Saki Sato,Kazuaki Tanabe,Hiroshi Ota,Yoshihiro Saeki,Hideki Ohdan
Successful management of multiple liver metastasis from gastric cancer with second conversion surgery: A case report
Gastric cancer,Nivolumab,Conversion surgery,Multiple conversion surgery
Introduction Most conversion surgeries for patients with stageIV gastric cancer are performed on patients who have responded to first-line chemotherapy. Although conversion surgery after third-line chemotherapy with nivolumab has been reported, there are no cases wherein second conversion surgery was performed after third-line chemotherapy with nivolumab. Presentation of case A 72-year-old man presented with gastric cancer and an enlarged regional lymph node, and early esophageal cancer was identified after endoscopic submucosal dissection. After S-1 plus oxaliplatin as first-line chemotherapy, staging laparoscopy was performed, and liver metastasis was confirmed. The patient underwent a total gastrectomy with D2 lymphadenectomy, hepatic left lateral segmentectomy, and partial hepatectomy. One year after conversion surgery, new liver metastases appeared. He received nab-paclitaxel plus ramucirumab and nivolumab as the second and third-line chemotherapy, respectively. Liver metastases were significantly reduced following these courses of chemotherapy. The patient underwent partial hepatectomy as second conversion surgery. Although nivolumab was continued after the second conversion surgery, new para-aortic lymph node metastasis and bilateral hilar lymph node metastasis appeared. However no new metastasis appeared in the liver and he survived for 60 months after first-line chemotherapy. Discussion A second conversion surgery with stageIV gastric cancer after third-line chemotherapy with nivolumab is rare. Multiple hepatectomy as conversion surgery may be an option to control liver metastases. Conclusion Multiple hepatectomy as conversion surgery may be effective in controlling liver metastases. However, when to perform conversion surgery and the adequate selection of the patient are the most difficult and important.
Successful management of multiple liver metastasis from gastric cancer with second conversion surgery: A case report

Most conversion surgeries for patients with stageIV gastric cancer are performed on patients who have responded to first-line chemotherapy. Although conversion surgery after third-line chemotherapy with nivolumab has been reported, there are no cases wherein second conversion surgery was performed after third-line chemotherapy with nivolumab.

A 72-year-old man presented with gastric cancer and an enlarged regional lymph node, and early esophageal cancer was identified after endoscopic submucosal dissection. After S-1 plus oxaliplatin as first-line chemotherapy, staging laparoscopy was performed, and liver metastasis was confirmed. The patient underwent a total gastrectomy with D2 lymphadenectomy, hepatic left lateral segmentectomy, and partial hepatectomy. One year after conversion surgery, new liver metastases appeared. He received nab-paclitaxel plus ramucirumab and nivolumab as the second and third-line chemotherapy, respectively. Liver metastases were significantly reduced following these courses of chemotherapy. The patient underwent partial hepatectomy as second conversion surgery. Although nivolumab was continued after the second conversion surgery, new para-aortic lymph node metastasis and bilateral hilar lymph node metastasis appeared. However no new metastasis appeared in the liver and he survived for 60 months after first-line chemotherapy.

A second conversion surgery with stageIV gastric cancer after third-line chemotherapy with nivolumab is rare. Multiple hepatectomy as conversion surgery may be an option to control liver metastases.

Multiple hepatectomy as conversion surgery may be effective in controlling liver metastases. However, when to perform conversion surgery and the adequate selection of the patient are the most difficult and important.

Although the incidence and mortality of gastric cancer are steadily declining, it remains the fifth most common cancer in the world and the third leading cause of death [1]. Furthermore, over 70 % of the cases were reported from the Asian population [2]. Despite the development of chemotherapy for gastric cancer, the prognosis associated with stageIV gastric cancer remains poor; the median overall survival (OS) of patients with stageIV gastric cancer is 13–16 months [2]. A recent retrospective global cohort study (“CONVO-GC-1”) reported that the median survival time (MST) of 1206 stageIV gastric cancer patients who underwent surgery after chemotherapy was 36.7 months [3]. Most conversion surgeries are performed on patients who have responded to first-line chemotherapy. There are cases in which conversion surgery for patients with stageIV gastric cancer aimed at R0 resection in patients with a good response to chemotherapy can be expected to improve the prognosis. Although there are a few reports of conversion surgery after third-line chemotherapy with nivolumab [[4], [5], [6]], there are no reported cases of second conversion surgery after third-line chemotherapy with nivolumab. We report a rare case of stageIV gastric cancer who underwent a second conversion surgery after nivolumab as the third-line chemotherapy. This case is reported according to the SCARE 2020 criteria [7].

A 72-year-old man complained of epigastric pain and was diagnosed with advanced gastric cancer and early esophageal cancer at his local hospital. He was referred to our hospital to undergo treatment. Esophagogastroduodenoscopy (EGD) revealed a typeII tumor extending from the middle to lower portions of the gastric body, as well as a type 0-IIc esophageal tumor at the middle thoracic esophagus (Fig. 1a-b). A biopsy of the gastric cancer revealed poorly differentiated adenocarcinoma with negative human epidermal growth factor receptor type 2 (HER2) and microsatellite instability (MSI). Although preoperative computed tomography (CT) and positron emission tomography-computed tomography (PET-CT) revealed a primary tumor without invasion of the surrounding organs and enlarged one lymph node (LN) along the left gastric artery, no distant metastasis was identified (Fig. 2a-c); the clinical stage was cT4aN1M0, cStageIII. First, endoscopic submucosal dissection (ESD) was performed for the esophageal cancer. The pathological diagnosis was stage pT1b-SM2 (250 μm), INFb, ly(+), V0; therefore, it was necessary to perform additional surgical resection. We planned staging laparoscopy to confirm a peritoneal dissemination; however, a liver metastasis was identified in the staging laparoscopy. Postoperative magnetic resonance imaging (MRI) also revealed four liver metastases in segments 2, 3, and 6 (Fig. 3a). The prognostic factor was gastric cancer; hence, we planned conversion surgery for gastric cancer if there were no new metastases after chemotherapy. The patient received the S-1 (120 mg/body/day) plus oxaliplatin (130 mg/m2) (SOX) regimen as first-line chemotherapy. After four courses of the SOX regimen, MRI showed no change in size of the primary tumor but a reduction in the size of the regional LNs and the liver metastases (Fig. 3b). The patient underwent total gastrectomy with D2 lymphadenectomy, hepatic left lateral segmentectomy, and partial hepatectomy (segment 6 and 7). Histological findings suggested poor-to-moderately differentiated adenocarcinoma, stage ypT2 (MP), Ly1, and V2, N3(7/66) M1(H1). The therapeutic effect was Grade 2. After the conversion surgery, the patient received the S-1 (100 mg/body/day) regimen. Due to adverse events of neutropenia (Grade 3) and thrombocytopenia (Grade 2), S-1 was continued while reducing the dose. After seven courses of the S-1 regimen, CT and MRI revealed new two liver metastases in segment 4 and 5 (Fig. 4a). Therefore, we changed the chemotherapy regimen to nab-paclitaxel (100 mg/m2) (PTX) plus ramucirumab (8 mg/kg) (RAM) as the second-line chemotherapy. Due to adverse events of neutropenia (Grade 4), this regimen continued for six courses while reducing the dose. After six courses, the liver metastases had enlarged (Fig. 4b). Therefore, we changed the chemotherapy regimen to nivolumab (240 mg/body) as the third-line chemotherapy. After seven courses of nivolumab, the liver metastases were significantly reduced and new metastatic lesions were not detected (Fig. 4c). The patient then underwent partial hepatectomy (segments 4 and 5). The patient was discharged 10 days after surgery without postoperative complications. Although the patient underwent two hepatectomies, residual liver function did not deteriorate. Moreover, current residual liver function is normal. I think this is related to the patient's preoperative Child-Pugh classification A and the amount of liver resection (first hepatectomy was 136 g and second hepatectomy was 72 g). The pathological findings suggested that there was no residual carcinoma in the excised liver. Although the patient continued with the nivolumab regimen after the second conversion surgery, CT revealed new para-aortic LNs metastases. After 28 courses of nivolumab (13 months after the second conversion surgery), CT showed a reduction of the para-aortic LNs. However, CT revealed new bilateral hilar lymph node metastases. No new metastasis had appeared in the liver. PET-CT showed a positive response in the bilateral hilar LNs. Moreover, the patient developed interstitial pneumonia. We changed the chemotherapy regimen to trifluridine/tipiracil hydrochloride (TFTD), and the patient has survived for 60 months after first-line chemotherapy.

In recent years, the emergence of immune checkpoint inhibitors such as nivolumab has contributed to improving the prognosis of patients with unresectable advanced and recurrent gastric cancer. Patients with advanced gastric or gastro-esophageal junction cancer who had been previously been treated with two or more chemotherapy regimens have a poor prognosis. The ATTRACTION-2 study showed that nivolumab improves the overall survival (OS) and progression-free survival (PFS) after third or later-line chemotherapy in patients with advanced gastric or gastro-esophageal junction cancer [8,9]. Moreover, the combination of nivolumab and chemotherapy showed a significant prolongation of OS and PFS in patients with unresectable/recurrent gastric cancer in the CheckMate649 study, and a significant prolongation of PFS in the ATTRACTION-4 study [10,11]. The use of nivolumab is expected to increase in first-line chemotherapy in the future, and the number of cases for which conversion surgery is possible is expected to increase. Conversion surgery is defined as surgical treatment aimed at R0 resection after a good response to induction chemotherapy [2]. Patients treated with conversion surgery had significantly longer OS and PFS times than those treated with chemotherapy alone. Moreover, patients who underwent R0 resection had a significantly longer OS than did those who underwent R1 and R2 resection [2,[12], [13], [14]]. Fukuchi et al. reported that non-type 4, histologic grade of G1 or G2, and one noncurative factor with R0 resection were significantly associated with a better OS [12]. Therefore, the number of noncurative factors and R0 resection are important in conversion surgery. One noncurative factor and R0 resection in our patient suggested that conversion surgery contributed to prognosis prolongation. However, even if R0 resection can be achieved, as in our case, recurrence/new metastasis can eventually appear after conversion surgery. For stageIV gastric cancer with liver metastases, surgical removal of liver metastases remains controversial, because in most cases, multiple recurrences of the liver metastases can appear after hepatectomy [15,16]. The MST of gastric cancer patients with liver metastasis is approximately 10–15 months, with a 3-year survival rate below 10 % when treated with chemotherapy alone [17]. On the other hand, the MST of patients with complete resection of the primary gastric cancer and liver metastasis after chemotherapy is approximately 26 months with a 5-year survival rate of 11–40 % [18]. Fujitani et al. reported that the R0 resection rate of liver metastasis (1–4 lesions, maximum diameter ≤ 5 cm) was 68.5 % with acceptable surgical morbidity and mortality in a prospective multicenter study; further survival analysis is awaited [19]. Our patient had a long-term prognosis after conversion surgery, so conversion surgery after chemotherapy could be a potential treatment strategy. Moreover, no recurrence of liver metastasis occurred after the second conversion surgery. Although the control of liver metastasis may be the effect of continuation of nivolumab, no study for R0 resectable stageIV gastric cancer has compared continuation of nivolumab with conversion surgery. Hepatectomy as conversion surgery may be an option for the control of liver metastases. Immune-related adverse events (irAEs) after nivolumab are associated with prognosis, and patients who develop irAEs have a significantly better prognosis than those who do not [20]. However, there are cases in which nivolumab cannot be continued due to irAEs. Conversion surgery should be considered when R0 resection is possible. No reports have examined the effectiveness of multiple conversion surgeries. When to perform conversion surgery and the adequate selection of the patient are the most difficult and important. If one noncurative factor and R0 resection is possible, as in our case, conversion surgery may be considered.

We report a case of successful multiple conversion surgery for stageIV gastric cancer after third-line chemotherapy with nivolumab. Conversion surgery after chemotherapy could be a potential treatment strategy. Moreover, no recurrence of liver metastasis occurred after the second conversion surgery, thus, hepatectomy as conversion surgery may be able to control liver metastasis. When to perform conversion surgery and the adequate selection of the patient are the most difficult and important. If one noncurative factor and R0 resection is possible, it would be meaningful to consider conversion surgery.

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

This study conforms to the provisions of the Declaration of Helsinki. The patient provided informed consent, and patient anonymity was preserved. This study is exempt from ethical approval in the Ethical Committee Hiroshima University Hospitals, Hiroshima, Japan.

No funding.

SS and KT drafted the manuscript. SS, KT, HO, YS, and HO contributed to patient care. SS and KT performed the literature search. SS, KT, HO, YS, and HO participated in the critical revision of the manuscript. All authors have read and approved the final manuscript.

Kazuaki Tanabe.

None

The authors declare that they have no competing interest.