NSCLC Radiotherapy Prof Corinne Faivre-Finn Manchester Radiotherapy Related Research Group Manchester Lung Cancer Group The Christie, Manchester, UK 17 th ESO-ESMO Masterclass 25 th March 2018
Early stage disease SABR Objectives Locally advanced disease Standard radiotherapy Standard chemotherapy Metastatic disease Role of WBRT Case discussions
Early stage NSCLC
78 yr old male Chest infection CXR LUL lesion PMH COPD, emphysema, MI, ex smoker 52 pack year history WHO PS=2, MRC RS 3 FEV1 32% predicted KCO 36% predicted PETCT- LUL lesion SUV 15 CT guided biopsy SCC Clinical case Treatment options Lobectomy + mediastinal exploration Wedge resection+ mediastinal exploration CHART Standard conformal RT SABR
SABR Surgical resection is the optimal curative treatment, but <50% of patients are medically fit for this With standard RT local control (<50%) and survival are inferior to surgery (<30%@ 5 years) What is SABR? High dose RT Hypofractionation (3-8) Allowing precise RT delivery to the tumour Allows to spare nearby healthy organs Requires 4DCT and IGRT SABR offers local tumour control (>90%) comparable with surgery SABR delivered routinely in most academic European centres Roach. JTO 2015
Study No. of patient s RT Dose fractionatio n Baumann 138 30-48 Gy in 2-4 fractions Lagerwaard 206 3 x 20 Gy 5 x 12 Gy BED (Gy) Median fu (months) Local control 60-120 33 85% @ 3 years 180 Gy 132 Gy 12 94% @ 2 years Nagata 45 4 x 12 Gy 106 Gy 30 98% @ 2 years Survival Toxicity 55%@5yrs Atelectasis: 2%* Pneumonitis: 1%* Rib fractures: 4%º 64%@2yrs Pneumonitis: 3%* Rib fractures: 2%º 83%@3yrs stage Ia 72%@3yrs stage Ib Nyman 45 3 x 15 Gy 113 Gy 43 80% 55%@3yrs 30%@5yrs Onishi 257 18-75 Gy in 1-22 fractions Timmerman 70 3 x 20 Gy 3 x 22 Gy Umetsu 50 50-60 Gy in 5-10 fractions Various 38 84% if BED 100 Gy @ 5 years 180 Gy 122 Gy Guidelines ASTRO ESMO EORTC BTS SABR is a treatment option for medically inoperable, peripheral, early stage NSCLC 18 96% @ 2 years Pneumonitis: 0%* Pneumonitis: 0%* Rib fractures: 4%º 47%@ 5 yrs Pneumonitis: 5%* 54%@2 yrs Various 36 94% 66%@3 yrs (some operable pts) Pericardial Effusion: 1% (grade 5) Bleeding: 1% (grade 5) Pneumonitis: 6% (grade 5) Pneumonitis: 0%* Rib fractures:4%º
SABR in central tumours Phase II- n=70-t1 or T2 ( 7 cm), N0, M0, biopsy-confirmed NSCLC 60 to 66 Gy/3 fractions. Lung or bone tissue density corrections were not used Dose prescribed to the margin of the PTV, which corresponded to the 80% of isocentre dose volume 8 patients experienced Grade 3+ toxicity (pulmonary function tests, pneumonias, pleural effusions, apnea, and skin reaction) SABR may have contributed to the events leading to the death of 6 patients (4 bacterial pneumonia, 1 pericardial effusion and 1 massive hemoptysis). 4/6 had central tumours Tumour location (hilar/pericentral v peripheral) was a strong predictor of toxicity (p=0.004) x11 Timmerman et al. JCO 2006 Fakiris Int J Radiat Oncol Biol Phys 2009 No fly zone= 2cm radius from main airways and proximal bronchial tree
SABR in central tumours Chang. JTO 2015 Need to define OAR constraints Haasbeek. JTO 2011; Chang, Int J Radiat Oncol Biol Phys 2008; Xia. Int J Radiat Oncol Biol Phys 2006; Mangona Int J Radiat Oncol Biol Phys 2014 Acceptable regime 45 50 Gy/4# 50 60 Gy/5# 60 Gy/8# 70 Gy/10 # EORTC LungTech study ongoing
SPACE trial-randomised phase II 102 patients - SABR 66 Gy in 3 fractions (one week) - 3DCRT 70 Gy (7 weeks) Nyman. Radiother Oncol. 2016 66 Gy/33 fr Primary endpoint-pfs Fewer cases with pneumonitis (19 vs. 34%) and oesophagitis (8 vs. 30%) in the SABR arm. No grade 5 events. QOL worse dyspnea (p = 0.01), chest pain (p = 0.02) and cough (>10 points difference).
SABR vs 3DCRT for Peripheral Early Stage NSCLC CHISEL Trial Ball. WCLC 2017 Freedom from LF HR 0.29, 95% CI 0.13, 0.66 P = 0.002 Randomised phase III 101 medically inoperable patients or refuse surgery Histologic/cytologic confirmation T1-T2a N0 (PET staged) ECOG PS 0-1 Peripheral tumours Overall survival HR 0.51 95% CI 0.29, 0.91 P = 0.020
RCTs SABR vs Surgery (completed) SABR: 10% G3 events Surgery: 44% G3-4 events SABR could be an option for treating operable stage I NSCLC Pooled analysis STARS and ROSEL Chang. Lancet Oncol 2015
SABR Take home messages Standard of care in medically inoperable, peripheral stage I NSCLC Local control>90% Convenient for patients and RT departments Results from RCTs comparing SABR vs. surgery awaited Patients with central tumours should be treated in prospective clinical trials
Locally advanced NSCLC
Metastatic relapse The problem ~30% stage III Role surgery is limited Survival is poor 10-30% at 5 yrs Need for CTRT combinations Local relapse Median survival 17-28 months
53yr old female Locally advanced NSCLC Clinical case Presented with right facial pain, no respiratory symptoms V20 33.1% PMH hiatus hernia, ex smoker 35 pack year MLD 19.4Gy history Max SC 47.9 Gy WHO PS=0, MRC RS 0 PFTs - FEV1 80% predicted KCO 105% predicted Bronchoscopy - no endobronchial abnormality CT scan - RUL mass and enlarged 4R, 7 lymph nodes T3 N2 M0 EBUS station 4R moderately differentiated adenocarcinoma PET-CT - FDG avid right supraclavicular lymph nodes T3 N3 M0 MR brain - clear 7field IMRT Treatment options Sequential CTRT or Concurrent CTRT CT+Palliative RT 3DCRT or IMRT Induction or consolidation CT?
Aupérin. JCO 2010 2010 by American Society of Clinical Oncology Meta-analysis concurrent vs. sequential CTRT (A) Survival curves (B) progression-free survival curves 6 RCTs 1,205 patients HR 0.83 (p=0.04); absolute benefit survival 4.5% at 5 years Improved local control Increased acute oesophageal toxicity HR= 4.9 (p < 0.0001)
P 4DCT PETCT
60-66 Gy in 30-33 fractions OD=standard of care CHART study TD>OD RT (54 Gy/36 # over 12 consecutive days vs 60 Gy/30 #/6 weeks) Saunders. Lancet 1997 Altered fractionation>conventional fractionation Mauguen. JCO 2012 No defined role for dose escalation Dose limited by normal tissues Lung - V20, MLD Spinal cord Brachial plexus Oesophagus Heart What RT? Christodoulou. EJC 2014 De Ruysscher. JCO 2010
S T R A T I F Y RT Technique 1.3D-CRT 2.IMRT Zubrod 1.0 2.1 PET Staging 1.No 2.Yes Histology 1.Squamous 2.Non- Squamous RTOG 0617 Study Design R A N D O M I Z E Concurrent Treatment Arm A Concurrent chemotherapy* RT to 60 Gy, 5 x per wk for 6 wks Arm B Concurrent chemotherapy* RT to 74 Gy, 5 x per wk for 7.5 wks Arm C Concurrent chemotherapy* and Cetuximab RT to 60 Gy, 5 x per wk for 6 wks Arm D Concurrent chemotherapy* and Cetuximab RT to 74 Gy, 5 x per wk for 7.5 wks *Carboplatin and paclitaxel 90% patients PET staged 185 centres n=464 (high dose vs standard dose; n=544 cetuximab vs no cetuximab) Consolidation Treatment Arm A Consolidation chemotherapy* Arm B Consolidation chemotherapy* Arm C Consolidation chemotherapy* and Cetuximab Arm D Consolidation chemotherapy* and Cetuximab Bradley. Lancet Oncol 2015
MS (95% CI) Oesophagitis G3+ Treatment related death RTOG 0617 60 Gy 28.7 months (24 1 36 9) 7% 3 74 Gy 38% greater risk for death in 74 Gy arms Heart dose (V5 and V30) associated with poor survival 20.3 months (17 7 25 0) 15% 8 Bradley. Lancet Oncol 2015
Why Cisplatin as a backbone in the cctrt setting? PE can be combined at full dose with RT Challenged by RTOG 0617 Auperin et al. J Clin Oncol 2010
Comparison of concurrent use of carboplatin-paclitaxel versus cisplatin-etoposide with RT for stage III NSCLC Limited data comparing CE vs. CP for definitive chemort for stage III NSCLC. Liang et al, Ann Oncol 2017 - phase III 200 patients. Median survival 23.3 months EP arm and 20.7 months PC arm (p 0.095, HR 0.76, 95%CI 0.55 1.05). Grade 2 radiation pneumonitis higher in the PC arm (33.3% versus 18.9%, p 0.036), Grade3 esophagitis higher in the EP arm (20.0% versus 6.3%, p 0.009). Wang et al, Lung Cancer 2012 small randomized phase II improved PFS and OS for CE vs. CP Santana-Davila et al, JCO 2015 VA retrospective study no difference in PFS or OS, with improved toxicity for CP Literature based meta-analysis 1985-2015, 79 studies (3090 patients from 31 CE studies and 3728 patients from 48 CP studies) Stauer JAMA Oncol 2017
Proclaim- Pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy in stage III NSCLC Senan. JCO 2016
Why induction or consolidation CT? Are 2 or 3 cycles of concurrent CT sufficient concurrently with RT? Concurrent CTRT optimizes local control but distant spread is still a major problem Further systemic chemotherapy to optimize treatment of distant disease?
Vokes. JCO 2007 Induction chemotherapy CALGB 39801 CTRT CT CTRT p N 161 170 Oesophagitis (grade 3-4) 32% 36% ns Pneumonitis (grade 3-4) 4% 10% ns Median survival 12 months 14 months 0.3 2 year survival 29% 31%
Consolidation chemotherapy Docetaxel cctrt (59.4Gy) EP x2 +/- docetaxel x3 Gefitinib cctrt (61Gy) EP x2 docetaxel x3 +/- gefitinib to PD or 5yrs Hanna et al., J Clin Oncol 2008 Kelly et al. J Clin Oncol 2008
Consolidation chemotherapy - KCSG-LU05-04 Multicentre randomised Ph III trial CTRT Cis/Docetaxel weekly x6; RT 66 Gy/33 F CTRT alone v CTRT + Cis/Docetaxel consolidation n=437 Ahn, JCO 2015
Systematic review Consolidation chemotherapy Pooled analysis of the literature Data from phase II/III concurrent CTRT trials (1995 2011) 41 trials (7 phase III, 34 phase II) 45 trial arms With consolidation CT (CCT+ ) or without Consolidation CT (CCT- ) Tsujino. JTO 2013
Role of immunotherapy in stage III NSCLC PACIFIC trial Patients with unresectable Stage III NSCLC No progression following platinum-based ccrt N = 702 Arm 1 Durvalumab 10 mg/kg Q2W for up to 12 months (Max 26 doses)) 2:1 Day 1 Max 42 days after the end of CRT Arm 2 Placebo Q2W iv for up to 12 months (Max 26 doses) OS PFS using PI assessments according to RECIST 1.1* * Disease progression requires confirmation, treatment with MEDI4736 will continue between the initial assessment of progression and confirmation for progression. Co-Primary endpoints: OS and PFS Follow-up Period
PFS probability No. at risk Durvalumab Placebo PACIFIC PFS by BICR (Primary Endpoint; ITT) 1.0 (N=476) Median PFS (95% CI), 0.9 months 0.8 12-month PFS rate (95% CI) 0.7 18-month PFS rate (95% 0.6 CI) 0.5 0.4 0.3 0.2 Durvalumab Placebo 0.1 0.0 0 3 6 9 12 15 18 21 24 27 Time from randomization (months) 476 377 301 264 159 86 44 21 4 237 163 106 87 52 28 15 4 3 1 0 Durvalumab Placebo (N=237) 16.8 (13.0 18.1) 5.6 (4.6 7.8) 55.9% (51.0 60.4) 35.3% (29.0 41.7) 44.2% (37.7 50.5) 27.0% (19.9 34.5) Stratified hazard ratio, 0.52 (95% CI, 0.42 0.65) Two-sided P<0.0001 Antonia. NEJM 2017
PACIFIC-Safety Summary Durvalumab (N=475) Placebo (N=234) Any-grade all-causality AEs, n (%) 460 (96.8) 222 (94.9) Grade 3/4 142 (29.9) 61 (26.1) Grade 5 21 (4.4) 13 (5.6) Leading to discontinuation 73 (15.4) 23 (9.8) Any-grade treatment-related AEs, n (%) 322 (67.8) 125 (53.4) SAEs, n (%) 136 (28.6) 53 (22.6) Any-grade immune-mediated AEs, n (%) 115 (24.2) 19 (8.1) Grade 3/4 16 (3.4) 6 (2.6) Pneumonitis (grouped terms) or radiation pneumonitis, n (%)* Durvalumab (N=475) Placebo (N=234) Any grade 161 (33.9) 58 (24.8) Grade ¾ 16 (3.4) 6 (2.6) Grade 5 5 (1.1) 4 (1.7) Leading to discontinuation The 30 Christie (6.3) NHS Foundation 10 (4.3) Trust
Combined CTRT Summary Concurrent CTRT is the standard of care in selected good PS patients Standard regime 60Gy in 30 fractions+platinum based chemo Immunotherapy improves PFS in stage III NSCLC. OS data awaited No consensus on the optimal CT regimen No evidence to support the addition of induction and consolidation CT to concurrent CTRT No evidence to support targeted No personalisation of the systemic or RT treatments Lim. Thorax 2010 (BTS guidelines) Bayman. Lung Cancer 2014 Vansteenkiste. Ann Oncol 2013 (ESMO guidelines)
Improvement in survival in last 4 decades with CTRT 10.8m 14 m 17 m 28.7m TRT RT Chemo TRT Chemo + TRT Chemo + TRT 1970 1980 1990 2000 2010 RTOG0617 28.7m SOCCAR 27.4 m CONCEPT 31 m IDEAL 29 m When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states
Stage IV
MDACC: Ph II Trial of local therapy & SOC vs SOC in synchronous oligo-metastatic NSCLC 49 patients Median F/U 12 mths PFS 12 vs 4 mths in favour of local consolidation (LCT) Imbalance in histology? Squamous 4% LCT vs 17% control Mut + Adeno 20% LCT vs 12% control Gomez et al Lancet Oncol 2016
Trials in oligometastatic disease Synchronous Untreated Distant Metastasis Untreated Primary Lesion A clinical scenario in which oligometastatic disease is detected at the time of diagnosis of the primary tumour Metachronous Oligo-Recurrent Untreated Distant Metastasis Treated Primary Lesion A clinical scenario in which the development of oligometastatic disease after treatment of the primary tumour Oligo-Progressive Uncontrolled Lesion Controlled Lesions A clinical scenario in which progression of a limited number of metastatic deposits occurs while all other metastases are controlled on systemic therapy SARON CORE HALT
QUARTZ Trial Randomised Controlled Non-Inferiority Design Aim-to exclude >1 week reduction in QALYs with omission of WBRT 80% power March 2007- August 2014 Histologically proven NSCLC with brain metastases non-resectable and unsuitable for stereotactic Radiosurgery Stratification Centre, sex, PS, status of BM (progressive disease vs newly diagnosed), status of primary disease (absent, controlled, uncontrolled) R Control Arm: Optimal Supportive Care Dexamethasone + Whole Brain Radiotherapy 20Gy in 5 daily # Investigational Arm: Optimal Supportive Care Dexamethasone Primary outcome quality adjusted life years (QALYS) Weekly phone call Secondary outcomes overall survival symptom scores Subsequent / simultaneous (extra cranial) palliative RT permitted Subsequent systemic treatment permitted at clinician s discretion
0 Average QoL.2.4.6.8 1.00 0.75 0.50 0.25 0.00 At risk OSC + WBRT OSC alone QUARTZ Components of the Primary Outcome Measure Overall survival (all patients) 0 8 16 24 32 40 48 56 Time from randomisation (weeks) 269 144 66 32 17 11 9 5 269 141 64 32 16 11 8 5 Overall Survival Better Worse OSC+WBRT Health Utility index EuroQoL EQ-5D 0 8 16 24 32 40 48 56 Time from randomisation (weeks) OSC Alone --------- OSC+WBRT ------- OSC Alone --------- OSC+WBRT ------ OSC Alone Mulvenna. Lancet 2016 OSC+WBRT OSC alone Median survival (weeks) 9.3 weeks (7.4, 10.7) 8.1 weeks (7.6, 9.0) HR 1.05 (0.89, 1.26) P-value 0.52 Quality of Life Weekly-12 weeks Then 4 weekly
0.2.4.6.8 QUARTZ Primary Outcome Measure: Quality Adjusted Life Years --------- OSC+WBRT OSC+WBRT ------- OSC Alone OSC Alone No clinically relevant difference 0 8 16 24 32 40 48 56 Time from randomisation (weeks) QALY OSC+WBRT OSC alone Difference Mean QALY (days) 43.3 days 41.4 days -1.9 days 90% CI (Bootstrap) (-9.1, 6.6) Non-inferiority boundary -7 days -9.1-7 -2 0 6.6 OSC+WBRT OSC alone better better Aim-to exclude >1 week reduction in QALYs with omission of WBRT 80% power DAYS
Conclusions QUARTZ Trial Only large randomized trial of WBRT vs no WBRT for brain metastases from NSCLC WBRT does not appear to be a steroid-sparing modality Similar overall median survival (9.3 weeks vs 8.1 weeks) Similar QALYs (43.3 days vs 41.4 days) The estimate of the difference in QALYs suggests WBRT provides no additional clinically significant benefit for this group of patients However.WBRT should not disappear as a treatment option, consider WBRT in patients with favourable prognosis (TBD) Consider the changing landscape in terms of systemic treatments Khalifa. JTO 2016
Stage I-II Role of RT in NSCLC SABR=standard of care Stage III for peripheral disease for medically inoperable patients Concurrent CTRT =standard of care Stage IV For palliation of symptoms Oligometastatic disease (RCTs ongoing) Guidelines BTS Guidelines. Thorax 2010 EORTC guidelines. JCO 2010 ESMO guidelines. Ann Oncol 2012 ESMO consensus conference. Ann Oncol 2014 American College of Chest Physicians. Chest 2013