Hadron therapy W. De Neve
Context •
Generic name
•
Belgium
•
– Hadrons: particles susceptible to strong (nuclear) forces (άδρός = strong) – Neutrons, pi-mesons, protons and other atomic nuclei – Radiotherapy using photons or electrons – Hadron therapy is not available
Europe
– 14 operational centers • Protons: 12 • Carbon ions and protons: 2
– 18.000-40.000 €/patient
•
World – ~ 50 centers (USA: 11; Japan: 9) – Cost/patient • USA: ≥100.000 $ /patient • Japan: ~40.000 € /patient
•
Very few Belgian patients are referred for hadron therapy
Dimitri Mendeleev’s periodic table of elements
Electrons
Helium
Protons
Carbon
Anti-Protons
Iron
Physics rationale: Little in front, almost nothing behind Photon
Proton
Carbon ion
10 mm
10 μ
Intra-cellular distribution of ionizations
W. De Neve
Biological rationale for carbon ions: harder downstream in tumor Protons or photons
1 nm
10 mm W. De Neve
Relative biological effectiveness (RBE) • RBE is the inverse ratio of the doses required for a biological response • The standard of comparison is cobalt gamma-rays or megavoltage x-rays RBE(exp) = D(cobalt)/D(exp)
RBE as function of LET in normal tissues
RBE
1
10
100
LET
LET-RBE: challenges for clinical use • Proton therapy – Similar to x-ray therapy – Conversion factor ~1.1
• Carbon ion therapy – RBE varies • • • •
Along the beam trajectory With LET, fractionation Between normal tissues Between cancers
– Tolerance data: 10,000 patients, 2 centers
Batterman et al. Eur. J. Cancer 17: 539-548; 1981 Equal growth delay
RBE =
D(photon) D(neutron)
Photon RT Variety of tumors Variety of RBE-values
Neutron RT
Tumor RBE-values generally higher than the 3.0-3.5 value, measured for normal tissues
Adenoid Cystic Carcinoma: RBE-values ≈ 8
Adenoid cystic carcinoma; local control in unresectable disease C-ion boost
p = 0.08
C-ion at NIRS
Photon
Schulz-Ertner D., et al. Cancer 2005; 104:338–44 Hasegawa at NIRS-MedAustron meeting 2013: 186 ACC, 64 GyE/16 F, 75% LC
From biophysics to clinical use • Hadrontherapy – 2 to 8 times less dose in normal tissues
• Protontherapy: reducing toxicity – Children • Preserving growth and development • Minimizing cancer induction
– Adults
• Carbon ions: resistant cancers – Mainly adults
Medulloblastoma Proton
Photon
Incidence of second malignancies in adult patients Matched-pair analysis proton therapy versus x-ray therapy METHODS AND MATERIALS: We performed a retrospective cohort study of 558 patients treated with proton radiation from 1973 to 2001 at the Harvard Cyclotron in Cambridge, MA and 558 matched patients treated with photon therapy in the Surveillance, Epidemiology, and End Results (SEER) Program cancer registry. Patients were matched by age at radiation treatment, sex, year of treatment, cancer histology, and site. The main outcome measure was the incidence of second malignancies after radiation. RESULTS: The median duration of follow-up was 6.7 years (interquartile range, 7.4) and 6.0 years (interquartile range, 9.3) in the proton and photon cohorts, respectively. The median age at treatment was 59 years in each cohort. Second malignancies occurred in 29 proton patients (5.2%) and 42 photon patients (7.5%). After we adjusted for sex, age at treatment, primary site, and year of diagnosis, proton therapy was not associated with an increased risk of second malignancy (adjusted hazard ratio, 0.52 [95% confidence interval, 0.32-0.85]; P=.009).
Chung CS1, Yock TI, Nelson K, Xu Y, Keating NL, Tarbell NJ. Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys. 2013 Sep 1;87(1):46-52.
Proton therapy practice • Procedures similar to x-ray therapy – More frequent use of surgical aids • Markers • Spacers
• Pediatrics – Protocols of international study groups – Chemotherapy in proton centers
• Adults – Fractionation as in x-ray therapy
Carbon ion therapy practice • Very frequent use of surgical aids • Few pediatric indications • Hypofractionation (average of 12 fractions) – NIRS, Chiba, Japan • 4 fractions/week; 1-16 fractions • Combinations with other modalities • No RCTs
– HIT, Heidelberg, Germany • Hybrid schedules with x-ray therapy • RCTs
Why is hadron therapy not the standard? accelerator
HIT Heidelberg HIT Heidelberg
NIRS treatment facility • Operating: 240 days/year (4-5days/wk) – 6 hrs treatment, 2hrs dosimetry – Maintenance: May & Aug
• Dual ring synchrotrons. – Circumference: 63M
• Existing treatment facility (passive beam) – Experimental room x2 – Treatment room x3 (fixed beam ports) – Simulation room x 1
• New treatment facility (active beam) – Treatment room x 3 (fixed ports x2, gantry x1) – Simulation room x2 – Preparation room x6
Indications treatable using established technology Proton centre
Pediatric indications
Carbon-ion centre
Non-resectable osteosarcoma
32
2
Standard indications in adults 10 24
8 24 8 21
Chordoma and chondrosarcoma Various sarcomas Melanoma (aerodigestive) Adenoid cystic carcinoma Paranasal Meningeoma Low-grade glioma
Re-imbursed
65 24 71
Model indication level I 50 82
Major salivary gland tumors Locally recurrent rectal cancer H&N cancer re-irradiation
NOT re-imbursed
156
382
195
255
choices
106
545 103
p
C
81
(Proton+carbon-ion)-centre
CancerPlan Action 30
Model indications in adults No.
TNM classification
Pathology
Cancer entity
1
Pancreatic cancer
Locally advanced
Rectal cancer
Locally recurrent
C
Stage III Inoperable Primary & recurrent R ?1* or inoperable Perineural invasion
5
Head & neck tumors
Non-small cell lung cancer (NSCLC) Major salivary glands tumors other than adenoid cystic carcinoma Any
p
4
Digestive tract tumors Digestive tract tumors Lung & pleural tumors Head & neck tumors
Type of hadron therapy C
6
Lung & pleural tumors
Non-small cell lung cancer (NSCLC)
Stage I Medically inoperable/refusal
7
Digestive tract tumors
Hepatocellular carcinoma
Primary & recurrent (Child-Pugh grade A or B) Size of < 3 cm: adjacent tovessels or bile ducts or the gastrointestinal tract Size of > 3cm
2 3
C
Re-irradiation
Prostate and breast cancer: not studied
5
30
21
Carbon ions
21
6
Adenoid cystic carcinoma of head & neck (all stages) Paranasal tumors (all stages)
110
65
Protons
65
7
Meningioma benign and malignant
572
24
Protons
24
Low-grade glioma (grade 1 & 2)
236
71
Protons
71
Carbon-ions Protons
61 162
Carbon-ions
401
NIRS
Carbon-ions
82
NIRS MDAH
8
Remarkable results in common cancers
Model indications 9
Pancreatic cancer (all stages)
1338
78
Locally advanced inoperable 10
Rectal cancer (primary & recurrent)
2347
1956
Local recurrence 11
NSCLC (stage III)
Protons
588
12
Major salivary gland tumors other than 107 50 Carbon-ions adenoid cystic carcinoma (aal stages) Recurrent Unresectable Rectal Cancer Head Locally & neck cancer (primary & recurrent) 2574 1560
50
13 14 15
1229
Chemo(x-ray)therapy Re-irradiation 5-y NSCLC (stage I) survival 0-20% 1054 Hepatocellular carcinoma stages) 0-50%455 5-y local (all control Primary & recurrent size <3 cm: adjacent to vessels or bile ducts or the C-ion no previous irradiation gastrointestinal tract; Primary & recurrent size >3 cm 5-y survival: 45%
588
179
Protons
156
Carbon-ions
179
16 Carbon-ions
364
(NIRS, n=136)
5-y local control: 93% TOTAL (all indications) C-ion re-irradiation (NIRS, n=23) 3-y survival: 65% 3-y DS survival: 51%
Durante et al. Lancet Oncology (in-press)
Carbon-ions Protons Carbon-ions Protons
1076 744 1137 906
Locally advanced pancreatic cancer • • • • • •
1/3 of pancreatic cancers at diagnosis Unresectable due to local invasion No distant metastasis Standard treatment focuses on palliation Autopsy: 1/3 free of M+ disease n ≈ 400/y (B)
Pancreatic cancer Anatomical challenges
Biological challenges • Severe radioresistance of pancreatic cancer • High-LET trials before the CT-scan era – Neutrons [1,2] – Negative pi-mesons [3,4]
• High-LET compared to photons – Beter palliative effects – Tumor disappearance at autopsy
• Normal tissues exposed to high-LET – Severe toxicity 1. Thomas FJ, et al. Am J Clin Oncol. 1989 Aug;12(4):283-9 2. Cohen L, et al. Cancer. 1985 Sep 15;56(6):1235-41 3. Bush SE, et al. Int J Radiat Oncol Biol Phys. 1982 Dec;8(12):2181-6 4. Kligerman MM,et al. J Can Assoc Radiol. 1980 Mar;31(1):13-8
Modern randomized controlled trials of photon radiochemotherapy for locally advanced unresectable pancreatic cancer Study ECOG: Klaassen 1985 [1] Fluorouracil alone RT (40 Gy) + fluorouracil
No. of patients
Median survival (months)
44 47
8.2† 8.3†
Overall survival, (months) 21% (18) 11% (18)
GITSG 1988 [2] SMF only RT (54 Gy) + fluorouracil and SMF
Toxicity Grade NR: 27% 51% Grade ≥ 3: NR 50%
21 8* 0% (18)* Standard treatment: IMRT-gemcitabine 22 10.5* 18% (18) * FFCD/SFRO: Chauffert 2008 [3] Grade 3-4: Median survival: ≤ 12 months Gemcitabine alone 60 13* 53% (12)* 40% 65.5% RT (60 Gy) + fluorouracil + cisplatin 59 8.6* (12)* High-grade toxicity: 20-50% of32%patients ‡
‡
ECOG: Loehrer 2011 [28] Gemcitabine alone RT (50.4 Gy) + gemcitabine
37 34
9.2* 11.1*
5% (24)* 12% (24)*
Grade 4-5: 9% 41%
Abbreviations: ECOG: Eastern Cooperative Oncology Group; RT: photon radiotherapy; NR: not reported; GITSG: Gastrointestinal Tumor Study Group; SMF: streptozocin, mitomycin and fluorouracil chemotherapy; MMC: mitomycin-C; FFCD-SFRO: Federation Francophone de Cancerologie Digestive and Societe Francaise de Radiotherapie Oncologique. *statistically significant; †not statistically significant; ‡during induction phase of treatment. 1. Klaassen DJ, et al. J ClinOncol. 1985;3:373-378 2. Gastrointestinal Tumor Study Group. J Natl Cancer Inst. 1988 Jul 20;80(10):751-5. 3. Chauffert B, et al. Ann Oncol. 2008;19:1592-1599 4. Loehrer PJ Sr, et al. J Clin Oncol. 2011;29:4105-4112
GEM+CIRT for Locally Advanced Pancreatic Cancer Tadashi Kamada, NIRS, Japan Local Control Overall Survival
Total dose
n
12mo
24mo
43.2GyE
24
68%
28%
45.6GyE-50.4GyE
26
65%
65%
43.2GyE
24
71%
21%
45.6GyE-50.4GyE
26
67%
50%
G4 toxicity: 3 cases
Local Control
Overall Survival
0.4
Outcome comparison • Chemo(radio)therapy – Median survival: 8.5-13 months – Severe toxicity: 30-50% G4-5
• C-ion+gemcitabine (NIRS high-dose) – Median survival: 24 months – Severe toxicity: 3/26 pts G4
• Concurrent gemcitabine at 1,000 mg/m2 • Single institute, small cohort
Locally advanced unresectable pancreatic cancer Conclusions regarding C-ion + gemcitabine 1. Doubling of median survival 2. Reduced toxicity 3. Safety window for concurrent chemotherapy 4. External validity: neutron data 5. Cost-effective compared to chemotherapy alone (± €10000/QALY or LYG) 6. Borderline cost-effective compared to gemcitabine + photon radiotherapy (± €21 000/QALY or LYG) 7. Uncertainties
Verwijzing naar buitenlands hadrontherapiecentrum • E112/S2 document – Carbonionen: HIT Heidelberg, CNAO, Pavia – Protonen: Orsay Paris, PSI Villigen – Snelle en vlotte procedure
• 2014 nieuw KB, RIZIV initiatief – Stop E112/S2 procedure – Procedure met offerteaanvraag
RIZIV-procedure 14 stappen
Aanvraagprocedure 1.
2.
3.
4.
5.
Rechthebbende krijgt MOC waarin hadrontherapie wordt voorgesteld en contacteert via zijn behandelde arts een erkend radiotherapiecentrum, het “verwijzend centrum”. Het verwijzend centrum stuurt een vraag naar het RIZIV, Dienst Geneeskundige Verzorging, DGV, om dossier te openen (via
[email protected]) en vraagt in parallel een advies tot behandeling aan het hadroncentrum. DGV, geeft een dossiernummer in afwachting van het volledige aanvraagdossier. Het Hadroncentrum geeft zijn akkoord tot behandeling (of niet) aan het verwijzend centrum. Bij een negatieve antwoord wordt door het verwijzend centrum advies gevraag aan een andere hadroncentrum. Het verwijzend centrum stuurt het volledige gemotiveerde aanvraagdossier en het positief advies tot behandeling in het hadroncentrum, met kostenramingen, naar DGV (per aangetekend schrijven). DGV bezorgt het volledige aanvraagdossier binnen 5 werkdagen na datum van ontvangst aan de leden van de Akkoordraad ter advies (via “beveiligde site”).
Beslissing akkoordraad(1) 6. Binnen 5 dagen na ontvangst van het dossier bezorgen de leden van de Akkoordraad hun advies aan de DGV via mailbox a. b. c.
Een positieve beslissing in geval van unaniem positief advies (min. 2 adviezen per “bank”) Een vraag om bijkomende inlichtingen, waarna de procedure per mail zich herhaalt In geval van negatieve adviezen (te motiveren) zonder consensus, uitstel van beslissing tot na samenroeping in persoon van de akkoordraad op het volgende voorziene vast vergadermoment ( 2x per maand voorzien). Bij blijvende onenigheid beslist de voorzitter. Opmerking : niet adviseren voor “eigen patiënt / rechthebbende”.
7. DGV deelt de definitieve beslissing binnen vijf werkdagen mee : - aan het verwijzend centrum die de beslissing met betaalgarantie aan het hadroncentrum meedeelt - aan de rechthebbende - aan de VI van de rechthebbende
Indien de beslissing van de akkoordraad positief is worden de kosten van de behandeling en de eventuele transport- en verblijfskosten van de rechthebbende en zijn (eventuele) begeleider ten laste genomen (betaalgarantie – mogelijkheid tot voorschot betalen is voorzien).
Beslissing akkoordraad(2) • Minstens 2 leden van elk groep/”bank” moeten stemmen om de Akkoordraad toe te laten een geldige beslissing te nemen (1 bank = Hospitalen (univ+non-univ) en 1 bank = Verzekering Instellingen). De Riziv vertegenwoordigers stemmen niet. • Elk negatief advies moet gemotiveerd worden. • Elk niet unaniem negatief advies geeft aanleiding tot een tweede ronde om advies te vragen, eerst via 2de mail ( met synthese van de eerste adviezen). Indien geen consensus per mail, zal het dossier tijdens de eerstvolgende plenaire vergadering (2 X/maand – vast geprogrammeerd) besproken worden; in geval van blijvend meningsverschil neemt de Voorzitter (RIZIV) een beslissing. • Er is geen beroepsprocedure bij de Akkoordraad voorzien.
Facturen 8. Factuur voor het positief behandelingsadvies en voor de behandeling door het hadroncentrum 9. Facturen van het hadroncentrum (zie punt 8) en factuur voor forfait coördinatie door het verwijzend centrum 10. Facturen van eventuele reis- en verblijfskosten van de rechthebbende en zijn begeleider, via verwijzend centrum naar het Riziv gestuurd
Betalingen 11. Betaling van de kosten van de behandeling* (*rekening houdende met een eventueel betaald voorschot)
12. Vergoeding van de reis- en verblijfskosten van de rechthebbende (en zijn begeleider) 13. Betaling van advies aan het behandelend hadroncentrum 14. Betaling van coördinatie aan het verwijzend centrum
Procedure E112/S2 (boven) versus RIZIV (onder) E112/S2
Week 1
Week 2
Voorbereiding H-therapie
Week 3
MOC H-Centrum accepteert
Start H-therapie
Week 4
Voorbereiding H-therapie
Week ++ Stap 6b
Week 1
1. 2. 3. 4.
Week 2
Week 3
Week 4(+x)
Week 5(+x)
Stappen 1-4 Stap 5 Stap 6 Stap 7 MOC Dossier Advies Communicatie Dossiernummer Akkoordraad Akkoordraad advies Akkoord H-Centrum ≤ 5d ≤ 5d Akkoordraad Aanvraagdossier/offerte ≤ 5d
Week 6(+x)
Start H-therapie
Week 7(+x)
Resultaat: enkel verliezers • • • •
Patient Verwijzende zorgverstrekkers Leden Akkoordraad Belastingbetaler
Conclusions • Lowering unwanted radiation dose • Biological advantages of high-LET hadrons • Main issue is cost – Equipment-size reduction – Improving patient throughput – Severe hypo-fractionation
• Radiotherapy of the future if cost issues can be resolved – – – – –
Fractionation: weeks (x-rays) to day(s) (high-LET hadrons) Excellent patient tolerance Improved repeatability Control of large and x-ray resistant tumors Better integration with systemic therapy and surgery
• Miserable Belgian RIZIV/INAMI referral procedure
Pediatric brain tumors treated at MGH, Boston METHODS: HRQoL data were prospectively collected on PRT-treated patients aged 2-18 treated at Massachusetts General Hospital (MGH). Cross-sectional PedsQL data from XRT treated Lucile Packard Children's Hospital (LPCH) patients provided the comparison data. RESULTS: Parent proxy HRQoL scores were reported at 3years for the PRT cohort (PRT-C) and 2.9years (median) for the XRT cohort (XRT-C). The total core HRQoL score for the PRT-C, XRT-C, and normative population differed from one another and was 75.9, 65.4 and 80.9 respectively (p=0.002; p=0.024; p<0.001). The PRT-C scored 10.3 and 10.5 points higher than the XRT-C in the physical (PhSD) and psychosocial (PsSD) summary domains of the total core score (TCS, p=0.015; p=0.001). The PRT-C showed no difference in PhSD compared with the normative population, but scored 6.1 points less in the PsSD (p=0.003). Compared to healthy controls, the XRT-C scored lower in all domains (p<0.001). CONCLUSIONS: The HRQoL of pediatric brain tumor survivors treated with PRT compare favorably to those treated with XRT and similar to healthy controls in the PhSD.
Yock T, et al. Quality of life outcomes in proton and photon treated pediatric brain tumor survivors. Radiother Oncol. 2014 Oct 7 [Epub ahead of print]
