Updated Adjuvant Chemotherapy for Gastric Cancer

Surgical resection is currently the best curative approach for gastric cancer (GC); however, the prognosis of patients with advanced GC remains poor even with curative resection. For this reason, perioperative chemotherapy has been combined with surgery to reduce the risk of postoperative recurrence. Standard perioperative chemotherapy for resectable advanced GC varies from region to region. Postoperative S-1 therapy was standardized via the ACTS-GC study in East Asia, perioperative ECF (Epirubicin + Cisplatin + Fluorouracil) was standardized via the MAGIC study in Europe, and postoperative chemoradiotherapy was standardized via the US intergroup study in North America. Since then, more intensive regimens have been developed. In recent years, perioperative therapy using novel agents, such as molecular-targeted drugs and immune checkpoint inhibitors (ICIs), has also been tested and evaluated in the three major regions (East Asia, Europe, and North America) with promising results. Perioperative chemotherapy has become an integral part of many treatment strategies and requires continued research and evaluation.


Introduction
GC is a highly malignant cancer with high morbidity and mortality rates worldwide.With more than 1 million newly diagnosed cases, GC remains the leading cause of cancer death every year [1].
Surgical resection is currently the most reliable curative approach for GC.Although improvements in surgical techniques and perioperative care have led to decreased surgical morbidity and mortality, the prognosis of patients with advanced GC remains poor even after complete resection [2,3].The reason is that minimal residual disease (MRD) can remain in the body even after curative resection.Patients with MRD have a high probability of disease recurrence.
Recently, circulating tumor DNA (ctDNA) has been recognized as an important biomarker to assess the recurrence risk of bladder, breast, and colorectal cancers [4][5][6][7].Postoperative ctDNA can be considered an MRD biomarker offering useful prognostic information regarding recurrence [8].It has also been reported that ctDNA may be involved in the recurrence of resectable GC [9][10][11].However, ctDNA assays have not been established in actual clinical practice and need to be further developed and streamlined.
Perioperative chemotherapy has been used worldwide since the 2000s to minimize the risk of recurrence by eliminating MRD.
In recent years, various clinical trials have been conducted in all regions to improve survival by enhancing perioperative chemotherapy.
This article summarizes the perioperative chemotherapy approaches by region.

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.
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 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.

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 nodepositive GC.However, this study did not confirm the efficacy of radiotherapy.

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).3 and 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.

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.
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].

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.
This study showed the effectiveness of neoadjuvant DOS in Korea.

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.
Perioperative SOX showed clinically meaningful benefits compared with postoperative CapeOX, and postoperative SOX was non-inferior to postoperative CapeOX.

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.

Europe
3.1.Perioperative Chemotherapy in Europe (Tables 5 and 6) The European Society for Medical Oncology (ESMO) clinical practice guidelines suggest gastrectomy with D2 lymph node dissection be performed and recommend perioperative chemotherapy preferentially for patients with stage IB-III GC.
This section summarizes pivotal clinical trials on perioperative chemotherapy in Europe.

MAGIC
A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) has been reported to improve survival in patients with incurable locally advanced or metastatic GC in Europe [32][33][34].However, numerous phase III trials at these times did not show the survival benefits of adjuvant chemotherapy.
The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial was conducted to prove the efficacy of perioperative ECF for patients with potentially resectable GC [35].
This study enrolled patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus.A total of 503 patients were randomly assigned to either the perioperative ECF group or the surgery-only group.The ECF regimen consisted of a 3-week cycle of intravenous epirubicin and cisplatin on day 1, plus continuous intravenous infusion of fluorouracil on days 1 to 21. Patients assigned to the ECF group received three preoperative and three postoperative cycles of ECF.The primary endpoint was OS.
This study showed a significant improvement in OS in the perioperative ECF group compared to the surgery-only group (HR for death, 0.75; 95% CI: 0.60-0.93;p = 0.009; 5-year survival rate, 36% vs. 23%), as well as an improvement in PFS (HR for progression, 0.66; 95% CI: 0.53-0.81;p < 0.001).The resected tumors were smaller and less advanced in the perioperative ECF group.The adverse effects of ECF were similar to those previously reported among patients with locally advanced and metastatic GC.
Based on the results of this study, ECF has become the standard of perioperative chemotherapy in Europe.

FLOT4
ECF regimens have been considered standard perioperative chemotherapy.However, the overall survival rate is not satisfactory.Docetaxel has shown efficacy in metastatic GC, both first-line (docetaxel, cisplatin, and fluorouracil (DCF)) [22] and second-line (docetaxel monotherapy) therapy [36].However, the parental DCF regimen was associated with high toxicity, so a regimen was developed to replace cisplatin with oxaliplatin to reduce toxicities.The combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) was evaluated for locally advanced and metastatic GCs and gastroesophageal junction adenocarcinoma in several phase II studies, and showed that FLOT was better tolerated than DCF and induced stronger tumor response than other regimens, including anthracycline-based triplets [37][38][39][40][41][42].
FLOT4 was conducted to evaluate the efficacy of FLOT as a perioperative chemotherapy for patients with locally advanced, resectable GC [43].This study enrolled patients with histologically confirmed advanced clinical stage cT2-4 or nodal positive stage (cN+), or both, resectable tumors, with no evidence of distant metastases (cM0).Patients were randomly assigned to either the ECF/ECX group (three preoperative and three postoperative 3-week cycles of epirubicin and cisplatin on day 1 plus either fluorouracil or capecitabine on days 1 to 21) or the FLOT group (four preoperative and four postoperative 2-week cycles of docetaxel, oxaliplatin, leucovorin, and fluorouracil as a 24 h infusion on day 1).The primary endpoint was OS.
A total of 716 patients were randomly assigned to either the ECF/ECX group or the FLOT group.OS improved in the FLOT group compared with the ECF/ECX group (HR 0.77 (95% CI: 0.63-0.94);median OS, 50 months (38.33 to not reached) vs. 35 months (27.35 to 46.26)).The number of patients with related serious adverse effects was similar in the two groups (27% in the ECF/ECX group vs. 27% in the FLOT group).Hospitalization for toxicities was necessary in 26% of ECF/ECX patients and 25% of FLOT patients.
FLOT improved OS without increasing perioperative complications compared with perioperative ECF/ECX in resectable gastric or gastroesophageal junction adenocarcinoma.

Final Notes
Perioperative chemotherapy using triplet regimens (fluorinated pyrimidines, platinum, and taxanes) is the standard treatment in Europe.However, ESMO guidelines recommend postoperative chemotherapy or chemoradiotherapy for patients who undergo gastrectomy without preoperative therapy [33].Postoperative chemotherapy has been adopted in Europe based on the results of the ACTS-GC and CLASSIC studies.Although chemoradiotherapy has been established in North America, the ESMO guidelines indicate it is only for suboptimal surgery with less lymphadenectomy and suspicious micrometastases [44,45].

North America
4.1.Chemoradiotherapy in North America (Tables 7 and 8) Postoperative chemotherapy in East Asia and preoperative chemotherapy in Europe have been considered the standard treatments, but postoperative chemoradiation therapy has been considered the standard in North America.
The National Comprehensive Cancer Network (NCCN) guidelines agree that gastrectomy with D2 lymph node dissection is associated with low mortality and reasonable survival benefits.However, the NCCN guidelines recommend gastrectomy with D1 or modified D2 lymph node dissection and also emphasize that D2 lymph node dissection should be performed only by experienced surgeons because of its technical difficulty [46,47].
Therefore, different perioperative treatments are recommended in North America compared to other regions.This section summarizes the situation with a focus on postoperative chemoradiotherapy.The curative treatment for GC is resection, but most patients were not successfully treated via surgery alone in the 1990s in North America.This study was designed to prove the efficacy of postoperative chemoradiotherapy for patients with resectable adenocarcinoma [24].
A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomized to the surgery plus postoperative chemoradiotherapy group or the surgery-only group.The adjuvant treatment consisted of fluorouracil plus 20 mg/m 2 /day of leucovorin, for five days, followed by 4500 cGy of radiation at 180 cGy/day, administered five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and last three days of radiotherapy.
One month after the completion of radiotherapy, two five-day cycles of fluorouracil plus leucovorin were administered one month apart.
In a later updated analysis, this study demonstrated strong persistent benefits from postoperative chemoradiotherapy [48].This study established postoperative chemoradiotherapy in North America.The NCCN guidelines now recommend it only for patients who undergo gastrectomy with less than a D2 lymph node dissection [49].

Final Notes
Postoperative chemoradiotherapy was established in North America and is still recommended in certain cases.Perioperative chemotherapy is also recommended, according to the results of the FLOT4 study [43].Regarding postoperative chemotherapy, the NCCN guidelines state that it is difficult to apply the results of the ACTS-GC and CLASSIC studies because gastrectomy with D2 lymph node dissection is rarely performed in North American hospitals [50].Postoperative chemotherapy with XELOX is included only as an option for patients who undergo D2 or modified D2 lymph node dissection [51].In North America, perioperative treatment is selected based on the circumstances described above.

New Agents for Adjuvant Chemotherapy
In recent years, new drugs such as molecular-targeted drugs and ICIs have improved the prognosis of GC [52][53][54][55].Next, we summarize the trials of perioperative treatment using these agents.Many of these trials were designed around existing regimens containing fluoropyrimidines, platinum, and taxanes.Also, unlike previous trials, these were conducted across multiple regions.
5.1.Molecular-Targeted Drugs (Table 9) The RAMSES-AIO study examined the utility of a trial treatment adding ramucirumab to perioperative FLOT therapy [56].The results suggested that the addition of ramucirumab may increase the R0 resection rate.
The PETRARCA-AIO study examined the addition of trastuzumab to conventional FLOT for HER2-positive cancer, and the results suggested an increase in pCR and nodal negativity rates [57].
EORTC also conducted the INNOVATION study to verify the efficacy of perioperative chemotherapy, comparing XP/FP only to experimental treatments with the addition of trastuzumab or trastuzumab and pertuzumab for HER2-positive GC [58].

Immune Checkpoint Inhibitors (Table 10)
The usefulness of immune checkpoint inhibitors has been tested in perioperative treatment as well as in palliative chemotherapy.
The KEYNOTE 585 study evaluated the addition of pembrolizumab to perioperative XP/FP/FLOT [59], and the MATTERHORN study evaluated the addition of durvalumab to perioperative FLOT [60].
In addition, the DANTE study examined the benefits of adding atezolizumab to perioperative FLOT [61].
The results of these clinical trials are expected to change future treatment strategies for GC.

Conclusions
The perioperative treatment of GC has undergone significant development in various regions since the 2000s.Perioperative regimens were initially established by drawing from the treatment protocols used for metastatic GC.Consequently, treatment advancements began with S-1 in East Asia and ECF in Europe.Variations in surgical techniques may have also influenced the intensity of chemotherapy, including whether doublet or triplet regimens were employed, as well as the incorporation of radiation therapy.Particularly, in East Asia, more trials have been conducted than in other regions due to the large number of GCs.In this way, perioperative chemotherapy has evolved independently in each region.Now, perioperative chemotherapy based on fluorinated pyrimidines with added platinum and taxanes has been established in all regions with improved outcomes.Perioperative therapy using novel agents has also been tested and evaluated in the three major regions with promising results.Perioperative chemotherapy has become an integral part of many treatment strategies and requires continued research and evaluation.

Table 1 .
Pivotal randomized controlled clinical trial for postoperative chemotherapy in East Asia.

Table 2 .
Postoperative chemotherapy regimens in East Asia.

Table 3 .
Pivotal randomized controlled clinical trial for neoadjuvant chemotherapy in East Asia.

Table 4 .
Neoadjuvant chemotherapy regimens in East Asia.

Table 5 .
Pivotal randomized controlled clinical trial for perioperative therapy in Europe.

Table 6 .
Perioperative chemotherapy regimens in Europe.

Table 7 .
Pivotal randomized controlled clinical trial for postoperative chemoradiotherapy in North America.

Table 8 .
Chemoradiotherapy regimen in North America.

Table 9 .
New agents for adjuvant chemotherapy/Molecular-targeted drugs.

Table 10 .
New agents for adjuvant chemotherapy/Immune checkpoint inhibitors.