2.1. Postoperative Chemotherapy in East Asia (Table 1 and Table 2)
In East Asia, radical gastrectomy with D2 lymph node resection has been the standard surgery for GC. Many studies have investigated postoperative adjuvant chemotherapy, and it is now also considered a standard treatment.
This section summarizes pivotal clinical trials on postoperative chemotherapy.
2.1.1. The ACTS-GC Study
The first convincing evidence from a randomized clinical study for the efficacy of S-1 adjuvant chemotherapy was the phase III Adjuvant Chemotherapy Trial for Gastric Cancer (ACTS-GC) study [
12].
In this study, 1059 patients with stage II-III GC who underwent curative gastrectomy with D2 lymph node dissection were enrolled. Patients were randomly assigned to either the S-1 chemotherapy group or the surgery-only group. The primary endpoint was overall survival (OS). The 3-year OS rate was 80.1% in the S-1 group and 70.1% in the surgery-only group. The death hazard ratio (HR) in the S-1 group, as compared with the surgery-only group, was 0.68 (95% confidence interval (CI): 0.52–0.87;
p = 0.003). The HR for recurrence-free survival (RFS) at 3 years was 0.62 (95% CI: 0.50–0.77). This analysis was updated after 5 years of follow-up and demonstrated consistent results [
13], showing a significant 10.6% improvement in 5-year OS with adjuvant S-1 chemotherapy group compared to the surgery-only group (71.7 vs. 61.1%, HR 0.669, 95% CI: 0.540–0.828), as well as a 12.3% improvement in 5-year RFS compared to the surgery-only group (65.4 vs. 53.1%, HR 0.653, 95% CI: 0.537–0.793). Along with the marked efficacy, low rates of grades 3 and 4 toxicities were observed (6.0% anorexia, 3.7% nausea, and 3.1% diarrhea). Based on this study, S-1 was established as a standard regime of postoperative adjuvant chemotherapy in East Asia for patients with locally advanced GC who underwent radical surgery.
However, it is not clear whether the efficacy of adjuvant S-1, as demonstrated in the ACTS-GC study, is also achievable in Western populations where this drug is poorly tolerated because of CYP2A6 polymorphisms, by which tegafur present in S-1 transforms in the body to 5-FU [
14].
2.1.2. The CLASSIC Study
Capecitabine is an oral fluoropyrimidine agent administered worldwide. The Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study was a phase III study that was conducted in East Asia. This study reported a significant efficacy regarding disease-free survival (DFS) after 6 months of adjuvant (postoperative) capecitabine plus oxaliplatin (XELOX) following gastrectomy with D2 lymph node dissection compared to surgery alone [
15].
In this study, 1035 patients from 37 Asian centers with stages II–IIIB gastric adenocarcinoma who underwent curative gastrectomy with D2 lymph node dissection were randomly assigned to either the surgery-only group or the adjuvant XELOX group. Patients assigned to the XELOX group had significantly improved 3-year DFS (74 vs. 59%, HR 0.56, 95% CI: 0.44–0.72), with only a borderline statistically significant improvement in 3-year OS rate (83 vs. 78%, HR 0.72, 95% CI: 0.52–1.00) at a median follow-up of 34.2 months.
However, with longer follow-up, the improved OS with XELOX became statistically significant (5-year OS 78 vs. 69%, HR 0.66, 95% CI: 0.51–0.85) [
16]. The adjuvant XELOX group had a higher rate of grades 3 and 4 toxicities (56 vs. 6% for the surgery-only group), most commonly neutropenia, nausea, vomiting, thrombocytopenia, and anorexia, requiring chemotherapy dose modifications in 90% of patients. Only 67% of patients assigned to the adjuvant XELOX group completed 6 months of chemotherapy compared to 78% in the ACTS-GC study. The CLASSIC study established XELOX as one of the new treatment options for postoperative chemotherapy in GC patients who underwent gastrectomy with D2 lymph node dissection.
2.1.3. The JACCRO GC-07 Study (START-2)
Docetaxel (DTX) has shown efficacy in advanced or recurrent GC not only as a monotherapy but also in combination with fluoropyrimidine plus cisplatin [
17,
18,
19,
20,
21,
22].
The JACCRO GC-07 was a phase III study conducted to prove the superiority of postoperative S-1 plus DTX. This study enrolled patients who underwent curative resection via D2 or more extensive gastrectomy and were diagnosed with stage III GC. They were randomly assigned to either postoperative S-1 plus DTX or postoperative S-1 alone [
23].
Chemotherapy was to be started within 6 postoperative weeks. Patients assigned to the S-1 plus docetaxel group were treated with S-1 on days 1 to 14 of a 3-week cycle during the first course. In the second to seventh courses, patients received intravenous infusion of DTX on day 1 of each cycle and S-1 on days 1 to 14 of a 3-week cycle. From the eighth course, treatment with S-1 continued on days 1 to 28 of 6-week cycles for up to 1 year. Patients assigned to the S-1 group were treated with S-1 every 6-week cycle for up to 1 year. The primary endpoint was 3-year RFS.
The interim analysis of RFS proved the superiority of the S-1 plus DTX (HR 0.632; 99.99% CI: 0.400–0.998; p < 0.001), with a 3-year RFS of 66% (95% CI: 59–73%) in the S-1 plus DTX group and 50% (95% CI: 41–58%) in the S-1 group. Median RFS was not reached in the S-1 plus DTX group, whereas in the S-1 group, it was 34.5 months (95% CI: 29.5 months—not reached).
The S-1 plus DTX group had a higher incidence of grades 3 or 4 toxicities, especially neutropenia and leukopenia, than the S-1 group, but all toxicities were manageable.
2.1.4. The ARTIST 2 Study
In North America, the Intergroup-0116 study [
24] reported the effectiveness of adjuvant chemoradiotherapy. However, the effectiveness of chemoradiotherapy in patients who underwent gastrectomy with D2 lymph node dissection remains controversial, despite positive data being reported [
25]. This study compared three adjuvant regimens: oral S-1 for 1 year, S-1 plus oxaliplatin (SOX) for 6 months, and SOX plus radiotherapy 45 Gy (SOXRT) in a 1:1:1 ratio [
26]. The primary endpoint was 3-year DFS; a 33% reduction in the HR for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful.
In this study, 546 patients were randomly assigned to either the S-1, SOX, or SOXRT group. After a median follow-up of 47 months, the 3-year DFS rates were 64.8, 74.3, and 72.8% in the S-1, SOX, and SOXRT groups, respectively. HR for DFS in the control arm (S-1 group) was lower than that in the SOX and SOXRT groups: S-1 versus SOX, 0.692 (p = 0.042); S-1 versus SOXRT, 0.724 (p = 0.074). There was no statistical difference in DFS between SOX and SOXRT (HR 0.971; p = 0.879). The regimens were generally well tolerated, and adverse events were manageable.
This study showed the efficacy of SOX or SOXRT in patients who underwent curative gastrectomy with D2 lymph node dissection, specifically those with pStage II or III node-positive GC. However, this study did not confirm the efficacy of radiotherapy.
2.1.5. Final Notes
Postoperative adjuvant chemotherapy can improve the cure rate after resection and is, thus, recommended for pStage II to III. Although combination therapy is recommended for pStage III, it is not clear what therapy is more effective because there is no direct comparison of the three regimens (S-1/docetaxel, SOX, and XELOX).
Table 1.
Pivotal randomized controlled clinical trial for postoperative chemotherapy in East Asia.
Table 1.
Pivotal randomized controlled clinical trial for postoperative chemotherapy in East Asia.
Study | N | Published Year | Area | Setting | Disease Type | Recommended Resection | Treatment | Survival | HR | Reference |
---|
ACTS-GC | 530 | 2007 | Japan | Stage II/III | gastric cancer 100% | D2 | Surgery alone | 5-year OS: 61% | 0.669 | [12,13] |
529 | AC 100% | S-1 | 5-year OS: 72% |
CLASSIC | 515 | 2014 | Korea | Stage II/IIIB | gastric cancer 98%,GEJ 2% | D2 | Surgery | 5-year OS: 69% | 0.66 | [15,16] |
520 | AC 100% | XELOX | 5-year OS: 78% |
JACCRO GC-07 | 459 | 2019 | Japan | Stage III | gastric cancer 100% | D2 | S-1 | 3-year RFS:50% | 0.632 | [23] |
454 | AC 100% | S-1 + DTX | 3-year RFS:66% |
ARTIST 2 | 182 | 2021 | Korea | Stage II/III | gastric cancer 100% | D2 | S-1 | 3-year DFS:65% | - | [26] |
181 | SOX | 3-year DFS:74% | 0.692 |
AC 100% |
183 | SOX + RT (45 Gy) | 3-year DFS:73% | 0.724 |
Table 2.
Postoperative chemotherapy regimens in East Asia.
Table 2.
Postoperative chemotherapy regimens in East Asia.
Regimen | Frequency | Drug | Dose | Period |
---|
S-1 | 6 weeks | S-1 | 40–80 mg/body, twice daily | days 1–28 | every 6 weeks for 1 year |
XELOX (CapeOx) | 3 weeks | Capecitabine | 1000 mg/m2, twice daily | days 1–14 | 8 cycles |
Oxaliplatine | 130 mg/m2 | day 1 |
S-1 + DTX | (1) 3 weeks | S-1 | 40–80 mg/body, twice daily | days 1–14 | 1 cycle |
(2) 3 weeks | S-1 | 40–80 mg/body, twice daily | days 1–14 | 6 cycles |
Docetaxel | 40 mg/m2 | day 1 |
(3) 6 weeks | S-1 | 40–80 mg/body, twice daily | days 1–28 | every 6 weeks for total 1 year |
SOX | 3 weeks | S-1 | 40–80 mg/body, twice daily | days 1–14 | 8 cycles |
Oxaliplatine | 130 mg/m2 | day 1 |
SOX + RT | (1) 3 weeks | S-1 | 40–80 mg/body, twice daily | days 1–14 | 2 cycles |
Oxaliplatine | 130 mg/m2 | day 1 |
(2) 5 weeks | S-1 | 40–80 mg/body, twice daily | 5 days a week, over 5 weeks |
Radiotherapy | 45 Gy/25 Fr |
(3) weeks | S-1 | 40–80 mg/body, twice daily | days 1–14 | 4 cycles |
Oxaliplatine | 130 mg/m2 | day 1 |
2.2. Neoadjuvant Chemotherapy in East Asia (Table 3 and Table 4)
As mentioned above, postoperative chemotherapy is the standard treatment in East Asia.
On the other hand, neoadjuvant chemotherapy (NAC) has also been investigated, and the results are reported below.
2.2.1. JCOG0501
Even with standard perioperative therapy and curative surgery, GCs with linitis plastica (Borrmann type 4) and large ulcero-invasive-type (≥8 cm, Borrmann type 3) have a very poor prognosis. JCOG0501 is a randomized phase III study conducted to evaluate the survival benefit of neoadjuvant (preoperative) chemotherapy of SP (S-1 + CDDP) for postoperative S-1 in resectable type 4 and large type 3 GCs in Japan [
27].
Patients assigned to Arm A underwent total or distal gastrectomy with D2 or D3 lymph node dissection. Patients in Arm B received preoperative chemotherapy with SP (S-l administered for the first 3 weeks of a 4-week course, and Cisplatin administered on day 8 of each course). All patients who underwent curative gastrectomy received postoperative chemotherapy with S-1 orally on days 1–28 of each 6-week cycle for 1 year.
A total of 300 patients were enrolled in this study. The 3-year OS rates were 62.4% (95% CI: 54.1–69.6) in Arm A and 60.9% (95% CI: 52.7–68.2) in Arm B. The HR in Arm B, as compared with Arm A, was 0.916 (95% CI: 0.679–1.236).
For Borrmann type 4 or large type 3 GC, the addition of preoperative chemotherapy with SP did not show a survival benefit. The
Japanese Gastric Cancer Treatment Guidelines do not recommend neoadjuvant chemotherapy, and still continue to recommend D2 gastrectomy followed by postoperative chemotherapy [
28].
2.2.2. PRODIGY
This study was conducted to evaluate whether neoadjuvant (preoperative) docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant (postoperative) S-1 could improve outcomes versus standard treatment (surgery and adjuvant S-1) in patients with resectable GC in Korea [
29].
Patients with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma (clinical TNM staging: T2-3N1 or T4N any) were enrolled. They were randomly assigned to either D2 surgery followed by adjuvant S-1 (SC group) or neoadjuvant DOS before D2 gastrectomy, followed by adjuvant S-1 (CSC group). The primary endpoint was PFS.
In this study, 266 patients were assigned to either the SC group or the CSC group. After a median follow-up of 38.6 (interquartile range, 23.5–62.1) months, PFS was significantly longer in the CSC (HR for PFS adjusted for stratification factors, 0.70; 95% CI: 0.52–0.95; stratified log-rank p = 0.023). The 3-year PFS rates were 66.3% (95% CI: 59.6–72.1) with CSC and 60.2% (95% CI: 53.6–66.3) with SC. Two Grade 5 adverse events (febrile neutropenia and dyspnea) occurred during neoadjuvant chemotherapy. Other than that, treatments were well tolerated.
This study showed the effectiveness of neoadjuvant DOS in Korea.
2.2.3. RESOLVE
This study was conducted to evaluate the efficacy of perioperative (preoperative and postoperative) SOX (S-1 + oxaliplatin) compared with adjuvant (postoperative) CapeOX (Capecitabine + oxaliplatin) in patients with resectable GC undergoing gastrectomy with D2 lymph node dissection in China [
30].
This study enrolled patients with histologically confirmed cT4a, N+, M0 or cT4b, N any, M0 gastric or gastroesophageal junction adenocarcinoma who underwent D2 gastrectomy. Patients were randomly assigned (1:1:1) to receive postoperative CapeOX (eight cycles), postoperative SOX (eight cycles), or perioperative SOX (three preoperative cycles and five postoperative cycles followed by three cycles of S-1 monotherapy). The primary endpoint was 3-year DFS to assess the potential superiority of perioperative SOX compared with postoperative SOX and the non-inferiority of postoperative SOX compared with postoperative CapeOX.
A total of 1022 patients were enrolled and randomly assigned to either the postoperative CapeOX group, the postoperative SOX group, or the perioperative SOX group. Three-year DFS was 51.1% (95% CI: 45.5–56.3) in the postoperative CapeOX group, 56.5% (95% CI: 51.0–61.7) in the postoperative SOX group, and 59.4% (95% CI: 53.8–64.6) in the perioperative SOX group. The HR was 0.77 (95% CI: 0.61–0.97; Wald p = 0.028) for the perioperative SOX group compared with the postoperative CapeOX group and 0.86 (95% CI: 0.68–1.07; Wald p = 0.17) for the postoperative SOX group compared with the postoperative CapeOX group.
Perioperative SOX showed clinically meaningful benefits compared with postoperative CapeOX, and postoperative SOX was non-inferior to postoperative CapeOX.
Table 3.
Pivotal randomized controlled clinical trial for neoadjuvant chemotherapy in East Asia.
Table 3.
Pivotal randomized controlled clinical trial for neoadjuvant chemotherapy in East Asia.
Study | N | Published Year | Area | Setting | Disease Type | Recommended Resection | Treatment | Survival | HR | Reference |
---|
JCOG 0501 | 149 | 2021 | Japan | Borrmann type 3 (≧8 cm) | gastric 100% | D2/3 | NAC SP → Adj S-1 | 3-year OS: 62% | 0.916 | [27] |
151 | Borrmann type 4 | AC 100% | Adj S-1 | 3-year OS: 61% |
PRODIGY | 238 | 2021 | Korea | Stage II/III | gastric 94%,GEJ 6% | D2 | NAC DOS → Adj S-1 | 3-year PFS: 66% | 0.69 | [29] |
246 | AC 100% | Adj S-1 | 3-year PFS: 60% |
RESOLVE | 337 | 2021 | China | Stage III | gastric 64%, GEJ 36% | D2 | Perioperative SOX | 3-year DFS:59% | 0.77 | [30] |
340 | Adj SOX | 3-year DFS: 56% |
AC 100% | 0.86 |
345 | Adj Capox | 3-year DFS:51% | ⁻ |
Table 4.
Neoadjuvant chemotherapy regimens in East Asia.
Table 4.
Neoadjuvant chemotherapy regimens in East Asia.
Study | Regimen | Frequency | Drug | Dose | Period |
---|
JCOG0501 | SP | 4 weeks | S-1 | 40–80 mg/body, twice daily | days 1–21 | Preoperative; 2 cycles |
Cisplatine | 60 mg/m2 | day 8 |
S-1 | 6 weeks | S-1 | 40–80 mg/body, twice daily | days 1–28 | Postoperative; every 6 weeks for 1 year |
PRODIGY | DOS | 3 weeks | Docetaxel | 50 mg/m2 | day 1 | Preoperative; 3 cycles |
Oxaliplatine | 100 mg/m2 | day 1 |
S-1 | 40–80 mg/body, twice daily | days 1–14 |
S-1 | 6 weeks | S-1 | 40–80 mg/body, twice daily | days 1–28 | Postoperative; every 6 weeks for 1 year |
RESOLVE | SOX | 3 weeks | Oxaliplatine | 130 mg/m2 | day 1 | Preoperative; 3 cycles |
S-1 | 40–80 mg/body, twice daily | days 1–14 | Postoperative; 5 cycles |
S-1 | 3 weeks | S-1 | 40–80 mg/body, twice daily | days 1–14 | After above; 3 cycles |
2.2.4. Final Notes
As mentioned above, perioperative chemotherapy is also being evaluated in East Asia.
In China, the RESONANCE trial, a phase III study, using SOX as NAC for clinical stages (cStage) IIA-IIIC, reported that 67.8% of patients receiving NAC showed pathological efficacy, and 23.6% showed complete response without significant differences in short-term surgical outcomes [
31].
Treatment strategies may further change depending on the results of other ongoing studies.