Radiation therapy (RT) is one of several treatment types for cancer in both curative and palliative settings. It is used in more than 30% of patients (in addition to other treatments and modalities), and more than half of cancer patients will receive radiation as part of their care. In other words, it’s an important part of cancer treatment in the US, and many patients benefit from it.
But how does it work, and how does it fit into the radiation therapy regimens that are included in the Eviti Evidence-Based Library? Perhaps more importantly, where is it headed in the future?
Let’s start at the beginning with a definition.
What is Radiation Therapy?
Radiation therapy uses ionizing radiation (radiation that can break chemical bonds) to treat medical conditions, most often malignancy.
This process of ionizing radiation damages the DNA of cells directly or indirectly by forming free radicals and reactive oxygen species. Cancer cells are usually undifferentiated and cannot repair the damage.
There are two main types of radiation therapy: external beam radiation therapy and brachytherapy.
External beam radiation therapy (EBRT) occurs when a beam (or multiple beams) of radiation is directed through the skin to the cancer and the immediate surrounding area to destroy cancer cells.
Several types of external beam radiation therapy are differentiated mostly based on how the planning process occurs. These include 3-D conformal radiation therapy, Intensity-modulated radiation therapy (IMRT), Image-guided radiation therapy (IGRT), Stereotactic radiosurgery (SRS), and Stereotactic body radiation therapy (SBRT).
The different types of Brachytherapy are Low-dose rate (LDR) implants and High-dose rate (HDR) implants.
Radiation Therapy and Eviti’s Evidence-Based Library
The Eviti Evidence-Based Library currently has 391 active radiation therapy regimens. In order to be included, treatment must be recommended and endorsed by one of the nationally recognized oncology organizations, such as the National Comprehensive Cancer Network (NCCN), US Food and Drug Administration (FDA), American Society for Therapeutic Radiology and Oncology (ASTRO), American Society of Clinical Oncology (ASCO), American College of Radiology (ACR), American Brachytherapy Society (ABS), etc. In addition, data from a Definitive/Pivotal Clinical (Phase II/III) trial must be available before it can be added to the library.
Doses and Fractions
Doses and fractions in the library regimens are ranged in all lines of therapy. Doses are also described in detail by NCCN. Method of deliveries used in the library regimens are external beam RT and brachytherapy.
Delivery Techniques
Delivery techniques describe the therapy administration method and is a key element in driving the billing codes. Library regimens include several delivery techniques including simple, intermediate, or complex delivery.
Toxicities and Expected Outcomes
The library regimens also include toxicities and expected outcomes. Toxicity scales used in radiation trials include CTCAE, RTOG, QUANTEC and Lent Soma. Toxicities are collected from the cited published reference source(s). Toxicities are based on Common Terminology Criteria for Adverse Events (CTCAE) standards, dependent on how they are reported in the publication. Outcomes are collected from the cited published reference source(s). As Radiation Therapy is not a systemic therapy, reported outcomes in the regimens focus on local control and recurrence rate.
Clinical Team Curation
These evidence-based regimens are curated by the clinical content team comprised of nurses, physicians, the Director of Clinical Knowledge Management, and the Chief Medical Officer, with participation from other physicians. Every regimen is reviewed annually in compliance with URAC requirements. The annual review ensures that the library regimens continue to meet inclusion criteria and remain consistent with the most recent consensus guidelines.
Looking Ahead
As we look toward the future, there are numerous opportunities for further studies on proton beam therapy, radiobiology, and flash radiation. Let’s take a look at each of these below.
Proton Beam Therapy: Limitations and Opportunities
Proton Beam Therapy (PBT) is a form of external beam radiotherapy that uses high-powered energy to treat cancer and some non-malignant tumors.
PBT uses positively charged particles rather than X-ray beams or photons to treat a precise target deep in the body. Unlike X-ray beams, proton beams do not scatter radiation throughout the body; instead, they stop once they reach their target (the tumor). Researchers believe this may decrease the amount of normal tissue exposed to radiation, reducing significant side effects caused by damage to healthy tissue. However, these findings are based largely on nonrandomized, retrospective studies.
PBT has shown promise in treating several types of cancer and seems to have several advantages over traditional photon radiotherapy. Since Radiation Oncologists have more control over where PBT delivers its highest energy concentration, it is believed that less radiation is released into healthy tissue, lowering the risk for short- and long-term side effects and secondary cancers.
Potential Benefits of PBT
Some studies show that PBT is useful in treating patients who have a tumor recurrence even after prior radiation treatment. PBT is commonly used in pediatric cancer care; since children’s tissues are still growing and developing, they have a higher risk for deformity and/or secondary malignancies from radiation. PBT allows doctors to treat pediatric patients with higher doses of radiation and may improve disease control and quality of life during and after radiation.
Downside of PBT
The downside to PBT is that it is not widely available. There are a limited number of operating Proton centers across the country, currently only 41, meaning patients may have to travel far distances for treatment. PBT is typically more expensive than traditional radiation, and not all insurance companies cover the cost of the treatment.
It’s important to note that PBT is not an appropriate treatment for all cancer types and does still cause some treatment-related side effects. Current evidence is limited for PBT, and further randomized phase III trials are needed for head-to-head comparisons with traditional radiation.
Radiobiology
Radiobiology focuses on the effects of ionizing radiation on cells.
The sequence of events from DNA damage can be direct, resulting in cell death. It can also indirectly affect the tumor cells, healthy cells, and nearby organs when the radiation hits the water molecules of the cell, causing the production of free radicals. The indirect effect can allow a cell to repair itself and is at risk for mutation and tumor development of different organs.
Guidelines recommend dose limits for most tissues and surrounding organs. The rate of cancer cell death or resistance from radiation is dependent on the degree of differentiation of the cell, mitotic rate, and the cumulative and fractional radiation dose.
Higher Oxygen Levels
Higher oxygen levels have correlated with increased DNA damage. Therefore, an oxygenated cell is more radiosensitive, and a hypoxic cell is resistant to radiation. Studies have revealed that based on the dose, radiation to a tumor can increase and suppress the immune response. The immune system cells may be vulnerable to radiation because of rapid division of these cells. There can be lethal damage in bone marrow stem cell precursors of monocytes and granulocytes induced by radiation. In certain instances, the immune system may be enhanced by an antigen-specific immune response.
Fractionation of Radiation
Delivering conventional radiation over a period of time enables tumor control and sparing of normal tissue. Fractionation of radiation utilizes the 4 R’s of Radiobiology:
- Repair of sublethal damage;
- Redistribution of cells within cell cycle;
- Repopulation of normal cells after radiation;
- Reoxygenation of tumor cells as tumor shrinks.
- There is also a 5th R – Radiosensitivity: the response to radiation varies by tumor intrinsic and individual radiosensitivity
- And a 6th R –Reactivation of immune response by radiaton
Cells in the human body can be either dividing or nondividing. The cycle phases display different radiosensitivity. For example, cells in M phase are usually most radiosensitive, while the cells in the S phase are generally more radioresistant than cells in G1 and G2 phase. Fractionation of the radiation dose allows tumor cells in a radioresistant cell cycle phase to “redistribute” into more radiosensitive phases before the next fractions.
Flash Radiation (FLASH-RT) is examining whether using ultra-high dose radiation is beneficial.
Animal studies indicate that using ultra-high radiation delivered in a shorter time of exposure enables normal tissues to tolerate higher dosing. For example, FLASH-RT is delivered in microseconds compared to conventional dose rate of minutes. Observations indicate that this technique leads to relative protection of normal tissues compared with conventional dose rate radiotherapy. The FLASH RT dose rate of ≥40 Gy/s, whereas conventional radiation (CONV) uses dose rates of 0.01–0.1 Gy/s. Due to different delivery times, CONV radiation takes place during chemical and biological responses, whereas FLASH does not interact with these biochemical steps.
FLASH Radiation with Protons
FLASH radiation with protons is the first in human clinical trial with FAST-01(NCT04592887).
This trial included 10 patients aged ≥18 years with up to 3 painful bone metastases in the extremities participated, which included patients who would have received conventional radiation therapy at the same dose as they were given with FLASH RT. The same regimen was used, but it was delivered with FLASH dose-rate radiation. Patients were given 8 Gy of radiation in a single fraction, delivered at ≥40 Gy per second via a FLASH-enabled proton therapy system. Following FLASH RT, seven of the 10 patients experienced complete or partial pain relief. Of the 12 treated sites, pain was relieved completely for six sites and partially for two additional sites. Temporary pain flares occurred in four of the 12 sites treated. FLASH RT could be more useful in treating hard-to-kill cancers where healthy tissue surrounding tumors is particularly vulnerable to radiation exposure.
Further clinical trials can reveal new and improved ways of treating cancer patients with radiation therapy.
