Conflicts of Interest

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1 Dose Constraints to Prevent Radiation-Induced Brachial Plexopathy for Unresectable Lung Cancer Amini A*, Yang J, Williamson R, McBurney ML, Erasmus J, Allen PK, Karhade M, Komaki R, Liao Z, Gomez D, Cox J, Dong L, Welsh J MD Anderson Cancer Center *UC Irvine School of Medicine Conflicts of Interest Authors have nothing to report. 1

2 History of Plexus Dose Constraints Emami et al (IJROBP 1991) 5% risk of plexopathy at 5 years: 1/3 of the plexus received 62 Gy 2/3 received 61 Gy 3/3 received 60 Gy 50% risk of plexopathy at 5 years: 1/3 of the plexus received 77 Gy 2/3 received 76 Gy 3/3 received 75 Gy Most studies since: 66 Gy The Problem Local Failure rates for NSCLC continue to be high (85%) with standard guidelines of concurrent chemo with 60 Gy in 2 Gy fractions Dose Escalation trials to control local disease But what about the Plexus? Purpose of Study Identify a threshold radiation dose at which plexopathy becomes evident with radiation delivered using modern-day techniques Look for possible contributing factors Address difficulties in contouring the brachial plexus consistently - - > Deformable Registry 2

3 Materials and Methods Retrospective analysis of 90 patients with superior sulcus tumors or those involving upper mediastinum and supraclavicular regions From March 2007 September 2010 Inclusion Criteria Minimum 55 Gy to 0.1 cm 3 Mimimum 4 months follow up Contouring the Plexus 3

4 Deformable Image Registration Deformable Image Registration 4

5 Grading of Plexopathy Common Terminology Criteria for Adverse Event (CTCAE) v4.03 Grade 1: minor clinical symptoms with no medical intervention Grade 2: moderate symptoms requiring pain medication with good response Grade 3: severe symptoms treated with multiple pain medications including neuropathic drugs or steroid injections Table 1. Patient Value or No. of Patients (%) Age median (range) 64 (33-85) Sex Female 41 (45.6%) Male 49 (54.4%) Disease stage I 6 (6.7%) II 5 (5.6%) III 69 (76.7%) IV 7 (7.8%) Limited 3 (3.3%) Tumor histology Squamous cell 33 (36.7%) Adenocarcinoma 34 (37.8%) NSCLC NOS 18 (20.0%) Other 5 (5.6%) Karnofsky Performance Status score (34.4%) (43.3%) < (22.2%) Smoking status Current 32 (35.6%) Former 50 (55.6%) Never 8 (8.9%) BMI median (range) 25.7 ( ) Diabetes Yes 15 (16.7%) No 75 (83.3%) 5

6 Table 2. Treatment and Outcomes Value or No. of Patients (%) Radiation dose, Gy median (range) 70( ) RT Treatment Photons 74(82.2%) Protons 16(17.8%) Concurrent Chemotherapy Yes 81(90.0%) No 9(10.0%) Max. Brachial Plexus Dose median (range) 0.1 cm 3 (Gy) 69.7( ) 0.5 cm 3 (Gy) 67.8( ) 1.0 cm 3 (Gy) 66.7( ) 2.0 cm 3 (Gy) 65.8( ) Median Dose to Plexus (Gy) median (range) 41.9( ) Plexopathy Before RT Yes 13(14.4%) No 77(85.6%) Plexopathy After RT None 76(84.4%) Grade 1 8(8.9%) Grade 2 4(4.4%) Grade 3 2(2.2%) Time to Plexopathy (mo) median (range) 6.5( ) Table 3. Dose Constraints and Plexopathy With Plexopathy Total OR 95% CI P-value Brachial Plexus Dose Max. Dose 0.1 cm 3 >75 Gy Gy 9 74 Max. Dose 0.5 cm 3 >75 Gy Gy Max. Dose 1.0 cm 3 >75 Gy Gy Max. Dose 2.0 cm 3 >75 Gy Gy Median Dose >75 Gy Gy Median Dose >69 Gy Gy Brachial Plexus Dose Constraints Median plexus dose at 69 Gy (p=0.005) >69 Gy: 60% (3/5) with plexopathy 69 Gy: 13% (11/85) with plexopathy Multivariate: OR , 95% CI

7 Brachial Plexus Dose Constraints Max. 2.0 cm 3 plexus dose at 75 Gy (p=0.038) >75 Gy: 43% (3/7) with plexopathy 75 Gy: 13% (11/83) with plexopathy Multivariate: OR 4.909, 95% CI Table 4. Patient and Risk for Plexopathy With Plexopathy Total OR 95% CI P-value Gender Male Female 6 41 Body Mass Index (BMI) > Diabetes Yes No Concurrent Chemotherapy Yes No 1 9 Plexopathy Before RT Yes No 9 77 Ferrante (Muscle Nerve 2004), Kori et al (IEEE Trans Med Imaging 2004), Burns et al (Clin Exp Neurology 1978) Study Limitations Brachial Plexus plans based on non-contrast CT images Dose limitations do not include those with hypofractionated regimens or surgical intervention Toxicity based on clinicians notes Low number of events 7

8 Conclusion Median dose to the brachial plexus should be maintained below 69 Gy Maximum dose to 2 cm 3 should be below 75 Gy Plexopathy before treatment is associated with greater risk of plexopathy after treatment Deformable Registry can be used to contour the brachial plexus and has potential to reduce variability Acknowledgements Dr. James Welsh Dr. Lei Dong Dr. Jinzhong Yang Ryan Williamson Michelle McBurney Dr. Jeremy Erasmus Dr. Pamela Allen Dr. Mandar Karhade Dr. Ritsuko Komaki Dr. Daniel Gomez Dr. James Cox Dr. Zhongxing Liao 8