Megavoltage radiation therapy is a treatment that uses ionising radiation of a high energy. Radiation produced by a linear accelerator can be used to treat cancerous and non-cancerous conditions as a single modality or in conjunction with surgery and/or chemotherapy. Irradiation may precede or be used after surgery. Chemotherapy, in turn, can be introduced as neoadjuvant or adjuvant therapy and can be carried out simultaneously with radiotherapy.
The treatment regimen depends on histological tumour type, tumour grade, staging results, concurrent comorbidities and the patient’s age. Treatment regimens should be carefully established before treatment begins by a group that includes the pet owner, a general practitioner, a surgeon and a medical and radiation oncologist. Linear-based radiotherapy is painless, and there is no inherent radioactivity (Bloomfield, 2015; LaRue and Custis, 2014; McEntee, 2006; Nolan and Gieger, 2019).
Mechanism of action for megavoltage radiotherapy
DNA is the principal target for the biological effects of radiation, which means normal cells in addition to cancer cells are affected by radiation therapy. The photons produced in the linear accelerator interact with the tumour and surrounding healthy tissues. There are two mechanisms of action in radiotherapy that cause damage to cellular DNA:
- The direct effect is the damage to DNA structures by free electrons that result from photon absorption
- The indirect effect occurs as a result of the impact of an electron previously ejected from the atom by photons on a water molecule (radiolysis of water) and the formation of free hydroxyl radicals (unstable molecules with high chemical reactivity). These cause damage to cellular DNA, changing the structure of DNA by breaking chemical bonds. Chemical and biochemical changes consequently cause biological damage
In treatment with linear accelerator photons, approximately 70 to 75 percent of DNA damage results from an indirect mechanism and approximately 25 to 30 percent from a direct mechanism.
Choosing a treatment method
The patient’s qualification for radiotherapy should be based on a thorough clinical examination and additional tests. Based on a thorough assessment of the tumour type, histological grade and clinical advancement of the disease, it is necessary to determine the type of radiotherapy protocol to be used and its usefulness so the owner has all the necessary information to make an informed decision about radiotherapy. Depending on the above-mentioned factors, the patient has a chance of an improved quality of life.
It is necessary to determine the type of radiotherapy protocol to be used and its usefulness so the owner has all the necessary information to make an informed decision about radiotherapy
The main goal of megavoltage radiotherapy is to completely or partially decrease clinical symptoms associated with the tumour, control the pain and achieve long-term control until the cancer recurs (extending the patient’s life or improving the prognosis), or completely cure the patient (Bloomfield, 2015; LaRue and Custis, 2014; McEntee, 2006; Nolan and Gieger, 2019).
Radiotherapy goals
Radiotherapy can be administered with either definitive or palliative intent. The goal of definitive radiotherapy is to either completely cure the patient or achieve long-term control of the growth of the tumour using definitive or stereotactic protocols (Tables 1 and 2).
| Tumour type | Radiation therapy type | |
|---|---|---|
| Macroscopic tumours | Nasal tumour | Palliative irradiation |
| Oral tumour | ||
| Appendicular osteosarcoma | ||
| Apocrine gland anal sac adenocarcinoma | ||
| Injection site sarcoma | ||
| Thyroid tumour | ||
| Soft tissue sarcoma | ||
| Mast cell tumour | ||
| Brain tumour | ||
| Urothelial carcinoma | ||
| Histiocytic sarcoma (localised) | ||
| Infiltrative lipoma | ||
| Localised lymphoma | ||
| Nasal tumour | Stereotactic radiation therapy | |
| Brain tumour: meningioma, TNST | ||
| Pituitary tumour | ||
| Multilobular osteochondrosarcoma | ||
| Adrenal tumour | ||
| Heart-based tumour | ||
| Pheochromocytoma | ||
| Pulmonary carcinoma | ||
| Nasal tumour | Definitive radiation | |
| Brain tumour | ||
| Spinal tumour | ||
| Pituitary tumour | ||
| Oral tumours: squamous cell carcinoma in dogs, acanthomatous epulis in dogs | ||
| Heart based tumour | ||
| Thymoma | ||
| Injection site sarcoma (before surgery) | ||
| Prostatic carcinoma | ||
| Microscopic disease (cancer cells left behind post-surgery, incomplete resection) | Soft tissue sarcoma | |
| Mast cell tumour | ||
| Apocrine gland anal sac adenocarcinoma | ||
| Injection site sarcoma (after surgery) | ||
| Oral tumour (excluding melanoma) | ||
| Brain tumour | ||
| Histiocytic sarcoma (localised) | ||
| Infiltrative lipoma | ||
Radiotherapy is used in patients with localised cancer without metastases; however, there are a few exceptions. Definitive radiotherapy protocols are usually given to patients with microscopic disease, such as incompletely resected mast cell tumours or soft tissue sarcomas, but they are also sometimes given in macroscopic settings (eg nasal or brain tumours). Stereotactic protocols are always given to macroscopic disease.
Palliative radiotherapy aims to reduce pain, decrease inflammation and temporarily inhibit tumour growth, thus improving the patient’s quality of life (in appendicular osteosarcoma, nasal tumour, etc). It is implemented in advanced inoperable primary cancer lesions and often in the case of presented cancer metastases to bone or other tissues (Bloomfield, 2015; LaRue and Custis, 2014; McEntee, 2006; Nolan and Gieger, 2019; McDonald et al., 2012; Tollett et al., 2016).
| Definitive radiotherapy | Stereotactic radiotherapy | Palliative radiotherapy |
|---|---|---|
| “Curative” or long-term control (1+ year(s)) | Long-term control (1+ year(s)) | Hospice care Improvement of clinical signs Increased quality of life (usually six months) |
| Large total dose | Intermediate total dose | Small total dose |
| Large number of fractions Usually 16 to 25 fractions | Small number of fractions Usually 1 to 5 fractions | Small number of fractions Usually 4 to 5 fractions |
| Low dose per fraction Usually 2.5 to 3.0Gy | High dose per fraction Usually 8.0 to 20.0Gy | High dose per fraction Usually 4.0 to 8.0Gy |
| Monday to Friday, daily | One day, Monday to Wednesday Monday to Friday, daily | Monday to Friday, daily (4Gy) Three to four fractions, weekly (8Gy) |
| Approximately 3 to 5 weeks | Approximately 1 day to 1 week | Approximately 1 to 4 weeks |
| Harder on tumours | Harder on tumours | Easier on tumours |
| Early side effects common Late side effects uncommon | Possible early side effects Possible late side effects | Early side effects uncommon Possible late side effects |
Megavoltage radiotherapy regimens
In accelerated-based radiotherapy, the total radiation dose is divided into parts called “fractions”. Treatments are divided into many small doses to try to kill as many cancer cells as possible while allowing the normal cells time to recover. The patient is always under general anaesthesia (15 to 20 min) during radiation therapy delivery.
Treatments are divided into many small doses to try to kill as many cancer cells as possible while allowing the normal cells time to recover
In definitive conventional radiotherapy, fraction doses vary between 2.5 to 3.0 Gray (Gy). Hence, the total dose is quite high, generally around 48 to 60Gy. It is administered over three to four weeks. Fractions are administered once a day from Monday to Friday, with a break on Saturday and Sunday.
In the case of palliative radiotherapy, the fraction dose varies, usually between 4.0 and 8.0Gy, and the total dose is low, around 8 to 32Gy. Treatment ranges from one week to two to four weeks: for example, five fractions delivered from Monday to Friday or two to four fractions administered weekly, respectively.
Modern techniques such as stereotactic ablative radiotherapy enable the delivery of one to five fractions, each usually 8 to 12Gy, with a high total dose of 24 to 36Gy. The entire treatment period is no longer than one week. Advanced computer planning software, image guidance/cone beam computed tomography (CT) (Figure 1), modern linear accelerators (Figures 2 and 3) and rigid positioning devices (Figure 4) are required to deliver stereotactic treatments safely and with high accuracy (McDonald et al., 2012; Tollett et al., 2016).
Indications for radiotherapy in small animals
In dogs and cats, radiotherapy is most often used in the case of:
- Oral cancers (melanoma, squamous cell carcinoma, fibrosarcoma, ameloblastoma, localised lymphoma)
- Nasal cancers (carcinoma, sarcoma, lymphomas)
- Brain tumours (most often gliomas, meningiomas, choroid plexus tumours)
- Pituitary gland tumours (macroadenomas)
- Various cutaneous and subcutaneous tumours (mast cell tumour, melanoma)
- Mesenchymal tumours (soft tissue sarcomas)
It is also a useful method for the treatment of thyroid tumours (carcinoma), anal gland tumours (apocrine gland anal sac adenocarcinoma), thymoma, localised histiocytic sarcoma, osteosarcoma when amputation is not possible and localised lymphoma, among others (McDonald et al., 2012; Tollett et al., 2016).
Outcome post-megavoltage radiotherapy
Responses to megavoltage radiation therapy may vary. Therefore, the expected progression-free interval and median survival time should be determined for each patient, as well as their ranges based on previously published studies.
The median survival time after palliative radiotherapy is usually six months. Of course, due to many coexisting prognostic factors, this time may be longer or shorter. When discussing prognosis with owners, it should be emphasised, once again, that the main goal of palliative radiotherapy is to alleviate the symptoms of the disease and improve the quality of life, thus postponing the need for immediate euthanasia of the patient.
The goal of definitive radiotherapy, however, is long-term tumour control or complete cure. After definitive radiotherapy, the median survival time for most patients ranges from over a year to complete recovery (McDonald et al., 2012; Tollett et al., 2016).
Side effects of megavoltage radiotherapy
While radiotherapy destroys cancer cells, it also damages healthy cells in the treated area. The degree of cell damage depends on several factors. Healthy tissue tolerance to irradiation determines the limits of the radiation doses used. Side effects of radiotherapy can be broadly divided into two categories: early and late (Collen and Mayer, 2006, 2008; Gieger and Nolan, 2017; Harris et al., 1997; Poirier et al., 2023).
Early side effects of radiotherapy
Early damage is often seen after definitive radiotherapy but is rarely seen post-stereotactic or palliative treatment. The affected tissues are the ones constantly dividing, such as epithelial cells of the oral cavity, digestive, respiratory or urinary tract, the epidermis and bone marrow cells (Figures 5 and 6). These effects appear at the end of radiotherapy or just after irradiation, and the time of occurrence depends on the lifespan of the cells. Mucosal epithelial cells, for example, live for about two weeks, so the reaction appears in the third week; mature cells are not sensitive to radiation as only those that are dividing are sensitive. The peak of early toxicity usually occurs seven days after the last megavoltage radiotherapy fraction. Stem cells that survived irradiation provide a source for tissue reconstruction. The severity of early post-radiation reactions depends on several factors.
The appearance of side effects is often a cause of anxiety and stress for the owner, especially if they have not been thoroughly informed about this possibility. Early side effects cause discomfort and pain in the patient, so painkillers should be used to make the patient feel comfortable during their occurrence. The most important thing to consider when creating a treatment plan for these side effects is the patient’s quality of life, especially as the owner must be prepared to administer several medications simultaneously at home. The patient must not be allowed to scratch or lick at the radiotherapy field; the more areas that are irritated, the longer they will take to heal.
Although rare, when signs of a bacterial infection appear, a broad-spectrum antibiotic should be administered. Less than 10 percent of patients need this; for those that do, it is most often after radiotherapy of the oral cavity, rectum or nasal cavity. Patients should be given anti-inflammatory drugs before early side effects appear (glucocorticoids or non-steroidal anti-inflammatory drugs). Painkillers must be selected individually, according to the patient’s needs. However, these are most often a combination of two to four drugs, such as gabapentin, amantadine, tramadol, buprenorphine, fentanyl, codeine, ketamine, morphine and others. Acupuncture can be used as an additional method of pain relief if the owner is interested in this unconventional method.
Acute side effects are reversible, and the healing process usually takes from 7 to 14 days after the peak (Collen and Mayer, 2006, 2008; Gieger and Nolan, 2017; Harris et al., 1997; Poirier et al., 2023).
Late side effects of radiotherapy
Late toxicities of radiotherapy can appear several months or even years after radiotherapy treatment (Figure 7). Late side effects occur in slowly proliferating normal tissues, such as muscle, bone, cartilage and nerves. They arise from changes in the organ parenchyma and blood vessels. Late complications, unlike early ones, are irreversible, sometimes require surgery and, sadly, may result in the patient’s euthanasia. The probability of occurrence of clinically significant late side effects is usually around 5 percent within three to five years after definitive radiotherapy.
These late effects are more likely if palliative or stereotactic protocols are used. Slowly dividing tissues are sensitive to the fractional dose of radiation and, to a much lesser extent, the total dose. Therefore, high single fractions are usually used in palliative treatment (high fractional dose) when it is known that the patient will most likely not survive until late side effects appear. They are not usually used in patients whose prognosis exceeds at least one year of survival (Collen and Mayer, 2006, 2008; Gieger and Nolan, 2017; Harris et al., 1997; Poirier et al., 2023).
With the state-of-the-art linear accelerator and powerful treatment planning software (Figures 8 and 9), it is now possible to spare much more of the healthy tissues and deliver higher doses directly to the tumour. This ensures the patient is much more comfortable (as minimal to no acute toxicity is present) and achieves better outcomes (Bloomfield, 2015; LaRue and Custis, 2014; Nolan and Gieger, 2019).
Monitoring the patient after megavoltage radiotherapy
After treatment, the patient should be monitored by an oncologist or primary care veterinarian. After definitive radiotherapy, clinical follow-up examinations and imaging rechecks are recommended every three months for a period of 18 months and then every six months following this (Figures 10 and 11). After palliative radiotherapy, meetings with the veterinarian are held as needed, usually every one to three months.
Summary
In summary, radiation therapy is a crucial component of a multimodal approach for veterinary cancer patients. As we are making significant advances in linear-based megavoltage radiotherapy, it is important to have a basic understanding of the various aspects related to radiation therapy.
