Chirurgia Avanzata Del Carcinoma Ovarico Nuove Strategie A Confronto Ovarian Cancer Advanced Surgery New Strategies in Comparison

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1 Peritoneal dissection and intraperitoneal chemotherapy under hyperthermic conditions. If you select the right patients long-term survival can be achieved. Chirurgia Avanzata Del Carcinoma Ovarico Nuove Strategie A Confronto Ovarian Cancer Advanced Surgery New Strategies in Comparison Bergamo, Italy 5-6 May 2011 Paul H. Sugarbaker, MD, FACS, FRCS Program in Peritoneal Surface Malignancy Washington Cancer Institute Washington, DC, USA

2 Alternative Title: Discussion regarding the poor long-term results with CRS and HIPEC: 1. High PCI (concept of extent of disease) 2. Extensive prior surgery (concept of the peritoneum as the first line of defense against carcinomatosis) 3. Extensive prior systemic chemotherapy (concept of natural or acquired drug resistance)

3 Discussion regarding the poor long-term results with CRS and HIPEC: 4. Inadequate perioperative hyperthermic chemotherapy (concept of pharmacologic drug selection). 5. Imperfect cytoreduction (concept of CRS requiring visceral resections and peritonectomy) 6. Lack of application to ovarian tumors of low malignant potential (concept of favorable tumor biology)

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5 Extent of disease and survival Bristow et al., 2007

6 Tentes et al., 2009 PCI <13 vs. >13

7 Are there modifications in patient management that will result in a reduced PCI at the time of CRS and HIPEC? 1. CRS + HIPEC as primary management 2. CRS + HIPEC after neoadjuvant chemotherapy 3.?

8 CONCEPT The peritoneum is the first line of defense of the host against peritoneal dissemination of cancer. If this barrier is disrupted in the presence of cancer cells, fibrin entrapment at the wounded site will cause progression deep to the peritoneum. Subsequent efforts to treat carcinomatosis by cytoreductive surgery and peritonectomy with perioperative intraperitoneal chemotherapy will be jeopardized.

9 Prior Surgical Score Regions dissected PSS-1 1 PSS PSS-3 6-9

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11 Tumor cell entrapment as seen on pelvic CT

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13 Effect of prior systemic chemotherapy Helm et al., 2010

14 Inadequate perioperative hyperthermic chemotherapy requires pharmacologic engineering of drugs with established cytotoxicity Heat synergized chemotherapy: Melphalan Cyclophosphamide Ifosfamide Heat augmented chemotherapy: Cisplatin, oxaliplatin Doxorubicin 5-fluorouracil Mitomycin C Etoposide No heat effects: Paclitaxel Docetaxel

15 Bidirectional chemotherapy (intraperitoneal and intravenous)

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17 Application to low malignant potential (LMP) ovarian tumors with carcinomatosis that have a less aggressive natural history 1. Low grade papillary serous 2. Mucinous ovarian 3. Granulosa cell 4. Gliomatosis peritonei 5. Pseudomyxoma from ruptured dermoid cyst

18 Conclusions 1. The low perceived benefit from CRS and HIPEC derives from poor patient selection and suboptimal treatments. 2. Meticulous cytoreduction combined with perioperative multidrug therapy are needed in continuing phase II explorations.

19 Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Prevention and Treatment of Peritoneal Surface Malignancy 2011 I. Basic Principles II. Recent results of treatment A. Appendiceal B. Mesothelioma C. Colorectal D. Gastric E. Ovarian

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22 Pharmacologic concept of bidirectional (IV and IP) chemotherapy for peritoneal tumor nodules Outer Layer Inner core

23 Intraperitoneal 5-fluorouracil

24 Intravenous 5-fluorouracil Given in the Operating Room

25 Intraperitoneal Gemcitabine

26 Intravenous Ifosfamide Given in the Operating Room

27 Doxorubicin ( g/ml) Intraperitoneal Doxorubicin Given in the Operating Room with Heat in Patients with Mucinous Cancer Tumor nodules 1 Perit. Fluid 0.1 Plasma Time (minutes)

28 Area Under the Curve (IP/IV) for Chemotherapy Agents Used for HIPEC Drug Molecular Wt. (Da) AUC ratio 5-fluorouracil Mitomycin C Doxorubicin Cisplatin Paclitaxel Gemcitabine Melphalan

29 Advantages of moderate hyperthermic intraoperative intraperitoneal chemotherapy General Reversal of systemic hypothermia from long surgery Normalization of blood clotting Minimal toxicity for normal tissue (<43ºC) Potentiation of other therapies Stimulation of host immune system With chemotherapy Increased cytotoxicity of chemotherapeutic agents Increased drug penetration into tissue by increasing membrane permeability Inhibition of chemotherapy repair mechanisms Reversal of drug resistance With manual distribution Mechanical debridement of cancer cells from tissue surfaces Uniform treatment of hyperthermia and chemotherapy solution Absence of unexposed surfaces Absence of suture line recurrence

30 Credits and debits of two different technologies for hyperthermic intraperitoneal chemotherapy Open abdomen manually distributed Closed abdomen Efficiency Allows continued cytoreduction of bowel and mesenteric surfaces No surgery possible during chemotherapy Environmental hazard No aerosols detected Perception of increased safety Distribution Pressure Pharmacology Abdominal incision and suture lines Diaphragm perforation with peritonectomy Uniform distribution of heat and chemotherapy solutions, tissues close to skin edge not immersed No increased intraabdominal pressure Allows pharmacokinetic monitoring of tumor and normal tissue Treated prior to performing the suturing Pleural space treated by hyperthermic chemotherapy may prevent seeding of pleural space Possible poor distribution to dependent sites and closed spaces Increased intraabdominal pressure may increase chemotherapy penetration into tissue Tissue uptake of chemotherapy cannot be determined Risk of recurrence in abdominal incision and suture lines Diaphragm closed prior to hyperthermic intraperitoneal chemotherapy so pleural space is not treated Intestinal perforation Detected by observing immersed bowel loops Not detected Hyperthermia Increased heat necessary to maintain 42 C Less heat required to maintain 42 C

31 The peritoneum is the First Line of Defense for cancer spread in the abdomen and pelvis. Surgical interventions in the presence of free intraperitoneal cancer cells can promote deep implantation and jeopardize benefit from CRS (Cytoreductive Surgery) and PIC (Perioperative Intraperitoneal Chemotherapy).

32 Survival by Histopathology in Appendiceal Cancer: DPAM vs. PMCA All Patients A; Patients with complete cytoreduction B

33 Extent of Disease as Measured by the Peritoneal Cancer Index

34 Survival by Peritoneal Cancer Index in Appendix Cancer: 1-20 vs DPAM and PMCA

35 Survival by Extent of Prior Surgery in Appendix Cancer: DPAM and PMCA

36 Survival by Completeness of Cytoreduction: DPAM and PMCA

37 Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience Tristan D. Yan, Marcello Deraco, Dario Baratti, Shigeki Kusamura, Dominique Elias, Olivier Glehen, Francois N. Gilly, Edward A. Levine, Perry Shen, Faheez Mohamed, Brendan J. Moran, David L. Morris, Terence C. Chua, Pompiliu Piso, and Paul H. Sugarbaker J Clin Oncol 27: , 2009

38 Survival after CRS and HIPEC in 401 Patients with Peritoneal Mesothelioma

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40 Peritoneal Colorectal Carcinomatosis Treated With Surgery and Perioperative Intraperitoneal Chemotherapy: Retrospective Analysis of 523 Patients From a Multicentric French Study Dominique Elias, François Gilly, Florent Boutitie, François Quenet, Jean-Marc Bereder, Baudouin Mansvelt, Gérard Lorimier, Pierre Dubè, Olivier Glehen J Clin Oncol 28:63-68, 2010

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45 Peritoneal carcinomatosis from gastric cancer: a multi-institutional study of 159 patients treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy Olivier Glehen, Francois Gilly, Catherine Arvieux, Eddy Cotte, et al. Annals of Surgical Oncology (in press)

46 Survival and Disease-Free Survival of 159 Gastric Cancer Patients with Carcinomatosis Treated with CRS and HIPEC

47 Survival of Gastric Cancer Patients by Completeness of Cytoreduction

48 Survival of Gastric Cancer Patients by Peritoneal Cancer Index

49 A Systematic Review and Metaanalysis of the Randomized Controlled Trials on Adjuvant Intraperitoneal Chemotherapy for Resectable Gastric Cancer Tristan D. Yan, Deborah Black, Paul H. Sugarbaker, Jacqui Zhu, et al. Ann Surg Oncol,14: , 2007

50 Forest Plot of Overall Survival at 3 Years

51 Hyperthermic intraperitoneal chemotherapy in ovarian cancer. First report of the HYPER-O Registry Cyril W. Helm, Scott D. Richard, Jianmin Pan, David Bartlett, et al. Int J Gynecol Oncol, 20:60-61, 2010

52 Kaplan-Meier Curve Survival Probability by Platinum Response

53 Kaplan-Meier Curve Survival Probability by CC Score

54 Kaplan-Meier Curve Survival Probability by Time Point HIPEC Used

55 Conclusions 1. A strong rationale from tumor biology and the pharmacologic advantages of local-regional chemotherapy combine to recommend treatments to manage carcinomatosis. 2. When treatments are available at experienced centers CRS and PIC are reasonable treatment options for appendiceal cancer, mesothelioma and low volume carcinomatosis.

56 3. Adjuvant perioperative intraperitoneal chemotherapy has been found beneficial in numerous single institution phase III trials. 4. The standard of care for peritoneal surface malignancy varies greatly around the globe form experimental to standard of care.