Alberto Marchet

The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymphadenectomy: results from an Italian multicentric study in 1853 patients.

Purpose:To investigate whether the ratio between metastatic and examined lymph nodes (N ratio) is a better prognostic factor as compared with traditional staging systems in patients with gastric cancer regardless of the extension of lymph node dissection. Patients & Methods:We retrospectively reviewed the data of 1853 patients who underwent radical resection for gastric carcinoma at 6 Italian centers. Patients with >15 (group 1, n = 1421) and those with ≤15 (group 2, n = 432) lymph nodes examined were separately analyzed. N ratio categories (N ratio 0, 0%; N ratio 1, 1%–9%; N ratio 2, 10%–25%; N ratio 3, >25%) were determined by the best cut-off approach. Results:After a median follow-up of 45.5 months (range, 4–182 months), the 5-year overall survival of N0, N1, and N2 patients of group 1 versus group 2 was 83.4% versus 74.2% (P = 0.0026), 54.3% versus 44.3% (P = 0.018), and 32.7% versus 14.7% (P = 0.004), respectively, suggesting that a low number of excised lymph nodes can lead to the understaging of patients. N ratio identified subsets of patients with significantly different survival rates within N1 and N2 stages in both groups. At multivariate analysis, the N ratio (but not N stage) was retained as an independent prognostic factor both in group 1 and group 2 (HR for N ratio 1, N ratio 2, and N ratio 3 = 1.67, 2.96, and 6.59, and 1.56, 2.68, and 4.28, respectively). In our series, the implementation of N ratio led to the identification of subgroups of patients prognostically more homogeneous than those classified by the TNM system. Conclusion:N ratio is a simple and reproducible prognostic tool that can stratify patients with gastric cancer also in case of limited lymph node dissection. These data may represent the rational for improving the prognostic power of current UICC TNM staging system and ultimately the selection of patients who may most benefit from adjuvant treatments.

Ratio Between Metastatic and Examined Lymph Nodes Is an Independent Prognostic Factor After D2 Resection for Gastric Cancer: Analysis of a Large European Monoinstitutional Experience

Background: In view of the lack of consensus on the level and number of lymph nodes to be examined for accurate staging of patients with gastric cancer, our aim was to evaluate the prognostic significance of lymph node status in a large European monoinstitutional experience.Methods: A review was made of our prospective database from 1980 to 2000, when 314 of 445 patients operated for gastric adenocarcinoma underwent radical resection (R0) with D2 lymphadenectomy. Survival was determined by the Kaplan-Meier method and differences were assessed by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model in forward stepwise regression.Results: In 277 evaluable patients, 5-year survival was 57% (median follow-up, 48 months; range, 2–251). A total of 7668 lymph nodes were examined (median, 27; range, 11–62). The 5-year survivals according to the metastatic/examined lymph nodes ratio (N ratio) were 14%, 50%, 61%, and 82% in the group of patients with N ratio >25%, 11%–25%, 1%–10%, and 0%, respectively (P < .0001). At multivariate analysis, the N ratio was the best single independent prognostic factor (P = .000).Conclusions: After R0 resection for gastric cancer, the N ratio is a potent prognostic factor. It should therefore be considered in the clinical decision making process.

A multicentric Western analysis of prognostic factors in advanced, node-negative gastric cancer patients

Background:The presence of lymph node metastasis is one of the most important prognostic factors in patients with gastric carcinoma. Node-negative patients have a better outcome, nevertheless a subgroup of them experience disease recurrence. Aim:To analyze the clinicopathological characteristics of lymph node-negative advanced gastric carcinoma patients submitted to gastrectomy and D2 lymphadenectomy with a retrieved number of nodes greater than 15, after an actual follow-up of almost 5 years, and to evaluate outcome indicators. Study Design:The records of 301 patients who underwent curative gastrectomy for gastric carcinoma and were adequately staged as N0 between 1992 and 2002 were retrospectively analyzed from the prospectively collected database of 7 centers participating to the Italian Research Group for Gastric Cancer. Results:Disease-specific and disease-free survival after 3, 5, and 10 years were 90.4%, 86.1%, 75.9%, and 72.1%, 57.3%, 57.3%, respectively. Mortality was 1.7%. The factors associated with a better disease-free survival at univariate analysis were age <60, T2 tumors, distal location, intestinal histotype, and number of retrieved nodes >25; depth of infiltration and histotype were the only 2 independent predictors of 5-year recurrence-free survival at multivariate analysis. Conclusion:These parameters must be considered to stratify node-negative gastric cancer patients for an adjuvant treatment and follow-up scheduling. Survival was similar to that previously reported by Eastern Centers. Lymphadenectomy is suggested to be effective, and retrieval of more than 25 nodes may be warranted.

Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer.

PURPOSE In a randomized clinical trial (European Organization for the Research and Treatment of Cancer [EORTC] no. 40813) on adjuvant chemotherapy in gastric cancer, results obtained after administration of the FAM2 regimen (fluorouracil [5-FU], doxorubicin, and mitomycin) were compared with results obtained after surgery alone to assess the effect of this regimen on overall survival, time to progression, and disease-free interval. PATIENTS AND METHODS Three hundred fourteen patients who had undergone curative resection for stage II or stage III (International Union Against Cancer [UICC] 1978) gastric adenocarcinoma were randomized to receive chemotherapy (treatment arm) or no further treatment (control arm). The chemotherapy schedule was repeated every 43 days for seven cycles. The log-rank test and the Cox model were used for statistical analysis. RESULTS Of 314 patients, 159 comprised the control group and 155 the FAM2 group. Nineteen FAM2 patients never received chemotherapy. The median number of cycles was five. Of the patients started on adjuvant treatment, severe hematologic and nonhematologic toxicity (grades 3 or 4, World Health Organization [WHO] scale) occurred, respectively, in 6% to 9% and in 1% to 29% of cases. The overall 5-year survival rate was 70% for stage II and 32% for stage III patients. No statistically significant difference was found between overall survival of the two treatment arms (P = .295). However, time to progression was significantly delayed in the FAM2 arm (P = .020) and disease-free survival showed borderline significance (P = .068). CONCLUSION FAM2, in view of its high toxicity, cannot be advocated as standard adjuvant treatment for gastric cancer. Large-scale clinical trials using more active, less toxic regimens are required to demonstrate whether adjuvant chemotherapy provides any real benefit.

EUS for the staging of gastric cancer: a meta-analysis

BACKGROUND The role of EUS in the locoregional staging of gastric carcinoma is undefined. OBJECTIVE We aimed to comprehensively review and quantitatively summarize the available evidence on the staging performance of EUS. DESIGN We systematically searched the MEDLINE, Cochrane, CANCERLIT, and EMBASE databases for relevant studies published until July 2010. SETTING Formal meta-analysis of diagnostic accuracy parameters was performed by using a bivariate random-effects model. PATIENTS Fifty-four studies enrolling 5601 patients with gastric cancer undergoing disease staging with EUS were eligible for the meta-analysis. MAIN OUTCOME MEASUREMENTS EUS staging accuracy across eligible studies was measured by computing overall sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). RESULTS EUS can differentiate T1-2 from T3-4 gastric cancer with high accuracy, with overall sensitivity, specificity, PLR, NLR, and DOR of 0.86 (95% CI, 0.81-0.90), 0.91 (95% CI, 0.89-0.93), 9.8 (95% CI, 7.5-12.8), 0.15 (95% CI, 0.11-0.21), and 65 (95% CI, 41-105), respectively. In contrast, the diagnostic performance of EUS for lymph node status is less reliable, with overall sensitivity, specificity, PLR, NLR, and DOR of 0.69 (95% CI, 0.63-0.74), 0.84 (95% CI, 0.81-0.88), 4.4 (95% CI, 3.6-5.4), 0.37 (95% CI, 0.32-0.44), and 12 (95% CI, 9-16), respectively. Results regarding single T categories (including T1 substages) and Bayesian nomograms to calculate posttest probabilities for any target condition prevalence are also provided. LIMITATIONS Statistical heterogeneity was generally high; unfortunately, subgroup analysis did not identify a consistent source of the heterogeneity. CONCLUSIONS Our results support the use of EUS for the locoregional staging of gastric cancer, which can affect the therapeutic management of these patients. However, clinicians must be aware of the performance limits of this staging tool.

Gene Expression Profile of Primary Gastric Cancer: Towards the Prediction of Lymph Node Status

BackgroundThe identification of gastric tumors associated with a higher risk of lymph node metastasis could help surgeons select patients who may benefit from extended lymph node dissection. The aim of this study was to screen the genome in the search of primary gastric cancer gene expression profiles that might predict lymph node status.MethodsThe gene expression profile was evaluated in frozen tumor samples obtained from 32 patients with primary gastric adenocarcinomas. The array consisted of a duplicated spot panel of 5,541 human genes. To classify node-positive (N+) and node-negative (N−) cases, a logistic regression model was fitted optimizing the Akaike Information Criteria after a stepwise gene selection. The accuracy was evaluated by means of leave-one-out cross validation.ResultsAll patients underwent radical gastrectomy and extended lymphadenectomy. Of all the cases, 21 were N+ and 11 demonstrated no lymph node involvement (N−). After quality filtering, the analysis of variance selected a set of 136 genes potentially correlated with nodal involvement (P value <.05). Of these 136 genes, 5 were differentially expressed (adjusted P value <.05). After a stepwise gene selection, only three genes (Bik, aurora kinase B, eIF5A2) were retained in the logistic model, which could correctly predict lymph node status in 30 of 32 cases.ConclusionsIf our findings were confirmed, the identified gene pattern might be used to tailor the extent of lymph node dissection on a single patient basis.

Indexes of Surgical Quality in Gastric Cancer Surgery: Experience of an Italian Network

BackgroundShort-term results of gastric cancer surgery vary remarkably worldwide, and international surgical quality criteria are urgently needed. To contribute to defining these criteria, we reviewed short-term results of gastrectomy for gastric cancer in three centers of the Italian Research Group for Gastric Cancer, with an average of 24.7, 29.5, and 18 gastrectomies per year.MethodsBetween 1988 and 2002, 1,032 patients underwent gastrectomy for gastric cancer in Verona, Siena, and Padua. D1, D2, and D3 lymphadenectomy were performed, respectively, in 228, 584, and 220 cases.ResultsThe median number of retrieved lymph nodes was 14 (interquartile range 9–18.75) after D1, 29 (21–38) after D2, and 46.5 (37–57) after D3. Fewer than 15 nodes were retrieved in 54.5%, 6.2%, and 1.4% of cases undergoing, respectively, D1, D2, and D3. Adjacent organ removal was rare during D1 (splenectomy: 6.1%, splenopancreasectomy: 1.8%), and quite common during D3 (11.4%, 11.4%). Forty patients (3.9%) died postoperatively. Neither postoperative morbidity nor mortality was significantly associated with extension of lymphadenectomy.ConclusionWe conclude that at least D2 lymphadenectomy is necessary to achieve adequate disease staging (≥15 nodes retrieved). Spleen and pancreas tail are more frequently removed during D3, but this removal is not associated with higher postoperative morbidity or mortality.

METACHRONOUS HEPATIC METASTASES FROM GASTRIC CARCINOMA: A MULTICENTRIC SURVEY.

BACKGROUND The treatment of hepatic metastases from gastric cancer is controversial, due to biologic aggressiveness of the disease. OBJECTIVE To survey the clinical approach to the subset of patients presenting with metachronous hepatic metastases as sole site of recurrence after curative resection of gastric cancer, focusing on the results achieved by different therapies and to investigate the prognostic factors of major clinical relevance. METHODS Retrospective multi-center chart review evaluating 73 patients, previously submitted to D >or= 2 gastrectomy for gastric cancer, who developed exclusive hepatic recurrence. Prognostic factors related to the patient, to the gastric malignancy and its treatment, and to the metastatic disease and its therapy were evaluated. RESULTS Forty-five patients received supportive care, 17 were submitted to chemotherapy, and 11 to hepatic resection. Survival was independently influenced by the variables T (p=0.019), N (p=0.05) and G (p=0.018) of the gastric primary and by the therapeutic approach to the metastases (p<0.005). In particular, T4 gastric cancer, presence of lymph-node metastases and G3 tumor displayed a negative prognostic value. Therapeutic approach to the metastases was the principal prognostic variable: 1, 2, and 3 years survival rates were 22.2%, 4.4% and 2.2%, respectively, for patients without specific treatment; 44.9%, 12.8% and 6.4% after chemotherapy (p=0.08) and 80.8%, 30.3% and 20.2% after surgical resection (p<0.001). CONCLUSIONS Our data suggest some clinical criteria that may facilitate selection of therapy for patients with hepatic recurrence after primary gastric cancer resection. The best survival rates are associated with surgical treatment, which should be chosen whenever possible.

Changing clinical and pathological features of gastric cancer over time

The aim of the present multicentre observational study was to evaluate potential changes in clinical and pathological features of patients with gastric cancer (GC) treated in a 15‐year interval.

Multivisceral Resection for Locally Advanced Gastric Cancer: An Italian Multicenter Observational Study

IMPORTANCE The role of multivisceral resection, in the setting of locally advanced gastric cancer, is still debated. Previous studies have reported a higher risk for perioperative morbidity and mortality, with limited objective benefit in terms of survival. Conversely, recent studies have shown the feasibility of enlarged resections and the potential advantage of extended resection for clinical stage T4b gastric adenocarcinoma with good long-term results. OBJECTIVE To analyze the role of multivisceral resection for locally advanced gastric cancer with particular attention to the brief and long-term results and to the prognostic value of clinical and pathologic factors. DESIGN Prospective multicenter study using data from between January 1, 1995, and December 31, 2008. SETTINGS Seven Italian surgery centers. PATIENTS A total of 2208 patients underwent curative resections for gastric carcinoma at the centers. Among them, 206 patients presented with a clinical T4b carcinoma. One hundred twelve underwent a combined resection of the adjacent organs with a gastrectomy owing to suspicion or direct invasion of these organs by the gastric cancer. MAIN OUTCOMES AND MEASURES Clinical and pathologic variables were prospectively collected and the feasibility and efficacy of multivisceral resection for locally advanced clinical T4b gastric cancer were assessed. RESULTS Postoperative mortality and complication rates of patients who underwent a gastrectomy with a combined resection of the involved organs were 3.6% and 33.9%, respectively. Pathologic factors revealed that the nodal involvement was present in about 89.3% of patients and the mean (SD) number of pathologic lymph nodes was 14.8 (16.6). The overall 5-year survival rate was 27.2%. The completeness of resection and lymph node invasion represent independent prognostic parameters at multivariate analysis. CONCLUSIONS AND RELEVANCE Our study indicates that patients undergoing extended resections experience acceptable postoperative morbidity and mortality rates, and an en bloc multivisceral resection should be performed in patients when a complete resection can be realistically obtained and when lymph node metastasis is not evident.