A case of advanced gastric cancer achieved a pathological complete response by chemotherapy

Background Although chemotherapy is the first recommended treatment of unresectable gastric cancer, a pathological complete response is a rare event. Case presentation A 58-year-old male was diagnosed as gastric cancer with a bulky tumor, lymphadenopathy, and suspicious peritoneal dissemination. The patient underwent chemotherapy with S-1 and cisplatin. After three courses of chemotherapy, a computed tomography showed dramatic improvements in gastric wall thickening, shrinkage of lymphadenopathy, and disappearance of disseminated peritoneal lesion. The patient underwent potentially curative resection by total gastrectomy with D2 lymph node dissection. Histological examination revealed the absence of malignant cells not only in the resected specimen but also in the harvested lymph nodes. At present, more than 7 years after the initial surgery, the patient is still alive without any recurrence. Conclusions We obtained a pathological complete response by chemotherapy with S-1 and cisplatin for advanced gastric cancer. Although a pathological complete response is a rare event, it would be associated with the long-term survival of patients with advanced gastric cancer.


Background
Gastric cancer is the second leading cause of cancer-related deaths worldwide. The prognosis of gastric cancer with distant metastasis is extremely unfavorable because of only 15% chance of survival for the next 5 years [1]. According to the guidelines, chemotherapy is the first recommended treatment of unresectable gastric cancer based on clinical trials [2,3]. The clinical response rate reported for chemotherapy for unresectable advanced or recurrent gastric cancer is 28-54% [4][5][6][7][8][9]. Oral 5-FU was considered gold standard until recently S-1 + cisplatin (SP) replaced it [2,4]. Several novel combined chemotherapy regimens occasionally have good response for unresectable gastric cancer and subsequently allow potentially curative gastrectomy [10][11][12]. However, a pathological complete response (pCR) is a rare event even if these powerful regimens are used.
Herein, we demonstrate a case achieved a pCR by chemotherapy with S-1 in combination with cisplatin regimen followed by surgery for advanced gastric cancer.

Case presentation
A 58-year-old male suffering from epigastralgia was referred to our hospital. Upper gastrointestinal endoscopy revealed a type 3 tumor, measuring 95 × 75 mm in diameter in the anterior wall of the gastric corpus. Pathological examination of biopsy specimen revealed moderately differentiated tubular adenocarcinoma (Fig. 1). Computed tomography (CT) showed gastric wall thickening, and a high density of fat around the gastric wall, suggesting tumor infiltration into the gastric serosa. In addition, perigastric lymphadenopathy and multiple nodules in the upper peritoneal cavity were observed. These findings confirmed that the diagnosis of this patient as advanced gastric cancer with suspicious peritoneal dissemination. We diagnosed this patient as T4aN3M1(P). The tumor markers were within normal levels. Then, the patient underwent chemotherapy with the following treatment regimens, considered as one course: S-1 (120 mg/day, days 1-21) and cisplatin (90 mg/body, day 8). After three courses of chemotherapy, upper gastrointestinal endoscopy revealed remarkable tumor shrinkage (Fig. 2a, b). In addition, CT revealed a notable improvement in gastric wall thickening, shrinkage of lymphadenopathy, and disappearance of disseminated lesions in the peritoneal cavity ( Fig. 3a-d). Because of the partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST ver 1.1) [13], we aimed to perform potentially curative resection after obtaining informed consent from the patient. The diagnosis at the time was T3N1M0. No disseminated tumors and only scar were observed intraoperatively, and the patient successfully underwent potentially curative resection by spleen-preserving total gastrectomy with lymph node dissection of the splenic hilum (No.10). Histological examination of the resected specimen and the harvested lymph nodes revealed that a pCR was achieved because no malignant cells were found (Fig. 4a, b). Furthermore, cytological examination provided no evidence of cancer cells. The postoperative course of the patient was uneventful. The patient received S-1 chemotherapy postoperatively for a period of 1 year and has been regularly attending our clinic for follow-up examination with CT every 6 months. The patient is still alive without any evidence of local recurrence or metastatic disease 7 years after the initial surgery.

Discussion
Chemotherapy is a standard treatment for stage IV gastric cancer, but the effect remains unsatisfactory. In the present report, we have experienced a rare case achieved a pCR by chemotherapy with SP. So far, various regimens such as SP, capecitabine + oxaliplatin (XELOX), and capecitabine + cisplatin (XP) + trastuzumab were used for stage IV gastric cancer. Nowadays, several molecular targets have been developed, showing survival benefits to patients with stage IV gastric cancer [14,15]. However, most of these chemotherapeutic regimens have a low potential for achieving a complete response (Table 1) [ [16][17][18]. Regarding to the impact of a pCR on the longterm survival of patients with gastric cancer, Cho et al. demonstrated that the overall survival and recurrence-free survival rates at 3 and 5 years were 96 and 85 and 91 and 75%, respectively [19]. However, this study included patients with various stages of gastric cancer (resectable stage 15/22; unresectable stage 7/22); not all patients were in stage IV. In our case, the patient is still alive with no evidence of recurrence or metastatic disease 7 years after the initial surgery. Therefore, a pCR induced by chemotherapy could be associated with long-term survival.   [20]. Actually, it is difficult to diagnose peritoneal dissemination prior to treatment. Reportedly, the sensitivity of CT for peritoneal dissemination of gastric cancer was 43-77%, with a specificity of 82-92% [21][22][23]. The accuracy of positron emission tomography (PET) for peritoneal dissemination was demonstrated 89%, with a sensitivity and specificity of 35-63 and 89-99%, respectively [21][22][23]. Kawanaka et al. recently indicated high accuracy for detecting peritoneal dissemination with the combination of CT and PET [24]. Therefore, the combination of CT and PET may be useful for diagnosis of peritoneal dissemination.
On the other hand, perioperative staging laparoscopy has often been used to detect occult peritoneal metastases in gastrointestinal cancers [25]. In the present case, we did not perform staging laparoscopy prior to chemotherapy because we detected multiple nodules enhanced inhomogeneously in extra gastric area, which suspected the presence of peritoneal dissemination.
Previous reports have demonstrated that the best timing for the operation after chemotherapy was after 2 or 4-6 cycles [20,26]. Although it is difficult to decide the best timing, former reports suggested that partial response after chemotherapy may be a good indicator for surgery. In this case, we chose surgical treatment after three courses of chemotherapy because of good response. Surgery after chemotherapy is considered to be complicated because of the presence of bulky tumor b a d c Fig. 3 Computed tomography findings. a Thickening of the gastric wall, high density of fat around the gastric wall (arrow), and perigastric lymphadenopathy (arrowhead). b Perigastric lymphadenopathy (arrow) and multiple disseminated lesions (arrowhead). c Improvement of gastric wall thickening after chemotherapy. d Shrinkage of lymphadenopathy and disappearance of disseminated lesions after chemotherapy Fig. 4 Histological findings by hematoxylin and eosin staining. a Malignant cells had disappeared in the resected stomach. b Fibrotic tissue was found to have replaced the cancer tissue in the dissected lymph node or post-chemotherapy compared to surgery without chemotherapy. There might be increased blood loss due to prolonged operation time because of fibrotic changes, adherence to adjacent organs, and a wet operative field which may be caused by chemotherapy. Previous reports have demonstrated that the incidence of complications is not significantly higher than that in patients who underwent conventional radical surgery for gastric cancer [17,27]. Indeed, in our case, the postoperative course of the patient was uneventful. In the future, the morbidity and mortality in such patients who underwent additional surgery should be evaluated using welldesigned clinical trial.

Conclusions
We encountered a rare case achieved a pCR with advanced gastric cancer treated by standard regimen (SP). It is suggested that a pCR induced by chemotherapy and potentially curative resection after intensive chemotherapy could enhance the probability of longer survival.