GC remains the leading cause of cancer-related mortality worldwide [1]. Despite the ongoing developments in treatment strategies, patients diagnosed with stage IV GC continue to have a poor prognosis.

Advanced GC with liver metastasis is characterized by limited therapeutic options, while the poor prognosis poses a significant clinical challenge. In recent years, immunotherapy, particularly the integration of ICIs, has emerged as a promising approach for improving outcomes in this challenging patient population. Nivolumab combination chemotherapy has further been anticipated as a potentially curative treatment option for such scenarios, and is recommended as a first-line regimen in the Japanese GC guidelines [9]. Consequently, an increasing number of patients with stage IV GC are now considered eligible for conversion surgery after combination therapy. According to classifications such as that designed by Yoshida, in which categories 1 and 2 may eventually undergo conversion surgery [11], there is growing acceptance that chemotherapy for stage IV GC is undeniably associated with survival advantages. Chemotherapy for stage IV GC downsizes the tumor, increases the likelihood of radical resection, and eliminates micrometastases from cancer cells [12]. Recent studies have highlighted the prognostic value of conversion surgery [10, 13]. While the optimal timing for conversion surgery remains controversial, a variety of factors have been identified as prognostic indicators during this evaluation process. Traditional features such as primary tumor size, margin status, and number of lymph nodes may no longer be entirely applicable to cases that have achieved clinical downstaging after chemotherapy. Instead, attention has shifted to pathological grade as a potential prognostic factor. For digestive cancers, including GC, but not for stage IV cancers, Tao Wan et al. concluded that pCR correlates with favorable survival outcomes compared to non-pCR after surgery following chemotherapy [14]. Furthermore, for patients who successfully underwent surgery after chemotherapy, achieving pCR emerged as an independent prognostic factor, with a 3-year overall survival (OS) of 70.9%, surpassing the 48.8% OS of patients who did not achieve pCR after conversion surgery [15]. TRG (tumor regression grade (TRG) could also be an independent prognostic factor affecting the OS of GC patients [15]. These results suggest that even if chemotherapy is not completely effective, a greater efficacy is still associated with better prognosis. As such, treatment combining stringent chemotherapy with nivolumab could improve the prognosis of GC.

Regarding conversion surgery, achieving R0 resection, where the surgical margin is microscopically negative, is the most critical prognostic factor [11]. The results of the ongoing RENAISSANCE/AIO-FLOT (NCT02578368) phase III trial aimed to evaluate conversion surgery for gastric and gastroesophageal junction cancers with limited metastases are awaited [16].

Against this backdrop, our case of stage IV remnant GC with liver metastasis is significant, particularly in the context of the consideration of conversion surgery and achieving pCR after nivolumab combination chemotherapy. There are currently limited reports on achieving pCR after chemotherapy for stage IV GC. A PubMed search using the keywords < gastric cancer (GC) > , < Stage IV > , and < pathological CR > from the 1990s to 2023 yielded only 6 case reports [17,18,19,20,21,22], all treated with ICI, more specifically a programmed death-1 (PD-1) inhibitor combination chemotherapy (Table 1). Among these cases, including ours, the latest four were treated with ICI combination chemotherapy as the first-line regimen, whereas the others received ICI as the third or later regimen. All patients included in our study underwent conversion surgery with R0 resection and achieved a histological response grade 3, indicating eventual pCR. Our case had the longest follow-up duration among all reported patients treated with ICI as first-line therapy. In addition, unlike some patients who experienced adverse effects from ICI, our patient did not. This is noteworthy as the onset of adverse events can prompt the cessation of ICI or chemotherapy, guiding subsequent treatment steps, such as conversion surgery.

The number of cases following a favorable clinical course with ICI is expected to increase in the near future, necessitating further discussion on the merits and efficacy of ICI as a prospective treatment, along with determining the necessary duration of administration. Deciding the timing of conversion surgery remains controversial. Hence, it is imperative that more case reports and prospective studies are published to enhance our understanding and improve patient survival outcomes.

Finally, regarding postoperative treatment, there is no evidence for adjuvant chemotherapy after conversion surgery for Stage IV GC, and Japanese GC guidelines do not specify a treatment policy for such cases. Thus, we referred to the ongoing Japan Clinical Oncology Group (JCOG) study as follow.

In Japan, a randomized phase III trial, JCOG1509 called NAGISA trial [23], is currently underway to evaluate the superiority of neoadjuvant chemotherapy in locally advanced GC followed with gastrectomy and postoperative chemotherapy. In this trial, patients with cT3-4N1-3 advanced GC are divided into two groups: Group A [surgery (gastrectomy with D2 lymphadenectomy) and postoperative adjuvant chemotherapy] and Group B [neoadjuvant chemotherapy (S-1 and Oxaliplatin for 3 courses), surgery (gastrectomy with D2 lymphadenectomy) and postoperative adjuvant chemotherapy]. The aim is to compare the prognosis of both groups and to verify the effectiveness of neoadjuvant chemotherapy for advanced GC. In this trial, the regimen used for postoperative adjuvant chemotherapy consists of S-1 therapy for 1 year for ypStage 0–II cases and DS therapy for 1 year for ypStage III–IV cases.

Although this trial is not designed for stageIV GC and now ongoing, based on the fact that this case was ypStage0 after chemotherapy followed by R0 surgery, we followed the regimen of this trial, and oral S-1 monotherapy was administered for 1 year as postoperative adjuvant chemotherapy.