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 characteristicsAge (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

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

Total 102 lesions in 96 patients

Treatment characteristics (2)

Mean Median Range

CIconformality index

1.23 1.21 1.05 - 1.61

nCInew conformality index

1.31 1.27 1.13 - 2.10

HIHomogeneity index

1.26 1.25 1.25 - 1.30

No Beams 156 150 52 – 263

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: 3-17 months– Median FU: 8.5 months

• Number of events:– Deaths 4– Local progression 4

• Comments: – Short follow-up – Crude numbers!– Limited patient number

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%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 FNRSPredictive 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– 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 : 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– 3 x 15 Gy (central) 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 18FFPPRGD2 tracer binding to v3 integrin in endothelial cells, to visualize and possibly quantify angiogenesis near hypoxic areas

The 18FFPPRGD2 tracer targets v3 integrin

v3 integrin is a trans-membrane receptor, located at the surface of endothelial cells and tumor cells.

v3 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 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 ratioQALY = quality adjusted life yearBase 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 - Prof. Philippe LambinAachen - Prof. Michael EbleLiege - Prof. Philippe Coucke and

teamLOC (Limburg) - Dr Paul BulensEindhoven - Dr Katrien De Jaeger

• 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)

ROCOCO – EuroCat

Radiation Oncology COllaborative COmparison

Acknowledgement:In alphabetical order:

V. Baert, physicist

M. Devillers, physicist

N. Jansen, MD radiation oncologist

L. Jánváry, MD radiation oncologist

E. Lenaerts, physicist (HEA)

N. Withofs, MD nuclear medicine

…and others