Multidisciplinary treatment strategy for locally advanced gastric cancer: A Systemic Review

Kotaro Sugawara a, Yoshikuni Kawaguchi b, Yasuyuki Seto a, Jean-Nicolas Vauthey c

Abstract

Background: Multidisciplinary management of patients with locally advanced gastric cancer (LAGC) remains unstandardized worldwide. We performed a systemic review to summarize the advancements, regional differences, and current recommended multidisciplinary treatment strategies for LAGC.
Methods: Eligible studies were identified through a comprehensive search of PubMed, Web of Science, Cochrane Library databases and Embase. Phase 3 randomized controlled trials which investigated survival of patients with LAGC who underwent gastrectomy with pre-/perioperative, postoperative chemotherapy, or chemoradiotherapy were included.
Results: In total, we identified 11 studies of pre-/perioperative chemotherapy, 38 of postoperative chemotherapy, and 14 of chemoradiotherapy. In Europe and the USA, the current standard of care is perioperative chemotherapy for patients with LAGC using the regimen of 5-FU, folinic acid, oxaliplatin and docetaxel (FLOT). In Eastern Asia, upfront gastrectomy and postoperative chemotherapy is commonly used. The S-1 monotherapy or a regimen of capecitabine and oxaliplatin (CapOx) are used for patients with stage II disease, and the CapOx regimen or the S-1 plus docetaxel regimen are recommended for those with stage III Gastric cancer (GC). The addition of postoperative radiotherapy to peri- or postoperative chemotherapy is currently not recommended. Additionally, clinical trials testing targeted therapy and immunotherapy are increasingly performed worldwide. Conclusions: Recent clinical trials showed a survival benefit of peri-over postoperative chemotherapy and chemoradiotherapy. As such, this strategy may have a potential as a global standard for patients with LAGC. Outcome of the ongoing clinical trials is expected to establish the global standard of multidisciplinary treatment strategy in patients with LAGC.

Keywords:
Gastric cancer
Perioperative chemotherapy
Adjuvant chemotherapy
Chemoradiotherapy

1. Introduction

Gastric cancer (GC) is the third leading cause of cancer-related death and the fifth most common cancer diagnosed worldwide [1]. The past 20 years have seen a number of advances in the management of patients with GC, which led to an improvement in their survival, including refinement of surgical techniques for gastrectomy [2,3], better understanding of the GC biology, and the establishment of multidisciplinary treatment strategies [4]. Nevertheless, GC remains an important health burden, especially in Eastern Asia and South America [4,5].
Radical gastrectomy is the mainstay of treatment for this patient group. However, studies reported that combination of surgery and medical therapy improve long-term outcomes, especially in patients with locally advanced GC (LAGC) (i.e., T2-T4 and/or node-positive disease) [6]. Accordingly, treatment guidelines recommend that the combination of radical gastrectomy with preoperative neoadjuvant chemotherapy, perioperative chemotherapy, and postoperative adjuvant chemotherapy (±radiotherapy) in patients with LAGC [1,6,7]. Importantly, current treatment practices differ depending on the region (e.g., Europe and the USA vs. Eastern Asia). Perioperative chemotherapy is recommended in Europe and the USA [6,7], postoperative adjuvant chemotherapy is recommended in Eastern Asia [1], and postoperative chemoradiotherapy is an optional approach in the USA [7].
To clarify regional differences and effectiveness of treatment strategies for LAGC, we aimed to detail the outcomes of randomized controlled trials and summarize recent developments in the management of patients with LAGC.

2. Material and methods

2.1. Literature search strategy

We performed a systematic literature review of articles published in peer-reviewed English journals about survival outcomes of patients with GC who underwent the following three treatment strategies A-C; (A) preoperative chemotherapy and surgery with or without postoperative chemotherapy (i.e., pre- or perioperative chemotherapy plus surgery), (B) upfront surgery plus postoperative chemotherapy, and (C) pre- and/ or postoperative chemoradiotherapy plus surgery. Our systematic review protocol was in compliance with the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) extension statement.
Electronic databases including PubMed, Web of Science, Cochrane Central Register of Controlled Trials and Embase were comprehensively reviewed from inception to 30th August 2020. The full search strategies are shown in Supplementary Table 1.
Screening of titles and abstracts to determine eligibility was performed by the first author (KS), and screening of full-text records was examined independently by two authors (KS and YK). In cases of duplicated data, only the study that reported the most updated information was included. Disagreements were solved by discussion.

2.2. Inclusion and exclusion criteria

We included studies that met the following criteria: (1) trials investigating patients who received pre-, post-, or perioperative chemotherapy (or chemoradiotherapy) and surgery for gastric or gastroesophageal junction (GEJ) adenocarcinoma, (2) phase 3 randomized controlled trials, and (3) trials evaluating survival outcomes including overall survival (OS), recurrence-free survival (RFS) or disease-free survival (DFS). The following studies were excluded: (1) systematic reviews, meta-analyses, case studies, letters to the editor, and abstracts with no available full-text, (2) the same registered studies which had interim, repetitive, and explanatory analyses (for these studies, we only included those with the longest follow-up period), (3) studies in which more than 80% of the included patients had GEJ adenocarcinoma, and (4) studies which evaluated auxiliary therapeutics including anti-inflammatory medications, supportive methods, and immunomodulators.

3. Results

3.1. Study selection

Based on the search strategy (Supplementary Tables 1) and 2457 potentially relevant articles for strategy A (pre- or perioperative chemotherapy plus gastrectomy), 4141 articles for strategy B (gastrectomy plus postoperative chemotherapy), and 2457 articles for strategy C (pre- or perioperative chemoradiotherapy plus gastrectomy) were identified. After screening abstracts and assessing full-text articles, we finally included 11 randomized phase 3 trials for strategy A (Supplementary Figs. 1) and 38 for strategy B (Supplementary Figs. 2) and 14 for strategy C (Supplementary Fig. 3).

3.2. Strategy a, pre- or perioperative chemotherapy plus surgery

Patient characteristics, study design and results of the strategy A studies (n = 11) are detailed in Table 1. In 2004, the Dutch group reported the first randomized phase 3 trial that investigated efficacy of preoperative chemotherapy for resectable GC [8]. This trial failed to show a survival benefit of preoperative use of 5-FU, doxorubicin and methotrexate (FAMTX regimen) over surgery alone, with a statistically insignificant difference in the 5-year OS (34% vs. 21%, respectively; P = 0.17). In the same year, the Japanese group showed that preoperative use of tegafur/uracil (UFT) followed by surgery improved OS, as estimated by the Kaplan-Meier curve, compared to surgery alone in GC patients with stage II-III disease (OS of approximately 70% vs. approximately 50%, respectively; P = 0.049) [9]. Because the combination of epirubicin, cisplatin (CDDP) and 5-FU (ECF regimen) was more effective than the FAMTX regimen in patients with esophageal cancer [10], the UK group tested preoperative use of the ECF regimen in patients with resectable GC (the MAGIC trial). In 2006, this landmark trial compared patients with resectable LAGC who received the ECF regimen and underwent surgery with those who underwent surgery alone. The trial showed that the preoperative use of ECF regimen decreased tumor size and stage, and improved OS compared to surgery alone (5-year OS of 36.3% vs. 23.0%, respectively; P =0.009) [11]. Afterwards, the FNCLCC and FFCD 9703 studies showed that the curative resection rates (84% vs. 73%, respectively; P = 0.04), the 5-year DFS (34% vs. 19%, respectively; P = 0.003), and the 5-year OS (38% vs. 24%, respectively; P = 0.02) were significantly higher in patients receiving perioperative CF (CDDP and 5-FU) regimen plus surgery than in patients undergoing surgery alone [12]. Given these promising results, perioperative ECF or CF regimen gradually became the mainstream in patients with LAGC. Nonetheless, the survival of patients who received perioperative ECF or CF regimen and underwent gastrectomy remained unsatisfactory (5-year OS: perioperative ECF plus surgery, 36.3%; perioperative CF plus surgery, 38%). At the period when these trials were performed, another study showed that docetaxel was effective in both first- and second-line settings in patients with metastatic gastric cancer. This result encouraged clinicians to use a docetaxel-based regimen in patients with resectable GC.
Recently, the FLOT4 trial tested a regimen of 5-FU, folinic acid, oxaliplatin and docetaxel (FLOT) vs. the ECF regimen or a regimen of epirubicin, CDDP, and capecitabine (ECX) for patients with resectable LAGC [13]. This trial showed that the rates of stage ypT1 tumors (25% vs. 15%, P = 0.008), stage ypN0 tumors (49% vs. 41%, P = 0.025), and R0 resection (85% vs. 78%, P = 0.016) were significantly higher, and that the median OS (50 months vs. 35 months, P = 0.010) was significantly longer in patients receiving the FLOT regimen preoperatively than in those receiving the ECF/ECX regimen perioperatively. Accordingly, the FLOT regimen is now recommended for patients with LAGC if tolerated. Fig. 1A shows a timeline of the changes in chemotherapy regimens for the strategy A.
Importantly, most trials supporting the efficacy of pre- or perioperative chemotherapy for patients with LAGC were performed in Europe. Blue color, landmark study and regimen; gray color, negative study.. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
As such, European guidelines recommend pre- or perioperative chemotherapy followed by surgery for treating LAGC. In contrast, in Eastern Asia, preoperative chemotherapy for resectable GC has been used only for patients with poor prognostic factors including scirrhous type pathology [14,15], and extensive lymph node metastasis [16–18]. Recently, a Japanese group performed a randomized phase 3 trial (JCOG0501) to investigate the efficacy of preoperative use of S-1 and CDDP (SP) regimen in patients with cStage III (cT3–4N1–3) type 4 GC or large type 3 GC. The JCOG0501 trial did not show a survival benefit in patients receiving the SP regimen preoperatively and the S-1 regimen postoperatively compared to those undergoing upfront surgery followed by postoperative S-1 (3-year OS, 60.9% vs. 62.4%, respectively; P = 0.28) [19]. Currently, the Japanese guideline recommends the use of the SP regimen preoperatively for patients with extensive nodal metastasis only [1]. Nonetheless, the strategy of pre- or perioperative chemotherapy may be increasingly adopted because a number of recent phase 3 trials in Asia (NCT01516944 [20], PRODIGY study [21], and RESOLVE study [22]) showed a survival benefit for peri-over postoperative chemotherapy alone. Ongoing trials of strategy A are summarized in Fig. 2A.

3.3. Strategy B, postoperative chemotherapy

Patient characteristics, study design and results of the 38 studies about strategy B are summarized in Table 2. In the 1990s, 14 randomized phase 3 trials which investigated the efficacy of postoperative adjuvant chemotherapy for patients with GC were reported in Europe [23–31], the USA [32,33], and Eastern Asia [34–36]. Of these, two studies showed that the use of adjuvant mitomycin C (MMC) was associated with better survival in patients with GC [24,25], and one study showed that the 5-year OS was higher in patients undergoing gastrectomy and postoperative chemotherapy using MMC and tegafur (the MF regimen) than in those undergoing gastrectomy alone (5-year OS, 56% vs. 36%, respectively; P = 0.04) [31]. In contrast, most studies failed to demonstrate a survival benefit of postoperative chemotherapy over gastrectomy alone.
Given the limited survival benefit of adjuvant chemotherapy shown by these studies, European groups, except the Italian group, shifted to investigate pre- and perioperative chemotherapy for patients with LAGC as clarified in the previous section [37–42]. In 2001, Neri B et al. showed that patients undergoing gastrectomy and receiving the ECF chemotherapy regimen postoperatively had better survival than those undergoing gastrectomy alone (median OS, 31 months vs. 18 months, respectively; P < 0.01) [37]. However, subsequent trials in Europe failed to show a survival benefit for the following seven postoperative adjuvant chemotherapy regimens: 1) etoposide, adriamycin and CDDP (EAP regimen) plus 5-FU [38], 2) epirubicin, leucovorin (LV), 5-FU and etoposide (ELFE regimen) (GOIM 9602 Study) [39], 3) CDDP, epirubicin, LV and 5-FU (PELF regimen) (GISCAD study, GOIRC study) [40, 41], 4) irinotecan and 5-FU/LV (FOLFIRI regimen) followed by docetaxel plus CDDP (ITACA-S study) [42], 5) the CF regimen (FFCD8801 trial) [43], 6) the FAMTX regimen (EORTC and ICCG trial) [44], and 7) the EAP regimen [45].
Contrary to the outcomes of the trials in Europe and the USA, clinical trials in Eastern Asia showed a survival benefit for postoperative adjuvant chemotherapy in patients with LAGC [46,47]. In 2007, a NSAS-GC study in Japan showed that for patients with serosa-negative, node-positive GC, the 5-year OS was significantly higher in patients undergoing gastrectomy and receiving the UFT chemotherapy postoperatively than in those undergoing gastrectomy alone (86% vs. 73%, P = 0.017) [48].
Results of two landmark Asian trials led to the strategy of gastrectomy plus postoperative chemotherapy becoming the standard management for patients with LAGC. In 2011, an ACTS-GC trial in Japan showed that for patients undergoing curative surgery with D2 lymphadenectomy for stage II or III GC, postoperative use of S-1 monotherapy was associated with better OS and RFS than gastrectomy alone (5-year OS, 71.7% vs. 61.0%, HR 0.669, 95% CI 0.540–0.828; 5-year RFS, 65.4% vs. 53.1%, HR 0.653, 95% CI 0.537–0.793, respectively) [49]. The CLASSIC trial in Korea, reported one year later, demonstrated that for the same patient group, postoperative use of capecitabine and oxaliplatin (CapOx regimen) was associated with better DFS than gastrectomy alone (3-year DFS, 74.0% vs. 59.0%, respectively; P < 0.001) [50].
Based on the promising results of these two landmark trials, radical gastrectomy and adjuvant chemotherapy with S-1 monotherapy or CapOx regimen is now the standard of care for patients with LAGC in Eastern Asia [1]. Because the ACTS-GC trial showed that S-1 adjuvant monotherapy regimen did not improve OS in patients with stage IIIB GC compared to gastrectomy alone [49], the same group tested the S-1 and docetaxel regimen for patients with stage III GC (a JACCRO GC-07 trial) [51,52]. Recently, the trial demonstrated that for patients with stage III GC, RFS survival was significantly better in patients undergoing gastrectomy and receiving the S-1 plus docetaxel regimen postoperatively than in patients undergoing gastrectomy and receiving the postoperative S-1 regimen alone (3-year RFS, 66.0% vs. 50.0%, respectively; P < 0.001) [51]. Chronological trends and ongoing trials of postoperative chemotherapy in patients undergoing curative gastrectomy are shown in Figs. 1B and 2B, respectively.

3.4. Strategy C, pre- or postoperative chemoradiotherapy

Patient characteristics, study design and results of the 14 strategy C studies are shown in Table 3. Clinical trials about chemoradiotherapy were mainly performed in patients who underwent curative gastrectomy (i.e., the postoperative adjuvant setting) (Table 3). In 1984, a group in the USA reported that postoperative adjuvant use of 5-FU and radiotherapy (RT) provided no survival benefit over gastrectomy alone [53]. Similarly, in 1994, the British Stomach Cancer Group trial showed no survival benefit of gastrectomy plus adjuvant RT compared with gastrectomy alone (5-year OS, 12% vs. 20%, respectively) [54]. Two trials suggested the potential efficacy of perioperative RT [55,56]; however, the survival benefit of chemoradiotherapy remained unclear.
In 2001, a landmark trial, the INT-0116 study, showed that risks for OS (HR for death 1.35, 95% CI 1.09–1.66, P = 0.005) and recurrence (HR for recurrence 1.52, 95% CI 1.23–1.86, P < 0.001) were higher in patients undergoing gastrectomy only than in those undergoing gastrectomy plus postoperative chemoradiotherapy (5-FU plus LV and RT) [57]. These results were confirmed in the recently reported 10-year follow-up (HR for OS 1.32, 95% CI 1.10–1.60, P = 0.0046; HR for recurrence 1.51, 95% CI 1.25–1.83, P < 0.001) [58]. Results of this trial should be understood in the context of the following: 1) the high rate of adverse events (41% and 32% of patients developed grade 3 and 4 toxicities, respectively), 2) 10%, 36%, and 54% rates for D2, D1, and D0 lymph node dissection, respectively, and 3) only 64% of patients completed the planned treatment [57].
Between 2000 and 2010, clinical trials of chemoradiotherapy were rarely performed. From 2012 to 2016, four randomized phase 3 trials suggested a survival benefit for adjuvant chemoradiotherapy over gastrectomy alone [59–62]. However, most randomized phase 3 trials with a large number of patients failed to demonstrate an advantage for chemoradiotherapy [63–68]. In 2015, the ARTIST trial showed that OS and DFS did not differ significantly between patients undergoing gastrectomy and adjuvant capecitabine and CDDP (XP regimen) alone and those undergoing gastrectomy and the XP regimen followed by RT (OS, HR 1.130, 95% CI, 0.775–1.647, P = 0.5272; DFS, HR 0.740, 95% CI 0.520–1.050, P = 0.0922) [65]. Subsequently, the same group conducted the ARTIST-2 trial which tested chemoradiotherapy using S-1 plus oxaliplatin (SOX regimen) vs. the SOX regimen alone. The trial did not show a significant difference in DFS (HR 0.910, P = 0.667) [66]. The recent CRITICS trial in Netherland also failed to show a survival benefit of adjuvant chemoradiotherapy using the XP regimen over chemotherapy alone using adjuvant ECX or epirubicin, oxaliplatin and capecitabine (EOX regimen) in patients with resectable GC who received preoperative ECX or EOX chemotherapy followed by gastrectomy (median OS, 37 months vs. 43 months, respectively, P = 0.90) [67].
Based on the results of these trials together with INT-0116 and CALGB 80101 trials [57,68], the postoperative use of chemoradiotherapy (5-FU plus LV and RT) is not recommended after radical gastrectomy with D2 lymphadenectomy, except for patients with high-risk of relapse (those with limited (D1) lymphadenectomy, R1 resection or remnant disease) [6,7]. Chronological trends and ongoing trials of chemoradiotherapy in patients undergoing curative gastrectomy are shown in Figs. 1C and 2C.

4. Discussion

Our systemic review showed that the recommended treatment approaches for patients with LAGC differ by region: peri-/preoperative chemotherapy in Europe and the USA, postoperative chemotherapy in Asia. Additionally, adjuvant chemoradiotherapy is performed for high- risk subgroups in the USA. The outcomes of randomized controlled trials and regional differences in epidemiology, tumor biology [69,70], and clinical outcomes of patients with GC [11,12,49,50] led to the management of resectable LAGC to be regional. As such, a barrier exists to establish a global standard treatment for patients with LAGC.
In Europe and the USA, perioperative chemotherapy and gastrectomy is the standard of care for patients with LAGC [6]. On the basis of the FLOT4 trial [13], the taxane-containing FLOT regimen is the current standard regimen for this patient group, instead of the anthracycline- and platinum-containing regimens [11,12,71]. In Asia, upfront surgery and postoperative chemotherapy is the standard treatment strategy for patients with LAGC [1]. The S-1 monotherapy regimen and the CapOx regimen are commonly used for patients with stage II disease based on the results of the ACTS-GC study [49], the CLASSIC study [50], and the other clinical trials [72–79]. For patients with stage III GC, the CapOx regimen and the S-1 plus docetaxel regimen are recommended [50,51], because the S-1 monotherapy regimen did not improve survival for this patient group [49]. In the USA, the postoperative use of chemoradiotherapy (5-FU plus LV and RT) was used; however, it is currently not the standard of care for this patient group [7].
Preoperative neoadjuvant chemotherapy has perceived advantages over postoperative adjuvant chemotherapy [80]. First, the dose intensity is generally higher in the former [11,12]. Studies showed that the rates of administration and completion of postoperative chemotherapy in patients with pStage II/III were low (administration rate; 49.5–65.6%, completion rate; 22.9–55.0%) [11–13,71]. Second, preoperative chemotherapy may down-stage patients allowing for a higher R0 resection rate [71]. Lastly, preoperative chemotherapy allows for assessing the response of chemotherapy regimens and provides information to tailor postoperative treatments [71]. Nonetheless, given the high rate of stage migration [81], preoperative chemotherapy has the limitation of overtreatment for patients with early stage disease because the indication of preoperative chemotherapy is determined on the basis of the clinical stage [81]. Two studies showed that the survival outcome did not differ significantly between patients receiving preoperative chemotherapy (docetaxel, CDDP, and 5-FU) (TCF regimen) [82], or the SOX or CapOX regimens [83], and patients undergoing the same regimens postoperatively. The recent Asian phase 3 trials demonstrated a survival benefit for peri-over postoperative chemotherapy [21,22]. These findings may increase the use of pre- or perioperative chemotherapy for patients with LAGC in Asian countries [84], where preoperative chemotherapy was less common and used only for selected patients who had deleterious prognostic factors [14,16–19]
Chemoradiotherapy is a treatment option for patients with LAGC, especially in the USA [7]. The INT-0116 study showed a survival benefit for chemoradiotherapy. However, the results of this study are not widely accepted worldwide because approximately 90% of patients underwent insufficient lymph node dissection (i.e., D0 or D1) [57]. Indeed, subsequent European randomized controlled trials showed that the addition of radiotherapy to chemotherapy was not associated with better OS than chemotherapy alone in patients undergoing sufficient lymph node dissection (i.e., D1 or D2 lymphadenectomy) [65–67]. As such, adjuvant CRT after D2 gastrectomy is not commonly performed in the clinical practice. Ongoing clinical trials to evaluate the efficacy of preoperative radiotherapy plus perioperative chemotherapy for patients with LAGC include TOPGEAR [85], CRITICS-II [86], Neo-CRAG [87] and PREACT [88].
Despite the recent advancements in multidisciplinary treatment strategies, the outcomes of patients with LAGC need further improvement. Recent studies emphasized the importance of individually- tailored treatment strategies combined with treatment response [89], accurate survival prediction and prognostic stratification [90], and detailed molecular and immune profiling of GC [91]. As such, studies focusing on the efficacy of immune checkpoint inhibitors and targeted therapies are increasing: immune checkpoint inhibitors, nivolumab and ipilimumab (the VESTIGE study) [92], atezolizumab (the DANTE study) [93], nivolumab (the ATTRACTION-05study) [94], and pembrolizumab (the KEYNOTE-585 study) [95]; anti-HER2 therapy (INNOVATION study [96], FLOT6 study [97], and JCOG1301C study [98]); VEGF-R2 inhibitor (FLOT7 study [99]). Of these ongoing trials, the MRC ST03 trial failed to show a survival benefit for bevacizumab in combination with perioperative ECF chemotherapy [100]. The findings of these ongoing trials may change the standard clinical practice for managing patients with LAGC.

5. Conclusions

The current standard treatment strategies of patients with resectable LAGC differ by region. Given the recent positive outcomes of peri-over postoperative chemotherapy, perioperative chemotherapy may have the potential to become the standard of care for this patient group worldwide. The combination of novel drugs including targeted therapy and immunotherapy with traditional cytotoxic agents is expected to improve the survival outcome in patients with LAGC.

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