Cyberknife for lung tumors : the first Belgian experience at CHU Liege and initiated research projects

Cyberknife for lung tumors:

the first Belgian experience at CHU-Liège

+ initiated research projects

(Philippe A. Coucke)

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

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

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

Treatment characteristics

Fiducials Xsight Lung Xsight spine 42 lesions 8 lesions 52 lesions

Dose : (prescribed at ~ 80%) ~ 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

Treatment characteristics

Mean

Median

Range

CI

conformality index

1.23

1.21

1.05 - 1.61

nCI

new conformality index

1.31

1.27

1.13 - 2.10

HI

1.26

1.25

1.25 - 1.30

N

Beams

156

150

52 – 263

72min

OAR dose contraints

Timmerman RD.

Early results

• Survival figures:

– Crude OS 96%

• Follow-up:

– FU-range: 3-17 months

– Median FU: 8.5 months

• Number of events:

• Comments:

Response evaluation

(early benchmarking on 67 patients with >3m follow-up)

~ 60 Gy

< 45 Gy

Complete response

+

Partial Response

41/48 (85%)

14/19 (74%)

Stable disease

_{7/48 (15%)}

_{1/19 (5%)}

No progression

_{48/48 (100%)}

_{15/19 (79%)}

Progression

_{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%

Initiated projects

1. Translational research:

– Predicting local response

– Predicting DFS

2. Health economic analysis:

– Markov models

3. Dosimetric comparison:

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

non-small 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

Trial design

• Bronchoscopy

– Biopsy for pathology and confirmation of NSCLC

– Laser micro-dissection for obtaining isolated tumor cells

• Double PET-CT:

– First :

in the context of CK® planning

– Second :

15 days after treatment

– Third :

90 days after treatment

• Cyberknife® treatment, standard technique

– 3 x 20 Gy (peripheral)

over 1 week

• Primary endpoints:

– Identify markers predicting:

• Local response after CyberKnife® treatment • Metastatic potential 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

FFPPRGD2

tracer binding to 



integrin in endothelial cells, to

visualize and possibly quantify angiogenesis near

hypoxic areas

The 18FFPPRGD2 tracer targets _v₃ integrin

_v₃ integrin is a trans-membrane receptor, located at the surface of endothelial cells and tumor cells. _v₃ 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.

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

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

early-stage NSCLC (costs based on CHU Liege data)

In euro

5 years

10 years

Cost

Utility

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%

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 - Prof. Philippe Lambin Aachen - Prof. Michael Eble

Liege - Prof. Philippe Coucke and team LOC (Limburg) - Dr Paul Bulens

• 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

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

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)

•

Explore further hypofractionation with different

techniques (the number of fractions heavily influences

the treatment costs)

ROCOCO – EuroCat

Radiation Oncology COllaborative

Acknowledgement:

In alphabetical order:

V. Baert,

M. Devillers,

N. Jansen, MD

L. Jánváry, MD

E. Lenaerts,

N. Withofs, MD