Yutaka Yonemura

Disposition Kinetics of Taxanes in Peritoneal Dissemination

Treatment of cancers in the abdominal cavity, such as peritoneal dissemination, is difficult, but in principle intraperitoneal administration of anticancer drugs is expected to be preferable to systemic administration. Taxane anticancer drugs are used to treat gastric cancer patients with peritoneal dissemination. They are administered as micellar preparations, Taxol and Taxotere, which consist of paclitaxel in Cremophor EL (crEL) and docetaxel in Polysorbate-80 (PS-80), respectively. In this paper we review the disposition kinetics of taxane anticancer drugs after intraperitoneal administration in peritoneal dissemination patients and animal models and also discuss the effect of the surfactant vehicle on the behavior of taxanes.

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.

Management of Special Issues

Past three decades, management of peritoneal metastases of appendiceal mucinous neoplasms, colorectal cancer and malign mesothelioma has dramatically changed with cytoreductive surgery and heated intraperitoneal intraoperative chemotherapy applications. This comprehensive management is also promising approach as a gold standard of care for peritoneal metastases of gastric and ovarian cancer. In this chapter, we will summarize the diseases with peritoneal metastases and management with combined treatment approaches and prognosis of these diseases with peritoneal metastases.

Recent advances in the treatment of peritoneal metastasis from gastric cancer

Background: Peritoneal metastasis (PM) from gastric cancer (GC) was once considered a lethal disease. After the late 1990s, the therapeutic goal changed from palliative to curative intent because of a development a comprehensive treatment combining cytoreductive surgery (CRS) and perioperative chemotherapy. Methods: Recent advances in the treatment of PM from GC reported in 18 studies including 2327 patients were reviewed. Results: In patients with PM, systemic chemotherapy alone had a limited and non-curative effect. In contrast, radical gastrectomy plus neoadjuvant intraperitoneal/systemic chemotherapy (NIPS), early postoperative intraperitoneal chemotherapy (EPIC), or postoperative S1 treatment was shown to improve the survival of patients with cytology-positive (Cy1) peritoneal lavage fluid without macroscopic PM (P0) (P0Cy1). After 5 years, 23 among 154 patients were disease free. For the treatment of patients with macroscopic PM (P1), exploratory laparotomy to determine the peritoneal cancer index (PCI) and neoadjuvant laparoscopic hyperthermic intraperitoneal perfusion (LHIPEC) were performed. The combination of NIPS and LHIPEC was effective in patients with P1, but NIPS or LHIPEC alone were ineffective and all patients receiving one or the other died. In contrast, the 5-year survival rate after cytoreductive surgery (CRS) +HIPEC ranged from 6% to 13%, and 18 among 284 patients were disease free at 5 years. Conclusion: Although CRS and NIPS have an important role in treatment of PM from GC, complete cytoreduction by gastrectomy and peritonectomy after NIPS combined with intraoperative HIPEC, EPIC, and late postoperative chemotherapy may cure the patients with P0Cy1 or P1 disease. Yutaka Yonemura1*, Emel Canbay1, Haruaki Ishibashi1, Masamitu Hirano1, Akiyoshi1, Mizumoto1, Nobuyuki Takao1, Masumi Ichinose1, Kousuke Noguchi1, Yang Liu1, Satoshi Wakama1, Shinya Shimada2, Federico Coccolini3, Keizou Taniguchi4 and Sachio Fushida5 1Peritoneal Surface Malignancy Treatment Center, Kishiwada Tokushukai Hospital and Kusatsu General Hospital, Oosaka, Shiga, Japan 2Department of General Surgery Department, Kumamoto General Hospital, Yatushiro, Japan 3Department of General Surgery, Ospedola, Maggiore, Parma, Italy 4Department of Surgery, Teikyou University Hospital, Yokohama, Japan 5Department of Gastroenterological Surgery, Kanazawa University, Kanazawa, Japan Yutaka Yonemura, et al., Journal of Cancer and Cure Remedy Publications LLC. 2018 | Volume 1 | Issue 1 | Article 1003 2 Limits of systemic chemotherapy for peritoneal metastasis from gastric cancer Table1 shows the effect of systemic chemotherapy on survival in GC patients with macroscopic PM (P1 group). In patients in P1 group treated with systemic chemotherapy alone, median survival time (MST) ranged from 5.0 to 13.0 months, and the onead 5-year survival rates after systemic chemotherapy alone were reported to be 7.7%-13.0% and 0%-3.4%, respectively. [2,4-7] Hong SH reported that overall survival (OS) was associated with the extent of PM [6]. Although a small number of patients survived longer than 5 years after systemic chemotherapy and gastrectomy, all patients died of PC within 8 years after chemotherapy. Accordingly, the effect of systemic chemotherapy on survival improvement is limited, and systemic chemotherapy alone cannot cure patients with PM. The reasons include the existence of the plasma-peritoneal barrier [11] and cancer stem cells [12]. Treatment for intraperitoneal micrometastasis (cytologypositive (Cy1) peritoneal lavage fluid without macroscopic PM (P0); (P0Cy1 group) by systemic chemotherapy or IPC The 5-year survival rate after radical gastrectomy alone in P0Cy1 patients is reported to be only 2% [13]. Therefore, P0Cy1 patients are considered to have peritoneal metastases, and P0Cy1 gastric cancer is classified as stage IV [14]. As shown in Table 1, survival is significantly better in patients after radical gastrectomy plus postoperative oral S1 treatment than after gastrectomy alone [13,15,16]. Furthermore, disease-free survival longer than 5 years has been reported after gastrectomy [15,16]. Table 2 shows the outcomes of P0Cy1 patients treated with gastrectomy plus IPC. Fujiwara Y [17] and Yonemura Y [18] treated PoCy1 patients with radical gastrectomy after neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) using oral S-1 + IP docetaxel with or without IP CDDP. After NIPS, positive cytology became negative cytology in 75%-78% of patients [17,18]. The 5-year survival rate after NIPS + gastrectomy was 42% and 2 patients remained in disease-free 5 years after NIPS [10]. In their P0Cy1 patients, a 3 arm randomized study, Kuramoto et al. [19] found that patients treated with extensive intraoperative peritoneal lavage (EIPL) + gastrectomy + early postoperative intraperitoneal chemotherapy (EPIC) (2-hour IP administration of CDDP at the time of abdominal closure) survived significantly longer than those treated with gastrectomy + EPIC or gastrectomy alone. In EIPL, the peritoneal cavity is extensively shaken and washed after intraperitoneal injection of 1L of saline, and the saline is completely aspirated. This procedure is done 10 times [19]. EIPL removes both peritoneal free cancer cells and those adhering to the peritoneal surface. EIPL + EPIC significantly improve the 5-year survival rate in P0Cy1 patients, because it significantly decreases the number of cancer cells in the peritoneal cavity [19]. Imano et al. also reported that gastrectomy +EPIC using paclitaxel (PTX) changed positive cytology to negative cytology in 100% (10/10) of P0Cy1 patients, and that 5-year survival rate was 25% [20]. These results strongly indicate that postoperative oral S1, NIPS, or EPIC can eradicate intraperitoneal micro-metastasis in 25%-44% of P0Cy1 patients, bringing about cure [17,18,20,21]. Intraperitoneal chemotherapy (IPC) for peritoneal metastasis (P1 group) Recently, IPC has shown encouraging results for the treatment of PM, and has the following advantages: 1) The drugs act directly on not only cancer cells floating in the peritoneal fluid but also metastatic nodules on the peritoneal surface. Authors treatments and tumor status No. of Patients MST Response rate 1 year 5 year No. of disease free survivors Side effects survival rate survival rate after 5 years Grade 3,4,5 (Grade 5) Macroscopic peritoneal metastasis (P1 group) Nishina T [4] 5-FU+(MTX) 49 7.7 m Not described 27.10% 0% 0 0-28.6% (0%) `Paclitaxel 51 7.7m Not described 31.40% 0% 0 0-17.6% (0%) Koizumi W [2] S1+CDDP 148 (51)# 13.0m 54% 54.10% NR 0 0-11% (0%) S1 150 (36)# 11.0m 31.00% 46.70% NR 0 0-40% (0%) Imamoto H [5] Paclitaxel 64 5.0m 31.30% 20% 0% 0 7.9-22.2% (-%) Hong SH [6] Various regimens

A case of ovarian growing teratoma syndrome treated by cytoreductive surgery

211 Measurable disease 74 11.6m Not described 49.80% NR 0 Non-measurable disease 137 18.0m Not described 68.40% 12% 0 Gastrectomy+ chemotherapy 44 29.3m Not described 85.40% 7.70% 0 chemotherapy alone 61 12.5m not described 54.30% 3.40% 0 Wilke H [7] Ramucirumab 330 (163)# 9.6m 17% 42% NR NR 81% (12%) Ramucirumab+paclitaxel 335 (152)# 7.4m 28% 30% NR NR 63% (16%) Cytology-positive peritoneal lavage fluid and without macroscopic peritoneal metastasis (P0Cy1 group) Yonemura Y [14] Gastrectomy+S-1 35 18.3m 83% 36.80% 4 0-9% (0%) Gastrectomy alone 66 8.8m 37% NR Kodera Y [15] Gastrectomy + S-1 48 23.5m 78% 32% 1 2-13% (0%)

A New Comprehensive Treatment for Peritoneal Metastases Using Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Chemoperfusion

: 5-FU/CDDP:155 #(): Number of patients with peritoneal metastasis Taxan/CDDP:25, FOLFIRI:12 oral 5-FU: 12, others: 7 Table 1: Outcome of patients with peritoneal metastasis from gastric cancer treated by systemic chemotherapy alone. Yutaka Yonemura, et al., Journal of Cancer and Cure Remedy Publications LLC. 2018 | Volume 1 | Issue 1 | Article 1003 3 2) IPC achieves a significantly higher drug concentration in the peritoneal cavity as compared with systemic chemotherapy. 3) The half-life of high molecular weight drugs in the peritoneal cavity is prolonged and systemic toxicity is reduced. However, IPC does not work in patients with peritoneal adhesions. Accordingly, IPC is mainly used preoperatively. Additionally, drug penetration distance from the peritoneal surface is different from drug to drug. The depth of penetration from the peritoneal surface is just several hundred μm for methotrexate, 5FU, paclitaxel, and carboplatinum [22-24,25]. Accordingly, multiple intraperitoneal administrations of anticancer drugs are necessary to treat big nodules larger than the depth of penetration of each locally applied anticancer drug. [25] Additionally, combining IPC with systemic chemotherapy extends the treatable area of subperitoneal tissue. Systemic chemotherapy can be effective against deep seated tumors that are accessible through subperitoneal arterial capillaries but inaccessible through IPC. This strategy is known as neoadjuvant intraperitoneal/ systemic chemotherapy (NIPS). Taxans are high molecular weight compounds. IP administered taxans are gradually absorbed through lymphatic stomata or omental milky spots, and migrate into lymph nodes and thoracic ducts [25,26]. In contrast, low molecular weight compounds like mitomycin C (MMC) or CDDP are rapidly absorbed from peritoneal surface into subperitoneal blood vessels. The area under the curve ratios of the intra-abdominal space to the plasma after IP administration of the drugs are about 1000 for paclitaxel (PTX), 207-552 for docetaxel (DTX), 10-24 for MMC, and 12-21 for CDDP [27-30]. To achieve high loco-regional dose intensity in the peritoneal cavity and to reduce systemic toxicities, taxans (PTX and DTX) are the ideal drugs for IPC [31,29]. From the phase I studies, the maximum tolerated dose (MTD) and recommended dose (RD) were 90 mg/m2 and 80 mg/m2 for PTX, [27] and 50 mg/m2 and 45 g/ m2 for DTX [28]. Table 3 shows the clinical outcomes of NIPS using IP administration of taxans for PM from gastric cancer. The incidence of Grade 3, 4, or 5 side effects after IPC was lower after IPC with taxans (6.3% to 18.5%), [18,3

Molecular Mechanism of Peritoneal Metastases

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.

Anatomy of Peritoneum and Preoperative Assessment of Patients with Peritoneal Surface Malignancies

A game-changing therapy for peritoneal metastasis (PM), now called “comprehensive treatment” was first established in the late 1990s. The treatment consists of aggressive cytoreductive surgery (CRS) combined with perioperative intraperitoneal/systemic chemotherapy. PM is considered as local disease, and the rationale behind the treatment is to remove macroscopic tumors and eradicate residual micrometastasis using perioperative chemotherapy (POC). Comprehensive treatment consists of laparoscopic evaluation of the tumor load, POC, and CRS. POC includes six procedures including laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC), neoadjuvant intraperitoneal/systemic chemotherapy (NIPS), hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC), extensive intraoperative peritoneal lavage (EIPL), early postoperative intraperitoneal chemotherapy (EPIC), and late postoperative systemic chemotherapy. In a study of gastric cancer patients with P0/Cy1 status that employed comprehensive treatment, POC was confirmed to eradicate intraperitoneal micrometastasis. For clinical standardization of HIPEC, the concept of the thermal dose should be introduced. One thermal dose is equivalent to 30-min treatment at 43 °C. In gastric cancer, one thermal dose of HIPEC has been shown to reduce the peritoneal cancer index of 3.5, and changed the peritoneal cytology from positive to negative in 70 % of patients.

Peritoneal Surface Malignancies

Peritoneal metastases represent a devastating form of cancer progression that is considered to be a lethal. Three different molecular pathways can be described according to origin of peritoneal metastases: (1) dissemination from primary tumour to the peritoneum, (2) Dissemination of primary peritoneal tumours (3) Clonal difference between primary tumour and peritoneal tumour [1]. These mechanisms may combine with each other as a pathobiology of disease.

Results of two times-cytoreduction for patients with pseudomyxoma peritonei

Cytoreductive surgery of peritoneal surface malignancies (PSM) and hypethermic intraperitoneal chemotherapy applications have become a gold standard in pseudomyxoma peritonei, diffuse malign peritoneal mesothelioma, peritoneal metastases of colorectal cancer and primary peritoneal cancers. They have also promising results for peritoneal metastases originated from gastric cancer and ovarian cancer as well as other intraabdominal cancers, sarcomas and stromal tumours. Our group has pioneered aggressive management strategies for the long-term survival of patients with PSM of gastric cancer as well as PSMs originated from other intraabdominal organs. It is essential that surgeons throughly understand the peritoneal spaces and the ligaments and mesenteries that form their boundaries in order to localize disease to a particular peritoneal space and formulate a differential diagnosis on the basis of that location. In this chapter, we describe in detail the normal anatomy of the peritoneal spaces and the appearance of pathologic involvement of the peritoneal spaces, ligaments, and mesenteries at cross-sectional imaging. Then, preoperative assessment of patients with peritoneal surface malignancies with computed tomography, estimation of extent of disease with clinical staging systems, classification of peritoneal surface malignancies and patient selection will be reviewed.