Proton- Radiotherapy: Overview of Clinical Indications

Transcription

1 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

2 Complication Free Survival Complication-free Tumor Control

3 Complication free survival Complication-free Tumor Control

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

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

6 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

7 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

8 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

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

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

11 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 %.. 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.

12 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

13 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)

14 Prostate Ca > 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 CGE at CGE per fraction Follow-up mean 63 mos., median 62 mos. (range 1-132) Stage 1A/1B 1C 2A 2B 2C 3 Patients

15 Disease-free Survival (%) Prostate Cancer-LLUMC 10 YEAR Effect of Initial PSA on Disease-free Survival p = Years post Proton Radiation 90% < % 62% 43%

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

17 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: 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, ) years.

18 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

19 Zietman, A. L. et al. JAMA 2005;294: 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.

20 Zietman, A. L. et al. CPT JAMA 2005;294: 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.

21 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:

22 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) Zietman AL, Rossi C, et al. IJROBP 2009, 75:3, S11 ASTRO Median follow-up: 8.9 years.

23 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 GyE: 10-year BF rates (ASTRO) 35.3% vs % (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.

24 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

25 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

26 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), Gy x 5 = 36.25Gy) Where is the hypothesis-driven trial??

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

28 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

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

30 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

31 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 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

32 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

33 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

34 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

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

36 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 Mean dose (%) +/- SD

37 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)

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

39 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

40 Hypofractionated Proton Beam Radiotherapy for Stage I Lung Cancer. Bush et al. Chest 126(4), % 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.

41 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)

42 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 % 100% 27 (24-54) Salazar 2008 SBRT % 100% 38 (2-84) STAGE III Rowell 2004 CCR 1065 NR various NR NR various Auperin 2007 CCR 1205 NR various NR NR various Bush 1999 Proton Shioyam a % NR 14 (3-44) 2003 Proton % NR 30 (18-153)

43 Carbon-Ion Therapy for NSC-Lung Ca

44 Clinical Study on Carbon Beam Therapy for Stage I Non-Small Cell Lung Cancer (From: H. Tsjii, NIRs, Japan) Phase I/III (1994) 18 fr / 6 wks 47 pats Dose-escalation escalation 59.4GyE Phase I/II (1997) 9 fr / 3 wks 34 pts 68.4GyE 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

45 Local Control vs. Carbon Ion Dose for Different Fractionations in NSCLC 1.0 Local Control(%) Fr. 9 Fr GyE (TCP=0.95) 4 Fr. GyE 18 Fr. Patients data : 9 Fr. : 18 Fr. : 4 Fr.

46 Local Control in Single Fraction Treatment of Stage I NSCLC Total Dose Gy(RBE) No. 6mo. 12mo. 18mo. 24mo. 30mo. 36mo Currently, single fraction of 46GyE is being evaluated.

47 Local Control of Single Fraction C-ion RT(#0201) <34.0GyE vs. >36.0GyE P= GyE (n=105): 84.3% 2834GyE (n=67): 52.5% Months after RT

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

49 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

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

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

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

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

54 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) Not reported No. of patients evaluable for recurrence % 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

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

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

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

58 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 ± V105 (PTV1) [%] 4.8 ± ± V95 (PTV2) [%] 94,6 ± ± V105 (PTV2) [%] 36.1± ± IMRT PT Mean difference p-value D2 (spinal cord) [Gy] 15.1 ± 6, ± < 0,01 D2 (spinal cord) [Gy] 35.6 ± ± < 0,01 Dmean (ipsi. kidney) [Gy] 11,4 ± ± V15 (ipsi. Kidney) [%] 25.4 ± ± Dmean (heart) [Gy] 26,5 ± 6, ± < 0,01 V45 (heart) [%] 5.8 ± 2,0 2.3 ± Dmean (lung) [Gy] 9,6 ± ± < 0,01 V5 (lung) [%] 67.7 ± ± < 0,01 V13 (lung) [%] 24.1 ± ± V20 (lung) [%] 9.4 ± ±

59 2 legs of Proton Radiation Therapy High Dose Tumor application Reduction of low-dose volume of normal tissues

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

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

62 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

63 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

64 Pediatric Proton-- Radiotherapy

65 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 )

66 Proton RT CPT Proton RT after >35 years and > 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.

67 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?

68 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 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)

69 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)

70 The Confusing World of Precision- RT

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

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

73 ..more on trials and the ethics of trials on Wednesday THANK YOU!