Lung. Jing Zeng, MD University of Washington.

Transcription

1 Lung Jing Zeng, MD University of Washington

2 Disclosure Employer: University of Washington I have no conflicts of interest to disclose.

3 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

4 Table of Contents Background NSCLC Stage I Stage II Stage III Special Topics Small Cell

5 Epidemiology Estimated new cases for 2017: 116,990 in men, 105,510 in women Siegel RL et al. CA Cancer J Clin Jan;67(1):7-30.

6 Survival SEER Cancer Statistics Review

7 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 Mao et al. Surg Oncol Clin N Am Jul;25(3):

8 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 Mar 1;193(5): Dobson Amato KA et al. J Thorac Oncol Jul; 10(7): Roach MC et al. Pract Radiat Oncol Jan-Feb; 6(1):

9 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 Feb 6. pii: S (17) Team NLSTR. N Engl J Med 2011; 365: pp. 395.

10 National Lung Screening Trial (NLST) Eligibility: 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.

11 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):

12 Management of Lung Nodules NCCN, Fleischner Society Guidelines Different guidelines for solid, semi-solid, and not-solid (ground-glass) nodules NCCN v1.2017

13 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

14 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 Oct 4;8 Spec No A:S Madsen PH et al. Eur J Nucl Med Mol Imaging Oct;43(11):

15 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 Nov 24;304(20): Kuijvenhoven JC et al. JAMA Sep 13;316(10):

16 Staging AJCC 7 th Edition AJCC 7 th edition effective through end of AJCC 8 th edition starting 1/1/2018. NCCN v

17 Staging-AJCC 8 th Edition: Changes in Bold Goldstraw P et al. J Thorac Oncol Jan;11(1):39-51.

18 Staging-AJCC 8 th Edition: Changes in Bold Goldstraw P et al. J Thorac Oncol Jan;11(1):39-51.

19 Staging-AJCC 8 th Edition: Changes in Bold Goldstraw P et al. J Thorac Oncol Jan;11(1):39-51.

20 Survival-7 th versus 8 th AJCC Editions Goldstraw P et al. J Thorac Oncol Jan;11(1):39-51.

21 Management of Stage I NSCLC

22 Stage I

23 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 Sep;60(3):

24 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 FEV 1 (B) changes Okada M et al. J Thorac Cardiovasc Surg Oct;132(4):

25 CALGB 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

26 VATS Advantage over thoracotomy in terms of morbidity Society of Thoracic Surgeons database , propensity score matched VATS lobectomy: lower morbidity and hospital stay, but longer procedure Paul S. J Thorac Cardiovasc Surg Feb;139(2):

27 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 Aug 10;32(23):

28 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 Aug 10;32(23):

29 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 Sep;15(10):e

30 SBRT for High Risk Patients First author 30-day mortality Complications Follow-up (y) (med) Surgery Median OS (y) 1-yr OS 3-yr OS 5-yr OS Magdeleinat 8% >90% ICU stay % 63% 44% >45% with 4.7 complications Lau 25% (open lobectomy), 7% Median hospital stay: 8 12 days; Segmentectomy or VATS: % 66% 50% (segmentectomy <10% admitted to or VATS) ICU Open lobectomy: % 31% 8% SBRT Henderson 0% ~8% Grade % 43% Stephans 0% 0 Grade 3+ pneumonitis 1.5 Not reached 95% 70% Palma 0% 3% Grade 3 toxicity % 47% 28% Adapted from Palma D et al. Int J Radiat Oncol Biol Phys Mar 1;82(3):

31 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, 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 Jun;16(6):630-7.

32 SABR versus Surgery >100,000 patients in NCDB Median OS favored surgery group, but only 5% of patients had SBRT, especially early on Selection bias 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). Puri V et al. J Thorac Oncol Dec;10(12):

33 SABR versus Surgery SEER database, 9093 pts with N0 NSCLC 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 Dec;149(12):

34 SABR in Operable Patients Moghanaki D and Chang JY. Transl Lung Cancer Res Apr;5(2):183-9.

35 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)

36 SABR for Stage I Inoperable Padda SK et al. Semin Oncol Feb;41(1):40-56.

37 SABR versus Conventional RT SPACE Trial: Stage I medically inoperable NSCLC: SBRT (66Gy/3 fractions) or 3DCRT (70Gy/35 fractions) 102 patients total, 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 Nyman J et al. Radiother Oncol Oct;121(1):1-8.

38 Central vs Peripheral?

39 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 Oct;77(1):83-7. Onishi H et al. J Thorac Oncol Jul;2(7 Suppl 3):S

40 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 Nov 15;93(4):757-64

41 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 Mar 1;76(3):

42 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 Feb 1;82(2):

43 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 Nov 1;75(3):

44 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.

45 7.5 Gyx8 in Central Tumors VUMC: 80 pts with PTV<2 cm from PBT 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 Oct;117(1):64-70.

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

47 VUMC v RTOG0813 Constraints Tekatli H et al. Radiother Oncol Oct;117(1):64-70.

48 Imaging Changes After SBRT Early CT findings: 5 categories No change Diffuse Consolidation Diffuse Ground-Glass Opacity (GGO) Patchy Consolidation & GGO Patchy GGO Linda A. Eur J Radiol Jul;79(1):

49 Imaging Changes After SBRT Late CT findings: 4 categories No changes Modified Conventional Pattern Mass-Like Pattern Scar-Like Pattern Linda A. Eur J Radiol Jul;79(1):

50 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 (1):51 57.

51 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

52 Management of Stage II NSCLC

53 Stage II T1-2N1, T2b-T3N0

54 Stage II NCCN v4.2017

55 Management of Stage III NSCLC

56 Stage III

57 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

58 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 Oct 1;4(1):15-8.

59 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 Aug;18(16):

60 RTOG 0617 Current Standard of Care in Unresectable NSCLC Open-label randomized, two-bytwo 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 Feb;16(2):

61 RTOG 0617 Bradley JD et al. Lancet Oncol Feb;16(2):

62 RTOG 0617 IMRT versus 3D Conformal No difference in OS, PFS, LR, or distant mets Chun SG et al. J Clin Oncol Jan;35(1):56-62.

63 RTOG 0617 IMRT versus 3D Conformal Chun SG et al. J Clin Oncol Jan;35(1):56-62.

64 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 Mar;2(3):

65 Concurrent Chemoradiation Better Than Sequential Auperin A et al. J Clin Oncol May 1;28(13):

66 RTOG 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 Oct 5;103(19):

67 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 Feb;117(2):

68 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 Sep 4;88(17):

69 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 Aug 1;30(22):

70 60 Gy RT Dose: RTOG 7301 Highest local control at 60 gy, no survival diff. Perez CA et al. Cancer Jun 1;45(11):

71 Chemo Regimens NCCN v4.2017

72 Carbo/Taxol versus Cisp/Etop Santana-Davila R et al. J Clin Oncol Feb 20;33(6):

73 Chemo Regimen and Pneumonitis Palma DA et al. Int J Radiat Oncol Biol Phys Feb 1;85(2):

74 How About More Chemo + ChemoRT? Voles EE et al. J Clin Oncol May 1;25(13):

75 How About ChemoRT + More Chemo? Hanna N et al. J Clin Oncol 26: ,2008

76 How About ChemoRT + Targeted Therapy? SWOG S0023 Unselected population Unclear for selected population with newer targeted agents Kelly et al. J Clin Oncol 26: ,2008

77 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 No induction chemo or consolidation chemo after definitive 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

78 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 May 3;383(9928):

79 Chemo After Surgery Pignon JP et al. J Clin Oncol Jul 20;26(21):

80 Chemo Before or After Surgery? Spanish Lung Cancer Group 3 cycles of paclitaxelcarboplatin Pre-op: 97% started planned chemotherapy Post-op: 66% started planned chemotherapy 94% of patients underwent surgery Felip E et al. J Clin Oncol Jul 1;28(19):

81 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 No induction chemo or consolidation chemo after definitive 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

82 Role of Surgery v RT After Chemo EORTC: Randomized trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 nonsmall-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 Mar 21;99(6):

83 Role of Surgery After Chemoradiation INT 0139: concurrent induction chemoradiation to 45 Gy, surgery versus uninterrupted chemoradiation up to 61 Gy PFS p=0.017 OS p=0.24 Lobectomy OS Pneumonectomy OS Albain KS et al. Lancet Aug 1;374(9687):

84 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 Gy (arm A) Closed after 246/500 patients 5-yr OS 44% for surgery and 40% for chemort Eberhardt WE. J Clin Oncol Dec 10;33(35):

85 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 No induction chemo or consolidation chemo after definitive 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

86 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 Sep 12;386(9998):

87 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 Gy in both arms if positive margins or unresectable 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 Thomas M et al. Lancet Oncol Jul;9(7):

88 Post-Op RT PORT Meta-analysis Trialists Group. Lancet Jul 25;352(9124):

89 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 Nov 1;72(3):

90 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, to 1.113; P =.127) did not have a significant impact on survival N0: PORT was associated with a significant decrease in survival (HR = ; 95% CI, to 1.376; P =.0435) N1: PORT was associated with a significant decrease in survival (HR = 1.097; 95% CI, to 1.186; P =.0196) N2: PORT was associated with a significant increase in survival (HR = 0.855; 95% CI, to 0.959; P =.0077) Lally BE et al. J Clin Oncol Jul 1;24(19):

91 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 Oct 26;343(17):

92 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 , 110 patients pcr or minimal microscopic disease 56% 5-year OS 44% Rusch VW et al. J Clin Oncol Jan 20;25(3):313-8.

93 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

94 Special Topics

95 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 Dec;17(12):

96 Targeted Therapy + RT RTOG 1306.

97 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)

98 Management of Small Cell Lung Cancer

99 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 Jan;67(1):7-30.

100 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

101 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 Apr 1;34(10):

102 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

103 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= yr OS: 15% vs. 10% Pignon et al. NEJM 1992

104 RT Timing: SER Important Predictor of Outcome De Ruysscher et al. JCO 2006

105 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

106 Dose/Fractionation - CALGB CALGB 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.

107 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 year OS was 56% (BID) vs 51% and median OS 30 months (BID) vs 25 months (HR 1.17, 95% CI ; 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

108 Dose/Fractionation-CALGB Ongoing

109 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 Jan 20;6(1):e

110 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 Sep;80(3): Van Loon J et al. Int J Radiat Oncol Biol Phys Jun 1;77(2):

111 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

112 PCI Dose , 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 May;10(5):

113 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 May; 22(5)

114 PCI Neurocognitive Effects: RTOG 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.

115 Thoracic RT-Extensive Stage RT: 54 Gy/36 fx BID Jeremic et al. JCO 1999

116 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 Jan 3;385(9962):36-42.

117 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.

118 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

119 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= ; 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= ) No significant difference in AEs greater than Grade 2 Seto T et al. ASCO 2014

120 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

121 Thank you. Jing Zeng, MD University of Washington Contact: