Biophysical Aspects

The carbon ion beam has both biologic and dose localization advantages over lighter ions such as protons, and has the best biologically corrected depth-dose distribution of all charged particles. The ratio of dose in the tumor to that in the entrance region is maximized, and the beam penumbra is sharper. The rate at which charged particles lose energy when penetrating material increases with the mass of the particle and can be quantified as linear energy transfer (LET). Values of LET increase as charged particles slow down. The LET for 1-meV electrons is 0.25 keV/µm. Particles with a LET value of less than 30 to 50 keV/µm are called low-LET particles, whereas those with higher LET values are categorized as high-LET particles. High-LET particles are biologically more damaging primarily because they cause more severe, less reparable damage per unit track length than low-LET radiations. For carbon ions, enough high LET is present to provide significant differences in deoxyribonucleic acid damage and suppression of radiation repair. Similar to proton RT, the energy deposition of carbon ion beams increases with penetration depth up to a sharp maximum at the end of their range. This region is called the Bragg peak. Dose abruptly drops beyond the Bragg peak. The particle range in tissue is determined by the energy of the incoming particles. Favorable dose distributions with much steeper dose gradients at the field borders and better sparing of normal tissues surrounding the tumor can be achieved with carbon ion beams. As a consequence, the application of higher tumor doses is enabled at the same level of toxicity. In comparison with proton beams, carbon ion beams offer a sharper lateral dose fall-off in depth, which makes them ideal for treatment of deep-seated tumors.

Relative Biologic Effectiveness

The concept of relative biologic effectiveness (RBE) arose from observations that ionizing particulate radiations can be several times more effective per unit dose in producing biologic effects than x-rays. RBE is defined as the ratio of absorbed doses of two radiations required to produce the same biologic effect. One extension of this concept has been the clinical use of the terminology gray-equivalent (GyE) dose. This is the dose of a particle modality that yields an equivalent biologic response to a dose of megavoltage x-ray or cobalt-60 gamma-rays. For 160- to 230-meV proton beams, the RBE is generally considered to be approximately 1.1 to 1.2, and for heavier particles (helium, carbon, neon, silicon), the RBE ranges from 1.2 to 4.5. RBE depends on dose fraction size as well as the type of tissue irradiated and the position on the depth-dose curve at which it is measured. No single RBE value is adequate to characterize the variable range of RBE values in the stopping carbon ion beam, whether delivered by passive or active scanning techniques. When different clinical situations are considered, the biologic advantages of carbon ions over photons and protons are expected to be most pronounced for tumors that have a low radiosensitivity when treated with photons and for situations in which the tumor is surrounded by radiosensitive normal tissues. Values for RBE can be as high as 4 for carbon ion RT and depend on many factors, which have to be addressed during treatment planning. Experiments conducted with fast neutrons and carbon ions have demonstrated that increasing the dose per fraction results in a decrease of the RBE of both the tumor and normal tissues. The tumor RBE did not decrease as rapidly as the normal tissue RBE.^8,9 As a consequence, short-course hypofractionation schemes are likely to enhance the therapeutic ratio in carbon ion RT. At the National Institute of Radiological Sciences (NIRS) in Chiba, Japan, hypofractionated carbon ion RT has been systematically investigated and a significant reduction of overall treatment time has been accomplished for many tumors without increasing toxicity.^10–12

Oxygen Enhancement Ratio

The oxygen enhancement ratio (OER) is the ratio of dose needed to inactivate severely hypoxic or anoxic tumor cells relative to the dose needed to inactivate well-oxygenated tumor cells. It has a value of approximately 3 for low-LET photons, electrons, or protons, but is diminished with the use of high-LET irradiations to approximately 1.6 to 1.7 at LET values of about 100 keV/µm. The degree to which the OER is reduced is an indication of high-LET biologic effectiveness.

Decreased Radioresistance of Tumor Cells to High-Let Radiation

Although factors other than hypoxia are important in tumor control, most tumors have significant numbers of hypoxic cells that are preferentially killed with high-LET irradiations. Whether high-LET RT is effective in treating a given disease depends on the relative values of the tumor and normal-tissue RBE, as well as on reduction in the OER. Recent work with radioresistant tumor cells under even aerobic conditions in vitro indicate that stopping carbon ions can overcome tumor resistance as a result of the over-expression of Bcl-2, an anti-apoptotic protein that is frequently over-expressed in 30% to 50% of tumors and is associated with radioresistance.¹³ Carbon ions have also been shown to increase the gene expression of another protein, SPHK1 (a kinase related to cell growth and control of proliferation), in human oral squamous cell carcinoma in a manner not seen with x-ray doses.¹⁴ Qualitative differences between low-LET and high-LET molecular mechanisms of cell killing such as these need further study. Gene expression profiles are being used to identify novel candidate genes as biomarkers in human normal tissues and tumor cells associated with carbon ion radiosensitivity.^15,16

Decreased Repair of Radiation Injury

Decreased repair of radiation injury imparted by high-LET particles is evidenced by the absence of a shoulder on the cell-survival dose response curve for high-LET radiation, also implying that the RBE for high-LET particles is larger for smaller fraction sizes than it is for larger doses per fraction. Using smaller doses per fraction of high-LET irradiation will not help spare normal tissues as in low-LET radiation. Shortening the overall treatment schedule for high-LET RT to 1 to 3 weeks also minimizes the proliferation of tumor cells during treatment.

Less Variation in Radioresistance Throughout the Cell Cycle

High-LET radiation can overcome cell cycle–dependent resistance and is advantageous in either fast-growing tumors with a large proportion of cells in the S phase or in slowly proliferating tumors with a large fraction of cells in G1 or G0.

Accelerated Tumor Reoxygenation

Carbon ion irradiation has been shown experimentally to accelerate the reoxygenation of murine fibrosarcoma compared with x-ray irradiation.¹⁷ This suggests that high-LET radiations would be effective with shortened treatment durations compared with low-LET RT.

Possible Increased Risk of Carcinogenesis and Other Late Radiation Effects

In high-LET RT the cost-benefit analysis must include an awareness of enhanced late sequelae, including undesirable tissue fibrosis, vascular damage, central nervous system (CNS) toxicities, genomic instability, and secondary cancers. In the clinical trial at LNBL, relatively short-term follow-up (24-173 months, mean of 67 months) of neon-ion treated patients suggested a radiation-induced tumor rate of approximately 2%.¹⁸ There was no increase over conventional x-ray rates for the helium patients. Carbon ion late effects should be similar to or slightly increased over helium ion effects. In the laboratory, there is clear genetic variability in the susceptibility to carbon ion–induced mammary carcinoma among rat strains studied.¹⁹ Sprague-Dawley rats were more susceptible to carbon ion–induced mammary carcinomas in a mechanism without the common H-ras and Tp-53 mutations seen with low-LET radiation-induced tumors. Further basic investigations should explore these molecular differences further with powerful new genomic and proteomic tools.

Preliminary Clinical Studies at Lawrence Berkeley National Laboratory with Heavy Ions

Clinical studies with fractionated Bragg peak charged-particle therapy, including carbon ions, were carried out from 1975 to 1992 at LBNL^20,21 in collaboration with the Medical Center at the University of California, San Francisco. Helium ions were used instead of protons at LBNL, as they were readily produced in the LBNL accelerators at about 232 meV/U, giving a range in tissue of approximately 26 cm. They deposit a small amount of high LET, which must be accounted for in treatment planning. Their clinical effects are similar to protons, with normal-tissue RBE values of 1.2 to 1.4 compared with megavoltage x-rays (except in CNS, in which the RBE is approximately 1.6). Approximately 700 patients were treated with helium ions, and demonstrated excellent tumor control in critical sites in the skull base, eye, head and neck, and paraspinal-sacral regions, similar to results with protons.^22–26

Carbon ions were used for the first time in the treatment of human tumors at LBNL in 1977. These studies were preliminary in nature, aimed primarily at assessing toxicity and tumor effect. Interestingly, the first patient treated with carbon ions in a skin RBE comparison with 6-meV electron-beam RT lived for more than 10 years. The late skin irradiation RBE values obtained for carbon ions of approximately 2.5 to 2.7 in the middle of a 4-cm spread Bragg peak was in line with estimates made later in Japan and Germany. A small number of patients with advanced tumors were treated with carbon ions in phase I studies at LBNL in 1977 and 1978. Subsequently, neon ions were picked over carbon ions for extended study at LBNL largely because of their greater potential for high-LET advantage. From 1978 through 1992, 433 patients at LBNL were treated with neon ion RT, of whom 299 received at least 10 Gy (approximately 30 GyE) of neon ions. A small number of patients (approximately 20) received treatment with silicon ions, and two patients were treated with argon ions. The LBNL clinical studies showed that neon and carbon ions could be delivered safely, providing careful treatment planning and delivery occurred, with evidence of beneficial effect especially in slow-growing tumors.^{21,27–30,30a} Late reactions were increased in CNS tissues and GI tissues with neon ion RT. Concerns over significant late effects in normal tissues^31–33 halted further study of silicon and argon ions.

In the nearly 2 decades that elapsed from the treatment of the first carbon patient at LBNL in California to the construction of a dedicated medical accelerator for ion therapy in Japan, extensive preclinical biology and phase I clinical trials with various ion beams pointed to carbon ions as the preferred ion for human therapy. Regrettably, the Bevatron was closed to patient treatment in 1992 by the U.S. Department of Energy before carbon ion trials could be reinitiated.

Fortunately, both German and Japanese colleagues came often to LBNL and spent much effort in studying heavy ions beams and preparing for their own ion beam clinical projects. With the LBNL Bevatron closure, the impetus for carbon ion studies shifted to Japan and Germany. Major credit for the current clinical emphasis on carbon ion therapy goes to the NIRS program in Japan, followed by the Gesellschaft für Schwerionenforschung (GSI) program in Germany, whose clinical successes have drawn the attention of the world.

Concomitant with the development of accelerator-based methods to provide carbon ion beams has been the advancement in tumor and normal-tissue imaging and beam-delivery techniques, including beam scanning and three-dimensional (3-D) and four-dimensional (4-D) breathing-gated delivery to provide individually-tailored image-guided dose plans.^26,34–37 New technologies are also being developed commercially to accelerate carbon ions in facilities having a much smaller footprint and energy requirement for operation.³⁸

Clinical Results of Carbon Ion Radiation Therapy in Japan and Germany

Carbon ion RT became available for the first time in a medically dedicated facility in 1994 when the NIRS in Japan started the first extensive clinical trials with carbon ions. The second carbon ion therapy facility, which began clinical operation in 1997, was developed by Kraft and associates^39,40 at the GSI in Germany. This work will be continued at a new clinical heavy ion medical facility at the University of Heidelberg. A third carbon ion therapy facility began patient treatments at the Hyogo Ion Beam Medical Center facility in Harima, Japan, in 2004.⁴¹ Additional medical proton-carbon ion therapy facilities are planned or under construction in Italy, France, Germany, Austria, the United States, and Japan.

Beam Delivery Techniques at NIRS and GSI

Beam delivery is performed with passive methods using modulators, collimators, and compensators at the NIRS. The advantage of passive beam delivery systems is that the treatment planning for this system is simple. This approach has already been applied in many clinical situations, including in the treatment of moving targets such as lung cancer and liver cancer. The major disadvantage is that a significant amount of the dose is also delivered along the entrance path that often includes nontarget normal tissue. As an alternative to passive beam delivery, active beam delivery using the raster scan method has been developed. At GSI, focused pencil beams produced in a Synchroton are deflected laterally by two magnetic dipoles while the energy of the incoming beam is varied during the treatment. Thus 3-D intensity-modulated carbon ion RT can be accomplished, and the dose distribution can be tailored optimally to any irregular tumor shape without adding passive absorbers, compensators, or collimators.⁴² The dose distribution can also be conformed to the proximal edge of the target volume, and normal tissue that resides along the entrance channel of the beam can thus be spared. For both passive and active beam delivery techniques, patient immobilization and its day-to-day reproducibility need to be consistent with the high spatial accuracy achievable with particle beams. Precision head and body immobilization systems, stereotactic target localization, and image guidance with pretreatment correction of even small patient set-up deviations are commonly used at modern particle therapy centers. Using passive beam delivery, interfractional and intrafractional movements are addressed by adding a safety margin to ensure that the clinical target volume (CTV) is fully covered during treatment. For active beam delivery, adding a safety margin around the CTV is not sufficient, because movement of the target during the scanning process can cause regions already irradiated to again move into the path of the beam, whereas regions that have not been irradiated can escape the path of the beam. Different strategies of tumor tracking are currently being explored.^43–45 The use of an active beam delivery system also has implications in terms of the treatment planning procedure, which becomes more complex and requires biologic plan optimization. New computational modeling strategies to optimize the LET distribution over the tumor volume are under development for each type of beam delivery mode.^46,47 The physical advantages of particle-beam therapy can only be properly exploited when it is possible to use multiple fields at the same level of complexity commonly used for modern photon therapy. Although gantries for proton therapy have been installed at several facilities, carbon ion RT is delivered with fixed-beam lines. The charged-particle therapy facility at Heidelberg University is the first to be equipped with a rotating gantry for proton and carbon ion RT. The optimal design of a modern particle therapy facility is still actively being discussed.

Uveal Melanoma

RT of uveal melanoma aims at local tumor control and eye retention. Although brachytherapy and proton RT are accepted function-preserving alternatives to surgery with 5-year local control rates in the range of 96% and eye retention rates between 75% and 92%,^22,48–54 carbon ion RT has been investigated recently at the NIRS in a dose-escalation trial in large-size uveal melanoma. Data is preliminary because of the limited patient number and follow-up time. Between January 2001 and February 2006, 59 patients with locally advanced or unfavorably located choroidal melanoma were enrolled in a phase I and II trial investigating an optimal dose of carbon ion RT. The primary endpoint of the study was morbidity, and local control and overall survival were secondary endpoints. Local control, overall survival, and disease-free survival rates at 3 years were 97.4%, 88.2%, and 84.8%, respectively. Twenty-three patients (40%) developed neovascular glaucoma and three patients underwent enucleation.⁵⁵ It was found that the volume of the ciliary body irradiated to more than 50 GyE and irradiation of the optic disc were independent risk factors for development of neovascular glaucoma after carbon ion RT in choroidal melanoma.⁵⁶

Skull-Base Chordoma and Low-Grade Chondrosarcoma

Chordoma is a rare tumour with a slow growth pattern. Thirty-five percent of chordomas occur in the skull-base region, displaying a challenge for neurosurgeons as well as radiation oncologists. Complete resection is exceptional and local recurrences are common. The results after treatment of chordoma and low-grade chondrosarcoma with conventional photon RT and stereotactic photon RT have been poor, with prognosis ranging between 17% and 50% at 5 years.^57–59 At the Massachusetts General Hospital, 375 patients with skull-base chordoma and chondrosarcoma have been treated with proton RT between 1975 and 1998. Local control rates at 5 and 10 years were reported to be 73% and 54% for chordoma and 98% for chondrosarcoma, respectively.⁶⁰ Other proton centers report similar results.^61–63 Currently, proton RT is considered the treatment of choice for patients with chordoma and low-grade chondrosarcoma of the skull base.

Carbon ion RT also offers biologic advantages in treatment of these tumors, particularly chordoma. Between 1997 and 2001, a clinical phase I and II study was carried out at GSI to investigate the feasibility and effectiveness in chordoma and chondrosarcoma of the skull base. Sixty-seven patients with chordoma (n = 44) and low-grade chondrosarcoma (n = 23) were enrolled in the study and received a full course of carbon ion RT with a median total tumor dose of 60 cobalt gray equivalent (CGE) (range 57 to 70 CGE/20 fractions/20 days). A typical carbon ion treatment plan of a patient with skull-base chordoma is shown in Fig. 70-1. Median follow-up was 32 months (range 3 to 66 months). Local control rates for chordoma and low-grade chondrosarcoma of the skull base were 74% and 87% at 4 years, respectively. Overall survival at 4 years was 86% and 100% for chordoma and chondrosarcoma, respectively. Acute toxicity was very mild. No patient developed acute skin reaction greater than the National Cancer Institute common toxicity criteria (NCI-CTC) grade 2. Only three patients developed grade 3 mucositis.⁶⁴ A follow-up analysis in 2005 of this study included 96 patients with chordoma and 54 patients with chondrosarcoma. Cumulative local control and overall survival rates at 4 years were 89.8% and 98.2% for chondrosarcoma.⁶⁵ Local control and overall survival rates at 5 years were 70% and 88.5% for chordoma of the skull base.⁶⁶ Severe late toxicity was observed in less than 5% of all patients, and overall treatment time was significantly reduced to 3 weeks.

FIGURE 70-1 • Axial (A) and sagittal (B) dose distribution of carbon ion radiation therapy in a patient with chordoma of the clivus. C, Dose-volume histogram. Total dose 60 GyE, weekly fractionation 7 × 3.0 GyE. Orange line, 90% isodose line.

(Reprinted by permission from Macmillan Publishers Ltd: Nature Nov 1, 414(6859):105–111, 2001.)

Carbon ion RT–induced toxicity to the temporal lobes was analyzed in 59 patients with chordoma and chondrosarcoma treated between 2002 and 2003 at GSI with carbon ion RT. Of these 59 patients, 10 developed circumscribed white-matter changes in the temporal lobes during their regular follow-up with magnetic resonance imaging. In most of these patients, the white-matter changes were of a temporary nature and diminished without treatment. Only two patients developed neurologic deficits. Analysis of the dose-volume histograms revealed that age and maximum dose, after subtracting the maximum dose volume of 1 ml, significantly influenced the risk for white-matter changes after carbon ion RT. The 5% and 50% probabilities for temporal-lobe injury after carbon ion RT were determined to be 68.8 and 87.3 GyE,⁶⁷ consistent with highly conformal photon and proton irradiations.

When the local control rates in chordoma were analyzed together with the data available for proton RT, a dose-response relationship could be derived for chordoma of the skull base. The optimal dose is estimated to be between 75 and 85 GyE.⁶⁶

The results of carbon ion RT at NIRS in 29 patients with chordoma and seven patients with chondrosarcoma were recently reported.¹² The total dose was escalated from 48.0 to 60.8 GyE given in 16 fractions for 4 weeks. Overall local control was achieved in 74% of chordoma patients and in 100% of those with chondrosarcoma. With higher total doses, an improvement in tumor control was observed with no severe adverse reactions. For chordoma, the fractionation regimen of 60.8 GyE given in 16 fractions for 4 weeks yielded the best local control of 91% at 5 years, whereas local control was only 60% after 48.0 to 57.6 GyE. The overall 5-year survival rates were 88% in chordoma and 54% in chondrosarcoma. There were three deaths with chondrosarcoma, all with intercurrent disease.

Taking into account the excellent results at GSI and NIRS of carbon ion RT in patients with chordoma and chondrosarcoma, postoperative high-dose carbon ion therapy can be regarded as an alternative to proton RT for chondrosarcoma, and may be superior for chordoma. Randomized phase III trials comparing proton and carbon ion RT are not yet available.

Glioblastoma Multiforme

The current treatment in glioblastoma multiforme is surgical removal with adjuvant radiochemotherapy using photons and temozolomide.⁶⁸ A tumor dose of 60 Gy given in conventional fractionation is recommended. The planning target volume (PTV) includes a visible tumor volume plus a generous margin of 3 to 5 cm for subclinical disease. The overall prognosis of these patients remains poor, with a median survival time of 14.6 months and further improvements are strongly needed. The addition of new agents with antitumor activity is under investigation. Another strategy to improve effectiveness of therapy in these tumors is to use beams with a higher biologic effectiveness such as carbon ions.

The first clinical phase I and II trial investigating optimal dose in carbon ion RT in patients with anaplastic glioma and glioblastoma was performed at the NIRS between 1994 and 2002. A total of 48 patients were treated with combined conventional photon RT with 50 Gy in 25 fractions followed by eight fractions of carbon ion RT given within 2 weeks. Carbon ion dose was increased from 16.8 to 24.8 GyE in 10% incremental steps. Nimustine hydrochloride (ACNU) was administered twice at a dose of 100 mg/m² concurrently in week 1 and in week 4 or 5 of photon RT. The median survival time was 35 months in patients with anaplastic glioma and 17 months in patients with glioblastoma. Increased progression-free survival with dose was found in glioblastoma patients.⁶⁹ The results of this trial are promising and may be further improved by replacing ACNU by temozolomide. A clinical phase I and II trial combining carbon ion RT with temozolomide is currently being prepared in NIRS and Heidelberg.

Prostate Cancer

Dose escalation has been found to be favorable, especially for locally advanced prostate cancer in a number of photon intensity-modulated radiation therapy (IMRT) and proton trials. Disease-free survival rates at 5 years in patients with intermediate-risk prostate cancer are reported to be 51% after conventional RT with doses less than 76 Gy versus 82% for doses larger than 76 Gy.⁷⁰ However, the delivery of such high tumor doses is limited by the close vicinity of the prostate to the anterior rectal wall, which might result in a higher rate of severe radiation reactions of the rectum. Modern RT techniques such as intensity-modulated photon RT might help spare organs at risk and at the same time escalate the dose to the prostate. The resulting clinical benefit is being evaluated in clinical photon trials.⁷¹

Prostate cancer cells are considered to show a low radioresponsiveness against photons represented by relatively low α/β values in the range of 1.5 Gy, whereas a higher radiosensitivity is assumed for dose-limiting, late-reacting tissues such as the rectal wall.⁷² Hypofractionated carbon ion RT has been applied to more than 760 patients at NIRS.⁷³ After the early dose escalation study was conducted,⁷⁴ patients were successively treated with three different fractionation regimens using 66 GyE in 20 fractions for 5 weeks, 63 GyE in 20 fractions, and 57.6 GyE in 16 fractions.^12,75 The fractionation of 66 GyE in 20 fractions for 5 weeks was used until January 2005, when the total dose was reduced to 63 GyE given in the same fractions and treatment period. Patients were immobilized prior to carbon ion RT in a low-temperature thermoplastic material. When the anterior beams were applied for 4 out of 16 fractions, the bladder was filled with 100 ml of sterilized water for both the treatment-planning CT and prior to each treatment. The rectum was emptied as much as possible by the patient, or by the use of a laxative or enema. The CTV included the prostate and seminal vesicles, irrespective of T stage or other risk factors. The PTV1 included the CTV and anterior and lateral safety margins of 10 mm and a posterior margin of 5 mm. To reduce the dose to the rectum, a rectum-sparing target volume (PTV2) was defined. Irrespective of the size of the spread-out Bragg peak (SOBP), the RBE value for carbon ions was estimated to be 3.0 at the distal part of the SOBP. Carbon ion RT was given once a day, 4 days per week.

Patients with high-risk status (T_2b/T₃, Gleason score ≥ 7, or serum prostate-specific antigen [PSA] value ≥ 20 ng/ml) received antihormonal therapy in combination with carbon ion RT. Prior to carbon ion RT, neoadjuvant hormonal therapy such as medical or surgical castration with or without antiandrogen medication was performed for 2 to 6 months. After carbon ion RT, adjuvant antihormonal therapy was continued for at least 1 year. Patients in a low-risk group (T₁/T_2a, Gleason score < 7, and a serum PSA < 20 ng/ml) received carbon ion RT alone.

Of the 466 patients treated with 63 or 66 GyE in 20 fractions for 5 weeks and observed for 6 months or longer, the 5-year local control rate was 99.2%, the 5-year survival rate was 94.8%, the 5-year cause-specific survival rate was 98.6%, and the 5-year biochemical nonrecurrence rate was 89.9%.¹² Analysis of prognostic factors using the biochemical nonrecurrence rate as an endpoint revealed that the clinical T stage and the Gleason score determined by the same pathologist were significant prognostic factors.

In an effort to further reduce the treatment period from 5 weeks to 4 weeks, a total dose of 57.6 GyE given in 16 fractions is currently the standard regimen for all prostate cancers. Following treatment with 57.6 GyE in 16 fractions in 122 patients, only one patient had biochemical recurrence, and none died. This treatment is expected to produce results comparable to or better than carbon ion RT given in 20 fractions.

Lung Cancer

Surgical resection is the treatment of choice for localized non–small cell lung cancer (NSCLC). Primary photon RT is considered in medically inoperable patients. With fractionated proton RT, 5-year in-field control rates of 89% and 39% have been observed in stage IA and stage IB NSCLC patients, respectively. Overall survival rates were 70% and 16% for stage IA and stage IB patients, respectively.⁷⁶ Similar results have been found in other proton trials.^77,78

At the NIRS, the first phase I and II study investigating carbon ion RT in localized NSCLC was conducted from 1994 to 1999 to determine the optimal dose in stage I tumors. Irradiation was applied in 18 fractions over 6 weeks in 47 patients (protocol #9303) and in nine fractions over 3 weeks in 34 patients (protocol #9701). According to protocol #9303, dose was escalated from 59.4 to 95.4 GyE in 10% increments and in protocol #9701 from 68.4 to 79.2 GyE in 5% increments, respectively. Carbon ion irradiation was applied 3 to 4 days per week. Before treatment planning two or three iridium seeds were placed into the lung parenchyma in close vicinity to the tumor using a video bronchoscope. Patients were treated with two to four portals, with one portal applied in each session using a respiratory gating system.⁷⁹ Digital orthogonal x-ray images were taken prior to radiation, set-up deviations were determined with the help of the iridium seeds, and misalignments greater than 1 mm were corrected. The optimal dose fractionation scheme of carbon ion RT in stage I NSCLC was determined to be 68.4 to 79.2 GyE given in nine fractions. Local control probability at 5 years was 84%; 3 out of 81 developed grade 3 pneumonitis.⁸⁰

As a next step, a phase II study employing 72.0 GyE in nine fractions over 3 weeks was carried out in 50 patients at the NIRS from April 1999 to December 2000. The local control rate was 94.7%. The 5-year overall and cause-specific survival rates were 50% (stage IA: 55.2%, IB: 42.9%) and 75.7% (stage IA: 89.4%, IB: 55.1%), respectively.⁸¹

A further hypofractionated carbon ion RT plan was investigated in a phase I and II study for stage I NSCLC in NIRS.⁸² Seventy-nine patients were included in the study and were treated with a fixed dose of 52.8 GyE for stage IA tumors and with 60.0 GyE for stage IB tumors in four fractions during 1 week. The local control rate was 90% for all patients (T₁: 98%, T₂: 80%) and the overall survival rate was 68%. No radiation-induced lung toxicity greater than grade 3 was detected.

At present, single-fraction carbon ion RT is being investigated for stage I NSCLC at the NIRS.¹² A single total dose has been escalated from 28.0 GyE to 44.0 GyE at increments of 5%. The starting dose of 28 GyE was estimated on the basis of an NIRS modification of the linear quadratic model for the end point of local tumor control.^83–85 The biologically effective dose (BED) was calculated based on the result of the first dose escalation study using 18 fractions. The dose response of the BED was fitted by a sigmoid function and the curve for a single fraction treatment was derived, from which a single dose of 28.0 GyE was calculated to yield 90% of tumor control probability.

So far, almost 200 patients have been treated, in whom no serious adverse events have been observed and in whom the local control appears to be improving with increases in total dose. A typical patient treated with a single fraction of carbon ion RT given from four directions is shown in Fig. 70-2.

FIGURE 70-2 • Adenocarcinoma of the lung (T₂-N₀-M₀) treated with single fraction of 28 GyE with carbon ion beams. A, Radiation was delivered with four portals. B, For positioning of the patient, metal markers were implanted in the lung field. Computed tomography images before (C) and after (D) carbon ion radiotherapy (RT). Positron emission tomography images before (E) and after (F) carbon ion RT.

There has been no data available comparing proton and carbon ion RT with modern stereotactic photon RT. A comparative study is particularly warranted for large-sized T₂ tumors (>3 cm).

Hepatocellular Carcinoma

Common therapy modalities for hepatocellular carcinoma (HCC) are hepatectomy, transcatheter arterial embolization, percutaneous ethanol injection (PEI) therapy, and radio-frequency ablation (RFA) therapy. Treatment outcomes are, however, still disappointing, especially in large tumors. RT of HCC is therefore a treatment option, especially for inoperable cases. Toxicity to the liver parenchyma is considered to be the dose-limiting endpoint. Local control and overall survival rates at 5 years reported after proton RT are in the range of 86.9% to 87.8% and 23.5% to 55.6%, respectively.^86–88 Toxicity has been shown to be low, but coexisting liver cirrhosis has been shown to adversely affect overall survival.^86,87 Any therapeutic method applied to HCC must be used with caution so as to retain sufficient liver function.

The first clinical phase I and II trial was conducted at NIRS between 1995 and 1997 to evaluate the safety and effectiveness of carbon ion RT in patients with HCC.⁸⁹ Twenty-four patients were treated in 15 fractions delivered in 5 weeks. The total dose ranged from 49.5 to 79.5 GyE. The dose per fraction was increased in the absence of early and late reactions of the normal tissue. The PTVs included the tumor plus a 1.0-cm margin (Fig. 70-3). Respiratory gating was employed at the acquisition of the planning CT scan and during irradiation. The local control and overall survival rates were 92% and 92% at 1 year, 81% and 50% at 3 years, and 81% and 25% at 5 years.

FIGURE 70-3 • Hepatocellular carcinoma. A, Dose distribution and three-dimensional appearance of the tumor (yellow) and surrounding organs (B). Computed tomography images before and after carbon ion radiotherapy are shown in C and D, respectively.

Further phase I and II trials were performed to confirm the safety and efficacy of short-course therapy regimes: (1) 12 fractions within 3 weeks in 33 patients, (2) eight fractions within 2 weeks in 22 patients, and (3) four fractions within 1 week in 28 patients. In these trials, the dose was escalated by increasing the fraction dose in increments of 10% with fixed fractions and treatment period. The largest number of 75 patients was treated with a total dose ranging from 48.0 to 52.8 GyE in four fractions. Of them, 61 patients were treated with 52.8 GyE, and their 3-year local control and 5-year survival rates were 94% and 34%, respectively. In 20 patients with a tumor diameter of 3 to 5 cm, the 3-year and 5-year survival rates were 75% and 70%, respectively. These results are comparable or superior to the results after proton RT. Survival was strongly associated with the presence of liver cirrhosis.

Since 2003, a dose escalation study has been performed in 36 HCC patients, delivering a total dose of 32 to 38.8 GyE in two fractions over 2 days.⁸⁹ No patients developed severe side effects, and the 3-year local control and survival rates were 84% and 77%, respectively. It was decided for the two-fraction RT to adopt a total dose of 38.8 GyE or larger. Carbon ion RT can be given to patients with small restrictions because of liver function (Child-Pugh grade A or B). In small lesions of 3 cm or less, carbon ion RT might be offered to patients not eligible for PEI or RFA for any reason. For patients with lesions larger than 3 cm, effective tumor control is rarely achieved with PEI or RFA alone. These patients are ideally suited for carbon ion RT. The results with carbon ion RT are particularly encouraging for large lesions exceeding 5 cm.

Head and Neck Tumors

Most head and neck cancers are squamous cell carcinomas. Less common histopathologic tumor types in the head and neck region include adenocarcinoma, adenoid cystic carcinoma, mucoepithelial carcinoma, and malignant melanoma. The rationale to use carbon ion RT in locally advanced head and neck tumors is that local control rates after conventional treatment with surgery, chemotherapy, and photon RT remain unsatisfactory.

The clinical phase I and II dose-escalation study was carried out at the NIRS between 1994 and 1997, in which a total of 36 patients with locally advanced head and neck tumors were treated with carbon ion RT. Patients received 18 fractions in 6 weeks (group A) and 16 fractions in 4 weeks (group B). Total doses were escalated in increments of 10% after careful observation of at least three patients treated at the same dose level. Local control was 75% at 5 years for all patients. Subanalysis showed the local control rates of 100% in malignant melanoma, 50% in adenoid cystic carcinoma, and 34% in squamous cell carcinoma. Toxicity was acceptable.⁹⁰

Although the outcome in patients with squamous cell carcinoma does not seem to be superior to outcome reported after photon or proton RT, local control rates in malignant melanoma and adenoid cystic carcinoma appear very promising as compared with results obtained with low-LET irradiation.⁹¹ Between April 1997 and August 2007, a total of 295 patients were treated in a third study at NIRS using 57.6 or 64.0 GyE given in 16 fractions over 4 weeks.¹² Local control was achieved in 75% to 81% of the patients with adenocarcinoma, adenoid cystic carcinoma, and malignant melanoma. The most common histologic type has been malignant melanoma, and a total of 95 patients with this tumor were treated. Local control was 75%, but survival was only 36% because of distant metastases. Based on this result, a new protocol was designed for treatment of malignant melanoma, using carbon ion RT and concomitant chemotherapy. To date, a total of 64 patients have been treated and the 5-year local control and survival rates are 78.8% and 48%, respectively. It is possible that better tumor control will reduce distant metastases and result in improved survival in malignant melanoma.

In locally advanced adenoid cystic carcinoma treatment results after primary or postoperative conventional low-LET RT are poor. Neutron RT has been found to be superior to photon RT in a clinical phase III trial. Local-regional control rates were 56% versus 17% after neutron RT versus photon RT at 10 years.⁹² The drawback of neutron RT is, however, the high rate of late toxicity. In a meta-analysis of 570 patients with adenoid cystic carcinoma treated with neutron RT at different European neutron facilities, a rate of 10.6% has been noted for severe late effects.⁹³

At GSI and Heidelberg University a clinical phase I and II trial has been carried out investigating combined photon RT plus carbon ion boost in patients with locally advanced adenoid cystic carcinoma. The results have been compared with results obtained with photon IMRT alone in similar patients treated at Heidelberg University. Twenty-nine patients were treated with combined photon IMRT and a carbon ion RT boost within this clinical phase I and II study. The CTV covered the course of the involved cranial nerves to the point where they enter the base of the skull. The gross tumor volume included the macroscopic tumor with a safety margin of 1 to 2 mm. The CTV was treated with combined stereotactic photon RT (fractionated stereotactic RT or intensity-modulated stereotactic RT) to a total dose of 54 Gy in a weekly fractionation of 5 × 1.8 Gy and a carbon ion boost of 18 GyE in a weekly fractionation of 6 × 3.0 GyE to the macroscopic tumor residual. At a median follow-up of 16 months (range 2 to 60 months) 4-year locoregional control rates were 77%. The 4-year overall survival rate was 75.8%. Toxicity was acceptable, and severe late toxicity grade 4 occurred in one patient only. When the local control rates were compared with the control rates obtained for 23 patients with locally advanced adenoid cystic carcinoma treated with photon IMRT alone, outcome appeared to be improved after combined treatment, and toxicity was comparable.⁹⁴

Bone and Soft-Tissue Sarcoma

Bone and soft-tissue sarcomas consist of a variety of histologic subtypes. Complete resection is the treatment of choice, followed by adjuvant therapy in large and high-grade tumors. Although tumors of the extremities are accessible to complete surgery in most patients, a great proportion of bone and soft-tissue sarcomas of the trunk and paraspinal tumors are considered unresectable, or microscopic and macroscopic tumor residuals remain after surgery. Results with photons are poor because of the inability to deliver the needed target doses while respecting the tolerance doses of the neighboring organs at risk such as the spinal cord, liver, kidneys, and small bowel.⁹⁵ In the past, proton RT has been investigated especially for chordoma and chondrosarcoma of the spine. In studying treatment of axial osteo and chondrogenic tumors, Hug and colleagues report 5-year actuarial local recurrence–free survival rates of 53% for chordoma and 100% for chondrosarcoma after proton RT.⁹⁶ In a small group of patients with bone sarcoma, mainly in the spine, treated at LBNL with helium or neon particles, 5-year actuarial local control and survival were 59% and 45% respectively.⁹⁷

At NIRS, a dose-escalation trial has been carried out in patients with different bone and soft-tissue tumors such as osteosarcoma, chondrosarcoma, chordoma, and retroperitoneal sarcoma. Customized cradles and a low-temperature thermoplastic sheets were used for immobilization. Respiratory gating for both CT acquisition and therapy was performed whenever indicated. Irrespective of the size of the SOBP, the RBE value of carbon ions was estimated to be 3.0 at the distal part of the SOBP. Compensators were fabricated for each patient. Carbon ion RT was applied 4 days a week (16 fractions within 4 weeks). The total dose ranged from 52.8 to 73.6 GyE in 16 fractions. To determine the maximum tolerated dose (MTD), patients were divided into the following three groups: spinal tumors, pelvic tumors, and extremity tumors. A total dose of 73.6 GyE was determined to be the MTD. The local control rate increased as the total dose increased from 52.8 to 73.6 GyE, reaching more than 80% in patients treated with 70.4 GyE or more.⁹⁸ In the up-date analysis for the same patients, the 3-year local control rate was 63%, and 3-year and 5-year survival rates were 47% and 36%, respectively. To confirm these findings, a phase II clinical trial was initiated at NIRS. A total dose of 73.6 GyE was prescribed in cases with no subcutaneous tumor, and 70.4 GyE in patients presenting with subcutaneous tumor invasion. A total of 323 lesions in 307 patients were treated between 2000 and August 2007, and the 5-year local control and survival rates were 80% and 56%, respectively. Severe side effects in the form of skin and soft-tissue toxicities developed in approximately 3% in the previous study, which has since been reduced to zero following changed techniques to decrease the skin doses. In 58 patients with osteosarcoma in the pelvis or spine, the 5-year local control and survival rates were 65% and 29%, respectively, as compared with 5-year survival rates of 10% or less reported in the literature for conventional RT.^99–102

Imai and colleagues retrospectively analyzed the subgroup of patients with sacral chordoma treated with carbon ion RT. A high local control rate of 96% was found.^102,103 The result is favorably compared to other sacral and spinal chordoma series treated with high-dose proton RT and other charged particles.^29,104 The results obtained with carbon ions alone provide evidence that carbon ion doses between 70.4 and 74 CGE are highly effective in controlling chordoma within the target volume. An example of carbon ion treatment of chordoma is shown in Fig. 70-4.

FIGURE 70-4 • Large sacral chordoma treated with 64 GyE of carbon ions. A, Dose distributions and treated volume. Magnetic resonance images before (B) and after (C) carbon ion radiotherapy.

Carbon ion RT is an effective local treatment for patients with unresectable bone and soft-tissue sarcoma. In contrast to neutron RT, the morbidity has been quite acceptable in carbon ion RT.¹⁰⁵

Recurrent Rectal Cancers

For postoperative pelvic recurrence of rectal cancer, surgical resection has been the first choice of treatment, but often these tumors prove unresectable. If the pelvic recurrent lesion is successfully resected, however, the 5-year survival rate after resection is relatively favorable at around 30%.¹⁰⁶ This means that, if the local recurrent lesions can be securely controlled, a favorable prognosis may be expected, but the prognosis with conventional RT alone is not satisfactory, with many reports describing a 50% survival period of 12 months and a 3-year survival rate of approximately 10%.¹⁰⁷ After carbon ion RT with a total dose of 73.6 GyE, the 5-year local control rate was 92.7% and the 5-year survival rate was 57.4%, both favorably comparable to the results of surgical resection and superior to conventional RT.

At the NIRS, a total of 95 lesions in 90 patients with locally recurrent rectal cancers were treated with carbon ion RT. Total doses of 67.2 GyE, 70.4 GyE, and 73.6 GyE were delivered in 16 fractions for 4 weeks.¹⁰⁸ The treatment results were favorable; the overall local control rate was 88.6% at 3 years and 80.5% at 5 years, and the overall survival rate was 60.0% at 3 years and 42.8% at 5 years. With respect to side effects, none of the patients developed severe reactions of NCI-CTC grade 3 or worse, either acute or late, in the gastrointestinal tract, urinary tract, or subcutaneous tissues. With increases in total dose, improvements of both local control and survival rates were observed in 63 lesions in 61 patients treated with 73.6 GyE in 16 fractions for 4weeks, and their 5-year local control and survival rates were 92.7% and 57.4%, respectively (Fig. 70-5), both favorably comparable to the results of surgical resection and superior to conventional RT.

FIGURE 70-5 • Pelvic recurrence of rectal cancer indicated by arrows in (A). Computed tomography images before (A) and after (B) carbon ion radiotherapy (RT), with a spacer placed between the tumor and intestine is indicated by arrows. Positron emission tomography images before (C) and after (D) carbon ion RT show marked reduction of tumor.

Carbon ion RT is a safe and effective modality in the management of locally recurrent rectal cancer, providing good local control and offering a survival advantage with acceptable morbidity.

Carcinoma of the Uterine Cervix

The treatment results for uterine cervix cancer have been favorable when a combination of intracavitary brachytherapy and external-beam RT with or without chemotherapy is used. In the case of advanced lesions, however, the results are not satisfactory. Carbon ion RT has been used mainly for locally advanced tumors in an attempt to make a new breakthrough in treating tumor stages in which there have been poor treatment results. In dose escalation trials at the NIRS, carbon ion RT was found to be effective in 44 patients with locally advanced carcinoma of the uterine cervix, including squamous cell carcinoma,^107a adenocarcinoma, and adenosquamous carcinoma. Local control rates were encouraging even in patients with stage IVA tumors. With the total doses of more than 62.4 GyE delivered in 16 fractions to the pelvis and eight fractions to the primary tumor site, 5-year local control rates of 69% and 64% were reached in stage IVA tumors and in tumors with a dimension of at least 6.0 cm. No patient developed severe acute toxicity, but eight patients developed major late gastrointestinal complications. These were patients treated with doses higher than 60 Gy E to the intestine.¹⁰⁹

A total of 46 patients with uterine adenocarcinoma, unsuitable for surgical resection, were also treated with carbon ion RT alone. The total dose was escalated from 62.4 GyE to 74.4 GyE given in 20 fractions over 5 weeks. The 5-year local control and survival rates in 38 patients were 64% and 42%, respectively.

Future Perspectives

More than 4500 patients have been treated worldwide using carbon ion RT. Most of the patients treated with carbon ion RT have been included in prospective clinical phase I and II and phase II trials. Carbon ion RT has been found to be effective in a number of prospective nonrandomized trials for non–squamous cell head and neck tumors, locally advanced adenoid cystic carcinoma, chordoma and chondrosarcoma, prostate cancer, lung cancer, HCC, and locally advanced bone and soft-tissue tumors.¹¹⁰ The physical and biologic benefits of carbon ion RT have permitted significantly shorter courses of RT, which means that a carbon therapy facility can be operated more efficiently, treating a larger number of patients than is possible with other modalities during the same time. Further investigation of carbon ion RT with controlled clinical trials comparing particle therapy with modern photon and proton RT with respect to tumor control, toxicity, and treatment cost is clearly warranted.¹¹⁰ Current and future developments in molecular biology, targeted therapy, imaging, and radiation technology need to be fully integrated into the charged-particle therapy process.¹¹¹ The future must also contain further attempts to reduce morbidity, especially in children and young adults.¹¹² Protons and light ions offer the best chance to reduce dose to normal tissue, with concomitant reduction in long-term morbidity and incidence of secondary tumors. It will be particularly important to study combined therapy in which chemotherapy and ion beam therapy is used. Carbon ion RT and the associated disciplines of physics, biology, and engineering represent a rapidly growing field with an encouraging prospect for better control of human cancers.