Thierry M. Muanza, MSc, MD, FRCPC,, McGill University Segal Cancer Centre, Jewish General Hospital Montreal, QC, Canada

Déclarations Aucun conflit d intérêt

Objectifs d apprentissage Évolution de la radiothérapie pour les tumeurs du SNC Tumeurs Statistiques Radiothérapie Imagerie/planification Hydrontherapie: particules chargées TTF: champ traitant les tumeurs Essais cliniques

Canadian Cancer Statistics 2017

Statistiques Canadiennes 2017 Tumeurs du SNC 3,000 Canadians will be diagnosed with brain and spinal cord cancer. 2,400 Canadians will die from brain and spinal cord cancer. 1,700 men will be diagnosed with brain and spinal cord cancer and 1,350 will die from it. 1,300 women will be diagnosed with brain and spinal cord cancer and 1,050 will die from it.

Tumeurs du SNC Primary astrocytes oligodendrocytes ependymal cells Secondary Metastasis Lung, breast, melanoma, renal cell etc Low-grade (noncancerous) tumours grow slowly High-grade (cancerous) tumours grow quickly

Histopatholigical classification nuclear atypia mitosis, WHO Pilocytic astrocytoma WHO Grade I St Anne/Mayo criteria 0 criterion endothelial proliferatio n-'piled-up' endothelial cells. NOT hypervascularity Diffuse astrocytoma Anaplastic astrocytoma II III 1 criterion (a) 2 criteria (a+b necrosis. Glioblastom a IV 3-4 criteria (a+b[+/- c]+d)

Classification WHO 2016

Response to Therapy Inactive methylated MGMT Active unmethylated MGMT

IDH mutation and survival GBM

Radiothérapie

Chromosomal Damage Apoptosis Reproductive death Necrosis

Tumor Oxygenation

Effect of Oxygen

Re-oxygenation

Percent Depth Dose

Radiotherapy delivery : External beam radiotherapy: Photons: X-rays: Linear accelerators. γ-rays: Cobalt machines. Particles: Electrons. Neutrons. Protons. Brachytherapy: Interstitial. Intracavitary.

Linear Accelerator

LINAC

Radiotherapy indications CNS tumors Benign: Meningioma Acoustic schwannoma Pituitary adenoma Malignant Primary: astrocytoma, oligodendroglioma, ependymoma Secondary: Metastasis lung, breast, melanoma

Patient referral to oncology Investigations Cancer staging Multidisciplinary Tumor Board Radiotherapy Treatment Sequence History, physical examination, imaging, biopsy, pathology T = tumor size N = lymph node extension M = metastasis Surgeon, radiation oncologist, medical oncologist, pathologist & radiologist CT simulation: immobilisation, isocenter, marking CT planning: image fusion (US/MRI/PET) Target volumes delineation Treatment planning/dosimetry Treatment recommendations / clinical trials

XRT Treatment Volumes

Timing and clinical manifestation of radiation injury 1. Acute clinical period 2. Sub-acute period 3. Chronic clinical period 4. Late clinical period 0-6 months 6-12 months 1-5 years

Acute versus late injury Timing depends on cell cycle kinetics Clinical importance: reversible versus irreversible Correlation between acute and late complications

Factors affecting radiation damage 1. Volume to be irradiated 2. Total dose 3. Fraction size 4. Concomitant treatment

Total body irradiation Dose Effects Group I 0.5-1.5 Gy Minimal Group II 1.5-4 Gy Mild N/V Group III 4-6 Gy Hemopoietic Group IV 6-14 Gy GI Group V > 50 Gy CNS

Radiation-Induced Malignancy 1. There is no threshold 2. Long latent period 3. Within the radiation ports 4. Different organ sensitivity Thyroid, breast, lungs Skeletal muscle

Dose Volume Histogram

Types de Radiothérapie Three-dimensional conformal radiation therapy (3D-CRT): 3D-CRT uses the results of imaging tests such as MRI and special computers to map the location of the tumor precisely. Several radiation beams are then shaped and aimed at the tumor from different directions. Each beam alone is fairly weak, which makes it less likely to damage normal tissues, but the beams converge at the tumor to give a higher dose of radiation there.

Image guided RT CT scan Glioma C+/_ MRI C+

Immobilization: mask

Immobilization: stereotactic frames

Whole Brain radiotherapy: WBRT

Linac_Tomotherapy

IMRT Intensity modulated radiation therapy (IMRT): IMRT is an advanced form of 3D therapy. It uses a computer-driven machine that moves around the patient as it delivers radiation. Along with shaping the beams and aiming them at the tumor from several angles, the intensity (strength) of the beams can be adjusted to limit the dose reaching the most sensitive normal tissues. This may let the doctor deliver a higher dose to the tumor. Many major hospitals and cancer centers now use IMRT.

MLC

GBM IMRT plan

VMAT Volumetric modulated arc therapy (VMAT) is a novel radiation technique, which can achieve highly conformal dose distributions with improved target volume coverage and sparing of normal tissues compared with conventional radiotherapy techniques.

Proton Conformal proton beam radiation therapy: Proton beam therapy is related to 3D-CRT and uses a similar approach. But instead of using x-rays, it focuses proton beams on the tumor. Protons are positive parts of atoms. Unlike x-rays, which release energy both before and after they hit their target, protons cause little damage to tissues they pass through and then release their energy after traveling a certain distance. Doctors can use this property to deliver more radiation to the tumor and do less damage to nearby normal tissues. This approach may be more helpful for brain tumors that have distinct edges (such as chordomas), but it is not clear if it will be useful with tumors that are infiltrative or mixed with normal brain tissue (such as astrocytomas or glioblastomas). There are only a handful of proton beam centers in the United States at this time.

Percent Depth Dose

Radiosurgery: SRS Stereotactic radiosurgery/stereotactic radiotherapy: This type of treatment delivers a large, precise radiation dose to the tumor area in a single session (radiosurgery) or in a few sessions (radiotherapy). (There is no actual surgery in this treatment.) It may be used for some tumors in parts of the brain or spinal cord that can t be treated with surgery or when a patient isn t healthy enough for surgery.

SRS

G-knife

SRS

C-knife

FSRT Pituitary MacroAdenoma

GBM 3D plan

Spine SRS

CSI: planning

CSI: 3D vs. Tomotherapy

CSI: photon vs. proton

CSI_proton

Base of skull: photon vs proton

In conclusion Integration of MRI and particles therapy into mainstream radiation oncology has the potential to further our ability to target brain tumors while sparing critical regions of normal brain tissue A. Shagal, P Brown, Neuro-Oncology, 19, 2017

Future directions MRI-linacs TTFs Clinical trials

MRI Linac

Optune_TTFs

Optune_EF-14_GBM_phase III trial

Clinical Trials 1071 1270 BN002 NCCTG N0577/Endorsed Study: Phase III Intergroup Study of Radiotherapy versus Temozolomide Alone versus Radiotherapy with Concomitant and Adjuvant Temozolomide for Patients with 1p/19q Codeleted Anaplastic Glioma Open III NCCTG N107C/Endorsed Study: A Phase III Trial of Post-Surgical Stereotactic Radiosurgery (SRS) Compared With Whole Brain Radiotherapy (WBRT) for Resected Metastatic Brain Disease Open III Phase I Study of Ipilimumab, Nivolumab, and the Combination in Patients With Newly Diagnosed Glioblastoma Open I BN001 Randomized Phase II Trial of Hypofractionated Dose-Escalated Photon IMRT or Proton Beam Therapy Versus Conventional Photon Irradiation With Concomitant and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma Open II R

Clinical trials 1470 1072 Alliance A071101/Endorsed Study: A Phase II Randomized Trial Comparing the Efficacy of Heat Shock Protein-Peptide Complex-96 (HSPPC-96) (NSC #725085, ALLIANCE IND# 15380) Vaccine Given With Bevacizumab Versus Bevacizumab Alone in the Treatment of Surgically Resective Recurrent Glioblastoma Multiforme (GBM) Open II R ECOG E3F05/Endorsed Study: Phase III Study of Radiation Therapy with or without Temozolomide for Symptomatic or Progressive Low-Grade Gliomas Temp Closed III Novocure EF-25 METIS The METIS trial (also known as the EF-25 trial ) is a pivotal (analogous to drug Phase III), randomized, controlled trial, designed to test the efficacy and safety of Tumor Treating Fields (TTFields), generated by a medical device, the NovoTTF-100M System [About TTFields] in patients with 1-10 newly diagnosed brain metastases from non-small cell lung cancer (NSCLC). TTFields are administered to patients concomitantly with the best standard of care treatments which would normally be used to treat lung cancer. The trial is expected to enroll a total of 270 patients.

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