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 are those of the presenter and do not necessarily reflect the views or policies of Accuray Incorporated or its subsidiaries. No official endorsement by Accuray Incorporated or any of its subsidiaries of any vendors, products or services contained in this presentation is intended 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

Gating Treatment Field

2. Beam Off Beam On

4. Beam On Beam Off = Over-treated healthy tissue

Treatment beam is turned on and off as tumor enters and exits a static treatment field Tracking

External position sensor

Internal fiducial 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

Imaging (CT, MRI, etc.) Tumor motion

Total Treatment planning Patient setup Clinical Accuracy

Patient Beam delivery movement 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 Trials Trial 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 Studies

Trial Treatment No. of Med OS Pts 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 Neoadjuvant Chemo Neoadjuvant Chemo and Therapy and Surgery (NeoC-S) SBRT (NeoC-SBRT) (TNT)

Chemo Chemo Chemo

SBRT Surgery SBRT

Surgery Results – Overall Survival

Treatment Number Median Overall Group Survival (Months) TNT 25 36.5 p=0.03 NeoC-SBRT 49 19.3 p=0.1 7 p=0.98 NeoC- 6 22.2 Surgery Results – Local Regional Recurrence FOLFIRINOX SBRT FOLFIRINOX SBRT Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Balaban EP1, Mangu PB1, Khorana AA1, Shah MA1, Mukherjee S1, Crane CH1, Javle MM1, Eads JR1, Allen P1, Ko AH1, Engebretson A1, Herman JM1, Strickler JH1, Benson AB 3rd1, Urba S1, Yee NS1.

J Clin Oncol. 2016 Aug 1;34(22):2654-68 Resected Pancreas Cancer R1 Resection Resected Pancreas Cancer ChemoRT 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 adenocarcinoma

Raut 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

Median Survival 2-Year Survival 5-Year Survival Cohort N (months) (Actuarial) (Actuarial) Overall 157 22 45% 24%

Negative Margins (R0) 95 27 51% 28%

Positive Margins (R1) 62 19.5 36% 17% Untreated 20 14 16% Chemo/RT 19 19.5 36% Chemo/RT + CK 23 29.5 50% Study No/Total(%) R1 No/Total(%) Local Median Survival

Resection Recurrence 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 Partial volume tolerance of the liver to radiation

Dawson LA, Ten Haken RK

Semin Radiat Oncol. 2005 Oct;15(4):279-83 Worldwide Incidence of Hepatocellular Carcinoma HCC Epidemiology Worldwide Incidence of Hepatocellular Carcinoma

El-Serag HB, High (> 30:100,000) Gastroenterology Intermediate (3-30:100,000) 2004 Low or data unavailable (< 3:100,000) Treatment Options

A. Surgical resection B. Ablation Cryotherapy Radiofrequency ablation Laser interstitial thermal therapy (LITT) Microwave coagulation therapy C. Chemotherapy Intra-arterial Systemic Chemoembolisation D. Radiotherapy Stereotactic body radiation Selective interstitial radiation therapy E. Liver transplantation

RFA

TACE ODDS RATIO 6m SURVIVAL Comparison between radioimmunotherapy and external beam radiation therapy for patients with hepatocellular carcinoma

Zeng ZC, Tang ZY, Yang BH, Liu KD, Wu ZQ, Fan J, Qin LX, Sun HC, Zhou J, Jiang GL

Eur J Nucl Med Mol Imaging. 2002 Dec;29(12):1657-68 Radioembolization with Yttrium-90 microspheres in hepatocellular carcinoma: Role and perspectives

Mosconi C, Cappelli A, Pettinato C, Golfieri R.

World J Hepatol. 2015 Apr 18;7(5):738-52 Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma

Bujold A1, Massey CA, Kim JJ, Brierley J, Cho C, Wong RK, Dinniwell RE, Kassam Z, Ringash J, Cummings B, Sykes J, Sherman M, Knox JJ, Dawson LA.

J Clin Oncol. 2013 May 1;31(13):1631-9 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.

J Gastroenterol Hepatol. 2013 Mar;28(3):530-6 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

PLoS One. 2013 Oct 11;8(10):e77472

Hepatocellular carcinoma: comparison between liver transplantation, resective surgery, ethanol injection, and chemoembolization

Colella G1, Bottelli R, De Carlis L, Sansalone CV, Rondinara GF, Alberti A, Belli LS, Gelosa F, Iamoni GM, Rampoldi A, De Gasperi A, Corti A, Mazza E, Aseni P, Meroni A, Slim AO, Finzi M, Di Benedetto F, Manochehri F, Follini ML, Ideo G, Forti D

Transpl Int. 1998;11 Suppl 1:S193-6. Stereotactic body radiation therapy in recurrent hepatocellular 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

Int J Radiat Oncol Biol Phys. 2012 Oct 1;84(2):355-61

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 Stereotactic body radiotherapy for patients with unresectable primary hepatocellular 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

Int J Radiat Oncol Biol Phys. 2010 Nov 15;78(4):1073-80 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 Stereotactic Body Radiotherapy (SBRT) for Intrahepatic and Hilar Cholangiocarcinoma

Mahadevan A1, Dagoglu N1, Mancias J1, Raven K2, Khwaja K2, Tseng JF2, Ng K3, Enzinger P3, Miksad R4, Bullock A4, Evenson A2 • 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

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 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 • 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

Radiother Oncol. 2011 May;99(2):120-3 Stereotactic body radiotherapy for unresectable cholangiocarcinoma

Kopek N, Holt MI, Hansen AT, Høyer M

• 27pts • 45Gy in 3 fractions • Frame Immobilization with abdominal Compression • PTV = CTV +10mm(Craniocaudal), 5mm(all around)

Radiother Oncol. 2010 Jan;94(1):47-52 PFS = 6.7m OS = 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/Hilar Cholangiocarcioma

R1 Resection Stratify R2/Unresectable

2 Cycles of Gemctabine/Cisplatinu m Chemotherapy

Restageing CT Torso

No Metastasis Metastasis

Cycle 3 Off Study Chemo/Fiduc Second Line ials/Planning Chemo

3 Fraction SBRT Between Cycles 3-4

Continue Systemic therapy to Tolerance, 6Cycles or Progression 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 Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases

Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, Chidel MA, Pugh TJ, Franklin W, Kane M, Gaspar LE, Schefter TE

J Clin Oncol. 2009 Apr 1;27(10):1572-8

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, Fuerweger C, 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) Reirradiation for 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