Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy are irradiated with protons, which have physical advantages compared to X-rays but a similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue) and be exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and a reduced oxygen enhancement ratio compared to X-rays. Some radiobiological properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different "drug" in oncology, and may elicit favorable responses such as an increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results.

https://www.mdpi.com/2072-6694/12/10/3022/pdf

Carbon Ion Radiobiology.

The treatment of cancer with proton radiation therapy was first suggested in 1946 followed by the first treatments in the 1950s. As of 2020, almost 200,000 patients have been treated with proton beams worldwide and the number of operating proton therapy facilities will soon reach one hundred. Proton therapy has long moved from research institutions into hospital-based facilities that are increasingly being utilized with workflows similar to conventional radiation therapy. While proton therapy has become mainstream and has established itself as a treatment option for many cancers, it is still an area of active research for various reasons: the advanced dose shaping capabilities of proton therapy cause susceptibility to uncertainties, the high degrees of freedom in dose delivery offer room for further improvements, the limited experience and understanding of optimizing pencil beam scanning, and the biological effects differ from photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because proton therapy treatments are, on average, still more expensive compared to conventional photon based treatment options. This roadmap highlights the current state and future direction in proton therapy categorized into four different themes, "improving efficiency", "improving planning and delivery", "improving imaging", and "improving patient selection".

/pdf/roadmap-proton-therapy-physics-and-biology-7we91n1uu8.pdf

Roadmap: proton therapy physics and biology

The original rationale for proton therapy was its highly conformal depth‐dose distributions compared to photons, which allow greater sparing of normal tissues and escalation of tumor doses, thus potentially improving outcomes. Additionally, recent research has revealed previously unrecognized advantages of proton therapy. For instance, the higher relative biological effectiveness (RBE) near the end of the proton range can be exploited to increase the difference in biologically effective dose in tumors versus normal tissues. Moreover, the smaller “dose bath,” that is, the compact nature of proton dose distributions, has been found to reduce the exposure of circulating lymphocytes and the immune organs at risk. There is emerging evidence that the resulting sparing of the immune system has the potential to improve outcomes.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/pro6.1149

A review of proton therapy – Current status and future directions

PURPOSE Dosimetric studies show that proton therapy can reduce the low/intermediate radiation dose to uninvolved tissue in children with low-grade glioma (LGG). For this reason, LGG is the fourth most common pediatric tumor treated with proton therapy, yet clinical outcome data on efficacy and toxicity are limited. METHODS AND MATERIALS We reviewed the medical records of 174 children (≤21 years old) with nonmetastatic LGG enrolled on a prospective protocol and treated with proton therapy between 2007 and 2017. We assessed clinical outcomes and toxicity and analyzed patient, tumor, and treatment-related variables. RESULTS The median age was 10.2 years (range, 2-21). Fifty-eight percent of tumors were World Health Organization grade 1 and 30% were grade 2; 12% were diagnosed on imaging characteristics alone. The most common histology was pilocytic astrocytoma (47%). The most common tumor subsites were diencephalon/optic pathway (52%), caudal brainstem (16%), and cerebellum (13%). Forty-two percent received chemotherapy before radiation therapy. The median follow-up was 4.4 years. The 5-year actuarial rates of local control, progression-free survival, and overall survival were 85% (95% confidence interval [CI], 78%-90%), 84% (95% CI, 77%-89%), and 92% (95% CI, 85%-95%), respectively. On univariate analysis, brainstem/spinal cord tumor location (62% vs 90% elsewhere) and dose <54 GyRBE (67% vs 91% for 54 GyRBE) were associated with inferior local control (P < .01 for both). Twenty-two patients (12.6%) experienced acute nausea or vomiting requiring ondansetron; 2 patients (1.1%) required corticosteroids. Serious toxicities (4% of patients) included brainstem necrosis requiring corticosteroids (n = 2), symptomatic vasculopathy (n = 2), radiation retinopathy (n = 1), epilepsy (n = 1), and death from radiation-induced high-grade glioma (n = 1). Thirty-nine patients (22%) developed new-onset central hormone deficiency. Pseudoprogression was observed in 32.1%. CONCLUSIONS Compared with modern photon series, proton therapy reduces the radiation dose to developing brain tissue, diminishing acute toxicities without compromising disease control.

Outcomes Following Proton Therapy for Pediatric Low-Grade Glioma.

Precision radiotherapy, which accurately delivers the dose on a tumor and confers little or no irradiation to the surrounding normal tissue and organs, results in maximum tumor control and decreases the toxicity to the utmost extent. Proton beam therapy (PBT) provides superior dose distributions and has a dosimetric advantage over photon beam therapy. Initially, the clinical practice and study of proton beam therapy focused on ocular tumor, skull base, paraspinal tumors (chondrosarcoma and chordoma), and unresectable sarcomas, which responded poorly when treated with photon radiotherapy. Then, it is widely regarded as an ideal mode for reirradiation and pediatrics due to reducing unwanted side effects by lessening the dose to normal tissue. During the past decade, the application of PBT has been rapidly increasing worldwide and gradually expanding for the treatment of various malignancies. However, to date, the role of PBT in clinical settings is still controversial, and there are considerable challenges in its application. We systematically review the latest advances of PBT and the challenges for patient treatment in the era of precision medicine.

/pdf/proton-beam-therapy-for-cancer-in-the-era-of-precision-3m13bxar3g.pdf

Proton beam therapy for cancer in the era of precision medicine

Purpose Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. Methods and Materials Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. Results The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. Conclusions Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury.

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National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury.