1. 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

2. 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

3. 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 !!!

4. 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)

5. 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

6. 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)

7. 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

8. Intestinal thermal injuryID
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

9. Intestinal thermal injuryID
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

10. 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)

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

12. 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 D Trastizumab 3 cyc mg/kg IV D1
HIPEC: cisplatin 75 mg/m2 IP; Mitomycin 15mg/m2 IP; 60min, > 41°C

13. GastriPEC Trial
Indication: peritoneal metastasis in gastric cancer including AEG
Study: started
ongoing, n=65/180 ( )
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

14. 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

15. 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.

16. 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.