1. RTOG1106: Randomized Phase IIR Trial of Personalized Adaptive Radiotherapy Based on Mid-treatment FDG-PET in Locally Advanced NSCLC P.I.: Feng-Ming (Spring) Kong, M.D., Ph.D. Study Team Mitchell Machtay, M.D. Jeffrey D. Bradley, M.D. Jean Moran, Ph.D. Vera Hirsh, M.D. Barry Siegel, M.D.

2. RTOG 1106/ACRINxxxx Estimated Sample size: ~120 patients (85% power to detect 20% difference in 2-yr. local PFS) RTOG 0617 arm: Standard dose script Study arm: Individual adaptive RT

3. Treatment including Radiation Therapy post-treatmentoutcome Weeks to months Months to years The Traditional Approach CT PET 1-3 months Background - 1

4. ACRIN 6668/RTOG 0235: FDG-PET REGISTERREGISTER FDG- PET with SUV Chemo-RT +/- ‘adjuvant’ chemo Eligibility Stage III NSCLC plan for conc. chemo-RT PS 0-1 Primary Endpoint: Survival as a function of post-RT SUV Sample Size: 250 FDG- PET with SUV 2-3 months after XRT

5. ACRIN 6668/RTOG 0235 Update Activation Date: 3/1/2005. Closed to Accrual: 5/15/2009. Total Accrual: 251 pts.  236 verified eligible (94%). Total # Participating Sites: 37. Central Review in Process.  Qualitative, SUV peak, MTV Primary Outcome Analysis in Early/mid 2011.

6. RTOG 0515 Results Exploratory trial of pre-Tx FDG-PET for XRT planning N=47 VariableCT OnlyPET/CTDifferencep Mean GTV (cc)98.786.2-12.5%<0.0001 Mean # involved nodes 2.12.414%0.41 Mean Lung dose (Gy) 19 Gy17.8 Gy-6%0.06 Mean esophageal dose (Gy) 28.7 Gy27.1 Gy-6%0.30 Bradley et al. ASTRO 2009

7. Hypotheses Use of mid-treatment FDG-PET is as useful or more useful than pre-RT FDG-PET and/or 3- month post-RT PET. Mid treatment PET can be used to individualize (and escalate) XRT dose will result in improved outcomes (2-yr. LPFS) compared with standard XRT.

8. Treatment including Radiation Therapy post-treatmentoutcome Weeks to months Months to years The Traditional Approach CT PET 1-3 months Post-RT PET response is highly correlated with pathologic response. Post-RT PET is predictive of long term survival and pattern of failure (Mac Manus et al, 2003) RTOG235/Acrin688 results awaited. However, post-RT PET tumor response does not provide an opportunity to change the treatment plan. When should PET be done?

9. PET during RT? PET scan can be performed during-RT  University of Michigan study, ASTRO 2005  MAASTRO study, ASTRO 2005  Stanford study, ASTRO 2007  Princess Margaret Hospital, ASTRO 2008 UM has demonstrated that PET response at 45 Gy during-RT was highly correlated with post-RT response in a small pilot study. The above finding has been recently validated in another 50+ patients from Michigan. Kong et al, JCO, 2007

10. Individualized RT Escalation Is Feasible Michigan trial usees PET-MTV guided isotoxicity adaptive plan to escalate tumor dose:  30 daily treatments, 2.2-3.8 Gy per fraction, 66 Gy~85.5 Gy  To NTCP of 17% (mean lung dose 20 Gy), with concurrent and adjuvant carbo and taxol, maximum at102 Gy in 2 Gy equivalent dose for lung (=ED2) (92 Gy ED2 for tumor). 14 patients completed treatments per study, all patients treated >74 Gy ED2 (median=92 Gy for tumor), majority of them received the maximum dose. 6 patients followed up for 1.5 years, no local failure thus far, 2 brain mets, only 1 death thus far from GI bleeding (gastric and esophageal ulcers).

11. Tumor Response During-RT Pre- RT Heart Heart Tumor Tumor Tumor Tumor During-RT at 45 Gy Example-1

12. CT-lunGwindowCT-mediastinum window FDGPET Pre-RT During-RT 3 mo post 9 mo post 16 mo post UM002 MTV: 353 cm 3 GTV: 468 cm 3 GTV: 402 cm 3 MTV: 268 cm 3 GTV: 174 cm 3 MTV: 12 cm 3 This 48 YO male received 85.5 Gy (120 Gy BED) had grade 0 clinical toxicity thus far. He works full time now with heavy duty. Patient-2

13. FDG Activity & PET-MTV Reduction PET results during RT correlates well with post-RT results

14. PET-MTV Decreased More than CT-GTV CTPET Pre-RT During-RT During-RT 50 pts 88 tumors

15. Mid-course FDG-PET and PFS 1 Year Progression-Free Survival (Kong et al, ASTRO 2009)

16. Mid-course FDG-PET and Survival NSUV During-RT < 3.0 NSUV During-RT > 3.0 NSUV During-RT < 3.0 (Kong et al, ASTRO 2009) Overall Survival Local Progression Free Survival NSUV=tumor SUVmax/Aorta SUVmean.

17. Proposed RTOG/ACRIN Trial Followup to ACRIN 6668/RTOG 0235. FDG-PET during RT  Validate UM results  Study adaptive RT/dose escalation  Randomization to assess the efficacy of mid-treatment FDG-PET Opportunity to study a novel tracer (e.g. F-Miso) in limited institution sub-study.

18. RTOG 1106/ACRINxxxx Estimated Sample size: ~120 patients (85% power to detect 20% difference in 2-yr. local PFS) RTOG 0617 arm: Standard dose script Study arm: Individual adaptive RT

19. Secondary Aims To compare toxicity between such a PET image-guided adaptive dose escalation and conventional RT. To validate recent findings from a single institution that a tumor metabolic response during-RT predicts long term local tumor control, LPFS and overall survival. To perform a pilot study to assess whether a novel PET tracer (F-Miso) is more predictive than FDG-PET. To obtain blood and tissue samples to explore relationships between imaging findings, biomarkers and outcomes (both anti-tumor efficacy and toxicity).

20. FLT versus F-Miso FLTF-Miso Ease of use √√ Sensitivity relative to FDG Specificity relative to FDG √ Relevance to Radioresistance √ Which is the ‘better’ exploratory agent?

21. Other Issues Still to be Resolved ACRIN Co-PI TBA. Radiotherapy Fractionation issues. Randomization, stratification issues. Sample size for FLT/FMISO sub-study. Insurance company reimbursement for mid course PET.

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