11/28/2018. Proton Therapy for Liver Cancer: Who, Why, and How. Disclosures. Michael Chuong, MD. None

Transcription

1 Proton Therapy for Liver Cancer: Who, Why, and How Michael Chuong, MD Disclosures None 1

2 Rationale for proton therapy Hepatic toxicity Biliary toxicity GI toxicity Potentially significant benefit especially for HCC patients } Less rationale Hepatic toxicity Radiation induced liver disease (RILD, classic) Anicteric hepatomegaly Ascites Elevated liver enzymes (ALP > AST/ALT) Non-classic RILD Elevation of transaminases Reactivation of Hepatitis B Liver function decline (CP) Risk of liver toxicity Diagnosis (HCC vs. non-hcc) Baseline liver function (CP A vs. B vs. C) RT dose Dose to non-target liver CP score decline at 3 months after SBRT Liver mets: <5% Early stage HCC: ~10% Advanced stage HCC (PVTT): ~30% CP B HCC: ~30-50% High dose to partial liver volumes is safe MEAN and LOW dose are most important Dawson et al. IJROBP

3 Grade 3+ liver enzyme increase Miften M, Dawson LA, M.D. 8 Radiation Dose-Volume Effects for Liver SBRT. AAPM Working Group on Biological Effects: SBRT Normal Tissue Complication Probability 6 fraction SBRT toxicity for metastases 81 patients with 1-6 liver mets Transient G1-2 hepatic toxicity within 3 months 61% transaminitis 28% albumin decline No grade 3-5 hepatic toxicity Higher risk if increased dose to 700 cc of non-targeted liver All patients No worsening Liver enz. Any worsening Liver enz. No. of patients (%) 81 (100) 32 (39.5) 49 (60.5) Prescription Dose Mean Gy (Range), 6 # 43 (28 60) 46 (28 60) 42 (28 60) Mean Liver Dose Mean Gy (Range) 16 (3 26) 15 (3 26) 17 (5.2 23) Dose to spared 700cc Mean Gy (range) 11 (0.3 29) 8.7 (0.3 25) 12.6 (0.6 29) Pts with 700cc 20Gy, 6 # % (ratio) 88 (71/81) 44 (31/71) 56 (40/71) Barry, PRO fraction SBRT toxicity for HCC: Toronto 102 patients All CP A 6 fractions to Gy Median tumor size 7.2 cm 29% developed worse CP score within 3 months after SBRT Bujold et al, JCO

4 QUANTEC liver constraints (5-6 fractions) HCC CP A Mean liver (minus GTV) <13-18 Gy >800 cc <18 Gy CP B Mean liver (minus GTV) <6 Gy Mets Mean liver (minus GTV) <15-20 Gy >700 cc <15 Gy Pan et al, IJROBP, 2009 VMAT PROTON LOW DOSE ZERO DOSE Kim, Acta Oncologica, 2017 Kim, Acta Oncologica,

5 V0-30 was significantly a/w liver function at 12 months after PBT preferred V0 <30% V0 was the most useful index for measurement of retention of normal liver function Mizumoto et al. IJROBP 2012 Proton therapy in Japan Igaki et al. Int J Clin Oncol, 2017 University of Tsukuba Prof Toshiyuki Okumura 5

6 66 Gy in 10 fractions Prof Toshiyuki Okumura Prof Toshiyuki Okumura Median follow up 55 months N=129 Child A 78%, B 22% Median tumor 3.9 cm (1-13.5) PVTT 12% Multiple tumors 26% Passive scattering Fiducials Gating CTV = GTV mm ITV = CTV + 5 mm PTV = ITV mm 6

7 Tsukuba long-term results Local control 5-yr 94% (stage A), 87% (B stage), 75% (C stage Overall survival 5-yr 69% (stage A), 66% (B stage), 25% (C stage) No grade 3 toxicity Large HCC Median, 11 cm (range, cm) Median, 72.6 GyE in 22 fractions No grade 3+ toxicity 2-year LC 87% Fig. 2. Local control rates in 22 patients with hepatocellular carcinoma exceeding 10 cm treated with proton beam therapy. Sugahara S, et al. Int J Radiat Oncol Biol Phys

8 Hypofractionation Tsukuba >2 cm from porta hepatis: 66 Gy(RBE) in 10 fxn <2 cm from porta hepatis: 72.6 Gy(RBE) in 22 fxn <2 cm from GI tract: 77 Gy in 35 fxn Loma Linda 63 Gy(RBE) in 15 fxn MGH/MDACC/PENN >2 cm from porta hepatis: 67.5 Gy(RBE) in 15 fxn <2 cm from porta hepatis: Gy(RBE) in 15 fxn Child Pugh change Mizumoto et al (IJROBP 2011) 9% increase score by 2 points after 6 months Kim et al (Radiother Oncol 2017) 2.4% increased score by 1 after 3 month Hong et al (JCO 2016) 3.6% increased class after 6 months PMH SBRT 29% increased class after 3 months 8

9 Group 1 = medically necessary When to use protons??? All HCC patients? RILD serious complication Protons provide optimal liver sparing Potential future liver-directed therapies Non-HCC patients? THERE ARE NO RANDOMIZED DATA 9

10 Pract Radiat Oncol. 2015; 5(4): Photons Protons Dome 3 cm Central 3 cm 3 cm Gandhi et al. Pract Radiat Oncol. 2015; 5(4):

11 2018 Miami Liver Proton Therapy Working Group Meeting Focused discussion on patient selection Larger tumors High tumor:normal liver Moderately to severely cirrhotic patients (CP-B/C) History of prior liver radiation (external or internal) RILD risk higher in CP-B+ patients University of Indiana 4/8 (50%) CP-B8+ pts developed progressive liver failure Fatal RILD in 2 of these patients (25%) Princess Margaret Hospital 29 CP-B/C pts (69% CP-B7), PVTT 76% CP score + 2 or more: 34% at 3 months The liver dose was limited in 89% of cases Andolino et al. Int J Radiat Oncol Biol Phys 2011 Culleton et al. Radiother Oncol 2014 Lasley et al. Pract Radiat Oncol

12 Safety of Protons for CP-B/C Patients Study # Pts CP Class RILD Definition Tsukuba CP-A 76% CP-B 22% Loma Linda 2 76 CP-A 29% CP-B 47% CP-C 24% CP score + 1 CP score + 2 AST, ALT, ALP, T-bili, albumin, INR 1 month RILD Rate Mean Liver (EQD 3 ) 1-yr 16% 1-yr 11% NR 0% NR MGH/ MDACC/ UPenn 3 44 CP-A 73% CP-B 21% CP class progression 3.6% 9.6 GyE 1 Mizumoto et al. Int J Radiat Oncol Biol Phys Bush et al. Cancer Hong et al. J Clin Oncol 2016 Proton therapy for cholangiocarcinoma? For unresectable ICC, chemotherapy is standard of care Gemcitabine/cisplatin per ABC-02 trial In patients who do not progress after chemotherapy, can proton therapy improve local control and survival? ABC-02 OS PFS Valle et al, NEJM

13 Ablative dose and survival Local Control (%) P= Time of Follow-Up (months) Overall Survival (%) P= Time of Follow-Up (months) Tao R, et al JCO 2016 Multi-institutional Phase 2 trial MGH/MDACC/UPENN HCC (n=44) and IHC (n=39) Sample size calculated to demonstrate >80% LC at 2 years Eligibility No cirrhosis or Child Pugh A/B ECOG PS 0-2 No extrahepatic disease Maximum tumor size 12 cm 15 fractions 67.5 GyE if > 2 cm from the porta hepatis GyE if within 2 cm of the porta hepatis Hong et al, JCO

14 Ablative proton therapy for liver mets? Jeong et al. Clin Can Res, pts Median 2.5 cm ( ) 23 pts had >6 cm tumor Median dose 40 GyE in 5 fractions (83% of >6 cm tumors received at least 40 GyE) No grade 3+ toxicity The motion problem Fundamentally the same between PBS and US/DS US / DS has more washout of the motion effect PBS is more susceptible to the motion effect, but this can be overcome Motion management Repainting Larger spot size From Tony Lomax 14

15 Repainting and gating Conclusions Why HCC: normal liver sparing Non-HCC: dose escalation/ablation Who HCC: larger tumor, more limited normal liver volume, worse baseline liver function Non-HCC: larger tumor with limited or no extrahepatic disease How Hypofractionation (smaller fraction size in close proximity to GI luminal structures) Mitigation of motion interplay effects 15

16 THANK YOU 16