Journal of Surgical Oncology 2015;111:840–847
Hyperthermic Intraperitoneal Chemotherapy Plus Simultaneous Versus Staged Cytoreductive Surgery for Gastric Cancer With Occult Peritoneal Metastasis XIAOJIANG WU, MD, ZIYU LI, MD, ZIRAN LI, MD, YONGNING JIA, MD, FEI SHAN, MD, XIN JI, ZHAODE BU, MD, LIANHAI ZHANG, MD, AIWEN WU, MD, AND JIAFU JI, MD*
MD,
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China
Background: Our aim is to evaluate the safety and efficacy of two treatment strategies, hyperthermic intraperitoneal chemotherapy (HIPEC) plus simultaneous versus staged cytoreductive surgery (CRS) in patients with occult peritoneal metastasis of gastric cancer (GC). Methods: We retrospectively reviewed 26 GC patients who were potential curatively resectable by pre-operative evaluation and found occult peritoneal metastasis by diagnostic laparoscopy. Patients were treated by HIPEC plus either simultaneous CRS (CRSþHIPEC group, n ¼ 11) or staged CRS after systematic chemotherapy (HIPECþChemoþCRS group, n ¼ 15). Results: There is no mortality observed in both groups. The treatment complications in two group is comparable (P ¼ 0.683), with 26.7% (4/15) in HIPECþChemoþCRS group, and 36.4% (4/11) in CRSþHIPEC group, respectively. The compliance of patients undergoing subsequent chemotherapy is higher in HIPECþChemoþCRS group (93.3%, 14/15) than that of CRSþHIPEC group (45.5%, 5/11) (P ¼ 0.021). The mean interval time between CRS and first post-CRS systematic chemotherapy were 42.0 12.0 days in HIPECþChemoþCRS group versus 69.8 36.3 in CRSþHIPEC group (P ¼ 0.163), respectively. The median OS in the HIPECþChemoþCRS group was 25.0 months, while 28.2 months in the CRSþHIPEC group (P ¼ 0.738). Conclusion: For resectable GC patients with laparoscopic findings of occult peritoneal metastasis, HIPEC plus staged CRS is with better tolerance and compliance than simultaneous CRS.
J. Surg. Oncol. 2015;111:840–847. ß 2015 Wiley Periodicals, Inc.
KEY WORDS: gastric cancer; occult peritoneal metastasis; diagnostic laparoscopy; hyperthermic intraperitoneal chemotherapy; cytoreductive surgery
INTRODUCTION Gastric cancer (GC) is one of the most common cancers in the world, and also one of the leading causes of cancer death in both sexes in China [1,2]. Gastric cancer is usually diagnosed at advanced stages and several long-term results of large-scale studies showed that peritoneal spread is the most common pattern of GC metastasis [3–5]. The conventional diagnosis for peritoneal metastasis is usually by radiological evaluation with findings of irregular mass or thickening of peritoneum and ascites. The treatments for patients with peritoneal metastasis include best supportive care and palliative systemic chemotherapy. There is no consensus first line regimen for this situation [6,7]. These patients have a very poor prognosis and median survival of less than 1 year [8–11]. Occult peritoneal metastasis of GC is defined as peritoneal spread that is detected by diagnostic laparoscopy, without any specific signs of metastasis by preoperative radiological examinations [12,13]. These patients show scattered peritoneal nodules (Pþ) or free cancer cells (cytology positive, CYþ) in peritoneal lavage during the diagnostic laparoscopy. Because of the limited metastasis and good performance status, these patients might benefit from a more aggressive surgical intervention [14,15]. Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) have been developed over the past 3 decades to treat a variety of peritoneal metastasis of cancer diseases, taking advantages of surgery to reduce visible tumor burden and regional hyperthermic intraperitoneal chemotherapy to eradicate micro-metastases [16]. Thus, this technique has expanded cancer surgery from resection of primary tumor to surgical management of peritoneal metastatic diseases.
ß 2015 Wiley Periodicals, Inc.
However, there is no standard management for occult peritoneal metastasis of GC by far [4]. In this study, we retrospectively reviewed GC patients with occult peritoneal metastasis in our center. For these patients who are willing to accept surgical CRS plus HIPEC, two strategies exist. One is to treat the patient by simultaneous CRS and HIPEC (CRSþHIPEC) and then systematic chemotherapy afterward when patient recovered. The other is to treat by HIPEC first and then systematic chemotherapy for two cycles followed by staged CRS (HIPECþChemoþCRS), and then continuous systematic chemotherapy afterward when patient recovered. The safety, efficacy, and benefit of two strategies were evaluated.
Grant sponsor: Open Fund of Key Laboratory of Carcinogenesis.; Grant sponsor: Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute. Xiaojiang Wu, Ziyu Li, and Ziran Li contributed equally to this study. * Correspondence to: Jiafu Ji, MD, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China. Fax: 86-10-88196896. E-mail: [email protected]; or [email protected] Received 9 November 2014; Accepted 2 January 2015 DOI 10.1002/jso.23889 Published online 10 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
HIPEC Plus Cytoreductive Surgery in GC
MATERIALS AND METHODS Patients The medical records of patients with GC in the Department of Gastrointestinal Surgery at Peking University Cancer Hospital between January 2010 and April 2014 were reviewed. All GC patients with occult peritoneal metastasis who received HIPEC plus simultaneous or staged CRS were included. The inclusion criteria include the following: (1) clinical stage of patients by preoperative evaluation (workup) was cT2-4N0-3M0 and patient was deemed as operable for a potential curative resection after reviewing by a multidisciplinary team based mainly on radiology findings. There is no radiological evidence of distant metastasis including peritoneal metastasis; (2) patients were found with occult peritoneal metastasis, such as scattered peritoneal nodules (Pþ) and/or free cancer cells (CYþ) in peritoneal lavage, by diagnostic laparoscopy; (3) patient received HIPEC plus simultaneous CRS or staged CRS after two cycles of systematic chemotherapy; (4) a completely cytoreductive surgery (cCRS) could be potential achieved by surgeon’s judgment. Patients with hepatic metastasis, ovarian metastasis, or other organ metastasis found by diagnostic laparoscopy were excluded. Patients with incomplete follow-up information were also excluded. Treating these patients by these methods has been previously approved by the ethic committee of our hospital and informed consents were obtained from all the patients. The TNM staging of GC is followed the 7th edition of classification recommended by the American Joint Committee on Cancer (AJCC) [17]. Follow-up was performed by regularly calling the patients and accessing outpatient records. The overall survival (OS) was defined as the period between the date of first
Fig. 1.
diagnostic laparoscopy and either the date of the last follow-up or the date of death. A death due to gastric cancer was considered to be an endpoint event.
Workup and Treatment The management of these patients is showed in Figure 1. The workup of patients include upper GI endoscopy and biopsy followed by pathological diagnosis, chest X-ray/CT, abdominopelvic enhanced CT scan, and endoscopic ultrasonography (EUS). After the preoperative evaluation, diagnostic laparoscopy is regular performed to evaluate for peritoneal spread and free cancer cells in peritoneal lavage by cytology examination. The protocol of cytology examination is as followed: About 250 ml of warm normal saline is infused into subphrenic space, subhepatic space, omentum, bilateral paracolic sulci, and the pouch of Douglas. The irrigate is not administered over the primary tumor. After gentle agitation of the lower abdomen, 100 ml of fluid is aspirated from the subphrenic space, subhepatic space, and Douglas’ pouch. The fluid is immediately sent for cytological examination. After centrifuge 2000 rpm for 10 min, the precipitates are smeared and fixed by 95% ethanol for 15 min and then routinely hematoxylin eosin stained. Diagnosis is judged by a board-certificated pathologist in our pathology department. When occult peritoneal spread was found, peritoneal carcinomatosis index (PCI) was calculated, based on size and distribution as illustrated by Sugarbaker [18]. And the surgeon judged whether a completely cytoreductive surgery (cCRS) could be potential achieved. Then HIPEC plus simultaneous CRS or staged CRS after systematic chemotherapy were performed. Treatment
Treatment strategies for GC patients with occult peritoneal metastasis.
Journal of Surgical Oncology
841
842
Wu et al.
allocation for each patient was determined preoperatively by patient’s preference and prospectively scheduled. If a cCRS could not be achieved by surgeon’s judgment, palliative systemic chemotherapy and best supportive care were given afterward. In simultaneous CRSþHIPEC group, patients received CRS followed by intra-operative HIPEC, and then received a maximum of eight cycles of systematic chemotherapy when recovering from the surgery. In staged CRS group, patients received HIPEC and two cycles of systematic chemotherapy when recovering from the surgery. Then patients were evaluated again by workup. Only patients with complete or partial response, or stable disease were eligible to receive a second diagnostic laparoscopy and CRS. After recovering from the surgery, patients continued a maximum of six cycles of systematic chemotherapy. In both group, patients received chemotherapy when recovering from surgical procedures. The criteria to start chemotherapy include oral intake semi-liquid food, ECOG (Eastern Cooperative Oncology Group) performance score 2, and eligibility for hematological examinations.
outflow tubes for perfusion were separately placed in the pelvis cavity around Douglas’s pouch, while one inflow tube was placed in subphrenic area. Approximately 3 L of heated 5% glucose containing oxaliplatin (345 mg/m2) was circulated for 30 min. After removal of the glucose, 3 additional liters of heated saline containing paclitaxel (260 mg/m2) was sequentially circulated for another 30 min. The abdomen was gently rocked during perfusion to distribute the drug evenly throughout the abdominal cavity. The heated perfusion solution was infused into the peritoneal cavity at a rate of 500–800 ml/min through the inflow tube, which was introduced by an automatic hyperthermia perfusion device (RHL-2000B, Madain Medical Devices Co., Ltd., Jilin, China). The temperature of the perfusion solution in the inflow tube and outflow tube was monitored in real time. The temperature of the perfusion solution in the peritoneal cavity was maintained at 43.0 0.5 °C. The inflow and outflow temperature curves were stored in the device. After the HIPEC procedures were completed, as much perfusion fluid as possible was removed from the abdominal cavity.
Statistical Analysis Chemotherapy Chemotherapy regime is SOX [19,20], a 3-week cycle of S-1 [21] (Tegafur, Gimeracil, and Oteracil Potassium Capsules, 60 mg/ >1.5 m2, 50 mg/1.25–1.5 m2, 40 mg/
Hyperthermic Intraperitoneal Chemotherapy Plus Simultaneous Versus Staged Cytoreductive Surgery for Gastric Cancer With Occult Peritoneal Metastasis XIAOJIANG WU, MD, ZIYU LI, MD, ZIRAN LI, MD, YONGNING JIA, MD, FEI SHAN, MD, XIN JI, ZHAODE BU, MD, LIANHAI ZHANG, MD, AIWEN WU, MD, AND JIAFU JI, MD*
MD,
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China
Background: Our aim is to evaluate the safety and efficacy of two treatment strategies, hyperthermic intraperitoneal chemotherapy (HIPEC) plus simultaneous versus staged cytoreductive surgery (CRS) in patients with occult peritoneal metastasis of gastric cancer (GC). Methods: We retrospectively reviewed 26 GC patients who were potential curatively resectable by pre-operative evaluation and found occult peritoneal metastasis by diagnostic laparoscopy. Patients were treated by HIPEC plus either simultaneous CRS (CRSþHIPEC group, n ¼ 11) or staged CRS after systematic chemotherapy (HIPECþChemoþCRS group, n ¼ 15). Results: There is no mortality observed in both groups. The treatment complications in two group is comparable (P ¼ 0.683), with 26.7% (4/15) in HIPECþChemoþCRS group, and 36.4% (4/11) in CRSþHIPEC group, respectively. The compliance of patients undergoing subsequent chemotherapy is higher in HIPECþChemoþCRS group (93.3%, 14/15) than that of CRSþHIPEC group (45.5%, 5/11) (P ¼ 0.021). The mean interval time between CRS and first post-CRS systematic chemotherapy were 42.0 12.0 days in HIPECþChemoþCRS group versus 69.8 36.3 in CRSþHIPEC group (P ¼ 0.163), respectively. The median OS in the HIPECþChemoþCRS group was 25.0 months, while 28.2 months in the CRSþHIPEC group (P ¼ 0.738). Conclusion: For resectable GC patients with laparoscopic findings of occult peritoneal metastasis, HIPEC plus staged CRS is with better tolerance and compliance than simultaneous CRS.
J. Surg. Oncol. 2015;111:840–847. ß 2015 Wiley Periodicals, Inc.
KEY WORDS: gastric cancer; occult peritoneal metastasis; diagnostic laparoscopy; hyperthermic intraperitoneal chemotherapy; cytoreductive surgery
INTRODUCTION Gastric cancer (GC) is one of the most common cancers in the world, and also one of the leading causes of cancer death in both sexes in China [1,2]. Gastric cancer is usually diagnosed at advanced stages and several long-term results of large-scale studies showed that peritoneal spread is the most common pattern of GC metastasis [3–5]. The conventional diagnosis for peritoneal metastasis is usually by radiological evaluation with findings of irregular mass or thickening of peritoneum and ascites. The treatments for patients with peritoneal metastasis include best supportive care and palliative systemic chemotherapy. There is no consensus first line regimen for this situation [6,7]. These patients have a very poor prognosis and median survival of less than 1 year [8–11]. Occult peritoneal metastasis of GC is defined as peritoneal spread that is detected by diagnostic laparoscopy, without any specific signs of metastasis by preoperative radiological examinations [12,13]. These patients show scattered peritoneal nodules (Pþ) or free cancer cells (cytology positive, CYþ) in peritoneal lavage during the diagnostic laparoscopy. Because of the limited metastasis and good performance status, these patients might benefit from a more aggressive surgical intervention [14,15]. Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) have been developed over the past 3 decades to treat a variety of peritoneal metastasis of cancer diseases, taking advantages of surgery to reduce visible tumor burden and regional hyperthermic intraperitoneal chemotherapy to eradicate micro-metastases [16]. Thus, this technique has expanded cancer surgery from resection of primary tumor to surgical management of peritoneal metastatic diseases.
ß 2015 Wiley Periodicals, Inc.
However, there is no standard management for occult peritoneal metastasis of GC by far [4]. In this study, we retrospectively reviewed GC patients with occult peritoneal metastasis in our center. For these patients who are willing to accept surgical CRS plus HIPEC, two strategies exist. One is to treat the patient by simultaneous CRS and HIPEC (CRSþHIPEC) and then systematic chemotherapy afterward when patient recovered. The other is to treat by HIPEC first and then systematic chemotherapy for two cycles followed by staged CRS (HIPECþChemoþCRS), and then continuous systematic chemotherapy afterward when patient recovered. The safety, efficacy, and benefit of two strategies were evaluated.
Grant sponsor: Open Fund of Key Laboratory of Carcinogenesis.; Grant sponsor: Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute. Xiaojiang Wu, Ziyu Li, and Ziran Li contributed equally to this study. * Correspondence to: Jiafu Ji, MD, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China. Fax: 86-10-88196896. E-mail: [email protected]; or [email protected] Received 9 November 2014; Accepted 2 January 2015 DOI 10.1002/jso.23889 Published online 10 April 2015 in Wiley Online Library (wileyonlinelibrary.com).
HIPEC Plus Cytoreductive Surgery in GC
MATERIALS AND METHODS Patients The medical records of patients with GC in the Department of Gastrointestinal Surgery at Peking University Cancer Hospital between January 2010 and April 2014 were reviewed. All GC patients with occult peritoneal metastasis who received HIPEC plus simultaneous or staged CRS were included. The inclusion criteria include the following: (1) clinical stage of patients by preoperative evaluation (workup) was cT2-4N0-3M0 and patient was deemed as operable for a potential curative resection after reviewing by a multidisciplinary team based mainly on radiology findings. There is no radiological evidence of distant metastasis including peritoneal metastasis; (2) patients were found with occult peritoneal metastasis, such as scattered peritoneal nodules (Pþ) and/or free cancer cells (CYþ) in peritoneal lavage, by diagnostic laparoscopy; (3) patient received HIPEC plus simultaneous CRS or staged CRS after two cycles of systematic chemotherapy; (4) a completely cytoreductive surgery (cCRS) could be potential achieved by surgeon’s judgment. Patients with hepatic metastasis, ovarian metastasis, or other organ metastasis found by diagnostic laparoscopy were excluded. Patients with incomplete follow-up information were also excluded. Treating these patients by these methods has been previously approved by the ethic committee of our hospital and informed consents were obtained from all the patients. The TNM staging of GC is followed the 7th edition of classification recommended by the American Joint Committee on Cancer (AJCC) [17]. Follow-up was performed by regularly calling the patients and accessing outpatient records. The overall survival (OS) was defined as the period between the date of first
Fig. 1.
diagnostic laparoscopy and either the date of the last follow-up or the date of death. A death due to gastric cancer was considered to be an endpoint event.
Workup and Treatment The management of these patients is showed in Figure 1. The workup of patients include upper GI endoscopy and biopsy followed by pathological diagnosis, chest X-ray/CT, abdominopelvic enhanced CT scan, and endoscopic ultrasonography (EUS). After the preoperative evaluation, diagnostic laparoscopy is regular performed to evaluate for peritoneal spread and free cancer cells in peritoneal lavage by cytology examination. The protocol of cytology examination is as followed: About 250 ml of warm normal saline is infused into subphrenic space, subhepatic space, omentum, bilateral paracolic sulci, and the pouch of Douglas. The irrigate is not administered over the primary tumor. After gentle agitation of the lower abdomen, 100 ml of fluid is aspirated from the subphrenic space, subhepatic space, and Douglas’ pouch. The fluid is immediately sent for cytological examination. After centrifuge 2000 rpm for 10 min, the precipitates are smeared and fixed by 95% ethanol for 15 min and then routinely hematoxylin eosin stained. Diagnosis is judged by a board-certificated pathologist in our pathology department. When occult peritoneal spread was found, peritoneal carcinomatosis index (PCI) was calculated, based on size and distribution as illustrated by Sugarbaker [18]. And the surgeon judged whether a completely cytoreductive surgery (cCRS) could be potential achieved. Then HIPEC plus simultaneous CRS or staged CRS after systematic chemotherapy were performed. Treatment
Treatment strategies for GC patients with occult peritoneal metastasis.
Journal of Surgical Oncology
841
842
Wu et al.
allocation for each patient was determined preoperatively by patient’s preference and prospectively scheduled. If a cCRS could not be achieved by surgeon’s judgment, palliative systemic chemotherapy and best supportive care were given afterward. In simultaneous CRSþHIPEC group, patients received CRS followed by intra-operative HIPEC, and then received a maximum of eight cycles of systematic chemotherapy when recovering from the surgery. In staged CRS group, patients received HIPEC and two cycles of systematic chemotherapy when recovering from the surgery. Then patients were evaluated again by workup. Only patients with complete or partial response, or stable disease were eligible to receive a second diagnostic laparoscopy and CRS. After recovering from the surgery, patients continued a maximum of six cycles of systematic chemotherapy. In both group, patients received chemotherapy when recovering from surgical procedures. The criteria to start chemotherapy include oral intake semi-liquid food, ECOG (Eastern Cooperative Oncology Group) performance score 2, and eligibility for hematological examinations.
outflow tubes for perfusion were separately placed in the pelvis cavity around Douglas’s pouch, while one inflow tube was placed in subphrenic area. Approximately 3 L of heated 5% glucose containing oxaliplatin (345 mg/m2) was circulated for 30 min. After removal of the glucose, 3 additional liters of heated saline containing paclitaxel (260 mg/m2) was sequentially circulated for another 30 min. The abdomen was gently rocked during perfusion to distribute the drug evenly throughout the abdominal cavity. The heated perfusion solution was infused into the peritoneal cavity at a rate of 500–800 ml/min through the inflow tube, which was introduced by an automatic hyperthermia perfusion device (RHL-2000B, Madain Medical Devices Co., Ltd., Jilin, China). The temperature of the perfusion solution in the inflow tube and outflow tube was monitored in real time. The temperature of the perfusion solution in the peritoneal cavity was maintained at 43.0 0.5 °C. The inflow and outflow temperature curves were stored in the device. After the HIPEC procedures were completed, as much perfusion fluid as possible was removed from the abdominal cavity.
Statistical Analysis Chemotherapy Chemotherapy regime is SOX [19,20], a 3-week cycle of S-1 [21] (Tegafur, Gimeracil, and Oteracil Potassium Capsules, 60 mg/ >1.5 m2, 50 mg/1.25–1.5 m2, 40 mg/
