Cancer is the most common and severe disease that humanity has to withstand. According to the World Health Organization statistics, every fifth death worldwide is due to cancer, more than 14 million of new cases of this disease are registered each year. Cancer can affect any human body organ or tissue.
In compliance with the Verkhovna Rada Committee for Health Care, recently we can observe significant increase in cancer incidence and death rate in Ukraine. About 90.000 of people die from cancer each year, more than a third are active working age persons. Every day about 450 Ukrainians are diagnosed with cancer and this rate continues to increase.
In compliance with the Centre for Medical Statistics of the Ministry of Health of Ukraine, more than 1 million persons are registered as patients in oncology clinics of Ukraine. More than 134 thousands of new cancer patients are registered each year (313.6 per 100 thousand), 49% of them are active working age persons.
Cancer results in 15% of deaths in Ukraine and is second only to heart diseases. In general, 5-year survival rate for cancer patients makes up to 56% (in European countries it makes about 80% and in the United States ― 90%). Cancer incidence in children makes 13.2 per 100.000 of children aged from 0 up to 17 years. More than 1000 of new cancer cases developed among children are registered every year.
Early diagnostics and modern therapy methods help to cure from cancer. Each cancer type requires specific therapy method or even a combination of several methods. Surgery, systemic therapy, including chemotherapy, biotherapy, palliative care, tomotherapy, embolization therapy, immunotherapy, targeted therapy are in the arsenal of contemporary cancer treatment science but the most common therapy method is radiotherapy.
Contemporary medicine has high radiation technologies which use ionizing radiation for diagnostic and therapeutic purposes. Many of these technologies are used in Ukraine.
Currently 133 gamma therapy units (40 of them are used for contact therapy) and 24 electron accelerators are used in Ukraine. Also there are 2 PET-CT Centers. About 60 thousand of radiotherapy procedures are performed every year.
Radiotherapy (RT) is a constituent part of the majority of state-of-the-art treatment protocols and considered to be safe method used to cure the disease almost at all stages either separately or in combination with other methods. In compliance with IAEA data, about 52% of cancer patients in developed countries receive radiotherapy. In case of cervix carcinoma, pituitary tumors, deeply located gliomas, nasopharyngeal carcinoma and early stage of poorly differentiated lymphomas (including Hodgkin’s disease), radiotherapy has the highest cure rate and/or less probability of side effects compared to other procedures. And in case of advanced cervix carcinoma, nasopharyngeal carcinoma or similar tumors, the treatment is possible only with the help of radiotherapy.
This method is preferred over surgery when surgery will result in the loss of an organ or function and the tumor control rate is equivalent. Examples include laryngeal cancer and prostate cancer.
Radiotherapy has a pivotal role in the curative treatment of breast cancer, cervical cancer, cancer of the mouth/pharynx/larynx and others. Depending on the stage of disease, this modality can reduce the risk of recurrence, improve survival or provide palliation of symptoms.
In general, different forms of radiotherapy are used to withstand cancer diseases for more than a hundred years.
Radiotherapy functional concept and types
Fundamentally, the radiotherapy is a treatment with target effect of controlled radiation dose on cancer cells to damage their nuclear DNA, it makes impossible the reproduction of cancer cells and prevent the start of self-destruction mechanism. When destruction processes in the tumor supersede the recovery processes and in surrounding normal cells – on the contrary, it means that radiotherapy has worked. The main objective of this treatment method is to minimize damage to surrounding normal cells through the delivery of an adequate dose aimed and timed accurately to destroy tumor cell.
Radiation used for radiotherapy can be both wave radiation (X-rays, gamma-rays) or particle radiation (alpha and beta-particles, neutrons, protons, carbon ions).
Radiation dose can be delivered to the affected organ through the human skin (external beam radiation therapy) with the help of external sealed radiation source or with the help of the source implanted in the body.
If sealed radiation source is directly implanted inside the tumor to affect a certain part of the tissue, it is called brachytherapy or contact radiation therapy. Sealed ionizing radiation sources for external beam radiation therapy and brachytherapy are cobalt-60, cesium-137, californium-252, iridium-192, iodine-125, etc. Brachytherapy is most often used to treat breast, prostate, cervix and skin cancer. The radiation sources are implanted in the form of capsules, needles, balls, wires, flexible catheters.
According to radiation source insertion areas in the target, brachytherapy is divided into the following types:
- intracavity — radiation source is implanted into the natural cavity in the body close to the tumor. Direct contact of the radiation source with the tumor allows to obtain high absorbed dose in abnormal focus. It is used for malignant tumors of the mouth (alveolar cancer, tongue, palate, lip, mucous membrane cancer, etc.), esophageal cancer, rectal cancer, vagina cancer, cervix cancer, endometrial cancer, etc. The intracavitary brachytherapy procedure envisages the use of gamma-therapy hose.
- intratissual (interstitial) — radiation source is implanted directly into tumor tissue.
There is a differentiation between intratissual (interstitial) gamma and beta-therapy. Gamma-ray preparations (sealed or open radiation sources) are used at gamma-therapy. Also, medical devices of special form are used: needles, beads, tubes, suture material with cobalt-60 granules, etc. The intratissual method is demonstrated both as an independent method and in combination with radical or palliative surgery for breast cancer, lung cancer, malignant soft tissue tumors, etc.
The intratissual (interstitial) beta-therapy is characterized by the use of open radiopharmaceuticals (colloidal solutions and suspensions of gold-198 radionuclides, yttrium-90 silicate, zirconium phosphate or chrome phosphate with phosphorus-32)
- intravascular — effective method for treatment of blood vessels, for example, coronary vessels. Beta and gamma-emitting sources integrated into the vessel lumen for a certain time period are used. This method is used worldwide but it is too complicated for practical implementation.
- intraluminal — radiation source is inserted directly to the channel with the tumor and used for treatment of esophagus and bronchus.
- surface (application) — radiation source is placed at the surface of the target. It is used for early superficial malignant tumors (skin cancer, oral mucosa cancer, lower lip cancer). Radioactive beta or gamma-emitting sources are placed inside prefabricated plastic applicator which form complies with irradiation area.
According to the absorbed dose rate applied to an organ/tissue, brachytherapy is divided into:
- low-dose brachytherapy — 0.4 Gy/h – 2 Gy/h per target volume;
- intermediate-dose brachytherapy — 2 Gy/h – 12 Gy/h per target volume;
- high-dose brachytherapy — 12 Gy/h and more per target volume;
- pulsed-dose brachytherapy — dose is introduced periodically during a certain period.
According to radiation source introduction tools, brachytherapy is divided into:
- manual — radiation source is set manually;
- remote brachytherapy — using special automated tools.
If open radionuclide in the form of a liquid (radiopharmaceutical) is delivered orally or through a catheter then it is called systemic radiation therapy (other names are molecular radiotherapy, radionuclide therapy).
This method is based on the ability of separate radionuclides to accumulate selectively in the certain type of tissue affected by cancer cells. In particular, radiotherapy is widely used at treatment of bone metastases: beta-emitting strontium-89, samarium-153 (lexidronam) or radium-223 pass over healthy bones and, accumulating in the affected areas, hit the cancer cells.
Also, by the intake of iodine-131 it is possible to treat thyroid cancer or thyrotoxicosis; injections of lutetium-177, indium-111, yttrium-90, etc., combined with hormones, treat neuroendocrine tumors (peptide receptor radionuclide therapy). Yttrium-90 or holmium-166 microspheres are instilled selectively into the hepatic artery.
Radionuclide therapy is a separate method for treatment of a number of benign and malignant tumors using open sources: strontium-89, samarium-153, gold-198, phosphorus-32, strontium chloride-99, iodine-131, rhenium-186, rhenium-188, stannum-117, etc.
High performance in achieving the main goal of the therapy ― destruction of cancer cells with maximum preservation of healthy cells ― is the advantage of radionuclide therapy.
Radionuclides are concentrated even in not yet manifested and diagnosed disease focuses. The absence of side effects for healthy tissues makes possible to repeat the irradiation.
In certain clinical cases, doctors can combine remote and contact radiotherapy methods.
Remote radiotherapy methods for curative intent
Radiation therapy is the most technologically advanced branch of contemporary medicine. The use of advanced achievements of fundamental sciences in combination with the latest information technologies has significantly extended the possibilities of traditional radiotherapy methods of treatment of oncological diseases and also application of unique radiotherapy technologies.
Currently the remote radiotherapy is the most widespread and, accordingly, most commercial available type of the radiotherapy. Conformal radiation methods are now firmly in place as modern radiotherapy standard of curative intend treatment of many oncological diseases.
The procedures are carried out with the help of specific equipment – linear accelerators with gamma sources (more often cobalt-60, also iridium-192, cesium-137, previously ― radium-226) equipped with multileaf collimators. Arrangement of leaves in different positions allows to generate photon beam which precisely conforms the shape of the tumor (that is why the radiation is “conformal” ― from the word “confirmation”). Form of radiation (so called “field of radiation”) and dose are controlled by the computer.
Trends in the development of conformal radiation therapy are aimed at improving the accuracy of delivering a dose to a tumor to reduce radiation exposure to healthy organs and tissues. Accordingly, a number of the following improved methods are actively used:
- Three-dimensional conformal radiotherapy (3D-CRT) involves determination of dimensions, shape and location of the tumors using three-dimensional planning (computed magnetic resonance or positron emission tomography (PET)) and specialized dose delivery equipment. At three-dimensional conformal radiotherapy the dose distribution is planned to match the target shape. Radiation beams (gamma rays) are focused at the tumor from different angles. Requires rigid immobilization of the patient.
- Intensity-modulated radiation therapy (IMRT) is the most advanced form of 3-D conformal radiation therapy which allows to change the intensity of radiation exposure to a tumor depending on the distance to it, significantly increase the dose delivered to the tumor compared to standard treatment procedures and reduce the total duration of radiation exposure by more than 50%. This treatment procedure allows to treat several areas with higher radiation doses while sparing the surrounding normal tissues. Radiation beam is divided into many tiny rays of specific intensity each. This ensures safe delivery of much higher therapy dose to the tumor, for example, up to 90 Gy to prostate tumor and up to 70-76 Gy to head and neck tumor. This method is intended for these cancer types. In certain cases it is possible to treat lung cancer with the help of IMRT. Currently, IMRT is considered to be the most advanced method of remote radiotherapy.
- Image guided radiation therapy — image of patient is taken before treatment and each time before subsequent radiotherapy session. It allows to track changes in tumor location and shape and shape better the treatment beams to match the tumor. It is used for tumors in lungs, liver, prostate and when the tumor is located very close to vital organs or tissues.
- Respiratory-gated radiotherapy (4D-radiotherapy) is innovative method used when it is necessary to achieve exceptional accuracy in dose delivery to those body areas which naturally move as a result of respiration what critically change the internal anatomy. This refers to radiotherapy of the chest and abdominal organs. Fourth dimension here is the time considered by the program to adjust the linear accelerator to the patient’s respiratory rhythm. When the tumor extends beyond the planned target volume the linear accelerator disables the beam and enables it when this volume takes previously set position.
- Intensity-modulated arc therapy (volume-modulated rotational radiation) is the most advanced method of treatment with the help of linear accelerator. It allows high conformal radiation doses to be delivered to the target without affecting normal tissues. It is achieved by rotation of the gantry (movable head which contains the radiation source) around the patient’s body with variation of speed and shape of the beam and the dose rate. It reduces the exposure time to two minutes. This method has proven to be effective in treatment of nasopharyngeal, pharyngeal and subpharyngeal carcinomas.
Hadron therapy (corpuscular or ion radiation therapy) is specific radiotherapy method which uses high-energy charged particles ― protons, neutrons or other positively charged ions ― instead of gamma-ray photons. Physical characteristics of particles allow to damage cancer cells at any depth inside the human body with minimal radiation dose to surrounding healthy tissues. This phenomenon, when ionization peak occurs immediately at strictly specified depth before the particles come to rest, is called the Bragg peak.
Most of hadron therapy centers existing in the world use exposure of protons or heavy carbon ions accelerated in cyclotrons or synchrotrons (phazotrons).
Cyclotrons are accelerators which generate fixed frequency proton exposure. Synchrocyclotrons are more compact version of cyclotrons which generate proton or heavy ion beams with variable acceleration frequency.
Proton beam therapy is the most commonly used type of hadron therapy. It allows to treat choroidal melanoma without eye removal as it was before. Biological effectiveness of carbon ions is greater compared to protons that is why heavy ion therapy is used to treat certain types of cancer.
Currently, fast neutron radiotherapy is under development but it already has several advantages. First of all, it is biologically more effective for tumor treatment compared to other types of particle therapy. Neutrons are capable to kill certain types of radioresistant tumors which means that this method is more effective in treating such cancers as salivary gland cancer, adenocystic carcinoma and certain types of brain tumors (in particular, poorly differentiated gliomas). Secondly, neutron therapy requires less treatment time due to that neutron effective dose makes one third of proton dose to kill the same number of cancer cells.
The main obstacle for hadron therapy spreading is the size and high cost of cyclotrons and synchrocyclotrons. For example, in 2019 there were 92 proton accelerators used for treatment (Particle Therapy Co-Operative Group data). Most of them are concentrated in the United States (31), Japan (20) and Germany (8). Neutron therapy equipment (cyclotrons, reactors and linear accelerators) is available only in the United States, Russia, Germany and South Africa.
Currently the hadron therapy is considered to be a rare type of radiotherapy and is used in certain clinical cases. But it has a great potential since research and technology improvement are ongoing.
Stereotactic radiosurgery (or radiosurgery) is another specific radiotherapy method. Its functional concept consists in single precisely-targeted high dose irradiation of the tumor. With this purpose highly detailed images of organs are used (set of CT, MRT or PET three-dimensional anatomо-topographic images). Due to exceptional accuracy of this method the most common cases when it is used are brain and spine tumors and metastases when it is necessary to avoid irradiation of surrounding vital organs and tissues.
Radiosurgery procedure provides for the usage of different types of equipment: Leksell gamma knife, cyberknife, modified linear accelerators, proton accelerators, etc. (names of separate devices and treatment methods may differ depending on device trademark).
Gamma knife functional concept is to focus 201 radiation beams (cobalt-60) on the target through stereotaxic frame and with the help of lens system. Method error makes no more than 0.15 mm.
CyberKnife facility consists of linear accelerator which generates electromagnetic radiation and robotic arm which delivers radiation to any part of the human body with pinpoint accuracy.
Modified linear accelerators envisage the use of both radiosurgical and therapeutic methods of treatment. First option is used when it is referred to 3-4 cm tumors (single dose of 15-25 Gy), second option is used when the tumors are large (respectively, dose is divided into 3-6 fractions of 5-6 Gy). Gamma knives can work the same. Fractioned dose treatment method is called stereotactic radiotherapy. Stereotactic localization of intracranial targets (brain stem, optic chiasm or optic nerves) envisages on skull fixation of the head frame attached to the bite block.
Radiosurgery is indicated not only for cancer diseases (malignancies, metastases) but also for vascular diseases, functional dysfunctions, trifacial neuralgia, epilepsy, etc.
Also there are situations when radiotherapy is delivered to the exposed area at the end of the surgery. It is called intraoperative radiotherapy (IORT).
The main goal of radiotherapy is curative intent – achievement of complete resorption of the tumor. 40% of cancer patients were cured with the help of radiotherapy either as separate method or in combination with surgery or chemotherapy. Primary tumor site and regional metastasis area undergo radiation in case of curative intent treatment by means of conformal therapy methods. The total dose to the primary tumor site makes, as a rule, 60-75 Gy, to the metastasis area ― 45-50 Gy.
Usually treatment course takes 6-11 weeks. The total dose is divided into fractions (most often it is 2 Gy fractions) delivered to the patient five days a week. Due to this, normal tissues affected by radiation have time for regeneration between treatment sessions. However, there are radiotherapy methods which envisage daily delivery of several fractions to the patient.
First, the patient attends simulation session, that is, treatment planning session. The patient is positioned on the treatment table exactly in that position which he shall take during radiotherapy sessions. After that, radiation technician, using any of radiologic imaging methods, takes a picture of that part of the patient’s body where the tumor is located. After receiving of the image, the doctor draws up a radiation plan, where he prescribes in detail the dose, number and form of radiation beams and number of therapy sessions.
At radiotherapy sessions the patient’s skin gets special markings or marking particles are implanted into the tumor for precise targeting of radiation beam. Sometimes human body is fixed so that changes in body position not to result in radiation beam displacement against the target. During session the patient is alone in therapy room, however, the radiotherapist, who controls the equipment from adjacent room, keeps visual and verbal contact with the patient. One treatment session usually lasts for 10-20 minutes.
Patients undergo systemic radiation therapy in separate departments of oncology clinics. Medication by high dose radiopharmaceuticals (3500 MBq for iodine-131, up to 500 MBq for strontium-89, 200 MBq for gold-198) requires special conditions for patient management and observation. This method envisages patient isolation for 5-14 days depending on medication radionuclide. During treatment the patient himself becomes a source of radiation so he can be released only when his dose rate does not exceed 10 μSv/h. Patient’s personals and clothes are stored in clinic storage room until radioactivity level is decreased and then returned to the patient.
In compliance with findings of the World Health Organization the radiotherapy success depends for 50% on tumor radiosensitivity, for 25% on the hardware and for another 25% on the effective treatment plan and accuracy of its implementation from session to session.
Also, radiotherapy is effective as palliative care at advanced cancer. When complete and sustained remission cannot be achieved, the main objective of radiotherapy is inhibition of tumor growth and prolongation of patient’s life. Also, palliative radiotherapy can help in situations of severe bleeding from the tumor, compression of superior vena cava and other situations that pose a threat to life.
Partial tumor regression, intoxication decrease, pain disappearance and partial recovery of the affected organ are observed due to irradiation with total doses (40-55 Gy). The most common situation for the use of palliative radiotherapy program is relief of the pain caused by bone metastases, in addition, relief of the pain caused by tumors resulting in bleeding or compression syndromes (spinal cord compression, brain metastasis). From 40 to 70% of radiotherapy courses are aimed at alleviation of patients’ state and under such circumstances this method is indispensable.
Radiotherapy side effects
Radiotherapy is painless since the patient does not feel negative effect of radiation. However, repeated delivery of ionizing radiation to the human body can result in certain adverse reactions. The experts of the National Cancer Institute of Ukraine concluded that skin reactions are rare and are limited to erythema or dry radiation dermatitis at the use of contemporary remote radiotherapy methods. Radiation fibrosis of subcutaneous tissue is most typical since when using high-energy radiation most of the dose penetrates deeply into the human body.
The patient can safer from the following common reactions to ionizing radiation:
- general unwell: low-grade fever, vertigo, weakness;
- loss of appetite, nausea, diarrhea, vomiting;
- tachycardia, retrosternal pain;
- hematopoietic disorders: leukopenia, neutropenia, lymphopenia, trobocytopenia, eosinophilia.
Local reactions to radiation can occur due to irradiation of vital organs and tissues.
Radiation to maxillofacial area can result in redness and inflammation of gingival membrane, mouth and throat, dry mouth and changes in taste.
Radiotherapy to breast tumors can result in breast pain and swelling which disappear immediately after the end of treatment or gradually with the time. Accumulation of fluid can cause the irradiated breast increase and tissue fibrosis can result in its decrease.
If chest organs are exposed to radiation then there is a probability of radiation-induced esophagitis. It is characterized by swallowing problems. Treatment of tumors in pelvic organs (rectal cancer, etc.) results in rectal mucosa radiolesion. Moreover, in some cases pain and blood, especially at difficult bowel movements, are observed.
The majority of reactions disappear in 2-3 weeks without any special treatment.
Inflammation of bladder mucous membrane caused by radiotherapy can result in frequent painful urination and temperature increase. Sometimes, urinary blood is observed. In such cases, doctor prescribes medication.
Also, radiotherapy causes radiation injury, that is, organic and functional changes in organs and tissues that require special treatment. Radiation injuries are classified as follows: early radiation injuries (occur in the process of radiotherapy or within subsequent three months) and delayed radiation injuries (after six months, year and a half and more).
Early radiation injuries regard with more radiosensitive tissues which are easily recovered, delayed radiation injuries result in injury of more radio-resistant structures. Delayed local radiation injuries progress with years due to considerable histochemical and histological changes. First of all, it is necessary to consider bowel radiation injury since intestinal epithelium is one of the most radiosensitive systems of the human body. These different degree complications cover 70-100% of patients. In addition, there is a possibility of radiation cystitis, lymphedema, fistulas, pneumonitis, radiation injury of skin and normal tissues (radiation fibrosis, necrosis and ulcer), chronic radiation sickness, etc.
Complications can be conditioned by the exceedance of normal tissue tolerance to irradiation, increased sensitivity, preliminary inflammatory processes, biological characteristics of the tumor, gastrointestinal inflammations, cardiovascular and endocrine system abnormalities, etc.
Delayed radiation complications undergo comprehensive treatment using local and general medication. It is necessary to point out that in compliance with medical data there were no study cases of patient’s death due to delayed radiation complications.
Where can you get radiotherapy treatment?
The National Cancer Institute of the Ministry of Health of Ukraine, Romodanov Neurosurgery Institute of the National Academy of Medical Sciences of Ukraine, Kyiv City Clinical Oncology Centre, Grigoriev Institute for Medical Radiology and Oncology of the National Academy of Medical Sciences of Ukraine, Ukrainian National RF-surgery Centre of Feofaniya Clinical Hospital, National Children’s Specialized Hospital “OKHMATDYT”, Regional Oncology Clinics — in total about 40 public health institutions of municipal and government ownership and also private clinics provide radiotherapy in Ukraine.
- Data of the State Nuclear Regulatory Inspectorate of Ukraine.
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