Gastric cancer surgery in the era of immunotherapy

Authors: Li Ziyu, Jia Yongning, Lu Xinxing, Guan Guangmin, Wang Qi

Source: Chinese Journal of Surgery, 2024, 62(5)

summary

With the widespread use of immune checkpoint inhibitors, chemotherapy combined with immunotherapy has shown good results in the treatment of a variety of malignant tumors. Especially in the treatment of gastric cancer, this combination therapy strategy is gradually expanding from advanced first-line treatment to perioperative treatment. Compared with neoadjuvant chemotherapy alone, chemotherapy combined with immunotherapy can not only improve the pathological remission rate, but also reduce the tumor stage more effectively, especially in patients with specific subtypes of gastric cancer such as human epidermal growth factor receptor 2 positive, mismatch repair defect, PD-L1 comprehensive positive score of ≥5, and Epstein-Barr virus positive. Combination therapy offers the possibility of reducing the scope of gastrectomy surgery, function-sparing surgery, and even non-surgical treatment strategies. Exploring the best combination of immunotherapy and chemotherapy, possible indications for function-preserving surgery, improvement of surgical methods, and de-surgical strategies are hot issues in gastric cancer surgery in the era of immunotherapy.

In recent years, immunotherapy has made rapid progress in the drug treatment of gastric cancer. Chemotherapy combined with immunotherapy has achieved definite results in patients with advanced gastric cancer, and perioperative chemotherapy combined with immunotherapy for locally advanced gastric cancer has also entered a new stage of exploration, and a number of phase II and III clinical trials are being carried out in an orderly manner. The development of immunotherapy has brought a series of new problems and challenges to the surgery of gastric cancer, and the selection of surgical indications and surgical methods must be further explored and improved.

1. Comprehensive perioperative treatment has become the standard treatment mode for locally advanced gastric cancer

Current guidelines recommend comprehensive perioperative therapy as the standard treatment modality for locally advanced gastric cancer [1, 2]. Compared with surgery alone, comprehensive therapy can reduce tumor restage, improve R0 resection rate, and improve overall survival without compromising the safety of surgery [3]. R0 resection rates were 79 percent and 86 percent in the Magic study and 86 percent in the FNCLCC/FFCD study, respectively, compared with 23 percent and 34 percent for surgery alone [4, 5]. In the FLOT4 study, neoadjuvant therapy with the FLOT regimen (fluorouracil + leucovorin + oxaliplatin + docetaxel) improved five-year survival from 36 to 45 percent compared with the ECF regimen (epirubicin + cisplatin + fluorouracil) [6]. The results of the PRODIGY and RESOLVE studies further confirmed the efficacy of perioperative chemotherapy + surgery mode compared with surgery + adjuvant chemotherapy mode. However, the response rate of neoadjuvant chemotherapy for locally advanced gastric cancer is still low, and the pathological complete response (pCR) rate is only 6%~10%, and more than half of the patients have poor efficacy [7, 8].

二、免疫检查点抑制剂可明显提高新辅助化疗主要病理学缓解（major pathologic response，MPR）率

In recent years, chemotherapy combined with immunotherapy has achieved good results in multiple tumor types. With the establishment of chemotherapy combined with immunotherapy in the treatment of advanced gastric cancer, researchers have begun to explore the value of this model in the neoadjuvant treatment of locally advanced gastric cancer.

(1) Chemotherapy combined with immunotherapy to improve the MPR rate of locally advanced gastric cancer

At present, most of the relevant clinical studies are phase I or phase II small-sample single-arm studies. Li et al. [9] conducted a systematic analysis of 687 patients in 21 phase I or phase II clinical trials, with a pCR rate of 21%, an MPR rate of 41%, an R0 resection rate of 94%, and a grade 3 or above adverse reaction rate of 23%. Among the various treatment modalities, immunotherapy combined with chemotherapy + radiotherapy had the strongest efficacy, followed by combined chemotherapy + anti-vascular targeted drugs and combined chemotherapy + radiotherapy, and immunotherapy alone had the weakest effect. They also included the results of 21 chemotherapy alone as comparators, with a pCR rate of 8%, an MPR rate of 22%, an R0 resection rate of 84%, and a grade 3 and above adverse reaction rate of 28%.

At the same time, randomized controlled trials of perioperative chemotherapy combined with immunotherapy versus chemotherapy alone have also yielded preliminary results. Results from the Phase II B randomized controlled trial DANTE showed that atezolizumab plus FLOT resulted in more significant tumor downstaging preoperatively than FLOT alone (pCR rate: 24 versus 15 percent) [10]. According to the results of the KENOTE-585 study, the pCR rate of pembrolizumab combined with chemotherapy was 12.9%, which was better than that of 2% in the chemotherapy group, but the event-free survival was not prolonged, and the incidence of grade 3~4 adverse reactions was similar between the two groups [11]. In another large phase III clinical trial, the MATTERHORN study showed a pCR rate of 19 percent in the durvalumab plus FLOT group, which was better than 7% in the FLOT alone group, and the incidence of grade 3~4 adverse reactions was similar in both groups, and event-free survival has not been reported [12].

(2) Immunotherapy has a better effect on specific subtypes of gastric cancer

1. Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer: HER2-positive gastric cancer accounts for 8%~23% of all gastric cancers [13, 14, 15]. In the ToGA study, trastuzumab in combination with first-line chemotherapy increased the objective response rate from 34.5 to 47.3 percent for HER2-positive advanced gastric cancer [16]. Data from the third interim analysis of the KEYNOTE-811 study showed that the addition of pembrolizumab to chemotherapy plus targeted therapy further increased the objective response rate to 74.4 percent in HER2-positive advanced gastric cancer [17]. Based on the application of advanced gastric cancer, early data from the NEOHX study [18], the HER-FLOT study [19], the PETRARACA study [20], and the TRIGGER study [21] for locally advanced gastric cancer showed that chemotherapy combined with HER2-targeted therapy could improve the pCR rate or R0 resection rate of HER2-positive gastric cancer. The results of small SHR1210 studies suggest that the addition of PD-1 monoclonal antibody to chemotherapy and targeted therapy can further increase the pCR and MPR rates to 31.3 and 56.3 percent, respectively [22]. With the upgrade of HER2-targeted drugs, we are leading a Phase II randomized controlled study (reg. number: NCT06155383) to explore the effects of vedicitumab (RC48) in combination with toripalimab (JS001) and further conventional chemotherapy in locally advanced gastric cancer.

2. Microsatellite unstable gastric cancer: Microsatellite instability is a pan-tumor marker that can clearly benefit from immunotherapy. The high frequency of gene mutations not only induces tumorigenesis and progression, but also triggers the production of neoantigens and a special immune microenvironment, providing a molecular basis for immunotherapy to play a role [23]. Zhang et al. [24] counted the data of 43 246 patients in 134 gastric cancer cohorts and found that microsatellite instability accounted for about 14.5%. RESULTS FROM TWO RECENT SINGLE-ARM PHASE II TRIALS, THE GERCOR NEONIPIGA STUDY AND THE INFNITY STUDY, DEMONSTRATED PCR RATES OF 59 AND 60 PERCENT FOR NEOADJUVANT THERAPY WITH PD-1/PD-L1 ANTIBODIES AND CTLA-4 ANTIBODIES, RESPECTIVELY [25, 26]. Therefore, the 2023 NCCN guidelines for gastric cancer officially recommend perioperative immunotherapy for mismatch repair-deficient or high-microsatellite unstable advanced gastric cancer [27]. This subtype also became the first gastric cancer subtype to be prioritized for chemotherapy removal in the neoadjuvant or first-line setting.

3. PD-L1 combined positive score (CPS) ≥ 5 for gastric cancer: patients with advanced gastric cancer with a CPS score of ≥5 can have better benefits after receiving chemotherapy combined with immunotherapy. In locally advanced gastric cancer, the pCR rate of neoadjuvant chemotherapy combined with immunotherapy was 18% in PD-L1-negative patients and 23% in PD-L1-positive patients. In contrast, the pCR rate was 30 percent in patients with a CPS score of ≥5 and 35 percent in patients with a CPS score of ≥ 10 [9]. At present, the domestic PD-1 inhibitor HLX10 has entered the phase III trial stage (registration number: NCT04139135), mainly including patients with CPS score ≥5, which is expected to provide an important evidence-based basis for neoadjuvant chemotherapy combined with immunotherapy for locally advanced gastric cancer.

4. EBV-positive gastric cancer: Epstein-Barr virus-positive gastric cancer accounts for less than 10% [28], and immunotherapy may be of potential value compared with EBV-negative gastric cancer because of its immune-activated tumor microenvironment [29]. Kim et al. [30] reported the use of PD-1 inhibitors for the treatment of EBV-positive advanced gastric cancer, and all six patients achieved objective remission. In the phase II trial conducted by the Sun Yat-sen University Cancer Center, six patients with EBV-positive advanced gastric cancer were treated with camrelizumab and had an objective response rate of 0 [31]. The above opposite application results suggest that there may be some heterogeneity in EBV-positive gastric cancer, and a single index cannot accurately predict the effect of immunotherapy.

Current guidelines recommend that neoadjuvant chemotherapy combined with immunotherapy for locally advanced gastric cancer should be administered in a clinical research mode. Our center has accumulated some clinical application experience in patients with the above subtypes of gastric cancer, as shown in Table 1.

Gastric cancer surgery in the era of immunotherapy

3. Combined immunotherapy neoadjuvant therapy promotes the development of function-preserving surgery for gastric cancer

The iteration of anti-cancer drugs not only improves the efficacy, but also promotes the renewal of the concept of surgical treatment of gastric cancer. With the inclusion of immunotherapy in neoadjuvant therapy and the significant increase in PCR rate and MPR rate, gastric cancer surgeons need to re-examine the value of surgery in the era of immunotherapy in locally advanced gastric cancer, such as: whether patients with obvious neoadjuvant therapy response still need to undergo D2 radical surgery; what are the prospects for function-preserving surgery and some reduction procedures in such patients; whether all patients require surgical resection; All of the above questions need to be explored by researchers.

(1) Indications for function-preserving surgery

The target population of gastric function preservation surgery is patients with early-stage gastric cancer, and theoretically patients who have achieved significant downstage after neoadjuvant therapy may have indications for function preservation surgery. Among the 44 patients with special subtypes of gastric cancer who received neoadjuvant chemotherapy combined with immunotherapy in the early stage of our center, 23 achieved MPR (Table 1), of which 2 still had residual lymph node metastasis (ypN1, stage II), and the rest were ypN0 (stage I). Obvious post-drug response could be observed in the lymph nodes of 12 patients who achieved MPR, suggesting that ypN0 stage was down-staged, and the pCR rate of lymph nodes may be higher than that of the primary lesion.

(2) Reasonable surgical methods for function-preserving surgery

Gastric function preservation surgery is to reduce the scope of surgery and reasonably choose the method of digestive tract reconstruction to preserve the function of the stomach as much as possible under the premise of ensuring the radical resection of the tumor. The three main elements include reduced gastrectomy extent, preservation of pyloric function, and preservation of the vagus nerve [32, 33]. The fourth edition of the Japanese Gastric Cancer Management Protocol defines gastrectomy surgery with a reduction in the scope of gastrectomy <two-thirds and/or lymph node dissection (D1, expanded D1) as gastric reduction surgery [34]. The definitions are similar, but the concepts are different. Gastric function preservation surgery emphasizes the preservation of the structure or function of the cardia, pylorus, and vagus nerve in order to improve postoperative nutritional status and quality of life; Gastric reduction surgery focuses on reducing the scope of resection, simplifying the surgical process, reducing trauma and reducing the incidence of complications.

Gastric function preservation surgery mainly includes local gastrectomy, segmental gastrectomy and proximal gastrectomy, and the premise of its implementation is the radical curability of the tumor, that is, the safe resection margin of gastric lesions and the thorough dissection of metastatic lymph nodes, and how to ensure the thorough dissection of metastatic lymph nodes is the key and difficult point. Although most of the results are still retrospective, it is preliminarily suggestive that proximal gastrectomy after neoadjuvant therapy has certain safety and feasibility after neoadjuvant therapy for advanced esophagogastric junction cancer and superior gastric cancer.

1. Radical tumor cureability: In patients with advanced esophagogastric junction cancer and superior gastric cancer, the absence of metastasis of distal lymph nodes in groups 4d, 5, 6, and 12a is the key basis for selecting proximal gastrectomy after neoadjuvant therapy. For esophagogastric junction cancer, Mine et al. [35] retrospectively analyzed the lymph node metastasis of 226 patients with locally advanced Siewert type II esophagogastric junction adenocarcinoma in 7 clinical centers in JapanAt <3 cm, the rate of lymph node metastasis in the greater curvature and pyloric region was only 2.2%. In addition, it has been reported that the metastasis rate of distal perigastric lymph nodes is extremely low when the maximum diameter of esophagogastric junction carcinoma is ≤4 cm [36]. For upper gastric cancer, Yura et al. [37] considered that the lymph node metastasis rate in groups 4d, 12a, 5, and 6 of patients with stage T2~T3 was less than 1%, and dissection should not be performed. We recently used a propensity score matching method to retrospectively analyze patients with esophagogastric junction and supragastric cancer who received neoadjuvant chemotherapy, compared the prognosis of proximal gastrectomy (39 patients) and total gastrectomy (71 patients), and explored whether the extent of surgical resection has an impact on the prognosis in patients with different maximum diameters of the primary lesion through subgroup analysis, hoping to accumulate evidence for the identification of related problems.

2. Quality of life: Gastroesophageal reflux is a common problem faced by patients after proximal gastrectomy. At present, the digestive tract reconstruction techniques after proximal gastrectomy mainly include esophageal residual gastric anastomosis, jejunal interstitial and dual-channel reconstruction, among which esophageal residual gastric anastomosis is widely used due to its simple operation. When the residual stomach is small, the latter two reconstruction methods can be used, among which interstitial jejunal reconstruction is gradually replaced by double-channel reconstruction due to the high probability of food retention. Dual-channel reconstruction can significantly reduce gastroesophageal reflux, but the actual utilization rate of residual gastroduodenal access is low in some patients after surgery, and its advantages in improving nutrition and preserving residual gastric function cannot be fully utilized. Esophageal residual gastric anastomosis was reduced and the quality of life was improved with the help of various improvement measures such as cast-type gastric casts, side-overlap [38], and double muscle flap anastomosis (Kamikawa method) [39]. At present, dual-channel reconstruction, tubular gastric reconstruction and modified "arch bridge" reconstruction of muscle flap are commonly used methods for gastrointestinal reconstruction after proximal gastrectomy in our center. The latter two reconstruction modalities should be selected according to the degree of esophageal invasion, and when the length of the invasion exceeds 2 cm, tubular gastric reconstruction should be preferred. The modified "arch bridge" reconstruction based on the tunneling principle simplifies the operation and shortens the operation time, while retaining the advantages of the Kamikawa method and ensuring the quality of the muscle flap [40, 41]. We plan to build on the completed single-center study (IDEAL Phase 2) and further validate its effectiveness and feasibility through a multi-center study.

and (3) the potential risks of function-preserving surgery

An increased rate of local recurrence is a major risk for function-sparing surgery. Traditional function-sparing surgery is only used for early-stage gastric cancer, and the scope of surgery has not been reported in the literature after neoadjuvant therapy for locally advanced gastric cancer. Taking low rectal cancer as an example, some patients can achieve complete clinical remission after neoadjuvant chemoradiotherapy, and the anal function can be preserved by waiting for observation strategy or local resection instead of traditional surgery to achieve a better quality of life. This concept has been controversial since it was proposed. Most studies have shown that the local resection and wait-and-see strategies are comparable to traditional total mesorectal resection in terms of oncology, but the reoperation rate and complication risk of local excision are relatively high, while the wait-and-stay strategy tends to have a higher local regeneration rate and the need for closer follow-up [42]. In breast cancer, a meta-analysis of 10 randomized controlled trials showed that although neoadjuvant chemotherapy was able to shrink the primary tumor and improve breast preservation, the rate of local recurrence after surgery was higher than that of patients who did not receive neoadjuvant therapy [43]. Referring to the above progress and combined with the clinical practice of gastric cancer, we believe that it is particularly important for the multidisciplinary team to discuss and formulate a reasonable surgical plan and postoperative follow-up plan before the implementation of gastric function preservation surgery. In addition, physicians need to fully communicate with patients and their families about the pros and cons of functional preservation surgery, ensure that patients fully understand the potential risks and expected outcomes of surgery, and achieve doctor-patient decision-making.

(4) De-surgical strategy

In the past, due to the high heterogeneity of gastric cancer and the low overall pCR rate of chemoradiotherapy, the de-surgical strategy has not entered the field of clinical research and application. As immunotherapy has become an important means of neoadjuvant therapy, and the pCR rate of 20%~40% has been achieved in combination with chemotherapy, targeted therapy and radiotherapy, the de-surgical strategy has become a hot topic in gastric cancer surgery. Among them, the pCR rate of dual-agent immunotherapy for microsatellite unstable gastric cancer can reach 60% [25, 26], making it a priority candidate for the study of de-surgical strategy. Cohort 2 of the INFINITY study (reg. number: NCT04817826) has begun to explore de-operative strategies with deferred surgery and close monitoring (gastroscopy, thoraco-abdominal and pelvic CT, PET-CT, and primary and lymph node biopsy) in patients with gastric cancer who are in complete clinical remission.

However, whether it is a function-sparing surgery or a de-operative strategy, the key to its development is to accurately assess the tumor stage and improve a series of diagnostic criteria for clinical complete remission after neoadjuvant therapy for locally advanced gastric cancer. Existing practical experience in other cancer types, such as the use of imaging and pathological biopsy to more accurately determine tumor remission status; To explore more accurate lymph node reflux rules, use lymph node status to judge the risk and prognosis of recurrence, and determine the specific scope of dissection; To understand the changes in molecular status after neoadjuvant therapy, to provide more information for predicting the response of tumors to adjuvant therapy, etc.; All these provide useful references for carrying out similar practices in gastric cancer patients.

Fourth, summary and outlook

For a long time, radical surgery has been the core of the comprehensive treatment model for locally advanced gastric cancer due to the limited effect of chemotherapy. Immunotherapy has shown great potential in gastric cancer, which may change the status quo and demand of gastric cancer surgery while further consolidating the comprehensive perioperative treatment model. Nowadays, the goal of surgical treatment of gastric cancer has expanded from only pursuing the radical treatment of tumors to improving the quality of life of patients after surgery. Gastric cancer surgeons must understand a series of challenges brought by relevant drug treatments to surgical techniques and perioperative management, embrace the opportunities, keep pace with the times, and continue to play an important role in the comprehensive treatment of gastric cancer by improving the precision and quality of treatment strategies in the era of immunotherapy.

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