Radiation therapy for primary bone tumors

Introduction

Primary malignant tumors of the bone represent less than 1% of all cancer cases in the European population. The world age-standardized incidence rate is in the range of 0.5–2/100,000/year [ ]. In 2020, an estimated 3600 new cases and 17,200 deaths are expected, with 5-year relative survival of 66% [ ]. The age-standardized incidence rate is 0.249 for osteosarcoma, 0.064 for chondrosarcoma and chordoma, and 0.071 for Ewing's sarcoma [ ]. Other entities described in the WHO classification include pleomorphic sarcoma, fibrosarcoma, and giant cell tumors of bone [ ].

The vast majority of bone cancers are sporadic. Risk factors for bone cancer include Paget disease, exposure to ionizing radiation, or chemical carcinogens. A small percentage occurs in the context of a genetic predisposition to cancer whom most frequent syndrome are Li–Fraumeni (LFS) and hereditary retinoblastoma. LFS, linked to germline mutations in the TP53 gene, is diagnosed in approximately 5% of patients under the age of 30 with osteosarcoma [ ]. Osteosarcoma is also the most common type of sarcoma to develop in individuals with LFS, who are generally at a very high lifetime risk of cancer [ ]. Hereditary retinoblastoma is an autosomal dominant syndrome caused by germline mutation in the RB1 gene, leading to a high risk of retinal tumor in early ages. Survivors also have an increased risk of other malignancies, including bone and soft-tissue sarcoma, especially osteosarcoma. Other bone tumor predisposition syndromes include Bloom syndrome, multiple osteochondromas (alterations of genes EXT1 or EXT2 ), and tuberous sclerosis (genes TSC1 , TSC2 , or TSC3 ). Recognizing tumors that occur in the context of cancer predisposition is crucial, as the risk of higher long-term toxicity, especially of second malignant neoplasms, with cytotoxic agents (including chemotherapy and ionizing radiation) has repeatedly been shown in patients with LFS and hereditary retinoblastoma [ , ].

Complete surgery is the cornerstone of local treatment for bone tumors. Radiation therapy (RT) is systematically considered in Ewing's sarcoma and chordoma, and discussed for the other entities, especially in case of incomplete resection. Over the past century, several irradiation techniques have been developed and used for the treatment of bone cancer, from conventional RT (using X-rays/photons) to hadrontherapy (heavy ions), going through neutron therapy.

The aim of this chapter is to provide details of the role of RT in the treatment of bone tumors, considering radiobiology knowledge, irradiation techniques, and the most frequent histologies. We also discuss the indications for hadrontherapy, and expose the implications of irradiation in the care of patients with LFS, one of the most common cancer predisposition syndromes.

Radiobiology of bone tumors

Response to ionizing radiation depends on several factors related to the tumor cells but also to the tumor microenvironment.

One key factor is the intrinsic radiosensitivity of the tumor cells. Clonogenic survival assay of cell lines is an in vitro technique considered as the gold standard to assess radiosensitivity. The radiosensitivity of cell lines is expressed by the surviving fraction of cells after 2 Gy referred as SF2. The unit of ionizing radiation dose is the Gray and is defined as 1 J of absorbed energy per kilogram of matter.

When irradiated with photons, bone cancer cells' intrinsic radiosensitivity is heterogeneous. Ewing's sarcoma is considered as a radiosensitive tumor with low SF2 [ , ]. On the contrary, osteosarcoma, chondrosarcoma, and chordoma are considered as radioresistant tumors as they exhibit higher surviving fraction after irradiation [ ]. Intrinsic radiosensitivity may also vary between cell lines from the same type of tumor; this may be explained by the variability in the biological characteristics of the cells. For instance, chondrosarcoma tumor cells exhibiting mutation in the pRb pathway were found to be more resistant to irradiation than the ones with no alteration [ ]. One advantage of hadrontherapy, especially with the use of carbon ions, is its higher biological efficacy against tumors cells in comparison to photons and protons at equivalent physical dose [ ]. Indeed the use of this irradiation technique may enable to overcome the radioresistance (to photon) of bone tumor cells, and is promising for the treatment of this type of tumor as discussed below.

Other important factors that influence the tumor response to irradiation are host in the microenvironment. Hypoxia is a common feature of tumor especially of bone tumors and has been known as a detrimental factor for irradiation efficacy for decades. Different mechanisms have been suggested to explain this effect. One of the most accepted hypotheses is that DNA damages due to the reactive oxygen species induced by ionizing radiation are less frequent in hypoxic conditions [ ]. Other mechanisms may be involved. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor accumulating in hypoxic cell essential for maintaining cellular oxygen homeostasis and adapting hypoxia. HIFs allow cells to survive under hostile conditions. Not only HIFs aid to preserve cell function but also promote tumor progression and the formation of metastases [ ].

To conclude, bone tumors are usually considered as low sensitive tumors to irradiation with photon, which explains the high doses that are usually recommended for treating these tumors. Current developments to overcome this resistance include the use of particles with higher relative biological effectiveness, and strategies to reduce the negative impact of hypoxia.

Radiation therapy techniques

Irradiation treatment aims to expose the tumor to ionizing radiations to induce cellular damages and death. Several techniques of irradiation delivery are available. The election made by the radiation oncologist depends on the treatment strategy (curative or palliative intent), the tumor type, prescribed dose, and the localization of the tumor and surrounding organs at risk. The most routinely used technique irradiation is photontherapy, delivered as conformal RT, intensity-modulated radiation therapy (IMRT), or stereotactic RT, with varied fractionation, from normofractionated irradiation using a dose of 1.8–2 Gy per fraction, five fraction a week, to hypofractionated treatment using a limited number of fractions with a dose above 2 Gy. Other particles have been used for the treatment of bone tumors including neutrons, protons, and carbons. Neutrons showed good local control in this indication but have been largely underused with respect to concerns about radioprotection [ ].

Ewing's sarcoma