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					 Yttrium-90 Radioembolization for Hepatocellular Carcinoma:
Comprehensive Analysis of Long-term Outcomes in 291 Patients




        Robert J. Lewandowski, Ahsun Riaz, Robert K. Ryu, Ramona
           Gupta, Vanessa L. Gates, Kent T. Sato, Reed Omary,
                               Riad Salem

                     Northwestern Memorial Hospital
                              Chicago, IL
                  Disclosures


Consultant, Advisory Boards, Research Support

• MDS Nordion, Sirtex Medical
              Y90 Radioisotope


•   100% pure beta emitter, 0.9367 MeV
•   Physical half-life of 64.2 h
•   Irradiates tissue with average range of 2.5 mm
•   Maximum penetration of approx. 1.0 cm
•   A constituent of an insoluble glass matrix
•   Microsphere diameter 25µ - 35µ
            Methodical Approach to Y90:
                10 year experience
•   Investigated each concept
     – Safety
     – Angiographic Technique
     – Dosimetry
     – Niche Applications
          • Portal vein thrombosis
          • Radiation Lobectomy
          • Radiation Segmentectomy
     – Lung dose, Distribution
     – Liver Metastases
          • CRC
          • NET
          • Cholangiocarcinoma
     –   Imaging criteria
     –   Pathologic analyses  comparison with TACE
     –   Biomarkers
     –   Long term Survival
     –   Combination with Systemic Agents
          • Capecitabine
          • Sorafenib
               Northwestern 5-yr Experience
                    291-Patient Cohort


• December 2003  December 2008
  – Open label protocol: Y90 glass microspheres
• All baseline CT/MR
  – 1250 CT/MRI scans, total 4.3 scans per patient
  – Strict imaging definition of metastases at baseline
  – Comprehensive review at each stage in time for
     development of metastases (CT chest, bone scans)
  – Prospectively followed all patients
       RECIST (Uni-dimensional) Guideline


       System            Classification                  Definition



                                          100% decrease in maximum diameter of
                              CR
                                          target lesion


                                          ≥30% decrease in maximum diameter of
                              PR
     Response                             target lesion
Evaluation Criteria in
   Solid Tumors
     (RECIST)                             <30% decrease to ≤20% increase in
                              SD
                                          maximum diameter of target lesion



                                          >20% increase from maximum response of
                              PD
                                          target lesion
            Clinical Outcomes


• TTP: Progression defined as any of the
  following: progression by WHO, EASL, UNOS
  stage or appearance of new lesions
• Survival: from first treatment
• Univariate (Kaplan-Meier with Logrank) and
  Multivariate (Cox Regression Model) were
  used
        Baseline Demographics
                                   N (%)

                    < 65          138 (47)
Age (years)         ≥ 65          153 (53)
                    ≥ 75          63 (22)
                    Male          223 (77)
 Gender
                   Female         68 (23)
                 Caucasian        208 (71)
               African American   37 (13)
 Ethnicity
                    Asian         29 (10)
                  Hispanic         17 (6)
               Etiology
                              N (%)

                HCV          100 (34)
               Alcohol       56 (19)
             Cryptogenic     54 (19)
                HBV           26 (9)
            HCV + Alcohol     23 (8)
Etiology       NASH           6 (2)
             Autoimmune      4 (1.3)
           Hemochromatosis   4 (1.3)
             HCV + HBV        3 (1)
                PBC          1 (0.6)
              Unknown         14 (5)
          Imaging Characteristics
                                         N (%)

                       Solitary         78 (27)
 Distribution
                      Multifocal       213 (73)
                       Bilobar         139 (48)
Tumor location
                      Unilobar         152 (52)
                 Uninodular & <50%      73 (25)
 Morphology      Multinodular & <50%   180 (62)
                  Massive or >50%       38 (13)
                       0-25%           223 (76.6)
                      26-50%            48 (16)
Tumor Burden
                      51-75%             19 (7)
                      76-100%           1 (0.4)
         Imaging Characteristics
                                    N (%)

                    None           166 (57)

   PVT             Branch          58 (20)

                    Main           67 (23)

                    None           245 (84)

Metastases           LN            29 (10)

                    Other           17 (6)
       Tumor Size

                    N       Mean (Range)

                                  7
       Overall     291
                              (1.2-22)

                                 3.4
       < 5 cm    116 (40)
                              (1.2-4.9)
Size
                                 7.1
       5-10 cm   123 (42)
                               (5-10)

                                14.9
       > 10 cm   52 (18)
                              (10.1-22)
             Baseline Stage
                                  N (%)

                        A        131 (45)
Child Pugh              B        152 (52)
                        C         8 (3)
                            A1    3 (1)

                 A          A2    22 (8)
               (n=39)       A3    8 (2)
  BCLC                      A4    6 (2)
                        B        66 (23)
                        C        178 (61)
                        D         8 (3)
            Treatment Characteristics


               Number of
                            Median dose    Mean dose
 Location      Treatments
                               (Gy)       (Gy) [Range]
                   (N)

                                              112
   Liver          526          103
                                           (18-1693)
Lung (per                                      8.8
                  526           5.4
treatment)                                 (0.09-89.9)
   Lung                                       15.7
                  291           9.3
(cumulative)                               (0.09-110)
                 Clinical Toxicities
 Adverse Event        No. of Patients   %

    Fatigue                167          57

Abdominal Pain              67          23

Nausea/Vomiting             57          20

   Anorexia                 45          15

  Fever/Chills              10          3

   Diarrhea                 7           2

 Weight Loss                4           1
                                  Liver-only disease
                                               EASL                     TTP            Overall Survival
Child’s                                                  WHO PR
            PVT        UNOS           N         PR                     Median              Median
Class                                                     N (%)
                                               N (%)                  (95% CI)            (95% CI)

               Overall CP A        116 (113)   78 (69)    59 (52)    10.8 (7.4-14)       17.2 (14.9-24)

                        Overall     81 (79)    61 (77)    42 (53)   15.5 (10.7-25.9)    22.1 (17.2-32.5)

                        T1/T2       27 (25)    22 (88)    13 (52)      27.1 (8, -)      20.5 (14.9-27.4)
          PVT Absent
  A
                          T3        27 (27)    24 (89)    17 (63)   21.9 (10.9-25.8)    35.7 (18.3-44.4)

                         T4a        27 (27)    15 (56)    12 (44)      8.6 (6, -)        14.9 (7.3-22.2)

            PVT
                         T4b        35 (34)    17 (50)    17 (50)    5.6 (2.3-7.6)       10.4 (7.2-16.6)
           Present

               Overall CP B        122 (114)   59 (52)    44 (39)    8.4 (5.9-12.3)       7.7 (6.5-11.2)

                        Overall     65 (64)    43 (67)    30 (47)   13.0 (8.4-18.1)      14.8 (11.8-29.1)

                        T1/T2       22 (22)    15 (68)    8 (36)     13.0 (6.3-25)        29.1 (17.1, -)
  B       PVT Absent
                          T3        21 (21)    18 (86)    12 (57)   17.4 (8.4-33.9)      38.3 (6.9-41.7)

                         T4a        22 (21)    10 (48)    10 (48)    8.8 (3.6-18.1)       11.8 (6.2-19)

            PVT
                         T4b        57 (50)    16 (32)    14 (28)    5.9 (4.2-7.9)        5.6 (4.5-6.7)
           Present
              Northwestern 5-yr Experience
                   291-Patient Cohort


• Significant findings:
  – 273/291 (94%) of patients had FU imaging
  – All as outpatients
  – 58% downstaged T3 T2
  – 32 transplanted
  – No GI ulcers
          AFP 8.0


AFP 800
Pre treatment   6 months post
AFP  2200        treatment
                  AFP  4.5
After 2 treatments
Pre treatment   22 months
                 Pre Tx: AFP 1368




36 months post
 Tx: AFP 9.5
               Northwestern 5-yr Experience
                    291-Patient Cohort

• Continues to be evolving role of Y90 in HCC
• Cohort data permits
   – Exploratory subgroup analyses
      •   Who benefits
      •   Who doesn’t
      •   Where should research be focused?
      •   Downstaged to potential cures (transplant/resection)
      •   Treatment in portal vein thrombosis patients
• Next considerations
   – Y90 vs chemoembolization
   – Y90 +/- Sorafenib (various combinations)
                      Acknowledgements
Radiology:           Hepatology/Oncology:
Robert Lewandowski   Laura Kulik
Reed Omary
Bob Ryu              Mary Mulcahy
Kent Sato            William Small
Paul Nikolaidis      Al Benson
Frank Miller         Michael Abecassis
                     Daniel Ganger
MR Physicists:       Steve Flamm
Andrew Larson

Post-Doc Fellows:
Saad Ibrahim
Ahsun Riaz
Nurses:
Karen Marshall
Sharon Coffey
Krystina Salzig
Peggy Gilbertsen
Jennifer Karp
Elizabeth Gonda