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Flashcards in Small Cell Lung Cancer Deck (18):
1

How common is small cell lung cancer amongst all the lung cancers?

15-20%

2

What is the expected RR to fist line combination chemotherapy?

50-70%

3

What is the prognosis for small cell lung cancer?

Limited stage:
OS 14-20months
5y OS at best 10%

Extensive stage:
OS 8-13m
5y OS

4

Is RT important in the treatment of limited-stage SCLC?

Pignon 1992 NEJM
Meta-analysis 13 RCTs, 2500 patients
Excluded extensive disease
Compared Chemo alone vs Combined ChemoRT

CONCLUSIONS:
1) Thoracic RT led to 14% reduction in the mortality rate (p sig) = 5% increase in the 3y survival rate
2) Benefit of RT was greatest in those

5

CAV vs EP for extensive stage SCLC. Which is better and why?

Bruce Roth JCO 1992
2 Aims:
(1) Determine the efficacy/toxicity of CAV and EP
(2) Whether the rapid alternation of CAV and EP would be superior to either regimen alone.

N=400

3 arms:
(A) EP X 4 (12 weeks)
(B) CAV (18 weeks)
(C) CAV/EP (18 weeks)

RESULTS:
RR ~ 50-60%

6

Cisplatin vs Carboplatin. Any difference?

Seems to be equivalent in terms of efficacy, but different toxicity profile.

2 studies.
1) Skarlos Annals of Oncology 1994
N=150; 2 arms: EP vs EC
Included both limited and extensive stage disease, with Limited stage Responders and ext stage CR receiving RT from #3 onwards + PCI
CDDP more toxic with leukopenia, neutropenia infections, nausea/vomiting, neurotoxicity, hypernergic reactions
CRR 57% and 58%
Survival 12.5m vs 11.8m

2) Rossi JCO 2012
Meta-analysis 4 RCTs with 650 patients.
Med OS 9.6m (CDDP) vs 9.4m
Med PFS 5.5 vs 5.3m
ORR 67% vs 66%
Hematologic toxicity higher with Carbo
Non-hematologic toxicity higher with CDDP

7

How can we intensify the dose? Any benefit?

Slight improvement in efficacy,but increased toxicity and mortality

1) Adding drug --> Triplet. Regimens tried:
- Paclitaxel/Etoposide/Carbo
- Carbo/Etoposide/Vincristine
- Paclitaxel/Etoposdie/CDDP
2) Dose Dense
- 2weekly vs 3-weekly ACE
- 2weekly vs 4weekly ICE
- High vs low dose ICE, supports with PBPCs
3) Transplant
- Ifosfamide/Etoposide/Epiruicin/CDDP + APSCT

8

What are the triplet therapies that you know about?

(A) Lung Cancer 2006, Reck et al
Pac/Carbo/Etoposide > Vincristine/Carbo/Etoposide
N=600 Stage I-IV SCLC
Med OS 12.5m vs 11.7
5y OS 14% vs 6%

(B) 2001 Annals of Oncology Mavroudis
Paclitaxel/Etoposide/CDDP vs Etoposide/CDDP
N=130, tx-naive SCLC (LD and ED)
Trial terminated early due to toxicities
- 8 toxic deaths in TEP arm, vs 0 in EP arm
CR+PR similar at 50%
Duration of response, 1y OS and OS similar in both arms
Med TTP 11m (TEP) vs 9m (p sig)

9

What dose dense regimens do you know?

1) Thatcher JCO 2000
N=400
- 2 arms:
> Doxorubcin/Cyclophosphamide/Etoposide (ACE) q2w + GCSF
> ACE q3w
- Results:
> CRR 40% (GCSF) vs 30% (P sig)
- ORR ~80%
- 1y OS 50% (G) vs 40%
- 2y OS 13% vs 8%

2) Lorigan et al JNCI 2005
SCLC prognostic score 0-1
N=300
2 arms:
- Ifosfamide/Carboplatin/Etoposide (ICE) q4w
- ICE q2w + GCSF + blood-progenitor-cell support
Results:
- ORR 80% vs 88% (Q2w) p not sig
- Med OS ~ 14m
- 2y OS 20% ~
- No. Of neutropenic sepsis stat sig in standard arm

10

Any role for maintenance chemo in SCLC?

Yes:
1) Bozcuk Cancer 2005
- Meta-analysis of 14 RCTs, n=2500
- maintenance chemo improved 1y OS by 9% (30% to 39%) and 2yOS from 10 to 14%
==========
No
1) Rossi - Lung Cancer 2010
Meta-analysis of 21 RCTs, n= 3700
No statistical advantage in OS or PFS for maintenance/consolidation therapy.

Even with the other targeted agents, at most PFS improved, but no OS benefit
Other agent tried:
1) HOG by Hanna Onco 2002
- Maintenance oral Etoposide X 4m after #4 EIP in ext SCLC
- no OS benefit. PFS benefit
2) ECOG study by Schiller JCO 2001
- Maintenance Topotecan x3m after 4# EP in ext stage
- PFS bentter, no OS benefit
3) Temsirolimus - no benefit
4) Continuation maintenance with Irinotecan after induction IP - no benefit

11

For limited stage SCLC, which is better? Concurrent or sequential CRT and why.

Concurrent is better

1) Takada JCO 2002 (JCOG 9104)
N=200
2arms:
- Concurrent CRT where RT starts with #1 chemo
- Sequential Chemo--> RT
RT: 45 Gy BD over 3 weeks 1.5Gy BD
EP x4
Concurrent yielded better survival than RT
Med survival 20m vs 27m (concurrent arm)
5y OS 24% vs 18%
Oesophagitis 9% in CRT vs 4% in seq

12

How about the role of hyper fractionation of RT? Any value?

2 studies, 1 with OS benefit, one without.

With OS benefit:
1) Turrisi NEJM 1999
EP X 4.
2 arms:
- Concurrent 45 Gy BD RT
- concurrent 45 Gy OD RT
Results:
- Median OS 23m vs 19m (OD)
- 5y OS 26% (BD) vs 16%
- oesophagitis worse with BD RT 27% vs 11%

Without OS Benefit:
Schild Int J Radiat Oncol Bio Phys 2004
All s/p 3#EP, then randomize to 2 arms:
- 2EP + Daily RT
- 2EP + Split course BD RT
Then #6 EP then PCI
Results:
- OS 21m both arms
- 5yOS 20%~
- G3 oesophagitis worse in BD RT; G toxicity in 3% with BD RT

13

How frequent are asymptomatic brain mets in ES-SCLC?

15%

14

PCI in ES-SCLC. Any role?

(1) Seto ASCO 2014 published JCO 2014

N=160, study closed early after interim analysis showing futility.
As long with response to 1st line platinum-doublet chemo, randomized to:
- PCI (25Gy 10#)
- observation
Brain MRI prior to enrollment required.

Results:
- med OS 10m for PCI and 15m for Obs
PCI significantly reduced the risk of brain mets as compared to Obs 30% vs 60%
PFS 2m~

Conclusion: PCI after response to chemo had a negative impact on OS in pts with ES-SCLC

(2) Ben Slotman EORTC NEJM 2007
ES-SCLC, n=300
s/p chemo with response, randomized to 2 arms:
- PCI
- Observation control top.
Results:
- s/p PCI - lower risk of symp brain mets HR 0.3, p sig
- cumulative risk of brain mets 1y = 15% (PCI) vs 40%
- med DFS 12w to 15w (PCI)
- med OS 5.4m to 6.7m (PCI)
- 1y OS 27% vs 13% (obs)

15

What about PCI in LS-SCLC?

Yes, role is present.

1) Auperin NEJM 1999
- meta-analysis of 7 trials
- PCI vs observation after CR from chemo
- 5% increase in 3yOS from 15% to 20%, reduces brain mets incidence

2) Arriagada 2002 Ann Oncol
- PCI vs no PCI in those achieving CR
- both LS and ES
- Reduced rate of brain mets from 60% to 40%
- OS ~15%

3) Patel Cancer 2009
- SEER database, retrospective analysis
- n=670
- LS-SCLC s/p PCI
- those receiving PCI had almost double OS at 5y 10% vs 20%

4) Schild Ann Oncol 2012
- pooled analysis
- PCI in pt achieving SD/better after chemo/ChemoRT for both ES and LS
- 3y OS 18% vs 5% (sig)

5) Gregor EJC 1997
- LS-SCLC with CR to induction randomized to PCI vs observation
- reduced brain met, non-sig OS advantage

16

Any role for Consolidation thoracic RT in ES-SCLC?

1) Jeremic JCO 1999
N=200 s/p 3# EP
Those with CR/CR at local/distant levels + CR/PR at distant/local level randomized to:
- Thoracic Accelerated Hyperfractionated RT with 54Gy in 36# over 18/7 + Carboplatin/Etoposide concurrently x2#
- 4# Carboplatin/Etoposide
All pts with CR at distant level received PCI.
Results:
- med survival time 9m
- 5y survival rate 3%
- survival rate 17m vs 11m (4#)
- 5y survival rate 9% vs 4%

2) Don Yee Radiotherapy and Oncology 2012
Phase 2
ES-SCLC, had objective response to chemo
N=30
Offered PCI + chest RT (40Gy in 15#)
Med TTP 4m
Med OS 8m

3) Slotman Lancet 2014
N=500
Confirmed ES-SCLC who responded to chemo. Randomized to:
- Thoracic RT 30Gy in 10#
- No Thoracic RT
* All underwent PCI
Results:
- 1y OS not sig. 33%(RT) vs 28%
- 2y OS 13% (RT) vs 3%
- 6m PFS 24% s 7%

17

Any role for immunotherapy?

1) ASCO 2015: Keynote 028
- Pembrolizumab in ext SCLC
- RR 35%, time to response 8.5 weeks, median duration of response 29 weeks

2) ASCO 2015 Checkmate 032
- Nivolummab +/- ipilumumab
- RR 18% with Nivolumab, 17% with Nvo/IPI
- Disease control rate 38% with Nivo, 54% with Nivo/IPI
- response independent of PD-L1 status

18

What is the expected IHC for SCLC diagnosis?

Synaptophysin
Chromogranin A
CD56
Thyroid Transcription Factor 1
MIB-1