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Introduction

Radiotherapy seeks application of a curative dose to tumor with maximum sparing of healthy normal tissue. Newer photon techniques achieve highly conformal treatment at the cost of increased integral dose to normal tissue with higher risk of secondary malignancy. Particle therapy offers improved conformity of dose distribution with the possibility of further dose escalation and thus higher tumor control probability (TCP). Particle therapy is also able to reduce the integral dose and the dose to specific normal tissues. Consequently, the normal tissue complication probability (NTCP) remains nearly constant, whereas the TCP increases. So far, the risk of secondary malignancy seems to be lower. Protons have almost the same biological effectiveness, whereas carbon ions provide a higher biological effectiveness. New accelerator, treatment planning, and beam delivery technology has been widely disseminated and introduced in clinical practice. As of October 2015, 50 centers worldwide treat patients with cancer with protons and eight centers use carbon ions. Thirty-two additional facilities for protons and four facilities for carbon ions are under construction, and 15 proton facilities are planned. Thus far, over 120,000 patients worldwide have been treated with particle therapy. Despite its relatively high costs compared with that of photon therapy, more and more health insurance policies cover particle therapy for selected tumors, such as chordomas and chondrosarcomas of the skull base and spine, with need for doses and proximity to sensitive structures. The biological and physical advantages of carbon ions promise further improvement in tumor control compared with photons and protons. In this chapter, the physical and biological characteristics of carbon ions will be compared with those of protons and photons and the indications, technique, and results of carbon ion treatment in patients with chordomas and chondrosarcomas will be discussed.

Radiobiological and Physical Principles

Proton and carbon ion beams provide dose distributions superior to those of photon beams because of their finite range in tissue. The initial energy and the tissue characteristics determine the depths of penetration of the particle beam. In contrast to photons, whose energy deposition reaches a maximum after a few centimeters of tissue penetration and declines thereafter, the energy deposition of particles slowly increases with the penetration depth. At the end of the particle’s range, this increase is extremely steep, resulting in a very narrow and high peak, the so-called Bragg peak ( Fig. 35.1 ). A steep decline in the energy deposited at the field’s borders reduces the integral dose to normal tissue and accounts for the safety advantages of particle therapy. Carbon ions are fragmented in nuclear interactions with atoms of the irradiated tissue. Some of the low-energy carbon ions deposit their energy beyond the range of C12 particles in the so-called fragmentation tail. This tail has to be included into the planning software calculations to prevent dose hotspots in organs at risk. Carbon ions produce a smaller dose penumbra, defined as dose band lateral to the field edge in which the dose decreases from 80% to 20% of that of maximum, than do protons. This smaller penumbra underlies the higher conformity of carbon ion radiotherapy ( Fig. 35.2 ).

Depth–dose curve of photon and carbon ion: the photon curve (red) reaches the dose maximum after a few centimeters of tissue penetration, followed by a decrease in energy deposition. The carbon ion curve (blue) shows a slow increase in energy deposition with penetration depth. At the end of the range the dose increase is extremely steep and results in a very narrow and high peak, the Bragg peak. The spread out Bragg peak curve (green) represents the carbon ions of different energies with Bragg peaks at different depths.

Plan comparison for a brain tumor. The plan with carbon ions shows a smaller dose penumbra (above) compared with the plan with protons (below).

Biological Characteristics

Since the rate of energy loss to tissue of charged particles is proportionate to the particle mass, the linear energy transfer (LET) is higher for carbon ions than for protons. The low LET of proton beams, as used clinically, results in a relative biological effectiveness (RBE) similar to that of photons. The International Commission on Radiation Units and Measurements (ICRU) recommends an RBE of 1.10 for protons in clinical use. Thus the advantage of RBE of protons compared with that of photons is only 10%. In contrast, carbon ions offer an RBE of between 3 and 5, depending on multiple factors. The RBE of carbon ions is low in the entrance channel and reaches its highest value within the Bragg peak at the end of its range. The RBE in high-LET radiation decreases as the dose per fraction increases in both tumor and normal tissue, but rate of decrease in tumor is slightly less than that in healthy tissue. This effect is based on the greater ability of normal cells to repair sublethal radiation-induced damage. Thus hypofractionation permits both increase of dose to the tumor and improved sparing of organs at risk. In conclusion, carbon ions have both physical and biological advantages.

Indications

In the past, chordomas and chondrosarcomas were considered radioresistant. This is only partially true, because a dose–response correlation exists. The rate of 5-year local tumor control in chordoma increases from 25% after a dose less than 60 Gy, to 50% after a dose of 60–70 Gy, and up to 80% after a dose over 70 Gy. A similar dose–response relationship can be found in the treatment of chondrosarcoma, although the required dose seems to be slightly lower. Thus the value of a radiation technique that permits dose escalation without increased toxicity. Carbon ions meet this requirement; with their physical and biological properties, they offer higher TCP without increasing tumor and normal tissue NTCP.

Skull Base Chordoma

Chordomas arise from notochordal remnants and are mostly located alongside the neuraxis. Although relatively rare, metastasis in lung, bone, and liver can occur in very late diagnosed or dedifferentiated chordomas. Metastases are present in 5% of patients at initial diagnosis and in 65% patients with advanced-stage tumors. Nevertheless, because of their locally aggressive growth and high recurrence rates, local control is still the most important prognostic factor for survival. En bloc resection or gross total resection is often difficult to achieve because of local invasive growth that involves adjacent critical neurovascular structures of the skull base ( Fig. 35.3 ). Complete resection results in the best long-term survival, but even after complete resection, there is a high rate of recurrence. R2 resection and high-dose proton/photon therapy result in rates of 5- and 10-year local tumor control of 73% and 54%, respectively, compared with 47% and 42%, respectively, after resection only. Thus a nerve-sparing partial resection or biopsy followed by hig-dose radiation (of at least 70 Gy) with particles result in better local tumor control rates than radical resection alone. Highly conformal techniques such as particle therapy should be used to optimize the ratio of TCP to NTCP.

Magnetic resonance imaging (wT2 stir) in axial (left) and sagittal (right) view of a clivus chordoma.

Skull Base Chondrosarcoma

Chondrosarcomas arise from the cartilage; approximately 5%–12% arise at the skull base ( Fig. 35.4 ). Metastatic disease in chondrosarcomas is very rare in grade I/II chondrosarcoma of the skull base, and local tumor control is the most important determinant of outcome. As with clivus chordomas, complete resection of a skull base chondrosarcoma is nearly impossible and risk of recurrence is high. Bloch et al., reviewing 560 patients, found a 5-year recurrence rate of 44% after surgery alone, 19% after radiation alone, and 9% after surgery and radiation. Furthermore, surgery of skull base chondrosarcomas has a high risk of neurological complication rates (33.3%) and of cerebrospinal fluid leakage (10.3%). Thus conservative tumor surgery with minimal morbidity followed by radiotherapy with hadrons is recommended. For local tumor control, high-dose radiation treatment is necessary because of the relatively high radioresistance to irradiation with conventional techniques. Application of total doses up to 80 GyE is possible when using particles.

Magnetic resonance imaging (wT1 contrast enhanced) in axial view of a chondrosarcoma of the left skull base ( green arrow ).

Technical Characteristics

Particle therapy is very complex, expensive, and demanding of specially trained staff. Most centers use passive techniques with modulators, collimators, and compensators to disperse protons and carbon ions for treatment. The advantages of passive beam are the relatively easy planning and beam delivery and their robustness in treatment of a moving target. The disadvantages of passive techniques are the higher dose to the normal tissue in the entrance path and the consequent increase in the risk of secondary malignancies compared with those with active techniques. Active beam delivery can be used for spot scanning or raster scanning. At the Paul Scherrer Institu (PSI) in Switzerland, the target volume is covered with dose using one-dimensional spot scanning in combination with movement of the patient couch during the treatment. At the Gesellschaft für Schwerionenforschung (GSI) in Darmstadt, since 2009 at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, and since 2015 at the Marburg Ion Beam Therapy Center (MIT) in Marburg, active raster scanning beam delivery has been used for proton and carbon ion treatment. Focused pencil beams produced in a synchrotron are deflected laterally by magnetic dipoles. Use of different energy levels affords a three-dimensional intensity modulated particle beam for therapy. The advantages of active raster scanning technique are the high conformity of treatment and fewer beam paths to deposit entrance dose. However, the active techniques are highly sensitive to inter- and intrafractional movement. In consequence, treatment and planning procedures are more complex than with passive techniques. Fixed beams and/or rotating gantries are used with protons to optimize treatment. Using a rotating gantry for carbon ion treatment is much more complex and expensive. The first rotating gantry for carbon ion began patient treatment in 2012 in Heidelberg ( Fig. 35.5 ).

The first gantry for carbon ion beam treatment worldwide residing in Heidelberg has a diameter of 13 m and a length of 25 m. Patient treatment room (left) and the 670 t gantry construction behind the treatment room (right).

Results

Skull Base Chordoma

Currently, reports of results of carbon ion beam therapy are few and they should be considered in the context of results from photon and proton therapy. Mixed photon and proton irradiation of 169 patients with clivus chordoma at the MGH achieved 5- and 10-year local tumor control rates of 73% and 54%, respectively, and overall patient survival rates of 80% at 5 years and 54% at 10 years after treatment. Among 100 patients from the Centre de Protontherapie d’Òrsay treated with a combination of protons and photons rates of 4-year local tumor control and overall survival were 54% and 80%, respectively. Results of treating smaller groups of patients with a combination of photons and protons at the Loma Linda University Medical Center Group and with protons alone at the PSI are listed in Table 35.1 .

Table 35.1

Results of Patients With Skull Base Chordoma After Proton Treatment

References	Radiation	TD (Gy RBE)	Dpf (Gy RBE)	n	FU (months)	LC (%)	OS (%)
Munzenrider and Liebsch	P + Ph	66–83	1.8–1.92	169	41	5 years: 73 10 years: 54	5 years: 80 10 years: 54
Noel et al.	P + Ph	67 (60–71)	1.8–2.0	100	31	2 years: 86 4 years: 53	2 years: 94 4 years: 90
Hug et al.	P + Ph	71.9 (66.6–79.2)	1.8	33	33.2	3 years: 67 5 years: 59	3 years: 87 5 years: 79
Weber et al.	P	73.5 (67–74)	1.8–2.0	42	38	3 years: 87 5 years: 81	5 years: 62

 

Dpf , dose per fraction; FU , follow-up (median); LC , local control; n , number of patients; OS , overall survival; P , proton therapy; PH , photon therapy; TD , total dose.

The NIRS in Chiba, Japan, treated 33 skull base chordomas with three different hypofractionated carbon ion protocols between 1995 and 2007. Four patients were treated in a pilot study with 48.0 Gy (RBE) and 16 tumors were treated in the phase I/II dose escalation study with 48.0 Gy (RBE), 52.8 Gy (RBE), 57.6 Gy (RBE), or 60.8 Gy (RBE). In the phase II study, 14 tumors were treated with 60.8 GyE. All treatments involved 16 fractions within 4 weeks, resulting in a dose per fraction of 3.0–3.8 Gy (RBE). Rates of 5- and 10-year local control for the entire group were 85% and 64%, respectively. The 19 patients who received 60.8 Gy (RBE) had a local control rate of 100% at the time of publication. The rates of overall survival for the whole cohort were 87.7% at 5 years and 67% at 10 years. Among 47 patients with skull base chordoma who received 60.8 Gy (RBE) in 16 fractions, the rate of 5-year survival was 87% and of local tumor control was 88% at 5 years and 80% at 10 years. At the GSI 155 patients with clivus chordoma were treated between 1998 and 2008 with 60 Gy (RBE) carbon ion in 20 fractions applied within 3 weeks using the active raster scanning method ( Fig. 35.6 ). The 3-, 5-, and 10-year rates of local tumor control for the whole cohort were 82%, 72%, and 52% and of overall patient survival were 95%, 85%, and 75%, respectively ( Table 35.2 ).

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