Current Approaches to Gastric Cancer in Korea

Abstract

Gastric cancer remains a significant global health problem and is the most common cancer in Korea. Surgery is the only curative treatment for localized gastric cancer, but most cases present at an advanced stage. The proportion of early gastric cancer and the incidence of gastric cancer located in the upper third of the stomach have increased in Korea. The majority of patients in Korea receive surgery alone or surgery plus chemotherapy. Over 50% of the surgeries have been performed in five major hospitals, with most surgeons performing extended lymph node dissection (D2 or D3). The 5-year survival rate with curative resection is 55.6%–66.0%, with rates of 92.9%–98.0%, 84.2%–92.0%, 69.3%–72.0%, 45.8%–54.0%, 29.6%–36.5%, and 9.2%–23.9% according to TNM stages of Ia, Ib, II, IIIa, IIIb, and IV, respectively. Although convincing phase III data are lacking, postoperative immunochemotherapy with 5-fluorouracil (5-FU) plus mitomycin for 2 months followed by OK-432 plus doxifluridine for 24 months has been widely used in Korea. A phase III trial of adjuvant capecitabine/oxaliplatin is ongoing in curatively resected disease (CLASSIC study). The modified 5-FU/cisplatin regimen has become popular since the mid 90s, and various combinations including taxanes, oral 5-FU prodrugs, oxaliplatin, and irinotecan have been evaluated. Recently, Korean investigators have played pivotal roles in studies initiated by global pharmaceutical companies, and the Korean Cancer Study Group has initiated 14 multicenter trials, including phase III trials in gastric cancer and international cooperative trials. Future international cooperative trials are anticipated.

Although the incidence of gastric cancer and associated mortality are decreasing on a worldwide basis, Korea continues to have one of the highest rates of gastric cancer.^1,2 According to the Korea Central Cancer Registry and Local Cancer Registries Data, gastric cancer remains the leading malignancy in both sexes, despite a recent decrease in incidence.² The agestandardized incidence rate for gastric cancer was 58.6 per 100,000 for males and 30.8 per 100,000 for females from 1999 to 2001.² Curative surgery is the treatment of choice, and overall survival has improved recently. However, mortality for those diagnosed with gastric cancer remains high, because many patients are diagnosed with advanced-stage disease. In fact, more than two thirds of patients presenting with gastric cancer have unresectable disease.

Gastric cancer patients in Korea usually receive surgery alone (50.5%) or surgery plus chemotherapy (14.0%).³ Of 13,272 gastric cancer surgeries performed in Korea in 2005, 6,987 (52.6%) were performed in five major hospitals, with most surgeons performing more than 100 surgeries per annum. More than 20 hospitals perform more than 150 surgeries per annum. No consensus has been reached yet with respect to postoperative treatment, though various combinations of adjuvant chemotherapy are widely used, especially 5-fluorouracil (5-FU) and/or cisplatinbased chemotherapy.

Recently, Korean investigators have played pivotal roles in studies conducted by global pharmaceutical companies, and the Korean Cancer Study Group (KCSG) itself has initiated 14 multicenter trials, including phase III trials in gastric cancer and international cooperative trials. In this article, we review current standards of care for gastric cancer in Korea, summarize ongoing trials, and discuss future directions of research in Korea toward the cooperative goal of developing a worldwide standard for gastric cancer care. for gastric cancer in Korea, summarize ongoing trials, and discuss future directions of research in Korea toward the cooperative goal of developing a worldwide standard for gastric cancer care.

CLINICOPATHOLOGIC CHARACTERISTICS

The proportion of new cases diagnosed with early disease has increased from 7.7% in the 1970s to 19.1% in the 1980s, 29.0% in the 1990s, and 35.6% in 1996, based on data from Seoul National University Hospital. According to a report issued by the Korean Gastric Cancer Association (KGCA), the proportion of patients with early stage gastric cancer increased from 28.6% among 5,380 undergoing surgery in 1995 to 32.8% among 6,772 patients in 1999.⁴ This trend was also noted in a report from a single institution, which found that early stage gastric cancer was diagnosed much more frequently in 1997–2001 than in 1989–1996 (40% vs. 27%). This increase was found to be statistically significant at P = .000.⁵ However, the 1997–2001 rate is still lower than that in Japan, where reports show diagnosis of early disease in up to 50% of patients due to a mass screening program.⁶

In Korea, the incidence of gastric cancer located in the upper third of the stomach increased from 5.8% in the 1970s and 1980s to approximately 13% in the 1990s, with a KGCA report indicating a slight increase from 11.2% in 1995 to 12.5% in 1999.⁴ Another study showed an increase from 6.6% in 1989 –1996 to 9.4% in 1997–2001.⁵ The incidence of upper third gastric cancer in Korea, however, is still much lower than incidence rates in Western countries.

The grade of differentiation of gastric cancer in Korean patients has not changed significantly over the past 10 years, while retrospective data from the United States showed a small decrease in rates of welldifferentiated carcinoma over this period.⁷ According to one retrospective study, 23.6% vs. 19.6% of tumors were well differentiated, 27.5% vs. 30.6% were moderately differentiated, and 48.8% vs. 49.3% were poorly differentiated during 1991–1995 vs. 1996–2000.⁸

RISK FACTORS

A wide variety of etiologic risk factors have been investigated for gastric cancer, and none of the epidemiologic factors examined thus far have been sufficient to account for the pathogenesis of gastric cancer as single causal factors. Infection with Helicobacter pylori, one of the risk factors of gastric cancer, causes inflammation of gastric mucosa. Infection per se does not appear to be sufficient to cause gastric cancer, however, since there is a low gastric cancer incidence relative to high infection rates with H. pylori.⁹ The seroprevalence of H. pylori infection in Korean adults decreased from 80% in the 1980s to 67% in the 1990s.⁹ Although previous reports from areas with a high incidence of gastric cancer have failed to demonstrate a relationship between H. pylori infection and gastric cancer,^10–12 one case-control study from Korea revealed that H. pylori infection was one of the important risk factors for the development of gastric cancer, with an odds ratio of 1.82.¹³

Among such environmental factors as socioeconomic status, alcohol consumption, smoking, dietary habits, and refrigerator use, diet appears to be one of the most important, with such practices as higher intake of salty foods and carbohydrates and a high intake of cooked vs. fresh vegetables being suggested as risk factors in Koreans.⁹ Case-control studies showed an increased risk of gastric cancer among those with high consumption of stewed foods, such as soybean paste stew and hot pepper-soybean stew, and broiled fish, as well as in people who preferred salty food.^14,15

Another possible risk factor for gastric cancer is genetics. In Korea, the relative risk in first-degree relatives of gastric cancer patients is 3.1,¹⁶ which is similar to that in Western countries. Hereditary gastric cancer is estimated to account for 0.3%–3.1% of all gastric cancers in Korea, according to the criteria of the International Gastric Cancer Linkage Consortium.⁹

SURGICAL TREATMENT

In Korea, most surgeons perform extended lymph node dissection (D2 or D3) rather than limited dissection (D1).^9,17 Park et al⁵ reported that gastrectomy with D2 lymph node dissection was performed in 74% of patients during 1989–1996 and 83% during 1997–2001 (P = .000).⁵ Another report from a single center showed that 77.2% of 606 patients with advanced gastric cancer underwent D2 or greater lymph node dissection with an average 37.2 lymph nodes retrieved (range, 4–108).¹⁷ Curative resection was possible in 80.8%–87.0% of patients who underwent surgical resection.^5,6,17

The 5-year survival rate of Korean gastric cancer patients receiving curative resection was 55.6%–66.0%. In terms of TNM stage, 5-year survival rates for Ia, Ib, II, IIIa, IIIb, and IV were 92.9%–98.0%, 84.2%–92.0%, 69.3%–72.0%, 45.8%–54.0%, 29.6%–36.5%, and 9.2%–23.9%, respectively.^5,6,17 The overall 5-year survival rate during the period 1997–2001 was significantly higher than during 1989–1996, and this increase was largely attributed to a higher rate of detecting early gastric cancer.⁵ However, survival of patients with advanced gastric cancer has not improved. Peritoneal recurrence was the most common pattern of treatment failure,⁵ which is probably due to adequate locoregional control obtained by extended lymph node dissection.

Reported prognostic factors in patients who have undergone surgical resection are preoperatively assessed surgical curability, depth of invasion, and ratio of involved lymph nodes to resected lymph nodes.⁶ Another report identified depth of invasion (relative risk [RR] = 2.83), lymph node metastasis (RR = 2.33), peritoneal metastasis (RR = 3.59), and lymphatic and vascular invasion (RR = 1.91 and 1.44, respectively) as independent prognostic factors.⁵ A previous study found that lymph node metastasis was the only independent prognostic factor in early gastric cancer, and the risk factors for lymph node metastasis were depth of invasion, tumor size, histologic differentiation, and macroscopic type.¹⁸

In an analysis of patients with pN3 gastric cancer, extent of gastric resection (total gastrectomy vs. subtotal gastrectomy) and metastatic lymph node ratio were identified as independent predictors of long-term survival by multivariate analysis. ¹⁹ However, since radical lymph node dissection is routinely performed by most gastric cancer surgeons in Korea, the ratio of involved lymph nodes to resected lymph nodes would appear to have greater prognostic value than the number of involved or resected lymph nodes.⁶

Since the proportion of patients diagnosed with early stage gastric cancer has increased in Korea, minimally invasive treatments have been applied more frequently in recent years. These treatments encompass a variety of techniques, such as endoscopic mucosal resection, function- preserving surgery, and laparoscopic surgery.²⁰ The proportion of early gastric cancer patients that undergo laparoscopicassisted distal gastrectomy is rapidly increasing, because this procedure allows surgeons to perform limited lymph node dissection. .²¹

Preoperative Therapy

Preoperative chemotherapy for resectable gastric cancer has been evaluated in clinical trials in Korea. In a phase III trial of neoadjuvant chemotherapy followed by surgery vs. surgery alone in 107 locally advanced gastric cancer patients, Kang et al²² detected no significant differences in overall survival (3.58 vs. 2.48 years in the neoadjuvant and surgery arms, respectively; P = .114) or in surgical morbidity and mortality between the two arms. The curative resection rate was higher in the neoadjuvant arm (37/47) than in the surgery arm (33/54) (P = .049); in addition, postoperative stages were significantly lower in the neoadjuvant arm, suggesting that preoperative chemotherapy was effective in downstaging locally advanced disease.

Recently, promising results were reported by Chun et al²³ in a randomized phase II study comparing neoadjuvant vs. adjuvant docetaxel plus cisplatin and by Im et al²⁴ in a phase II study of perioperative FOLFOX (folinic acid [leucovorin]/5-FU/oxaliplatin) chemotherapy. The potential benefits of these approaches need to be assessed in large-scale phase III studies.

Postoperative Therapy

Although convincing data from large-scale phase III trials are lacking, postoperative immunochemotherapy consisting of 5-FU plus mitomycin for 2 months followed by OK-432 plus doxifluridine for 24 months has been widely used by Korean gastric surgeons. The adoption of this postoperative immunochemotherapy regimen was largely based on reports from Japan and reports by Kim and colleagues comparing the effectiveness of immunochemotherapy plus surgery, surgery plus chemotherapy, and surgery alone.²⁵ Kim et al²⁵ reported 5- year survival rates of 45.3%, 29.8%, and 24.4%, respectively, for these approaches. However, only 138 patients with curatively resected stage III gastric cancer were randomized to postoperative immunochemotherapy and surgery-alone groups in this study, resulting in inadequate power of the statistical analysis to determine significant differences. In a second study, 370 patients were randomized to three arms (170 to immunochemotherapy plus surgery, 100 to postoperative chemotherapy, and 100 to surgery alone); however, more than 10% of patients (n = 40) were excluded from evaluation due to discontinuation or a treatment change, which hampered interpretation of the results of the study.

Since the majority of Asian adjuvant chemotherapy studies have demonstrated a benefit, and there was a tendency to believe that surgery-alone as a control arm might be considered ethically inappropriate, postoperative chemotherapy usually has been recommended and a treatment control commonly has been used in clinical trials. Chang et al²⁶ conducted a phase III randomized trial of FAM (5-FU/doxorubicin/mitomycin) vs. 5-FU plus mitomycin vs. 5-FU alone in curatively resected gastric cancer and found no significant survival differences between treatment groups.

Although Intergroup study INT-0116 reported that chemoradiotherapy significantly improved survival after resection of stage Ib-IV gastric cancers,²⁷ it remains debatable whether adjuvant chemoradiotherapy can confer survival benefit in patients who have undergone extensive lymph node dissection (D2). A nonrandomized comparative study conducted at one institute found that chemoradiotherapy was associated with an increase in the median duration of relapse-free survival. ²⁸ We await the final results of a randomized phase III trial of adjuvant capecitabine plus cisplatin (XP) vs. XP plus radiotherapy for resected gastric cancer patients who have undergone D2 dissection.

At present, evidence is inadequate to support adjuvant chemotherapy for gastric cancer patients with D2 dissection in Korea. However, an ongoing large randomized phase III trial of adjuvant capecitabine plus oxaliplatin in curatively resected patients (CLASSIC study) is expected to provide definitive data in this area. This trial includes a total of 1,024 patients from Korea, China, and Taiwan with pathologic stage II, IIIa, and IIIb disease who are undergoing D2 curative resection.

SYSTEMIC CHEMOTHERAPY FOR ADVANCED DISEASE

The treatment of advanced gastric cancer in Korea has followed the practices reported in other countries. In the 1980s, the FAM regimen was adopted as standard chemotherapy, and until the mid 1990s, clinical trials in Korea mainly replicated studies of well-known therapeutic regimens or modified original protocols to improve toxicity profiles.

Based on the results of a pivotal study conducted at Seoul National University, the modified 5-FU plus cisplatin (FP) regimen has been popular in Korea since the mid- 1990s. This randomized phase III trial showed that the objective response rate was higher with FP vs. 5-FU and FAM (51% vs. 26% and 25%, respectively), but no significant difference was found between the three treatments in terms of survival (37 vs. 31 and 29 weeks, respectively). ²⁹

Oral 5-FU prodrugs have received increased interest since the mid-1990s, because of ease of administration and pharmacodynamic advantages in terms of mimicking protracted 5-FU infusion. Moreover, UFT (a combination of uracil and ftorafur) has shown an overall response rate of about 28% in various phase II studies.³⁰ The oral fluoropyrimidine capecitabine was designed to preferentially generate 5-FU in tumor tissue, and capecitabine monotherapy was reported to have an overall response rate of 28% with good tolerability in a phase II study in previously untreated advanced gastric cancer patients.³¹

The combination of an oral fluoropyrimidine plus cisplatin has been investigated in attempts to improve response rates. As first-line treatment in previously untreated patients, XP demonstrated an overall response rate of 55% and median survival of 10.1 months.³² This regimen was also active in patients with relapsed disease after fluoropyrimidine-based adjuvant chemotherapy, with a response rate of 28% and median survival of 11.2 months.³³ A retrospective analysis of 223 patients treated with XP in a routine clinical setting showed an overall response rate of 45.5% and median survival of 11.1 months.³⁴ Based on these promising findings, an international, large-scale phase III study (ML17032) comparing XP with FP in advanced gastric cancer has been initiated, and the primary study objective of demonstrating the noninferiority of XP has been met.

The combinations of epirubicin/cisplatin/UFT/leucovorin and epirubicin/cisplatin/capecitabine have been examined in the context of replacing continuous infusion 5- FU in the ECF regimen.^35,36 Phase II studies of capecitabine combined with irinotecan or doxorubicin have also been undertaken. ^37,38 However, the most attractive combination regimen containing capecitabine in the treatment of gastric cancer is capecitabine plus oxaliplatin (XELOX). Two recent phase II studies of XELOX as firstline therapy in advanced gastric cancer reported overall response rates of 63% and 65%,^39,40 with these studies also showing that XELOX had an excellent safety profile. On the basis of its high activity and good safety profile, XELOX was adopted in the phase III CLASSIC study, noted above, in which adjuvant XELOX is being compared with surgery alone in stage II and III gastric cancers after D2 dissection.

S-1 is a new oral dihydropyrimidine dehydrogenase inhibitor fluoropyrimidine consisting of tegafur, 5-chloro-2,4- dihydroxypyridine, and potassium oxonate at a molar ratio of 1:0.4:1. This formulation is designed to exploit biochemical modulation to retain a high level of antitumor activity while reducing potential for gastrointestinal toxicity.⁴¹ Although a Korean phase II study of S-1 alone produced a response rate of only 19.3%,⁴² which was much lower than response rates reported in Japan (44%–49%), the combination of S-1 plus cisplatin resulted in a response rate of 48% with a favorable toxicity profile.⁴³ Various combinations incorporating S-1 are being studied in clinical trials in Korea. Notably, S-1 is being evaluated in combinations including oxaliplatin, a taxane, or irinotecan.

Taxanes have been actively investigated in gastric cancer chemotherapy in Korea. The combination of paclitaxel, cisplatin, and 5-FU appears to be highly active with acceptable toxicity,⁴⁴ yielding an overall response rate of 51% and complete response rate of 10% in a study in 41 patients with advanced gastric carcinoma. The combination of paclitaxel, infusional 5-FU, and leucovorin produced a response rate of 31.7% and a median survival of 60 weeks in 60 advanced gastric cancer patients.⁴⁵ Promising results were also reported for various doses and schedules of paclitaxel plus cisplatin, with overall response rates of 36.5% to 44.0%, median times to progression of 4.7 to 6.0 months, and overall survival durations of 10.8 to 12.1 months being reported.^46,47 In addition, paclitaxel plus carboplatin had a response rate of 22% in patients previously treated with 5-FU and a platinum.⁴⁸ In one phase II study comparing paclitaxel plus 5-FU with docetaxel plus 5-FU as first-line treatment in patients with metastatic gastric cancer, no significant difference in efficacy between the regimens was observed, although paclitaxel/5-FU was associated with fewer grade 3 or 4 toxicities and better quality of life outcomes.⁴⁹

Docetaxel at 75 mg/m² produced a response rate of 15.9% in Korean gastric cancer patients.⁵⁰ It is of interest that the response rate with docetaxel monotherapy was similar in chemotherapy-naïve and previously treated patients.⁵¹ Several investigators have assessed docetaxel plus cisplatin in advanced gastric cancer, reporting overall response rates of 17.1% to 43.5% and median survival durations of 5.8 to 11.5 months.^52–54 Based on the finding of synergy between docetaxel and 5-FU in a preclinical study, docetaxel was administered with infusional 5-FU and lowdose leucovorin in 66 advanced gastric cancer patients, yielding response rates of 34.2% in chemotherapy-naïve patients and 14.2% in previously treated patients.⁵⁵

Various doses and combination schedules of docetaxel and capecitabine have been examined in advanced gastric cancer. In a study of weekly docetaxel plus capecitabine in 55 patients, treatment with docetaxel 36 mg/m² intravenously on days 1 and 8 and capecitabine 1,000 mg/m² orally twice daily on days 1–14 every 3 weeks until progression resulted in an overall response rate of 40.4% and median survival of 12.0 months.⁵⁶ When docetaxel was administered every 3 weeks at 75 mg/m² with capecitabine at 1,250 mg/m² twice daily on days 1–14, a greater response rate of 60% was achieved, with median survival of 10.5 months.⁵⁷ However, this regimen was associated with high rates of stomatitis and hand-foot syndrome as dose-limiting toxicities, which prevented continuous treatment. When the capecitabine dosage was reduced to 1,000 mg/m² in this regimen, the incidence of hand-foot syndrome was reduced, but response rate also was reduced to 43.8%.⁵⁸

Since a phase III trial showed a significantly longer time to progression, longer overall survival, and higher response rate for DCF (docetaxel/cisplatin/5-FU) vs. CF,⁵⁹ modifications of the dosages and schedules of the three agents have been attempted to improve convenience and/or toxicities. ^60,61 In addition, oral 5-FU prodrugs have been used in combination with docetaxel and cisplatin to avoid the cumbersome long-term 5-FU infusion.⁶² In one study, the combination of docetaxel/cisplatin/oral UFT/leucovorin produced an overall response rate of 50%, including 4 complete responses (7.7%) and 22 partial responses (42.3%).⁶² The major toxicity was neutropenia, which was grade 3/4 in 36 patients (69.3%). Median time to progression was 22 weeks (4 to 156+ weeks), survival duration was 48 weeks (4 to 156+ weeks), and response duration was 24 weeks (6 to 152 weeks). Epirubicin was added to DC to test the feasibility of the triple combination for the treatment of advanced gastric cancer, and the response rate was similar to those achieved with other triplet combination chemotherapies (47%).⁶³

Oxaliplatin is a third-generation platinum compound with broad antitumor activity. Oxaliplatin appears to have a better safety profile than cisplatin, and its cross-resistance with cisplatin is minimal. A combination of oxaliplatin, 5-FU, and leucovorin was found to be highly active (57% response rate in 21 evaluable patients) with mild toxicity in previously untreated advanced gastric cancer (unpublished data), and a response rate of 26% was reported for the same treatment in previously platinum-treated patients.⁶⁴ Thus, it appears that the 5-FU/folinic acid/oxaliplatin combination is an active regimen with acceptable toxicity for the treatment of advanced gastric cancer.

New chemotherapeutic agents developed by Korean pharmaceutical companies are in clinical trials, and results to date have been promising. SKI-2053R, a new platinum derivative from SK Chemicals, produced a 17% response rate in 35 evaluable patients.⁶⁵ Final results from a phase III trial of SKI-2053R plus 5-FU vs. cisplatin plus 5-FU should be available in the near future. Results of a variety of combination chemotherapy regimens for advanced gastric cancer studied in Korea are summarized in Table 1.^{32–35,37,43,44,46,53,57,61–63,66–72}

Table 1.

Results of palliative combination chemotherapy for advanced gastric cancer in Korea.

Study	Regimen	Evaluable patients	Response rate (%)	Median survival (mo)
Kim et al32	Capecitabine + cisplatin	38	54.8	10.1
Kang et al33	Capecitabine + cisplatin	32	28.0	11.2
Lee et al34	Capecitabine + cisplatin	123	45.5	11.1
Cho et al35	Epirubicin + capecitabine + cisplatin	50	59.0	9.6
Baek et al37	Capecitabine + irinotecan	38	46.3	8.6
Lee et al43	S-1 + cisplatin	42	48.0	10.0
Kim et al44	Paclitaxel + 5-FU + cisplatin	41	51.0	6.0
Kim et al46	Paclitaxel + cisplatin	52	36.5	10.8
Park et al53	Docetaxel + cisplatin	86	43.5	11.5
Park et al57	Capecitabine + docetaxel	38	60.0	10.5
Oh et al61	Docetaxel + 5-FU + cisplatin	40	42.5	9.0
Oh et al62	Docetaxel + cisplatin + UFT + leucovorin	52	50.0	11.1
Lee et al63	Epirubicin + docetaxel + cisplatin	30	47.0	11.0
Ahn et al66	5′-DFUR + cisplatin	19	27.7	5.7
Min et al67	5-FU + heptaplatin	47	21.0	6.2
Shin et al68	Paclitaxel + cisplatin	34	33.3	8.9
Cho et al69	Paclitaxel + 5-FU + leucovorin	37	45.9	11.1
Park et al70	Docetaxel + irinotecan	46	45.7	8.2
Oh et al71	Irinotecan + capecitabine	55	43.6	11.0
Oh et al72	Oxaliplatin + 5-FU + leucovorin	42	50.0	7.7

Abbreviations: 5-FU = 5-fluorouracil

MULTICENTER COOPERATIVE TRIALS LED BY THE KCSG

The Korean Cancer Study Group (KCSG) was established in 1998 by a small group of medical oncologist members of the Korean Cancer Association (KCA) as a nonprofit organization designed specifically to address issues concerning cooperative clinical studies. The KCSG has 225 members and 145 associate members drawn from 95 Korean institutes and hospitals. Its membership consists of clinical oncologists representing all oncology disciplines (mainly medical and radiologic oncology) and other practitioners, including physicians and other health-care professionals who participate in approved oncology training programs, oncology nurses, and other health-care practitioners with a primary interest in oncology. The society conducts the majority of its cooperative clinical trials through various disease subcommittees composed of KCSG members—ie, Gastric Cancer, Colorectal Cancer, Lung Cancer, Breast Cancer, Lymphoma, Head & Neck Cancer, Hepatobiliary Cancer, and Palliative Care subcommittees.

To date, the KCSG has been involved in 14 multicenter clinical trials, including three phase III trials (Table 2).^42,73,74 Eleven of these trials have been completed and three are ongoing. Two of these trials are international cooperative studies and two more international cooperative clinical trials will be started in the near future. The first Japanese-Korean cooperative gastric cancer clinical study was completed successfully in 2006,⁷³ and another large scale Japanese-Korean comparative gastric cancer clinical trial (START study) of S-1 plus docetaxel vs. S-1 alone in patients with advanced gastric cancer is ongoing. This study is enrolling more than 600 patients to detect a median survival difference of 100 days (estimated median survival of 300 days in the S-1 arm vs. 400 days in the docetaxel/S-1 arm). Patient enrollment was started in March 2006 and the estimated study completion date is in September 2008.

Table 2:

Gastric cancer clinical trials conducted by the Korean Cancer Study Group.

Protocol No.	Study title	No. pts	No. participating institutions
KCSG-ST06-04	Prospective phase II study of cetuximab in combination with XELOX(capecitabine plus oxaliplatin) in patients with advanced gastric cancer	43	3
KCSG-ST06-03	Phase II study of cetuximab in combination with oxaliplatin, 5-FU, and leucovorin in untreated patients with advanced gastric cancer	40	12
KCSG-ST06-02	Phase II study of docetaxel plus oxaliplatin in relapsed gastric cancer patients previously related with fluoropyrimidine- or cisplatin-containing adjuvant chemotherapy	44	10
KCSG-ST05-02	Phase II study of S-1 plus irinotecan combination chemotherapy as first-line treatment in patients with advanced gastric cancer	45	7
KCSG-ST06-01	START: S-1 and docetaxel for advanced gastric cancer: randomized phase III trial	180	14
KCSG-ST05-01	Phase II study of TS-1 plus paclitaxel combination chemotherapy in patients with unresectable advanced or relapsed gastric cancer	56	11
KCSG-ST03-0142	Phase II study of S-1 chemotherapy in patients with unresectable advanced or relapsed gastric cancer	62	6
KCSG-ST04-0173	Phase II study of biweekly paclitaxel and cisplatin combination chemotherapy in advanced gastric cancer: Korea-Japan Collaborative Study Group	50	7
KCSG 03-06-2574	Phase II study of pemetrexed and cisplatin in patients with advanced gastric cancer	51	8
KCSG 03-04-22	Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients with advanced gastric cancer	80	4
KCSG 00-06-22	Randomized phase III trial of heptaplatin/cisplatin vs. continuous infusion of 5-FU/cisplatin in patients with advanced gastric cancer	184	13
KCSG 02-10-31	Phase II study of paclitaxel chemotherapy in patients with advanced or relapsed gastric cancer	36	9

Abbreviations: 5-FU = 5-fluorouracil

In addition to these cooperative efforts, several phase I, II, and III studies initiated by global pharmaceutical companies currently are under way in Korea.

DISCUSSION

Gastric cancer remains the leading malignancy in Korea among both sexes. As part of the National Cancer Control Program of Korea, an Early Cancer Detection Program was initiated in 2003, including a recommendation for gastrofiberscopy or upper gastrointestinal barium examination for early detection of gastric cancer in persons aged 40 years or older. The implementation of this program and enhanced general health awareness has resulted in an increase in the proportion of patients diagnosed with early stage gastric cancer.

For resectable gastric cancer patients, gastrectomy with extended lymph node dissection (D2 or D3) is standard of care in Korea. No consensus has been reached yet with respect to postoperative treatment, though various combinations of adjuvant chemotherapy are widely used, especially 5-FU and/or cisplatin-based chemotherapy. Such newer agents as oxaliplatin, taxanes, capecitabine, S-1, and irinotecan are available and are reimbursable by the Korean National Health Insurance Agency for the treatment of metastatic or relapsed gastric cancer. At the time of writing, 250 medical oncologists were actively participating in various clinical trials to define a standard chemotherapy for the treatment of advanced gastric cancer and for adjuvant treatment. According to the PubMed database (www.ncbi.nlm.nih.gov/pubmed), from 2002 to 2006, 296 articles were published on gastric cancer in Korea, compared with 84 papers from 1997 to 2001; 74 articles were published during the period of January to July of 2007 alone, indicating that the interest and activity in this area continue to increase.

It is hoped that these clinical and basic research activities will contribute to the development of a worldwide standard for gastric cancer care. The KCSG will continue to play a central role in Korean gastric cancer clinical trials and in international cooperation with Japan, China, and the Western cooperative oncology groups.