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PROTON THERAPY

S. Ternier, Ph.D. Ion Beam Applications, S.A. Chemin-du-Cyclotron 3, B-1348 Louvain-La-Neuve.

1.

A N I NTRODUCTION

TO

P ROTON T HERAPY

Cancer is the second major cause of death in the developed countries. Cure from cancer is nowadays achieved for about 45% of all cancer patients using the currently available therapeutic strategies: surgery, radiation therapy and chemotherapy. When a tumor is detected in its early stages and still well localized, the use of local therapies like surgery and radiation therapy offer the patient a reasonably good chance of survival and cure. It is obvious that in such cases screening plays an important role in the early detection of the tumor. Although improvements in surgical techniques have not reduced the utilization of traditional radiation therapy, the preferred therapeutic choice remains the radical surgical excision of the disease. Surgery is the most successful therapy since it contributes 22% to the overall cure rate. Radiation therapy (RT) is the second most effective modality. RT is used with curative intent when the tumor is inoperable but is still well localized in a specific region of the body. RT contributes 12% to the cure rate alone and 6% in combination with surgery. When the disease has already spread in the whole body (with distant metastases) the chances of cure are correspondingly lower. Chemotherapy is then used with the intent to eliminate the diffused cancer cells. Chemotherapy and the other remaining modalities account for the last 5% of the total cure rate. It is foreseen that even in the immediate future surgery and radiation therapy will continue to play a major role in the control of primary solid tumors. About 50% of all cancer patients receive radiation therapies during the course of their treatment and the majority are treated by external beam therapies. Proton therapy is an advanced form of external radiation therapy that emerged from the search to devise a method to reduce the treatment volume so as to approach the target volume as close as is technically feasible. Protons offer the possibility to increase the dose in a confined treatment volume while reducing the effect on the healthy surrounding tissues. As a consequence of their physical properties, proton beams have greatly improved the dose distributions compared with photons. Proton therapy is widely acknowledged today to be the most effective method in the selective destruction of cancer cells with a large and precise dose deposit in the tumor volume. In the US, proton therapy has been recognized on a federal level for in-hospital use, satisfying criteria for efficacy and safety of patient treatments.

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Proton Therapy

2.

T HE H ISTORY

OF

P ROTON T HERAPY

In 1946 Robert Wilson proposed that proton beams would provide superior dose distributions and should be considered for clinical radiation treatment. First tests were directed at intracranial targets and used single dose protocols. The first treatments using proton or helium ion beams were at the University of California at Berkeley (1955), University of Uppsala, Sweden (1957), Massachusetts General Hospital (1961), Physics Research Institute, Dubna, Russia (1964) and the Institute for Experimental and Theoretical Physics, Moscow (1969) Today some 19 proton treatment centers are established worldwide. The Particle Therapy Cooperative Group (PTCoG) is collecting valuable information about the total number of patients receiving proton therapy, according to the most recent information (July 2001) more then 32,000 patients have received treatment by proton therapyi. Details taken from the Particles website can be found in Table 1.
Table 1: Most recent information about total patient numbers from PTCOG
WHO Berkeley 184 Berkeley Uppsala Harvard Dubna Moscow Los Alamos St. Petersburg Berkeley Chiba TRIUMF PSI (SIN) PMRC (1), Tsukuba PSI (72 MeV) Dubna Uppsala Clatterbridge Loma Linda Louvain-la-Neuve Nice Orsay iThemba LABS MPRI UCSF - CNL HIMAC, Chiba TRIUMF PSI (200 MeV) G.S.I Darmstadt Berlin NCC, Kashiwa PATRO, Hyogo PMRC (2), Tsukuba NPTC, MGH PATRO, Hyogo INFN-LNS, Catania Wakasa Bay WHERE CA. USA CA. USA Sweden MA. USA Russia Russia NM. USA Russia CA. USA Japan Canada Switzerland Japan Switzerland Russia Sweden England CA. USA Belgium France France South Africa IN USA CA USA Japan Canada Switzerland Germany Germany Japan Japan Japan MA USA Japan Italy Japan WHAT DATE DATE FIRST LAST RX RX p 1954 1957 He 1957 1992 p 1957 1976 p 1961 2002 p 1967 1974 p 1969 1974 1982 p 1975 ion 1975 1992 p 1979 1979 1994 1980 1993 p 1983 2000 p 1984 p 1987 p 1989 p 1989 p 1990 p 1991 1993 p 1991 p 1991 p 1993 p 1993 p 1994 C ion 1994 p 1995 p 1996 C ion 1997 p 1998 p 1998 p 2001 p 2001 p 2001 C ion 2002 p 2002 p 2002 RECENT DATE PATIENT OF TOTAL TOTAL 30 2054 June-91 73 9115 Apr-02 84 3445 Oct-01 230 1029 June-98 433 June-91 145 Apr-02 367 Dec-93 503 700 July-00 3429 Dec-01 88 Feb-02 311 Jan-02 1102 Dec-00 7176 May-02 21 1951 June-02 1894 Jan-01 417 June-02 34 Dec-99 448 July-02 1187 Feb-02 70 June-02 99 Dec-01 106 Jan-02 277 June-02 113 May-02 30 Jan-02 51 Apr-02 101 July-02 28 July-02 8 July-02 2 June-02 1100 pions 3808 ions 32243 protons TOTAL 37151 all particles

3.

T HE P HYSICS

OF

P ROTON T HERAPY

Accelerating the proton beam to the correct energy, the range of the proton in a patient is well controlled. A proton loses its energy in tissue through coulomb
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Proton Therapy

interactions with electrons, although a small fraction of energy is transferred through nuclear collisions. The energy loss per unit path length is relatively small and constant until near the end of the proton range, where the residual energy is lost over a short distance, resulting in a steep rise in the absorbed doseiiii. This portion of the particle track where energy is rapidly lost over a short distance, is know as the Bragg Peak as shown in Figure 1.

Figure 1: Depth dose curves for an unmodulated proton beam (Bragg peak), a modulated proton beam (spread-out Bragg peak SOBP), 22 MeV X-rays, 22 MeV electrons, 60Co -rays and 200 kV X-rays.

The initial low-dose region in the depth-dose curve, before the Bragg peak, is referred to as the plateau of the dose distribution and is 30% to 40% of the maximum dose. A single Bragg peak is too narrow to treat average target volumes. For the irradiation of typical target volumes, the beam energy is modulated to spread out the Bragg peak, which is accomplished by superimposing several beams of closely spaced energies to create a region of uniform dose over the depth of the target. In general such extended regions of uniform dose are referred to as Spread-Out Bragg Peaks or SOBPsii. The biological impact of different radiation beams is evaluated in terms of a Relative Biological Effectiveness (RBE). The RBE of a proton beam is the ratio of the dose required to produce a specified effect using a reference radiation, usually 60Co photons, to the proton dose required to produce the same effect. Protons have comparable biological effects in tissue relative to high energy x-rays used in conventional radiotherapy; in fact the RBE value of protons is approximately 1.1. Measured RBE values can be found in Table 2.

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Proton Therapy

Table 2: RBE values of modulated proton beams at the Bragg peak compared to 60 Coiii.
Reference Tepper (1977) Tissue Crypt cell Crypt cell Skin Fibrosarcoma Mammary ca. Lens Lung Testis Tail vertebrae Fibrosarcoma Fibrosarcoma Mouse Skin Endpoint Survival Survival Acute reaction Survival TCD 50/120 Cataract LD 50/100 Weight loss Growth Survival Survival LD 50/30 Contraction Proton energy (MeV) 160 160 160 160 160 160 160 160 160 70 250 250 250 No. fractions 1 20 20 1-10 1 1 1 1 1 1 1 1 10 RBE 1.19 1.23 1.13 1.16 1.11 1.09 1.02 1.23 1.32 1.06(1.01-1.12) 1.06(1.03-1.09) 1.09 1.03

Urano (1980) Urano (1984)

Anso(1985) Tatsuzaki(1993)

4.
4.1

C LINICAL R ESULTS A CHIEVED


Indications for proton therapy

IN

P ROTON T HERAPY

During the years it has become increasingly clear that the strength of proton therapy lies in the local control of the superior dose deposition efficiency (i.e. the Bragg peak). Especially in cases where the Target Volume lies closely adjacent to a radiation sensitive organ at risk. This is not so much because of the better penumbra with respect to high energy x-rays but due to the reduced dose that protons deliver outside the target volumeiv. Also when the target volume is wrapped around a sensitive organ proton will offer the best treatment. Due to the sharp distal fall-off (protons have a finite range) the dose distribution can be shaped to create complexly shaped dose distributions. At the Northeast Proton Therapy Center (NPTC) linked to Massachusetts General Hospital in Boston (U.S.) the medical staff will be able to rely on almost 40 years of proton therapy practice at the Harvard Cyclotron Laboratory. The equipment designed and installed by IBA started treating patients in November 2001. To date more then 200 patients have received treatment. In Table 3 a list of conditions, which will be treated in the coming years at the NPTC, is given.

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Table 3: Proton beams will be used at NPTC for the following treatment sites: (* Sites already treated at Harvard Cyclotron Laboratory)
Chordoma and chondrosarcoma* Craniopharyngioma* Meningioma* Thoracic and lumbar spine tumors* Pediatric tumors* Prostate tumors* Choroidal melanoma* Retinoblastoma* Age related Macular Degeneration* Malignant tumors of the orbit* Arteriovenous malformations (AVMs)* Pituitary tumors* Paranasal sinus* Nasopharynx Carcinoma of the rectum Medulloblastoma Non small cell lung cancer Hepatocellular carcinoma Pediatric soft tissue sarcomas

Good long-term follow-up data is available for several clinical sites. Five-year survival rates for chordomas and chondrosarcomas of the base of skull, are about twice as good with proton therapy compared to x-rays. Good results are obtained for choroidal melanomas (tumors of the eye), which are often treated by surgically removing the eye. Protons have also been shown to be very effective in the treatment of arteriovenous malformations, prostate and paranasal sinus. Clinical trials for several treatment sites are in progress at MGH/MEEI/HCL and other proton therapy centers worldwide 4.2 Overview of Clinical Results after 30 years of Proton Therapy

The clinical benefits of proton therapy over conventional radiation therapy can be summarized as follows. Increased tumor control, due to the ability of depositing a larger dose in the targeted volume Reduced occurrence of treatment related side effects due to the precision of the dose delivery and the resulting limited amount of radiation delivered to healthy tissues adjacent to the treatment volume. Increased long-term disease free survival rates for many types of tumors, due to the superior local tumor control rate in proton therapy. Increased dosage to the tumor, reducing the number fractions needed to treat a patient.

In 1998 an overview of proton therapy protocols was published be Krengli et alv and only recently an overview of clinical results was published by Spiro et alii. The following paragraphs try to highlight the most important results in these two publications. The complete references are however attached to this paper. 4.2.1 Prostate Carcinoma A phase III trial at MGH comparing 67.2 Gy of photons versus 75.6 Cobalt Grey Equivalent ( CGE) using a conformal perineal proton boost, was completed. From 1982-1992, 202 patients with T3-T4 prostate cancer received 50.4 Gy by four field photons. Patient then received a 25.2 CGE with conformal protons or a 16.8 Gy photon boost. No differences were found in overall survival or local recurrence-free survival in the two groups. The local recurrence free survival rate at 7 years for
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Proton Therapy

patients with poorly differentiated tumors was 85% on the proton arm and 37% on the photon arm although the proton boost did not lead to increase total survival in any subgroup. Based on the results of this first trial however, another study was proposed, also since long-term follow up of T1-T2 irradiated patients demonstrated biochemical disease free survival rates of 50%, 35% and 20% for well, moderate and poorly differentiated tumors respectively. The study that randomized patients for two different proton boost dose levels is now closed. 390 patients entered and analysis is ongoing. Results of the Loma Linda University experience in treating early stage prostate cancer have been publishedvi. 319 men with T1-T2b tumors were treated with 74 to 75 CGE proton or combined protons and x-rays. The overall 5-year biochemical disease free survival rate was 88%. 4.2.2 Uveal Melanoma As of October 1998, 2586 patients were treated with protons for uveal melanoma at MGH in collaboration with the Massachusetts Eye and Ear Infirmaryvii. Patients were treated with 70 CGE in five fractions over 7 to 9 days. The 5-year actuarial local control rate is 96% for all site within the globe with an 80% survival. The probability of eye retention at 5 years was estimated to be 90% for the entire group and 97%, 93% and 78% for patients with small, intermediate and large tumors respectivelyv. Other trials were setup with lower doses delivered in order to study a possible decrease in the number of patients that suffered from deteriorating vision. The results were positive in that there was no reduction in local control or survival rates but there was also no marked improvement in the visual outcome. 4.2.3 Sarcomas of the Skull Base and Cervical Spine A study at Massachusetts General Hospital included 169 patients with Chordoma and 165 patients with chondrosarcoma, treated with protons between 1975 and 1998viii. The 5-year actuarial control rate for skull base chondrosarcomas was 98% and 73% for chordomas. For cervical spine patient local control rates were 54% for chondrosarcoma and 48% for chordoma patients. At Loma Linda University the experience for skull base tumors showed 5-year actuarial control rates of 75% for chondrosarcoma and 59% for chordomaix. 4.2.4 Optic Pathway Glioma Seven patients were treated with optic pathway glioma at Loma Linda University between 1992 and 1997x. At median follow up of 37 months, all patients were locally controlled. Proton therapy was shown to reduce the dose to the contralateral optic nerve by 47% compared to 3D photon techniques. 4.2.5 Astrocytoma Between 1993 and 1998, 48 patients were treated for nonresectable grade II and III intracranial tumors at the Center for Proton Therapy in Orsay, Francexi. With a median follow up of 18 months, local control was 97% for nonparenchymal lesions and 43% for parenchymal lesions. 23 patients with the diagnosis of glioblastoma multiform were treated to 90 CGE with protons. The survival rate for this group is comparable to that of the best
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brachytherapy or radiosurgery series. A trend towards larger and less accessible tumors was seen in this patient population. The regimen achieved an apparent high frequency of tumor eradication in the 90 CGE volume although toxicity has been significant. 4.2.6 Benign Meningioma Meningiomas account for approximately 20% of all primary intracranial neoplasms, with an estimated 2000 new cases occurring annually in the US. 46 patients with incompletely resected or recurrent benign Meningioma were treated with a combined proton-photon technique at Harvard Cyclotron Laboratory between 1981 and 1996. The median dose was 59 CGE. Overall survival at 5 and 10 years was 93% and 77% respectively and recurrent free survival at 5 and 10 years was 100% and 88%. Few side effects were identified. 19 patients with inextirpable skull base meningiomas were treated at the Svedberg Laboratory in Uppsala, Sweden with 24 Gy in four fractions. With a minimum follow-up time of 36 months, no patients have experienced disease progressionxii. 4.2.7 Paranasal Sinus Carcinoma 32 patients with carcinomas of the paranasal sinuses were treated on an accelerated dose proton photon protocol between 1991-1996. The mean observation period was 2.7 years. Actuarial disease free survival at 3 years was 62%. The 3-year actuarial local control was 89%. These local control results appear to constitute a substantial gain over conventional surgery and photon treatment techniques. 4.2.8 Hepatocellular Carcinoma 122 patients with primary Hepatocellular carcinoma were treated with proton radiation at the Tsukuba University, Japanxiii. Impressive long term control and survival results were reported. The 7-year local control and survival results were reported as 94% and 27%. Proton therapy did not cause clinically symptomatic changes in the liver function. 4.2.9 Lung Carcinoma 37 patients with medically inoperable stage I-IIIa lung cancer were treated at Loma Linda University between 1994 and 1998xiv. With a median follow up time of 14 months, disease-free survival at 2 years was 63% for stage III patients and 86% for stage I patients. 4.2.10 Proton Radiosurgery 2987 patients were treated with single fraction proton therapy between 1961 and 1993 at Massachusetts General Hospital. The majority of patients were treated for inoperable arteriovenous malformations and pituitary adenomasxv. In 1991 a second proton radiosurgery technique was developed using a patient positioning system capable of stereotactic alignment for radiosurgery (STAR)xvi. Early results with Arteriovenous malformations, acoustic neuromas and brain metastases are comparable with those produced by other stereotactic technologies (Gamma Knife, Linear Accelerator, Elecktra Corporation, Stockholm, Sweden)

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4.2.11 Macular Degeneration with Hypervascularization Macular degeneration is the leading cause of severe visual impairment in patient over 65 years in the US. Preliminary results of 21 patients at Loma Linda University with protons in a single fraction have been reported. Regression of stabilization was found in 53% while visual acuity was improved or unchanged in 75%. A more recent analysis of 70 patients treated with 8 versus 14 CGE showed stable or improved vision in 65% of the cases after a 30-month follow up. No difference was found between the two levels of dosexvii. 4.2.12 Retinoblastoma Retinoblastoma is the most common primary ocular malignancy in childhood. In the US 200-350 new cases are estimated to occur each year. Conventional radiotherapy was employed wherever possible to avoid radical surgery, but still a number of complications exist. Proton therapy can reduce the treated volume, sparing some eye structures, the orbit bone and the soft tissues. So the incidence of complications and the risk of induction of second malignancy should decrease. Between 1986 and 1994, 16 eyes in 12 patients were treated at MGH-HCL. In all 16 eyes local control was achieved and at a follow up of 0.5-8 years no enucleation was needed. Some side effects were reported but he overall encouraging experience was the basis for the protocol for a phase II study. 4.2.13 Artero-Venous Malformations Since 1961, proton therapy has been used to treat AVMs at MGH-HCL. A single fraction between 10 and 50 CGE has been used, depending on lesion size and expected toxicityxviii. 20% complete obliteration rate is reported. A recent study to compare the dose distributions of different stereotactic techniques found that protons had a distinct advantage (in terms of dose uniformity to tumor and sparing of adjacent brain tissue) for large and irregular target volumesxix. In summary: Virtually all initial clinical findings have been positive and the treatment is clinically effective and safe. Proton therapy has demonstrated highly effective cancer disease control with excellent long-term survival rates While the clinical trial groups to date have been small they are comparable to the clinical trial groups used for three-dimensional conformal radiation treatment. Clinical findings and peer-reviewed journal articles indicate that the side effects of proton therapy are virtually minimal to non-existent when compared to conventional radiation therapy and three-dimensional conformal radiation treatment, which will be of paramount importance for the treatment of children. This subject is separately discussed in the following paragraph.

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CASE FOR

P AEDIATRIC R ADIATION O NCOLOGY .

4.2

The pediatric risks of proton therapy

Generally, compared to adults, cancerous tumors in children are rare but when apparent they can represent clinically very challenging cases. Often children can be cured of their tumors but the therapy can leave them with devastating late effects from the radiation. Radiation for example can have important delayed effects on the central nervous system such as radiation necrosis of nervous tissues but also benign and malignant intracranial tumors can develop in irradiated fields, particularly in childrenxx. The issues of depositing radiation in non-tumor tissues in the pediatric population are well known. It increases the risk for second malignancies caused by the radiation and children run a higher risk of radiation-induced tumors then adults. The radiation can also cause either atrophy or stops growth of tissues receiving radiation as well as dysfunction and fibrosis of the organ it irradiates. 4.2 What can protons bring

Therefore a growing interest is developing in limiting treatmentassociated toxicity in paediatric patients for example diagnosed with medulloblastoma. Accurate conformal treatment should reduce the early and late side effects associated radiation therapy without a negative impact on curexxi. Protons provide the ultimate in conformity while keeping the integral dose to normal tissues low. A number of cases have already been described in literature, all yielding for more support to the proton treatment modalities to be used in pediatric cases. In the pediatric patient, avoidance of even moderate amounts of irradiation to normal tissues is of paramount importancexxii. Local control and survival can be improved in histologies requiring high radiation dose without increased incidence of late toxicities. Proton Therapy offers a high degree of conformity to target volumes and steep dose gradients, thus leading to substantial normal tissue sparing in high and low dose areas. A study published 1999 shows that it is expected that this will result in decreased long-term toxicity in the maturing childxxiii. A more recent study about the use of proton radiation therapy in children with aggressively recurring tumors after major skull base surgery, shows it can offer a considerable prospect of tumor control and survival. Longer follow-up is however necessary to assess the real value of protons in particular in regard to bone growth and cosmetic outcomexxiv. 4.2 Intensity modulated proton therapy

Modulated proton beams may also help to significantly reduce the irradiation of normal brain while optimally treating the supratentorial subsites at higher risk for relapse. A decrease in morbidity can be expected from protons and both optimised proton plans compared to whole brain irradiationxxv and a risk assessment of secondary cancer incidence after treatment of Hodgkins with photon and proton irradiation showed that scanning techniques can decrease the avoidable cancer incidence by a factor of two with respect to photon treatmentxxvi
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A recent study estimated secondary cancer incidence using a model based on Publication No. 60 of the International Commission on Radiologic Protectionxxvii. This model allows estimation of absolute risks of secondary cancer for treatment plans based on dose-volume distributions for the not-target organs. The incidence of treatment related secondary cancers may be significantly reduced by using proton beams instead of standard X-ray beam (with or without intensity modulated radiation therapy) in paediatric patients and the potential for a significant reduction of these secondary cancers represents a strong additional argument for the support of the development of proton therapy for most radiotherapy indications in paediatric oncology. (Miralbell 2002)

6.
6.1

P ROTON T HERAPY L INKS


America

Northeast Proton Therapy Center: http://cancer.mgh.harvard.edu/cancer_radonc_nptc_home.htm LLUMC, California: http://proton.llu.edu U of California, Davis: http://crocker.ucdavis.edu/cnl/research/eyet.htm Midwest Proton Radiation Institute: http://www.iucf.indiana.edu National Association for Proton Therapy: http://www.proton-therapy.org TRIUMF, Canada protons: http://www.triumf.ca/welcome/proton_thrpy.html TRIUMF, Canada pions: http://www.triumf.ca/welcome/pion_trtmt.html Harvard Cyclotron Laboratory: http://neurosurgery.mgh.harvard.edu/hcl/ 6.2 Europe

CPO, Orsay, France: http://www.sop.inria.fr/epidaure/personnel/bondiau/CPO_base/cpo_base.htm PSI, Switzerland: http://www.psi.ch/ Proton Oncological Therapy, Project of the ISS, Italy: http://top.iss.infn.it TERA foundation, Italy: http://www.tera.it Catania, Italy: http://lnsuni2.lns.infn.it/~catana/ GSI homepage: http://www.gsi.de The Svedborg Laboratory, Sweden: http://www.tsl.uu.se Clatterbridge Centre for Oncology: http://synaptic.mvc.mcc.ac.uk/simulators.html ITEP, Moscow, Russia: http://www.protontherapy.itep.ru 6.3 Asia

Tsukuba, Japan: http://www-medical.kek.jp Tsukuba, Japan - new facility plans: http://www-medical.kek.jp/devnewfac.html HIMAC, Chiba, Japan: http://www.nirs.go.jp/ENG/particl.htm (ENG case sensitive) 6.4 Africa

NAC, South Africa: http://medrad.nac.ac.za/index.htm

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7
7.1

R EGULATORY O VERVIEW .
FDA

Proton Therapy has been recognized by the United States Food and Drug Administration (FDA) and the IBA system received FDA 510k approval in July 2001. 7.2 CE marking

IBA is an ISO 9001 and EN46001 certified company. IBA also received the CE marking for its proton therapy system in August 2001. 7.3 Others

In many other countries the regulatory affairs agencies refer to either CE marking or FDA approval. Gradually, as projects arise, IBA will work with the appropriate agencies in order to obtain the necessary manufacturer certificates in different parts of the world. IBA is currently in the process of filing for the SDA in China and the KFDA in Korea.

T HIRD P ARTY C OVERAGE

AND

P AYMENT

In the US, Proton Therapy has already been integrated into the reimbursement system of several private insurance companies in acknowledgement of its superior efficiency and its impact on reducing the overall costs of treatment. In certain states in the US, reimbursement rates for Proton Therapy Treatments have been fixed per fraction. An average weighted revenue per patient in the US is estimated at 21,473$. Extrapolation of this information to other regions in the world will need careful considerations regarding the similarities and differences with the US coverage system. For each possible treatment site, the percentage to the total amount of patients will need to be estimated and an estimation for the reimbursement rates for the different sites must be taken into account. The total reimbursement per site can differ according to diagnostic times needed and fractions needed to complete a treatment. If different coverages exist an estimation of a number of patients supported by different coverage systems must be taken into account.

9
9.1

T HE F UTURE

OF

P ROTON T HERAPY

Intensity Modulated Treatments

In recent years also in conventional radiation therapy, technological advances were made leading to the new approach of Intensity Modulated Radio Therapy (IMRT). While IMRT is certainly a large improvement for the conventional radiotherapy and some medical professionals may estimate the photon IMRT will become established enough to make proton therapy redundant, some physics aspects must be looked into. It is true that IMRT may come very close to the dose distribution achieved in passive scattering methods with protons, but a comparative study was published recently
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where a comparison was made between IMRT and Intensity Modulated Proton Therapy. The best comparison today can be made by looking at the treatment plans for the different approaches, where as shown in the example Figure 2 it takes 9 photon fields to construct a highly conformal dose distribution with a good sparing of the brain stem for the treatment of a nasopharyngeal tumorxxviii. The availability of a large amount of degrees of freedom in the beam delivery and the strength of the mathematical methods make it possible to produce very satisfying dose distributions, shaped in all 3 dimensions to conform precisely to the target volume.

Figure 2: An example of intensity modulated treatment planning with photons. Through the addition of 9 fields it is possible to construct a highly conformal dose distribution with good dose sparing in the region of the brain stem XXII.

Protons are charged particles and narrow beams can be magnetically scanned onto any target volume. In Figure 3 an example is shown for the same patient as in Figure 2, where a very high degree of conformity with target volume is shown using only four dose fields with protons.

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Figure 3:Example of intensity modulated therapy with protons. A high degree of conformity is achieved using a low number of dose fields. The advantage compared with photons is the general reduction of dose burden outside of the target volume XXII.

Another important comparison point is the integral dose delivered during the course of the treatments in the different treatment modalities. While IMXT can come close in target conformity to the standard methods of delivering Proton Therapy, the total dose deliverd in the treatments is substantially higher. A possibility to deliver also proton in an intensity modulated treatment will allow to reduce slightly the integral dose while increasing substantially the conformity to the target volume. Figure 4, illustrating these principles was presented by Dr. J. Loeffler from the NPTC at the Astro conference in 2001. high

IMPT Conformity 3D PT

IMXT

3D-XRT

high Integral Dose Figure 4: Illustration of the expected integral dose versus the tumor conformity in the different treatment modalities. Low IBA is working on the development of what is called the Pencil Beam Scanning treatment mode. In this treatment mode, a pencil beam will be magnetically scanned over the target volume while simultaneous control of both the beam intensity and the beam spot speed is achieved. Since IBA pencil beam scanning does not use patient specific collimators and compensators, the setup time for each patient will most likely be reduced allowing a higher patient throughput. The pencil beam scanning algorithm has been tested at the NPTC and has proven it functionality. The design and building of the prototype is currently underway and test measurements will be performed with the prototype in the autumn of 2002. Only

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when the pencil beam scanning prototype is fully cleared by regulatory agencies, will IBA start marketing the system. 9.2 New Treatment Centers

PTCog collects information regarding possible new treatment facilities in the world. The status as known in July 2001 is reflected in Table 4.
Table 4: Proposed New Facilities for Proton &Ion Beam Therapy
INSTITUTION Bratislava IMP, Lanzhou Shizuoka Cancer Center Rinecker, Munich Wanjie, Zibo PSI PLACE Slovakia PR China Japan Germany China Switzerland TYPE p, ion C-Ar ion p p p p p p p p p, ion p p p, ion p, ion p p p p p p p 1ST RX? 2003 2003 2003 2003 2003 2004 2005 2006 2001? ? 2004? 2004? 2004? 2005? 2007? ? ? ? ? ? ? ? COMMENTS 72 MeV cyclotron; p; ions; +BNCT, isot prod. C-ion from 100MeV/u at HIRFL expand to 900 MeV/u synchrotron 235 MeV; 2 gantries; 1 horiz; funded. 4 gantries, 1 fixed beam, 230 MeV, scanning beams. Under construction. 230 MeV synchrotron, 2 treat rooms. Addition of a 250MeV cyclotron, 2nd gantry, new 1 fixed 235 MeV cyclotron, 2 gantries, 1 horiz. 230MeV,1 gantry,1 horiz.+30o beams,1 horiz.+15o.beams 250MeV synchrotron/230MeV cyclotron;3 gantry,1 fixed 4 treatment rooms, some with gantries. synchrotron; 2 gantry;1 fixed beam rooms;1 exp. room Accelerator, 3 gantries; 1 fix + 1 exp beam rooms 235MeV cyclotron; 2 gantries; 1 fix + 1 exp beam rooms 2p gantry;1 ion gantry;1 fixed p;1 fixed ion;1 exp room Contract signed with IBA. cyclotron; 1 gantry; 1 fixed 230 MeV cyclotron; part of the CASIM project 70 MeV linac; expand to 200 MeV? including 320 MeV; compact, probably no gantry 60 MeV proton beam. 300 MeV protons; therapy & lithography

NCC, Seoul Korea IThemba LABS, Somerset South Africa West CGMH, Northern Taiwan Taiwan Erlangen CNAO, Milan & Pavia Germany Italy

M. D. Anderson Cancer TX, USA Center University of Florida FL, USA Heidelberg Med-AUSTRON Xi an, Shanxi Province Central Italy Clatterbridge TOP project ISS Rome 3 projects in Moscow Germany Austria China Italy England Italy Russia

Krakow Poland Proton Development N.A. IL USA Inc.

10

C ONCLUSIONS

Over the course of the last 30-40 years, proton therapy has shown without a doubt its superiority for conforming a radiation dose to a target volume. Over 30,000 patients have been treated worldwide and in the next months the second hospitalbased facility in the US will start patient treatment. Proton therapy is recognized by FDA for in-hospital use, satisfying criteria for efficacy and safety and is also recognized by Medicare in the US. Reimbursement rates have been set on a federal level. Especially the FDA approval will allow proton therapy to proliferate substantially, when proton therapy becomes widely available, it will be technically possible to offer an objectively better treatment to a large number of patients. Thanks to the ongoing efforts both in industry and renowned research institutes, the future of proton therapy will be secured as improvements to the technology are already emerging in the form of sophisticated scanning systems providing again superior dose distributions.
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11.

R EFERENCES

http://neurosurgery.mgh.harvard.edu./hcl/ptles.htm

Spiro et al, Chapter 65 of Cancer, Principle and Practise of Oncology 6th edition. (ISBN: 0-7817-2229-2)
ii iii

Sumitomo Heavy Industries, Private Communication

iv

M. Goitein, 5th International Meeting on Progress in Radiation Oncology ICRO/OCGO 5, Salzburg, Austria 10-14 May 1995.

Krengli et al, Review of current protocols for protontherapy in USA, Tumori 1998;84:209 Slater et al,Conformal proton therapy for early-stage prostate cancer Urology, 1999;53,978 Munzenrider ,Proton therapy for uveal melanomas and other eye lesions, Sthralentherapy und Onkology 1999;175[suppl 2],57

vi

vii

viii

Munzenrider et al, Proton therapy for tumors of the skull base [Review] Strahlentherapie und Onkologie, 1999; 175 [Suppl 2]:68

Hug et al, Proton radiation therapy for chordomas and chondrosarcomas of the skull base, J. Neurosurg 1999;91:432
ix x

Fuss et al, Proton Radiation Therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique, Int. J. Radiat Oncol Biol Phys 1999;45:1117

Habrand et al, Radiotherapy using a combination of photons and portons for locally aggressive intracranial tumors. Preliminary results of protocol CPO94-C1, Cancer Radiother 1999;3:480
xi xii

Gudjonsson et al, Stereotactic irradiation of skull base meningiomas with high energy protons, Acta Neurochir (Wien) 1999;141:933

xiii

Matsuzaki et al, New, effective treatment using proton irradiation for unresectable Hepatocellular carcinoma, Intern Med 1995;34:302

Bush et al, Proton-beam radiotherapy for early stage lung cancer, Chest 1999;116:1313
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Amin-Hanjani et al, Stereotactic radiosurgery for cavernous malformations: Kjellbergs experience with proton beam therapy in 98 cases at the Harvard cyclotron, Neurosurgery 1998;42:1229
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Harsh et al, Stereotactic proton radiosurgery,Neurosurg. Clin. North Am 1999;10:243

Yonemoto et al, Phase I/II study of proton beam irradiation for the treatment of subfoveal choroidal neovascularization in age related macular degeneration: treatment
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Proton Therapy

techniques and preliminary results, Proceedings 37th Annual ASTRO meeting, October 8-11,1995 Kjellberg et al, Bragg peak proton-beam therapy for arteriovenous malformation of the brain, N. Engl J Med 1983;309:269
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Serago et al, Comparison of proton dose distributions with multi-arc conformal linac techniques for radiosurgery applications Med Phys 1993; 20:868

Salvati et al, Radiation induced Shwannomas of the nervous system. Report of five cases and review of the literature J.Neurosurg Sci. 2003 Jun;47(2):113-116 xxi St-Clair et al, Advantages of protons compared to IMRT in the treatment of medulloblastoma, Proceedings of the 42nd ASTRO meeting, 138
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Hug et al, Proton radiation therapy for paediatric malignancies: status report. Strahlenther. Onkol. 1999 Jun Suppl2:89-91

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Fuss et al, Proton Radiation Therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique, Int. J. Radiat Oncol Biol Phys 1999;45:1117

Hug et al, Proton radiotherapy in management of pediatric base of skull tumors Int. J. Radiat. Oncol. Biol. Phys. 2002 ;52(4):1017-1024
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Miralbell et al, Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume Int. J. Radiat. Oncol. Biol. Phys. 1997 ;38(3):477-484
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Schneider et al, Comparative risk assessment of secondary cancer incidence after treatment of Hodgkins disease with photon and proton radiation Radiat Res 2000 Oct;154 (4):382-388

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Miralbell et al. Potential reduction of the incidence of radiation-induced second cancers by using proton beam in the treatment of pediatric tumors Int. J. Radiat. Oncol. Biol. Phys. 2002 ;54(3):824-829

E. Pedroni , Will we need proton therapy in the future, Europhysics News 2000); 31, No 6.
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