Metastatic NSCLC Flashcards
What are the risk factors for lung cancer?
Smoking Exposure to Asbestos Arsenic Radon Non-tobacco-related polycyclic aromatic hydrocarbons
What is the standard testing for detecting ALK fusion?
Break-apart fluorescence-in-situ-hybridization (FISH) test
PCR may be successful
- requires adequate overage of the many possible fusion genes
- challenged by the availability of adequate quality nuclei can acid from typical samples and by the method itself
What does Crizotinib block?
Dual ALK and MET TKI
MET = Mesenchymal Epithelial Transition Factor
What do you understand from the term, “Continuation maintenance”?
Maintained use of an agent included in 1st-line treatment
What do you understand from the term “switch maintenance”?
Introduction of a new agent after 4# of platinum-based chemotherapy
What is the definition of oligometastases?
Maximum of 5 metastatic lesions in the body
Can be synchronous or metachronous.
Synchronous:
- diagnosed within 1 month before or after primary tumor was identified.
Metachronous:
- if they appear after treatment of the primary
What do you do when there is a solitary lesion in the contra lateral lung?
In most cases, this should be considered as a synchronous secondary primary tumor, and treated, if possible, with surgery and adjuvant chemo if indicated, definitive radiotherapy or ChemoRT.
Tell me about the AJCC staging system (7th edition)
T1:
- Tumor 3cm or less. No evidence of invasion into the main bronchus.
T2: - Tumor >3cm, but 7cm or less. - Or with any of the following features: >> involves main bronchus >> 2cm or more distal to the carina >> Invades visceral pleura (PL1 or PL2) >> A/w atelectasis >> A/w obstructive pneumonia is that extends to the hilar region, but does not involve the entire lung
T3: - >7cm - or one that directly invades any of the following: >> parietal pleura >> Chest wall (including superior sulcus tumors) >> diaphragm >> phrenic nerve >> Mediastinal pleura >> Parietal pericardium - Tumor in the the main bronchus >> > or associated atelectasis or obstructive pneumonia is of the entire lung >> separate nodule In the same lobe
T4: - Tumor of any size that invades any of the following: >> Mediastinum >> Heart >> Great vessels >> trachea >> Recurrent laryngeal nerve >> Esophagus >> vertebral body >> carina >> Separate tumor nodule in a different ipsilateral lobe
Tell me about the AJCC 7th edition staging for NSCLC - N
N0 : No regional LN
N1:
- Ipsilateral peri bronchial and/or
- ipsilateral hilar LN and intrapulmonary LN
- Including involvement by direct extension
N2:
- Ipsilateral mediastinal and/or
- Ipsilateral sub Cardinal LN
N3:
- Contralateral mediastinal,
- Contralateral hilar
- Ipsilateral or Contralateral scalene
- Ipsilateral or Contralateral supraclavicular LN
Tell me about the T1 staging of the AJCC 7th edition for NSCLC
T1:
- Tumor 3cm or less, without bronchoscopic evidence of invasion more proximal than the lobar bronchus
T1a Tumor 2cm or less
T1b Tumor >2cm, but 3cm or less
Tell me about the T2 staging from the AJCC 7th edition for NSCLC?
T2: - Tumor >3cm, but 7cm or less; or - Tumor with any of the following: >> Involves main bronchus >> 2cm or more distal to the carina >> Invades visceral pleura - a/w atelectasis or obstructive pneumonitis that extends to the hilar region but does NOT involve the entire lung
T2a: Tumor >3cm, but 5cm or less
T2b: Tumor > 5cm, but 7cm or less
Tell me about the T3 of the AJCC 7th edition
T3: - >7cm; or - one that directly invades any of the following: >> Parietal pleura >> Chest wall, including superior sulcus tumors >> Diaphragm >> Phrenic nerve >> mediastinal pleura >> Parietal pericardium - tumor in the main bronchus,
Tell me about the T4 of the 7th edition AJCC staging
T4: Tumor of any size that invades any of the following:
- mediastinum
- heart
- great vessels
- trachea
- recurrent laryngeal nerve
- esophagus
- vertebral body
- carina
- separate tumor nodule in a different Ipsilateral lobe
Some conclusions about the Stage for NSCLC
N1 is at least a stage IIA disease
N2 is at least a stage IIIA disease
N3 is at least a stage IIIB disease
T4 is at least a stage IIIA disease
What are 3rd generation cytotoxics in NSCLC?
Gemcitabine
Vinorelbine
Paclitaxel
Docetaxel
What is the Schiller paper about?
NEJM 2002
Aim:
Pac/Cis was standard of care.
To compare if any of the 3 regimens was superior to Pac/Cis
N=1200
Advanced NSCLC
4arms: A) Pac/Cis - Pac 135mg/m2 CI; Cis 75 Day2 q21d B) Gem/Cis - Gem 1000mg/m2 D1,8,15, Cis 100mg/m2 D1 q28d C) Docetaxel/Cis - Docetaxel (75); Cis (75) D1 q21d D) Pac/Carbo - Pac (225) over 3 hours D1; Carbo AUC6 q21d
Results: NO DIFFERENCE
- RR 20%, median survival 8m
- 1y survival rate 30%, 2y survival rate 10%
- Gem/Cis gave better PFS, but a/w 3x ore G3/4/5 renal toxicity (9% vs 3%)
» 3.4m in Pac/CDDP vs 4.2m Gem/CDDP
Conclusion: All 4 regimens similar
What is the evidence for using Pemetrexed/CDDP in non-squamous histology for lung CA?
Scagliotti JCO 2008
Aim: To assess that Pem/Cis is non-inferior to SOC
N=1700
Chemo-naive, Stage IIIB/IV
Non-inferiority study
2arms: A) Gem/CDDP - Gem (1250) D1,8, CDDP (75) D1 q21days x6 B) Pem/CDDP - Pem (500) D1, CDDP (75) D1 q21days x6
Results:
1) OS Pem/CDDP = Gem/CDDP
2) AdenoCA & Large cell: OS superior for Pem/CDDP
- 12.6m vs 10.9m
3) Sqaumous: Gem/CDDP > Pem/CDDP
- 10.8m vs 9.4m
4) G3/4 neutropenia/anemia/thrombocytopenia lower than Gem/CDDP
5) G3/4 nausea more common with Pem/CDDP
What is the pre-clinical data that explains why squamous histology is not as responsive to Pemetrexed?
Preclinical data indicated that:
1) overexp of thymidylate synthase correlated with reduced sensitivity to Pemetrexed.
Study in chemo-naive patients showed that baseline expression of thymidylate synthase Gene and protein were significantly higher in Sqaumous cell CA cf adenoCA.
What is Pemetrexed?
Pemetrexed is a potent inhibitor of thymidylate synthase and other folate-dependent enzymes.
This includes:
- dihydrofolate reductase
- glycinamide ribonucleotide formyl transferase
What about the evidence between Vinorelbine/CDDP vs Gem/CDDP or Pac/Carbo?
Scaglotti JCO 2002
Aim: To compare: - Vinorelbine/CDDP (Control) >> Vino(25mg/m2/week) x 12 weeks --> alternate week + CDDP (100) D1 q28d - Gem/CDDP >> Gem (1250) D1,8 ,CDDP (750) D2 q21d - Pac/Carbo >> Pac (225) over 3 hours, Carbo AUC 6 D1 q21d
N=600
Advanced NSCLC
Results: No difference in OS/Time to disease progr/TTF
- median suvival ~9-10m
- Neutropenia higher on VC arm
» 40% vs PCb 35% vs GC 17%
Between Gem/Carbo and Pemetrexed/Carbo, which would you choose and why?
Non-squamous histology, Pem/Carbo.
Besides Scagliotti study, there is also a Norwegian study by Gronberg JCO 2009.
Aim of the study:
- compare Pem/Carbo vs Gem/Garbo
2arms up to 4#: A) Pem/Carbo - Pemetrexed (500) + Carbo (AUC5) D1 Q3w B) Gem/Carbo - Gem (1000) D1,8 + Carbo (AUC5) D1 Q3w
N=450
Results: NO Significant differences in:
- primary HRQoL end points
- OS
Gem/Carbo had higher G3/4 hematologic toxicities, and required more supportive treatment
Any benefit with Bevacizumab?
Alan Sandler NEJM 2006
Phase 3 study comparing Pac/Carbo vs Pac/Carbo/Bev
N=900
Recurrent or advanced NSCLC (Stage IIIB/IV)
Exclusion criteria:
- Sqaumous Cell CA
- brain mets
- clinically significant hemoptysis
- inadequate organ function
- PS >1
2 arms:
A) Pac/Carbo q3w
B) Pac/Carbo/Bev q3w + Bev q3w until PD/Toxic
Results:
- med OS 12m vs 10m (Chemo alone)
- med PFS 6.2 and 4.5m
- RR 35% vs 15%
- Rates of clinically significant bleeding 4.5% vs 0.7%
- 15 treatment-related deaths in the Bev group, including 5 from pul hemorrhage.
Any other evidence for Bev besides ECOG study?
AVAiL study by Martin Reck JCO 2009
Aim: to investigate efficacy + Safety of Gem/CDDP/Bev
N=1000
2 arms:
A) Gem 1250 mg/m2 + CDDP 80mg/m2 + low dose Bev 7.5mg/kg
B) Gem 1250 mg/m2 + CDDP 80mg/m2 + High dose Bev 15mg/kg
C) Gem 1250 mg/m2 + CDDP 80mg/m2 + Placebo
* up to 6 cycles with Bev/placebo continuing until PD
Results:
- PFS: 6.7m (LD) vs 6.1 (placebo) vs 6.5m (HD)
- ORR 20% (Pl) 34% (LD) 30% (HD)
- median OS>13m in all treatment groups, but not significantly increased with Bev.
What is the PRONOUNCE study about?
Zinner JTO 2015
Aim: to prove that Pem/Carbo > Pac/Carbo/Bev in terms of PFS without G4 toxicity.
2 arms (4cycles followed by maintenance): A) Pemetrexed (500) + Carbo (AUC6) --> Pemetrexed maintenance B) Pac (200) + Carbo (AUC6) + Bev (15mg/kg) --> Bev maintenance
Results:
G4PFS 3.9m for Pem/Carbo vs 2.9 (not significant)
What is the PointBreak study about?
Patel et al JCO 2013
Comparing 2 groups:
A) Pem/Carbo/Bev –> Maintenance Pem/Bev
B) Pac/Carbo/Bev –> Maintenance Bev
Advanced Stage IIIB/IV NSCLC
ECOG 0/1
N=900
Results:
- NO survival advantage
- PFS HR 0.8 6m vs 5.6m (PacCBev)
- ORR similar about 33%
- DCR 65-70% similar
What do you know about Oral S-1 usage in NSCLC?
JCO 2010, W.Japan Oncology Group. Okamoto
Aim: to prove that S-1/Carbo was non-inferior to Pac/Carbo in terms of OS
N=560
Chemo-naive advanced NSCLC
2arms:
A) Carbo (AUC6) + Pac (200mg/m2) D1 q21 days
B) Carbo (AUC6) D1 + S-1 (40mg/m2) D1-14 q21days
Results:
- median OS 15m (S-1) vs 13m (Pac)
- 1yr OS 57%vs 56%
- Diff toxicities
- Carbo/S-1 more delays than Carbo/Pac
Conclusions = S-1+Carbo no inferior in terms of OS
