Cancer Cure by radiation treatment: research and clinical outcome

Cancer Cure by radiation treatment: research and clinical outcome Prof. Dr. Michael Molls Klinik für Strahlentherapie und Radiologische Onkologie Klinikum rechts der Isar, Technische Universität München Prague, 24.06.2013

Radiation Oncology/ Clinical Characteristics Radiation treatment of all malignant diseases including carcinomas, sarcomas, brain tumors and lymphomas (adults, children) Curation, palliation

Radiation Oncology/ Research and Innovations Radiation Biology of Normal and Malignant Tissues Physics, Informatics, Engineering Clinical Studies

Department of Radiation Oncology of TU München Treatment of 1.500 patients per year Biology group Prof. Multhoff Medicine group Prof. Molls/ PD Röper Physics group Prof. Wilkens

Department of Radiation Oncology of TU München professors 5 (2 guests) physicians 23 ± physicists 10 ± biologists 10 ± technicians 20 ± nurses 14 ± management assistants and secretaries 8 ± students (doctor thesis, mostly students of medicine) 40 ± guest scientists variable - 4 linear accelerators; neutron radiation treatment at the research reactor of TUM - brachytherapy (afterloading, seeds) - treatment planning including software packages, CT, MRT, PET, simulator device - polyclinics - ward (24 ± beds; chemotherapy in addition to radiation, special radiation concepts, etc.)

Cancer Treatment Surgery removes the local tumor, invasive Radiation oncology irradiates the local tumor and kills the cancer cells, non invasive with the exception of interventional radiation treatment (brachytherapy) Medical oncology i. v. application of medicaments (chemotherapy, etc.), compared with radiation the cell kill of medicaments is much lower

Tumor control by radiation (e.g. head and neck cancers) Radiation kills cancer cells! Palliative 3 weeks radiation treatment Curative 7 weeks radiation treatment Palliation/ pain relief tumor control of a metastatic neck lymph node Curation complete regression of a larynx cancer

High precision radiation treatment: eradication of tumor and optimal sparing of normal tissues tumor

Multileaf - Collimator The moving of the leafs is precalculated and takes place during radiation Shaping of the beam in dependance of tumor contour

Linear accelerator with multileaf-collimator

Radiation treatment in Prostate cancer patient: H. G. age: 73 Jahre ct1c cn0 cm0 G2 Gleason Score: 6 biopsies: 1/8 positiv

Treatment planning: Primary curative radiation therapy of prostate cancer (Textbook Radiation Oncology 2009, Bamberg, Molls, Sack) organ movement microscopic tumor prostate urethra The periphery of the tumor must not move out of the beam during radiation treatment! (Tumors are mostly located in the posterior part of the prostate) position variations (35 radiation treatments) The front third of the rectum is located within the high dose area, independent of the type of radiation (photons, protons)

Prostate Rectum Femur IMRT inhomogenous fluence for all fields, allowing for very complex dose distributions Isodoses (%) 30 50 70 90 95 100 3D

Dose distribution/ IMRT

Vol % DVH: Dose-Volume-Histogram DVH tumor IMRT 3D Dose %

DVH: Dose-Volume-Histogram Vol % DVH rectum IMRT 3D Dose %

Vol % DVH: Dose-Volume-Histogram DVH urinary bladder IMRT 3D Dose %

Fractionation schedule in curative radiation treatment of prostate cancer About 35 to 40 single fractions with single doses of 2 Gy CONVENTIONAL FRACTIONATED RADIATION TREATMENT

Radiation induced death of cancer cells (2 Gy reduce the cell number by 50%, theoretical example) day dose cell number 1 2 Gy 500.000 2 4 Gy 250.000 3 6 Gy 125.000 4 8 Gy 62.500 5 10 Gy 31.250 16 32 Gy 16 20 40 Gy 1 23 46 Gy 0,12

Image Guided Radiation Therapy (IGRT) with Cone Beam CT Volumetric acquisition of CT images in one rotation

Lateral shift Left-Right Longitudinal shift Cranial- Caudal Vertical shift Ventral-Dorsal Yaw, pitch and roll are used in aerospace to define a rotation between a reference axis system and a vehicle-fixed axis system

Prostate cancer/ IMRT Results 8-year disease-free survival (no PSA recurrence) 97% bei 80 Gy 85% bei 76 Gy 58% bei 70 Gy (early stage: <T2b, PSA < 10, Gleas. Sc. < 7) Leibel et al. Semin Oncol, 2003 Late side effects Grade III side effects: 4% GI (bleeding) 6% Uro (urinary retention, bleeding) No grade IV side effects! Side effects are reversible in approx. 50% of the patients Geinitz Molls et al., Radioth. Oncol, 2006

Side effects: Radiation of the urethra cannot be avoided Inflammation of urethra (in any type of treatment: photons, protons, seeds)

Side effects Acute side effects: inflammation during radiation treatment Late side effects: might occur after months and persist might impair the quality of life

Tolerance doses in dependence on irradiated volume TD 5/5 in Gy 1/3 Vol 2/3 Vol 3/3 Vol Spinal cord 50 ( 10 cm) 47 (~ 20 cm) Brain 60 50 45 Kidney 50 30 23 Lung 45 30 17.5 Heart 60 45 40 Liver 50 35 30 Oesophagus 60 58 55 Stomach 60 55 50 Small Intestine 50 40 Colon 55 45 Rectum 60 (100 cm 3 ) TD 5/5 : probability of complications in 5% of irradiated patients within 5 years after radiation

Fractionation schedule in stereotactic radiation treatment Several comparatevily high single doses (7 Gy ±) STEREOTACTIC FRACTIONATED RADIATION TREATMENT

Lung cancer: stereotactic radiation treatment High dose to the tumor Excellent sparing of the lung 3 x 12.5 Gy (periphery) 5 x 7.0 Gy (central) 60% isodose Margins: 4-6 mm and depending on breathing movements V20 (ipsilateral lung volume/ 20 Gy): 8 % D mean (ipsilat. lung): 5.7 Gy

Local recurrence free survival Local recurrence free survival Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie Lung carcinoma, 92 patients Local control (no progression in CT or PET) p = 0,04 T1: 3 cm or less T2: > 3 cm 1 y 88% 2 y 83% 3 y 83% 1 y 100% vs. 83% 2 y 100% vs. 77% 3 y 100% vs. 77% complete remission after 18 months Zimmermann Molls, Acta Oncol 2006 Andratschke Molls et al., Radiother Oncol 2011

Schedule in radiosurgery 1 single, stereotactic radiation treatment with a comparatevily high single dose (16 20 Gy) RADIOSURGERY

Radiosurgery 1993: renal cell-ca 1994: brain metastasis, operation 1995: recurrency, hemianopsia LINAC- Radiosurgery, 20 Gy 1995 6,5% of patients with single brain metastases are long term survivors (Kondziolka et al. 2005) 2010: CR

Gamma-Knife PERFEXION Stereotactic RT Varian True Beam Cyber-Knife Vero LINAC mit Micro-MLC GyroKnife TomoTherapy

Cure rates in early cancer stages Radiotherapy alone Operation alone Chemotherapy alone Prostate 66 79 % (10-y) 75 85 % Ø Lung Larynx 6 50 % or more Stereotact. Radiotherapy 75 80 % (preservation of voice) 30 80 % Ø ~ 75 % Ø Cervix uteri 63 91 % 74 91 % Ø Anus 60 80 % (preservation of continence) results comparable to RT Ø Skin up to 100 % up to 100 % Ø Ø: no data in the literature: CHEMOTHERAPY alone is unable to cure solid tumors of adults (exception: testicular carcinomas)

cancers: radiation versus medical treatment according to Minchinton & Tannock, Nature Reviews Cancer 2006 Molls et al. in: The Impact of Tumor Biology on Cancer Treatment and Multidisciplinary Strategies, Springer, 2009 Medicaments radiation source Radiation

Quantitative CELL KILL tumor cells Tannock, Lancet 1998, Nature 2006 10 10 10 8 6 cycles chemotherapy 10 6 10 4 10 2 surgery 0 0 1 2 3 4 5 6 months macroscopic tumor: > 10 6 10 7 cells, tumors 5 mm microscopic tumor: 1 10 6 cells, tumors < 5 mm

Radiation Biology: tumor and normal tissue Cell kill Mechanisms of cell kill 4 R's (Repair of DNA, Repopulation, Reoxygenation, Redistribution) RT/ ChT Protection of normal tissues

Cell death/ clonogenic survival

Cell survival curve for 4 human tumour cell lines: HX142, neuroblastoma HX58, pancreas HX156, cervix RT112, bladder carcinoma. from Steel (1991)

Relative Radiosensitivity Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie Hypoxia reduces the radiosensitivity of tumor tissues Partial Pressure of Oxygen - mmhg Withers, in: Principles and Practice of Radiation Oncology, Lippincott/Philadelphia, pp.64-96, 1992

po 2 measurements % 25 20 patient 1 normoxic 15 10 5 0 0 10 20 30 40 50 60 po2 (mm Hg) % 25 20 patient 2 hypoxic 15 10 5 0 0 10 20 30 40 50 60 po2 (mm Hg) Blood Perfusion and Microenvironment of Human Tumors (Molls, Vaupel), Springer 1998

Overall survival [%] Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie Hypoxic Subvolume (HSV) and Prognosis Head & Neck cancer, 59 patients (Stadler... Molls, IJROBP, 1999) HSV 6 cm³ n = 33 (14 RT, 19 RChT) HSV > 6 cm³ n = 26 (13 RT, 13 RChT) Months

Imaging of Hypoxia by PET/ CT [18F]FAZA (Azomycin arabinoside) CT axial cor sag PET/CT Fusion Hypopharyngeal SCC 4 h after inj. T/B ratio 3.2 (Piert et al., TUM)

Dose Painting Maximizing dose to hypoxic subvolumes (FAZA-PET)

Dose painting in 2 hypoxic subvolumes 2.5 Gy 2 Gy Grosu Molls IJROPB 2007

Inclusion criteria SCC Oral cavity Oropharynx Hypopharynx Stage III-IV Inoperability Age: > 18 years R A N D O M I S A T I O N Radiotherapy DEV = GTV( 3mm) DEV 2,3 Gy ad 80,5 Gy Chemotherapy Cisplatin 20 mg/m² Radiotherapy GTV2.0 Gy ad 70.0 Gy Chemotherapy Cisplatin 20 mg/m² Experimental arm 5 fractions / Week Control arm 5 fractions / Week DEV dose escalated volume GTV gross tumor volume TRANSLATIONAL PART OF THE STUDY (TUMOR HYPOXIA) Investigating whether tumor hypoxia can be visualized by 18F-FMISO-PET before start of radiation treatment and whether the PET hypoxic subvolumes of a single tumor are constant over a time axis of 2-3 days (Molls and Pigorsch, 2010 sponsoring by DFG)

The 3 main questions Improves dose escalation the locoregional tumor control? Is there a volume or a hypoxia effect in dose escalation? How reliable is the PET visualization of tumor hypoxia? (Molls and Pigorsch, 2010)

Munich Centre for Advanced Photonics (MAP)/ LMU, TUM, MPI 2006 2018: ca. 65 Mio. Imaging of biomolecules Real-time analysis and control of molecular processes Developing electronics to their ultimate limits (frequency of light) Controlling electron motion in microscopic systems Medical Applications Laser-generated particle beams for tumor therapy Medical imaging with brilliant X-rays Investigating quantum phenomena for information technology Probing fundamental laws of nature with unprecedented accuracy Development of high-power lasers for the production of laser-generated X-rays and particle beams MAP has established close cooperation between health professionals and physicists. Co-funded by Siemens Healthcare. worldwide networking

MAP The mission of MAP Only about 50% of cancer patients can be cured The number of cancer patients increases with increasing life expectancy of modern societies Improving cancer cure is a big medical and socio-economic challenge in research The scientific cooperation between physicists, physicians and biologists in MAP offers innovative perspectives to significantly improve cancer cure D. Yach et al., JAMA 291, 2616 (2004)

Vision of MAP Macro Micro 10 7 Imaging Today Future Imaging Clinical evidence Solid tumors at a size of about 10 6 10 7 cells (about 1mm 3 ) have not yet metastasized. Thus, efficient local treatment in very early cancer stages is curative! Limited efficiency of medical cancer treatment Strategy to combat cancer Early tumor detection (diameter of 1mm) Local radiation therapy with ions is curative and spares normal tissues Cost efficiency is important to ensure sustainability Gordon Steel, Basic Clinical Radiobiology, 2002

Phase-Coherent X-ray Imaging Experiments performed using the Synchrotron/ Grenoble (Group of: F. Pfeiffer/ TUM) conventional CT phase-contrast CT phase-coherent X-rays Synchrotron heart mouse heart mouse brain tumor/ rat Better contrast of soft tissues: Advantage for the visualization of smaller tumors (1 mm tumor!) Perspectives: in vivo histology

Dose Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie Depth Dose Curves: X-rays and protons Theoretical advantage of protons: better sparing of normal tissues Depth

Setup of the cell irradiation experiment with the ATLAS laser Protons are produced via high intensity laser interaction with the DLC (Diamond like Carbon) target The mini-quadrupole magnets act as an energy filter and produce a line focus of energy 5.3 ± 0.15 MeV. The dose distribution is assessed using radiochromic film (Gafchromic EBT2) Bin et al. Applied Physics Letters, 2012

First biological results: DNA damage after laser irradiation Exemplary dose map of the line focus γ-h2ax γ-h2ax: red, 53BP1: green: DNA double strand breaks RBE: 1.3 ± 0.3 relative to 200 kv X-rays The RBE obtained in this study for laser-driven protons is in agreement with RBE values in conventional proton beams Single shot irradiation up to 7 Gy Bin et al. Applied Physics Letters, 2012

Vision of MAP: Laser based Image Guided Radiation Therapy Today Future/ Laser Linac with CT brilliant x-rays protons ions intetgrated system for imaging and radiation treatment (tumors of smaller and larger sizes) www.varian.com

from bed to bench, and from bench to bed

Thank you

RESEARCH (Klinik für Strahlentherapie/ TU München) MEDICAL PHYSICS (High precision radiotherapy, X-rays, protons and heavy ions) 1. Intensitiy Modulated and Image Guided Radiotherapy with TOMOTHERAPY Multimodal Image-Guided Helical Tomotherapy a novel method for high precision radiation treatment PD Dr. Frank Zimmermann, PD Dr. Anca-Ligia Grosu, PD Dr. Carsten Nieder, Prof. Dr. Peter Kneschaurek, Prof. Dr. Michael Molls DFG, 2006-2010 2. High Precision Radiotherapy Exploration of dose escalation protocols for the treatment of early stage lung cancer and solitary lung and liver metastases by hypofractionated stereotactic radiotherapy Prof. Dr. Hans Geinitz, PD Dr. Nicolaus Andratschke, Dr. Sabrina Astner, Prof. Dr. Peter Kneschaurek Bayerisches Staatsministerium für Umwelt, Gesundheit und Verbraucherschutz, 2010-2013 3. DFG Cluster of Excellence: Munich Centre for Advanced Photonics (MAP) (M. Molls: Co-Speaker of the Cluster) The radiooncological sub-projects of the MAP cluster are devoted to the development of laser generated proton- and heavy ion therapy including dosimetry and radiobiological investigations Prof. Dr. Michael Molls, PD Dr. Barbara Röper; Dr. Thomas Schmid, Prof. Dr. Peter Kneschaurek; Prof. Dr. Fridtjof Nüsslin, Prof. Dr. Jan Wilkens The junior research group "Advanced Technologies in Radiation Therapy of the MAP cluster investigates the physical aspects of radiotherapy with laser-accelerated particle beams (protons, heavy ions) by developing new concepts for dose delivery and treatment planning Prof. Dr. Jan Wilkens DFG, 2007-2012 4. A Unified Framework for Biological Optimization in Ion Beam Radiation Therapy Development of biologically-guided treatment planning strategies for ion beams including their radiobiological effectiveness Prof. Dr. Jan Wilkens DFG, 2011-2014

RESEARCH (Klinik für Strahlentherapie/ TU München) BIOLOGY I (Immunity and tumor biology, targeted therapy) 1. Helmholtz Zentrum München, Clinical Cooperation Group: Innate Immunity in Tumor Biology Tumor immunology and development of innovative treatment strategies targeting on heat shock proteins in different cancer entities Prof. Dr. Gabriele Multhoff Helmholtz Zentrum München, 2007-2015 2. Tumor-specific membrane transport and export of Hsp70 Analysis of intra- and extracellular trafficking of heat shock proteins in tumors Prof. Dr. Gabriele Multhoff DFG, 2006-2008 3. EU-TRANSNET Identification of genomic and biological markers as predictive/ diagnostic/ therapeutic tools for use in allogeneic stem cell transplantation: Translational research towards individualised patient medicine Prof. Dr. Gabriele Multhoff EU, 2006-2008 5. EU-STEMDIAGNOSTICS Development of new diagnostic tests, new tools and non-invasive methods for the prevention, early diagnosis and monitoring of graft versus host disease in haematopoietic stem cell transplantation (intra- and extracellular trafficking of heat shock proteins) Prof. Dr. Gabriele Multhoff EU, 2007-2010 6. BMBF BioChance Plus Development of a targeted drug delivery systems based on immuno-liposomes and tumor-specific Hsp70 membrane expression Prof. Dr. Gabriele Multhoff, Dr. Claus Botzler BMBF, 2005-2008

RESEARCH (Klinik für Strahlentherapie/ TU München) 7. SFB824/1: Imaging for Selection, Monitoring and Individualization of Cancer Therapies Sub-Project: Hsp70 antibody and peptide for in vivo imaging of tumors Prof. Dr. Gabriele Multhoff DFG, 2009-2013 8. MOBITUM: Watching Tumor Biology by Molecular Imaging Sub-Project: Validation,engineering, and humanization of recombinant Hsp70 Fab fragment for monitoring of tumor growth and metastatic dissemination during radioimmunotherapy Prof. Dr. Gabriele Multhoff, Prof. Dr. Arne Skerra BMBF, 2008-2012 9. Leading-Edge Cluster m 4 Personalized Medicine and Targeted Therapies Sub-Project: Determination of immune- and tumor-parameters in tumor patients Prof. Dr. Gabriele Multhoff BMBF, 2010-2013 BIOLOGY II (X-rays, protons and heavy ions radiation biology; tumor hypoxia and micromilieu) 1. RS225 X-ray Source The RS225 (Gulmay) is used for experimental irradiation of cells and tumors in mice Prof. Dr. Gabriele Multhoff DFG, 2010 2. Translational DFG Multicenter Cooperation Group Hypoxia Sub-Project: Influence of hypoxia and irradiation on the plasminogen activation system and VEGF in squamous cell carcinomas Dr. Christine Bayer, Prof. Dr. Michael Molls DFG, 2006-2010

RESEARCH (Klinik für Strahlentherapie/ TU München) 3. MOBITUM: Watching Tumor Biology by Molecular Imaging Sub-Project: "Hypoxia": Validation of tumor hypoxia as an approach to biology adapted radiotherapy (BART) Dr. Sabrina Astner, Prof. Dr. Michael Molls BMBF, 2008-2012 4. KVSF: Kompetenzverbund Strahlenforschung Sub-Project: Individual sensitivity towards irradiation and genomic instability Prof. Dr. Gabriele Multhoff, Prof. Dr. Mike Atkinson BMBF, 2009-2012 5. EU-CARDIORISK: The mechanisms of cardiovascular risks after low radiation doses (M. Molls: project leader) Work package: Project Management PD Dr. Nicolaus Andratschke, Prof. Dr. Michael Molls, Fa. GABO:mi Work package: Irradiation, preparation of tissue samples and primary cell culture of endothelial cells Prof. Dr. Gabriele Multhoff, PD Dr. Nicolaus Andratschke Work package: Training and Dissemination PD Dr. Nicolaus Andratschke, Prof. Dr. Michael Molls, Fa. GABO:mi EU-EURATOM (FP7, 12 international project partners), 2008-2011 6. DFG Cluster of Excellence: Munich Centre for Advanced Photonics (MAP) (M. Molls: Co-Speaker of the Cluster) The radiobiological sub-project of the MAP cluster is devoted to in vitro and in vivo investigations with continous and pulsed protons and heavy ions (different "end points" such as DNA-repair, apoptosis, tumor regrowth and others) Prof. Dr. Michael Molls, PD Dr. Barbara Röper; Dr. Thomas Schmid, DFG, 2007-2012

RESEARCH (Klinik für Strahlentherapie/ TU München) CLINICAL TRIALS 1. Randomized Multicenter Trial Does selective radiation dose escalation and tumor hypoxia status impact the locoregional tumor control after radio-chemotherapy of head and neck tumors? Dr. Steffi Pigorsch, Prof. Dr. Michael Molls (principal investigators) DFG, 2009-2012 2. Randomized Multicenter Trial Targeted Natural Killer (NK) cell based adjuvant immunotherapy after radiochemotherapy of patients with Non Small Cell lung cancer Prof. Dr. Gabriele Multhoff; Prof. Dr. Michael Molls (principal investigators) BMBF, 2009-2013 3. Randomized Multicenter Trial Intraoperative Radiation Therapy in Breast Cancer (International Study Group) Dr. Steffi Pigorsch, Dipl.-Phys. Sabine Schill, Prof. Dr. Michael Molls (local responsibility) International and in house funding, 2005-2012 4. Phase II Trial Optimization of local radiation treatment in soft tissue sarcoma by innovative radiation techniques PD Dr. Barbara Röper, Prof. Dr. Michael Molls (principal investigators) Wilhelm Sander-Stiftung, 2010-2012

Phase-coherent X-Rays Protons/ heavy ions Today (highly expensive) 2x Soccer stadiums 1x Soccer stadium Diagnostic with phase-coherent x-rays Therapy with protons/ heavy ions Future (cheap) Tabletop Laser (ATLAS) Hospital room size