Outcome of gastric cancer patients after successful gastrectomy: influence of the type of recurrence and histology on survival.

BACKGROUND: The effect of the location of disease recurrence after curative (R0) gastrectomy on patient survival has not been elucidated. The authors hypothesized that the location of recurrence would have a significant influence on survival. METHODS: Medical records of all patients who received treatment for gastric cancer at The University of Texas M. D. Anderson Cancer Center between 1985 and 1998 were reviewed. Patients who underwent R0 resection for gastric cancer and subsequently developed localized (anastomotic) recurrence (LR), lymph node (regional) recurrence (NR), or distant metastases (DM) were analyzed for overall survival (OS). All study factors were entered into a Cox proportional hazards model to provide multivariate hazard ratios. The model was adjusted for the effects of primary site of recurrence, histologic grade, patient age, and location of the primary tumor. RESULTS: This retrospective analysis included 227 consecutive patients. The median survival of patients who developed NR (11 months) was similar to that of patients who developed LR (10 months), but both groups had significantly longer median survival compared with patients who developed DM (7 months; log-rank P = .03). Patients who had well differentiated or moderately differentiated tumors had a longer OS (11 months) than patients who had poorly differentiated tumors (8 months; log-rank P = .02). In this cohort, location of the primary cancer and age at recurrence had no significant impact on OS. CONCLUSIONS: The data from this study suggested that, among patients who undergo R0 gastrectomy for gastric cancer, LR and NR versus DM should be considered a valid stratification factor for randomized trials based on significant differences in survival. Determining whether this stratification should apply to histologic differentiation will require further investigation in a larger multicenter cohort.

Surgical pathology stage by American Joint Commission on Cancer criteria predicts patient survival after preoperative chemoradiation for localized gastric carcinoma.

BACKGROUND: Preoperative chemoradiation for localized gastric cancer can modify baseline stage, as determined by surgical pathology stage. Therefore, the authors hypothesized that surgical pathology stage would be a better prognosticator of overall survival (OS) than baseline stage. METHODS: Patient populations were combined from 2 prospectively conducted, preoperative chemoradiation trials that used the same therapeutic strategy. Patients must have had localized gastric adenocarcinoma and were staged extensively, including endoscopic ultrasonography and laparoscopy. Patients had to be fit for surgery medically with a technically resectable cancer. All patients provided written informed consent. Patients first received induction chemotherapy for up to 2 months followed by chemoradiation (45 grays) and an attempted surgery. OS was correlated with pretreatment and posttreatment parameters, including surgical pathology stage according to American Joint Commission on Cancer criteria. RESULTS: Of 74 patients who were registered, 69 patients (93%) had undergone surgery. Nineteen patients (26%) had a pathologic complete response (pathCR), and 55 patients (81%) had a curative (R0) resection. None of the pretreatment parameters correlated with OS; however, longer OS correlated with lower pathologic stage (P < .0001), R0 resection (P < .001), clinical response noted prior to surgery (P = .002), pathCR (P = .004), lower pathologic lymph node classification (P = .006), and lower pathologic tumor classification (P = .03). Pathologic stage and R0 resection were independent prognostic factors for OS (multivariate Cox model; both P = .05). CONCLUSIONS: When preoperative chemoradiation strategy was employed for gastric cancer, the surgical pathology stage, a reflection of cancer's biologic heterogeneity, was a better prognosticator of OS than the baseline clinical stage. Surgical pathology stage, in this setting, may serve as an intermediate endpoint for Phase II/III trials.

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

Roles of E. coli double-strand-break-repair proteins in stress-induced mutation.

Special mechanisms of mutation are induced during growth-limiting stress and can generate adaptive mutations that permit growth. These mechanisms may provide improved models for mutagenesis in antibiotic resistance, evolution of pathogens, cancer progression and chemotherapy resistance. Stress-induced reversion of an Escherichia coli episomal lac frameshift allele specifically requires DNA double-strand-break-repair (DSBR) proteins, the SOS DNA-damage response and its error-prone DNA polymerase, DinB. We distinguished two possible roles for the DSBR proteins. Each might act solely upstream of SOS, to create single-strand DNA that induces SOS. This could upregulate DinB and enhance mutation globally. Or any or all of them might function other than or in addition to SOS promotion, for example, directly in error-prone DSBR. We report that in cells with SOS genes derepressed constitutively, RecA, RuvA, RuvB, RuvC, RecF, and TraI remain required for stress-induced mutation, demonstrating that these proteins act other than via SOS induction. RecA and TraI also act by promoting SOS. These and additional results with hyper-mutating recD and recG mutants support roles for these proteins via error-prone DSBR. Such mechanisms could localize stress-induced mutagenesis to small genomic regions, a potentially important strategy for adaptive evolution, both for reducing additional deleterious mutations in rare adaptive mutants and for concerted evolution of genes.

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.

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.