Cancer Radiation Therapy
Radiotherapy can be used with several aims in cancer therapy. These include shrinking early-stage tumors, preventing cancer recurrence in specific locations, and minimizing symptoms. Although radiation is directed at the tumor, non-cancerous tissues surrounding the tumor will inevitably be affected as well. A key goal of radiotherapy is maximizing the dose of radiation to tumor cells while minimizing the dose to healthy cells, thus limiting unwanted side effects. Radiation therapy is often combined with surgery, chemotherapy, or immunotherapy to treat cancer (Baskar 2012; Trikalinos 2009b; NCI 2010; ACS 2014a).
How Radiation Kills Cancer Cells
Radiotherapy uses high-energy radiation, usually x-rays, to destroy cancer cells. The radiation damages tumor cell DNA and disrupts cellular division. Radiation can also produce highly reactive molecules called free radicals that further damage the DNA of tumor cells. Cancer cells are usually more susceptible to the effects of radiation because they divide more rapidly than healthy cells. Healthy cells can usually repair radiation-induced damage faster than cancer cells (ACS 2014b; Baskar 2014).
Radiation therapy does not kill cancer cells right away. It takes hours, days, or even weeks of treatment before cancer cells begin to die. Cancer cells continue dying for weeks to months after radiation therapy ends. This delayed effect applies to healthy cells too, which can explain why some side effects take time to manifest. Rapidly dividing cells, such as those of the skin, bone marrow, and intestinal lining, are often the first to show signs of damage. Slower-dividing cells, such as those from the brain and spinal cord, are more susceptible to later effects (ACS 2014a; Baskar 2012; Chapel 2013; Akita 2014; Prasanna 2012).
Radiation Therapy Dose Fractioning
Radiation therapy is often administered as several treatments over time. Treatment sessions are called “fractions.” This dosing strategy is necessary to maximize effectiveness and minimize damage to normal tissues. Fractionated radiotherapy gives normal cells time to recover from radiation-induced damage between each radiation session (Baskar 2012; Schreiber 2013; Trikalinos 2009b). Another benefit is that fractionation increases the likelihood that cancer cells will be exposed to radiation at the points in the cell cycle when they are most susceptible to DNA damage (Schreiber 2013). Also, tumor tissue that may have been oxygen-depleted (hypoxic) can re-oxygenate between fractions. This can increase the likelihood that radiation will kill tumor cells during the next treatment session because the presence of oxygen increases production of cell-killing free radicals (Joiner 2009).
In most patients, fractionation typically entails therapy five days a week for five to eight weeks, but the regimen depends on the unique situation of each patient (ACS 2017a). Different radiotherapy schedules may be used when five to eight weeks of treatment are inconvenient or an altered schedule may work better.
The Five R’s of Radiobiology
Many factors influence how tumors respond to radiation therapy. Knowledge of these factors can be helpful when planning cancer radiotherapy. A concept in radiation oncology, the five R’s of radiobiology, is a framework to better understand cellular characteristics that influence tumor response (Steel 1989; Pajonk 2010; Good 2013; Olbryt 2014; De Meerleer 2014; Blanco 2011; Stinauer 2011; Witkowska 2015; Cognetti 2008):
- Repair. Healthy and cancerous cells can repair the damage caused by radiation. This helps healthy cells, but contributes to treatment failure in cancer cells. Cancer cells in which DNA repair mechanisms have been disrupted may be more susceptible to the effects of radiation. This is the basis for therapeutic DNA repair inhibitors used in cancer treatment in some cases.
- Redistribution. Most cells, including cancer cells, go through a replication process called the cell cycle. Cells are least sensitive to radiation when they are replicating their DNA for the new cell (S-phase) and most sensitive when they are actively dividing into two cells (mitosis). Since cells progress through all phases of the cell cycle, giving radiation in fractionated doses increases the likelihood that cancer cells in the radio-resistant S-phase during one radiotherapy session will be in the sensitive phase during a subsequent session.
- Repopulation. Between radiotherapy doses, viable cells—healthy and malignant—divide and repopulate. Healthy cell repopulation is desirable, but cancer cell repopulation can lead to treatment failure. Long breaks between radiation treatments can cause cancer cell repopulation. This is one reason why adhering to a planned radiotherapy fractionation schedule is so important.
- Reoxygenation. The presence of oxygen in tumor cells increases their sensitivity to radiation. The oxygen reacts with radiation to produce cell-killing free radicals. Lack of oxygen, or hypoxia, in tumor cells has been associated with poor treatment prognosis. Radiotherapy, especially large doses, causes a tumor to become hypoxic. Tumors must be allowed to re-oxygenate between radiation fractions to avoid irradiating radio-resistant hypoxic cells. Reoxygenation can take from hours to several days.
- Radiosensitivity. Some cancers are naturally more susceptible to the effects of radiation than others. Renal cell carcinomas and melanomas, for example, are often more radioresistant than other cancers. Hodgkin’s lymphoma and head and neck carcinomas tend to be highly radiosensitive.
The five R’s provide a basis for understanding the success or failure of radiation therapy and for developing strategies to target cancer cells (Pajonk 2010; Joiner 2009). These concepts are discussed throughout this protocol, and there are many natural and pharmaceutical agents that can help overcome one or more of these biological challenges when combined with radiotherapy.