Principles of Radiation Oncology in (advanced stage) NSCLC

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Principles of Radiation Oncologyin (advanced
stage) NSCLC

• Stephan Bodis
• Kantonsspital Aarau

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The Tools for the Radiation Oncologist

• Sophisticated treatment machines
• (dual energies, multileaf-collimator, 3 paired
  laser beams for patient set-up, integrated CT,
  IMRT, stereotactic treatment)
• Tumor volume definition CT-MRI-PET fusion
  imaging, dedicated planing CT (lasersystem, large
  diameter)
• Treatment planing Standardized dose prescription
  to tumor (maximal) and to normal tissue
  (minimal), dose-volume histogram for tumor and
  each organ at risk
• Treatment delivery fix RT-field, moving RT-field
  (infield movement IMRT), image guidance,
  respiration correction
• Fractionated (daily) radiotherapy to a defined
  total dose

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Integration of Molecular Biology

• Biology, Physics and Clinical Oncology
• are the 3 pillars of Radiation Oncology
• Defined biologic model systems available
• gt 20 years experience in classic radiobiology
• Molecular key targets for radiosensitization
  (search) for novel RT-sensitizers
• Stem cell research, human genome project,
  microarray technology Implications for clinical
  radiation oncology

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Life inside a LINAC Prototype
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Ionizing Radiation The physical tools

• Photons - High energy X-rays (MV for LINAC)
• - Skin sparing effect
• - Dose decrease 2-5 /cm tissue
• Electrons - Charged light particles
• - No skin sparing effect, limited depth
• - Steep dose decrease after a few cms
• Protons - Charged heavy particles
• - unique dose distribution (matterhorn
  like Bragg Peak)

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Imaging for RT Planing (incl. CT-MRI/PET) Stage
shift up to 30
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Preclinical research Metabolic image guided RT
(mIGRT) with repeated FDG-PET during RT?
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Intensity modulated RT (IMRT)Voxel by voxel RT
for complex volumes (high/low dose)
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IMRT Maximal dose in the tumor (red),minimal
dose in the adjacent normal tissue (blue)
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Therapeutic Index of RT Reason for fractionated
radiotherapy (daily low dose)
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There is nothing magic about fractionation

• Small fractions (daily dose) high total dose
• Large fractions (daily dose) low total dose
• Equivalent effect 5 x 8 Gy 30 x 2 Gy
• (Various math. models for effective dose (NSD,
  E/alpha)
• E.g. Large, radioresistant tumors with
  radiosensitive adjacent normal tissue need a
  small daily dose and high total dose

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Radiotherapy in NSCLC
75 of lung cancer patients need
radiotherapy Primary radical radiotherapy (Stage
I IIIB) Adjuvant, radical radiotherapy (Stage
IIB IIIA) Radical radiotherapy in local
recurrence (Stage I III) Palliative
radiotherapy (Any stage)
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NSCLC Stage I/IIThe role of radical radiotherapy

• - Radical surgery Gold-standard
• Radical RT 10-30 less effective (historic)
• - Is state of the art radical RT more effective
  ?
• (e.g. CT-PET, stereotactic RT, IMRT, image guided
  RT, breath-triggered RT)
• Assumption better therapeutic index with smaller
  RT- volume, higher total dose, higher daily dose)

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NSCLC Stage I/IIThe role of adjuvant
radiotherapy

• R0-resection No proven benefit of adjuvant
  radiotherapy
• R1/R2-resection and no 2nd surgery Postoperative
  RT indicated (meta-analysis)
• Small volume radiotherapy (involved field)
• Dose 50 to gt 60 Gy (if 2 Gy/day and 5x/week)

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NSCLC Stage IIIAThe role of radiation oncology

• Multimodality therapy (patients should be
  enrolled in international clinical trials)
• Heterogeneous patient population often lack of
  subststaging (IIIA1/2 IIIA3 IIIA4 and biology)
• Optimal RT is still controversial IIIA1/2 adj.
  CT (RT), IIIA3 (?), IIIA4 (CT-RT?)
• Historical toxicity of RT has to be re-considered
  with current state of the art RT

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NSCLC Stage IIIAThe role of radiation oncology

• Phase III trials RT Surgery OR Surgery RT
  vs. Surgery same or worse OS, more toxicity
  (NCI LCSG-Weisenberger 1985,
  Dautzenberg 1999)
• Benefit for preop. RT for Pancoast Tumors
  (Paulson 1995)
• Postop. phase III trials (EORTC, Villejuif)
• S w/wo CT RT vs. S w/wo CT lower OS with
  older trials using RT, same OS with recent
  trials more toxity - reason for lower OS in
  metanalyis better LC with most recent studies)

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NSCLC Stage IIIBThe role of radiation oncology

• Multimodality therapy (patients should be
  enrolled in international clinical trials)
• Optimal combination and sequence is
  controversial Too many small studies
• Survival benefit of additional chemotherapy
  modest max 5 in 2 meta-analysis (2y, 5y OS)
  (BMJ 1995 Auperin, Annals Onc. 2006)
  

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NSCLC Stage IIIBThe role of radiation oncology

• Phase III trials CT-RT vs. RT (data from 5 rand.
  trials)
• CT-RT (2y OS of 14-26) vs. RT (2 y OS 6 to
  17)
• (e.g. leChevalier, Dillmann)
• Phase III trials conc. CT-RT vs. sequential
  CT-RT
• (3 rand. trials) concurrent CT better (modest
  gain in OS)
• (e.g. Furuse, Curran)
• median survial 17 months vs. 14 months, higher
  toxicity
• (grade ¾ acute non-hem 40 vs. 0!)
• Metaanalysis a) conc. CT-RT vs. RT OS at 2y.
  (25 / 21) b) conc. vs. seq. CT-RT cc
  CT-RT better OS, more toxic deaths
• (Auperin, Ann. Onc. 2006 Rowell Cochrane
  Library 2005

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NSCLC advance stagepalliative/elective local
therapy

• Published RT-concepts 10x3 or 5x4 Gy (3-4x/week)
• Immediate vs. deferred local RT in low symptom
  patients no difference (Falk, BMJ 2002)
• Elective whole brain RT for stage III NSCLC in CR
  (PR/metabolic CR sufficient?)

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Pre-clinical research Potential molecular
targets for RT-sensitizers in lung cancer
Radiobiology 2008
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