ABORDAJE TERAPÉUTICO DEL CÁNCER MICROCÍTICO DE PULMÓN
Rosario García CampeloServicio de Oncología Médica
Complejo Hospitalario Universitario A Coruña
SCLC accounts for approximately 18.31% (female) and 13.68% (male) of all lung cancers in 2003
SCLC and NSCLC
Wahbah et al. Ann Diagnostic Pathol 2007; 11: 89–96.
LAS CIFRAS DEL CÁNCER EN ESPAÑA
ENFERMEDAD RARA O HÚERFANA:
incidencia < 0.05%
4177 CMP anuales en España28.000 muertes anuales en el mundo
7ª causa de mortalidad por cáncer en el mundoEs el 3er subtipo histológico más frecuente de cáncer de pulmón
NO ES RARO…PERO SÍ PROBABLEMENTE HUÉRFANO…
SMALL CELL LUNG CANCER SURVIVAL
Median survival without treatmentLS: 4 monthsES: 2 months
Extensive StageLimited Stage
Govindan, JCO 2006
Median survival with treatmentLD 16 monthsED 9 months
5 YS men: 7.5%
5 YS female: 12%
5 YS male: 3.5%
5 YS female: 5%
My main objectives today
STATE OF THE ART
AND SOME FUTURE PERSPECTIVES…
U.S National Cancer Institute Levels of EvidenceHow do we change our clinical practice?
Study Design
Randomized controlled trials
Non-randomized controlled trials
Population based consecutive series
Consecutive case series
Non- consecutive case series
+
-
Meta-analysis
LIMITED STAGE:Progress in treatment
Standard combinations
Platinum combinations
• Cisplatin – Etoposide (PE)
• Carboplatin – Etoposide (CE)
• Ifosfamida – carboplatin – Etoposide (ICE)
• Cisplatin- Epirubicin
Anthracyclines combinations
• CTX- adria - VCR (CAV)
• Adria – CTX – etoposide (ACE)
Platinum vs Anthracycline combinationsRandomized trials
Author CT N Median Survival(months)
All LS ES
2 y survival (%)
All LS ES
SundstromJC0 02
CEV
PE
218
218
7.8
10.2
9.7
14.5
6.5
8.4
6
14
8
25
1
4
p 0.0004 0.001 NS 0.0004 0.001 NS
BakaBJC 08
ACE
PE
139
141
10.1
10.7
11.8
12.6
8.8
7.8
14
12
21
17
0
3
P 0.76 0.67 0.78 0.76 0.67 0.7
Meta-analysis of cisplatin vs non cisplatin randomized clinical trials
Pujol et al. B J Cancer 2000
Survival: Increased of 4.4% of 1 yearSurvival
20% mortalityResponse: Increase of 9%No differences in toxicity
CIS OR CARBO…
.
Rossi A et al. JCO 2012;30:1692-1698
The choice of a platinum compound for1st line should take into account• Expected toxicity profile• Age• Patient´s organ function• Patient´s comorbilities
¿Cisplatino o carboplatino en enfermedad limitada?
Cisplatino -etoposido vs Carboplatino-etoposido + radioterapia concurrente en pacientes > 65 añosEstudio de Cohorte SEER-Medicare
• Objetivo 1º: Supervivencia
• Edad mediana 72 (66-81
• 611 pacientes
– Cis-etoposido: 229 pacientes
– Carbo-etoposido: 382 pacientes
• # CSS: Cause Specific Survival
16.03 m/22.8%
15.01m/25.21%
mCSS#/ 5 años
13.7m/10.51%B:CE
13.3m/10.11%A:PE
mSG/ 5 años
Kim E. ASCO 14
Resultados
Is radiotherapy necessary?Two meta-analysis
Pignon et al (NEJM 1992) evaluated 13 randomized trials:
Thoracic Radiotherapy in LS-SCLC: an absolute benefit in overallsurvival of 5.4% at 3 years and a 14% reduction in mortality.
Warde and Payne (JCO 1992) evaluated 11 randomized trials:
The addition or RT to Chemotherapy showed an overall survivalbenefit of 5.4% at 2 years.
Chemo-TRT
“The sequence”
Autor Sequence N patients MS(meses)
2Y survival (%) P
Gregor, 1997 Concurrent
Sequential335
14
15
26
23
No significant
Lebeau, 1999 Concurrent
Alternante
82
74
13.5
14
NR
NR
No significant
Takada 2002 Concurrent
Sequential
114
114
27.2
19.7
5a23.7
18.3
SignificantP= 0.02
Chemo-TRT“The moment”
Author “Timing” N patients
MS(month
s)
2 year Survival
(%)
StatisticalSignification
Perry, 1987 EarlyLateNone
125145129
13.114.613.6
15258
Advantage for arms with RT, No differences in timing.
Murray, 1993 EarlyLate
155153
20.015.0
4033
Significant
Jeremic, 1997 EarlyLate
5251
3426
7153
Significant
Work, 1997 EarlyLate
99100
10.512.0
2019
No significant
Spiro 2006 EarlyLate
13.715.1
No significant
Fried, D. B. et al. J Clin Oncol; 22:4837-4845 2004
Two-year overall survival risk ratio forest plot for early v late thoracic radiation therapy (RT)
“Early vs Late” Thoracic Radiation
Meta-análisis
TRTThe fractionation
Autor Fraccionamiento Nº pacientes MS
(meses) Supervivencia
(%) Significación estadística
Turrisi, 1999
Fraccionada No fraccionada (en 1º ciclo)
211
206
23
19
2 años 47 41
5 años 26 16
Significativo
Bonner, 1999 Schild 2003
Fraccionada No fraccionada (en 4º ciclo)
130
132
20.4
20.5
45
47
22 21
No significativo
HF-RT vs RT
Conclusión: Si la radioterapia comienza de forma temprana, el hiperfraccionamientopuede ser beneficioso en supervivencia.Pero si la radioterapia comienza de forma tardía, probablemente el hiperfraccionamiento no es beneficioso
HOW IMPORTANT IS THE SER CONCEPT
The time from the start of any treatment to the end of chest
irradiation
(A) The survival at 5 years as a function of the start of any treatment and the end of radiotherapy (SER).
Dirk De Ruysscher et al. JCO 2006;24:1057-1063
Spiro et al. J Clin Oncol 2006
El beneficio de la Radioterapiatemprana sólo existe en aquellos estudios en los que se administran
todos los ciclos de la quimioterapia programada
Study N CT CT-RT RR MS 2y S
Bogart 2004 63 T To CaE/70Gy 92% 22 48%
Miller 2007 65 TToE CaE/70Gy 81% 20 35%
Schild 2007 76 PE PE/60Gy - 22 46%
CT-TRT
The dose
Prophylactic cranial irradiation
Auperin et al. NEJM 1999
16% reduction in mortality
5.4% increase in 3 year survival rate
PCI decreases cumulative incidence of brainmetastasis in 25.3%
PCI significant increases the rate of diseasefree survival and disease free of brain mets.
Benefit observed in LS patients with CR or PR
Standard vs higher dose PCI in SCLC-LSPCI at 25 Gy should remain the standard of care in limited-stage SCLC.
Le Pechoux et al. Lancet Oncol 2009
OS DFS
Local relapseBrain met incidence
Pignon – NEJM 1992 * Turrisi –NEJM 1999 * Auperin –NEJM 1999 * Warde – JCO 1992*Fried – JCO 204 * Perry – NEJM 1987 * Pujol – BJC 2000 * Macaux – Lung Can 2000
1960 SCLC chemo-sensitive
1987 Perry: CT-RT > QT
Turrisi: Hf-RT (45Gy) > RT
1992
1999
Pignon / Warde: CT-RT > QT
Auperin: Holocranial RT
Pujol: CDDP > no-CDDP
CDDP-VP16 remains gold standard 2000
2004 Fried: Early RT > Late RT with HF-RT
LD-SCLC
18-23mo2-4 mo
Some conclusions for the daily practice
QT: Platinum-etoposide
Concomitant QT+RT better than sequential
Early RT: as soon as posible…better outcomesin the first 30 days
RT: dose, HF-RT??? Early RT > Late RT with HF-RT
PCI improves survival
Extensive Stage SCLCTHE LAST 10 or 20 YEARS SUMMARY…
SCLC is highly sensitive to chemotherapy and radiotherapy
Despite the high chemosensitivity, median survival remainspoor for patients with ES ranges only from 7 to 11 months
Platinum-etoposide is the standard of care in first linetreatment since the 1980s• ORR: 50-60%
• Median Survival: 9-12 months
• Topotecan is the standard of care in second-line therapy
SOME AND RELEVANT QUESTIONS in the 1st line setting…
What is the best 1st line regimen?
Is there a role for dose-intensive chemotherapy?
Is there a role for maintenance chemotherapy?
Is there a role for antiangiogenic agents?
Is there a role for inmunotherapy treatments?
Is there a role for preventive brain irradiation ?
Is there a role for thoracic radiotherapy?
CIS OR CARBO…
.
Rossi A et al. JCO 2012;30:1692-1698
4 RCT32% LD 68% SDNo differences in RR, PFS and OS
The choice of a platinum compound for1st line should take into account• Expected toxicity profile• Age• Patient´s organ function• Patient´s comorbilities
Have we found any way to improveplatinum-etoposide results?
Compare new platinum regimens toplatinum etoposide
• Irinotecan- Platinum
• Topotecan- Platinum
• Pemetrexed- Platinum
• Amrubicin-Platinum
JCOG 9511
Noda et al NEJM 2002
North American/Australian study
Hanna et al. JCO 2006
Platinum-Irinotecan vs Platinum-Etoposide
Irino 60mg/m2 d1,8,15P 60mg/m2 d1
Q4 weeks x 6 cycles
E 100mg/m2 days 1 to 3P 80mg/m2 day 1
Q3 weeks x 6 cycles
RANDOMIZATION
RANDOMIZATION
Irino 65mg/m2 d1,8P 30mg/m2 d1 and 8Q3 weeks x 4 cycles
E 120mg/m2 days 1 to 3P 60mg/m2 day 1
Q3 weeks x 4 cycles
Platinum-Irinotecan vs Platinum-Etoposide
Noda et al, NEJM 2002 Hanna et al, JCO 2006
S0124: A randomized Phase III trial of Cisplatin+Irinotecan vsCisplatin+ Etoposide in patients with SCLC ED
Lara et al. JCO 2009
MA Irinotecan/Platium vs Etoposide/Platinum
Shao et al. J Thorac Oncol 2012
RR: no difference
OS:better IP
PFS: No difference
Oral Topotecan-Platinum vs Platinum-Etoposide
Eckardt et al, JCO 2006
IV Topotecan/cisplatin vscisplatin/etoposide
Fink TH et al. J Thorac Oncol 2012
Phase III study of Pemetrexed plus Carboplatin vs Etoposideplus Carboplatin in patients with SCLC ED. GALES/JMHO Trial
Socinski et al. JCO 2009
Satouchi M et al. JCO 2014;32:1262-1268
Is there a role for dose- intensity chemotherapy?
43 published papers: There is no evidence that thetreatment of SCLC can be improved by increasing the
dose intensity, peak dose, or total dose of chemotherapy, so intensification strategy should be
probably abandoned
Criveralli et al. The Oncologist 2007
MA RESULTS OF INTENSIFIED CHEMOTHERAPY IN SCLC
Rossi et al. Cancer Treat Rev 2013
7505: Study Design
STAD-1 TRIAL
Morabito et al. ASCO 2015
No Difference Between the PFS and OS
Morabito et al. ASCO 2015
Is there a role for maintenance therapy?
ECOG e7593 Phase III trial: Topotecan vs Observation after Cisplatin Etoposide (Schiller etal JCO 2001)
FNCLCC cleo04–IFCT 00-01 Phase III trial Thalidomide vs Observation after Cisplatin-Etoposide (Pujol et al JCO 2007)
BR20 Phase II trial: Vandetanib vs placebo after complete or partial response toinduction chemotherapy with or without radiation therapy (Arnold et al JCO 2007)
EORTC BR.12: Prospective, Randomized, Double-Blind, Placebo-Controlled Trial ofMarimastat After Response to First-Line Chemotherapy in Patients With Small-Cell LungCancer (Shepherd et al JCO 2002)
ECOG E1500: A Randomized Phase II trial of two dose levels of Temsirolimus in Patientswith Extensive Stage Small Cell Lung Cancer who have responding or stable disease afterinduction chemotherapy (Panda et al JTO 2007)
NEGATIVE TRIALS
Rossi et al Lung Cancer, Volume 70, Issue 2, 2010, 119 - 128
MAINTENANCE OR CONSOLIDATION THERAPY: MA
3,688 patients, 11 RCTs employingchemotherapy, 6 interferons, and 4 otherbiological agents
The maintenance or the consolidationapproach failed to improve theoutcomes of SCLC.
A survival advantage is suggested formaintenance chemotherapy andinterferon-alpha, but its clinical impactneeds to be confirmed by furtherstudies
Author Drug/Target NPts
RR%
mPFSmonths
MSmonths
HornJCO 2009
ECOG –E3501 PE + BVZ 63 63.5 4.7 10.9
ReadyJCO 2011
CALGB 30306PI + BVZ 72 75 7.0 11.6
SpigelJ Thor Oncol 2009 CI + BVZ 51 84 9.1 12.1
Spigel et alJCO 2011
Phase II SALUTE
PE+BVZvsPE
52
50
48
58
5.5
4.4
9.4
10.9
Pujol et alAnn Oncol 2015
PE+BVZvsPE
75
80
5.3
5.5
11.1
13.3
Fase II/III trials of CT+ BVZ in ES- SCLC
REDIFINING THE ROLE OF RADIOTHERAPY IN ED SCLC
PCI in ES chemotherapy respondingpatients
Slotman et al. NEJM 2007
1 year S: 27.1% vs 13.3%
HR: 0.68 p0.003
MA of PCI in SCLC
Vianaa et al. J Bras Pneumol 2012
16 RCT collectively involving1,983 patients
Overall mortality was 4.4% lowerin the patients submitted to PCI,especially in those showing acomplete response afterinduction chemotherapy and inthose submitted to PCI after thattreatment, regardless of thestage of the disease
THORACIC RT: CREST TRIAL
Slotman et al. Lancet 2014
2-year overall survival was 13% vs 3% p=0.004
PFS at 6 months was 24% vs 7% p=0.001
Treatment paradigm for relapsed SCLC
Relapsed disease
NO
Refractory
BSC or active treatment
YES
Non-cross resistantchemotherapy
Paclitaxel, Irinotecan,Gem, Topotecan
Amrubicin
ResistantTFI <90 days
SensitiveTFI ≥90 days
Re-challengefirst-line
SensitiveTFI >6months
SensitiveTFI >3-6months
TopotecanOther
Performance status and Sensitivity to 1st line QT are significant prognostic factors for patients receiving second-line treatment
Kim et al. Cancer 2008
Survival according to PS Survival according to sensitivity
Single agent activity in relapsed SCLC
Agent No. of studies Total patients Response rates
Paclitaxel 2 41 29%-36%
Docetaxel 2 38 25%-30%
Vinorelbine 2 49 14%-31%
Irinotecan 3 91 16%-47%Topotecan for Injection
3 129 11%-33%
Gemcitabine 2 71 0%-12%
Ardizzoni A, Hansen H, Dombernowsky P, et al. J Clin Oncol. 1997;15:2090-2096; Depierre A, von Pawel J, Hans K, et al. Lung Cancer. 1997;18(suppl1). Abstract 126; DeVore RF, et al. Proc Am Soc Clin Oncol. 1998;17. Abstract 1736; Fernandez-Rodriguez, et al. Proc Am Soc Clin Oncol. 2001;20. Abstract 2883; Furuse K, Kubota K, Kawahara M, et al. Oncology. 1996;53:169-172; Hoang, et al. Proc Am Soc Clin Oncol. 2002; 21. Abstract 2690; Jassem J, Karnicka-Mlodkowska H, van Pottelsberghe C, et al. Eur J Cancer. 1993;29A:1720-1722; Kurata T, et al. Proc Am Soc Clin Oncol. 2002;21.
Abstract 1350; Le Chevalier T, et al. Proc Am Soc Clin Oncol. 1997;16:450a; Masters G, et al. J Clin Oncol. 2003;21(8):1550-1555; Masuda N, et al. J Clin Oncol. 1992;10:1225-1229; Nakamura H, et al. Proc Am Soc Clin Oncol. 2001;20.
Abstract 2872; Smit EF, Fokkema E, Biesma B, et al. Br J Cancer. 1998;77:347-351; Smyth JF, Smith IE, Sessa C, et al. Eur J Cancer. 1994;30A:1058-1060.
Topotecan in relapsed SCLC
JCO 1999 V Pawel
IV Topotecanvs CAV
JCO 2006 O´Brien
JCO 2007 Eckardt
Oral Topotecan vs
BSC
IV Topotecan vs Oral Topotecan
Median survival p=0.795:
IV topotecan= 25.0 weeks
CAV =24.7 weeks
Median survival
Oral topotecan= 25.9 weeks
BSC alone=13.9 weeks
Median survival
Oral = 33.0 weeks
IV=35.0 weeks
Some other options for 2nd line setting
Taxol combinations
Author CT RR (%) MS/ TTPmonths
3-4 Toxicity
DómineASCO 01
Gemcitabina 1250 mg/m2 d 1 y 8Taxol: 175 mg/m2 d 1Cada 21 d
46S 56R 31
7.1/4.9 Np: 7.5% Tp 5% An 5%
Dongiovanni ASCO 04
Gemcitabina 1000 mg/m2 d 1 y 8Taxol: 80 mg/m2 d 1, 8 y 15Cada 21 d
26S 29R 20
4/3 Np: 26% Tp 25% Astenia 13%
MoriCanc Chem Ph 06
Taxol 100 mg/ m2 d 1 y 8Carbo AUC 2 d 1 y 8Cada 3 -4 semanas
69%S 83R 45
P< 0.001
6.8/3.87.8/10.85.3/3.9P< 0.00
NP 55%, Tp 35, Np 55%
Old combinations: Gemcitabine plus campthotecin analogues
Author CT RR (%) MS/TTPmonths
G 3-4 toxicity
Dómine, IASLC 03 Gemcitabina 1500 mg/m2CPT-11: 150 mg/m2
2 weeks
31S 38R 22
7.3/6 0%
Castellanos, IASLC 03
Gemcitabina 2000 mg/m2CPT-11: 175 mg/m2
2weeks
50 8.5/8 Np 14%
Agelaki, Oncology 04
Gemcitabina 1250 mg/m2 d 1 y 8
CPT-11: 300 mg/m2 d 8Cada 21 d
10 6/? Np: 29%, Tp: 13%, D: 10%
Rocha -LimaAnn Oncol 07
Gemcitabina 1000 mg/m2 d 1 y 8
CPT-11: 100 mg/m2 d 821 d
S 31R11
7.1/3.53.1/1.6
Np: 43%, Tp: 36%, D: 9%
OkanoWCLC 07
P1-225
Gemcitabina 1000 mg/m2 d 1 y 15
CPT-11: 175 mg/m2 d 1 y 15
28 d
39.3%14.4
S 14,4R 7.4
Np: 42% Tp: 3% D: 9%
Amrubicina in 2nd line setting
Onoda, S. et al. JCO 2006
MS: 10.3 m Refractory
MS: 11.6 m Sensitive
Relapsed SCLC: is Amrubicin better than topotecan?
Author Regimen ORR PFS(m)
OSm
EttingerJCO 2010Phase II
R
Amrubicin40mg/m2 iv
D1-3
21.3% 3.2 m 6.0m
JotteJCO 2011Phase II
S
AmrubicinTopotecan
44%15%
P 0.021
4.53.3
9.27.6
InoueJCO 2008Phase II
S&R
AmrubicinTopotecan
53% (S) 17%(R)
21% (S) 0%(R)
3.9 (S) 2.6 (R)3 (S) 1.5 (R)
9.9 (S) 5.3 (R)11.7 (S) 5.4 (R)
Von PawellJCO 2014Phase III
AmrubicinTopotecan
31.116.9
P 0.001
4.13.5
P 0.0182
7.5 7.9
P 0.170
Is there a role for targeted agents?
No…is time to optimism?
Target Agent Trial phase ActivityC-kit imatinib II No
EGFR gefitinib II No
Ras R115777 II No
VEGF Bevacizumab II +/-
Thalidomide III No
Vandetanib II No
Cediranib II No
Sorafenib II No
mTor Temsirolimus II/III No
Src Dasatinib II NA
Bcl-2 Oblimersen II No
Have we made any progress?
I have my own personal opinion and it’s not too positive …
Why son many failures?
Reasons for the failure
Wrong design of clinical trials
Wrong drugs
Wrong targets
Wrong doses
Unknown molecular mechanisms of the disease
…….
Some ideas for the future…
Define SCLC biology to identify new actionablemolecular targets
Increase the diversity of agents
To abandon empiricism in favor of molecularlybased clinical trial design.
IO agents may be a good option for the future…
Novel molecular targets in SCLCSome hope for the future…
Hedgehog/ Smoothened
Slide 6
Mutations in small cell lung cancer
Immunotherapy – The Beginning of the End for Cancer:<br />Transforming Cancer into Chronic Disease
Slide 3
Reck M et al. Ann Oncol 2013;24:75-83
Phase II Study of Ipilimumab in SCLC
Phased schedule shows trendfor improved OS
Phase III ongoing
Abstract No: 7502 Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028.
ORR 35% GOOD DURABILITY
Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. Abstract No: 7503
ORR 32,7%PROMISING ACTIVITY OVERALL IN PLATINUM REFRACTORYPDL-1 EXPRESSION DOESN´T SEEM PREDICTIVEDON´T FORGET THE TOXICITY OF THE COMBINATION…NO CHANGES IN OUR CLINICAL PRACTICE…FUTURE MAYBE!!!!
MEANWHILE…THE MA BASED EVIDENCE
First-Line CT Recommended CT vs BSC
Platinum-based regimens Platinum-based regimens are the standard
CDDP vs CBDCA No difference in ED (toxicity profile)
Platinum/ etoposide combinationPE should be consider estándar of care, specially in caucasians
Maintenance Is not recommended
ICHP and CSF use Data do not support the use of ICHP and CSF
PCI PCI is recommended in responding patients
Thoracic RT NO MA
Second- line CT Limited benefit of CT vs BSC