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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
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
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 a, NEGM 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
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
2 more items...
ES-SCLC
Treatment
Concurrent plat/etop &
IO
x4 cycles (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
AteZOlizumab & plat/etoposide (doublet) + maintenance AteZOlizumab
plat/etoposide (doublet)
Median OS
IO arm: 12 mo
:trophy:
doublet: 10mo
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%
Target volumes
residual gross 1º disease
all
initially involved LN stations
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
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 617
1 more item...
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%
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
stage II-stage III, select IIIb, since we have good NAC+ IO(adds a lot), almost all patients.
(except
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
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
Stage II : NAC IO CHT.
Adjuvant IO
IMPOWER 010 : Adj
Atezo
CHT mandatory
no EEEGFR ALK
Drven by high PDL 1, associated with high OS
PEARL study: Adj Pembro
CHT not-mandatory
some EGFR ALK
Not correlated to PDL1
Atezo: STAGE 2 of higher PDL1 Positive: TPS > 1%
Atezo not really benefitting TPS 1-49%
Pembro: stage 1b or higher, no PDL1 status needed. (basically everyone gets this)
PDL1 negative: offer nothing
1-49: offer
50%: strongly advise pembro
.77 HR for DFS for both studies.
Turrisi: BID is SoC
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
QUARTZ trial
30825-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