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 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

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)

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 doseThis 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 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

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

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 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)

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

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

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

• 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

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)

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, 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

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)

Dose Response
0
20
40
60
80
100
0 10 20 30 40 50 60 70
Total Dose in 3 Fractions
4-yearLocalControl

• 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

Zone of the Proximal Bronchial Tree

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

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%)

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%

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%

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

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%)

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

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)

• 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

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%

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)

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.

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

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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