Application of Laparoscopic HIPEC with Bidirectdional Chemotherapy for Gastric Cancer with Peritoneal Carcinomatosis – Initial experience 腹腔鏡腹腔熱化療合併雙向性化療應用於胃癌併腹腔轉移 -- 初始經驗 Mao-Chih Hsieh Chang-Yun Lu Wei-Wen Chang Ping-Kun Hsiao Tse-Jia Liu Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University 謝茂志 呂長運 張渭文 蕭炳昆 劉自嘉 臺北醫學大學-北醫‧萬芳醫院-外科部-一般外科

Peritoneal Carcinomatosis (PC) in Gastric Cancer Peritoneal carcinomatosis (PC) : very frequent Linitis plastica, scirrhous type gastric cancer PC = poor survival/prognosis (MST 3-9m) MST of AGC 9-12 mon (phase III studies) Need to find ways to improve this

Peritoneal Carcinomatosis (PC) in Gastric Cancer Systemic chemotherapy (response rate to chemotherapy is 50% with stage IV gastric cancer, but RR was the lowest in patients with PC in different alimental tract cancers) Peritoneal metastases are usually relatively resistant to intravenously administered cytotoxic drugs Surgery: Cytoreduction, can never be therapeutic Microscopic residual disease progression Surgery alone or chemotherapy alone is not an adequate management for gastric cancer patients with PC !!!

Intraperitoneal (IP) Chemotherapy Regional treatment modality High intraperitoneal drug concentration and exposure Drug penetration: estimated to be 3–5 mm at maximum under Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Bidirectional Chemotherapy Attack Peritoneal Carcinomatosis from both sides of peritoneum, not only from the peritoneal cavity but also from the subperitoneal blood vessels 內外夾攻

NIPS (Neoadjuvant Intraperitoneal-Systemic Chemotherapy ) Treatment of PC Neoadjuvant Chemotherapy  PC Cytoreductive Surgery (CRS) Reduce the Visible Tumor Burden NIPS (Neoadjuvant Intraperitoneal-Systemic Chemotherapy ) HIPEC and/or Early Postoperative IP Chemotherapy (EPIC)

L-HIPEC + Bidirectional Chemotherapy X 3 Cycles  Re-evaluation Oral TS-1 60 mg/m2 for 14 days, Q3W IP Docetaxel + cisplatin D1, D8 Docetaxel 40 mg Cisplatin 30mg/m2 X 3 Cycles Cytoreduction Surgery + HIPEC +/- Peritonectomy

Intestinal thermal injury ID Sex Age Initial PCI CRS Post-NIPS TS-1® or 5-FU CC score Morbidity Status/ Months* Remarks 1 鄭/M 52 39 Yes 22 TS-1 2 Neutropenia Alive 32 m Lung metastasis, found at 26 months 洪/F 32 13 3 Diarrhea 21 m No recurrence 林/F 61 30 No - Dead 8 m Disease progression 4 黃/F 40 18 8 Wound poor healing 18 m 5 陳/F 56 17 14 14 m 6 蔡/F 48 Intestinal thermal injury 6 m No IP chemotherapy due to morbidity 7 鄒/F 57 29 5 m 季/F 46 9 Ileus 10 m 謝/F 33 Under treatment protocol *Months after initiation of bidirectional chemotherapy

Intestinal thermal injury ID Sex Age Initial PCI CRS Post-NIPS TS-1® or 5-FU CC score Morbidity Status/ Months* Remarks 1 鄭/M 52 39 Yes 22 TS-1 2 Neutropenia Alive 32 m Lung metastasis, found at 26 months 洪/F 32 13 3 Diarrhea 21 m No recurrence 4 黃/F 40 18 8 Wound poor healing 18 m Disease progression 季/F 46 9 Ileus 10 m 謝/F 33 6 m Under treatment protocol 林/F 61 30 No - Dead 8 m 5 陳/F 56 17 14 14 m 6 蔡/F 48 Intestinal thermal injury No IP chemotherapy due to morbidity 7 鄒/F 57 29 5 m *Months after initiation of bidirectional chemotherapy

Taxotere 30 mg/m2 cisplatin 30mg/m2 Effects of Neoadjuvant Intraperitoneal/Systemic Chemotherapy (Bidirectional Chemotherapy) for the Treatment of GC Patients with Peritoneal Metastasis Objective To verify the Effects of Neoadjuvant Intraperitoneal/Systemic Chemotherapy (Bidirectional Chemotherapy) Key patient inclusion criteria Histologically or cytologically proven peritoneal carcinomatosis ECOG PS 0–2 Absence of hematogenous metastasis and remote lymph node metastasis *NIPS X 2 cycle (N=96) CRS (N=82) Oral S-1 60 mg/m2 for 21 days, q4w IP Taxotere+cisplatin Taxotere 30 mg/m2 cisplatin 30mg/m2 D1, D8, D15 +/- HIPEC +/-peritonectomy *NIPS (Neoadjuvant IntraPeritoneal-Systemic chemotherapy protocol) Yutaka Yonemura et al., International Journal of Surgical Oncology (2012)

Survival Difference after CC-0 and CC-1~3 Resection

GastriPEC Trial Arm A => 3X EOX Laparoscopy  Randomize Arm B => 3X EOX 3X EOX HIPEC Laparotomy + Surgical Cytoreduction 3X EOX Her-2 (-): epirubicin 80mg/m2 IV D1 + oxaliplatin 130mg/m2 IV D1 + capecitabin 625mg/m2 PO D1-21 Her-2 (+): cisplatin 80mg/m2 IV D1 + capecitabin 1000mg PO D1-14 + Trastizumab 3 cyc 8-6-6 mg/kg IV D1 HIPEC: cisplatin 75 mg/m2 IP; Mitomycin 15mg/m2 IP; 60min, > 41°C

GastriPEC Trial Indication: peritoneal metastasis in gastric cancer including AEG Study: started 2014-10-01 ongoing, n=65/180 (2016-7-11) 1st aim: efficacy of HIPEC, increasing OS 2nd aim: 30-D morbidity, PFS, DFS, QOL, toxicity, surgical intervention, hospital stay Conclusion: staging laparoscopy, avoid CRS if PCI>15, complete cytoreduction

PHOENIX-GC trial (phase III) Gastric cancer with peritoneal metastasis ❷ IP PTX + S-1/PTX R ❶ S-1/CDDP Key Eligibility Criteria No or <2mo prior chemo No other distant metastasis No prior gastrectomy No frequent ascites drainage Stratification Institution Prior chemo +/- Peritoneal meta P1/P2-3 Primary Endpoint Overall survival Secondary Endpoint Response rate Safety

PHOENIX-GC trial (phase III) Primary analysis for OS: median OS IP: 17.7 m; SP: 15.2m, Log-rank test p=0.080 Sensitivity analysis for OS: median OS IP: 17,7m; SP: 14.2m, Log-rank test p=0.022 Ascites: IP better, p=0.015 Conclusion: Clinical efficacy of IP PTX in gastric cancer with peritoneal metastasis.

Conclusions Laparoscopic HIPEC (L-HIPEC) with bidirectional chemotherapy (NIPS) was feasible in advanced gastric cancer patients. No surgical mortality, and surgical morbidity was possible avoidable. The most frequent side effect: neutropenia. There was no intraperitoneal bleeding. It may provide as an alternative method of “neoadjuvant” treatment.