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sbrt for inoperable lung cancer

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  • 1. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Stereotactic Body Radiotherapy (SBRT) for the Inoperable Early Stage Lung Cancer Patient Lucien A. Nedzi, M.D.Lucien A. Nedzi, M.D. Department of Radiation OncologyDepartment of Radiation Oncology Univ. of Texas Southwestern Medical CenterUniv. of Texas Southwestern Medical Center
  • 2. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Early Stage Lung Cancer Risk Groups 3 broad groups:3 broad groups: ­ Average RiskAverage Risk Generally can tolerate removal of anGenerally can tolerate removal of an entire lobeentire lobe ­ High RiskHigh Risk Can tolerate partial removal of a lobeCan tolerate partial removal of a lobe ­ MedicallyMedically InoperableInoperable Cannot tolerate surgery for lung cancerCannot tolerate surgery for lung cancer
  • 3. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Circa 1995: A new treatment called “Extracranial Stereotactic Radioablation” (later SBRT) • GammaKnife-like treatments in the bodyGammaKnife-like treatments in the body • Swedish pioneers Ingmar Lax and HenricSwedish pioneers Ingmar Lax and Henric BlomgrenBlomgren • Japanese pioneer Minoru UematsuJapanese pioneer Minoru Uematsu • Facilitated by technology (immobilization, motionFacilitated by technology (immobilization, motion control, 3-D dosimetry, image-guidance)control, 3-D dosimetry, image-guidance)
  • 4. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY What Characterizes Stereotactic Body Radiation Therapy (SBRT)?
  • 5. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Spread out the entry radiation damage
  • 6. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Punishing Radiation Target Dose ­This dose defines tumor control (place it well)This dose defines tumor control (place it well)
  • 7. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Steep Radiation Gradients to Normal Tissue ­This intermediate doseThis intermediate dose ­Can kill microscopic tumor tentaclesCan kill microscopic tumor tentacles ­BUT, accounts for toxicity.BUT, accounts for toxicity.
  • 8. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Very large low dose radiation volume - SBRT (and radiosurgery) Assumption: A little dose to a lot of- SBRT (and radiosurgery) Assumption: A little dose to a lot of normal tissue is better than a lot of dose to a little normal tissuenormal tissue is better than a lot of dose to a little normal tissue
  • 9. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY SBRT Treatment Logistics OutpatientOutpatient No Sedation orNo Sedation or AnesthesiaAnesthesia (painless)(painless) 1-5 Treatments1-5 Treatments qd or qodqd or qod 20-60 Minutes20-60 Minutes Per TreatmentPer Treatment Immediate ReturnImmediate Return To ActivitiesTo Activities Entire course ofEntire course of Rx in 1-2 weeksRx in 1-2 weeks
  • 10. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Tissue Effects After SBRT • Dramatic tumor responses even in solid organsDramatic tumor responses even in solid organs • Solid organ–sloughing unlikely contributing to responseSolid organ–sloughing unlikely contributing to response • Implies SBRT preserves competence of immune systemImplies SBRT preserves competence of immune system to carry out phagocytosisto carry out phagocytosis Pre-treatmentPre-treatment 6 weeks6 weeks post-treatmentpost-treatment 3 years3 years post-treatmentpost-treatment
  • 11. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Tissue Effects After SBRT • Normal tissue collateral damage does occurNormal tissue collateral damage does occur ­ Dose and location dependantDose and location dependant ­ Adjacent tissue doesn’t function (ablated)Adjacent tissue doesn’t function (ablated)
  • 12. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Summary of SBRT • Very convenient and non-invasiveVery convenient and non-invasive • Technology intensive and dependantTechnology intensive and dependant • In contrast to CFRT, local immune function appears mostlyIn contrast to CFRT, local immune function appears mostly preservedpreserved ­ Dramatic tumor responsesDramatic tumor responses ­ Avoidance of necrosisAvoidance of necrosis • Immediately surrounding normal tissue is damaged to theImmediately surrounding normal tissue is damaged to the point of dysfunctionpoint of dysfunction ­ Decreased organ reserve (?symptomatic)Decreased organ reserve (?symptomatic)
  • 13. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY 3-5 Year Outcome in Early Stage Lung Cancer Rx ModalityRx Modality % alive% alive • Stage IStage I SurgerySurgery 60-80%60-80% Stage I*Stage I* Conventional XRTConventional XRT 15-45%15-45% *clinically staged and mostly medically inoperable (some*clinically staged and mostly medically inoperable (some refused surgery)refused surgery) Conventional RT generally 60-66 Gy delivered in 6-7 weeksConventional RT generally 60-66 Gy delivered in 6-7 weeks
  • 14. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Early Investigations of SBRT • Mostly ad hoc, retrospectiveMostly ad hoc, retrospective • Treated typical drug discovery phase I populationTreated typical drug discovery phase I population ­ Incurable patientsIncurable patients ­ Metastatic cancerMetastatic cancer ­ Near end of lifeNear end of life • Difficult to draw conclusionsDifficult to draw conclusions
  • 15. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY SBRT in Early Stage NSCLC • First prospective trials were in medicallyFirst prospective trials were in medically inoperable patients with stage I NSCLCinoperable patients with stage I NSCLC ­ Those refusing surgery (confounders) not allowedThose refusing surgery (confounders) not allowed • Intent, originally, was to improve tumor controlIntent, originally, was to improve tumor control ­ probably at the expense of increased toxicityprobably at the expense of increased toxicity • Experience has been that tumor control isExperience has been that tumor control is improved and treatment is surprisingly wellimproved and treatment is surprisingly well toleratedtolerated
  • 16. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY • Classic phase I designClassic phase I design • Low starting dose 8 Gy X 3 = 24 GyLow starting dose 8 Gy X 3 = 24 Gy • Dose escalation to very high doses 20-Dose escalation to very high doses 20- 24 Gy X 3 = 60-72 Gy24 Gy X 3 = 60-72 Gy
  • 17. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Tumor Control Definitions • Follow-up policy and control definitions:Follow-up policy and control definitions: ­ CT scan q3 monthsCT scan q3 months ­ Progressive CT consolidation within or adjacent toProgressive CT consolidation within or adjacent to tumor prompt PETtumor prompt PET ­ If PET has uptake similar to initial staging (EORTCIf PET has uptake similar to initial staging (EORTC criteria), then score as tumor recurrencecriteria), then score as tumor recurrence ­ Otherwise continue to follow (NED)Otherwise continue to follow (NED)
  • 18. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY 72 yo female with T1N0M0 NSCLC s/p SBRT 54Gy/3 fractions to 73% dose line, dose at iso=73.97Gy, 10 beams Example
  • 19. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Treatment Plan
  • 20. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Follow-up • 3 month scan with good response3 month scan with good response • 6 months post SBRT develops cough, fever,6 months post SBRT develops cough, fever, SOB, and chest wall painSOB, and chest wall pain • Original PET SUV 9-10, repeat PET SUV 3-5Original PET SUV 9-10, repeat PET SUV 3-5
  • 21. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Follow-up • Treated with incentive spirometry, prednisoneTreated with incentive spirometry, prednisone taper, albuterol nebulizers for pneumonitistaper, albuterol nebulizers for pneumonitis • Symptoms improve graduallySymptoms improve gradually Pre SBRTPre SBRT 2 years post SBRT2 years post SBRT
  • 22. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Dose_Levels 2400 to 3600 4200 to 5400 6000 to 7200 Local Control 0 12 24 36 48 60 72 84 96 100 90 80 70 60 50 40 30 20 10 0 Months from Therapy LocalRecurrenceFreeSurvival(%) P = 0.01 (log rank)
  • 23. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Dose Response 0 20 40 60 80 100 0 10 20 30 40 50 60 70 Total Dose in 3 Fractions 4-yearLocalControl
  • 24. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY • IU 70 patient phase II studyIU 70 patient phase II study • 20 Gy X 3 for T120 Gy X 3 for T1 22 Gy X 3 for T222 Gy X 3 for T2 • NO restriction on tumorNO restriction on tumor locationlocation
  • 25. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Zone of the Proximal Bronchial Tree
  • 26. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY RTOG 0236 • Non-small cell lung cancer - biopsy provenNon-small cell lung cancer - biopsy proven • T1, T2 (T1, T2 (≤≤ 5 cm)5 cm) • Medical problems preclude surgeryMedical problems preclude surgery (e.g. emphysema, heart disease, diabetes)(e.g. emphysema, heart disease, diabetes) • No other planned therapyNo other planned therapy Staging was non-invasive (PET/CT)Staging was non-invasive (PET/CT) Only invasive step
  • 27. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Primary Tumor Control One patient failed within 2 cm of the primary tumor LocalControl(%) 0 25 50 75 100 MonthsafterStartofSBRT 0 6 12 18 24 30 36 0 25 50 75 100 0 6 12 18 24 30 36 Patients atRisk 55 54 47 46 39 34 23 Fail: 1 Total: 55 / / / / / /// / / // / // / / / / / // / // // // // 36 month primary tumor Control = 98% (CI: 84-100%)
  • 28. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Local Control • Local recurrence is primary tumor failure and/orLocal recurrence is primary tumor failure and/or failure within the involved lobe of the lungfailure within the involved lobe of the lung • 1 patient had primary tumor failure1 patient had primary tumor failure ++ 3 patients had failure within the involved lobe3 patients had failure within the involved lobe • 3-year Kaplan Meier local control = 90.7%3-year Kaplan Meier local control = 90.7%
  • 29. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Regional Recurrence • 2 patients have reported a regional failure, both2 patients have reported a regional failure, both after 2 years (2.8 and 3.0 years)after 2 years (2.8 and 3.0 years) • Patients avoiding both local and regionalPatients avoiding both local and regional recurrence (loco-regional control) is 87.2%recurrence (loco-regional control) is 87.2%
  • 30. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Disseminated Recurrence • Eleven patients (20%) have experiencedEleven patients (20%) have experienced disseminated failuredisseminated failure ­ 8 of these patients had failure prior to 2 years8 of these patients had failure prior to 2 years
  • 31. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Overall Survival OverallSurvival(%) 0 25 50 75 100 MonthsafterStartofSBRT 0 6 12 18 24 30 36 0 25 50 75 100 0 6 12 18 24 30 36 Patients atRisk 55 54 47 46 40 35 24 Dead: 26 Total: 55 MST: 48.1 (95%CI): (29.6,notreached) / // / / //36 month overall survival = 56% (CI: 42-68%)
  • 32. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Severe Toxicity • No grade 5 toxicities (treatment deaths)No grade 5 toxicities (treatment deaths) • Two (4%) grade 4 protocol specifiedTwo (4%) grade 4 protocol specified toxicity (decline in PFTs to <25%toxicity (decline in PFTs to <25% predicted & hypocalcemia)predicted & hypocalcemia) • Seven (13%) grade 3 protocol specifiedSeven (13%) grade 3 protocol specified toxicitiestoxicities
  • 33. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Protocol Specified Grade 3 Toxicities • 1 patient: low oxygen in blood (O1 patient: low oxygen in blood (O22 required)required) • 2 patient: radiation inflammation of lung2 patient: radiation inflammation of lung (O(O22 required)required) • 3 patients: decline in pulmonary3 patients: decline in pulmonary function, (25-50% of predicted value)function, (25-50% of predicted value) • 1 patient: decline in pulmonary function1 patient: decline in pulmonary function and coughand cough = 7= 7 patients (all pulmonary toxicity)patients (all pulmonary toxicity)
  • 34. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY • SBRT has become a standard of care for medicallySBRT has become a standard of care for medically inoperable patientsinoperable patients ­ No randomized trial deemed necessaryNo randomized trial deemed necessary ­ Up to 10,000 patients per year in USUp to 10,000 patients per year in US • Successful clinical model using hypofractionatedSuccessful clinical model using hypofractionated radiotherapy:radiotherapy: • Rigorously conducted, highly scrutinizedRigorously conducted, highly scrutinized • Multicenter QAMulticenter QA • Rapid acceptanceRapid acceptance
  • 35. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Multicenter Phase II Trials Medically Inoperable • Dutch InvestigatorsDutch Investigators ­ 206 patients with Stage I206 patients with Stage I ­ Risk adapted approach well toleratedRisk adapted approach well tolerated ­ Primary tumor recurrence 3%, regional failure 9%, 2 year OSPrimary tumor recurrence 3%, regional failure 9%, 2 year OS 64%64% • JCOG 0403JCOG 0403 ­ Peripheral T1a, N0, M0Peripheral T1a, N0, M0 ­ 100 patients – still enrolling100 patients – still enrolling • Nordic Study GroupNordic Study Group ­ peripheral T1-T2, N0, M0peripheral T1-T2, N0, M0 ­ completed accrual of 57 patients 9/2005completed accrual of 57 patients 9/2005 ­ Primary tumor recurrence 7%, 2 year OS 65%Primary tumor recurrence 7%, 2 year OS 65%
  • 36. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Future Directions • Refine SBRT for medically inoperable patientsRefine SBRT for medically inoperable patients ­ Refine dose constraints with dosimetry databases andRefine dose constraints with dosimetry databases and patient outcomespatient outcomes ­ Refine dose prescription comparing variousRefine dose prescription comparing various fractionation regimens (RTOG 0915)fractionation regimens (RTOG 0915) ­ Refine dose prescription for centrally located tumorsRefine dose prescription for centrally located tumors via phase I trial (RTOG 0813)via phase I trial (RTOG 0813) ­ Refine therapy in combination with systemic therapiesRefine therapy in combination with systemic therapies • Explore use of SBRT in an operable patientExplore use of SBRT in an operable patient subset (RTOG 0618)subset (RTOG 0618)
  • 37. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY ACOSOG Z4099 / RTOG 1021 PIs: Hiran C. Fernando, MD (ACOSOG); Robert Timmerman, MD (RTOG) Patients randomized to SBRT will receive 18Gy in three fractions, for a total dose of 54Gy. Brachytherapy is allowed with SR. All registered patients will be followed for study endpoints, regardless of the status of their treatment. That includes patients receiving adjuvant therapy for any reason.
  • 38. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Conclusions • SBRT for lung cancer is effective and tolerableSBRT for lung cancer is effective and tolerable ­ Prospectively studiedProspectively studied ­ Encouraging and reproducible resultsEncouraging and reproducible results ­ Admittedly imperfect therapy with both failure and harmAdmittedly imperfect therapy with both failure and harm • SBRT is an established standard therapy forSBRT is an established standard therapy for medically inoperable patientsmedically inoperable patients • SBRT should be compared to less invasive/lessSBRT should be compared to less invasive/less radical surgery in high risk operable patientsradical surgery in high risk operable patients ­ Momentum extremely strong for SBRT, but ideallyMomentum extremely strong for SBRT, but ideally studies will be donestudies will be done
  • 39. DEPT OF RADIATION ONCOLOGYDEPT OF RADIATION ONCOLOGY Acknowledgements • UTSW Rad OncUTSW Rad Onc ­ Robert Timmerman, M.D.Robert Timmerman, M.D. ­ Hak Choy, M.D.Hak Choy, M.D. ­ Ramzi Abdulrahman, M.D.Ramzi Abdulrahman, M.D. ­ Lech Papiez, Ph.D.Lech Papiez, Ph.D. ­ Timothy Solberg, Ph.D.Timothy Solberg, Ph.D. • UTSW CT SurgeryUTSW CT Surgery ­ Michael Wait, M.D.Michael Wait, M.D. ­ Michael Dimiao, M.D.Michael Dimiao, M.D. • UTSW Med OncUTSW Med Onc ­ Joan Schiller, M.D.Joan Schiller, M.D. ­ David Gerber, M.D.David Gerber, M.D. • RTOG HeadquartersRTOG Headquarters ­ Rebecca Paulus, Ph.D.Rebecca Paulus, Ph.D. ­ Linda Walters, M.S.Linda Walters, M.S. • RTOG CollaboratorsRTOG Collaborators ­ Jeff Bradley, M.D.Jeff Bradley, M.D. ­ Harvey Pass, M.D.Harvey Pass, M.D. • RPCRPC ­ Goeff Ibbott, Ph.D.Goeff Ibbott, Ph.D. ­ David Followill, Ph.D.David Followill, Ph.D. • ATC/ITCATC/ITC ­ Jeff Michalski, M.D.Jeff Michalski, M.D. ­ Walter Bosch, Ph.D.Walter Bosch, Ph.D. ­ Bill Straube, Ph.D.Bill Straube, Ph.D.