DIAGNÓSTICO Y TERAPIAS LOCALES. Rosario García Campelo Servicio de Oncología Médica Complejo Hospitalario Universitario A Coruña

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1 DIAGNÓSTICO Y TERAPIAS LOCALES Rosario García Campelo Servicio de Oncología Médica Complejo Hospitalario Universitario A Coruña

2 SIDNEY 2013 THE CHALLENGE

3 THE THREE SISTERS: IMAGING, PATHOLOGY AND LOCAL THERAPIES

4 PARADIGM SHIFT Diagnosis and staging in the molecular era Integration of imaging, histopathology, molecular-genomic and clinical data

5 DIFFUSION WEIGHTED MAGNETIC RESONANCE IMAGING IN MALIGNANCY Advantages of DW MRI Goals: tissue characterisation, monitoring treatment response, separating treatment effects from residual tumour, detectic recurrent disease

6 Diffusion-weighted magnetic resonance imaging at 3.0- T vs FDG PET/CT for detection of malignant pulmonary nodes N= 113 patients 77 malignant/ 36 benign Comparison to ki67 DW MRI is a more specific and accurate diagnostic tool than FDG PET/ CT quantitatively Tang et al. E

7 What about DWI-MRI our clinical practice?

8 What about DWI-MRI our clinical practice? Limited to thorax

9 What about DWI-MRI our clinical practice? Limited to thorax Accuracy in heterogeneous lesions (cystic, necrotic, mucinous..)

10 What about DWI-MRI our clinical practice? Limited to thorax Accuracy in heterogeneous lesions (cystic, necrotic, mucinous..) Need for standardisation: divergence among and between vendor/ sites/ validation and reproducibility

11 What about DWI-MRI our clinical practice? Limited to thorax Accuracy in heterogeneous lesions (cystic, necrotic, mucinous..) Need for standardisation: divergence among and between vendor/ sites/ validation and reproducibility Effect on management Proposed algorithm: CT and MRI? MRI alone

12 O23.03: Metabolic imaging based prognostic model predicting survival of patients with stage I NSCLC. Hyun S RATIONAL Limitation of TNM staging system Additional prognostic biomarkers to stablish risk-adapted treatment strategies Gene expression biomarkers not validated up to now METHODS 198 pathologic stage I NSCLC (56.1% ADC; 35.9% SqCC, 8.1% other

13 Results Multivariate analysis Survival curves by age and SUV

14 Staging strategies for NSCLC Focusing on nodal staging

15 ENDOSONOGRAPHY FOR MEDIASTINAL STAGING OF LUNG CANCER WHAT WE KNOW Invasive mediastinal staging is required prior curative NSCLC resection Identification of N2 or N3 disease has significant therapeutic and prognostic implications INVASIVE MEDIASTINUM STAGING Surgical staging EBUS TBNA EUS FNA

16 ENDOSONOGRAPHY EBUS+ EUS DON T ACHIEVE COMPLETE MEDIASTINAL STAGING 2R & 4R: easier with EBUS 8 & 9: only accesible to EUS 5 and 6 problematic for both 3a not accesible to any of the technique

17 EBUS vs EUS, which one first? EBUS-centered vs EUS-Centered mediastinal staging in lung cancer a randomized controlled trial. Kang et al 80 patients Diagnostic accuracy EBUS 93.2 Not improved by EUS Total time: 38 min Complications: 12 Tolerance score: 4 80 patients Diagnostic accuracy EUS 97.3 Significantly improved by EBUS Total time: 39 min Complications: 17 Tolerance score: 4.8

18 EBUS vs EUS, which one first? EBUS-centered vs EUS-Centered mediastinal staging in lung cancer a randomized controlled trial. Kang et al

19 EBUS vs EUS, which one first? EBUS-centered vs EUS-Centered mediastinal staging in lung cancer a randomized controlled trial. Kang et al

20 In other words, let s be practical If PET+ stations 3a, 5 or 6: DON T LOSE YOUR TIME If enlarged nodes are located in stations 3p, 8 or 9: START WITH EUS In other cases, EBUS SHOULD BE CONSIDERED FIRST in mediastinal staging of operable NSCLC

21 PATHOLOGY

22 WE DO KNOW HISTOLOGY IS IMPORTANT After so many years

23 WE DO KNOW HISTOLOGY IS IMPORTANT After so many years

24 O04.01 O04.03 (Fernandez-Cuesta et al, Jen et al) Discovered of novel fusion transcripts by RNA-seq In Mucinous lung Adenocarcinoma: CD7-NRG1, 4/15 (27%) Mutually exclusive with Kras mutation Correlated with ERBB3 phosphorylation and activated PI3K- AKT pathways In never smokers: SND1-BRAF (3%) This fusion activates MEK and ERK proteins

25 O04.02 Using NGS for mutational profiling of NSCLC in the clinical setting. Simon et al. 262 NSCLC 228 ADC 15 SCC 8 NOS FFPE samples: core needle biopsies, resections, cytology, cell blocks 10ng of DNA Mutations in46 genes with Torrent PGM platform TP53 mutation is the most frequent one NGS-based mutational profiling using small amounts of DNA derived from FFPE samples and cytoloty is feasible and can direct therapy in the clinical setting

26 TO TAKE INTO ACCOUNT CHALLENGES Availability and cost of NGS platforms Few NGS are able to perform clinical testing for fusions and gene copy number

27 LOCAL THERAPIES

28 SURGERY CHALLENGE

29 SURGERY CHALLENGE

30 SURGERY CHALLENGE

31 SURGERY CHALLENGE

32 When you think of early stage NSCLC The standard mode of parenchymal pulmonary resection in 2013 still remains AT LEAST 6 LN (3 mediastinal, always 7)

33 When you think of early stage NSCLC The standard mode of parenchymal pulmonary resection in 2013 still remains AT LEAST 6 LN (3 mediastinal, always 7) What about Lobe Specific Nodal Disection? Challenges for the less invasive surgery: VATS Is there a role for limited resections?

34 O Lobe-specific lymphadenectomy for NSCLC presenting as a pulmonary node. Yang et al. Retrospective study 415 patients with SPN (<3 cm) All underwent complete lymphadenectomy

35 O Lobe-specific lymphadenectomy for NSCLC presenting as a pulmonary node. Yang et al. Retrospective study 415 patients with SPN (<3 cm) All underwent complete lymphadenectomy

36 O Lobe-specific lymphadenectomy for NSCLC presenting as a pulmonary node. Yang et al. Retrospective study 415 patients with SPN (<3 cm) All underwent complete lymphadenectomy This approach requires validation Low morbility of systematic LND

37 MS06. Video-assisted thoracoscopic surgery vs axillary thoracotomy for resection of early-stage NSCLC. Hao et al

38 MS06. Video-assisted thoracoscopic surgery vs axillary thoracotomy for resection of early-stage NSCLC. Hao et al

39 MS06. Video-assisted thoracoscopic surgery vs axillary thoracotomy for resection of early-stage NSCLC. Hao et al 425 NSCLC p (20.9% excluded for final analysis) VATS approach is a safe approach for the treatment of early stage NSCLC VATS approach might be superior to axillary thoracotomy approach in terms of Operation time (150m vs 170m p0.033) intraoperative blood loss (100 vs 150 p<0.001) acute surgical injuries (12.6% vs 13% p0.09) and post-operative QoL

40 M002. Video-Assisted Thoracic surgery, hybrid, vs open thoracotomy for stage I-A propensity score analysis based on a Multi-institutional registry. Wang D et al 2485p 8 institutions

41 Concluding regarding to VATS

42 Concluding regarding to VATS VATS vs Open: THE DEBATE IS OVER

43 Concluding regarding to VATS VATS vs Open: THE DEBATE IS OVER Just about ACCESS

44 Concluding regarding to VATS VATS vs Open: THE DEBATE IS OVER Just about ACCESS If both surgical and oncological quaility are maintained any approach is valid

45 Concluding regarding to VATS VATS vs Open: THE DEBATE IS OVER Just about ACCESS If both surgical and oncological quaility are maintained any approach is valid Next topic will be single VATS vs 3-4 ports VATS

46 Concluding regarding to VATS VATS vs Open: THE DEBATE IS OVER Just about ACCESS If both surgical and oncological quaility are maintained any approach is valid Next topic will be single VATS vs 3-4 ports VATS

47 Survival of 1963 lobectomy-tolerable patients who underwent limited resection for c-stage I non-small cell lung cancer. Yano et al Retrospective-multi-institutional study T1-T2N0M0 NSCLC, fit for lobectomy Wedge-resection: 37.6% Segmentectomy: 62.4% Excellent results of limited resection Overall and recurrence free survival: 93.7% and 90.4% at 5 y Prognosis and recurrence was not affected by the method of limited resection (segmentectomy/ partial resection)

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49 Limited Resection trial for pulmonary GGO Nodules: case selection based on high resolution computed tompraphy: Interim results. Yoshida et al Prospective study T< 2cm (7-20mm) N= Surgical procedure: Wedge 86 segmentectomy 9 Most of the cases were non-invasive tumors Pathologically positive margin: 1 patient No recurrence so far (median follow-up 69 m)

50 O Is limited surgical resection appropiate for NSCLC more than 2 cm in diameter. Proposed surgical indication by the presence of GGO of the tumor on thin-section CT scan. Maevashiki T 306 p Part-solid GGO measured less than 30mm, N0 4.6%: Pathological LN mets Size of solid component on thin-section CT scan and consolidation tumor ratio were significant predictors of pathological node involvement (p<0.05)

51 To summarize Partial resection may be not recommended for SqCC HRCT appears to reliably predict non/ or minimally invasive GGO lung cancer Is limited resection curative? Less 2 cm: Be still careful More 2 cm: solid component matters, but no solid recommendation can be done

52 Definitive answers will come from prospective studies

53 SBRT A resurrection of an old trick to give large doses Highly focused raditation, using many beams, concentrated on small tumors SBRT is standard of care for peripheral early-stage NSCLC in high-risk patients (ESMO 2013, SEOM 2013 guidelines) Local control rates of 90% at 5 years Close to 100% of patients develop fibrosis changes

54 All these challenges are important because.. Cumulative adoption of SBRT is increasing Pan et al. Cancer 2011

55 All these challenges are important because.. Cumulative adoption of SBRT is increasing Pan et al. Cancer 2011

56 All these challenges are important because.. Cumulative adoption of SBRT is increasing Pan et al. Cancer 2011

57 SBRT Challenges What is the optimal fractionation/ dose? There exists a wide variability in SBRT fractionation How to define tumor recurrence on CT scan? Which patients will develop rib fractures as late toxicity?

58 OPTIMAL FRACTIONATION O RTOG 0915: A randomized Phase II study comparing 2 SBRT Schedule for medically inoperable patients with stage I peripheral NSCLC. Videtic G et al.

59 OPTIMAL FRACTIONATION 94 patients Median follow-up: 20.6m

60 HOW TO DEFINE TUMOR RECURRENCE? Local recurrence vs fibrosis Fibrosis after SBRT is extremely common and complicates detection of local recurrence after SBRT High-risk features (HRF): Enlargement of mass Sequential enlargement on CT Growing mass after 12 months Bulgin margin Linear margin disappears Air broncograms disappear Huang K. Radioth Oncol 2012

61 Blinded assessment of radiological changes after SBRT for early stage lung cancer. Senthi et al 3 radiation oncologists blinded to outcome 12 patients with pathology-proven LR, matched to patients without LR (N=24) Results: All established HRFs were significantly associated with local recurrence (p<0.01) The best indiviual predictor was enlarging opacity after 12 months (100% sensitivy, 83% specifity, p<0.001) The presence of > 3HRFs in an individual patient was highly sensitive and specific for recurrence (both>90%) This approach may reduce unnecessary diagnostic procedures, and ensure earlier use of salvage therapies

62 Dose-response analysis of radiation induced rib fractures after SBRT for NSCLC. Stam B 453 p, stage I or II peripheral NSCLC, < 5 cm 349 p NSCLC treated with 3x 18Gy 11% with rib fractures 2.6% symptomatic The risk is significantly related to dose: Risk of rib fracture <5% if biological dose under 222 Gy What is the role of other factors (female sex, obesity, diabetes ) Chest wall doses: EORTC recommendations : a dose <30Gy, delivered in three to five fractions on a volume of <30mL

63 IASLC President reflections Lung Cancer is a lonely illness Science is a lonely business The road of investigation is usually long and isolated Science for lung cancer does not have to be lonely and in fact, it shouldn t be Tony Mok, WCLC 2013 News

64 IASLC President reflections Lung Cancer is a lonely illness Science is a lonely business The road of investigation is usually long and isolated Science for lung cancer does not have to be lonely and in fact, it shouldn t be CHALLENGE We must be united and develop cohesive strategies and this has proved to be challenging Tony Mok, WCLC 2013 News