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