lung - american society for radiation oncology …staging – ajcc 7th edition ajcc 7th edition...

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

• Small Cell

Epidemiology

• Estimated new cases for 2017: 116,990 in men, 105,510 in women

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

Survival

SEER Cancer Statistics Review 1975-2013.

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%

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

Tanner NT et al. Am J Respir Crit Care Med. 2016 Mar 1;193(5):534-41. Dobson Amato KA et al. J Thorac Oncol. 2015 Jul; 10(7): 1014–1019. Roach MC et al. Pract Radiat Oncol. 2016 Jan-Feb; 6(1): 12–18.

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?

• NELSON CT screening trial

Horeweg N et al. Lancet Oncology. 2014;15(12):1332-1341.

Management of Lung Nodules

• NCCN, Fleischner Society Guidelines • Different guidelines for solid, semi-solid, and not-solid (ground-glass) nodules

NCCN v1.2017

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, Npasin A positive

• Neuroendocrine: CD56, chromogranin, synaptophysin

• Mesothelioma: WT-1, calretinin, CK5/6, HMBE-1

• Molecular testing: EGFR, KRAS, ALK, ROS-1, 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 7th Edition

AJCC 7th edition effective through end of 2017. AJCC 8th edition starting 1/1/2018.

NCCN v4.2017.

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

https://www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq#section/_134

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

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

Stage I Operable

• Other studies disagree with LCSG results

• 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)

D

VATS

• Advantage over thoracotomy in terms of morbidity

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

• Brachytherapy did not reduce LR after SR

• May be due to closer attention to parenchymal margins by surgeons in this study

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

High Operable Risk 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.

SBRT for High Risk Patients First author 30-day mortality Complications Follow-up (y)

(med) Median OS (y)

1-yr OS 3-yr OS 5-yr OS

Surgery

Magdeleinat 8%∗ >90% ICU stay 3.4

† 4.2 84%

∗ 63%

∗ 44%

>45% with complications

4.7†

Lau 25% (open lobectomy)

∗, 7%

(segmentectomy or VATS)

∗

Median hospital stay: 8–12 days; <10% admitted to ICU

Segmentectomy or VATS:

5.5∗ 86%

∗ 66%

∗ 50%

∗

Open lobectomy:

0.8∗ 45%

∗ 31%

∗ 8%

∗

SBRT

Henderson 0%∗ ~8% Grade 3 2.2

† 1.6 91%

∗ 43%

∗

Stephans 0%∗ 0 Grade 3+

pneumonitis 1.5

† Not

reached∗

95%∗ 70%

∗

Palma 0% 3% Grade 3 toxicity 1.7 2.7 79% 47% 28%

Adapted from Palma D et al. Int J Radiat Oncol Biol Phys. 2012 Mar 1;82(3):1149-56.

http://www.sciencedirect.com/science/article/pii/S0360301611004561#tbl3fnlowast

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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

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

SABR versus Surgery

• >100,000 patients 1998-2010 in NCDB

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

• Selection bias

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

A, 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

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

SABR in Operable Patients

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

• POSTILV: Randomized Phase II Trial of Radical Resection Vs. Ablative Stereotactic Radiotherapy in Patients With Operable Stage I NSCLC

• 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)

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%, p=0.26)

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

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

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

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 any toxicity (grade 1-5)

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

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.

Chest Wall/Rib Dose

• 134 pts, 60 Gy in 3 fx

• 10 pts with late CW toxicity (grade 1 in 4 pts, grade 2 in 6 pts)

• V30Gy-V70Gy all highly significant, although weakened for V65 and V70

• On MVA, tumor volume no longer correlated with toxicity, only V30-V60 remained statistically significant

Stephans KL et al. Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):974-80.

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 highest dose level

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


VUMC v RTOG0813 Constraints


Imaging Changes After SBRT

• 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

• T1-2N1, T2b-T3N0


Stage II

NCCN v4.2017

Management of Stage III NSCLC

Stage III


Role of Each Modality in Stage III NSCLC

• Chemotherapy • Definitely, for both resectable and unresectable, either concurrent or

sequential with radiation, either neoadjuvant or adjuvant with surgery

• 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.

RTOG 0617 – Current Standard of Care in Unresectable NSCLC

• 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

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

RTOG 0617 – IMRT versus 3D Conformal

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

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

RTOG 0617 – IMRT versus 3D Conformal

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.

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

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

Sequential Chemo+RT versus RT

• 2 months of cisplatin, vinblastine

• 60 Gy at 2 Gy per fraction, or 69.6 at 1.2 Gy BID

Sause W et al. Chest. 2000 Feb;117(2):358-64.

Sequential Chemo+RT versus RT

• 5 weeks of chemotherapy with cisplatin and vinblastine

• 60 Gy in 2 Gy fractions

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

RT Alone Hyperfractionation

• Significantly higher rate of esophagitis with hyperfractionation

• 5-yr absolute benefit in OS of 2.5 %

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.

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

Chemo Regimens

NCCN v4.2017

Carbo/Taxol versus Cisp/Etop

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

Chemo Regimen and Pneumonitis

Palma DA et al. Int J Radiat Oncol Biol Phys. 2013 Feb 1;85(2):444-50.

How About More Chemo + ChemoRT?

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

How About ChemoRT + More Chemo?

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

How About ChemoRT + Targeted Therapy?

• SWOG S0023

• Unselected population

• Unclear for selected population with newer targeted agents

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


• Chemotherapy • Definitely, for both resectable and unresectable, either concurrent or sequential with

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



Chemo Before Surgery

All cisplatin regimens, so if not cisplatin eligible, some do not recommend neoadjuvant chemotherapy, others consider carbo/taxol

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

Chemo After Surgery

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

Chemo Before or After Surgery?

• 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

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

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

55%, rade 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

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

• 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

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

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

• 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

• 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 also an option

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

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

Targeted Therapy + RT

RTOG 1306.

Proton Therapy • Not beneficial for everyone!

• Likely superior dosimetry when treating the mediastinum

• Bayesian randomized trial of IMRT vs. 3D proton therapy in stage III NSCLC showed no difference in treatment failure (G3 RP or LF) although proton arm had bigger PTVs and higher tumor dose (Liao Z et al, ASCO 2016)

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. 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

• If N+, add mediastinal RT

• Consider SBRT if medically inoperable

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

Limited Stage SCLC History

• Before 1960s: surgery or RT, 2-yr OS <10%

• 1960s: single agent chemo, 2-yr OS ~10%

• 1970s: combination chemo, 2-yr OS ~20%

• 1980s: chemo and daily RT: 2-yr OS ~40%

• 1990s: chemo and BID RT: 2-yr OS ~45%

• Recurrences often follow response, most commonly at sites of initial bulk disease

• High rates of distant metastasis

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%

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 feasability of 70 Gy QD with cc chemo for LS-SCLC in 63 patients

• Induction paclitaxel/topotecan x 2 cycles followed by cc CE with 70 Gy in 2 Gy/fx

Bogart et al. IJROBP 2004.

Dose/Fractionation-CONVERT

• 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 1.17, 95% CI 0.95-1.45; p = 0.15)

• Toxicities were comparable except for significantly more grade 3/4 neutropenia (74% BD vs 65% OD, p = 0.03)

Faivre-Finn, C. et al. ASCO 2016

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.

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

Le Pechoux C et al. Ann Oncol. 2011 May; 22(5) 1154-1163.

PCI Neurocognitive Effects: RTOG 0212

• 25 Gy in 10 fx or 36 Gy in 18 fx or 36 Gy in 24 BID fx

• Pre-PCI assessments already revealed neurocognitive impairments

• Decline in cognitive functioning in QLQ-C30 across all groups, but no significant difference across the 3 treatments arm

• High dose and age both significant factors for developing chronic neurotoxicity • Age >60: 83% chronic neurotoxicity at 12 months after PCI

• Age <60: 56% chronic neurotoxicity

Wolfson AH et al. IJROBP 2011 Sept;81(1):77-84.

Thoracic RT-Extensive Stage

• RT: 54 Gy/36 fx BID

Jeremic et al. JCO 1999

Thoracic RT-Extensive Stage

• 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.

Thoracic + Consolidative RT-Extensive Stage

• RTOG 0937, terminated, accrued 97/154 target • 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 53.5 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. Late Breaking Abstracts. IJROBP January 1, 2016Volume 94, Issue 1, Page 5.

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

• Abstract, no manuscript

• 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

• Median OS was 10.1 and 15.1 months for PCI (n=84) and Obs (n=79), (HR=1.38, 95%CI= 0.95-2.01; stratified log-rank test, P=0.091). • PCI reduced risk of BM (32.4% vs 58.0% at 12 months; Gray’s test, P<0.001)

• PFS was comparable (median, 2.2 vs. 2.4 months; HR=1.12, 95%CI=0.82-1.54)

• No significant difference in AEs greater than Grade 2

Seto T et al. ASCO 2014

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) and/or 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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