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Flashcards in Stage 3 Lung CA Deck (42):
1

What is Pancoast tumors also known as?

Superior sulcus tumors

2

What are the ways you can go about investigating the mediastinal lymph node status?

1) PET-CT
2) Endoscopic Bronchial US (EBUS)
3) endoscopic Ultrasound (EUS)
4) Cervical mediastinoscopy
5) Video-assisted Thoracoscopy (VATS) including Video-assisted mediastinal lymphadenectomy

3

If PET-mediastinal findings are negative, there are still some instances when invasive mediastinal staging is indicated. When are these?

1) Primary tumor >3cm large axis
2) Central tumors
3) cN1
4) CT-enlarged LN with small axis >1cm

4

What are the pulmonary function testing required in the assessment prior to surgery?

1) Spirometry
2) Diffusion capacity of the Lung for CO
3) Split function studies
- ESP perfusion scintigraphy
4) Exercise tests
- ESP peak oxygen consumption

5

What are the possible strategies in managing a pre-op Dx of Stage IIIA (N2) disease?

1) Induction chemo --> Surgery
2) Induction chemoRT --> Surgery
3) Concurrent definitive ChemoRT

6

Is Stage III disease = no surgery?

No.
Technically feasible for Stage IIIA, non-T4 disease if lung function permits

7

What is the evidence for Hyperfractionated RT?

CHART - Continuous Hyperfractionated accelerated RT
= 36# of 1.5Gy TDS = 54Gy in 12 consecutive days

Saunders Lancet 1997
Locally advanced NSCLC in whom radical RT was chosen as the definitive management
N=560

2 arms:
1) CHART
2) Conventional RT
- 30# 2Gy each = 60Gy in 6 weeks

RESULTS:
- 24% reduction in RR of death
- 2y OS 20% vs 30%
- largest benefit with Squamous cell CA (34% reduction in RR of death, with 2y OS improvement from 19% to 33%)
- Severe dysphasia occurred more often in CHART rout than in conventional RT group 19% vs 3%

8

What is the rationale for combining chemo and radiotherapy?

1) RT is meant to act on the main tumor bulk at the primary tumor site, chemo has an effect on systemic micro metastasis.

2) Chemo and RT may modify different tumor sub clones and combining both modalities should thus lead to an increased tumor cell death

3) Chemo and RT could potentially lead to different states of oxygenation of the tumor tissue.
- following induction chemo, the vascularization and oxygenation of residual tumor could be improved, consequently leading to a more favorable response to RT

9

Tell me about RTOG 9410

Curran JNCI 2011
Aim: To invx if sequential or concurrent CRT is better

N=600
3 arms:
1) CDDP (100) D1,29
Vinblastine (5mg/m2)/week X 5 weeks
60Gy RT from Day 50

2) CDDP (100) D1, 29
Vinblastine (5mg per week X 5)
60 Gy RT once daily from D1

3) CDDP 50mg/m2 D1,8,29 and 36
PO Etoposide (50mg) BD X 10 weeks on Days 1,2,5,6
RT 69.6Gy as 1.2Gy BD from D1

RESULTS:
- median survival times: 14.6m 17m and 15.6m
- 5y OS 10% vs 16% vs 13%


10

Tell me about the Kathy Albain Study

Kathy Albain
Lancet 2009

Aim: to compare concurrent CRT--> Resection vs concurrent CRT

N=400
T1-3pN2M0 NSCLC. 2 groups:
- Concurrent induction chemo/RT --> Surgery --> 2#
- Concurrent induction chemo/RT --> RT up to 61Gy --> 2#
Chemo = Cisplatin (50) D1,8, 29,36 + Etoposide (50) D1-5, D29-33

Results:
- Median OS 24m vs 22m (p not sig)
- 5y OS 27% vs 20% (p not sig)
>> if N0 at Thoracoscopy, med OS 34m
- PFS 12.8m vs 10.5m
- 5y DFS: 20% vs 10%
- main toxicities - neutropenia and oesophagitis
- treatment related deaths 8% vs 2%

11

Tell me about the meta-analysis by Anne Apuerin re: concurrent vs sequential CRT

Lancet 2010

NSCLC Collaborative group
6 trials, 1200 patients
F/u 6 years
2 groups: concurrent versus sequential ChemoRT.

RESULT:
3y OS 6% (18% to 23%)
5y OS benefit of 4.5%
Concurrent ChemoRT decreased locoregional progression, but effect similar on distant progression
Concurrent ChemoRT increased acute esophageal toxicity from 4% to 18%, RR 4.9
No difference on acute pul toxicity

12

What is the PROCLAIM study about?

Vokes, Clin Lung Cancer 2009
Suresh Senan JCO 2016

Aim: Evaluate the efficacy of Pem/CDDP+RT-->consolidation Pem in Unresectable Stage IIIA/B NSCLC

No squamous histology
N=550

2 arms:
A) 3# Pem (500)/CDDP (75) q3w concurrent with TRT 60-66Gy --> Consolidated with Pemetrexed Q3w for 4#
B) 2# Etoposide (50)/CDDP (50) q4w concurrent with TRT --> 2# platinum-based doublet chemo (non Pem)

RESULTS:
Stopped early because of futility
OS 26.8m vs 25m (B) (P not sig)
A with lower incidence o drug-related G3-4 Adverse events

13

Some generalizations about Stage 3 staging.

All T3 and All T4 = Stage III
All N3 disease = Stage IIIB

14

What is the success of surgery in NSCLC dependent on?

1) Achieving anatomical resection
2) Negative margins

15

Is PET staging sufficient for Stage 3 Lung CA?

Sensitivity 80-90%
Specificity 85-95%
Good negative predictive value, but PPV not so good

16

What may not be detected on PET scan?

Tumors > 3cm
Central
cN1
CT LN 1cm only

17

When is mediastinal staging not necessary and can proceed straight for surgery?

1) No enlarged LN
2) Peripheral (outer 1/3)
3) Small tumor

18

What are the mediastinal staging methods?

1) Non-invasive/endoscopic approaches
- Bronchoscopy/EBUS
- EUS-FNA
2) Invasive methods:
- Mediastinoscopy
- VATS if AP Window LN

19

What are mediastinal LN?

Paratracheal (2)
Pre-vascular
Retro-tracheal
Sub-Carinal
Para-esophageal (Below Carina)
Pulmonary Ligament

20

What is N1 disease?

Ipsilateral peribronchial
Peribronchial
Ipsilateral hilar
Intrapulmonary nodes

21

What is mediastinal sampling vs dissection?

Sampling = dissection of suspected LN only

Complete lymphadenectomy = systemic LN dissection
- enbloc dissection of all ipsilateral compartments
- R 2R, 4R, 6, 7, 8, 9, 10, 11
- L 2L, 4L, 5, 6, 7, 8, 9, 10, 11

22

Tell me what is ASCOG Z0030 about.
Re: Mediastinal LN sampling vs complete lymphadenectomy during pulmonary resection

Darling J Thor Cardiovascular Surg 2011

Patient undergoing resection for N0/non-hilar N1, T1/2 NSCLC
s/p sampling of:
- 2R, 4R, 7, 10R for right-sided tumors
- 5, 6, 7, 10L for left sided tumors

If positive LN obtained through sampling -- > Complete mediastinal LN dissection.
If negative LN obtained, the pts are randomized into:
(1) No further sampling
(2) Complete mediastinal LN dissection

==========
Non-hilar N1 = ipsilateral peribronchial, Intrapulmonary nodes
N1 nodes = hilar, inter lobar, lobar, segmental, subsegmental

2 = upper paratracheal
4 = lower paratracheal
5 = subaortic
6 = para-aortic
7 = Subcarinal
10 = hilar
==========

RESULTS:
- No difference in survival between Mediastinal LN Sampling and dissection if systematic and thorough pre-resection sampling of mediastinal and Hilar LN is negative
- CANNOT extrapolate to those with higher-staged disease or staged radiographic ally

23

What are N1 nodes?

Hilar (10)
Inter lobar (11)
Lobar (12)
Segmental (13)
Subsegmental (14)

24

What are the different stage III tumors?

1) Post-op Stage III (Incidental)
- I.e. Classified as Stage I/II pre-op and incidental intra-op N2 disease
2) Superior sulcus Stage III
3) Standard Stage III
4) IIIA : role of surgery

25

What do you do with post-op Stage III disease?

These are usually patients who were classified as pre-op Stage I/II disease and were incidentally found to have N2 disease intra-operative lay.

2 scenarios:
1) R0 resection
- Adjuvant chemotherapy recommended
- RT controversial a no phase III data showing benefit.
- SEER data showed potential benefit in resected N2 disease for RT
- If giving RT, sequential therapy is recommended
2) R1/2 resection
- Discuss individually
- Chemo needed +/- RT
- Sequential or concurrent ChemoRT to be considered

26

What are superior sulcus tumors?

Stage III disease, separate entity.

Situated at the apex of the thoracic inlet
A/w Pancoast syndrome

T3/4 by definition
Distant mets less common

TREAT BY:
INDUCTION CRT --> Surgery --> Chemo
** Sx should be performed within 4w of end of RT

27

What do you know about the treatment of Superior Sulcus tumors ?

Induction ChemoRT --> Surgery --> Chemo

SWOG 9416 (Rusch JCO 2007)
Phase 2 study
N=100

All s/p
CDDP (50) D1, 8, 29, 36 (W1 and W5)
Etoposide (50) D1-5, 29-33
RT 180cGy daily X 5 weeks (45 Gy)

Then restage disease.
1) PD
- off protocol and continue f/ u
2) CR/PR/SD (86% of all patients)
- Medically unfit/refuse Sx
- Surgery --> 2# cycles of chemo
R0 resection rates 75%
5y OS 44% for all patients

28

How did RT become the backbone of treatment?

Stage III generally considered inoperable

1st Randomized trial of RT > placebo to treat NSCLC in 1966

RTOG 7301
Perez Cancer 1987
4-arm study
(I) 40Gy/10#, split course
(II)40Gy/20#
(III) 50Gy/25#
(IV) 60Gy/30#
RESULTS:
Lowest intra-thoracic failure with 60Gy/30#
- a/w median survival 10/12, 5yOS 5%

29

What are the 2 trials that showed improvement of OS by 10% with sequential CRT as opposed to RT alone?

1) CALGB 8433 study
Dillman EJM 1990 JNCI 1996
2 arms:
1) 2# CDDP/Vinblastine--> RT
2) RT alone

Outcomes:
14m vs 10m (RT)
==========
2) RTOG 8808/ECOG 4588
Sause Chest 2000

3 arms:
(I) CDDP/Vinblastine-->RT
(II) RT
(III) Hyperfractionated RT

OS 13m vs 11.5m vs 12m
5y OS 8%, 5%, 6%

30

Is sequential RT better or concurrent CRT better?

Concurrent better.

1) RTOG 9410, Curran JNCI 2011
3 arms:
- CDDP/Vinblastine (Seq)
- CDDP/Vinblastine (concurrent)
- EP+Hyperfractionated RT
RESULTS:
- OS 14.5m, 17m, 15.5m
- OS 10%, 15%, 13%
===============
2) Meta-analysis by Auperin JCO 2010
- Concurrent better due to better LR control with absolute benefit in survival of 4.5% at 5 years
- Concurrent a/w increased esophageal toxicity 18% vs 4%
===============
Other trials generally all show at least a trend towards favoring concurrent CRT with a trend towards improved OS
(A) WJLCG Furuse JCO 1999
(B) EORTC study by Schaake-Koning NEJM 1992
- Daily/weekly CDDP+(Split-course) RT vs split course RT alone
- Daily CDDP improved OS
(C) Glot-GFPC
- EP+RT---> CDDP/Vinorelbine vs CDDP/Vinorelbine sequentially.
- Trend favoring concurrent OS 21% s 14%
(D) LAMP phase II study. 3 arms:
- Sequential Pac/Carbox2 --> RT
- Induction Pac/Carbox2 --> CRT with weekly Pac/Carbo
- CRT/Consol Concurrent CRT + Weekly Pac/Carbo --> consolidation chemo2#
- Trend favoring concurrent consolidation 16m

31

Explain Elective nodal irradiation (ENI) and Involved field TRT

ENI = treats adjacent Nodal regions without evidence of adenopathy as prophylaxis
- may be a/w more toxicity to lungs/heart

Involved field TRT = treats only enlarged/hype retablos LN
- allows tumor dose escalated
- a/w lower risk of isolated nodal relapse

32

What is the evidence for IF-TRT>ENI?

Elective nodal irradiation = treats adjacent nodal regions without evidence of disease as prophylaxis

IF-TRT treats only enlarged/hyper metabolic LN

Phase III study IFRT vs ENI with chemo
- Chen, Biomed Res Int 2013
- no increase in risk of local failure with IF-TRT, trend towards better outcomes with IF-TRT

33

Tell me about the 2 CALGB Vokes trials regarding induction chemotherapy before ChemoRT

1) CALGB 9431 Vokes JCO 2002, Phase 2
3arms:
(A) 2# CDDP/Gem --> RT (with reduced dose chemo during RT)
(B) 2# CDDP/Pac --> RT (with reduced dose chemo during RT)
(C) 2# CDDP/Vinorelbine --> RT (with reduced dose chemo during RT)

RT up to 66 Gy
RESULS:
- MS 17months
- 2 to 3y OS not better than 2nd gen trials, inferior to SWOG 9504
==========
2) CALGB 39801 Vokes JCO 2007
2 arms:
(A) CRT arm: Pac/Carbo weekly + RT
(B) IND arm: 2# Pac/Carbo --> weekly Pac/Carbo + RT
RESULTS:
- OS 12m vs 14m
- Inferior survival cf other CRT studies
- more neutropenia with induction

34

What are the induction chemo trials that you know about?

1) CALGB 9431 Vokes JCO 2002
2) CALGB 9534 Clin Lung Ca 2005
- 2# Pac/Carbo--> Pac/Carbo+RT
- MS 15m
3) LAMP randomized phase 2 study
- SEQ Arm: 2#Pac/Carbo-->RT
- IND Arm: 2#Pac/Carbo -- Weekly Pac/Carbo+RT
- CRT/CONSOL Arm: Weekly Pac/Carbo+RT--> 2# consolidation chemo
-Results:
>>OS 16m, non-sig trend favoring concurrent/consolidation

4) CALGB 39801 Vokes JCO 2007

35

After Concurrent CRT, any role for consolidation chemotherapy?

No.

1) SWOG 9019 (Phase II)
- EP+RT --> 2# EP
- 15m OS, 3yOS 17%
2) SWOG 9504(Phase II)
- EP+RT --> Docetaxel
- OS 26m, 3yOS 37%
3) HOG LUN 01-24 (Phase III study by Hanna JCO 2008, Jalal Ann Oncol 2012)
- 2 arms: EP+RT--> Docetaxel VS EP+RT
- OS 21m vs 23m (EP+RT) (Trend)
- Significant increased toxicity
>> Pneumonitis 10%, FN 10%, Death 5.5%)

4) SWOG 0023 (Phase III study by Kelly JCO 2008)
(A) EP+RT--> Docetaxel --> Gefitinib
(B) EP+RT--> Docetaxel --> Placebo
- Gefinitib a/w worse survival than placebo 23m vs 35m
- Gefinitib also a/w toxicities like diarrhea and rash

5) Rusch JCO 2007

6) Albain Lancet 2009 INT 0139

7) RTOG 0617 Bradley Lancet Oncol 2015

8) PROCLAIM study (Senan JCO 2016)

36

Tell me about the PROCLAIM Study

Senan JCO 2016

Stage IIIA/B NSCLC
Unresectable non-squamous

2 arms:
(A) 3# Pem/CDDP + RT --> 4# Pem
(B) 2# EP+RT --> 2# Platinum-doublet

Choice of platinum doublet:
- EP
- Vinorelbine/CDDP
- Pac/Carbo

RT:
- 60-66Gy

Closed early use to futility

Med OS:
27m vs 25m

37

Tell me about the Albain trial INT 0139

2 arms:
A) 2#EP+RT --> Sx --> 2#EP
B) 2#EP+RT --> Complete RT --> 2#EP

5y OS 20%

38

What are the Altered radiation schedules that you know about?

1) Conventional fractionation
2) Dose escalation, conventional fractionation
- RTOG 0617
3) Hyperfractionation
4) Acceleration
5) Accelerated Hyperfractionation
6) Hypofractionation (high is also accelerated)

39

Tell me about dose-escalated RT RTOG 0617

Bradley Lancet Oncol 2015

2 aims:
(1) Does dose escalated TRT + Chemo improve outcomes? Vs conventional RT+ Chemo
(2) Does addition of Cetuximab to ChemoRT improve outcomes?

4arm, 2x2 factorial design:
(A) Pac/Carbo/RT 60Gy
(B) Pac/Carbo/RT 74Gy
(C) Pac/Carbo/Cetuximab/RT 60 Gy
(D) Pac/Carbo/Cetuximab/RT 74Gy

Weekly Pac(45) + Carbo (AUC2) during RT --> Consolidation with 2# Pac (200) and Carbo (AUC6) +/0 Cetuximab after RT

RESULTS:
- No increase in toxicities with high-dose RT
- G3 pneumonitis similar, G3 esophagitis 21% vs 7%
- Cetuximab a/w higher toxicities
- OS: 29m (60Gy) vs 20m (74Gy)
- OS 25m (Cetux) vs 24m (No Cetux)


CONCLUSIONS:
1) NO. Worse outcomes
2) No difference in outcomes

40

Any evidence for Hypofractionated Accelerated RT?

Walraven Radiother Oncol 2016:
Netherlands Stage III

N=100
Stage II/IIIA/IIIB NSCLC

2 arms:
1) 24# RT X 2.75Gy + Concurrent Daily CDDP (6)
2) 24# RT X 2.75Gy + Concrrent weekly Cetuximab

RESULTS:
Med OS 33m vs 30m
5y OS 37.5%
But good overall OS.
Role of Hypofractionation in treatment of Stage III NSCLC

41

What are the trials that look at surgery/tri-modality treatment for Stage III NSCLC?

All without OS benefit

1) EORTC 08941 (Van Meerbeeck JNI 2007)
- Unresectable Stage IIIA (N2)
- N=580 2 arms:
>> CT-S vs CT-RT
>> 3#plat-based chemo-->CR/PR then randomized into RT vs surgery
- No OS benefit. 5yO 16% vs14%
- Comparator arm is RT alone, ideally should be CRT
- slightly more advanced IIIA disease as only 50% could be randomized after induction

2) INT 0139 (Albain Lancet 2009)
- potentially resectable Stage IIIA (N2)
- n=430 2 arms:
>> CRT-S vs CRT
>> 2#EP+RT 45-->Complete RT to 61 --> 2#EP
>> 2#EP+RT 45--> Surgery --> 2# EP
- No OS benefits 22m vs 23.5m (CRT-S)
- 5y OS 27% vs 20%
- oesophagitis 10% vs 23% (CRT)
- Increased PFS (sig) 10.5m vs 13m (CRT+S)

3) ESPATUE study (Eberhardt JCO 2015)
- n=250
- 2 arms:
>> CT-CRT-S vs CT-CRT-CRTb
>> 3# CDDP/Pac --> RT 45Gy/CDDP (50) D2,9 + Vinorelbine (20) D2,9
>> Re-evaluate after ChemoRT if resectable. Then 2arms:
>>>> ChemoRT boost Risk adapted to 65Gy/71Gy
>>>> Surgery
- no OS benefit
- 5y Survival 44% vs 41%
- 65% deemed resectable after induction.

4) SAKK 16/00 study (Pless Lancet 2015)
- Resectable IIIA (N2) with 230 patents
- 2arms:
>> CT-RT-S vs CT-S
>> 3# Docetaxel/CDDP-->RT 44Gy/22#/3w--> Surgery
>>3# Doceaxel/CDDP --> Surgery
- No OS benefit. No EFS benefit either
- 5y OS 40% vs 35%

42

Margin-positive resected NSCLC, Do you need post-op RT?

Yes