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How to combine chemotherapy, targeted agents and radiotherapy in locally advanced NSCLC?

Dirk De Ruysscher, MD, PhDRadiation OncologistProfessor of Radiation OncologyLeuven Cancer InstituteDepartment of Radiation OncologyLeuven, Belgium

Combining chemotherapy andradiotherapy of the chest

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Better survival with concurrent chemo-radiotherapy vs. sequential (Pre-PET era; 2D radiotherapy…)

Aupérin et al. J Clin Oncol 2010

The overall survival benefit is associatedwith improved local control

Local tumour control better Same incidence of distantLocal tumour control better Same incidence of distantstill 30-40 % local progression metastases

Aupérin et al. J Clin Oncol 2010

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Most series used - 60-66 Gy in 2 Gy/day fractions, 5 times per week- Concurrently with

- cisplatin-etoposide (“optimal schedule unknown”)- cisplatin-etoposide ( optimal schedule unknown )- cisplatin-vinorelbine- carboplatin-paclitaxel

Much improvement is needed for systemic and local control

“Radioresistance does not exist”

Fowler et al. Int J Radiat Oncol Biol Phys 2004

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Radiation dose escalation withconcurrent chemotherapy andprolongation of the overall treatment time

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But,… RTOG0617 shows• That the OS with “current 60 Gy” is better than in the past (patient• That the OS with current 60 Gy is better than in the past (patient

selection, staging, imaging integration in radiotherapy planning, planning and delivery …)

• … which leads to “reasonable” median survival rates of 21 months

Dummy run shows that many centres could improve their results by emphasising the quality of the whole treatment chain!

Many ongoing dose-intensification trials

• Biological dose escalation dose intensification• Biological dose escalation dose intensification– Standard total doses, shorter overall time

• Individualisation– Physical– Biological, including molecular imaging

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Influence of overall treatment time of radiotherapy on survival in stage I-III NSCLC without concurrent chemo-radiotherapy

Mauguen et al. J Clin Oncol 2012

INDividualised Accelerated Radiotherapy (INDAR)

• Escalate the dose to the maximum tolerancethe maximum tolerance

• Delivered in a short overall treatment time

• Directed to areas that are 18F deoxyglucose (FDG) positive18F-deoxyglucose (FDG) positive

De Ruysscher et al. Int J Radiat Oncol Biol Phys 2008

Van der Wel et al. Int J Radiat Oncol Biol Phys 2005 De Ruysscher et al. Radiother Oncol 2005 De Ruysscher et al. Int J Radiat Oncol Biol Phys 2005

Van Baardwijk et al. Int J Radiat Oncol Biol Phys 2008

Van Baardwijk et al. Int J Radiat Oncol Biol Phys 2008

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T3N0M0 pT4pN2M0 pT4pN2M0 54 Gy/ 30 F/ 3 wks54 Gy/ 30 F/ 3 wks 79.2 Gy/ 44 F/ 4.4 wks79.2 Gy/ 44 F/ 4.4 wks

Survival by stage (large volume, multi-level N+, 25 % WHO PS 2), sequentialchemo-radiation

1,0

IIII A

II III B

Act

uaria

l ove

rall

surv

ival

0,8

0,6

0,4

st I

st II

st IIIA

st IIIB

time (months)4842363024181260

0,2

0,0

st II

van Baardwijk et al. J Clin Oncol 2010

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Individualised, accelerated iso-toxicradiotherapy with concurrent chemotherapyin stage III NSCLC

van Baardwijk et al. Eur J Cancer 2012

Median OS: 25 months; estimated 4-year survival: 30 %

Isolated local recurrence: 5 %; isolated regional recurrence: 4 %, combined local and regional recurrence: 5 %; distant relapse only: 27 % (57 % brain only)

Individualised, accelerated iso-toxicradiotherapy with concurrent chemotherapyin stage III NSCLC

Median OS: 33 months (2,7 years)

Median OS Region 7 nodal disease: 24 months Median OS for other nodes: not reached

Median OS: 55 months (4.6 years)

Single nodal stage cT4N0-1

Reymen et al. Submitted 2012

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Early response: FDG changes during first week of chemo-RT and survival

2y OS: 80%

• FDG-PET:– Cut-off: 15% (EORTC response)

2y OS: 34%

– Changes in maximum SUV and mean SUV significant predictivefor 2-year overall survival

• HR 1.26 (95% CI: 1.09 – 1.45) per 5% decrease of SUV

• CT (volume)– Tumour volume pre RT is

3,5 y OS: 63%

3,5 y OS: 28 %

p=0.010 (log rank)HR = 1.26 (95% CI: 1.09 – 1.45) per 5% decrease

predictive for survival• HR 1.040 (95% CI: 1.005 – 1.076)

per 10 cm3 increase– Change in tumour volume (CT) is

not correlated to survival

Van Elmpt W et al. J Nucl Med 2012

Conclusions• Radiotherapy to a dose of 60-66 Gy in 2 Gy per day, 5 days perRadiotherapy to a dose of 60 66 Gy in 2 Gy per day, 5 days per

weeks remains the standard when delivered concurrently withchemotherapy (arguments in favour of high-dose, acceleratedradiotherapy in non-concurrent schedules)

• Individualised (accelerated, isotoxic) radiotherapy schedules are being investigated in many clinical trials and are still of muchimportance

• Improvement the quality of the whole diagnostic and treatment chain most probably improves overall survivalchain most probably improves overall survival

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Combining targeted agents andradiotherapy of the chest

Rationale

• Improved local tumour control leads to increased overall survival at 5 years

• Dose-limiting organs (e.g. main bronchi, blood vessels, lungs, oesophagus, …) remain problematic for optimising radiation doseradiation dose

• Concurrent chemo-radiotherapy is toxic and for many patients already now too heavy [De Ruysscher et al. 2009]

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Rationale

Id ll t t ti i t ll l• Ideally agents targeting intracellular pathways that are know to modulate the RT response, enhancing tumour cell killing while having moderate effect on normal tissues should be considered in combination with thoracic RT

Koh et al. Cancer Treat Rev 2012

Choice of the drug does matter: Cetuximab, but not gefitinib, blocks nuclear transport of pEGFR.

Nyati MK et al. Nature Reviews Cancer 2006

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EGFR inhibition : Influence of cell line type

Gurtner et al. Radiother Oncol 2011

@EGFR (sc-03)

Uptake of Uptake of 8989Zr Zr –– cetuximab is heterogeneouscetuximab is heterogeneous

T47D

1

1,2

1,4

1,6

1,8

B ra

tio

(n = 6)

MAb-N-succinyldesferal-89Zr (MAb-N-sucDf-89Zr) (*)

48h p.i.A431

0

0,2

0,4

0,6

0,8

1h p.i. 4h p.i. 24h p.i. 48h p.i. 72h p.i. 96h p.i.

T/B

(*): van Dongen, Nuclear Medicine VUMC, The Netherlands

Aerts et al. J Nucl Med 2009

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Uptake of Uptake of 8989Zr Zr –– cetuximab is heterogeneouscetuximab is heterogeneous

EGFR IntermediateHT29

Liver

Heart

(48 hours after injection)Aerts et al. J Nucl Med 2009

General conclusions

• Combining radiotherapy with targeted agents: Highly rational

• Selection of patients, treatment technique of utmost importance

• Resistance mechanisms for targeted agents alone may not be the same whenagents alone may not be the same when these drugs are used as radiosensitisers

• Not yet in standard practice!