Transcript Cyberknife for lung tumors: the first Belgian experience at CHU-Liège + initiated research projects (Philippe A.

Cyberknife for lung tumors:
the first Belgian experience at CHU-Liège
+ initiated research projects
(Philippe A. Coucke)
Nicolas Jansen
History of CK in Belgium
• Construction of a dedicated
CK facility July-December
2009.
• Installation of the CK and
acceptance January-April
2010.
• Go live in end of April 2010.
• Shut down in July and
August (lack of competent
RTT’s during summer
holidays).
• In September 2011, >170
patients treated with the CK
Clinical data lung treatments
• Patient characteristics
• Treatment characteristics
• Early results
Selection criteria
• Treatment april 2010 - june 2011
– Minimum FU 3 months for present report
• Not candidates for surgery
– Older age
– Bad respiratory function
– Comorbidities
– Technically inoperable
Patient characteristics
Age (all patients)
Median 70
Mean 71
All lesions
(n=102)
Lesions with
histological
confirmation
Primary lung tumor
58
40 / 58
Recurrent primary
Or
Intrapulmonary metastasis from primary
20
13 / 20
Lung metastases from other primary
24
7 / 24
Patient characteristics - stage
Histologically confirmed primary
69%
40/58
Primary NSCLC T1N0M0/T1N1M0:
36/3
Primary NSCLC T2N0M0/T2N1M0:
11/1
Primary NSCLC T3N0M0:
4
Primary NSCLC T4N0M0:
1
Primary Small cell, limited disease
1
Treatment characteristics (1)
Technique : 3 fractions over one week (M-W-F)
Fiducials
Xsight Lung
Xsight spine
42 lesions
8 lesions
52 lesions
~ 60 Gy
Mean: 59 Gy
< 45 Gy
Mean: 44 Gy
Primary lung tumor
43 lesions
15 lesions
Recurrent primary
Or
intrapulmonary metastasis from primary
10 lesions
10 lesions
Lung metastases from other primary
18 lesions
7 lesions
Dose :
(prescribed at ~ 80%)
Total 102 lesions in 96 patients
Treatment characteristics (2)
CI
Mean
Median
Range
1.23
1.21
1.05 - 1.61
1.31
1.27
1.13 - 2.10
1.26
1.25
1.25 - 1.30
156
150
52 – 263
conformality index
nCI
new conformality index
HI
Homogeneity index
No Beams
Treatment duration
per fraction
including set up
72min
OAR dose contraints
Timmerman RD.
Semin Radiat Oncol. 2008 Oct;18(4):215-22.
Early results
• Survival figures:
– Crude OS
96%
• Follow-up:
– FU-range:
– Median FU:
3-17 months
8.5 months
• Number of events:
– Deaths
– Local progression
• Comments:
– Short follow-up
– Crude numbers!
– Limited patient number
4
4
Response evaluation
(early benchmarking on 67 patients with >3m follow-up)
Complete response
+
Partial Response
Stable disease
No progression
Progression
~ 60 Gy
< 45 Gy
41/48 (85%)
14/19 (74%)
7/48 (15%)
1/19 (5%)
48/48 (100%)
15/19 (79%)
0 (0%)
4/19 (21%)
Response assessment by PET-CT
Patients with pre-treatment PET-CT scan in treatment position : 99%
Response evaluation by PET-CT scan >4m after treatment : 82%
Patients with QoL documentation : 100%
Initiated projects
1. Translational research:
– Predicting local response
– Predicting DFS
2. Health economic analysis:
– Markov models
3. Dosimetric comparison:
– Within EUROCAT/ROCOCO
1. Research project in NSCLC
• To predict response using the
association of:
– Biological markers
– Imaging modalities
• A “single marker” is not reliable enough
in predicting response, whether local or
distant
Submitted to FNRS
Predictive response and outcome in
patients with early stage T1-T2 nonsmall cell lung cancer treated by
robotic CyberKnife®
• Promotors:
–
–
–
–
–
Prof. P.A. Coucke, Radiotherapy
Prof A. Noël, Laboratory of Biology of Tumor Development
I Struman, PhD, Molecular Biology and Genetic Engineering
Prof. L. Willems, Molecular and Cellular Epigenetics
Prof. R. Hustinx, Nuclear Medicine
Trial design
• Bronchoscopy
– Biopsy for pathology and confirmation of NSCLC
– Laser micro-dissection for obtaining isolated tumor cells
• Double PET-CT:
– First :
– Second :
– Third :
in the context of CK® planning
15 days after treatment
90 days after treatment
• Cyberknife® treatment, standard technique
– 3 x 20 Gy (peripheral)
– 3 x 15 Gy (central)
over 1 week
over 1 week
• Primary endpoints:
– Identify markers predicting:
• Local response
• Metastatic potential
after CyberKnife® treatment
after CyberKnife® treatment
– Possible markers :
• Angiogenesis
• Micro-RNA
• Circulating tumor cells
– Aim:
• To determine which early-stage NSCLC might be eligible
for
– Further dose-increase
– Adjuvant chemotherapy
• Secondary endpoints in the context of a
comprehensive “outcome” analysis:
– Prospective assessment of QoL after ablative
CyberKnife® treatment
• To define utilities to feed a Markov model
– Evaluation of crude costs
– Cost comparison to surgery and conventional
radiotherapy:
• Direct & indirect costs
• Cost/effectiveness
• ICER/Qualy
Markers to predict response:
• Angiogenesis
• marker for radiation response
• angiogenesis remodeling : marker for tumor
progression and metastasis.
• Hypoxic regions can be identified as markers of
radio-resistance and could possibly be specifically
“targeted” = dose painting
Markers to predict response:
• Angiogenesis evaluation before and after the
treatment
– Angiogenic factors in circulation (immuno-assays):
•
•
•
•
VEGF
bFGF
PDGF
Soluble VEGF-R1 , VEGF-R2 , VEGF-R3 (Endoglin - CD 105)
– Pre and post treatment PET-CT with 18FFPPRGD2
tracer binding to avb3 integrin in endothelial cells, to
visualize and possibly quantify angiogenesis near
hypoxic areas
The 18FFPPRGD2 tracer targets avb3 integrin
avb3 integrin is a trans-membrane receptor, located at the surface of endothelial cells and tumor cells.
avb3 integrin expression is possibly linked to invasiveness and metastatic potential.
A hot spot indicates potentially angiogenesis and may be used as an early marker of response.
It is an suitable marker for lung lesions, as there is no background signal in normal lung parenchyma.
Markers to predict response
• Micro-RNA:
– Search for miRNA signatures before
the treatment
– Follow the miRNA signature after
CK®, indicative of :
• Local recurrence
• Distant metastases
(retrospective study)
Markers to predict response
• Circulating Tumor Cells
– Changes in number of CTC
– Changes in phenotype of CTC
(laser micro-dissection to
isolate cells from initial tumor)
• Analysis of transcriptome
• Analysis of presence or
absence of specific mutations
2. The cost issue
Cost-utility analysis in medically inoperable
early-stage NSCLC
• Purpose:
– To compute cost-utility and cost-effectiveness ratios
– Help in policy decision to rationalize implementation and
reimbursement
• Method:
– Markov model
– Utility values and recurrence risks are collected from published data
and from prospectively collected data (QLQ-C30 and QLQ-C13)
– (Multivariate sensitivity analysis and simulations of non-normal
distribution of variability of input factors to evaluate validity of the
model)
Cost-utility analysis in medically inoperable earlystage NSCLC (costs based on CHU Liege data)
In euro
5 years
Cost
Utility
10 years
Cost
Utility
CK®
13.420
3,01
15.599
4,57
3D-CRT
8.329
2,82
9.897
3,83
ICER
26.795 /QALY
7.705 /QALY
ICER
=
incremental cost-effectiveness ratio
QALY
=
quality adjusted life year
Base case scenario :
- patient 67yrs
- LR probability at 3 years 12% vs 37%
- RR probability at 2 years 9%
3. Dosimetric comparisons
ROCOCO – EuroCat
Radiation Oncology COllaborative
COmparison
In Silico clinical trial in early stage Non Small Cell Lung
Cancer, comparing 3DCT, IMRT, SBRT, Cyberknife
and Arc Therapy: a multicentric planning study based
on a reference dataset of patients
Maastricht
Aachen
Liege
LOC (Limburg)
Eindhoven
-
Prof. Philippe Lambin
Prof. Michael Eble
Prof. Philippe Coucke and team
Dr Paul Bulens
Dr Katrien De Jaeger
ROCOCO – EuroCat
Radiation Oncology COllaborative
COmparison
• More sophisticated techniques (RapidArc or
Cyberknife) as compared to more
conventional radiotherapy (IMRT or 3DCT) :
– are likely to have a lower complication rate (at
least 10%)
– will have higher tumor control rates (at least
10%) on moving tumours (but not on non
moving tumours)
ROCOCO – EuroCat
Radiation Oncology COllaborative
COmparison
Primary endpoints (purely dosimetrical) :
– Lung:
V30, V20, V13, V5
mean lung dose (MLD)
– Spinal cord: Dmax
– Esophagus: Dmax, mean dose (MD), V55, V35
– Heart:
total dose (TD), MD
V65,V45, V40, V30, V20, V10
– Large vessels and main bronchi: Dmax
– Integral dose
– Low dose areas/volumes
ROCOCO – EuroCat
Radiation Oncology COllaborative
COmparison
Secondary endpoints:
•
NTCP (normal tissue complication probability)
calculation based on exposure of organs at risk, using
the Lyman models for pneumonitis, oesophagitis, etc.
•
Explore dose escalation by irradiating at an isotoxic
level will be explored in order to increase tumor control
probability (TCP) based on normal tissue dose constraints used for all
plans.
•
Explore further hypofractionation with different
techniques (the number of fractions heavily influences
the treatment costs)
Acknowledgement:
In alphabetical order:
V. Baert,
M. Devillers,
N. Jansen, MD
L. Jánváry, MD
E. Lenaerts,
N. Withofs, MD
…and others
physicist
physicist
radiation oncologist
radiation oncologist
physicist (HEA)
nuclear medicine