Clinical Study Received: August 3, 2014 Accepted after revision: October 30, 2014 Published online: January 14, 2015
Oncology 2015;88:281–288 DOI: 10.1159/000369497
Impact of S-1 plus Cisplatin Neoadjuvant Chemotherapy on Scirrhous Gastric Cancer Chikara Kunisaki a Hirochika Makino a Jun Kimura a Ryo Takagawa a Amane Kanazawa a Mitsuyoshi Ota a Takashi Kosaka b Hidetaka A. Ono b Hirotoshi Akiyama b Itaru Endo b
Department of Surgery, Gastroenterological Center, and b Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
Key Words Scirrhous gastric cancer · Neoadjuvant chemotherapy · S-1 · Cisplatin · Histological response
Abstract Objective: This retrospective study aimed to address the therapeutic outcome for scirrhous gastric cancer patients by evaluating the effect of neoadjuvant chemotherapy prior to gastrectomy. Methods: Two cycles of a 3-week regimen of fluoropyrimidine S-1 (40 mg/m2, orally, twice daily), together with cisplatin (60 mg/m2, intravenously, day 8), were administered to patients, separated by a 2-week rest period. Surgery was performed 3 weeks later in the neoadjuvant group (n = 27). We retrospectively evaluated overall survival and prognostic factors in these patients. Results: Univariate analysis showed that positive lavage cytology indicated significantly worse prognoses. In the 15 patients who also underwent curative gastrectomies after S-1 plus cisplatin chemotherapy, the pathological response grade was a significant prognostic factor for 5-year survival. Additionally, lymph node metastasis tended to be an adverse prognostic factor. Conclusion: After S-1 plus cisplatin neoadjuvant chemother-
© 2015 S. Karger AG, Basel 0030–2414/15/0885–0281$39.50/0 E-Mail [email protected] www.karger.com/ocl
apy, a grade 2–3 pathological response may predict favorable outcomes in scirrhous gastric cancer patients receiving curative gastrectomy, but further studies are needed to confirm these results. © 2015 S. Karger AG, Basel
Introduction
Although the incidence of gastric cancer has been decreasing, it remains the second most common cause of cancer-related death in the world [1]. Moreover, the prognosis for advanced gastric cancer remains unsatisfactory, despite multidisciplinary treatment strategies [2, 3]. Scirrhous gastric cancer is a particular type of gastric cancer, which clinically presents mainly in young women, with the whole stomach distended beneath the gastric mucosa, usually at an advanced stage at diagnosis, showing peritoneal dissemination at recurrence, and with a poor prognosis [4–6]. No adequate therapeutic strategy for scirrhous gastric cancer has been established [7]. Some basic research has suggested that fibroblasts play an important role in the progression, growth, and spread Dr. Chikara Kunisaki Department of Surgery, Gastroenterological Center Yokohama City University, 4-57 Urafune-cho Minami-ku, Yokohama 232-0024 (Japan) E-Mail s0714 @ med.yokohama-cu.ac.jp
Downloaded by: Univ. of California Santa Barbara 198.143.33.33 - 7/6/2015 4:18:26 AM
a
D
A’
B’
Fig. 1. Assessment of the effect of neoadjuvant chemotherapy on
primary tumors. Primary tumor responses were assessed in upper gastrointestinal X-ray series in standing patients. A vertical line was drawn from the angle of His (C′) to the level of the oral margin (D′) on the lesser curvature at the site of the tumor (A′). A line was drawn horizontally from A′ to the tumor site on the greater curvature (B′). The small gray area was calculated as the tumor area. The dilatation rate was calculated as postneoadjuvant area/preneoadjuvant area × 100%.
of scirrhous gastric cancer [8, 9]. Growth factors produced by organ-specific fibroblasts have been identified as closely associated with the malignancy of scirrhous gastric cancer, and a variety of genes have been associated with the progression and invasiveness of this type of gastric cancer [10, 11]. Recently, several studies have reported the effectiveness of neoadjuvant chemotherapy for advanced gastric cancer [12, 13], but its effectiveness in scirrhous gastric cancer has not been fully examined. A phase III trial has shown that S-1 plus cisplatin (SP) chemotherapy was a promising treatment for advanced gastric cancer [14]. In this study, we aimed to assess the impact of SP as neoadjuvant chemotherapy on scirrhous gastric cancer. Patients and Methods Patients Between April 2004 and March 2012, a total of 1,400 gastric cancer patients underwent gastrectomy with curative intent at the Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama, Japan and its related institutions. Seventy-six of these patients were treated for scirrhous gastric cancer, of whom 46 underwent total gastrectomy. In these patients, the total gastrectomies were curative (R0 resections) in 22 cases, and 15 of these patients received SP neoadjuvant chemotherapy.
282
Oncology 2015;88:281–288 DOI: 10.1159/000369497
Diagnosis and Surgery The preoperative diagnoses of scirrhous gastric cancer used imaging techniques and the analysis of endoscopic biopsies. All patients underwent a barium swallow study and computed tomography scans. Some patients also underwent positron emission tomography to investigate distant metastases. The staging and definition of lymph nodes were principally based on the tumor-nodemetastasis classification [15], with clinicians making preoperative diagnoses based on this classification and experienced pathologists making the final pathology-based diagnoses after surgery. From April 2009, diagnostic laparoscopies were carried out in 10 of the 27 patients treated with SP neoadjuvant chemotherapy, with their informed consent. D1 gastrectomies were performed in 5 patients, D2 gastrectomies in 17 patients, and 5 patients underwent D3 (D2 plus para-aortic lymph node dissection) gastrectomies. Neoadjuvant Chemotherapy Twice-daily doses of 40 mg/m2 S-1 were given orally for 3 consecutive weeks, with 60 mg/m2 cisplatin given intravenously on day 8. After a 2-week rest period, this regimen was repeated and surgery was performed 3 weeks after the second 3-week chemotherapy cycle. Adverse toxicities were described according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0). When grade 3 or 4 adverse toxicities occurred, treatment was discontinued and only resumed after recovery from the adverse symptoms and at reduced doses. Assessment of Neoadjuvant Chemotherapy Primary tumor responses were assessed in upper gastrointestinal X-ray series in standing patients, according to the Japanese Classification of Gastric Carcinoma by the Japanese Gastric Cancer Association [16]. Figure 1 shows the dimensions used to calculate tumor areas. The dilatation rate of the stomach was calculated as: postneoadjuvant area/preneoadjuvant area × 100%. Patients were classified into 2 groups: those with dilatation rates ≥110% and those with dilatation rates
Oncology 2015;88:281–288 DOI: 10.1159/000369497
Impact of S-1 plus Cisplatin Neoadjuvant Chemotherapy on Scirrhous Gastric Cancer Chikara Kunisaki a Hirochika Makino a Jun Kimura a Ryo Takagawa a Amane Kanazawa a Mitsuyoshi Ota a Takashi Kosaka b Hidetaka A. Ono b Hirotoshi Akiyama b Itaru Endo b
Department of Surgery, Gastroenterological Center, and b Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
Key Words Scirrhous gastric cancer · Neoadjuvant chemotherapy · S-1 · Cisplatin · Histological response
Abstract Objective: This retrospective study aimed to address the therapeutic outcome for scirrhous gastric cancer patients by evaluating the effect of neoadjuvant chemotherapy prior to gastrectomy. Methods: Two cycles of a 3-week regimen of fluoropyrimidine S-1 (40 mg/m2, orally, twice daily), together with cisplatin (60 mg/m2, intravenously, day 8), were administered to patients, separated by a 2-week rest period. Surgery was performed 3 weeks later in the neoadjuvant group (n = 27). We retrospectively evaluated overall survival and prognostic factors in these patients. Results: Univariate analysis showed that positive lavage cytology indicated significantly worse prognoses. In the 15 patients who also underwent curative gastrectomies after S-1 plus cisplatin chemotherapy, the pathological response grade was a significant prognostic factor for 5-year survival. Additionally, lymph node metastasis tended to be an adverse prognostic factor. Conclusion: After S-1 plus cisplatin neoadjuvant chemother-
© 2015 S. Karger AG, Basel 0030–2414/15/0885–0281$39.50/0 E-Mail [email protected] www.karger.com/ocl
apy, a grade 2–3 pathological response may predict favorable outcomes in scirrhous gastric cancer patients receiving curative gastrectomy, but further studies are needed to confirm these results. © 2015 S. Karger AG, Basel
Introduction
Although the incidence of gastric cancer has been decreasing, it remains the second most common cause of cancer-related death in the world [1]. Moreover, the prognosis for advanced gastric cancer remains unsatisfactory, despite multidisciplinary treatment strategies [2, 3]. Scirrhous gastric cancer is a particular type of gastric cancer, which clinically presents mainly in young women, with the whole stomach distended beneath the gastric mucosa, usually at an advanced stage at diagnosis, showing peritoneal dissemination at recurrence, and with a poor prognosis [4–6]. No adequate therapeutic strategy for scirrhous gastric cancer has been established [7]. Some basic research has suggested that fibroblasts play an important role in the progression, growth, and spread Dr. Chikara Kunisaki Department of Surgery, Gastroenterological Center Yokohama City University, 4-57 Urafune-cho Minami-ku, Yokohama 232-0024 (Japan) E-Mail s0714 @ med.yokohama-cu.ac.jp
Downloaded by: Univ. of California Santa Barbara 198.143.33.33 - 7/6/2015 4:18:26 AM
a
D
A’
B’
Fig. 1. Assessment of the effect of neoadjuvant chemotherapy on
primary tumors. Primary tumor responses were assessed in upper gastrointestinal X-ray series in standing patients. A vertical line was drawn from the angle of His (C′) to the level of the oral margin (D′) on the lesser curvature at the site of the tumor (A′). A line was drawn horizontally from A′ to the tumor site on the greater curvature (B′). The small gray area was calculated as the tumor area. The dilatation rate was calculated as postneoadjuvant area/preneoadjuvant area × 100%.
of scirrhous gastric cancer [8, 9]. Growth factors produced by organ-specific fibroblasts have been identified as closely associated with the malignancy of scirrhous gastric cancer, and a variety of genes have been associated with the progression and invasiveness of this type of gastric cancer [10, 11]. Recently, several studies have reported the effectiveness of neoadjuvant chemotherapy for advanced gastric cancer [12, 13], but its effectiveness in scirrhous gastric cancer has not been fully examined. A phase III trial has shown that S-1 plus cisplatin (SP) chemotherapy was a promising treatment for advanced gastric cancer [14]. In this study, we aimed to assess the impact of SP as neoadjuvant chemotherapy on scirrhous gastric cancer. Patients and Methods Patients Between April 2004 and March 2012, a total of 1,400 gastric cancer patients underwent gastrectomy with curative intent at the Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama, Japan and its related institutions. Seventy-six of these patients were treated for scirrhous gastric cancer, of whom 46 underwent total gastrectomy. In these patients, the total gastrectomies were curative (R0 resections) in 22 cases, and 15 of these patients received SP neoadjuvant chemotherapy.
282
Oncology 2015;88:281–288 DOI: 10.1159/000369497
Diagnosis and Surgery The preoperative diagnoses of scirrhous gastric cancer used imaging techniques and the analysis of endoscopic biopsies. All patients underwent a barium swallow study and computed tomography scans. Some patients also underwent positron emission tomography to investigate distant metastases. The staging and definition of lymph nodes were principally based on the tumor-nodemetastasis classification [15], with clinicians making preoperative diagnoses based on this classification and experienced pathologists making the final pathology-based diagnoses after surgery. From April 2009, diagnostic laparoscopies were carried out in 10 of the 27 patients treated with SP neoadjuvant chemotherapy, with their informed consent. D1 gastrectomies were performed in 5 patients, D2 gastrectomies in 17 patients, and 5 patients underwent D3 (D2 plus para-aortic lymph node dissection) gastrectomies. Neoadjuvant Chemotherapy Twice-daily doses of 40 mg/m2 S-1 were given orally for 3 consecutive weeks, with 60 mg/m2 cisplatin given intravenously on day 8. After a 2-week rest period, this regimen was repeated and surgery was performed 3 weeks after the second 3-week chemotherapy cycle. Adverse toxicities were described according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0). When grade 3 or 4 adverse toxicities occurred, treatment was discontinued and only resumed after recovery from the adverse symptoms and at reduced doses. Assessment of Neoadjuvant Chemotherapy Primary tumor responses were assessed in upper gastrointestinal X-ray series in standing patients, according to the Japanese Classification of Gastric Carcinoma by the Japanese Gastric Cancer Association [16]. Figure 1 shows the dimensions used to calculate tumor areas. The dilatation rate of the stomach was calculated as: postneoadjuvant area/preneoadjuvant area × 100%. Patients were classified into 2 groups: those with dilatation rates ≥110% and those with dilatation rates
