In the present study, the final analysis showed that two cycles of SOX NAC, followed by gastrectomy with D2 lymphadenectomy, exhibited good survival outcomes for patients with resectable, high-risk, advanced GC.
Table 4 shows a summary of various trials of NAC for advanced GC [3, 8–27]. These trials included various regimens, such as the doublet regimens (CS, SOX, paclitaxel plus S-1, and capecitabine plus oxaliplatin) and the triplet regimens (docetaxel, oxaliplatin/cisplatin, and S-1, fluorouracil plus leucovorin, oxaliplatin and docetaxel, and epirubicin, cisplatin, and fluorouracil/capecitabine), and various courses from two to four. However, all trials, including ongoing trials and different phases, had a relatively high R0 rate (73–100%), pRR (41–68%), and 3-year OS rate (59–80%). A simple comparison of the results for the 3-year OS rate was challenging. This might be because the treatment targets and adjuvant chemotherapy regimens differed slightly in each trial.
For type 4 GC in particular, there is still room for improvement in the treatment. In the present study, patients with type 4 GC had a significantly worse 5-year OS than those with non-type 4 GC. Hosoda et al. suggested that the optimal therapy for type 4 and large type 3 GCs may need to be separately developed with consideration of target molecules [26]. Therefore, we need to develop a different treatment strategy for type 4 GC.
In many studies, there was little information regarding the long-term prognosis after NAC for GC according to the macroscopic type or Lauren’s classification. In the KDOG1001 trial, 18 patients (45%) had type 4 GC with a 5-year OS rate of 48%, whereas that of those with non-type 4 GC was 86% (p < 0.001) [26]. Furthermore, the JCOG0501 trial, in which 61% of patients had type 4 GC, failed to demonstrate the efficacy of NAC with CS [3]. The possible reasons indicated were the low pathological complete response rate (2.2%), the difference in efficacy of chemotherapy for signet-ring cells (SRC), and the low completion rate of planned treatment (47%), compared with the FLOT4 trial [3]. The present study showed a relatively high pRR but a low pathological complete response rate (7%). All patients received the planned treatment, and three had type 4 GC; however, none of their histological types was SRC. The rates of previously reported SRC were 28% [18] and 41% [3], whereas that in our study was 6.7% (two patients). Notably, these differences may have influenced the results of NAC. SRC accounts for > 60% of type 4 or large type 3 GC cases and is considered to reflect resistance to chemotherapy [3]. However, taxane-based preoperative chemotherapy may have potential benefits for treating SRC [280]. Triplet or higher drug combinations, including docetaxel, may help to further improve the outcome of patients with type 4 GC, especially SRC.
In Japan, the number of older patients with GC is increasing with the proportion of older people [29]. Therefore, selecting a more suitable regimen for older patients with GC is necessary. In the oxaliplatin regimen, unlike the cisplatin regimen, forced hydration is unnecessary. For this reason, we believe the oxaliplatin-based regimen is useful for older patients. The G-SOX trial showed that for older patients (≥ 70 years) with advanced GC, grade ≥ 3 adverse events occurred less frequently with the SOX therapy than with the CS therapy [30]. This trial also indicated that SOX demonstrated favorable efficacy and safety compared with CS for older people with advanced GC [30].
Whether the number of NAC cycles is determined is still controversial. PRODIGY suggested delivering more cycles because of the higher platinum dose intensity [22]; however, we doubt the suggestion is accurate. The difference between the present study and the RESOLVE trial (S-1: 40–60 mg bid, d1-14; oxaliplatin: 130 mg/m2 d1, q3W) regarding NAC with SOX was the number of cycles (two or three) [12]. Table 4 shows that there were few differences between the two trials. Too many cycles may not improve NAC efficacy but instead increase adverse event rates. Furthermore, the COMPASS trial showed that the pathological complete response was achieved in only 10% of the patients treated with four courses of the CS and paclitaxel plus cisplatin regimens; however, the pathological response was almost equivalent between two and four courses of those regimens [31]. In addition, Aoyama et al. showed that the pRR, defined as a complete response or < 10% residual cancer remaining, in two and four cycles of CS were 19.4% and 19.4%, respectively; however, in two and four cycles of docetaxel, cisplatin, and S-1 (DCS), they were 12.1% and 18.8%, respectively [27]. The RESONANCE-II trial is ongoing to evaluate the efficacy and safety of different cycles of NAC with SOX [15]. We await further detailed reports to help select the number of NAC cycles.
Table 4 shows that the completion rate of the planned protocol (NAC plus gastrectomy) of the oxaliplatin-based regimens tended to be relatively higher than that of the cisplatin-based regimens. This may result from differences in the rate of adverse events (Table 5). In the present study, only 10% of patients (n = 3) had grade ≥ 3 adverse events compared with previous studies that reported 19.7% [9, 3] and 67.5% [25, 26] with CS and DCS regimens, respectively. In the present study, only 6.7% of patients (n = 2) had grade ≥ 3 non-hematological adverse events compared with previous studies that reported 15% [8] and 20.8% [23, 24] with CS and DCS regimens, respectively. Grade ≥ 3 neutropenia/anorexia occurred in 19–55%/9.4–20% of patients using the cisplatin regimen and 6.4–51%/2.1–8% using the oxaliplatin regimen. Furthermore, six patients who used the docetaxel regimen had chemotherapy-related toxicity resulting in death [22, 18]. These severe toxicities may delay the timing of the surgery and cause a negative prognosis. In addition, all patients in the present study completed the planned two courses of NAC with SOX and underwent surgery. The minimal toxicity of SOX and the resulting high relative dose intensity may have contributed to the favorable R0 resection and OS rates. The low frequency of adverse events and high completion rate of our planned protocol suggest that the SOX regimen may be more useful and suitable than the CS regimen, especially in older patients with advanced GC.
This study has some important limitations. First, this trial had a single-arm, phase II design and a limited number of patients. Second, we could not set the same regimen for adjuvant chemotherapy. Twenty-four patients received adjuvant chemotherapy with S-1 after gastrectomy; however, the duration greatly differed (1–24 months, median: 12 months). Furthermore, two patients received adjuvant chemotherapy with docetaxel and S-1, one with capecitabine, and one with capecitabine and oxaliplatin. These differences in adjuvant chemotherapy may have affected OS and DFS. In Japan, the current standard treatment for resectable, high-risk, advanced gastric cancer is upfront gastrectomy with D2 lymphadenectomy, followed by adjuvant chemotherapy [6]. The standard regimens of adjuvant chemotherapy are regarded as S-1 for pathological stage II, docetaxel and S-1 for pathological stage III, and S-1/capecitabine plus oxaliplatin for pathological stage II or III based on the ACTS-GS trial [32, 2], JACCRO GC-07 trial [33], ARTIST 2 trial [34], and CLASSIC trial [35, 36]. The analysis of the JCOG1509 trial [13], which is the phase III trial to evaluate the efficacy of NAC SOX, followed by D2 gastrectomy with adjuvant S-1 for locally advanced GC, is awaited.