Gastric cancer is the third leading cause of death among men and the fifth leading cause of cancer death among women worldwide [1]. Globally, 1,000,000 new cases of gastric cancer are diagnosed annually, and half of these cases occur in East Asia [2]. Korea has reported the highest incidence of gastric cancer, along with Japan, and has an agestandardized incidence of 56.8 cases per 100,000 men, affecting nearly 30,000 patients in 2013 [3]. Complete surgical resection is the primary therapy used, but a substantial number of patients with a more advanced stage disease (e.g., beyond submucosa or metastasis and into the lymph nodes) experience locoregional, peritoneal, or systemic recurrences after receiving curative gastrectomy alone [4]. Clinical trials have been conducted to reduce the risk of recurrence and mortality, but no international consensus concerning the best oncological strategy has been reached [5,6].

The survival benefit of adjuvant chemoradiotherapy (CRT) for curatively resected gastric cancer was established by the Intergroup (INT)-0116 trial in 2001 [7]. However, recent data from ARTIST and CRITICS trials showed that there was no significant survival benefit in the CRT group over chemotherapy alone for D2-resected patients [8,9]. To date, several underpowered studies have propounded an opinion that some selected patients may still benefit from adding radiotherapy (RT) to chemotherapy even after D2 surgery [10]. At the same time, two multi-institutional phase III trials from Korea and Japan demonstrated the merits of adjuvant chemotherapy [11,12].

Given the controversial and limited data available, the role of RT has been heavily criticized for gastric cancer patients undergoing D2 gastrectomy, which has currently become the standard of care in Europe and the United States as well as in East Asia [13,14]. Furthermore, neither patterns of care nor national data for RT specifically have been explored among nonmetastatic gastric cancer patients in Korea. Therefore, the purpose of this study was to examine RT usage trends for neoadjuvant and adjuvant patients in Korea and to estimate the impact of the available evidence on clinical practice using data from a Korean national cohort from 2002 to 2013. Secondarily, we also examined survival benefits and net medical cost advantages of adding RT in neoadjuvant and adjuvant treatment.

All citizens in Korea are obligated to enroll in the single-payer, national health insurance, and medical aid program administered by the National Health Insurance Corporation. The present study used data from the National Health Insurance Service-National Sample Cohort (NHIS-NSC), which included 1,025,340 representative subjects (approximately 2.2% of the country’s population), who were randomly stratified and selected based on age, sex, insurance type, income, residential region, and individual total medical costs. Rates were calculated and shown per 1,000,000 population. Details of the NHIS-NSC database are available in a previous report [15].

This study highlights the national patterns of neoadjuvant and adjuvant RT use for gastrectomy patients in Korea as well as the sociodemographic factors associated with its use. The results showed that RT usage was exceedingly low and primarily concentrated in one large-volume hospital. In comparison, there was a low rate of, but growing interest in, neoadjuvant chemotherapy (one-third of the hospitals in the nation). Adjuvant chemotherapy accounted for about 90% of the therapy modalities used and was mainstream in nearly all hospitals. These practice patterns are concerning given that RT, which has already been verified and accepted as an essential adjuvant therapy modality for gastric cancer in the Unites States [18], has not had enough opportunity to develop the evidence in D2-dissected patients.

We found that only 4% of patients received RT as an adjuvant or neoadjuvant treatment. Furthermore, our results contradict the results of the previous Surveillance, Epidemiology, and End Results studies [19]. For example, in the United States, the proportion of patients who underwent surgery alone after 2000 decreased by at least 13%, but the proportion of patients who underwent CRT increased from 8%-14% to 25%-33%. This implies that, in Korea, the results of the INT-0116 trial, unlike in the United States [19,20], did not affect treatment practices.

The discrepancy between patterns and trends in the United States and Korea may be explained by the extent and safety of lymphadenectomies performed in East Asia [21]. According to the 2004 the Korean Gastric Cancer Association (KGCA) nationwide survey, the quality of extensive D2 lymphadenectomy, represented by the number of retrieved lymph nodes, was assured in most of the 57 hospitals belonging to the KGCA regardless of hospital volume [22]. In contrast to the high postoperative mortality rate (~10%) in trials conducted in Western countries [23-25], the very low mortality rate (< 1%) for D2 dissection observed in prior Phase III trials in Korea [12] and Japan [26] was reaffirmed on a population level in the present study (0.6%). Although we found that patients who were ≥ 70 years old, had a high comorbidity burden (CCI ≥ 4), and who had a more severe cancer stage (having undergone total gastrectomy) were associated significantly, we found only a slight increase in the risk of postoperative mortality.

In addition, our data showed that the majority of RT patients were concentrated in one large-volume hospital [8]. The proportion of RT administered in this hospital was greater in magnitude (52%) than the proportion of RT administered in all other 25 hospitals combined. Otherwise, RT was more likely to be utilized in small- or medium-volume hospitals located in nonmetropolitan areas. Although we were not able to investigate whether tumor factors, such as cancer stage or adverse pathologic features, influenced the consideration of RT, we found significant interhospital variations (Fig. 1A). This indicates that cultural predispositions rather than universal criteria guide clinical decisions.

Furthermore, being over 60 years old and having a low income (≤ 20th percentile) were barriers to receiving RT. On the other hand, we found that patients with a high comorbidity burden were more likely to receive RT. This is most likely because trimodal therapy including RT is used for patients who may be intolerant to full-dose chemotherapy, such as those with a high comorbidity burden. In our opinion, studies are needed to determine the role of RT in the clinical setting among patients that might be intolerant to full-dose chemotherapy.

Moreover, the absolute proportion of patients receiving adjuvant chemotherapy ranged 83.2%-89.1%. Furthermore, the 5-year OS and the 5-year DSS outcomes in this study (66.5% and 71.5%, respectively) were consistent or lower when compared to the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) [12] and the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC) [11] trials; however, these two trials included younger patients with fewer comorbidities than observed in the general population, which may account for any discrepancies. The overwhelming use of adjuvant chemotherapy found in our study might be rooted, to some degree, in a propensity for clinicians to depend heavily on evidence generated from our country. Nevertheless, this consistent usage, which existed before 2007, is worrisome because it may indicate that these practices were determined before maturation of emerging evidence.

The addition of RT to adjuvant/neoadjuvant chemotherapy increased the mean cost of $3,734 in Korea that has single-payer health care system. We could not find that addition of RT reduced the net medical cost during follow-up that indirectly reflected recurrence preventing treatment effects. In addition, it was found that RT did not increase the 5-year DSS rate (RT vs. no RT, 68.7% vs. 71.4%), yet consistent with previous findings of ARTIST trial (5-year OS, 75% vs. 73%) and CRITICS trial (5-year OS, 40.9% vs. 41.3%). Although we felt that use of RT in (neo-)/adjuvant setting (before)/after D2 surgery increased the total medical cost but not the survival rate in these general population, such a precondition would require (1) that the clinical indication was not different between patients with CRT and those with chemotherapy alone, and (2) that all other confounders, which were not identified in this study, were well balanced. Although previous reports imply the fulfillment of preconditions [27], we cannot justify these findings without details including tumor stage or residual tumor burden, but may question the importance and necessity of RT in D2-dissected patients [28]. However, several studies have demonstrated loco-regional recurrence usually occurs in the nodal basin outside the D2 dissection surgical field [28,29] and a considerable rate of locoregional recurrence is observed in high-risk patients (e.g., N+) even after D2 surgery [30]. In the ARTIST trial, there was a significant benefit in a subgroup of patients with N+ with postoperative CRT. A subsequent ARTIST II trial is currently underway to refine the role of RT in patients with positive lymph node metastasis.

We also found that sociodemographic factors such as being ≥ 60 years old, having a high comorbidity burden, and receiving medical aid were associated with poorer survival outcomes. Therefore, when making treatment decisions for individual patients, physicians should consider sociodemographic factors.

The current study has some limitations. For example, the NHIS-NSC database lacks information on gastric cancer staging and recurrence; therefore, the analyses of stage-specific patterns of care and the impact of neoadjuvant and adjuvant treatment on survival were limited. In our study, standardized incidences were not calculated, as the Korean Statistical Information Service do not provide the incidence information of the intersection of two sets (diagnosed as gastric cancer and underwent gastrectomy). Since our findings were computed in the crude rates which result from the specific composition which prevails in our sampled population, we caution against direct comparing other study populations with respect to actual numerical values. We also lacked direct clinical data regarding pathologic factors (such as residual tumor burden), radiation specifics (e.g., dose, fractionation, and field), performance status, and treatment compliance. Information on chemotherapy regimen was also unavailable for some patients, further limiting the analyses of chemotherapy patterns of care. Therefore, further studies examining the impact of RT on survival in well-designed prospective trials as well as in the general population are necessary. However, despite these limitations, this study also has a strength that the NHIS-NSC database represents nearly all patients in Korea, allowing us to generalize to the entire population in Korea.

The present study is the first large study to analyze the use of RT in the neoadjuvant and adjuvant management of gastric cancer in East Asia. We observed that RT was uncommonly utilized and that RT patients were concentrated heavily in one hospital. Considering the sizable cost overrun and lack of survival advantage for RT in general population, better risk stratifying D2-dissected patients is utterly critical to refine the role of RT in D2-dissected patients. It is important to recognize the cultural predispositions highlighted in our study since they might continue to influence physician practices and attitudes toward RT, despite emerging evidence.