Introduction
In recent years, the aging of populations, particularly in highly developed countries, has become a notable demographic trend that significantly affects the epidemiological profile of cancer [ 1 ]. According to reports by the World Health Organization (WHO), the percentage of people aged 60 and over has increased significantly, and forecasts indicate that by 2050, the number of people in this age group worldwide will exceed 2 billion [ 2 , 3 ]. The above data show that as the percentage of elderly people increases, so will the oncological burden–both in terms of the number of new cases and the number of patients already diagnosed who require treatment and rehabilitation. The high risk of developing cancer in old age results from the accumulation of exposure to risk factors (such as smoking, alcohol, occupational exposure, and chronic inflammatory processes), a decline in the body's biological reserve, changes in immune function, and an increased time in which mutations leading to cancerous transformation can accumulate.
Cancer is defined as a heterogeneous group of diseases characterized by abnormal cell cycle regulation, leading to uncontrolled proliferation and loss of normal cell differentiation [ 4 ]. Under physiological conditions, cell division is strictly regulated by a network of control mechanisms, including suppressor proteins, growth factors, DNA repair pathways, and apoptosis processes. In cancer cells, however, there is an accumulation of genetic and epigenetic changes — such as mutations activating proto-oncogenes, inactivating suppressor genes, DNA repair mechanism disorders, and epigenome deregulation — which lead to the breakdown of these control mechanisms. As a result of uncontrolled proliferation, cancer cells form a primary tumor mass [ 5 ]. These cells are also characterized by their ability to acquire a phenotype different from that of the parent tissue cells, which manifests itself in the loss of mature differentiation, the ability to grow under restrictive conditions, and resistance to signals that inhibit proliferation. These phenomena have been described as “hallmarks of cancer” and form the basis of the modern understanding of cancer biology [ 6 , 7 ].
Depending on the degree of aggressiveness and ability to invade tissues and spread through blood vessels, lymphatic vessels, or implants, tumors are classified as benign or malignant [ 8 ]. Benign tumors are characterized by limited growth, inability to invade adjacent structures, and lack of metastasis, although depending on their location, they can cause significant clinical symptoms. Malignant tumors, on the other hand, are characterized by their ability to invade surrounding tissues, destroy anatomical structures, and form distant metastases, which are the main cause of death in cancer patients [ 9 ]. Metastasis is a multi-stage process and includes, among other things, the detachment of cells from the primary tumor, migration through the extracellular matrix, intravasation into vessels, survival in circulation, extravasation, and colonization of new tissues. In light of current knowledge, cancer should therefore be viewed not as a homogeneous disease entity, but as a complex set of biological processes whose common denominator is deregulated proliferation, impaired differentiation, and invasive and metastatic potential [ 10 , 11 ]. The most common cancers are breast cancer (in women) and lung cancer (in men). A significant percentage of diagnoses are head and neck cancers.
Head and neck cancers are a diverse group of malignant tumors that can develop in many different anatomical locations—the oral cavity, larynx, nasal cavity, nasopharynx, and lower throat [ 12 – 14 ]. Most head and neck cancers are squamous cell carcinomas that develop from the epithelium lining the upper respiratory and digestive tracts. These cancers are characterized by diverse etiology, clinical presentation, and prognosis. The main factors contributing to their development include smoking, excessive alcohol consumption, prolonged irritation of the mucous membranes, occupational exposure to chemicals (including wood dust or formaldehyde), and, in the case of the oropharynx, infection with the human papillomavirus (HPV).
According to epidemiological data published by the International Agency for Research on Cancer (IARC) as part of the GLOBOCAN project, head and neck cancers are one of the most common types of malignant tumors in the world, ranking approximately ninth in terms of the number of new cases globally [ 15 – 17 ]. In 2018, approximately 880,000 new cases of these cancers were reported, accounting for about 4.5% of all cancer diagnoses. In subsequent years, a systematic increase in the number of cases was observed — according to epidemiological analyses from 2022–2023, the number of new cases of head and neck cancers approached 900,000 per year, accounting for approximately 5% of all cancers diagnosed worldwide. Epidemiological analysis has also revealed clear differences in the incidence of these cancers depending on gender. In the male population, head and neck cancers are among the most commonly diagnosed malignant tumors — in some studies, they even rank fifth in terms of incidence. In women, the incidence is significantly lower, but in recent years there has been an increase, particularly in relation to throat cancers associated with HPV infection.
Surgical resection, radiotherapy, chemotherapy, and targeted therapies significantly affect the condition of bones, mucous membranes, and soft tissues, and consequently the possibilities and limitations of prosthetic rehabilitation. [ 18 ]. The choice of a specific type of therapy depends mostly on the clinical features of the tumor, like its location, stage, presence of metastases, and, most importantly, the patient's overall condition. Despite the upgrade of therapeutic procedures, which have significantly contributed to prolonging patient survival, the therapies currently used are still not free from side effects, especially those affecting the oral cavity and craniofacial structures. This is mainly due to the delicate anatomical structure of these structures, which makes them prone to complications [ 19 , 20 ].
To this day, oncological surgery remains the basis for the treatment of many cancers developing in the head and neck area. Surgical procedures often involve extensive resection, including the jawbones, mandible, tongue, throat, and muscle structures of the oral cavity floor [ 21 , 22 ]. The undesirable effects of these procedures may include hard and soft tissue defects, impaired chewing, speech, and swallowing functions, as well as aesthetic disorders. In many cases of undesirable effects, functional and structural restoration is often not possible despite significant advances in microsurgical techniques. In addition, resection of bone structures may also affect the stability and retention of prosthetic restorations, further complicating the dental rehabilitation process.
Another type of therapy, either on its own or as a supplement to another method, is radiotherapy. It involves exposing the affected tissue to ionizing radiation, causing a number of beneficial or undesirable changes. [ 23 ]. The beneficial effects of radiotherapy include, among others: complete cure of cancer or long-term control of its growth, alleviation of symptoms in advanced stages of the disease, such as pain, bleeding, or pressure on important structures of the head and neck [ 24 ]. Complications associated with the use of radiotherapy mainly include xerostomia resulting from damage to the salivary glands, inflammation of the oral mucosa, taste disorders, and increased susceptibility to tooth decay and fungal infections. In addition, osteoradionecrosis may occur in the bone tissue of the skull, which significantly affects bone strength and the possibility of using implants or other forms of fixed prosthetics. Other complications may include impaired wound healing, soft tissue fibrosis, and reduced elasticity of anatomical structures, which hinders both surgical interventions and the fabrication and use of prostheses [ 25 – 27 ].
The most common type of therapy used in combination schemes is chemotherapy. It is a systemic treatment, which can lead to complications in the oral cavity, such as severe mucositis, aphthous ulcers, secondary infections, and hematological disorders that impair the healing process. Chemotherapy often exacerbates the toxic reactions associated with radiotherapy, which increases the incidence of severe complications of the mucosa and deep tissues [ 28 , 29 ]. A new approach to treating cancer patients involves targeted therapies (e.g., EGFR inhibitors such as cetuximab) and immunotherapy (e.g., PD-1 inhibitors), which are an important alternative or supplement to traditional treatment. Despite their targeted mechanism of action, their use is not without complications. The most common complications include mucositis, skin and mucosal changes, and healing disorders [ 30 , 31 ]. Further considerations focus on the consequences of oncological treatment used in head and neck cancers and their impact on oral tissues and the facial part of the skull. Of particular importance here is the impact of surgical resection, radiotherapy, chemotherapy, and targeted therapies on the condition of bones, mucous membranes, and soft tissues, and consequently on the possibilities and limitations of prosthetic rehabilitation. Taking these relationships into account is crucial for proper planning of reconstructive treatment and ensuring safe, functional, and long- term care for patients [ 32 ].
In animal studies, other cytotoxic medications commonly used in oncology, such as cyclophosphamide, methotrexate, anthracyclines, and etoposide, have also been linked to reduced trabecular thickness, decreased bone formation, and impaired growth- plate function. This suggests that multi- agent chemotherapy may cumulatively compromise osseointegration. A number of pharmacological classes, from traditional cytostatics to more recent targeted therapies and some widely used chronic medications, can have a substantial impact on implant outcomes through their effects on bone metabolism, immune response, and microvascular function, according to narrative and systematic reviews on medication-related effects on implants [ 33 , 34 ]. This study aims to identify complications and difficulties in oncology patients undergoing dental implant osseointegration, considering the impact of treatment on the microarchitecture of the craniofacial region, the microbiome, and inflammation in the oral cavity.
The impact of drugs used in cancer therapies on calcium and phosphate metabolism
Calcium and phosphorus are key building blocks of bones. Insufficient calcium can impair maximum bone mass in the diet [ 35 ]. Furthermore, studies have shown that higher dietary calcium intake may be associated with a lower risk of tooth decay in children and adolescents. Cells that sense changes in extracellular calcium and release hormones that regulate calcium levels regulate calcium levels [ 36 ]. The targets of hormones that respond to changes in calcium mobilization, excretion, and uptake are also important in this system. These include three hormones: parathyroid hormone (PTH), 1,25-dihydroxycholecalciferol (1,25(OH)2D), and calcitonin, which are also responsible for phosphate metabolism. 1,25(OH)2D and PTH increase the supply of calcium and phosphorus from the bones to the serum and stimulate bone formation [ 37 ]. In addition, 1,25(OH)2D increases the absorption of calcium and phosphorus from the intestines and reduces their excretion in the kidneys. On the other hand, PTH only reduces calcium excretion but increases phosphate excretion. Calcitonin lowers serum calcium and phosphate levels because it inhibits bone resorption and increases their excretion by the kidneys. Another hormone that affects calcium and phosphorus levels is fibroblast growth factor 23 (FGF23), which inhibits the production of 1,25(OH) 2 D and the reabsorption of phosphates [ 37 ]. Researchers have identified it in some mesenchymal tumors, and osteoblasts and osteocytes are its major producers. Sex hormones such as estrogens and androgens can also influence calcium-phosphate homeostasis [ 36 ]. Estrogens inhibit the stimulating effects of cytokines on osteoclasts, stimulate calcitonin secretion, and reduce the action of PTH. Worth noting is that estrogen deficiency during menopause in women, as well as androgen deficiency in older men, contributes to the development of osteoporosis [ 38 ]. Bone is a special form of connective tissue with a collagen skeleton impregnated with Ca 2 + and PO4 3 − salts [ 36 ]. Osteoblasts are responsible for its formation, while osteoclasts are responsible for its resorption. It is believed that bone is resorbed throughout life and new bone is formed. Calcium in bones is replaced at a rate of 100% per year in infants and 18% in adults. It is estimated that approximately 98% of the 1–2 kg of calcium and 85% of the 1 kg of phosphorus in an adult human body is found in the bones [ 37 ]. Bones perform protective functions, but also provide rigidity and structural support for our bodies. It is suggested that bone mineral abnormalities can lead to cellular dysfunction, structural support disorders, and loss of hematopoietic capacity.
It is believed that certain medications may hurt bone health. Glucocorticoids are most commonly mentioned among them [ 35 ]. They can affect bone tissue through several mechanisms, including: influencing osteoblast function, stimulating bone resorption, impairing calcium absorption and increasing its loss in urine, and influencing androgens and estrogens. The latter mechanism may be associated with glucocorticoid myopathy. In the case of malignant tumors that respond to glucocorticoids (multiple myeloma and other related lymphoproliferative diseases), these drugs have a lytic effect. For this reason, some of the effects they cause may be related to changes in tumor mass [ 37 ]. On the other hand, in these diseases, they may inhibit the secretion and reduce the effectiveness of cytokines secreted by these tumors, which stimulate osteoclastic bone resorption [ 39 ].
Excessive doses of thyroid hormones are also believed to result in bone loss. This may occur in some thyroid cancers. They can be detected in patients with hyperthyroidism.Such patients have a poorer prognosis, which is associated with the increased aggressiveness and invasiveness of these tumors [ 40 ]. Hyperparathyroidism is believed to be a risk factor for thyroid nodule malignancy [ 41 ]. In addition, low calcium levels have been shown to predict the development of non-medullary thyroid cancer in patients with hyperparathyroidism and thyroid nodules.
Patients undergoing transplants and treated with immunosuppressive drugs such as cyclosporine or tacrolimus are also at excessive risk of bone loss [ 37 ]. Cyclosporine is an immunosuppressive drug that has been extensively studied for its inhibition of osteointegration of titanium bone implants The use of cyclosporine impaired bone repair in CSD, and this effect can be partially explained by the suppression [ 42 ]. It is believed to impair bone repair by altering the expression of proteins involved in bone formation and maturation, lowering D3 levels, reducing osteoblast differentiation, and increasing osteoclast activity. It has also been shown that this drug can reduce the resorption of biomaterials after transplantation and impair bone repair in critical defects filled with various osteoconductive bone substitutes. Another study also demonstrated its negative impact on bone healing around dental implants [ 43 ]. Another study showed that cyclosporine A negatively affects the microstructure of bone trabeculae and the healing of bone defects under normal and osteopathic conditions [ 44 ]. This mechanism may be due to its effect on the expression of genes related to interleukin (IL)−1 and IL-6, as well as prostaglandin E2 (PGE2) and tumor necrosis factor alpha (TNF-α), increasing osteoclast activity by facilitating their differentiation [ 45 ]. This may also be related to the suppression of BMP2 and osteocalcin expression [ 46 ]. Interestingly, it has also been shown that cyclosporine A can inhibit the activity of osteoclast calcineurin [ 47 ]. But this does not affect acid transport activity in isolated membrane vesicles or on bone resorption by osteoclasts. However, there are also conflicting reports. Among other things, the bone and periodontal response around submerged dental implants in organ transplant patients did not differ from the control group after one year of cyclosporine use [ 48 ]. Similar results were also obtained in another study [ 49 ]. It has also been noted that the effect of bone remodeling with cyclosporine prevents steroid-induced osteopenia (prednisone) after kidney transplantation [ 50 ]. This drug, with a reduced dose of prednisone, led to temporary stimulation of bone remodeling after six months, which counteracts the harmful effects of steroids on bone formation. It has been shown that folic acid may be one of the methods of preventing bone loss after administration of cyclosporine A [ 51 ]. In a study on rats, it prevented bone loss after administration of cyclosporine A. Another study also showed that administration of transforming growth factor-β (TGF-β) can benefit bone remodeling, thereby reducing the harmful effects of cyclosporine A [ 52 ].
Another drug that affects calcium metabolism is tacrolimus [ 53 ]. This drug is used to prevent and treat transplant rejection. It belongs to the group of calcineurin inhibitors. It has been observed that individuals with higher concentrations of this drug in their blood were more prone to bone loss [ 54 ]. It has also been shown that tacrolimus can cause bone disorders associated with accelerated bone resorption. Another study observed that six months of calcium, vitamin D, and hormone administration in hypogonadism led to bone mineralization regeneration in heart transplant patients treated with tacrolimus [ 55 ]. Interestingly, it has been observed that switching from cyclosporine A to tacrolimus therapy reverses treatment-induced bone loss [ 56 ]. This mechanism is believed to be due to reduced production of IL-1β, IL-6, and TNF-α.
Anthracyclines are also among the drugs that disrupt calcium and phosphate metabolism. These drugs include: Doxorubicin, Epirubicin, Daunorubicin, and Idarubicin [ 57 ]. These are anticancer drugs. Their anticancer effect is associated with the formation of free radicals, lipid peroxidation, direct interaction with the cell membrane, and enzymatic interaction. It was observed in one study in rats that treatment with doxorubicin resulted in reduced radial growth of the femoral shaft, smaller trabecular bone volume, fewer trabeculae, and greater separation between them [ 58 ]. As well, in another study, doxorubicin caused a reduction in the net volume of trabecular bone, decreasing the volume and thickness of osteoid in a rat model [ 59 ]. Similar observations were also made in another study in women with metastatic breast cancer [ 60 ]. Administration of doxorubicin accelerated bone loss. Interestingly, treatment with anti-TGFβ antibody had beneficial effects in these patients. It is worth noting that in one study, the use of doxorubicin monotherapy in the treatment of sarcomas worsened the structure of cortical and trabecular bone [ 61 ]. Importantly, in mice without sarcomas, doxorubicin caused changes only in the cortical bone structure. These results may be significant because sarcomas can also develop in the oral cavity [ 62 ]. The mechanism influencing bone loss is considered to be the effect of doxorubicin on the increase in autophagy via the mitochondrial ROS/TRPML1/TFEB axis in osteoclasts in colon cancer [ 63 ]. Researchers suggest that modulation of the autophagy axis may be one of the therapeutic targets for reducing bone complications after treatment with doxorubicin.
Polytherapy is often used in the treatment of breast cancer. In one study, it was shown that chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide caused a slight increase in bone markers, suggesting early bone loss [ 64 ]. In another study conducted in a population of Chinese women, the treatment regimen of epirubicin + cyclophosphamide-docetaxel and/or trastuzumab reduced bone mineral density (BMD) more than any other treatment regimen analyzed. It has been suggested that vitamin D and calcium supplementation may improve bone turnover markers, bone metabolism indicators, and affect BMD [ 65 ]. Combination therapy with doxorubicin and cyclophosphamide for four cycles resulted in a reduction in trabecular bone volume in the metaphysis, as well as a decrease in serum 25 -hydroxyvitamin D3 and alkaline phosphatase in serum, and a decrease in the density of osteocytes and bone lining cells was observed [ 66 ]. It's interesting that in postmenopausal women with breast cancer treated with tamoxifen, the average bone mineral density of the lumbar spine increased by 0.61% per year. A decrease in serum osteocalcin and alkaline phosphatase levels was also observed [ 67 ]. Similar results were also obtained in another study, in which this drug increased bone density and reduced the number of fractures in postmenopausal women [ 68 ].
Cyclophosphamide is also a drug used to treat breast cancer, but also other cancers such as multiple myeloma and sarcoma [ 69 ]. It belongs to the group of DNA alkylating drugs. This drug has been shown to worsen bone condition during chemotherapy [ 70 ]. In one study on mice, cyclophosphamide caused osteoporosis. This mechanism was due to the drug's inhibitory effect on the Wnt/β-catenin signaling pathway. In addition, it had an inhibitory effect on RANKL-dependent osteoclastogenesis. Researchers have shown that changes in bone formation, but not bone resorption, caused by this drug play a role in bone loss. Another study showed that treatment with cyclophosphamide in early postnatal life in rats can cause permanent changes in the morphology of the mandible, including its size, and a reduction in both its load capacity and stiffness [ 71 ]. It has been shown that the treatment also affects the adaptation of the mandibular bone architecture to body growth, preventing full compensation due to inadequate distribution of resistance material in its cross-section, rather than qualitative impairment of the cortical bone. The effect of cyclophosphamide on bone tissue architecture and morphology was also observed in another study [ 72 ]. This drug reduced the survival/proliferation of growth plates and metaphysical osteoblasts and decreased the height of metaphysical trabecular bone. This was also confirmed in another study, in which the drug induced apoptosis in the proliferative zone of the growth plate, affected the surface of osteoblast cells, and reduced the height of the trabecular bone in the metaphysis [ 72 ].
Cisplatin, used to treat solid tumors and hematological cancers, is a cytostatic drug that can also affect calcium-phosphate balance [ 73 ]. Its molecule contains platinum, which binds to purine bases, causing DNA strands to break, which in turn leads to apoptotic/non-apoptotic cell death.
It has been shown that this drug inhibits bone healing during distraction osteogenesis, causing a reduction in new bone formation in a mouse model [ 74 ]. This was also confirmed in another study, which showed that the action of this drug is directed at osteoblasts that proliferate and differentiate. Its action primarily affected the implant-bone interface [ 75 ]. In contrast, another study found no differences in cisplatin-treated groups in osteoclast activity or delayed secondary bone formation during remodeling [ 76 ].
Another cytostatic agent acting on the skeletal system is etoposide. It belongs to the topoisomerase II inhibitors, acting in the late phases of the S and G2 cell cycle [ 77 ]. One study demonstrated that etoposide inhibited chondrocyte proliferation, damaged osteoblast cell surfaces, and impacted the height of primary and secondary trabecular bone [ 72 ]. Another study also observed the effect of etoposide on bone formation processes. Acting on the bone marrow, it induced apoptosis, leading to a reduction in bone tissue volume, including a decrease in bone volume, trabecular thickness, and cortical bone volume [ 78 ].
Methotrexate, which belongs to folic acid antagonists, may also affect bone metabolism [ 78 ]. One study showed that it reduced trabecular bone volume by 26.9% and bone formation rate by almost 60%, and reduced osteoid volume and thickness [ 79 ]. However, there are conflicting reports on the effect of methotrexate on the skeletal system. In most studies involving populations treated with methotrexate, no effect on the skeletal system or bone tissue was observed [ 80 – 82 ].
2. The impact of cancer therapy on the oral microbiome
The bacterial flora found in the oral cavity is also known as the oral microbiome [ 83 , 84 ]. It is part of the oral ecosystem. This also includes saliva and micro-niches in the oral cavity with various anatomical structures. The oral microbiome contains a large number of diverse groups of organisms such as viruses, bacteria, archaea, fungi, and protozoa. Such bacterial flora can be suspended in the liquid secretion that is saliva (organisms in the planktonic phase) or attached to the surface of the oral cavity in the form of dental plaque. In addition to these locations, it is also found in the gingival sulcus, on the tongue, cheeks, and hard and soft palate. However, sometimes the balance of microflora is disturbed as a result of current or past illnesses. Severe illness can cause irreversible changes. Medications taken to cure the illness often disrupt the homeostasis of beneficial microorganisms. People with cancer usually have to undergo chemotherapy or radiotherapy. Such treatments harm the condition and functioning of the oral microbiome. The introduction of foreign bodies into the oral cavity also causes damage and adverse changes in the composition of the bacterial flora.
Cancer therapy, which includes radiotherapy and chemotherapy, often leads to inflammation of the oral mucosa (Fig. 1 ) [ 85 , 86 ]. This results in the appearance of many complex mucosal and submucosal changes. This has a significant impact on the further course of therapy. An example of this is ulcerative mucositis. This condition leads to a delay or interruption in cancer therapy and, as a consequence, to a deterioration in the patient's well-being. In addition, a secondary infection may already occur in the existing ulceration associated with mucosal inflammation. This phenomenon increases the occurrence of polybacteriosis, where streptococci play an important role. The development of ulcerative mucositis leads to an immediate increase in bacterial flora. This is a factor that influences the duration and severity of the inflammation [ 87 ]. This is because such organisms produce compounds in their cell walls that penetrate the submucosal membranes to stimulate inflammatory cells, macrophages, pro-inflammatory cytokines, and other mediators of tissue damage. In addition, the products formed from the cell walls of these organisms penetrate and accelerate innate immunity. This leads to the development and prolongation of mucosal inflammation. Oral hygiene is essential for combating inflammatory processes in this area [ 88 ]. In addition, thoughtful oral hygiene measures protect against systemic sepsis caused by oral pathogens. The guidelines recommended by MASCC/ISOO propose the use of a standardized oral care protocol. This is to prevent the occurrence of oral mucositis in all types of cancer treatment. Fig. 1 The impact of cancer therapy on the oral microbiome
The cancer treatment regimen plays an important role in the incidence and severity of oral mucositis [ 87 ]. Important factors in chemotherapy are the type of drug used, its dose, and its duration. In the case of radiotherapy, the following factors play a significant role: total radiation dose, fractionation regimen, volume of irradiated mucosa, and concurrent chemotherapy. Chemotherapy leads to oral complications such as mucosal inflammation [ 89 ]. Its cytotoxic effect on the rapidly dividing epithelium of the oral cavity contributes to the development and exacerbation of damage in this area. Cancer drugs have various mechanisms that can impair DNA replication and repair, inhibit the cell cycle, damage DNA, and lead to cell death. These mechanisms are responsible for their cytotoxic effects.
Examples of such drugs include methotrexate, doxorubicin, and 5-fluorouracil. These cytotoxic drugs have a direct toxic effect on rapidly dividing cells in the oral mucosa [ 90 , 91 ]. This effect leads to inflammation and damage to the epithelium. In such a situation, the already damaged epithelium of the oral mucosa may become infected. This is because local defense mechanisms are impaired. Changes in the flow rate and composition of saliva, one of the most important defense mechanisms in the oral cavity, are also visible. In addition, many chemotherapy regimens cause myelosuppression and/or immunosuppression during cancer treatment. Patients are then more susceptible to viral, bacterial, or fungal infections, which are treated with antibiotics and antifungal drugs.
In one study, patients were treated with a regimen consisting of two or more drugs such as doxorubicin, 5-fluorouracil, methotrexate, cyclophosphamide, cisplatin, bleomycin, and paclitaxel [ 92 ]. The combination of cyclophosphamide and doxorubicin showed the highest risk of mucositis. However, doxorubicin, methotrexate, 5-fluorouracil, and bleomycin were found to be cytostatic drugs that frequently cause oral mucositis.
The presence of bacterial flora in the oral cavity interacts with the mucosal tissues, leading to changes in the action of the cytostatic drug. In addition, this drug also affects the oral microbiome. An adverse change in the bacterial flora is possible in the form of impairment of various components involved in maintaining its commensal state [ 89 ]. Inflammation of the oral mucosa caused by a cytostatic drug led to changes in the microbiome. The number of common commensals associated with health decreased significantly. These included bacteria of the genera Streptococcus spp. , Actinomyces spp. , Gemella spp. , Granulicatella spp., and Veillonella spp. On the other hand, there was an increase in the number of Gram-negative bacteria – Fusobacterium nucleatum a nd Prevotella oris.
Chemotherapy and radiotherapy are also likely to impede saliva flow [ 93 ]. Saliva is an important basic defense mechanism in the oral cavity. Modification of its composition may reduce the body's defense against external pathogens. In addition, it has been noted that chemotherapy reduces the diversity of α bacteria in saliva. The diversity of β bacteria in saliva is also affected. Only the fungi present in saliva remain unchanged [ 89 ]. In addition, there is a slight increase in the number of Gram-negative bacteria such as Prevotella spp., Selenomonas spp., Leptotrichia spp., Tannerella spp., Campylobacter spp., Capnocytophaga spp., and Parvimonas spp. The severity of oral mucosal inflammation also affects the composition of saliva. Myelosuppression associated with chemotherapy leads to impaired neutrophil availability in the oral cavity. This results in a more favorable environment for harmful oral microorganisms. Other commonly known methods of treatment with antibiotics during chemotherapy also affect the oral bacterial flora. In addition, cytostatic drugs have antimicrobial effects, which significantly contribute to changes in the microbiome during treatment. Bacteria found in the oral mucosa may be sensitive or resistant to certain cytostatic drugs, such as 5-fluorouracil [ 94 ]. Bacteria that are highly resistant to 5-fluorouracil include Klebsiella oxytoca , Streptococcus salivarius , Streptococcus mitis, Streptococcus oralis, Pseudomonas aeruginosa, and Lactobacillus salivarius . Bacteria such as Lactobacillus oris, Lactobacillus plantarum, Streptococcus pyogenes, Fusobacterium nucleatum, and Neisseria mucosa showed a significant reduction in their viability and, above all, a significant reduction in growth under the influence of low doses of 5-fluorouracil.
Dysbiosis of the oral microbiota is often associated with inflammation of the oral mucosa [ 89 , 95 ]. The severity of this inflammation correlates positively with the enrichment of saliva with bacteria such as Fusobacterium nucleatum, Clostridiales , and Treponema maltophilum. As a result of the intensification of mucosal inflammation, a reduction in the amount of oral bacterial flora by 24 species of salivary bacteria has also been observed, some of which are essential for oral health. These include Streptococcus spp., Actinomyces spp., Gemella spp., Granulicatella spp., Veillonella spp.These observations led to the conclusion that oral mucosal inflammation is associated with the depletion of common commensals that play an important role in human health and an increase in the number of Gram-negative species. Such dysbiotic changes are also similar in gingivitis and periodontitis.
Studies have been conducted suggesting that dysbiosis caused by chemotherapy may affect epithelial responses, which is important in the course of oral mucosal inflammation modification [ 89 ]. In this experiment, the potential of dysbiotic changes in the microbiota, which were related to the severity of mucosal inflammation, to influence epithelial reactions was analyzed. The oral epithelium was exposed to the symbiotic bacterium S. salivarius. This microorganism disappears during oral mucosal inflammation. As a result, there was minimal induction of innate immune response genes. The same experiment was also conducted with the potential pathobiont F. nucleatum subsp. Vincentii, which is associated with severe mucosal inflammation. This resulted in a dramatic increase in the expression of TNF, IL17C, CCL20, CXCL2, and, above all, PMAIP1, which led to the demonstration of cell death in the apical layer by tissues.
The use of removable dentures also contributes to the development of inflammation of the oral mucosa [ 96 , 97 ]. Contact between dentures and oral tissues often causes mechanical injuries, which exacerbate the damage to the epithelium caused by cytostatic drugs. Dentures are also one of the factors responsible for the development of commensals in the oral cavity. This leads to further damage to the mucosa.
Neutropenia resulting from chemotherapy causes modifications in the bacterial and fungal flora in the oral cavity. Opportunistic colonization may also occur, which has an infectious effect in a local or distant site [ 98 ]. This relationship leads to impairment of the physical barrier function of the oral mucosa and the digestive system, which promotes systemic infection, shock, and sepsis. The oral microbiome is responsible for the development of sepsis in patients with neutropenic cancer. In addition, green streptococci have been found in isolated blood cultures from these individuals. Bacteria such as Streptococcus spp., Staphylococcus spp., Enterobacter spp., and Klebsiella spp. are often found in patients undergoing chemotherapy [ 99 ]. A study was conducted among an outpatient population to determine the species of bacteria present in the oral cavity before and after cancer chemotherapy. A total of 435 clones of the 16S rRNA gene from samples taken before and after chemotherapy from all study participants were analyzed. Forty-one different bacterial species were detected, 36 of which had not previously been observed in patients treated with anticancer drugs. The dominant bacteria here were Gemella spp. and Streptococcus spp.. Microorganisms that were only observed after chemotherapy are bacteria from the Lachnospiraccae family.
Another important infection associated with the human oral cavity is candidiasis, which can result from existing mucosal inflammation or neutropenia. Candidiasis is mainly caused by fungi of the genus Candida spp. They can form commensal relationships with bacteria, which promotes their colonization on the surface of the oral cavity and dental prostheses [ 100 ]. This leads to the development of local dysbiosis. The result of this action may be the creation of a habitat for pathogens that is dangerous to health. Cytostatic drugs used in the treatment of leukemia contribute to the development of oral mucositis and, above all, to a reduction in the number of bacteria in this organ. This, in turn, leads to the emergence of a dominant species of bacteria, which may also be associated with yeast colonization and oral mucositis. The most common species is Candida albicans . During histopathological examinations of oral epithelial dysplasia associated with malignant transformation, it was shown that the occurrence of candidiasis is associated with inflammation [ 101 ]. Antifungal drugs are commonly used to combat candidiasis, a side effect of cytostatic drugs. Candidiasis contributes to significant pain in the oral cavity and difficulty eating. Sometimes, the fungal infection can spread throughout the body, leading to a life-threatening condition for the patient [ 102 ]. In addition, in patients undergoing chemotherapy for cancer, it has been found that the use of drugs that are absorbed or partially absorbed from the gastrointestinal tract leads to a reduction in the incidence of oral candidiasis. These drugs have also been shown to be more effective in combating candidiasis than drugs that are not absorbed from the gastrointestinal tract.
In summary, cancer therapy hurts the bacterial flora of the oral cavity. This is because this organ undergoes many changes during intensive oncological chemotherapy. Oral mucositis, which is a common complication of cytostatic drugs, greatly promotes the growth of pathogens. By reducing the level of beneficial bacteria, there is an increase in microorganisms that exacerbate inflammation in the oral cavity. Well-chosen dental treatment during chemotherapy can prevent adverse changes in the oral cavity. Controlling bacterial dysbiosis can help prevent inflammation of the mucous membrane of this organ.
3. Inflammation of the oral cavity as a barrier to prosthetic treatment
Inflammatory problems of the mucous membrane (e.g., inflammation directly related to dentures, contact dermatitis, xerostomia with secondary inflammation, chronic ulcers) are very common in wearers of plate and removable dentures (Fig. 2 ). The most common form of inflammation associated with prosthetic treatment is denture stomatitis (DS). DS is a complex multifactorial process with diverse etiology; according to the literature, it may account for 15% to 70% of cases of inflammation in patients treated with plate and removable dentures. The main damaging factors in this case are mechanical injuries and the often co-occurring phenomenon of biofilm formation by Candida albicans [ 103 , 104 ]. Fig. 2 Dentures and inflammation of oral mucosa
In the case of inflammatory processes developing in the oral cavity, the oral epithelium constitutes the front line and the basis of the microenvironment of this process. The inflammatory process begins when the pathogen Candida spp. (both yeast and hyphal forms) adheres to the surface of the oral cavity, including the surface of dentures and epithelial cells, using proteins from the adhesin family (e.g., Als3, Hwp1) [ 105 ]. Subsequently, oral epithelial cells and local immune cells that express toll-like receptors (including TLR2, TLR4), C-type lectin receptors, and other pattern recognition receptors (PRRs) bind β-glucan, mannan, and other components of the C. albicans cell wall [ 106 ]. Activation of these receptors triggers two parallel cascades: the first leads to the activation of the transcription factor NF-κB, which triggers the expression of pro-inflammatory genes in the cell nucleus, and the second, in which a signal from the adaptor protein MyD88 activates the MAPK kinases p38, JNK, and ERK, causing the expression of proinflammatory genes and genes encoding adhesion molecules [ 107 , 108 ]. The measurable effect is the transcription of major proinflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), which intensify the inflammatory process. In addition, the hyphal forms of C. albicans can produce the peptide candidaisin, which causes pores to form in the epithelium [ 109 ]. In inflammatory conditions, the influx of calcium ions through the pores damages the mucous membrane and causes a strong release of inflammatory mediators [ 110 ]. This is a feature that distinguishes pathogenic inflammation from inflammation as a compensatory mechanism in response to a damaging stimulus.
An important component of the inflammatory response are the cells that form the microenvironment of inflammation. When inflammation is induced in the oral cavity, neutrophils are among the first inflammatory cells to arrive at the site. Neutrophils are activated by interleukin IL-8 (CXCL8), which, as one of the strongest chemotactic factors, recruits and attracts neutrophils and other immune cells to the site of inflammation. Once they reach the oral cavity, neutrophils begin to eliminate the pathogen through phagocytosis, the production of reactive oxygen species (ROS), and the formation of extracellular neutrophil networks (NETs) [ 111 ]. When the biofilm formed by microorganisms persists for a long time and chronic irritation of the oral mucosa occurs, neutrophils remain in a state of prolonged activation—they produce chemotactic factors, perform phagocytosis, and produce ROS in excess. These processes cause damage to the epithelium and matrix, contributing to the chronicity of the inflammatory process. In addition to neutrophils, macrophages play an important role in the inflammatory process. These cells are divided into two subpopulations: M1 and M2. M1 macrophages are responsible for enhancing the inflammatory response through the production and secretion of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 [ 112 , 113 ]. The change in macrophage phenotype to M2 is important for suppressing the inflammatory response. Certain factors, including advanced age and metabolic diseases, can interfere with the change in macrophage phenotype, causing inflammation under the prosthesis to persist.
As mentioned earlier, C. albicans can form biofilms on denture materials (acrylics, PMMA) and interact with bacteria found in the oral cavity (e.g., Streptococcus spp., Staphylococcus spp.). https://www.mdpi.com/2073-4360/14/5/908 Interactions between these microorganisms facilitate biofilm stabilization, increase hyphae adhesion, and modify the host response against pathogens. The co-created biofilm is more resistant to pharmacotherapy and neutralization by the immune system than individual microorganisms. Additionally, an important aspect in the context of C. albicans infections is the production of interleukin IL-17 by γδ T lymphocytes, ILC3, and memory cells. [ 114 , 115 ]. IL-17 stimulates the epithelium to produce defensins and chemokines that attract neutrophils. However, excessive or chronic activation of IL-17 may contribute to the perpetuation of inflammation and damage to the oral mucosa [ 116 ]. In the inflammatory process in the oral cavity, there may also be a delay in the regeneration of damaged tissues. Epithelial cells and fibroblasts, stimulated by chemotactic factors such as IL-1β and TNF-α, increase the expression of metalloproteinases (e.g., MMP-9), which causes degradation of collagen and other ECM components, weakening of epithelial adhesion, and delayed healing of damaged tissues [ 117 ].
As mentioned earlier, neutrophil activity in the inflammatory process is associated with the production of reactive oxygen species (ROS). After detecting a pathogen and inducing the recruitment and influx of neutrophils to the site of inflammation, neutrophils activate NADPH oxidase (mainly the NOX2 complex). NOX2 generates superoxide (O₂•⁻) in the phagosome or at the cell membrane, which increases the rate of ROS production and oxidative stress [ 118 ]. An additional stimulus inducing oxidative stress is the formation of extracellular neutrophil networks, as this process requires ROS expenditure and also causes the release of strong oxidants (e.g., HOCI), which exacerbates the oxidative damage caused by the inflammatory process in the oral cavity. In addition to neutrophils, macrophages can use similar mechanisms (NADPH oxidase), and the mitochondria of these cells can also generate ROS in response to inflammatory signals [ 119 ]. The predominance of the M1 (pro-inflammatory) phenotype is associated with increased ROS production. Pathogens that cause inflammation can also be a source of oxidative stress in themselves. In mucosal infections, Candida albicans not only adheres to the prosthesis, but in the hyphal stage produces the peptide candidalysin, which damages the epithelial membrane, causes Ca 2 ⁺ influx, mitochondrial stress, and directly increases ROS production in host cells, causing mitochondrial dysfunction [ 120 ].
As is well known, all of the above mechanisms have a negative impact on the implications of prosthetic treatment in patients prone to inflammation. First and foremost, the presence of inflammation is associated with pain and hypersensitivity in the oral cavity. Both of these factors can prevent reliable impression taking and denture fitting tests, resulting in the patient being unable to tolerate attempts to correctly position the denture. Disorders of oral mucosal healing after procedures (e.g., implants, surgical procedures) are also important. High levels of pro-inflammatory cytokines, the presence of ROS, and MMP activity disrupt proliferation and remodeling processes, increasing the risk of integration failure [ 121 ]. In patients prone to inflammation, dentures themselves can also cause reinfection. The formation of biofilm on or under the surface of the prosthesis causes rapid recurrence of the inflammatory response even after local therapy and makes it difficult to control the response [ 122 ]. In addition, inflammation can cause atrophy and morphological changes in the oral cavity, which affects the structural changes in the supporting tissues and the stability of the prosthesis in the oral cavity [ 123 ].
Chemotherapy is one of the basic methods of cancer treatment, used to eliminate cancer cells. However, despite its effectiveness, it is associated with numerous complications, one of the most common of which is inflammation of the oral mucosa (Latin: mucositis) [ 124 ]. Oral mucositis manifests itself as redness, swelling, and then ulceration. These changes significantly impair basic oral functions such as speaking, swallowing saliva, and eating. The severity of the changes is greatest approximately 7–10 days after chemotherapy. During this period, the redness turns into ulceration, causing the patient to experience severe pain and discomfort, which requires pain relief in the form of opioids and dietary modifications. After this period, the inflammation of the mucous membrane gradually subsides within 2–3 weeks after the administration of the chemotherapeutic agent, leaving no scars.
The following describes how chemotherapy drugs cause inflammation of the oral mucosa. Chemotherapy leads to direct damage to epithelial cells [ 89 ]. Oral epithelial cells are among the fastest-dividing cells in the body, which makes them sensitive to the toxic effects of cytotoxic drugs. Chemotherapy drugs inhibit DNA replication, leading to cell damage and disruption of the regeneration process.As a result, the epithelium deteriorates and ulcers form, which can lead to bacterial and fungal infections [ 125 ]. Damage to epithelial cells leads to the release of inflammatory mediators—cytokines (TNF-α, IL-1β, IL-6)—which induce an inflammatory response in the oral mucosa [ 126 ]. This results in increased permeability of blood vessel walls, which promotes the accumulation of inflammatory cells such as neutrophils and macrophages. In addition, inflammatory mediators stimulate apoptosis, leading to further damage to the epithelium and worsening of mucosal lesions [ 127 ].
Chemotherapy also induces oxidative stress, which plays a key role in damaging the cells of the oral mucosa. Chemotherapy drugs cause the formation of reactive oxygen species (ROS), which damage cell membranes, proteins, and DNA, leading to further tissue damage [ 128 ]. Oxidative stress also promotes inflammatory processes and delays the regeneration of damaged cells. Epidermal growth factor (EGF) regulates the proliferation, growth, and migration of epithelial cells, supporting mucosal regeneration and wound healing [ 129 ]. Its deficiency in saliva is associated with a more severe course of oral mucositis. Transforming growth factor beta (TGF-β), on the other hand, has an antiproliferative effect – it inhibits epithelial cell division, which may reduce inflammation. Dysregulation of these factors during chemotherapy delays regenerative processes and exacerbates mucosal damage.
Inflammation of the oral mucosa is primarily a complication of cancer treatment, but its chronic form creates conditions conducive to secondary carcinogenesis.
4. Difficulties in osseointegration of implants in oncology patients
Implant-supported prosthetic rehabilitation greatly improves mastication, speech and general quality of life in patients after head and neck cancer therapy, but it is consistently linked with a greater incidence of biological and technical difficulties than in non-oncologic populations. Large clinical series and systematic studies on implant survival in this group reveal overall survival rates in the range of about 80- 90%, but with markedly higher failure rates in irradiated jaws, grafted bone parts and in patients treated to combination chemoradiotherapy. Tens of thousands of implants were included in recent umbrella and systematic reviews that revealed survival rates of 81- 86% in irradiated bone compared to 90- 95% in non-irradiated bone. The relative risk of failure in irradiated patients was approximately 1.6- 2.0, and there was an additional increase in risk when radiotherapy was combined with chemotherapy or when implants were placed in grafted rather than native bone. These poor prognostic indicators translate into an increased likelihood of peri- implant mucositis and peri-implantitis, soft- tissue ulcerations, marginal bone loss, partial loss of osseointegration and, in severe situations, osteoradionecrosis or medication-related osteonecrosis of the jaws [ 130 – 133 ]. Soft-tissue issues comprise another big group of post-implantation disorders. Prosthetic components can easily traumatize scarred, fibrotic, and thinned mucosa following surgery and radiation therapy. This can cause chronic ulcerations, mucosal hyperplasia, prosthesis-related stomatitis, and recurrent dehiscence of the soft tissues covering cover screws or implant shoulders. These lesions are sometimes aggravated by ill-fitting transitional prosthesis, by diminished salivary lubrication and by Candida- rich biofilms that develop under detachable dentures. Because persistent inflammation and microbial load at the time of surgery compromise wound stability and promote early peri- implant mucositis, chronic denture stomatitis or mucosal micro- trauma in the planned implant region should be considered a relevant risk factor for early failure [ 132 ]. Osteoradionecrosis or medication-related osteonecrosis of the jaws are additional post-implantation problems that may occur in patients receiving antiresorptive or antiangiogenic medications and exposed to high cumulative radiation exposures, especially to the mandible. In these instances, implant surgery and subsequent prosthetic loading act as additional local triggers on already hypovascular, hypocellular bone. Implant insertion in high-risk fields must be preceded by careful risk assessment, trauma should be minimized, and long-term follow-up should concentrate on early indicators of bone exposure, suppuration, or non-healing extraction/implant sites, according to recent reviews and guidelines[ 134 , 135 ].
From a biological standpoint, post-implantation problems in cancer patients are driven by a locally changed tissue environment and by systemic therapeutic effects. Radiotherapy generates chronic endarteritis, hypocellularity and fibrosis in bone and soft tissues, which impede remodelling and vascular supply around implants and make peri-implant tissues more prone to plaque-induced inflammation. Chemotherapy and targeted drugs, in turn, cause persistent dysbiosis, xerostomia and mucosal fragility, which exacerbate biofilm deposition on prosthetic components and raise the risk of peri-implant mucositis and peri-implantitis even with comparably small plaque loads. Clinical studies involving head and neck cancer patients consistently demonstrate that implant failures and marginal bone loss are concentrated in irradiated, grafted, or flap- reconstructed areas, while implants positioned in non-irradiated native mandibles display survival rates comparable to those found in typical implant populations [ 132 , 136 ]. Difficulties in osseointegration in oncology patients arise not only from bone- related factors, but also from the condition of the overlying mucosa. Aphthous- like ulcerations, pseudomembranous candidiasis (thrush) and erosive lesions are extremely common during and shortly after chemoradiotherapy for head and neck malignancies, as part of the oral mucositis spectrum. The affected mucosa is erythematous, edematous and ulcerated, with impaired barrier function and markedly reduced mechanical resistance. Under these conditions, flap elevation and suturing for implant placement are associated with a higher risk of wound dehiscence, secondary infection and exposure of implant components [ 132 , 137 ].
Chronic inflammation at the proposed implant site also interferes with the molecular mechanisms essential for stable bone- implant interaction. RANKL- mediated osteoclastogenesis is driven and osteoblast differentiation is suppressed by pro- inflammatory cytokines such TNF-Bα, IL- 1β, and IL- 6 that are generated in response to prolonged mucosal damage, biofilms dominated by Candida, or plaque retention surrounding temporary prostheses. In irradiated or transplanted bone, when vascularity and cellularity are already damaged, this shift towards bone resorption translates into increased marginal bone loss and a higher chance of early or late loss of osseointegration. Radiation therapy almost doubles the probability of implant failure when compared to non-irradiated bone, according to meta-analyses on implant survival in irradiated jaws. This effect is especially noticeable when implants are inserted into irradiated bone grafts or free flaps [ 133 , 138 , 139 ].
Beyond the inflammatory microenvironment, systemic cytostatic therapy exerts direct negative effects on osseointegration. A number of chemotherapeutic agents have been shown in experimental models to alter bone remodelling dynamics, reduce trabecular bone volume and impair mechanical properties at the bone- implant interface. Among these drugs, cisplatin a key component of many chemoradiation protocols for head and neck cancer has been investigated most thoroughly. In a rat tibia model, Al-Mahalawy et al. demonstrated that cisplatin-treated animals exhibited significantly reduced removal torque values, lower bone–implant contact and a more disorganised trabecular pattern around titanium implants compared with controls, indicating delayed and quantitatively impaired osseointegration [ 140 , 141 ].
5. Types of prosthetic restorations in oncology patients
The selection of prosthetic restoration in oncology patients is dictated by the defect's location and severity, the nature of oncological treatment (surgery, radiotherapy, chemotherapy, targeted therapy), the status of the remaining dentition, and the quality and volume of residual bone and soft tissues. In modern practice, prosthetic rehabilitation is organized as a key part of the oncologic treatment plan, with surgeons, oncologists, and prosthodontists working closely together. For edentulous or partially edentulous jaws without major continuity defects, conventional complete or partial removable dentures remain a basic and widely used option. Their main advantages are reversibility, relatively low biological cost, and the possibility of easy modification if tumour surveillance or further surgery is required [ 142 , 143 ]. Conventional complete or partial removable dentures are still a common and basic option for edentulous or partially edentulous jaws without significant continuity issues. Reversibility, minimal biological cost, relatively cheap maintenance, and the potential for simple adjustment when tumor surveillance, re-biopsy, or re-resection are needed are some of its benefits. During the healing process following radiation therapy or ablative surgery, conventional prostheses are also commonly utilized as temporary restorations. However, research shows that removable prostheses in irradiated mucosa are linked to an increased risk of traumatic lesions that could cause osteoradionecrosis, particularly in the mandible, as well as a higher frequency of mucosal ulcerations and denture stomatitis caused by Candida [ 142 , 143 ].
Obturator prostheses, face prostheses, and implant-retained maxillofacial prostheses are commonly utilized in patients with segmental mandibulectomy, maxillectomy, or composite abnormalities involving bone and soft tissue. For rehabilitation following a partial or complete maxillectomy, maxillary obturators continue to be the gold standard. They greatly improve swallowing and speech intelligibility by reestablishing the space between the nasal and oral chambers. According to clinical research, obturators can significantly lessen nasal regurgitation and restore up to 70- 90% of preoperative speech intelligibility. However, the amount of hard palate that remains, the presence of undercuts for retention, and mucosal tolerance after radiation therapy all have a significant impact on their performance. Two significant long-term issues are poor retention and widespread soft-tissue scarring [ 144 , 145 ].
Implant-supported obturators greatly enhance patient outcomes when anatomical abnormalities limit stability or retention. Adding osseointegrated implants to support obturators improves masticatory efficiency, decreases speech nasality, and increases retention, according to randomized and cohort studies. Even in patients who have had radiation, implant-supported obturators greatly enhance quality of life as compared to traditional obturators as long as implant integration is stable [ 146 , 147 ].
Osteointegrated implants inserted in non-irradiated craniofacial bone, such as the temporal bone, zygoma, or frontal bone, are frequently used to preserve extra-oral craniofacial prostheses (orbital, nasal, and auricular) in extensive composite deficits. In these areas, titanium fittings have outstanding survival rates (> 95%) unless the radiation dose surpasses 55–60 Gy. According to reports, 87–100% of implant-retained auricular prosthesis survived, with radiation or skin deterioration surrounding abutments being the most frequent causes of failure [ 148 , 149 ].
Implant-supported fixed prostheses and implant-supported overdentures are the most practical options for oral rehabilitation when bone has been maintained or rebuilt. In cancer survivors, implant overdentures, particularly mandibular two-implant overdentures, significantly improve masticatory function and patient satisfaction. According to clinical research, chewing comfort significantly improves and masticatory function rises by 20–300% when compared to traditional dentures. Depending on the radiation dose, the timing of insertion (primary vs. delayed), and the quality of the local bone, the survival rate of implants supporting overdentures in irradiated jaws varies from 75 to 90% [ 150 , 151 ]. Microvascular free flap grafts (e.g., fibula, scapula, DCIA) are commonly used in patients undergoing major oncologic resections. Even after significant bone loss, these flaps allow for implant implantation and permanent repair. However, flap-related variables have a significant impact on results: different flap types have different bone density, cortical thickness, vascularity, and flap volume. According to meta-analyses, scapula flaps and fibula flaps had the best implant survival rates, while iliac crest flaps have more problems with resorption and soft-tissue instability [ 152 , 153 ].
Digitally designed immediate or early implant placement during oncologic resection surgery is a new category (primary implant placement). This approach seeks to shorten the rehabilitation period and enhance implant alignment with prosthetic requirements. Although early clinical reports indicate encouraging results, implant failure rates are still greater than in delayed protocols because to flap remodeling, radiation effects, and worse wound healing [ 154 , 155 ].
Lastly, modified removable prostheses, soft-liner prostheses, or magnet-retained hybrid prostheses may be used to distribute forces more evenly and lessen trauma in patients for whom implants are contraindicated (e.g., high radiation dose fields, uncontrolled osteonecrosis risk, severe mucosal atrophy). Although these treatments are less physiologically intrusive, careful monitoring is necessary to avoid mucosal deterioration.
6. Post-implantation complications
Because oncological therapy causes significant structural and functional changes in oral tissues, post-implantation problems in cancer patients provide a significant clinical challenge. Local effects, such as radiation-induced vascular impairment, mucosal atrophy, dysbiosis, reduced epithelium turnover, and systemic metabolic disruptions that impede immunological and bone remodeling, combine to cause these problems (Fig. 3 .). When combined, these elements considerably impair peri-implant tissue homeostasis, which lowers implant survival and raises the risk of peri-implant disease [ 156 – 158 ]. Fig. 3 The overall impact of anticancer therapy on oral and craniofacial structures
Jawbone degeneration is a core hard-tissue problem caused by decreasing mineral density, diminished vascularity, and impaired bone turnover. Radiation therapy causes fibrosis, hypocellularity, and chronic endarteritis in the mandibular and maxillary bone, which significantly reduces regeneration potential and increases the risk of early marginal bone loss and impaired osseointegration (Table 1 ). Clinical studies suggest that compared to non-irradiated bone, irradiated jaws exhibit significantly greater rates of peri-implant radiolucency and early failure. Moreover, systemic disorders like calcium insufficiency, which is frequently seen in cancer patients receiving rigorous treatment, worsen demineralization and have a detrimental impact on bone quality and peri-implant stability [ 158 , 159 ]. Table 1 Comparison of major post-implantation complications in oncology patients Type of complication Pathophysiological mechanism Clinical consequences Prevalence Source Jawbone deterioration Radiation-induced hypoxia, fibrosis; Ca/P imbalance; impaired osteoblast function Marginal bone loss, implant failure, osteoradionecrosis High in irradiated jaws [ 156 , 158 , 158 , 159 ] Peri-implant mucositis/peri-implantitis Dysbiosis, xerostomia, impaired immunity Soft-tissue inflammation, bone loss, implant failure 20–40% in irradiated jaws [ 158 , 159 ]; Radiation-induced dental caries Reduced salivary flow, acidic pH, loss of remineralisation Rapid decay, fractures, prosthetic destabilisation Very high > 50 Gy [ 157 ] Gum disease (gingivitis, periodontitis) Impaired neutrophils, anaerobic dysbiosis, chronic inflammation Periodontal pockets, attachment loss, implant loss High with xerostomia [ 158 ] Delayed/incomplete osseointegration Hypovascularity, impaired remodeling, oxidative stress Delayed healing, mobility, failed osseointegration Moderate–high, dose-dependent [ 156 , 159 ]
Table 1
Comparison of major post-implantation complications in oncology patients
| Type of complication | Pathophysiological mechanism | Clinical consequences | Prevalence | Source |
| Jawbone deterioration | Radiation-induced hypoxia, fibrosis; Ca/P imbalance; impaired osteoblast function | Marginal bone loss, implant failure, osteoradionecrosis | High in irradiated jaws | [ 156 , 158 , 158 , 159 ] |
| Peri-implant mucositis/peri-implantitis | Dysbiosis, xerostomia, impaired immunity | Soft-tissue inflammation, bone loss, implant failure | 20–40% in irradiated jaws | [ 158 , 159 ]; |
| Radiation-induced dental caries | Reduced salivary flow, acidic pH, loss of remineralisation | Rapid decay, fractures, prosthetic destabilisation | Very high > 50 Gy | [ 157 ] |
| Gum disease (gingivitis, periodontitis) | Impaired neutrophils, anaerobic dysbiosis, chronic inflammation | Periodontal pockets, attachment loss, implant loss | High with xerostomia | [ 158 ] |
| Delayed/incomplete osseointegration | Hypovascularity, impaired remodeling, oxidative stress | Delayed healing, mobility, failed osseointegration | Moderate–high, dose-dependent | [ 156 , 159 ] |
In addition to bone degradation, cancer patients frequently experience biological soft-tissue problems. Xerostomia and mucosal atrophy brought on by radiation therapy impair salivary buffering, reduce lubrication, and increase plaque retention. Chemotherapy also impairs neutrophil-mediated innate immunity and epithelial regeneration, allowing Candida biofilms and periopathogenic species to colonize. Peri-implant mucositis and its irreversible counterpart, peri-implantitis, are more common among cancer survivors than in healthy populations due to this environment. The frequency of peri-implantitis in irradiated jaws is routinely reported in the literature to be between 20 and 40 percent, with faster marginal bone loss and a higher risk of implant exposure. Radiation-induced tooth decay is another long-term issue that affects individuals with or without implants. Because of the loss of salivary gland function, acidic changes in oral pH, and the loss of remineralization capacity, radiation caries advances quickly. Decayed natural teeth next to implants serve as reservoirs for anaerobic pathogens, Lactobacillus species, and Streptococcus mutans in patients who are partially edentulous. This increases the peri-implant microbial load and destabilizes prosthetic occlusion. The biomechanics of implant-supported restorations may be jeopardized by tooth loss brought on by caries [ 158 , 160 ].
Gum disease, which includes gingivitis and periodontitis, is another significant inflammatory complication that is a good predictor of peri-implant pathology. By decreasing keratinized mucosa thickness, changing the composition of biofilms, and limiting neutrophil activity, cancer treatments increase the risk of periodontal disease. Research shows that cancer patients had deeper periodontal pockets, more bleeding when probed, and higher expression of inflammatory cytokines, all of which work in concert with radiation-induced dysbiosis to hasten the loss of peri-implant attachment [ 158 ].
Conclusion
This article focuses on the multidimensional impact of cancer treatment, with particular emphasis on the implications for prosthetic treatment and oncological risk. Cancer treatment leads to permanent biological changes in the bones, including disturbances in calcium and phosphate metabolism and impaired bone remodeling. In addition, increased susceptibility to inflammation, microbiome dysbiosis, and reduced healing capacity are observed in oncology patients. These processes result in significant limitations in prosthetic rehabilitation, including an increased risk of implant failure, inflammatory complications, and osteonecrosis. It is worth emphasizing that due to the complexity of the processes occurring in the oral cavity of oncology patients, prosthetic treatment planning should be interdisciplinary, involving an oncologist, surgeon, prosthodontist, and conservative dentist.
Key References
Fan, S.; Diaz, L.; Sáenz-Ravello, G.; Valmaseda-Castellon, E.; Al-Nawas, B.; Schiegnitz, E. Comprehensive Update on Implants in Patients With Head and Neck Cancer (2021–2024): Systematic Review and Meta-Analysis of the Impact of Radiotherapy and Chemotherapy on Implant Survival. Clinical Oral Implants Research 2025, 36, 1035–1052, https://doi.org/10.1111/clr.14450 . A recent meta-analysis on implant survival in patients with head and neck cancer. As a systematic review covering the years 2021–2024, it serves as a direct source of clinical data for the main topic of this study. Padure, A.; Horhat, R.; Talpos-Niculescu, I.C.; Scheusan, R.; Anghel, M.D.; Rusu, L.-C.; Lungeanu, D. Oral Mucositis in Adult Cancer Patients Undergoing Chemotherapy: Six-Month On-Treatment Follow-Up. J Clin Med 2024, 13, 5723, https://doi.org/10.3390/jcm13195723 . A prospective clinical observation of cancer patients documenting the course and severity of oral mucositis during chemotherapy provides up-to-date clinical data that complements the experimental data cited in the study. Peng, B.; Wu, J.; Tian, S.; Qu, X.; Liang, X.; Feng, J.; Chen, Y.; She, R.; Ma, C.; Song, J.; et al. Effect of Chemotherapy and Different Chemotherapy Regimens on Bone Health among Chinese Breast Cancer Women in Different Menstrual Status: A Self-Control Study. Support Care Cancer 2023, 31, 540, https://doi.org/10.1007/s00520-023–07960-8. An original clinical study evaluating the impact of various chemotherapy regimens on bone mineral density in women with breast cancer confirms the clinical significance of bone metabolism disorders as a complication of cancer treatment. Pacheco, M.C.D.; Prado, A.H. dos R.; Costa, D.V. da; Arantes, L.C. de; Portela, C.F.T.; Campos, T.P.R.; Oliveira, A.H. de Survival of Dental Implants in Irradiated Head and Neck Cancer Patients Compared to Non-Irradiated Patients: An Umbrella Review. PLOS ONE 2025, 20, e0324388, https://doi.org/10.1371/journal.pone.0324388 . Umbrella review-the highest level of evidence synthesis-comparing implant survival in irradiated and non-irradiated tissues; this directly supports the higher risk of osseointegration failure described in the study.
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Authors’ Contribution
M.K- writing, original draft preparation, conceptualization; Ł.W- writing, original draft preparation, drafted the manuscript, conceptualization, review and editing; B.T.—writing, drafted the manuscript; M.P. -writing original draft; J.R.M- review and editing; M.L- review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data Availability
No datasets were generated or analysed during the current study.
Declarations
Competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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