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Stereotactic Body Radiotherapy for Hepatobiliary and Pancraetic Cancer
Anand Mahadevan MD FRCS FRCR Chairman– Division of Radiation Oncology
Geisinger Health Geisinger Commonwealth School of Medicine
Disclosure & Disclaimer
• An honorarium is provided by Accuray for this presentation
• The views expressed in this presentation arethose of the presenter and do not necessarilyreflect the views or policies of AccurayIncorporated or its subsidiaries. No officialendorsement by Accuray Incorporated or anyof its subsidiaries of any vendors, products orservices contained in this presentation isintended or is inferred.
Objectives
• Non Surgical Ablative treatment for Liver and Pancreas tumors
• Techniques and Challenges of SBRT (Stereotactic Body Radiotherapy)
• SBRT as Primary Treatment• SBRT for Recurrence and Metastasis• Future Directions
Fundamental Principles
• Surgery is the primary curative treatment for Cancer
• Systemic therapy is essential component in the multimodality management of cancer
• Radiation therapy is more about protecting normal tissue than treating cancer
Radiosurgical Ablation
• When not surgical candidates• Patient preference• Surgical recovery delays are not ideal• Systemic therapy (eg. Anti angiogenic
therapy) interferes with surgical recovery
Radiosurgical Ablation
• When not surgical candidates• Patient preference• Surgical recovery delays are not ideal• Systemic therapy (eg. Anti angiogenic
therapy) interferes with surgical recovery
Conventional Stereotactic Radiosurgery Systems
• Limitations:– Primarily used for intracranial targets– Limited scope for tracking movement– Need rigid Immobilization of target
• Invasive frames• Discomfort
Moving Targets
• Unpredictable Fixed movements– Patient Movement– Internal Organ Movement– Bowel/Bladder filling/emptying
• Respiratory Movement
Unpredictable Movements
• Conventional Radiation
Respiratory Movements Conventional Radiation - PTV
Respiratory Movements - SBRT
• 4D CT and ITV
• Dampening– Active Breathing Control
• Gating
• Tracking
Respiratory Movements Conventional Radiation- 4D Imaging
Dampening
Active Breathing Control
Gating
Beam Off
Beam OffBeam On
Beam On
Treatment Field
2.
4.
Gating
Treatment beam is turned on and off as tumor enters and exits a static treatment field
= Over-treated healthy tissue
External position sensor
Internal fiducial
Tracking
Modern SBRT Systems
• Allow continuous tracking of the target– Fiducial based targeting
• Respiratory motion tracking systems• Examples
– Novalis– Trilogy– True Beam– CyberKnife® System
Fiducial Markers
• Gold Seeds– 5.0mm x 0.8 mm– Preloaded in 18-19G
needle– Free seeds can be
placed at surgery or laparoscopically
– Easy to place– 4-7 days from insertion
to scan
Intraoperative
CT Guided
Ultrasound Guided
Endoscopic Ultrasound
Endoscopic Ultrasound
Defining Accuracy
Tumor motion
Patient setup
Patient movement
Imaging (CT, MRI, etc.)
Treatment planning
Beam delivery
Total Clinical
Accuracy
Modern SBRT Accuracy
• Mechanical Accuracy = 0.2 mm
• Total Clinical Accuracy –Stationary lesions: 0.95 mm–Moving lesions: 1.5 mm
Total Clinical
Accuracy
Total Clinical Accuracy
Techniques
GANTRY LINAC PARTICLE BEAM ROBOTIC
Pancreas Cancer
Perspective
SBRT in Pancreas Cancer
• Clinical scenarios– Resected Pancreas cancer– Locally advanced– Local recurrence– Oligometastatic Pancreas Cancer
Locally Advanced Pancreas Cancer
Classic Trials: RT vs. ChemoRT and Chemo vs. ChemoRT
Gemcitabine Based Chemotherapy Trials
Modern Chemo-radiation TrialsTrial Treatment No of Pts Med OS
RTOG 9812 50.4Gy+Taxol 122 11.3m
RTOG 0020 50.4Gy+Taxol/Gem 154 11.7m
RTOG0411 50.4Gy+Xeloda/Avastin 94 11.9m
FFCD-SSRO 60Gy+5FU/Cisplat 59 8.6m
ECOG 4201 50.4Gy+Gem 34 11.0m
FFCD-SFRO
• Would Better systemic therapy made a difference – Gem Abraxane, FOLFIRINOX
• Would earlier Radiation help?• Shorter radiation (SBRT) without interrupting systemic therapy?
SBRT
• Stanford Phase I• Stanford EBRT+ Boost• Stanford Gem SBRT• Danish Phase II• UPMC• Sinai, Baltimore• BIDMC Upfront SBRT• BIDMC Gem SBRT• Tampa
Tolerance Based Approach
Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer
Mahadevan A1, Jain S, Goldstein M, Miksad R, Pleskow D, Sawhney M, Brennan D, Callery M, Vollmer C.
Department of Radiation Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
Int J Radiat Oncol Biol Phys. 2010 Nov 1;78(3):735-42
Toxicity• Acute(<3m)
– 22pts(56%) – Fatigue– 9Pts(23%) Grade 2 Nausea/Vomiting– No acute Grade 3 or 4 toxicity
• Chronic(>3m)– 3(8%) Grade 3 Toxicity
• 2 GI Bleed (one associated with Tumor Progression)
• 1 Gastric outlet Obstruction (with tumor progression)
Toxicity
Borderline Resectable
Modern Single Institution StudiesTrial Treatment No. of
PtsMed OS
MD Anderson 50.4Gy+Xeloda/Avastin 47 14.4m
UCSF 50.4Gy+Avastin 17 17.0m
MSKCC 50.4Gy+Gem/Erlotinib 20 18.7m
U of Michigan 50-60Gy+Gem 27 23.1m
MD Anderson 50.4Gy+Gem/Cetuximab 69 18.8m
Total Neoadjuvant Therapy
Total Neoadjuvant Therapy
(TNT)
Chemo
SBRT
Surgery
Neoadjuvant Chemo and Surgery (NeoC-S)
Chemo
Surgery
Neoadjuvant Chemo and SBRT (NeoC-SBRT)
Chemo
SBRT
Results – Overall Survival
Treatment Group
Number Median Overall Survival (Months)
TNT 25 36.5
NeoC-SBRT 49 19.3
NeoC-Surgery
6 22.2
p=0.03
p=0.98p=0.17
Results – Local Regional Recurrence
FOLFIRINOX SBRT
FOLFIRINOX SBRT
J Clin Oncol. 2016 Aug 1;34(22):2654-68
Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical
Practice GuidelineBalaban EP1, Mangu PB1, Khorana AA1, Shah MA1, Mukherjee S1, Crane CH1, JavleMM1, Eads JR1, Allen P1, Ko AH1, Engebretson A1, Herman JM1, Strickler JH1, Benson AB 3rd1, Urba S1, Yee NS1.
Resected Pancreas Cancer R1 Resection
Resected Pancreas CancerChemoRT vs. Observation
• “ChemoRT Improves Overall Survival vs Observation”– GITSIG Study
• Significant Increase in Med Survival (20m vs 11m)• Significant increase in 5-yr Survival (18% vs 8%)
ESPAC 4
• Adjuvant Gem vs GemCAP• Primary endpoint OS• 2008-2014, 730 pts, Med age 65yrs• 60%R1, 80% N=, 40% Poorly differentiated• Med OS: 28m v 25.5m p=0.032• 5% yr Survival: 29% vs 16 % • No diff in Grade ¾ Toxicity.
• Is this the end of adjuvant Radiation therapy for resected Pancreas Cancer?
Local Control after Whipple+ChemoRT
+ve margin (%) Local Failure (%)
GITSG 0 47
EORTC 19 51
ESPAC 28 63
CONKO 19 37
RTOG 34 25
Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic
adenocarcinomaRaut CP, Tseng JF, Sun CC, Wang H, Wolff RA, Crane CH, Hwang R, Vauthey JN, Abdalla EK, Lee JE, Pisters PW, Evans DB
Ann Surg. 2007 Jul;246(1):52-60
Post OP R1 Resection
• Fiducials placed at surgery• One planning CT with oral and IV contrast• 1000cGy to +ve margins 3-4 weeks post
OP• 5040cGy 5-6 field IMRT6-8 weeks postOP• Concurrent Xeloda• Adjuvant Gemcitabine
Overall Survival – Median 22m
Survival By Margin• R1: 62pts (40%)• R0: 95 Pts (60%)• Median Survival
– 19.5m vs. 27m• 2yr Survival
– 36m vs.51m• 5yr Survival
– 17% vs.28%
R1(Pos. Margin)- Survival by Treatment
Negative Margins vs. Positive Margins + CK Boost
• Median Survival– 27m vs. 29.5m
• 2yr Survival– 51.3% vs.50.4%
• 4yr Survival– 37% vs. 42%
• p=0.7881
Local Control
P=0.0002
Results Summary
50%
36%16%
36%
51%
45%
2-Year Survival (Actuarial)
29.523Chemo/RT + CK
19.519Chemo/RT
1420Untreated
17%19.562Positive Margins (R1)
2795Negative Margins (R0)
24%
28%
22157Overall
5-Year Survival (Actuarial)
Median Survival (months)NCohort
50%
36%16%
36%
51%
45%
2-Year Survival (Actuarial)
29.523Chemo/RT + CK
19.519Chemo/RT
1420Untreated
17%19.562Positive Margins (R1)
2795Negative Margins (R0)
24%
28%
22157Overall
5-Year Survival (Actuarial)
Median Survival (months)NCohort
Study No/Total(%) R1
Resection
No/Total(%) Local
Recurrence
Median Survival
mo.
GITSG 0 7/15(47%) 21
EORTC 20/104(19%) 34/67(51%) 17.1
ESPAC1 19/147(28%) 99/158(63%) 20.1
CONKO-001 34/179(19%) 37(NA) 22.1
RTOG97-04 152/451(34%) 84/328(26%) 18.8
Current Study 20/20(100%) 3/20(15%) 22.1
Stereotactic Radiosurgery for Liver Tumors
Dose-volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular
carcinoma patients treated with three-dimensional conformal radiotherapy
Kim TH, Kim DY, Park JW, Kim SH, Choi JI, Kim HB, Lee WJ, Park SJ, Hong EK, Kim CM
Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):225-31
Whole Liver Tolerance
Semin Radiat Oncol. 2005 Oct;15(4):279-83
Partial volume tolerance of the liver to radiationDawson LA, Ten Haken RK
Worldwide Incidence of Hepatocellular Carcinoma
High (> 30:100,000)
Low or data unavailable (< 3:100,000)Intermediate (3-30:100,000)
Worldwide Incidence of Hepatocellular Carcinoma
HCC Epidemiology
El-Serag HB, Gastroenterology 2004
A. Surgical resectionB. Ablation
Cryotherapy
Radiofrequency ablation
Laser interstitial thermal therapy (LITT)
Microwave coagulation therapy
C. ChemotherapyIntra-arterial
Systemic
ChemoembolisationD. Radiotherapy
Stereotactic body radiation Selective interstitial radiation therapy
E. Liver transplantation
Treatment Options
RFA
TACE
ODDS RATIO 6m SURVIVAL
Eur J Nucl Med Mol Imaging. 2002 Dec;29(12):1657-68
Comparison between radioimmunotherapy and external beam radiation therapy for patients with
hepatocellular carcinomaZeng ZC, Tang ZY, Yang BH, Liu KD, Wu ZQ, Fan J, Qin LX, Sun HC, Zhou J, Jiang GL
World J Hepatol. 2015 Apr 18;7(5):738-52
Radioembolization with Yttrium-90 microspheres inhepatocellular carcinoma: Role and perspectivesMosconi C, Cappelli A, Pettinato C, Golfieri R.
Sequential phase I and II trials of stereotactic bodyradiotherapy for locally advanced hepatocellular carcinoma
Bujold A1, Massey CA, Kim JJ, Brierley J, Cho C, Wong RK, Dinniwell RE, Kassam Z, RingashJ, Cummings B, Sykes J, Sherman M, Knox JJ, Dawson LA.
J Clin Oncol. 2013 May 1;31(13):1631-9
J Gastroenterol Hepatol. 2013 Mar;28(3):530-6
Stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma
Honda Y, Kimura T, Aikata H, Kobayashi T, Fukuhara T, Masaki K, Nakahara T, Naeshiro N, Ono A, Miyaki D, Nagaoki Y, Kawaoka T, Takaki S, Hiramatsu A, Ishikawa M, Kakizawa H, Kenjo M, Takahashi S, Awai K, Nagata Y, Chayama K.
PLoS One. 2013 Oct 11;8(10):e77472
Stereotactic body radiation therapy for hepatocellular carcinoma: prognostic factors of localcontrol, overall survival, and toxicity
Bibault JE, Dewas S, Vautravers-Dewas C, Hollebecque A, Jarraya H, Lacornerie T, Lartigau E, Mirabel X
Hepatocellular carcinoma: comparison between livertransplantation, resective surgery, ethanol injection, and chemoembolization
Colella G1, Bottelli R, De Carlis L, Sansalone CV, Rondinara GF, Alberti A, Belli LS, GelosaF, Iamoni GM, Rampoldi A, De Gasperi A, Corti A, Mazza E, Aseni P, Meroni A, Slim AO, FinziM, Di Benedetto F, Manochehri F, Follini ML, Ideo G, Forti D
Transpl Int. 1998;11 Suppl 1:S193-6.
Int J Radiat Oncol Biol Phys. 2012 Oct 1;84(2):355-61
Stereotactic body radiation therapy in recurrenthepatocellular carcinoma
Huang WY, Jen YM, Lee MS, Chang LP, Chen CM, Ko KH, Lin KT, Lin JC, Chao HL, Lin CS, Su YF, Fan CY, Chang YW
SBRT for Liver Tumors
• Tumor control is good for small tumors– Is it as good as RFA?
• RFA control rates are poor for intermediate (3-7cm) and large( >7cm) lesions– Can combination Therapy (RFA+SBRT) work
• TACE is poor for Large and multiple lesions– Can addition of SBRT help
Combination therapies• SBRT + Radio Frequency Ablation• SBRT + Chemotherapy (i.e.
Chemoembolization)• SBRT + Biologics (e.g. Sorafanib)
Dose Constraints
• Liver– >750cc of Uninvolved Liver– V15 < 50%– V21 < 30%
• Kidney– V12 < 33% of Rt. Kidney
• Bowel– <800cGy/Fraction to < 1/3rd of Circumference
Int J Radiat Oncol Biol Phys. 2010 Nov 15;78(4):1073-80
Stereotactic body radiotherapy for patients with unresectable primaryhepatocellular carcinoma: dose-volumetric parameters predicting the hepatic complication
Son SH1, Choi BO, Ryu MR, Kang YN, Jang JS, Bae SH, Yoon SK, Choi IB, Kang KM, Jang HS
Cholangiocarcinoma
Intrahepatic Cholangiocarcinoma Morphological Types
Mass Forming Type
Periductal Infiltrating Type
Intraductal Type
Mixed Types
Surgery is the only Curative Treatment
Mayo Clinic Experience
Extent of Surgery
Unresectable IHCC/HCC -Chemotherapy
Unresectable – Radiation
Unresectable: Radiation + Brachy Boost
Unresectable - Chemoradiation
• Unresectable or R1 Resection• Induction Gemcitabine/Cisplatinum x 2• If non metastatic
– Continue cycle 3– Fiducial and plan SBRT
• 3 Fraction SBRT (24-45Gy in 3 Fractions between cycles 3 and 4
• Total 6 Cycles chemo
J Cancer. 2015 Aug 1;6(11):1099-104
Stereotactic Body Radiotherapy (SBRT) for Intrahepatic and HilarCholangiocarcinoma
Mahadevan A1, Dagoglu N1, Mancias J1, Raven K2, Khwaja K2, Tseng JF2, Ng K3, EnzingerP3, Miksad R4, Bullock A4, Evenson A2
Local Control – Treated Lesion
Progression Free Survival
Median PFS 13m
Overall Survival
Median OS 17m
Toxicity
• Majority of patients had transient fatigue• 5 Patients: persistent nasuea(25% Grade
II)• 4 Grade III Toxicity
– 2 duodenal ulceration– 1 cholangitis– 1 Liver abscess
• 10 Patients• Standard Dose Gemcitabine• 30Gy in 3 fractions CK SBRT• 2 yr survival 80%, 4 Year Survival 30%,
Median Survival 35.5m• 3/10 Grade III toxicity
Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma. Results of a five year experience
Polistina FA1, Guglielmi R, Baiocchi C, Francescon P, Scalchi P, Febbraro A, Costantin G, Ambrosino G
Radiother Oncol. 2011 May;99(2):120-3
• 27pts• 45Gy in 3 fractions• Frame Immobilization with abdominal
Compression• PTV = CTV +10mm(Craniocaudal),
5mm(all around)
Stereotactic body radiotherapy for unresectablecholangiocarcinomaKopek N, Holt MI, Hansen AT, Høyer M
Radiother Oncol. 2010 Jan;94(1):47-52
PFS = 6.7mOS = 10.7m
Toxicity
• 6/27: Duodenal Ulceration and Bleeding• 4/24 : Duodenal Obstruction• V21, V24, V27 and V31 associated with
Grade III toxicity • Dmax 1cc < 25.3 Gy associated with no >Gr
II toxicity• Duodenal dose constraint <8Gy/# in our
study• 2/20 Grade III ulceration
Intrahepatic/HilarCholangiocarcioma
StratifyR1 Resection
R2/Unresectable
2 Cycles of Gemctabine/Cisplatinu
m Chemotherapy
RestageingCT
Torso
No Metastasis
Cycle 3 Chemo/Fiducials/Planning
3 Fraction SBRT
Between Cycles 3-4
Continue Systemic therapy to Tolerance, 6Cycles or
Progression
Metastasis
Off StudySecond Line
Chemo
SBRT for Liver Metastasis
Hypothesis
• When patients present with Clinical Oligometastasis …..
• If systemic therapy is the standard of care….
• Does additional ablative treatment improve their outcome?
Combining bevacizumab and panitumumab with irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as second-line treatment in patients with metastatic colorectal cancer
Liang HL, Hu AP, Li SL, Liu JY
Med Oncol. 2014 Jun;31(6):976
Systemic Therapy
• Is needed and effective• Selective in response• Limited response rates• Toxicity – often cumulative• Can ablative treatment limit potentially
toxic systemic?
Radiosurgical Ablation
• When not surgical candidates• Patient preference• Surgical recovery delays are not ideal• Systemic therapy (eg. Anti angiogenic
therapy) interferes with surgical recovery
Surgical Resection Liver Metastasis- Colorectal cancer
Single vs. OligoMetastasis
Clinical Risk Score – Colorectal Liver Metastasis
SBRT for Liver Metastasis
J Clin Oncol. 2009 Apr 1;27(10):1572-8
Multi-institutional phase I/II trial of stereotacticbody radiation therapy for liver metastasesRusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, Chidel MA, Pugh TJ, Franklin W, Kane M, Gaspar LE, Schefter TE
Percutaneous radiofrequency ablation (RFA) or robotic radiosurgery(RRS) for salvage treatment of colorectal liver metastases
Stintzing S1, Grothe A, Hendrich S, Hoffmann RT, Heinemann V, Rentsch M, FuerwegerC, Muacevic A, Trumm CG
Acta Oncol. 2013 Jun;52(5):971-7
Phase II Clinical Trial
• Patients with Oligometastasis– ECOG performance ≤ 1– No contraindication for systemic therapy– Reasonable Life expectancy– Lesions treatable with SBRT
Schema
• Registration • 2 cycles of systemic therapy• Restage…. If non metastatic• Randomize
– SBRT and further systemic therapy Vs.– Continue Systemic therapy until progression
or Tolerance
Re Irradiation
• Despite improvements in Surgery, Systemic therapy and Radiation techniques local failures occur.
• Initial Radiation is often given to tolerance of dose limiting structures
• If dose to critical organs can be limited –can SBRT useful for re-irradiation.
Local Control after Whipple+ChemoRT
+ve margin (%) Local Failure (%)
GITSG 0 47
EORTC 19 51
ESPAC 28 63
CONKO 19 37
RTOG 34 25
Stereotactic Body Radiotherapy (SBRT) Reirradiationfor Recurrent Pancreas Cancer
Dagoglu N, Callery M, Moser J, Tseng J, Kent T, Bullock A, Miksad R, Mancias JD, Mahadevan A
J Cancer. 2016 Jan 10;7(3):283-8
Dagoglu N, Callery M, et al. J Cancer. 2016 Jan 10;7(3):283-8
Dagoglu N, Callery M, et al. J Cancer. 2016 Jan 10;7(3):283-8
Future Directions• Better understanding of the radiobiology of SBRT• Phase II/III studies needed to define the role for
SBRT
• Need for better definition of Normal tissue tolerance for SBRT Hypofractionation
RadioImmunotherapy
Summary• Surgery is still the primary curative treatment for
cancer• Stereotactic radiosurgery is not a substitute but
an alternative when indicated• Systemic therapy is vital in the curative
multidisciplinary management of “micro” metastatic cancer.
• Stereotactic Radiosurgery is becoming a component in the multidisciplinary treatment of Cancer
Thank you