Scott A. Hundahl

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.

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.

Low Maruyama Index Surgery for Gastric Cancer: Blinded Reanalysis of the Dutch D1-D2 Trial

A quantitative estimate of residual nodal disease after gastric cancer surgery, the Maruyama index of unresected disease (MI), proved to be a strong independent predictor of survival in a large U.S. adjuvant chemoradiation study in which surgical undertreatment was frequent. Data from the Dutch D1-D2 Lymphadenectomy Trial permit an opportunity to assess the prognostic value of this variable in a cohort with lower-stage disease treated with minimum D-1 lymphadenectomy and no adjuvant chemoradiation. Blinded to survival, and excluding those cases with missing information, the MI was calculated for 648 of the original 711 patients treated with curative intent. Survival was assessed by log-rank and multivariate Cox regression analysis. All patients have been followed for a minimum of 11 years. Overall Dutch trial findings were not affected by the absence of 63 cases with incomplete data. As expected, the median MI was 26, much lower than in the previous U.S. study. In contrast to the D level, MI < 5 proved to be a strong predictor of survival by both univariate and multivariate analysis. The MI was an independent predictor of both overall survival [P = 0.016; hazard ratio (HR) = 1.45; 95% confidence interval (CI) 1.07–1.95] and relapse risk (P = 0.010; HR = 1.72; 95% CI 1.14–2.60). A strong dose-response reaction with respect to the MI and survival was also observed. We conclude that in this trial low-MI surgery is associated with enhanced survival, whereas outside of certain subgroups routine D2 lymphadenectomy is not. This observation suggests that surgeons might have more of an impact on patient survival by achieving a low-MI operation than a particular D level. A compelling dose-response effect reveals that the MI is a quantitative yardstick for assessing the adequacy of lymphadenectomy in gastric cancer.

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.

Low maruyama index surgery for gastric cancer.

Background: Japanese definitions and treatment guidelines have dominated extent-of-surgery concepts in gastric cancer for over 4 decades, despite the fact that such definitions/guidelines have changed considerably over time, and the fact they have largely failed to improve survival in prospective, randomized clinical trials. Aim: To briefly review lessons from previous surgical trials in gastric cancer, and, more specifically, to review data validating the concept of “low Maruyama Index surgery” as a data-driven guide to surgical treatment. Methods: Review of results from blinded multivariate analyses of two separate, prospective, randomized clinical trials: a) the Macdonald Trial of adjuvant postoperative chemo-radiation, Intergroup 0116, conducted in North America; and b) the Dutch D1-D2 Trial. Results: Blinded univariate and multivariate analysis of both trials establish “Maruyama Index of Unresected Disease” (MI) <5 as a strong independent predictor of better disease-free and overall survival in gastric cancer. Moreover, a strong “dose response” effect for MI versus survival is apparent. Conclusions: In contrast to surgery focused on achievement of a particular Japanese-defined D-level, “low Maruyama Index surgery” is associated with increased disease-free and overall survival. Further, the dose-response effect suggests MI can be used to quantify the adequacy of lymphadenectomy for a given patient. Low MI surgery can be pro-spectively planned by using the Maruyama Computer Program pre-operatively or intra-operatively.

The potential value of bursectomy in operations for trans-serosal gastric adenocarcinoma

In the current issue, Fujita, Kurokawa, Sugimoto et al. describe interim results of an interesting two-armed noninferiority trial that was designed to justify the potential elimination of bursectomy (also known as ‘‘omentobursectomy’’) from a standard D2 operation for advanced gastric cancer. This is probably one of the last purely surgical trials to be reported for advanced disease, given the currently established role for adjuvant therapy [1–3]. The trial was prematurely halted as a result of the convincing S-1 Trial [3], which clearly demonstrated the value of adjuvant therapy in Asian patients following high-quality D2 resection. The current Osaka Bursectomy Trial illustrates a number of valuable lessons: the way new evidence and clinical trial ethics can upset accrual plans; the value of a strong Data and Safety Monitoring Committee; the value of exploratory subgroup analysis, even in an underpowered prospective randomized clinical trial such as this; and, finally, that even experienced, expert gastric surgeons can occasionally ‘‘miss’’ on their predictions. And indeed, by missing on their initial predictions but subjecting them to an exploratory, non-inferiority randomized test, they have potentially enlightened us all! The continued practice of bursectomy over the years, despite its unverified therapeutic value, stems from its utility in facilitating: (a) precise, complete resection of disease from the head of the pancreas; (b) complete clearance of the (high-risk) subpyloric station #6 nodes, and; (c) an aesthetic, clean, celiac-based node dissection. But what about the potential value of bursectomy in eliminating micrometastatic disease in the peritoneum of the lesser sac? For patients with posterior gastric wall trans-serosal (pT3 or pT4) disease, such micrometastases can constitute the seeds of later recurrence. Their early removal might prove beneficial. Between July 2002 and January 2007, 210 patients with C cT2 disease were randomized intraoperatively to receive either bursectomy (N = 104) or not (N = 106) during their D2 operation. The two groups were generally well balanced with respect to gender (73 vs. 77% male), clinical T stage (61 vs. 67% T2), total gastrectomy (21 vs. 25%), and splenectomy (11.5 vs. 13.2%). R-0 resection was accomplished in almost all patients, and the few R-1 cases (3 vs. 4) were almost all due to positive peritoneal cytology. The performance of bursectomy was associated with a slightly longer operative time (an additional 27 min on average) and higher blood loss (an additional 125 ml). Interestingly, drain amylase levels on postoperative day 1 were not significantly different between the two groups (p = 0.543). Also, node counts did not seem to differ much between the groups, even for the station #6 subpyloric nodes. In the current report, three-year overall survival rates were 85.6% for the bursectomy group and 79.6% in the non-bursectomy group (HR for death without bursectomy 1.44, p = 0.443 for non-inferiority). Analysis of the 48 cases with pathology-proven trans-serosal disease in this trial indicates a biologically reasonable but statistically non-significant advantage to bursectomy. Among the 48 cases with pT3 or T4 disease, three-year overall survival was 69.8% for the bursectomy group and 50.2% for the non-bursectomy group (HR for death 2.16 for the nonbursectomy group; p = 0.791 for non-inferiority due to the small sample size). Despite the underwhelming p value, S. A. Hundahl (&) Sacramento VA at Mather, VA Northern California Health Care System, University of California at Davis, 10535 Hospital Way (112), Mather, CA 95655-1200, USA e-mail: scott.hundahl@va.gov

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/m2 IV over 60 minutes day 1, followed by 5-FU 500 mg/m2 IV bolus and LV 200 mg/m2 IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours × 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.

Diagnosis and Management of Soft Tissue Sarcoma

In 1982, Murray Brennan initiated Memorial Sloan-Kettering’s now-famous 4,500-case prospective sarcoma database. This effort has generated more practical information in two decades than in the two millennia since Galen’s first description. Building on the pioneering efforts of Dr. James Ewing and others, it represents a worthy institutional continuation of their work. This comprehensive synthesis of international literature and Brennan et al.’s two-decade clinical experience covers the history, incidence, etiology, pathology, classification, clinical features, staging, prognostic factors, and management, including multimodal primary therapy, follow-up, and treatment of recurrence. Convenient organization, generally by both site and histology, facilitates the text’s use as a quick reference. Microscopic, surgical, and radiographic images, as well as clear graphs, populate over half the pages and serve to illuminate the concepts with marvelous clarity. Surgeons can certainly use the book as a surgical atlas. Somehow, despite the complexity of the subject and the comprehensive treatment, Brennan and Lewis have transformed what could have been simply one more desiccated medical textbook into a compellingly simple and readable reference. It ranks as a “must have” for any surgical oncologist or radiation oncologist. Additionally, no general or orthopedic surgeon should depart a residency or hazard a board exam without scanning it, particularly Chapter 8 (“Principles of Management”). Highly recommended.