Lung - astro.org · •Helpful to differentiate between tumor from collapsed lung •SUV > 2.5 has...

Lung

Jing Zeng, MD

University of Washington

[email protected]

Disclosure

• Employer: University of Washington

• I have no conflicts of interest to disclose.

Learning Objectives

• Understand workup and staging of lung cancer

• Understand the general management principles for non-small cell lung cancer

• Understand the general management principles for small cell lung cancer

Table of Contents

• Background

• NSCLC • Stage I

• Stage II

• Stage III

• Special Topics for Stage IV

• Small Cell

Epidemiology

• Second in incidence, first in mortality

Siegel RL et al. CA Cancer J Clin. 2018 Jan;68(1):7-30.

Survival

SEER Cancer Statistics Review 1975-2014.

Risk Factors

• Smoking!!! • Single most important risk factor

• Globally, responsible for 80% of cases in men, 50% of cases in women

• Risk increases with duration, quitting at any age decreases risk

• <20% of smokers develop lung cancer

• Others: • Air pollution, second hand smoke, radon, occupational exposure (aluminum,

arsenic, asbestos, nickel, beryllium, etc.), genetics, radiation

• Lung disease such as COPD

• Hormone replacement therapy in woman inconclusive

Jemal A et al. CA Cancer J Clin 2011; 61: pp. 69-90. Mao et al. Surg Oncol Clin N Am. 2016 Jul;25(3):439-45.

Smoking Cessation

• National Lung Screening Trial: each year of smoking abstinence = 9% decrease in the risk of lung cancer death in those screened with LDCT, all-cause mortality decreased by 3% per 5-pk years

• Survival is higher for patients who quit smoking after treatment for lung cancer, both for surgery and radiation (right)

Tanner NT et al. Am J Respir Crit Care Med. 2016. Dobson Amato KA et al. J Thorac Oncol. 2015. Roach MC et al. Pract Radiat Oncol. 2016.

HR 1.79 (95% CI 1.14-2.82)

Screening

• Standard dose CT ~ 8 mSv/scan

• Low dose screening CT ~ 1.5 mSv/scan

• Chest X-ray ~ 0.1 mSv/scan

• Six large RCTs of CXR +/- sputum cytology screening in high risk patients led to earlier lung cancer detection but no reduction in lung cancer mortality

• National Lung Screening Trial (NLST) first to show survival benefit to screening

Al Mohammad B et al. Clin Radiol. 2017 Feb 6. pii: S0009-9260(17)30029-6. Team NLSTR. N Engl J Med 2011; 365: pp. 395.

National Lung Screening Trial (NLST)

• Eligibility: 55-74 yrs old, >30 pk years, current smoker or quit <15 yrs ago, no CT chest for >18 months, no unexplained weight loss of >15 lbs, no hemoptysis • 26,722 screened with low-dose CT, 26,732 screened with CXR • 3 screenings at 1 year intervals • Protocol compliance: 93-95% completed screening. CXR group had average

annual rate of CT chest of 4.3%

• Rate of positive result 24.2% in CT group v 6.9% in CXR group • 96.4% false positive rate in CT group, 94.5% in CXR group • Lung cancer incidence 645 versus 572 per 100,000 person –years in CT v CXR • CT reduced lung cancer mortality by 20% (relative), all-cause mortality by

6.7% (relative) Team NLSTR. N Engl J Med 2011; 365: pp. 395.

Management of Lung Nodules

• How big is it?

• How fast is it growing?

• Pretest probability

• NELSON CT screening trial • Netherlands and Belgium • 15,822participants, LDCT v no

screening • 50-75 yrs, ≥15 cig/day for ≥ 25

years or ≥ 10 cig/day for ≥ 30 years, active smoker or stopped <10 yrs ago

Horeweg N et al. Lancet Oncology. 2014.

Management of Lung Nodules

• NCCN, Fleischner Society Guidelines, Lung RADS • Different guidelines for solid and sub-solid (ground-glass/part-solid) nodules

NCCN v2.2018. MacMahon et al. Radiology 2017.

Workup

• Imaging • CT chest with IV contrast

• PET/CT

• Brain MRI (stage II/III/IV)

• Tissue • Preferred biopsy site can both diagnose and stage (nodes > primary)

• Core biopsies preferred over FNA/cytology

• Primary lung adenocarcinoma: TTF-1 positive, CK7 positive, Napsin A positive

• Neuroendocrine: CD56, chromogranin A, synaptophysin

• Mesothelioma: WT-1, calretinin, CK5/6, D2-40

• Molecular testing: EGFR, KRAS, ALK, ROS-1, BRAF, PD-L1

PET/CT

• Primary tumor • Helpful to differentiate between tumor from collapsed lung • SUV > 2.5 has PPV ~ 90% and NPV ~85% for malignant versus benign nodules

• Nodal status • For larger nodes (>1 cm), improved sensitivity and specificity compared to CT

(85% and 90% versus 61 and 79%, respectively) • For small nodes, decreased sensitivity and specificity • Pathologic evaluation of mediastinum still gold-standard

• Metastatic disease • Superior than CT alone, 10-20% upstaging • Not good for brain imaging

Rankin S. Cancer Imaging. 2008 Oct 4;8 Spec No A:S27-31. Madsen PH et al. Eur J Nucl Med Mol Imaging. 2016 Oct;43(11):2084-97.

Mediastinal Evaluation

• ASTER trial: EUS-TBNA alone similar sensitivity as mediastinoscopy (85% v 79%) with lower complications rate (1% v 6%) • If EUS-TBNA negative, NNT=11 to identify one positive patient on

mediastinoscopy • Operator-dependent procedure

• 5-year OS 35% in both arms Annema JT et al. JAMA. 2010 Nov 24;304(20):2245-52. Kuijvenhoven JC et al. JAMA. 2016 Sep 13;316(10):1110-2.

Staging-AJCC 8th Edition: Changes in Bold

Goldstraw P et al. J Thorac Oncol. 2016 Jan;11(1):39-51.

Survival-7th versus 8th AJCC Editions

Goldstraw P et al. J Thorac Oncol. 2016 Jan;11(1):39-51.

Management of Stage I NSCLC

Stage I

• When reading studies, beware of how stage is defined

• Small (<4 cm) tumor, can involve main bronchus, or visceral pleura, or causing atelectasis

NCCN v2.2018

Stage 1 Operable

• Standard curative treatment for medically fit patients with stage I NSCLC is lobectomy, ideally via by video-assisted thoracoscopic surgery

• Lung Cancer Study Group randomized trial, 276 pts with T1-2N0 NSCLC

Ginsberg RJ and Rubinstein LV. Ann Thorac Surg. 1995 Sep;60(3):615-22.

Stage I Operable

• Other studies disagree with LCSG results • < 2cm tumor with >2 cm

margins • Anatomic resection

• Japanese series: cT1N0M0 NSCLC < 2cm, 305 patients, nonrandomized

• Left: DFS (A) and OS (B)

• Right: FVC (A) and FEV1 (B) changes

Okada M et al. J Thorac Cardiovasc Surg. 2006 Oct;132(4):769-75.

CALGB 140503

• Peripheral lung nodule ≤ 2 cm on CT and presumed to be lung cancer

• Center of tumor in outer third of lung

• Tumor location suitable for lobar or sublobar resection (wedge or segment)

• 61% randomized (not cancer or N+)

VATS

• Advantage over thoracotomy in terms of morbidity • Less pain, faster recovery, fewer

complications • No compromise in cancer

outcomes

• Society of Thoracic Surgeons database • 2002-2007, propensity score

matched • VATS lobectomy: lower morbidity

and hospital stay, but longer procedure

Paul S. J Thorac Cardiovasc Surg. 2010 Feb;139(2):366-78.

Radiation + Sublobar Resection?

• ACOSOG Z4032: 224 High-risk operable patients with NSCLC ≤ 3 cm randomized

• Brachytherapy did not reduce LR (LP+lobe+n1 nodes) after SR

• May be due to closer attention to parenchymal margins by surgeons in this study (local progression (at staple line) 7.7%)

Fernando HC et al. J Clin Oncol. 2014 Aug 10;32(23):2456-62.

High Risk Operable Patients

• Who are high risk operable patients?

• Depends on the surgeon

• ACOSOG trial definition on right • ≥1 major criteria

• OR ≥2 minor criteria

Fernando HC et al. J Clin Oncol. 2014 Aug 10;32(23):2456-62.

SABR/SBRT in Stage I Lung Cancer

• Both acronyms commonly used

• Stereotactic ablative radiotherapy/stereotactic body radiation therapy: very few treatments of high dose radiation given to a small area

• Requires advanced technology for imaging and planning

Zeng J et al. Lancet Oncol. 2014 Sep;15(10):e426-34.

SABR for Stage I Inoperable

Padda SK et al. Semin Oncol. 2014 Feb;41(1):40-56.

SABR versus Conventional RT

Nyman J et al. Radiother Oncol. 2016 Oct;121(1):1-8.

• SPACE Trial: Stage I medically inoperable NSCLC: SBRT (66Gy/3 fractions) or 3DCRT (70Gy/35 fractions)

• 102 patients total, 2007-2011

• OS, PFS same between groups (70% SBRT versus 59% around 2.5 yrs, p=0.26)

• Pneumonitis 19% (SBRT) v 34%, p=0.26

• Esophagitis 8% (SBRT) v 30%, p=0.006

• QOL: SBRT less dyspnea (p=0.01), less chest pain (0.02), less cough

• SBRT more convenient!

SABR versus Surgery in Operable Patients • Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a

pooled analysis of two randomised trials

• 58 patients, 35-40 months median follow up

• 3-yr OS 95% v 79% p=0.037, RFS 86% v 80% p=0.54

• Critiques: small #s, 4% mortality from surgery (only 1 patient), why OS difference if no RFS difference?

Chang JY et al. Lancet Oncol. 2015 Jun;16(6):630-7.

SABR versus Surgery

• >100,000 patients with clinical stage I NSCLC 1998-2010 in NCDB

• Median OS favored surgery group, but only 5% of patients had SBRT, especially early on

• Selection bias (median age 67.9 for surgery and 74.7 for SABR)

Puri V et al. J Thorac Oncol. 2015 Dec;10(12):1776-84

Kaplan–Meier survival of patients undergoing surgery

versus SBRT. This is an unmatched comparison (A) and

propensity score matched comparison (B). Kaplan–Meier

survival of patients undergoing sublobar resection

(wedge or segmentectomy) versus SBRT. This is an

unmatched comparison (C) and propensity score

matched comparison (D).

SABR versus Surgery

• SEER database, 9093 pts with N0 NSCLC 2003-2009

• Median age 75, 79% lobectomy, 16.5% sublobar, 4.2% SABR

• Propensity score matching analysis of well-matched SABR and lobectomy cohorts show similar OS (SABR > lobectomy in first 6 mo OS, worse after 6 mo)

Shirvani SM et al. JAMA Surg. 2014 Dec;149(12):1244-53.

SABR in Operable Patients

• Local control: VU = 93% at 3 years; JCOG = only 1 isolated local failure; RTOG = 2-yr primary tumor failure 7.7%

Moghanaki D and Chang JY. Transl Lung Cancer Res. 2016 Apr;5(2):183-9.

Ongoing Trials of SABR versus Surgery

• SABRTOOTH: A Study to Determine the Feasibility and Acceptability of Conducting a Phase III Randomised Controlled Trial Comparing Stereotactic Ablative Radiotherapy With Surgery in paTients With Peripheral Stage I nOn-small Cell Lung Cancer cOnsidered Higher Risk of Complications From Surgical Resection • UK trial, goal 54 patients over 21 months, closed 1/31/2017, opened 7/1/2015

• POSTILV: Randomized Phase II Trial of Radical Resection Vs. Ablative Stereotactic Radiotherapy in Patients With Operable Stage I NSCLC • International/Varian/NRG, goal 76 patients

• STABLE-MATES: JoLT-Ca A Randomized Phase III Study of Sublobar Resection (SR) Versus Stereotactic Ablative Radiotherapy (SAbR) in High Risk Patients With Stage I Non-Small Cell Lung Cancer (NSCLC) • US and Canada, goal 272 patients

Central vs Peripheral?

Fractionation in Peripheral Tumors

• Several in common use, goal: BED>100 to periphery

• 18 Gyx3, 12 Gyx4, 12.5 Gyx4, 10 Gyx5, 34 Gyx1

Wulf J et al. Radiother Oncol. 2005 Oct;77(1):83-7.

Onishi H et al. J Thorac Oncol. 2007 Jul;2(7 Suppl 3):S94-100.

http://www.sciencedirect.com/science/article/pii/S1556086415325387#gr4

RTOG 0915: 34 Gy/1 Versus 48 Gy/4

• No difference in protocol specified toxicity: 10.3% in 34 Gy arm v 13.3% in 48 Gy arm

• Grade 2 toxicities: fatigue 10% v 0% (34 Gy v 48 Gy), MSK disorders (8% v 0%), injury including fracture (8% v 2%), respiratory disorders (13% v 4%)

• Similar trend for all toxicity (grade 1-5)

• Median f/u 3.8 yrs (ASTRO 2017 update) • 5-yr OS 28.8% for 34 Gy, 40.2% for 48 Gy

• Median OS 4.1 vs 4.0 yrs

Videtic GM et al. Int J Radiat Oncol Biol Phys. 2015 Nov 15;93(4):757-64.

Videtic GM et al. Int J Radiat Oncol Biol Phys. 2017 Oct 1;99(2):S15-16.

Chest Wall/Rib Dose

• 13 rib fractures in 7/33 patients treated to 45 Gy in 3 fractions (Sweden)

• If D2cm3 < 21 Gy, ~0% risk of rib

fracture

• If D2cm3 < 27.3 Gy, 5% risk of rib

fracture

• If D2cm3 < 49.2 Gy, 50% risk of rib

fracture

• RTOG 0915, rib 1cc<32 Gy for 4 fx

Pettersson N et al. Radiother Oncol. 2009 Jun;91(3):360-8.

Chest Wall/Rib Dose

• Multi-institution experience, 60 pts treated with 3-5 fxs SABR

• 17 with grade 3 CW pain, 5 rib fractures

• V30Gy best predicted severe CW pain or rib fracture

• V50 or V60Gy

Dunlap NE et al. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):796-801.

Central Tumors

• Phase II trial from Indiana University of 70 patients • 6 possible deaths from SABR: 4 tx for possible pneumonia, 1 pericardial

effusion, and 1 hemoptysis for a carinal tumor with local recurrence

• Perihilar or central tumor location predictor of grade 3 to 5 toxicity on MVA with 2-year freedom from severe toxicity of only 54%

• For the RTOG 0236 trial of SBRT to 60 Gy in 3 fractions, central tumors were excluded • 7 cases (13%) of grade 3 toxicity and 2 cases (4%) of grade 5 toxicity

• No deaths attributed to SBRT

Fakiris AJ et al. Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):677-82.

5 fractions in Central Tumors

• RTOG 0813: Grade 5 hemoptysis seen at multiple dose levels (10.5, 11.5, and 12 Gy), 2 G5 in 11.5 Gy cohort, 1 G5 in 12 Gy (pulm hemorrhage)

• 7.2% risk of dose limiting toxicity at 60 Gy/5fx

• 0/8 grade 3+ toxicity at 50 Gy/5 fx

Bezjak A et al. ASTRO 2016.

7.5 Gyx8 in Central Tumors

• VUMC: 80 pts with PTV<2 cm from PBT 2008-2013

• Median fu 47 months • 3-yr OS 53%, similar to

peripheral tumors

• 3-yr LC >90% on prior publications

• 5/78 patients with grade 3 toxicity

• No grade 4 toxicity

• Grade 5 toxicity possible in 3 pts and likely in 3 pts Tekatli H et al. Radiother Oncol. 2015 Oct;117(1):64-70.

VUMC Toxicity

Tekatli H et al. Radiother Oncol. 2015 Oct;117(1):64-70.

VUMC v RTOG0813 Constraints • 40% of patients with

Dmax≥60 Gy in PBT

• 26% of patients with Dmax≥60 Gy to aorta

• 55% of patients with Dmax≥60 Gy to heart

• Mean D0.1 cc for PBT 41 ±22 Gy (SD), max 79 Gy

• 68% exceeded extrapolated RTOG0813 point dose limits for ⩾1 OARs

Tekatli H et al. Radiother Oncol. 2015 Oct;117(1):64-70.

10 Fractions in Central Tumors • MD Anderson

• 100 patients, 88 tx with 50 Gy/4fx, 18 with 70 Gy/10 fx (if unable to meet dose constraints for 4 fx)

• All tumors were within 2 cm of central structures

• 3-yr LC 96.5%

• 1% grade 3 pneumonitis, no grade 4/5 toxicity

Chang JY et al. IJROBP. 2014 Apr 1;88(5):1120-8.

15 Fractions in Central Tumors

• Canadian NCIC CTG BR.25.

• 80 patients, technically “peripheral” but defined as not involving the mainstem bronchus, <5 cm size.

• 3D conformal treatment planning. PTV=GTV+1-1.5 cm.

• Maximum permissible doses were 35 Gy, 45 Gy, 50 Gy, and 50 Gy to the spinal canal, esophagus, heart, and trachea/mainstem bronchi, respectively. No constraint for the lung or great vessels.

• 2-yr primary tumor control 87%; 3-yr is 82.7%.

• Most common grade 3+ toxicities were fatigue (6.3%), cough (7.5%), dyspnea (13.8%), and pneumonitis (10.0%). One fatal hemoptysis in patient on anticoagulation.

Cheung P et al. JNCI. 2014 Jul 29;106(8).

Imaging Changes After SABR

• Early CT findings: 5 categories • No change

Linda A. Eur J Radiol. 2011 Jul;79(1):147-54.

Diffuse Consolidation Patchy Consolidation

& GGO Diffuse Ground-Glass

Opacity (GGO) Patchy GGO

Imaging Changes After SBRT

• Late CT findings: 4 categories • No changes

Linda A. Eur J Radiol. 2011 Jul;79(1):147-54.

Modified Conventional Pattern Scar-Like Pattern Mass-Like Pattern

Imaging Assessment After SABR • High-risk CT features:

• Enlarging opacity

• Cranio-caudal growth

• Sequential enlargement

• Enlarging opacity after 12 months

• Loss of linear margins

• Bulging margin

• Loss of air bronchograms

Huang K et al. Radiotherapy and Oncology. 2013. 109(1):51–57.

Stage I Summary

• Stage 1 operable: lobectomy plus mediastinal lymph node evaluation is standard of care. SABR also an option.

• Stage 1 inoperable: SABR

• Stage 1 high risk: sub-lobar resection may be acceptable for some tumors. SABR also a good option.

• SABR preferred over conventionally fractionated radiation

• Central tumors continue to present a management challenge

• Follow up of SABR treated tumor require expertise

Management of Stage II NSCLC

Stage II

• Hilar nodes positive (N1)

OR

• >4 cm tumor

OR

• Invading pleura, chest wall, parietal pericardium, phrenic nerve, separate tumor nodules in same lobe

NCCN v2.2018

Stage II ~ 10% of Patients at Diagnosis

NCCN v2.2018

Management of Stage III NSCLC

Stage III

•

•

•

•

Role of Each Modality in Stage III NSCLC

• Systemic Therapy • Chemotherapy: definitely, for both resectable and unresectable, either concurrent or

sequential with radiation, either neoadjuvant or adjuvant with surgery • Immunotherapy: adjuvant after chemoradiation

• Surgery • If unresectable, then no surgery • If resectable and no radiation, then definitely surgery • If radiation given (to definitive dose), questionable

• Radiation • If unresectable then yes to radiation • Can be given neoadjuvantly with chemo before resection • If after surgery, then yes with R1/R2 resection, probably with N2 disease

What is Unresectable Stage III NSCLC?

• Depends on the surgeon

• R0 margin is the goal

• Tumor: T4 is most likely unresectable • Minimal invasion into mediastinal fat is generally resectable

• Invasion of a mediastinal structure is generally not resectable (exceptions: sleeve resections, bypass, atrial resections)

• Nodes • N3 is unresectable

• N2: bulky, ECE, or multiple nodes typically poor prognosis

Quint LE. Cancer Imaging. 2003 Oct 1;4(1):15-8.

N2 Involvement and Surgical Outcomes

• Poor N2 prognostic factors • Multi-station N2

• Bulky N2

• Lymph node station

• 702 patients in France undergoing resection for N2 NSCLC

Andre F et al. J Clin Oncol. 2000 Aug;18(16):2981-9.

PACIFIC Trial – Current Standard of Care in Unresectable Stage III NSCLC – Part 1 • Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung

Cancer

• Patients • Stage III, locally advanced, unresectable NSCLC

• Excluded: grade 2+ pneumonitis from chemorads, grade 2+ unresolved toxic effects

• Treatments • 2+ cycles of platinum-based chemotherapy (containing etoposide, vinblastine,

vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed)

• Concurrently with definitive radiation therapy (54 to 66 Gy) • Mean lung dose <20 Gy OR V20Gy<35%

• Durvalumab 10 mg/kg or placebo q2weeks for 1 year (2:1 randomization)

Antonia SJ et al. NEJM 2017 Nov 16;377(20):1919-1929.

PACIFIC Trial – Current Standard of Care in Unresectable Stage III NSCLC – Part 1


PACIFIC Trial – Current Standard of Care in Unresectable Stage III NSCLC – Part 1 • Analysis of OS not planned at this interim analysis of PFS

• Adverse events: • Up to 7 weeks between chemoradiation and randomization

• Grade 3 or 4 in 29.9% of durvalumab group and 26.1% of placebo group

• Grade 5 in 4.4% of durvalumab group and 5.6% of placebo group

• Most frequent AEs leading to discontinuation of durvalumab and placebo were pneumonitis (in 6.3% and 4.3%, respectively) and pneumonia (in 1.1% and 1.3%)

• Immune-mediated adverse events of any grade: 24.2% durvalumab vs 8.1% placebo; grade 3 or 4 immune-mediated adverse events 3.4% and 2.6%, respectively


RTOG 0617 – Current Standard of Care in Unresectable NSCLC –Part 2

• Open-label randomized, two-by-two factorial phase 3 study

• Concurrent carboplatin (AUC 2) / paclitaxel (45 mg/m2), 2 cycles of consolidation (AUC 6/200 mg/m2)

Bradley JD et al. Lancet Oncol. 2015 Feb;16(2):187-99.

RTOG 0617

• Unclear why 74 Gy worse, results remain unchanged after accounting for radiation therapy quality. No diff in G3+ toxicity (76 v 79%).

Bradley JD et al. Lancet Oncol. 2015 Feb;16(2):187-99.

RTOG 0617 – IMRT versus 3D Conformal

Chun SG et al. J Clin Oncol. 2017 Jan;35(1):56-62.

RTOG 0617 – IMRT versus 3D Conformal

• No difference in OS, PFS, LR, or distant mets

• IMRT= lower grade 3+ pneumonitis, and lower heart dose (but no survival difference)

Chun SG et al. J Clin Oncol. 2017 Jan;35(1):56-62.

RTOG 0617 QOL

• Baseline QOL was an independent prognostic factor for survival

• Few differences in clinician-reported toxic effects between treatment arms, but clinically meaningful decline in QOL in the 74-Gy arm at 3 months

Movsas B. JAMA Oncol. 2016 Mar;2(3):359-67.

Concurrent Chemoradiation Better Than Sequential

Auperin A et al. J Clin Oncol. 2010 May 1;28(13):2181-90.

3-yr OS 18.1% v 23.8%

RTOG 9410

• 5-OS highest in concurrent arms: 10% arm 1, 16% arm 2, 13% arm 3

• Higher rates of severe acute esophagitis in concurrent arms

• Less local progression in concurrent arms than sequential arm with same distant metastasis rate, so perhaps local control does matter for survival

Curran WJ et al. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60.

Sequential Chemo+RT versus RT

• Intergroup trial (RTOG/ECOG/SWOG) 2 months of cisplatin, vinblastine

• 60 Gy at 2 Gy per fraction (after chemo or alone), or 69.6 at 1.2 Gy BID (alone)

• 5-yr OS superior in chemoradiation arm (8%) v HFX (6%) v RT (5%) Sause W et al. Chest. 2000 Feb;117(2):358-64.

Sequential Chemo+RT versus RT

• CALGB 8433

• 5 weeks of chemotherapy with cisplatin and vinblastine

• 60 Gy in 2 Gy fractions (after chemo if given)

• 7-yr OS 13% v 6%

Dillman RO et al. J Natl Cancer Inst. 1996 Sep 4;88(17):1210-5.

RT Alone Hyperfractionation

• Significantly higher rate of acute severe esophagitis with hyperfractionation (9% v 19% OR 2.44,95% CI 1.90-3.14, p<0.001)

• 5-yr absolute benefit in OS of 2.5 %, but CHART is main standalone trial with HR<1 (54 Gy in 12 days TID over 36 fx, v 60 Gy in 30 fx over 6 weeks)

Mauguen A et al. J Clin Oncol. 2012 Aug 1;30(22):2788-97.

60 Gy RT Dose: RTOG 7301

• Highest local control at 60 Gy

• No survival diff but 60 Gy curve appears to be on top

Perez CA et al. Cancer. 1980 Jun 1;45(11):2744-53.

Chemo Regimens

• Some thought cisplatin may be superior

NCCN v2.2018

Carbo/Taxol versus Cisp/Etop

Santana-Davila R et al. J Clin Oncol. 2015 Feb 20;33(6):567-74.

All patients

Near-far matched cohort

EP-encouraging centers or not

Propensity matched

Chemo Regimen and Pneumonitis

• Carboplatin/paclitaxel may be related to an increase in radiation pneumonitis

• Individual patient meta-analysis, 836 patients treated with chemoradiation

• Overall rate of symptomatic pneumonitis was 29.8% (n=249), with fatal pneumonitis in 1.9%

Palma DA et al. Int J Radiat Oncol Biol Phys. 2013.

How About More Chemo + ChemoRT?

• Carbo/taxol with 66 Gy or 2 cycles of carbo/taxol and then chemrads

• 40% grade 4 event overall in induction arm v. 26% without

Voles EE et al. J Clin Oncol. 2007 May 1;25(13):1698-704.

How About ChemoRT + More Chemo?

• SWOG, consolidation docetaxel after cisplatin/etoposide with 59.4 Gy

• 28.8% hospitalization during docetaxel (v 8.1%), and 5.5% died

Hanna N et al. J Clin Oncol 26:5755–5760,2008

How About ChemoRT + Targeted Therapy?

• SWOG S0023

• Cisplatin/etoposide with 61 Gy followed by 3 cycles of docetaxel

• Closed after interim analysis, median survival 23 mo for gefitinib and 35 mo for placebo

• Unselected population

• Unclear for selected population with newer targeted agents

Kelly et al. J Clin Oncol 26:2450–2456,2008



sequential with radiation, either neoadjuvant or adjuvant with surgery. No induction chemo or consolidation chemo after definitive chemoradiation.

• Immunotherapy: adjuvant after chemoradiation



Chemo After Surgery-LACE Meta-Analysis

Pignon JP et al. J Clin Oncol. 2008 Jul 20;26(21):3552-9.

Chemo Before Surgery

NSCLC Meta-analysis Collaborative Group. Lancet. 2014 May 3;383(9928):1561-71.

Chemo Before or After Surgery?

• NATCH trial, Spanish Lung Cancer Group

• 3 cycles of paclitaxel-carboplatin • Pre-op: 97% started planned

chemotherapy

• Post-op: 66% started planned chemotherapy

• 94% of patients underwent surgery

• Critiques: lots of stage I patients and lacking statistical power

Felip E et al. J Clin Oncol. 2010 Jul 1;28(19):3138-45.

Role of Surgery v RT After Chemo

• EORTC: Randomized trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer

• 3 cycles of platinum-based induction chemotherapy, RT ~60 Gy in 2 Gy fractions with ~44 Gy to mediastinum

• Response rate of 61% to induction chemo • Surgery group: 5% pCR, 4% mortality • PORT in 40% • RT group: compliance to RT prescription 55%,

grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%

Van Meerbeeck JP et al. J Natl Cancer Inst. 2007 Mar 21;99(6):442-50.

Role of Surgery After Chemoradiation

• INT 0139: concurrent induction chemoradiation to 45 Gy, surgery versus uninterrupted chemoradiation up to 61 Gy

• PFS superior in surgery arm but no difference in OS (blue line=surgery)

• Unplanned subset analysis: lobectomy superior to chemoradiation (which included patients that would have undergone a pneumonectomy since we can’t figure out who is who)

• 40% perioperative mortality in right sided pneumonectomy

Albain KS et al. Lancet. 2009 Aug 1;374(9687):379-86.

PFS p=0.017

Pneumonectomy OS Lobectomy OS

OS p=0.24

Role of Surgery After Chemo+Chemoradiation

• ESPATUE: 3 cycles of cisplatin/paclitaxel, then concurrent chemoRT to 45 Gy (1.5 Gy BID), then surgery (arm B) or chemoRT to 65-71 Gy (arm A)

• Closed after 246/500 patients

• 161 patients randomized

• 5-yr OS 44% for surgery and 40% for chemoRT

Eberhardt WE. J Clin Oncol. 2015 Dec 10;33(35):4194-201.

Neoadjuvant Chemo or Chemo + RT? • Chemo: 3 cycles of cisplatin and docetaxel • RT: 44 Gy in 22 fractions over 3 weeks given AFTER chemo • Surgery for everyone. No diff in outcomes between 2 arms

Pless M et al. Lancet. 2015 Sep 12;386(9998):1049-56.

Neoadjuvant Chemo or Chemo+RT?

• German Lung Cancer Cooperative Group • Control: 3 cycles cisplatin/etoposide, then surgery, then RT (54 Gy)

• Intervention: 3 cycles cisplatin/etoposide, then chemoRT (45 Gy BID 1.5 Gy/fx) with carboplatin/vindesine, then surgery

• More RT to 68-69 Gy in both arms if positive margins or unresectable

Thomas M et al. Lancet Oncol. 2008 Jul;9(7):636-48.

• If complete resection, mediastinal down-staging (46 v 29%, p=0.02) and pathological response (60 v 20%, p<0.0001) favor RT group

• If pneumonectomy, higher mortality with RT 14% vs 6%

OS (shown) and PFS similar between groups

Post-Op RT • Critiques: 25% T1N0 disease, cobalt-60 in 4 trials, lateral beams in

older trials, 60 Gy in 3 Gy fractions used

PORT Meta-analysis Trialists Group. Lancet. 1998 Jul 25;352(9124):257-63.

ANITA

• ANITA: randomized trial of adjuvant cisplatin and vinorelbine vs. observation in completely resected Stages IB to IIIA

• Use of PORT was recommended for pN+ disease but was not randomized or mandatory

• Each center decided whether to use PORT before initiation of the study

Douillard JY et al. Int J Radiat Oncol Biol Phys. 2008 Nov 1;72(3):695-701.

SEER

• SEER database, 7465 patients, stage II/III NSCLC with lobectomy or pneumonectomy

• On MVA of all patients, use of PORT (HR = 1.048; 95% CI, 0.987 to 1.113; P = .127) did not have a significant impact on survival • N0: PORT was associated with a significant decrease in survival (HR = 1.1176;

95% CI, 1.005 to 1.376; P = .0435)

• N1: PORT was associated with a significant decrease in survival (HR = 1.097; 95% CI, 1.015 to 1.186; P = .0196)

• N2: PORT was associated with a significant increase in survival (HR = 0.855; 95% CI, 0.762 to 0.959; P = .0077)

Lally BE et al. J Clin Oncol. 2006 Jul 1;24(19):2998-3006.

Post-Op Chemoradiation? Not for Everyone • ECOG study, stage II-IIIA NSCLC • After surgery: RT alone (50.4 Gy) or RT concurrent with cisplatin/etoposide

Keller SM et al. N Engl J Med. 2000 Oct 26;343(17):1217-22.

Superior Sulcus

• INT 0160/SWOG 9416: Induction chemoradiation and surgical resection • T3-4N0-1 NSCLC

• 2 cycles of cisplatin/etoposide concurrently with radiation (45 Gy), surgery if stable/response, then 2 more cycles of chemo

• 1995-1999, 110 patients • pCR or minimal microscopic disease 56%

• 5-year OS 44%

Rusch VW et al. J Clin Oncol. 2007 Jan 20;25(3):313-8.

Stage III Summary

• If unresectable: definitive chemoradiation plus durvalumab

• If resectable: • Unexpected stage III at surgery, follow with chemo +/- RT for N2 or

positive margin

• If known stage III at diagnosis, neoadjuvant chemo or chemoradiation, then surgery, then radiation if did not receive it neoadjuvantly, for N2 or positive margin

• Definitive chemoradiation plus durvalumab also an option

Stage IV Special Topics

Oligometastatic Disease

• Stage IV NSCLC with three or fewer metastases with lack of progression after first line systemic therapy: randomized to local consolidative therapy or maintenance treatment

• Local therapy: intent to ablate all residual disease with surgery, radiotherapy, or both

• Median f/u 12 months, OS data immature, 49 patients total

Gomez D et al. Lancet Oncol. 2016 Dec;17(12):1672-1682.

Med PFS 11.9 mo v 3.9 mo

Oligoprogressive Disease

• All patients on TKI will eventually progress

• Some will have oligoprogression (15-45%?)

• 38 pts on crizotinib, 27 pts on erlotinib • Median PFS 9 months on crizotinib, 13.8

months for erlotinib

• 51/65 patients progressed, 25/51 were candidates for local ablative therapy and continuation of same targeted therapy

• 24/25 treated with RT, 1 with surgery

• RT: 7 brain SRS, 6 WBRT, 16 SBRT, 2 XRT

• Post-ablative local therapy, median PFS 6.2 months

Targeted Therapy + RT

RTOG 1306

Immunotherapy + RT

• Current indications for immunotherapy in NSCLC • Stage 3

• After definitive chemoradiation, consolidation with durvalumab

• Stage 4 • 1st line

• Pembrolizumab (PD-L1 ≥ 50%) – Keynote 024

• Pembrolizumab + carboplatin + pemetrexed (adenocarcinoma) – Keynote 021

• 2nd line • Pembrolizumab (PD-L1 ≥ 1%) – Keynote 010

• Nivolumab – CheckMate-057, CheckMate-017

• Atezolizumab – OAK

Immunotherapy Adverse Events

Postow MA et al. NEJM 2018.

• Most common: gastrointestinal tract, endocrine glands, skin, liver

• Also: CNS, cardiovascular, pulmonary, musculoskeletal, and hematologic systems

Immunotherapy + RT Luke JJ et al. J Clin Oncol. 2018

• 73 patients, SBRT to 2 sites in 69/73 • Target volume <65 ml (5 cm tumor) • 30 Gy/3fx for bone/spinal • 45 Gy/3 fx for peripheral lung/liver/abd/pelvis • 50 Gy/5 fx for central lung/mediastinal/cervical • Pembrolizumab within 7 days after end of SBRT

• Median f/u 5.5 months • 6 grade 3 toxicity (3 pneumonitis, 2 colitis, 1 hepatitis) • Objective RR 13.5% (2 CR, 8 PR, 21 SD, 38 PD)

Management of Small Cell Lung Cancer

Basics

• SMOKING!!! Very rare to have small cell lung cancer in non-smoker

• Small round blue cell tumor/stains for neuroendocrine markers

• Paraneoplastic syndromes

• Often present with central obstructive symptoms (i.e. cough, dyspnea, SVC syndrome)

• About 2/3 of patients present with extensive stage disease

Siegel RL et al. CA Cancer J Clin. 2017 Jan;67(1):7-30.

Staging

• Per AJCC, same as NSCLC

• Practical staging: • Limited stage: can be treated with radiation and meet dose constraints • Extensive stage: all others

• NCCN: stage I-III is limited stage, unless multiple lung nodules or nodal disease makes the volume too large for radiation

• VA Lung Study Group: limited stage is confined to ipsilateral hemithorax, excluding malignant pleural or pericardial effusions

• Imaging: • PET/CT required to confirm limited stage • MRI brain required

Stage I SCLC

• <5% of patients

• Often incidentally found at surgery

• Surgery: lobectomy plus mediastinal evaluation

• Chemo for all

• If N+, add mediastinal RT

• Consider SBRT if medically inoperable

• Remember PCI Yang, CF et al. J Clin Oncol. 2016 Apr 1;34(10):1057-64.

Role of Surgery • 328 patients, limited state SCLC

• 217 pts (66%) had CR/PR

• 146 randomized

• Only 19% had cT1-2N0M0 disease

Lad T et al. Chest 1994.

Role of RT

• Meta-analysis of 13 trials, 2140 pts to evaluate if thoracic RT results in increased OS in LS-SCLC compared to chemo alone

• No individual trial had conclusively shown benefit in OS with chemoRT

• 433 extensive stage patients excluded • RR of death 0.86 (chemo RT vs. chemo)

P=0.001 • 3yr OS: 15% vs. 10% • RT in limited stage improves local control

25-30%

Pignon et al. NEJM 1992

RT Timing: SER Important Predictor of Outcome

De Ruysscher et al. JCO 2006

Dose/Fractionation - Turrisi

• 1.5Gy BID vs 1.8Gy QD to 45Gy • Concurrent EP x 4 cycles

• PCI for complete responders: 2.5 Gy to 25 Gy

• Improved OS for BID • 5-yr OS 26% vs. 16%

• Grade 3 esophagitis significantly more common in BID (27%) vs. QD (11%)

Turrisi et al. NEJM 1999

Dose/Fractionation - CALGB

• CALGB 39808 - study to evaluate feasibility of 70 Gy QD with concurrent chemo for LS-SCLC in 63 patients

• Induction paclitaxel/topotecan x 2 cycles followed by 3 cycles of concurrent carboplatin/etoposide with 70 Gy in 2 Gy/fx

• PCI for partial or complete response

Bogart et al. IJROBP 2004.

Dose/Fractionation-CONVERT

• Europe and Canada

• 45Gy (BID in 30 fx) or 66Gy (33 daily fractions) • RT concurrent with week 4 of

cisplatin/etoposide (total 4-6 cycles) • PCI if indicated (86-88% in each arm

received it) • 547 patients 2008 - 2013

• 2-year OS was 56% (BID) vs 51% and median OS 30 months (BID) vs 25 months (HR 1.18, 95% CI 0.95-1.45; p = 0.14)

Faivre-Finn, C. et al. Lancet Oncol. 2017 Aug;18(8):1116-1125.

Dose/Fractionation-CONVERT

• Toxicities • More grade 4 neutropenia (49% BID vs 38% OD, p = 0.05)

• Otherwise comparable: grade 3-4 esophagitis (19% both arms), grade 3-4 pneumonitis (3% BID vs 2% QD)

• Primary endpoint = OS (randomisation until death from any cause) • 12% higher OS at 2 years for QD vs BID considered to be clinically significant

to show superiority of QD regimen

• Since trial was designed to show superiority of QD and not powered to show equivalence, the implication is that BID should continue to be considered the standard of care in this setting

Faivre-Finn, C. et al. Lancet Oncol. 2017 Aug;18(8):1116-1125.

Dose/Fractionation-CALGB 30610 Ongoing

RT Volumes • Turrisi

• Target volume: gross tumor on CT and bilateral mediastinal and ipsilateral hilar lymph nodes. No uninvolved supraclavicular fossae.

• Inferior border extended 5 cm below the carina or to a level including ipsilateral hilar structures, whichever was lower. Clinically determined volume was expanded by a margin of 1 to 1.5 cm.

• CALGB 30610/RTOG 0538: • GTV: primary tumor and clinically positive lymph nodes seen either on the pretreatment CT (>

1 cm short axis diameter) or pretreatment PET scan (SUV > 3) • CTV-1 includes GTV plus ipsilateral hilum. Elective treatment of the mediastinum and

supraclavicular fossae will not be done.

• CONVERT: • GTV: tumor and nodes >1 cm on CT. If PET available, include PET positive nodes in GTV. • CTV: GTV + 5 mm with manual adjustment as needed • PTV: CTV + 8 mm radial and 1 cm sup-inf • Prophylactic nodal irradiation should not be employed

Faivre-Finn C et al. BMJ Open. 2016 Jan 20;6(1):e009849.

RT Volumes

• If using only CT scan to delineate target volume, selective nodal irradiation leads to 11% isolated nodal failure (LEFT table), but with PET-based selective nodal irradiation, only 3% isolated nodal failure

De Ruysscher D et al. Radiother Oncol. 2006 Sep;80(3):307-12. Van Loon J et al. Int J Radiat Oncol Biol Phys. 2010 Jun 1;77(2):329-36.

PCI-Limited Stage

• Meta-analysis of 7 trials

• 987 patients with SCLC in CR randomized to PCI vs. no PCI

• CR in some trials assessed by CXR

• Endpoint: does PCI improve survival

• 3-yr OS: 20.7% vs. 15.3%

• 3-yr brain mets rate: 59% vs. 33%

Auperin et al. NEJM 1999

PCI Dose

• 1999-2005, 720 patients with limited-stage SCLC in CR after chemo+RT

• Standard (25Gy/10 fx) or higher PCI dose (36 Gy/18 fx or 36 Gy/24 fx BID)

Le Pechoux et al. Lancet Oncol. 2009 May;10(5):467-74.

2 yr brain mets 29% (25 Gy) v 23% (36 Gy)

2 yr OS 42% (25 Gy) v 37% (36 Gy)

PCI Neurocognitive Effects

• Prior to PCI, 23-25% of patients had an abnormal QoL-cognitive functioning score, increasing to 35-47% at 2-3 years

• No significant difference in decline between 2 dose groups

• Confirms the importance of age as a cofactor of neurocognitive decline • Age >60: 83% chronic neurotoxicity

at 12 months after PCI • Age <60: 56% chronic neurotoxicity

Le Pechoux C et al. Ann Oncol. 2011 May; 22(5) 1154-1163. Wolfson AH et al. IJROBP 2011 Sept;81(1):77-84.

PCI-Extensive Stage

• Phase III trial with 286 pts randomized to +/- PCI following response to chemo

• Fractionation schedules • 20 Gy/5 fx (89 pts) • 30 Gy/10 fx (23 pts) • 30 Gy/12 fx (9 pts) • 25 Gy/10 fx (7 pts)

• 1-yr OS 27.1% vs. 13.3%

• PCI had side effects but did not have a clinically significant effect on global health status

• Brain imaging was not part of standard staging and follow-up procedures, unless symptoms suggestive of brain metastases were present

Slotman et al. NEJM 2007

PCI-Extensive Stage

• ED-SCLC with any response to first-line platinum doublet chemotherapy randomized to PCI (25Gy/10 fractions) or observation • MRI required prior to enrollment • Planned interim analysis with 163 pts reached futility. 224

patients enrolled total.

• Median OS 11.6 vs 13.7 months for PCI vs Obs, (HR=1.27, 95%CI= 0.96-1.68; P=0.094). • 2-year OS 15% in PCI group vs 18.8% in obs group • PCI reduced risk of BM (48% vs 69%; Gray’s test, P<0.001) • PFS was comparable (median, 2.3 vs. 2.4 months; HR=0.98,

95%CI=0.75-1.29, p=0.75)

Takahashi T et al. Lancet Oncol. 2017 May;18(5):663-671.

PCI-Extensive Stage

• Most frequent grade 3+ AEs: • Anorexia (6% in PCI group vs 2%)

• Malaise (3% vs <1%)

• Muscle weakness in a lower limb (<1% vs 5%)

• MMSE scores did not differ significantly between the two groups at baseline, 12 months, or 24 months

• RT given for brain metastases in 46% of PCI group and 83% of obs group

Takahashi T et al. Lancet Oncol. 2017 May;18(5):663-671.

Thoracic RT-Extensive Stage

• RT: 54 Gy/36 fx BID Jeremic et al. JCO 1999


• Dutch CREST trial

• ES-SCLC with response to chemotherapy

• RTL 30 Gy in 10 fx to chest or not. PCI for all.

• 1-yr OS 33% v 28% p=0.066 (primary endpoint)

• 2-yr OS 13% v 3% p=0.001, favoring RT

• No severe toxic effects

Slotman B et al. Lancet. 2015 Jan 3;385(9962):36-42.


• Exploratory analysis in Author response to comments

• Of 495 patients included in ITT analysis, 434 had residual intrathoracic disease after chemo and 61 did not (on CT chest) • Equal randomization to two arms as this as a stratification factor

• With residual intrathoracic disease

• OS longer with RT (HR 0·81, 95% CI 0·66–1·00, p=0·044). 1-year OS 33% (95% CI 27–40) vs 26% (95% CI 21–33). 2-year OS 12% (95% CI 8–19) vs 3% (95% CI 1–8)

• PFS significantly longer with RT

• Intrathoracic progression, either with or without progression elsewhere, 43·7% with RT vs 81·3% (p<0·0001)

• No such benefit seen in patients without residual intrathoracic disease

Slotman B et al. Lancet. 2015 Apr 4;385(9975):1292-3.

Thoracic + Consolidative RT-Extensive Stage

• RTOG 0937, terminated, accrued 97/154 target • Randomized phase II, PCI or PCI+cRT, 1-4 extracranial mets, CR/PR to chemo

• Crossed futility barrier on planned interim analysis

• 1 yr OS not significantly diff (60.1% for PCI v 50.8% for PCT+RT, p=0.21)

• 69% of patients received >45 Gy to thorax in PCI+RT arm, 94.2% of all patients received 25 Gy PCI

• 3- and 12-months rates of any progression were 53.3 and 79.6% for PCI and 14.5 and 75% for PCI+RT. Time to any progression favored PCI+RT with HR 0.53 (P=0.01)

• 1 grade 5 toxicity in PCI+RT group, 1 grade 4 toxicity per arm Gore EM et al. J Thorac Oncol. 2017 Oct;12(10):1561-1570.

Systemic Therapy – NCCN Guidelines

NCCN Small Cell Lung Cancer v2.2018.

Carboplatin vs Cisplatin

• 4 randomized trials with 663 patients, mix limited and extensive stages

• Median OS 9.6 months for cisplatin and 9.4 months for carboplatin (HR 1.08; 95% CI, 0.92 to 1.27; P = .37)

• No difference based on sex, stage, performance status, or age

• Myelosuppression higher with carboplatin, more emesis, neurotoxicity and nephrotoxicity with cisplatin

Rossi A et al. J Clin Oncol. 2012 May 10;30(14):1692-8.

Immunotherapy

Reck M et al. J Clin Oncol. 2016. Antonia SJ et al. Lancet Oncol. 2016. Hellmann M et al. JTO 2017 (abstract).

1st line: Phase III Etoposide+Platinum+/-Ipilimumab 2nd+ line: Checkmate 032 Nivolumab+/-Ipilimumab

• 1-yr OS 33% for nivo, 43% nivo 1 mg/kg+ipi 3 mg/kg, 35% nivo 3 mg/kg+ipi 1 mg/kg

• Overall response rate 11% for nivo, ~20% for nivo+ipi • Response did not correlate with PD-L1 expression

Small Cell Lung Cancer Summary

• Limited Stage • Concurrent chemoradiation with RT ASAP for patients with adequate

performance status • RT to involved disease • 45 Gy/30 fx or 60-70Gy/30-35 fx acceptable, BID if good performance status

• PCI with any response

• Extensive Stage • Platinum doublet chemotherapy • +/- Thoracic RT (palliative doses for residual disease) +/- PCI for

responders

• Beware of PCI toxicity for older patients

Thank you.

Jing Zeng, MD

University of Washington

Contact: [email protected]

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