CARBON ION THERAPY

Dr Umesh V

Introduction Heavy ion therapy is a novel technique of high precision external radiotherapy. It yields a better perspective for tumor cure of radio-resistant tumors

The advantages of using heavy ion therapy are

Higher tumor dose and improved sparing of normal tissue in the entrance channel

More precise concentration of the dose in the target volume with steeper gradients to the normal tissue

Higher radiobiological effectiveness for tumors which are radio-resistant during conventional therapy

These properties make it possible to treat radio-resistant tumors with great success - including those in close vicinity to critical organs

The term “heavy ions” is used here for ions heavier than helium ions. The primary rationale for radiotherapy with heavy charged particles is the sharp increase of dose in a well-defined depth (Bragg peak) and the rapid dose fall-off beyond that maximum

HistoryFull-scale clinical studies with carbon ion therapy started in 1994 at the NIRS (National Institute of Radiological Sciences) in Chiba, Japan using the HIMAC (Heavy–ion Medical Accelerator in Chiba) synchrotron, and clinical trials with carbon at the GSI (Helmholtzzentrum für Schwerionenforschung GmbH) in Darmstadt, Germany followed.

Until 2009, almost 4000 patients have been treated by NIRS and 400 patients by GSI with extremely good results.

Encouraged by these results, other facilities also started carbon-ion therapy or construction of particle accelerators for radiotherapy; Hyogo Ion Beam Medical Center, Japan and the Institute of Modern Physics, China started carbon-ion therapy in 2002 and 2006, respectively.

The Heidelberg Ion Beam Therapy Center (HIT) in Germany started proton/carbon ion therapy in 2010 while the following four synchrotrons are currently under construction: Gunma University Heavy Ion Medical Center at Maebashi in Japan, CNAO (Italian hadrontherapy center) at Pavia in Italy, and two new facilities in Germany, the Kooperative Ionen Therapie Zentrum at Marburg and NRock North European Radiooncological Center at Kiel

Carbon Ion beam characteristicsWhen a beam of monoenergetic heavy charged particles enters the patient body, the depth-dose distribution is characterized by a relatively low dose in the entrance region (plateau) near the skin and a sharply elevated dose at the end of the range (Bragg peak)

To treat an extended target, the Bragg peak is spread out to cover the required volume by modulating the energy of the particles to form a spread-out Bragg peak (SOBP).

For treating small targets, where the sharpness of the lateral dose fall-off is essential, the choice of the heavier ion beam becomes important

The Bragg peaks appear almost unchanged for the two carbon-ion beams one collimated and other uncollimated ; whereas, the Bragg peak is much suppressed for the collimated proton beam

Penetration depth can be varied by changing the ion energy

Relative biological effectivenessHeavy ions, such as carbon exhibit much larger RBE values and a greater variation over a larger area of the range

For an extended tumor volume the RBE increases to the distal part, i.e., to the maximal range because there Bragg peak ions contribute mostly to the dose.

In the region closes to the surface, i.e., the proximal part of the target volume, the fraction of plateau ions is large and consequently the RBE is small.

In order to achieve a homogeneous biological effect across the complete tumor, the physical dose has to be decreased to the distal end.

Comparison of measured RBE values in an extended volume as a function of penetration depth. A simulated tumor volume was exposed to different doses as shown in the upper row. The dose is modulated such that a homogenous cell death should be reached across the complete tumor region (middle curve). From the measured cell survival the relative biological effectiveness RBE was determined (lower curve). The results show that the RBE increases with depth and is largest for small carbon doses.

Protons:

Locally correlated DNA damage can only be produced by increasing the macroscopic dose

Carbon ions:

Many electron tracks are produced that cause locally multiply damaged sites within the DNA

Ion Beams kill Hypoxic cells more

BEDBiological effective dose is optimized: for each small volume element (voxel) the actual RBE is calculated.

For this procedure, the RBE values of the carbon ions of the different energies in the irradiation field and their fragments are calculated separately.

After the local RBE values are calculated, the biological effective dose BED is calculated point by point:

BED= RBE* DOSE

Chances of second malignancies high with Carbon ion

Radiobiological RationaleThe radiobiological rationale for using Carbon ions for therapy

The high resistance of hypoxic cells relative to oxic cells is reduced when irradiated with high-LET radiation,

Slowly proliferating cells (in G0 or long G1 phase in the cell cycle) show a similar increase in sensitivity, if irradiated with high-LET radiation

Overall treatment time with high-LET radiation can be shortened since fewer fractions of larger doses may be used instead of multiple fractions of small doses, where the surrounding normal tissue damage using fewer fractions can be kept comparable to that using standard low-LET fractions.

There is an advantage in using multiple, small fractions of low-LET radiation for sparing late damage.

Radiobiological research showed that carbon ions represent the ideal beam for the treatment of deep-seated and radio-resistant tumors

The low dose in the entrance channel causes mostly repairable damage

The high dose at the end of the beam combined with the high radiobiological effectiveness guarantees a very effective inactivation of radio-resistant tumors.

Minimal lateral scattering results in millimeter precision at the target.

In addition, the use of carbon beams made it possible to localize the beam inside the patient for the first time: carbon beams produce a small amount of instable isotopes during their passage through the tissue of the patient.

Some of these isotopes such as 10C and 11C are positron emitters.

Using a camera for positron emission tomography PET, the decay of these isotopes can be measured from the outside of the patient.

This allows reconstructing their position and hence the monitoring of particle delivery.

As a result, the beam in radiotherapy can be controlled for the first time inside the patient during the course of therapy

Beam Production and Beam Delivery SystemsA proton beam of 150 MeV can penetrate 16 cm in water, the same radiological depth is achieved with carbon ions of 3000 MeV or 250 MeV/u (energy per nucleon).

To accelerate particles to such high energies, synchrotrons are better suited than cyclotrons

To inject the ions into a synchrotron ring, they have to be accelerated first in a linear accelerator (Linac) injector to several MeV/u

Such a Linac consists of a radiofrequency cavity and a drift tube and has several meters length.

An isocentric gantry for carbon ions is expected to have weight of about 600 tons at a diameter of 13 m

There exist two principle methods to shape the beam and thus to tailor the dose to the target volume

Principle of the passive dose delivery system used for proton and ion beams. Shown is the incoming broadened beam that is modulated in depth. The variable range shifter has to shift the modulated dose to the desired depth, whereas collimator and compensator are patient specific devices. The lines in the body represent the distal dose fall-off that can be shifted in depth with the range shifter

Principle of the active raster scan system used at GSI for carbon ions. A small pencil beam is scanned in vertical and horizontal direction, using two pairs of scanner magnets. By switching the energy of the synchrotron, the position of the Bragg peak can be chosen so that each scanned area is adapted to the extent of the target in depth

Patient PositioningDue to the high spatial accuracy that is achievable with ion beams, patient fixation and positioning requires special attention.

Patient fixation is usually achieved with individually prepared mask systems or whole-body moulds.

Highest accuracy during the initial positioning can be achieved by the use of stereotactic methods.

Prior to every fraction, the position is verified using X-ray imaging in treatment position.

The X-ray images are compared against digitally reconstructed radiographs obtained from the treatment planning CT

Clinical applicationsConsidering the physical and biological properties of carbon ions, a potential benefi t for carbon ion radiotherapy can be assumed for all tumors with a low Alpha/Beta ratio and which are surrounded by critical structures.

A low Alpha/Beta ratio has been shown for

Chordomas

Low-grade chondrosarcomas

Malignant salivary gland tumors such as adenoid cystic carcinomas and other head and neck tumors.

Additional potential indications are bone and soft tissue sarcomas, lung cancer, and prostate cancer

Clinical Trials at BerkeleyPioneering work in the fi eld of radiotherapy with heavy ions was performed at the University of California, Berkeley.

The Bevalac provided the scientific and technological basis for many of the current developments in the field of ion radiotherapy

The GSI FacilityAt the research laboratory GSI in Darmstadt (Germany), a therapy unit began its clinical operation in 1997

Since December 1997, more than 220 patients have been treated with carbon ion radiotherapy at GSI.

Patients with chordomas (n=44) and low-grade chondrosarcomas (n=23) of the skull base were treated within a clinical phase-I/II trial with carbon ion radiotherapy only.

Median dose was 60 Gy (20 fractions, each 3 Gy).

In February 2003 the median follow-up was 20 months.

Actuarial 3-year local control rate was 100% for chondrosarcomas and 81% for chordomas of the skull base.

Actuarial 3-year overall survival was 91%. Toxicity correlated with radiobiological model estimations. Late toxicity greater than common toxicity criteria (CTC) grade 3 was not observed

These results substituted Proton therapy as the treatment of choice for these tumors

A clinical phase-I/II study of combined photon radiotherapy plus a carbon ion boost for sacral/spinal chordomas and low-grade chondrosarcomas is ongoing

In December 2002 local control was achieved in 8 of 9 patients with cervical spine tumors. Mucositis CTC grade 3 was observed in 3 patients with chordomas of the cervical spine, but none of the patients developed severe late effects to the spinal cord

A clinical phase-I/II study for combined photon radiotherapy with a carbon ion boost in locally advanced adenoid cystic carcinomas is ongoing.

An interim analysis on 21 patients in December 2002 (median follow-up 14 months) showed an actuarial locoregional control rate of 62% at 3 years; disease- free survival and overall survival were 40 and 75% at 3 years, respectively

The HIMAC FacilityThe HIMAC started its clinical operation in Chiba, Japan, in 1994

As of February 2002, 1187 patients have been treated with carbon ions (Tsujii et al. 2002). Two redundant synchrotrons deliver carbon ion beams at energies of 290, 350, and 400 MeV/u.

Other facilitiesThe Hyogo Ion Beam Medical Center (HIBMC) started operation with protons in 2001 and with carbon ions in 2002 at Harima Science Garden City, Japan. It is the fi rst facility offering carbon ion and proton treatment at the same facility. As of mid-2002, 28 patients have received carbon ion therapy

The Italian project is driven by the CNAO (“Centro Nazionale Adroterapia”) and will set up the facility in Pavia near Milan. It will exhibit a synchrotron of about 25 m diameter that is capable of accelerating protons and carbon ions up to energies of 400 MeV/u.

The currently most ambitious and advanced project is the Heavy Ion Therapy accelerator (HIT) which will be installed at the Heidelberg University Hospital

There are proposals for hospital based heavy ion facilities in Lyon (France), Pavia (Italy), Stockholm (Sweden), and Vienna (Austria).

In Lanzhou (China) an existing heavy ion research facility is preparing for clinical patient treatments with ions.

Further researchFor tumors with proven effectiveness of carbon ion radiotherapy, such as chordomas and low-grade chondrosarcomas of the skull base, clinical phase- III trials are necessary to determine the advantages of carbon ion radiotherapy over other radiotherapy modalities such as modern photon techniques (like IMRT) or proton radiotherapy which is currently considered to be the treatment of choice

Encouraging results have been obtained in Lung, Bone and soft tissue sarcomas which may warrant a phase III/IV trials

Further investigation is needed in the field of multimodality treatments

A combination of different radiotherapy modalities, such as photon IMRT plus carbon ions or protons, might be favorable for a number of indications

Due to the biological properties of carbon ion radiotherapy, hypofractionation might be considered for a number of tumor entities

The potential advantages of ions can be summarized in four points:

(1) The physical selectivity of ion beams is comparable to, or better than, the best low LET therapy techniques. The penumbra is narrow and the dose ratio between the SOBP and entrance plateau is better than with the best low LET radiation (protons). Nuclear fragmentation of the ion beams is a potential disadvantage because some energy is deposited beyond the Bragg peak. However, this aspect is probably not clinically significant because the dose is low and the fragments are lower LET particles.

(2) The LET in the ion beam, and consequently the RBE, increases with depth, and this increases the ratio of the biologically weighted doses between the SOBP and the entrance plateau. The RBE is comparable to neutrons, but the physical dose selectivity is vastly improved for ions.

(3) At the level of the SOBP, where the PTV is located, high LET makes heavy ion beams specifically effective for the treatment of some tumour types that are resistant to low LET radiation.

(4) After fractionated irradiation, there is reduced possibility for repair for cells in the PTV located in the SOBP, because the LET is highest there. In contrast, the normal tissues located outside the SOBP, in the entrance plateau region, are exposed to lower LET radiation and thus may benefit from an increased repair opportunity. Therefore, from a radiobiological point of view, fractionation in ion therapy should bring a significant advantage and should be exploited. It is recognized, however, that this radiobiological advantage may be balanced by the advantage of reducing treatment times to reduce the effect of tumour cell repopulation and also by some economic consideration

THANK U