hermes summer school - ers-educationintroduction aims • to describe the treatment principles and...
TRANSCRIPT
HERMES SUMMER SCHOOL
18/05/2016
Session 6 – Thoracic Tumours
NSCLC – Management
Rudolf M. Huber
University of Munich
Thoracic Oncology Centre Munich
Conflict of interest disclosure I have the following, real or perceived direct or indirect conflicts of interest that
relate to this presentation:
Affiliation / financial interest Nature of conflict / commercial company name
Grants/research support (to myself, myinstitution or department):
Funding by German Ministry of Education and Research (BMBF), German Research Society (DFG), Wilhelm-Sander-Stiftung
Advisory boards, presentations: Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Clovis, Lilly, Novartis, Roche
Other support or other potentialconflict of interest:
Clinical trials with Amgen, Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Clovis, DaichiSankyio, MSD, Novartis, Pfizer, Pierre Fabre, Roche
IntroductionAIMS
• To describe the treatment principles and
modalities in NSCLC with emphasis on the
relevance of staging
• To understand the rationale of multimodality
treatment
• To analyse the differential indications of
treatment modalities in stage III disease
• To describe the relevance of patient factors and
histology / biology for systemic therapy
• To outline the development of molecular
targeted therapy and immunooncology
NON SMALL CELL LUNG CANCER (80% of lung cancer)
50–55%* 35–40%† 10%*
Adeno-Ca Squamous cell Ca Large cell Ca
Images used with permission:*Image from www.surgical-pathology.com; †Image from http://www.lmp.ualberta.ca/resources/pathoimages/PC-S.htm
Various
subtypes of
adenocarcinoma
Lungcancer
SIGNS AND SYMPTOMS
• Cough (40 – 75 %)
• Dyspnoea (30 – 40 %)
• Haemoptysis (15 – 35 %)
• Recurrent pneumonia (15 – 25 %)
• Dull thoracic pain (20 – 40 %)
• Loss of body weight (40 – 50 %)
... No symptoms, paraneoplasia, seizure
NSCLC – TREATMENT MODALITIES
• Internal Medicine
– local treatment (interventional pneumology)
– systemic therapy
• Surgery
• Radiotherapy
• Multimodality approaches
0
5
10
15
20
25
30
35
40
45
Stage I Stage II Stage III Stage IV
NSCLC STAGING AT PRESENTATION
Mod. from Mountain CF, Semin Surg Oncol. 2000
Primarily radical local treatment
± systemic therapy
Primarily systemic
therapy
± local interventions
30 resectable 70 unresectable
20
resectable10
technicallyresectable
40
metastasized
30
locally advanced disease
25-40 %
5-year-survival
Lung Cancer
100 patients with
NSCLC
15 % < 5 % < 5 %
Lungcancer DISTRIBUTION OF NSCLC
Performance Status
6247
Also relevant:
- Weight loss
- In part LDH ...
- Biology
PROGNOSTIC FACTORS
IN LUNG CANCER
Huber
Infections
Gastro-
enterology
Hematology
Nephrology
CrCl
ultrasound
PneumologyAge
Gender
BMI
Neurology
CNS
PNP
Cardio-
vascular
ORGAN SYSTEMS
Smoking and age cause damages to many organs
SURGERY OF LUNG CANCER
Pneumonectomy
Lobectomy
Segmentectomy
Parenchyma sparinganatomical resections
SURGERY OF LUNG CANCER
• Anatomical resection!
• Systematic lymphadenectomy
• Thoracotomy
– Anterolateral
– Posterolateral
– Sterniotomy
• Minimal-invasive surgery (VATS)
COURSE OF LUNG FUNCTION AFTER RESECTION
Values are presented as mean +/- SD. * p<0.05 compared with preoperative value. # p<0.05 compared with previous test.
Circles indicate lobectomy (n=62), triangles pneumon-ectomy group (n=20)
Nezu K ea. Chest 113 (1998)
COURSE OF LUNG FUNCTION AFTER RESECTION
Values are presented as mean +/- SD. * p<0.05 compared with preoperative value. # p<0.05 compared with previous test.
Circles indicate lobectomy (n=62), triangles pneumon-ectomy group (n=20)
Nezu K ea. Chest 113 (1998)
Lobectomy: permanent functional loss is
about 10 %, exercise capacity slightly
reduced.
Pneumectomy: permanent loss of about 33
% of lung function and of 20 % of exercise
capacity
LUNG CANCER: MORTALITY OF SURGICAL
RESECTION (EUROPE)
• Lobectomy 1.4 % - 2.7 %
• Pneumonectomy 5.7 % - 7.9 %
• Roxburg ea. (1991): Ann Thorac Surg 51: 800 – 803
• Damhuis ea. (1996): Eur Respir J 9: 7 – 10
• Licker ea. (1999): Eur J Cardio-Thorac Surg 15: 314 -
319
RADIOTHERAPY
• Can be curative, depending on the
dosage and the tumour volume
• Local control depending from the
applied dose
• At least 60 Gy in 30 fractions at 2 Gy,
better 66 Gy and more necessary for
radical treatment
• Loss of lung function – in contrast to
surgery delayed
RADIOTHERAPY
• Greatest limitation to definitive radio-
therapy, apart from acute esophagitis, is
radiotherapy-induced lung toxicity
• Limited by lung function, volume of
irradiated lung (especially with more than
20 Gy) and mean lung dose
• Palliative applications for metastases
• Stereotactic radiotherapy comparable to
surgery
NON SURGICAL RADICAL TREATMENTS
• Percutaneous thoracic radiotherapy
• Stereotactic radiotherapy
• Brachytherapy
• (simultaneous) Radiochemotherapy
• Chemotherapy (plus other local
therapy)
• Chemotherapy can also impair
pulmonary function
ENDOSCOPIC INTERVENTIONS
Situs NdYAG-Laser Dilatation Prothetics Brachytherapy
Exophytic
central *** 0 0 **
periphery * 0 0 *
compression /mural growth
central 0 ** ** ***
periphery 0 * * **
bronchial instability 0 0 *** 0
Stenosis by scar * *** ** 0
HDR-BRACHYTHERAPY – EFFICACY
Vergnon J-M, Huber RM, Moghissi K. Eur Respir J 2006; 28: 200–218
Tumour before first brachytherapy session and 3 weeks later(before the second session)
Huber
NSCLC: Stage at diagnosis, therapy and 5-year-survival
55%
20%
25%
Stage I–II
Surgery ± RT ± CT
24–61%
Stage IIIA/IIIB
RT ± CT ± surgery
5–13%
Stage IV
CT + supportive
measures
1%
RT = radiotherapy
CT = chemotherapy Mod. from Mountain C. Chest 1997;111:1710–17
recurrence in 50% of pts.
Almost always recurrence or
progression
EXPECTED OUTCOME AFTER SURGICAL RESECTION IN OPERABLE NSCLC
Surgical Stage
5-Yr Survival
(%)
Relapse (%)
Local Distant
IA T1N0M0 67 10 15
IB T2N0M0 57 10 30
IIA T1N1M0 55
IIB T2N1M0 39 12 40
T3N0M0 38
IIIA T3N1M0 25 15 60
T1-3N2M0 23
Pisters and Le Chevalier. J Clin Oncol. 2005;23:3270-3278
Local-
Regional
Relapse
Distant
Relapse
INOPERABLE STAGE III NSCLC
Recurrence Patterns after Chemoradiotherapy
Adapted from Furuse K et al. JCO 17:2692-2699, 1999
33%56%
4%
MULTIMODALITY TREATMENT
• Surgery
– Local control +++
– Metastases -
• Radiotherapy
– Local control ++
– Metastases -
• Chemotherapy
– Metastases ++
– Local control (+)
• But: Toxicity increased
Combination: local control and systemic efficacy
= increased toxicity
NSCLC – LOCALLY ADVANCED
Multimodality Treatment
• Inoperable stage
– Radiochemotherapy
• Operable stage
– Neoadjuvant concepts
– Adjuvant therapy of operable NSCLC
Huber
The absolute effect of chemo-therapy at 5 years was a decrease of 6.9% for lung cancer death and an increase of 1.4% for non–lung cancer death.
N = 4584
LUNG ADJUVANT CISPLATIN EVALUATION: A
POOLED ANALYSIS BY THE LACE COLLABORATIVE GROUP
Pignon J-P ea. JCO; 26:3552-3559 2008
Benefit of chemotherapy & stage
CT may be detrimental for stage IA
META
Stage IA 102 / 347 1.41 [0.96;2.09]
Stage IB 509 / 1371 0.92 [0.78;1.10]
Stage II 880 / 1616 0.83 [0.73;0.95]
Stage III 865 / 1247 0.83 [0.73;0.95]
CategoryNo. Deaths
/ No. Entered
Hazard ratio(Chemotherapy / Control) HR [95% CI]
Test for trend: p = 0.051
Chemotherapy better | Control better0.5 1.0 1.5 2.0 2.5
Stage IA 102 / 347 1.41 [0.96;2.09]
Stage IB 509 / 1371 0.92 [0.78;1.10]
Stage II 880 / 1616 0.83 [0.73;0.95]
Stage III 865 / 1247 0.83 [0.73;0.95]
CategoryNo. Deaths
/ No. Entered
Hazard ratio(Chemotherapy / Control) HR [95% CI]
Test for trend: p = 0.051
Chemotherapy better | Control better0.5 1.0 1.5 2.0 2.5
vinorelbine in combination with 320 - 400 mg/m² cisplatin probably preferable (HR 0.80)
Huber
LACE
Non-small cell lung cancer: Therapy options RT / CT
sequential RCT
concomitant RCT
Induction conc. RCT
Conc. RCTConsolidation
RT dose escalation orhyperfractionated?
HuberERS, 28.11. 2008
BROCAT study CTRT 99/97 Disease-free Survival
Huber RM ea. JCO 2006
Inoperable stage IIIA, mostly IIIB NSCLC
HuberVancouver, 19. 10. 2011
BROCAT study CTRT 99/97 Survival of patients with CR/PR after induction
Multivariate analysis:
independent factor
Huber RM ea. JCO 2006
Resectable / Non-
resectableLung Cancer
Radiation
Daily Fractions
Hyperfractio-nated
SurgeryRadiation and Chemotherapy
Sequential Concurrent Combined
Surgery and Chemotherapy
Local
control
Systemic
control
THERAPY OPTIONS IN LOCALLY ADVANCED
NON SMALL CELL LUNG CANCER
HuberAmsterdam, 26. 9. 2011
André F ea. JCO 18 (2000)
PROBLEM N2 – MEDIASTINUM
RESECTED N2 NSCLC
N2 Subgroups and survival
NSCLC: IIIA N2 – subsets
• IIIA1 incidental nodal metastases found on final surgical pathology
• IIIA2 single nodal metastasis, recognized intraoperatively
• IIIA3 Mediastinal nodal metastases, detected preoperatively by mediastinoscopy or PET
• IIIA4 „Bulky“, multi-station
Adapted from ACCP Guideline. Chest 2003
Huber
CHEMOTHERAPY IN ADDITION TO SUPPORTIVE CARE
IN ADVANCED NSCLCSimple (nonstratified) Kaplan-Meier curve for survival by
treatment
NSCLC Meta-Analyses Collaborative Group, J Clin Oncol; 26:4617-4625 2008
Survival
Hazard ratio 0,77 (95 % CI 0,71 – 0,83),p < 0.0001
Huber
Delbaldo C ea. JAMA. 2004;292:470-484
1 vs. 2Reduction of mortality by 17 %
2 vs. 3no reduction of mortality
Usually doublet : Platin + „new“ substance (Taxane, Gemcitabine, Vinorelbine)
NSCLC Stage IV1 vs. 2, 2 vs. 3 substances
Huber
COMBINATION THERAPY OF NSCLC
Schiller J ea. Proc. ASCO 2000
ECOG 1594 survival
Similar data for Cis/Vinorelbin in SWOG-trial
„TARGETED THERAPY“ AND BIOLOGICAL MARKERS IN THORACIC TUMOURS
• Individualisation
– Patient
– Histology
– Predictive / prognostic markers
• „targeted therapy“
• Immunooncology
CISPLATIN VS. CARBOPLATIN META-ANALYSIS: MORTALITY
Huber
Ardizzoni A ea. J Natl Cancer Inst 2007;99: 847 – 57
HR = 1.1295 % CI 1.01-1,23
Subgroup analysis
CIS/PEM VS. CIS/GEM IN FIRST-LINE OF
NSCLC – OVERALL SURVIVAL
G. V. Scagliotti et al., JCO 26 (2008), 3543-51
p= 0.03 p=0.05
Non squamous Squamous
Same signal in 2nd line and maintenance therapy
PROPERTIES OF A TUMOUR CELL
Hanahan D, Weinberg RA. Cell 100 (2000)
PROPERTIES OF A TUMOUR CELL
Hanahan D, Weinberg RA. Cell 144 (2011)
BIOLOGICAL TARGETS
Hanahan D, Weinberg RA. Cell 144 (2011)
ALK-, ROS1 inhibition: Crizotinib, Ceritinib
Gefitinib, Erlotinib, Afatinib, Osimertinib. Necitumumab
Multi-Tyrosinkinaseinhibitors, Antibodies
PD1/PDL1inhibition: Nivolumab
45
Cancer Immunotherapy
Chen DS, Mellman I. Immunity. 2013.
Cancer cells may express tumor-specific antigens due to the presence of mutations
These antigens may induce an immune response
Up-regulation of PD-L1 in the tumor microenvironment enables cancers to evade T-cell−mediated killing
Inhibition of the PD-L1/PD-1 and PD-L1/B7.1 interaction may restore antitumor T-cell activity
Lisbon, 15. 6. 2016 Huber
GERMAN S3-GUIDELINE 2010
NSCLC IV – First Line: Platinum-based combination
– Poor PS / comorbidity: Monotherapy or non-Platin-
based combination
– optionally Bevacizumab (non-squamous)
– Gefitinib with activating EGFR mutation
Second Line: monotherapy
– Docetaxel, Erlotinib, Pemetrexed (non-squamous)
Cisplatin
(Carboplatin)
Pemetrexed (non-squamous)
Gemcitabin
Docetaxel
Paclitaxel
Vinorelbin
SYSTEMIC THERAPY IN STAGE IV
• First Line : – Platinum-based combination (+/- Bevacizumab)
– Gefitinib monotherapy (EGFR mutation)
– Erlotinib / Afatinib monotherapy (EGFR mutation)
– Crizotinib monotherapy (EML4-ALK Fusion)
– Necitumumab with Gemcitabin/Cisplatin (squamous)
• Maintenance therapy (Pemetrexed)
SYSTEMIC THERAPY IN STAGE IV
• Second Line: monotherapy – Docetaxel +/- Nintedanib (Adeno) or Ramucirumab,
Erlotinib, Afatinib (squamous), Pemetrexed (non-squamous)
– Osimertinib monotherapy (EGFR T790M mutation)
– Ceritinib monotherapy (EML4-ALK Fusion)
– Immune check-point inhibitors: Nivolumab
• Third und further lines– Erlotinib, Afatinib (squamous), Met-, BRAF-, HER2-
Inhibition **
– Immune check-point inhibitors: Nivolumab
** not yet registered
Lung Cancer Mutation Consortium
Incidence of Single Driver Mutations
Mutation found in 54% (280/516) of
tumors completely tested (CI 50-59%)Kris, ASCO 2011
Individualised Therapy?
51
Individualised Therapy?
ROS-1
HER-2
B-RAF
RET
EGFR-TKIChemotherapy
Cisplatin … ?EGFR antibody?
Antiangiogenesis … ?
1921
20?
ALK
PD1/PDL1
WHAT ARE THE OBJECTIVES OF THE
TREATMENT LUNG CANCER ?
Improvement of
• survival
• symptom control
• quality of life
Interdisciplinary management and
multidisciplinary approach, especially
for stage III
Conclusion
Stage I: surgery
Stage II: surgery, adjuvant chemotherapy
Stage IIIA: surgery in combination with (neo-)adjuvant chemotherapy
Stage IIIB or inoperable IIIA: (simultaneous) radiochemotherapy
Stage IV: palliative systemic therapy
Local interventions
“You just cannot call it lung cancer anymore”