Principles of Radiation Oncology in (advanced stage) NSCLC Stephan Bodis Kantonsspital Aarau

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

Integration of Molecular Biology Biology, Physics and Clinical Oncology are the 3 pillars of Radiation Oncology Defined biologic model systems available: > 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

Life inside a LINAC Prototype

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 cm‘s Protons: - Charged heavy particles - unique dose distribution (matterhorn like – Bragg Peak)

Imaging for RT Planing (incl. CT-MRI/PET) Stage shift up to 30%

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

Intensity modulated RT (IMRT) Voxel by voxel RT for complex volumes (high/low dose)

IMRT: Maximal dose in the tumor (red), minimal dose in the adjacent normal tissue (blue)

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

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

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)

NSCLC Stage I/II The 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)

NSCLC Stage I/II The 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 > 60 Gy (if 2 Gy/day and 5x/week)

NSCLC Stage IIIA The 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

NSCLC Stage IIIA The 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)

NSCLC Stage IIIB The 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)

NSCLC Stage IIIB The 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

NSCLC advance stage palliative/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?)

Pre-clinical research: Potential molecular targets for RT-sensitizers in lung cancer Radiobiology 2008 1970