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Stage I Lung Radiosurgery: Overview, Results, and Current RTOG Studies

Stage I Lung Radiosurgery: Overview, Results, and Current RTOG Studies. Douglas Johnson, MD, FACR Florida Radiation Oncology Group ACRIN Sept 2010 Annual Meeting. Stereotactic Body Radiotherapy. High ablative dose SRS= single Fx SBRT= 2-5 Fx

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Stage I Lung Radiosurgery: Overview, Results, and Current RTOG Studies

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  1. Stage I Lung Radiosurgery: Overview, Results, and Current RTOG Studies Douglas Johnson, MD, FACR Florida Radiation Oncology Group ACRIN Sept 2010 Annual Meeting

  2. Stereotactic Body Radiotherapy • High ablative dose • SRS= single Fx SBRT= 2-5 Fx • Overwhelms repair/repopulation mechanisms • BED important? (>100) • Short time (1-5 treatments) • Tight targets and rapid dose fall-off • Damages everything in high dose area • Critical to limit toxicity • Need target tracking or gating system

  3. 100 multiple 2 Gy fractions Survival 10-1 single fraction 10-2 68 4 2 Dose (Gy) Disrupts Clonagenicity

  4. 90% tumor control toxicity PROBABILITY 10% DOSE OF RADIATION Tumor on Plateau,Toxicity on Transition

  5. Conformal high dose • This constitutes the tumor control (place it well) • Being conformal is easy – especially with many beams or arcs

  6. Compact intermediate dose This is the hardest part of the SBRT process and distinguishes a good plan from a poor plan! - This accounts for toxicity. All of this dose is in normal tissues - Infinite possibilities – some much more toxic than others

  7. SRS: from BrainBody • Radiosurgery: initially CNS • Leksell Gamma Knife • >80-90% control for benign and malignant tumors, AVM’s, trigeminal neuralgia • Limited tumor motion within skull • Motion definition and compensationcritical in body radiosurgery sites • To limit normal tissue dose • Cyberknife (CK)—respiratory modeling for tracking • Linac-based (Novalis NTX)—gating compensation

  8. Evolution of Technological Innovation

  9. CyberKnife

  10. Respiratory Gating

  11. Lung SBRT Literature

  12. Nyman et al, SahlgrenkaUniv Hosp (Sweden): Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer—Mature results for medically inoperable patientsLung Cancer 51: 97-103 (2006) • SELECTION: Stg IA & IB, tumors < 5cm and noncentral, any PFTs • PATIENT MIX: 45 pts, 40% IA, med age 74, med KPS 80%, 20% without histology • STAGING: CT staging only • EQUIPMENT: Linac-based, body frame, abdominal compression for motion compensation • PTV MARGIN: 5mm axial, 10mm craniocaudal • DOSE: 45Gy in 3 Fx(BED 112.5), Dmax approx 140%, 100% PTV coverage • ACUTE TOXICITY: 40% Grade 1, 9% Grade 2 (skin, cough, LRI) • LATE TOXICITY: 11% (rib fx, Atx/fibrosis) • OUTCOMES: Med F/U 43 mo, LC 80%, FFDM 80% OS 1/2/3/5 yr = 80/71/55/30% Med OS 39 mo • NOTES: RCT underway--SBRT vs standard FxEBRT

  13. Lagerwaard et al, VU Univ Med Ctr (Amsterdam): Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small cell lung cancerIJROBP 70(3): 685-692 (2008) • SELECTION: Stg IA & IB, tumors < 6cm, any PFTs • PATIENT MIX: 206 pts, 59% IA, med age 73, 69% without histology • STAGING: PET staging • EQUIPMENT: Linac-based, 4DCT for motion compensation • PTV MARGIN: ITV + 3mm • DOSE: Risk-adapted: 3 x 20Gy (BED 180), 5 x 12Gy (132) or 8 x 7.5Gy (105) based on potential for toxicity • ACUTE TOXICITY: 49%, most Grade 1 (fatigue, nausea, SOB, cough, CW pain) • LATE TOXICITY: 7% (symptomatic RP, rib fx, thoracic pain) • OUTCOMES: Med F/U 12 mo, LC 97%, FFDM 85% OS 1/2 yr = 81/64%, med OS 34 mo DFS 1/2 yr = 83/68% (signifcorrel with T stage) • NOTES: Longer F/U needed

  14. Van Zyp et al, Erasmus Med Ctr (Rotterdam): Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: Clinical outcomeRadiother and Oncol 91: 296-300 (2009) • SELECTION: Stg IA & IB, noncentral tumors, any PFTs • PATIENT MIX: 70 pts, 56% IA, med age 76, 49% without histology • STAGING: PET staging • EQUIPMENT: CyberKnife (real-time tracking for motion comp.) • PTV MARGIN: 5mm • DOSE: Most 3 x 20Gy (BED 180), early pts 3 x 15Gy (112.5) • ACUTE TOXICITY: 46% Grade 1-2 (fatigue, SOB, cough) • LATE TOXICITY: 10% Grade 3 (symptomatic RP, CW pain) • OUTCOMES: Med F/U 15 mo, crudeFFDM 90% 2yr LC 96% (60Gy) vs. 78% (45Gy) OS 1/2 yr = 83/62%, DSS 94/86% • NOTES: Confirms dose response; no diff in outcomes with/without pathology

  15. Fakiriset al (Timmerman group): Stereotactic body radiation therapy for early-stage non-small cell lung carcinoma: Four-year results of a prospective phase II studyIJROBP 75(3): 677-682 (2009) • SELECTION: Stg IA & IB, <7cm, any location, medically inoperable • PATIENT MIX: 70 pts, 49% IA, med age 76, all with histology • STAGING: PET staging • EQUIPMENT: Linac-based, body frame immobilization, abdominal compression for motion compensation • PTV MARGIN: 5mm axial, 10mm craniocaudal • DOSE: 3 x 20Gy (T1), 3 x 22Gy (T2) • GR 3-5 TOXICITY: 20% (pna, effusion, hemoptysis, decr PFTs, resp failure) Diff in tox for peripheral vs central tumors NS • OUTCOMES: Med F/U 50 mo, median OS 32 mo (signifcorrel to T stg) 3yr LC 88%, FFDM 87% 3yr OS = 43%, DSS = 82%

  16. Inoue et al (Japan): Clinical outcomes of stereotactic body radiotherapy for small lung lesions clinically diagnosed as primary lung cancer on radiologic examinationIJROBP 75(3): 683-687 (2009) • SELECTION: Stg I, lesion with increasing CT size or PET + • PATIENT MIX: 115 pts, 81% IA, med age 77, none with histology • STAGING: Either CT alone or PETCT • EQUIPMENT: Linac-based, abdominal compression and/or gating • PTV MARGIN: “Appropriate” • DOSE: Varies, 30-70 Gy in 2-10 fx • GR 3-5 TOXICITY: 0% for <2cm, 7% for >2cm (RP, CW pain, rib fx) • OUTCOMES: Med F/U 14 mo 3/5yr OS = 90/90% for <2cm vs. 61/53% for >2cm • NOTES: Non-prospective, multi institutions & regimens

  17. Preliminary FROG results for Stg I NSCLC 2009 • SELECTION: Stg I, any PFTs, medically inoperable (6 pts refused surgery) 118 pts treated, 74 with at least 6mo F/U and adequate data • PATIENT MIX: Of those 74 pts: 88% IA, med age 74 3 with “suspicious” rather than definitive pathology • STAGING: PETCT, a few with mediastinoscopy/EBUS • EQUIPMENT: CyberKnife with real-time tracking 32% treated without fiducial markers With percutaneous marker placement, 10% Ptx rate • DOSE: 4 x 12-12.5Gy (central, some pleural-based) 3 x 20Gy (IA), 3 x 22Gy (IB) for parenchymal lesions • GR 1-2 TOXICITY: 5% (fatigue, cough) • GR 3-5 TOXICITY: 4% (sub-acute RP, persistent late CW pain/fibrosis) • OUTCOMES: Med F/U 15 mo 2yr LC = 93%, 2yr = FFDM 90% 2yr OS = 74%, 2yr = DFS 94% (NS)

  18. Outcomes After Stereotactic Lung Radiotherapy or Wedge Resection for Stage I Non-Small Cell Lung Cancer Grills, Mangona, et al William Beaumont Hospital, Detroit JCO Feb 2010

  19. Study characteristics • Nonrandomized, retrospective, single-institution experience (SBRT patients treated prospectively on Ph II trial) • 124 pts, all ineligible for anatomic lobectomy, all staged w/contrast CT & PETCT • First published direct comparison of SBRT to any form of surgery for Stg I NSCLC • Outcomes examined = recurrence, metastasis, survival, complications • Median F/U 2.5 yrs (30 mo)

  20. Surgery • 69 pts, all judged ineligible for lobectomy preoperatively • 30% had mediastinoscopy prior to surgery • 20% open thoracotomy, 52% VATS, 28% VATSconvert to open • 71% had either preopmediastinoscopy, intraop LND, or both • Pathologic T4 lesions/synchronous primaries excluded from analysis

  21. SBRT • 58 pts, 95% medically inoperable but technically resectable • Treated prospectively on Phase II trial • Staging • contrast CT, PETCT, brain MRI, bone scan • 20% had mediastinoscopy • Linacradiosurgery with isocentric planning, daily cone-beam CT target registration • GTV defined on 10 different phases of respiration to form ITV, total of 9mm margin added to ITV • 48Gy in 4 fx for T1, 60Gy in 5 fx for T2, given QOD • Conservative normal tissue constraints

  22. Median time to LR = 10.5 mo for SBRT, 25 mo for wedge Median time to RR or DM = 9 mo for SBRT, 25 mo for wedge

  23. Conclusions • For medically inoperable/borderline operable pts, SBRT provides outcomes equivalent to limited resection, with shorter recovery time & fewer significant complications. • Randomized clinical trials comparing SBRT to limited resection are justified and needed

  24. Current SBRT Issues • Appropriate margin • Appropriate dose for central vsparenchymalvs peripheral lesions • Interpretation of CT & PET changes following SBRT • Can/Should we treat PET-positive apparent Stg IA disease without pathology?

  25. Location, location, location… Current RTOG Lung SBRT trials

  26. RTOG 0915: A Randomized Phase II Study Comparing 2 Stereotactic Body Radiation Therapy (SBRT) Schedules for Medically Inoperable Patients with Stage I Peripheral Non-Small Cell Lung Cancer • Activated September 2009 • Intergroup RTOG/NCCTG • N: 88 patients (32 or 88 enrolled as of 9/13/2010) • Primary endpoint: to compare >grade 3 toxicities at 1 year • Secondary endpoints: compare 1 year control rates, survival, DFS, FDG PET SUV changes, PFT’s, biomarkers

  27. RTOG 0813Seamless Phase I/II Study of Stereotactic Lung Radiotherapy (SBRT) for Early Stage, Centrally Located, Non-Small Cell Lung Cancer (NSCLC) in Medically Inoperable Patients • Activated Feb 2009 • N: 94 patients (21 enrolled as of 9/13/2010) • Central caution: Timmerman showed 11 fold increase in G>3 complications with 3 Fx 20Gy • Primary endpoint: Determine Max Tolerated Dose (MTD) with 5 Fx over 2 weeks, and local control at that MTD • MTD = 20% chance of designated adverse event • Secondary endpoint: see if circulating molecular marker levels before and after treatment predict control and adverse events

  28. Lung SBRT Summary • Excellent local control rates (85-97%) seen in single institution series • Already replacing open surgery in Europe • Questions remain: • Can results be duplicated in multi-institution settings • Ideal dose and fractionation • How best to measure response • Difficulties with follow-up studies

  29. Doug Johnson, MD, FACR 904-202-7020 djohnson@frogdocs.com www.frogdocs.com Questions?

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