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

2. 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

3. 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

4. Life inside a LINAC Prototype

5. 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)

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

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

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

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

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

11. 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 = 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

12. 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)

13. 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)

14. 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)

15. 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

16. 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)

17. 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)

18. 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

19. 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?)

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