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Lung Cancer ASTRO refresher 2022,

Lung Cancer ASTRO refresher 2022

Small Cell Lung Cancer

Staging
AJCC
Limited stage vs. Extensive stage

Limited stage

Treatment

Concurrent platinum/etoposide based CHT x4 w/ chest RT 45 Gy / 30 fractions (CREST Trial)

1.5Gy daily BID

Target

if Free breathing (fb), use motion management

contour w/ mediastinal and lung windows

GTV: fb, GTV: min, GTV max = iGTV or ITV

CTV: +5mm (variable)

PTV: institudion specific (4mm radial, 7mm sup/inf)

+/- PCI pending restaging

HA-PCI 25Gy/10fx

Enrollment on the ADRIATIC study:

Randomized study of consolidative immunotherapy in LS-SCLC

Tx considerations

Concurrent > Seq

Shorter time from start to end of RT assd. Improved outcomes

Targets

Involved nodal irradiation: initially involved nodal regions are included

post CHT volume can be targeted

if not starting concurent on D1

Elective nodal irradiation (ENI)

evolving—not really done for SCLC

current studies use nodal staging as long a

Does the timing of CHT and completion of RT drive outcomes?

Meta-analysis of 4 randomized studies in LS-SCLC

De Reysscher D, JCO 2006

metric of SER (start to end of RT)

Low SER had improved 5 yr survival

ea wk extending SER beyond the shortest SER studied decreased absoluet 5y OS by 1.83%

confounders drive timing of tx

but, decreased SER improves outcomes in LS-SCLC

Why involved nodal versus elective for RT?

Selective Nodal Irradiaiton on basis of FDG PET Scans in LS-SCLC: prospective study.

Van Loon et al, IJROBP 2010

n=60

RT 45 Gy/30fx BID w/ concurrent plat/etop CHT

targets: only 1º tumor and mediastinal LN involved on pretreatment PET

Results:

A difference in involved nodal stations between CT alone and PET/CT was found in 30% of patients.

Isolated regional failure rate: 3% (2 patients): v. low

Grade 3 esophagitis: 12% low

Conclusion

If PET/CT is used for target delineation, involved nodal RT planning can be used with low risk of elective nodal failure

Why BID in LS-SCLC?

CONVERT trial:

BID vs QD CRT in LS-SCLC, open label phase 3 randomized superiority trial

Faivre-Finn, Lancet 2017

n = 547

Cis/etop 66/33 vs Cis/etop 45/30

Median OS

BID: 30 mo :trophy:

QD: 25 mo

2y OS: 56% vs 51%

:biohazard_sign: No diff in G3/G4 esophagitis (19%)

was designed to show superiority of QD RT, not equivalence.

BID should continue to be considered SoC

RTOG 0538
LS-SCLC definitive CRT

OS

n=927

median F/up 4 y:

statistically insignificant difference btw QD vs BID

Cord constraints
Dmax 42Gy in the BID arm
Dmax 48Gy in the QD arm
Lung constraints
Lung-PTV
V20 <35%

Superiority studies:
Is 66 better than 45? No? Then we know its not superior, but we dont have an answer for if 66 is better for patients who can’t get BID.

THORA
phase II
60/40 had higher OS rate than 45/30 (74% vs 48%)

TRISS
phase III
45/30 SIB 50

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Plan Evaluation

get a sense of what you are treating and attention to DVH

safety

coverage

isodose lines: hot and cold spots

recheck prescriptions

dose limits are generally the same as QD vs BID

exception is spinal canal

< 31

<41

Coverage

100% of Rx dose to GTV

99% to CTV

95% to PTV

if tx begins >1wk after CTV

carefully look at daily image guidance

adapt plan if necessary

treatment toxicity :biohazard_sign:

watch CBC, if neutropenic they will have esophagitis concurently

often hospitalized in the week after finishing CRT

Response

After x4 cycles CRT

CT CAP

Brain MRI

Next?

PCI

PCI

No single study shows OS benefit

Metaanalysis: PCI for pts with LS-SCLC

Auperin, NEJM 1999

7 trials

n = 987

3y OS: PCI had 5.4% absolute improvement (20% vs 15%)

incidence of brain mets decreased (59% vs 33%)

Limitations of the study era

complete remission was defined as results of CXR

:pencil2:60% of untreated patients get brain mets in 3 years
30% of treated (PCI) patients get brain mets in 3 years

PCI Dosing
RTOG 0212
if CR to CRT
Rx: 25Gy/10
2Y brain mets 25/10
vs dose escalated

Hippocampal Avoidance Studies
Dutch
Spanish
NRC-CC03 -American: Positive trial

Hopkins verbal learning test

Neurocognitive function failure (HR 0.77, p= 0.03)

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Frontiers in LS-SCLC

Dose escalation

consolidative IO

HCP avoidance PCI

Consolidative IO

Phase III randomized, double blind, placebo controlled, Durvalumab vs Durvalumab & Tremelimumab for consolidation in LS-SCLC:
ADRIATIC

Placebo vs. PDL1i vs. PDL1i & CTLA4i

High Dose vs Std Dose BID RT with LS-SCLC Phase 2

Henning B, Lancet 2021

n = 176

60 Gy/ 40 :trophy:

2y OS: 74%

PFS: HR = 0.75 (p=.13)

40 Gy / 30

2y OS: 48%

Toxicity :biohazard_sign:

about equal

both groups 85% got PCI

HCP Avoidance (HA) PCI

NRG CC001: for brain mets

HA-PCI vs PCI

lower rates of neurocog failure

no diff in

OS

CNS relapse

toxicity

Dr Cho says this is Dutch? Spanish study says there is effect.

Other HA PCI studies

RTOG CCOO3

enrolling

NKI/Dutch Cancer Agency

negative study

Spain/PREMER

positive study

limited replication of the endpoint

:pencil2: Duke series: no benefit to PCI in small tumors

PCI
Turrisi ECOG
Murray CONVERT
CALGB

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ES-SCLC

Treatment

Concurrent plat/etop x4-6 C & concurrentIO (IMPOWER133)

after, assess response and

Chest RT

CREST: 30Gy/10fx 3DCRT

MRI brain surveillance

mostly defer PCI

maintenance IO

Immunotherapy in ES-SCLC

IMpower 133: randomized Phase 3
NEJM

AteZOlizumab & plat/etoposide (doublet) + maintenance AteZOlizumab

plat/etoposide (doublet)

Median OS

IO arm: 12 mo :trophy:

doublet: 10mo

also improved PFS
in the trial they kept giving IO for at least a year and beyond

CASPIAN

Durva EC
Drva Trem EC

Chest RT :warning:

consolidative chest RT with definitive doses should be used with caution

However, in patients with good PS, excellent response CHT, a higher dose of thoracic RT

(i.e. 45 Gy in 15 fractions)

(from ASTRO clinical practice guidelines for SCLC)

Jeremic B, JCO 1999

RT in combined modality for ES-SCLC: randomized study

n=210

If CR/PR in distant sites

x3 more CRT 60Gy/40 :trophy:

OS: 17 mo vs. 11 mo

3yS: 22% vs. 9%

5yS: 9% vs 4%

x3 CHT along

Definitive CRT improves outcomes in ES-SCLC
Caveats

This hasnt been replicated

Gore, JTO 2017

RTOG 0937: Randomized phase 2 comparing PCI to PCI w/ Consolidative RT for ES-SCLC

consolidation: 3Gy x 45

distant sites: 4Gy x 10

n = 97

PCI vs PCI with Consolidative RT to chest and other met sites

ended early, futile study, negative study

1yS

PCI: 60%

PCI w/ Chest: 51%

CREST: Thoracic RT for ES-SCLC, randomized phase 3

Slotman, Lancet 2015

PCI

PCI w/ RT, 30Gy/10fx

nondefinitive dose

1yS; no diff : ~30%

2yS: 13% vs 3%

6m PFS: 24% vs 7%

Progression sites??
w/ CREST PCI the recurrence is about 40% of non-PCI brain mets
Target volumes

residual gross 1º disease

all initially involved LN stations

GTV to CTV: 1.5 cm

Caveats: :thinking_face:

Patients with brain metastases and malignant effusions were not included.

The 2 year OS and 6-month PFS outcomes were unplanned secondary analysis

Pts w/ CR did not benefit from CREST consolidation

Constraints
V20 <37%
Mean Heart dose? Probably not achievable
V60 <7% predicts for esophagitis

full lumen coverage is assd w/ toxicity (try to underdose half)

Surveillance
q3m

Pneumonitis concern?
walking O2 sat drops from baseline O2
Check CT Chest
1mg/kg up to 60mg for 1 wk
Taper slow (eval for about 6wk)
PPI
bactrim

PCI

Slotman, NEJM 2007

PCI vs None

ES-SCLC

PCI :trophy:

less symptomatic brain mets: HR 0.27

cum risk of brain mets at 1y: 14% vs 40%

1yOS: 27% vs 13%

Caveats :thinking_face:

CNS staging not required prior to study entry

CNS imaging done only for symptomatic disease, not for routine surveillance.

occult brain mets possible in randomization

Takahasi, Lancet Onc 2017

PCI vs obs in ES-SCLC, randomized, open label, phase 3

n = 224

Brain imaging prior to enrollment

imaging throughout observation course

Negative study

PCI

MOS: 12 mo

however trends to benefit PCI

6m incidence: 15% vs. 46%

12m incidence: 33% vs 59%

18m incidence: 40% vs 64%

Obs

MOS: 14 mo

Caveats :thinking_face:

study was terminated early because of futility on interim analysis

Brain RT given to 83% of patients who developed brain mets in the observation group.

maybe there's no need for PCI if theres close f/up

If PCI is deferred in ES-SCLC, brain MRI every 3 months is critical!

3 m MRI scans in Japan, no matter what. So tend not to favor PCI after chemo for ES SCLC.

Staging completed, Nonmetastatic given PCI vs no PCI, However randomization was done prior to staging.

Chemo doesnt penetrate the brain. So those who had

Non Small Cell Lung Cancer

Oligomets

Caution :warning:

The studies that showed benefit:

Had limited numbers

Had significant toxicity

Were largely not done in the immunotherapy era.

Who should get consolidative RT?

Good performance status

Shared decision making

Enroll on NRG-LU002 : Maintenance Systemic vs SBRT

Local Consolidative Therapy

Local Consolitative therapy(LCT) vs Maintenance or Obs in Oligomet NSCLC, Phase 2, randomized

Gomez JCO 2019

crit: ≤ 3 mets, no prog s/p 3m systemic tx

Maintenance/obs (MT/O)

LCT :trophy:

PFS: 4.4m vs. 14m

OS: 41m vs 17m

Caveats :thinking_face:

Closed at interim analysis of PFS benefit in LCT arms

LCT given to all active disease sites

Role of LCT in the era of IO is being defined

this was not examined

LCT was non-uniform and optimal dose, fractionation and technique needs to be defined.

Consolidation in Oligomets

SABR-COMET: SABR vs SoC palliative in Oligomets, Randomized phase 2, open label

Inc.crit: Life exp ≥6m, ECOG 0-1, 1-5 mets

Randomized to

SoC

SoC then SABR

OS: 28m vs 41m

PFS: 6m vs 12m

Caveats :thinking_face:

Only 18% of patients had primary lung cancer (n = 20)

~50% of all mets from any histo were to the lung

3 treatment related deaths

Oligomets EGFR mutated NSCLC: Role of Consolidative RT

SINDAS

EGFR mut.

Oligo-mets (≤5 mets, ≤ 2 lesions in any organ)

No brain metastases

Randomization

1st Generation TKI alone

1st Generation TKI+RT to all metastases and primary tumor/involved regional lymphatics. (25-40 Gy in 5 fractions)

Outcomes:

Progression Free Survival

Overall Survival

Toxicity

Digression:
Principles of local therapy

old paradigm

local therapies early

systemic therapies late

more often now consider

systemic therapy in early disease

local therapy in late disease

in General, consider local therapies in Lung cancer for

Palliative

CNS disease

Oligomets

Isolated progressive disease

Oligomets vs Isolated Progression

Oligo

limited # of mets sites

treated w/ definitive therapy

then consolidative therapy to primary

Isolated Progressive

Mets treated with systemics

favorable response

some area with isolated progression

ablative therapy to this area

can continue to use effective systemic therapies

Locally Advanced

Many Treatment options

Induction CRT :radioactive_sign: followed by resection :hocho:(Albain)

Def. CRT :radioactive_sign: followed by consolidative IO :pill:(PACIFIC)

Induction CHT :pill: followed by resection :hocho: (Pless) ?(PORT)

Induction chemoIO :pill: followed by resection :hocho:(CheckMate 816)

NCCN is a compendium for IO and CHT. NAC is key.
All the NAC trials needed to be resectable at baseline.
IO path CR rates 18-24%
5-20% dont mate it to sx. of them 50% have progression while on CHT/IO NAC
Path CR: EFS 80-90%

Albain

Trimodality is not as good, surgery deaths (5) remove benefit

Induction CRT :radioactive_sign: followed by resection :hocho:(Albain)

Stage III NSCLC

phase 3, randomized controlled

n= 202

Randomized

Arm 1: Cis/Etop (2 cycles)/RT (45 Gy) → rescan (no progression) → resection :hocho: → 2 cycles chemo

MOS: no diff. (~23m)

PFS: 13m vs 11m

Arm 2: Cis/Etop/RT (61 Gy) → 2 cycles chemo

Unplanned exploratory analysis :thinking_face:

Improved OS for lobectomy
(vs. chemoRT alone)

not for patients who underwent pneumonectomy (vs chemoRT)

Negative study: no evidence for resection :hocho: with stage III disease

however selecting for lobectomy, may be appropriate

PACIFIC: non surg (unresectable)

Def. CRT :radioactive_sign: followed by consolidative IO :pill:(PACIFIC)

randomized, Double blind, placebo controlled

inc.crit: unresectable, st. III NSCLC :-1::skin-tone-5:w/o progression after ≥2 cycles plat. CRT

WHO PS 0-1

PDL1 status doesnt matter

n=713

Until progression

Durvalumab(PD-L1i) ≤1 year

5y PFS: 17m vs 6m

5y OS: 48m vs 29m

Placebo ≤1 year

Tox
Grade 3 pneumonitis: 15%

NCCN guidelines endorse IO after chemoRT in stage III unresectable disease

no EGFR/ALK: we dont know what to do for these mutations.

LAURA study ASCO loc adv following chemoRT, unlimited Osimertinib

ALK several studies show no benefit.
low PDL1, no benefit

TPS only includes tumor cells

CPS both immune and tumor cells

benefit for starting Durva w/in 2 weeks

PORT

Induction CHT :pill: followed by resection :hocho: (Pless) ?(PORT)

Operative st. IIIa/N2 NSCLC :+1:

n = 232

Randomized to

chemo x 3 cycles →RT alone (44 Gy/22 fr) →resection

chemo x 3 cycles → resection

Negative study

event free or OS

CHT alone is reasonable

disappointing nodal downstaging (to N1 or N0)

CRT (65%); CHT (53%)

Caveats :thinking_face:

sequential CHT and RT; not done today

Dose is wrong (44Gy/22)

CheckMate 816 neo adj IO only 3C

Induction chemoIO (NIVOlumab) (PD-1i) :pill: followed by resection :hocho:(CheckMate 816) 2021

randomized, open label, Phase III

n = 358

inc.crit: newly dx resectable st. IB to IIIA NSCLC :+1:

stratified by IB, IIA, IIB, IIIA

no EGFR or ALK mut

ECOG PS 0-1

... Nivo killed it

pCR

IB: 40% vs 0%

IIA: 25% vs 3%

IIB: 24% vs 9%

IIIA: 23% vs 1%

prelim improvement in OS.

updates will include event free survival improved.

not yet published

FDA approved(can use the regimens and insurance wll cover)

Centilmab: from China
not FDA improve

Keynote 671

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AGEAN
also Durva
not yet FDA approved. No improvement in OS.

New study for introducing Durva during CRT- negative trial
wait 1 month then PET, then start Durva if PCR.

Evaluating locally advanced disease. How to do it rationally

LA-NSCLC
Medical inoperability

Will pt medically tolerate it?

NAC wont change medical operability of pt

mostly wont change extent of resection either

unclear if induction ChemoIO converts bulky disease into resectable (prob not)

caution using Checkmate 816 for unresectable disease to turn an inoperable into operable (not good practice)
Technical inoperability

Can oncologic resection be achieved?

Nature of N2 disease

single vs multistation

bulky vs not

R0 resection possible

Extent

Lobectomy vs. Pneumonectomy

Pulmonary reserve allows this to occur

PFT

quant V/Q
Patient preference

Dose

Studies (ROTG 0617) fail to show benefit in unresectable NSCLC >60Gy
Neoadjuvant CRT

Studies have gone higher than Albain #

60Gy instead of 45 Gy

RTOG 0617

60Gy vs 74 Gy

mOS: 29m vs 20m

IMRT vs 3D

IMRT

larger PTV

more stage IIIB disease in cohort

No OS, PFS, LC, met control difference

fewer gr. 3 pneumonitis (3.5% vs 8%)

lower heart :<3: dose; lower V40

RTOG 0229

61.2Gy preop

14% gr. 3 pulm complications

3% gr. 5 tox

2yOS = 54%

higher dose both reasonable and safe to consider

Technique

IMRT vs 3D

RTOG 0617

Technique

Protons vs. Photons

Liao, JCO 2018

n=149

Protons= 57

nonsurgical locally adv. NSCLC

proton plans had better heart sparing

no diff in lung or eso dose

IMRT had better 12 mo gr. ≥3 pneumonitis (6.5% vs 10.5%)

loc failure at 12m no diff

Caveats :thinking_face:

enrollment required acceptable plans for both IMRT and PSPT

Passive Scatter protons is now antiquated

PSPT had diff rates of pneumonitis depending if enrolled early (31%) vs late (13.1%)

there may be a learning curve

ongoing phase II study of IMRT vs next gen Protons

Unresectable Stage III disease

Most with unresectable St. III lung cancer will get CCRT (concurrent CRT) regimen followed by IO

SOC: CCRT → Durva

Where are we going? Unresectable Stage III

NAC+IO → CCRT + Pembro

PARPi

other novel therapies

Keynote 799

Jabbour JAMA onc 2021

NAC chemoIO → CCRT + Pembro

outstanding obj response rate

6m: 90%

12m: 75-80%

2 diff chemo regimens

Toxicity :biohazard_sign:

Gr 5 4%

Resectable disease

Checkmate 816 and Albain

if induction given with CRT, higher mediastinal clearance, but no data shows it improves outcomes over chemo alone

if induction given with CHT, PORT should be cautiously administered.

pN2 disease can improve mediastinal relapse, but PORT hasnt shown OS benefit.

pN2 after resection

PORT metaanalysis

suggested PORT was harmful

retrospective data and subgroup analysis shows improvement in PORT with N2

ANITA subgroup

Doullard IJROBP 2008

NCDM, JCO 2015

Robinson JCO 2015

Lung-ART

Le Pechoux Lancet 2022

RCT PORT after resection for N2 st. III NSCLC

n= 501

R0 resection and x4 cycles platinum CHT

pre- and or post op CHT

3y DFS not changed in PORT vs no PORT

3yOS: no diff

Mediastinal relapse PORT benefit (25% from 46%)

in N2 mediastinal resected disease, PORT had 8% CV :<3: deaths vs. 0%
:pencil2: No 3DCRT for pN2 dz, heart dz.

PORT-C

N2 NSCLC with R0 resection & x4 cycles platinum CHT

3y DFS no diff

mDFS no diff

Per protocol analysis

3yDFS PORT (43%) vs no PORT (31%)

Some use PORT-C to justify PORT
IMRT didnt improve outcomes vs. Lung-ART, but had better LC and cardiac profile

stage II-stage III, select IIIb, since we have good NAC+ IO(adds a lot), almost all patients.
(except

Stage II : NAC IO CHT.

Adjuvant IO
PORT IS EXCLUDED FROM THESE TRUALS

IMPOWER 010 : Adj
Atezo
CHT mandatory
no EGFR ALK
Drven by high PDL 1, associated with high OS

PEARL study: Adj Pembro
CHT not-mandatory

some EGFR ALK

Not correlated to PDL1

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.77 HR for DFS for both studies.

KEYNOTE 091
DFS benefit of adj pembro in stage IB-IIIA

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Early Stage

Resection?

both therapeutic and diagnostic

SoC if lobectomy

LCSG 821
classic randomized study of surgical considerations

lobectomy vs Limited resection

T1N0

n=122

LRR: x3 in limited resection group (17% vs 6%)

OS better in lobectomy (70% vs 61%)

On boards: Lobectomy is SoC

However...
JCOG0802
Segmentectomy vs Lobectomy in small peripheral NSCLC

clin stage 1A peripheral or nodule ≤ 2cm

Lobectomy (n=554) vs Segementectomy (n=552)

5yOS: Segmentectomy (94%) vs Lobectomy (91%)

higher recurrence in Segmentectomy (12%) vs Lobectomy (8%)

not meaningful survival difference

We may see smaller resection surgeries become more popular or SoC

CALGB
outer 1/3 of lung

SABR?

SoC if considering sublobar

ASTRO Guidelines: rec Bx for all pulm nodules prior to resection

if Pt declines Bx, empiric SABR maybe reasonable

50Gy / 5fx

breath hold to limit motion

no CTV expansion (GTV → PTV)

dont limit PTV to meet CW constraints

tell pt there may be CW pain

remember to contour skin, as overdose is common

prescribe using non-homogenous dose optimization

Rx btw 60-90%

achieves high dose falloff if low homogeneity

dose falloff inversely correlated with homogeneity

higher mean dose to tumor = better control

less dose to surrounding tissue

SABR Dose

BED +100 Gy

Onishi JTO 2007

n=257

st I NSCLC w/ SABR

Local Progression assd. w/ higher RT doses

and OS

SABR Technique
Single (34Gy/1fx) vs Multi (48Gy/4fx)

Videtic, IJROBP 2015

2yOS: 1 fx (61%) vs 4 fx (78%)

2yDFS: 1 fx(56%) vs 4 fx (61%)

1y primary tumor control: 1fx(97%) vs 4fx(92%)

SABR Technique
Central Tumors

Bezjak JCO 2019

n=120

central tumors T1-2

Dose escalating 5 fx SBRT

started at 10Gy, increasing 0.5 Gy per fraction until 12Gy x 5 fx cohort filled.

no dose limiting toxicities :biohazard_sign: occured to prevent escalation

Dose limiting Toxicity (DLT); 7% in 12Gy x 5 fx group

~90% local control at 2Y… pretty good

2yOS: 70%

n=2 Gr 5 events

toxicity :biohazard_sign:can come late, ie after finishing RT

Defined central tumor: within/contacting 2cm radius around prox bronchial tree or immediately adjacent to mediastinal or pericardial pleura

this study did not look at ultra-central tumors

Comparable outcomes to peripheral SABR
Central SABR is an emerging SoC

Suggestions for treating Central Tumors

Fraction patterns

50 Gy / 5 fx

60 Gy / 15 fx (hypofx)

66 Gy / 33 fx (conventional fx can be reasonable)

Meet published normal tissue constraints

NCCN : (RTOG 0618, 0813, & 0915)

TG101

RTOG0813

Treat central tumors safely

Motion management

breath holding

3D and 4D CBCT

0813: central
0915: peripheral
SUNSET/HILUS: ultracentral

[ Turrisi: BID is SoC]
Intergroup 0096
(https://www.icloud.com/iclouddrive/001F46hfiioNmHtF5kLaqJjkQ#Turrisi_Twice-Daily_Compared_with_Once-Daily_Thoracic_Radiotherapy_in_Limited_Small-Cell_Lung_Cancer_Treated_Concurrently_with_Cisplatin_and_Etoposide)
Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide.
1999, NEJM

Turrisi didnt believe in a dose response curve beyond 45

Murray in 45 BID sequential

Cord Constraint
Dmax 36Gy in the BID arm
for 1 week field covered the cord, then use of obliques

QUARTZ trial30825-X/fulltext)
Histo
PS
Age difference

Whole brain NSCLC

Concurrent CRT is SoC

Furuse Japan 1999 JCO: Phase III Concurrent CRT (CCRT) vs Sequential RT

RTOG 9410: Curran 2011 JNCI: Phase III CCRT vs. Sequential

Goustave-Roussy Meta-A 2010