1. No category

Liver directed therapy – a critical
analysis: selective radiotherapy drug
eluting beads or other
Philippe Rougier, Digestive Oncology
J. Taieb, O. Dubeuil, O. Pellerin, M.
Sappoval, M. Faraggi, JP Pelage
Hopital Européen Georges Pompidou
75015 Paris ; France
And Hopital Ambroise Paré
92100 Boulogne, UVSQ
Rational for Selective Internal Radiation
Therapy (SIRT)
• Rational:
– Tumor vascularisation
– Radiosensitiviy
• Future: Multimodality approach
• Limits: Liver induce lesion by radiotherapy
Colorectal Cancer – liver local therapies
-Intra-arterail Chemotherapy (1960); floxuridine, 5FU,
MMC, THP-adriamycin, oxaliplatin, Irinotecan...
-Chemoembolisation (1964); Mitomycin, oxaliplatin
-Local Ablative Therapies; RadioFrequency, Cryotherapy,…
-Drug-eluting Beads; irinotecan, doxorubicin
-External radiotherapy: conformationnal RT, respiratory gating,
tomotherapy, cibernife...allowing “radiosurgery”
-Radioembolisation; Yttrium-90 microspheres (SIR-Spheres,
TheraSpheres)
Rational for liver directed therapy?
The liver has a dual blood supply
Portal Vein
: 75%
Hepatic Artery : 25%
Tumor blood supply (> 5mm)
portal vein < 5%
hepatic artery: 95%
50% of CRC patients develop Liver Metastases
90% blood supply of hepatic metastases comes from
the hepatic artery. it is heterogeneous.
compared to normal liver (Tc99m AMA) :
30% are hypervascularized,
40% are isovascularized
30% are hypovascularized
Concept of Selective Internal Radiation Therapy (SIRT)
(aka Radioembolization; Hepatic Artery Brachytherapy; Microbrachytherapy )
• To selectively target a very high radiation dose to all tumours
within the liver.
• low radiation dose to the normal liver.
• Infusion via hepatic artery, using differential blood supply to
liver tumours thereby preferentially targeting tumours
• Uses 90Yttrium-labelled SIR-Spheres® microspheres
–
–
–
–
–
123-MAR-PPP rev. 0
Diameter approx. 30 µm (microns)
Half life: 64 hours
Beta 0.93 MeV
Penetrates mean 2.5 mm tissue;
max 11 mm
Achieves doses of 100–1,000+ Gy to tumour
Deposition of SIR-Spheres in Pre-Capillary Vessels
123-MAR-PPP rev. 0
Deposition of SIR-Spheres in Pre-Capillary Vessels can
be synergised in 3 ways
irradiation
+/- Chemotherapy
Embolisation
=> Increased anti-tumoral effect
90Y
microspheres
•
Allow a more precise targeting of the tumor volume
•
Limited side effects and morbidity
•
Limited irradiation of the normal liver (95% vs. 25-30%)
SIR-Spheres
TheraSphere
biocompatible resin-based spheres
(32µm)
insoluble glass microspheres
40-80.106 microspheres/vial (5 ml)
22000 - 73000 microspheres/mg
activity/microsphere = 50 Bq (average)
activity/microsphere = 2500 Bq
(average)
tumor burden
target liver volume
(20-30µm)
Micro-Dosimetry in Explanted
Livers
Monte Carlo Dose Kernel
123-MAR-PPP rev. 0
Kennedy et al. Int J Rad Oncol Biol Phys 2004; 60: 1520–1533.
3-d Micro-Dosimetry in Explanted Livers
100 Gy Dose Volume
123-MAR-PPP rev. 0
1000 Gy Dose Volume
Kennedy A. Personal Communication.
Liver Tolerance & Tumour Sensitivity to Radiation
SIRT
RILD – Radiation-Induced Liver Disease
Gy: 20
30
Effective Dose:
Testicular Ca
Lymphoma
Myeloma
123-MAR-PPP rev. 0
40
50
60
70
80
90
100
Curative Doses:
Adenocarcinoma
Preoperative
Radiation:
Rectal Ca
Kennedy et al. Int J Rad Oncol Biol Phys 2004; 60: 1520–1533.
12
1- Selective Internal Radiation Therapy (SIRT) or
radioembolisation for the treatment of
unresectable CRC liver metastases ?
2- How to Integrate radioembolisation in the
multi-modality treatment for liver-dominant
metastatic disease ?
Exclusion Criteria for SIRT/Radioembolisation
(relative contra-indications unless stated)
•
•
•
•
•
•
•
Ascites or other clinical signs of liver failure on physical exam [absolute]
Pregnancy
[absolute]
Previous radiation therapy to the liver
Excessive tumour burden with limited hepatic reserve
Compromised portal vein, unless selective/super-selective delivery is
performed
Capecitabine within previous or subsequent 2 months
Abnormal organ or bone marrow function as determined by:
–
–
–
–
–
total bilirubin level >2.0 mg/dL (>34 μmol/L) in absence of reversible cause
serum albumin <3.0 g/dL
AST (SGOT)/ALT (SGPT) >5 x institutional ULN
creatinine >2.5 mg/dL
platelets <60,000/μL; leukocytes <2,500/μL; absolute neutrophil <1,500/μL
Following work-up procedure:
• Pre-treatment scan showing >30 Gy exposure to the lungs
• Non-correctable shunting to the GI tract
123-MAR-PPP rev. 0
[absolute]
[absolute]
Kennedy et al. Int J Radiat Oncol Biol Phys 2007;68:13–23.
Consultation – Tumour Board
Medical Oncology Radiation Oncology
Surgical Oncology Nuclear Medicine
Interventional Radiology
Consensus for liver-directed therapy with 90Y-microspheres
1–2 weeks
Tumour mapping
Abdominal
CT and/or MRI
Liver-predominant disease
PreTreatment
Screening
Evaluations
1–2 weeks
Team reviews imaging,
proposed dose, planned
tumour volume, and
optimal catheter placement
for radioembolization
Vessel mapping
Hepatic angiogram,
protective embolization
of extra-hepatic vessels
and 99mTc-MAA scan
Safe delivery achievable
1 week
Delivery of 90Y-microspheres to
the planned treatment volume
same day
123-MAR-PPP rev. 0
Bremsstrahlung (gamma) scan
Post-implant QA documentation
Kennedy A et al.
Int J Radiat Oncol Biol Phys 2007; 68: 13–23.
Most Frequent Side Effects
AE
Incidence
Characteristics
Prevention/Action
>50%
mild / on
Tx day for up to 1 week
none normally
required
Abdominal
~50%
normally <24 h
acute during T
~10% grade 3–4
may require
iv analgesia
Nausea
~40%
<5% grade 3–4
frequent
normally <24 h
Fatigue
~40%
<5% grade 3–4
onset / 1st month postSIRT, normally
< 2 weeks
adequate nutrition &
hydration;
oral steroids
+++ if in combination
with CT ;
transient; resolves in
days (ALT, AST), weeks
(bilirubin) or months (alb.)
none normally
required
Fever
Abnormal
~20–40%
LFTs
1–6% grade 3–4
prophylactic anti-emetics
* CTC
123-MAR-PPP rev. 0
2.0
Studies of RadioEmbolisation as Salvage of mCRC
Author
- Van den
Eynde
Therapy
90Y-microspheres
+
5FU
5FU > salvage with 90Ymicrospheres at PD
n
ORR
SD
TTP/PFS
(mths.)
Survival
(mths.)
44
0%
0%
85%
35%
5.5/4.8
2.1
9.9
7.4
- Ricke
90Y-microspheres
Matched-pair BSC
29
29
n.r.
n.r.
n.r.
n.r.
5.5
2.1
8.3
3.5
- Cosimelli
90Y-microspheres
50
24%
24%
4
13
- Jakobs
90Y-microspheres
41‡
17%
61%
5.9
10.5
- Kennedy
90Y-microspheres
208‡
35.5%
55%
7.2
n.r.
10.5
4.5
responders
nonresponders/controls
‡
retrospective data
Van den Eynde et al. ASCO 2009; Abs. 4096; Ricke et al. WCGIC 2009; Abs PD-0002
Cosimelli et al ASCO 2008, Abstr. # 4078; Jakobs et al, J Vasc Interv Radiol 2008; Kennedy et al. Int J Radiat Oncol Biol Phys 2006.
90Y-microspheres
+ Chemotherapy (1st-line mCRC) does
improve outcomes in 3 studies
Investigator
n
Treatment
ORR
TTP/†PFS
Survival
Gray
74
HAC + 90Y-microspheres
HAC (FUDR)
44%
18%
15.9 mo
9.7 mo
39% at 2 yr
29% at 2 yr
van Hazel
21
5FU/LV + 90Y-microspheres 91%
5FU/LV
0%
18.6 mo
3.6 mo
29.4 mo
12.8 mo
Sharma
20
FOLFOX4 +
90Y-microspheres
9.2 mo†
14.2 mo*†
nr
phase II/III studies using FOLFOX4
statistically significant data
nr: not reported;
90%
27–59% 7.6–9.2 mo† 16.2–20.7 mo
*
in patients with liver-only disease
Gray et al. Annals Oncology 2001; 12: 1711–1720. van Hazel et al. J Surg Oncology 2004. 88: 78–85.
Sharma et al. J Clin Oncology 2007; 25: 1099–1106. Madajewicz et al. ASCO GI 2005; Abs 220.
De Gramont et al. ASCO 2004; Abs 3525. Kalofonos et al. Annals Oncology 2005; 16: 869–877.
90Y-microspheres
+ intra arterial CT vs intra arterial CT
N= 74 pts with bilobar non resectable LM
RR : 44% vs 17% ; p=0.01 ;
Survival
(yrs)
Chemo + Sirt
1,2
1
Chemo
0,8
P< 0.01
0,6
0,4
0,2
90Y-microspheres
HAC
+ HAC
1
72 %
68 %
2
39 %
29 %
3
17 %
6.5 %
5
3.5 %
0
0
6
12
18
24 months
Median time to disease progression:
9.7 vs 15.9 months (p<0.01)
Overall survival: trend
for a benefit ... but NS
Gray et al, Ann Oncol 2001
90Y-microspheres
+ 5FU/LV in mCRC:
Overall Survival
n = 21
1
5FU/LV +
Median Survival
90Y-microspheres
29.4 months
Proportion surviving
5FU/LV
12.8 months
Hazard Ratio 0.33 (95% CI 0.12–0.91); P =0.025
0.8
0.6
0.4
0.2
0
0
6
12
18
24
30
36
Months from randomisation
MAR-PPP-0003 rev. 1
van Hazel et al. J Surg Oncol 2004; 88: 78–85.
90Y-microspheres
+ iv CT vs iv CT ; Prospective randomized
study
- Hepatic intra-arterial Yttrium-90 microspheres + protracted IV 5FU vs
- 5FU CI alone for liver-limited metastatic CRC refractory to standard CT
Randomize
90Y
resin microsphere on day 1
(D1) Cycle 1 (C1)
+
5FU 300 mg/m²/day D1-D14 q3w
continuous IV infusion
Until progression
90Y
5FU 225mg/m²/day D1-D14 (1) and
300 mg/m²/day D1-D14 q3w
thereafter continuous IV infusion
Until progression
resin microspheres
Van den Eynde et al. ASCO 2009, J Clin Oncol 2009; 27 (Suppl 7s): Abs. 4096.
Colorectal Cancer – Salvage Therapy
Primary Endpoint using 90Y as Salvage Therapy
Time to Liver Progression, median
5FU
2.1 months
5FU + 90Y-microspheres 5.5 months
HR 0.38; 95% CI: 0.20–0.72; p=0.003
Van den Eynde et al. ASCO 2009, J Clin Oncol 2009; 27 (Suppl 7s): Abs. 4096.
90Y-microspheres
+ 5FU/LV in mCRC:
Patient Assessment of Quality of Life (FLIC questionnaire)
Median FLIC Score
Better
150
5FU/LV (baseline
145
5FU/LV +
)
90Y-microspheres
(baseline)
P =0.03 at 3 months
140
135
130
125
120
115
110
Worse
Baseline
Patient data (n)
5FU/LV
7
SIRT
10
3
6
9
12
15
18
21
24
27
2
1
Time from Randomization (months)
5
8
3
8
1
3
6
6
3
4
van Hazel G et al. ASCO GI 2009; Abs 419.
90Y-microspheres
+ iv CT vs iv CT ; Results
- Hepatic intra-arterial Yttrium-90 microspheres + protracted IV 5FU vs
- 5FU CI alone for liver-limited metastatic CRC refractory to standard CT
• Median TTP(liver), mths.
5FU, n=23
5FU + 90Y, n=21
2.1
5.5
HR 0.38
(0.20 – 0.72), p=0.003
2.1
• Median TTP, mths.
4.6
HR 0.51
(0.28 – 0.94), p=0.03
7.4
• Median OS, mths.
9.9
HR 0.92
(0.47–1.78), p=0.80
• Stable disease, n (%)
8 (35)
18 (85)
p=0.001
• Worst toxicity per patient,
Grade 3/4, n (%)
8 (35)
1 (4)
p=0.02
Van den Eynde et al. ASCO 2009, J Clin Oncol 2009; 27 (Suppl 7s): Abs. 4096.
Selective internal radiation therapy for liver metastases from CRC.
Townsend A, Price T, Karapetis C.
Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007045
• Cochrane Central Register of Controlled Trials (CENTRAL),
MEDLINE
(1966 to 2008), EMBASE, + Pubmed (October 2008) + proceedings of ASCO + ASCO GI.
• SELECTION CRITERIA: Randomised controlled trials on SIRT +/- chemotherapy
(CT).
• DATA COLLECTION AND ANALYSIS: individual patient data ; analysed
•
separately for pts with and without extra-hepatic disease.
MAIN RESULTS:
– one study of 21 pts : SIRT + systemic CT (FU/FA) vs CT alone =>
significant improvement in PFS & OS with SIRT (total population
& M limited to the liver)
– one study of 63 eligible pts compared SIRT + IAH floxuridine vs
IAH alone=> NS in PFS & OS with SIRT (total group or for disease
limited to the liver).
– There is no randomised studies comparing SIRT vs best
supportive care and no in pts with resectable liver metastases.
Selective internal radiation therapy for liver metastases from CRC.
Townsend A, Price T, Karapetis C.
Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007045
AUTHORS' CONCLUSIONS:
« There is a need for well designed, adequately powered phase III
trials assessing the effect of SIRT when used with modern
combination chemotherapy regimens ».
« Further studies are also needed for patients with refractory
disease with a particular focus on the impact on quality of life. »
Radioembolisation in CRC : conclusions
• RCT of radioembolisation using 90Y microspheres+ 5FU is
efficient vs. 5FU alone in salvage therapy of patients with
colorectal liver metastases in one limited phase III study
• There are other indirect evidences that radioembolisation
may have a beneficial effect on tumor growth for carefully
selected patients with isolated unresectable LM.
• Local complications (gastric, hepato-biliary) may exist in case
of inappropriated technique.
• Even if radioembolisation is now available in many countries
• Need for complementary well conducted randomized trial:
SIRFLOX (folfox +/- 90Y-microspheres)
+ FOLFOX4 in mCRC:
CT Response
90Y-microspheres
Patient 2: Baseline CT scan pre-SIRT
Patient 2: CT scan 6 months post-SIRT
MAR-PPP-0004 rev. 1
Sharma et al. WCGIC Ann Oncol 2006;17(Sup 6):vi78 Abs P-191. Data on file; Sirtex Medical Limited.
First-line Treatment of mCRC: Overall Survival
in Randomised Studies
chemotherapy + biologicals
ns
ns
P=0.001
ns
ns
P=0.06
P<0.025
29.4
30
capecitabine 5FU/LV vs.
IFL vs.
vs. XELIRI
FOLFIRI
IFL/Bev vs.
[seq vs. comb] vs. FOLFOX 5FU/LV/Bev
EHD (%)
Immature data
5FU/LV + 90Y microspheres †
5FU/LV
12.8
Not quoted
FOLFIRI [KRAS wild type]
FOLFIRI + Cetuximab
21.0
19.9
18.6
FOLFIRI
5FU/LV + Bev
IFL + Bev
IFL
FOLFOX
FOLFIRI
0
5FU/L
V
5
XELIRI
10
21.3
XELOX/FOLFOX + Bev
15
XELOX/FOLFOX
20
20.3
19.9
16.7
18.3
15.6
17.4 13.9–
16.3
15.4
15.2
FOLFIRI + Cetuximab [KRAS wild type]
24.9
25
capecitabine
Median overall survival (months)
35
chemotherapy + SIRT
FOLFOX
or XELOX
+ Bev
FOLFIRI
+ Cetuximab
FUDR +
5FU/LV +
FOLFOX4 +
90Y†
90Y †
90Y †
(CAIRO 1)
(n = 820)
(FOCUS 2)
(n = 2,135)
(Hurwitz et al 3,4)
(n = 923)
(NO16966 5)
(n = 1,401)
(CRYSTAL 6)
(n = 1,198)
(Gray et al 7)
(n = 74)
(van Hazel
et al 8)
(n = 21)
(Sharma et al 9)
(n = 20)
29%
not stated
not stated
not stated
21%
0%
24%
65%
FOXFIRE & SIRFLOX Studies: Design
Patients
recruited
Stratified by:
• institution;
• presence of EHD, no./site of mets;
• extent of liver tumour involvement
(<25%; >25%).
Randomisation
Arm A:
FOLFOX
chemotherapy alone
Arm B:
FOLFOX
chemotherapy + 90Ymicrospheres
SIRFLOX + FOXFIRE = 810 patients
Study Objectives
SIRFLOX
•
FOXFIRE
Primary endpoints:
– Progression Free Survival
•
– Overall Survival (810 patients)
Secondary endpoints:
– Overall Survival
–
–
–
–
–
–
Progression Free Survival
– % receiving 2nd-line Tx
– Interval: randomn to 2nd-line Tx
– Healthcare costs/health econ.
Response Rate
Resection Rate
Quality of Life
Safety and Toxicity
Liver-specific Progression Free Survival
Colorectal Cancer – Salvage Therapy
Patient’s Profile for Salvage RadioEmbolisation
- Unresectable Liver-dominant,-only disease
- Acceptable Life expectancy (> 12 weeks)
- Adequate Performance Status (ECOG/WHO 0-2)
- Resistant to chemotherapy and/or biologicals
- Limited shunting based on MacroAggregated Albumin scan
- Adequate liver (bilirubin < 2.0 mg/dl), renal (creatinine < 2.5 mg/dl)
and marrow function (platelets > 60,000/µL; leucocytes > 2,500/µL;
neutrophils > 1,500/µL)
Where should 90Y-microspheres be
considered?
•
•
•
•
Salvage therapy
K-RAS-mutant liver predominant
–
First-line FOLFOX + bevacizumab 3 months
–
Not sufficiently down-sized for liver resection
–
Use 90Y-microspheres to try to convert to resection/RFA
K-RAS-wild type liver predominant
–
First-line FOLFOX + cetuximab 3 months
–
Not sufficiently down-sized for liver resection
–
Use 90Y-microspheres to try to convert to resection/RFA
First-line patients not suitable for bevacizumab or
cetuximab
General Conclusions and Future Projects
1. 90Y-microspheres are effective and feasable as
salvage therapy in liver-dominant CRC and
prospective trials will precise its place in our
“armament”.
2. 90Y-microspheres -related toxicity is manageable.
3. Future projects are in progress to better define the
place of 90Y-microspheres in the current
management of mCRC, mNET and other liver
metastases
•
•
•
Front-line treatment
Maintenance treatment
Bridge to surgery
Thanks !
• Marc Peeters, University Hospital, Gent,
Belgium
• Ricky Sharma, Gray Institute for Radiation
Oncology & Biology, Univ. Oxford, UK
• Harpreet Wasan, Imperial College
Healthcare NHS Trust, London, UK
For their help and advises