| Treatment | Stratification* | Grade I recommendations | Grade II recommendations | Grade III recommendations |
|---|---|---|---|---|
| Neoadjuvant therapy e, f | Non‐EGJ gastric cancer: cT3‐4aN+M0, stage cIII | Neoadjuvant chemotherapy: SOX regimen (Evidence 1A) | Neoadjuvant chemotherapy:
|
Neoadjuvant chemotherapy:
|
| Gastric cancer invading the EGJ: cT3‐4aN+M0, stage cIII | Neoadjuvant chemoradiotherapy: DT 45‐50.4 Gy (concurrent 5‐fluorouracil, platinum or taxanes) (Evidence 1B) | Neoadjuvant chemotherapy:
|
Neoadjuvant Radiotherapy (patients unsuitable for chemotherapy) (Evidence 2B) | |
| Neoadjuvant therapy e | cT4bNanyM0, stage cIVA (without non‐resectable factors) | MDT discussion for optimal personalized treatment |
|
Encourage participation in clinical trials |
| R1/R2 resection after neoadjuvant therapy | MDT discussion for optimal personalized treatment | Encourage participation in clinical trials | ||
| Localized disease progression after neoadjuvant therapy | MDT discussion for optimal personalized treatment | Encourage participation in clinical trials |
Abbreviations: AJCC/UICC, American Joint Cancer Committee/Union Internationale Contre le Cancer; cTNM, clinical tumor‐node‐metastasis; EGJ, esophagogastric junction; DT, dose of therapy; SOX, S‐1 and oxaliplatin; MDT, Multidisciplinary Team; FOLFOX, folinic acid (leucovorin), 5‐fluorouracil (5‐FU), and oxaliplatin; XELOX, capecitabine (Xeloda) and oxaliplatin (Eloxatin); DOS, docetaxel, oxaliplatin and S‐1; FLOT4, 5‐fluorouracil, leucovorin, oxaliplatin, docetaxel‐4.
According to the 8th AJCC/UICC clinical staging system (cTNM) for gastric cancer
Notes
Adjuvant treatment for resectable gastric cancer
There are several large phase III clinical trials supporting the use of adjuvant chemotherapy for patients who have undergone D2 radical gastrectomy [80, 81, 82, 83]. The indications of adjuvant chemotherapy for resectable gastric cancer are D2 radical gastrectomy and no prior neoadjuvant therapy for stage pII/III patients. For stage II patients, the recommended regimen is S‐1 (oral till 1 year after operation) or capecitabine combined with oxaliplatin [80, 81]. In the JACCRO GC‐07 study [82, 84], the investigators found that S‐1+docetaxel (oral S‐1 on days 1‐14 with 7 days of rest followed by 6 cycles of S‐1 combined with docetaxel on day 1 of each cycle, then 4 further cycles of S‐1 on days 1‐28 every 42 days) was associated with improved survival of patients with stage III gastric cancer compared to S‐1 monotherapy (3‐year recurrence‐free survival [RFS] rate: 65.9% vs. 49.6%, P = 0.0007) and suppressed all types of recurrences, including hematogenous, lymphatic and peritoneal recurrences. The RESOLVE trial [85] showed that for locally advanced cT4a/N+M0 or cT4b/NxM0 gastric cancer, adjuvant S‐1 plus oxaliplatin (SOX) was not inferior to adjuvant capecitabine plus oxaliplatin (XELOX) (3‐year disease‐free survival [DFS] rate: 60.3% vs. 54.8%, P = 0.162). The ARTIST‐II trial [86] enrolled 900 stage II/III gastric cancer patients with positive lymph nodes who underwent D2 radical gastrectomy and investigated the curative effects of 1‐year S‐1 monotherapy versus 6‐month SOX chemotherapy versus SOX chemotherapy plus radiotherapy (SOXRT). The results showed that compared to S‐1 monotherapy, adjuvant SOX or SOXRT could significantly prolong DFS, but compared to adjuvant SOX regimen, adjuvant SOXRT had no additional survival benefit. In recent years, there have been studies investigating the applicability of survival prediction models, such as nomograms, based on tumor and patient characteristics to evaluate the survival benefits of individualized adjuvant chemotherapy for stage II/III gastric cancer. Wang et al. [87] reviewed the data of 1,464 pT3‐4 or N+ gastric cancer patients who received adjuvant fluoropyrimidine plus oxaliplatin (F‐OX) after D2 gastrectomy at three major centers across China. The results showed that, compared to the 7th AJCC gastric cancer classification, the nomogram was superior in stratifying patients for predicting benefit from F‐OX. Using the nomogram, patients in the low‐risk group had no improvement in survival with F‐OX, while for those classified in the intermediate‐ and high‐risk groups, F‐OX could reduce the risk of death by over 20%; thereby, the nomogram could more accurately guide the selection of gastric cancer patients who would benefit from F‐OX adjuvant chemotherapy.
At present, it is not clear whether patients with stage pI gastric cancer would benefit from adjuvant chemotherapy. It is suggested for stage pI patients with high‐risk factors, such as younger age (<40 years old), high histological grade or low differentiation, and nervous plexus, vascular or lymphatic invasion, investigational treatment can be offered.
For resectable gastric cancer, the results of phase III clinical studies investigating the efficacy of chemoradiotherapy after radical surgery were different in the East and the West. The INT0116 study [88], from the US, confirmed that concurrent radiotherapy and 5‐fluorouracil (5‐FU) chemotherapy after surgery improved OS compared to surgery alone, but the surgery performed was mainly D0/D1 gastrectomy, while in countries such as China, Korea and Japan, mostly D2 gastrectomy is performed. The ARTIST study [89] from South Korea, which compared 6 cycles of adjuvant capecitabine plus cisplatin (XP) versus 2 cycles of XP followed by concurrent capecitabine combined with RT (XP/XRT/XP) plus 2 additional cycles of XP in gastric cancer patients after D2 R0 gastrectomy, found no significant reduction in recurrence between the two therapies in the overall population (3‐year DFS rates, XP/XRT/XP arm: 78.2% vs. XP arm: 74.2%; P = 0.0862), but in subgroup analysis of patients with positive pathologic lymph nodes, patients from the XP/XRT/XP arm had superior DFS than the XP arm (3‐year DFS rate: 77.5% vs. 72.3%, P = 0.0365). However, the ARTIST‐II study [86], performed in patients with D2‐resected, stage II/III, node‐positive gastric cancer, did not confirm that the combination of the SOX regimen with radiotherapy improves survival. Thus, for resectable patients who can undergo R0 and D2 resection, adjuvant chemoradiotherapy is not recommended unless they are diagnosed with advanced pathological stage and associated with high‐risk factors, including insufficient dissection distance from tumor margin (<2 cm), vascular tumor thrombus, perineural invasion, N3 or metastatic lymph node ratio >25%, then, after systemic therapy adjuvant radiotherapy could be considered. For those who did not achieve R0 resection (without distant metastasis), adjuvant chemoradiotherapy [90] or MDT discussion is recommended.
At present, adjuvant chemotherapy for gastric cancer invading the EGJ is mostly based on the findings of studies from Asia. Among four large‐scale phase III clinical studies, the rate of EGJ‐gastric cancer was 23.4% in the JACCOR GC‐07 study [82, 84], 4.8% in the ARTIST study [81], 2.3% in the CLASSIC study [80], and 1.4% in the ACTS‐GC study [91]. However, there is still a lack of randomized controlled trials investigating the significance of adjuvant chemotherapy or chemoradiotherapy for EGJ carcinoma.
Preoperative and perioperative chemotherapy for advanced gastric cancer
Perioperative therapy (neoadjuvant chemoradiotherapy + surgery + adjuvant chemotherapy/chemoradiotherapy) for gastric cancer has been proven to be superior to surgery alone in Western countries as it could downstage the tumor, increase the rate of radical resection, and improve survival whilst not increasing the risks of postoperative complications and deaths [92, 93]. Also, neoadjuvant chemotherapy prior to radical gastrectomy in Asian studies has been associated with significantly improved tumor remission rates, R0 resection rates, and treatment safety [94, 95]. The survival benefits of perioperative chemo‐/radiotherapy, as compared with postoperative chemotherapy after radical D2 gastrectomy, remain to be determined in large phase III clinical trials. The RESOLVE study [85], a large‐cohort randomized controlled phase III clinical study led by Chinese investigators aiming at comparing the efficacy and safety of adjuvant XELOX (arm A) or adjuvant SOX (arm B) after D2 radical gastrectomy against perioperative SOX (neoadjuvant SOX followed by 5 cycles of adjuvant SOX and 3 cycles of S‐1; arm C) in locally advanced gastric cancer patients, found that perioperative SOX was superior to adjuvant XELOX (3‐year DFS rate: 62.0% vs. 54.8%, P = 0.045) for locally advanced gastric cancer at stage cT4a/N+M0 or cT4a/NxM0 while adjuvant SOX was non‐inferior to adjuvant XELOX (3‐year DFS rate: 60.3% vs. 54.8%, P = 0.162). Therefore, 3 cycles of neoadjuvant SOX chemotherapy and 5 cycles of adjuvant SOX followed by 3 cycles of S‐1 monotherapy is recommended as the perioperative treatment for locally advanced gastric cancer. In addition, during the same period, the PRODIGY study [96] reported that for locally advanced gastric cancer staged as cT2/3N+M0 or cT4/NxM0, 3 cycles of neoadjuvant docetaxel plus oxaliplatin plus S‐1 (DOS) chemotherapy plus 8 cycles of postoperative S‐1 monotherapy, compared to surgery followed by 8 cycles of S‐1 monotherapy, was associated with tumor downstaging and significant improvement in 3‐year DFS. The 2022 MATCH study demonstrated that in preoperative neoadjuvant treatment, the major pathologic response (MPR) rates for the DOS group and SOX group were 25.45% and 11.8%, respectively, and the corresponding R0 resection rates were 78.9% and 61.8%, with 3‐year progression‐free survival (PFS) rates of 52.3% and 35%, respectively [97]. Thus, the DOS regimen can be recommended for preoperative chemotherapy in gastric cancer.
Currently, the recommended neoadjuvant chemotherapy regimens for gastric cancer include XELOX [98], FOLFOX [99], cisplatin combined with S‐1 (SP) [100], and SOX [101]. Results of the large prospective phase III FLOT4‐AIO study [102] showed that compared with epirubicin plus cisplatin (ECF)/epirubicin plus cisplatin and capecitabine (ECX) regimen, the docetaxel combined with oxaliplatin, leucovorin and 5‐FU (FLOT) regimen was associated with improved 3‐year OS and DFS and had higher pathological response rate and R0 resection rate. Therefore, the FLOT regimen can also be used as the recommended regimen for preoperative chemotherapy of gastric cancer. In recent years, there have been studies on neoadjuvant anti‐HER2 treatment for HER2‐positive gastric cancer and chemotherapy plus immunotherapy for HER2‐negative gastric cancer. However, the sample sizes in these studies are small, and the evidence level is low. Thus, there is no sufficient evidence for standard recommendations. Therefore, we prioritize recommending these patients to participate in clinical trials. For patients with dMMR status, the use of immunotherapy in the neoadjuvant and adjuvant settings is an emerging trend. Both the GERCOR NEONIPIGA study [103] and the INFINITY study [104] have reported promising results, showing pathologic complete response (pCR) rates of 59% and 60%, respectively, when PD‐1/PD‐L1 antibodies were combined with cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) antibodies in neoadjuvant treatment. There is also ongoing research on neoadjuvant immunotherapy in combination with chemotherapy and radiotherapy for pMMR gastric cancer. However, data from these studies is currently insufficient for drawing definitive conclusions. The DANTE study [105], which has the largest sample size, confirmed that the addition of atezolizumab to FLOT chemotherapy can improve tumor regression compared to FLOT alone, with pCR rates of 24% and 15%, respectively. Notably, the pCR rate for MSI‐H patients was promising, at 63%. Therefore, it is advisable to prioritize the inclusion of these patients in clinical trials to further explore and optimize treatment options.
Results of the international multicenter CRITICS study [106] showed that compared with adjuvant chemotherapy alone, adjuvant chemoradiotherapy did not improve survival for stage IB‐IVA resectable gastric cancer or EGJ cancer patients who received neoadjuvant epirubicin, cisplatin or oxaliplatin, and capecitabine (ECC/EOC) chemotherapy followed by curative intent gastrectomy with adequate lymph node dissection (D1+ accounted for 86% of the study population). However, the completion rate of the study was only 50%, and 60% of the investigated cohort were stage I‐II patients. As such, the local control rate of radiotherapy could not be fully determined and decreased its clinical referential value.
For gastric cancer patients with T4b disease and without unresectable factors, based on current research evidence [107, 108, 109], the following points could be considered as treatment options: 1) R0 resection is an independent prognostic factor for survival; 2) the rate of complications after combined organ resection is very high, close to 40%, among which pancreatoduodenectomy is the highest risk procedure; 3) surgery for peripheral organ involvement is very complex, and it is difficult to formulate a standard treatment principle. Therefore, it is suggested that such cases should undergo MDT discussion for an individualized treatment plan. Further, neoadjuvant therapy could improve the R0 resection rate and can be used as a treatment option. For patients who can achieve R0 resection, combined organ resection is acceptable, but combined pancreatoduodenectomy should be carefully assessed for risk and benefits.
A multinational individual patient data meta‐analysis [110] explored the associations of MSI status with postoperative prognosis and perioperative chemotherapy efficacy in patients with resectable gastric cancer enrolled in the CLASSIC [80], ARTIST [81], MAGIC [92] and ITACA‐S trials [111]. The results showed that for resectable dMMR/MSI‐H gastric cancer patients, the prognosis of patients who underwent only surgery was better than those who underwent surgery plus adjuvant chemotherapy. Currently, small sample size retrospective studies have shown that the prognosis of dMMR and MSI‐H patients was good but had conflicting results regarding the benefits of adjuvant chemotherapy [112]. Overall, considering the small proportion of the population in these studies, there is still some controversy to implement it in clinical practice. Taking adverse reactions related to chemotherapy and patients’ financial implications into account, it is suggested that for dMMR/MSI‐H patients, (neo)adjuvant treatments such as immunotherapy in clinical trial settings could be first considered, unless unwillingness from the patient's side, after detailed discussion with the patient and families about the risk and benefits of different treatment strategies, postoperative observation or chemotherapy can be considered.
For gastric cancer located in the middle to distal part of the stomach, the efficacy of preoperative chemoradiotherapy, especially the comparison of perioperative modes of chemotherapy, still needs to be verified by the ongoing phase III clinical trials. Several clinical trials are actively exploring the regimens of preoperative chemoradiotherapy for gastric cancer, such as the international multicenter TOPGEAR trial (NCT01924819) [113], Netherlandish CRITICS‐II study (NCT02931890) [114], the multicentral trial from Sun Yat‐sen University (NCT01815853) and the trial from the Cancer Hospital of the Chinese Academy of Medical Sciences (NCT04062058).
The efficacy of neoadjuvant therapy should be evaluated in a timely manner using EUS, CT, or PET/CT imaging modalities. Compared with CT and other non‐invasive imaging examinations, laparoscopic laparotomy can improve the diagnostic rates of occult metastasis within the abdominal cavity, including radiologically undetected small liver metastases. It can be carried out alongside a cytological examination of intraperitoneal washings [115]. As such, prior to neoadjuvant therapy (for T3‐4 or N+ cases), explorative laparoscopic staging and cytological examination of intraperitoneal washings are recommended.
For surgically resected specimens diagnosed as pCR after neoadjuvant therapy, it is recommended that the same neoadjuvant regimen be continued postoperatively. Till present, there is no sufficient evidence attributing to the survival differences between those who undergo different adjuvant regimens as to their initial neoadjuvant regimens or abstain from adjuvant therapies.
For patients who underwent neoadjuvant therapy and achieved R0 resection, if the preoperative imaging or pathological assessments showed improvement in shrinking the cancerous lesion, it is recommended that the same neoadjuvant regimen be continued postoperatively.
In case of disease progression following neoadjuvant therapy, surgery should be considered if R0 resection can be achieved. If not, the treatment protocol should be discussed via an MDT panel.
For patients who could not achieve R0 gastrectomy despite the absence of distant metastasis after neoadjuvant chemotherapy, either adjuvant chemoradiotherapy or MDT discussion is recommended. If neoadjuvant chemoradiotherapy was performed, the subsequent treatment should be discussed via an MDT panel, else palliative treatment is recommended.
Neoadjuvant treatment for EGJ cancer
The choice of perioperative treatment for EGJ cancer has some particularity because of the differences in clinical research designs and results between Eastern and Western countries. In clinical studies of postoperative adjuvant chemotherapy with positive results in multiple Asian countries, the proportion of patients with EGJ cancer included in the studies was very low, and although the overall population benefited from postoperative adjuvant chemotherapy in terms of survival, it is still uncertain whether patients with esophagogastric junction cancer in Asian countries can benefit from such treatment. Comparatively, in European clinical trials that investigated perioperative treatment for gastric cancer, the proportion of patients with EGJ cancer was higher, e.g., 60% in the FFCD study [116] and 56% in the FLOT4‐AIO study [102], suggesting that perioperative chemotherapy was indeed an effective treatment for patients with EGJ cancer in Western countries. In the RESOLVE study [85], EGJ cancer patients comprised 36.5% of the study population, suggesting that perioperative chemotherapy could also be an effective treatment in the Asian population.
For adenocarcinomas of the EGJ or squamous cell carcinoma in the middle to lower esophagus, clinical research supports neoadjuvant chemoradiotherapy followed by surgery and adjuvant chemotherapy to effectively achieve tumor downstaging, improve R0 resection rate and prolong OS, without increasing postoperative complications or mortality rates [117, 118], and it is considered the standard treatment. Long‐term follow‐up results from the German POET study [119], which involved neoadjuvant chemoradiotherapy combined with adjuvant chemoradiotherapy versus neoadjuvant chemotherapy for esophagogastric adenocarcinomas (Siewert I‐III), suggest a tendency towards reduced recurrence and prolonged survival compared to neoadjuvant chemotherapy alone, with no significant increase in treatment toxicity or perioperative complications. Multiple multicenter phase II clinical studies, including the US RTOG‐9904 trial [120], have demonstrated the favorable efficacy of preoperative chemoradiotherapy for locally advanced gastric cancer. As a result, the currently recommended indication for the treatment approach involving preoperative chemoradiotherapy followed by D2 surgery is stage III EGJ cancer. Synchronous chemotherapy regimens may include combinations of paclitaxel with fluoropyrimidines or platinum agents, as well as fluoropyrimidines with platinum agents.
Research on neoadjuvant chemotherapy and perioperative chemotherapy for esophageal or gastric adenocarcinoma (including EGJ) has been increasing and has yielded definitive results, categorizing it as Class I evidence. Similar to previously published studies like MAGIC [92], FLOT4‐AIO [102], EORTC40954 [121] and FFCD9703, recent Asian studies such as RESOLVE [85], PRODIGY [96] and RESONANCE [122] have included subsets of EGJ cancer patients. In the PRODIGY study [96], which included 5.6% EGJ cancer cases, neoadjuvant chemotherapy using the DOS regimen showed tumor‐shrinking effects, improved R0 resection rates and extended PFS. In the RESOLVE study [85], where EGJ cancer accounted for 36.5%, the neoadjuvant SOX regimen outperformed adjuvant XELOX chemotherapy by increasing R0 resection rates and prolonging DFS. A propensity score‐matched study conducted at the Zhongshan Hospital of Fudan University [123] indicated that the DOS regimen was more effective than the XELOX regimen in terms of both PFS and OS, with EGJ cancer accounting for 32% of cases. Based on these studies, the DOS and SOX regimens can also be considered for neoadjuvant chemotherapy in EGJ cancer. Moreover, there has been research comparing preoperative neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for EGJ cancer. The POET study [119] demonstrated the potential advantages of preoperative chemoradiotherapy for EGJ cancer. However, a meta‐analysis suggested that compared to neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy increased the pCR rate and reduced local recurrence but did not prolong OS, which differs from the findings of the POET study [124]. In 2021, the NEO AEGIES study [125] conducted a comparison between intensified three‐drug perioperative chemotherapy and preoperative chemoradiotherapy using the CROSS regimen for the treatment of EGJ cancer. The findings indicated that intensified perioperative chemotherapy did not result in worse OS compared to the CROSS regimen, with a 3‐year estimated survival probability of 57% and 56%, respectively, and that the preoperative chemoradiotherapy demonstrated superior tumor regression without additional negative effects.
In summary, based on the current research evidence for EGJ cancer, perioperative chemoradiotherapy or intensified three‐drug perioperative chemotherapy may be more suitable than adjuvant chemotherapy, although further data on Chinese patients are needed.