Transcript HCC - Med-IQ

Faculty
Jorge A. Marrero, MD, MS
Professor of Medicine
Chief, Clinical Hepatology
Medical Director, Liver Transplantation
UT Southwestern Medical Center
Dallas, TX
Activity Planners
Shari J. Dermer, PhD
Manager, Educational Strategy and Content
Med-IQ
Baltimore, MD
Lisa R. Rinehart, MS, ELS
Director, Editorial Services
Med-IQ
Baltimore, MD
Trends in Incidence and Mortality for HCC
2001 to 2010
Trends in SEER Incidence Rates
Thyroid
Liver & Intrahepatic Bile Duct
Kidney & Renal Pelvis
Melanoma of the Skin
Pancreas
Corpus & Uterus, NOS
Testis
Myeloma
Oral Cavity & Pharynx
Non-Hodgkin Lymphoma
Hodgkin Lymphoma
Brain & Other Nervous System
All Sites Except Lung
Leukemia
All Cancer Sites
Urinary Bladder
Breast (Female)
Lung & Bronchus (Female)
Esophagus
Stomach
Cervix Uteri
Ovarya
Larynx
Lung & Bronchus (Male)
Prostate
Colon & Rectum
Trends in US Cancer Death Rates
-
6.3*
3.6*
2.4*
1.5*
0.9*
0.9*
0.6*
0.4
0.2
0.1
0
-0.3
-0.5*
-0.5*
-0.6*
-0.6*
-0.6
-0.7*
-0.9*
-1.1*
-1.7*
-1.7*
-2.1*
-2.2*
-2.3*
-2.6*
-10 -8 -6 -4 -2 0
2
4
6
8 10
Annual Percent Change, 2001 to 2010
*The APC is significantly different from zero (P < 0.05).
aOvary excludes borderline cases or histologies 8442,
8451, 8462, 8472, and 8473.
Liver & Intrahepatic Bile Duct
Thyroid
Pancreas
Melanoma of the Skin
Corpus & Uterus, NOS
Urinary Bladder
Testis
Brain & Other Nervous System
Esophagus
Lung & Bronchus (Female)
Kidney & Renal Pelvis
Leukemia
Oral Cavity & Pharynx
All Sites Except Lung
All Cancer Sites
Cervix Uteri
Myeloma
Ovary
Breast (Female)
Larynx
Hodgkin Lymphoma
Lung & Bronchus (Male)
Non-Hodgkin Lymphoma
Stomach
Colon & Rectum
Prostate
2.4*
1.2*
0.5*
0.5*
0.5
0.1
-0.3
-0.5*
-0.6*
-0.9*
-1.0*
-1.0*
-1.3*
-1.4*
-1.5*
-1.5
-1.8*
-1.8*
-2.0*
-2.4*
-2.5*
-2.5*
-2.8*
-2.9*
-2.9*
-3.4*
-10 -8 -6 -4 -2 0
2
4
6
8 10
Annual Percent Change, 2001 to 2010
Howlader N, et al. SEER Cancer Statistics Review. www.seer.gov.
Risk Factors for HCC
• Cirrhosis
– 87%-93% of patients with
HCC have cirrhosis at
autopsy and controlled
studies1,2
• Chronic liver disease
leading to cirrhosis3
– Hepatitis B
– Hepatitis C
• Male gender
• Increased age
• Diabetes
1. Tiribelli C, et al. Hepatology. 1989;10:998-1002;
2. Stroffiolini T, et al. J Hepatol.1998;29:944-52;
3. Fattovich G, et al. Gastroenterology. 2004;127:S35-50.
Staging Classifications in HCC
Variables Measured
Staging
Classification Tumor Staging
CLIP
Tumor morphology (uninodular and extension ≤
50%, multinodular and extension ≤ 50%, massive
or extension > 50%), PVT
BCLC
Tumor size, number of nodules, PVT
GRETCH
PVT
US nomogram Resection margin status, tumor size > 5 cm,
satellite lesions, vascular invasion
Liver Function
Performance
Status
Year
Serum Tumor
Published
Markers
Child-Pugh
No
AFP
1998
CLIP investigators
Child-Pugh, bilirubin,
portal hypertension
PST
No
1999
Llovet et al.
Bilirubin, alkaline
phosphatase
Karnofsky
AFP
1999
Chevret et al.
No
Age, operative
blood loss
AFP
2008
Cho et al.
Ascites, albumin,
bilirubin
No
No
1985
Okuda et al.
Ascites, bilirubin,
alkaline phosphatase
Presence of
symptoms
AFP
2002
Leung et al.
Study
Okuda
Tumor size (</> 50% of liver)
CUPI
TNM fifth edition
JIS
Japanese TNM fourth edition
Child-Pugh
No
No
2003
Kudo et al.
bm-JIS
Japanese TNM fourth edition
Child-Pugh
No
AFP, AFP-L3,
DCP
2008
Kitai et al.
SLiDe
Stage and liver damage categories from the
Japanese TNM fourth edition
No
No
DCP
2004
Omagari et al.
Tokyo
Size and number of tumors
Albumin, bilirubin
No
No
2005
Tateishi et al.
BALAD
No
Albumin, bilirubin
No
AFP, AFP-L3,
DCP
2006
Toyoda et al.
ALCPS
Tumor size, PVT, lung measures
Ascites, Child-Pugh,
alkaline phosphatase,
bilirubin, urea
Abdominal pain,
weight loss
AFP
2008
Yau et al.
Reprinted with permission from Meier V, Ramadori G. Clinical staging of hepatocellular carcinoma. Dig Dis. 2009;27:131-141.
BCLC Staging Classification
Stage 0
Stage A-C
PST 0, Child-Pugh A
Very early stage (0)
Single < 2 cm
Carcinoma in situ
Early stage (A)
Intermediate stage (B)
Single or 3 nodules Multinodular, PST 0
< 3 cm PST 0
Advanced stage (C)
Portal invasion,
N1, M1, PST 1-2
Terminal
stage (D)
3 nodules < 3 cm
Portal pressure/bilirubin
Increased
Resection
Okuda 3, PST > 2,
Child-Pugh C
Okuda 1-2, PST 0-2, Child-Pugh A-B
Single
Normal
Stage D
Associated
diseases
No
Liver transplantation
(CLT/LDLT)
Curative treatments
50%-70% at 5 years
Portal invasion,
N1, M1
Yes
PEI/RFA
Chemoembolism
Sorafenib
Randomized controlled trials
40%-50% at 3 years vs. 10% at 3
years
Symptomatic
treatment
Reprinted with permission from Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907-1917.
RECIST Version 1.1
RECIST
CR
Disappearance of all target lesions
PR
30% decrease in the sum of the longest diameter of
target lesions
PD
20% increase in the sum of the longest diameter of
target lesions
SD
Small changes that do not meet above criteria
Eisenhauer EA, et al. Eur J Cancer. 2009;45:228-47.
SHARP: RECIST Response
Patients (%)
Sorafenib
Placebo
(n = 299)
(n = 303)
ORR*
CR
PR
SD
PD
Median duration of treatment, weeks
TTSP (as assessed by FHSI-8)
*Independent review by RECIST.
0
7 (2.3)
211 (71)
54 (18)
23
0
2 (0.7)
204 (67)
73 (24)
19
No significant differences
between treatment groups
(P = 0.77)
Llovet JM, et al. N Engl J Med. 2008;359:378-90.
Modified RECIST
RECIST
mRECIST
CR
Disappearance of all target lesions
Disappearance of any intratumoral arterial
enhancement in all target lesions
PR
At least a 30% decrease in the
sum of diameters of target lesions,
taking as reference the baseline
sum of the diameters of target
lesions
At least a 30% decrease in the sum of
diameters of viable (enhancement in the
arterial phase) target lesions, taking as
reference the baseline sum of the diameters
of target lesions
SD
Any cases that do not qualify for
either PR or PD
Any cases that do not qualify for either PR or
PD
PD
An increase of at least 20% in the
sum of the diameters of target
lesions, taking as reference the
smallest sum of diameters of
target lesions recorded since
treatment started
An increase of at least 20% in the sum of the
diameters of viable (enhancing) target lesions,
taking as reference the smallest sum of
diameters of viable (enhancing) target lesions
recorded since treatment started
Lencioni R, et al. Semin Liver Dis. 2010;30:52-6.
Validation of mRECIST
1.0
Log rank P
CR vs. PR
< 0.001
PR vs. SD
0.002
SD vs. PD
0.023
0.8
OS
0.6
CR
0.4
PR
0.2
PD
SD
0.0
0
20
40
60
Time, months
80
100
Compared RECIST, WHO, EASL, and mRECIST
Reprinted with permission from Shim JH, Lee HC, Kim SO, et al. Which response criteria best
help predict survival of patients with hepatocellular carcinoma following chemoembolization?
A validation study of old and new models. Radiology. 2012;262(2):708-718.
Palliation of HCC: Sorafenib
Probability of Radiologic
Progression
Time to Radiologic Progression
1.00
Sorafenib
Placebo
0.75
0.50
0.25
P < 0.001
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Mos Since Randomization
Pts at Risk, n
Sorafenib
Placebo
Probability of Survival
• Before 2007, no therapy was of
benefit in advanced HCC
• SHARP trial: CTP A patients with
advanced HCC randomized to
sorafenib 400 BID vs. placebo
• Sorafenib delayed progression and
prolonged survival from 7.9 to 10.7
months
• Led to approval by the FDA in 2007
for palliation of advanced-stage HCC
• It remains the only approved
systemic therapy for HCC
299 267 155 101 91 65 37 23 18 10
303 275 142 78 62 41 21 11 10 3
4
1
2
1
0
0
OS
1.00
Sorafenib
Placebo
0.75
0.50
0.25
P < 0.001
0
0 1 2 3 4 5 6 7 8 9 10 11 12 1314 1516 17
Pts at Risk, n
Sorafenib
Placebo
Mos Since Randomization
299 290 270 249 234 213 200 172 140 111 89 68 48 37 24
7
1
0
303 295 272 243 217 189 174 143 108 83 69 47 31 23 14
6
3
0
Reprinted with permission from Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in
advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390.
www.FDA.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109030.htm.
Novel Therapeutics in Development
Target/Mechanism
Select Example(s)
Trial Design
Status
Anti-angiogenic mAb
Ramucirumab* vs. placebo (REACH)
AMG 386 + sorafenib
RP3
Phase 2
In follow up
In follow up
c-MET inhibition
Cabozantinib* vs. placebo
Tivantinib* vs. placebo (Metiv-HCC)
RP3
RP3, MET-high
In development
Enrolling, TPS 4159
Chemotherapy
combinations with
sorafenib
SECOX
Sorafenib ±GEMOX
Sorafenib ±DOX (CALGB 80802)
Phase 2
RP2
RP3
Abstract 4117
Abstract 4128
Enrolling
Immune modulation
Nivolumab* (anti-PD1)
Pexa-Vec* (poxvirus) vs. BSC
Tremelimumab* (anti-CTLA4)
Phase 1
RP2b, phase 2
Phase 2
Enrolling, TPS 3111
TPS 4161, Abstr. 4122
Sangro J Hepat. 2013
Metabolism/other
ADI-PEG20* vs. placebo
GC33* (anti-glypican 3) vs. placebo
RP3
RP2 (GPC-3
stratified)
Enrolling
Enrolling
mTOR pathway
Everolimus* (EVOLVE) vs. placebo
CC-223
RP3
Phase 1/2
In follow up
Enrolling
Multikinase/VEGFR
inhibition
Brivanib* vs. sorafenib
Brivanib vs. placebo
Linifanib* vs. sorafenib
Regorafenib* vs. placebo
Sunitinib* vs. sorafenib
Sorafenib ±erlotinib*
RP3
RP3
RP3
RP3
RP3
RP3
Johnson AASLD 2012
Llovet EASL 2012
Cainap GI ASCO 2013
Enrolling, TPS 4163
Cheng ASCO 2011
Zhu ESMO 2012
*Investigational
Reprinted with permission from Robin K. Kelley.
http://slides.asco.org/main/viewslide.asp?tpc=453&slide=97749&from=mtg&view=mtg.
Ramucirumab*
• VEGFR-2 and its ligands (including VEGF-A, -C, and -D) are
important mediators of angiogenesis, and angiogenesis is
integral to HCC carcinogenesis and pathogenesis
• Angiogenesis inhibition has been efficacious in both in vitro and
in vivo HCC models, and results of clinical studies also suggest
potential to inhibit disease growth
• Ramucirumab is a recombinant human IgG1 mAb that binds to
the extracellular domain of VEGFR-2 with high specificity and
affinity
• Ramucirumab was well tolerated in two phase 1 studies
involving patients with advanced refractory solid tumors; two
HCC patients (receiving doses of 10 mg/kg q2w) achieved
disease stabilization on-study for 9 and 14 months, respectively
*Investigational
Zhu AX, et al. ILCA 2010. Abstract O-033;
Zhu AX, et al. Clin Cancer Res. 2013;19:6614-23.
Phase 2 Ramucirumab* First-Line Study
in Unresectable HCC: OS
Survival Outcome
Median OS, mos
95% CI
1-year OS, %
95% CI
All Pts
(N = 42)
BCLC C
Child-Pugh A
(n = 31)
BCLC C
Child-Pugh B
(n = 11)
12.0
18.0
4.4
6.1-19.7
6.1-23.5
0.5-9.0
51.4
62.9
0
34.0-66.4
38.6-79.8
--
Treatment-related toxicities (≥ grade 3): hypertension (14%),
GI hemorrhage (7%), infusion reactions (7%), and fatigue
(5%); there was 1 death due to GI hemorrhage
*Investigational
Zhu AX, et al. ILCA 2010. Abstract O-033;
Zhu AX, et al. Clin Cancer Res. 2013;19:6614-23.
c-MET Inhibition in HCC
• Over-expression in
approximately 50% by IHC
(ARQ data)
• Retrospective series
Foundation Medicine: MET
amplification by NGS
28/2,223 (1.2%) samples
– 2/78 (2.5%) HCC
Santoro A, et al. Lancet Oncol. 2013;14:55-63.
Hand-Foot Skin Reaction
• Hand-foot skin reaction is a group of symptoms affecting the hands
and/or feet1,2
– Varying degrees of severity that tend to decrease during the course of
therapy
• Side effects of antiangiogenic therapies usually occur during the first
few weeks of treatment3
• Patients may require2,3,4:
– Topical treatments
– Temporary suspension of treatment or dose reduction until the episode
resolves
– Permanent dose reduction (in severe or persistent cases)
Grade 1
Incidence: 8%*
*Incidence reported
from the SHARP
trial.[4]
Grade 2
Incidence: 6%*
Grade 3
Incidence: 8%*
1. Moldawer N, Figlin R. Oncol Nurs Forum.2008;4:699-708;
2. Wood LS. Commun Oncol. 2006;3:558-62;
3. Alexandrescu DT, et al. Clin Exp Dermatol. 2007;32:71-4;
4. Nexavar (sorafenib) PI. June 2013.
Photos courtesy of Elizabeth Manchen, RN, MS, OCN.
Management of Hand-Foot Skin Reaction
• Early intervention may prevent progression of
symptoms and avoid treatment interruption or
dose reduction1
• Patients are advised to1,2,3:
– Wear comfortable soft-soled footwear (eg, gel insoles)
– Apply hydrating cream, preferably containing urea
– Bathe regularly in lukewarm water containing Epsom
salts (magnesium sulphate)
• If possible, patients should consult a podiatrist
before starting treatment
1. Wood LS. Commun Oncol. 2006;3:558-62;
2. Anderson R, et al. Oncologist. 2009; 291-302;
3. Robert C, et al. Lancet Oncol. 2005;6:491-500.
Diarrhea
• Loperamide is usually effective1,2,3
– If ineffective, consider using adjunctive codeine
– Ensure that patients are not dehydrated by monitoring urea
and electrolytes
– If severely dehydrated, patients may need to be admitted for
administration of IV fluids
• Patients experiencing treatment-induced diarrhea
should1,3:
– Monitor bowel habits and report any increase in activity above
normal
– Avoid spicy or fatty foods (plain, simple food is best)
– Avoid fruit and caffeine
– Maintain a good fluid intake to avoid dehydration
1. Wood LS. Commun Oncol. 2006;3:558-62.
2. Moldawer N, et al. Oncol Nurs Forum. 2008;4:699-708.
3. Benson AB, et al. J Clin Oncol. 2004;22:2918-26.
Fatigue
• Not always attributable to drug therapy
• Usually managed by educating the patient
• Advise patients to:
– Stay as active as possible because that will
help them sleep better
– Maintain normal work and social schedules
– Take breaks as needed
– Tell their doctor or nurse if they cannot tolerate
activity or if their fatigue worsens
Wood LS. Commun Oncol. 2006;3:558-62.
Acknowledgement of Commercial Support
This activity is supported by educational grants from
Bayer HealthCare Pharmaceuticals, Onyx
Pharmaceuticals, Celgene Corporation, Daiichi
Sankyo, Inc., and Lilly. For further information
concerning Lilly grant funding visit
www.lillygrantoffice.com
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