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Early-Stage Gastric Cancer: A Highly Treatable Disease

From the Department of Surgery, Ioannina University School of Medicine, Ioannina, Greece.

Correspondence: Address correspondence to: Dimitrios H. Roukos, MD, Department of Surgery, Ioannina University School of Medicine, GR–451 10 Ioannina, Greece; Fax: 30-26510-97094; E-mail: droukos{at}cc.uoi.gr

Little progress in the management of stomach adenocarcinoma during the last decades has contributed to the wide notion in the West that gastric cancer is a fatal disease with limited treatment potential. Intensive research work has focused on the development of aggressive perioperative multimodality treatment with new chemotherapeutic agents combined with radiotherapy aimed at improved survival. These efforts, however, are only slightly effective today. The potential of an extensive lymph node dissection (D2 resection) to provide cure has received less attention in the western word. Lack of evidence from randomized controlled trials (RCT) for the superiority of D2 resection until such was recently reported from Japan was the major argument against a wide clinical use of D2 surgery in the West. Now, a RCT¹ that shows fascinating survival results for Japanese patients with serosa-negative cancer, even for those with nodal metastasis, confirms previous favorable reports. The question is old but now more apparent: Would a Japanese-style treatment improve the survival of western patients with gastric cancer?

Prognosis for patients with gastric cancer in the western world is poor, with recent 5-year survival rates of only 22% overall and 59% for localized disease in the United States.² Comparing these findings with corresponding rates of 88% overall and 97% for localized disease, respectively, for breast cancer in the United States,² a first conclusion is that carcinoma of the stomach is likely a miserable disease with late diagnosis and limited therapeutic potential. Time trends results comparison of these two cancer types between patients in the United States and those in Japan suggests that substantial improvements in clinical outcomes might be achieved, even in cases of gastric cancer.³ Results of survival rates with extensive D2 node dissection in Japan⁴ are clearly superior to those reported from the West with limited (D0 or D1) dissection. D2 dissection has been the standard surgical procedure in recent treatment guidelines⁵ by the Japan Gastric Cancer Association (JGCA). According to the evidence-based principles, however, such a recommendation could not be made in the West. The two large European RCT available showed significantly increased rates of in-hospital mortality and morbidity after D2 dissection rather than D1 dissection without a long-term survival advantage in favor of extensive node dissection.^6,7

Excellent findings from a recent Japanese RCT comparing surgery alone and surgery plus adjuvant chemotherapy,¹ now provide credible evidence that patients with serosa-negative cancer can expect a good prognosis, irrespective of metastasis to the regional lymph nodes, if their disease is treated appropriately. In this multicenter, phase III clinical trial, 252 patients with serosa-negative cancer from 13 cancer centers in Japan were assigned randomly to adjuvant chemotherapy or surgery alone. The chemotherapy was composed of intravenous mitomycin (1.33 mg/m²), fluorouracil (FU) (166.7 mg/m²), and cytarabine (13.3 mg/m²) twice weekly for the first 3 weeks after surgery, and oral FU (134 mg/m²) daily for the next 18 months for a total dose of 67 g/m². D2 or greater node dissection was performed in 98% of patients, with a hospital mortality rate of only 0.4%. There was no significant difference between the chemotherapy arm and surgery alone arm in 5-year relapse-free (88.8% vs. 83%) and overall survival rates (91.2% vs. 86.1%), respectively. Although adjuvant chemotherapy reduced the overall recurrence rate by approximately 50% (13.8% vs. 7.1%), this difference did not reach statistical significance. It is likely that the small number of patients in the trial and the excellent unexpected survival in the surgery alone arm (5-year survival 86% instead 70% in the study design) are possible explanations for not finding a significant difference with chemotherapy observed in this trial.

Surgery is the cornerstone in the management of gastric cancer and still remains the only modality capable of cure. Long-term survival, however, can be achieved only when both the tumor stage⁸ and the surgeon’s ability⁹ result in a curative resection without any macroscopic or microscopic evidence of residual tumor, namely an R0 resection in American Joint Committee on Cancer classification. It is of paramount importance to state that the term R0 resection should include the complete removal of both the primary tumor by gastrectomy and the affected regional lymph nodes by lymphadenectomy.^8–10 Although little or no debate exists to what extent the stomach should be resected, the extent of lymph node dissection remains strongly controversial.

Considering this background, what conclusions can we drawn from this trial? First, the study confirms multiple previous reports and finds no doubt that extensive lymph node dissection in experienced hands is a safe procedure.¹¹ Second, D2 resection achieves both excellent local control (1.6% recurrence rate) and good prognosis (86% 5-year survival) in patients who are serosa-negative, irrespective of their nodal status and chemotherapy. This finding becomes much more impressive in that 48% of patients had node-positive cancer and 13.8% N2 or greater disease. Overall recurrence rate at 69 months in the surgery alone arm was 13.8%, which when compared with a corresponding rate of 21% in a recent prospective western study with D2 dissection,¹² provides optimism for the reproduction of similar results in the West. Third, in agreement with multiple other RCT, the study confirms that the beneficial effect of adjuvant chemotherapy after curative surgery remains controversial.⁸ The encouraging results with chemotherapy in this trial and the small, but significant, survival benefit with adjuvant chemotherapy found in several recent meta-analyses¹³ urgently suggest the need for a large-scale RCT to definitively solve the problem of chemotherapy effectiveness in gastric cancer.

Adjuvant chemoradiotherapy after gastrectomy has been the established standard in the United States on the basis of the results of a multicenter RCT.¹⁴ Relapse and survival rates with limited (D0 or D1) node dissection in this trial, despite adjuvant treatment, however, seem to be worse compared with D2 surgery alone in reports from Japan,⁴ specialized institutions,^11,12 and in the Dutch trial.⁶ Data indicate the effectiveness of chemoradiotherapy after limited D0 or D1 node dissection but greater benefits may be expected with D2 surgery alone rather than with this multimodality therapy.¹⁵

Is it feasible and possible to improve the clinical outcome of western patients with gastric cancer? Surgical undertreatment represents a current serious problem in the United States, according to the conclusion of the National Cancer Data Base report on 50,169 patients with gastric cancer.¹⁶ Thus, substantial benefits could come from appropriate surgical treatment, although the high survival rates in the Japanese study probably cannot be reached in the West where many other factors influence clinical outcomes. These factors include the Japanese surgeon’s experience and skill in performing an appropriate, complete, and effective D2 and greater node dissection, which seems to be an important prognostic factor,¹⁷ a higher proportion of worse prognosis-associated proximal tumors in the West, and differences in staging systems and biological behavior of the disease between patients in the East and West.

Despite these limitations, the findings reported by Nashimoto et al.¹ provide evidence supporting the hypothesis that if the gastric serosa at treatment is intact, irrespective of nodal status, cancer is still a localized and not a systemic disease.^12,18 This assessment underlines the ability of an appropriate local treatment (e.g., a complete D2 dissection) to result in a true R0 resection that can achieve both tumor control and long-term survival in most western patients with an early-stage gastric cancer.

D2 dissection, however, is undoubtedly a dangerous operation in inexperienced hands. Surgeons should be well practiced in this technique to be able to perform it safely and effectively. A balance of risks and benefits of D2 resection for individual patients is needed outside highly specialized institutions. Critical review analysis of data available¹⁹ reveals a wide variation in the benefit of extended lymphadenectomy, with the greatest gains expected in patients with node-positive disease and especially in those with N2 disease^19–22 according to the Japanese anatomic nodal classification. The hypothesis of nodal stage-specific benefit first published in 1998²⁰ by the author of the present article, was recently confirmed by the final 11-year survival results of the Dutch trial.²³ Interestingly, 20% of N2-positive patients after D2 dissection are still alive.²³ This noteworthy survival advantage, which is identical in the randomized Dutch trial²³ and in the previous study,²⁰ provides convincing evidence for the benefit of D2 dissection in western patients. Therefore, a tailored use of D2 dissection in patients with node-positive disease²⁴ might be a rational approach; currently, however, preoperative nodal status prediction is not sufficiently perfected to allow such a guide node dissection. Promises of an accurate prediction of nodal status in the future provide the technique of sentinel node biopsy,³ as well as a preoperative gene expression profile of the primary tumor with the use of the new technology of DNA-microarrays.^25,26 These new techniques will facilitate a tailored extent of lymph node dissection according to the nodal spread in the individual patient.

A tailored tumor stage-stratified approach aimed at reducing adverse effects of overtreatment and increasing survival of patients whose disease is undertreated is increasingly receiving attention.^18,24 Serosa status at treatment is an independent predictor of survival, with a crucial role in treatment decision-making in both Japan and the West.^12,18 The ability of appropriate D2 surgery to control the disease by intact serosa appears to have lost its power when serosa has been invaded by the tumor. Appropriate D2 dissection in serosa-positive cancer has likely little effect in reducing the risk of peritoneal recurrence. Here, the urgent need for effective adjuvant treatment is apparent. Research has been focused on the development of innovative multimodality treatments, and prospective studies with neoadjuvant therapies and intraperitoneal chemotherapy are under way in an attempt to improve the outcome of patients with serosa-positive cancer.

For serosa-negative cancer, the evidence-based data provided by Nashimoto et al.¹, and multiple other non–evidence-based studies^{4,11,12,18,23} indicate that efforts for improvement of western patients’ clinical outcomes should be focused on increasing the rate of appropriate D2 surgery rather than on the development of effective adjuvant treatment. The 5-year survival rate of more than 86% with D2 surgery alone in the Japanese trial allows little opportunity for future adjuvant trials to detect a significant difference for this patient subpopulation. Either highly effective adjuvant treatment should be developed or a large sample with current adjuvant therapies available is needed, both of which in the near future seem less realistic than an increase in the rate of appropriate D2 dissection in the West.

Received for publication October 28, 2003. Accepted for publication November 24, 2003.

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