Radiotherapy in Localized and Locally Advanced Lung Cancer

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Radiotherapy in Localizedand Locally Advanced
Lung Cancer

• Marc Wygoda
• Radiotherapy Unit
• Hadassah University Hospital
• Oncology State of the Art ISCORT
• June 26th, 2009

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XRT in Non Small Cell Lung Cancer

1. PORT (Post Operative Radiation Therapy)
2. Radiotherapy in stage III
3. Radiotherapy in stage I-II

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PORT Meta-analysis
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PORT Meta-analysis Methodology

• Trials of PORT vs Observation only
• All Trials published and unpublished (Cochrane
  derived)
• 1965-1995
• Intent to Treat Analysis
• 9 Trials found
• 2128 patients

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PORT Meta-analysis Trials
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PORT Meta-analysis Results Survival
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PORT Meta-analysis Results
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PORT Meta-analysis Subgroups Results
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PORT Meta-analysis Conclusions

• 21 relative increase in the risk of death
• Equivalent to an overall reduction in survival
  from 55 to 48 at 2 years

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Why is the jury still out about PORT?

• Benefit could be limited to N2 patients
• Postoperative radiotherapy were more detrimental
  among patients with stage I disease than among
  those with stage II disease
• For stage III patients alone, there was no clear
  evidence of a detrimental effect of RT
• Optimal dose not determined
• New techniques might improved therapeutic ratio

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Benefit could be limited to N2 patients PORT
SEER Data on 7465 pts
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PORT SEER DataAll patients
No PORT
PORT
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PORT SEER DataNO and N1 patients
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PORT SEER DataN2 patients
PORT
No PORT
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Conclusions about PORT in SEER Data

• PORT is associated with a decrease in survival
  for N0 and N1 patients.
• PORT significantly improved survival for N2
  patients.
• The SEER data are retrospectively collected, and
  thus, the potential for error or bias may exist.

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2) Optimal dose of RT and New techniques might
improved therapeutic ratio

• Techniques used in Meta-analysis trials
• Majority of pts treated on Cobalt machines
• Some patients were treated with just one daily
  field (alternate AP and PA) ? suboptimal dose
  distributions, which may potentially increase
  toxicity
• More than 30 were participants in one trial
  (French GETCB) allowing physicians to treat to 60
  Gy in 2.5 Gy fx.
• Are modern RT techniques going to overcome the
  toxicity induced by older ones??

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U Penn PORT Analysis

• 202 patients
• Pathologic stage II or III disease (97)
• Median dose 55 Gy in 1.8 to 2 Gy fx.
• Techniques
• Linac
• Target volume
• mediastinum, ipsilateral hilum, bronchial stump,
  ( supraclavicular fossa)
• No contralateral hilum
• Resimulation for off-Cord Cone down after 40-46
  Gy

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U Penn PORT Analysis

• Results
• 4yr rate of Death from Intercurrent Disease
• 13.5 after Radiotherapy
• 10 in matched general population ns
• 4yr rate of DID by RT dose
• 0 for XRT 54 Gy
• 17 for XRT gt 54 Gy p 0.06

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U Penn PORT Analysis
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• Clinical data can be explained by a simple model
  that suggests that RT-induced mortality is
  strongly dependent on field size and at least
  partly offsets the benefit afforded by PORT.
• Smaller RT fields, tailored to treat the areas
  most at risk for recurrence, provide the highest
  therapeutic ratio.

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Treatment Fields

• The post-operative fields of today include the
  bronchial stump and one or two levels of the
  involved nodes
• Patients tolerate this treatment extremely well
  without long-term toxicity

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PORT in the era of effective Adjuvant Chemo
ANITA 5-Year Survival According to Nodal Status
and Treatment
N2 N1 N0 Nodal Status
Treatment
16.6 31.4 62.3 Observation
34.0 56.3 59.7 Chemo
21.3 42.6 43.8 PORT
47.4 40.0 44.4 CT PORT
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Conclusions on PORT

• Patients who underwent a complete resection of
  the primary tumor with mediastinal lymph node
  dissection showing no mediastinal involvement
  (pN0 and pN1) should not have PORT
• N2 patients might benefit from PORT based on
  meta-analysis subset analysis, and on
  retrospective data
• N1 patients with inadequately dissected/sampled
  mediastinum should also be considered for PORT
• A new large European phase III, Lung Adjuvant
  Radiotherapy Trial (Lung ART), will compare 3D
  conformal PORT to no PORT, and will include
  patients who have proven N2 disease and a
  complete resection

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Hadassah Policy and algorithm

• Indications for PORT
• R1 dissection (positive stump margins)
• pN2 patients (NCCN approved)
• pN1 with no mediastinal dissection or inadequate
  sampling
• 3D planned as small as possible fields, based
  on tumors location and knowledge of LN stations
• Dose 54 Gy
• Optimal sequencing with chemo is unestablished
• Chemo ? PORT
• Concomitant ChemoRadiotherapy??

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Radiotherapy in stage III NSCLC

1. Combined Modality Treatment
2. Radiotherapy Volume and Dose issues
3. Trimodality Therapy CMT Surgery
4. Radiotherapy and Targeted Therapies

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Combined Modality Treatment Sequential Therapy

• In the early 1990s RT alone was standard of care
  with OS rates of 5-10
• Initial development of Chemotherapy in Stage III
  NSCLC was sequential
• Two studies CALGB and SWOG showed a significant
  benefit to SEQ CT-RT over RT alone

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Concurrent CT-RT

• Six randomized trials have now shown a conclusive
  advantage of CON-CT/RT over SEQ CT/RT
• RTOG 9410
• GLOT
• WJLCG
• CZECH

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Chemotherapy proven Regimens all Platinum based
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LAMP Phase II randomized trial

• Induction (Carbo/Taxol) followed by Concomitant
  (CT/RT)
• versus
• Concomitant (RT/CT) followed by Consolidation

Belani et al JCO 05
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CALGB 39801 Phase III TrialConcomitant vs
Induction?Concomitant
Vokes et al. JCO 07
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CALGB 39801 Phase III TrialConcomitant vs
Induction?Concomitant

• Median OS 12 (IND) vs 14 months (CON)
• Neither arm performed well
• But results are not different from LAMP results
  minus consolidation chemotherapy

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SWOG 9504

• Phase II trial
• Stage IIIB patients
• Cis/VP-16 (50/50)
• RT to 61 Gy
• Consolidation with Docetaxel

Median OS-26 months 3-yr 38 5-yr 29
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Patterns of Failure

• In CALGB Study (n366)
• Local Failure 35
• Distant Failure 46
• SWOG 9504 (n97)
• Local Failure 21
• Distant Failure 29
• The use of immediate and initial full dose CRT
  produces improvement both local and distant
  control

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SLCG 0008 (Pilar et al. ) Spanish Trial

• GEM/Taxotere ? CT/RT (carbo/taxotere)
• vs CT/RT ? GEM/Tax
• No difference in OS 14.3 vs. 14.7 months
• 10 grade 3 pneumonitis for induction GEM

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Korean Phase III Trial (n134)

• GEM/Cis x2
• vs Cis/Taxol/RT alone
• Overall Survival ---
• Induction 12 months 2yr 25
• Concurrent- 18.2 months-43 (p0.04)
• WLCC Seoul 07

CT/RT(Cis/Taxol) 66 Gy
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Summary

• Results Favor CON or Consolidation
• This despite some of these trials delivering less
  therapy

You shall remember! The more is not necessarily
the better.
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Sequencing Summary

1. No evidence to support Induction chemotherapy
   before Concurrent CT/RT probably worse
2. Best results appear to be with Cisplatin/VP-16
   without consolidation
3. This is also reflected in the current NCCN
   guidelines which encourage concurrent CT/RT with
   either Cis/VP-16 or Carbo-Taxol

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Dose Escalation

• RTOG 7301 Dose Escalation Study
• Local Failure
• 40 Gy split course, 49
• 40 Gy 4 weeks, 44
• 50 Gy 39
• 60 Gy 33
• This established 60 Gy as standard RTOG regimen

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Theoretical Evidence for Escalation

• Martel et al. ( Lung Cancer 99) calculated TCP-
  tumor control probability for NSCLC
• Based on retrospective data from Michigan in 76
  patients treated with RT alone from 60-84 Gy.
• Primary goal was to attempt to correlate LC with
  dose

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Evidence for Dose Escalation

• Rengen et al MSKCC reported dose escalation study
  with Con CT
• Divided patients with stage III NSCLC into two
  group based on median radiation dose of 64 Gy

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High Dose CT/RT

• Two Cooperative group phase I/II trials have
  evaluated dose escalated radiotherapy with
  concurrent chemotherapy
• CALGB- Two arm trial

Carbo/taxol
RT to 74 Gy
Gem (35) Q/wk
Gem arm closed due to toxicity but Carbo/taxol
arm was completed Median OS 24 months
Blackstock ASCO 06
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RTOG 0117

• Phase I/II trial of Dose escalated RT in Stage
  III A and IIIB patients
• Carbo(AUC 2)/Taxol (50) with RT concurrent
• 30 Patients have completed with acceptable
  toxicity and median OS of 21 months

Bradley ASCO 06
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Proof for Dose Escalation
Multiple of High dose SBRT to the lung for T1 and
T2 disease have shown excellent LC and OS with
doses of 20 Gy x3 or 12 Gy x5
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RTOG 0617/NCCTG N0628/CALGB 30609/ECOGStage III
NSCLC
Chemo XRT (60Gy)
Chemotherapy
Randomization
Chemotherapy
Chemo XRT (74Gy)
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Dose Escalation Summary

• Multiple Groups have reached 74 Gy of RT with
  concurrent platinum based therapy
• Gemcitabine is not recommended for treatment with
  RT
• Phase III trial is needed

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Definition of the target volume

• Conventional XRT
• 3 DCRT
• IGRT

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Traditional 2D design of treatment portals
depending on location

• Historically, treatment portals are designed
  with a 2-cm margin around any GROSS TUMOR seen in
  PA radiographies and approximately a 1-cm
  around electively treated regional LN areas.

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Today

• No elective nodal Radiotherapy (gtToxicity)
• PET based volumes

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• There are no current recommendations supporting
  the treatment of uninvolved LNs.
• Existing guidelines are against the routine use
  of ENI in RT of NSCLC
• European Organization for Research and Treatment
  of Cancer
• National Institute for Clinical ExcellenceUK
• Scottish Intercollegiate Guidelines Network.
• The newly activated RTOG and EORTC trials are not
  recommending ENI.
• Use PET to define involved nodes but plan GTV
  based on CT images (usually larger)

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3DCRT delineation of GTV and OARs
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Thanks for your attention