Combining chemotherapy and radiotherapy of the chest

Size: px

Start display at page:

Download "Combining chemotherapy and radiotherapy of the chest"

Randall Jacobs
6 years ago
Views:

1 How to combine chemotherapy, targeted agents and radiotherapy in locally advanced NSCLC? Dirk De Ruysscher, MD, PhD Radiation Oncologist Professor of Radiation Oncology Leuven Cancer Institute Department of Radiation Oncology Leuven, Belgium Combining chemotherapy and radiotherapy of the chest 1

2 Better survival with concurrent chemoradiotherapy vs. sequential (Pre-PET era; 2D radiotherapy ) Aupérin et al. J Clin Oncol 2010 The overall survival benefit is associated with improved local control Local tumour control better still % local progression Same incidence of distant metastases Aupérin et al. J Clin Oncol

3 Most series used Gy in 2 Gy/day fractions, 5 times per week - Concurrently with - cisplatin-etoposide ( optimal (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

4 Radiation dose escalation with concurrent chemotherapy and prolongation of the overall treatment time 4

5 But, RTOG0617 shows 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 Standard total doses, shorter overall time Individualisation Physical Biological, including molecular imaging 5

6 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 tolerance Delivered in a short overall treatment time Directed to areas that are 18F-deoxyglucose (FDG) positive Van der Wel et al. Int J Radiat Oncol Biol Phys 2005 Van Baardwijk et al. De Ruysscher et al. Radiother Oncol 2005 Int J Radiat Oncol Biol Phys 2008 Van Baardwijk et al. De Ruysscher et al. Int J Radiat Oncol Biol Phys 2005 Int J Radiat Oncol Biol Phys 2008 De Ruysscher et al. Int J Radiat Oncol Biol Phys

7 54 Gy/ 30 F/ 3 wks 79.2 Gy/ 44 F/ 4.4 wks T3N0M0 pt4pn2m0 Survival by stage (large volume, multilevel N+, 25 % WHO PS 2), sequential chemo-radiation 1,0 0,8 Actuarial overall survival 0,6 0,4 II III A III B I st I st IIIA st IIIB st II 0,2 0, time (months) van Baardwijk et al. J Clin Oncol

8 Individualised, accelerated iso-toxic radiotherapy with concurrent chemotherapy in stage III NSCLC 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) van Baardwijk et al. Eur J Cancer 2012 Individualised, accelerated iso-toxic radiotherapy with concurrent chemotherapy in stage III NSCLC Single nodal stage ct4n0-1 Median OS: 33 months (2,7 years) Median OS: 55 months (4.6 years) Median OS Region 7 nodal disease: 24 months Median OS for other nodes: not reached Reymen et al. Submitted

Early response: FDG changes during first week of chemo-rt and survival FDG-PET: Cut-off: 15% (EORTC response) Changes in maximum SUV and mean SUV significant predictive for

076) per 10 cm 3 increase Change in tumour volume (CT) is not correlated to survival Van Elmpt W et al. J Nucl Med 2012 2y OS: 80% 2y OS: 34% p=0.010 (log rank) HR = 1.

45) per 5% decrease 3,5 y OS: 63% 3,5 y OS: 28 % Conclusions Radiotherapy to a dose of 60-6666 Gy in 2 Gy per day,5days days per weeks remains the standard when delivered

9 Early response: FDG changes during first week of chemo-rt and survival FDG-PET: Cut-off: 15% (EORTC response) Changes in maximum SUV and mean SUV significant predictive for 2-year overall survival HR 1.26 (95% CI: ) per 5% decrease of SUV CT (volume) Tumour volume pre RT is predictive for survival HR (95% CI: ) per 10 cm 3 increase Change in tumour volume (CT) is not correlated to survival Van Elmpt W et al. J Nucl Med y OS: 80% 2y OS: 34% p=0.010 (log rank) HR = 1.26 (95% CI: ) per 5% decrease 3,5 y OS: 63% 3,5 y OS: 28 % Conclusions Radiotherapy to a dose of Gy in 2 Gy per day,5days days per weeks remains the standard when delivered concurrently with chemotherapy (arguments in favour of high-dose, accelerated radiotherapy in non-concurrent schedules) Individualised (accelerated, isotoxic) radiotherapy schedules are being investigated in many clinical trials and are still of much importance Improvement the quality of the whole diagnostic and treatment chain most probably improves overall survival 9

10 Combining targeted agents and radiotherapy 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 dose Concurrent chemo-radiotherapy is toxic and for many patients already now too heavy [De Ruysscher et al. 2009] 10

considered in combination with thoracic RT Koh et al.

11 Rationale Ideally agents targeting ti intracellular l 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

EGFR inhibition : Influence of cell line type

Radiother Oncol 2011 Uptake of 89 Zr cetuximab is

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

T/B ratio 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0 (n =

12 EGFR inhibition : Influence of cell line type Gurtner et al. Radiother Oncol 2011 Uptake of 89 Zr cetuximab is (sc-03) T47D MAb-N-succinyldesferal- 89 Zr (MAb-N-sucDf- 89 Zr) (*) A431 48h p.i. T/B ratio 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0 (n = 6) 1h p.i. 4h p.i. 24h p.i. 48h p.i. 72h p.i. 96h p.i. (*): van Dongen, Nuclear Medicine VUMC, The Netherlands Aerts et al. J Nucl Med

13 Uptake of 89 Zr cetuximab is heterogeneous Heart EGFR Intermediate HT29 Liver (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 when these drugs are used as radiosensitisers Not yet in standard practice! 13

Allan Price NHS Lothian, Edinburgh, UK

Allan Price NHS Lothian, Edinburgh, UK Radiotherapy Dose Volume Timing Technique PCI Surgery Systemic agents 1 Study Dose Time Induction CT Ann Arbor 65.1-75.6 Gy Duke 73.6-80 Gy RTOG 77.4 Gy 74 Gy 6.5-7.5