Making Sense of Hepatic Tumor Post-therapy Imaging-Limitations of RECIST Frank Miller, M.D. Chief, Body Imaging Section and Fellowship Medical Director, MR Imaging Chief, GI Radiology Professor of Radiology Northwestern University, Feinberg School of Medicine, NMH Chicago IL

OUTLINE

• Discuss liver directed therapy-TACE (transarterial chemoembolization) and Yttrium

• Unique aspects of imaging interpretation related to liver directed therapy-limitations of size criteria

ANATOMIC IMAGING BIOMARKERS

• Traditional chemotherapeutic agents are cytotoxic and eliminate neoplastic cells

• As result, change in tumor size and disappearance of lesion-only widely accepted and validated radiological marker of treatment response – Unfortunately often does not apply for local therapy

in HCC

Pre treatment 1 month3 months1 year16 months22 months

CHALLENGES WITH INTERPRETATION

Courtesy Dr. Riad Salem

TOWER OF BABEL / ALPHABET SOUP: NO UNIVERSAL LANGUAGE ESPECIALLY FOR HCC RX

• WHO • RECIST 1.0 / RECIST 1.1 • EASL • mRECIST • CHOI • RECICL • PERCIST

COMPETING METHODS OF ASSESSING RESPONSE

1. Uni-dimensional – Response Evaluation Criteria in Solid Tumors

(RECIST) - longest diameter of target lesions

2. Bi-dimensional – World Health Organization (WHO)

3. Volumetric measurements 4. European Association for the Study of the

Liver (EASL) 5. Functional: Diffusion-Weighted (DW) MR

Imaging (ADC), Perfusion weighted MR and PET Scans

Courtesy Dr. Robert Lewandowski

COMPETING METHODS OF ASSESSING RESPONSE

1. Uni-dimensional – Response Evaluation Criteria in Solid Tumors

(RECIST)

2. Bi-dimensional – World Health Organization (WHO) - cross

product of target lesions

3. Volumetric measurements 4. European Association for the Study of the

Liver (EASL) 5. Functional: Diffusion-Weighted (DW) MR

Imaging (ADC), Perfusion weighted MR and PET Scans

Courtesy Dr. Robert Lewandowski

COMPETING METHODS OF ASSESSING RESPONSE

1. Uni-dimensional – Response Evaluation Criteria in Solid Tumors

(RECIST)

2. Bi-dimensional – World Health Organization (WHO)

3. Volumetric measurements 4. European Association for the Study of the

Liver-necrosis as reduction in enhancement 5. Functional: Diffusion-Weighted (DW) MR

Imaging (ADC), Perfusion weighted MR and PET Scans

Courtesy Dr. Robert Lewandowski

INTERPRETATION OF IMAGES AFTER IR TREATMENT

• Among the most difficult in radiology • No one fights to read these cases • Paradoxical increase in size is seen with ablative

therapies such as RF ablation, TACE and Y90 radioembolization-result of hemorrhage and necrosis

• No uniform standard of interpretation • Ring enhancement mistaken for tumor and may be

post treatment changes including scar tissue or reactive edema

EMBOLIZATION: BACKGROUND

• Normal liver has hepatic arterial and portal venous blood supply

• Tumors especially HCC almost completely supplied by hepatic artery

• Tumors treated by directly injecting hepatic artery with embolic material, chemotherapy or radioembolization (Y90)

TACE

Pretreatment Trip Post-treatment Trip

ASSESSMENT OF RESPONSE

• ANATOMIC – Decrease in tumor size-classic approach for therapy

• WHO, RECIST, Volume – Necrosis-defined as a lack of enhancement of lesion

• EASL

• FUNCTIONAL – Changes at diffusion-weighted MRI – Metabolic activity at FDG PET-especially mets – Serum tumor marker reduction

• OTHERS – Angiographic response – Clinical improvement

Pre Tx Post Tx

NECROSIS: SIZE NOT CHANGED- FOCUS ON NECROSIS

NECROSIS

Necrotic HCC

Live HCC

CHALLENGES

• Different institutions report findings differently which affects transplantation and treatment assessment – size of lesion including necrotic part vs.

just enhancing part (tumor)

NECROSIS

HCC AND TACE: PRETHERAPY AND ETHIODOL POST THERAPY

Pretherapy Post-RX CT

MAY BE DIFFICULT TO ASSESS ENHANCEMENT AFTER THERAPY- SIZE UNCHANGED

T1 FS Precontrast Postcontrast

POST TACE: SUBTRACTION IMAGES ARE HELPFUL

T1 FS Precontrast Postcontrast

Subtraction

METABOLIC ACTIVITY AT FDG PET: NOT APPLICABLE FOR ALL HCC

AFP 850 AFP 80 AFP 4

TUMOR MARKER REDUCTION

Yttrium-90 microspheres

• Local radiation therapy for unresectable liver tumors

• Mechanism: Tumors are supplied predominately from the hepatic artery, Y90 trapped in capillaries resulting in >3x radiation exposure of tumor relative to normal liver

LESION SIZE MAY NOT REFLECT TREATMENT RESPONSE

MR - Pre tx 3.1x3cm CT - 1m post tx 7.5x4.6cm

TREATMENT RESPONSE WHO (size) RECIST (size) % NECROSIS

Complete response Disappearance of lesion

Disappearance of lesion Total necrosis

Partial response >50% decrease >30% decrease >30-50% ?

Stable Disease <50% decrease or <25% increase

<30% decrease or <20% increase

<% defined for partial

Progressive Disease

>25% increase or appearance of new lesions

>20% increase or appearance of new lesions

• Retrospective review of 42 pts, 52 lobes, 76 treated HCC’s, imaged w/ CT or MR

Treatment Response WHO RECIST Necrosis Combined criteria

= RECIST + Necrosis

Complete response Disappearance Disappearance 100%

Greatest change determined response

Partial Response ≥50% decrease ≥ 30% decrease ≥ 30%

Stable disease <50% decrease to <25% increase

< 30% decrease to <20% increase <30%

Progressive disease

≥25% increase or new lesions

≥ 20% increase or new lesions NA

AJR 2007; 188:768–775

Treatment Response by Patient (n = 42):

Treatment Response WHO RECIST Necrosis Combined

Complete response 26%

78% 23%

78% 57%

NA 59%

88% Partial Response

Stable disease

Progressive disease 22% 22% NA 12%

Keppke et al. (AJR 2007) Imaging of HCC after treatment with 90Y Microspheres

NWU: IMAGING OF HCC AFTER TREATMENT WITH 90Y Microsphere

IMAGING OF HCC AFTER TREATMENT WITH 90Y Microspheres

• Other Conclusions: – Time to response:

• WHO/RECIST criteria: 120 days (median)-TOO LONG • Necrosis: 30 days (median)

Keppke et al. (AJR 2007) Imaging of HCC after treatment with 90Y Microspheres

MR - Pre tx CT - 1m post tx

BRIDGE TO LIVER TRANSPLANTATION

• Partial response using necrosis not RECIST/WHO – Mural nodule of

enhancement • Completely

necrotic at explant

NODULE AFTER Y90

• May be residual enhancing nodule-residual tumor or slower treated tumor/post treatment changes

• Often does not metastasize or grow with Y90 • Different from RFA or TACE when typically is

tumor and need treat early

Pre treatment 6 weeks post treatment

}

3 years post treatment

FUTURE DIRECTIONS: PRIMARY INDEX LESION

• Patients with locoregional therapy have at least 1 dominant lesion: “Primary Index Lesion” targeted during initial session – alternative biomarker for response in HCC

• Do not need to follow all the lesions but only the dominant primary index lesion

• Response applies for WHO, RECIST and/or EASL • Statistical significant correlation with disease

progression and survival

Riaz A, Miller FH, Kulik LM, et al. Imaging Response in the Primary Index Lesion and Clinical Outcomes Following Transarterial Locoregional Therapy for Hepatocellular Carcinoma. JAMA 2010; 303: 1062-1069.

LIMITATIONS OF ANATOMIC ASSESSMENT

• Anatomic response lags behind functional changes • Difficult to prospectively predict tumor response

Salem et al JVIR Dec 2005 Pre Tx 1 month3 months6 months10 months15 months

DIFFUSION MR

• Difficult to assess treatment following therapy [RF Ablation, transhepatic arterial chemoembolization (TACE) or Yttrium]

• Lesions often don’t change in size or may grow from hemorrhagic necrosis

• Diffusion MR can play role

• Detects altered water mobility • cellularity • integrity of the cell membrane

Diffusion-weighted (DWI)

Anatomic

Functional

FUNCTIONAL IMAGING-DIFFUSION

• Percentage enhancement on arterial and portal venous phases • extracellular space • tumor vascularity

T1 post-gadolinium

DIFFUSION: OVERSIMPLIFICATION

• Bright on DWI (dark ADC)-restricted diffusion-live tumor

• Dark on DWI-favorable response • Successful treatment-dark on DWI and shows

increase in ADC

HCC PRETREATMENT

Bright

HCC POST TREATMENT

Post contrast Post Treatment DWI Post Treatment

Post Treatment DWI Pretreatment

Dark

J Vasc Interv Radiol 2006; 17:505–512

• 38 HCC patients/Imaging 4-6 weeks post TACE • Targeted tumors demonstrated:

– targeted tumors DID NOT change significantly in size – mean decrease in arterial enhancement of 30% – mean decrease in venous enhancement of 47% – Tumor ADC value increased from 0.0015-0.0018 mm2/sec

after treatment-LESS RESTRICTED DWI

DWI TUMOR RESPONSE

• 58 yo male – Y90

therasphere

195 135

Initi

al

24 mm 0.9 x 10-3 mm2/s

130 176

1 m

o po

st

22 mm 2.0 x 10-3 mm2/s

180 171

3 m

o po

st

15 mm 1.6 x 10-3 mm2/s

POST - 90Y REACTIVE EDEMA

• DW-MRI may differentiate tumor from peripheral reactive edema after therapy related to Y90 or TACE

Post-Treatment CE-MRI Post-Treatment DW-MRI

Venous Phase

Arterial Phase

ADC

DWI

DWI

CONCLUSIONS

• Tumor response assessment is challenging especially following local therapy such as Yttrium, TACE, or RFA

• Need to evaluate not just traditional size (RECIST, WHO) criteria but also necrosis

• Consider functional techniques: DW and perfusion weighted MR and PET scans to show response earlier

ACKNOWLEDGEMENTS-HUGE THANKS

• Dr. Shawn Haji-Momenian • Dr. Laura Kulik • Dr. Andrew Larson • Dr. Robert J Lewandowski • Dr. Reed Omary • Dr. Riad Salem • Dr. Yi Wang

REFERENCES • Atassi B, Bangash AK, Bahrani A, Pizzi G, Lewandowski BJ, Ryu RK, Sato KT, Gates VL, Mulcahy MF, Kulik L, Miller F,

Yaghmai V, Murthy R, Larson A, Omary RA, Salem R. Multimodality imaging following Yttrium-90 radioembolization: A comprehensive review and pictorial essay. RadioGraphics 2008; 28: 81-99.

• Deng J, Miller FH, Rhee TK, Sato KT, Mulcahy MF, Salem R, Omary RA, Larson AC. Diffusion-Weighted MRI for Determination of Hepatocellular Carcinoma Response to Yttrium-90 Radioembolization. J Vasc Interv Radiol 2006; 17: 1195-1200

• Kamel IR, Bluemke DA, Ramsey D, et al. Role of diffusion-weighted imaging in estimating tumor necrosis after chemoembolization of hepatocellular carcinoma. AJR Am J Roentgenol 2003;181(3):708–710.

• Keppke AL, Salem R, Reddy DH, Huang J, Jin J, Larson A, Miller FH. Imaging of hepatocellular carcinoma after treatment with Yttrium-90 microspheres. AJR. 2007: 188: 768-775.

• Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003; 228:235–240.

• Lewandowski RJ, Kulik LM, Riaz A, Senthilnathan S, Mulcahy MF, Ryu RK, Ibrahim SM, Sato KT, Baker T, Miller FH, Omary R. Abecassis M, Salem R. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization vs. radioembolization. American Journal of Transplantation 2009; 9:1-9.

• L

REFERENCES • Eleni Liapi, Jean-Francois Geschwind, Josephina A. Vossen, Manon Buijs, Christos S. Georgiades, David A. Bluemke, and Ihab

R. Kamel. Functional MRI Evaluation of Tumor Response in Patients with Neuroendocrine Hepatic Metastasis Treated with Transcatheter Arterial Chemoembolization. Am. J. Roentgenol., Jan 2008; 190: 67 - 73.

• Miller FH, Keppke AL, Reddy DH, Huang J, Jin J, Mulcahy MF, Salem R. Response of liver metastases after treatment with Yttrium-90 microspheres: role of size, necrosis, and PET. AJR. 2007: 188:776-783.

• Rhee TK, Naik NK, Deng J, Atassi B, Mulcahy MF, Kulik LK, Ryu RK, Miller FH, Larson AC, Salem R, Omary RA. "Tumor Response after Yttrium-90 Radioembolization for Hepatocellular Carcinoma:Comparison of Diffusion-weighted Functional MR Imaging with Anatomic MR Imaging." J Vasc Interv Radiol 2008; 19: 1180-1886.

• Riaz A, Kulik L, Lewandowski RJ, Ryu, RK, Spear GG, Mulcahy MF, Abecassis M, Baker T, Gates V, Nayar R, Miller FH, Sato KT, Omary RA, Salem R. Radiologic-Pathologic correlation of hepatocellular carcinoma treated with internal radiation using yttrium-90 microspheres. Hepatology. 2008 Nov 19;49(4):1185-1193.

• Riaz A, Miller FH, Kulik LM, et al. Imaging Response in the Primary Index Lesion and Clinical Outcomes Following Transarterial Locoregional Therapy for Hepatocellular Carcinoma. JAMA 2010; 303: 1062-1069

• Sato KT, Lewandowski RJ, Mulcahy MF, Atassi B, Ryu RK, Gates VL, Nemcek A, Barakat O, Benson A, Mandal R, Talamonti M, Wong CY, Miller FH, Newman SB, Shaw JM, Thurston KG, Omary RA, Salem R. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres--safety, efficacy, and survival. Radiology 2008; 247:507-515.

• Welsh JS. Radiographically identified necrosis after 90Y microsphere brachytherapy: a new standard for oncologic response assessment? AJR. 2007: 188: 765-767