Currently, clinical trial design is based on the assumption that the same biological effective dose is administered by photons, protons, or carbon ions. However, it is necessary to equate these doses, breaking the use of the traditional reference to photon dose. Therefore, it is important to look at differences in RBE and tissue type in order to create the best therapeutic ratio.

The design of future clinical screenings should address the differences in radiosensitivity between radio-resistant cells for low-LET RT and sensitivity for carbon ion RT to enable proper selection of histologies and patients who may benefit from this modality based on biomarkers and imaging. Patient selection should follow the protocol outlined in figure [4], acknowledging that none of the individual measures, whether hypoxia, alpha/beta ratio, or tumor proliferation, may represent the tumor microenvironment and true radiosensitivity of the tumor.

In Fig. 5.1, a cumulative score greater than or equal to 5 describes a radio-resistant tumor for low LET irradiation with standard of care (SOC), causing significant toxicity. Tumor histology and patients with 0–1 score have significant benefits from SOC treatment. The use of carbon ion therapy is sensitive when the advantages of using carbon ions exceed the therapeutic advantages that can be obtained with fractionated photon RT. With the advent of personalized medicine, those tumors that respond well to other radiation species should continue to be treated with these species, while a rare malignancy or patients who do not respond should be treated with carbon ions in an individualized way.

Carbon ion therapy has demonstrated benefits for the following:

With the unique properties of carbon ions, treatment can be completed in a shorter period of time and with smaller fractions. Future directions of carbon ion therapy depend on the interaction between radiobiology, radiation oncology, and physics accelerators, which combined with the clinical results make it a very promising technique.

The clinical advantages of carbon ions include improved therapeutic gain, hypofractionated radiotherapy, and potential suppression of metastases, as discussed in the following sections.

More than 38 centers worldwide have treated more than 100,000 cancer patients with particle therapy. Most patients have been treated using protontherapy, but the use of carbon ions is increasing. Unfortunately, despite recent advances in radiotherapy, there is still the risk of cancer arising in a location that was previously free of disease, caused by the treatment itself and not metastasis. There is always the possibility of developing cancer under these conditions because of secondary neutrons, which are inevitably produced in treatments involving particle beams [10]. Quantifying these risks requires a detailed knowledge of a range of parameters and a multidisciplinary team.

Traditional radiotherapy has been improved as a consequence of the development of IMRT, which has enabled improved targeting of conventional X-rays and a reduction in the radiation dose exposure of healthy normal tissue. It is the state of the art in photonics therapy. However, this technique is less effective than carbon ion therapy (as used at HIT). IMRT requires two to three times more monitoring units to deliver a specific radiation dose to the tumor target, when compared with conformal radiotherapy delivered in three dimensions (3D-CRT). Using IMRT instead of 3D-CRT increases the risk of developing secondary cancer by a factor of approximately 2. It is important to remember that particle therapy beams deposit most of their energy near the end of their tracks in the region of the Bragg peak. This peak is spread out to cover the entire tumor volume, and the dose beyond the tumor is lower than in photon therapy.

The neutrons produced during radiation therapy collide with protons in water and generate additional charged particles that can ionize the surrounding molecules. However, this problem can be addressed by using magnetically scanned beams rather than passively scattered beams. It is worth noting that the characteristics of cancer vary from organ to organ, and there is no evidence that the tumor dose–response curves are the same for different organs.

Ionizing radiation is recognized by the World Health Organization (WHO) as a carcinogen. In regions exposed to high doses, ionizing radiation directly kills cells in the field; however, the resulting tissue inflammation and DNA damage to cells in the normal tissue surrounding the tumor can promote cancer. In children, cancer is fortunately relatively rare; when it occurs, radiotherapy is used to treat children with lymphoma, leukemia, brain tumors, sarcomas, Wilm’s tumor, neuroblastoma, and liver cancer [11]. In the radiotherapy of pediatric patients, the primary concern is low-dose exposure to distal organs; for adults, high radiation doses induce inflammation.

To estimate the risk of developing cancer from protons, we must rely entirely on animal and in vitro cell experiments. Estimates of the RBE of neutrons are largely based on animal studies, although atomic bomb survivors have also been exposed to neutrons and some data are available. However, considerable uncertainty remains in predicting the late effects of heavy ions in humans. These ions are effective in inducing inflammation. In general, only the organs in the beam path are exposed to heavy ions, while the distal organs receive scattered neutrons and protons.

There is good epidemiological evidence that radiation therapy can contribute to the long-term survival of children with cancer, but it also causes a high incidence of secondary malignancy among survivors. However, the data suggest that hadron therapy leads to a reduced risk of secondary malignancy as compared with conventional radiotherapy modalities that employ X-rays. When using heavy ions, the radiation dose to healthy normal tissues is very low. In addition, the production of neutrons by these ions is lower than is the case for protons, because fewer ions than protons are needed to achieve the same dose in the tumor target.

The lack of resources on hadron therapy has led to inadequate recommendations of continued conventional radiotherapy in cases of cancer recurrence. This has prevented proper treatment with hadron therapy techniques using carbon ions, leading patients to undergo chemotherapy as the only treatment, which is not always satisfactory.

Fifteen trials were initiated at HIT since November 14, 2009, when the first patient was treated. A brief description of each trial follows [12]:

Assays were initiated to assess the role of carbon ions and protons in the treatment of a variety of cancer types. In the future, these will be included in HIT trials with moving targets. For example, the INKA test will start neoadjuvant radiotherapy using raster scanned carbon ions in patients with locally advanced sulcus superior tumors. The role of ions for radiotherapy in the treatment of pancreatic cancer will be developed, as well as the use of carbon ions for inoperable esophageal cancer [12].