Control Theory to Manage Spatial and Temporal Biologic Changes

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1 5 th AAPM Meeting Houston, July 8 Control theory and tumor radiobiology Control theory: a theory that deals with influencing the behavior of dynamical systems Control Theory to Manage Spatial and Temporal Biologic Changes Wikipedia Søren M Bentzen, Ph.D., D.Sc. Departments of Human Oncology; Medical Physics; Biostatistics and Medical Informatics, UW Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, USA To what extent is this a useful framework for developing biological adaptive radiation therapy? bentzen@humonc.wisc.edu Control theory and tumor radiobiology Tumor response to fractionated radiotherapy as a dynamic system From discrete volumes to D maps 6 Cu-ATSM scan - UW PET map RT planning & delivery RT PET map Modified Prescription Bioeffect model Wikipedia Do we have an appropriate PET tracer? And if so, what should a desirable PET map look like? ~98 ~99 8+

2 Dose-painting by numbers Dose painting by numbers Frequency SUV Normo-oxic Anoxic 6 Cu-ATSM Dose in 5 F (Gy) Bentzen Lancet Oncology 6: (5) Bowen et al. (in preparation) Flynn et al. Phys Med Biol 5: 45 (8) Change in TCP from biological targeting Model-based dose painting Analytical population-based TCP model: Difference in TCD-5 (Gy) % 5% 5% -compartment model OER is parameterized following Wouters and Brown (997) Redistributed dose (Gy) K m is the oxygen pressure where OER =.5 x OER max Bentzen Cancer Treat Res 9: 4 (8) Søvik et al. Phys Med Biol 5: 449 (7)

3 Control theory and tumor radiobiology Tumor response to fractionated radiotherapy as a dynamic system What s the reference output? Ideally: clonogen density! PET map RT planning & delivery Wikipedia Do we have an appropriate PET tracer? And if so, what should a desirable PET map look like? RT Modified Prescription Bioeffect model PET map Brahme and Ågren (987) showed that the optimal dose map before each fraction produces iso-survival after this fraction BUT No current surrogate for clonogen density Clongen surrogate: Is it FDG PET? FDG PET is the workhorse in staging, response evaluation, and experimentally for auto-contouring of GTV s Phase I/II trials of boosting FDG avid regions (DeNeve et al.) in Attempts to estimate radiosensitivity (α eff ) from repeat FDG scans (Alber) FDG uptake in breast tumors 55 breast cancer patients scanned peroperatively followed by immuhisotchemistry & histopathological evalauation FDG uptake correlated with glucose transporter (Glut-) expression (P <.), mitotic activity index (P =.), amount of necrosis (P =.), number of tumor cells/volume (P =.9), expression of hexokinase I (P =.9), number of lymphocytes (P =.), microvessel density (P =.5) Bos JCO : 79 ()

4 FDG PET response prediction in esophageal cancer Systematic review of studies including a total of 4 patients receiving pre-operative chemoradiation therapy (CRT) followed by surgery Post-RT inflammation & FDG PET Canine lung cancer patient scanned 6 weeks after fractionated radiotherapy Nine studies assessed FDG response AFTER (typically -6 weeks) CRT Generally good predictive accuracy for pathological response Two studies assessed FDG response DURING (after or weeks) CRT Wiederer et al. (4) found a correlation between change in SUV and pathological response in 8 patients Gillham et al. (6) found NO such correlation in a series of patients Gillham et al. World J Surg Oncol 5: 97 (7) Thanks to Lisa Forrest and Robert Jeraj Meta-analysis of po in P=.5 Oxygenation, then? Overall survival (%) Well-oxygenated Hypoxic Eppendorf polarographic electrode measurements 45 patients with clinical stage III-IV 7 centres: Aarhus, IGR Paris, Stanford, Duke, Halle, Heidelberg, Munich. Follow-up (years) Nordsmark, Bentzen et al. R&O 77: 8 (5) 4

5 Hypoxia dose painting (IMPT) Clinical outcome vs. PET hypoxia imaging Tracer Tumor site Sample size, N Hypoxic descriptor Clinical endpoint Significance of association Reference 7 Max T/B, FHV Survival T/B: P=.6 FHV: P=. Rajendran 6 Max SUV Local relapse P=.45 Thorwarth 6 * h and 4h Clinical response h: P=.6 4h: P=.4 Eschmann 5 45 Qualitative consensus score by two blinded observers Clinical response after chemoradiation therapy ± tirapazamine Significant interaction between hypoxic status and response to tirapazamine Richin 5 NSCLC 8* h and 4h Clinical response h and 4h: P=NS Eschmann 5 gliomas 4 uptake (yes/no) Survival P=. Cher 6 FETNIM FHV Survival P=.4 Lehtio 4 8º IMPT Arc Cu-ATSM Cu-ATSM NSCLC Uterine cervix 4 8 Mean T/M T/M>.5 Clinical response PFS and causespecific survival (CSS) P=. PFS: P=.6 OS: P=.4 Dehdashti Dehdashti 8 8 F-MISO PET assessed reoxygenation Hypoxia signaling: HIF-α pathway Locally advanced NSCLC Koh et al. IJROBP : 9 (995) AL Harris Nat Rev Cancer : 8 () 5

6 HIF-α and CA-9 in 98 pts from CHART trial Loco-regional control (% ) HIF (-) / CA9 (-) HIF (+) / CA9 (-) HIF (-) / CA9 (+) HIF (+) / CA9 (+) 9% 9% So, how about proliferation? % 9% Follow-up (years) Koukourakis, Bentzen et al. JCO 4(5): 77 (6) 8 F-FLT: a PET surrogate for proliferation FDG and FLT scans at baseline in patient with NSCLC 8 F-labeled -deoxy--fluorothymidine (FLT) is a thymidine analogue used as a PET surrogate for proliferation FLT is not incorporated into DNA Retained in cells after phosphorylation by the thymidine kinase (TK) enzyme TK is expressed in late G and S phase FLT uptake is a surrogate for tumor cell growth fraction FDG FLT UW Madison Clinical correlation 8 F-FLT v. Ki-67 Tumor site Lung Lung Lung Lung NSCLC Esophagus Lymphoma Lymphoma Head and neck Breast Colorectal Sample size (regions) 6 (5) 8 5 (9) Correlation coefficient P-value. <. <... n.s. <.5 <. n.s. <. <. Author Vesselle Buck Buck Yap 6 Yamamoto 7 Van Westreenen 5 Wagner Buck 6 Linecker 8 Kenny 5 Francis 6

7 Cell Cycle Effects of Radiation Control hours Control hours Gray hours T pot as a predictor in? Study No. of pts. Cut-point Method P value Begg et al, d Median. Cooke et al, d Median.96 Wilson et al, 995 6? Median NS Nylander et al, d Median. Corvo et al, d Median.4 Antognoni et al, d Median NS Eschwege et al, d Mean NS Zackrisson et al, d Median <.5 Struikmans et al, d Mean. Hoyer et al, d Median.48 Begg et al, d Quartiles.8 GDW Cancer stem cells? The modern view of the cell cycle The modern view of the cell cycle p5 +ve WAF p -ve cdk PCNA cyclin E cdc cyclin B S phospho rylation G M MAP kinase G p5 +ve B BAX +ve Cyclins Bcl- -ve A D,, +ve E G cdk4 cyclin D -ve Apoptosis EF Rb Rb P p6 Dirks Nature 444: 687 (6) G.D. SMBWilson 8/ 7

8 Ki-67 labelling and benefit from CHART Staining for EGFR LRCadvantage fromchart (pct. points) % -4% >4% 4 patients randomized to CHART v conventional RT Wilson et al. EJC 4: 6 (6) EGFR and strongly accelerated RT Anti-EGFR and 8 F-FLT EGFR index < median N=5 EGFR index > median N=8 A4 vulvar SCC xenograft Loco-regional control (%) P=.76 CHART Conv. Loco-regional control (%) Test for interaction: P<.5 P=.8 CHART Conv. Follow-up (years) Follow-up (years) Bentzen et al. JCO : 556 (5) Atkinson et al. Head and Neck : 79 (8) 8

9 NSCLC 8 F-FLT PET NSCLC 8 F-FLT PET & dose plan Mid-treatment ( wk of XRT) Mid-treatment ( wk of XRT) Pre-treatment Pre-treatment Prototypical imaging schedule Before During After Clinical outcome - week before RT - weeks into RT 5-8 weeks after RT years after RT Metabolism 8 F-FDG 8 F-FDG Local failure Proliferation 8 F-FLT 8 F-FLT Local failure Distant relapse Hypoxia 6 Cu-ATSM 6 Cu-ATSM Local failure Distant relapse BIOLOGICALLY ADAPTIVE RT? CONTROL THEORY? YES! NO SUITABLE SURROGATE TO BE USED AS A REFERENCE 9