SBRT/SABR for Early Stage Lung Cancer: A Brief Overview

Stereotactic BodyRadiotherapy (SBRT)

forEarly Stage Lung

Cancer:A Brief Overview

Todd J. Scarbrough, M.D. / Medical Director, NEARMC Rad Onc

COC SurveyApril 26, 2016

A Payor’s Definition of SBRT

1. Tx with high degree of accuracy (i.e. use of image guidance)

2. Tx with high degree of precision (“conformality”)

3. Tx with a high fraction dose ≥5 Gy for ≤5 fractions

Precision vs. accuracy in radiation oncology:IMRT (precise) vs. IGRT (accurate)

IMRT: intensity modulated radiotherapyIGRT: image guided radiotherapy

Ting JY, Scarbrough TJ. Intensity-modulated radiation therapy and image-guided radiation therapy: small clinic implementation. Hematol Oncol Clin North Am. 2006

Feb;20(1):63-86.

What’s so specialabout SBRT?

*HOT TOPIC*Already 622 published studies of lung SBRT for lung CA by 2016!

DVH(dose volume histogram; a graphical representation of doses delivered to tumor targets and normal organs)

tumor

100% dose volume

50% dose volume

In general, we desire maximum dose conformality in our plans…

The relatively rapid fall-off of dose from the 100% to 50% region indicates a relatively very conformal plan in this situation…

DVH(dose volume histogram; a graphical representation of doses delivered to tumor targets and normal organs)

tumor

100% dose volume

50% dose volume

In general, we desire maximum dose conformality in our plans…

The relatively rapid fall-off of dose from the 100% to 50% region indicates a relatively very conformal plan in this situation…

Whether treating “standard dose” (e.g. 70 Gy/35 fx) or SBRT (e.g. 60 Gy/3 fx), maximum conformality is desirable and achievable. Increased conformality is empirically expected to lower complication probabilities (in this case, lung and soft tissue) no matter the fractionation scheme.

Again… “standard” XRT for early stage lung CA is different how?

1. Tx with high degree of accuracy (i.e. use of image guidance)

2. Tx with high degree of precision (“conformality”)

3. Tx with a high fraction dose ≥5 Gy for ≤5 fractions

“[SBRT] techniques are unusual in the high technology realm of radiation treatment in that they require more specialized training of physicians and physicists rather than specialized equipment.” Timmerman et al, Technology in Cancer Research and Treatment – 2003

SBRT: A complete paradigm shift in how we dose & prescribe radiation therapy,

and more of a revolution clinically than technologically…

ALTHOUGH… image guidance technology was not widely available in 2003,

and few would do SBRT without IGRT in 2016!

IMAGING AT TREATMENT TIME:

The Cone Beam CT

Stereotactic BodyRadiotherapy

(SBRT):Why more effective than older-style

XRT?Technology, dose… and the

immune system?

“Linear quadratic” formalism whereBED = biologically effective dosen = number of treatment fractionsd = dose per fraction (Gy)α/β = 10 Gy for tumor kill; 3 Gy for late effects

Total Dose (Gy)

No. fractions Late effects(Gy3)

Tumor kill(Gy10)

Equiv. total dose in 2 Gy fractions for tumor kill

70 35 117 84 70

48 4 240105% hotter

10626% hotter

88

50 5 21785% hotter

10019% hotter

84

60 4 360208% hotter

15079% hotter

126

60 3 460293% hotter

180114% hotter

150

SB

RT

regi

men

s

We mitigate against this using conformality (IMRT e.g.) and accuracy (IGRT e.g.).

This is desirable (i.e., the more the better), but is tempered against late and/or acute effects.

Radiation “abscopal” effects are seen much more commonly with high-dose SBRT treatments

“… reduction of tumor burden after ablative RT largely depends on T-cell responses. Ablative RT dramatically increases T-cell priming in draining lymphoid tissues, leading to

reduction/eradication of the primary tumor or distant metastasis in a CD8+ T cell-dependent fashion.”

Generation of a tumour-specific immune response through modification of the tumour and its microenvironmentChanges in an irradiated tumour (A) promote rejection by effector T cells (B). Dendritic cells loaded with tumour antigens migrate to lymph nodes (C) and activate T cells that inhibit metastases (D). Tumour-associated macrophages promote progression by secreting factors that include matrix metalloproteinases and immunosuppressive cytokines (E). HMGB-1=high-mobility-group protein B1. CXCL16=CXC chemokine 16. ICAM-1=intercellular adhesion molecule 1. MHC-1=major histocompatibility complex class I. VCAM-1=vascular cell adhesion molecule 1. MDSC=myeloid-derived suppressor cells.

Radiation treatment field for a patient in the abscopal pilot trial with thymic carcinoma. Sagittal (A) and coronal (B) views of two metastatic lesions in a case of poorly differentiated thymic carcinoma.Two parallel opposed radiation fields treated the most caudal metastasis, deliberately excluding the apical one.

The Standard of Care in Early Stage Lung CA• American College of Chest Physicians Evidence-based Clinical Practice Guidelines in 2007

determined that “surgical resection remains the treatment of choice for stage I and II NSCLC.”

• Lobectomy or greater anatomical resection has consistently been reported to achieve local control rates of >90% for stage I NSCL. ACCP guidelines: lobectomy preferred over sublobar resections (with wedge resection or segmentectomy).

• In patients able to tolerate operative interventions but thought not to be able to undergo a lobectomy, ACCP clinical practice guidelines recommend sublobar resection over radiation therapy or other ablative techniques if medically operable.

• HOWEVER… resection as “the” standard does have several limitations. • 15-20% of patients are unable to undergo or refuse definitive surgical resection. • National Cancer Data Base study assessing 124,418 major lung resections from 2007

to 2011 found a 30-day mortality rate of 2.8% and 90-day mortality rate of 5.4% (whereas these rates are ~0% with radiation approaches). Pezzi et al. Ninety-day mortality after resection for lung cancer is nearly double 30-day mortality. J Thorac Cardiovasc Surg 2014;148:2269-77.

• Although lobectomy is considered the standard-of-care surgical procedure for stage I NSCLC, 5-15% of patients require a bilobectomy and another 4-15% require a pneumonectomy which are known to increase the risk of perioperative mortality compared with lobectomy.

Stereotactic BodyRadiotherapy

(SBRT):Selected Results for Early Lung CA

Timmerman et alRTOG 0236

2004-06N = 55

Phase II prelim results

Estimated 3 year “lobar” control rate: 91%

3y LRC: 87%

Retrospective cohort, from Wm. Beaumont, 2003-08Stage IA/B NSCLC

Median f/u = 2.5y

Surgery N=69SBRT N=58

Surgery: wedge resection, “ineligible” for lobectomy

SBRT: Medically inoperable, but technically resectable

TUMOR LYMPH NODES

TUMOR or NODES ANY FAILURE

Chang et al. Lancet Oncol 2015;16:630-7.

• The STARS (in the US @ MD Anderson) and ROSEL (@VU Netherlands) trials were designed to analyze the SBRT vs. surgery question.

• Patients had to have path dx in the STARS but not in the ROSEL. All patients had to be medically/surgically operable and have T1-2N0 (assessed by staging with suspicious nodes assessed by sampling) tumors <4 cm.

• 19 lobectomies5 VATS lobectomies1 wedge1 VATS N+1 aborted (distant dz)

• Small patient numbers, OS p=0.037 in favor of SBRT. Not overwhelming! Recent matched pair analyses (abstract only, 286 patients total… http://bit.ly/1QxmuyO) suggest better OS for surgery… but, again, selection bias?

• The idea of radiation and surgery being equals is provocative however… or maybe not (head/neck cancer, anal cancer, cervical CA, breast mastectomy vs lumpectomy+XRT, bladder CA, skin CA, etc etc).

• Overall survival (OS) and local control (LC) outcomes on 8 patients over a ~2.5 year period

• Low patient numbers, but remember two international trials over several years at large cancer centers accrued 31 patients!

• OS = 100%

• LC = 100%

• Median survival and LC not calculable at this point due to zero death or failure events

NEARMC Anniston

SBRT outcomes2013-2016

Stereotactic BodyRadiotherapy

(SBRT):Would you use a cute baby in

a presentation about lung cancer?

Pre-SBRT, March 2010 Post-SBRT, December 2011

SBRT patient A.B.

Stage IA NSCLC (adenosquamous)56 Gy/4 fx

PET SUV Max 7.8PRE-TREATMENTAUGUST 2013

POST-TREATMENTAPRIL 2016

PET SUV Max 1.6

NEARMC 1st SBRT patientAlive & well ~2.5 years after treatment

SUMMARY• Lung SBRT differs primarily from standard lung XRT (in the “modern clinic”) in

terms of dose/fractionation (this difference is large!)… the difference in terms of “lung sparing” and precision/accuracy is small because high precision/high accuracy treatments were already being utilized.

• Lung SBRT is a valid (superior?) treatment option for all patients with Stage I NSCLC based on the available data. It seemed clear in the past that surgical methods had higher control rates than radiation therapy… but with SBRT, this seems much less clear now.

• SBRT dose regimens deliver lower (15-30% less) total treatment regimen doses than standard radiation therapy, but much higher (500 to 1000% more) daily fractional doses. It’s the latter difference that likely accounts for higher local control rates.

• Abscopal effects of XRT are found to be higher at “ablative” doses secondary to T-cell mediated immune responses. These effects may have clinical implications.

• Active trials in America and Europe are underway looking at surgery vs. SBRT for Stage I NSCLC. But based on available evidence, SBRT for lung cancer patients is likely being under-offered/underutilized.