Introduction to Heavy Ion Therapy

Cancer radiation therapy historically has pursued two main goals:

  • To closely match the shape of deposited radiation dose to the tumor target (dose “conformity”), with the aim of putting more therapeutic dose to the target while maintaining the same healthy tissue irradiation.
  • To increase the biological effects of the deposited energy in the target, with the aim of causing more biological damage with the same amount of deposited physical radiation dose (again, while maintaining a safe dose to surrounding healthy tissue).

Keeping in mind these two goals, clinicians and scientists have evaluated various forms of ionizing radiation technology over the years.

At first only superficial tumors were treated because only low-energy X-rays were available, prohibiting the irradiation of deeply seated tumors. As technology advanced, it became possible to treat deeply seated tumors with high-energy X-rays. Further technological improvements in X-ray collimation and modulation and the introduction of accelerated protons allowed even higher dose conformity to the target, though the biological effects of the absorbed dose remained more or less unchanged.

The introduction of accelerated heavy ions (ions heavier than protons) to cancer care has revolutionized the field of radiation oncology because their usage allows for meeting both of the goals stated above. In the following four sections we will describe the physical, biological, and clinical rationale for heavy ion cancer therapy as well as the technology needed for its clinical implementation.

Physical advantages of heavy ion cancer therapy

Heavy ion chart
Figure 1 shows how low-energy X-rays, high-energy photons, and carbon ions deposit their doses at various depths in a simulated patient body.

Figure 1 shows how low-energy X-rays, high-energy photons, and carbon ions deposit their doses at various depths in a simulated patient body. Low-energy X-rays exhibit an exponential decrease in their dose over distance, making them unfit to be used for deeply seated tumors. High-energy photons, like the 18MV photon beam in Figure 1, are more suitable for deeply located tumors, but a substantial dose is absorbed by healthy tissue upstream and downstream of the tumor target.

In contrast, the depth profiles of heavy charged particles exhibit a significant increase in deposited dose at the end of their range, the so-called Bragg peak. The position of the Bragg peak can be made to coincide with tumor depth by carefully selecting the incoming heavy ion’s kinetic energy. A therapeutic carbon nucleus (12C6+) with a range of 12.75 cm initially carries a kinetic energy of about 3000 MeV and loses about 0.01 MeV per micrometer when it enters tissue. At the Bragg peak this loss is 10 times greater.

Heavy ions have another huge advantage in comparison to photons and protons in terms of how rapidly the dose falls off at the beam lateral edges (called the penumbra, the lateral distance where the dose falls from 80 percent to 20 percent of its peak value). At tumor depths beyond 7 cm this penumbra is larger than 10 mm for photons and even larger for protons, while the carbon ion beam fall-off is below a couple of mm even for the largest therapeutic depths. This allows placement of the heavy ion beam very close to critical organs. 

Radiobiological Advantages of Heavy Ion Beams

Radiation with different particles produces different levels of biological and clinical effects. The relative biological effectiveness (RBE) of a heavy ion refers to the amount of dose needed to achieve the same biological endpoint as treatment with a reference particle such as photons. The RBE depends on several parameters such as tissue type, biological endpoint, amount of absorbed dose, heavy ion type, linear energy transfer (LET), and oxygen content of the tissue.

Treatment of oxygen-deficient (hypoxic) tumors with conventional radiotherapy is a significant challenge because these tumors tend to be radioresistant, often needing three times more dose to achieve the same tumor kill as in norm-oxic tumors. Heavy ion irradiation shows promise in that this ratio is substantially decreased and approaches the value of one. Furthermore, the RBE for hypoxic cells is greater than those of norm-oxic ones, indicating a strong potential role for heavy ion irradiation.

In vitro radiobiological experiments have shown that the energy at which RBE reaches its maximum depends on the heavy ion type. For example, the RBE max occurs at around 25keV/micron for protons but at around 200keV/micron for carbon ions. This is a consequence of differences between lighter and heavier ions in their track structure (or spatial distribution of dose across a trajectory). This fact explains the huge biological advantage carbon ions exhibit with respect to photons and protons, namely that their RBE is relatively low and close to that of photons or protons in the entrance region of the body (where healthy tissue is located) but their RBE is high at the Bragg peak placed at the tumor. The magnitude of this maximum RBE strongly depends on the tissue’s biological properties. Cells with poor repair capacities show little or no RBE increase for heavy ions with respect to protons, but cells with strong repair capabilities (i.e., radioresistant tumors) exhibit large RBE maxima and therefore are clinically well suited for heavy ion irradiation.

Heavy Ion Therapeutic Beam Technology

The production of therapeutic photon radiation is relatively inexpensive and simple. Protons and heavier ions need much greater acceleration to reach therapeutic depth. This is done via circular accelerators (cyclotrons or synchrotrons) of about 20 meters in diameter.

Charged particles have another unique advantage over photons: their electric charge can be utilized to control their lateral direction of motion by a magnetic field, which can be used to precisely position the heavy ions within the tumor lesion. This delivery technique is called pencil beam scanning.

Clinical Experience with Heavy Ion Radiotherapy

Charged particle therapy for cancer treatment began in the mid-1950s in Berkeley, California, at a facility initially designed for basic particle physics research subsequently known as the Lawrence Berkeley National Laboratory (LBNL). Clinical studies of various types of charged particle irradiation, including proton, helium ion, neon ion, and carbon ion therapy, continued at the LBNL through 1992. This pioneering research laid the framework for subsequent clinical investigations into the utility of heavy ion radiotherapy.

In 1994, investigators at the HIMAC facility located at the National Institute for Radiological Sciences (NIRS) in Chiba, Japan, began treating patients with carbon ion radiotherapy, and in 1997 the Gesellschaft fur Schwerionenforschung (GSI) facility in Darmstadt, Germany, also began a carbon ion cancer treatment program.  The latter program was subsequently discontinued, and the Heidelberg Ion-Beam Therapy (HIT) Center began operations in 2009. Multiple other carbon ion treatment programs have initiated patient treatments at various facilities in Japan and Europe over the past 15 years.  Although there are numerous proton treatment centers in the United States, there have been no active treatment facilities delivering heavy ion therapy in the U.S.  since the closing of the heavy ion cancer treatment program at the LBNL.

A systematic approach to dose-escalation studies with carbon ion radiotherapy was instituted at NIRS at the program’s inception, and to date well more than 7,000 patients have been treated with carbon ion irradiation at this center. Phase I and II protocols at NIRS primarily evaluated hypofractionated treatment regimens. Multiple tumor types have been studied, including (given the unique physical and biological aspects of carbon ion irradiation) salivary gland and skull base tumors previously deemed appropriate for clinical study with neutron and proton radiotherapy. More common malignancies such as lung, breast, and prostate cancer have also been studied. 

Early-phase studies established tolerable and effective dose-fractionation regimens (with or without concurrent chemotherapy) for various tumor sites. In general, these studies have shown carbon ion radiotherapy to be a safe and efficacious treatment for a broad spectrum of tumors, including those commonly considered to be radioresistant. How these results compare to the best results seen with contemporary X-ray-based irradiation or chemo-irradiation is a subject of much debate.

So far there are no phase III randomized clinical trials comparing carbon ion radiotherapy with X-ray or proton radiotherapy. Such lack of randomized comparisons between unconventional and conventional radiation methods has been a major source of contention over the expansion of proton facilities in the U. S. (where the controversy stems from lack of proton versus X-ray studies). However, there is growing interest in conducting such studies. Promising results from such trials may help facilitate the growth of carbon ion radiotherapy facilities in the U.S.