Download Slides - 5th Annual Winship Gastrointestinal Cancer

Stereotactic Body Radiation Therapy for
Unresectable Liver Tumors
Laura A. Dawson, M.D.
Princess Margaret Cancer Centre
University of Toronto, Toronto, Ontario
5th Annual Winship State-of-the Art Multidisciplinary Management of
Gastrointestinal Cancers Symposium
Disclosures
• Research funding from Bayer
paid to institution, > 1 year ago
• Research funding from Elekta
paid to institution, > 5 years ago
Why Radiation Therapy for Liver Cancer?
• Local-regional therapies are effective in liver cancer
•
Many patients refractory to or unsuitable for standard tx
• Liver cancers tend to be a hepatic/hepatic vascular
confined cancer (versus diffusely metastatic)
•
Rationale for local therapies
• Radiation therapy is an established cancer treatment
•
Used in ~ 50% of cancer patients
• Ablative RT doses can be safely delivered to focal liver
tumors
•
Partial liver tolerance to RT much better understood
Hypotheses
• Radiation therapy should lead to improved outcomes in liver cancer
patients who are not candidates for standard local therapies:
–
–
–
–
Symptom improvement
Quality of life
Local control
Cure
Palliative
Radical
• Focus today:
– Hepatocellular carcinoma (HCC)
– Intrahepatic cholangiocarcinoma (IHC)
– Hilar cholangiocarcinoma (Klatskin)
Strategies to Deliver High Dose Radiation Therapy
• External beam radiotherapy (EBRT)
–
–
–
–
–
Conformal radiotherapy (CRT)
Intensity modulated radiation therapy (IMRT)
Stereotactic body radiation therapy (SBRT)
Proton therapy
Ion therapy (e.g. Carbon)
• Brachytherapy
– Interstitial
– Interluminal
• Intra-operative RT (IORT)
– Mobile electron unit
•
Radioisotopes
– Iodine 131 Lipiodol
– Yttrium 90 microspheres
Stereotactic Body Radiotherapy, SBRT
•
•
•
•
•
•
•
Very conformal dose distribution
Many beams or arc(s)
Potent doses
Motion management
Image guidance (‘stereotactic”)
High dose per fraction
Few number of fractions (3 - 6)
– ≤ 5 for billing in US
– May be delivered in any fractionation
• Widely available
Typical HCC 5 Fraction SBRT Plan
Avoidance of
normal tissues a
priority
Dose dependent
on normal tissues
• Volume of
spared liver
• Proximity to
luminal GI
organs
35 Gy 25 Gy 10 Gy
Biologic Rationale for SBRT
• High dose/fraction specific effects
– Preclinical models
– Threshold ~ 8 Gy/ fraction
• Postulated mechanisms of RT injury
• Ablative direct cell kill
• Endothelial target
– Rapid injury enhances RT response (Fuks)
• Immune
– RT increases tumor Ag-specific immune response
• Absgopal effect
– Local therapy causes systemic response
Lugade AA et al. J Immunology. 2005;174:7516-7523.
Finkelstein S, et al. Clin Dev Immunol. Nov 2011;439752
Park HJ, et al. Radiat Res. 2012:177:311-327.
How to Deliver Liver RT Safely
• Appropriate patient selection
• Multidisciplinary collaboration
• Ensure
Much enough
better understanding
of thefrom
partial
residual liver spared
RT liver
radiation
tolerance
liver now (versus 15 years ago)
– > 800 cc liver
< 18 Gy into
5 fractions
– Keep irradiated volumes as small as possible
advanced
RT technologies
•• Use
Ablative
radiation
doses can be delivered safely to
– Multi-phasic
and multi-modality
imaging
focal
HCCs (involving
~ < 60%
of the liver)
– Breathing motion control
– Computer optimization → conformal RT doses
– Image guidance
•
Specialized training and education programs for radiation
oncologists
Image Guided Radiotherapy (IGRT)
MV EPID
MV CT
kV Fluoroscopy + markers
MV cone
beam CT
And more: combined technologies, MR-linac, …
Dawson LA, et al. J Clin Oncol. 2007;25(8):938-461.
Ultrasound
kV Cone-beam CT
kV CT
HCC BCLC: Where RT may fit
Dawson LA, et al. Semin Radiat Oncol. 2011;21(4):241-246
HCC Proton Therapy
• Chiba, Clin Cancer Res, 2005
– 162 HCC, 33-88 Gy/10-30 fractions
– 3 late biliary toxicities (dose/#>4Gy) 1-3 yrs post
• Fukumitsu, IJROBP, 2009
– Prospective study n=51 HCC, >2 cm from porta
– 66 GyE in 10#
5 yr local control 88%
Chiba, T et al, Clin Can Res. 2005;11:3799-3805.
Fukumitsu N et al. Int J Radiat Oncol Biol Phys. 2009;74(3):831-6.1
5 yr survival 39%
HCC Proton Therapy
• Chiba,
ProtonClin
(and
ion) therapy
units not widely available
Cancer
Res, 2005
•
– 162 HCC, 33-88 Gy/10-30 fractions
Far higher costs than photon therapy
– 3 late biliary toxicities (dose/#>4Gy) 1-3 yrs post
• Fukumitsu, IJROBP, 2009
– Prospective study n=51 HCC, >2 cm from porta
– 66 GyE in 10#
5 yr local control 88%
Chiba, T et al, Clin Can Res. 2005;11:3799-3805.
Fukumitsu N et al. Int J Radiat Oncol Biol Phys. 2009;74(3):831-836.
5 yr survival 39%
SBRT: Korean Registry
N=93 HCC patients (26% CP B)
•
–
Dose: 30 - 40 Gy in 3- 4#
•
–
–
•
All refractory or unsuitable for TACE
Size: median 2 cm (1-6 cm)
Improved local control for smaller HCC (100% < 2cm, 93% 2-3cm, 76% 3-6)
Toxicity: Decline in CP score in 9.7% (gr 5, n=1 CP B pt)
3 yr local control 92%
3 yr survival 54%
Yoon SM et al. PLoS One. 2013;8(11): e79854.
SBRT: Japanese Retrospective Series
N=221 (~84% T1) HCC patients (CP A:B=178:27)
•
–
Dose: 40 Gy in 5#
•
–
–
–
•
56-61% received TACE < 3 months prior to SBRT
35 Gy: for CP B, and so < 20% liver ≥20Gy, n=48
Size: median 2.7 cm (35 Gy), 2.4 cm (40 Gy), max 5.0 cm
No sign. differences in outcomes for 35 vs 40 Gy
Toxicity: Decline in CP score in 10% (gr 5, n=2 CP B pts)
3 yr local control 91%
Sanuki N, et al. Acta Oncol. 2013;53(3):399-404.
3 yr survival 70%
SBRT: Japanese Retrospective Series
N=221 (~84% T1) HCC patients (CP A:B=178:27)
•
–
Dose: 40 Gy in 5#
•
–
–
–
•
56-61% received TACE < 3 months prior to SBRT
35 Gy: for CP B, and so < 20% liver ≥20Gy, n=48
Size: median 2.7 cm (35 Gy), 2.4 cm (40 Gy), max 5.0 cm
No sign.Outcomes
differences in≈outcomes
35 vsprotons,
40 Gy
those for
from
RFA
Toxicity: Decline in CP score in 10% (gr 5, n=2 CP B pts)
3 yr local control 91%
Sanuki N, et al. Acta Oncol. 2013;53(3):399-404.
3 yr survival 70%
HCC BCLC: Where RT may fit
Dawson LA, et al. Semin Radiat Oncol. 2011;21(4):241-246
RT & TACE vs TACE - HCC: Korea
• 73/ 105 HCC incomplete response to TACE
– 35 TACE repeated
– 38 received conformal RT (~ 50 Gy, 2 Gy/#)
• Multivariate analysis sign. factors (survival)
– Tumour size
– Treatment
2 yr survival
All
5-7 cm
8-10 cm
RT no RT
37% 14%
63% 42%
50% 0%
Shim SJ, et al. Liver Int. 2005;25(6):1189-1196.
Can RT control HCC with portal vein thrombosis (PVT)?
• RT for HCC with PVT: High variability in series
– Some studies combine RT with TACE
– Prognostic factors: Child score, HCC burden, main PVTT,
complete occlusion, extrahepatic disease
• Recanalization of portal vein thrombosis occurs in
~ 50% of patients post RT
• Median time to maximal response ~ 6 months
• Median survival 4 – 13 months
– > 800 patients reported on
– Retrospective and non-randomized prospective data
Selected Series of RT for Locally Advanced HCC
Author
Year
Bujold et al
2013
102
Xi et al
2013
Choi et al
Grade ≥3
Toxicity
PVT %
Dose (Gy)
No. Fx
9.9 (1.8-43.1 ) cm
55%
36 (24-54)
6
17 (PVT-11.0;
No PVT-20.5)
36%
41
NA
100%
36 (30-48)
6
13
2%
2008
31
3.9-47.7 mL
30%
36 (30-39)
3
8
6%
Han et al
2008
40
NA
100%
45
25
13.1
Huang et al
2009
326
≥10cm in 39%
100%
60
20-30
3.8
Kim
2005
59
11 cm
100%
30-54
10 to 24
10.7
Rim et al
2012
45
1.5–17.3 cm
100%
61.2 (38-65)
20-30
13.9
Toya
2007
38
4 (0.9 – 9.3) cm*
100%
17.5 - 50.4
15 to 25
9.6
Yoon et al
2012
412
2-21 cm
100%
40 (21-60)
8 to 30
10.6
SBRT
No. Pts Tumor Size (range)
median survival
(months)
Conformal RT
Dawson, et al. Haddock, Hepatobiliary Cancer, Gunderson, Tepper Text 2015.
0%
2%
0%
Clinical Case: Resolution of PVT w RT
Jan 2009
AFP 10,000
Tumor thrombosis
Sept 2009
AFP 24
Toronto Phase I/II HCC Study
•
N=102 HCC patients unsuitable for resection,
transplant, TACE or RFA
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•
•
•
•
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Hep B : Hep C: alcohol
39% : 39% : 25%
Prior therapies
50%
Portal vein thrombosis
55%
Extrahepatic disease
12%
Size: median
9.9 cm (2 – 43 cm)
Median dose 36 Gy in 6# (24 – 54 Gy, 6 #)
Bujold A, et al. J Clin Oncol. 2013;31(13):1631-1639.
Local control
•
•
1 year local control 87% (95% CI 78-93%)
Dose response observed (> 30 Gy in 6 #)
Bujold A, et al. J Clin Oncol. 2013;31(13):1631-1639.
Tumor marker response (AFP)
Bujold A, et al. J Clin Oncol. 2013;31(13):1631-1639.
Overall survival, n=102
Median survival 17 months
Survival by thrombosis
Median survival
No thrombosis 20.5 mo (95% CI 12.9, 36.9)
Thrombosis
11.0 mo (95% CI 11.3, NA)
Bujold A, et al. J Clin Oncol. 2013;31(13):1631-1639.
Survival by trial
Trial 1
Trial 2
Med Survival
11.1 months (95% CI 7.4-19.0)
25.5 months (95% CI 11.3, NA)
The bad news….
•
102 patients had death 1.1 – 7.7 months post
SBRT, possibly related to therapy
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–
–
•
3 liver
1 biliary (with gross HCC invasion to bile duct)
1 duodenum bleed (post re-RT to LN)
~ 30% of all patients had a decline by 2 or more in
Child Pugh score at 3 months
RTOG1112: Ph III study for locally advanced HCC
• Primary endpoint:
Overall survival
• Secondary endpoints: TTP, PFS, vascular tumor response,
toxicity, QOL
• Sample size: 368
RTOG1112 Key Eligibility 11/7/2014
Inclusion Criteria
• Measureable HCC
• Unsuitable for or refractory to:
– Surgery
– RFA
– TACE
• Child Pugh A
• BCLC B or C
• Platelets > 70 000 bil/L
• INR < 1.7
• Albumin ≥ 28 g/L
• AST, ALT < 6x ULN
Exclusion Criteria
Prior Sorafenib (> 60 days)
Prior abdominal RT or Y-90
> 15 cm single HCC
> 20 cm sum of max diameters
> 5 discreet HCC
Extrahepatic disease > 3 cm
HCC extension to stomach
HCC extension to CBD
Thrombolytic therapy within
28 days of study entry
• Bleeding within 60 days
requiring transfusion
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•
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•
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•
•
•
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Can RT be used safely in Child-Pugh B/C HCC pts?
Toronto review 1/2004- 7/2012, n= 40 HCC pts
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N=11 bridge to liver transplant pts excluded
N=29 treated with definitive SBRT
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–
•
•
•
•
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14 on prospective study (< 10 cm, < CP B9)
76% portal vein tumor thrombosis
69% Child Pugh B7
Median AFP: 4491 (0-94,921)
Median HCC volume 133 cc
Median survival: 7.9 months (2.8 – 15.1 mo)
Prognostic factors
•
•
–
–
Child Pugh B7 vs higher (med OS 8.4 vs. 2.8 mo)
AFP < 4491 (correlated with disease burden)
Culleton S, et al. Radiother Oncol. 2014;111(3):412-417.
Cholangiocarcioma
• Most RT experience is with fractionated RT +/- brachytherapy
• SBRT/hypofractionation (without stents) may precipitate biliary
obstruction, late strictures
Peripheral IHC
most well
suited for
SBRT
Extra-hepatic
better suited
for standard
fractionation
Intrahepatic Cholangiocarcinoma (IHC) SBRT - Toronto
•
•
•
•
Ph I SBRT study for IHC, 30-54 Gy in 6 #
10 IHC patients unsuitable for other therapies
Med survival 15 months (6.5-29 mo)
Toxicities:
– 2 transient biliary obstruction
– 2 decline in CP score at 3 mths
• Recommendations:
1. Standard fractionated RT
2. SBRT, modest dose (30-36 Gy in 5-6 fractions) in selected pts
– Stent pre-RT
– Steroids pre-RT
Tse RV, et al. J Clin Oncol. 2008;26(4):657-664.
Other Cholangiocarcinoma SBRT Series
IHC
• Ibarra: n=11,
37.5 Gy in 3#,
Med OS 12 mo
• Barney: n=10,
55 Gy in 5#,
Med OS 14 mo
– 22% serious toxicity (1 gr 3 biliary stenosis, 1 gr 5 liver, 20 mo)
Hilar CC
• Kopek: n=26,
45 Gy in 3#,
– n=9 ≥ gr 3 duodenal ulcer
– n=21 ≥ gr 3 ALP
– n=8 ≥ gr 3 bilirubin
– n=3 duodenal stenosis
– n=1 liver failure
• Polistina: n=10,
30 Gy in 3#,
– Gem & SBRT
– n=1 duodenal ulcer
– n=2 duodenal stenosis
Ibarra RA, et al. Atca Onc. 2012;51(5):575-583.
Barney BM, et al. Radiat Oncol. 2012;7(67).
Kopek N, et al. Radiother Onc. 2010;94(1):47-52.
Polistina FA, et al. Radiother Onco. 2011;99(2):120-123.
Med OS 11 mo
Med OS 36 mo
NRG-GI0001: Ph III study for locally advanced IHC
• Key eligibility: Unresectable IHC < 12 cm, portal LN < 2 cm
• Primary endpoint: Overall survival
• Secondary endpoints: PFS, local, regional and distant control, toxicity
• Sample size: 182 (to see increase in 2 year OS from 18 to 40% w RT)
R
E
G
I
S
T
E
R
Gemcitabine/Cisplatin
x3
Evaluate to
confirm no
progression:
Patients without
progression,
will be
randomized
S
T
R
A
T
I
F
Y
Tumor
size
(≤ 6cm vs.
> 6cm)
Satellite
lesions
(Yes vs.
no)
R
A
N
D
O
M
I
Z
E
Arm 1:
Gem/Cis x 1 -> Liverdirected Radiation
Therapy -> Gem/Cis x 4
(Maintenance gemcitabine
may be given after
completion of Gem/Cis)
Vs.
Arm 2:
Gem/Cis x 5
(Maintenance gemcitabine
may be given after
completion of Gem/Cis)
If patients become a surgical candidate, -> surgery
Conclusions
• SBRT can treat focal liver cancer safely
– Advanced RT techniques, individualized RT and multi-disciplinary team
needed
– Outcomes best if Child Pugh A, < 10 cm, no PVT
• SBRT should be considered for early stage HCC or IHC
unsuitable for resection or RFA
– Longer fractionations to be considered in cholangiocarcinoma
• Randomized trials needed
– RTOG1112: Ph III locally advanced HCC trial accruing
– NRG0001: Ph III locally advanced IHC trial activated
– Opportunity for education, peer review and quality improvement for
RT centers
Acknowledgements
Alexis Bujold
Anand Swaminath
Charles Cho
Mark Lee
Regina Tse
Maria Hawkins
John Kim
Rob Dinniwell
Jim Brierley
Rebecca Wong
Jolie Ringash
Bernard Cummings
Anthony Brade
Rob Case
Cynthia Eccles
Gerry Ruby Foundation
Elekta, Bayer, RMP
Kristy Brock
Mike Velec
Jean Pierre Bissonnette
David Jaffray
Doug Moseley
Catherine Coolens
Mike Sharpe
Teo Stanescu
Tim Craig
Tom Purdie
PMH RMP planners, therapists
Kawalpreet Singh
Gina Lockwood, Christine Massey
HCC tumor board – Morris Sherman
All referring MDs
ASCO CDA, Canadian Cancer Society
CIHR
The Toronto Accelerated Education Program
Upcoming Courses
Head & Neck IM/IGRT – November 13-15, 2014
Led By: Drs John Waldron & Meredith Giuliani
Liver SBRT IGRT – March 5-7, 2015
Led By: Dr Laura Dawson
Accelerator Technology – April 13-17, 2015
Led By: Dr Marco Carlone & Bern Norrlinger
www.aepeducation.ca
[email protected]
@AEPcme

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