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MON 2011 - Slide 25 - C. Faivre-Finn - SCLC
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MON 2011 - Slide 25 - C. Faivre-Finn - SCLC

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  • Decrease in incidence of SCLC- decrease in incidence of smokers, change of cigarette composition (decreased tar and nicotine)
  • IASLC - LD-SCLC is defined as tumour confined to one hemithorax with regional lymph node metastasis including both ipsilateral and contralateral hilar, supraclavicular and mediastinal nodes, as well as ipsilateral pleural effusion [1]. However, most studies have excluded LD patients with pleural effusion. More recently t he International Association for the Study of Lung Cancer recommended the use of the new TNM classification for the staging of SCLC based on an analysis of 8088 cases of SCLC
  • Donc, comment est-ce qu’on en est arrive la?
  • L’etude de Sundstrom a montre que les regimes contenant des anthracyclines etaient inferieurs. CEV-cyclophosphamide/epirubicin/vincristine
  • We have 2 meta-analyses that show survival benefit for platinum, but a recent meta-analyisi that shows no difference. How can you resolve this. Well there may be a benefit in ED, this is modest and not reliable. Furthermore, some non-platinum regimens are also good. oxicity is also an isues, particularly with cisplatin, and ongoing toxicity means poorer uptake of RT. He answer probably lies somewhere in this combination o factors
  • Donc comment est-ce que l’on peut ameliorer la toxicite de nos traitements?… En particulier, a toxicite renale et la nausee. Cela-dit le cisplatine reste le traitement optimale pour les patients de stade limite…
  • Le cisplatine est radiosensibilisant. Il y a une synergie entre le cisplatine et la radiotherapie. Le but du traitement est de guerir le patient.
  • Est ce que l’intensite de dose peut augmenter le taux de survie? ICi, les courbes de survie demontre que l’augmentation des doses de chimiotherapie n’ameliore pas le taux de survie.
  • Cette etude a demontree une augmentation du taux de survie pour les patients avec une augmentation de l’intensite de dose (qu’ils soient de stade localise ou etendu) mais il n’y a actuellement aucun consensus pour l’intensite de dose car la plupart des essais, dont une meta-analyse etaient negatifs. Taux de survie a 1an 47% et 39% pour les groupes G et C et 13% et 8% a 2ans. Plus de thrombocytopénie (36% vs 25%) et de transfusions sanguines (25% vs 18%) dans le groupe G mais moins de neutropénie par rapport au group C (21% vs 83%). (WHO grade 2-4)
  • La, ca devient plus deprimant…. Nous savons que toutes ces chimiotherapies sont actifs en traitements de deuxieme ligne en tant qu’agents seuls. Je vais me concentrer sur les 4 derniers mais les resultats d’essais sont decevants.
  • Alors, l’irinotecan…. Il y a eu une vague d’excitation dans le monde d’oncologie medicale quand les resultats de l’essai JAponais de Noda et coll ont ete publies. Cet essai a demontre que l’ajout du CPT11 au cisplatine etait superieur en termes de survie que le regime EP. Mais malheureusement, ca n’a pas dure car l’etude americaine de Hanna et coll n’a pas demontre que l’irinotecan etait superieur. Pourquoi cette difference? Elle a ete explique par les differences pharmacogenetiques entre les populations asiatiques et occidentales. Notamment le gene UGT1A1*28 qui est implique dans le metabolisme du CPT11. Ce gene est plus prevalent dans les populations occidentales….
  • Alors, encore plus decevant est le pemetrexed… Le pemetrexed est un agent de chimiotherapie qui est tres bien tolere mais malheureusement n’a pas ete demontre comme etant mieux que le regime carboplatine/etoposide.
  • Alors, le topotecan represente une avance importante dans le traitement de deuxieme ligne du CPC. Le topotecan est le premier agent chimiotherapeutique qui ete demontre comme etant superieur que les soins de support en traitement de deuxieme ligne. C’est un agent qui peut etre donne a voie orale ce qui est important dans le contexte palliatifs puisque les patients n’ont pas a etre hospitalise.
  • L’amrubicine est peut-etre plus prometteur. Des essais sont en cours pour evaluer ce traitement.
  • Phase III studies ongoing - Amrubicin vs Carboplatin + Etoposide Amrubicin vs Topotecan Amrubicin + Cisplatin vs Etoposide + Cisplatin
  • Meta-Analysis 3688 pts Maintenance/consolidation metaanalysis 14 RCTs CT increased OS 1 yr by 9% , 2yr by 4% Bozcuk et al Cancer 2005 To my mind, hard to say there isn’t something in it, and 9% increase in 1 year survival not to be laughted at. It reminds me of the argument in NSCLC Toxicity was less of a problem for chemotherapy than for IFN and other agents, and few patients discontiued maintenance therapy because of toxicity
  • Jusqu’a present aucune therapie ciblee a ete demontre comme etant efficace pour le traitement du CPC. L’espoir pour les therapies ciblee est que l’on puisse maintenir les reponses apres la chimiotherapie d’induction avec ou sans la radiotheraie avec un traitement de maintien. Que l’on puisse augmenter les taux de reponse et la duree de reponse apres le traitement initial en associant la chimio a une therapie ciblee. Que l;on puisse identifier de meilleurs traitements de 2eme et 3eme ligne. At least X agents have been, are currently or are proposed for testing in SCLC X have been tested in phase III (or randomised ) trials Do we have a targeted therapy yet ------no Are we close ? Here is a snapshot of targeted agents that have either been tested or are currently undergoing testing in SCLC Major focus on antiangiogenics
  • Slides for the sceptics! ACE/PE median FU for patients alive is still only 2.5 years Komaki- concurrent CTRT 5 year survival in PCI group 32% BD vs 19% OD G 3 Oesophagitis 21% BD vs 9.2% OD Retrospective Study done between 1985-98 324 patients
  • ?what is done in the UK AP survey
  • Show CT William Parkinson
  • Poumon atelectatique Volume large (>15 cm cranio-caudale)
  • LU21 15 months in VICE arm
  • Trials published after 1985 Seven RCT
  • Modern RT techniques=conformal, no ENI
  • Phase II For the limited-stage small-cell lung cancer trial, 29 patients were enrolled beginning April 2006, and closed early due to toxicity in March 2007 (14-month median follow-up). (one resulting in death), prompting early study closure.Athird patient died from an aerodigestive hemorrhage (autopsy not performed). All three patients had grade 3 esophagitis during chemoradiotherapy and bevacizumab induction therapy.
  • Participation RTOG IPC trt standrd dans LSSCLC Metaanalyse-gain a 3 ans de 6% chez les patients en RC ( bas é sur RP)
  • New agents combined with RT once we have established a standard of care for LSSCLC

MON 2011 - Slide 25 - C. Faivre-Finn - SCLC MON 2011 - Slide 25 - C. Faivre-Finn - SCLC Presentation Transcript

  • Small cell lung cancer Dr C Faivre-Finn Manchester Lung Cancer Group Manchester Radiation Related Research Group 10 th ESO-ESMO Masterclass 6 th April 2011 Manchester Lung Cancer Group
    • ‘ Progress in the therapy of SCLC has been painfully slow’. In fact you could argue that little or no therapeutic advances have been made for extensive- stage SCLC in more than 20 years’
    Gandara and Lara. J Clin Oncol 2008; 26: 4236-38
  • Facts
    • Incidence of SCLC is declining-less than 10-15% of all lung cancer cases
    • Govindan JCO 2006
    • One third present with limited stage disease
    • Excellent responses to CT and RT but few patients will be long term survivors
    • High risk of local relapse
    • High risk of distant spread (brain)
  • How do we stage SCLC?
    • Veterans classification TNM classification
    0 2 4 6 8 Survival (Years) 0% 20% 40% 60% 80% 100% IA IB IIA IIB IIIA IIIB IV 26 21 15 12 13 11 6 Median survival (months) 8008 patients
    • CHEMOTHERAPY
    • Platinum-etoposide
    • is the standard CT regime for the treatment of SCLC
  • Anthracyclines Sundstr øm et al. J Clin Oncol 2002; 20: 4665 - 4672
      • 436 patients with LS and ES
      • EP CEV
    • Survival 10.2 7.8 p = 0.0004
    • LS 14.5 9.7 p = 0.01
    • ES 8.4 6.5 p = ns
    EP CEV CEV-cyclophosphamide/epirubicin/vincristine EP-etoposide/cisplatin
  • Platinum vs non-Platinum
    • 21 trials extensive stage SCLC
      • cisplatin vs no cisplatin
      • median survival 9.5 vs 7.1 months, p = 0.002
      • cisplatin based therapy independent predictor of survival p = 0.04
    • Chute et al, J Clin Oncol 1999
    • Meta-analysis 19 trials 4054 pts
      • cisplatin vs no cisplatin
      • Cisplatin - 4.4% survival benefit at 1 year
      • Pujol et al Br J Cancer 2000
    • Cochrane meta-analysis 2008
      • 29 trials, 5530 patients
      • No difference in 6, 12 or 24 month survival
      • No difference OR rate
      • Higher CR rate for platinum
      • Higher toxicity rates with platinum
      • Amarasena et al. Cochrane Library 2009
  • Carboplatin
    • A reasonable alternative to cisplatin in patients with poor prognostic factors
    • Less toxicity compared to cisplatin
    • Median survival with cispatin-etoposide is comparable to with carboplatin-etoposide in ES patients. Toxicity was significantly less for carboplatin arm. Study not powered for equivalence
    • Skarlos et al. Ann Oncol 1994
    • Cisplatin is the best radiosensitiser
    • Cisplatin plays a major role in the treatment of LS-SCLC
    • EP can be delivered at full dose with thoracic RT with an acceptable toxicity profile
    CTRT combinations
  • Pujol et al. J Clin Oncol, 1997. 15: 2082-9
    • 125 patients with ES
    • PCDE q28 6#
    • 1200/100/40/225
    • vs
    • PCDE q28 4# with GCSF
    • 1800/120/60/330
    • No significant difference
    • Cumulative doses equivalent in
    • each arm except cisplatin dose
    • increased by 80%
    Dose intensity PCDE-cisplatin/CPM/epirubicin/etoposide
  • ACE with primary prophylaxis Thatcher et al. J Clin Oncol, 2000. 18: 395-404 ACE with GCSF q14 (LS) ACE without GCSF q21 (LS) ACE with GCSF q14 (ES) ACE without GCSF q21 (ES) 1 yr survival - 47% G vs. 39% C 2 yr survival -13% G vs. 8% C
  • New Treatments… 47% Topotecan RR Phase II -2 nd line Single agent 52% Amrubicin 39% Pemetrexed 39% Irinotecan 26% Gemcitabine 34-41% Paclitaxel
  • Irinotecan Noda NEJM 2002 Hanna JCO 2006 MS 12.8 vs 9.4 months 1 yr S 58.4% vs 37.7% (p=0.002) MS 9.3 vs 10.2 months 1 yr S 35% vs 35.2% (p=0.074)
  • Meta-analysis Irinotecan /Platinum and Etoposide /Platinum in ES Jiang et al J Thor Oncol 2010 Irinotecan + Platinum not inferior to EP
    • p=0.044
    • p=0.163
  • Pemetrexed
    • Phase III (GALES trial)
    • 1822 patients (stopped early - 733 patients)
    • Extensive stage
    • Carbo- Etop vs Carbo-Pem
    • Median survival
    • 9.6 months CE vs 7.3 months CP
    Socinski, M. A. et al. J Clin Oncol 2009
  • Topotecan – 2nd line
    • Von Pawel et al JCO 1999
    • Ph III (ES) 2nd line CAV vs T
    • Less neutropenia but more thrombocytopenia with T
    • Less SOB/ fatigue /loss of appetite
    • O’Brien et al JCO 2006
    • 2 nd line oral T vs BSC
    • 6 months survival 49% vs 26%
    • Eckhart et al JCO 2007
    • 2 nd line T (o) vs T (iv)
    • Equivalent
  • Amrubicin
    • Two phase II second line studies have demontrated encouraging survival rates
    • A number of phase III studies are ongoing to evaluate this treatment in the first and second line setting
  • EORTC 08062 First Line
    • Extensive Stage
    • No prior chemotherapy regimen
    • ECOG performance status 0-2
    • Measurable disease
    • 99 Pts
    R A N D O M I S E O`Brien et al ASCO 2010 AMR AMR/Cis Cis/Etop OR 61% 77% 63% PFS mos 5.2 6.9 5.8 OS mos 11.7 11.1 10.0 ARM A Amrubicin 45 mg/m 2 d 1-3 ARM B Amrubicin 40 mg/m 2 d 1-3 + Cisplatin 60 mg/m 2 d 1 ARM C Cisplatin 75mg/m 2 ,d1 + Etoposide iv 100 mg/m 2 d1-3, iv 100 mg/m 2 d1 , po 200 mg/m 2 d2,3
  • Maintenance or Consolidation Therapy Rossi et al Lung Cancer 2010
    • N = 3688
    • All (n=21) HR 0.93 (0.87-1.00) p=0.05
    • CT (n=11) HR 0.89 (0.81 0.98) p=0.02
    • IFN α (n=4) HR 0.78 (0.64-0.96) p=0.02
    ‘ Clinical impact of maintenance chemotherapy needs to be confirmed by further studies’
  • TARGETED THERAPIES FOR SMALL CELL LUNG CANCER The Hallmarks of Cancer : Hanahan and Weinberg, Cell 2000 ANGIOGENESIS INHIBITORS INHIBITORS OF GROWTH AND PROLIFERATION APOPTOSIS PROMOTERS
  • Conclusions
    • High RR with chemotherapy
    • BUT high rates of local and distant relapses
    • Many newer combinations as good, but none convincingly better
    • PE is the standard treatment in SCLC
    • Disappointing results so far with targeted therapies
    • The way forward - a better understanding of the biology of the disease in order to develop more effective therapies
  • RADIOTHERAPY
  • Limited-stage SCLC
  • Progress in LS-SCLC? CT alone Sequential CTRT Concurrent CTRT BD conc CTRT Komaki et al-BD Komaki et al-OD 0 10 20 30 5 year survival (%) <10 10-15 20-25 25-30 25 (32) 12 (19)
  • Treatment options
    • Sequential CTRT
    • Pros: reduction in tumour volume, reduced toxicity
    • Cons: delayed RT -> repopulation ->poorer outcome
    • Concurrent CTRT
    • Pros: radiosensitisation, early RT, short overall TT, better outcome
    • Cons: for selected patients only, toxicity
    RT CT CT CT CT CT RT CT (CT)
  • Concurrent CTRT
    • Selection Crit eria
    • PS
    • Comorbidities
    • Tumour volume
    • Lung volume
    • Dose normal tissues
    • (age)
    • (lung function)
  • Sequential CTRT
  • Current evidence
    • Concurrent CTRT >sequential CTRT (Takada)
    • Early RT >late RT (Fried , Cochrane review)
    • Best survival results achieved with early BD concurrent CTRT (Turrisi, Jeremic)
    • RT doses up to 70 Gy can be safely delivered
    • concurrently with CT (CALGB 39808 and 30002)
  • Timing of thoracic RT with chemotherapy J Clin Oncol. 2004;22:4837-45 7 RCTs Advantage of early (<9 weeks) radiotherapy 2 yr % NNT for benefit P All (1524) Platinum Platinum+ HART +5.2 [0.6-9.7] 20 0.03 +9.8 [3.8-15.9] 10 0.001 +16.7 [9.4-26] 6 0.001
  • Standard of care in LS-SCLC
    • Early twice daily concurrent CTRT
    • Turrisi trial
    • PE remains the standard CT
      • Irinotecan trials
      • Pemetrexed trial
    • PCI
    • Establish a standard regimen in LS-SCLC
    • Toxicity and outcome data with
    • modern RT techniques
    • Importance of
      • the RT dose ?
      • the overall treatment time ?
    • Translational research
    Why CONVERT
  • Once daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 RT 66Gy/45D/33F Twice daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 RT 45Gy/19D/30F Limited Stage Small Cell Lung Cancer SD, PR,CR  PCI If<SD  No PCI Registration Randomisation Restage Chemotherapy Radiotherapy CONVERT STUDY PS 0-2 No age limit Manchester Lung Cancer Group
  • Targeted agents and RT Spigel et al. J Clin Oncol 2010 Phase II -29 LS-SCLC patients recruited Early trial closure Two patients developed tracheoesophageal fistulae One patient died from an aerodigestive hemorrhage
  • Prophylactic cranial irradiation
    • Why?
      • Major risk of spread to brain-50 to 60%
      • Eradicates micrometastatic disease
      • PCI can reduce the risk of spread by 50%
      • PCI improves survival (6% @ 3 years)
      • Auperin N Engl J Med 1999
    • When?
      • After concurrent CTRT
      • With consolidation thoracic RT if sequential CTRT is given
    • Toxicity
      • Acute
        • lethargy
        • raised ICP ->steroids
        • scalp reaction, hair growth will be delayed
      • No reports of increased long term neurological sequalae in RCTs compared to control
  • PCI 99-01 EORTC 22003-08004 - RTOG 0212
    Le Pechoux et al. Lancet Oncol 2009
    • Multicentre randomised phase III
    • standard dose 25 Gy/10  /12 days
    • high dose 36 Gy in 18  /24 days or 24#/16 days
    • 720 patients in CR were randomised (146 from RTOG institutions)
    • Immediate toxicity was equivalent in both arms
    0.05 1.20 (1.00-1.44) 37% (32%-42%) 42% (37%-48%) Survival
        • 0.18
    0.80 (0.57-1.11) 23% (18%-29%) 29% (24%-35%) Incidence BM
        • p
    HR 36Gy/18  25 Gy/10  2 years
  • Extensive stage SCLC
  • Prophylactic cranial irradiation in ES-SCLC (EORTC 08993-22993) PCI 20-30 Gy in 5-12 fractions No PCI Random Any response PS 0-2 Age  75 < 5 weeks 4-6 weeks No response Chemotherapy (4-6 cycles) Slotman et al. N Engl J Med 2007
  • Prophylactic cranial irradiation in ES-SCLC EORTC 08993-22993
  • Jeremic B. et al. J Clin Oncol 1999 100 50 57.5 115 Months p=0.041 Group 1-RT 2-no RT MST (months) 17 11 2yr 65 46 5yr 9.1 3.7 % Alive % Alive Thoracic RT for ES-SCLC?
  • Dutch-UK TRT EDSCLC Study Design PCI alone Random Any response PS 0-2 < 4 weeks 4-6 weeks No response Chemotherapy (4-6 cycles) PCI 20 Gy/5# or 30 Gy/10# TRT 30 Gy/10# +PCI
  • Conclusions
    • Major progress in both LS-SCLC and ES-SCLC in the last two decades with RT
    • Progress translating into improvements in both local control and survival
    • Future directions
      • New agents combined with RT
      • Thoracic RT in ES-SCLC?
      • Translational research