RCR NSCLC Curative-Intent Radiotherapy Audit Survival at Two Years

1. RCR NSCLC Curative-Intent Radiotherapy Audit Survival at Two Years Dr J McAleese, Dr S BALUCH K Drinkwater We are indebted to audit leads and our colleagues in the cancer centres for their meticulous and conscientious approach to data collection, with minimal additional resources, without whose help, this project could not have been completed.

2. Background • Lung cancer is the leading cause of cancer related death in the UK 45,525 new cases and 35,371 deaths in 2013 [1]. • Non-small cell lung cancer (NSCLC) is the commonest form of lung cancer with 38,525 cases in England and Wales in 2013 . • After surgery, radiotherapy is the second most frequently used curative treatment for NSCLC 20%. • Surgery resection rates are monitored in the NLCA audit and have increased over the past decade. References 1. CRUK http://www.cancerresearchuk.org/cancer-info/cancerstats/mortality/cancerdeaths/uk-cancer-mortality-statistics-for-common-cancers

3. Background- Lung Cancer • In comparison to Europe the UK has worse survival rates stage by stage (ICBP) • Proposed reasons; • UK lung cancer population frailer than European • Decreased access to newer techniques that could improve survival. • Fewer patients receive any radical therapy References Walters S et al “Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004-2007” Thorax 2013 published on line

4. Background: Radiotherapy Drives The NSCLC Cure Rate Survival of all Stage I >75yr olds Amsterdam cancer registry study; (cohort) SABR introduced in 2004/5 References “Impact of introducing Stereotactic Lung Radiotherapy for elderly patients with stage I Non-small cell lung cancer: a population-based time –trend analysis” Palma D et al J Clinical Oncology 2010 28(35); 5153-5159 “Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: A meta-analysis” Grutter JA et al Rad Oncol 2010 95; 32-40

5. Background : Quality of Radiotherapy Matters Within radiotherapy trials deviation from the protocol is associated with reduced survival 1,2 and increased toxicity 2 One review noted an association between number of patients entered per centre and quality 2 Quality assurance is a key component of radiotherapy clinical trials 3 “Patients receiving radiotherapy with curative intent should be part of a national quality assurance programme” 4 Forest plot of hazard rations describing the association between radiotherapy protocol deviations and overall survival Ohri N et al JNCI 2013 Lung Cancer Trials References • Ohri N et al “Radiotherapy protocol deviations and clinical outcomes: a meta-analysis of co-operative group clinical trials” JNCI 2013; 105: 387-393 • Weber D eta L “QA makes a clinical trail stronger: Evidence-based medicine in radiation therapy” Radiotherapy and Oncology 2012; 105: 4-8 • Bekelman J et al “Redesigning radiotherapy quality assurance: opportunities to develop and efficient, evidence-based system to support clinical trails – report of the National Cancer Institute Work Group on Radiotherapy Quality Assurance” IJRBOP 2012; 8393): 782-790 • NICE CG 121 guidance.nice.org.uk/cg121 April 2011

6. NSCLC Radical Radiotherapy Audit Aims The audit aimed to • Describe UK practice • Gain insight into why the selected techniques of CHART, Stereotactic radiotherapy and concurrent chemoradiation are not used more frequently. • Assess quality of radiotherapy against RCR standards In addition • To compare UK NSCLC radical radiotherapy usage and its impact on survival to a European cohort. Methodology • Links to an online data collection system were sent to all radiotherapy centres in the UK • Centres were asked to complete a proforma for all curative-intent NSCLC patients starting their first fraction of radiotherapy between Monday 14th October 2013 and Friday 6th December  2013(8 weeks).

7. Data Collection Results • 82% of centres returned 317 questionnaires. • A median of 4 questionnaires were returned for each department (range 0 to 25). • 6 centres did not have any suitable patients in the audit period. • Two centres collected for only two weeks because of the volume of patients going through their departments.

8. Overall Results

9. Access to Quality of Radiotherapy Some improved access References Prewett et al “The management of lung cancer: A UK survey of oncologists” Clin Onc 2012 24 402-409

10. Access to Radiotherapy ; Comparison to European cohorts**excluded concurrent chemoradiation patients • Comparison with previously published cohorts from Holland and Belgium. All PET/CT staged. • Compared to Patients selected for curative intent NSCLC radiotherapy in Europe • UK Cohort is • Slightly older • Worse Performance status • Fewer locally advanced • Less tumour bulk • (same results with chemorad patients included) • Evidence of frailer patients in UK • AND • Evidence of bulkier disease not considered for curative-intent radiotherapy Cohorts “Development and external validation of prognostic model for 2 year survival of non-small-cell lung cancer patients treated with chemoradiotherapy” Dehing-Oberjie C et al IJRBOP 2009 74(2) 355-362

11. Access to Radical Lung Radiotherapy • UK centres have a target of surgical resection in 16% of lung cancer patients • We estimated that only 8% (CI 7% to 9%)of patients with NSCLC in England received radical radiotherapy • Variability in Access seen in RCR Audit • Preliminary data from NLCA confirms a marked variation in access across English centres • Historical data from other regions shows similar variability ( Northern Ireland 12%, Scotland 4%) References NCIN conference 2015 “Actual versus optimal utilization of radiotherapy in lung cancer: Where is the shortfall?” Vinod S et al Asia-Pacific Journal of Clinical Oncology 2007; 3:30-36 “Variability in comorbidity and clinical management in patients newly diagnosed with lung cancer in four Scottish centers” Grose D et al JTO 2011; 6: 500-509

12. Limited access to Guideline Recommended Therapy

13. 48% SABR (stereotactic ablative radiotherapy) SABR increases the cure rate compared to conventional radiotherapy 2 When implemented in Holland SABR increased the survival of over 70s diagnosed with Lung Cancer 3 SABR uses 5 fractions compared to 20 conventional treatments and is no more toxic.4 48% of elderly patients in the UK who could have SABR cannot access it, compared to 22% of younger patients 40% 70% Alive at 2 years radiotherapy No SABR Alive at 2 years SABR 64% 70yr Most (62%) of all those diagnosed with lung cancer are aged over I cant leave my elderly wife I know it’s a higher cure rate How will I travel? I cant leave my home More elderly patients refuse SABR because its not available locally Who will look after the grandkids 5 x

14. Tumour size distribution for patients receiving CRT vs Those where Tumours felt too big for CRT.

15. Curative Radiotherapy Access Limited by • Technology – SABR without VMAT/FFF more than twice as long on table • Closeness to Centre • Fear of toxicity

16. How can we maximise the chance of cure for NSCLC patients? • Improving Quality of radiotherapy delivered 33% access to 4DCT, 66% access to cone beam • Developing better radiotherapy – clinical trials • Maximising Access to the most effective treatments Only 69% got SABR, 64% CRT, 26% CHART • Increasing the overall radical radiotherapy rate Access rate in England is 8%

17. 2 Years Survival Update Methods • Centres were asked to provide follow up information 24 months after the audit (Nov 2015) • 184 patient records had usable survival data. (58% of all records) References 1. Dehing-Oberije C et al “Development and external validation of prognostic model for 2 year survival of non-small-cell lung cancer patienst treated with chemoradiotherapy” IJRBOP 2009; 74(2) 355-362 2. Seabag-Montefiore D et. al. 30 and 90 day mortality after 40,670 courses of external beam radiotherapy in unselected patients. NCRI cancer conference 6-9Nov 2011. Abstract available at http://www.ncri.org.uk/ncriconference/2011abstracts/abstracts/a21.html

18. Survival cohort was a reliable sample of overall cohortDemographics similar

19. 90 Day Death Rate ; 6% (95% CI 3% to 10%) • A marker of appropriate selection for radiotherapy (early progression) • A marker for toxicity of treatment (toxic death) • Global target for all radical/ adjuvant radiotherapy for all cancers ≤5% Some centres have reported 90 day death rate; variability but within same range

20. Overall Survival ; 2 year OS 40% * from start of radiotherapy

21. Survival compared to Europe • MAASTRO clinic risk groups defined by %FEV1, GTV size and lymph node involvement. From Dutch and Belgian data (2002 -2006) • In the UK Audit population • This grouping model is highly predictive (AUC 0.73) • Risk Group for Risk Group survival is the same • UK Cohort has the same survival as Europe • References • Dehing-OberijeC et al “Development and external validation of prognostic model for 2 year survival of non-small-cell lung cancer patients treated with chemoradiotherapy” IJRBOP 2009; 74(2) 355-362 • http://predictcancer.org/Main.php?page=LungSurvivalModel

22. Comparison to European cohorts- Stage III/I * from start of radiotherapy (2002 -2011 cohort) • “A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients” Oberije C et al IJRBOP 92(4) 935-944 • Louie AV, Haasbeek CJ, Mokhles S, et al. Predicting Overall Survival After Stereotactic Ablative Radiation Therapy in Early-Stage Lung Cancer: Development and External Validation of the Amsterdam Prognostic Model. Int J RadiatOncolBiol Phys 2015;93(1):82-90.

23. Comparison to European cohorts- Stage III/I * from start of radiotherapy (2002 -2011 cohort) • “A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients” Oberije C et al IJRBOP 92(4) 935-944 • Louie AV, Haasbeek CJ, Mokhles S, et al. Predicting Overall Survival After Stereotactic Ablative Radiation Therapy in Early-Stage Lung Cancer: Development and External Validation of the Amsterdam Prognostic Model. Int J RadiatOncolBiol Phys 2015;93(1):82-90. c c

24. Determinants of survival Univariate analysis showed NO differences by • Technology (cone beam, 4DCT) • Centre Size • Access to Peer Review • Staging (CT brain)

25. Conclusions (2013 Survival Update) • Overall survival is as expected • Survival for those treated is no worse than Dutch and Belgian (historical) cohorts • 90 day death rate is 6%, and there may be variance between centres

26. Radiotherapy survival is acceptable (1) BUT Overall lung cancer survival is low, stage for stage (2) Is the answer increasing the number treated with radical radiotherapy (access)? Survival Analysis Outside Target Within Target All NSCLC Could have Radical RTX (? 12%) Radical RTX (8%) Surgery (15%) Could have CHART, SABR, CRT (89%) Received CHART, SABR, CRT (34%) • References • RCR survival audit update • Walters S et al “Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004-2007” Thorax 2013

27. Access to radical radiotherapy in UK; marked variability • RCR Audit estimated access rate in UK at 8%. • 7% >70 year old vs 9% < 70 year old. • Marked variability in access by cancer network • Range 1% to 18%. IQR 4% to 9% • NCRAS/ NCIN report estimates access in England at 6.5% • Range 0.4% to 16.4%. Interquartile range 4% to 8% • No relationship with surgical resection

28. Factors that may increase access • Awareness ( conservative approach) (colleague- peer review) • NI ; access rate increase from pre-peer review 6% to 12% post peer review • Technology • FFF Arc SABR reduces treatment time 1.5 vs 8.3mins (1) • IMRT/VMAT reduces toxicity and allows larger volumes to be treated (2) • 4DCT reduces treatment volume and 4DCT gated therapy can further reduce toxicity in tumours with greater respiratory motion (3) • Re-aligning service model • Elderly patients • have reduced access to radical radiotherapy 7% vs 9% in our study • Reduced access to guideline recommended therapy 40% vs 60% • Mainly due to lack of local facilities/ social support References “Volumetric modulated arc therapy with flattening filter free (FFF) beams for stereotactic body radiation therapy (SBRT) in patients with medically inoperable early stage non small cell lung cancer (NSCLC)” Navarria P et al Radiotherapy and Oncology 2013; 107: 414-418 “Intensity-modulated radiotherapy in the treatment of lung cancer” Bezjak A et al ClinOnc 2012 24(7) “Investigating the potential impact of four-dimensional computed tomography (4DCT) on toxicity, outcomes and dose escalation for radical lung cancer radiotherapy” Cole A et al ClinOnc 2014; 26(3) 142-150

29. Overall conclusions • The audit has described UK practice and documented improved access to technology • Overall survival of treated patients is similar to Europe • To improve overall survival for lung cancer, increasing access to NSCLC radical radiotherapy may be of most importance • There is evidence of a more conservative selection of patients compared to Europe • There is evidence that elderly patients are being disadvantaged because of social and travel concerns • Technological developments can increase access • (FFF Arc SABR reduces treatment time) • (IMRT/VMAT allows larger volumes to be treated) • (4DCT reduces treatment volume in 25%) • It would be of benefit to monitor access to radical radiotherapy, with a counterbalance of 90 day death rate

30. Action Plan • 5 Years over all Survival • Re-Audit in 5 Years • Access Target

31. Any ?s