Proton- Radiotherapy: Overview of Clinical Indications

Proton- Radiotherapy: Overview of Clinical Indications Eugen B. Hug (with emphasis on indications treated at PSI For comprehensive clinical reviews: ESTRO or PTCOG seminars) HUG 11/07

Complication Free Survival Complication-free Tumor Control

Complication free survival Complication-free Tumor Control

Proton-Radiotherapy for skull base tumors: 2 tumor (target volume) Lomax, Phys. Med. Biol. 44:185-205, 1999 brainstem

Early clinical Phase: Proof of Safety and Efficacy 1973 Massachusetts General Hospital und Harvard Cyclotron, Boston und Cambridge, USA

Paradigm of proton therapy in the 70 s s and 80 s: Increase tumor dose = increase in local tumor control and Cure Early biologic models (Long-term outcomes data): eye tumors (uveal melanomas) skull base tumors paraspinale tumors of various histologies Unresectable sarcomas = excellent tumor models, but low incidence

Proton RT CPT Proton Radiation Therapy since the 70s and 80s the longest follow up data Uveal Melanomas Chordomas and Chondrosarcomas Skull Base and Paraspinal G. Goitein C. Ares C. Ares / E. Hug Sarcomas (occasional Pediatrics, Prostate-Ca) B. Timmermann

Tumors of the base of skull (examples) Primary skull base tumors: Chordoma, Chondrosarcoma Secondary infiltration from intracranial tumors: Meningioma Secondary infiltration from primary H&N tumors: Nasopharynx CA, Paranasale Sinus CA, Adenoid-cystic CA A.o. Nasopharynx Ca

Chordomas of the Base of Skull 5-year Local Control rates(%) 100 80 60 40 20 Photons Romero 1993 Zorlu 2000 SRT Heidelb. 2000 Protons MGH 1999 PSI 2007 LLUMC 1999 C-Ions GSI 20 40 60 80 100 Dose [ Gy (RBE)]

Chordomas of the Base of Skull 5-year Local Control rates(%) 100 80 60 40 20 Small Chordomas Chondrosarcomas High dose C-ions Photons Romero 1993 Zorlu 2000 SRT Heidelb. 2000 Protons MGH 1999 PSI 2007 LLUMC 1999 C-Ions GSI 20 40 60 80 100 Dose [ Gy (RBE)]

Proton Radiotherapy: - Results of the early clinical era- High-dose and/or hypofractionated therapy concepts increased tumor control compared to conventional photon RT by approx. 10 30 %.. and for the first time offered cures for selected, previously uncurable tumors (chondrosarcomas from 25-30% to 80% at 10 years) Examples: Skull Base Chordomas, Chondrosarcomas and adenoid Cystic Carcinomas, subgroups of Uveal Melanomas, Unresectable Sarcomas.

Clinical Phase of the 90 s: Start of hospital-based Proton Radiotherapy Introduction of Gantry High-capacity patient treatments Additional clinical Indications: 1. Exploring high-frequeny diseases (prostate, lung) 2. New emphasis on Normal tissue sparing (pediatrics) Loma Linda, 1991

Protons for Prostate Ca: Multiple comparisons published Difference mainly in decreased Integral Dose Volume Comparison of Proton Therapy and Intensity-Modulated Radiotherapy for Prostate Cancer Vargas et al,ijrobp 2008, 70(3):744 Combined rectal dose volume curves for proton therapy and intensitymodulated radiotherapy (IMRT) (n = 20 plans)

Prostate Ca > 12 000 Patients treated Loma Linda University Medical Center (Drs. Rossi, Slater ) 1255 patients treated between 10/91 and 12/97 Patients had no prior surgery or hormonal therapy 74-75 CGE at 1.8 2.0 CGE per fraction Follow-up mean 63 mos., median 62 mos. (range 1-132) Stage 1A/1B 1C 2A 2B 2C 3 Patients 35 314 291 248 283 50

Disease-free Survival (%) Prostate Cancer-LLUMC 10 YEAR Effect of Initial PSA on Disease-free Survival 100 90 80 70 60 50 40 30 20 10 0 p =.0001 0 1 2 3 4 5 6 7 8 9 10 Years post Proton Radiation 90% < 4.1 4.1-10.0 10.1-20.0 20.1-50.0 81% 62% 43%

Treatment Morbidity RTOG Scale Grade 2 Grade 3 & 4 GI 3.5% 0 GU 5.4% 0.3% Total 9% 0.3%

Prospective, randomized trial: Comparison of Conventional-Dose vs High-Dose Conformal Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate: A randomized controlled trial Zietman AL et al. JAMA 2005; 294:1233-1239 1996-1999 393 patients enrolled 2 US academic institutions (LLUMC and HCL/MGH) Stage T1b through T2b prostate cancer Prostate-specific antigen (PSA) levels less than 15 ng/ml. Median PSA level was 6.3 ng/ml Median follow-up was 5.5 (range, 1.2-8.2) years.

Randomized Trials: protons versus protons PROG 9509 T1b-2b prostate cancer PSA <15ng/ml r a n d o m i z a t i o n ACR/RTOG Proton boost 19.8 GyE Proton boost 28.8GyE 3-D conformal photons 50.4 Gy 3-D conformal photons 50.4 Gy Total prostate dose 70.2 GyE Total prostate dose 79.2 GyE

Zietman, A. L. et al. JAMA 2005;294:1233-1239. Freedom From Biochemical Failure (ASTRO Definition) Following Either Conventional-Dose (70.2 GyE) or High-Dose (79.2 GyE) Conformal Proton / Photon Radiation Therapy Copyright restrictions may apply.

Zietman, A. L. et al. CPT JAMA 2005;294:1233-1239. Acute and Late Genitourinary and Gastrointestinal (Rectal) Morbidity, by Assigned Radiation Therapy Dose and Toxicity Grade Authors conclusions: Men with clinically localized prostate cancer have a lower risk of biochemical failure if they receive high-dose rather than conventional-dose conformal radiation. This advantage was achieved without any associated increase in RTOG grade 3 acute or late urinary or rectal morbidity. Copyright restrictions may apply.

JAMA 2008: Correction Authors discovered incorrect coding in data base: Intended: biochem. failure = 3 successive PSA increases (ASTRO Def.) Coded: biochem. Failure = any 3 failures Result: higher # of pts. incorrectly coded as failures 79% 91% corrected 2008 incorrect 2005 Copyright restrictions may apply. JAMA 2008;299:899-900.

Randomized Trials: protons versus protons A Phase III Trial Employing Conformal Photons with Proton Boost in Early-stage Prostate Cancer: Conventional Dose (70.2 GyE) Compared to High-dose Irradiation (79.2 GyE): Long-term Update analysis of Proton Radiation Oncology Group (PROG)/American College of Radiology (ACR) 95-09 Zietman AL, Rossi C, et al. IJROBP 2009, 75:3, S11 ASTRO Median follow-up: 8.9 years.

Zietman, A. L. et al. IJROBP 2009;75:3, S11 Freedom From Biochemical Failure (ASTRO Definition with backdating) Following Either Conventional-Dose (70.2 GyE) or High-Dose (79.2 GyE) Conformal Proton / Photon Radiation Therapy 70.2 vs. 79.2 GyE: 10-year BF rates (ASTRO) 35.3% vs. 16.3 % (p=0.0001) Low risk: 29% vs. 6.1% (p=0.0001) Intermed. Risk: 44.6 vs. 28.6% (p=0.06) No diff. in OS: 83.4 vs. 78.4% (p=0.45) No diff. in high Grade, late toxicity (> Gr. 3): overall 2.1% Higher toxicity, if Grade 2 included: (> Gr. 2): 29.4 vs. 39.4% (p=0.045) Authors conclusions: This RCT shows a long-term advantage in terms of freedom from biochemical failure for men with low and intermediate risk prostate cancer receiving high-dose vs. conventional dose conformal radiation delivered with mixed proton and photon beams. This advantage was achieved without any associated increase in Grade >3 late urinary or rectal morbidity.

Status of Proton-Radiotherapy for Carcinoma of Prostate: Thus far a conservative approach Similar dose levels and fractionation regimen compared to modern photon RT (IMRT, IGRT, SBRT etc.) Similar rates of tumor control as had to be expected indications of decreasing rates of severe side effects for protons. approx. 50% of all patients treated world wide with Protons are treated for prostate CA

The conservative approach for Prostate Ca continues: New Protocol for early-stage Prostate Ca at LLUMC: 60 Gy (RBE) at 3 Gy / fract. Reduces treatment time from 45 frct. In 9 weeks (81 GyE at 1.8) to 20 frct. In 4 weeks

The conservative approach for prostate Ca continues unabated: New Protocol for early-stage Prostate Ca at LLUMC: 60 Gy (RBE) at 3 Gy / fract. Already done with photon-rt Primary goal reduce Tx-time time, economic concerns Very conservative hypofractionation compared to Cyberknife (King et al. IJROBP, 73(4), 2009 7.25 Gy x 5 = 36.25Gy) Where is the hypothesis-driven trial??

Proton Therapy for Malignancies of the Chest and Thorax: Breast-CA (Non-Small Cell) Lung CA Mesothelioma

Particle Therapy for Malignancies of the Chest and Thorax: Breast-CA CA: Partial Breast RT Whole Breast / Chestwall +/- regional LN RT (Non-Small Cell) Lung CA Mesothelioma

Partial Breast (accelerated) Irradiation: The goal: replace whole breast RT for low-risk breast Ca patients Interstitial Brachytherapy MammoSite

IMRT: Jagsi R, U. Michigan, IJROBP, in press Partial Breast (accelerated) Irradiation Helical Tomotherapy: Kainz K, Med. Coll. Wisconsin, IJROBP 74(1):275, 2009 Protons: Kozak K at MGH, IJROBP 65(5), 2006 plus intraoperative RT

Proton Therapy for Breast Ca: Accelerated Partial-Breast Proton Therapy: Initial MGH Experience Kozak, Taghian et al. IJROBP 66(3):691, 2006 Phase I/II trial. 20 women with T-1 breast Ca, neg. margins after lumpectomy PTV: lumpectomy cavity plus 1.5-2.0 cm, minimum 5mm distance to surface/skin 32 Gy(RBE) total dose: 4 Gy (RBE) B.I.D. over 4 days 1-3 field arrangements overall, 1 field treated per day only Skin dose per field approached maximum dose, Single field per day = full 4 Gy skin dose. (MGH, passive scatttering ) Observation: Median F/U 12 months (8-22) increased acute toxicity: 80% moderate to severe skin color changes 22% severe moist desquamation

Accelerated Partial-Breast Proton Radiotherapy: Initial MGH Experience Kozak, Taghian et al. IJROBP 66(3):691, 2006 Despite significant resolution of acute skin toxicities by 6 months, concerns persist Authors suggest: Multiple field arrangements, fields should not overlap at skin, all fields treated per fraction Note: acute toxicity did not translate into early-late toxicity

Particle Therapy for Malignancies of the Chest and Thorax: Breast-CA CA: Partial Breast RT Whole Breast / Chestwall +/- regional LN RT (Non-Small Cell) Lung CA Mesothelioma

3D-CRT, IMRT, IMPT Comparison for local and locoregional breast RT (Ares for PSI, IJROBP Epub 2009) PTV1 scenario Whole Breast only Scenario #1: Whole breast 3D-CRT IMRT IMPT PTV2 scenario Whole Breast, MSC, LSC and AxIII Scenario #2: Whole breast, axillary LN, supraclav. LN 3D-CRT IMRT IMPT

PTV3 scenario Whole Breast, MSC, LSC, AxIII and IMC 3D-CRT IMRT IMPT Scenario #3: Whole breast, axillary LN, supraclav. LN IMC

Loco-regional RT (PTV-3) comparison Left lung V5 OAR s mean doses +/- SD Left lung V20 Right lung V5 Right lung V20 IMPT IMRT 3D-CRT Heart V5 Heart V22.5 Right breast mean 0 20 40 60 80 100 Mean dose (%) +/- SD

Planned Pilot-Study at PSI: Proton Therapy for Breast Ca requiring locoregional Irradiation Eligibility criteria (draft version) female patients, non metastatic left-sided breast cancer with 4 positive axillary lymph nodes ( indication for inclusion of IMC nodes: internal quadrant tumors, or positive IMC uptake on lymphoscintigraphy or positive CT or PET-CT, or biopsy proven positive IMC nodes)

Particle Therapy for Malignancies of the Chest and Thorax: Breast-CA (Non-Small Cell) Lung CA Mesothelioma

Proton-Radiotherapy for early Stage Lung Cancer Hypofractionated Proton Radiotherapy for Stage I Lung Cancer. Bush et al. Chest 126(4), 2004 Proton radiotherapy only 68 patients, T1 (29 patients) and T2 (39 patients), NO,MO medically inoperable Non-small-cell Lung CA Dose: 51 cobalt Gray equivalent (CGE) in 10 fractions over 2 weeks. Subsequently 60 CGE in 10 fractions. Median follow-up time 30 months Before PRT After PRT

Hypofractionated Proton Beam Radiotherapy for Stage I Lung Cancer. Bush et al. Chest 126(4), 2004 87% No symptomatic pneumonitis or late esophageal or cardiac toxicity 3-year local control: 74%; 3-year disease-specific survival: 72% Local tumor control T1 vs T2 tumors = 87% vs 49% Trend toward improved survival.

Effect of dose on Overall Survival: 3-year OS-rate 55% (60CGE) versus 27% (51 CGE) (p=0.03) Present LLUMC- Protocol: 70 CGE / 10 frct. ( approx. 100 Gy at 2 Gy/frct)

Studies on stage II and III NSCLC First Author STAGE II Year Txtype Pt. # Frct. dose (Gy) Frct. #: Total dose (Gy) % tumor < 3cm % medic. Inop. Median FU in months (range) Xia 2006 SBRT 18 7 10 70 42% 100% 27 (24-54) Salazar 2008 SBRT 9 13 4 52 75% 100% 38 (2-84) STAGE III Rowell 2004 CCR 1065 NR various 45-70 NR NR various Auperin 2007 CCR 1205 NR various 49-66 NR NR various Bush 1999 Proton 8 1.8-5.1 Shioyam a 10-41 51-74 44% NR 14 (3-44) 2003 Proton 8 2-6 7-32 49-93 32% NR 30 (18-153)

Carbon-Ion Therapy for NSC-Lung Ca

Clinical Study on Carbon Beam Therapy for Stage I Non-Small Cell Lung Cancer (From: H. Tsjii, NIRs, Japan) 9303 9701 9802 0001 0201 Phase I/III (1994) 18 fr / 6 wks 47 pats Dose-escalation escalation 59.4GyE 64.8 72.0 79.2 86.4 90.0 95.4 Phase I/II (1997) 9 fr / 3 wks 34 pts 68.4GyE 72.0 75.6 79.2 Dose recommended 90GyE 72 GyE Phase (4/99-11/00) 9 fr / 3 wks 50 pats 72GyE Total 129 pats Phase I/II (12/00-11/03) 4 fr / 1 wk 79 pats 52.8GyE for stage IA 60.0GyE for stage IB Phase I/II (12/03 ~) Singledose 84 pats 28GyE 30 34 36 38 40 42 44

Local Control vs. Carbon Ion Dose for Different Fractionations in NSCLC 1.0 Local Control(%) 0.5 1 Fr. 9 Fr 0 0 20 40 60 80 100 30 GyE (TCP=0.95) 4 Fr. GyE 18 Fr. Patients data : 9 Fr. : 18 Fr. : 4 Fr.

Local Control in Single Fraction Treatment of Stage I NSCLC Total Dose Gy(RBE) No. 6mo. 12mo. 18mo. 24mo. 30mo. 36mo. 28.0 6 100.0 66.7 50.0 50.0 50.0 50.0 32.0 27 96.2 72.9 72.9 68.8 64.8 64.8 34.0 34 100.0 79.1 69.2 69.2 65.4 65.4 36.0 18 100.0 94.4 94.4 94.4 94.4 94.4 38.0 14 100.0 92.3 92.3 92.3 92.3 40.0 15 100.0 86.7 86.7 79.4 68.1 42.0 15 100.0 85.7 85.7 85.7 44.0 30 100.0 90.8 79.4 Currently, single fraction of 46GyE is being evaluated.

Local Control of Single Fraction C-ion RT(#0201) <34.0GyE vs. >36.0GyE 1.8.6.4.2 P=0.0014 3644GyE (n=105): 84.3% 2834GyE (n=67): 52.5% 0 0 10 20 30 40 50 60 70 Months after RT

Single fraction 34GyE Pneumonitis appeared corresponding to the high dose area. From: Dr. Tsujii ESTRO Teaching course 2009

Particle Therapy for Malignancies of the Chest and Thorax: (Non-Small Cell) Lung CA present status a) Peripheral lung lesions: multiple modalities offer good local control (particles, SBRT, Cyberknife, Tomotherapy) area of great progress compared to standard EBRT. Local Control IA > 80%, lesser LC for IB.? Added benefit for particles? b) Central lung / mediastinum: remains a challenge for photons mainly due to V5-V20, MLD dose. Excellent opportunity for particles. c) The co-morbid patient: reduced lung function due to chronic lumonary disease (asthma, emphysema etc.) with little functional reserve to spare opportunity for particles Protons: evolving, essentially only few data, passive scattering only, active scanning technology presently not solved (except possibly by using anesthesia) Carbon Ions: very promising data, outstanding effort from NIRS, needs to be confirmed specifically toxicity profile

Particle Therapy for Malignancies of the Chest and Thorax: Breast-CA (Non-Small Cell) Lung CA Mesothelioma

Asbestos From Asbestos to Mesothelioma Asbestos fibre From Asbestosis to chrysotile Mesothelioma

Standard Therapy for Mesothelioma: Trimodality Therapy / Triple Therapy Surgery (Extrapleural pneumonectomy) Chemotherapy Radiotherapy

Radiotherapy for Mesothelioma Conventional XRT (Plan from R. Cameron, UCLA, 2004) IMRT-Plan from MDAnderson CC)

Mesothelioma: high failure rate after triple-therapy CPT Comparison of Patterns of Failure After Extrapleural Pneumonectomy With or Without Adjuvant Therapy (Sugarbaker, 1997) Variable Sugarbaker 1997 Lung Cancer Study Group [1991] Cleveland Clinic [1994] Treatment EPP, CAP, RT EPP EPP or P, CT Median follow-up (mo) 18 14 Not reported No. of patients evaluable for recurrence 46 17 18 % of patients with recurrence 54% 76% 67% Recurrence site Recent series: approx. 30% Local % of all patients 35% 41% 56% % of recurrences 67% 54% 83% Abdomen % of all patients 26% 29% Not stated % of recurrences 50% 38% Contralateral thorax % of all patients 17% 29% Not stated % of recurrences 33% 38% Distant % of all patients 8% 35% 28% a % of recurrences 17% 46% 42% a

Mesothelioma: risk of contralateral lung damage by IMRT IJROBP 2006 6 / 13 patients developed FATAL pneumonitis after 54 Gy with IMRT

Mesothelioma: IMRT / Proton comparison U. Zürich / PSI collaboration Krayenbühl, Hartmann, Cziernik, Lomax (IJROBP submitted) IMRT Protons

Mesothelioma: IMRT / Proton comparison U. Zürich / PSI collaboration Krayenbühl, Hartmann, Cziernik, Lomax

Mesothelioma: IMRT / Proton comparison U. Zürich / PSI collaboration Krayenbühl, Hartmann, Cziernik, Lomax IMRT PT Mean difference p-value V95 (PTV1) [%] 96.0 ± 2,9 96,2 ± 2.66 0.24 0.3 V105 (PTV1) [%] 4.8 ± 5.1 2.61 ± 2.12-2.19 0.2 V95 (PTV2) [%] 94,6 ± 4.0 95.32 ± 1.27 0.73 0.2 V105 (PTV2) [%] 36.1± 20.7 33.42 ± 17.51-2.64 0.2 IMRT PT Mean difference p-value D2 (spinal cord) [Gy] 15.1 ± 6,6 3.71 ± 3.98-11.4 < 0,01 D2 (spinal cord) [Gy] 35.6 ± 3.9 28.61 ± 2.98-7.0 < 0,01 Dmean (ipsi. kidney) [Gy] 11,4 ± 6.1 7.04 ± 4.04-4.3 0.8 V15 (ipsi. Kidney) [%] 25.4 ± 13.7 18.62 ± 10.37-6.8 0.02 Dmean (heart) [Gy] 26,5 ± 6,2 5.99 ± 4.64-20.8 < 0,01 V45 (heart) [%] 5.8 ± 2,0 2.3 ± 3.39-3.5 0.47 Dmean (lung) [Gy] 9,6 ± 2.7 0.35 ± 0.42-9.3 < 0,01 V5 (lung) [%] 67.7 ± 20.3 1.04 ± 1.83-66.7 < 0,01 V13 (lung) [%] 24.1 ± 16.2 0.4 ± 0.8-23.7 0.04 V20 (lung) [%] 9.4 ± 6.8 0.2 ± 0.5-9.2 0.04

2 legs of Proton Radiation Therapy High Dose Tumor application Reduction of low-dose volume of normal tissues

Orbital Rhabdomyosarcoma: Protons versus Photons Hein, Hug et al. IJROBP 62, 2005 Hug, et al. IJROBP, 47, 2000 Photons Protons

Orbitales Rhabdomyosarkom: Protonen versus Photonen Hein, Hug et al. IJROBP 62, 2005 Hug, et al. IJROBP, 47, 2000 Photonen Protonen

The Integral Dose Differential Comparative dose distributions for 9-field photon intensitymodulated photon (IMXT) and 3-field intensity-modulated protonradiation (IMPT) treatment plans for a patient with pelvic Ewing s sarcoma. IMXT IMPT (Courtesy of A.R. Smith and A.J. Lomax, in Delaney, Cancer Control, 2005) IMXT - IMPT

Pediatric Proton-- Radiotherapy

Protons for Pediatric Malignancies the accepted paradigm Reduction of the irradiated volume ( Integral Volume ) = Reduction of Late Effects Improved Quality of Life = Reduced risk of induction of Second Malignancy (Scanning Technologie )

Proton RT CPT Proton RT after >35 years and > 60 000 patients treated no single disease entity ever treated with protons was later found unsuitable no publication has raised the issue of unexpected acute or late toxicity. (exception: Taghian et al., PBRT) The initial concept of physical dose distribution and biologic effectiveness has not been called into question by clinical results Proton-Radiotherapy has therefore successfully passed any reasonable requirements for treatment safety and feasibility.

Proton RT CPT Proton-RT: Status of Clinical Evidence Retrospective single-institution reports Prospective data accumulation Phase I and Phase II studies What about the evidence? What about randomized, prospective trials?

Level 1 Evidence for Proton Therapy (?) Randomized trial photons versus protons: Has not been done, EXCEPT: MGH/HCL Prostate trial: 67.2 Gy photons vs. 75.6 Gy protons/photons, T3 and T4 Randomized Trials: protons versus protons PROG 9509: Prostate CA, mixed photon/proton versus mixed photon/proton dose escalation: MGH + LBL+ LLUMC Chordoma and Chondrosarcoma Skull Base and C-spine randomized protocol (PROG) MGH/MEEI/HCL: Uveal Melanoma, dose de-escalation trial 70 vs. 50 Gy(RBE)

Proton RT CPT Proton RT Introduction of new radiotherapy technology has thus far never required randomized trials as long as safety and at least equivalency with prospect of superior outcomes have been demonstrated. (Examples: IMRT, Tomotherapy, Cyberknife)

The Confusing World of Precision- RT

The Confusing World of Precision- RT Clinical trial required Clinical trial required Clinical trial required

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