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The Evolution of Modern Isolated              Hepatic Perfusion for Patients with              Unresectable Hepatic Metast...
DisclosuresJames F. Pingpank, Jr., MD  Scientific Advisory Board (Delcath Systems, Inc; New York, NY)  Research Support (D...
Unresectable Hepatic Cancers                     -Therapeutic Options-                           Systemic Treatments      ...
Rationale for Regional TherapyRegional therapy allows dose escalation to the   cancer-bearing region or organ of the body ...
Treatment of Hepatic Metastases                    Regional Therapy  Unresectable cancers (primary or metastases)     conf...
Schematic of IHP Circuit and Operative            Dissection (290 procedures)                                             ...
Improved Technique – Combined Percutaneous and                     Open Procedure   OR Time 12.5                        ...
Background: Isolated Hepatic Perfusion                           Colorectal Metastases                             n=120 p...
Percutaneous Hepatic Perfusion          Melphalan Phase I MTD: 3.0 mg/kg (based upon IBW)Thursday, March 31, 2011
Protocol Schema   On Study Evaluation                       Interval Evaluation                    Post Treatment Evaluati...
Chemotherapy Levels During Therapy                                       IHP vs PHP        Isolated Hepatic Perfusion     ...
Phase I PHP: Metastatic Melanoma                           Radiographic Treatment Response                                ...
Randomization and Treatment Schema                                            H                                           ...
Phase III Random-Assignment PHP vs.                Best Available Care     Accrual goal: 92 patients (Cross-over at Hepati...
Results: Primary Endpoint   -Hepatic Progression Free Survival (ITT) -                              Hazard Ratio: 0.301   ...
Results: Secondary Endpoint    -Overall Progression Free Survival (ITT)-                               Hazard Ratio: 0.404...
Results: Secondary Endpoint                      -Overall Survival (ITT)-                                       Hazard Rat...
Metastatic Ocular Melanoma                                   Pre-PHP: Baseline                           Post Treatment: 9...
PHP Patient Demographics                      Neuroendocrine Tumors (n=23)             Median no. of hepatic lesions      ...
PHP Response: Neuroendocrine Tumors                                     (n=23)                  NE (Toxicity*, Incomplete ...
Hepatic Progression-Free Survival After PHP                           Metastatic Neuroendocrine Tumor (n=20)              ...
Metastatic Glucagonoma                                    54 year-old female                                    Metastatic...
Metastatic Glucagonoma              Pre-Treatment         Post-PHP x 2   Follow-up (22m)                April 2003        ...
Conclusions     High-dose Melphalan, delivered via intra-arterial       administration is effective against hepatic metast...
Conclusions     High-dose Melphalan, delivered via intra-arterial       administration is effective against hepatic metast...
The Evolution of Modern Isolated              Hepatic Perfusion for Patients with              Unresectable Hepatic Metast...
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Dcth isolation perfusion

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DCTH James Pingpank presentation 2010 WICO

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Dcth isolation perfusion

  1. 1. The Evolution of Modern Isolated Hepatic Perfusion for Patients with Unresectable Hepatic Metastases James F. Pingpank, Jr., MD, FACS Associate Professor of Surgery Division of Surgical Oncology, Department of Surgery University of Pittsburgh, Pittsburgh, PA June 10, 2010 WCIO Annual Meeting- Philadelphia PAThursday, March 31, 2011
  2. 2. DisclosuresJames F. Pingpank, Jr., MD Scientific Advisory Board (Delcath Systems, Inc; New York, NY) Research Support (Delcath Systems, Inc; New York, NY)All participating institutions received research support from studysponsor, Delcath Systems, Inc (New York, NY)Intra-arterial melphalan and Delcath double balloon catheter underIND (FDA)Thursday, March 31, 2011
  3. 3. Unresectable Hepatic Cancers -Therapeutic Options- Systemic Treatments Regional Therapies Local ablative therapy Cryotherapy Radiofrequency ablation EtOH injection Infusional therapy Hepatic Artery Infusion (HAI) HAI with hemofiltration Chemoembolization Isolated Hepatic Perfusion Selective Internal RadiationThursday, March 31, 2011
  4. 4. Rationale for Regional TherapyRegional therapy allows dose escalation to the cancer-bearing region or organ of the body while minimizing systemic exposure and toxicity, via complete separation of the regional and systemic circulationEliminates or significantly reduces systemic toxicity, and dose escalation of therapeutic agents is limited largely by the tissue tolerance of the perfused organ/limb - Improved efficacy/tumor responseBased on its unique vascular anatomy the liver is a favorable site for delivery of regional therapy - Established tumors in liver derive the majority of blood flow from the arterial tree (tumors: 100% versus normal liver: 25%)Potential for delivery of clinically relevant levels of hyperthermia or biologic agentsThursday, March 31, 2011
  5. 5. Treatment of Hepatic Metastases Regional Therapy Unresectable cancers (primary or metastases) confined to liver are a significant clinical problem: Colorectal cancer: 30,000/yr Hepatocellular carcinoma: 16,000/yr Ocular melanoma: 2,000/yr Neuroendocrine tumors: 2,000/yr Other histologies: ? Therapeutic options are limited and survival after diagnosis of liver metastases is short. Morbidity and mortality in this setting is invariably secondary to disease progression in the liver.Thursday, March 31, 2011
  6. 6. Schematic of IHP Circuit and Operative Dissection (290 procedures) Supra-Hepatic IVC Retro-Hepatic IVC Porta Hepatis DissectionThursday, March 31, 2011
  7. 7. Improved Technique – Combined Percutaneous and Open Procedure  OR Time 12.5  OR Time 4.5 hours hours  LOS 12 days  LOS 7 daysThursday, March 31, 2011
  8. 8. Background: Isolated Hepatic Perfusion Colorectal Metastases n=120 pts RR: 60%, Median OS: 17.4m SSO2007 (Abstract 14) Ocular Melanoma Metastases n=29 pts RR:62%, Median OS: 12.1 m Clin Cancer Res 2003 15;9(17):6343-9. Neuroendocrine Metastases n=13 pts RR: 50%, Median OS: 48 mThursday, March 31, 2011
  9. 9. Percutaneous Hepatic Perfusion Melphalan Phase I MTD: 3.0 mg/kg (based upon IBW)Thursday, March 31, 2011
  10. 10. Protocol Schema On Study Evaluation Interval Evaluation Post Treatment Evaluation Treatments 1 and 2 Treatments 3 and 4 - Melphalan - Melphalan - Angiogram (Celiac, SMA) - Angiogram (Celiac, SMA) - GDA assessment (Treatment #1) - GDA assessment 4-5 Weeks 4-5 Weeks 4-5 Weeks 4-5 Weeks 16 weeksThursday, March 31, 2011
  11. 11. Chemotherapy Levels During Therapy IHP vs PHP Isolated Hepatic Perfusion Percutaneous Hepatic Perfusion 1.5 mg/kg 3.0 mg/kgThursday, March 31, 2011
  12. 12. Phase I PHP: Metastatic Melanoma Radiographic Treatment Response (n=16) Response n % Duration Overall 8 50 Complete 2 13 10, 15 Partial 6 37.5 2+,8, 8, 12, 15, 16 Stable Disease 4 25 7, 7, 8, 8+ Progressive Disease 4 25 Not Evaluable 2 13 (vascular anomaly) Follow-up Status DOD (Dead of disease) 16 100 Site of Disease Recurrence/Progression (n=12 responders) Hepatic 6 50 Systemic 4 33 Both 2 17 + censored with stable or responding hepatic disease with systemic progression Finalized June 2007Thursday, March 31, 2011
  13. 13. Randomization and Treatment Schema H E P A PHP Arm T Follow-up R (n= 44) I A C N Melanoma D Metastatic P O Cross over to PHP to liver R M (n=27) O (n = 93) I G Z R E E BAC Arm S Follow-up 1:1 (n = 49) S I O NThursday, March 31, 2011
  14. 14. Phase III Random-Assignment PHP vs. Best Available Care Accrual goal: 92 patients (Cross-over at Hepatic progression) 12 Institutions Total Accrual: 93 patients (PHP: 44, BAC: 49, Crossover: 27) Melphalan dose: 3.0 mg/kg Stratification: Cutaneous vs. Ocular Primary endpoint: Hepatic PFS Secondary endpoints: 1. Response rates, DFS with best available therapy 2. Response rates for patients treated with PHPThursday, March 31, 2011
  15. 15. Results: Primary Endpoint -Hepatic Progression Free Survival (ITT) - Hazard Ratio: 0.301 (CI: 0.183-0.497)Thursday, March 31, 2011
  16. 16. Results: Secondary Endpoint -Overall Progression Free Survival (ITT)- Hazard Ratio: 0.404 (CI: 0.252-0.648)Thursday, March 31, 2011
  17. 17. Results: Secondary Endpoint -Overall Survival (ITT)- Hazard Ratio: 0.920 (CI: 0.524-1.615)Thursday, March 31, 2011
  18. 18. Metastatic Ocular Melanoma Pre-PHP: Baseline Post Treatment: 9 months (active)Thursday, March 31, 2011
  19. 19. PHP Patient Demographics Neuroendocrine Tumors (n=23) Median no. of hepatic lesions 15 Mean diameter of largest lesion 4.8 cm Extrahepatic Disease 9 (39%) Subsequent Resection: n=7 Percentage hepatic replacement <25% 12 (52%) 25-50% 5 (22%) >50% 6 (26%) Primary Tumor Histology Carcinoid 6 PNET 17Thursday, March 31, 2011
  20. 20. PHP Response: Neuroendocrine Tumors (n=23) NE (Toxicity*, Incomplete Tx, OLT) 4 PD at interval evaluation 1 SD/MR 3 PR 13 CR 2 Overall Response Rate (19 patients) 15 (79%) 100 75 50 Maximum response 25 0 -25 -50 -75 -100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 PatientsThursday, March 31, 2011
  21. 21. Hepatic Progression-Free Survival After PHP Metastatic Neuroendocrine Tumor (n=20) Median: 39 months 20 Treated Censored for death from extra-hepatic disease (n=4) Not Evaluable due to hepatic toxicity (n=1) On Active Treatment (n=2)Thursday, March 31, 2011
  22. 22. Metastatic Glucagonoma 54 year-old female Metastatic pancreatic neuroendocrine tumor Primary in place, treated post PHP with XRT PHP#1 PHP#2 XRT Pancreas BedThursday, March 31, 2011
  23. 23. Metastatic Glucagonoma Pre-Treatment Post-PHP x 2 Follow-up (22m) April 2003 November 2003 March 2005Thursday, March 31, 2011
  24. 24. Conclusions High-dose Melphalan, delivered via intra-arterial administration is effective against hepatic metastases from ocular melanoma and neuroendocrine tumors Increased drug delivery achieved through novel regional therapeutic approaches may increase efficacy of a given agent (vs. systemic administration) by overcoming a low therapeutic index. Metastatic Melanoma Retreatment of patients with a previous therapeutic benefit from melphalan appears to be effective (n=5) A Multi-center Phase III licensing trial is completed and will be presented at ASCO in June 2010.Thursday, March 31, 2011
  25. 25. Conclusions High-dose Melphalan, delivered via intra-arterial administration is effective against hepatic metastases from ocular melanoma and neuroendocrine tumors Increased drug delivery achieved through novel regional therapeutic approaches may increase efficacy of a given agent (vs. systemic administration) by overcoming a low therapeutic index. Neuroendocrine Tumors Tumor reduction from PHP routinely results in durable control of hormone-related symptoms A Multi-center licensing trial is awaiting FDA approvalThursday, March 31, 2011
  26. 26. The Evolution of Modern Isolated Hepatic Perfusion for Patients with Unresectable Hepatic Metastases James F. Pingpank, Jr., MD, FACS Associate Professor of Surgery Division of Surgical Oncology, Department of Surgery University of Pittsburgh, Pittsburgh, PA June 10, 2010 WCIO Annual Meeting- Philadelphia PAThursday, March 31, 2011

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