Cancer Therapy Vol 4, 231-240, 2006

Proton radiation therapy in oncology: Review of present clinical indications

Review Article

Maurizio Amichetti*, Augusto Lombardi, Carlo Algranati, Marco Schwarz

ATreP, Provincial Agency for Proton Therapy, Trento-Italy

__________________________________________________________________________________

*Correspondence: Maurizio Amichetti M.D., ATreP, Provincial Agency for Proton Therapy, Via Perini, 181, 38100 Trento-Italy; Tel: 39 0461 390409; Fax: 39 0461 391648; e-mail: amichett@ect.it

Key words: proton therapy, radiotherapy, cancer

Abbreviations: “quality adjusted life years”, (QALY); 3D-conformal radiation therapy, (3D-CRT); Gray equivalent, (GyE); industrial provider, (IBA); Intensity-Modulated Radiation Therapy, (IMRT); organ at risk, (OAR); proton therapy, (PT); relative biological effectiveness, (RBE); stereotactic radiotherapy, (SRT)

Received: 7 July 2006; Accepted: 11 July 2006; electronically published: July 2006

Summary

Radiotherapy has been rapidly changing in recent years moving towards the ability to reduce the radiation exposure of normal tissue and to increase treatment conformality, i.e. the ability to concentrate radiation dose in the intended target area. Due to their physical properties, proton beams are a very attractive radiation source to address this issue. Protons have a unique advantage over photons because of the superior ability of confining the high-dose region to the target while minimizing the dose to the surrounding normal tissues. These characteristics translate in an improved therapeutic ratio and have been exploited in treating more and more frequently several tumors in adults and children with very promising results. The availability of protons in hospital-based facilities currently planned and built in Europe, Asia, and United States will soon increase the role of protons in the multimodal approach to cancer therapy.

I. Introduction

Radiotherapy is based on the principle of using ionizing radiation to cause irreparable damage to the DNA of tumor cells, thus inhibiting their duplication. From the point of view of physical interaction with radiation, tumor cells are not different from normal cells, so the irradiation is not causing per se a selective damage in tumors. Consequently, methods have to be devised to maximize the effect of radiation on tumor cells and to spare the surrounding healthy tissues as much as possible.

Charged particle beams of accelerated protons accomplish the function of an almost ideal external radiation source for cancer therapy. The main property is that fast moving protons, once stopped in a body, can be directed to deliver most of their energy in an uniform manner in the target. None or very little energy is left for potential damages beyond the target volume. In clinical terms, that means depositing a high radiation dose in the tumor and a low dose outside. This property allows irradiating tumor targets located next to critical structures with high doses avoiding or reducing important side effects in organ at risk (OAR).

After the first proposal of their clinical utility in the seminal article by Wilson in 1947, protons have been extensively studied in the 70’s and 80’s mainly in research laboratories dedicated to nuclear physics where the accelerators (cyclotrons or synchrotrons) were located. Only recently, on the basis of positive clinical results, there is a growing interest in hospital-based clinical facilities. Beginning with the first patients treated in the fifties more than 40.000 patients have now been treated worldwide (Table 1), (Sisterson, 2005). Several centers are proposed or under construction and the clinical indications increasingly expand following the pioneering treatments of ocular and base of skull tumors.

II. Physical properties

External radiotherapy treatments are usually delivered with photon beams. The physical interaction of photons with biological tissues is such that for all practical purposes it is impossible to control the penetration depth of photons in tissue. In other words, photons give a radiation dose significantly different from zero over a large thickness of tissue (Figure 1), thus delivering dose to the patient not only in the tumor volume but also in the surrounding tissue.

The technique typically used in photon radiotherapy to minimize the dose to the healthy tissues consists in irradiating the tumor from many different directions, thus creating a high dose region on the target and a low dose region elsewhere. Conventional radiotherapy plans are typically designed by defining a number of beam directions (typically two to seven), each beam direction having a single portal. In other words, for a given beam direction, a uniform intensity profile is applied. While in the past field sizes and shapes were defined on 2-D anatomy projection obtained with fluoroscopy, in the 90’s the so-called 3D-conformal radiation therapy (3D-CRT) was introduced, where CT data were available to define

Table 1. Patients treated with protons worldwide until December 2004

WHO	WHERE	WHAT	DATE	DATE	RECENT	DATE
			FIRST	LAST	PATIENT	OF
			RX	RX	TOTAL	TOTAL
Berkeley 184	CA. USA	p	1954	— 1957	30
Berkeley	CA. USA	He	1957	— 1992	2054
Uppsala (1)	Sweden	p	1957	— 1976	73
Harvard	MA. USA	p	1961	— 2002	9116
Dubna (1)	Russia	p	1967	— 1996	124
ITEP, Moscow	Russia	p	1969		3785	Dec, 2004
Los Alamos	NM. USA	p -	1974	— 1982	230
St. Petersburg	Russia	p	1975		1145	Apr, 2004
Berkeley	CA. USA	ion	1975	— 1992	433
Chiba	Japan	p	1979		145	Apr, 2002
TRIUMF	Canada	p	1979	— 1994	367
PSI (SIN)	Switzerland	p	1980	— 1993	503
PMRC (1), Tsukuba	Japan	p	1983	— 2000	700
PSI (72 MeV)	Switzerland	p	1984		4182
Uppsala (2)	Sweden	p	1989		418	Jan, 2004
Clatterbridge	England	p	1989		1372	Dec, 2004
Loma Linda	CA. USA	p	1990		9585	Nov, 2004
Louvain-la-Neuve	Belgium	p	1991	– 1993	21
Nice	France	p	1991		2555	Apr, 2004
Orsay	France	p	1991		2805	Dec, 2003
iThemba LABS	South Africa	p	1993		468	Nov, 2004
MPRI (1)	IN USA	p	1993	– 1999	34
UCSF - CNL	CA USA	p	1994		632	Jun, 2004
HIMAC, Chiba	Japan	C ion	1994		1796	Feb, 2004
TRIUMF	Canada	p	1995		89	Dec, 2003
PSI (200 MeV)	Switzerland	p	1996		209	Dec, 2004
G.S.I Darmstadt	Germany	C ion	1997		198	Dec, 2003
H. M. I, Berlin	Germany	p	1998		546	Dec, 2004
NCC, Kashiwa	Japan	p	1998		300	Oct, 2004
Dubna (2)	Russia	p	1999		296	Dec, 2004
HIBMC, Hyogo	Japan	p	2001		483	Dec, 2004
PMRC (2), Tsukuba	Japan	p	2001		492	Jul, 2004
NPTC, MGH	MA USA	p	2001		973	Dec, 2004
HIBMC, Hyogo	Japan	C ion	2002		30	Dec, 2002
INFN-LNS, Catania	Italy	p	2002		82	Oct, 2004
WERC	Japan	p	2002		19	Oct, 2004
Shizuoka	Japan	p	2003		100	Dec, 2004
MPRI (2)	IN USA	p	2004		21	Jul, 2004
Wanje, Zibo	China	p	2004		1	Dec, 2004
					1100	pions
					4511	ions
					40801	protons
				TOTAL	46412	all particles

Figure 1. Energy deposition plots comparing various radiation sources.

treatment fields based on the 3D anatomy of targets and organs at risk. In 3D-CRT the dose distributions are therefore shaped by defining beam number and orientation, field shape and weight.

In the last decade, the possibility of achieving additional dose conformality was significantly increased with the introduction of Intensity-Modulated Radiation Therapy (IMRT) (Webb, 2001). IMRT is a technical improvement of CRT, aiming at an increased capability of applying non–uniform (modulated) intensity of radiation over the treatment field allowing the best compromise between tumor irradiation and OAR sparing. The irradiation patterns of IMRT are characterized by a large number of fields, each with its own shape and weight, which are obtained with to a highly computerized treatment planning procedure. Thanks to that, and to the technical improvements of the delivery methods at the linear accelerator, with IMRT it is possible to generate dose distributions that follow more accurately the shape of the target volume, thus reducing the volume of organs at risk irradiated at high doses

As we said earlier, with photons it is possible to modulate the dose only in two-dimension, while modulation in the third dimension (i.e. along the beam axis) is impossible due to the properties of physical interactions between photons and matter.

With protons, on the contrary, the penetration depth can be controlled within very few millimeters by just properly ‘tuning’ the energy (Figure 1). The physics of interaction of protons with tissues is such that protons deliver little dose in their path and then, just before stopping, lose most of their energy, thus delivering most of the dose at the point referred to as the ‘Bragg peak’. As a consequence, while photon fluence can be controlled just in the plan orthogonal to the beam direction by properly shaping the beam apertures, proton fluence can be controlled in all three dimensions of space, including along the beam directions. The most evident effect of the sharp distal dose fall of is that it allows to spare those OARs located just downstream of the target along the beam direction.

In addition, proton beams used for the clinical treatments have very good ballistic and geometrical qualities. The geometrical definition is of the order of a millimeter and also the precision for spotting the target is of the same magnitude. The energy deposition depth, as shown in the picture (Figure 1), is very well controlled specially in the beam direction with a sharp distal dose fall off.

Finally, from a radiobiological point of view, protons show a small benefit compared to X-rays, having a relative biological effectiveness (RBE) of 1.1 (Paganetti et al, 2002).

III. Equipment and beam delivery

Figure 2 schematically demonstrates the basic features that constitute a proton therapy (PT) apparatus: the high energy proton source which is an accelerator delivering protons at predetermined velocity (cyclotron or synchrotron) the beam transport line, which brings the protons to a certain space position preserving their geometrical properties the beam delivery line. This is the most demanding part from the technology point of view. It can be designed as a fixed beam delivery line or as a rotating system (gantry). In the second option, the beam can be delivered to the patient from any angle (360°) similar to the conventional X-ray radiotherapy linear accelerator.

The patient couch for the proper positioning and centering of the body on the axis Figure 3 shows a possible layout.

IV. Clinical indications

The attractiveness of proton beam from a clinical point of view is based on its capability to deposit its energy at precise and controllable depths and to stop in the target.

Proton therapy has been historically used in quite rare tumors located close to critical normal tissues and, in particular, close to serially organized tissues (i.e. spinal cord) where it is difficult to achieve an adequate radiation dose and avoid fatal complications even with a small local overdose or unwanted small dose deposition. Even though PT has been delivered for more than 40 years, the accumulated experience in the clinical setting can still be considered limited and PT is probably far from having reached its best performances. However, many types of tumors have been treated and interesting results obtained. A review of the results obtained for selected tumor sites is reported below.

A. Eye

Uveal melanoma is the most frequently observed ocular tumor. Enucleation has been for years the standard treatment method of cure for this tumor, but it has been recently reassessed due to other therapeutic developments. Conservative methods such as trans-scleral local resection, transretinal resection, diode laser phototherapy and radiotherapy techniques (brachytherapy with radioactive plaques, stereotactic radiotherapy (SRT), proton

Figure 2. Schematic of the basic equipment involved in the proton therapy.

Figure 3. Possible layout proposed by an industrial provider (IBA) with one cyclotron, two gantries, and one fixed beam delivery systems.

irradiation) are an adequate alternative to enucleation depending on tumor size, location and growth rate (Damato, 2006).

Radiotherapeutic treatments induce growth arrest within the tumour and its slow involution over several years. Given the proximity to the tumor of critical structures of the eye, including cornea, lens, optic nerve and fovea, conventional radiotherapy is not able to preserve useful vision and special techniques as the above mentioned are needed. Although ocular retention rates are excellent, regrowth of tumors due to resistance and neovascular glaucoma can lead to enucleation of up to 10% of affected eyes. The goal of irradiation techniques is to maintain an useful vision by employing a treatment with a few side effects as possible. Protons and other charged particles offer significant advantages for tumors near the optic nerve and macula and large tumors in comparison with radioactive plaques (Gragoudas and Lane, 2005) and seem favourable in term of side effects development rates (Puusaari et al, 2004). In comparison with SRT, protons can result in similar levels of dose conformation but with better dose homogeneity and with a better sparing of the homolateral structures most important for visual acuity, lacrimal gland, and of all the contralateral OAR (Weber et al, 2005, Hocht et al, 2005).

Ocular tumors are treatable with protons in non-hospital designed facilities in a relatively simple fashion with fixed fields of low energies (60-70 MeV), due to the intrinsic dose localization properties of the beam and the relative ease of head immobilization. The most significant experiences in the definitive treatment of uveal melanoma are those of the Massachusetts General Hospital (Munzenrieder, 1999), Paul Scherrer Institute (Egger et al, 2003), Orsay (Dendale et al, 2006), Nice (Courdi et al, 1999), Clatterbridge (Damato et al, 2005) and Berlin (Hocht et al, 2004) where thousands of patients have been treated obtaining local control rates between 89% and 97% and eye preservation in 87.5-92% of cases (Table 2) with limited side effects. These results indicate that the conservative treatment with PT can be considered the treatment of choice for uveal melanoma, especially if deeply located and large in size, having resulted in a comparable risk of incidence of metastasis respect to enucleation.

Very good results are reported also in the treatment of retinoblastoma approaching a local control of 100% (Krengly et al, 2005), orbital rhabdomyosarcoma (Yock et al, 2005), and choroidal metastases (Tsina et al, 2005).

Another field of interest is that of macular degeneration disease of the retina, a typical non-oncological disease of the old age where PT can reach a stabilization or an improvement in 75% of the cases (Yonemoto et al, 1996). However, the discussion of the appropriate treatment and of the definitive role of PT in this disease remains still open (Ciulla et al, 2002).

B. Skull base and paraspinal tumors

Tumors of the base of the skull are typically located very close to dose-limiting tissues (brain, brainstem, optic chiasm, optic nerves, spinal cord, pituitary) and are represented mainly by chordomas and chondrosarcomas; these often slow-growing lesions have a low potential of metastatization and therefore local tumor control can result in cure of the patient (Mendenhall et al, 2005). These tumors cannot generally be resected completely and the dose traditionally safely deliverable with conventional radiotherapy was often limited to typical levels of 60-65 Gy (Catton et al, 1996; Zorlu et al, 2000). The results of PT are clearly superior in comparison with those obtained by conventional radiotherapy, even though other new radiotherapeutic modalities such as SRT with Cyberknife (Gwack et al, 2006) or IMRT and tomotherapy (Soisson et al, 2006) could be a potentially valuable treatment option once the long-term results are defined.

Results of the literature show that with protons it is possible to deliver high doses of radiation (up to 70-74 Gy) to the tumor while observing a low risk of damage to critical organs. Specifically for chondrosarcomas and subgroups of chordomas postoperative PT after maximal surgery can be now considered the treatment of choice (Table 3 for a summary of the results).

Benign meningiomas in general do not require radical dose levels for long term tumor control and can well be treated with modern photons radiotherapy (Metellus et al, 2005; Milker-Zabel et al, 2005). Here proton radiation therapy is reserved for hard-to-treat unresectable disease in order to minimize risks of side effects since these patients can live for a long time. However, for Atypical and Malignant Meningiomas the results after conventional RT are still disappointing and high dose RT as delivered by PT has demonstrated some encouraging results (Table 3). Prospective studies in this field are needed.

Table 2. Five-year results of proton therapy in uveal melanoma

Institutio / (Authors)	years	N.	LC	Eye ret.	Surv.
MGH / (Munzenrider et al, 1999)	1975-98	2586	96%	90%	80%
Nice / (Courdi et al, 1999)	1991-96	538	89%	- -	77%
PSI / (Egger et al, 2003)	1984-99	2645	95%	89%	73%
Clatterbridge / (Damato et al, 2005)	1993-03	349	96.5%	90.6%	90%
Berlin / (Hocht et al, 2004)	1998-03	245	°95.5%	°87.5%	-
CPO / (Dendale et al, 2006)	1991-01	1406	96%	92%	79%

Abbreviations: MGH: Massachussets General Hospital; PSI: Paul Sherrer Institute; CPO: Centre de Protontherapie de Orsay; LC: local control; Surv.: survival; N.: number; ret.: retention ° at three years

Table 3. Results* (five-year local control rate) achieved with protons in tumors of the base of the skull

	MGH	NAC	^PSI	°CPO	Tsukuba
Meningioma	88%	89%	91.7%	98%
Chordoma	73%	76%	87.5%	53.5%	46%
Chondrosarcoma	98%	92%	100%	85%

Abbreviations: MGH: Massachussets General Hospital; PSI: Paul Sherrer Institute; CPO: Centre de Protontherapie de Orsay; LLUMC: Loma Linda University Medical Center; NAC: National Accelerator Centre, South Africa

*data obtained from the reports of Munzenrider and Liebsch 1999; Hug et al, 1999; Wenkel et al, 2000; Vernimmen et al, 2001; Noel et al, 2003, 2005a,b, 2005; Weber et al, 2004a,b; Igaki et al, 2004.

^: data at 3 years; ° data at 4 years obtained with mixed beams (protons/photons)

Another very similar clinical situation is represented by the juxtaspinal cord tumors that are rarely completely resectable. Usually they invade or adhere to spinal cord, vertebrae or peripheral nerve roots. Moreover, spinal cord represents a dose limiting organ for conventional radiotherapy, as the maximum doses safely deliverable to this organ are in the range of 45-55 Gy, and therefore inadequate specifically for macroscopic residual disease. The dose given to residual or compressing masses could be safely increased in comparison with three-dimensional conformal photon treatment (Isaccson et al, 1997). High rates of local control can be observed with the use of protons (Fagundes et al, 1995).

C. Arteriovenous malformations of the brain

Arteriovenus malformations can be treated with interesting results and a high rate of obliteration particularly in large sized lesions (Miralbell and Urie, 1993; Amin-Hanjani, 1999; Vernimmen et al 2005). Non resectable lesions or not fully embolizable ones are usually treated at MGH and LLUMC with two fractions of 10 Gy (Laramore and Phillips, 2004).

D. Prostate

The treatment of prostate cancer could benefit from an improved dose distribution (Sandler et al, 1992). This is the only site until now where protons have been used in a randomized trial to test the effect of dose escalation (Shipley et al, 1995). After a pelvic dose of 50.4 Gy with photons, a 25.2 Gy equivalent proton boost was compared with 16.8 Gy photon boost. Results of proton boost were favorable only in a subgroup of patients with poorly differentiated tumors but late toxicity was increased (Benk et al 1993). It is however to note that in this trial, due to the limitation of the beam, simple techniques were used. Further studies have been developed with more modern proton facilities showing favorable results with more than 70% of biochemical control in an unselected population (Slater et al, 2004, Rossi et al, 1998, Hara et al, 2004) with minimal morbidity. A recently published phase III trial (Zietman et al, 2004) performed a dose escalation with a conformal proton boost of 19.8 or 29.8 Gray equivalent (GyE) followed by a 3D X-ray pelvic treatment to total doses of 70.2 GyE and 79.2 GyE, respectively. Higher radiation doses resulted in an increase of biochemical failure-free survisal without any comparable increase in high-grade acute or late morbidity. The published series are however limited and even if they compare well with those of radical surgery, brachytherapy, and of the most modern radiotherapeutic approaches (3-D conformal radiotherapy and IMRT), they have relatively short follow-up periods and require further confirmation in larger, possibly controlled, trials.

E. Head and neck

Some tumors of the head and neck, such as the maxillary sinus tumors, represent a challenge in radiotherapy for their shape, dimensions and location that make it very difficult to deliver curative doses (Miralbell et al, 1992). PT can offer potential improvement in the outcome of these tumors. Many tumors have been treated in this anatomic area with encouraging results and quite limited toxicity (Tokuuye et al, 2004). PT has been used also in nasopharyngeal recurrent carcinoma (Lin et al, 1999) oropharyngeal tumors (Slater et al, 2005) with mixed photon-protons therapy and with a multimodal approach in neuroendocrine tumors of the sinonasal tract (Fitzek et al, 2002). Excellent results can be obtained in the treatment of acoustic neuroma (Bush et al, 2002) particularly in large and irregularly shaped tumors with radiosurgical methods or with a fractionated course.

F. Lung

The current standard dose for definitive radiotherapy is 60-66 Gy, which is significantly lower than the dose required for more than 50% local control; a dose of about 80 Gy is required for a probability of LC of 90% (Martel et al, 1999; Murshed et al, 2004). Unfortunately, significant toxicities at normal lung, spinal cord, esophagus, and heart limit the possibility of dose escalation for conventional fractionated RT. At LLUMC patients with inoperable (for medical reasons) non-small cell lung cancer were treated with hypofractionated protons obtaining particularly favorable response in stage I patients (86% disease free at 2 years) (Bush et al, 1999). Recent data of the same group (Bush et al, 2004) and (Shioyama et al, 2003) confirm these favorable results in this stage.

These results have to be compared with recent data of stereotactic hypofracionated RT (McGarry et al, 2005; Beitler et al, 2006; Nyman et al, 2006) where, however, results seems to be inferior and toxicity greater, particularly in larger tumors.

G. Pediatric tumors

The greatest challenge for the treatment of pediatric tumors is to attain the highest probability of cure with the least morbidity. It is essential in radiating children with cancer to limit the high-dose treatment area to the tumor only and minimize the radiation dose to the surrounding tissues (Lin et al, 2000). Even though the clinical relevance of the integral dose is not well known, the reduction of the dose (low-dose region and median-dose region) widespread outside the target is of utmost importance in pediatric tumors. In these patients it is very important not only to deliver the dose with high conformality but also to spare normal tissues in the development stages, minimizing the risk of late side-effects and radiation-induced malignancies. Many examples of therapy with proton beam are available in the literature such as the treatment of patients with medulloblastoma, retinoblastoma, rhabdomyosarcoma, craniopharyngioma (Archambeau et al, 1992; Yuh et al, 2004; Krengli et al, 2005; Luu et al, 2006) where protons have demonstrated their capability of superior target dose coverage and sparing of normal structures (Lee et al, 2005). In particular in the treatment of medulloblastoma, PT shows the advantage to reduce toxicity (Yuh et al, 2004) and to be cost-effective (Lundkvist et al, 2005).

A strong additional argument supporting the use of PT in young patients is the potential significant reduction of secondary cancers (Miralbell et al, 2002; Hall and Wuu, 2003)

H. Gastrointestinal and abdominal tumors

In many mucosal and glandular sites of the enteric apparatus, proton beam therapy showed to be feasible and well tolerable. Many data are reported in the literature based on the experiences made primarily in Japan on esophageal tumors (Koyama and Tsujii, 2003; Sugahara et al, 2005), and pancreatic cancer (Hsiung-Stripp et al, 2001). In the context of a renewed interest in the irradiation of hepatocellular carcinoma (Ben-Josef and Lawrence, 2005), proton therapy showed to be efficacious and well tolerated in the treatment of these lesions (Bush et al, 2004; Chiba et al, 2005; Hata et al, 2005; Kawashima et al, 2005).

V. Cost considerations

The overall cost is one of the most important limitations for a wider availability of this method of treatment. Many factors contribute to the overall cost of proton therapy-specifically the high capital cost of equipment. In the future, the various components of the cost (equipment, building, operating and maintenance cost, work-up, treatment planning and delivery) need to be reduced.

The economics of proton therapy are critical and in evolution. If recovery of the initial capital investment was not an issue, it is possible to estimate a cost greater of a factor 1.3-1.6 only with respect to the conventional radiotherapy in the near future (Goitein and Jerman, 2003).

This cost should be evaluated in a cost/effectiveness analysis in the frame of the efficacy that this treatment modality will be able to show. It is possible that higher treatment costs will be acceptable in certain subsets of patients (Lundqvist et al, 2005a) taking into consideration of the “quality adjusted life years” gained (QALY). We should not restrict our thinking to the mere cost of the treatment but consider the total cost for the health care system of a patient cured without severe side effects. This is valid mainly in oncology where radiotherapy has to be considered substantially cheaper in comparison to many other forms of treatment (Lievens and den Bogaert, 2005).

VI. Conclusions

During a period of about 40 years PT has been available mainly in research institutions where particle accelerators built for physics research were used to treat patient, thus limiting the take full clinical benefit of this technology. The current trend, however, sees an increased interest in protons from clinically oriented centers. Increasing popularity, acceptance, and availability of protons will result in increasing use. Additional indications are being currently actively explored and under investigation.

Due to their physical properties (absence of exit dose), the high-energy protons can deliver a highly conformal dose distribution in comparison to x-rays, when comparable techniques are used, allowing the ultimate expression of conformal irradiation. This technology can reduce the irradiation of normal tissues and improve the possibility of dose escalation with greater chances of local control.

It is of utmost importance in the near future to demonstrate that these potential advantages will result in better outcome for cancer patients by conducting appropriate clinical trials and comparing this technology with other competitive X-ray treatment modalities.

Aknowledgements

The authors thanks Eugene B. Hug for his critical reading of the manuscript and for the helpful suggestions.

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Maurizio Amichetti