Radiotherapy is an important part of cancer treatment, and its main goal is to deprive cancer cells of their proliferation potential. Radiation is a physical factor that stores energy in the cells of the tissues it passes through, and then this deposited energy can kill cancer cells or cause genetic changes that lead to cancer cell death [367]. The main mechanism of killing cells by high-energy radiation involves damaging their genetic material of DNA, thereby blocking their ability to further divide and proliferate [367,368]. The goal of improving radiation therapy is to maximize the radiation dose to cancer cells while, at the same time, minimizing the exposure of healthy cells that are adjacent to cancer cells or are exposed to radiation [367]. Radiotherapy is also used in conjunction with other treatments, such as surgery, chemotherapy, or immunotherapy.

Currently, brachytherapy and teleradiotherapy are commonly used. Brachytherapy involves treatment with the use of a radiation source that must be as close to the tumor as possible. The mechanism of brachytherapy is based on the use of radiation in direct contact with the tumor. However, when it comes to teleradiotherapy, the source of radiation is located at a certain distance from the tissue within the area of the cancer. In the context of radiotherapy, the so-called 5R principle that occurs during radiotherapy: redistribution, repopulation, reoxygenation, repair, and radiosensitivity is worth highlighting [369]. Radiation can be classified as ionizing radiation (e.g., X and gamma radiation) or particle radiation with electrons, protons, alpha particles, and neutrons. The biological mechanism of action depends on the type of radiation (e.g., relevance of linear transfer energy and cell damage). On the other hand, cancerous tissue parameters can provoke effects, such as the increase in sensitivity of cancer cells to ionizing radiation if the activity during the division of cancer cells is also greater. However, a higher level of differentiation makes cells less sensitive to radiation. The level of tumor oxygenation is also an important factor. When tumor is more hypoxic, the cancer cells are less sensitive to radiation (oxygen enhancement ratio is 2.5–3 times bigger for a well oxygenized tissue). In context of radiotherapy, there is a very interesting strategy to treat malignant eye tumors—protonotherapy. This technique uses Bragg’s pick to deposit energy into the tumor, and the healthy tissue around the tumor is kept safe at the same time [370]. It was shown that proton radiation can inhibit the metastatic potential of primary cancer cells.

In the outcome of radiotherapy methods and mechanisms, temporary inhibition of tumor growth or growth retardation and tumor regression may take place. There are many factors that have to be considered, although these mechanisms can be influenced by the duration of the cell cycle, the size of the cell growth fraction or the rate of cell loss.

From the perspective of potential needs for combination treatment involving the use of radiotherapy, a few factors should be taken into consideration. Regarding the above-mentioned cell sensitivity to radiation (e.g., cell cycle, oxygen enhancement), the main need is to overcome radioresistance. For example, melanomas are quite resistant to radiation therapy due to their melanin accumulation (accumulation of pigment that acts as a radioprotector). Additionally, cancer cells that contain melanin are hypoxic and, therefore, more resistant to low LET radiation. A high level of cell differentiation also contributes to this resistance [371]. In the treatment of melanoma where melanin is present, its role is to scavenge free radicals. This mechanism allows putting this pigment in the radioprotector category. It protects melanin against the impact of ionizing radiation, for example X-radiation. What is worth emphasizing is that this pigment increases radiation resistance by inactivating free radicals that are formed during the course of radiation. A well-applied complementary treatment can increase melanoma sensitiveness to ROS.

The limitations of radiotherapy, such as insufficient tissue oxygenation can be overcome by using complementary therapies. One such technique is hyperthermia, which is usually a complementary method that involves heating the tumor in order to inhibit the proliferation of cancer cells, destroy them, or make them sensitive to various treatments, including radiation therapy. The combination of hyperthermia and radiotherapy shows a synergistic effect and enhances the killing effect on cancer cells, especially those in the S phase of the cell cycle, which are usually resistant to radiation when applied alone [19]. The synergistic effect of heat and radiation is defined as the thermal enhancement ratio (TER), which defines the magnitude of thermal hypersensitivity to radiation as the survival fraction quotient after irradiation alone and in combination with hyperthermia [372]. The effects of hyperthermia include, but are not limited to, inhibition of the repair of radiation-induced DNA damage, thereby increasing the cytotoxic effect of radiotherapy [372]. Moreover, by reducing the metabolic activity of target cells, heat reduces the oxygen demand of the tumor and increases the oxygenation of the tumor tissue as well, making hyperthermia one of the most powerful radiosensitizers available [373].

Another approach to overcome the limitations of radiation therapy is to combine it with photodynamic therapy. Photodynamic therapy uses photosensitizers that are activated by visible or near-infrared light and transfer energy to molecular oxygen, thus generating reactive oxygen species [373]. Under certain conditions, some photosensitizers can act as radiosensitizers. Combining radiation therapy with photodynamic therapy, i.e., using ionizing radiation tissue penetration and photodynamic therapy can reduce penetration depth problems and can allow radiation dose reduction without decreased clinical efficacy [374], while minimizing damage to healthy tissues. Moreover, the combination of an appropriate photosensitizer with radiation therapy can lead to a significant increase in the cytotoxic and apoptotic death of cancer cells [375]. The combination of photodynamic therapy and radiation therapy, the primary goal of which is to kill cells through nuclear DNA damage, offers the possibility of synergism in killing cells, as photodynamic therapy does also induce several types of DNA damage [376]. In addition, photodynamic therapy does also improve the immune system’s response by inducing inflammation and an immune response against cancer cells. Potential mechanisms of immune stimulation by photodynamic therapy include an acute inflammatory response that can enhance tumor antigen presentation to activate dendritic cells and to guide them to regional and peripheral lymph nodes, ultimately stimulating cytotoxic T lymphocytes and NK cells, accompanied by the formation of immune memory and growth suppression tumor in the future [255].

Chemotherapy is a very broad category of anti-cancer treatment. The induction of apoptosis and the inhibition of mitosis as well as the cell cycle disorder are caused by the use of chemotherapeutic agents. Cytostatic drugs can be grouped into alkylating agents, alkaloids, antibiotics, and antimetabolites. Inhibitor of tyrosine kinases are also very important novel drugs. They affect cell proliferation by targeting cellular DNA or RNA and metabolism with antimetabolites acting on purine or pyrimidine metabolic enzymes, while alkaloids act on the cytoskeleton and mitosis [377]. One of the main problem with chemotherapy is the effective, safe, and selective drug delivery. Chemotherapy is associated with the presence of side effects that include immediate signs of toxicity (effects can be seen on skin and hair, bone marrow and blood, gastrointestinal tract and kidneys, etc.) as well as late signs of chronic toxicity (drug resistance, carcinogenicity) [377]. In order to increase the effectiveness of chemotherapy and reduce side effects, a combination of various drugs with different mechanisms of action is used. Moreover, when several chemotherapeutic agents are used, drug resistance could be counteracted. Overall results of chemotherapy are also improved due to the use of combinations of drugs that do not have overlapping toxicities. Then, we can increase the dose of drugs in the tumor without fearing undesirable negative side effects of the therapy. This approach is used very often to reduce side effects since increasing the dose of only one drug can cause toxicity; therefore, it seems that combining drugs from different groups is less toxic and more effective due to the higher therapeutic dose applied. The same happens when we use drugs that have different mechanisms of action. In this case, cells that are insensitive to one drug are already sensitive to the other drug from this combination. Treating drug-resistant cancers is a significant problem not only in chemotherapy. This mechanism of drug resistance may be influenced by the fact that the chemotherapeutic agent alone is not able to reach the inside of the tumor directly. Still, other challenges face this approach as well, such as improving drug perfusion and increasing the accumulation of the therapeutic compound in the tumor. Hyperthermia, which causes changes in cells and their surroundings due to high temperature, seems to be a good complementary technique. In addition to direct ablation of cancer cells, elevated temperatures can also trigger drug release, especially for heat-sensitive carriers [378]. It is also known that raising the temperature from 37 °C to 43 °C such increases the permeability of the cell membrane, accelerating the absorption of nanoparticles, and it may increase the interaction of carriers with the cell membrane as well [379]. In particular, energy-dependent pathways, such as clathrin- and caveolae-mediated endocytosis are involved in increasing the permeability of the cell membrane at high temperature, thus increasing the internalization of drugs and carriers [378,379]. Hyperthermia also affects blood flow and, hence, changes the drug distribution. Certainly, the heat-induced change in blood flow in tumors differs from the one that occurs in regular tissues because the tumor vasculature is less able to dissipate heat and is more susceptible to damage during hyperthermia treatment. However, it is worth noting that mild heat increases blood flow in the tumor, allowing chemotherapy to have a greater effect on cancer cells [373]; thus, in some types of tumors, blood flow increases when heated to relatively low temperatures. On the other hand, higher temperatures (43 °C or 44 °C) result in stronger and longer-lasting vascular closure [380].

In addition to allowing more efficient drug delivery, heat can also modify the cytotoxicity of many chemotherapeutic agents. In many cases, synergism can be seen as a continual change in the rate at which the drug kills cells as temperature increases. The cytotoxicity of most alkylating agents, platinum compounds, and also nitrosoureas increases linearly with the temperature increase, typically by thermal enhancement, including increased alkylation rate constants, increased drug absorption, and inhibition of repair of lethal or sublethal drug-induced damage [381].

Additionally, hyperthermia may increase the killing effect on tumor cells located at the hypoxic centers of tumors that are relatively resistant to chemotherapy due to poor drug delivery. In addition, some chemotherapy drugs also require oxygen to generate free radicals in order to induce tumor cytotoxicity. It is known that elevated temperatures can increase the rate of biochemical reactions, increasing cellular metabolism, which can result in an increased oxidative stress. The level of reactive oxygen species may increase after exposure to elevated temperatures, possibly due to dysfunction of the mitochondrial respiratory chain or by increased activity of the enzymes NADPH oxidase and xanthine oxidase [382].

Surgery is one of the three most popular treatments for cancer today, and also the oldest one. It plays the most important role in the treatment of cancer. Its application ranges from the diagnosis of lesions, i.e., taking biopsies for diagnosis, through reducing the tumor mass, to radical treatment in order to completely excise the lesion together with a margin of healthy tissues. Complete tumor excision with cutting out a healthy tissue margin is the most effective form of treatment in the case of early stage neoplasms, especially when there are no metastases yet. Such achievement of a sufficiently negative margin during oncological surgery minimizes the risk of adverse treatment outcomes and recurrence of the disease [383]. In some cases, the unfavorable location of the tumor or the presence of disseminated metastases can make it impossible to remove the tumor. Hence, it is not always possible to obtain the necessary margin, in particular in case of surgery in the vascular system area, in case of other critical areas, and in case of tumor involvement in adjacent tissues. This problem applies to such neoplasms as hepatocellular carcinoma, pancreatic ductal adenocarcinoma (PDAC), neuroblastoma, or neuroendocrine tumors of the gastrointestinal tract. Involvement of a blood vessel can sometimes be resolved by surgical resection and reconstruction of the affected vessel, such as a vein or artery, but these procedures are associated with an increased risk for the patient, especially in the case of arteries [384,385].

In conclusion, failure to obtain adequate surgical margins increases both the surgical and oncological risk of poor prognosis, which is usually the case when tumors have invaded large blood vessels [385]. If it is impossible to remove the entire neoplastic lesion, the combination of surgery and radiation therapy is often used. Postoperative radiotherapy reduces the risk of cancer recurrence and also helps destroy any remaining cancer cells, especially when only the tumor was removed and only a small amount of regular tissue around it was removed, or a margin is left that is positive for cancer cells. Indications for postoperative radiotherapy include not only insufficient resection margin, but also uncertain radicality of resection, infiltration of tissue with diffuse cancer foci, and low tumor differentiation. Therefore, in most cases, only combinations of treatments such as surgery combined with radiation therapy are usually the only way to destroy cancer cells [373].

Returning to the issue of tumor areas that cannot be surgically excised due to the fact that their location is too close to inoperable vessel, there is one interesting complementary method: the use of local, mild hyperthermia. By applying uniform and gentle heating, we can destroy tumors that surround the vessels and, at the same time, protect these sensitive structures from damage [385]. It has been shown (on the example of pancreatic ductal adenocarcinoma) that an increase in temperature in the range of 41–46 °C leads to killing cancer cells, including the elimination of cancer stem cells, as well as changes in the proteomic profiles of cancer cells, with simultaneous protection of regular cells [385].

Another method that is complementary to surgery is photodynamic therapy, which is based on the complex cell killing phenomenon resulting from the interaction of a chemical compound (photosensitizer), light, and oxygen. Photodynamic therapy is recognized as a safe and effective method, and this is why it plays a unique role in the treatment of cancer with its targeting precision. It does not damage healthy structures surrounding the treated lesions, and it is applied in the treatment of cancerous tumors with limited access [386]. In systemic photodynamic therapy there is a wide distribution of photosensitizer, but there is also a higher potential for accumulation in cancerous tissues than in healthy tissues, and multi-site deep light, which can be performed intraoperatively in combination with standard or minimal surgical access [386]. Consequently, by using the preferential accumulation of photosensitizers in cancer cells with the appropriate selection of irradiation, it is possible to eliminate the remaining tumor fragments that cannot be surgically removed. Photodynamic therapy may be used in some cases before surgery as a neoadjuvant therapy to alleviate cancer.

In addition to destroying cancer cells, photodynamic therapy is closely related to the fluorescence phenomenon used in photodiagnostics to detect lesions. As noted, the optical properties of healthy and abnormal tissues in the ultraviolet and visible spectrum differ from each other. Due to endogenous chromophores, some tissues exhibit a characteristic fluorescence emission band that changes when the disease process occurs, changing these chromophore components [386]. Thus, using the appropriate wavelength, an image can be obtained that is used as the basis of autofluorescence photodiagnosis [386,387]. This method may be helpful in determining the optimal biopsy site for histological diagnosis. In addition to using endogenous chromophores, photosensitizers can be used as exogenous fluorophores to enhance fluorescence [386]. The use of such enhanced photodiagnostics is especially valuable in surgical operations where it can indicate residual neoplastic infiltration, which may be present at the margin of resection. In addition, it can be used in brain surgeries, in the removal of tumor remains that are invisible to the naked eye or with the use of microscopic surgical instruments [386,388].