Aim: To present the dental procedures necessary for the prevention, diagnosis, and treatment of oral toxicities related to cancer treatment.

Material and methods: A narrative literature review was carried out regarding the topics of interest. Articles in Portuguese and English, without the restriction of the year of publication and full text available in the databases Pubmed, Scielo, Cochrane, and Google Scholar were investigated.

Results: Through this search, 100 articles were selected, consisting of 9 systematic reviews, 3 systematic reviews with meta-analysis, 48 literature reviews, 3 randomized clinical trials, 4 prospective cohorts, 12 retrospective cohorts, 5 cross-sectional studies, 2 case-control studies, 5 case reports, 7 expert consensus panels, 1 letter to the editor and 1 qualitative study, published between 1976 and 2020. Dental procedures were classified according to the therapeutic modality (surgery and radiotherapy for head and neck cancer, chemotherapy, hematopoietic stem cell transplantation, and use of antiresorptive medications) and the time of treatment (prior, during, or after each one).

Conclusions: The consulted articles were unanimous regarding the need for dental care for cancer patients in the pre, trans, and post-treatment, highlighting the importance of inserting specialized dental surgeons in the oncology patient care team; thus, this professional should act in the prevention, early diagnosis, and treatment of oral toxicities, to minimize their consequences and improve patients' quality of life.

Keywords: dentistry, medical oncology, patient care team, radiotherapy, chemotherapy, hematopoietic stem cell transplantation, antiresorptive medications

According to data released by the International Agency for Research on Cancer (IARC) in 2020, cancer will be the second leading cause of premature deaths in most countries including Brazil, only surpassed by cardiovascular diseases.¹ Cancer is currently considered one of the most significant public health issues and has been increasing in both incidence and mortality in recent years.² According to Bray et al.³, there were 18 million new cases and 9.6 million deaths of cancer worldwide in 2018. In Brazil, in the 2020-2022 triennium, 625,000 new cases of cancer are expected.²

Due to the aggressiveness inherent to cancer treatment, patients can present a series of complications, both systemic and local; among these, the mouth may present a number of these intricacies.⁴ In addition to oral mucositis (OM), the dental foci are one of the main causes of systemic infections, since the colonizing microorganisms of the oral microbiota can migrate through the surface of the epithelium and reach the circulation due to loss of epithelial integrity.^5,6 Consequently, these sources of infections need to be treated or at least controlled before the patient is placed on antineoplastic therapy since the complications generated thereby can imply an increase in morbidity, mortality, and hospitalization costs.^4,7,8 Thus, the objective of this article is to present the dental procedures necessary for the prevention, diagnosis, and treatment of oral toxicities of cancer treatment.

This is a narrative literature review, regarding the role of the dental surgeon in the prevention, diagnosis, and treatment of oral toxicities related to cancer treatment. A comprehensive and random search was performed for scientific articles published on the subject in question. Articles available in the Pubmed, Scielo, Cochrane, and Google Scholar databases were investigated in Portuguese and English, without a time interval specification.

The research was conducted using different combinations of the following keywords: “surgery”, “chemotherapy”, “hematopoietic stem cell transplantation”, “antiresorptive medications”, “radiotherapy”, “oral toxicities”, “dental management” and “cancer patients”. Full articles that addressed the theme, published in scientific journals, without restriction as to the methodology were included. However, book chapters and abstracts of meetings were excluded.

The search resulted in 100 selected articles, consisting of 3 systematic reviews with meta-analysis, 9 systematic reviews, 48 literature reviews, 3 randomized clinical trials, 4 prospective cohorts, 12 retrospective cohorts, 5 cross-sectional studies, 2 case-control studies, 5 case reports, 7 expert consensus panels, 1 letter to the editor and 1 qualitative study, published between 1976 and 2020.

The articles approach dental care for patients who will be, are being, or have been subjected to surgery and radiotherapy (RT) for head and neck (H&N) cancer, chemotherapy (CT), hematopoietic stem cell transplantation (HSCT), and the use of antiresorptive medications. Dental procedures were classified according to the time of treatment: prior, during, or after each therapeutic modality addressed, when applicable.

Dental care for patients undergoing head and neck surgery

Surgery is the main treatment employed for H&N tumors, usually indicated for initial tumors, but in some cases, replaced by isolated RT.⁹ It is reserved for tumors in which resection with neoplasia-free margins and minimal functional disorder is possible, thus ensuring complete removal of the neoplasia;¹⁰ even so, it can result in aesthetic disfigurement and significant functionality loss, which can implicate in emotional changes and social interaction impairment.^9,11 Any H&N surgery patient must undergo a prior dental checkup.^12–14 This assessment must include oral hygiene instruction, the removal of infectious foci, and the production of a transurgical palatal obturator, for maxillary surgeries (Table 1).

Subsequently, these patients can be treated according to conventional dental standards; at follow-up appointments, it’s important to pay attention to recurrent or new lesions that may develop in the oral cavity^15,16 (Table 1). In the context of surgeries involving the jaws, it is crucial to highlight the importance of definitive rehabilitation, to allow their reintegration into society and their aesthetic standards.^17,18 In this sense, the maxillofacial prosthetics palatal obturator works as an aid in supporting the tissue, improving healing, reducing contamination and the possibility of infections; it also reduces the need for a nasoenteral tube, since it allows the patient to swallow efficiently and also an early initiation of oral feeding.¹⁹ Maxillary and mandibular adapted prostheses are essential to rehabilitating function and aesthetics. Its manufacture must follow the basic principles of dental prosthesis, which occasionally can be modified to adapt to an unusual anatomy²⁰ and intraosseous implants may be required for better retention and stability.²¹ The maxillofacial prosthesis is constituted of synthetic material and molded according to specific surgical defects, allowing the repair of deformities, contributing to the aesthetic and functional rehabilitation, and the consequent return of patients' self-esteem.¹⁷ An example can be observed in Figure 1.

Figure 1 Front view of a silicone eyelid prosthesis.

Dental care for patients undergoing head and neck radiotherapy

RT is a treatment modality for malignant tumors whose therapeutic agent is ionizing radiation, responsible for promoting ionization in the environment where it occurs. Most patients undergoing RT receive a total dose of 50-70Gy as a curative dose. These doses are divided into a period of 5-7 weeks, once a day, 5 days a week, with a daily dose of approximately 2Gy.²² Dental assessment before RT in patients with H&N cancer aims to minimize oral manifestations.²³ The patient must undergo a physical examination, including periodontal analysis through probing and a radiographic examination.²³ Dental planning must be programmed in a joint analysis with the estimated radiation dose for each oral site (Table 2).²³

During RT, routine dental treatment is not indicated; only evaluation and resolution of dental emergencies should be performed (Table 2). The dental surgeon must diagnose and treat the RT acute oral toxicities²⁴ (OM^25–27, dysgeusia,^12,22,28,29 infections, pain, and xerostomia) (Table 3), that implicate an inability to eat, speak, clean, increased costs with hospitalization, and reduced quality of life.^30–33

After completion of RT, the patient must be closely monitored to identify and manage possible complications. At first, dental follow-up appointments should be monthly, changing to quarterly after most acute toxicities are controlled. The dentist's actions must be preventive, to promote oral health, and procedures that involve bone manipulation (such as extractions and dental implants) should be avoided due to the risk of osteoradionecrosis (ORN)²⁴ (Table 2). Moreover, the chronic oral toxicities, which are a limited opening of the mouth (trismus) associated with mucosal fibrosis,²⁷ pain in the mucous membranes, second primary tumors, xerostomia,^12,32,34 radiation-induced dental caries^35–38 and ORN,^{30,32,39–41} should be diagnosed and treated (Table 3). Cases of radiation-induced dental caries and ORN are shown in Figures 2 and 3, respectively. Considering that RT is a local treatment, a dentist should, as previously stated in the surgery section, pay attention to possible recurrence, identifying, and forwarding to the oncologist as soon as possible for better management.

Figure 2 Intraoral aspect of a patient with generalized dental involvement due to radiation-induced dental caries after RT treatment.

Figure 3 Intraoral photograph of jaw ORN.

Dental care for patients undergoing chemotherapy

CT is the systemic treatment that uses antineoplastic drugs in regular intervals, according to the therapeutic regimen.⁴² It can be used in association with other treatment modalities, in adjuvant (to avoid tumor spread) or in neoadjuvant (to stimulate the reduction of the tumor), thus optimizing surgery or RT.⁴³ The therapeutic scheme of choice relies on histopathological and molecular diagnosis, clinical condition, functional capacity, and patient preference; monotherapy or polychemotherapy can be used.^44,45

Dental planning before CT may be more conservative when compared to the one for RT or HSCT. The prior dental evaluation must consist of an oral hygiene instruction, elimination of caries, periodontal disease, endodontic infections, and other possible foci of infection in the oral cavity that may be exacerbated during the neutropenic stage expected for these patients (Table 4).⁴⁶

Given CT is a systemic therapy, during treatment, especially in the period of immunosuppression, it may cause changes in the oral mucosa that may lead to a direct impact on the patient's quality of life, occasionally leading to treatment interruption.⁴⁷ Therefore, during CT, dental management should consist of emergency procedures - always considering laboratory exams (Table 4)- and the management of acute oral toxicities (OM, dysgeusia, xerostomia, bacterial, viral, and fungal infections^40,47–50 and neurotoxicity^27,51) (Table 3).

It is important to note that some CT drugs are more toxic to the tissues, being frequently associated with OM, such as methotrexate, 5-fluorouracil, cyclophosphamides, cisplatin, and purine analogs such as cytarabine.^52,53 Regarding OM caused by mTOR inhibitors,^54,55 tyrosine kinase inhibitors EGFR/HER1, Pan-HER, or EGFR-inhibiting monoclonal antibodies,⁵⁵ they have distinct clinical presentations and specific management (Table 3).

Considering that acute effects related to CT tend to cease soon after the organism's recovery, the patient undergoing CT does not need long-term post-treatment care that would differ from those dispensed in routine annual dental consultations (Table 4). Despite that, the dentist should pay attention to possible metastatic lesions that may manifest in the oral cavity.⁵⁶ These manifestations are rare in this area, indicate advanced disease progression,^57,58 and imply a poor prognosis when it comes to survival.^57,59 The identification and early management of these can significantly impact the management (thought palliative treatment-seeking maintenance of oral function and management of pain) and patient’s quality of life.^57,58

Dental care for patients undergoing hematopoietic stem cell transplantation

HSCT is the therapeutic modality for hematological diseases' treatment, whether benign or malignant, hereditary or acquired - among them are leukemias, lymphomas, and multiple myeloma.⁶⁰ It consists of providing the patient with hematopoietic stem cells that will be lodged in the bone marrow, to re-establish their function.⁶¹ HSCT can be autogenic, allogeneic, or syngeneic and the progenitor cells may come from bone marrow, peripheral blood, or umbilical cord.⁶²

Dental care before HSCT should be performed on all patients to minimize the complications during treatment,⁴⁶ according to Table 5. During the HSCT, acute oral toxicities⁶² (infections, OM,^63,64 xerostomia⁶³ and acute graft versus host disease (aGVHD))^65,66 must be controlled (Table 3) and emergency procedures performed,⁵¹ always considering laboratory exams (Table 5). Figure 4 illustrates one of the possible clinical presentations of aGVHD.

Figure 4 Oral manifestation of aGVHD.

The patient should be maintained in control via a semiannual consultation program or following specific needs after the immediate HSCT and annual control in late HSCT stages. In these consultations, the dentist must plan dental treatments according to Table 5 and diagnose and/or treat chronic toxicities such as xerostomia,⁶³ trismus, chronic graft versus host disease (cGVHD),^65,67 and second primary tumor^66,68–70 (Table 3). A case of cGVHD is represented in Figure 5. As previously reported in the CT section, the dentist should also pay attention, in the follow-up appointments, to oral lesions that could indicate metastasis from other tumors manifesting in the oral cavity. Patients with Fanconi anemia undergoing HSCT should be scheduled for control visits every 6 months, due to the increased risk of developing squamous cell carcinomas in the oral cavity.⁷¹

Figure 5 Oral manifestation of cGVHD.

Dental care for patients in the use of antiresorptive medications

In the oncological context, it is necessary to consider patients that use bisphosphonates (BPs) intravenous (IV) or orally or denosumab due to the association of these drugs with medication-related osteonecrosis of the jaws (MRONJ). Despite the low incidence, MRONJ causes an abrupt drop in patient’s quality of life.⁷² In this same context, it is important to also consider the use of antiangiogenic drugs, as this association increases the risks of developing MRONJ.⁷³

BPs are synthetic pyrophosphate-like drugs, which bind tightly to hydroxyapatite and reduce metabolism and bone remodeling. They are medications with a long half-life and thus remain in the bone tissue for more than 10 years after treatment interruption.⁷³ The main BPs associated with MRONJ cases are zoledronate, pamidronate, IV ibandronate, alendronate, oral ibandronate, risedronate, and clodronate.⁷⁴ These drugs are prescribed for patients at risk/evidence of bone metastasis, or for the treatment of multiple myeloma, Paget's disease, and disorders of calcium metabolism.^75–77

Denosumab is a monoclonal antibody that binds to the receptor-ligand responsible for the activation of the nuclear factor kappa B ligand (RANK-L), thus blocking the maturation, function, and survival of osteoclasts. It is also prescribed for patients presenting osteoporosis or risk/evidence of bone metastasis. Unlike BPs, this medicine has a half-life of 25 to 32 days.⁷³

The dentist is responsible for investigating the use of these drugs during anamnesis, both in cancer patients and in the general population, before defining the dental treatment plan. The ideal is that before starting the use of antiresorptive medications, patients should be evaluated and prepared by the dentist to minimize the subsequent need for invasive treatment,⁷² and the patient should be guided and managed similarly to those subject to RT for H&N tumors⁷⁷ (Table 2).

Patients using antiresorptive medications should be scheduled for a control visit every 6 months. Dental management is also similar to that employed after RT (Table 2), to maintain the status of adequate oral hygiene and perform an early diagnosis of MRONJ and eventual metastatic manifestations in the oral cavity. The MRONJ management is still controversial and can include non-surgical procedures, such as pain and infection control (oral hygiene care, periodontal disease management, chlorhexidine gluconate 0.12% mouthwash, antibiotic therapy, and systemic corticosteroid therapy) and surgical treatment when necessary.⁷²

After the start of therapy, given the absolute indication for surgical procedures with bone manipulation, the minimally invasive surgical technique should be employed, that is, avoiding osteotomy and seeking primary synthesis, as well as assessing the need for antibiotic prophylaxis; mouthwash with 0,12% chlorhexidine should be used preoperatively and postoperatively until healing; suspension of therapy according to each case should be assessed.^73,75,77,78 For patients who have had oral BP for less than 4 years and do not have associated risk factors, changes in surgical planning are not necessary. On the other hand, for patients using oral BP associated with corticosteroids and antiangiogenics, also for less than 4 years, it is suggested that the BP should be interrupted for 2 months before extractions until full bone healing. Likewise, it should be discontinued in patients treated for more than 4 years, that is, 2 months before the procedure until full bone healing. The maneuvers for suspending and resuming drug use must be agreed with the oncologist responsible for conducting the patient's treatment.⁷⁷

Regarding the interruption of IV BPs, data in the literature is still scarce, and there is no established guideline. However, in cases of MRONJ, the oncologist may consider interrupting antiresorptive therapy until soft tissue is fully healed over the jawbones, depending on the status of the disease. Regarding denosumab, it was observed that its antiresorptive effects dissipate approximately within 6 months after discontinuing the drug, however, there are no studies to support or refute this strategy for prevention or treatment of MRONJ, making further studies necessary.⁷⁷

It is also important to consider the use of antiangiogenics, prescribed mainly for cancer patients for inhibiting several mechanisms involved in tumor neoangiogenesis. In this group of drugs, bevacizumab (inhibitor of vascular endothelial growth factor), sunitinib (tyrosine kinase inhibitor), and everolimus (inhibitors of the target protein of rapamycin in mammals) stand out. These medicines do not tend to accumulate in the bone and their half-life range from 30 hours for everolimus to 20 days for bevacizumab, varying according to the medication.⁷³ It is important to note that the benefits versus risks of discontinuing therapies must be calculated jointly with the oncologist and the patient,⁷⁸ according to their systemic conditions.

The consulted articles were unanimous regarding the need for dental care in pre, trans, and post-treatment cancer patients, showing the importance of including specialized dental surgeons in the oncology care team. In this way, the dentist must act in the direction of prevention, early diagnosis, and treatment of oral toxicities. The dentist is responsible for minimizing its consequences and improving the quality of life of patients.

None.

The authors declare that there is no conflict of interest.

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