sbrt for inoperable lung cancer

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


Early Stage Lung Cancer Risk Groups

3 broad groups:3 broad groups: Average RiskAverage Risk

Generally can tolerate removal of Generally can tolerate removal of an entire lobean entire lobe

High RiskHigh Risk

Can tolerate partial removal of a Can tolerate partial removal of a lobelobe

Medically Medically InoperableInoperable

Cannot tolerate surgery for lung Cannot tolerate surgery for lung cancercancer


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 Henric Swedish pioneers Ingmar Lax and Henric BlomgrenBlomgren

• Japanese pioneer Minoru UematsuJapanese pioneer Minoru Uematsu

• Facilitated by technology (immobilization, Facilitated by technology (immobilization, motion control, 3-D dosimetry, image-motion control, 3-D dosimetry, image-guidance)guidance)


What Characterizes Stereotactic Body Radiation

Therapy (SBRT)?


Spread out the entry radiation damage


Punishing Radiation Target Dose

-This dose defines tumor control (place it well)This dose defines tumor control (place it well)


Steep Radiation Gradients to Normal Tissue

-This intermediate dose This intermediate dose -Can kill microscopic tumor tentaclesCan kill microscopic tumor tentacles-BUT, accounts for toxicity. BUT, accounts for toxicity.


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


SBRT Treatment Logistics

OutpatientOutpatient

No Sedation orNo Sedation orAnesthesiaAnesthesia(painless)(painless)

1-5 Treatments1-5 Treatmentsqd or qodqd or qod

20-60 Minutes20-60 MinutesPer TreatmentPer Treatment

Immediate ReturnImmediate ReturnTo ActivitiesTo Activities

Entire course ofEntire course ofRx in 1-2 weeksRx in 1-2 weeks


Tissue Effects After SBRT• Dramatic tumor responses even in solid organsDramatic tumor responses even in solid organs• Solid organ–sloughing unlikely contributing to Solid organ–sloughing unlikely contributing to

responseresponse• Implies SBRT preserves competence of immune Implies SBRT preserves competence of immune

system to carry out phagocytosissystem to carry out phagocytosis

Pre-treatmentPre-treatment 6 weeks6 weekspost-treatmentpost-treatment

3 years3 yearspost-treatmentpost-treatment


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)


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 In contrast to CFRT, local immune function appears mostly preservedmostly preserved Dramatic tumor responsesDramatic tumor responses Avoidance of necrosisAvoidance of necrosis

• Immediately surrounding normal tissue is damaged Immediately surrounding normal tissue is damaged to the point of dysfunctionto the point of dysfunction Decreased organ reserve (?symptomatic)Decreased organ reserve (?symptomatic)


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 *clinically staged and mostly medically inoperable (some refused surgery)(some refused surgery)

Conventional RT generally 60-66 Gy delivered in 6-7 Conventional RT generally 60-66 Gy delivered in 6-7 weeksweeks


Early Investigations of SBRT

• Mostly ad hoc, retrospectiveMostly ad hoc, retrospective

• Treated typical drug discovery phase I Treated typical drug discovery phase I populationpopulation Incurable patientsIncurable patients Metastatic cancerMetastatic cancer Near end of lifeNear end of life

• Difficult to draw conclusionsDifficult to draw conclusions


SBRT in Early Stage NSCLC• First prospective trials were in medically First prospective trials were in medically

inoperable patients with stage I NSCLCinoperable patients with stage I NSCLC Those refusing surgery (confounders) not Those refusing surgery (confounders) not

allowedallowed

• Intent, originally, was to improve tumor Intent, originally, was to improve tumor controlcontrol probably at the expense of increased toxicityprobably at the expense of increased toxicity

• Experience has been that tumor control is Experience has been that tumor control is improved and treatment is surprisingly well improved and treatment is surprisingly well toleratedtolerated


• 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 Dose escalation to very high doses

20-24 Gy X 3 = 60-72 Gy20-24 Gy X 3 = 60-72 Gy


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 Progressive CT consolidation within or adjacent

to tumor prompt PETto tumor prompt PET If PET has uptake similar to initial staging If PET has uptake similar to initial staging

(EORTC criteria), then score as tumor (EORTC criteria), then score as tumor recurrencerecurrence

Otherwise continue to follow (NED)Otherwise continue to follow (NED)


72 yo female with T1N0M0 NSCLC s/p SBRT 54Gy/3 fractions to 73% dose line,

dose at iso=73.97Gy, 10 beams

Example


Treatment Plan


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


Follow-up• Treated with incentive spirometry, Treated with incentive spirometry,

prednisone taper, albuterol nebulizers for prednisone taper, albuterol nebulizers for pneumonitispneumonitis

• Symptoms improve graduallySymptoms improve gradually

PreSBRTPreSBRT 2yearspostSBRT2yearspostSBRT


Dose_Levels2400to36004200to54006000to7200

LocalControl

0 12 24 36 48 60 72 84 96

100

90

80

70

60

50

40

30

20

10

0

MonthsfromTherapy

LocalR

ecurrenceFreeSurvival(%)

P = 0.01 (log rank)


Dose Response

0

20

40

60

80

100

0 10 20 30 40 50 60 70

Total Dose in 3 Fractions

4-ye

ar L

ocal

Con

trol


• IU 70 patient phase II IU 70 patient phase II studystudy

• 20 Gy X 3 for T120 Gy X 3 for T122 Gy X 3 for T222 Gy X 3 for T2

• NO restriction on tumor NO restriction on tumor locationlocation


Zone of the Proximal Bronchial Tree


RTOG 0236• Non-small cell lung cancer - biopsy Non-small cell lung cancer - biopsy

provenproven

• T1, T2 (T1, T2 ( 5 cm) 5 cm)

• Medical problems preclude surgeryMedical problems preclude surgery(e.g. emphysema, heart disease, (e.g. emphysema, heart disease, diabetes)diabetes)

• No other planned therapyNo other planned therapy

Staging was non-invasive (PET/CT)Staging was non-invasive (PET/CT)

Only invasive step


Primary Tumor ControlOnepatientfailedwithin2cmoftheprimarytumor

LocalC

ontro

l(%)

0

25

50

75

100

MonthsafterStartofSBRT0 6 12 18 24 30 36

0

25

50

75

100

0 6 12 18 24 30 36

PatientsatRisk 55 54 47 46 39 34 23

Fail: 1Total: 55

/ / / / / /// / / // / // / / / / / // / // // // //

36 month primary tumorControl = 98% (CI: 84-100%)


Local Control

• Local recurrence is primary tumor failure Local recurrence is primary tumor failure and/or failure within the involved lobe of and/or failure within the involved lobe of the lungthe lung

• 1 patient had primary tumor failure1 patient had primary tumor failure ++

3 patients had failure within the involved 3 patients had failure within the involved lobelobe

• 3-year Kaplan Meier local control = 90.7%3-year Kaplan Meier local control = 90.7%


Regional Recurrence

• 2 patients have reported a regional failure, 2 patients have reported a regional failure, both after 2 years (2.8 and 3.0 years)both after 2 years (2.8 and 3.0 years)

• Patients avoiding both local and regional Patients avoiding both local and regional recurrence (loco-regional control) is 87.2%recurrence (loco-regional control) is 87.2%


Disseminated Recurrence

• Eleven patients (20%) have experienced Eleven patients (20%) have experienced disseminated failuredisseminated failure 8 of these patients had failure prior to 2 8 of these patients had failure prior to 2

yearsyears


Overall Survival

OverallSurvival(%)

0

25

50

75

100

MonthsafterStartofSBRT0 6 12 18 24 30 36

0

25

50

75

100

0 6 12 18 24 30 36

PatientsatRisk 55 54 47 46 40 35 24

Dead: 26Total: 55

MST: 48.1(95%CI): (29.6,notreached)

/// / / //36 month

overall survival = 56% (CI: 42-68%)


Severe Toxicity• No grade 5 toxicities (treatment No grade 5 toxicities (treatment

deaths)deaths)

• Two (4%) grade 4 protocol specified Two (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 Seven (13%) grade 3 protocol specified toxicitiesspecified toxicities


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 2 patient: radiation inflammation of lung (Olung (O22 required) required)

• 3 patients: decline in pulmonary 3 patients: decline in pulmonary function, (25-50% of predicted value)function, (25-50% of predicted value)

• 1 patient: decline in pulmonary 1 patient: decline in pulmonary function and coughfunction and cough

= 7= 7 patients (all pulmonary toxicity)patients (all pulmonary toxicity)


• SBRT has become a standard of care for SBRT has become a standard of care for medically inoperable patientsmedically inoperable 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 Successful clinical model using hypofractionated radiotherapy:hypofractionated radiotherapy:• Rigorously conducted, highly scrutinizedRigorously conducted, highly scrutinized• Multicenter QAMulticenter QA• Rapid acceptanceRapid acceptance


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 Primary tumor recurrence 3%, regional failure 9%, 2

year OS 64%year OS 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%


Future Directions• Refine SBRT for medically inoperable patientsRefine SBRT for medically inoperable patients

Refine dose constraints with dosimetry databases Refine dose constraints with dosimetry databases and patient outcomesand patient outcomes

Refine dose prescription comparing various Refine dose prescription comparing various fractionation regimens (RTOG 0915)fractionation regimens (RTOG 0915)

Refine dose prescription for centrally located Refine dose prescription for centrally located tumors via phase I trial (RTOG 0813)tumors via phase I trial (RTOG 0813)

Refine therapy in combination with systemic Refine therapy in combination with systemic therapiestherapies

• Explore use of SBRT in an operable patient Explore use of SBRT in an operable patient subset (RTOG 0618) subset (RTOG 0618)


ACOSOG Z4099 / RTOG 1021

PIs:HiranC.Fernando,MD(ACOSOG);RobertTimmerman,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.


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 Admittedly imperfect therapy with both failure and

harmharm

• SBRT is an established standard therapy for SBRT is an established standard therapy for medically inoperable patientsmedically inoperable patients

• SBRT should be compared to less invasive/less SBRT 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 ideally Momentum extremely strong for SBRT, but ideally

studies will be donestudies will be done


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.

sbrt for inoperable lung cancer

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