MCO 2011 - Slide 26 - C. Faivre-Finn - Radiotherapy

  • 916 views
Uploaded on

 

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
No Downloads

Views

Total Views
916
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
1
Comments
0
Likes
2

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide
  • Allow for
  • Precise delivery Accurate positioning Cone beam verification
  • TABLE WITH SURVIVAL-SEE PAPER ON PATTERNS OF RECURRENCE Despite patient selection Low rates of acute toxicity Low rates of pneumonitis Main side effects Fatigue Chest pain Rib fracture Lack of long term data-late toxicity?
  • In the interest of time I could not detail all trial that have established the role of CT and RT in locally advanced NSCLC The findings from these trials are summarised on this slide NSCLCCG BMJ 1995-The meta-analysis did not provide an answer to the question of the optimal radiotherapy or chemotherapy regimen. HR 0.87-reduction in risk of death of 13% Auperin metaA conc vs seq Toxicity Increased risk of grades 3 et 4 œsophagitis with conc CTRT HR = 4.9 (CI 95 %: 3.1-7.8 ; p < 0.0001) No increase in risk of acute pneumonitis HR = 0,69 (CI 95 % : 0.42-1.12; p = 0.13) Long term toxicity?
  • R Storrie
  • (A) Survival curves and (B) progression-free survival curves. The numbers of person-years and of deaths observed each year during the first 4 years and after are given. RT, radiation therapy; HR, hazard ratio; conc, concurrent; CT, chemotherapy; seq, sequential.
  • Show CT William Parkinson
  • Poumon atelectatique Volume large (>15 cm cranio-caudale)
  • Conc>seq but not for all patients Short overall treatment time- reduces risk of repopulation and better for patient convenience
  • Terminated early on the basis of futility after an interim analysis febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel ( v 8.1% in observation arm), and 5.5% died as a result of docetaxel.
  • In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.
  • Ongoing Dutch trial
  • below the age of 75 (patients above 75 have not been included in clinical trials), Currently, there is no consensus on the optimal chemotherapy regimen when combined with radiotherapy. There is clinical trial data to support  the combination of cisplatin based chemotherapy. A number of regimens have been reported showing acceptable outcome and toxicity profiles. (EL: Refs 264-267 268-271) The choice of chemotherapy regimen with concurrent thoracic radiotherapy should be considered based on individual patient characteristics, toxicity profile and local experience
  • CTRT alone 23 months survival Hoosier study 26 months Kuira study
  • Addition of targeted agents With RT or CTRT? Consolidation treatment? Dissapointing in Swog
  • Update Cochrane Review 2005 (10 studies) adding the Trodella study in stage I NSCLC 2-year Survival: 58% 2-year Survival: 52% ‘ Thoracic RT is deleterious for pN0 and pN1 pts due to an excess of treatment-related toxicity in the PORT group’ ‘ Role of PORT in N2 tumours less clear and may warrant further research with newer techniques’
  • Stratification factors : Center, Administration of CT (no CT vs Post-op CT vs pre-op CT alone), Histology (SCC vs other), Extent of lymph node involvement (0 vs 1 vs2+), Histology (SCC vs others), use of pre- treatment PET-scan (yes/no)

Transcript

  • 1. NSCLC R adiotherapy 10 th ESO ESMO masterclass 6 th April 2011 Dr Corinne Faivre-Finn Manchester Radiotherapy Related Research Group Manchester Cancer Research Centre The Christie, Manchester, UK
  • 2. Introduction
    • Non-small cell cancer represents 80-85% of lung cancers
    • 20% of patients present with stage I-II
    • 30% of patients present with stage III
    • 50% of patients present with stage IV
    • New TNM classification UICC version 7
    • We are faced with 2 major issues
      • Local failure
      • Distant metastasis
  • 3. Role of Radiotherapy
    • Curative RT
      • Alone
      • Concurrent CTRT
      • Sequential CTRT
      • Adjuvant (N2/positive resection margins)
    • Palliative RT
      • Thorax
      • Bone
      • Brain
      • Nodes
      • Skin metastasis
    • Prophylaxis
      • Brain
  • 4. SBRT
    • For early stage disease, surgical resection is the optimal curative treatment, but <50% of patients are medically fit for this
    • With standard RT treatments local control and survival are inferior to surgery (<50%)
    • Five year survival<30%
    • SBRT is an exciting new technique
      • High dose RT
      • Hypofractionation (3-8)
      • allowing precise RT delivery to the tumour
      • while sparing nearby healthy organs
    • SBRT offers local tumour control (>90%) comparable with surgery
  • 5. Evidence based treatment?
    • First publication in 1994
    • > 100 papers published on lung SBRT
    • Large numbers of patients treated
    • Phase I and II data
    • Most evidence from single institution studies
    • Standard of Care in highly specialised centres in Asia, Europe and North America for peripheral inoperable stage I NSCLC
    • No evidence to support SBRT inmedically operable patients
  • 6. 66%@3 yrs 55.8%@3 yrs 64.8%@ 5 yrs if medically operable 35% if medically inoperable 55% @3yrs [email_address] 83%@3yrs stage Ia 72%@3yrs stage Ib [email_address] [email_address] [email_address] Survival Pneumonitis: 0%* Rib fractures:4%º 94%@3 yrs 36 Various 50-60 Gy in 5-10 fractions 50 (29 operable) Umetsu 3.6% G3+ pneumonitis 90.6% @ 3 years (locoregional control 87.2%) 34.4 151 Gy 3 x 18 Gy 59 Timmerman Pneumonitis G2+: 5.4%* 84.2% if BED ≥ 100 Gy @ 5 years vs 36.5% BED<100 Gy 38 Median 111Gy 18-75 Gy in 1-22 fractions 257 ( 99 operable) Onishi Pneumonitis: 0%* Rib fractures: 4%º 80% @3yrs 43 113 Gy 3 x 15 Gy 45 Nyman Pneumonitis: 0%* 98% @ 2 years 30 106 Gy 4 x 12 Gy 45 (18 operable) Nagata Pneumonitis: 3%* Rib fractures: 2%º 93% @ 2 years (locoregional control 83%) 12 180 Gy 132 Gy 105Gy 3 x 20 Gy 5 x 12 Gy 8 x7.5 Gy 206 Lagerwaard Atelectasis: 2%* Pneumonitis: 1%* Rib fractures: 4%º 85% @ 3 years 33 60-120 30-48 Gy in 2-4 fractions 138 Baumann Toxicity Local control Median fu (months) BED (Gy) RT Dose fractionation No. of patients Study
  • 7. Locally advanced NSCLC
  • 8. Stage III NSCLC
    • 25-30% of NSCLC pts have stage III disease
    • Very few locally advanced NSCLC patients are candidates for surgery
    • Survival is poor
      • stage IIIa 10-20%
      • stage IIIb 5-10%
    • Scope for improving local and distant control
    CTRT combinations
  • 9. Two decades of trials evaluating CTRT
    • CTRT>CT ( NSCLCCG )
      • HR 0.87 (p = 0.005)
      • Optimal CT or RT regimen not defined
    • CTRT>RT (L e Chevalier el al )
      • Sequential CTRT>RT HR 0.88 (p<0.01)
      • Concurrent CTRT>RT HR 0.87 (p<0.001)
    • Concurrent>Sequential CTRT ( Auperin et al, Cochrane review )
      • HR 0.83 (p=0.04); 5 yr survival gain 4.5%
      • oesophagitis HR = 4.9 (p < 0.0001)
    • Drugs
      • Feasibility of combining 3 rd generation drugs at reduced doses plus cisplatin with thoracic RT ( Vokes at al )
      • PE can be combined at full dose with RT (SWOG trials, Hoosier trial)
  • 10. Modern RT techniques
            • Definition of target volume
      • Nb beams, angles, energy, wedges
      • multi-leaf collimator
    Impact on LC and survival?
  • 11.
    • Dose 60-66 Gy in 30-33 fractions OD
    • No benefit for HF RT (RTOG 9410)
    • CHART study TD>OD RT
    • Dose escalation studies investigating doses > 60/66 Gy have not established an optimal RT dose, achieving a balance between local control and side effects
    • Dose limited by normal tissues
      • Lung - V20, MLD
      • Spinal cord
      • (Oesophagus)
      • (Heart)
    What RT? V20
  • 12. IMRT
    • Reduces high dose to lung tissue (V20, MLD, spinal cord, oesophagus) 1
    • But Increases low dose irradiation of the lung tissue
    • Indications
      • the tumours with complex shapes (eg-peripheral tumours associated with central lymph nodes)
      • tumours in close proximity to critical organs including spinal cord, oesophagus, heart
    • Can shift patients from the palliative to the radical setting 2
    1 Liao et al. Int. J. Radiation Oncology Biol. Phys; 2010 2 Shrimali et al. Lung Cancer 2011
  • 13. IMRT technique V-20= 35% 3-D Conformal technique V-20= 57% IMRT case: Female, 67 yrs, T2 N3 M0
  • 14. RCTs evaluating concurrent vs. sequential CTRT Bayman et al. Clin Lung Cancer 2008
  • 15. (A) Survival curves (B) progression-free survival curves Aupérin et al. J Clin Oncol 2010 ©2010 by American Society of Clinical Oncology Meta-analysis Concurrent vs. sequential CTRT
    • 6 RCTs
    • 1,205 patients
    • absolute benefit 4.5% at 5 years
    • improved local control
    • increased acute esophageal toxicity
  • 16. Selection of patients for concurrent CTRT
    • Selection Crit eria
    • PS
    • Comorbidities
    • Suitable for cisplatin
    • Tumour volume
    • Lung volume
    • Dose normal tissues
    • (age)
    • (lung function)
  • 17. Selection of patients for sequential CTRT
  • 18.
    • Sequential
      • Pros
      • Downsize tumour
      • Systemic doses
      • Less toxicity
      • Cons
      • Delayed definitive treatment
      • Accelerated repopulation
      • Survival
    • Concurrent
      • Pros
      • Short overall treatment time
      • Radiosensitisation effect of CT
      • Survival
      • Cons
      • Acute toxicity
      • Patient selection
      • Reduced doses of CT
    Sequential or Concurrent CTRT?
  • 19. Induction CT CALGB 39801 Vokes et al. J Clin Oncol 2007 ns 36% 32% Oesophagitis (grade 3-4) ns 10% 4% Pneumonitis (grade 3-4) 0.3 14 months 12 months Median survival 31% 29% 2 year survival 170 161 N p CT  CTRT CTRT
  • 20. Consolidation CT HOG 01-24 Docetaxel 75 mg/m²/3 w x 3 cycles Stage IIIAN2/IIIB 203 pts Cisplatin 50mg/m² D1,8,29,36 Etoposide 50mg/m² D1-5 and D29-33 RT 59.4 Gy/6w Observation Hanna et al. J Clin Oncol 2008 R < 0.001 8.1% 28.8% Hospitalisations 23.2 21.2 Median survival (months) 0.88 0.058 < 0.001 0.003 p 26.1% 27.1% 3 yr survival 1.4% 9.6% Radiation pneumonitis 0% 5.5% Deaths attributed to RT 0% 11% Infections Observation n=74 Docetaxel n=73 After randomisation
  • 21. Kelly et al. JCO 2008; 26: 2450-56 Consolidation CT SWOG 0023 1% of patients died as a consequence of pneumonitis R Docetaxel 75mg/m 2 / 3 w (3 cycles) Cisplatin 50mg/m 2 D1, 8, 29, 36 Etoposide 50 mg/m 2 D1-5, D29-33 RT 61 Gy Gefitinib 500 mg/d  250 mg/d Placebo 59% 46% 2 yr survival 0 2 (2%) Toxic deaths after randomisation 42 (78%) 61 (86%) Cancer deaths 54 71 Deaths 35 months 23 months Median survival Placebo n = 125 Gefitinib n = 118
  • 22. RTOG 0214 PCI in stage III NSCLC PCI 30 Gy 2 Gy/fraction NSCLC Stage IIIA/IIIB No PD after radical treatment Observation Target-1058 patients 356 patients included 340 patients evaluable Gore et al. J Clin Oncol 2009 Abstract 7506 p = 0.86 24.8 25.8 Median (months) PCI Control 1 year survival 75.6% 76.9% Brain mets 7.7% 18% p = 0.004 R
  • 23. Combined CTRT Summary
    • Concurrent CTRT is the standard of care in selected patients
    • The literature supports the use of concurrent CTRT in patients
      • below the age of 70/75
      • PS 0-1
      • with reasonable lung function
      • without major co-morbidities
      • and for whom the RT plan produces acceptable normal tissue doses
    • No consensus on the optimal CT regimen
      • PE is the CT regimen which has been the most extensively explored and reported in the literature (RTOG, Fournel, SWOG, Hoosier)
      • cisplatin-based chemotherapy combination (full dose?)
      • Pemetrexed under evaluation
      • At present, there is no evidence to support the addition of induction and consolidation CT to concurrent CTRT
  • 24. Have we made progress in inoperable stage III NSCLC? CAUTION! Will Rodger phenomenon Median survival (months) 2 yrs survival RT 10 15% CT -> RT 14 30% CTRT 17 (24-26) 35% (Up to 60%) CT -> CT/RT 14-19 40% CT/RT -> CT 20-35 60%
  • 25. The future?
    • Better CT regimen
    • Addition of targeted agents in selected population
      • In combination with RT alone or CTRT?
      • Consolidation treatment?
    • Optimisation of RT techniques
      • dose escalation, isotoxic RT
      • 4D CT, IMRT, PET-CT
    • Translational research
      • Better selection of patients
  • 26. Evidence for/against post-operative RT?
    • P ost- O perative R adio T herapy systematic review
    • 2128 pts (808 stage III) in 9 RCTs
    • 2 year survival
      • Surgery alone (1072 pts) 55% (58%)
      • Surgery + PORT (1056 pts) 48% (52%)
    • 21% relative increase in the risk of death at 2 years
    • (mortality HR= 1.21; 95% CI 1.08-1.34; p = 0.001)
    • 24% relative reduction of local recurrence
    Lancet 1998; 352 (9124): 257-63 (Lung Cancer 2005; 47(1): 81-3) . N Hazard Ratio RT better RT worse 0.0 0.5 1.0 1.5 2.0 0 1 2 Stage 1 2 3 Test for trend  2 (1) =13.194, p=0.0003 Test for trend  2 (1) =5.780, p=0.016
  • 27. LUNG ART phase III Trial IFCT 0503 R No RT Conformal PORT (54 Gy)
    • Population Completely resected NSCLC with mediastinal histogically or cytologically proven N2
    • Nodal stations to be explored: lymph node sampling or complete dissection
    • -Right lung: 4,7,10
      • - Left Lung: 4 (if accessible),5, 6,7,10
    • Primary end-point : DFS (secondary-LC, OS)
    • Statistics 700 pts needed to show a 10% difference in DFS (from 30% to 40%)
    adjuvant CT Pre-op and/or Post-op CT
  • 28. Thank you!