HIPEC with CRS in ADVANCED CARCINOMA OVARY

HIPEC IN OVARY

1. CRS + HIPEC in CA OVARY

2. Current status of treatment NCCN, 2017

3. Failure of systemic chemotherapy

4. The extent of cytoreduction has a direct impact on survival Maximal cytoreduction was found to be one of the most powerful determinants of survival among patients with stage III or IV epithelial ovarian cancer, in a meta-analysis of almost 7,000 patients Bristow et al, JCO, 2002

5. CRS with PCI calculation

6. C ompleteness of cytoreduction (CC) was scored as proposed by Sugarbaker The Gynecologic Oncology Group (GOG) has defined optimal debulking as residual implants less than 1 cm.

7. Patients with no residual tumor had a median survival advantage of 46.9 months over any residual tumor in stage IIIc and 30 months for stage IV favoring no residual disease. Similarly, patients with residual tumor size of 1–10 mm had a 4.9 months benefit over >10mm residual disease in stage IIIc Bristow etal , JCO, 2002

8. HIPEC ( Hyperthermic IntraPEritoneal Chemotherapy) HIPEC is the administration of chemotherapy at optimal temperatures between 42-43 °C. Synergy between heat and drug cytotoxicity starts at 39 °C and falls off at 43 °C. Temperatures above 44 °C cause apoptosis in normal cells

9. Pharmacology Cell cycle non specific drugs are used Cisplatin is the most common cytotoxic drug with Mitomycin c Mitoxantrone , carboplatin , doxorubicin, and gemcitabine also being used

10. When can it be applied front line treatment adjuvant therapy for recurrent disease.

11. GOG 172 study  following optimal surgical reduction, intraperitoneal chemotherapy with intravenous chemotherapy was associated with a longer median overall survival than intravenous chemotherapy alone (65.6 versus 49.7 months with a 21.6% reduction in death). The 10 year follow-up also showed the risk of death decreased by 12% for each cycle of intraperitoneal chemotherapy completed Armstrong et al, NEJM, 2006

12. Despite these survival benefits, intraperitoneal chemotherapy hasn't been widely adopted. Likely due to toxicity and tolerability issues, as more than half of the patients have difficulty completing all six cycles of intraperitoneal chemotherapy HIPEC may overcome the problems associated with repetitive intraperitoneal chemotherapy administration

13. Randomized trial of HIPEC in primary advanced peritoneal, ovarian, and tubal cancer No mortality was identified and postoperative morbidities were not statistically different between two groups except anemia and creatinine elevation in HIPEC group. The survival analysis did not show the statistical superiority of the HIPEC arm. Lim et al, JCO, May 2017

14. Methods:   184 patients staged III and IV were randomly allocated to trial arm (HIPEC, cisplatin 75 mg/m 2 , 90 min) or control arm (no HIPEC), intraoperatively based on residual tumor (size <1cm) Results:   Postoperative outcomes including extent of surgery, estimated blood loss, residual tumor , and hospitalization day were not different between both group, except operation time (487 vs. 404 min, p<0.001) due to HIPEC procedure. The most common adverse event was anemia : 67.4% in HIPEC and 50% in control group (p=0.025). The other toxicity common in HIPEC group is the elevation of creatinine (15.2% vs. 4.3%, p=0.026). Two-year PFS was 43.2% and 43.5% and 5-year PFS was 20.9% and 16.0% in HIPEC and control group, respectively (p=0.569). Five-year OS was 51.0% and 49.4% in HIPEC and control group, respectively (p=0.574). In women who received NAC, the median PFS for HIPEC and control group were 20 and 19 months, respectively (log-rank test, p = 0.137) and the median OS for HIPEC and control group were 54 and 51 months, respectively (log-rank test, p = 0.407). In the subgroup with NAC , 2-year PFS was 37.2% in HIPEC group and 29.5% in control group and 5-year OS was 47.9% in HIPEC group and 27.7% in control group. After 20 months in PFS and 30 months in OS, two survival curves in women who received NAC showed the trend of gradual distinction, favoring HIPEC group.

15. A phase 3 trial of IDS + HIPEC vs IDS alone for ovarian cancer The addition of HIPEC to interval cytoreductive surgery is well tolerated and improves recurrence free and overall survival in patients with stage III epithelial ovarian cancer Van Driel et al, JCO, 2017

16. 245 patients 3# P+C  stable diseaseRandomize per-operatively if residual mass <2.5mm 3 # P+C post-op ITT analysis, IDS + HIPEC associated with longer DFS than IDS alone (15 vs. 11 months) At the time of analysis, 49% of patients were alive, with a significant improvement in OS favoring HIPEC (48 vs. 34 months). Grade 3-4 adverse events was similar in both treatment arms (28% vs. 24%, p=0.61).

17. Four drains were positioned for HIPEC inflow/outflow and temperature monitoring . The inflow/outflow drains were connected to a closed extracorporeal sterile circuit 4 to 6 L perfusate was circulated by means peristaltic pump at a flow rate of 500 mL /min. Sterile circuit is heated by means of a thermal exchanger connected to the heating circuit

18. Open technique (Coliseum)

19. Closed technique

20. OPEN direct access during administration to manipulate the fluid and bowel to achieve a quick and homogenous temperature and distribution of drug All peritoneal surfaces are exposed equally throughout the therapy Potential downsides are rapid dissipation of heat and the potential exposure of operating staff to chemotherapy agents both by direct contact and aerosolized particles CLOSED reduces the issue of heat loss from peritoneal surfaces flow rates can be maintained for homogenous hyperthermia and exposure + instillation of positive pressure to enhance drug penetration

21. Complications INTRAABDOMINAL : Small bowel perforation , anastomotic leaks and intestinal fistula (4.5-19%), intra-peritoneal abscesses, pancreatic fistulas, biliary fistulas, chyle leak, prolonged ileus and gastric stasis. PULMONARY : peritonectomy of abdominal diaphragmatic surfaces significantly increases post-operative pleural effusions along with pneumonia (3.2–10 %) HEMATOLOGICAL : Neutropenia and thrombocytopenia (4-39 %) OTHERS : Renal insufficiency (2–4 %), venous thromboembolism (4–4.4 %), UTI

22. Risk Factors for Complications Age number of peritonectomy procedures number of visceral resections number of anastomosis incomplete cytoreduction dose of chemotherapeutic agent intra-abdominal HIPEC temperature

23. Summary of evidence Evidence where HIPEC has benefit IDS after upfront incomplete CRS for stage III EOC salvage CRS for recurrent EOC (two time-points representing failure to initial standard therapy.) Advanced Stage III requiring IDS after NACT

24. Summary of evidence Less indirect evidence for a potential benefit of HIPEC less advanced stages (III) for earlier time-points in the treatment of EOC (upfront, interval and adjuvant)

25. In conclusion Understand the aggressive nature of the treatment, perioperative mortality between 0 % and 18 % and morbidity between 30 % and 70 %. Understand the safety profile of this treatment modality and the risk factors associated with poor perioperative outcomes is essential. Should be restricted to high-volume institutions on a per protocol basis.

26. Emerging body of evidence that supports the use of HIPEC with CRS and systemic chemotherapy for advanced primary Stage IIIc and recurrent EOC compared to CRS and chemotherapy alone. Maximal cytoreduction remains essential for overall survival rates, even when HIPEC is used .