Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection.

PURPOSE: Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses. PATIENTS AND METHODS: In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy. RESULTS: Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect. CONCLUSION: Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.

Surgery for gastric cancer: what the trials indicate.

To optimize the therapeutic value of an operation for cancer, surgeons must weigh survival value against mortality/morbidity risk. As a result of several prospective, randomized trials, many surgeons feel that international opinion has reached a consensus. Reflexively radical surgical hubris has certainly given way to a more nuanced, customized approach to this disease. But issues remain. This article critically reviews existing data and emphasizes areas of continued controversy.

S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach.

OBJECTIVE: The primary objective of this trial was to evaluate the response rate for trimetrexate in conjunction with 5-FU and leucovorin (LV) (= TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting. METHODS: Patients with locally advanced, unresectable, or metastatic adenocarcinoma of the stomach received trimetrexate 110 mg/m IV over 60 minutes day 1, followed by 5-FU 500 mg/m IV bolus and LV 200 mg/m IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours x 7 doses, all weekly for 6 weeks followed by 2 weeks of rest, continued until progression. RESULTS: Characteristics for 37 eligible patients: median age 63 (range: 23-83); male/female: 69% of 31%; performance status 0/1/2 15/20/1. The confirmed response rate was 19%, and median overall survival was 6 months. Two patients died as a result of therapy, 1 because of infection without significant neutropenia, and 1 due to perforation of a responding gastric lesion. Seventy-two percent experienced grades 3 and 4 toxicity, most commonly diarrhea, fatigue, and lymphopenia. CONCLUSIONS: This regimen achieves response rates comparable to other 5-FU-based regimens, when used in treatment of incurable gastric cancer. Toxicity appears manageable.

Improved regional control and survival with "low Maruyama Index" surgery in gastric cancer: autopsy findings from the Dutch D1-D2 Trial.

Based on more than 11 years of follow-up, autopsy-based analysis of recurrence in the Dutch D1-D2 Trial permits meaningful assessment of patterns of failure with respect to the Maruyama Index (MI). We previously reported that a low Maruyama Index was an independent predictor of both overall and disease-specific survival. Autopsy results are available for 441 deaths on study. Distant-only failure (15% vs 13%) was no different between the MI categories, but isolated "regional" failure (8% for MI < 5 group vs 21%) and "regional + distant" failure (19% for MI < 5 group vs 36%) occurred less frequently in the MI < 5 group (P < 0.001). We conclude that "low Maruyama Index" surgery enhances regional control and survival but does not alter the occurrence of isolated distant metastases unassociated with regional failure. Our results speak to the substantial survival value of local-regional control in this disease.

Impact of hospital volume on recurrence and survival after surgery for gastric cancer.

BACKGROUND: Some, but not all, studies using registry data have suggested a small but significant long-term survival advantage following a curative surgical resection of gastric cancer at hospitals where the volume of such surgeries is high. However, because such data may be significantly influenced by the impact of postoperative mortality, and may be imbalanced for factors important to survival, the true nature of this relationship remains uncertain. METHODS: We conducted a nested volume-outcome study in a sample of 448 surgical survivors with stage IB through IV (M0) gastric and gastroesophageal junction adenocarcinoma, previously randomized to adjuvant chemoradiation after surgery or surgery alone, to measure the effect of hospital surgical volume, as assessed by Medicare claims data, on overall survival and gastric cancer recurrence. RESULTS: In this selected sample of postoperative survivors, hospital surgical volume was not predictive of overall survival (P = 0.46) or disease-free survival (P = 0.43) at a median follow-up of 8.9 years. However, patients who underwent either a D1 or D2 dissection at a high- or moderate-volume center experienced an adjusted hazard ratio of 0.80 (95% CI, 0.53-1.20) for overall survival and 0.78 (95% CI, 0.53-1.14) for disease-free survival compared with those patients resected at a low-volume hospital; these results were not statistically significant. When a D0 resection was performed, hospital procedure volume showed no impact on survival. CONCLUSIONS: Excluding the impact of perioperative mortality by utilizing prospectively recorded data from a large postoperative adjuvant trial, hospital procedure volume had no overall effect on long-term gastric cancer survival. The potential benefit of moderate- to high-volume centers for patients who underwent a D1 or D2 dissection requires confirmation in larger studies.

Gastric cancer: D2 dissection or low Maruyama Index-based surgery--a debate.

This article provides perspectives on the surgical approaches required optimally to manage patients with respectable gastric adenocarcinoma. The status of techniques of surgical resection in the management of gastric cancer is reviewed. The premise of this approach is that extended gastrectomy with D2 lymph node dissection is good. Also addressed are prognostic and predictive factors in the surgical treatment of stomach cancer.

Determinants for urinary and plasma isoflavones in humans after soy intake.

Consumption of soy foods leads to a biphasic appearance pattern of isoflavones (IFLs) in blood and urine, with peaks appearing at 1-2 h and 4-8 h after intake, but its causes are not understood. IFLs were measured repeatedly from plasma and/or urine after intake of soy foods, IFL glucosides, or aglycons without or with a mildly or radically reduced gut flora as a result of oral antibiotic (AB) treatment, or this combined with mechanical bowel preparation (AB+MBP). The typical biphasic IFL pattern in blood and/or urine was observed when a soy protein drink without (control) or with AB treatment or when IFL glucosides or aglycons were consumed. Soy intake combined with AB+MBP or consumption of puerarin led to a shift of the second peak to much later times. The first peak was absent after puerarin intake. Total urinary IFL recovery was more than 50% lower in the first 24 h, but overall 61% higher after AB+MBP vs. the control. When the area under the curves for corresponding time intervals were compared, individual or total urinary IFL excretion rates were highly correlated with individual or total plasma IFL levels (r=0.85-0.91; P <0.001). At the same urinary excretion rate three times more genistein than daidzein remained in the circulation. We conclude that urinary IFL excretion rates reflect circulating IFL levels, with daidzein appearing less in blood and more in urine than genistein. The first and second IFL peaks are due to uptake in the small and large intestine, respectively. The latter is the major locus of uptake (90%) at usual dietary IFL doses (0.15-1.5 mmol/kg body weight). A reduced gut flora delayed IFL uptake but led overall to increased urinary recovery because of less bacterial degradation in the intestine.

Time dependent ethnic convergence in colorectal cancer survival in Hawaii.

BACKGROUND: Although colorectal cancer death rates have been declining, this trend is not consistent across all ethnic groups. Biological, environmental, behavioral and socioeconomic explanations exist, but the reason for this discrepancy remains inconclusive. We examined the hypothesis that improved cancer screening across all ethnic groups will reduce ethnic differences in colorectal cancer survival. METHODS: Through the Hawaii Tumor Registry 16,424 patients diagnosed with colorectal cancer were identified during the years 1960-2000. Cox regression analyses were performed for each of three cohorts stratified by ethnicity (Caucasian, Japanese, Hawaiian, Filipino, and Chinese). The models included stage of diagnosis, year of diagnosis, age, and sex as predictors of survival. RESULTS: Mortality rates improved significantly for all ethnic groups. Moreover, with the exception of Hawaiians, rates for all ethnic groups converged over time. Persistently lower survival for Hawaiians appeared linked with more cancer treatment. CONCLUSION: Ethnic disparities in colorectal cancer mortality rates appear primarily the result of differential utilization of health care. If modern screening procedures can be provided equally to all ethnic groups, ethnic outcome differences can be virtually eliminated.

Surgical quality control in gastric cancer trials.

Quality control in prospective randomized surgical trials of gastric cancer treatment is reviewed. Progress and innovations in this area are described. Methodologic suggestions for future trials are made.

Staging, stage migration, and patterns of spread in gastric cancer.

Background concerning tumor node metastasis (TNM) staging of gastric cancer is presented, with special attention to the issue of stage migration. Patterns of spread are also reviewed and current problems in local-regional control are emphasized.

Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in gastric cancer: the effect of undertreatment.

BACKGROUND: Intergroup 0116 (Southwest Oncology Group 9008), a national, multicenter, two-armed, prospective, randomized trial of adjuvant postoperative chemoradiotherapy, has demonstrated significant benefit. METHODS: We prospectively captured complete surgical information, including the treatment of various lymph node stations, for 553 of the 556 eligible participants in this trial. Before any survival analysis, we coded D level by using the Japanese general rules and used the Maruyama program to estimate the likelihood of disease in undissected regional node stations, defining the sum of these estimates as the Maruyama Index of Unresected Disease (MI). We analyzed survival with Cox multivariate regression. RESULTS: Fifty-four percent of participating patients underwent D0 lymphadenectomy. The median MI was 70 (range, 0-429). In contrast to D level, MI proved to be an independent prognostic factor, even with adjustment for the potentially linked variables of T stage and number of positive nodes. We detected no significant interaction between surgical or pathologic variables and the favorable effect of adjuvant treatment, but the power to detect such interaction was generally low. CONCLUSIONS: MI, a measure of unresected regional nodal disease in gastric cancer, proved an independent predictor of survival. Surgical undertreatment, as observed in this trial, clearly undermined survival.