Annals of Surgical Oncology 9:394-400 (2002)
© 2002 Society of Surgical Oncology
Recurrence Patterns After Radical Gastrectomy for Gastric Cancer: Prognostic Factors and Implications for Postoperative Adjuvant Therapy
Roderich E. Schwarz, MD, PhD and
Kathryn Zagala-Nevarez, PA
From the Department of General Oncologic Surgery, City of Hope National Medical Center, Duarte, California.
Correspondence: Address correspondence and reprint requests to: Roderich E. Schwarz, MD, PhD, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, The Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08903-2681; Fax: 732-235-8098; E-mail: r.schwarz{at}umdnj.edu
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ABSTRACT
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Background: A recent Intergroup trial demonstrated a significant survival advantage of postgastrectomy chemoradiation in gastric cancer patients, primarily because of a reduction of a relative locoregional recurrence (LRR) rate exceeding 70% in control patients. Radical gastrectomy with extended lymphadenectomy may reduce LRR, possibly affecting adjuvant treatment strategies.
Methods: Information on patients undergoing gastrectomy for potentially curable gastric cancer between 1990 and 2000 was reviewed. Patterns of first disease recurrence, survival, and disease-free survival were calculated, and predictors were identified.
Results: Gastrectomies were performed in 73 patients, with R0 resections in 82%. The median lymph node count was 24; positive nodes were found in 64% of patients. The median actuarial survival was 27 months, with a 5-year survival of 37%. Disease recurred in 35 patients (48%) after a median interval of 7 months (range, .5–67). Recurrent disease patterns included distant only (37%), peritoneal only (23%), peritoneal/locoregional (17%), all sites combined (14%), locoregional only (6%), and distant/locoregional (3%). Recurrence predictors were N3 category for distant recurrence (hazard ratio [HR], 10.2; P = .005), T3/4 category for peritoneal recurrence (HR, 4.8; P = .008), peritoneal relapse (HR, 40; P = .002), and a prior abdominal operation for LRR (HR, 3.2; P = .01). N2 disease had a distant failure risk similar to N1 status and an intraperitoneal failure risk similar to an N3 category.
Conclusions: Isolated LRR of gastric cancer after gastrectomy and extended lymphadenectomy is rare in this series. Most recurrences appeared diffusely at distant or peritoneal sites, and most LRRs occurred in conjunction with relapse at extraregional sites. Pathologic predictors of intraperitoneal (T3/4) or systemic failure (>N1) could be used to guide individualized, risk-oriented, adjuvant treatment.
Key Words: Gastric cancer • Locoregional recurrence • Extended lymph node dissection • Recurrence rate
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INTRODUCTION
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A recent US Intergroup trial (INT-116) indicated a therapeutic benefit to postgastrectomy chemoradiation, primarily because of a reduction in the high locoregional recurrence rate of gastric cancer.1 This Intergroup trial, INT-116, was characterized by a node-positive rate of 85%, a limited lymphadenectomy extent (<D1, 54%; D1, 36%; D2, 10%),2 an overall recurrence rate in the control group of approximately 75%, and a relative locoregional recurrence rate exceeding 70%. Reduction in recurrence was dependent on the anatomical region (local relapses, 19% vs. 29%; regional relapses, including regional nodal, peritoneal, and hepatic sites, 65% vs. 72%; distant sites, 33% vs. 18%). Of note, only individuals who had undergone an R0 resection were enrolled onto this study. Resection extent and results seem comparable to the findings of an earlier survey and reflect the predominant surgical practice pattern in the United States; this pattern is characteristic for a limited resection and lymph node dissection extent.3,4 Despite the lack of survival benefit to gastrectomy with extended lymph node dissection (ELND) in two randomized European studies, the possibility for ELND to decrease locoregional recurrences seems plausible and can at least be construed from the published data of the Dutch study.5,6 We intended to identify whether the therapeutic rationale for postoperative chemoradiation, with its primarily demonstrable locoregional recurrence benefit, could remain valid when applied to those recurrence patterns observed at a tertiary care cancer center within the United States, where a more radical approach to gastrectomy and extended retroperitoneal lymphadenectomy has been generally maintained as a therapeutic standard during the past decade.
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PATIENTS AND METHODS
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Patients undergoing gastrectomy for potentially curable gastric cancer at the City of Hope National Medical Center were subjects of this analysis. All patients had received their operation, which included an attempt at complete tumor removal with wide negative margins and an extended retroperitoneal lymphadenectomy, at the center. All were then observed under a symptom-oriented clinical maintenance strategy. Information on clinicopathologic, therapeutic, and outcome parameters of patients undergoing potentially curative gastrectomy from July 1990 to June 2000 was collected retrospectively. Cancer staging was performed according to the fifth edition of the American Joint Commission on Cancer tumor-node-metastasis criteria.7 Primary outcome measures of interest were first disease recurrence pattern, overall survival, and disease-free survival. A locoregional recurrence was defined as any cancer recurrence within the regional resection area (below the diaphragm and liver, above the pancreas, yet inclusive of the anterior and cephalad pancreatic borders and anterior or lateral to the abdominal aorta) or at the local anastomotic sites (within the lower third of the esophagus, gastric remnant, or duodenal stump). This included regional nodes (D2 nodes and D4 para-aortic/suprapancreatic nodes, but not retropancreatic or lower para-aortic nodes). A peritoneal recurrence was determined to be any recurrence within the abdominal cavity due to intraperitoneal distribution and mesothelial implantation. Distant recurrences included visceral metastases, nodal metastases beyond the regional nodes, and cutaneous and musculoskeletal manifestations of cancer. All recurrences had been diagnosed clinically or radiographically and were confirmed by radiographic means, histopathologic means, or both. The radiographic standard for the recurrence diagnosis included computed tomographs of the chest, abdomen, and pelvis; head computed tomographs, bone scans, or other diagnostic tests were used only under special circumstances. Recurrences identified within 3 months from the first recurrence were considered synchronous and were charted as a simultaneous first recurrence event. For contingency analysis of categorical variables, 
2 analysis or Fisher’s exact test was performed. Clinicopathologic variables predicting recurrence were analyzed by multiple logistical regression by using a stepwise backward model approach. Overall survival and disease-free survival (time from gastrectomy to first recurrence) were calculated by the Kaplan-Meier method. For group comparisons, univariate log-rank testing and multivariate Cox regression analysis were performed. The software package for all statistical analyses was StatViewTM for Macintosh, version 5.0.1 (SAS Institute, Cary, NC). In all tests, the significance of differences was accepted at P < .05.
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RESULTS
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Patient Demographics and Treatment
From July 1990 to June 2000, 73 patients underwent gastrectomy with extended lymphadenectomy for gastric adenocarcinoma with curative intent. There were 38 men and 35 women, with a median age of 67 years (range, 31–98 years). The intragastric disease location was in the proximal third (36%), distal third (34%), body (22%), or the entire stomach (8%). Gastrectomy procedures included distal (n = 29; 40%), total (n = 26; 35%), and proximal (n = 18; 25%) resections. Nine surgeons performed the operations, with a median of seven gastrectomies per surgeon (range, 1–22). In 20 instances, other organ resections were performed to ascertain complete tumor or lymph node removal, including splenectomy (n = 9; 12%) and distal pancreatectomy (n = 3; 4%). R0 resection was accomplished in 82%; the median lymph node count (after gross identification in the specimen) was 24 (range, 0–108). The number of lymph nodes retrieved on the basis of the gastrectomy type is depicted in Fig. 1 (P = not significant). Positive nodes were found in 64% of patients (median positive node count, 4). Pathologic stage distribution included stages IA (11%), IB (15%), II (22%), IIIA (17%), IIIB (11%), and IV (23%), with one in situ carcinoma (1%). All stage IV assignments were due to a N3 category or a T4 classification in the presence of involved nodes. Thirty-four patients (47%) had serosal invasion (T3 or T4). Adjuvant treatment was given to 21 patients (29%), 14 of whom (19%; chemosensitized, n = 10) received radiation and 7 (10%) of whom were treated with systemic chemotherapy alone. These patients had more advanced disease than those not treated with adjuvant means (stages IIIA, IIIB, or IV, 76% vs. 40%; P = .02).
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FIG. 1. Lymph node count by gastrectomy type: box plots. The highest data point in the distal gastrectomy group (108) is not depicted.
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Postoperative Outcome, Survival, and Recurrence
The postoperative mortality was 0%, and the complication rate was 29%. Major complications (rate, 16%) included infections (n = 6), leak (n = 3), hemorrhage (n = 1), obstruction (n = 1), and reintubation need (n = 1). Minor complications (rate, 12%) were predominantly infectious (n = 8). The median length of stay measured 11 days (mean, 14.8; range, 9–122). At a median follow-up of 30 months (for survivors), the median actuarial overall survival was 27 months, with a 5-year overall survival of 37% (95% confidence interval, 24%–51%). Overall median survival was 16 months after adjuvant therapy, compared with 49 months without (P = .04). Disease recurred in 35 patients (48%) after a median interval of 7.3 months from resection (range, .5–67 months). Disease recurrence significantly affected survival (Fig. 2). Recurrence patterns are depicted in Fig. 3 and included distant sites (n = 19; 26%), intraperitoneal disease (n = 19; 26%), and locoregional recurrence (n = 14; 19%) in various combinations. Among the 35 patients diagnosed with recurrence, the relative rates for specific sites were distant only (37%), peritoneal only (23%), peritoneal/locoregional (17%), all sites combined (14%), locoregional only (6%), and distant/locoregional (3%). Therefore, local or regional disease recurrence was a component in 40% of patients experiencing relapse but was accompanied by diffuse peritoneal or systemic disease 86% of the time. Two patients with an isolated locoregional recurrence had esophageal or gastric involvement only but no nodal manifestation. The median time from gastrectomy to a diagnosis of recurrence varied between sites (distant, 6.2 months; peritoneal, 11.8 months; locoregional, 12.2 months). The recurrence rate was 67% in patients after adjuvant treatment, compared with 40% without adjuvant therapy (P = .04). In 46 patients who had undergone an R0 resection and who had not received adjuvant treatment, the recurrence rates varied by stage groups: 21% (stages IA and IB), 18% (stage II), 50% (stages IIIA and IIIB), and 88% (stage IV). Of 5 locoregional recurrences (11%) within this group, only 1 was isolated and did not coincide with peritoneal or distant disease; among 19 patients with disease stages II, IIIA, and IIIB, 1 recurrence (5%) involved the locoregional field.
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FIG. 3. Initial recurrence patterns after gastrectomy for gastric cancer. The numbers represent patients with recurrence (total, n = 73).
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Predictors of Recurrence
Cancer recurrence was primarily predicted by nodal status and T class. Predictors of significance by multiple logistical regression were N3 category for distant recurrence, T3/4 classification for peritoneal recurrence, and recurrent disease in the peritoneum plus prior abdominal operations for locoregional recurrence. Hazard ratios and significance levels are listed in Table 1. N2 disease had a distant failure risk similar to N1 status and an intraperitoneal failure risk similar to an N3 category (Table 2). The disease-free survival based on pathologic T and N categories is depicted in Figs. 4 and 5. Multivariate predictors of superior disease-free survival were distal gastrectomy (P < .0001; hazard ratio, .16) or proximal gastrectomy (P = .002; hazard ratio, .23) and absence of serosal invasion (T1/2; P = .009; hazard ratio, .37). Adjuvant therapy, despite its correlation with recurrence frequency, did not retain significance as an independent recurrence predictor.
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FIG. 5. Disease-free survival by N category. Cum. disease-free survival, cumulative disease-free survival.
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DISCUSSION
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The practice of dissecting second-echelon (D2) lymph nodes routinely during a potentially curative gastrectomy for gastric cancer has come into question after prospective trials have linked this to higher complications and mortality, without any demonstrable survival benefit.5,6 However, a high rate of splenectomy and distal pancreatectomy in these studies is the likely culprit for the high morbidity rate observed.8–10 Thus, avoiding resections of spleen or pancreas whenever feasible during the ELND, as practiced in our patients, may lead to a lower rate of complications. Prospective audits of patients undergoing gastrectomy and D2 dissection have proven its safety and acceptable morbidity.11–13 In addition, the frequent micrometastatic involvement of lymph nodes considered negative after routine histopathologic evaluation provides a rationale for a therapeutic role of extended lymphadenectomy.14 Furthermore, survival outcome in Western specialty centers that have adapted the Japanese lymphadenectomy approach has continuously improved to approximate that of centers within the East.15,16 For these reasons, we have continued to use ELNDs in our patients undergoing gastrectomy despite the lack of proven benefit in large phase 3 studies.
Our observations now suggest that a general operative approach that uses extended lymphadenectomy can result in a low locoregional recurrence rate of gastric cancer as well. Some possible shortcomings of these results are understood: they reflect a retrospective review of a single-center gastrectomy experience with limited patient numbers and with no uniform follow-up scheme. Nevertheless, the potential reduction of local or regional recurrences through more extended resections than those generally performed in INT-116 patients can be supported by data from the Dutch study, in which D2 dissections led to a 28% locoregional recurrence frequency, compared with 38% after D1 dissection (P = .004).5 The benefit to postoperative chemoradiation followed by chemotherapy with fluorouracil and leucovorin in the Intergroup trial is based on a reduction in overall recurrence frequencies17 from 64% to 43%. Significant reductions were seen in local (29% to 19%) and regional (72% to 65%), but not distant, relapses (18% vs. 33%). Unfortunately, the definitions of local (includes gastric bed) and regional (includes peritoneal and hepatic metastases) sites did not take the different mechanisms of disease progression into account (whether it spread via lymphatic, transserosal, or hematogenous dissemination). In light of these results, the question remains whether an inadequate resection extent accounts in part for the high rate of local and regional recurrence and whether the adjuvant treatment benefit relies primarily on a reduction in these locoregional recurrences. It is also unclear from the data presented to date whether a similar benefit to adjuvant treatment was obtained in the small subset of patients who had undergone a formal D2 dissection. Although the patient cohorts are not exactly comparable (patients in INT-116 had high-risk features such as positive lymph nodes in 84% and serosal involvement in 69%; nearly 80%, however, had a distal lesion located in the antrum or gastric body), the small numbers of locoregional recurrences in patients with stage II or III cancer after an R0 resection in our experience would lead us to question whether there is a similar benefit to postoperative chemoradiation if used routinely in this subgroup.
Our attempt to separately analyze the pattern of locoregional, peritoneal, and distant recurrences also demonstrates that isolated local or regional recurrences are exceedingly rare; most locoregional recurrences are accompanied by diffuse peritoneal or systemic relapse. Two larger Asian series of postgastrectomy patients, all diagnosed with gastric cancer recurrence, show comparable findings: peritoneal (43% and 46%) and distant (54% and 34%) hematogenous sites were the most common sites of recurrence, frequently in combination.18,19 Regional lymph node recurrences were observed in 12% or 7%, respectively. Serosal invasion and lymph node metastasis were the predominant risk factors for all patterns; a potentially curative reoperation for an isolated recurrence was feasible19 in only .2%. The importance of pathologic serosa– and lymph node–based parameters as indicators for recurrence after ELND has recently been validated in Western patients as well and confirms some of the prognostic implications of T and N classifications seen in our analysis.20
In another clinical series of patients undergoing D2 dissection, tumors with serosal invasion also predominantly led to intraperitoneal failure; those without led to systemic relapses.21 Biological mechanisms for diffuse intraperitoneal or systemic recurrence represent obvious limitations to the efficacy of postoperative adjuvant treatment, if this would primarily carry a benefit within the actual locoregional anatomic area. From 40% to 50% of patients with subserosal or serosal tumors are identified to have free intraperitoneal tumor cells.22,23 It is well understood that positive peritoneal cytology at the time of gastrectomy will lead to peritoneal recurrence in virtually all patients.22 More radical surgical approaches or additional regional therapy in the form of radiation will not beneficially affect outcome if intraperitoneal tumor cell spread has occurred through transserosal invasion; instead, approaches with intraperitoneal chemotherapeutic treatment seem more rational.24–26 Although it is unclear whether the chemoradiation regimen of INT-116 would significantly benefit patients at high risk for intraperitoneal cancer dissemination, this remains unlikely. Additionally, patients at high risk for distant failure (N3 status) may also not necessarily benefit from the radiation component and may be better approached with systemic chemotherapy regimens analogous to those that have proven adjuvant efficacy in smaller phase 2 or 3 studies.27,28
Microscopic residual disease or positive margins (R1 status) in gastric cancer can be equated with an incurable situation in nearly 90% of patients.3 The Intergroup trial did not permit entry of patients unless an R0 status could be confirmed. In our series, 18% of patients had R1 resections. It is interesting to note that none of these patients had experienced an isolated local or regional recurrence. Other series confirm that a positive resection margin rarely leads to a symptomatic anastomotic recurrence.29,30 In fact, an R1 (or R2) resection is usually obtained when the primary tumor stage is very advanced and the risk for systemic or peritoneal failure is high. Although postoperative chemoradiation has been demonstrated to reduce the locoregional recurrence rate in this setting,31 potentially curable patients with these advanced disease stages are probably better approached with preoperative combination therapy.32
In summary, our postgastrectomy recurrences, on the basis of clinical/radiological follow-up, rarely include local or regional sites, despite an R1 resection frequency of 18%. Most failures occur systemically or peritoneally and can be predicted by simple pathologic staging criteria, namely, a large number of metastatic lymph nodes and serosal invasion by the primary tumor. These results seem similar to Asian experiences that apply the routine use of ELND at the time of gastrectomy; they seem, however, to stand in sharp contrast to those of the US Intergroup trial. A more extensive retroperitoneal dissection may well decrease the locoregional recurrence risk, thus obviating the need for postoperative radiation treatment. Systemic or intraperitoneal investigational chemotherapy approaches, dependent on the pathologic risk determination, may represent more appropriate and potentially more effective ways of postoperative adjuvant treatment for patients at high risk for diffuse relapses. It therefore seems that even within the United States, the rationale for the locoregional component of adjuvant chemoradiation used routinely remains uncertain in the setting of a radical gastrectomy combined with extended lymphadenectomy, as discussed previously.33 The effect of the Intergroup postoperative adjuvant regimen should be specifically studied in patients who undergo D2 dissections during a potentially curative gastrectomy for gastric cancer before it is routinely recommended for this patient cohort.
Received for publication September 13, 2001.
Accepted for publication February 1, 2002.
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ABSTRACT
INTRODUCTION
