Masumi Ichinose

Safety and Efficacy of Bidirectional Chemotherapy for Treatment of Patients With Peritoneal Dissemination From Gastric Cancer: Selection for Cytoreductive Surgery

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. New bidirectional chemotherapy (neoadjuvant intraperitoneal‐systemic chemotherapy protocol (NIPS)) was developed. The aim of the present study was to assess the safety and efficacy of NIPS and to show the selection for cytoreductive surgery on PC from gastric cancer. Seventy‐nine patients with PC from gastric cancer were treated with NIPS. A peritoneal port system was introduced into the abdominal cavity. The peritoneal wash cytological examination through a port was done before and after NIPS. The patients were treated with oral TS‐1 twice a daily for 21 days, followed by a 1‐week rest. On day 1, 8, and 15 from the start of oral TS‐1 administration, 30 mg/m2 of Docetaxel and 30 mg/m2 of cisplatinum with 500 ml of saline were introduced into the peritoneal cavity through the port. A median course of oral TS‐1 was 2.1 course and a median time of IP chemoterapy was 5.8. Peritoneal free cancer cells (PFCCs) had been detected in 65 (82.2%) patients before NIPS, and the positive cytology changed to be negative in 41 (63.0%) patients after NIPS. After NIPS, 41 patients underwent laparotomy, and complete cytoreduction was done in 32 (78%) patients. Complete cytoreduction was done in 27 (51.9%) of 52 patients with negative cytology but in only 4 (14.8%) of 27 patients with positive cytology (P < 0.001). Patients with negative cytology after NIPS survived significantly longer than those with positive cytology. The adverse effects after NIPS were mild and there was no treatment‐related deaths. The grade 3/4 hematological adverse effects were found in 2 (2.6%) patients. Grade 3 renal toxicity and port site infection was found in three patients, respectively. NIPS using a port system is a safe and effective treatment for PC. Peritoneal wash cytology through a port system is a good indicator to select the patients to perform cytoreductive surgery. J. Surg. Oncol. 2009;100:311–316.

Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. A novel multidisciplinary treatment combining bidirectional chemotherapy [neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)], peritonectomy, hyperthermic intraperitoneal chemoperfusion (HIPEC) and early postoperative intraperitoneal chemotherapy has been developed. In this article, we assess the indications, safety and efficacy of this treatment, review the relevant studies and introduce our experiences. The aims of NIPS are stage reduction, the eradication of peritoneal free cancer cells, and an increased incidence of complete cytoreduction (CC-0) for PC. A complete response after NIPS was obtained in 15 (50%) out of 30 patients with PC. Thus, a significantly high incidence of CC-0 can be obtained in patients with a peritoneal cancer index (PCI) ≤ 6. Using a multivariate analysis to examine the survival benefit, CC-0 and NIPS are identified as significant indicators of a good outcome. However, the high morbidity and mortality rates associated with peritonectomy and perioperative chemotherapy make stringent patient selection important. The best indications for multidisciplinary therapy are localized PC (PCI ≤ 6) from resectable gastric cancer that can be completely removed during a peritonectomy. NIPS and complete cytoreduction are essential treatment modalities for improving the survival of patients with PC from gastric cancer.

Morbidity and Mortality Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy at a Single Institution in Japan

Background. Even though cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with a high morbidity and mortality rates, it has been reported that CRS and HIPEC improved survival of selected patients with peritoneal carcinomatosis. We aimed to report morbidity and mortality results of CRS and HIPEC from a single institution in Japan. Methods and Results. Total of 284 procedures of CRS were performed on patients with pseudomyxoma peritonei, peritoneal carcinomatosis (PC) from colon cancer and gastric cancer between 2007 and 2011 in our institution. The morbidity rate was 49% of all procedure, and grades I/II and grades III/IV complications were 28% and 17%, respectively. Most frequent complication was surgical site infections including intraabdominal abscess. The mortality rate was 3.5%, and reoperation was needed in 11% of all procedures. Univariate and multivariate analysis showed peritoneal carcinomatosis index (PCI) greater than 20 was the only significant factor for occurrence of postoperative complications (P < 0.01). In contrast, HIPEC significantly reduced postoperative complications (P < 0.05). Conclusions. The morbidity and mortality rates of our institution are comparable with previous reports that are in acceptable rates. Optimal patient selection such as patients with PCI less than 20 seems to be of paramount importance to CRS and HIPEC.

Laparoscopic Diagnosis and Laparoscopic Hyperthermic Intraoperative Intraperitoneal Chemotherapy for Pseudomyxoma Peritonei Detected by CT Examination

Background. Patients with early stage of pseudomyxoma peritonei (PMP) are sometimes difficult to diagnose the primary sites and intraperitoneal spread of tumor and to perform a cytological study. Methods. Patients without a definitive diagnosis and with unknown extent of peritoneal spread of tumor underwent laparoscopy. Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) was administered as part of the same intervention. The results of treatment were evaluated at the time of second-look laparotomy (SLL) as a subsequent intervention. Results. Eleven patients were managed by diagnostic laparoscopy followed by laparoscopic HIPEC (LHIPEC). The operation time of laparoscopic examination and LHIPEC was 177 ± 26 min (range 124–261 min). No intraoperative complication was experienced. The peritoneal carcinomatosis index (PCI) score by laparoscopic observation was 16.5 ± 6.4 (range 0–30). One patient with localized pseudomyxoma peritonei (PMP) mucocele did not received LHIPEC; the other 10 patients with peritoneal metastases (PM) were treated with LHIPEC. After LHIPEC, ascites disappeared in 2 cases and decreased in the amount in the other 8 cases. Nine patients underwent SLL and cytoreductive surgery (CRS) combined with HIPEC. The duration between LHIPEC and SLL ranged from 40 to 207 days (97 ± 40 days). The PCI at the SLL ranged from 4 to 27 (12.9 ± 7.1). The PCI at the time of SLL decreased as compared to PCI at the time of diagnostic laparotomy in 7 of 9 patients. Median follow-up period is 22 months (range 7–35). All 11 patients are alive. Conclusion. The early results suggest that laparoscopic diagnosis combined with LHIPEC is useful to determine the surgical treatment plan and reduce the tumor burden before definitive CRS at SLL.

Risk Factors for Recurrence after Complete Cytoreductive Surgery andPerioperative Chemotherapy in Peritoneal Metastases from GastricCancer

Background and objective: The aim of this study is to analyze anatomical distribution, timing and outcomes of recurrence after complete cytoreduction and perioperative chemotherapy for peritoneal metastasis from gastric cancer (GCPM). Method: Data of 193 GCPM patients who underwent a complete cytoreductive surgery (CRS) after treatment with neoadjuvant chemotherapy were entered into a prospective database and the recurrence was analyzed. Result: The median time to progression was 16.2 months, median overall survival (OS) was 21.6 months and 5-year survival rate was 18.1%. Five years after CRS, 11 patients were disease free survivors. Recurrence rate was 68.5% (126/184). Mutivariate analysis confirmed small bowel peritoneal cancer index of ≥3 and pathologic nonresponders after NAC as independent risk factors for recurrence. Patients were treated with systemic chemotherapy or second cytoreductive surgery for recurrence. However, survival after diagnosis of recurrence was poor with median survival of 2.9 months. The most common type of recurrence was diffuse peritoneal recurrence (71%, 90/126). Localized intra-abdominal recurrence was experienced in only 7 patients. Conclusion: Pathologic non-responders and small bowel PCI of ≥3 are independent risk factors for recurrence. Exploratory laparoscopy after NAC might be a useful strategy for the selection of patients for CRS.

Phase II Study of a Comprehensive Treatment Using Perioperative Chemotherapy Combined with Cytoreductive Surgery for Curatively Resected Gastric Cancer Patients with Positive Peritoneal Wash Cytology

Patients with curatively resected gastric cancer patients with positive peritoneal wash cytology are called P0/Cy1 status. The aim of the present study is to verify the survival benefit of the comprehensive treatment for patients with P0/Cy1 status. Twenty gastric cancer patients were diagnosed as P0/Cy1 by laparoscopy or laparotomy, and were treated with a comprehensive treatment consisting of neoadjuvant intraperitoneal/systemic chemotherapy (NIPS), cytoreductive surgery (CRS) consisting of gastrectomy with lymph node dissection and peritonectomy, intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and postoperative systemic chemotherapy. At the second look laparotomy, the peritoneal wash cytology became negative in 15 patients. No grade 3, 4, 5 complications were experienced after second look operations for CRS. Median follow-up time is 3.7 years. Eight patients died of recurrence, but the other 21 patients are alive without recurrence. Five-year survival rate was 42%. The present study demonstrated the efficacy and safety of the comprehensive treatment on the gastric cancer patients in P0/Cy1 status.

Photodynamic Detection of Peritoneal Metastases Using 5-Aminolevulinic Acid (ALA)

In the past, peritoneal metastasis (PM) was considered as a terminal stage of cancer. From the early 1990s, however, a new comprehensive treatment consisting of cytoreductive surgery and perioperative chemotherapy has been established to improve long-term survival for selected patients with PM. Among prognostic indicators after the treatment, completeness of cytoreduction is the most independent predictors of survival. However, peritoneal recurrence is a main cause of recurrence, even after complete cytoreduction. As a cause of peritoneal recurrence, small PM may be overlooked at the time of cytoreductive surgery (CRS), therefore, development of a new method to detect small PM is desired. Recently, photodynamic diagnosis (PDD) was developed for detection of PM. The objectives of this review were to evaluate whether PDD using 5-aminolevulinic acid (ALA) could improve detection of small PM.

Mechanisms of the Formation of Peritoneal Surface Malignancy on Omental Milky Spots from Low Grade Appendiceal Mucinous Carcinoma

Mechanisms of the Formation of Peritoneal Surface Malignancy on Omental Milky Spots from Low Grade Appendiceal Mucinous Carcinoma Purpose: Omental milky spot (OMS) is considered to have an important role in the formation of peritoneal surface malignancy (PSM). However, human OMS and cancer metastasis has not been fully clarified. The present study demonstrates the mechanisms of the formation of metastasis on the omental milky spots (OMS) from the low grade AMC. Methods and materials: To clarify the mechanism of the formation of peritoneal metastasis in low grade appendiceal mucinous carcinoma (AMC), 195 low grade AMC showing peritoneal cancer index (PCI) of ≤28 were studied for the distribution of peritoneal metastasis. Peritoneum was resected from 10 patients, and was prepared as whole-mount extending specimen. The specimens were studied by 5’-nucleotidase and alkaline phosphatase double stain and immunohistologic staining by D2-40, anti-CD31 and anti- Ki-67 monoclonal antibody. Furthermore, peritoneal parts were observed by scanning electron microscopy. Results: Pelvic and subdiaphragmatic peritoneum were involved in 164 (84%) and 143 (73%) patients. Greater omentum was involved in 135 (69%) patients. Under the SEM observation, no typical milky spots were observed on the peritoneum except for the greater omentum. Surface of OMS was covered with cuboidal mesothelial cells. Between the cuboidal mesothelial cells, many stomata were found. After digestion of OMS by 6N KOH, disk-like peritoneal pouch was detected at OMS. Small holes were found on the collagen plate covered on the bottom of the pouch. Below the pouch, initial lymphatic vessels closed to the pouch with stomata. Agglomerated blood capillaries distributed around the initial lymphatics. Metastasis foci were found around the stomata on OMS, but were not detected on the flat mesothelial cells on the greater omentum.. Conclusion: Peritoneal free cancer cells from low grade AMC may be adsorbed at stomata and adhere on the OMS. Then, they proliferate on OMS.

Management of Peritoneal Metastases Developed from Gastric Cancer:Laparascopic Hyperthermic Intraperitoneal Chemontherapy in NeoadjuvantSetting

Objective: Peritoneal Metastases (PM) of Gastric Cancer (GC) are lesions of peritoneal surfaces, which may cause the dissemination throughout the abdominal cavity. The role of laparoscopic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) as neoadjuvant purpose in the management of PM of GC is undefined. Methods: Fifty patients were enrolled into this study with histopathological diagnosis of PM of GC referred to our center between 2012 and 2013 All patients were underwent two cycles of neoadjuvant laparoscopic HIPEC. At the second session of LHIPEC, ascites volume, cytological status and PCI levels were compared with those at the 1st LHIPEC. Results: There was no intraoperative complication and mortality after LHIPEC. Four patients developed mild azotemia of Grade 2. Amount of ascites were completely abolished or decreased in 22 of 34 (64.7%) and positive peritoneal cytology changed to be a negative in 14 of 20 (70%) patients at the 2nd LHIPEC. Complete response was in 6 (12%), and peritoneal cancer indices (PCI) were significantly reduced from 14.3 ± 10.2 at the 1st LHIPEC to 10.8 ± 10.5 at the 2nd LHIPEC (p<0.05). Furthermore, total PCI scores on small bowel mesentery at 1st and 2nd LHIPEC were 6.56 ± 2.92 and 5.25 ± 3.78 (P=0.016). Conclusions: This study identified two outcomes. Diagnostic and therapeutic laparoscopy can be performed safely in patients with PM of GC. Laparoscopic HIPEC can be applied as a neoadjuvant treatment modality in order to reduce the tumor burden and disease control until complete managements to be achieved in patients with PM of GC.

A case of ovarian growing teratoma syndrome treated by cytoreductive surgery

Ovarian growing teratoma syndrome (GTS) is a rare disease characterized by growth of a benign tumor during or after chemotherapy, following the removal of germ cell gonadal cancers. Although benign, GTS tumors grow gradually and may compress surrounding organs. In addition, up to 3% of GTS cases can undergo malignant transformation. It is, therefore, needed to treat GTS. No standardized management protocol has been established to treat GTS; however, surgical resection is likely the only effective treatment because tumors in GTS are resistant to chemotherapy and radiation therapy. However, complete resection with conventional procedures is sometimes difficult when peritoneal metastasis is widespread. We report a rare case of ovarian GTS with widespread peritoneal metastases, which was totally resected by peritonectomy procedures. A 45-year-old Japanese woman was initially diagnosed with an immature teratoma grade 3, which was treated by hysterectomy and bilateral salpingo-oophorectomy. Adjuvant chemotherapy was performed after surgery with bleomycin, etoposide, cisplatin, and other chemotherapies. Due to recurrence of a chemoresistant tumor and normalization of tumor markers, GTS was suspected. She was referred to our institute, and complete cytoreductive surgery was performed using peritonectomy procedures, including parietal peritoneal resection, greater omentectomy, lesser omentectomy, rectosigmoid colectomy, diaphragm dissection, and cholecystectomy. A complete cytoreduction with no visible residual tumor tissue was achieved.