sbrt: radiating boldly in the present and future

AAMD Virtual 46th Annual Meeting

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SBRT: Radiating Boldly in thePresent and Future

Lindsay Puckett, MD

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CE Credits• To earn CE Credits for this session, you need to view the

entire session and complete both the assessment questions and evaluation. • These need to be completed by Thursday, July 15

[email protected]

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DISCLOSURES

• Radiation Oncologist

• Financial: None

We’re not radiologists We don’t use lasers

Won’t make you glow in the dark

Do treat cancer patients using radiation

Common Radiation Oncology Misconceptions

OBJECTIVES

Radiation BasicsDefine “SBRT” and how it differs from conventional radiation treatment

Reviewing guideline approved uses for SBRT in cancer care

Discuss the evolving area of SBRT for metastatic disease

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DOSE

•How much radiation?

How much dose is meaningful?

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B A N A N AE Q U I V A L E N T

D O S E

• Adapted from: https://www.universityofcalifornia.edu/longform/what-know-you-go-bananas-about-radiation

BEFORE YOU THROW OUT YOUR BANANAS..

• Adapted from: https://www.universityofcalifornia.edu/longform/what-know-you-go-bananas-about-radiation

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OTHER COMMON QUESTIONS?

• 6 months of eating food= 4000 bananas

• CT scan =100,000 bananas

• Smoking a pack per day for 1 year = 240,000 bananas

• Increased risk of death from cancer = ~1,000,000 bananas

• Take away: Many forms of radiation we are exposed to all together, still below the threshold for increased risk from cancer

RADIATION BASICS

Radiation therapy uses energy to kill cancer cellsDamages DNA prevents cancer* cells from being able to grow and divide, eventually they die

Many different types of radiation and ways they can be usedCancer vs. benign conditions (Keloids, Trigeminal neuralgia, and arrhythmias)

These treatments all use therapeutic (“high dose”) radiation

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RADIATION THERAPY (RT)– Units for treatment: Gray (Gy)

(For x-rays 1 Sievert= 1Gy)

– Course of cancer treatment: 20-90 Gy

• Per treatment day typically ~2 Gy-18 Gy

• Generally, to a focused area of the body– Example: can safely to give 18 Gy of RT to a small part of the body, not the whole

body

– Effect of radiation is not just the dose, but how you give the dose, and where

RADIATION DELIVERY

• Many ways to give radiation

• External Beam Radiation Therapy (EBRT)

– Photons

• Machines: LINACs

– Most modern machines are capable of giving focused radiation treatments

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SBRT/ SABR

• Stereotactic Body Radiation Therapy (SBRT)– Also known as stereotactic ablative body radiation therapy (SABR)

– “a method used to very precisely deliver a high dose of radiation to an extra-cranial target within the body, using either a single dose or a small number of fractions (hypofractionated)”

– The term ablative was added to reflect the aim of the treatment, which is to destroy the tumor cells both directly through delivery of radiation and indirectly through destruction of the supplying vasculature.

ABLATIVE POTENTIAL• Vascular volume decreases following large doses of RT.

Park et al. Radiation Res. 2012

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DOSING

• Conventional

• Small dose per day (~2Gy)

• Given over many weeks

• Chosen due to safety concerns

• Tolerance of nearby organs at risk

• Preferred for most sites within the body

• SBRT

• Large dose per day (~8Gy)

• Given over a short number of treatment sessions (~1-5fx), often over 1-2 weeks

• Chosen to be ablative and have a larger effect on the tumor

• Good for small isolated areas

RADIATION DOSING CAN BE COMPLICATED

• Dose to tumor

• Dose to areas around the tumor/ organs at risk (OARs)

• Low dose across the body

• SBRT bonus: Dose gradient

• Let’s start simple…

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HISTORICALLY

• “2-D” era

• Treat the target

• Use a generous margin

• Estimate dose

• Cons: higher dose to normal tissues higher risk of toxicities

• Still regularly used for emergencies or in centers without advanced imaging

AP-PA

High dose region: LargeIntermediate region: SmallLow dose region: Small

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3D CONFORMAL RADIATION TECHNIQUES

• High dose: Medium

• Intermediate dose: Medium

• Low dose: Large

Image: Silva, S. et al. Radiotherapy 2017

Image: Silva, S. et al. Radiotherapy 2017

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SBRT

• Highly conformal treatment

• High dose-Very small

– falls within the target

• Intermediate dose- small falls off quickly

• Low dose- small to medium

• Very low dose- covers a wider area

• Typically, center of the tumor gets a higher dose than periphery

S B R T I N C L I N I C A L P R A C T I C E

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SBRT SITES TO BE DISCUSSED

• Current:

– Lung

– Liver

– Spine

– Prostate

• Bonus:

– Metastatic disease

LANDSCAPE: LUNG

• Historically, medically inoperable patients received conventionally fractionated RT (2 Gy/Fx) as supportive care

• With this treatment, 40-60% had local control and ~30-40% died within 2 years

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LUNG SBRT

• One of the first disease sites adapted in practice

• In the US, this work was largely pioneered by Dr. Robert Timmerman (Indiana) in the early 2000s

• Initial trials included any location in the lung

• Results: Excellent control for early stage lung cancer

• Cons: several deaths, primarily in those with central tumors

ANY RANDOMIZED DATA?

• Initially, single institution studies.

• RTOG 0236 Timmerman et al. JAMA 2010, updated in 2014

• Phase II multi-institutional study of SBRT for medically inoperable stage I/II NSCLC

• Rx 60Gy/3fx (equivalent) ~54Gy/3 fx

• Well tolerated, grade 3 = 12.7%, grade 4 = 3.6%, no grade 5

• 2 year 56% OS, LC 98%, LRC 87%

• 5 years 40% OS, LC 93%, LRC 62%,

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HEAD TO HEAD COMPARISON?

• Nyman et al. SPACE trial, Radiother Oncol 2016

• Randomized Phase II, Conventional (70Gy/35fx) vs. SBRT (66/3fx)

• MFU= 37 months

• 70% of SBRT and 59% of conventional RT patients had not progressed at the end of the study (p=.26)

• Pneumonitis: 19% SBRT vs. 34% conventional (p=.26) Esophagitis: 8% vs. 30%

LUNG CANCER

SBRT:TODAY

Febbo et al. Radiographics 2018

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WHY NOT DO IT FOR EVERYONE WITH LUNG CANCER?

• Location

• Nodes

• Technique

• Dose Fall Off

WHO SHOULD GET IT?

• Early stage lung cancer patients

• Patients who are not eligible for surgery or refuse surgery

• Select lung locations– Do not use for ultracentral lung locations

• Caution: Severe COPD, overlap with organs at risk (OARs)

• Retreatment

• Next steps: Round up a skilled team with MD, physics, dosimetry, and therapists trained in using SBRT approach

• Review guidelines

Image credit: Dr. N Zaorsky

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NCCN GUIDELINES

• Combine with other slide

LUNG TAKE HOME POINTS

• SBRT is a reasonable option for many medically inoperable patients with early stage lung cancer, offers good rates of local control

– Surgery is still SOC for those eligible, but actively under investigation

• Doctors need to careful in explaining the side effects of treatment to patients

• Be careful in choosing who receives SBRT for their treatment (location)

• Safety- NCCN guidelines

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LIVER

• Primary lesions: Hepatocellular carcinoma (HCC)

• Secondary lesions: Metastases

• There are a number of techniques for ablating liver lesions

– Embolization (TACE)

– Radiofrequency ablation (RFA)

– Radioembolization (Y-90)

– SBRT

• Decisions are best made with a multi-disciplinary team

WHO SHOULD GET IT?

• Generally, more fit patients, no/ very limited extrahepatic disease

• Usually 1-3 lesions with sufficient areas of uninvolved liver

• Often used for those who have failed other modalities

• Lesions which can’t be safely targeted with other techniques

• Meets pre-specified lab criteria

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LIVER METASTASES

• Patient registry from multi-center, international patient registry

• 427 patients

• Median SBRT dose was 45Gy

• Median OS = 22 months

• LC was better for smaller tumors <40cm3 (52m vs 39m)

• Caveats: little toxicity data

• Other studies: Treatment-related toxicity included hepatic failure, colonic perforation requiring surgical management, and duodenal ulcerations

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LIVER TAKE HOME POINTS

• SBRT is a reasonable option for select medically inoperable patients with early stage HCC and also for isolated liver metastases, offers reasonable rates of local control

• Consider SBRT course training

• Be very careful in choosing who receives SBRT for their treatment (size/location)

• Monitor DVH parameters

• Safety First- NCCN guidelines and literature

SPINE

• SBRT considered in good performance status patients with bone metastases

– expected longevity, radioresistant histologies, also considered in retreatment

• Consensus guidelines are available for contouring (Cox et al. 2012 IJROBP)

• One short and long term risk is fracture, consider getting input from orthopedics prior to treatment

• Research: ongoing question is if SBRT offers better pain control in these patients

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ASTRO MEETING 2019: NEW RANDOMIZED DATA• Ryu et al. Abstract RTOG 0631. 2019

• Phase II study assessing feasibility and safety of spine radiosurgery (SRS) / SBRT vs. “conventional” palliative single fraction (8Gy/1fx)

• Epidural lesions needed to have at least a 3 mm gap between the cord and tumor

• 339 were randomized, 209 to SBRT, 130 to conventional RT single fraction

• No difference in pain improvement or number with pain response (40.3% SBRT vs 57.9% conventional RT, p=0.99). No difference in rates of adverse events.

SPINE TAKE AWAYS

• SBRT of the spine is a reasonable option for some patients with spine metastases, caution if too close to the cord

• Some patients may benefit from separation surgery prior to treatment

• Palliation on the whole– Consider the patient and the disease

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PROSTATE: KEY POINTS

• Hypofractionation has become very popular in prostate cancer treatment (28 vs 40+ treatments)

• SBRT or “Ultrahypofractionated” data in prostate has grown

– Many single institution reports with low, intermediate and high-risk patients receiving this treatment

• NCCN guidelines:

RANDOMIZED DATA?

• Yes, in 2019

• Multi-institutional Randomized Phase III Trial in 12 centers in Sweden and Denmark between 2005 and 2015

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RADIATION PLANNING

• Gold Fiducials placed for 90% of patients

• CTV= prostate only (on CT, MR permitted but not required*)

• PTV= 7mm for 90% of patients both arms

• Prescription: 42.7 Gy in 7 fractions over 2.5 weeks (prescribed as mean dose to PTV) vs. 78Gy in 39 fractions over 8 weeks

• OARs: rectum, anal canal, urinary bladder, penile bulb, and femoral heads

• Doses designed to be isoeffective for late tissue toxicity using α/β of 3

80% of patients treated with 3D CRT

Slide courtesy of Dr. Michael Straza

SBRT: NON INFERIOR

• Failure-free survival at 5 years was 84% (95% CI 80−87) in the ultra-hypofractionation group and 84% (80−87) in the conventional fractionation group (log-rank p=0.99

• Toxicity also very similar, early GU slightly worse with SBRT

Slide courtesy of Dr. Michael Straza

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P R O S TAT E S B R T C O N S I D E R AT I O N S

• Urethra

• Rectal and Bladder filling

• Need for MRI

• Prostate anatomy

PROSTATE SBRT TAKE AWAYS

• Included in NCCN guidelines as an option for low, intermediate, and high risk localized prostate cancer

• Specifications are still evolving

• Grown in popularity (with COVID)

• Caution in men with very large prostates and high IPSS scores

• Caution on margins

• Not appropriate for all prostate cancer patients

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DESSERT

O L I G O M E TA S TAT I C D I S E A S E , S B RT, A N D S U RV I VA L

OLIGOMETASTATIC DISEASE

Initially described in 1995 by Weichselbaum & Hellman• Intermediate stage of tumor progression between locoregionally confined cancer and

widespread distant metastases

Felt to represent a unique group of patients

Can portend a better prognosis

Slide courtesy of Dr. Monica Shukla

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WHAT IS OLIGOMETASTATIC DISEASE?• Potentially a more indolent biology, allowing for metastasis-directed therapy as a meaningful

intervention with potential long-term survival

• In most studies general defined as 5 or fewer metastases

• Number of metastases and organs involved cancer dependent

– May be best defined biologically

Slide courtesy of Dr. Monica Shukla

GROWING INTEREST IN OLIGOMETASTATIC DISEASE

• More widespread use of SBRT has fueled research in treating patients with oligometastases

– Some animal model data suggests there may be an immune benefit to giving large dose per fraction

• Several studies demonstrate excellent local control in virtually all parts of the body with a low proportion of patients experiencing severe side effects.

Courtesy of Dr. Monica Shukla

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PALMA ET AL., SABR-COMET, LANCET, 2019

Inclusion:

18 or older Controlled primary tumor 1 to 5 mets ECOG 0–1 Life expectancy of 6 moswere eligible

Randomized, phase 2 study carried out at 10 hospitals in Canada, Netherlands, Scotland, and Australia

Presented at ASTRO 2018; E-pub 4/11/2019

PALMA ET AL ., SABR-COMET, L ANCET, 2019

• MFU: 26 months

• Median OS was 28 months (95% CI 19–33) in the control group

• Median OS was 41 months (26–not reached) in the SABR group

• HR: 0.57, 95% CI 0·30–1·10; p=0·090

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PALMA ET AL ., SABR-COMET, LANCET, 2019

• Grade 2 AE: 9 vs 29%

– p = 0.026

• Treatment related deaths (Grade 5):

– 3/66 after SABR

– 0/33 control group

PALMA ET AL., SABR-COMET, LANCET, 2019

Conclusion: SABR was associated with an improvement in overall survival, meeting the primary endpoint of this trial, but three (4·5%) of 66 patients in the SABR group had treatment-related deaths

Phase 3 trials are needed to conclusively show an overall survival benefit, and to determine the maximum number of metastatic lesions wherein SABR provides a benefit

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TAKE AWAYS OLIGOMETASTATIC DISEASE• Early data looks intriguing, SBRT may be appropriate for select oligometastatic cases

• These cases are best delineated by a multidisciplinary team

• Be careful if you aren’t meeting constraints

– Consider lowering dose, prescribing differently

• Physicians need to be careful in who and how they treat these patients, this is aggressive treatment

• Looking forward to further data on what comes next!

OVERALL SBRT TAKE AWAYS

• SBRT is precisely delivering a high dose of radiation to a target within the body, using either one or several fractions.

• SBRT can be to treat patients with a variety of malignancies, primary and metastatic

• SBRT should generally be performed by a team with expertise in the disease site they are treating

• Radiate boldly, but safely

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THANK YOU!

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sbrt: radiating boldly in the present and future

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