[ROQs] Thoracic: Lung

Question 1

What is the TNM staging for Lung Cancer (AJCC 8th ed)?

Answer 1

Question 2

What are the NCCN guidelines re: the management of solid lung nodules detected on initial screening low-dose CT of the chest?

Answer 2

NCCN Lung Cancer Screening v 1.2025

Question 3

How are lung lobes situated anatomically and visualized on CT scans

Answer 3

Question 4

Approx what % of lung cancers are ADC vs. SqCC vs. other histologies?

Answer 4

• 40%: ADC → most common amongst non-smokers, and women
• 30%: SqCC → most commonly a/w smoking
• ~18%: Large Cell → far more common in men
• ~14% Small Cell → more common in women (3rd most common) than men

Question 5

What are the onc outcomes, including OS, for limited- and extended-stage SCLC?

Answer 5

Limted-stage SCLC:
- INT0096: BID vs. QD
– 5-yr OS: 26% vs.16% (SS)
- Convert: BID vs. QD
– Median OS: 30 mos vs. 25 mos (NS)
– 5-yr OS: 34% vs. 31% (NS)
- ADRIATIC trial: CCRT (45BID or 66QD) ± PCI →🏆 durvalumab vs. placebo (another arm, durva + trem was a failed arm)
– Median OS 55.9 vs. 33.4 mos
– 2-yr OS 68% vs. 59%
– 3-yr OS 57% vs. 48%
– Median PFS 16.6 vs. 9.2 mos
– 2-yr PFS 46% vs. 34%
– Pneumonitis 3.1% vs. 2.6%

Extended-Stage SCLC: Traditionally considered an incurable disease!
- Historical 5-yr OS: <5%
- CREST trial, controversial as primary EP was not met: Consolidation RT± PCI vs. PCI alone: Controversial since primary EP was not met
– 6-mo PFS: 24% vs. 7% (SS)
– Thoracic failure: 44% vs. 80% (SS)
– CR only 5% in both arms (NS)
– Tox equivalent in both arms
– 1-yr OS 33% vs. 28% (NS); This was the primary EP of the trial
– 2-yr OS 13% vs. 3% (SS); Found on secondary analysis
- **Per recent IO trials (CASPIAN, IMPOWER 133), OS may be improving to:*
– 1.5 yr OS ~30%
– Median OS 10 → 12-13 mos

Question 6

What are the oncologic outcomes, including OS, for early-stage and locally advanced NSCLC?

Answer 6

Early Stage NSCLC:
- RTOG 0236: 54/3 (orig. 60/3)
– 3/5-yr LRC 87%/74%
– 3/5-yr OS 40%
- RTOG 0813: 5 fx dose-esc 10-12
– 2-yr: LC 89%, OS 68%, PFS 52%, DM 15%
– Gr 5 tox reported in 11.5 Gy and 12 Gy arms
- RTOG 0915, Videtic trial: 34/1 vs. 48/4, tech not powered to compare LC, OS, and DM
– 5-yr Grade ≥3 tox: 2.6% vs. 11% (SS)
– 5-yr LC 89% and 93% (SS)
– 5-yr OS 30% and 41%
– Median OS 4.1 yrs and 4.6 yrs
- AEGEAN, Surgical trial: Peri-op durva vs. CHT
–1-yr EFS 65% vs. 73%
– pCR 4% vs. 17%
– Similar tox

Locally-Advanced NSCLC:
- RTOG 0617: 60 Gy vs. 74 Gy [technically a dose-esc trial, + 2 failed cetux arms)
– Median OS: 29 mos vs. 20 mos (SS) → Same as the PACIFIC control arm
– 2-yr OS 58% vs. 45% (SS); 5-yr OS 32% vs. 23% (SS)
– 1-yr LF: 35% vs. 25% (SS) but 2-yr LF 31% vs. 39% (NS), and 5-yr LF 38% vs. 46% (NS)
- PACIFIC: Adj. durva vs. obs
– Median OS 47.5 mos vs. 29.1 mos
– 2-yr OS 66% vs. 56%; 5-yr OS 43% vs. 33%
– 5-yr new lesions 24% vs. 33%
– 5-yr brain mets 7% vs. 12%
– Median DMFS 36.5 mos vs. 17.7 mos
– ORR 30% vs. 18%
– Median PFS 17.2 mos vs. 5.6 mos
– 1-yr PFS 56% vs. 35%; 5-yr PFS 33% vs. 19%
– Grade 3-4 toxicity 30% vs. 26%

Question 7

Compromise of which nerve is a/w hoarseness for lung cancers?

Answer 7

Recurrent laryngeal nerve (CN X)

Question 8

What is the SOC for small-sized NSCLCs?

Answer 8

Per NCCN:
- Size ≤ 2cm (T1ab) → sublobar resection w/ ≥ 2 cm margins and N1 nad N2 sampling, as feasible.
– Can also be considered for patients w/ poor pul reserve or comorbidities excluding lobectomy
- Size ≥ 2 cm → Minimally invasive lobectomy (VATS vs. robotic-assisted, both are non-inferior)

Question 9

Which studies established lobectomy as the SOC for early-stage NSCLC? Are there any studies showing the utility of sublobar excision for any subset?

Answer 9

Studies establishing lobectomy as SOC
- LCSG 821, phase III: NSCLC, T1 N0 → wedge resection with a 2 cm margin vs. lobectomy.
– Both groups were staged intraoperatively.
– Results: Lobectomy vs. segmentectomy : LR: 6% vs. 18% (SS)
- ACOSOG Z4032, phase III: NSCLC, ≤ 3 cm → sublobar resection (SR) w/ and w/o brachytherapy (SBR)
– Results: SR did not improve LC for any group

More recent data for segmentectomy for size ≤ 2 cm
- Japanese, Phase III (Saji et al. Lancet 2022): size ≤ 2 cm → sublobar vs lobectomy
– Results: segmentectomy vs lobectomy: ↑5-yr OS: 94% vs. 91% (SS)
- CALGB 140503, phase III (Altorki et al. NEJM 2023): NSCLC, size ≤ 2cm → sublobar vs lobectomy, non-inferiority trial
– Results: sublobar vs lobectomy → 5-yr DFS: ~64%, 5-yr OS ~79-80% for both establishing non-inferiority

Question 10

At and above what stage is MRI brian indicated for lung cancers?

Answer 10

MRI brain for lung cancers
- IB → Consider
- ≥ II → obtain

Question 11

When does radiation pneumonitis occur, and what is the treatment?

Answer 11

• Radiation Pneumonitis; subacute tox
• Timeline: 6 wks - 6 mos post-RT
• Mechanism:
  – Pneumocyte type I death, which line alveoli and participate in gas exchange
  – Proliferation of type II pneumocytes → ↑surfactant → ↑inflammation and damage
• Tx: High-dose corticosteroids, 40-60 mg/day (1 mg/kg) and slowly tapered over 8-12 weeks

Question 12

What is the most commonly used chest wall constraint for lung SBRT?

Answer 12

• Ideal: V30Gy ≤ 30 cc → 10-15% risk of CW tox
• Realistic [Mutter et al. IJORBP 2012]: V30 < 70 cc →

Question 13

What dose constraints should be used for the heart for patients undergoing conventionally fractionated RT for SCLC?

Answer 13

Per NCCN:
- V50 ≤ 25% (most sig. a/w worse survival, per SPeirs et al. JTO 2017)
- Mean ≤ 20 Gy

Per RTOG 0617 (rule of thirds):
- V60 < 1/3
- V45 < 2/3
- V40 < 100%

Per Atkins et al. JAM Onc 2021 [associated risk of major cardiac adverse events in pts w/o pre-existing CHD]
- LAD: V15 < 10% [0 → 5%]
- L circumflex CA: V15 < 14% [0.7 → 5%]
- Mean total CA dose < 7 Gy [ 0 → 5%]
- L Ventricle: V15 < 1% [0.4 → 5%]
– In pts w/ pre-existing CAD 4 → 8%

• For the lung and the heart, make sure you have 20/20 vision while planning (mean doses!)

Question 14

If a lung cancer plan is delivered w/o heterogeneity corrections, what is the ROT for actual dose delivered, as shown by RTOG 0236?

Answer 14

• w/o heterogeneity correction, 10% cooler at the periphery BUT 10% hotter at the isocenter (eg, per RTOG 0236, 60 Gy was 54 Gy at the PTV edge, but actually 66 Gy at the center)

Question 15

Is there any data for the use of PCI in NSCLC after definitive thoracic tx?

Answer 15

Yes, but these are all in the Durva era.
- More relevant data have overshadowed the maturation of this data, ala PACIFIC

RTOG 0214, JCO 2011, JAMA 2019
- Def thoracic tx NSCLC → PCI (30 Gy in 15 fx) or obs (NOTE: No durva era)
- 5-year results: PCI vs. obs.
– 5-yr BM rate: 17% vs. 28% (SS)
– 5-yr DFS: 19% vs. 16% (SS)
– 5-yr OS: 25% vs. 26% (NS)
- Conc; PCI improves BM and DFS but not OS in the non-durva era

NVALT-11/DLCRG-02, JCO 2018
- NSCLC s/p def CCRT or seq CRT ± surgery → PCI (36/18 or 30/12. or 30/10) vs. obs\
- Results: 48.5 mos FU, PCI vs. obs
– Rate of symptomatic BMs: 7% vs. 28% (SS)
– Time to symptomatic BMs sig. ↑ w/ PCI
– Memory impairment Gr 1-2 sig. ↑ w/ PCI
– OS: 24 most vs. 22 mos (NS)

The data above may be obsolete 2/2:
- PACIFIC: Durva vs. Obs.
– BM rate: 6% vs. 12 % (SS)
- There are some recently reported studies, such as the phase II PRot-BM trial, which has shown improved OS w/ PCI for locally advanced NSCLC adenocarcinomas

Question 16

What is the benefit of using IMRT/VMAT vs. 3DCRT for locally advanced NSCLC per the secondary analysis of RTOG 0617, Chun SG et al. JCO 2016?

Answer 16

• IMRT vs. 3D CRT [0617 Secondary analysis, Chun SG et al. JCO 2016]
  – Gr 3+ pneumonitis: 3.5% vs. 7.9%
  – Lung V20 is sig. a/w Gr 3+ penumonitis (but NOT lung V5)
  – Heart dose ↓ w/ IMRT
  – Heart V40 is sig. a/w OS
  – No diff in OS, PFS, LF, or DMFS

Question 17

Which patients receiving systemic of radiotherapy are considered to be at a high risk of cardiac dysfunction?

Answer 17

• High-dose anthracycline (doxorubicin ≥ 250 mg/m?, epirubicin ≥ 600 mg/m?)
• High-dose radiotherapy_(≥ 30 Gy) where the heart is in the treatment field
• Lower-dose anthracycline (doxorubicin < 250 mg/m?, epirubicin < 600 mg/m2) in combination with lower-dose RT (< 30 Gy) where the heart is in the treatment field
  – Treatment with lower-dose anthracycline followed by trastuzumab (sequential therapy)
• Lower-dose anthracycline or trastuzumab alone, and presence of any of the following risk factors:
  – Two or more cardiovascular risk factors, including smoking, hypertension, diabetes, dyslipidemia, and obesity, during or after completion of therapy
  – Older age (≥ 60 years) at treatment
  – Compromised cardiac function (borderline low left ventricular ejection fraction [50% to 55%, history of myocardial infarction, ≥ moderate valvular heart disease) at any time before or during treatment

[Armenian et al. JCO 2017]

Question 18

What are the findings of the LUNG-ART trial (EORTC 22055, Lancet Onc 2021)?

Answer 18

• Evaluated 3D conformal (11% IMRT) PORT for NSCLC s/p complete resection, pN2
  – 34% single cN2, 25% multi cN2; 41% were path N2 only
• Neoadj or adj CHT f/b resection → post-op 54 Gy/ 27-30 fx (included ENI) vs. 🏆 no RT
  – RT given 2-6 weeks after chemo, or 4-8 weeks after surgery if neoadj chemo given
• Results: 3D conformal PORT vs. no PORT
  – 3-yr DFS 47% vs. 44% (NS)
  – Median DFS 30.5 mos vs. 22.8 mos (NS)
  – Mediastinal relapse 25% vs. 46% (SS)
  – Deaths 15% vs. 5%. (SS)
  – 3-yr OS 67-69% (NS)
  – Deaths from recurrence 69% vs. 85% (SS)
  – Deaths from cardiopulmonary causes: 16% vs. 2% (SS)
  – 2nd cancer death 5% vs. 1% (SS)
  – 2nd cancer 11% vs. 7% (SS)
  – Other deaths 7% vs. 12% (SS)
  – Penumoniits: 5% vs. <1% (SS)
  – Cardiopulm Gr 3-5: 11% vs. 5% (SS)
• Conc(s);
  – Contrast w/ secondary analysis of 0617, which showed IMRT is far superior to 3D CRT
  – Additionally, PORT-C, another trial investigating PORT for N2 disease, did not show the increased risk of death, most likely 2/2 use of IMRT as opposed to mostly 3DCRT for lung-ART (11% had IMRT still)
  – ENI in lung RT often shows an OS detriment (Yuan 2007) and increased LRR (PET-PLAN 2020), so it is not surprising that more people died in this trial.
  – R1 or ENE were specifically used as exclusion criteria, so the role of PORT in these patients remains unclear.
  – Death from cancer is lower in the PORT arm, but death from cardiopulm causes is higher. Benefit vs. risk, but is it true if IMRT was used? Prolly not!
• MNEMONIC: LUNG Adjuvant RT

Question 19

For a 4D CT scan, what do 0% and 50% phases correspond to?

Answer 19

• 0% or 100%! → maximal (end) inspiration
• 50% → maximum (end) expiration

Question 20

What are the typical imaging findings of NSCLC, SCLS, and other mediastinal tumors?

Answer 20

Pathognomonic imaging findings:
- Coin lesion with ipsilateral mediastinal LAD → NSCLC
- A small peripheral tumor w/ scant to no mediastinal LAD → early-stage NSCLC
- Hilar mass w/ massive mediastinal LAD → SCLC
- Posterior mediastinal mass displacing aortic arch anteriorly → a neurogenic tumor, such as a nerve sheath tumor, sympathetic ganglion tumor, or paraganglionic cell tumor.

Question 21

Are there any trials comparing CFRT or hypofx RT vs. SBRT for early-stage NSCLC?

Answer 21

TROG 09.01, CHISEL trial (Ball et al. Lancet Onc 2019), phase III:
- T1-2N0M0, inoperable or refusing surgery
–→ 🏆 SBRT 54/3 (or 48 /4 if <2 cm from CW) vs. 3DCRT to 66 Gy, or 50 Gy/20 fx
- Results: SBRT vs. 3DCRT
– 2-yr LC: 89% vs. 65% (SS)
– Crude FFLF: 14% vs. 31%
– 2-yr OS: 77% vs. 59% (SS)
– Median OS: 5 yrs vs. 3 yrs (SS)
– CSS favored SBRT (HR 0.49, but p=0.092)
– Crude DM 16% vs. 12% (p not provided)
– Similar tox
- Conc: SBRT improves LC and OS, similar tox

LUSTRE (Swaminath et al. IJROBP 2022), phase III
- Stage I inoperable → SBRT (peripheral: 48/4, central: 60/8) vs. CRT (60/15; technically, hypofx)
- Results: Median FU 36 most, SBRT vs/ CRT
– 3-yr LC: 88% vs 81% (NS)
– Gr 3 tox: 1 pt in each arm
– 1 tx-related death w/ 60/8 to a central NSCLC
- Interpretations and Caveats: SBRT and CRT similar → LUSTRE lacked luster
– Trial was underpowered!
– CRT wasn’t technically CRT, more akin to HFRT

Question 22

Are there any trials supporting the use of SBRT for ultracentral lung tumors?

Answer 22

SUNSET (Meredith et al. IJROBP 2024), phase I:
- T1-T3, ≤6 cm (Only 1 T3)
– Ultracentral → PTV to touch or overlap the central bronchial tree, esophagus, pulmonary vein, or pulmonary artery
- RT → 60/8 (de-escalated if concern for excess tox)
– 4D CT and ITV were used to contour
– R_x to 60-90% IDL; Hotspot ≤ 120%
- Results: 3-ry
– LC 90%; RC 96%; DM 14%
– Gr 3-5 tox → n=7
– Gr 3 Dyspnea n=1
– Gr 5 pneumonia n=1
- Interpretation and Caveats:
– 60 Gy/ 8 fractions shows favorable toxicity and local control for ultracentral lung tumors

HILUS (Lindberg et al. J Thoracic Onc 2021), phase II
- Ultracentral tumors: ≤1 cm from PBT (median 0 mm)
– Stratified by Group A (tumors ≤ 1 cm from mainstem bronchus or carina) and Group B (all others)
- RT → 56/8; R_x to 67% IDL encompassing PTV
– NO 4D planning
- Results: 2-yr
– LC 83%, OS 58%”
– Grade 3+ tox: 34% (22/65 patients)
– Grade 5 tox: 15% (10/65 patients)!
– Group A: 8/39 died (7 bronchopulmonary hemorrhage, 1 pneumonitis)
– Group B: 2/26 died (1 esophageal fistula, 1 bronchopulmonary hemorrhage)
– Median time to fatal bronchopulmonary hemorrhage 15 mos (2-22 mos)
– All with fatal hemorrhage had EQD2 Dmax to mainstem bronchus/trachea > 100 Gy
- Interpretation and Caveats:
– 56/8 to the 67% IDL carries a high risk of high-grade tox and should not be used for tumors ≤ 1 cm from PBT
– No 4D CT means PBT may have received higher doses than planned

Question 23

Is there data to support the use of consolidation radiotherapy for extensive stage SCLC (ES SCLC)?

Answer 23

Consolidatiive RT for Extensive Stage Trial → CREST (Slotman et al. Europe Lancet 2014)
- ES-SCLC, no brain mets, who responded to 4-6 cycles chemo, ECOG 0-2 (90% had residual disease)
- →🏆 30/10 Gy thoracic RT + PCI vs. PCI alone (25/10)
- Results:
– 6-mo PFS: 24% vs. 7% (SS)
– Thoracic failure: 44% vs. 80% (SS)
– CR only 5% in both arms (NS)
– Tox equivalent in both arms
– 1-yr OS 33% vs. 28% (NS); This was the primary EP of the trial
– 2-yr OS 13% vs. 3% (SS); Found on secondary analysis
- Interpretation and Caveats:
– Controversial trial since OS at 1-yr time point, the primary EP of the trial, was NS!
– BUT Consolidative thoracic RT improves 2-yr OS in ES-SCLC that responded to chemo

Other studies that have suggested a benefit
- Jeremic et al. Yugoslavia JCO 1999: 5-yr OS 4% → 9 %
- Note that in the era of use of first-line IO for ES-SCLC (CASPIAN, IMPOWER 133), the role of consolidation thoracic RT is unclear as both trials did not allow for consolidation RT to the chest, but did allow PCI

Question 24

What size cut-off is used by MedOnc to offer CHT to LN- lung cancer patients?

Answer 24

Somewhat unclear:

• CALGB 9633:
  – ≥ 4 cm (T2b, Stage IIA) has improved outcomes w/ CHT
• LACE (Lung Adj. Cisplatin Eval):
  – 5% OS benefit at 5 yrs
  – But OS not improve in IA or IB

Question 25

What is the primary evidence for the use of BID RT as a SOC for LS-SCLC?

Answer 25

Turrisi et al. NEJM 1999 (INT 0096) - LS-SCLC -- Ipsilateral hilum, ipsilateral SCV, and bilateral mediastinum allowed. -- Exlusions: contralateral supraclavicle or hilum - → 45/25 QD vs. 🏆 45/30 BID -- concurrent cisplatin and etoposide x4 cycles q3weeks. RT started w/ cycle #1 -- Cisplatin 60 mg/m² and etop 120 mg/m² q3 weeks x4C - Results: -- Median OS 23 vs. 19 mos -- 2-yr OS 47% vs. 41% (NS) -- 5-yr OS 26% vs. 16% (SS) -- LF 36% vs 52% (NS) -- More grade 3 esophagitis 27% vs. 11% (SS) - Int and Conc: -- 45 QD and 45 BID are not BED equivalent!

Question 26

What is the evidence for QD vs. BID RT for LS-SCLC?

Answer 26

CONVERT trial: Designed as a superiority trial, not equivalence - LS SCLC -- cis/etoposide x1, then CCRT -- → 45 Gy BID/30 fx vs. 66 Gy/33 fx (RT starts w/ 2nd cycle; no ENI) -- 4-6 cycles cis/etoposide -- PCI if indicated - Results: Favor BID but not SS -- Median OS 30.0 mos vs. 25.4 mos (NS) -- 2-yr OS 56% vs. 51% (NS) -- 5-yr OS 34% vs. 31% (NS) -- Median local PFS 20.7 vs. 17.9 mos p=0.20 -- Median DM PFS 20.2 vs. 16.6 mos, p=0.24 -- More grade 4 neutropenia with BID RT 49% vs. 38% **-- late grade 3 esophagitis in n=0 vs 7** -- No difference in febrile neutropenia or grade 3-4 pneumonitis -- Stage I-II: median OS 50 mos, 2-yr OS 64%, 5-yr OS 49%, DM 41%, LRF 14% -- Stage III: median OS 25 mos, 2-yr OS 51%, 5-yr OS 28%, DM 57%, LRF 17%" - Conclusion: Trend towards BID superiority w/ ↑esophageal tox

Question 27

What is the evidence for IO in **Limited Stage** SCLC?

Answer 27

ADRIATIC trial - LS-SCLC → CCRT (45BID or 66QD) ± PCI f/b: -- durvalumab + tremelimumab vs. 🏆 durvalumab vs. placebo - Results: Durvalumab vs. placebo -- Median OS 55.9 vs. 33.4 mos -- 2-yr OS 68% vs. 59% -- 3-yr OS 57% vs. 48% -- Median PFS 16.6 vs. 9.2 mos -- 2-yr PFS 46% vs. 34% -- Pneumonitis 3.1% vs. 2.6% - Conc: Adjuvant durvalumab after chemoradiation for limited stage SCLC improves survival

Question 28

Which trial defines the current SOC for locally advanced NSCLC?

Answer 28

RTOG 0617 (Bradley et al. Lancet 2015, JCO 2019) - Unresectable stage III NSCLC - 2x2 design: -- →🏆 60 Gy vs. 74 Gy -- →cetuximab (concurrent and consolidation) vs. 🏆 no cetuximab -- Carbo/taxol concurrent weekly and adjuvant x2 in all - Results: 🏆 60 Gy vs. 74 Gy → Worsened OS / 74 Gy, all other metrics eq. -- Median OS: 29 mos vs. 20 mos (SS) → Same as the control arm on PACIFIC -- 2-yr OS 58% vs. 45% (SS) -- 5-yr OS 32% vs. 23% (SS) -- 1-yr LF: a5% vs. 25% (SS) -- 2-yr LF 31% vs. 39% (NS) -- 5-yr LF 38% vs. 46% (NS) -- 5-yr LRF 35.7% vs. 38.4% (NS) -- 5-yr PFS 18% vs. 13% (NS) -- Median PFS 1.0 vs. 0.8 yrs -- 5-yr DM 52% vs. 58% (NS) - Tox: -- Grade ≥3 esophagitis 5% vs. 17% -- Grade 5 toxicity n=3 vs. 9 -- Grade ≥3 pneumonitis 21% vs. 19% - The Cetuximab arm had more toxicity and no OS difference - Use of IMRT vs. 3DCRT not associated with outcome - Interpretation and Conclusions: -- 60 Gy is standard for locally advanced NSCLC. Dose escalation to 74 Gy worsened OS. -- This also led to the acceptance of carboplatin and taxol into common practice rather than cisplatin and etoposide -- Concurrent and maintenance cetuximab has no role in locally advanced NSCLC

Question 29

What is the evidence for IO in LA NSCLC?

Answer 29

PACIFIC trial: - NSCLC, stage III, s/p CCRT w/ no progression →🏆 consolidation durvalumab q2 wks (IV, 10 mg/kg) x 1 yr vs. placebo - Results: -- 2-yr OS 66% vs. 56% -- 5-yr OS 43% vs. 33% -- Median OS 47.5 mos vs. 29.1 mos -- 5-yr new lesions 24% vs. 33% -- 5-yr brain mets 7% vs. 12% -- Median DMFS 36.5 mos vs. 17.7 mos -- ORR 30% vs. 18% -- Median PFS 17.2 mos vs. 5.6 mos -- 1-yr PFS 56% vs. 35% -- 5-yr PFS 33% vs. 19% -- Grade 3-4 toxicity 30% vs. 26% - Tidbits: -- Effective in all PD-L1 tumor% except in <1% -- **No benefit in EGFR+, but low power (n=35)** → ADAURA trial demonstrated a DFS benefit w/ osimertinib for stage III lung ca pts s/p surgery -- Improved OS when started <14 days after RT - Conc: Paradigm-defining trial for NSCLC

Question 30

Is there data on the omission of CTV in patients undergoing def CCRT for stage II-III NSCLC or SCLC?

Answer 30

- Yes, omission of a CTV is not a/w increased failure if an ITV is utilized - It is a/w only 2% failure within the omitted CTV margin - Thus, a CTV can be omitted if needed to meet lung and other usual OAR constraints. [Kilburn, Cureus 2016]

Question 31

What is the protocol for preparing a patient for IV contrast administration before a CT scan?

Answer 31

Question 32

What is the definition of LS vs. ES SCLC?

Answer 32

- LS-SCLC: -- Can be treated with a reasonable radiation portal. -- Includes contralateral mediastinal or ipsilateral supraclavicular nodal disease. - ES-SCLC: -- Contralateral hilar involvement is often considered extensive stage. -- M1b disease, malignant effusions, or contralateral supraclavicular involvement.

Question 33

Are there any trials comparing surgery vs. SBRT for early-stage NSCLC?

Answer 33

No randomized trials, but: - NCDB-based study (Stokes et al. 2018): - Post-tx mortality (within 30 days): surgery vs. SBRT -- 2.07% vs. 0.73% - Post-tx mortality (within 90 days): surgery vs. SBRT -- 3.59% vs. 2.93%

Question 34

Is there any data for using IO or targeted therapies in lung ca pts s/p resection?

Answer 34

ADAURA trail, phase III - STage IB-IIIA, NSCLC, EGFR+, s/p complete resection -- Staging the CT head or MRI brain is allowed. PET is not required. -- Notice that the PACIFIC trial did not find a benefit to durva in stage III pts s/o CCRT →🏆 osimertinib x3 yrs vs. placebo x3 yrs (23% crossed-over to osimertinib) - Results: Osi vs. Placebo -- Stage II-IIIA, 5-yr OS 85% vs. 73% -- Overall, 5-yr OS 88% vs. 78% -- Median OS not reached in either arm -- Stage II-IIIA, 4-yr DFS 70% vs. 29% -- Overall, 4-yr DFS 73% vs. 38% -- Stage II-IIIA, 4-yr CNS recurrence 8% vs. 14% -- Overall, 4-yr CNS recurrence 6% vs. 11% - Conc: Osimertinib improves OS, DFS and reduces CNS relapse in completely resected EGFR+ NSCLC vs. control with minimal crossover. -- ↓ 80% relative risk reduction of the rate of death or recurrence -- Additionally, a secondary analysis showed an ↓82% risk reduction of CNS recurrence or CNS-related death -- Note that LAURA is the trial that showed improved PFS and possibly OS for Osimetrinib post CCRT (Median PFS: 6 → 39 mos w/ osimertinib)

Question 35

What mutation predicts worse OS in patients w/ NSCLC, adenocarcinoma subtype?

Answer 35

- KRAS: -- ~25% of ADA -- a/w the worst prognosis -- Predicts resistance to platinum-based chemo -- KRAS G12C mutation is targetable w/ Sotorasib (SATURN trial)

Question 36

What are the esophageal dose constraints for patients receiving conventionally fractionated RT?

Answer 36

- Esophageal dose constraints -- NCCN: V60 < 17% -- RTOG 0617: D_mean < 34 Gy

Question 37

What is the evidence for targeting only PET+ disease in locally advanced lung cancer patients and omitting any ENI?

Answer 37

PET-Plan trail, Nestle et al. Lancet Oncology 2020: - Locally advanced NSCLC -- →RT to PET FDG avid sites and 50 Gy ENI vs. 🏆 RT to PET FDG avid sites only -- 60-74 Gy as high as feasible, concurrent chemo. ENI was delivered to stations at ≥10% risk based on an algorithm - Results: Conv. vs. PET-only -- LRR 29% vs. 14% (SS) -- Higher doses in PET only group: 65.3 Gy vs. 67.3 Gy - Conc: Targeting FDG avid sites only, compared to doing so with ENI, reduces LRR. -- This is the first randomized trial to show no LRR benefit to ENI; previously, retrospective data were used to justify omitting RNI

Question 38

Is there any evidence for doing HF_EBRT for NSCLC patients who are not candidates for SBRT or chemotherapy (and CCRT, by extension)?

Answer 38

UT SW study, Iyengar et al, JAMA Onc 2021 - NSCLC, Stage II-III, not chemo candidates -- Zubrod PS ≥2; 10% weight loss in 6 months -- Imbaalnced cohorts: HF-EBRT had more N1; CF-EBRT had more N3 - Results: 60/30 vs 60/15 -- 1-yr OS 38% vs. 45%, p=0.29 -- Median OS 8.2 mos vs. 10.6 mos (NS) -- 1-yr PFS 6.4 mos vs. 7.3 mos (NS) -- Grade 2 esophagitis 22% vs. 8.7% (NS) - On MVA, receipt systemic therapy and max dose to esophagus most associated with OS - Interpretation, Conclusions, and Caveats: HF-EBRT is not superior to CF-EBRT -- Closed early due to futility -- Designed as a superiority trial, so it does NOT prove that HF-EBRT is non-inferior or. equivalent to CF-EBRT

Question 39

Does lung SBRT affect PFTs?

Answer 39

- No evidence of any sig. change in PFTs post SBRT

Question 40

What are the FEV and DLCO thresholds for determining surgical resection for SCLC patients?

Answer 40

- Suitable & safe -- FEV1 > 70% of predicted -- DLCO > 70% of predicted - Borderline -- FEV1: 40-70% of predicted -- DLCO: 40-70% of predicted - Not-suitable -- FEV1 < 40% of predicted -- DLCO < 40% of predicted

Question 41

What is the average FEV1 of a healthy adult?

Answer 41

- Healthy male: 3.5-4.5L -- 5 yr OS for someone w/ FEV1 < 1L → 50%, if < 0.75L → 33%! - Healthy female: 2.5-3.5L

Question 42

Are there any trials investigating safe SABR doses for patients w/ ILD?

Answer 42

- Yes, ASPIRE-ILD, Palma et al. - Results have not been published yet

Question 43

What lung dosimetric parameters are a/w increased risk of lung tox in patients w/ ILD undergoing SBRT?

Answer 43

MA by Chen et al., IJROBP 2017 - Treatment (SBRT)-related mortality -- V20 > 6.5% vs. ≤ 6.5: 11%→ 32% -- MLD > 4.5 Gy vs. ≤ 4.5: 11 → 33%

Question 44

What are some radiographic findings of ILD?

Answer 44

- Reticular pattern - Honeycombing - Fibrotic changes

Question 45

What % of lung cancers are related to smoking, radon gas exposure, and genetic mutations?

Answer 45

- Smoking → 90% - Radon → ~10% - EGFR, EML4-ALK fusioins → Minority

Question 46

Do we have pathologic data to confirm the effectiveness of SBRT? Alternatively, do we have data for using SABR/SBRT in early-stage NSCLC patients who are medically fit for surgery?

Answer 46

- Yes, MISSILE-NSCLC trial, Palma et al, JAMA 2019 - Operable NSCLC, T1-2, N0, M0 - SBRT→ VATS lobectomy or sublobar resection after 10 weeks -- SBRT doses: 54 Gy/3 fx if peripheral, 55 Gy/5 fx for chest wall contact or size >3 cm, 60 Gy/8 fx if within 2 cm of MS or brachial plexus - Results: Of those who had surgery: -- pCR 60%, major pCR 63% -- 5-yr LC 94% -- 5-yr RC 80% -- 5-yr DM 18% -- 2-yr OS 77%, 5-yr OS 67% -- No 30- or 90-day post op deaths -- Grade 3-5 toxicity in 17% - Conc: -- With SBRT followed by VATS resection, the pCR rate was lower than expected but higher than in many pre-op chemoimmunotherapy trials. Toxicity and post op deaths were similar to surgical series. -- Randomized trials are warranted to detect if pre-op SBRT results in any survival or DM benefit." -- One criticism of this trial is that 10 weeks was insufficient to detect the actual pCR from SABR/SBRT. Another trial, SABR-BRIDGE, investigates delaying surgery by 3-6 mos!

Question 47

What are some of the tx options and associated outcomes for primary tracheal malignancies?

Answer 47

- Limited data on how to treat primary tracheal malignancies - Medial survival for patients with malignant tracheal tumors -- Surgery+RT = 91 mos -- Surgery without RT = 42 mos -- RT alone = 12 mos -- No surgery or RT = 5 mos -In a patient with primary malignant tracheal tumors, consider using RT to improve OS.

Question 48

What is the timeline for the development of rib fractures from SBRT?

Answer 48

- ~2 yrs, although it can happen as soon as three mos - More common w/ higher doses, in females, low baseline mineral density, and location

Question 49

Which LN stations can be accessed via a cervical vs. a chamberlain (anterior) mediastinoscopy vs. EBUS?

Answer 49

- Cervical LN stations a/w the airway: -- Pretracheal: 1 -- Upper and Lower Paratracheal: 2, 4 -- Anterior subcarinal: 7 -- Hilar: 10 - Chamberlain (L anterior mediastinotomy) -- Lower pretracheal: 4 -- A-P window: 5 -- Para-aortic: 6 -- Subcarinal: 7 - EBUS: -- 2, 3P, 4, 7, 10-12 - EUS -- 2L, 3P, 4L, 7, 8, 9 NOTE: Mediastinoscopy is still considered the gold standard for nodal staging

Question 50

What is the gold standard for lung cancer patients' nodal, eg, mediastinal staging and when is it indicated?

Answer 50

- Mediastinoscopy - Mediastinotomy - EBUS - EUS Indicated when there is a suspicion for N2/N3 disease based on initial staging imaging

Question 51

What is the specificity and sensitivity of CT and PET/CT scans for the nodal, eg, mediastinal staging?

Answer 51

- CT -- SP: 81% -- SN: 55% - PET/CT -- SP: 88% -- SEN 80%

Question 52

What trials show the benefit of concurrent CCRT over sequential chemoradiotherapy for locally advanced NSCLC?

Answer 52

- Yes, RTOG 9410, Curran et al, JNCI, 2011 - Locally advanced NSCLC -- seq cis/vinbl then 60 Gy RT vs. 🏆 conc cis/vinbl 60 Gy RT →conc cis/etoposide RT BID - Results: -- Median OSL: 14.6 mos vs. 17.0 vs. 15.6 -- 5-yr OS: 10% vs. 16% vs. 13% (OS SS for arms 2 vs. 1, but not for 2 vs. 3) -- LF 39% vs. 30% vs. 29% (LC in arms 2 vs. 1 p=0.09, in 3 vs. 1 p=0.053) -- DM 45-47%, NS - Conc: -- CCRT with QD RT results in improved LF and OS over induction chemo or chemoRT with BID fx. -- RTOG 0617 had much improved survival outcomes. A number of advancements were applied in 0617, including the omission of ENI (elective nodes were treated to 45 Gy in 9410), the use of IMRT, VMAT, and carbo/taxol instead of cis/etop. - Goustave-Roussy, Auperin et al JCO 2010, MA - Meta-analysis of 6 trials evaluating 🏆concurrent vs. sequential chemoRT -- WJLCG, RTOG 9410, GMMA Ankara, GLOT-GFPC NPC, EORTC 09972, CALGB - Results: -- 5-yr OS increased, 15.1% vs. 10.6% (↑5% benefit) -- 5-yr LRF improved, 29% vs. 35% -- No difference in DM -- Acute grade 3-4 esophagus toxicity increased, 18% vs. 4% -- No difference in pulmonary toxicity - Conc: Concurrent chemoradiation improves OS compared to sequential chemoRT, with increased esophageal toxicity.

Question 53

What are the primary histologies of tracheal tumors?

Answer 53

_ Tracheal Malignancies -- 45% → SqCC: often multifocal, distal 1/3 of trachea, occurs in 6th decade of life, more often locally invasive -- 17% → Adenoid Cystic: More often in the prox bronchial tree, younger pts, slow growth and late distant mets, predisposition for PNI

Question 54

Which trials establish the safety of SBRT as a SOC for medically inoperable, peripherally located early-stage NSCLC?

Answer 54

- RTOG 0236, Timmerman et al, JAMA, 2010, JAMA Oncol, 2018 - NSCLC T1-T2, medically inoperable, peripheral lesions - Phase II: SBRT to 60 Gy/3 fx (closer to 54Gy/3 fx using heterogeneity corrections) rx to peripheral lesions; no CTV expansion! PTV = GTV + 5 mm radial + 10 mm CC. If 4D CT is used, 5 mm isometric expansion from the ITV - Results: -- 3/5-yr tumor + lobe control 91%/80% -- 3/5-yr primary control 98%/93% -- 3/5-yr LRC 87%/74% -- 5-yr RC 89% -- 3-yr OS 56%, 5-yr 40% -- 3/5-yr DM 22%/24% -- (5-yr DM 18% in T1, 46% in T2) -- DM in squamous 6%, nonsquamous 32% -- 5-yr DFS 26% -- Median DFS 3.0 yrs, OS 4.0 yrs -- 27% grade 3 toxicity and 4% grade 4 - Conc: SBRT for peripheral lung lesions is feasible and results in high LC and LRC. With longer follow-up, additional recurrences can occur.

Question 55

Which trials has investigated different dosing for SBRT of peripherally located early-stage NSCLC?

Answer 55

- RTOG 0915, Videtic et al, IJROBP, 2015, Videtic et al, IJROBP, 2018 - medically inoperable, T1-T2 N0 M0 NSCLC, peripheral lesions -- → 34 Gy/1 fx vs. 48 Gy/4 fx QD -- Primary EP: grade ≥3 adverse events <17% and LC >90% at 1 year - Results: 34 vs. 48 -- 5-yr report: Grade ≥3 tox: 2.6% vs. 11% (SS) -- 1-yr primary control 97% and 93% -- 5-yr primary control 89% and 93% (SS) -- 2-yr OS 61% and 78% -- 5-yr OS 30% and 41% -- Median OS 4.1 yrs and 4.6 yrs -- 1/3 causes of death unknown, 1/3 unrelated to cancer, 1/3 deaths cancer related -- 2-yr PFS 56% and 71% -- 5-yr PFS 19% and 33% -- 5-yr first failure DM 19% and 41% -- 5-yr 2nd primary 16% and 13% - Conc: Phase II trial, not powered to compare LF, PFS, and DM -- Both fractionations met the prespecified endpoints and warrant further testing.

Question 56

Which trials establish the safety of SBRT for medically inoperable, centrally located early-stage NSCLC?

Answer 56

- RTOG 0813, Bezjak et al, JCO, 2019 - Centrally located tumors, T1-T2 <5 cm, medically inoperable -- Dose escalation trial: SBRT to 10, 10.5, 11, 11.5, 12 Gy, all in 5 fx -- Endpoint: 1-yr grade ≥3 toxicity <20% - Results: 12 Gy was technically MTD -- 1-yr grade 3+ toxicity of 7.2% -- 2-yr: LC 89%, OS 68%, PFS 52%, DM 15% -- Within one year, a total 9% deaths (!) -- 11.5 Gy→ 3/25 deaths (esophageal ulcer erosion into vessel and 2 bronchopulmonary hemorrhages) -- 12 Gy had 1/21 die: (bronchopulmonary hemorrhage - Conc: The highest dose level allowed, 12 Gy x 5 fx, was tolerated as defined by the predetermined endpoint of grade 3+ toxicity <20% at short f/u of 1 year. - However, after 1 year, there were deaths with 11.5 and 12 Gy due to hemorrhage and ulceration. The trial was not powered to compare local control. - Editorialization: Consider anticoagulants a contraindication for higher doses, and only treat peripheral lesions with higher doses.

Question 57

Which studies provide evidence for using pre-op CCRT for NSCLC (trimodality therapy)?

Answer 57

- INT 0139, TROG 9309, Albain et al, Lancet 2009 -- T1-3N2, Stage IIIA, NSCLC, technically resectable -- 45 Gy w/ concurrent cis/etoposide → if no PD →surgery vs. → RT to 61 Gy total (uninterrupted) then adjuvant x2 cis/etoposide in both arms - Results: -- PFS 12.8 mos surgery vs. 10.5 mos -- 5-yr PFS 22% surg vs. 11% -- More tx-related deaths with surgery -- LR only 22% vs. 10% (Primary recurrence 14% vs. 2%) -- Median OS ~23 mos (NS) -- 5-yr OS 27% vs. 20% (NS) - In exploratory analysis, lobectomy had improved 5-yr OS 18% vs. 36%, but not pneumonectomy - Conc: -- The addition of surgery to chemoRT in Stage IIIA NSCLC did not result in OS benefit overall. -- On exploratory analysis, there is an overall survival benefit with radiation in those who had lobectomy. -- Some institutions treat to higher doses (60 Gy) w/ the advantage being delivering complete dose even if the pt does not undergo surgical resection

Question 58

What is the current SOC for Pancoast tumors (NSCLC)?

Answer 58

Neoadj. CCRT → Resection

Question 59

Which studies provide evidence for the use of pre-op CCRT and form the current SOC for superior-sulcus tumors?

Answer 59

- INT 0160, SWOG 9416, Rusch et al., JCO 2007 - Superior sulcus T3-4, N0-1 -- Apical tumor with Pancoast syndrome with or without inv chest wall or spine -- Superior or sulcus tumors with inv of chest wall, spine, or subclavian vessels - Cis/etop x 2C + 45 Gy → If no progression → Surgery in 3-5 weeks → cis/etop x2 -- Surgery was lobectomy/pneumonectomy - Results: -- 80% had surgery, 94% of these were R0 (75% of all) -- ***55% pCR or near CR (erroneous in abstract and pub. Numerically calculated, near pCR was 70%)*** -- 5-yr OS 44% -- Median OS 33 mos -- No difference in T3 vs T4 -- If R0: 5-yr OS 54%, Median OS 94 mos -- Crude DM 41% (calc from Table A5) - Conc & Int: -- For superior sulcus tumors, chemoRT followed by surgery and adjuvant chemo is feasible and leads to excellent outcomes. -- OS sig. Improved compared to 0617?

Question 60

What is the evidence for the use of CHT & IO combination for resectable NSCLC?

Answer 60

- NADIM, phase II trial (Provencio et al., Lancet Onc 2020) -- Resectable IIIA NSCLC → neoadjuvant NIVO x3C + CHT (Carbo/Taxol) f/b surgery f/b IV NIVO x 1 yr - -- pCR w/ CHT/IO: >50% -- ↑3-yr PFS 70% → 82% -- Paved the way for Checkmate 816 - CheckMate 816, Forde et al, NEJM, 2022, Awad et al, JCO, 2025\ - Stage IB - IIIA NSCLC -- 64% stage IIIA -- 50% had PD-L1 ≥1% - CHT alone vs. 🏆 Nivolumab + CHT q3w x3 vs. 🏆 IPI/NIVO + CHT q3w x3 → surg in 6 weeks - Primary endpoints: EFS, pCR - Results: CHT vs. CHT+IO -- Proceeded to surgery: 76% vs. 84% -- pCR: 2% vs. 24% nivo (PDL1 ≥50% → pCR 44%) (SS) -- Median EFS 20.8 vs. 30.2 mos (SS) -- 2-yr DMFS 76% vs. 57% -- RT for recurrence 22% vs. 11% -- 1-yr no disease progression/recurrence 63% vs. 76% -- grade 3+ toxicity 37% vs. 34% - IPI/NIVO amendment → unpowered for comparisons -- pCR 4.6 vs. 20.4 -- Median EFS 20.9 vs. 54.8 mos -- 3-yr OS 61% vs. 73% - Conc: -- Dose of neoadj nivo 360 mg -- Neoadjuvant nivolumab + chemo → surgery improves EFS and pCR compared to chemo alone in resectable NSCLC w/o increasing tox -- Neoadjuvant nivolumab plus ipilimumab also shows improvement in OS and EFS, though this arm was added to the protocol in a late addendum and is unpowered.

Question 61

What is the primary risk w/ using RFA for early-stage lung cancer?

Answer 61

RFA Risks for early stage lung cancers: - Pneumothorax: 52% - Pleural effusions: 19% - 30-day mortality: 2.6%

Question 62

What are the dose constraints for OARS per RTOG 0815?

Answer 62

- PBT (5 fx): -- V18 < 4cc; D_max -- < 105% of R_x

Question 63

How do you contour the PBT, per the protocol for RTOG 0815?

Answer 63

- Proximal Trachea: -- Sup: 10 cm superior to PTV or 5 cm superior to the carina (whichever is more exceptional). -- Inf: Continues inferiorly to the superior aspect of the proximal tree. - Proximal Bronchial Tree (PBT): -- Sup: Inferior 2 cm of the distal trachea -- Inf: End when lobar bronchi branch into segmental

Question 64

Which seminal, albeit outdated trial, established 60 Gy as the def dose for locally advances NSCLC?

Answer 64

- RTOG 7301, Perez et al, Cancer 1982 -- Compared: split course 40 vs. 40 vs. 50 vs. 60 -- Split course 40 had the worst OS and LF

Question 65

What were the findings of the Sundstrom trial (JCO 2004) investigating hypofx RT schedules for local control/palliation in people w/ lung cancer far too advanced for curable therapy?

Answer 65

- Sunstrom (JCO 2004): Inoperable, disease too advanced for curative therapies, chest sx of central tumor threatening airways - → 17 Gy in 2 fx given once weekly, 42 Gy in 15 fx, or 50 Gy in 25 fx - Result: Health-related QOL and median OS (~7-8 mos) eq. b/w all tx arms

Question 66

What is≥ Gr 2 pneumonitis risk w/ lung V20Gy < 30% per QUANTEC?

Answer 66

Risk of >- Gr 2 Radiation Pneumonitis - < 30% → 9.6% - 31-40% → 14.3% - > 40% → 47%

Question 67

How is CHT dosed for locally advanced lung cancer and SCLC patients receiving CCRT?

Answer 67

- NSCLC undergoing CCRT, per 0617 -- Paclitaxel: 45 mg/m² + Carboplatin: AUC 2 -- Given on days 1, 8, 15, 21, 29, 36 -- TL;DR: Given once weekly - Or Cisplatin etoposide -- Cisplatin 50 mg/m₂ (IV, days 1 and 8) + etoposide 50 mg/m₂ (IV on days 1-5) x q4weeks x 2C during RT and 2C adjuvantly - For SCLC: -- Cisplatin 80 mg/m² and etop 100 mg/m² q3 weeks x4C [CALGB 30610]

Question 68

What are the USPTF recommendations for who should receive lung cancer screening?

Answer 68

- USPSTF Lung Cancer Screening Guidelines -- Age 50-80 -- ≥ 20 pack year hx -- Active smokers -- Quit ≤ 15 years ago - Based on combined recommendations from the NLST and NELSON trials - Recommend screening w/ low-dose CT scans - Report relative risk reduction of 20% for lung cancer mortality

Question 69

Which trials have evaluated the role of PCI in ES or LS SCLC?

Answer 69

- NRG CC003: LS- or ES-SCLC →25 Gy/10 fx vs. 25 Gy/10 fx w/ hippocampal avoidance -- 12-mos intracranial recurrence ~15%, noninferior - No difference in HVLT-R or DR, but HA led to less neurocognitive failure - Takahashi et al., Lancet Oncol 2017 → ES-SCLC, responded well to CHT, no mets on Brain MRI -- → PCI 25 Gy/10 fx vs. MRI surveillance - Results: No OS benefit with PCI. BM improved -- 1-yr OS 54% vs. 48% (NS) -- 2-yr OS 15% vs. 19% (NS) -- Median OS 11.6 mos PCI vs. 13.7 mos (NS) -- 1-yr brain mets 33% vs. 59% (SS) -- Overall brain mets 48% vs. 69% (SS) - EORTC 08993/22993, Slotman et al, NEJM 2007: ES-SCLC - 4-6 cycles of chemo, wait 4-6 weeks, then if any response to therap→ PCI 20-30 Gy vs. obs - Results: MRI not required for randomization (before MRI era) -- 1-yr OS 27% vs. 13% -- median OS 5.4 mos vs 6.7 mos (after randomization) -- 1-yr symptom detected BM 15% vs. 40% -- median DFS 12.0 weeks vs 14.7 weeks -- 1-yr extracranial progression: ~90% (NS) - Context: MAVERICK Phase III trial, currently ongoing, is comparing MRI surveillance w/ PCI in SCLC patients, and may obviate the need for PCI. This is similar to the Takahashi trial noted above. -- A lot of practitioners are already pivoting to MRI surveillance in light of the Takahashi trial while waiting for the results of MAVERICK.

Question 70

Is there any benefit to using induction CHT before definitive CCRT for NSCLC?

Answer 70

- No, no level I evidence supports the use of CCRT - CALGB 39801, Vokes et al, JCO 2007 → no improvement in OS, increase in tox

Question 71

Which trials have contributed to the SOC of LA NSCLC?

Answer 71

1. RTOG 7301: ?? 2. CALBG 8433: ?? 3. RTOG 39801, Vokes et al: ?? 4. RTOG 9410, Curran et al: ?? 5. RTOG 0617: ?? 6. PACIFICL ??

Question 72

Which trials have established the use of IO as SOC for **ES**-SCLC?

Answer 72

- IMPOWER 133, Horn et al, NEJM, 2018, Lui et al, JCO, 2021 - Extensive stage SCLC with no prior therapy - → 🏆 atezolizumab (anti PD-L1) + carbo/etop vs. placebo + carbo/etop -- PCI allowed but NOT consolidative chest RT - Results: -- Median OS 12.3 mos vs. 10.3 mos -- 1.5-yr OS 34% vs. 21% -- Median PFS 5.2 mos vs. 4.3 mos -- CR 3% vs. 1% -- Benefit in any PDL1 status -- Time to intracranial progression -- 20.2 vs. 10.5 mos -- If no PCI, intracranial progression -- 16.7 vs. 9.8 mos -- Progression at initial sites 59% vs. 56% -- Progression at new sites 53% vs. 48%" Conc: First-line atezolizumab in extensive-stage SCLC improves OS and PFS and delays the time to intracranial progression. - CASPIAN, Goldman et al., Lancet, 2020 - Newly dx ES-SCLC → durvalumab + tremelimumab + plat/etop vs. 🏆 durvalumab + plat/etop vs. plat/etop -- PCI allowed in the control arm, but PCI and consolidation RT prohibited in the IO arms - Results: -- Median OS 10.4 vs. 12.9 vs. 10.5 mos -- CR 3% vs. 3% vs. 1% -- Serious toxicity 45% vs. 36% vs. 32% -- Treatment deaths 5% vs. 2% vs. 1% - Conc: -- Durvalumab + platinum/etoposide improves OS in extensive stage SCLC compared to chemo alone. -- The addition of tremelimumab to durvalumab + chemo did not improve outcomes.

Question 73

What is the current SOC for LS-SCLC and ES-SCLC?

Answer 73

- Per ASCO, -- LS-SCLC → CCRT: concurrent chemoradiotherapy with curative intent. Chemotherapy should be initiated as soon as possible and not deferred until radiation therapy can be started. The typical regimen includes cisplatin or carboplatin w/ etoposide -- ES-SCLC → CHT w/ IO First-line systemic therapy with a combination of platinum (cisplatin or carboplatin) and etoposide plus immunotherapy (atezolizumab or durvalumab), followed by maintenance immunotherapy if there are no contraindications to immunotherapy. This approach has been shown to improve overall survival and progression-free survival compared to chemotherapy alone

Question 74

What is the 5-yr OS for someone w/ severe COPD?

Answer 74

- ~60% (Gold C and Gold D

Question 75

Are there any trials comparing cabo/taxol or EP for stage III NSCLC?

Answer 75

- Liang et al. Ann Oncolo 2018: EP vs. PC -- EP was not SS superior to PC -- Median OS: 23.3 mos vs. 20.7 mos -- ≥ Gr 2 pneumonitits higher in PC -- ≥ Gr 3 esophagitis higher in EP

Question 76

What are the brachial plexus constraints for lung SBRT?

Answer 76

- 4 fx: Brachial plexus: -- D_max < 35 Gy -- V30 ≤ 0.2 cm³ - 5 fx: Brachial plexus -- 3cc < 6 Gy/fx

Question 77

Which paraneoplastic syndromes are a/w NSCLC?

Answer 77

- PTH-rP → hypercalcemia (↑ Ca within the blood by leaching it from bones, increasing reabsorption from the kidneys, and increasing absorption from the gut)

Question 78

Which paraneoplastic syndromes are a/w SCLC?

Answer 78

- Lambert Eaton - Cerebellar Ataxia - SIADH

Question 79

What are the results from the CROWN study (Solomon et al JCO 2024)?

Answer 79

- CROWN, Solomon et al., JCO 2024: -- Newly dx advanced ALK+ NSCLC, tx-naive → loratinib (100 mg QD) vs. crizotinib (250 mg BID) - Results Lora vs. crizo -- Median PFS: NR vs. 9.1 mos (SS) -- 5-yr PFS: 60% vs. 8% (SS) -- Median TTCP: NR vs. 16.4 mos (SS) -- Any intracranial response: 60% vs. 11% -- Intracranial complete response: 49% vs. 5% -- Median duration of intracranial response: NR vs. 12.8 mos - Conc: Loratinib is the crowned SOC for ALK+ NSCLC

Question 80

Is there any data for the use of accelerated hypofx for early stage NSCLC patients who are non-surgical candidates and cannot undergo SBRT?

Answer 80

- Cheung et a., JNCI 2014 - NSCLC, T1-T3 N0 → 60 Gy in 15 fx QD, 3D CRT w/o heterogeneity corr -- The GTV was the tumor only. The PTV was the tumor plus 1.5 cm (although decreased to 1 cm if adjacent to critical structures). - The max doses were 35 Gy, 45 Gy, 50 Gy, and 50 Gy to the spinal canal, esophagus, heart, and trachea/mainstem bronchi, respectively. There was no DVH constraint for the lung or great vessels. - Results: -- 2-yr tumor control: 87.4% -- 2-yr OS: 68.7% -- 2-yr regional relapse: 8.8% -- 2-yr distant relapse: 21.6% -- Toxicities (grade 3) = fatigue (6.3%), cough (7.5%), dyspnea (13.8%), and pneumonitis (10%) - Conc: 60 Gy in 15 fx has great local control rate!

Question 81

What are some reasonable esophageal constraints for patients receiving conv fx CCRT for lung ca?

Answer 81

- Conv fx: Esophagus Constraints -- D0.03cc < 105% -- V60Gy < 17% (best predictor of Gr 3+ esophagitis (Palma et al, IJORBP 2013) -- D_mean < 34 Gy -- Can also consider contralateral esophageal sparing

Question 82

How is the tx for a potentially resectable superior sulcus tumor tx planned and sequenced?

Answer 82

Superior Sulcus tumors (SWOG 9416 / INT0160): - Very challenging to plan due to prox of spinal cord and brachial plexus - Plan for full crative dose CCRT: 61.2 Gy in 34 fx -- Spinal cord D_max < 50 Gy; Brachial Plex D_max < 66 Gy - During the last week of the first 45 (5th week), repeat a CT scan and review w/ surgeon for possible resectability. - If not a surgical candidate, proceed to complete CCRT

Question 83

For relapsed SCLC, what is the preferred treatment option per NCCN?

Answer 83

- Relapse < 6 mos → Topotecan

Question 84

When should RT be initiated for LS-ESCLC?

Answer 84

- With cycle 1, or if downstaging is needed, w/ cycle 3 at the latest

Question 85

What recommended CTV margins per a pathological analysis (Giraud et al. IJROBP 2000) are needed to cover 95% of disease for SCC vs. ADC?

Answer 85

- SCC: 6 mm - ADC: 8 mm

Question 86

What are some motion management techniques recommended in ongoing SBRT lung cancer t

Question 87

What metric was used to evaluate lung doses for RTOG 0617?

Answer 87

- Lung - CTV - Note that other studies, like RTOG 1306, used lung - GTV - There is considerable heterogeneity in the doses used!

Question 88

What are the findings of the Keynote-671 trial?

Answer 88

- Keynote-671, Wakelee et al, NEJM, 2023, Spicer et al, Lancet, 2024 - Stage II, IIIA, or IIIB (N2) NSCLC -- → platinum-based chemo alone→ surgery vs. -- →🏆 Peri-op immunotherapy: Neoadjuvant pembrolizumab + platinum-based chemo → surgery → adjuvant pembrolizumab - Results: CHT alone vs. Peri-op CHT-IO -- pCR 4% vs. 18% -- major path response 11% vs. 30% -- 3-yr OS 64% vs. 71% -- 2-yr EFS 41% vs. 62% -- Grade ≥3 toxicity 38% vs. 45% -- Perioperative pembrolizumab for surgical NSCLC improves OS

Question 89

What are the findings of the AEGEAN trial for NSCLC?

Answer 89

- AEGEAN, Heymach et al, NEJM, 2023 - Stage II, IIIA, or IIIB (N2) NSCLC -- →platinum-based chemo alone vs. 🏆 Peri-op durvalumab + platinum-based chemo -- Durvalumab was given pre-op q3w x4 doses with chemo and post-op q4w x 12 doses. - Primary endpoint: pCR & EFS - Results: -- 1-yr EFS 65% vs. 73% -- pCR 4% vs. 17% -- in PDL1 ≥50%, pCR 23% but CIs overlap -- Grade 3-4 events similar at 42-43%" - Conc: Peri-op durvalumab improves EFS and pCR in NSCLC. - Memory hook: AEGEAN Sea → kinda like PACIFIC

Question 90

What is the consensus regarding using peri-op CHT/IO for borderline resectable NSCLC?

Answer 90

ChemoRT is preferred for those who are borderline candidates for surgery, those who are unlikely to proceed to surgery due to medical conditions, those with lower PDL1, or those with high PDL1 who have poor response on imaging to immunotherapy. Poor response to chemoimmunotherapy in a borderline surgical candidate places the patient in a worse position: they then must complete chemoradiation, which will be more difficult with already impaired bone marrow, and PET images are difficult to interpret after immunotherapy due to increase in indeterminate findings (see the LYRIC criteria in lymphoma for example, Cheson 2016). The Society of Thoracic Surgeons Expert Consensus (2025) states, "Patients who are deemed initially with unresectable disease should not be treated with neoadjuvant therapy in an attempt to render it resectable. This will only serve to delay or compromise definitive nonsurgical therapy." pCRs across pre-op immunotherapy trials are variable, and higher with PDL1 ≥50%. There is still room for improvement in pCR, indicating a role for radiaton therapy. Only one study, the phase II NADIM trial, had pCR >50%. CheckMate 77T pCR 52% if PDL1 ≥50% CheckMate 816 pCR 44% if PDL1 ≥50% CheckMate 77T overall pCR 27% CheckMate 816 overall pCR 24% AEGEAN pCR 17% NADIM II pCR 37% (used carboplatin AUC 5) (n=86) NADIM I pCR 63% (used carboplatin AUC 6) SWOG 0220 pre-op chemoRT pCR 28% INT0160 pre-op chemoRT pCR 36% (table A4) MISSILE SBRT pCR 60%

Question 91

Is there data for using pembrolizumab for advanced NSCLC in previously treated, PD-L1+, patients?

Answer 91

- Yes, Keynote-010, enrolled pts w/ PD-L1 >1% -- Keytruda (2mg/kg) or Keytruda (10 mg/kg) or Docetaxel -- Median OS if PD-L1 > 1%: 10.4 vs. 12.7 vs. 8.5 mos -- Median OS if PD-L1 > 50%: 14.9 vs. 17.3 vs. 8.2 mos -- Gr 3-5 tx tox: 13 vs. 16 vs. 35%

Question 92

What's the mnemonic for immune checkpoint inhibitors and their targets?

Answer 92

- CNP AADd IT -- PD-1: Cemiplimab, Nivolumab, Pembrolizumab -- PD-L1: Atezolizumab, Avelumab, durvalumab -- CTLA-4: Ipilimumab, Tremelimumab

Question 93

Which IO is indicated along w/first-line CHT for newly dx ES-SCLC?

Answer 93

- Concurrent and consolidation Atezolisumab - Durva is another option. Nivo is not currently indicated.

Question 94

What is the mean time to a symptomatic cardiac event for patients w/ locally advanced NSCLC who receive def dose-escalated (70 Gy+) CCRT per the study by Wang et al. JCO 2017?

Answer 94

- ~1 yr (26 mos) UNC, Wang et al, JCO 2017

Question 95

Should PET/CT scans be used to monitor treatment response in patients post SBRT?

Answer 95

No, since they can be confusing. They can cause inflammation for up to two years, which could be confused for disease progression.

Question 96

What imaging findings on surveillance CT scans are most concerning for disease recurrence post-SBRT?

Answer 96

- ≥3 high-risk features can indicate recurrence -- Bulging margin -- Enlarging opacity -- CC growth -- Loss of air bronchogram -- Linear margin disappearance -- ≥3 consecutive rises in volume Lee et al, IJROBP 2021

Question 97

Which tumor of patient-specific factors are predictive of radiation-induced lung injury (RILT) in patients post-SBRT?

Answer 97

Predictive: - Age! - Tumor size - Mean lung dose - Lung V20

Question 98

What proportion of patients are upstaged when they undergo surgery for early-stage NSCLC?

Answer 98

- ~1/3 to 1/4 (25-35%)! - This makes direct comparisons w/ radiation alone patients difficult as a lot of the stage I radiation alone patients may have underlying higher stage disease and you'll never know! CALBG 9761

Question 99

For ES-SCLC, how is consolidative RT sequenced w/ PCI?

Answer 99

They are given concurrently!

Question 100

How many lung cancer patients have re-arrangements of the ALK gene, and what are the typical patient characteristics?

Answer 100

- ALK mutation: 5% → most common mutation is, ALK EML4 - Typical pt characteristics -- Younger -- Female gender -- Never smoker or minimal smoking hx -- Adenocarcinoma w/ signet ring or acinar histology -- Mutually exclusive w/ EGFR, KRAS, or ERBB2 gene mutation

Question 101

What is the annual risk of a second malignancy in patients w/ NSCLC s/p def. tx?

Answer 101

Annual risk: - Other lung cancers: 1% - Also ↑ risk of other H&N, esophageal - SCLC has an even higher risk of second lung cancers; 6%

Question 102

What is the 3-yr risk of developing brain mets for LS-, ES-SCLC patients who do not receive PCI, NSCLC?

Answer 102

- LS-SCLC: 60% at 3 yrs [Meta-analysis, Auperin et al. NEJM 1999] - ES-SCLC: 60% at 1 yr - NSCLC, lifetime incidence: 15-20% -- If EGFR or ALK mutated → 50-60%

Question 103

How are the chemotherpay dosed for LS-SCLC, per the two main trials?

Answer 103

- CONVERT: Cis/etop [75/100 mg/m²] q3 wks x4-6C - Older, Turrisi: Cis/Etop [60/120 mg/m²] q3 weeks x 4C

Question 104

Is there any evidence for the use of TTFields for NSCLC?

Answer 104

- Yes, in the metastatic setting per LUNAR phase 3 trial [Leal et al. Lancer Oncol 2023] - Metastatic NSCLC w/ prog. on plat-based systemic therapies -- → SOC CHT/IO alone vs. TTFields + SOC CHT/IO - Results: -- Median OS: 9.9 mos → 13.2 mos (SS) -- 1 yr OS: 42% v→ 53% (SS) -- Median PFS: 4.1 mos → 4.8 mos - Conc: TTFields improves OS when added to SOC systemic therapies - THis has not been adopted into the NCCN guideline yet

Question 105

Can pemetrexed or bevacizumab be used for all histologies of lung NSCLC, like SqCC or ADC?

Answer 105

- No, they should NOT be used for squamous histologies -- Pemetrexed leads to a detrimental OS for squamous histologies [Scagliotti et al. JCO 2008] -- Bevacizumab leads to ↑ bleeding events in patients w/ SqCC, tumor necrosis, cavitation, and disease close to major blood vessels

Question 106

Which vessels should the "great vessels" contour include?

Answer 106

- Only the systemic vessels leaving or entering the hear : -- Sup and inf VS -- Aorta

Question 107

When should bevacizumab be stopped for patients planned for lung SBRT?

Answer 107

- No consensus - But, there is data thaƒadent for patients who had a 90 day period before and after bev did not experience any fatal hemorrhages

Question 108

What are some relative contraindications against surgery for superior sulcus tumors?

Answer 108

- Relative contraindications to surgery for superior sulcus tumors include the involvement of: -- Brachial Plexus -- Subclavian Artery -- Vertebral Body -- Esophagus -- Mediastinal LNs -- Distant Mets

Question 109

What new targeted therapies are available to patients w/ advanced NSCLC?

Answer 109

Question 110

Does radiation improve survival in patients w/ primary tracheal malignancies?

Answer 110

- Unclear: -- SEER analysis, Xie et al. IJROBP, 2012: RT improved 5-yr OS, 28.1 → 42.3% -- SEER analysis, Urdaneta et al. Am J Clin Onc 2011: NO benefit to RT

Question 111

What are the most common histologies for primary tracheal malignancies?

Answer 111

- SqCC: 49% - Adenoid Cystic: 20%

Question 112

What was the inferior 2D field border of the radiation field in the INTG 0096 trial for SCLC?

Answer 112

- Ipsilateral hilum and b/l mediastinum - Inferior: 5 cm below the cardina or at the bottom of the involved hilum, whichever is lower. -- Remember that this trial used plain films to design RT fields. You can see the shadow of the carina on plain films, and the hilum, but not much else!

Question 113

Within what time frame is PCI indicated for SCLC?

Answer 113

- within 3-6 weeks of finishing RT

Question 114

Which patients are appropriate vs. poor candidates for surgical resection for NSCLC?

Answer 114

Bukly: When the node(s) are large (size > 2-3 cm) or confluent or encase mediastinal structures

Question 115

Broadly speaking, what size cut-off is used for SBRT for lung tumors in the major clinical trials?

Answer 115

- Generally: 4-5 cm, hence the reluctance of some to not do SBRT beyond these - But TImmerman's original SBRT trial allowed up to 7 cm (T3)

Question 116

What are the RECIST criteria for grading solid tumor response to therapy?

Answer 116

The Response Evaluation Criteria in Solid Tumors (RECIST) criteria objectively assesses solid tumors' response to treatment. The most current version, RECIST 1.1, includes the following categories for grading tumor response: 1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to <10 mm. 2. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. 3. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. 4. Stable Disease (SD): Neither suf ficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. These criteria are based on unidimensional measurements of the longest diameters of target lesions and are widely used in clinical trials to standardize the assessment of tumor response to therapy.

Question 117

Per the Pignon et al NEJM 1992 MA of LS-SCLC, which age group benefits the most and the least from CCRT vs. CHT alone?

Answer 117

- Most: < 55 - Least: >70 (SS) -- Note that more recent pubs [Corso et al., JCO 2015] show benefit in select 70 YOs

Question 118

Which paraneoplastic syndromes are a/w NSCLCs and SCLCs?

Answer 118