Principles of Radiation OncologyPrinciples of Radiation Oncologyin (advanced stage) NSCLCin (advanced stage) NSCLC

Stephan BodisStephan Bodis

Kantonsspital AarauKantonsspital Aarau

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 dose to a defined total dose

Integration of Molecular BiologyIntegration of Molecular Biology Biology, Physics and Clinical Oncology Biology, 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 : (search) for novel RT-sensitizersnovel RT-sensitizers

Stem cell research, human genome project, microarray Stem cell research, human genome project, microarray technologytechnology: Implications for clinical radiation oncology: Implications for clinical radiation oncology

Life inside a LINAC PrototypeLife inside a LINAC Prototype

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)

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%

Preclinical research: Metabolic image guided RT Preclinical research: Metabolic image guided RT (mIGRT) with repeated FDG-PET during RT?(mIGRT) with repeated FDG-PET during RT?

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)

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)

Therapeutic Index of RT: Reason for Therapeutic Index of RT: Reason for fractionated radiotherapy (daily low dose)fractionated radiotherapy (daily low dose)

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 Gy 5 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 with E.g.: Large, radioresistant tumors with radiosensitive adjacent normal tissue need a radiosensitive adjacent normal tissue need a

small daily dose and high total dosesmall daily dose and high total dose

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)

NSCLC Stage I/IINSCLC Stage I/IIThe role of radical radiotherapy The role of radical radiotherapy

- - Radical surgery: Gold-standard Radical 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)

NSCLC Stage I/IINSCLC Stage I/IIThe role of adjuvant radiotherapyThe role of adjuvant radiotherapy

R0-resection: No proven benefit of adjuvant R0-resection: No proven benefit of adjuvant radiotherapyradiotherapy

R1/R2-resection and no 2nd surgery: Postoperative R1/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))

NSCLC Stage IIIANSCLC Stage IIIAThe role of radiation oncologyThe role of radiation oncology

Multimodality therapy (patients should be Multimodality therapy (patients should be enrolled in international clinical trials)enrolled in international clinical trials)

Heterogeneous patient population: often lack of Heterogeneous 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-considered Historical toxicity of RT has to be re-considered with current state of the art RTwith current state of the art RT

NSCLC Stage IIIANSCLC Stage IIIAThe role of radiation oncologyThe role of radiation oncology

Phase III trials: RT + Surgery OR Surgery + RT vs. Phase III trials: RT + Surgery OR Surgery + RT vs. Surgery: same or worse OS, more toxicity 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 Tumors Benefit 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 with older S w/wo CT + RT vs. S w/wo CT: lower OS with older trials using RT, same OS with recent trials; more trials using RT, same OS with recent trials; more toxity - „reason“ for lower OS in metanalyis; better toxity - „reason“ for lower OS in metanalyis; better

LC with most recent studiesLC with most recent studies))

NSCLC Stage IIIBNSCLC Stage IIIBThe role of radiation oncologyThe role of radiation oncology

Multimodality therapy (patients should be Multimodality therapy (patients should be enrolled in international clinical trials)enrolled in international clinical trials)

Optimal combination and sequence is Optimal combination and sequence is controversial: Too many small studies controversial: Too many small studies

Survival benefit of additional chemotherapy Survival 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)

NSCLC Stage IIIBNSCLC Stage IIIBThe 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%) b) conc. 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 deathsvs. 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

NSCLC advance stageNSCLC advance stagepalliative/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 symptom Immediate vs. deferred local RT in low symptom patients: no difference patients: no difference (Falk, BMJ 2002)(Falk, BMJ 2002)

Elective whole brain RT for stage III NSCLC in CR Elective whole brain RT for stage III NSCLC in CR (PR/metabolic CR sufficient?)(PR/metabolic CR sufficient?)

Pre-clinical research: Potential molecular Pre-clinical research: Potential molecular targets for RT-sensitizers in lung cancertargets for RT-sensitizers in lung cancer

1970Radiobiology 2008