver.

OBJECTIVE: The purpose of this study was to assess which of a number of methods of measuring attenuation on CT scans is best for prediction of hepatic fat content. MATERIALS AND METHODS: This retrospective study was approved by our institutional review board. Consecutively registered patients who underwent liver resection for metastatic disease formed the study group. Attenuation measurements were obtained from 12 regions of interest in the liver and three in the spleen on both unenhanced and portal phase contrast-enhanced preoperative hepatic CT images. Hepatic attenuation measurements were analyzed both with and without normalization with the spleen. Normalization included both differences and ratios between hepatic and splenic attenuation values. Pathologic fat content was graded semiquantitatively as a percentage of the nonneoplastic liver parenchyma of the resected specimen. Average attenuation values of the liver were compared with pathologic fat content, as were the differences and ratios between hepatic and splenic attenuation values. Linear regression analysis was conducted on a log-log scale. RESULTS: Data on 88 patients were analyzed. On unenhanced and contrast-enhanced CT images, all associations between pathologic fat content and attenuation measurements were significant (p < 0.0001). All series of R2 values for unenhanced CT scans were much higher than those for contrast-enhanced CT scans. The R2 values of liver-only measurement were higher than those of hepatic values normalized with splenic values on both unenhanced (0.646-0.649 > 0.523, 0.565) and contrast-enhanced (0.516 > 0.242, 0.344) CT. CONCLUSION: Measurement of attenuation of liver only on unenhanced CT scans is best for prediction of pathologic fat content.

Ataxia-telangiectasia mutated expression is associated with tobacco smoke exposure in esophageal cancer tissues and benzo[a]pyrene diol epoxide in cell lines.

Esophageal cancer is a substantial health problem because of its usually late stage at diagnosis and poor prognosis. Tobacco smoking and alcohol use are the most important risk factors in the development of esophageal squamous cell carcinoma (SCC). Our previous study demonstrated the binding of benzo[a]pyrene diol epoxide (BPDE), a carcinogen present in tobacco smoke and environmental pollution, to the ataxia-telangiectasia mutated (ATM) gene. To understand how this binding affects the alteration of ATM expression and to identify biomarkers for the detection of esophageal cancer, we analyzed ATM mRNA expression in tissue specimens from patients with esophageal SCC and premalignant lesions using in situ hybridization. We then performed in vitro experiments to verify and extend our ex vivo observations. We found that ATM expression was increased in esophageal SCC and its premalignant lesions when compared with normal tissues and that increased ATM expression was associated with tobacco smoke exposure and tumor de-differentiation. Moreover, BPDE induced ATM expression in esophageal SCC cell lines in a time-dependent manner. In summary, the BPDE in tobacco smoke may be responsible for increased ATM expression in premalignant and malignant esophageal tissues. Our findings suggest that the ATM gene should be further evaluated as a biomarker for the early detection of esophageal cancer and tobacco use in patients.

The addition of induction chemotherapy to preoperative, concurrent chemoradiotherapy improves tumor response in patients with esophageal adenocarcinoma.

BACKGROUND: Tumor viability assessed by pathologic analysis of resected specimens in patients with preoperatively treated esophageal adenocarcinoma (EAC) is a prognostic indicator. The feasibility of induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) and surgery for patients with locoregionally advanced EAC has been demonstrated. In this study, the authors evaluated the efficacy of CCRT compared with traditional concurrent chemoradiotherapy (CRT). METHODS: The authors retrospectively reviewed 247 consecutive patients with EAC who presented for planned surgery after treatment with either CCRT or CRT from January 1997 through August 2003. Patient demographics, comorbidities, and tumor characteristics were analyzed. Pathologic tumor response, overall survival, and disease-free survival were assessed according to treatment. RESULTS: One hundred seventeen patients received CCRT, and 130 patients received CRT before planned surgical resection. CCRT resulted in a 64% tumor response rate compared with a 51% tumor response rate in the CRT group (odds ratio, 1.73; P = .035). In the CCRT group, the median overall survival was 55 months, and the 3-year overall survival rate was 59%; in the CRT group, the median overall survival was 25 months, and the 3-year overall survival rate was 41% (hazard ratio [HR], 0.69; P = .041). In the CCRT group, the median disease-free survival was 43 months, and the 3-year disease-free survival rate was 54%; in the CRT group, the median disease-free survival was 18 months, and the 3-year disease-free survival rate was 36% (HR, 0.72; P = .047). Subset analysis of patients with clinical Stage III/IVA disease showed a median overall survival of 51 months with a 3-year overall survival rate of 58% in the CCRT group and a median overall survival of 20 months with a 3-year overall survival rate of 28% in the CRT group (HR, 0.57; P = .019). CONCLUSIONS: In patients with EAC, CCRT improved tumor response significantly compared with traditional CRT alone. Overall survival and disease-free survival were increased in patients who received CCRT, especially in the subset of patients who had more advanced disease.

Histologic subtypes as determinants of outcome in esophageal carcinoma patients with pathologic complete response after preoperative chemoradiotherapy.

BACKGROUND: The current study tested the hypothesis that the clinical outcome of patients with localized esophageal carcinoma after preoperative chemoradiotherapy (CTRT) depends on histology. METHODS: The authors stratified patients by adenocarcinoma (ACA) or squamous cell carcinoma (SCC) and compared the overall survival (OS) and patterns of failure among patients achieving pathologic complete response (pathCR) and or=0.05). In the ACA group, a greater portion of

Characterization of pathologic complete response after preoperative chemoradiotherapy in carcinoma of the esophagus and outcome after pathologic complete response.

BACKGROUND: The purpose of the current study was to test the hypothesis that a lower clinical TNM stage is associated with a higher rate of pathologic complete response (pathCR) in patients with esophageal carcinoma receiving preoperative chemoradiotherapy and to determine whether outcome after pathCR is related to clinical stage or treatment. METHODS: Clinical parameters and surgical specimens of patients with esophageal carcinoma undergoing preoperative chemoradiotherapy were analyzed to identify predictors of pathCR. In patients with pathCR, predictors of overall survival (OS), disease-free survival (DFS), and distant recurrence were studied. RESULTS: Sixty-nine (29%) of 235 patients achieved pathCR. In patients with American Joint Committee on Cancer (AJCC) Stage II carcinoma, the proportion achieving pathCR was significantly larger than that achieving

Failure patterns correlate with the proportion of residual carcinoma after preoperative chemoradiotherapy for carcinoma of the esophagus.

BACKGROUND: The current study was conducted to test the hypothesis that patterns of failure are correlated with the degree of residual carcinoma after preoperative chemoradiotherapy (CRT) in patients with esophageal carcinoma. METHODS: The authors analyzed the clinical characteristics of patients with carcinoma of the esophagus who underwent preoperative CRT. The residual carcinoma in the resected specimen was categorized into 3 groups (0%, 1-50%, and > 50%). The initial patterns of failure were analyzed according to these categories. RESULTS: Of the 235 patients who underwent CRT, 69 (29%) achieved a pathologic complete response (pathCR; Group A), 109 patients (46%) achieved a response but it was less than a pathCR (1-50% residual carcinoma; Group B), and 57 (24%) had no response (> 50% residual carcinoma; Group C). The time to locoregional recurrence was significantly longer for Group A compared with Group C (P = 0.05). The rate of distant metastases was significantly lower in Groups A and B compared with Group C (14% in Group A, 29% in Group B, and 33% in Group C; P = 0.03). The distant metastases-free survival was found to be significantly longer in Groups A and B compared with Group C (Group A vs. Group B, P = 0.01; Group A vs. Group C, P < 0.0001; and Group B vs. Group C, P = 0.03). A significantly higher proportion of patients in the responding groups (Groups A and B) had no disease recurrence compared with Group C (81% in Group A, 67% in Group B, and 61% in Group C; P = 0.04). The overall survival and disease-free survival were found to be significantly longer in Groups A and B compared with Group C. CONCLUSIONS: Data from the current study demonstrate that the proportion of residual carcinoma after preoperative CRT is significantly correlated with patterns of locoregional and distant failure. Future investigations should focus on reducing the proportion of residual carcinoma and metastatic disease progression in patients with esophageal carcinoma.

Loss of RUNX3 expression significantly affects the clinical outcome of gastric cancer patients and its restoration causes drastic suppression of tumor growth and metastasis.

Identification of precise prognostic marker and effective therapeutic target is pivotal in the treatment of gastric cancer. In the present study, we determined the level of RUNX3 expression in gastric cancer cells and gastric cancer specimens and the impact of its alteration on cancer biology and clinical outcome. There was a loss or substantial decrease of RUNX3 protein expression in 86 cases of gastric tumors as compared with that in normal gastric mucosa (P < 0.0001), which was significantly associated with inferior survival duration (P = 0.0005). In a Cox proportional hazards model, RUNX3 expression independently predicted better survival (P = 0.036). Moreover, various human gastric cancer cell lines also exhibited loss or drastic decrease of RUNX3 expression. Enforced restoration of RUNX3 expression led to down-regulation of cyclin D1 but to up-regulation of p27, caspase 3, 7, and 8 expression, cell cycle arrest, and apoptosis in vitro, and dramatic attenuation of tumor growth and abrogation of metastasis in animal models. Therefore, we offered both clinical and mechanistic evidence that RUNX3 was an independent prognostic factor and a potential therapeutic target for gastric cancer.

Proposed revision of the esophageal cancer staging system to accommodate pathologic response (pP) following preoperative chemoradiation (CRT).

OBJECTIVE: To determine the impact of pathologic response following preoperative chemoradiation (CRT) on the AJCC esophageal cancer staging system. SUMMARY BACKGROUND DATA: Increasing numbers of locoregionally advanced esophageal cancer patients are treated with preoperative CRT prior to surgical resection. METHODS: Five hundred ninety-three pts from 1985 to 2003 with esophageal cancer who underwent surgery with (n = 239) or without CRT (n = 354) were reviewed. Resected esophageal tumors were assessed for pathologic response by determining extent of residual tumor following CRT (P0, 0% residual; P1, 1%-50% residual; P2, >50% residual). RESULTS: After CRT down-staging, pTNM specific survival was similar, irrespective of treatment group (P = 0.98). The pTNM stage distribution was more favorable in the CRT group (P < 0.001) despite a more advanced initial cTNM stage distribution (P < 0.001). Following CRT, the pathologic response (pP) at the primary tumor as defined by extent of residual tumor predicted overall survival (3 years: P0, 0% residual = 74%; P1, 1%-50% residual = 54%; P2, >50% residual = 24%, P < 0.001) and stage specific survival with greater accuracy than pTNM stage alone. CONCLUSIONS: Our analyses demonstrate that following CRT, pTNM continues to predict survival. The extent of pathologic response following CRT is an independent risk factor for survival (pP) and should be incorporated in the pTNM esophageal cancer staging system to better predict patient outcome in esophageal cancer.

Comparison of clinical stage, therapy response, and patient outcome between squamous cell carcinoma and adenocarcinoma of the esophagus.

PURPOSE: To analyze the differences in clinical stage, pathologic response to chemoradiotherapy, patterns of failure, and overall survival (OS) between patients with squamous cell carcinoma (SCC) and adenocarcinoma (ACA) of the esophagus. PATIENTS AND METHODS: We stratified patients by two histologies, ACA and SCC, and statistically compared their clinical stage, post-therapy pathologic response, patterns of failure, and OS. RESULTS: Of the 235 patients who underwent preoperative chemoradiotherapy, 42 (18%) had SCC and 193 (82%) had ACA. Among the ACA patients, a significantly larger proportion was male (93% vs 7%; p <0.001), whereas sex was distributed similarly among SCC patients (55% male vs 45% female; p = 0.5). A significantly larger percentage of SCC patients were classified as lower TN and overall stage than ACA patients (T2 = 41% vs 28%, p <0.0001; N0 = 69% vs 48%, p = 0.01; stage II = 76% vs 55%, p <0.001). A significantly greater portion of SCCs was categorized as pathologic N0 after treatment (71% vs 65%; p = 0.02). Among the pathCR patients in clinical stage II, there were significantly greater proportion of SCC patients (77% vs 63%; p <0.001) than ACA patients. Among the pathCR patients in clinical stage III patients, a significantly greater proportion were ACA patients (38% vs 23%; p <0.001) than SCC patients. The median and 5-yr OS was 53 +/- 11 mo and 39% for ACA patients and 35 +/- 14 mo and 37% for SCC (median OS, p = 0.3). Among pathCR patients, median OS of ACA patients (133 mo) was longer than that of SCC patients but nonsignificant (29 mo; p = 0.07); results were similar for non-pathCR patients. DFS results were similar in all subgroups. Among the whole cohort, incidence of local-regional recurrence and distant metastases did not vary significantly. The median time to distant metastases did not vary significantly for pathCR and non-pathCR patients. CONCLUSIONS: We believe this is the first study that compares failure outcome of ACA and SCC patients with similar clinical stage after trimodality therapy. Our data suggest that significant differences in clinical stage and post-therapy pathologic stage exist between ACA and SCC. Frequent presence of malignant nodes in the resected specimens of ACA patients resulted in a shorter time-to-metastases suggesting that ACA patients need better systemic control.

Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer.

BACKGROUND: This study evaluates the utility of positron emission tomography (PET), endoscopic ultrasonography (EUS), and computed tomographic (CT) scans to predict pathologic response and survival following preoperative chemoradiation (CRT) in esophageal cancer. METHODS: One hundred three sequential patients with locoregionally advanced esophageal cancer, who were treated with CRT and esophageal resection between May 2001 and November 2003 at the University of Texas M.D. Anderson Cancer Center, were retrospectively reviewed. PET, EUS, and CT were performed before (pre) or after (post) CRT and before surgical resection. PET standardized uptake value (SUV) was defined as maximal uptake in primary tumor. RESULTS: Most patients were male (91 [88%]) with adenocarcinoma (90 [87%]). Pretreatment clinical stages were: IIA (42 [41%]), IIB (5 [5%]), III (50 [49%]), and IVA (6 [6%]). At the time of surgery, 58 patients (56%) had a pathologic response to CRT (< or =10% viable cells). Post-CRT measurements that correlated with pathologic response were: CT esophageal wall thickness (13.3 vs 15.3 mm, p = 0.04), EUS mass size (0.7 vs 1.7 cm, p = 0.01) and PET SUV (3.1 vs 5.8, p = 0.01). Post-CRT PET SUV equal to or greater than 4 had the highest accuracy for pathologic response (76%). Univariate and multivariate Cox regression analysis demonstrated that a post-CRT PET SUV equal to or greater than 4 was an independent predictor of survival (HR, 3.5, p = 0.04). CONCLUSIONS: The FDG-PET SUV is the most accurate noninvasive test to predict long-term survival after preoperative CRT and before surgical resection. Post-CRT FDG-PET cannot, however, rule out residual microscopic disease so esophagectomy should remain a therapeutic option even if the post-CRT imaging modalities are normal.