Principles of Radiation Oncology in (advanced stage) NSCLC

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Principles of Radiation Oncology in (advanced stage) NSCLC

  1. 1. Principles of Radiation OncologyPrinciples of Radiation Oncology in (advanced stage) NSCLCin (advanced stage) NSCLC Stephan BodisStephan Bodis Kantonsspital AarauKantonsspital Aarau
  2. 2. The Tools for the Radiation OncologistThe Tools for the Radiation Oncologist  Sophisticated treatment machinesSophisticated treatment machines (dual energies, multileaf-collimator, 3 paired laser beams for(dual energies, multileaf-collimator, 3 paired laser beams for patient set-up, integrated CT, IMRT, stereotactic treatment)patient set-up, integrated CT, IMRT, stereotactic treatment)  Tumor volume definitionTumor volume definition: CT-MRI-PET fusion imaging,: CT-MRI-PET fusion imaging, dedicated planing CT (lasersystem, large diameter)dedicated planing CT (lasersystem, large diameter)  Treatment planingTreatment planing: Standardized dose prescription to: Standardized dose prescription to tumor (maximal) and to normal tissue (minimal), dose-tumor (maximal) and to normal tissue (minimal), dose- volume histogram for tumor and each organ at riskvolume histogram for tumor and each organ at risk  Treatment deliveryTreatment delivery: fix RT-field, moving RT-field (infield: fix RT-field, moving RT-field (infield movement = IMRT), image guidance, respiration correctionmovement = IMRT), image guidance, respiration correction  Fractionated (daily) radiotherapyFractionated (daily) radiotherapy to a defined total doseto a defined total dose
  3. 3. Integration of Molecular BiologyIntegration of Molecular Biology  Biology, Physics and Clinical OncologyBiology, Physics and Clinical Oncology are the 3 pillars of Radiation Oncologyare the 3 pillars of Radiation Oncology  Defined biologic model systems availableDefined biologic model systems available:: > 20 years experience in classic radiobiology> 20 years experience in classic radiobiology  Molecular key targets for radiosensitizationMolecular key targets for radiosensitization:: (search) for novel RT-sensitizers(search) for novel RT-sensitizers  Stem cell research, human genome project,Stem cell research, human genome project, microarray technologymicroarray technology: Implications for clinical: Implications for clinical radiation oncologyradiation oncology
  4. 4. Life inside a LINAC PrototypeLife inside a LINAC Prototype
  5. 5. Ionizing Radiation: The physical toolsIonizing Radiation: The physical tools Photons:Photons: - High energy X-rays (MV for LINAC)- High energy X-rays (MV for LINAC) - Skin sparing effect- Skin sparing effect - Dose decrease 2-5% /cm tissue- Dose decrease 2-5% /cm tissue Electrons:Electrons: - Charged light particles- Charged light particles - No skin sparing effect, limited depth- No skin sparing effect, limited depth - Steep dose decrease after a few cm‘s- Steep dose decrease after a few cm‘s Protons:Protons: - Charged heavy particles- Charged heavy particles - unique dose distribution (matterhorn- unique dose distribution (matterhorn like – Bragg Peak)like – Bragg Peak)
  6. 6. Imaging for RT Planing (incl. CT-MRI/PET)Imaging for RT Planing (incl. CT-MRI/PET) Stage shift up to 30%Stage shift up to 30%
  7. 7. Preclinical research: Metabolic image guided RTPreclinical research: Metabolic image guided RT (mIGRT) with repeated FDG-PET during RT?(mIGRT) with repeated FDG-PET during RT?
  8. 8. Intensity modulated RT (IMRT)Intensity modulated RT (IMRT) Voxel by voxel RT for complex volumes (high/low dose)Voxel by voxel RT for complex volumes (high/low dose)
  9. 9. IMRT: Maximal dose in the tumor (red),IMRT: Maximal dose in the tumor (red), minimal dose in the adjacent normal tissue (blue)minimal dose in the adjacent normal tissue (blue)
  10. 10. Therapeutic Index of RT: Reason forTherapeutic Index of RT: Reason for fractionated radiotherapy (daily low dose)fractionated radiotherapy (daily low dose)
  11. 11. There is nothing magic about fractionationThere is nothing magic about fractionation Small fractions (daily dose) = high total doseSmall fractions (daily dose) = high total dose Large fractions (daily dose) = low total doseLarge fractions (daily dose) = low total dose Equivalent effect:Equivalent effect: 5 x 8 Gy = 30 x 2 Gy5 x 8 Gy = 30 x 2 Gy (Various math. models for „effective dose“ (NSD, E/alpha)(Various math. models for „effective dose“ (NSD, E/alpha) E.g.: Large, radioresistant tumors withE.g.: Large, radioresistant tumors with radiosensitive adjacent normal tissue need aradiosensitive adjacent normal tissue need a small daily dose and high total dosesmall daily dose and high total dose
  12. 12. Radiotherapy in NSCLCRadiotherapy 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)
  13. 13. NSCLC Stage I/IINSCLC Stage I/II The role of radical radiotherapyThe role of radical radiotherapy -- Radical surgery: Gold-standardRadical surgery: Gold-standard Radical RT: 10-30% less effective (historic)Radical RT: 10-30% less effective (historic) - Is „state of the art“ radical RT more effective ?- Is „state of the art“ radical RT more effective ? (e.g. CT-PET, stereotactic RT, IMRT, image guided RT, breath-(e.g. CT-PET, stereotactic RT, IMRT, image guided RT, breath- triggered RT)triggered RT) Assumption: better therapeutic index with smaller RT-Assumption: better therapeutic index with smaller RT- volume, higher total dose, higher daily dose)volume, higher total dose, higher daily dose)
  14. 14. NSCLC Stage I/IINSCLC Stage I/II The role of adjuvant radiotherapyThe role of adjuvant radiotherapy  R0-resection: No proven benefit of adjuvantR0-resection: No proven benefit of adjuvant radiotherapyradiotherapy  R1/R2-resection and no 2nd surgery: PostoperativeR1/R2-resection and no 2nd surgery: Postoperative RT indicated (meta-analysis)RT indicated (meta-analysis)  Small volume radiotherapy (involved field)Small volume radiotherapy (involved field)  Dose 50 to > 60 Gy (if 2 Gy/day and 5x/weekDose 50 to > 60 Gy (if 2 Gy/day and 5x/week))
  15. 15. NSCLC Stage IIIANSCLC Stage IIIA The role of radiation oncologyThe role of radiation oncology  Multimodality therapy (patients should beMultimodality therapy (patients should be enrolled in international clinical trials)enrolled in international clinical trials)  Heterogeneous patient population: often lack ofHeterogeneous patient population: often lack of subststaging (IIIA1/2; IIIA3; IIIA4 and biology)subststaging (IIIA1/2; IIIA3; IIIA4 and biology)  Optimal RT is still controversial: IIIA1/2 adj.Optimal RT is still controversial: IIIA1/2 adj. CT+ (RT), IIIA3 (?), IIIA4 (CT-RT?)CT+ (RT), IIIA3 (?), IIIA4 (CT-RT?)  Historical toxicity of RT has to be re-consideredHistorical toxicity of RT has to be re-considered with current state of the art RTwith current state of the art RT
  16. 16. NSCLC Stage IIIANSCLC Stage IIIA The role of radiation oncologyThe role of radiation oncology  Phase III trials: RT + Surgery OR Surgery + RTPhase III trials: RT + Surgery OR Surgery + RT vs. Surgery: same or worse OS, more toxicityvs. Surgery: same or worse OS, more toxicity (NCI; LCSG-Weisenberger 1985, Dautzenberg 1999)(NCI; LCSG-Weisenberger 1985, Dautzenberg 1999) Benefit for preop. RT for Pancoast TumorsBenefit for preop. RT for Pancoast Tumors ((Paulson 1995)Paulson 1995)  Postop. phase III trials (EORTC, Villejuif)Postop. phase III trials (EORTC, Villejuif) S w/wo CT + RT vs. S w/wo CT: lower OS withS w/wo CT + RT vs. S w/wo CT: lower OS with older trials using RT, same OS with recent trials;older trials using RT, same OS with recent trials; more toxity - „reason“ for lower OS in metanalyis;more toxity - „reason“ for lower OS in metanalyis; better LC with most recent studiesbetter LC with most recent studies))
  17. 17. NSCLC Stage IIIBNSCLC Stage IIIB The role of radiation oncologyThe role of radiation oncology  Multimodality therapy (patients should beMultimodality therapy (patients should be enrolled in international clinical trials)enrolled in international clinical trials)  Optimal combination and sequence isOptimal combination and sequence is controversial: Too many small studiescontroversial: Too many small studies  Survival benefit of additional chemotherapySurvival benefit of additional chemotherapy modest: max 5% in 2 meta-analysis (2y, 5y OS)modest: max 5% in 2 meta-analysis (2y, 5y OS) ((BMJ 1995 ; Auperin, Annals Onc. 2006)BMJ 1995 ; Auperin, Annals Onc. 2006)
  18. 18. NSCLC Stage IIIBNSCLC Stage IIIB The role of radiation oncologyThe role of radiation oncology  Phase III trials: CT-RT vs. RT (data from 5 rand. trials):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%)CT-RT (2y OS of 14-26%) vs. RT (2 y OS 6% to 17%) (e.g.(e.g. leChevalier, Dillmann)leChevalier, Dillmann)  Phase III trials: conc. CT-RT vs. sequential CT-RTPhase III trials: conc. CT-RT vs. sequential CT-RT (3 rand. trials): concurrent CT better (modest gain in OS)(3 rand. trials): concurrent CT better (modest gain in OS) (e.g.(e.g. Furuse, Curran)Furuse, Curran) median survial 17 months vs. 14 months, higher toxicitymedian survial 17 months vs. 14 months, higher toxicity (grade ¾ acute non-hem 40% vs. 0%!)(grade ¾ acute non-hem 40% vs. 0%!)  Metaanalysis: a) conc. CT-RT vs. RT: OS at 2y. (25 / 21%)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 deathsb) conc. vs. seq. CT-RT: cc CT-RT better OS, more toxic deaths (Auperin, Ann. Onc. 2006; Rowell Cochrane Library 2005(Auperin, Ann. Onc. 2006; Rowell Cochrane Library 2005
  19. 19. NSCLC advance stageNSCLC advance stage palliative/elective local therapypalliative/elective local therapy  Published RT-concepts: 10x3 or 5x4 Gy (3-4x/week)Published RT-concepts: 10x3 or 5x4 Gy (3-4x/week)  Immediate vs. deferred local RT in low symptomImmediate vs. deferred local RT in low symptom patients: no differencepatients: no difference (Falk, BMJ 2002)(Falk, BMJ 2002)  Elective whole brain RT for stage III NSCLC in CRElective whole brain RT for stage III NSCLC in CR (PR/metabolic CR sufficient?)(PR/metabolic CR sufficient?)
  20. 20. Pre-clinical research: Potential molecularPre-clinical research: Potential molecular targets for RT-sensitizers in lung cancertargets for RT-sensitizers in lung cancer 1970 Radiobiology 2008

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