new strategies in the management of …...van lienden kp, et al. cardiovasc intervent radiol....

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New Strategies in the Management of Hepatocellular Carcinoma

Marti Russell, MD, FACSAssistant Professor of Surgery

Emory University Hospital MidtownGrady Memorial Hospital

2Winship Cancer Institute | Emory University

Outline

• Background• Diagnosis• Surgery• Liver directed therapy• Radiation therapy• Systemic therapy• Treatment strategies to decrease the problem


Incidence• Fifth most common cancer in the world• Leading cause of cancer related mortality • Increasing incidence in the United States

• Hepatitis C induced cirrhosis• Nonalcoholic steatohepatitis/NAFLD

Ferlay J et al. Int J. Cancer. 2015;136:E359-E386.Seer.cancer.gov, accessed 07/07/17.


Risk Factors

Bruix J, et al. Hepatology. 2011;53(3):1020-1022.


Diagnosis

Bruix J, et al. Hepatology. 2011;53(3):1020-1022.


Staging

Dhir M, et al. Ann Surg. 2016;263(6):1112-1125.


Staging


Treatment Options for HCC

Surgery

IR Liver Directed

Radiation

Systemic


Surgical Resection


Surgery

• Degree of cirrhosis• Portal hypertension• Comorbidities• Insurance/citizenship status• Size of Lesions• Number of Lesions

Transplantation Resection


Milan Criteria

Overall Survival Recurrence-free SurvivalCriteria Met 85% 92%Criteria Not Met 50% 59%

Mazzaferro V, et al. N Engl J Med. 1996;334(11):693-699.


Organ Allocation


Proposed Changes 2017

Elwir S, et al. Gastroenterol Hepatol (N Y). 2016;12(3):166-170.


Extended Criteria for Transplant

Sapisochin G, et al. Nat Rev Gastroenterol Hepatol. 2017;14(4):203-217.


Downstaging

Yao FY, et al. Hepatology. 2008;48(3):819-827.


Downstaging

Gordon-Weeks AN, et al. Br J Surg. 2011;98(9):1201-1208. Pomfret EA, et al. Liver Transpl.2010;16(3):262-278.


Surgical techniques to increase pool



Increasing the Organs Available

Living donor transplant must be FLAWLESS.



Resection• Non-cirrhotic patients• Well-compensated cirrhosis (Child-Pugh A)• No portal hypertension

• Platelet count > 100,000 (150,000)• No splenomegaly• No varices• No patent umbilical vein• Wedge pressure <10mmHg

• MELD < 10

• High recurrence rates

22

Resection versus Transplant


23Winship Cancer Institute | Emory UniversitySquires MH 3rd, et al. J Surg Oncol. 2014;109(6):533-541.


Criteria Transplant Resection P valueWithin Milan Criteria N=131 N=45

5yr OS 65.7% 43.8% P=0.005RFS 85.3% 22.7% P<0.001

Milan + Hep C N=87 N=215yr OS 63.5% 23.3% P=0.001RFS 83.5% 23.7% P<0.001

Milan + MELD <8 N=12 N=305yr OS 62.5% 48.9% P=NSRFS 71.6% 30.8% P=0.08

Milan + Child Pugh A N=37 N=165yr OS 56% 35% P=0.7RFS 71% 37% P=0.04

Squires MH 3rd, et al. J Surg Oncol. 2014;109(6):533-541.


Future Liver Remnant

- 3-D CT reconstruction- TLV (cm3) =

-794.41 + 1267.28 x BSA (m2)- The standardized FLR:

FLR/TLV


• 44 articles with 1791 patients (20% with HCC)

• Technical success rate 99.3%• Clinical success rate 96.1%• Mean hypertrophy after PVE 37.9

+/- 0.1%• Major complications 2.5%• Mortality 0.1%

van Lienden KP, et al. Cardiovasc Intervent Radiol. 2013;36(1):25-34.


Laparoscopic Liver Resections

Nguyen NT, et al. Ann Surg.2009;250(5):631-641.


Laparoscopic Liver Resections

• Mortality 0.3%• Morbidity 10.5%• Negative surgical margins > 82%• Survival after resection HCC

• 50-75% 5 year OS• 31-38.2% 5 year DFS

• In experienced hands is safe with comparable oncologic outcomes

Nguyen NT, et al. Ann Surg.2009;250(5):631-641.


Robotic Liver Resections

Buchs NC, et al. Expert Rev Anticancer Ther. 2017;14(2):237-246.


Robotic Liver Resections



Robotic Liver ResectionsPerioperative Outcomes:• Operative Time: 137-507 minutes• Conversion Rate: 5.7-20%• Overall Complications: 7.8-46%• Hospital Stay: 6.1-11.7 days

So is it better than laparoscopy?• Hilum dissection• Biliary reconstruction• More data needed



Liver Directed Therapy


Locoregional Therapies

XMeza-Junco J, et al. Cancer Treat Rev. 2012;38(1):54-62.


Ablation

• Most suitable for tumors < 3cm• Recurrence based on size:

• <3cm = 14%• 3-5cm = 25%• >5cm = 58%

Chu KF, et al. Nat Rev Cancer. 2014;14(3):199-208.


Ablation

• Most suitable for tumors < 3cm• Recurrence based on size:

• <3cm = 14%• 3-5cm = 25%• >5cm = 58%



Resection versus Locoregional Therapy


• Post op complications worse in surgery group• 1, 2, 3, 4 year overall survival:

• PLAT 95.8, 82.1, 71.4, 67.9%• Resection 93.3, 82.3, 73.4, 64.0%

• 1, 2, 3, 4 year disease free survival• PLAT 85.9, 69.3, 64.1, 46.4%• Resection 86.6, 76.8, 69.0, 51.6%

• Conclusion: no difference in overall or disease free survival; PLAT with fewer complications

High risk of bias secondary to 19 patients randomized to PLAT who withdrew and were treated with surgery.

Chen MS, et al. Ann Surg. 2006;243(3):321-328.


• HCC meeting Milan• Childs A or B• 115 each RFA vs Resection with 7 crossovers from RFA to resection

P=0.001 P=0.017

Huang J, et al. Ann Surg. 2010;252(6):903-912.



P=0.001 P=0.017



• 2 or less tumors with maximum diameter of 4cm• Childs A or B• Treatment naïve• 84 patients in each group

Feng K, et al. J Hepatol. 2012;57(4):794-802.


• 2 or less tumors with maximum diameter of 4cm• Childs A or B• Treatment naïve• 84 patients in each group

P=0.342 P=0.122

Feng K, et al. J Hepatol. 2012;57(4):794-802.


Radiofrequency vs Microwave AblationRFA

• Temperatures 60-100 C are generated by high frequency alternating current which induces frictional heating causing cell injury

• Cytotoxic temperatures difficult to maintain near major blood vessel secondary to heat sink

MWA• Uses electromagnetic fields to

create rotating molecules that produce heat without electric current

• More suitable for tissues with higher impedance (lung/bone) and solid organs

• Achieves better heating of larger tumor volumes

• Lower susceptibility to heat-sink effect

• Multiple antennae to amplify effectChu KF, et al. Nat Rev Cancer. 2014;14(3):199-208.


• Retrospective Review

• 53 patients/68 lesions• Milan criteria• Unresectable• Child’s A or B

• Conclusion:• No significant difference

Vogl TJ, et al. Abdom Imaging. 2015;40(6):1829-1837.


• 288 patients, 477 lesions• Single lesion ≤ 8cm; ≤ 5 lesions with

max dimension of 6cm per nodule• No pvt or extrahepatic metastases, • PT < 25 seconds, plt > 40,000• Nodules 5mm away from bile duct or

hilum and bowel• Not eligible for surgery

Liang P, et al. Radiology. 2005;235(1):299-307.


• 80 patients/117 lesions• No more than 3 lesions• 3-8cm• Child’s A or B w/o extrahepatic mets or vascular invasion• Not amenable or refused surgery

Liu Y, et al. Clin Radiol. 2013;68(1):21-26.



Multivariate analysis identified tumor size as the only independent prognosis factor (p=0.008).Risk of death for patients with tumors 5-8cm was 2.3x higher than those with tumors 3-5cm.



TransArterial ChemoEmbolization (TACE)Indications:• Unresectable Child Pugh A or B multifocal HCC w/o vascular invasion

Contraindications:• Resectable tumors• Decompensated cirrhosis (Child-Pugh ≥8) including jaundice,

encephalopathy and refractory ascites• AFP > 1000/uL• Tumor replacement of both lobes• Intractable infection• Uncorrectable bleeding disorder

Graf D, et al. Eur J Intern Med. 2014;25(5):430-437.


TACE/cTACE/DEB TACE

Dhir M, et al. Ann Surg. 2016;263(6):1112-1125. Nishikawa H, et al. Anticancer Res. 2014;34(12):6877-6886.


Preoperative TACEAuthor Number Design Results

Wu et al - 24 preop TACE28 control

Large HCC Prior to resection

Preoperative TACE delays surgery, increases difficulty without survival benefit

Yamasaki et al 50 preop TACE47 control

Solitary hcc, 2-5cmPrior to resection

No survival advantage

Zhou et al 52 preop TACE56 control

Prior to resection No difference in recurrence, DFS or OS but did result in lower resection rate (p=0.017)

Kaibori et al 42 preop TACE39 TACE + lipiodolization43 control

Prior to resection No change in DFS or OS

Nicolini et al16 cTACE22 DEB-TACE

Prior to liver transplant 3 year RFS (p=0.0493)61.5%87.4%Significant increase inflammatory reaction

Frenette et al 76 cTACE35 DEB-TACE

Prior to liver transplant No difference in necrosis, recurrence or dropout

Nishikawa H, et al. Anticancer Res. 2014;34(12):6877-6886. Wu CC, et al. Br J Surg.1995;82(1):122-126. Yamasaki S, et al. Jpn J Cancer Res. 1996;87(2):206-211. Zhou WP, et al. Ann Surg. 2009;249(2):195-202. Kaibori M, et al. Dig Dis Sci. 2012;57(5):1404-1412. Nicolini D, et al. World J Gastroenterol. 2013;19(34):5622-5632. Frenette CT, et al. Transplantation. 2014;98(7):781-787.


Radioembolization• Either resin or glass microspheres• Loaded with y90 – high energy radiation source with half life of 2.67

days and a short tissue penetration (2.5mm)• Patients with non-metastatic unresectable disease who are not

candidates for transplant or ablation• Can be used in patient with portal vein thrombosis• Bridge to transplant and downstaging• Criteria:

• Good performance status• Adequate pulmonary reserve• Creatinine <2mg/dL• Plt > 50,000• Child-Pugh ≤7


Radioembolization

Salem R, et al. Hepatology. 2013;58(6):2188-2197. Edeline J, et al. Liver Cancer. 2015;4(1):16-25.


TARE versus TACE

P=0.7803

Conclusions:• Abdominal pain and increased

transaminase activity more frequent in chemoembo group (p<0.05)

• Time to progression longer following radioembo (13.3mo versus 8.4mo; p=0.046)

• Median Survival 20.5 vs 17.4 (p=0.232)

Salem R, et al. Gastroenterology. 2011;140(2):497-507.


Cochrane Review

Abdel-Rahman OM, et al. Cochrane Database Syst Rev. 2016;2:CD011313.


Cochrane Review



Potential advantages of TARE• Less toxicity, no inpatient stay, no pain management, improved quality

of life over TACE • Radiation segmentectomy – applying radiation to small sectors of the

liver• Radiation lobectomy – used for right lobe disease that is potentially

resectable but small FLR• Treats tumor while liver grows• As tumor treated, right sided atrophy and left sided hypertrophy• Wait time of 6-12 weeks allows biologic test of time

• Potential “downstaging” to transplant• 56% downstaging rate• Better downstaging than TACE (58% vs 31%; p<0.05)• Improved response rate (49% vs 36%; p=0.052)

Salem R, et al. Gastroenterology. 2011;140(2):497-507. Gilbertsen P, et al. J Vasc Interv Radiol. 2011;22:s79. Lewandowski RJ, et al. Am J Transplant. 2009;9(8):1920-1928. Kulik LM, et al. J Surg Oncol. 2006;94(7):572-586.


High Intensity Focused Ultrasound (HIFU)

• Under MRI or US, the ultrasound beam is directed a the target tissue resulting in a rapid local temperature increase followed by protein denaturation inducing coagulative necrosis

• Advantages: through the skin• Cons:

• Only available at a few centers• High cost (MRI guidance)• Time consuming • General or epidural anesthesia

• Limited data

Diana M, et al. Hepatobiliary Surg Nutr.2016;5(4):329-344.


Radiation Therapy


3D Conformal RT/IMRT

• Allows profile shaping of the beam of radiation to match the profile of the tumor

• Modification of Intensity-Modulated Radiation Therapy – highly conformal doses to target structures with decreased scatter – further improvement of CRT

• Image guidance and breathing motion management have made it possible to deliver ablative doses of radiation

• Increased dose to target tissue with less surrounding toxicity



Stereotactic Body Radiation

• Multiple highly accurate and precise beams to deliver radiation with rapid fall off doses away from the target

• Objective responses 37-90% with 2-year survival 43-82%• Complete path responses in 14-27% of patients• Risk for radiation induced liver disease, as well as progression of Child-

Pugh class, chest wall toxicity and biliary toxicity• Can be used as a bridge to transplant



SBRT

Klein J, et al. Int J Radiat Oncol Biol Phys. 2013;87(1):22-32.


Protons?

Skinner HD, et al. Semin Radiat Oncol. 2011;21(4):278-286.


Protons?

Considerations:• Portal vein invasion• Centrally located tumors• Not suitable for RFA – close to diaphragm

or major blood vessels• Locally advanced tumors Child Pugh B or C

Skinner HD, et al. Semin Radiat Oncol. 2011;21(4):278-286.


Systemic Therapy


Median Survival:6.5mo vs 4.2moP=0.014

Time to Progression2.8mo vs 1.4moP=0.0005

Cheng AL, et al. Lancet Oncol. 2009;10(1):25-34.


Median OSSorafenib 10.7 moPlacebo 7.9 moP<0.001

Llovet JM, et al. N Engl J Med. 2008;359(4):378-390.



Median timeSorafenib 4.1moPlacebo 4.9moP=0.77




Median timeSorafenib 4.1moPlacebo 4.9moP=0.77

TTPSorafenib 5.5moPlacebo 2.8moP<0.001



Signaling Pathways and Potential Targets

Siegel AB, et al. Hepatology. 2010;52(1):360-369. Finn RS. Semin Liver Dis. 2013;33 Supple 1: S11-19.

83Winship Cancer Institute | Emory UniversityFinn RS. Semin Liver Dis. 2013;33 Supple 1: S11-19.


Additional Trials

Finn RS. Semin Liver Dis. 2013;33 Supple 1: S11-19.

86Winship Cancer Institute | Emory UniversityBruix J, et al. Lancet Oncol. 2015;16(13):1344-1354.


Immunotherapy

Hong YP, et al. World J Hepatol. 2015;7(7):980-992.


Immunotherapy in HCC

Hong YP, et al. World J Hepatol. 2015;7(7):980-992. Sangro B, et al. J Hepatol. 2013;59(1):81-88.


Immunotherapy in HCC

Trememlimumab:PR – 17.6%Disease control 76%TTP 6 months

Hong YP, et al. World J Hepatol. 2015;7(7):980-992. Sangro B, et al. J Hepatol. 2013;59(1):81-88.

92Winship Cancer Institute | Emory UniversityEl-Khoueiry AB, et al. Lancet. 2017;389(10088):2492-2502.

93Winship Cancer Institute | Emory UniversityEl-Khoueiry AB, et al. Lancet. 2017;389(10088):2492-2502.


Immunotherapy

Harding JJ, et al. Cancer. 2016;122(3):367-377. Kudo M. Oncology. 2017;92(Suppl 1):50-61.


Future Combination Therapy



Future Combination TherapyGALNT14 genotype-guided, sorafenib in combination with transarterial chemoembolization in hepatocellular carcinoma: An interim report of a prospective randomized controlled trial.


http://abstracts.asco.org/199/AbstView_199_181490.html



A phase II study of sorafenib and yttrium-90 glass microspheres for advanced hepatocellular carcinoma, BCLC stage C.






Efficacy and safety of localized concurrent chemoradiation therapy and sorafenib sequential therapy in advanced hepatocellular carcinoma: A prospective phase II trial.







Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.








Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses.








Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses.

BBI608-503-103HCC: A phase Ib/II clinical study of napabucasin(BBI608) in combination with sorafenib or amcasertib (BBI503) in combination with sorafenib (Sor) in adult patients with hepatocellular carcinoma (HCC).




So what about prevention?

STOP


An ounce of CURE . . .

Slide courtesy of Dr. Lesley Miller

Hepatitis C is Deadly


And Hepatitis C is potentially curable!



Routine HCV Screening at Grady



12,419tested

871HCV Ab +

• 7% prevalence

714 HCV RNA tested

• 82% tested

471 HCV RNA positive

• 66% viremic

400 linked to care

• 85% linked

Grady HCV Care CascadeOctober 2012-September 2016



Current HCV medications



Over 400 patients predicted cured 2015-16



Conclusion• Surgery offers the best long term survival benefit but ablation for early

stage tumors may be very reasonable and considered curative.• Local regional treatments are considered palliative but can produce

long term results. • Exact role for Y-90 pending.

• Radiation is likely underutilized in HCC because of past toxicity but as it becomes more precise and with the development of proton therapy, still is a reasonable option.

• Like all cancers right now, we are looking for answers in the targeted therapy and immunotherapy realm with many trials pending.

• One mode of treatment may be prevention – the role of HCV treatment continues to evolve.

new strategies in the management of …...van lienden kp, et al. cardiovasc intervent radiol....

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