Adjuvant and preoperative chemotherapy for gastric cancer

Gastric cancer is the second most frequently diagnosed malignancy worldwide, and the risk of relapse remains high in the majority of patients undergoing resection. Attempts to reduce this risk and prolong survival have led to numerous adjuvant chemotherapy trials that either had no benefit for patients or occasionally had controversial results. The recently reported Intergroup 0116 trial shows conclusive evidence of survival benefit for patients treated with postoperative chemoradiotherapy. In this Intergroup trial, which involves over 600 patients, a regimen of postoperative chemotherapy plus chemoradiotherapy was shown to prolong overall and disease-free survival in gastric cancer patients with stage IB through IV disease following a curative (R0) resection. This approach should be considered the standard of care in patients with gastric cancer who have undergone curative resection. Preoperative chemotherapy shows promise in downstaging tumors and increasing the rate of curative resection, but randomized trials are needed to assess survival benefits. Efforts to combine existing treatment modalities and new agents with novel mechanisms of action hold promise for the future.     

Outcomes after emergency surgery for gastric perforation or severe bleeding in patients with gastric cancer

BACKGROUND AND OBJECTIVES: Free perforation and major bleeding in patients with gastric cancer are rare but serious conditions with potentially dangerous effects. To clarify the clinicopathologic characteristics of patients with these conditions and to determine the optimum management, we reviewed 16 cases of perforation and 13 cases of major bleeding in patients with gastric cancer who required emergency surgery. METHODS: We compared the clinical and histologic features of the patients with perforation and those with bleeding. Cox's multivariate regression analysis was used to compare survival rates between patients who underwent single-step surgery or a two-step radical procedure, between patients with stage I or II and stage III or IV cancer, between patients who underwent complete (R0) and incomplete (R1 or R2) resection, and between patients with bleeding and those with perforation. RESULTS: Many of the patients had advanced disease. There were no significant differences in clinicopathologic findings or survival between patients with gastric perforation and those with major bleeding. Patients who had major bleeding tended to have larger cancers. In the univariate analysis, gastrectomy (vs. no gastrectomy), R0 (vs. R1 or R2) resection, and lower stage (vs. higher stage) were highly correlated with improved survival time. CONCLUSIONS: Overall, patients with gastric cancers who underwent emergency gastrectomy had a poor prognosis, but it was better than that of patients who could not have gastrectomy because of the prXesence of advanced cancer. However, the survival rate was excellent in patients with early-stage cancer who underwent complete (R0) resection. We recommend complete resection when possible.     

Management of perforated gastric carcinoma: a report of 16 cases and review of world literature

Perforated gastric carcinoma is rare; however, it is a serious condition associated with complications. To understand the proper management of this disease and to characterize its clinical course we reviewed available data on 16 patients with perforated gastric carcinoma. We collected data on the age and sex of the patients as well as operative findings and histological features of the primary tumor. The depth of invasion and presence of lymph node metastasis were also recorded. The Union Internationale Contre Cancer stage, extent of resection, and surgical method used were reviewed. We also reviewed published information on the management of perforated gastric carcinoma. The carcinoma was stage I in three cases, stage II in one case, stage III in three cases, and stage IV in nine cases. Many patients had distant metastases. Fourteen patients underwent gastrectomy. Two patients whose preoperative condition was poor died of surgery-related complications, but patients with early-stage carcinoma underwent an R0 resection (resection of the primary tumor with negative margins) and had minimal complications. We conclude that the outcome of patients who were able to undergo radical surgery was good and correlated with the stage of cancer. It is important to perform gastrectomy rather than repair the perforation first, and a proper lymphadenectomy should follow--thus a two-step surgery when necessary.     

Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response.

PURPOSE: Despite aggressive chemotherapy, radiotherapy, surgery, or combination approaches, the survival rate of patients with esophageal cancer remains poor. Recent studies have suggested that constitutive activation of the Hedgehog (Hh) pathway in cancers of the digestive tract may contribute to the growth and maintenance of cancer. However, the relationship between Hh signaling and therapeutic response is unknown. EXPERIMENTAL DESIGN: The expression and temporal kinetics of Hh signaling and proliferation biomarkers after chemoradiotherapy were examined in esophageal tumor xenografts. Additionally, immunohistochemical analysis of Sonic Hh (Shh) and Gli-1 expression were done on residual tumors from patients who received neoadjuvant chemoradiotherapy followed by surgery. The ability of Shh signaling to induce proliferation in esophageal cell lines was determined. Expression of cell cycle checkpoint proteins was analyzed in cells in which Hh signaling was activated or inhibited. We further determined the effect of inhibiting Hh signaling in sensitizing esophageal tumors to radiation. RESULTS: We showed that the Shh signaling pathway was extensively activated in esophageal cancer xenografts and residual tumors after chemoradiotherapy and the temporal kinetics of Hh signaling preceded increases in proliferation biomarker expression and tumor size during tumor regrowth. We further showed that Hh pathway activity influences proliferation rates of esophageal cancer cell lines through up-regulation of the G1-cyclin-Rb axis. Additionally, we found that blocking Hh signaling enhanced radiation cytotoxicity of esophageal cancer cells. CONCLUSIONS: These results suggest that activation of the Hh pathway may promote tumor repopulation after chemoradiotherapy and contribute to chemoradiation resistance in esophageal cancers.     

Early detection of chemoradioresponse in esophageal carcinoma by 3'-deoxy-3'-3H-fluorothymidine using preclinical tumor models.

PURPOSE: Early identification of esophageal cancer patients who are responding or resistant to combined chemoradiotherapy may lead to individualized therapeutic approaches and improved clinical outcomes. We assessed the ability of 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography (FLT-PET) to detect early changes in tumor proliferation after chemoradiotherapy in experimental models of esophageal carcinoma. EXPERIMENTAL DESIGN: The in vitro and ex vivo tumor uptake of [(3)H]FLT in SEG-1 human esophageal adenocarcinoma cells were studied at various early time points after docetaxel plus irradiation and validated with conventional assessments of cellular proliferation [thymidine (Thd) and Ki-67] and [(18)F]FLT micro-PET imaging. Imaging-histologic correlation was determined by comparing spatial Ki-67 and [(18)F]FLT distribution in autoradiographs. Comparison with fluorodeoxyglucose (FDG) was done in all experiments. RESULTS: In vitro [(3)H]FLT and [(3)H]Thd uptake rapidly decreased in SEG-1 cells 24 hours after docetaxel with a maximal reduction of over 5-fold (P = 0.005). The [(3)H]FLT tumor-to-muscle uptake ratio in xenografts declined by 75% compared with baseline (P < 0.005) by 2 days after chemoradiotherapy, despite the lack of change in tumor size. In contrast, the decline of [(3)H]FDG uptake was gradual and less pronounced. Tumor uptake of [(3)H]FLT was more closely correlated with Ki-67 expression (r = 0.89, P < 0.001) than was [(3)H]FDG (r = 0.39, P = 0.08). Micro-PET images depicted similar trends in reduction of [(18)F]FLT and [(18)F]FDG tumor uptake. Autoradiographs displayed spatial correlations between [(18)F]FLT uptake and histologic Ki-67 distribution in preliminary studies. CONCLUSIONS: FLT-PET is suitable and more specific than FDG-PET for depicting early reductions in tumor proliferation that precede tumor size changes after chemoradiotherapy.     

Expression of annexin A1 in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome.

PURPOSE: Annexin A1 (ANXA1) is a calcium-binding protein involved in arachidonic acid metabolism and epidermal growth factor receptor tyrosine kinase pathway. ANXA1 has been implicated in early squamous cell carcinogenesis of esophagus and correlates with degree of tumor differentiation. However, the role of ANXA1 in esophageal adenocarcinoma is unclear. Our goal was to evaluate ANXA1 expression and determine its prognostic significance in adenocarcinoma of the esophagus and esophagogastric junction. EXPERIMENTAL DESIGN: This study included 104 consecutive patients with primary resected esophageal and esophagogastric junction adenocarcinomas (11 stage I, 24 stage II, 53 stage III, and 16 stage IV). ANXA1 protein expression in each tumor was assessed by immunohistochemical staining of tissue microarrays. ANAX1 expression level was classified as high (>/=25% of tumor cells with cytoplasmic staining), low (<25% of tumor cells with cytoplasmic staining), or negative; and was correlated with clinicopathologic features and patients' outcomes. RESULTS: High ANXA1 expression was present in 39% (41 of 104) of tumors and was associated with higher pathologic T stage (P = 0.03) and distant metastasis (P = 0.04). High ANXA1 expression correlated with increased recurrence rate (P = 0.004) and decreased overall survival (P = 0.003) in univariate analysis. In multivariate analysis, ANXA1 expression and pN stage significantly correlated with recurrence rate (P = 0.008 and P < 0.001, respectively) and overall survival (P = 0.02 and P < 0.001, respectively) independent of T stage. CONCLUSION: Our results indicate that high ANXA1 expression is frequent in esophageal and esophagogastric junction adenocarcinomas, correlates with more advanced pathologic T stage and the presence of distant metastasis, and is an independent prognostic factor for patient survival.     

Small cell carcinoma of the esophagus: the University of Texas M. D. Anderson Cancer Center experience and literature review

BACKGROUND: Small cell carcinoma of the esophagus is a rare disease with aggressive behavior and poor prognosis. Multidrug chemotherapy remains the treatment of choice given the systemic nature of the disease. Radiotherapy has been used concurrently with chemotherapy to enhance local control. The role of surgery in patients with limited disease is controversial. Limited data exist regarding the pathologic response of the tumor to chemoradiotherapy. The goal of the current study was to analyze the outcome of 8 patients treated at the M. D. Anderson Cancer Center, with particular focus on the histologic findings of the resected specimens. METHODS: Patient records were reviewed for demographics, presenting symptoms, diagnostic modalities, disease stage, treatment, and outcome. RESULTS: Two of eight patients had metastatic disease at the time of diagnosis and received combination chemotherapy. Six patients had limited stage disease. Four received combined modality treatment including esophagectomy, and two received radiotherapy only. All four patients who underwent esophagectomy had pure small cell carcinoma histology at diagnosis and received preoperative combination chemotherapy with or without radiotherapy. None of the four patients achieved a pathologic complete remission. Two patients had residual small cell carcinoma; one patient had squamous cell carcinoma and one adenocarcinoma. The median overall survival for the group of patients was 12.5 months (range, 5-57 months). CONCLUSIONS: In selected patients with limited stage disease, surgery with curative intent should be considered as part of multimodality treatment.     

Preoperative therapy for local-regional gastric cancer: rationale and review of trials

The standard approach for patients with local-regional gastric carcinoma is an attempted surgical resection to achieve a "curative resection" (also called an R0 resection) with adequate lymph node dissection. Western patients, who often get suboptimal surgery and have a high incidence of regional lymph node involvement, remain at higher risk of local and systemic relapse after an R0 resection than most Japanese patients. Numerous postoperative adjuvant therapy trials have not yet established an advantage for these patients. Thus in the West, the concept of preoperative therapy is appealing. The preoperative approach can potentially result in downstaging (or downsizing) of the primary tumor and, therefore, increasing the rate of R0 resection. Investigators are still refining the treatment strategies and defining ideal patient population for this approach. Undoubtedly, properly designed prospective randomized trials will be needed to establish any advantage with this approach. A number of newer agents hold a great deal of promise.     

Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation

BACKGROUND: In patients with locoregional carcinoma of the esophagus or esophagogastric junction who underwent preoperative chemoradiation, it is unclear whether survival was better predicted by pretherapy clinical stage or by posttherapy pathologic stage. METHODS: The authors studied 235 consecutive patients with pretherapy clinical Stage II, III, or IVA (according to American Joint Committee on Cancer criteria) carcinoma of the esophagus or esophagogastric junction who were treated with chemoradiation followed by esophagectomy. Posttherapy cancer status was classified using pathologic stage and semiquantitative assessment of residual carcinoma. Clinicopathologic features, residual carcinoma status, and pretherapy and posttherapy stage were compared with disease-free and overall survival. RESULTS: Posttherapy pathologic stage was Stage 0 in 29% of patients, Stage I in 11% of patients, Stage II in 34% of patients, Stage III in 20% of patients, and Stage IV in 6% of patients. Cancer downstaging occurred in 56% of patients. In univariate analysis, disease-free and overall survival were predicted by posttherapy pathologic stage (both with P < 0.001), margin status (P = 0.002 and P = 0.01, respectively), extent of residual carcinoma (both with P < 0.001), and downstaging (both with P = 0.001), but not by age, gender, type of cancer, pretherapy clinical stage, or preoperative regimen. However, in multivariate analysis, disease-free and overall survival were independently predicted by posttherapy pathologic stage (both with P = 0.02). Extent of residual carcinoma was a marginally significant predictor of overall survival (P = 0.04). CONCLUSIONS: Posttherapy pathologic stage was the best available predictor of outcome for patients with locoregional carcinoma of the esophagus or esophagogastric junction who underwent chemoradiation therapy followed by esophagectomy. The findings in the current study supported the concept of downstaging by preoperative therapy.