Mar 5th, 2007 Hua-His Wu, MD OB/GYN, VGH- TPE

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 NCI announcement 2006 standard treatment  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

H.H. Wu, MD Mar 5th, 2007 However, IP chemotherapy is still regarded as controversial issue. Why

H.H. Wu, MD Mar 5th, 2007 IP Chemotherapy  Principles  Pharmacology  Clinical aspects  Toxicities and QOL  Future directions

H.H. Wu, MD Mar 5th, 2007 Principles of IP C/T

H.H. Wu, MD Mar 5th, 2007 Basic pharmacologic concept of IP C/T

H.H. Wu, MD Mar 5th, 2007 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 )

H.H. Wu, MD Mar 5th, 2007 Basic concept of IP C/T  Penetration  Peritoneal dwelling  Solute transport model  Anatomy of the peritoneum and capillary vessels  Resistance to solute transport

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007 Peritoneal dwelling of anticancer drugs  Longer stay of anticancer agents  Higher drug concentration in the inner core Is a contrary phenomenon

H.H. Wu, MD Mar 5th, 2007 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 ( cm 2 )  Components Mesothelium Basement membrane Interstitium Microcirculation Visceral lymphatics

H.H. Wu, MD Mar 5th, 2007 Mesothelium, Interstitium  Mesothelium Monolayer of flattened cells about 0.5 mm thick Tight junction ; Gap junction subdiaphragmatic Absence of tight junction in the subdiaphragmatic area  directly absorbed into the lymphatic system  Interstitium The supporting structure Distance varies

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007 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 ( ml)

H.H. Wu, MD Mar 5th, 2007 Mechanism of solute transport between peritoneal cavity and capillary lumen

H.H. Wu, MD Mar 5th, 2007 Theoretical behaviors of anticancer agents  Larger molecular weight or water-insoluble anticancer 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 not  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

H.H. Wu, MD Mar 5th, 2007 Pharmacologic advantage for IP C/T Ratio of drug level, peritoneal cavity/plasma DrugMolecular weightWater solubilityPeakAUC Cisplatin Carboplatin Topotecan Mitomycin Melphalan Methotrexate Docetaxel FU Doxorubicin Gemcitabine Paclitaxel mitoxantrone (Modified from Markman M, Semin Oncol 1991)

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007 Pharmacology of IP drugs  Cisplatin  Carboplatin  Paclitaxel

H.H. Wu, MD Mar 5th, 2007 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 times higher levels of drug after IP administration  IP C/T might increase the therapeutic index for small tumors confined to the peritoneal cavity

H.H. Wu, MD Mar 5th, 2007 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 regional therapy systemic chemotherapy  IP infusion of carboplatin is feasible not only as an IP regional therapy but also as a more reasonable route for systemic chemotherapy 400 mg/m 2  The recommended dose of IP carboplatin was 400 mg/m 2 (Speyer and Sorich, 1992) (Speyer and Sorich, 1992)

H.H. Wu, MD Mar 5th, 2007 Paclitaxel  Dose-limiting toxicity: severe abdominal pain (when dose ≧ 175 mg/ ㎡ )  P/V ratio: peak & AUC : 1000-fold h  Paclitaxel persisted in peritoneum for more than 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)

H.H. Wu, MD Mar 5th, 2007 IP agents and risk (Makhija et al, 2001)

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 Clinical aspects of IP C/T  Front-line chemotherapy  Consolidation  2nd-line chemotherapy

H.H. Wu, MD Mar 5th, 2007 Phase III trials of IP vs IV cisplatin- based chemotherapy (Hamilton, 2006)

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 Main results  Eight randomized trials studied 1819 women receiving primary treatment for ovarian cancer. less likely to die  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. gastrointestinal effectspain fever  There may be greater serious toxicity with regard to gastrointestinal effects, pain and fever but less ototoxicity with the intraperitoneal than the intravenous route.

H.H. Wu, MD Mar 5th, 2007 Hazard ratio for time to recurrence (IP vs IV C/.T)

H.H. Wu, MD Mar 5th, 2007 Hazard ratios for time to death (IP vs IV C/T)

H.H. Wu, MD Mar 5th, 2007 GOG 104 (Alberts et al, 1996) OS

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007 Shorts of GOG 104  GOG 111 Median survival from 24 months (P+C) to 38 months ( P+T)

H.H. Wu, MD Mar 5th, 2007 GOG 114 (Markman et al, 2001) PFS OS

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007 Shorts of GOG 114  More complications in IP arm Neutropenia, thrombocytopenia G-I & metabolic toxicities  Carbopltin x 2 cycles ( AUC 9)

H.H. Wu, MD Mar 5th, 2007 GOG 172 (Armstrong et al, 2006) PFS OS

H.H. Wu, MD Mar 5th, 2007 GOG 172 residual tumor size & survival

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 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

H.H. Wu, MD Mar 5th, 2007 NCI Clinical Announcement, 1/5/06 Pooled survival benefit of IP regimens  Progression-free survival HR=0.79 (95%CI: )  Overall survival HR=0.79 (95%CI: )

H.H. Wu, MD Mar 5th, 2007 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 courses of IP C/T is adequate? How many courses  Effect of Dose intensity? IP regimen uses higher and more frequent dosing schedule than the IV regimen

H.H. Wu, MD Mar 5th, 2007 Cross-trial comparison of GOG 172 and GOG 158 IP C/T arm Of GOG-172 Carbo-/Paclitaxel arm of GOG-158 No gross residual38%35% Negative 2nd look57%53% PFS23.8 months20.7 months Overall survival65.6 months57.4 months 2-year survival83% 4-year survival64-65%61% Complete 6 cycles42%87%

H.H. Wu, MD Mar 5th, 2007 GOG 172: eligible patients in IP arm  Although fewer than half the patients assignedto the IP group received six cycles of IP treatment, the group as a whole had a significant improvement in survival as compared with the intravenous group. It is possible that most of the benefit of IP therapy occurs early, during the initial cycles, or that the benefit of IP therapy may be greater if more patients can successfully complete six cycles of treatment.

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 IP C/T as Consolidation (Hamilton, 2006)

H.H. Wu, MD Mar 5th, 2007 Potential IP consolidation regimens  Cisplatin alone (50 mg/m2)  Cisplatin + topotecan  Cisplatin + FUDR

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 IP C/T as 2nd-line C/T  Phase I or II studies  IP C/T is safe, feasible, and pharmacokinetically advantageous, but responses varied widely.  Critical factors for response Tumor burden at initial treatment Paltinum sensitivity  Few candidates for 2nd-line IP C/T Those with stage IV, macroscopic, platinum-resistant, or extraperitoneal dz are less likely to be benefit Extensive adhesion 2nd-look op become rare  recurrence is detected by palpable or imageable lesions and symptoms.

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 More Considerations  Catheter issues  Patient selection  Toxicity and QOL

H.H. Wu, MD Mar 5th, 2007 Complications of Catheter  Blockade  Leakage  Infection  Diarrhea  Bowel perforation  Fistula formation

H.H. Wu, MD Mar 5th, 2007 Catheter issues Timing of placement  34% discontinued IP C/T for catheter- specific complications (Walker et al, GO,2006)  Not associated with complication rate  Pre-operative counseling, if possible  Laparotomy, laparoscopy  Close the vaginal cuff

H.H. Wu, MD Mar 5th, 2007 Catheter issues Types of Catheter  Tenckhoff peritoneal dialysis catheter  Subcutaneous port implantation Port-A-cath BardPort peritoneal catheter system  JP, CWV catheters  Veress needles

H.H. Wu, MD Mar 5th, 2007 Tenckhoff tube

H.H. Wu, MD Mar 5th, 2007 Bardport catheter system

H.H. Wu, MD Mar 5th, 2007 Catheter issues Site of port placement  Goal To minimize patient discomfort, and Facilitate ease of access  Port site Superior and medial to the iliac crest, or On the inferior thorax, at the midclavicular line, overlying the ribs.

H.H. Wu, MD Mar 5th, 2007 Common port sites 2 1

H.H. Wu, MD Mar 5th, 2007 Patient selection issues  Patient characteristics eg.: renal function ; neuropathy (DM – associated)  Significant peritoneal adhesion  Ongoing abdominal infection, or indwelling IP catheter becomes infected or malfunction, will be unable to treated by this route of drug delivery  Size of residual tumor masses <0.5 cm, 1cm, or 2 cm ?  Onion skinning  Lt colon or rectosigmoid colon resection ?

H.H. Wu, MD Mar 5th, 2007 Toxicity and QOL  In GOG172, in IP more Bone marrow suppressions, constitutional, G-I, neurologic symptoms, and infections

H.H. Wu, MD Mar 5th, 2007 Who said all IP cisplatin therapy is more toxic than IV cisplatin therapy? ToxicityIP cisplatin (n=250) IV cisplatin (n=276) P-value Granulocytopenia Leukopenia Tinnitus Hearing loass515<0.001 Abdominal pain182<0.001 Hemoglobin thrombocytopenia (GOG 104)

H.H. Wu, MD Mar 5th, 2007 Quality of Life GOG 172

H.H. Wu, MD Mar 5th, 2007 How to reduce the toxicities from IP C/T?  IP cisplatin-related toxicites Replacing cisplatin with carboplatin GOG phase I study: IP carboplatin ( AUC 6-7 ) + IV Taxol ( 175 mg/m2, 3hr )  IP Paclitaxel-related toxicities IV Docetaxel: less neurotoxic than Taxol (SCOTROC trial) IP Docetaxel  no dose-limiting toxicities (Morgan et al)  IP catheter-related toxicities

H.H. Wu, MD Mar 5th, 2007

H.H. Wu, MD Mar 5th, 2007 Conclusion  IP cisplatin-based C/T has been shown to have a survival benefit over IV cisplatin- based C/T for advance ovarian cancer patients with optimal debulking.  However, there are a number of unanswered questions that should be resolved before IP C/T becomes truly a standard care in the ovarian cancer.

H.H. Wu, MD Mar 5th, 2007 Future Directions carboplatin 1.Is IP administration of carboplatin replacable to IP cisplatin as a less toxic alternative? docetaxel 2.Is IP administration of paclitaxel necessary or IP administration of docetaxel acceptable? optimal number 3.What is the optimal number of IP treatment? optimal type and material? 4.What is the optimal timing for the IP catheter placement and what is the optimal type and material? bulky residual tumor 5.Is IP C/T for ovarian cancer with bulky residual tumor as effective as those for small residual tumor? lymph node metastasis 6.How effective is IP C/T for retroperitoneal lymph node metastasis?

H.H. Wu, MD Mar 5th, 2007