SABR. Outline. Stereotactic Radiosurgery. Stereotactic Radiosurgery. Stereotactic Ablative Radiotherapy

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1 CAGPO Conference October 25, 2014 Outline Stereotactic Radiation for Lung Cancer and Oligometastatic Disease What Every GPO should know Dr. David Palma, MD, MSc, PhD Radiation Oncologist, London Health Sciences Centre Clinician-Scientist, Ontario Institute for Cancer Research Goal: To discuss the role of Stereotactic Radiotherapy in current Radiation Oncology practice 1. Stereotactic Radiotherapy for Primary Lung Cancer 2. Stereotactic Radiotherapy and the Oligometastatic Paradigm Stereotactic Radiosurgery Part I. Stereotactic Radiation for Stage I NSCLC Solberg et al, in Lo (ed) Stereotactic Body Radiation Therapy 2012 Leksell, JNNPsyc 1983 Stereotactic Radiosurgery Stereotactic Ablative Radiotherapy SABR Cyberknife (accuray.com) Planning Gamma Knife (elekta.com) Targeting TrueBeam (variantruebeam.com) Delivery Falchook et al, PRO

2 Older Techniques Features of Lung SABR Accounting for Motion 4D Planning Small tumour volumes Small margins Many Beam Directions 7-11 Beams / Arc Therapy Steep dose gradients Inhomogeneous target dose Accurate Targeting CBCT pre-rt High dose per fraction Short total treatment duration How We Target for SABR How We Target for SABR How We Deliver SABR How We Deliver SABR 2

3 How We Deliver SABR SABR eligibility Probability of malignancy = e x /(1+e x ) X = * age * smoking * prior cancer * diameter * spiculation * upper lobe SABR Outcomes: VUMC Amsterdam SABR Outcomes: VUMC Amsterdam 5 yr LC 89.5% 5 yr RC 87.3% 5 yr DC 80.1% Senthi et al Lancet Oncology 2012 A Risk-Adapted Strategy Systematic Review Tumor description T1 tumor surrounded by lung tissue T2 tumor or broad contact with chest wall Central tumor or near brachial plexus Dose 54 Gy/3 55 Gy/5 60 Gy/8 Ngyuen et al CTR

4 What happens when you implement SABR? SABR implementation Using the Amsterdam Cancer Registry, elderly patients divided into 3 time periods after the routine introduction of FDG-PET: Period A ( ): pre-sabr Period B ( ): some SABR availability Period C ( ): SABR fully available p<0.01 Palma et al JCO 2010 Palma et al JCO 2010 Palma et al JCO 2010 SABR implementation Operable Patients Palma et al JCO 2010 Onishi et al IJROBP 2011 The Debate In Search of Level 1 Evidence vs. 4

5 Randomized Trials Comparative Effectiveness Research Senan, Palma, Lagerwaard, J Thorac Dis 2011 Wedges Wedges SABR patients had better local control No differences in other types of recurrence or DSS SABR worse OS due to non-cancer deaths 124 patients with stage I NSCLC not fit for anatomic lobectomy 69 wedge, 55 SABR SABR patients significantly older, higher Charlson scores [SABR] may be equivalent, if not superior to, wedge resection for recurrence and CSS. High Risk: Severe COPD Systematic Review of the Literature Only 4 papers reported with subgroups of patients with severe/very severe COPD or ppo-fev1<40% All reported local control of 89% 30 day mortality: all SABR studies = 0%, surgical average = 10% Overall Survival (VUMC) [n=176] Overall Survival (Review) High Risk: Elderly Nested matched pair analysis (within population study) 60 SABR: 60 surgical Could not control for comorbidity 30-day mortality: 8.3% for surgery (5 deaths) 1.7% for SABR (1 death) Severe (FEV %) Very severe (FEV1<30%) Log-rank p=0.01 Overall Survival (p=0.22) Palma et al IJROBP 2011 Palma et al Radiother Oncol

6 SEER-Medicare Data Insights from Markov Modelling Markov model predicted a OS benefit for surgery of 2-3% at 5-years 1 quality-adjusted life month Highly sensitive to operative mortality rate: once mortality increased above 3-4%, SBRT was favored Shirvani et al IJROBP 2012 Beyond SABR vs. surgery Summary: SABR for Lung Cancer SABR provides high rates of local control, with a short treatment duration Convenience probably increases treatment utilization in elderly For operable patients, randomized data is not available, but patients at high operative risk should be considered for SABR How do we best individualize care? What are our patient s personal preferences? Can we better predict risk of toxicity? The Concept of Oligometastasis Cancer comprises a biological spectrum, extending from when a disease is localized to one that is systemic when first detectable but with many intermediate states. Part II. The Oligometastatic State and SABR An attractive consequence [of the] oligometastatic state is that some patients should be amenable to a curative therapeutic strategy Hellman and Weichselbaum, JCO

7 Synchronous vs. Metachronous A Hot Topic Synchronous Metachronous Niibe et al, Jpn J Clin Oncol 2010 Level 1 Evidence The Evidence Andrews et al Lancet 2004 Level 1 Evidence Hepatic Metastectomy Patchell et al NEJM 1990 Bilchik et al, Oncologis 7

8 Hepatic Metastectomy SABR for Oligometastases Morris et al, Brit J Surg, 2010 Rationale(s): Improved Overall Survival? Oligoprogression: Ability to Continue Systemic Therapy? Improved Pain Control? SABR for Lung Metastases SABR for Oligometastatic Disease 38 patients enrolled with 63 metastatic lesions Actuarial local control 100% at 1 year and 96% at 2 years 8% grade 3 toxicity, no grade 4 or 5 1 rib fracture, 1 pneumonitis, 1 skin Main mode of failure distant (63%) 2 year survival 39% Rusthoven et al, JCO 2009 US Adoption of SABR The Evidence Looks Exciting! Pan et al, Cancer

9 Gaps in the Evidence Adequate Controls But: Nearly all studies are single-arm studies Selection of very fit patients Slow tumor doubling times Appropriate controls lacking The only thing that s oligo is the amount of good evidence! Patients who fulfill the criteria for lung metastasectomy probably comprise a selected group with a particularly benign tumor-host relationship. Randomized studies are needed in all groups for which we do not have sufficiently strong evidence that metastasectomy contributes to the longevity of the patients. Levels of Evidence Immortal Time Bias DATE OF DIAGNOSIS METASTECTOMY Misclassified Immortal Time TREATED PATIENT Study Follow up Time DATE OF DIAGNOSIS CONTROL PATIENT Study Follow up Time Senan, Palma, Lagerwaard, J Thorac Dis 2011 Immortal Time Bias Immortal Time Bias DATE OF DIAGNOSIS METASTECTOMY TREATED PATIENT Excluded Immortal Time Study Follow up Time DATE OF DIAGNOSIS CONTROL PATIENT Study Follow up Time 9

10 Modeling for Immortality Progression is Quick Utley and Treasure, JTO 2010 Mission Creep: Pulmonary Metastectomy Mission Creep Ideal Candidate Single Metastasis Completely Resectable Long DFI Favorable Histology Intermullo et al JTO 2008 Intermullo et al JTO 2008 What s the Harm? Median Time to CNS progression 3 months ATS

11 Levels of Evidence Seminars in Radiation Oncology 2006 Senan, Palma, Lagerwaard, J Thorac Dis 2011 The Power of RCTs Cameron et al, Br J Cancer 74(12): Zujewski et al, JNCI. 90(3): Gratwohl et al Annals of Oncology 15: Statmauer et al NEJM 342: The Power of RCTs: Symptom Control The Power of RCTs 1939: Italian surgeons report that bilateral ligation of the internal mammary arteries dramatically improves angina ~75% with improvement ~25% with complete response Confirmed in other studies and soon became a standard treatment Hypothesis: ligation of IMAs improve collateral blood flow 11

12 The Power of RCTs Pain Control and the Placebo Effect NEJM 2009 PulMiCC: Pulmonary Metastatectomy Oligometastases: COMET Principal Investigators D. Palma, S.Senan Target Accrual 99 patients Active Sites London, Ontario Amsterdam Vancouver/BCCA Sudbury Hamilton Scotland (opening soon) Treasure et al, Thorax 2011 Treasure et al, Thorax 2011 RTOG 0631 Pain Control Closing Thoughts SABR achieves excellent rates of local control For lung cancer, the preponderance of evidence suggests that SABR is a significant improvement over older techniques SABR outcomes appear to rival those of surgery in well-controlled, well-matched studies Wedge resections are probably inferior to SABR. No RCT data anytime soon 12

13 Closing Thoughts Further Reading Review articles SABR can achieve local control for oligometastatic deposits Benefits for overall survival or quality of life have not been proven yet CAGPO Conference October 25, 2014 Stereotactic Radiation for Lung Cancer and Oligometastatic Disease What Every GPO should know Dr. David Palma, MD, MSc, PhD Radiation Oncologist, London Health Sciences Centre Clinician-Scientist, Ontario Institute for Cancer Research 13