10.1245/s10434-006-9059-z
Annals of Surgical Oncology 14:365-372 (2007)
© 2007 Society of Surgical Oncology
Outcome of Patients with Known Metastatic Gastric Cancer Undergoing Resection with Therapeutic Intent
Jason S. Gold, MD1,
David P. Jaques, MD1,
David J. Bentrem, MD1,
Manish A. Shah, MD2,
Laura H. Tang, MD3,
Murray F. Brennan, MD1 and
Daniel G. Coit, MD1
1 Department of Surgery, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
2 Department of Medicine, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
3 Department of Pathology, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Correspondence: Address correspondence and reprint requests to: Daniel G. Coit, MD; E-mail: coitd{at}mskcc.org
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ABSTRACT
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Background: Metastatic gastric cancer has a dismal prognosis. We identified a subset of patients where surgical resection with therapeutic intent was undertaken in the setting of known metastatic disease.
Methods: Review of a prospectively maintained database of gastric cancer patients at a single institution over a 19-year period was performed.
Results: Thirty-seven patients with metastatic disease known prior to resection with therapeutic intent were identified out of 3384 patients with gastric cancer (1%). Twelve patients had positive peritoneal cytology as the only evidence of metastasis, 21 had gross metastasis limited to peritoneal surfaces, one had peritoneal and ovarian metastasis, one had liver metastasis, one had retropancreatic lymph node metastasis, and one had a malignant pleural effusion. Thirty-six patients (97%) received chemotherapy prior to resection, and 30 (81%) received postoperative chemotherapy. The median time from diagnosis to resection was 4.5 months (range 1–22) in patients receiving preoperative chemotherapy. Median survival was 12 months after resection with no three-year survivors. Predictors of worse prognosis were cytologic or pathologic evidence of persistent metastatic disease at the time of resection or at laparoscopy within six weeks of resection (P < .01), N3 disease (P = .03), and total gastrectomy or additional organ resection (P = .04). Metastatic disease as evidenced by cytology only was not associated with improved prognosis.
Conclusions: Highly selected patients with metastatic gastric cancer undergoing surgical resection with therapeutic intent have a relatively poor prognosis. Persistent detectable metastatic disease after preoperative chemotherapy portends a particularly poor prognosis.
Key Words: Gastric cancer • Metastatic • Resection • Surgery • Cytology • Chemotherapy
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INTRODUCTION
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In the United States, metastatic disease is present in 32% of patients with gastric cancer at the time of diagnosis.1 Up to 25–30% of patients initially deemed to have resectable local–regional disease will have evidence of subradiologic intra-abdominal metastatic disease visible on laparoscopy.2 Still another 6.5% of patients without metastatic disease by imaging or laparoscopy and otherwise capable of having a curative (R0) resection have cytologic positive peritoneal aspirates or washings.3
There is no curative treatment for patients with metastatic gastric cancer. Overall, the five-year survival for patients with metastatic gastric cancer is 3.1%.1 Of patients with Stage IV gastric cancer treated with gastrectomy, 23% are alive one year after surgery.4
Given this dismal outcome, the nonoperative management of patients with metastatic gastric cancer is well-established. While previously it was believed that resection was warranted for palliation, recent data do not support this. In a study of 97 patients with metastatic disease diagnosed at laparoscopy and followed expectantly at our institution, 42% required a palliative procedure on the stomach. However, only 8% needed a surgical procedure to achieve this palliation, and only one patient (1%) was resected.5 The median survival of all 156 patients diagnosed with metastatic disease by laparoscopy in this series was ten months, and all patients died by 37 months.
It is difficult to determine retrospectively whether resection has a therapeutic benefit (i.e., prolongation of survival) in any subset of patients with metastatic gastric cancer. Available studies compare patients with metastatic disease found on laparotomy undergoing resection to patients with metastatic disease found on laparotomy and closed without gastric resection. There are intrinsic limitations to these studies. The decision to resect is often based on the extent of metastatic disease, the degree of patient symptoms, and the extent of gastrectomy required. It is difficult to segregate out surgeon intent (palliative or therapeutic). The group of patients resected may include more patients than would be offered resection with therapeutic intent had surgeons known of the metastatic disease preoperatively. Perhaps the best of these studies involves patients who consented for the Dutch Gastric Cancer Trial evaluating D1 versus D2 lymphadenectomy.6 These patients were all felt to have local–regional disease amenable to complete surgical resection, but on laparotomy were found to have metastatic disease. Surgeons could continue with the planned resection or not at their discretion, and all of the patients were followed prospectively. Of the 285 patients with metastatic gastric cancer on laparotomy in that series, 156 underwent resection. Patients who underwent resection had an 8.1-month median survival, compared to a 5.4-month median survival for the unresected patients (P < .001). Only 7% of patients undergoing resection were alive at three years compared to 2% of unresected patients.6 It is likely that patient selection on the part of the surgeons accounted for most if not all of the minimal observed survival difference. The impact of resection on quality of life in these studies was not evaluated.
As more patients with a minimal burden of metastatic disease, usually detected on laparoscopy and sometimes representing only positive peritoneal cytology without visible metastases, are followed over time, a small subset of patients with favorable biology is encountered. Often these patients have measurable disease responses to chemotherapy or are noted to have stable disease over prolonged periods of time. It is unknown whether resection of the primary tumor, thus leaving a minimal burden of disease to be potentially treated with chemotherapy, is of any benefit in these patients. The goal of this study was to determine the natural history of patients who underwent resection of gastric cancer with a therapeutic intent in the setting of metastatic disease known prior to operation, and to determine if any clinicopathologic variables could be used to select patients with a more favorable outcome.
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METHODS
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Patients
Patients were identified by reviewing a prospectively maintained institutional database of all patients admitted to the surgical service of Memorial Sloan–Kettering Cancer Center with a diagnosis of gastric cancer. The time period for the study was from inception of the database on July 1, 1985 through June 30, 2004. The database was queried for patients undergoing surgical resection with metastatic disease as defined by AJCC 6th Edition M1 disease7 or with peritoneal cytology positive for malignant cells. The AJCC definition of Stage IV gastric cancer includes any metastatic disease outside the stomach and regional lymph nodes (i.e., hepatoduodenal, retropancreatic, mesenteric, and paraaortic lymph node metastases are considered M1). Peritoneal cytology was included in our definition of metastatic disease based upon our previous work demonstrating a poor outcome for patients resected with positive cytology, similar to that of patients with metastatic disease.3,8 The presence of positive peritoneal cytology was determined in one of two ways: if present, ascites was aspirated and sent for cytology. In the absence of ascites, 50–100 mL of normal saline was instilled into the subhepatic space, the left upper quadrant and the pelvis, and washings were collected. Specimens were centrifuged, filter prepped, and stained by the Papanicolaou technique. A patient was considered to have positive peritoneal cytology if any adenocarcinoma cells were detected.
One hundred patients with metastatic disease undergoing gastrectomy were identified. Records were then reviewed to determine whether there was pathologic or cytologic confirmation of distant disease, whether it was known prior to the date of resection that there was metastatic disease, and whether the surgical intent was therapeutic. All three criteria needed to be met for inclusion in the study. Pathology or cytology read as "suspicious for" or "suggestive of" malignancy was not considered sufficient for diagnosis of distant disease. With regard to surgical intent, cases with palliative intent (i.e., for treatment of a specific symptom or pain, or for improvement of quality of life) were excluded, and the remaining cases were deemed "therapeutic" in that it was felt the surgeon undertook resection with the intent of either cure or more likely prolonging survival. Sixty-six of these cases were excluded for not meeting these criteria, leaving 37 patients for analysis.
Clinicopathological Variables and Statistical Analysis
Medical records were reviewed for pertinent patient, tumor, and treatment variables. Follow-up status was determined from the prospectively maintained database. Correlations were sought between clinicopathological variables and survival. Survival curves were generated by the Kaplan–Meier method9 and were compared by nonparametric survival analyses using the log-rank test with P values <.05 considered to be significant. SPSS 11.0 statistical software (SPSS, Chicago, IL) was used for analysis.
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RESULTS
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Patient Characteristics
Out of 3384 patients with a diagnosis of gastric cancer over a 19-year period, 37 (1%) underwent resection of gastric cancer with therapeutic intent in the setting of metastatic disease known prior to surgery. Pertinent patient and tumor variables are shown in Table 1
. The median age was 54 years (range 36–75) and 29 (78%) of the patients were male. Twelve patients (32%) had positive peritoneal cytology as their only evidence of metastatic disease prior to resection, 21 patients (57%) had visible peritoneal implants only, and one patient each (3%) had a liver metastasis, metastasis to the ovary and peritoneum, a retropancreatic lymph node with metastatic tumor, and a malignant pleural effusion. All but one patient presented with synchronous primary and metastatic disease. The remaining patient underwent a partial gastrectomy prior to presenting with simultaneous locally recurrent and metastatic disease.
No patient had either T1 or node-negative disease. Twenty-nine patients (78%) had T3 tumors (perforating serosa without adjacent organ invasion), and five patients (14%) had T4 tumors (adjacent organ invasion). Seven patients (19%) had N2 disease (7–15 lymph nodes involved) and eight (22%) had N3 disease (>15 lymph nodes involved).
Treatment
Thirty-six of the 37 patients (97%) received systemic chemotherapy prior to resection of their gastric tumors (treatment variables are shown in Table 2). The most common regimens used included 5-fluorouracil and cisplatin (ten patients), irinotecan and cisplatin (six patients), and FAMTX (5-fluorouracil, doxorubicin, methotrexate) (four patients). Five patients received multidrug combinations containing one or more of the agents listed above and/or paclitaxel, docetaxel, or capecitabine. In one patient, the preoperative chemotherapeutic regimen could not be determined retrospectively. For the patients who received preoperative chemotherapy, the median time between diagnosis of metastatic disease and resection was 4.5 months (range 1–22). In all but one case, a diagnostic laparoscopy was used to stage the intra-abdominal metastatic disease, and in seven cases (19%) more than one laparoscopy was performed in order to determine the impact of treatment on disease progression.
Twenty patients (54%) underwent total gastrectomy and 17 (46%) underwent partial gastrectomy. Eight patients (22%) had resection en bloc with an adjacent organ, most commonly spleen or distal pancreas. A D2 lymphadenectomy was performed in 28 cases (76%). Fourteen patients (38%) were felt to have an R0 resection with no gross residual disease and negative margins of resection (peritoneal cytology excluded), 11 (30%) had R1 resections (residual microscopic disease), and 12 (32%) had R2 resections (residual gross disease). Resection was associated with morbidity in 13 patients (35%) and one perioperative mortality (3%). Morbidity was most commonly related to an infectious complication: three patients had wound infections (one of these was associated with a fascial dehiscence), two patients had an anastomotic leak, and one patient had an intra-abdominal abscess. The median length of hospital stay was ten days (6–81 days for survivors).
A total of 30 patients (81%) received some postoperative treatment. Twenty-nine patients (78%) received postoperative intraperitoneal chemotherapy. This was most commonly floxuridine (23 patients), 5-fluorouracil (four patients), or both (one patient) combined with leucovorin. Additionally, three patients (8%) received systemic chemotherapy. Three patients received external beam radiation therapy in addition to chemotherapy.
Outcome and Correlation with Clinicopathologic Variables
Median survival of patients who underwent resection of gastric cancer with therapeutic intent in the setting of known metastatic disease was 12 months after surgical resection and 19 months from the time of diagnosis of metastatic disease (Fig. 1). All patients expired by three years from the diagnosis of metastatic disease.
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FIG. 1. A–B Overall survival of patients undergoing resection of gastric cancer with a therapeutic intent in the setting of metastatic disease known prior to the date of surgery. Panel A shows the survival in relation to time after resection. Panel B shows survival in relation to time after the diagnosis of metastatic disease.
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We sought correlations between clinicopathological variables and outcome. The impact of the variables analyzed with respect to survival after resection is shown in Table 3. Completeness of resection (R0 versus R1 or R2) was not associated with improved survival. Factors predictive of a worse outcome after operation included a resection involving either a total gastrectomy or adjacent organ resection (P = .04) (Fig. 2), N3 disease (P = .03) (Fig. 3), or presence of cytologic or pathologic evidence of persistent metastatic disease at the time of resection or at laparoscopy within six weeks of resection (P < .01) (Fig. 4). The subgroup of patients who had a negative peritoneal cytology in the presence of no pathologic evidence of persistent metastatic disease within six weeks of resection (i.e., sterilization of metastatic disease after chemotherapy) had a median survival of 16.4 months compared to 7.7 months for the group with persistent metastatic disease. The small size of this series did not permit multivariate analysis to evaluate the independent prognostic importance of these three variables.
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FIG. 2. Survival of patients undergoing resection of gastric cancer with a therapeutic intent in the setting of metastatic disease known prior to the date of surgery in relation to whether or not patients had a total gastrectomy or additional organ resection.
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FIG. 3. Survival of patients undergoing resection of gastric cancer with a therapeutic intent in the setting of metastatic disease known prior to the date of surgery in relation to whether or not they had N3 disease (> 15 positive lymphnodes). Only patients adequately staged with examination of  15 lymphnodes are considered.
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FIG. 4. Survival of patients undergoing resection of gastric cancer with a therapeutic intent in the setting of metastatic disease known prior to the date of surgery in relation to whether or not they had persistence of pathologic or cytologic evidence of metastatic disease within six weeks of resection.
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Patients with peritoneal cytology as their only evidence of metastatic disease had an equivalent outcome compared to the remainder of the patients who had gross metastatic disease (P = .78) (Fig. 5).
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FIG. 5. Survival of patients undergoing resection of gastric cancer with a therapeutic intent in the setting of metastatic disease known prior to the date of surgery in relation to whether or not patients had positive peritoneal cytology as the only evidence of metastatic gastric cancer.
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DISCUSSION
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This study describes the natural history of a small cohort of patients with metastatic gastric cancer who were offered gastric resection with therapeutic intent in the setting of known metastatic disease. At the authors’ institution, it is believed that nonpalliative gastric resection is unlikely to benefit the vast majority of patients with metastatic gastric cancer in improving either quality or duration of life. Thus patients are intensely evaluated for the presence of metastatic disease with high-quality cross-sectional imaging, laparoscopy, and peritoneal cytology before embarking upon resection. The majority of patients with metastatic disease will not require surgery. Nevertheless, in these unusual cases (1% of all patients with gastric cancer admitted to the surgical service), surgical resection was performed.
Despite the highly selected nature of these patients, the outcome was poor relative to the entire group of patients undergoing resection for gastric cancer. The median survival was approximately 12 months after surgery. No patient was cured of his or her disease, as evidenced by the fact that all patients were dead by three years after surgery. These findings corroborate the results of a number of other studies of resected metastatic gastric cancer showing a poor outcome.10–18 While some Asian studies suggest a more favorable outcome after resection of metastatic gastric cancer than what we have shown, particularly with regard to long-term survivors,12,14,15 other Asian studies show equivalent outcomes to those reported in Western populations.13,16–18
While it is not possible to determine the impact of therapy on outcome in this retrospective study, the survival after diagnosis of metastatic disease in this patient group is sufficiently similar to what we have seen for patients with low-volume metastatic disease treated nonoperatively5 (approximately 19 months versus ten months for median survival) to suggest that the impact of selecting of patients with more indolent biology and the lead time bias of predominantly choosing patients for resection who had survived a period of time on chemotherapy (median 4.5 months) may account for most if not all of the difference. A randomized trial would not be feasible, and this study does not suggest that such an endeavor would be worthwhile.
This study is notable in that it confirms that the biology of metastatic disease evidenced only by positive peritoneal cytology is the same as that of visible metastatic disease. We have previously shown that positive peritoneal cytology is associated with a dismal prognosis in the setting of an otherwise curative resection for gastric cancer.3 Similarly in this study, there was no correlation between peritoneal cytology as the only evidence of metastatic disease and outcome. Thus, the lack of visible metastatic disease should probably not influence the decision about whether to resect. Furthermore, the ability to "sterilize" the peritoneal cavity by preoperative chemotherapy is associated with only a marginal improvement in survival. The fact that controlling peritoneal disease at best has a minimal impact on outcome suggests that positive cytology is a predictor rather than a governor of poor prognosis. For this reason, we feel that positive peritoneal cytology should be considered equivalent to other established AJCC criteria for the diagnosis of metastatic (M1) gastric cancer.
In the present study, the only predictors of a more favorable outcome after resection of gastric cancer with therapeutic intent in the setting of metastatic disease known prior to surgery were the lack of need for total gastrectomy or additional organ resection, lower nodal status, and the absence of persistent cytologic or pathologic evidence of distant disease after preoperative chemotherapy. Tumors requiring more extensive resection and those with higher nodal stage are likely to be more advanced even when compared with other metastatic gastric cancers and thus associated with a worse prognosis. Alternatively, more extensive tumors and those with higher nodal stage at the time of resection in this group could represent a lack of response to chemotherapy, as all but one patient received preoperative treatment.
In fact, the lack of any demonstrable evidence of persistent metastatic disease after treatment with chemotherapy was the strongest predictor of improved outcome after resection in this study. The potential for a therapeutic benefit in the setting of resection of metastatic gastric cancer, which can be thought of as cytoreductive, may be limited to patients who have disease that is susceptible to chemotherapy. This model would be consistent with that of the most well-established indication for cytoreductive surgery, which is ovarian cancer, where the benefit is thought to be most pronounced for tumors that respond to chemotherapy.19
Improvements in the chemotherapy of gastric cancer may make reevaluation of the resection of metastatic gastric cancer worthy of investigation in the future. An attractive option is delivery of chemotherapy to the peritoneum preoperatively in the subset of patients who have limited metastatic disease confined to the peritoneal surfaces, with resection reserved for those patients who do not have positive cytology or pathologically confirmed viable metastases after treatment. This approach, however, hinges on whether peritoneal spread of gastric cancer is the predominant causative factor in the deterioration and death of a subset of patients or is simply a marker of the development of widespread metastatic disease. It should be noted that aggressive resection, peritonectomy, and hyperthermic intraperitoneal cytotoxic chemotherapy has been suggested by some as a treatment option for gastric cancer with limited intraperitoneal metastatic spread. In a few small preliminary series, surprisingly good results were achieved with prospects of long-term survivors.10,20,21 Other series have not confirmed these results and have outcomes similar to what is reported here for gastric resection alone in the setting of metastatic disease.22,23
In summary, the outcome of resection with therapeutic intent in the setting of gastric cancer with metastatic spread noted prior to resection is poor. Until better systemic therapy is available for the treatment of metastatic gastric cancer, therapeutic resection of metastatic gastric cancer should be offered only to highly selected patients with favorable tumor biology, if at all.
Received for publication November 22, 2005.
Accepted for publication March 11, 2006.
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- Glehen O, Schreiber V, Cotte E, et al. Cytoreductive surgery and intraperitoneal chemohyperthermia for peritoneal carcinomatosis arising from gastric cancer. Arch Surg 2004; 139(1):20–6.[Abstract/Free Full Text]
- Hall JJ, Loggie BW, Shen P, et al. Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for advanced gastric cancer. J Gastrointest Surg 2004; 8(4):454–63.[CrossRef][Medline]
- Yonemura Y, Kawamura T, Bandou E, et al. Treatment of peritoneal dissemination from gastric cancer by peritonectomy and chemohyperthermic peritoneal perfusion. Br J Surg 2005; 92(3):370–5.[CrossRef][Medline]
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ABSTRACT
INTRODUCTION
