Angiogenic blockade and Tomotherapy in hepatocellular carcinoma

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季匡華 Kwan-Hwa Chi, M.D.
Chairman, Section of Radiation Therapy and Oncology Shin Kong Wu Ho-Su Memorial Hospital, Taiwan Professor, School of Medicine
National Yang-Ming University

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Angiogenic blockade and Tomotherapy in hepatocellular carcinoma

  1. 1. Angiogenic blockade and Tomotherapy in hepatocellular carcinoma 季匡華 Kwan-Hwa Chi, M.D. Chairman, Section of Radiation Therapy and Oncology Shin Kong Wu Ho-Su Memorial Hospital, Taiwan Professor, School of Medicine National Yang-Ming University
  2. 2. Hepatoma Treatment Option Surgery 15-29% TAE/TACE 40-70% PEIT RFA 5→25% Radiotherapy 2→6% Background
  3. 3.  The Ideal Radiotherapy Facility for Hepatoma Treatment 1. Proton Therapy 2. Tomotherapy 3. Cyberknife Background
  4. 4.  Local control at 5 years 86.9% for all 192 tumor patients with median 72Gy/16fx.  T<5cm 87.8% with out portal vein thrombosis  T ≥5cm 82.1%  Overall survival 53.5% for child A of patient with solitary tumor. All case is 23.5% at 5 years. Proton Therapy: TsuKuba University (Clinical Cancer Research 2005;11(10):3799-805 )
  5. 5. Major determinants for clinical results interpretation 1. Not only the stage, but also the number of targets (patient selections). 2. Underlying liver function (patient selections). 3. Salvage treatment or primary treatment. 4. Concomitant treatment, adjunctive treatment (TACE, antiangiogeneic, maintenance AA, anti-viral treatment).
  6. 6. Moderate fractionation 250-500cGy/fx 10-20fx ( Proton, Tomot herapy) Conventional fractionation 200cGy/fx 25-35fx Extreme fractionation (SBRT) < 8fx, > 600cGy/fx Background
  7. 7. The difference of SBRT vs Tomotherapy SBRT 1. effective with HCCs ≦6cm 2. not close to critical organs 3. Stringent immobilization Tomotherapy with moderate fractionation 1. No size limitation 2. Multiple targets 3. SIBRT 4. Conventional immobilization
  8. 8. Figure 1 Cumulative dose-volume histograms (cDVH) of normal liver for IMRT plans (solid line) and SSPT plans (dashed line). (a) cDVH for patients with nominal diameter of GTV (a) 5.1cm, (b) 7.8cm and (c) 16.1 cm. Triangles in each figure were dose constrains for one-third and for two- thirds of the volume of the normal liver. Proton Therapy vs IMRT Radiation Oncology 2013, 8:48
  9. 9. Retrospectively reviewing our clinical experience of combined anti- angiogeneics and hypofractionated tomotherapy for patients with hepatoma. (Shin-Kong Memorial Hospital)
  10. 10.  Tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. (Garacia-Barros et al. Science 2003)  Drugs that neutralize VEGF signaling generate a window for tumor vasculature normalization within a few weeks. Then, hypoxia may followed. (Cancer Cell 2004)  Radiotherapy to liver may result in the outgrowth of previously dormant micro- tumor not in the irradiated field due to a surge of VEGF. A maintenance AA is important to prevent rebound. 。 Rationale of Combined AA and HRT
  11. 11. Our antiangiogeneics protocol Before 2009 Sunitinib 1# Bid ± maintenance After 2010 Sorafenib 1# Bid concomitant plus 3# maintenance (if Insurance Reimburse) Metronomic chemotherapy Cyclophosphamide 1# Qod Hydroxyurea 1# Qod (if no insurance)
  12. 12. Methods & Materials 1. Immobilized, diaphragm compression. 2. GTVs, 56Gy in 16 fractions initially planned by tomotherapy. 3. Ceiling on mean liver dose 18-20Gy. 4. Both intrahepatic and extrahepatic lesions are treatment simultaneously.
  13. 13. 1. Sunitinib 25mg p.o. at least one wk before, during and at least 2wk after RT. 2. Encouraged to maintenance use of sunitinib 2-3 tab/day till progression. 3. Lamivudine prophylactic treatment for HBV carriers. Methods & Materials
  14. 14. Response to Treatment in Assessable Patients (n=23) Outcome Targeted Therapy Plus Multiple-Target Tomotherapy (in field response) Number % Radiological CR 2 8.6 Radiological PR 15 65.4 Stable Disease 5 21.7
  15. 15. Univariate and Multivariate Cox Analysis of Survival Factor Univariate Multivariate HR 95% CI P HR 95% CI P Target: 1 v>1 0.64 0.16-2.615 0.534 In-field recurrence: No v Yes 0.18 0.04-0.80 0.024 0.36 0.08-1.70 0.194 Outside-field recurrence: No v Yes 0.68 0.08-5.61 0.718 Target size: < 5cm v >5cm 0.30 0.04-2.42 0.256 Vessel invasion: No v Yes 0.47 0.06-3.9 0.485 Maintenance sunitinib: No v Yes 3.96 0.92-17.14 0.065 12.04 1.19-121.64 0.035 Extrahepatic targets: No v Yes 0.68 0.14-3.42 0.642 Child classification: A v B 1.10 0.22-5.45 0.909 AFP level: < 400 v >400 0.58 0.14-2.43 0.455 NTD dose Gy2 (α/β=3 ) < 60Gy v ≧60Gy 3.83 0.90-16.22 0.069 9.10 0.96-86.23 0.054
  16. 16. Overall Sunitinib maintenance No maintenance 1-year survival 70% 89% 42% 1-year progression survival 12% 22% 0% Median survival 16m > 20m 9m Median TTP 7m 10m 4m
  17. 17. 1 10 100 1000 10000 100000 1000000 -14 0 14 28 42 56 70 84 98 112 Day AFP(ng/ml)
  18. 18. Table 1: Characteristics of all patients Characteristics n = 89 Age, years, median (range) 61(37-85) Gender Male 74 (83%) Female 15 (17%) Previous local treatment Yes 37 (42%) No 52 (58%) Stage I 3 (3%) II 19(22%) III IV 49(55%) 18(20%) Combined antiangiogenic treatment Sunitinib 39 (44%) Sorafenib 5 (5.6%) Metronomic chemotherapy 39 (44%) No antiangiogenic agent 6 (6.7%)
  19. 19. Images fusion under abdomen compression
  20. 20. Image Fusion Fusion based on R’t lobe liver Fusion based on L’t lobe liver
  21. 21. Tomo plan  Plan parameter:  Jaw: 2.5 cm  Pitch: 0.287  Modulation Factor(Actual) : 2.7 (1.732)  Tx time: 258 sec
  22. 22. Tomo plan tip  First Use 2.5 cm jaw instead of 1.0 cm jaw  Reduce motion effect  Higher modulation factor:  Modulation Factor(Actual) : 2.7 (1.732)  Split normal liver into two parts  To reduse dose in healthy liver 1cm beyond PTV  Normal liver (out):normal Liver – (PTV+1-2cm)  Higher importance than normal liver (in) to reduce the dose in healthy liver  Try to lower the volume of 10% prescription dose lower mean liver dose  Normal liver (in):normal Liver – Normal liver (out)  Try to lower the volume of high dose  make dose drop quickly
  23. 23. Tomo plan tip  Set constrain to normal-liver-out dose 1.5cGy/ml hepatocyte, mean normal liver dose 18-20Gy depended on Child class  Lower the coverage of target to get lower liver dose  Then increase the coverage of target  the liver dose doesn’t increase too much
  24. 24. 50% dose is comformal
  25. 25. Coronal Sagittal
  26. 26. Tx plan  Prescription Dose :  GTV- PVT (34.5 c.c.): 200 cGy x 20 = 40 Gy  GTV-left lobe (168.3 c.c.): 200 cGy x 20 = 40 Gy  Normal liver Dose  Normal liver = liver – PTV  Targets+1 cm margins determine normal-liver-out or in  Mean dose: 1916 cGy  Volume: 1475 c.c.  Normal-liver-out (893 c.c.) mean dose is 1066 cGy  Normal-liver-in (539 c.c.) mean dose is 3226 cGy
  27. 27. DVH Normal liver R’t kidney L’t kidney cord
  28. 28. Stage No. Median(m) Overall survival I 3 29.8 100 66.7 0 0 0 II 19 23.1 72.2 48.9 27.2 27.2 0 III 49 10.5 40.9 18.7 11.2 7.5 0 IV 18 22.3 70.8 45.1 24.1 24.1 24.1
  29. 29. No. Median (m) Overall survival 89 13.4 57.5 33.2 17.7 15.5 3.9 Overall survival
  30. 30. Prior No. Median (m) Overall survival Yes 37 18.2 64.7 37.0 31.7 25.4 12.7 No 52 12 49.8 30.1 10.0 10.0 - P=0.078
  31. 31. 1 10 100 1000 10000 100000 -100 100 300 500 700 900 1100 1300 AFPconc.(ng/ml) Days 謝** 葉** 游** 詹** 楊** 陳** 洪** 莊林**
  32. 32. 2007/04/12 2007/07/11 (pre-treat) (post-treat) (1+ months later)
  33. 33. 2007/04/15 2007/07/19 (pre-treat) (post-treat) (3+ months later)
  34. 34. 2007/12/31 2008/05/01 (pre-treat) (post-treat)
  35. 35. 2008/02/13 2008/05/21 (pre-treat) (post-treat)
  36. 36. 2008/02/18 2008/05/07 (pre-treat) (post-treat)
  37. 37. 2008/03/11 2008/07/09 (pre-treat) (post-treat)
  38. 38. 2008/04/11 2008/07/07 (pre-treat) (post-treat)
  39. 39. 2007/03/26 2007/06/22 2008/06/26 (pre-treat) (post-treat) (post-treat) (1+ months later) (15+ months later)
  40. 40. 2007/04/11 2007/07/10 2007/09/05 (pre-treat) (post-treat) (post-treat) (1+ months later) (4+ months later)
  41. 41. 2007/05/06 2007/07/06 2007/09/04 (pre-treat) (post-treat) (post-treat) (1+ months later) (3+ months later)
  42. 42. 2007/05/24 2007/08/29 2007/10/30 (pre-treat) (post-treat) (post-treat) (1+ months later) (3+ months later)
  43. 43. 2007/09/05 2007/11/26 2009/06/20 (pre-treat) (post-treat) (post-treat) (2+ months later) (21+ months later)
  44. 44. Summary  Antiangiogenics is not curative. The combination of antiangiogenics and radiotherapy may be curative.  Highly conformal tomotherapy may provide high quality plan for advanced HCC. High RR and AFP response not amenable to other treatment .  Prolong use of antiangiogenics can result in decreased microvascular density and increase tumor hypoxia and decrease radiosensitivity. Early use of radiotherapy may be mandatory.
  45. 45. Summary:  Hepatoma are prone to develop progressive disease outside the radiation fields. Combination of angiogenesis inhibitors seem able to prevent out-field surge of dormant tumor re-growth.  Hypofractionated schedule appears more promising than conventional schedule. Whether HRT is better than SBRT is unknown, but more user friendly.  RILD incidence seems not to be affected by the concomitant use of AA and anti-viral agents.
  46. 46. Summary:  Respiration motion control is a must be in era of HCC high conformal therapy.  More effective systemic treatment by combination of multi-angiogenics targets such as sorafenib, proteosome inhibitor, metronomic chemotherapy, zolendrotic acid, axitinib for a total blockage.  High quality images such as primovist MRI may be needed.
  47. 47. The End Thanks!

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