Updates in Thoracic Oncology Dr. Sameena Uddin MD FRCSC Thoracic Surgical Oncologist Division Head, Thoracic Surgery Trillium Health Partners 1
Faculty/Presenter Disclosure Faculty: Dr. Sameena Uddin MD, with the Mississauga Halton/Central West Regional Cancer Program: Primary Care Oncology Day Relationship with Commercial Interests: No affiliation (financial or otherwise) with a pharmaceutical, medical device or communications organization. 2
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Updates in Thoracic Oncology Lung Cancer Screening PET CT SBRT Targeted Molecular Therapy 4
Updates in Thoracic Oncology - Objectives Overview of Thoracic Oncology Lung Cancer Screening Staging o PET CT o EBUS Treatment o Surgery: VATS, RATS, MIE o Radiation: SBRT o Chemotherapy: Targeted Molecular Therapy 5
Thoracic Oncology Lung Cancer Gastroesophageal Cancer Mediastinal Masses Chest Wall Tumours Malignant pleural effusion Pulmonary Metastasis Suspicious Pulmonary Nodules 6
The Thoracic Team Medical Oncology Radiation Oncology Respiratory Therapy Respirology Gastroenterology General Surgery Palliative Care Anesthesia Radiology Pathology Nursing Nutrition Psychosocial Physiotherapy CCAC Primary Care 7
Mississauga Halton/Central West (MHCW) Regional Cancer Program Mississauga Halton LHIN 6 Central West LHIN 5 LEVEL 1 Regional Thoracic Surgery Program 8
LUNG CANCER SCREENING 9
Lung Cancer Screening Why? Lung Cancer Statistics Ontario: o Est. 2013 Incidence = 8,600 o Est. 2013 Mortality = 6,900 o 2006-2008: 5 year relative survival ratio (age standardized) = 19% o Refer to CCO s Primary Care Referral Guidelines for Suspected Lung Cancer @ http://www.cancercare.on.ca/pcresources 10
Lung Cancer Screening How? CXR +/- Sputum cytology o 7 large RCTs have not demonstrated benefit despite up to 20 years of follow-up LOW DOSE SPIRAL CT (LDCT): o Improved sensitivity, technique o 25% less dose than normal CT chest o 1999-2002 o 6 Prospective single arm studies o All showed improved sensitivity of LDCT for early stage lung ca o Not well designed or of enough power to show reduction in mortality 11
Lung Cancer Screening The Evidence National Lung Screening Trial 2002 o prct August 2002 April 2004 o n= 53 454 patients at high risk for lung ca o 55-70y, at least 30pk yr hx, if ex-smokers quit within last 15y o 3 annual screenings with LDCT vs control CXR o Primary End-Point: Reduction in Mortality o Secondary End-Points: Rate of death from any cause, and incidence of lung ca in both groups The National Lung Screening Trial Research Team, NEJM 2011 12
Lung Cancer Screening The Evidence Positive screens: 24.2% LDCT vs. 6.9% CXR False Positive: 96.4% LDCT vs. 94.5% CXR Positive = nodule >=4mm Incidence of Lung Cancer o 1060 cancers LDCT vs 941 cancers CXR (rate ratio 1.13) o 20.3% reduction in lung cancer mortality o 7% reduction in all cause mortality The National Lung Screening Trial Research Team, NEJM 2011 13
Incidental Findings = More tests Incidental findings = 19% (Roberts et al. CARJ 2011) o 22% cardiovascular o 78% noncardiovascular (mostly liver and kidney) o Most commonly recommended FU: Abdo US o 10 malignancies: 2 multiple myeloma 1 lymphoma 6 breast cancers 1 thyroid cancer 14
Who? What? When? Fleischner Criteria for pulmonary nodules 15
Lung Cancer Screening The Problems Lead time Bias: o Early detection before symptomatic phase...no change in time to death...need to be able to change outcome Length Bias: o Slow-growing tumours detected...but aggressive disease not detected or stopped...happened before annual exam Overdiagnosis Bias: o Extra diagnoses of indolent tumours without mortality impact...may have died of unrelated causes without symptoms 16
Lung Cancer Screening Questions CT technique Mortality Radiation exposure how long to screen? Impact of screening Screening Demographics Age? Female non-smokers? Follow-up Positive scans? Anxiety Cost! 17
CCO Statements CCO s Program in Evidence-Based Care (PEBC) has produced guidelines on the screening of high risk populations for lung cancer: Recommend the use of low-dose computed tomography as a screening modality for lung cancer in high risk populations through an organized screening program and administered by specialized centres with multi-disciplinary care teams CCO has engaged Sunnybrook Research Institute to conduct research to determine the feasibility of an organized lung cancer screening program in Ont Opportunistic screening of asymptomatic individuals is not recommended due to the considerable risks posed to patients outside of an organized program www.cancercare.on.ca/toolbox/qualityguidelines/clin-program/screening-ebs 18
PET CT 19
www.cancercare.on.ca/patientpathway 20
PET CT - Indications o Diagnosis of SPN Biopsy inconclusive Nodule inaccessible to biopsy Medical condition precludes biopsy o Staging of NSCLC o Staging of SCLC o Staging of esophageal cancer Pre-treatment Post-neoadjuvant treatment (chemorads) 21
PET CT - Technique Integrated Positron Emission Tomography with CT Functional imaging uses fluorodeoxyglucose (FDG) labelled with radioactive iodine to assess metabolic activity Procedure: o Patient fasting, resting to quiet muscular activity o Given bolus of FDG, then scanned in arms up position o Reconstruction of images completed and SUV values assigned, compared to bloodpool values o Formatted for use by Rad Onc 22
PET CT - Diagnosis Diagnosis o Core needle biopsy is recommended as first diagnostic approach o PET reserved for when Bx inconclusive or contraindicated o Sensitivity 96-97% o Specificity 78-66% o False negatives: slow growing malignancies, small <1cm o False positives: inflammatory conditions o No RCT s comparing PET in differentiating benign from malignant SPN 23
PET CT - Staging NSCLC, SCLC, Esophageal Cancer o Detects unexpected distant metastases in up to 15% o Eliminates the need for bone scan o For mediastinal lymph nodes there is a 4% false negative rate Invasive mediastinal staging required (EBUS, mediastinoscopy) 24
TREATMENT UPDATES: SBRT, TARGETED THERAPY 25
Surgery EBUS = Endobronchial Ultrasound VATS = Video assisted thoracoscopic surgery RATS = Robot assisted thoracoscopic surgery MIE = Minimally invasive esophagogastrectomy 26
SBRT = Stereotactic Body Radiotherapy SABR = Stereotactic Ablative Radiotherapy Definition: o High doses of radiation via multiple beams o Maximizes radiation dose to tumour o Limited # treatment sessions (high dose/fraction) o Image guided treatment (CT, MRI, PET) o Real time respiratory motion accommodation (4D planning) 27
SBRT Anatomic resection remains standard of care for operable, resectable patients with lung cancer But oelderly osevere COPD/Poor PFT s oother medical comorbidities ometastatic disease 28
SBRT vs Surgery for Stage 1 NSCLC- Senthi et al. Lancet Oncology 2012 Outcomes o Retrospective analysis of patterns of disease recurrence in early stage NSCLC; n=676 o 5yr Local control 89.5%; Regional control 87.3%, Distant mets 80.1% Grillis et at. JCO 2010: 3yr local control ~90% Onishi et al. JTO 2007: 5yr local control 84.2% Onishi et al. IJROBP 2010: Median F/U 55mon 5y LC = 86.7% (All) 5y OS 69.5% (All) 29
Study Pt #/ % IAs/ Med F/U Margins BED (Gy) LC OS DFS Sweden 45 40% IA 43mo 5mm axial 10mm cc 112 80% crude 2yr 71% 3yr 55% Amsterdam 206 59% IA 12mo ITV + 3mm 106-180 97% crude 2yr 64% 2yr 68% Rotterdam 70 56% IA 5mm 112-180 2yr 96/78% 2yr 62% 2yr 86% 15mo Hi/lo BED Timmerman 70 49% IA 5mm axial 10mm cc 180-212 3yr 88% 3yr 43% 3yr 82% 50mo Japan (no path) 115 81% IA Appropriate 95-180 3yr 90% <2cm 14mo 61% >2cm FROG CK 74 88% IA 15mo Custom, histology based 106-212 2yr 93% 2yr 74% 2yr 94% (NS) 30
SBRT vs Standard RT Advantages o Higher biologically equivalent dose (BED) o Less collateral damage (lung, cord, heart) o Low incidence of pneumonitis (< 5%) o Virtually no other side effects o Only 3-4 treatment sessions Disadvantages o Need for placement of fiducials o More expensive (but cheaper than surgery??) o Some side effects
SBRT - Challenges Heterogeneity of tumours size, location Heterogeneity of patients, comorbidities Selection bias Multiple descriptive endpoints, definitions o Overall survival, LR, LRR, freedom from death or LR Lack of randomized clinical trials o Long and slow process o 2 big RCT s: ROSEL and STARS ROSEL terminated due to poor accrual, STARS struggling 32
SBRT vs. Surgery Issues: o Tumour diagnosis? o Stage? Size? o Type of staging? o What risk patient? Surgery o Lobar? Sublobar? Both? o VATS? SBRT o Heterogeneous data o Dose/fractionation? o Central vs. peripheral location? 33
SBRT Summary Surgery is the gold standard for operable patients For inoperable, marginally operable patients with Stage 1 NSCLC, SBRT offers 80-90% local control rates, and similar survival to surgical approaches Randomized trials have failed to accrue for various reasons; patients and surgeons 34
EGFR and ALK EGFR epidermal growth factor receptor o Somatic mutations o Of tyrosine kinase receptor family o When signalling unregulated, will drive tumour cell proliferation o 15-20% of adenoca will have EGFR mutation ALK anaplastic lymphoma kinase o 2-7% of adenoca *Usually light/never smokers, women, Asian ethnicity (50% vs. 10%)* 37
Drugs and Toxicities Tarceva = erlotinib Iressa = gefitinib Gilotrif = afatinib Xalkori = crizotinib Toxicities: MINIMAL o Rash o Diarrhea o (interstitial lung disease) 38
Trial Number EGFR M+ Comparison EGFR TKIs in first line therapy Genotype RR PFS directed PFS HR therapy OS (%) (months) (95% CI) (mos) IPASS 261 Gefitinib Carboplatin/paclitaxel 71 47 9.6 6.3 0.48 (0.36-0.64) 21.6 21.9 NEJ002 228 Gefitinib Carboplatin/paclitaxel 74 31 10.8 5.4 0.32 (0.24-0.44) 27.6 26.6 WJTOG3 405 172 Gefitinib Cisplatin/docetaxel 62 32 9.6 6.6 0.52 (0.38-0.72) 35.5 38.8 OPTIMAL 165 Erlotinib Carboplatin/gemcitabine 83 36 13.7 4.6 0.16 (0.10-0.26) 22.7 28.8 EURTAC 174 Erlotinib Cis-carbo/doce-gem 64 18 9.7 5.2 0.37 (0.25-0.54) 19.3 19.5 Fukuoka et al. J Clin Oncol. 2011;29:2866-2874 Inoue et al. Ann Oncol. 2012;Epub ahead of print Mitsudomi et al. ASCO 2012 Zhou et al. ASCO 2012 Rosell et al. Lancet Oncol. 2012;13:239-46
Personalized Medicine Role for biomarker assessment o Accurate histology with IHC is mandatory (no NOS) o Routinely test adenoca for EGFR, ALK (do the right test) o Always for Stage IIIB, Stage IV NSCLC Reduced mortality! 40
Outcomes Gefitinib vs. Carboplatin/paclitaxel o Mok et al 2009 o Higher response rate (43% vs 32%) o Longer progression free survival with EGFR+ Crizotinib vs standard Chemo o Risk of progression reduced by 50% o Longer progression free survival (7.7 vs 3mos) 41
Improved Survival 1.Survival by mutation status. Median survival times: EGFR+, not reached; EGFR -, 3.6 years. p =.001 by log-rank test. Sequist L V et al. The Oncologist 2007;12:90-98 2. Survival by mutation status after adjusting for age, gender, and stage at diagnosis. Median survival times: EGFR+, 3.1 years; EGFR-, 1.6 years. 42
Updates in Thoracic Oncology Lung Cancer Screening PET CT SBRT Targeted Molecular Therapy 43