Carbon ion radiotherapy: Emergence of a new weapon in war against cancer

Tapesh Bhattacharyya

doi:10.4103/bjoc.bjoc_1_23

INVITED EDITORIAL

Year : 2022 | Volume : 2 | Issue : 1 | Page : 1-5

Carbon ion radiotherapy: Emergence of a new weapon in war against cancer

Tapesh Bhattacharyya
Consultant Radiation Oncologist, Tata Medical Center, Kolkata, West Bengal, India

Date of Submission	02-Jan-2023
Date of Acceptance	02-Jan-2023
Date of Web Publication	31-Mar-2023

Correspondence Address:
Tapesh Bhattacharyya
Consultant Radiation Oncologist, Tata Medical Center, Kolkata, West Bengal
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjoc.bjoc_1_23

How to cite this article:
Bhattacharyya T. Carbon ion radiotherapy: Emergence of a new weapon in war against cancer. Bengal J Cancer 2022;2:1-5

How to cite this URL:
Bhattacharyya T. Carbon ion radiotherapy: Emergence of a new weapon in war against cancer. Bengal J Cancer [serial online] 2022 [cited 2023 Jun 6];2:1-5. Available from: http://www.bengaljcancer.org/text.asp?2022/2/1/1/373310

Background

The last two decades have seen excellent progress in different radiotherapy techniques including IMRT (intensity-modulated radiotherapy), IGRT (image-guided radiotherapy), SRS (stereotactic radiosurgery), SRT (stereotactic radiotherapy), SBRT (stereotactic body radiotherapy), and many more. Those advancements in techniques enabled us to achieve excellent conformality, reduce the PTV (Planning target volume) margins, ultimately leading to reduced acute and late side effects of radiotherapy. The emergence of proton beam radiotherapy has made it further precise and conformal enabling further reduction in acute and late side effects. However these technological advances seem likely to reach a plateau in terms of tumor control and improvement in cancer outcome. Improvement in local control is possible only with a better understanding of tumor biology and the use of an approach that is radiobiologically more advantageous.

History

In search of optimal radiobiological approaches, clinicians and physicists had been exploring different possibilities such as neutrons, protons, helium, carbon, oxygen, etc. since the 1950s. The idea of using proton beam therapy in the field of medicine exploiting the Bragg peak and improving the physical dose distribution was first proposed by Dr. Robert Wilson, a physics student from the University of Berkley, California who later became director of FermiLab and was actively involved in Manhattan project during second World War II.^[1] Exploring heavier ions for cancer treatment was first proposed by Cornelius Tobias at LBNL (Lawrence Berkeley National Laboratory) with an idea that heavier ions have similar physical profiles like protons and have better radiobiological properties than protons and X-rays which can result in better oncological outcomes.^[2] Ion beam research was undergoing in a big way in LBL since 1950s. In the beginning of ion beam therapy at LBNL, two basic questions had to be solved: the shaping of the primary ion-beams to irradiate an extended target volume in the most conformal way and the choice of the optimal atomic number of the projectiles concerning physical and radiobiological properties. The physical advantages of particle dose delivery with protons started its application to radiotherapy in 1954 in the U.S. at LBNL. The Bevalac accelerator was used in 1977 to treat the first patient in 1977 with carbon ions. Between 1977 and 1992 multiple early phase clinical trials were conducted with heavy ions.^[3] However, clinical results of ion beams were not satisfactory as expected, probably because of inadequate imaging, suboptimal treatment dose calculation algorithms, lack of biological modeling, and unreliable access to beam in facilities intended for physics research. The baton shifted from the USA to Japan when the US dropped the idea of continuing carbon ion experiments further in 1992 and Japan realized the importance of materializing its use in clinical settings under the able leadership of NIRS (National Institute of Radiological Sciences). Established in 1957, the National Institute of Radiological Sciences, Chiba was the premier institute for conducting particle therapy research in Japan and became home to many scientists reaching from different parts of the globe. In the early 80s, after extensive study of different ions to achieve optimal physical and biological advantages, carbon particles were selected as the particle of choice in the HIMAC (Heavy Ion Medical Accelerator in Chiba). Building on prior experiences with particle beam therapy and the collaboration with the LBNL, the decision to build the HIMAC was born in 1984 as part of a long-term cancer control plan in Japan. It took about 10 years before the first patient was treated in 1994 at NIRS.^[4]With a futuristic vision and meticulous planning another 6 centers of Carbon ion radiotherapy evolved in Japan, starting from Hyogo (HIBMC) in 2001, Gunma(GHMC) in 2009, Saga (HIMAT) in 2013, Kanagawa (i-ROCK) in 2015, Osaka(HIMAK) in 2018, and latest Yamagata Carbon ion radiotherapy center in 2020. Parallelly in Europe, the Gesellschaft für Schwerionenforschung (GSI) was started in Darmstadt, West Germany, in 1969 and would become a center that established Germany as a leader in the clinical application of heavy ion therapy. The GSI in Darmstadt, Germany treated their first patient in 1997 with a dedicated medical irradiation room in which they developed and installed the first C-ion scanning technique as well as an inline PET(Positron Emission Tomography) camera. In an effort to expand the clinical application of particle therapy initiated at the GSI, the Heidelberg Ion Beam Therapy Center (HIT) opened in 2009 as a joint endeavor of the GSI and Siemens Medical Company.^[5] The wave of Carbon gradually hit Marburg in Germany, Pavia in Italy, and Medaustron in Austria subsequently. Apart from Japan, our neighbor China has two heavy ion centers at the moment, Lanzhou and Shanghai (SPHIC). Though the USA as a pioneer has paved the way forward for heavy ion therapy research, however not a single carbon ion therapy center exists in the USA, hopefully, it will see the light of the day at Mayo Clinic, Florida very soon.

According to latest PTCOG data 41,544 patients have been treated with Carbon Ion so far (1994–2021) with more than 20,000 at NIRS, Japan.^[6]

Carbon Physics and Biology

Carbon ion therapy is a specialized form of radiotherapy for the treatment of cancer which deposits ionizing radiation in cancer cells via accelerated charged carbon particles that are heavier than protons. A narrow pencil beam of carbon ions is accelerated in a particle accelerator to provide sufficient energy to the ions to penetrate to the depth of the tumor within the human body and kill cancer cells. The speed of the ion varies with the energy it carries. A speed of approximately 70% of the speed of light is required for the ions to achieve the energy needed to reach a deeply located tumor (around 30 cm). As the carbon ions reach the desired speed and energy, they are extracted from the accelerator and are magnetically directed to the treatment rooms. They enter through the patient’s skin and travel to the cancer to deposit the therapeutic dose of ionizing radiation. The incident pencil beam is magnetically scanned, and its energy modulated to effectively form a broad beam to paint the entire target volume of the tumor target from deep to superficial. Multiple such broad beams from different angles are used to conform the dose to the tumor, lower the dose outside the target volume and to optimally spare the surrounding normal tissues.^[7],[8]

Carbon ion is the most widely used heavy ion particle for the treatment of cancer. Like protons, carbon ions have a finite range in tissue. The speed of carbon ions is tuned in the accelerator in such a way that when they reach the cancer, they deposit most of their initial energy within the cancer and only a minor, often clinically insignificant energy spills beyond the cancer target. It has a similar kind of Bragg peak compared to protons with much reduced lateral penumbra and sharper lateral fall off which provide even better conformality than protons. However unlike protons carbon has a fragmentation tail beyond the distal edge of the Bragg peak because of its nuclear interaction and fragmentation into small particles with low atomic numbers. This fragmentation tail does not have clinically significant deleterious effect on critical organs at risk (OAR) because of rapid physical dose fall off and much lower LET of fragmented smaller particles in this area resulting in lesser biological dose.^{[9],[10],[11]}

An interesting point to note is that, compared to the rotational gantry of a photon beam, most of the heavy ion facilities in the world have fixed gantries where the couch only is rotated for angular flexibility during treatment. Hence radiation planning and execution are labor intensive and time consuming. Unlike protons, out of all the carbon ion centers only 3 centers Heidelberg Ion Therapy Center (HIT), NIRS and Yamagata carbon ion center are using rotating gantries for clinical purposes. HIT in 2009 became the first C-ion facility with a 360 degree rotating gantry. This rotational gantry built by HIT was huge in size with a weight of 600 tons, almost twice larger and five times heavier than standard proton gantry. Such a massive gantry was difficult to generate widely, operate and was too expensive. NIRS in collaboration with Toshiba (Toshiba Ltd, Tokyo, Japan) installed a compact rotating gantry of 300 tons and 13 m length in 2015 exploring the superconducting magnet technology as compared to HIT in Germany which was 600 tons and 25 m in length allowing a significant size and weight reduction. After undergoing several physical experiments the rotational gantry at NIRS became clinical for fixed and moving tumors in 2017 and 2018 respectively.^[12]

RBE (relative biological effectiveness) increases with increasing LET (linear energy transfer). LET depends on z2/v2 (z = atomic number, v = velocity). As the z or atomic number of carbon ions is 6, it has 36 times more LET as compared to protons.^[13] By virtue of much higher LET, carbon has stronger biological effects compared to photon or proton radiotherapy due to their inherent ability to produce complex or clustered DNA damage which is refractory to repair. When other heavy ions have a very high LET in the entrance channel, carbon represents an excellent compromise with a lower LET 11–13 keV/micron at the entrance channel and a fairly high LET on the SOBP of 40-80 kev/micron. That’s why carbon ion has a variable RBE ranging from 2 to5 throughout the track and has shown excellent tumor control in radioresistant malignancies with maximum sparing of OARs with minimal acute and late side effects. The effects of high LET carbon ion beams are also less dependent on molecular oxygen. Thus, for the high LET ranges, OER for CIRT can be as low as 1–2 indicating that carbon beams are more efficacious at killing cancer cells in hypoxic niches. Moderate and extreme hypofractionation is possible with carbon because of its excellent conformal dose distribution and by virtue of its higher LET, lack of oxygen dependence, cell cycle dependence.^[14],[15]

Carbon ions seem to produce immunogenic effects such as an increased production of tumor associated antigens, and antitumor effects, which may result in reduced ability to metastasize or recur further. Mouse studies have shown that combining heavy ion radiotherapy with immunotherapy may lead to a novel strategy of treating cancer, creating a hope for cancer patients with oligometastases at presentation. Such combination of therapies may be amongst the most effective forms of future cancer treatment.^[16],[17]

Because of the varying LET and RBE, LQ model does not work for carbon, complex biophysical models are taken into consideration for biological dose calculation. The pilot project at GSI adopted biologically optimized treatment plans based on local effect model I (LEM I), where the principal premise is that the local biological effect, that is, the organic damage in a small subvolume of the cell nucleus, is exclusively determined by the estimated value of the energy deposited in that sample and does not depend on the particular radiation type yielding the energy deposition. Despite its similarity to the microdosimetric approach, it applies to volumes in nanodimensions. Based on photon experience, LEMs predict the spatial distribution of particles on a nanometric scale. As LEM I directly links the cell nuclei’s local dose deposition pattern to the photon dose-response curve, European centers are more familiar with their practice of carbon-photon combination.^[18]

The NIRS team was looking for depth in the carbon beam SOBP, at which neutrons would demonstrate the same RBE. LET alone does not adequately detail the energy deposition distribution around a particle track. RBE also depends on variables, such as tissue type, fractionation, and total dose. The microdosimetric kinetic model (MKM) was adopted to explain the biological effects of radiation beams based on how carbon ions stochastically deposit energy at the micrometer level. As MKM was developed from prior neutron experience rather than a photon, and no robust formula or isodose platform exists to calculate the total biologically equivalent dose by adding photon and carbon doses. NIRS and other carbon ion centers in Japan usually practice carbon-based therapy alone rather than carbon–photon combination in relatively radioresistant histologies.^[19]

Clinical Experiences

The clinical data available thus far suggest promising outcomes in even hard to treat tumors, such as those that are deep seated, critically located, traditionally thought to be radio-resistant, or are recurrent and highly aggressive. Some of the exciting results are highlighted below.

Head and Neck

CIRT provides significant benefit in head and neck cancers in small surgically inaccessible areas close to critical organs and especially in histologies (sarcomas, melanomas and adenoid cystic carcinomas) resistant to conventional photon based radiation. J-CROS group has shown 2 year local control and overall survival of 83.9% and 69.4% respectively in head and neck malignant melanomas.^[20] The same group showed excellent results in adenoid cystic carcinomas with 2 year local control and overall survival of 88% and 94% respectively.^[21]

Bone and Soft Tissue Sarcomas

CIRT has been explored in locally advanced unresectable or recurrent bone and soft tissue sarcomas which have traditionally been considered as incurable and has extremely poor prognosis. Imai et al.^[22] evaluated the results of carbon ion radiotherapy in 128 patients with localized axial soft tissue sarcoma with a 5 year local control of 65% and overall survival of 46%. The recent nationwide multicentric study on sacral chordoma from Japan showed 5 year overall survival and local control rates of 84% and 72%.^[23]

Pancreatic Cancer

Pancreatic cancer is a leading cause of cancer-related death and is one of the most lethal cancers, especially in developed countries. The only curative treatment of pancreatic cancer is surgical resection, and even after resection, there is high rate of local and distant failure, with a 5-year survival of approximately 20%. Kawashiro et al.^[24] conducted a retrospective analysis of 72 patients with LAPC from 2012 to 2014 at 3 treated with high dose of CIRT along with Gemcitabine based chemotherapy. The prescribed dose of CIRT was 52.8 Gy (RBE) or 55.2 Gy (RBE), both delivered in 12 fractions, along with concurrent injection of gemcitabine at 1,000 mg/m2 on days 1, 8 and 15. OS (Overall survival) rates were 73% at 1 year and 46% at 2 years, constituting a median OS of 21.5 months. Cumulative local recurrence at 1 and 2 years were 16% and 24%, respectively. The CIPHER study, initiative of the University of Texas Southwestern Medical Center, is a phase III trial planned to compare IMRT (Intensity Modulated Radiotherapy) with CIRT for unresectable pancreatic cancer.

Hepatocellular Carcinomas

Hypofractionated CIRT from NIRS has shown promising results against localized HCC. The Japan Carbon Ion Radiation Oncology Study Group (J-CROS) conducted a multi-institutional evaluation of the efficacy of hypo-fractionated CIRT for HCC. Between 2005 and 2014, 174 patients were treated. Prescribed CIRT doses ranged from 48.0 Gy (RBE) in 2 fractions (n=46), to 52.8 Gy (RBE) (n=108) and 60.0 Gy (RBE) (n=20) in four fractions. Local control at 1, 2 and 3 years was 95%, 88% and 81%, respectively, while overall survival was 95%, 83% and 73%, respectively.^[25]

Locally Recurrent Rectal Cancers

CIRT has shown excellent results both in upfront and re-irradiation settings. Shinoto et al.^[26] conducted a multi-center retrospective evaluation of 224 LRRC patients treated with CIRT, reporting a 5-year OS rate of 73 % and an LC rate of 88 %. Yamada et al.^[27] assessed the safety and efficacy of carbon ion in reirradiation of 77 locally recurrent rectal cancer patients treated between 2005-2017. The overall local control rates (infield + out-of-field recurrence) were 69 % at 3 years and 62 % at 5 years.

Lung Cancers

Recently published long term results of single fraction carbon ion radiotherapy for NSCLC (nonsmall cell lung cancer) is really exciting. A total of 57 patients of T1T2N0M0 NSCLC were treated with single fraction 50GyRBE CIRT between 2011 and 2016 at NIRS, Japan. The 3- and 5-year local control rates were 96.4% and 91.8%, respectively. The 3- and 5-year overall survival rates were 91.2% and 81.7%, respectively. No case of ≥ grade 2 pneumonitis was recorded.^[28]

Areas of Uncertainty

One of the major concerns of carbon ion radiotherapy is dose uncertainty. With Bragg peak and sharp lateral penumbra there is a higher susceptibility to intrafraction motion compared to photon based radiotherapy there is higher likelihood that the Bragg Peak be in normal tissues with intrafraction motion.^[29]

The exact radiobiological effects on normal tissues still remain unclear. Additionally, there are not well established dose constraints for normal tissues as QUANTEC (quantitative analysis of normal tissue effects in the clinic) for photons, leading to uncertainty regarding the toxicity rates at a given dose.^[30]

The dose prescription of carbon ions calculated according to different biophysical models are different. For example, the prescribed dose according to the LEM Model adopted in Germany is different from prescribed dose according to the MKM model adopted in Japan. Hence it is difficult to compare results of carbon ion from different institutions. A consensus on the definition and calculation of RBE for CIRT is necessary prior to more widespread adoption.^[30]

Majority of carbon ion regimens are hypofractionated based on different biophysical models. It is difficult to compare them with LQ model based conventionally fractionated photon radiation.

Hurdles in Setting up Carbon Ion Facility

The elevated cost of a carbon ion facility as compared to conventional photon setup is mainly because of the complexity of the system needed to reach deeply seated tumors, which requires a particle accelerator, generally a synchrotron, measuring approximately 20 m in diameter. It also requires heavy electricity consumption and stringent quality assurance. The major obstacle in setting up a carbon ion facility is its initial capital investment, operational cost, higher maintenance charges and maintaining the project viability. The approximate cost of a state of art carbon ion therapy with a capacity to treat 800 to 1200 patients per year is roughly 2.5 to 3 times more than that of a proton center. Although there are modest numbers of phase 1/trials involving CIRT that have been completed in recent times or are currently being conducted, a minority are randomized, a smaller minority are phase III trials, and even fewer involve an OS primary endpoint. The hurdles in conducting such phase III randomized controlled trials are lack of large-scale fundings and absence of clinical equipoise to get ethical approval.

Summary and Future Directions

CIRT represents a promising new treatment modality, with early data suggesting that it is both safe and effective in hypoxic radioresistant tumors. Further prospective trials are needed to firmly establish and widespread adoption of carbon ion therapy in clinical practice. CIRT in combination with immunotherapy is going to be one of the most promising strategy in cancer management in near future. Given the promising clinical data and physical and biological advantages of CIRT in hard to treat malignancies India should intend to set up a carbon ion facility and be the leader in heavy ion research in South east Asia. It will not only help us fight against radioresistant malignancies in clinical settings, it will also open up a new horizon in the field of basic particle therapy research, translational research and also space radiobiology.

Financial support and sponsorship

Not applicable.

Conflicts of interest

There are no conflicts of interest.

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