Treatment of LS (Stage I-III) SCLC

Treatment of LS (Stage I-III) SCLC Prof C Faivre-Finn Manchester Lung Cancer Group Manchester Radiation Related Research Group ESMO-The Christie Preceptorship programme on Lung Cancer 9 th March 2018 @finn_corinne

Introduction Incidence of SCLC is declining-less than 10-15% of all lung cancer cases Govindan JCO 2006 Majority (> 95%) are associated with tobacco exposure One third present with stage I-III disease Excellent responses to CT and RT but few patients will be long term survivors High risk of local relapse High risk of distant spread (brain)

How do we stage SCLC? Veterans classification TNM classification 8008 patients 100% Median survival (months) 80% 60% 40% 20% IA IB IIA IIB IIIA IIIB IV 26 21 15 12 13 11 6 0% 0 2 4 6 8 Survival (years) Limited stage = T1-4 N0-3 M0 Role of PET controversial. Thomson. Lung cancer 2010

Stage I-III SCLC - Clinical case 76 year old male PMH HBP, mild COPD, ex smoker 30 PY PS1, MRC RS 1 Presented with a cough and SOB on exertion FEV1 55% predicted, KCO 46% predicted Bronchoscopy-tumour obstructing the L main bronchus CT thorax&abdomen Mass LUL Station 4R, 4L, 5 and 7 lymph nodes CT brain clear Treatment options Sequential CTRT Concurrent CTRT Dose fractionation 40 Gy/15F 50-55 Gy/20F >60 Gy/30+F 3DRT or IMRT? PCI?

Systemic treatment in stage I-III SCLC Cisplatin is the best radiosensitiser and has higher RR Cisplatin plays a major role in the treatment of LS-SCLC Cisplatin-Etoposide can be delivered at full dose with thoracic RT with an acceptable toxicity profile No change in systemic therapy in last 20 years No role for anthracyclines/pemetrexed/irinotecan No role for chemotherapy dose intensification No role for targeted agents

Radiotherapy Current evidence in stage I-III SCLC CTRT >CT (Pignon, Warde) Early RT >late RT (Fried, Cochrane review) Concurrent CTRT >sequential CTRT (Takada) Best survival results achieved with early BD concurrent CTRT (Turrisi, Jeremic, Faivre-Finn) PCI improves survival - 6% @ 3 years (Auperin)

Role of thoracic radiotherapy Meta-analyses Pignon et al. N Engl J Med 1992 13 randomised trials 2140 patients 3 year survival 8.9 % CT alone 14.3% CT+RT Thoracic RT benefited more younger patients RR of death in the CTRT as compared with CT group 0.72 for patients <55 years old (0.56-0.93) 1.07 (0.70-1.64) for patients over 70 Warde et al. JCO 1992 Limitations of the metaanalyses Response to treatment assessed on CXR Dated RT techniques (2D) 14% reduction in risk of death, p = 0.001

Timing of thoracic RT with chemotherapy 7 RCTs Advantage of early (<9 weeks) radiotherapy 2 yr % NNT for benefit p All (1524) +5.2 [0.6-9.7] 20 0.03 Platinum Platinum+ HART +9.8 [3.8-15.9] 10 0.001 +16.7 [9.4-26] 6 0.001 Fried et al. J Clin Oncol 2004

Standard of care for LS-SCLC Intergroup 0096 Once daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 5 yr survival 26% BD vs 16 % OD Limited Stage Small Cell Lung Cancer RT 45Gy/33D/25F Twice daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 CR PCI If<CR No PCI Registration RT 45Gy/19D/30F Randomisation Restage Chemotherapy (PE) Radiotherapy Turrisi et al. N Engl J Med 1999

Utilization of Hyperfractionated Radiation in SCLC and Its Impact on Survival National Cancer Database.1999-2012 25,045 patients diagnosed with nonmetastatic SCLC (22,626 had survival data) The utilization of BD radiation overall was 11.3% Treatment at an academic centre was associated with a higher likelihood of receiving BD treatment (OR: 2.29, p < 0.001). Median survival was 22.1, 17.2, 18.3, 19.2, and 19.5 months for patients receiving 45 Gy BD, 45 Gy OD, 46-59.4 Gy OD, 60-61.2 Gy OD, and 62-72 Gy OD (p < 0.001 for pairwise comparison to BD) Schreiber. JTO 2015

How can we improve survival rates further with radiotherapy?

Modern techniques 3D CRT/IMRT 4DCT and PETCT for RT planning IGRT Considerations for radiotherapy techniques Better local control = Improved survival Impact of advanced RT on outcome?

Intensity modulated radiotherapy V20 33.1% MLD 19.4Gy Max SC 47.9 Gy V20 35% MLD 20.1 Gy Max SC 35.3 Gy IMRT modulates the intensity profile of the radiation delivered to the patient allowing improved targeting of The the Christie radiation NHS dose Foundation Trust

3DCRT vs IMRT for stage I-III SCLC 223 patients treated at the MD Anderson between 2000-09 were retrospectively reviewed 119 receiving 3DCRT and 104 receiving IMRT Median age was 64 years (range 39-90 years) Radiation modality was not associated with differences in OS or DFS in either multivariable or propensity score-matched analyses Shirvani. Int J Rad Oncol Biol Phys 2013

CONVERT multinational, phase III randomised study D1 D3 D22 D24 D43 D45 D64 D66 PS 0-2 No age limit RTP after randomisation RT started on D22 cycle 1 3DCRT or IMRT No ENI QA programme RT 45Gy/30F/19D Twice-daily (BD) thoracic RT SD,PR,CR PCI Chemotherapy 4 to 6 cycles Cisplatin 25mg/m2 D1-3 or 75mg/m2 D1 Etoposide 100mg/m2 D1-3 Limited Stage Small Cell D1 D3 D22 D24 D43 D45 D64 D66 547 patients 8 countries 75 centres If<SD no PCI Stratification factors Centre No. of cycles chemo: 4 vs.6 PS: 0,1 vs. 2 Registration Randomisation RT 66Gy/33F/45D Once-daily (OD) thoracic RT Restage Chemotherapy Radiotherapy

Overall survival Alive (%) 100 80 60 40 20 0 OD BD Overall survival HR=1.18 with 95% CI 0.95-1.45 p=0.14 0 1 2 3 4 5 Years from randomisation 6 7 Number at risk OD 270 (5) 202 (1) 134 (17) 88 (30) 46 (22) 21 (13) 7 (3) 3 BD 273 (3) 224 (1) 151 (27) 92 (29) 54 (25) 25 (19) 6 (3) 2 Overall survival (n=543) Median (months) Primary objective-overall survival Trial hypothesis Expected survival BD arm 44% Projected survival OD arm 56% Median follow-up: 45 months BD OD Log-rank 30 (24-34) 25 (21-31) 1-year 83% (78-87) 76% (71-81) 2-year 56% (50-62) 51% (45-57) 3-year 43% (37-49) 39% (33-45) 5-year 34% (27-41) 31% (25-37) p=0.14 Faivre-Finn. Lancet Oncol 2017

Acute Toxicity Organ at risk Arm N Median (Range) Lung V5 (%) BD OD 246 234 56.2 (7.2-88.5) 60.8 (7.0-91.6) ARM BD (n=254) OD (n=256) p AE (grade) 1-2 n (%) 3 n (%) 4 n (%) 5 n (%) 1-2 n (%) 3 n (%) 4 n (%) 5 n (%) Lung V20 (%) BD OD 252 240 23.2 (0.1-35.4) 28.8 (8.0-40.5) Oesophagitis 159 46 1-135 47 - - 0 85 (62 6) (18 1) (0 4) (52 7) (18 4) Heart (% total dose) BD OD 240 229 2.0 (0-45.3) 1.4 (0-36.2) Spinal cord (max dose, Gy) BD OD 251 241 32.0 (1.3-45.8) 41.7 (1.3-52.6) Pneumonitis 51 (20 1) 3 (1 2) 1 (0 4) 1 (0 4)* 49 (19 1) 3 (1 2) 1 (0 4) 2 (0 8)* 0 70 Oesophagus (max dose, Gy) BD OD 248 236 45.7 (0.7-64.4) 65.9 (2.2-71.7) Oesophagus V35 (%) BD OD 246 230 34.0 (0-76.5) 38.8 (0-82.8) 1 patient in each arm not assessable for oesophagitis, 6 patients for pneumonitis *1 patient in BD arm and 2 patients in OD arm (1 received sequential CTRT) died from radiation pneumonitis Faivre-Finn. Lancet Oncol 2017

Late Toxicity Symptom Arm 0 1-2 3 4 p 0,1,2 vs 3,4 Dermatitis BD OD 233 (94.0) 216 (92.7) 15 (6.0) 17 (7.3) - - - Oesophagitis BD OD 219 (88.3) 191 (81.6) 29 (11.7) 39 (16.7) - 4 (1.7) - 0.06 Oesophageal stricture/fistula BD OD 240 (91.8) 226 (97.0) 8 (3.2) 6 (2.6) - 1 (0.4) - 0.48 Pulmonary fibrosis BD OD 125 (50.6) 120 (52.6) 119 (48.2) 106 (46.5) 3 (1.2) 2 (0.9) - 1.00 Pneumonitis BD OD 171 (69.0) 154 (67.0) 71 (28.6) 70 (30.4) 5 (2.0) 5 (2.2) 1 (0.4) 1 (0.4) 0.90 Myelitis BD OD 247 (99.6) 223 (96.5) 1 (0.4)* 8 (3.5)* - - - * Myelitis all grade 1 Other BD OD 92 (37.4) 99 (42.7) 131 (53.3) 113 (48.7) 20 (8.1) 18 (7.8) 3 (1.2) 2 (0.9) 0.78 The Christie NHS Foundation @finn_corinne Trust

CONVERT- CTC - Multivariate Analysis At-Risk Group PFS OS Models Positive Negative P HR 95% CI P HR 95% CI With 2-CTCs threshold 2 CTCs at baseline 2 < 2 0.021 1.85 1.10 to 3.12 0.006 2.15 1.25 to 3.70 ECOG PS 1 0 0.011 2.20 1.19 to 4.07 0.009 2.39 1.25 to 4.60 2 0 0.184 2.15 0.70 to 6.63 0.148 2.32 0.74 to 7.29 With 15-CTCs threshold 15 CTCs at baseline 15 < 15 <.001 6.03 3.00 to 12.08 <.001 6.19 3.08 to 12.42 ECOG PS 1 0 0.157 1.60 0.84 to 3.05 0.168 1.63 0.81 to 3.25 2 0 0.439 1.58 0.50 to 5.03 0.223 2.05 0.64 to 6.56 With 50-CTCs threshold 50 CTCs at baseline 50 < 50 0.002 3.59 1.58 to 8.18 0.003 3.42 1.52 to 7.67 ECOG PS 1 0 0.034 1.96 1.05 to 3.65 0.034 2.05 1.05 to 3.97 2 0 0.298 1.85 0.58 to 5.89 0.148 2.35 0.74 to 7.47 CTC count is highly prognostic for survival Independent from other clinical factors (eg PET staging) 15 CTCs predicted 2 years survival in 100% and 1 year survival in 70% of the patients Provides a hypothesis to stratify patients prospectively for CTC count in future clinical trials Fernandez-Guiterrez. World Lung 2016

Conclusions Practice defining trial Radiation-related toxicities were lower than expected likely due to the use of modern RT techniques Survival in both arms was higher than previously reported BUT OD RT did not result in a superior survival or worse toxicity than BD RT 45Gy in 30 # BD should continue to be regarded as standard of care because CONVERT is not an equivalence trial However OD RT (66 Gy in 33 fractions) can be considered an alternative regime BD RT cannot be delivered Faivre-Finn. Lancet Oncol 2017

Intergroup study CALGB 30610-RTOG 0538 45 Gy BID/ 3 weeks 45 Gy BID/ 3 weeks Limited SCLC PS 0-1 PE X 4 PCI Cycle 1 or 2 TRT 61.2 Gy CB/ 5 weeks 70 Gy QD/ 7 weeks Re-assess VS. Experimental TRT arm Primary endpoints = OS

Can we improve survival rates further with systemic treatment?

SCLC and targeted agents Study Target Agent Design Result NCI-C/EORTC BAYER ECOG CALGB HOG LLCG MMP Marimastat BAY 12-9566 +/- Maintenance +/- Maintenance VEGF BEV (B) Chemo + B Chemo + B Chemo + B Vascular stabilizer Negative Negative Positive Negative Negative Thalidomide Chemo +/- T Negative NCI-C VEGFR TKi ZD 6474 +/- Maintenance Negative SWOG VEGFR TKi Sorafenib Monotherapy Negative NCI VEGFR TKi ZD 2171 Monotherapy Negative Rudin Bcl-2 Oblimersen Chemo +/- Negative Langer Bcl-2 Obatoclax Chemo +/- Negative ECOG mtor CCI-779 +/- Maintenance Negative HOG EGFR gefitinib Monotherapy Negative Johnson Krug Dy Kit Imatinib Monotherapy Monotherapy Monotherapy Negative Negative Negative EORTC GD-3 BEC2/BCG +/- Maintenance Negative SWOG Proteosome Bortezomib Monotherapy Negative SWOG RAS/VEGF Sorafenib Monotherapy Negative

Targeted agents and RT Phase II -29 LS-SCLC patients recruited Early trial closure Two patients developed tracheoesophageal fistulae One patient died from an aerodigestive hemorrhage Spigel et al. J Clin Oncol 2010

Chemo-Radiotherapy: Consolidation vs observation: Screening: cis-/carboplatin + etoposide 4 cycles Tumour evaluation: induction maintenance max 1 year LD SCLC RT RT PCI yes PD off no R combination nivolumab/ipilimumab observation nivolumab Week from start of chemotherapy after randomisation 3 6 9-2 0 3 6 9 12 14 16 18 27 FDG-PET-CT or CT CT CT Brain MRI or CT Biomaterial for translationalresearch: RT (Thoracic Radiotherapy) : CT scans for tumourassessment accelerated schedule preferred - up to 18 months: every 9 weeks start: day 1 of chemo cycle 1 or - up to 2 years: every 12 weeks day 1 of chemo cycle 2 - years 3 & 4: every 6 months - at 5 years At progression: Serum Whole blood STIMULI Serum Whole blood Serum Whole blood Serum Biopsy: FFPE block or slides Voluntaryre-biopsy:? FFPE block

Progress in stage I-III SCLC CT alone <10 Seq CTRT 10-15 ConCTRT 20-25 BD CTRT 25 CONVERT BD 34 5 year survival (%)

Surgery for very limited SCLC?

Facts Stage I SCLC is diagnosed in ~5% of patients Paucity of prospective evidence in very early stage SCLC Staging, surgery and RT techniques have evolved dramatically in last decade

Surgery vs RT R MRC trial. 144 patients with no evidence of metastatic disease, operable and fit enough for resection Surgery. Patients allocated to surgery were to undergo thoracotomy with the intention of performing a total resection of all growth Radical radiotherapy. Patients allocated to radical RT were to be treated by the technique customarily used by the radiotherapists (11% pall RT, 4% no RT) Fox et al. Lancet 1973 No chemotherapy, no details on TNM

Surgery vs RT ECOG-EORTC 328 pts registered, 146 pts randomised, 13 pts stage I 50 Gy/25# Actuarial 2 year survival 20% Lad et al. Chest 1994

NCI recommendations Role of surgery The role of surgery in the management of patients with SCLC is unproven Evidence: Small case series and population studies have reported favourable outcomes for the minority of LD patients with very limited disease (level of evidence 3) A randomized study evaluating the role of surgery in addition to CTRT found no OS benefit with the addition of pulmonary resection [Lad et al] (level of evidence 1) Given the absence of data from randomized trials, the role of surgery in the management of individual patients with SCLC must be considered, both in terms of potential benefit and risk from the surgical procedure http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung

CONVERT EARLY STAGE 513 patients eligible for this subgroup analysis and 87 (17%) had early disease: 4 patients (4.6%) TNM stage I 83 patient (95.4%) TNM stage II Early Locally-advanced p=0.001 Toxicity (number evaluated early/ locally-advanced) Grade Early Locallyadvanced 0 32 (39%) 72 (18.3%) Chi-sq (p-value) Early Locallyadvanced Log rank Oesophagitis (82/ 393) 1-2 3 41 (50%) 9 (11%) 237 (60.3%) 84 (21.4%) <0.005 Median 50 months 95%CI 35,- 25 months 95% CI 21, 29 Pneumonitis (82/ 389) 0 1-2 3 59 (72%) 21 (25.6%) 2 (2.4%) 307 (78.9%) 74 (19%) 8 (2.1%) 0.52 1-year 83% 79% 2-year 64% 50% p=0.001

SUMMARY For clinical guidelines : ESMO Ann Oncol 2010, 2013 NCCN Thorax 2016 NCI recommendations Cisplatin etoposide is still standard in combination with RT Progress has been made with RT!! We should all CONVERT to BDRT Role of surgery for stage I-II SCLC not well defined We need to increase our understanding of the biology and individualise treatment