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A 62MeV proton beam for the treatment of ocular melanoma at Laboratori

Nazionali del Sud-INFN

Article in IEEE Transactions on Nuclear Science · July 2004

DOI: 10.1109/TNS.2004.829535 · Source: IEEE Xplore

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860 IEEE TRANSACTIONS ON NUCLEAR SCIENCE, VOL. 51, NO. 3, JUNE 2004

A 62-MeV Proton Beam for the Treatment of Ocular

Melanoma at Laboratori Nazionali del Sud-INFN
G. A. P. Cirrone, G. Cuttone, P. A. Lojacono, S. Lo Nigro, V. Mongelli, I. V. Patti, G. Privitera, L. Raffaele,
D. Rifuggiato, M. G. Sabini, V. Salamone, C. Spatola, and L. M. Valastro

Abstract—At the Istituto Nazionale di Fisica Nucleare-Labo-

ratori Nazionali del Sud (INFN-LNS) in Catania, Italy, the first
Italian protontherapy facility, named Centro di AdroTerapia e Ap-
plicazioni Nucleari Avanzate (CATANA) has been built in collab-
oration with the University of Catania. It is based on the use of
the 62–MeV proton beam delivered by the = 800 Supercon-
ducting Cyclotron installed and working at INFN-LNS since 1995.
The facility is mainly devoted to the treatment of ocular diseases
like uveal melanoma. A beam treatment line in air has been as-
sembled together with a dedicated positioning patient system. The
facility has been in operation since the beginning of 2002 and 66
patients have been successfully treated up to now. The main fea-
tures of CATANA together with the clinical and dosimetric features
will be extensively described; particularly, the proton beam line,
that has been entirely built at LNS, with all its elements, the ex-
perimental transversal and depth dose distributions of the 62-MeV
proton beam obtained for a final collimator of 25-mm diameter and
the experimental depth dose distributions of a modulated proton
beam obtained for the same final collimator. Finally, the clinical re-
sults over 1 yr of treatments, describing the features of the treated Fig. 1. View of the CATANA beam line. 1. Treatment chair for patient
diseases will be reported. immobilization. 2. Final collimator. 3. Positioning laser. 4. Light field
simulator. 5. Monitor chambers. 6. Intermediate collimator. 7. Box for the
Index Terms—Ocular melanoma, proton beam, protontherapy. location of modulator wheel and range shifter.

I. INTRODUCTION

T HE use of proton beams offers the advantage to improve

tumor control, especially for the treatment of small tu-
mors, where it is necessary to obtain a localized dose distri-
bution while sparing the surrounding normal tissues [1]–[3].
The hadrons allow conformation of the dose distribution better
than photons or electrons, so the use of these charged parti-
cles has developed rapidly in recent years. There are nearly 20
hadrontherapy facilities worldwide, among them about 10 in
Europe. In Italy, the first and actually unique protontherapy fa-
cility, the Centro di AdroTerapia e Applicazioni Nucleari Avan-
Fig. 2. The second tantalum scattering foil with the central brass stopper.
zate (CATANA) was built in Catania, at the Istituto Nazionale
di Fisica Nucleare-Laboratori Nazionali del Sud (INFN-LNS).
Here a 62-MeV proton beam, produced by a Superconducting less frequent lesions like choroidal hemangioma, conjunctiva
Cyclotron (SC), is used for the treatment of shallow tumors like melanoma, eyelid tumors, and embryonal sarcoma.
those of the ocular region. The CATANA project was devel-
oped to treat ocular pathologies like uveal melanoma, which is II. THE PROTON BEAM LINE
the most frequent eye tumor in adults. Moreover, we treat other The CATANA proton beam line has been entirely built at
INFN-LNS and its global view is shown in Fig. 1. The proton
Manuscript received November 11, 2003; revised March 15, 2004. beam exits in air through a 50- Kapton window placed at
G. A. P. Cirrone, G. Cuttone, P. A. Lojacono, I. V. Patti, D. Rifuggiato, and about 3 m from isocenter. Just before the exit window, under
M. G. Sabini are with the Istituto Nazionale di Fisica Nucleare-Laboratori
Nazionali del Sud, Catania 95123, Italy. vacuum, is placed the first scattering foil made from 15- tan-
S. Lo Nigro, V. Mongelli, and L. M. Valastro are with the Physics Department, talum. The first element of the beam in air is a second tantalum
University of Catania, Catania 95123, Italy. foil 25- thick provided with a central brass stopper of 4 mm
G. Privitera, L. Raffaele, V. Salamone, and C. Spatola are with the Radiologic
Institute, University of Catania, Catania 95123, Italy. in diameter (Fig. 2). The double foils scattering system is opti-
Digital Object Identifier 10.1109/TNS.2004.829535 mized to obtain a good homogeneity in terms of lateral off-axis
0018-9499/04$20.00 © 2004 IEEE
CIRRONE et al.: 62-MeV PROTON BEAM FOR THE TREATMENT OF OCULAR MELANOMA 861

Fig. 4. A view of the two monitor chambers and the four sectors chamber.

Fig. 3. Lateral dose distribution for a 62-MeV proton beam.

A plane-parallel advanced PTW 34 045 Markus Ionization
TABLE I Chamber has been adopted for reference dosimetry (beam
CLINICAL PERFORMANCE SPECIFICATIONS OF THE THERAPEUTIC PROTON calibration). The Markus chamber has an electrode spacing
BEAM AT CATANA FACILITY of 1 mm, a sensitive air-volume of 0.02 , and a collector
electrode diameter of 5.4 mm. The dose measurements are
performed in a water phantom, according to International
Atomic Energy Agency Technical Report Series (IAEA TRS)
398 Code of practice [6]. The absorbed dose to water per
monitor unit (cGy/M.U.) is measured at isocenter, for each
combination of modulator and range shifter used for treatment;
the measurement is carried out at the depth corresponding
dose distribution, minimizing the energy loss. Fig. 3 shows the
to the middle of SOBP, for the reference collimator [6]. The
experimental lateral dose distribution for the 62-MeV proton
clinical proton beam calibration is performed just before each
beam measured with a final 25-mm diameter circular brass col-
treatment fraction; the variation of dose/(monitor unit) on the
limator (reference collimator). Beam data are acquired with a
four consecutive days of treatment results within 3%. The
silicon diode in a water phantom, at the treatment depth of 12
proton beam calibration is strongly dependent on modulator
mm, corresponding to the middle of the Spread Out Bragg Peak
and range shifter adopted in the clinical practice; for the same
(SOBP). In Table I, the main characteristics of the lateral dis-
modulator, the decrease in dose/(monitor unit), when the
tribution, together with the clinical tolerances adopted in our
range shifter thickness increases from 6 to 12 mm, is about
facility, are reported.
35%. To investigate whether small irregular fields used in
Range shifter and range modulator are placed inside a box,
the clinical practice will affect the radiation output, an output
downstream of the scattering system. Two diode lasers, located
factor is determined, by using the Scanditronix Hi-p Si diode
orthogonally and coaxially to beam line, provide a system for
detector [7]. This diode has a 0.6 mm detector diameter and
the isocenter identification and for patient centering. The emis-
is designed for field measurements in small proton beams in
sion light of a third laser is spread out to obtain the simula-
water. The value of the output factor is determined [6] as the
tion field. A key element of the treatment line is represented
ratio of diode signals for the patient and reference collimators
by two transmission monitor ionization chambers (Fig. 4) and a
with the same M.U. setting. Considering the experience so
four-sector ionization chamber. The aim of the chambers is, re-
far gained, the dose/(monitor unit) decreases by less than
spectively, to provide the on-line control of the dose delivered to
3% for areas between 490 (reference collimator) and
the patient and of the beam symmetry. The last element before
100 . The latter represents the lower limit of collimator
isocenter is the patient collimator located at 8.3 cm upstream of
areas associated to the clinical practice. For relative dosimetry
the isocenter. Finally, two Philips X-ray tubes, with axes defined
we use radiochromic films, radiographic films [Kodak X
by crosshairs, are placed perpendicular and coaxial to beam line,
Verification (XV) and Kodak Extended Dose Range2 (EDR2)],
to provide lateral and axial view of the tumor, during simulation
ThermoLuminescent Detectors (TLD), natural and Chemical
of treatment [4], [5].
Vapor Deposition (CVD) diamond and silicon detectors [8],
[9]. Depth dose curves and transverse dose distributions,
III. DOSIMETRIC CHARACTERIZATION OF THE PROTON BEAM
either for the full energy or the modulated proton beams, are
The CATANA collaboration is planning to devote particular acquired with a water-tank system provided with three fully
care to the development of dosimetric techniques and two-di- computer-controlled stepping motors. A software, entirely
mensional (2-D) and 3-D dose distribution reconstruction. developed at INFN-LNS, controls this system and provides the
862 IEEE TRANSACTIONS ON NUCLEAR SCIENCE, VOL. 51, NO. 3, JUNE 2004

Fig. 7. Dose-response curves [Net Optical Density (N.O.D.) versus Dose

versus R ] of EDR2 film.
Fig. 5. Bragg peak of 62-MeV proton beam acquired in a water-tank with the
Markus ionization chamber at CATANA facility.

A. Use of Kodak EDR2 Films in CATANA Relative Dosimetry

The advantages of radiographic films to determine relative
dose distributions include a higher spatial resolution, a short
beam-time, and the ability to provide dose distributions in
a single exposure. A new type of radiographic film, Kodak
Readypack EDR2 film [12], has been tested for measurements
of lateral beam profiles at the horizontal eye beam line of the
CATANA protontherapy facility. Film calibrations were carried
out with the reference collimator; the films were placed in a
solid water phantom perpendicular to the proton beam axis and
irradiated to a dose up to 12 Gy. For the full energy proton
beam, the calibration curve was measured at 1 mm depth on
the entrance plateau of the Bragg peak, corresponding to a
30-mm Residual Range [6]. In addition, two calibra-
tions were carried out in modulated clinical proton beams, at
the depth of the middle of the SOBP, for
( , superficial iris lesion) and
Fig. 6. SOBP obtained with a modulator wheel.
( , extended lesion) [13]. Despite a significant
decrease of film sensitivity with decreasing the from 30
acquisition and dosimetric analysis data. Fig. 5 shows the depth up to 7 mm, the linear region of the calibration curves covers
dose distribution obtained with the Markus chamber for the the same dose range for the three tested energies
unmodulated full energy (62–MeV) beam. The maximum error (Fig. 7). This energy dependence may be related to different
on the relative dose is 0.5%. The Full Width at Half Maximum spatial energy distribution pattern. As shown in Fig. 7, at a
of the Bragg Peak is 2.76 mm. The 90%-10% and 80%-20% constant depth the ratio of doses is the same as the ratio of
distal fall-offs are 0.8 and 0.6 mm, respectively, and the peak to optical densities within the linearity range; therefore, EDR2
entrance ratio is 4.72. We have developed, in collaboration with films can be safely and conveniently used to measure the
the Clatterbridge Center for Oncology (UK), wheel modulators distributions perpendicular to proton beam direction [14].
to obtain therapeutic SOBPs. Proton beam energies lower The linearity range is much higher than in typically used ra-
than 62 MeV are obtained inserting PolyMethylMethAcrylate diotherapy Kodak XV films, so this represents a useful tool for
(PMMA) range shifters of different thickness along the beam dose profile measurements. Lateral off-axis profiles were ob-
path. Finally, Fig. 6 shows the SOBP obtained with the first tained at 1 mm depth in the unmodulated beam for the refer-
prototype of the modulator wheel. Actually a set of modulator ence collimator; moreover, transverse distributions were mea-
wheels (10, 12, 15, 20, 25 mm SOBP) has been tested and sured in modulated beams at different depths, corresponding
currently used in clinical practice. Experimental depth dose to the middle of 8, 17, 25 mm SOBPs for the shaped patients
profiles reported in Figs. 5 and 6, have been compared with a collimators; all the films were irradiated to a proton dose of 5
Monte Carlo simulation application, using the Geant4 toolkit, Gy. Lateral profiles measured with EDR2 films are well consis-
developed by us. Results of this comparison are extensively tent with the corresponding obtained with High Sensitivity (HS)
reported in [10] and [11]. [16] radiochromic films (Fig. 8), considered at the moment the
CIRRONE et al.: 62-MeV PROTON BEAM FOR THE TREATMENT OF OCULAR MELANOMA 863

Fig. 10. Thermoplastic mask and bite block.

IV. TREATMENT PROCEDURES

Fig. 8. Lateral X profile (EDR2 versus HS GAF) film. As explained before, protons allow a high dose deposition in
a small deep-seated space, with precise irradiation of the target.
The radiotherapist therefore needs to know the exact position of
the tumor. To do that, tantalum clips are placed around the le-
sion on the outer sclera by the opthalmologist, generally very
close to the tumor. The surgeon also defines the tumor posi-
tion and measurements, as transverse and longitudinal base di-
ameters, elevation or height, distance to the optic disk, to the
macula, to the limbus. He also makes the radiotherapist know
about the eye measurements (axial length, transverse diameter,
thickness of the coats, distance between anterior cornea and pos-
terior lens, limbus diameter) and clips measurements (distance
between clips to limbus, clips to clips and clips to tumor). The
final result is the drawing of a precise fundus view model with
tumor and clips locations. The ophthalmologist makes use of
A-mode and B-mode ultrasound scan, retinal fluorangiography,
wide-angle fundus photographs and, especially, surgical mea-
surements to define all those parameters. He also informs the
radiotherapist about the visual acuity of the effected as well as
the fellow eye, the presence of exudative retinal detachment, oc-
ular pressure and all other information he considers to be sig-
nificant. A total retinal detachment or the presence of a glau-
Fig. 9. Lateral penumbra versus R .
coma are contraindications to a conservative approach. Together
with the diagnosis, for all patients a systemic staging is pro-
detector of choice for measurement of lateral distributions, in vided through a total body spiral Computed Tomography (CT)
proton beams [15]. scan to exclude metastatic disease, which is, obviously, another
Beam profiles from both films are in agreement in the dosi- contraindication. After this first phase, the patient arrives at the
metric characterization of the proton beams, in terms of lateral INFN-LNS, where the workup by the physicist and radiothera-
penumbra, , , and symmetry. As results, we pist begins. First of all, a fixation device is made by means of a
could use both radiochromic and radiographic films to check customized thermoplastic mask and bite block, with the patient
the proton beam; in practice, however, we prefere to use a in a seated position (Fig. 10).
EDR2 film thanks to its less cost. So, before each treatment The patient is invited to gaze at a light point and two orthog-
period, we use a EDR2 film for a quick check of the lateral onal X-ray pictures (axial and lateral) are taken. This step is
profiles of the full energy beam for the reference collimator. repeated 3–6 times with the patient gazing at different points,
EDR2 films are also used to test every clinical setup, especially depending on the tumor position in order to make the physi-
to measure lateral penumbra, depending on modulator and cian sure about the position of the clips. A measurement of the
range shifter adopted (Fig. 9), , , and eyelid thickness and slope is also needed for the planning proce-
symmetry on principal and diagonal axes. In this way, we may dures. All the informations are then elaborated by means of 3-D
get a permanent hardcopy of the clinical shaped proton beam. therapy planning program EYEPLAN, developed at the Mass-
Work is in progress to verify the reliability of the 2-D dose achusetts General Hospital for eye tumor therapy using proton
distribution provided by EDR2 film. beams [17]. Actually, the improved version of EYEPLAN, by
864 IEEE TRANSACTIONS ON NUCLEAR SCIENCE, VOL. 51, NO. 3, JUNE 2004

Fig. 11. Typical output from EYEPLAN.

Sheen [18], is used in our facility. This software schematically

displays a model of the patient’s eye, including the lens, optic
nerve, and fovea, where the tumor is finally drawn by means of Fig. 12. Patient’s place of origin.
the specified measurements and position reference. In Fig. 11 is
shown a typical output from EYEPLAN. TABLE II
TUMOR CLASSIFICATION FOR UVEAL MELANOMA
Isodose levels for 90%, 50%, and 20% of the prescribed dose
are reported. Proton beam irradiates eye tumor, completely
sparing optic nerve and optic disc. A second simulation is
performed on the first day of the treatment week, with the eye
in the final position to verify and to accept the treatment. If the
eyelids cannot be retracted completely outside of the irradiation
field, they have to be calculated in the treatment plan. For
uveal melanoma a total dose of 60 Gray Equivalent (GyE) is
delivered in four fractions on four consecutive days, using a
constant Relative Biological Effectiveness (RBE) of 1.1 over
the modulated Bragg peak. Before each treatment fraction the T3 (75%), 13 stage T2 (21%), and 2 stage T1 (4%), according
eye position is verified and compared to the planned position. A to the new Tumor Node Metastasis (TNM) classification 2002
video camera is directed to the eye to verify its position outside (VI edition) [20]. The tumor infiltrated the choroid only in 35
the treatment room during the irradiation. The treatment time is patients (57%), choroid plus ciliar body in 23 patients (38%),
between . all uveal parts in 2 cases (3%), and iris only in 1 case.

B. Results
V. CLINICAL RESULTS
During the follow-up, the first data regarding local tumor con-
A. Patient Data trol are available only after 6–8 mo from the end of the treat-
Since March 2002, 66 patients with different ocular tumors ment. Actually, we have the preliminary results of the follow-up
have been treated at the CATANA facility. All patients had local- for 52 patients at 6–8 mo, and for 32 patients at 1 yr. The local
ized disease, with no systemic metastasis, and had specific indi- control is defined as a tumor shrinkage or cessation of growth at
cations for a conservative approach by means of proton beams, B-Mode ultrasonography, or as an increase of ultrasound reflec-
depending on their tumor size or location [19]. Most which tivity at A-Mode ultrasonography (a surrogate for tumor con-
of them suffered from uveal melanoma (61 pts, 92%), is the trol). A size reduction, especially regarding the thickness of the
most common tumor of the ocular region in the adult. We have tumor, was seen in 39 patients (75%), while 13 patients maintain
also treated other pathologies with proton beams, like conjunc- a stable dimensional lesion (25%). An increased A-Mode ultra-
tival melanoma (2 patients), conjunctival rhadbomyosarcoma sound reflectivity was detected in almost all patients. These data
(1), eyelid carcinoma (1), and conjuntival Mucosa-Associated clearly show a tumor control, particularly for those patients with
Lymphoid Tissue-Non Hodgkin Lymphoma (MALT-NHL) (1). 1 yr follow-up. No major side effects requiring eye enucleation
Twenty-six patients came from Sicily, 40 from the other Italian have been detected: an exsudative retinal detachment at the time
regions (Fig. 12). of the diagnosis was seen in 40% of the patients and it remains
Among the 66 patients, 34 were women (51%) and 32 men stable in about half of them. In 25 patients, a new cataract for-
(49%). Patient age ranged from 14–81 yr (mean 55.6). As show mation related to the treatment, generally at the periphery of the
in Table II, among the uveal melanomas, 46 patients were stage lens, was diagnosed. About 40% of the patients still maintain a
CIRRONE et al.: 62-MeV PROTON BEAM FOR THE TREATMENT OF OCULAR MELANOMA 865

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