Intraperitoneal chemotherapy for epithelial ovarian cancer

1. Intraperitoneal chemotherapy for epithelial ovarian cancer Hua-His Wu, MD OB/GYN, VGH-TPE

2. Epithelial ovarian cancer • Standard therapy • A maximum cytoreductive surgery followed by combination chemotherapy with paclitaxel and carboplatin • A chemo-sensitive tumor • However, most recur • Intraperitoneal spreading

3. History of IP C/T • Weisberger 1955 • Nitrogen mustard intraperitoneally for malignant ascites • Jones 1978 • signicantly greater concentrations of certain chemotherapeutic drugs in the peritoneal cavity than in the blood. • SWOG/GOG • The first phase III trial • since 1980s, presented in 1996 • In favor of IP arm

5. NCI announcement 2006 • Encouraging the GO community to consider IP chemotherapy as the standard treatment for optimally debulked advanced ovarian cancer patients • Based on a meta-analysis of three US trials and other phase III studies

6. However, IP chemotherapy is still regarded as controversial issue. Why

7. IP Chemotherapy • Principles • Pharmacology • Clinical aspects • Toxicities and QOL • Future directions

8. Principles of IP C/T

9. Basic pharmacologic concept of IP C/T

10. What is the ideal anticancer agent for IP C/T? • Very effective systemically against ovarian cancer • Penetrate deep into the tumor • Stays in the peritoneal cavity for prolonged period • Low incidence of systemic adverse effect but providing satisfactory drug concentrations in the inner core of tumor (有效 夠深 留得久)

11. Basic concept of IP C/T • Penetration • Peritoneal dwelling • Solute transport model • Anatomy of the peritoneum and capillary vessels • Resistance to solute transport

12. Penetration of anticancer agents • Doxorubicin • 4-6 layers (Ozols et al; Durand et al) • Methotrexate • By osteosarcoma spheroids and autoradiographs (West et al) • Limited ability in avascular tumor mass & ≧ 250 μm in dia. • Vinblastine & 5-FU • In glioma spheroids (Nederman and Carlsson)) • Penetration : 5-FU > vinblastine • Cisplatin • In mouse model (Los et al) • Concentration • in peripheral: IP > IV • In center : IP = IV

13. Peritoneal dwelling of anticancer drugs • Longer stay of anticancer agents • Higher drug concentration in the inner core Is a contrary phenomenon

14. Anatomy of the peritoneum • Primary interface between abdominal cavity & vessels • Parietal peritoneum (10%) & visceral peritoneum (90%) • The area is approximately to the body surface area (1.0 -2.0 cm2) • Components • Mesothelium • Basement membrane • Interstitium • Microcirculation • Visceral lymphatics

15. Mesothelium, Interstitium • Mesothelium • Monolayer of flattened cells about 0.5 mm thick • Tight junction ; Gap junction • Absence of tight junction in the subdiaphragmatic area  directly absorbed into the lymphatic system • Interstitium • The supporting structure • Distance varies

16. Blood vessels • Visceral peritoneum • Supplied by celiac and mesentary arteries with venous drainage via the portal vein • Rapid firstpass metabolism by the liver • Parietal peritoneum • Supplied by circumflex iliac, lumbar, intercostal, and epigastric arteries with venous drainage via the systemic circulation. • Effective peritoneal surface area • The density of the number of perfused capillaries • The number and the size of pores within the capillaies

17. Peritoneal lymphatics • Extensive in the subdiaphragmatic area • stoma exist, • basement membrane absent • Little resistance for the solute transport • Also present in parietal and visceral peritoneum • To maintain the relatively small volume of fluid (50-100 ml)

18. Mechanism of solute transport between peritoneal cavity and capillary lumen

19. Theoretical behaviors of anticancer agents • Larger molecular weight or water-insolubleanticancer drugs stay longer in the peritoneal cavity • Smaller molecular weight or water-soluble  can go into the inner core but stay shorter in the cavity • Small molecular weight agents that are metabolized in the liver to become active form should not be used for IP C/T. • Small molecular weight agents with already active form are suitable for IP C/T

20. Pharmacologic advantage for IP C/T (Modified from Markman M, Semin Oncol 1991)

21. Choice of drugs • If the IP C/T is considered to be a regional therapy  paclitaxel, mitoxantrone • If the IP C/T is hypothesized as a route of systemic chemotherapy  platinum agents

22. Pharmacology of IP drugs • Cisplatin • Carboplatin • Paclitaxel

23. Cisplatin • P/V ratio: peak 21; AUC 12 (Howell, 1982) • The mode of administration did not affect systemic toxicity(Pretorius, 1981) • The amount of drug recovered in the urine and the drug levels within the tissues were similar • The peritoneal lining had 2.5-8 times higher levels of drug after IP administration  IP C/T might increase the therapeutic index for small tumors confined to the peritoneal cavity

24. Carboplatin • After 4 hrs dwelling, P/V ratio: • Peak: 24; AUC 10 (Elferink, 1998) • Pharmacologic study after IP and IV (Miyagi, 2005) • 24-hr free platinum AUC in the serum is identical • 24-hr free platinum AUC in the peritoneal cavity was 17 times higher when which given via IP  IP infusion of carboplatin is feasible not only as an IP regional therapy but also as a more reasonable route for systemic chemotherapy • The recommended dose of IP carboplatin was 400 mg/m2 (Speyer and Sorich, 1992)

25. Paclitaxel • Dose-limiting toxicity: severe abdominal pain (when dose ≧175 mg/㎡) • P/V ratio: peak & AUC : 1000-fold • Paclitaxel persisted in peritoneum for more than 24-48 h after a single IP instillation (Markman, 1992) • Very slow peritoneal clearance (at dose level ≧ 60 mg/㎡, it can persist more than 1 wk with significant level  wkly IP Taxol ) • Low plasma concentration (Francis, 1995)

26. IP agents and risk (Makhija et al, 2001)

28. Strengths of IP C/T • Achieve dose intensification (as ‘high-dose’) • Treats both intraperitoneal tumor bed and extraperitoneal tumor via systemic recirculation • Reaches IP sites that may not be reached by IV route, especially when up to 2L dialysate are administered • Onion skinning effect– IP cisplatin can penetrate as far as 4mm into surface of IP tumors(by definition, <1cm in size) and up to 6 repeated administrations

30. Clinical aspects of IP C/T • Front-line chemotherapy • Consolidation • 2nd-line chemotherapy

31. Phase III trials of IP vs IV cisplatin-based chemotherapy (Hamilton, 2006)

33. Main results • Eight randomized trials studied 1819 women receiving primary treatment for ovarian cancer. • Women were less likely to die if they received an intraperitoneal (IP) component to the chemotherapy (hazard ratio (HR) =0.79; 95% confidence interval (CI): 0.70 to 0.90)and the disease free interval (HR =0.79; 95%CI: 0.69 to 0.90) was also significantly prolonged. • There may be greater serious toxicity with regard to gastrointestinal effects, pain and fever but less ototoxicity with the intraperitoneal than the intravenous route.

34. Hazard ratio for time to recurrence (IP vs IV C/.T)

35. Hazard ratios for time to death (IP vs IV C/T)

36. GOG 104(Alberts et al, 1996) OS

37. GOG 104: conclusions • As compared with IV cisplatin, IP cicplatin significantly improves survival and has significantly lower toxic effects in patients with stage III ovarian cancer and residual tumor mass of 2cm or less. • The only same “dose-intensity” in both arms phase 3 RCT

38. Shorts of GOG 104 • GOG 111 • Median survival from 24 months (P+C) to 38 months ( P+T)

39. GOG 114(Markman et al, 2001) PFS OS

40. GOG 114: conclusions • The 2nd phase 3 RCT to show IP cisplatin is superior to IV cisplatin in small volume residual advanced ovarian cancer • The 1st phase 3 trial in ovarian cancer to a median survival of >5 years • Trial demonstrated that IP cisplatin favorably impacts survival, even through IV paclitaxel is a component of regimen

41. Shorts of GOG 114 • More complications in IP arm • Neutropenia, thrombocytopenia • G-I & metabolic toxicities • Carbopltin x 2 cycles ( AUC 9)

42. GOG 172(Armstrong et al, 2006) PFS OS

43. GOG 172residual tumor size & survival

44. GOG 172: conclusions • Significantly survival benefit in IP arm • The 65.6 months median survival is the longest survival reported to date from a randomized trial in advanced ovarian cancer

45. Shorts of GOG 172 • The IP regimen uses higher and more frequent dosing than the IV regimen • Toxicities were greater on the IP arm • Fewer patients on the IP arm were able to complete 6 cycles of therapy

47. VGH-TPE: conclusions • Intravenous and intraperitoneal chemotherapy are associated with equivalent survival in patients with minimal residual stage III epithelial ovarian cancer after optimal cytoreductive surgery (<1m). • PEC or PAC regimens

48. NCI Clinical Announcement, 1/5/06Pooled survival benefit of IP regimens • Progression-free survival • HR=0.79 (95%CI: 0.70-0.90) • Overall survival • HR=0.79 (95%CI: 0.70-0.89)

49. New problems • The role of carboplatin • GOG 158 (non-inferiority test) • GOG 114 (moderately high dose IV Carboplatin before IP C/T) • Cross-trial GOG172 vs GOG 158 • How many coursesof IP C/T is adequate? • Effect of Dose intensity? • IP regimen uses higher and more frequent dosing schedule than the IV regimen

50. Cross-trial comparison of GOG 172 and GOG 158