Flashcards in Small Cell Lung Cancer Deck (18):
How common is small cell lung cancer amongst all the lung cancers?
What is the expected RR to fist line combination chemotherapy?
What is the prognosis for small cell lung cancer?
5y OS at best 10%
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
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
CAV vs EP for extensive stage SCLC. Which is better and why?
Bruce Roth JCO 1992
(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.
(A) EP X 4 (12 weeks)
(B) CAV (18 weeks)
(C) CAV/EP (18 weeks)
RR ~ 50-60%
Cisplatin vs Carboplatin. Any difference?
Seems to be equivalent in terms of efficacy, but different toxicity profile.
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
How can we intensify the dose? Any benefit?
Slight improvement in efficacy,but increased toxicity and mortality
1) Adding drug --> Triplet. Regimens tried:
2) Dose Dense
- 2weekly vs 3-weekly ACE
- 2weekly vs 4weekly ICE
- High vs low dose ICE, supports with PBPCs
- Ifosfamide/Etoposide/Epiruicin/CDDP + APSCT
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)
What dose dense regimens do you know?
1) Thatcher JCO 2000
- 2 arms:
> Doxorubcin/Cyclophosphamide/Etoposide (ACE) q2w + GCSF
> ACE q3w
> 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
- Ifosfamide/Carboplatin/Etoposide (ICE) q4w
- ICE q2w + GCSF + blood-progenitor-cell support
- ORR 80% vs 88% (Q2w) p not sig
- Med OS ~ 14m
- 2y OS 20% ~
- No. Of neutropenic sepsis stat sig in standard arm
Any role for maintenance chemo in SCLC?
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%
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
For limited stage SCLC, which is better? Concurrent or sequential CRT and why.
Concurrent is better
1) Takada JCO 2002 (JCOG 9104)
- Concurrent CRT where RT starts with #1 chemo
- Sequential Chemo--> RT
RT: 45 Gy BD over 3 weeks 1.5Gy BD
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
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.
- Concurrent 45 Gy BD RT
- concurrent 45 Gy OD RT
- 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
- OS 21m both arms
- 5yOS 20%~
- G3 oesophagitis worse in BD RT; G toxicity in 3% with BD RT
How frequent are asymptomatic brain mets in ES-SCLC?
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#)
Brain MRI prior to enrollment required.
- med OS 10m for PCI and 15m for Obs
PCI significantly reduced the risk of brain mets as compared to Obs 30% vs 60%
Conclusion: PCI after response to chemo had a negative impact on OS in pts with ES-SCLC
(2) Ben Slotman EORTC NEJM 2007
s/p chemo with response, randomized to 2 arms:
- Observation control top.
- 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)
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
- 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
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.
- 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
ES-SCLC, had objective response to chemo
Offered PCI + chest RT (40Gy in 15#)
Med TTP 4m
Med OS 8m
3) Slotman Lancet 2014
Confirmed ES-SCLC who responded to chemo. Randomized to:
- Thoracic RT 30Gy in 10#
- No Thoracic RT
* All underwent PCI
- 1y OS not sig. 33%(RT) vs 28%
- 2y OS 13% (RT) vs 3%
- 6m PFS 24% s 7%
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