Radiation Biology & Future Trends of SBRT. SBRT: radiobiological modeling University of Colorado SBRT: snapshot of the program

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1 Radiation Biology & Future Trends of SBRT Brian D. Kavanagh, MD, MPH Department of Radiation Oncology University of Colorado Comprehensive Cancer Center Radiation Biology & Future Trends of SBRT SBRT: radiobiological modeling University of Colorado SBRT: snapshot of the program Future trends AAPM Annual Meeting, 2009 Radiation Biology & Future Trends of SBRT SBRT: radiobiological modeling University of Colorado SBRT: snapshot of the program Future trends image search: SBRT and modeling Sporty Beauty Reversible Black Leather And Mink Coat Aspenfashions.com [not sure about the T] Apt metaphor? Radiobiological modeling for SBRT is A sport, or at least a parlor game Sometimes beautiful Something that can be reversed at any time Often politically incorrect

2 On the other hand, if you do a Pubmed search: SBRT and modeling or something similar, you will retrieve Dozens of theoretical papers The vast majority purely mathematical, with dependence on a variety of assumptions Some respiratory motion models (different topic) Exactly 2 in vivo animal studies of tumor response and an in vivo normal lung model A few protocols structured in a prospective manner with a particular model in mind A few post hoc analyses of actual clinical results In vivo animal study #1: Lotan et al. J Urol. 2006;175(5): Human C4-2 prostate cells implanted in the flank of nude mice Stereotactically irradiated when palpable: control 3 x 5 Gy 3 x 7.5 Gy 3 x 15 Gy A very straightforward pattern of dose-response tumor volume (figure) [note our group have had trouble giving >6 Gy or so per fraction, but maybe technical] In vivo animal study #2: Walsh et al. Eur Urol. 2006;50(4): Walsh et al, Eur Urol, 2006 In vivo RCC study, continued A maturation of the response over time Above: at 4 weeks, still viable tumor cells Human A498 RCC cells implanted in the flank of nude mice Streotactically irradiated when palpable: control 3 x 16 Gy Below, at 7 weeks, much more necrotic

3 The currently trendy and possibly correct explanation: Tumor response to high dose radiotherapy is largely driven by endothelial cell apoptosis Fibrosarcoma and melanoma models Growth delay after RT influenced by apoptotic capacity Apoptosisincompetent Apoptosiscompetent In vivo large animal and human evidence of apoptosis after high dose/fraction RT Tumor endothelial apoptosis after 3 Gy or 18 Gy dingle fraction. Larue et al, Rad Res Mtg, 2008 (abst) Serum marker of apoptosis n =14 pts [to be presented at ASTRO Dose-dependence of percent apoptosis in endothelial cells Garcia-Barros et al, Science, 2003 Threshold? (L-R) control, 3 Gy fraction, 18 Gy fraction Green = normal endothelium Red = apoptosis Cai et al, A rabbit irradiation platform for outcome assessment of lung sterotactic radiosurgery, IJROBP 2009 Conventional wisdom: Extra caution is needed when near the proximal airways 3 New Zealand rabbits, 3x20 Gy to 1.6cc lung Interesting results: No change ventilation perfusion 2+ months later Note: a prior attempt by the IU group to create a rodent model of proximal airway stenosis was not successful Timmerman et al, J Clin Oncol, 2006 large proximal airways serial architecture

4 Caveats about the IU proximal lesion caveats Doses calculated without heterogeneity correction Tumor volume was also a significant predictor of toxicity (p = 0.017) Grade 5 toxicities: 4 cases of pneumonia Note that pts with medically inoperable NSCLC are susceptible to this event, regardless 1 pericardial effusion after treatment of a tumor adjacent to the mediastinum superior to the hilum. 1 Toxic death from a local recurrence 2 responses to the IU proximal airway report UT-SA experience (above) n=9; dose = 3x12 Gy No serious toxicity Median f/u 11 mos (range, 3-42) MD Anderson experience N = 27; dose = 4x Gy No serious lung toxicity Median f/u 17 mos (range, 6-40) 1 brachial plexopathy (>40 Gy/4 fxns) BELOW: from Joyner et al, Acta Oncol 2006; 45: LEFT: from Chang et al, IJROBP 2008; 72(4) Sample proximal lesion case: treatment plan Sample case, proximal tumor Planning scan Dose distribution Planning target volume in zone of proximal bronchial tree

5 Pre- vs. 12 mos post-sbrt Another example case Aug, 2008: 59yo F with h/o metastatic NSCLC s/p surgery/wbrt 1 year ago only current site of disease = 5cm mass in rt mid lung. plan: SBRT to rt lung mass Segmental/Lobar atelectasis One year later: cough, dyspnea Bronchoscopy: mucus plug cleared from RML bronchus Lateral segment RML bronchus: Narrow but patent after clearing Coronal reconstruction, CT scan Chest x-ray

6 This can also happen after hyper-fractionated RT Miller et al, IJROBP 61: 64-69, 2005 Pre- and post-bronch to clear mucus plug Models of Radiation Injury Applied Prospectively in SBRT Lyman-Kutcher-Burman v Critical Volume LKB Model Converts whole organ tolerance dose into estimate of complication based on partial volume irradiation 1 t 2 x / 2 NTCP( t) = e dx 2π t = ( D TD ( v) /( m TD ( v)) n TD ( v) = TD (1) v Critical Volume Model Initially for spinal cord, where there should be no complication if a minimum number of fibers are undamaged N NTCP( N, M, P 50 fiber ) = 50 i= M B P i N i fiber (1 P 50 fiber ) N 1 Stavreva et al. Int. J. Radiat. Biol 77(6): , 2001

7 LKB v Critical Volume Models in SBRT PMH Phase I Trial of SBRT for HCC Tse et al, J Clin Oncol 26: , 2008 Rationale Strengths Weaknesses LKB Robust performance in conventionally fractionated liver RT Familiarity Built into some planning systems Relies on converting high dose per fraction volumes into a biological equivalent; might be outside LQ model range Critical Volume Analogy to surgical experiences Simplicity based on absolute dose, lack of need for DVH conversion Initial assumptions based on educated (?) guesses LKB model based dose escalation V eff -based stratification Eg, planned to go from 9 to 9.5 to 10 Gy/fxn for low V eff group, increasing projected rate of RILD from % RILD = anicteric hepatomegaly, ascites, elevated alkaline phos Definition of Veff [which I could not recite the last time I tried, so I am writing it down!] The effective liver volume (Veff) irradiated is defined as the normal liver volume, minus all GTVs, which if irradiated uniformly to the treatment dose would be associated with the same risk of toxicity as the non-uniform dose distribution delivered PMH Phase I HCC SBRT, methods JCO 26: , 2008 Technique 3-10 beams 6-18MV, breath hold Max to GI tract, 30 Gy to 0.5cc; max cord 27 Gy; max heart 40 Gy CTV = GTV+8mm, PTV = CTV+5mm or more IGRT with MV images of diaphragm as surrogate or CBCT Patient population 31 HCC, 10 IHC All Child-Pugh A Median PTV, 173 cc Median dose 36 Gy (24-54 Gy) /6 fractions/ 2 wk

8 PMH Phase I HCC SBRT, results JCO 26: , 2008 Toxicity No cases of RILD Though 7 pts progressed to Child-Pugh B 2 IHC pts with transient obstruction presbrt steroids recommended Patterns of failure (figure) Median OS: HCC, 23 mos IHC, 15 mos Eligibility 1-3 liver metastases Solid tumors No tumor diameter >6cm Liver and kidney function OK t bili <3 mg/dl, alb > 2.5 g/dl Liver enzymes <3xULN No ascites No systemic therapy within 14 days pre- or post-sbrt SBRT Dose Phase I escalation to 20 Gy x 3 20 Gy x 3 fractions for Phase II J Clin Oncol U. Colorado/Multi-center Phase I/II Liver SBRT Trial Methods Breathing motion control via breath hold or abdominal compression Generally frameless setup Target delineation: GTV based on CT +/or MRI fused to planning scan CTV = GTV PTV = GTV+ 5-7mm radial, 10-15mm sup-inf Arcs or multiple non-coplanar static beams Prescription 70-90% isodose line Image guidance with stereo kv images augmented by verification CT scan on d1 Liver and Non-liver Protocol Dose Volume Constraints Non-liver: Total kidney volume > 15 Gy to be < 35% Max spinal cord dose 18 Gy Max dose to stomach or intestine 30 Gy Later, max point to skin <21 Gy Modified critical volume method for liver: At least 700 cc had to receive < 15 Gy

9 Results: (1) no severe liver toxicity (2) tumor volume effect Phase II Results, Toxicity No RILD, no Gr 4-5 toxicity of any kind 1 case of grade III soft tissue toxicity 1 grade 3 skin toxicity due to inadvertent subcutaneous hotspot Insufficient number of fields Figure 2a: Actuarial Local Control Figure 2b: Actuarial Local Control by Size Local Control Local Control cm >3cm Months Months Lesions 49 at risk : cm : cm : Photo taken 8 mos after SBRT At last followup 17 post-sbrt, lesion controlled. Necrosis is slowly healing. Non-protocol patient: max pt to stomach >10 Gy/fxn A few post hoc analyses of actual clinical results Pale, denuded mucosa; progressed to ulceration but eventually healed in approx 3 mos A liver SBRT analysis Analyzing transient total liver volume reduction 2 lung SBRT analyses Analyzing incidence of chest wall pain and/or rib fracture

10 Typical post-sbrt normal liver image a few mos after SBRT Macroscipic effect: transient normal liver volume reduction Schefter et al. IJROBP 62(5) , 2005 Figure from Kavanagh et al. Stereotactic Irradiation of Tumors outside the Central Nervous System. In Principles and Practice of Radiation Oncology, 5th ed., Lippincott, Williams & Wilkins, Liver V30 and Mean dose versus percent volume change r 2 = 0.72 Olsen et al, 73(5): , 2009 r 2 = 0.56 Findings consistent with parallel architecture Comparison of the 2 lung SBRT chest/rib toxicity studies Dunlap, IJROBP 2009 U Virginia & U Colorado 60 patients, minimum point dose 20 Gy in 3-5 fractions to chest wall Endpoint: severe pain (narcotics) or rib fracture DVHs analyzed: Chest wall = all tissue (bone and soft tissue) peripheral to lung Pettersson, Radiother Oncol 2009 Sahlgrenska U, Sweden 81 ribs in 26 patients,minimum point dose 21 Gy/3 fractions received Endpoint: rib fracture on CT DVHs analyzed Ribs receiving >21 Gy contoured without margin for setup errors

11 Dunlap study definition of chest wall note: not all sections relevant here (suggest not using this entire volume to speed DVH calcs) Common finding: absolute volume predictive parameters Dunlap et al: Keep absolute V30 < 30 cc Petterssen et al: Keep D 2cc as low as possible Timmerman s suggested normal tissue constraints Sem Rad Onc. 18(4) : , 2008 Radiation Biology & Future Trends of SBRT SBRT: radiobiological modeling University of Colorado SBRT: snapshot of the program Future trends THERE IS NO SHAME IN STARTING WITH THESE!!!!

12 Relative measure of interest in SBRT within the field over the past 5 years National data not yet available, so a snapshot of UC data Papers published in IJROBP, 2004-present *2009 data projected based on published and in press July-Dec, 2008 % external beam treatments Estimated % of patients treated IMRT Non-IMRT Cranial /spinal 1 8 SBRT SRS 2 13 A wild guess about how many patients might eventually get SBRT or hypofractionated RT* note: everything is a rounded estimate Cancer type RT Patients per year, US Suitable for sbrt or hypofraction? Prostate 100,000 25,000 Breast 100,000 50,000 Lung 100,000 25,000 Head & Neck 40,000 0 Rectal 20,000? Everything else -- 25,000 *10 or fewer fractions in a curative setting? Hmmm am I forgetting anything that will have a lot more influence than some of us like to acknowledge? Maybe you have heard: Medicare is revising radiation oncology reimbursement rates stay tuned on that one

13 Thanks for your attention! And thanks to the UCD physics and dosimetry team: Francis, Kelly, Moyed, Wayne