Introduction

The increased accessibility to new technology (i.e., diagnostics and deep genomic sequencing), has contributed to a significant improvement in our knowledge base of cancer biology and cancer therapeutics. With the advent of targeted cancer therapy, advances in chemotherapeutics and radiation therapy, there have been significant advances in the field of cancer treatment. Although many advances have been made, the primary modalities of treatment remain as surgical resection, radiation therapy, and chemotherapeutics. Throughout these treatment modalities, it is important for periodontists and dental teams to have knowledge of the effects of cancer treatments. Knowledge of these cancer treatment strategies will allow dental providers to provide these patients with the highest standard of care before, during, and after the patient’s cancer treatment/management. Thus, the aim of this review is to provide dental practitioners with an updated review of the periodontal and restorative treatments in patients with cancer prior to, during, and after their oncology treatments.

Periodontal Therapy of Cancer Patients at the Time of Diagnosis

Cancer therapy has a number of associated comorbidities (e.g., neutropenia, anemia, impaired wound healing) that can complicate periodontal maintenance and treatment. As such, it is advisable to devise and complete the treatment plan prior to cancer therapy. In a recent study, Tsuji et al. (2015) [1•] completed a prospective study of dental intervention for patients with hematopoietic malignancy, reporting that patients who completed the partial pre-cancer therapy protocol had significantly lower incidence of systemic (15.8 vs. 37.4%) and dental complications (2.9 vs. 34.0%) compared to patients who did not complete any pre-cancer dental therapy. These complications were correlated with a higher degree of myelosuppression. Furthermore, Toljanic et al. (1999) [2] completed a prospective study for minimal treatment completed prior to intensive chemotherapy for cancer that reported 10% (two patients in the study population) of subjects had febrile episodes due to dental sources. More recently, Schuurhuis et al. (2011) [3] reported 3% of their total study population developed dental complications with minimal treatment completed prior to onset of cancer therapy. The variability in reports is likely due to the generic bias of research protocols, pre-existing dental conditions, dental care, and cancer therapy.

In the pre-treatment protocol for chemotherapeutics, periodontal treatment is beneficial if performed prior to high-dose chemotherapeutics [4,5,6]. Periodontal therapy includes physical disruption/debridement of bacteria/biofilm through scaling and root planing techniques and oral hygiene instruction. Oral hygiene instruction is often one of the most important and effective measures to prevent bacterial recolonization and maintenance of disease control. In conducting these procedures in immune-compromised individuals, complete and differential blood counts may be appropriate to determine if antibiotics should be adjunctively prescribed or if platelet transfusions are required prior to invasive periodontal treatment.

In a recent systematic review by Hong et al. (2017) [7], there are broadly three levels of dental treatment protocols prior to anti-neoplastic therapy and bone marrow transplants: complete, partial, and minimal.

  1. i.

    Complete treatment involves the treatment of all dental pathologies prior to cancer treatment or bone marrow transplantation.

    1. a.

      Dental pathologies include all caries (enamel and dentin penetration) and extraction of teeth exhibiting probing pocket depths of ≥ 6 mm, dentition with over 50% bone loss, and partially erupted third molars.

  2. ii.

    Partial treatment involves a graded approach to dental pathologies present prior to cancer treatment or bone marrow transplantation with the following criteria:

    1. a.

      Minor caries (carious lesions extending to or just beyond enamel) observed and not treated (Tsuji et al. 2015)[1•].

    2. b.

      Periapical lesions only treated if size ≥ 5 mm or symptomatic.

    3. c.

      Teeth extracted if probing pocket depth of ≥ 8 mm, teeth with more than 1 mm of mobility and vertical depression (Miller’s Class III mobility), and partially erupted third molars that exhibit purulence.

  3. iii.

    Minimal treatment includes symptomatic treatment or if there are limited time constraints prior to cancer therapy or bone marrow transplantation.

Personalization of these treatment protocols is ultimately required due to the inherent risk associated with more invasive dental procedures. Dental complications could induce a delay in cancer treatment, which could be detrimental to the long-term survival of patients depending on their systemic diagnosis or presentation.

Periodontal Therapy of Cancer Patients Currently Undergoing Treatment

Periodontal disease and/or periodontal infections may be exacerbated during cancer therapy and present a significant risk to neutropenic patients. Ulcerated periodontal pocket epithelium may serve as a portal of entry for the translocation of microorganisms into the blood stream. Additionally, inflamed/infected periodontal tissues may serve as a reservoir of endotoxin and pro-inflammatory mediators that have systemic effects [8]. Dental-related infections are a concern during cancer therapy (specifically anti-neoplastic chemotherapy). The prevalence of these infections was recently reported as 5.4% (standard error of 1.16, 95% confidence interval 3.14–7.7) [7]. Vozza et al. (2015) [9•] reported the prevalence of periodontal disease in a population with malignant solid tumors submitted to chemotherapy was 35.2% at the time of their cancer diagnosis, and periodontal treatment was effective in reducing plaque index, bleeding on probing, pocket depth, and maintaining attachment loss as these patients underwent chemotherapy. As such, care must be taken to properly assess and treat periodontal disease in patients with compromised immune systems following chemotherapy.

Gingivitis is assessed by gingival erythema and bleeding on probing in the absence of bone loss. Periodontitis is assessed by attachment loss, bleeding, gingival erythema, and etiological factors including presence of bacterial plaque and calculus. However, gingivitis may be affected by hematological status. For example, gingiva may appear pale in cases of anemia, while they might appear erythematous in the thrombocytopenic patient [10]. Further, gingiva may appear erythematous and enlarged in patients with acute myeloid leukemia [11].

During neutropenia, periodontal probing should be avoided, meaning that pre-treatment evaluation is of absolute importance to coordinate oral care [8]. Moderate to severe periodontitis in a patient who develops neutropenic fever should be considered a clinically defined infection, even if gingival signs and symptoms of inflammation are not observed [8]. Antimicrobial agents for anaerobic bacteria should be added to current antibiotic regimes in these situations (i.e., metronidazole). Culture of diseased periodontal pockets and culture of blood samples (in the case of bacteremia) will indicate origin of the infection and provide further infection management information [8].

Beyond bacterial and fungal infections, gingival lesions may also be attributed to reactivated viral infections. The viral footprint appears clinically as round 1- to 2-mm ulcerations coalescing together within the same area. Diagnosis of a viral infection can be confirmed by virus detection in exfoliated cells or by viral culture techniques [12].

Complications Associated with Periodontal Therapy in Cancer Patients

Head and Neck-Targeted Side-Effects

Head and neck cancers, due to the sites and treatment of these diseases with radiotherapy and chemotherapy, directly impact oral structures, oral intake, weight loss, and dehydration. Acute symptoms include the following: mucositis, swallowing disorders, xerostomia, and dysgeusia [13]. Late effects include dysphasia, pain, xerostomia, mucosal sensitivity, taste alterations, trismus, osteoradionecrosis, and dental disease [13]. Frequently, oral, enteral, and parenteral nutrition support are needed [14]. Oral mucositis may be highly influenced by the frequency of oral care in patients undergoing 20-Gy radiation [15]. Oral mucositis at 50 Gy is positively correlated with the number of artificial teeth [16]. Xerostomia is a significant contributor to decline of oral health in these patients [13]. Thus, palliative oral treatment is important in treating these patients, and continued support for oral hygiene is important to successfully achieve periodontal stability in these patients.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported following tooth extraction in patients [17•]. Hasegawa et al. (2017) [17•] completed a nonrandomized, multi-centered retrospective study including 1175 patients to determine the significant risk factors for ONJ in patients taking oral bisphosphonates. Overall, the study reported a 1.7% frequency of post-extraction ONJ in patients taking oral bisphosphonates. The study determined that concurrent disease status (i.e., cancer and diabetes) was not significant. However, local treatment factors including root amputation (OR = 6.64), extraction of a single tooth (OR = 3.7), severe tooth mobility (OR = 3.60), and unclosed wound (OR = 2.51) significantly contributed risk to the development of ONJ. The study also determined that a drug holiday did not significantly prevent development of ONJ post-extraction, probably attributable to the fact that the half-life of oral bisphosphonates are on the time span of decades.

In addition to well-known use of oral bisphosphonates for osteoporosis, bisphosphonates are also used as bone-targeted therapies to decrease the risk of skeletal metastases in cancer patients. Common uses of bisphosphonates in cancer therapy include men with castration-resistant prostate cancer and bone metastases, as well as treatment of bone metastases in women with breast cancer [18,19,20]. Previously, it was shown that monthly zoledronic acid infusions decreased the risk of skeletal-related events compared to placebo (38 vs 49%) in men with castrate resistant prostate cancer [21]. Moreover, denosumab, a monoclonal antibody against RANK ligand, is also used in this context and further reduces the risk of skeletal-related events and increased time to the first bony complication by 4 months when compared to zoledronic acid [22]. Vehmanen et al. (2017) [23•] completed a case series with 254 men with castrate-resistant prostate cancer and treated with zoledronic acid, denosumab, or both, who also received dental extractions by oral and maxillofacial surgeons. In total, 29 out of 254 men (11.4%) developed ONJ. Of the patients who developed ONJ, 2 received only zoledronic acid, 9 received only denosumab, and 18 received both zoledronic acid and denosumab. Seventeen of the 29 ONJ cases had chronic disability of the jaw or jaw necrosis that continued until the death of the patient. Thus, treatment of patients taking infusions of bisphosphonates who require dental extractions must be regarded with extreme caution, and complete tension-free closure of wound sites should be achieved to minimize risk of ONJ and further oral disability of these patients.

Osteoradionecrosis of the Jaws

Osteoradionecrosis (ORN) of the jaw is a well-known complication of radiation therapy to the head and neck with local risk factors that include tumor site, tumor stage, proximity of the tumor to bone, radiation field, dose of radiation, poor oral hygiene, and associated trauma (i.e., extractions before or after radiation therapy) [24]. It is defined as an area of exposed necrotic bone in an area previously irradiated that fails to heal over a period of 3–6 months [25].

In a recent case-control study by Owosho et al. (2017) [26•] at the Memorial Sloan Kettering Cancer Center, the authors determined the prevalence of ORN to be 4.3% during a median follow-up time of 52.5 months. Furthermore, the authors stated that patients treated for oropharyngeal cancer were prone to develop ORN earlier compared to patients with oral cavity cancer. In addition, these authors reported that poor periodontal status, history of alcohol use, and radiation dose were significant risk factors.

Despite our growing knowledge of this side effect in cancer patients, the treatment of ORN remains unreliable. A retrospective study by Chen et al. (2016) [27] reported a prevalence of ORN of 6.2%. A total radiation dose to the primary site ≥ 75 Gy, among others, was associated with ORN. However, after aggressive treatment using surgical intervention with/without hyperbaric oxygen, only 93.3% of the patients healed completely.

In a retrospective study that observed outcomes of hyperbaric oxygen therapy in 509 patients, Dieleman et al. (2017) [28•] reported that the cause of ORN was most commonly extractions after radiation therapy (22%) or prosthetics (22%) followed by periodontal disease (11%) and tumor-related surgery (11%). Interestingly, treatment with hyperbaric oxygen is only significantly effective for lower stages of ORN, while higher stages of ORN still require segmental resection of the affected structure. Thus, it is important to for periodontists and physicians alike to identify those at risk and avoid unwanted complications.

Periodontal Status Affected by Aromatase Inhibitors

Aromatase inhibitors (AIs) are an adjunctive therapy, which mechanistically is used to interfere with estrogen production in post-menopausal women with hormone receptor positive early-staged breast cancer. AIs are typically prescribed for long periods of time, approximately 5 and 10 years [29]. Systemic side effects of AI therapy in breast cancer patients include accelerated bone loss and osteoporotic fractures [30]. Interestingly, patients on AIs also had poorer oral hygiene, poorer health-related quality of life, lower salivary flow, and periodontal health [31]. Periodontal health including deeper periodontal probing depths, more clinical attachment loss, and alveolar bone loss was reported over the18 months of AI therapy [31]. As such, these patients may need to be placed on more frequent hygiene recall appointment status until periodontal stability can be successfully achieved long term.

Summary and Management Considerations (Fig. 1)

Pre-Treatment

Preventive periodontal and dental therapies are very important aspects in treating the cancer patient. Diagnosis, treatment, and establishment of regular maintenance protocols are essential in the treatment of periodontal disease through neutropenic periods and prevent excessive oral bacterial shift changes in head and neck radiation changes. Further, extraction of untreatable teeth is also important to minimize risks of ONJ prior to onset of bisphosphonate infusions.

Fig. 1
figure 1

These are key points to remember depending on the stage at which a patient presents to the periodontal clinic in his/her cancer treatment

Full size image

During Treatment

Periodontal maintenance should be continued in these patients in combination with good oral hygiene. Use of fluoride products may help to prevent dental caries in post-head and neck radiation patients, and if plaque accumulation continues, use of chlorhexidine mouth rinse (0.12%) once or twice daily can be prescribed. However, side effects of chlorhexidine (staining, calculus buildup, and temporary changes in taste) should be emphasized. Regarding tooth restorations, use of composite resins, resin-modified glass ionomer cements, and amalgam restorations are suggested compared to glass ionomer cements alone due to the requirement of frequent replacements from break down of margin integrity (Fig. 1). Communication between health providers (i.e., dentist, periodontist, and oncologist) is crucial for the dental treatment of cancer patients. Communication materials can be crucial and are provided by NIDCR to facilitate this communication [32].

Post-Treatment

Periodontal maintenance should be continued in patients with careful evaluation of their periodontal and dental status. For patients experiencing xerostomia, fluoride trays can be fabricated for caries prevention. In addition, periodontal maintenance should be performed regularly to maintain oral hygiene and prevention of further attachment loss. These preventive steps are of utmost importance in patients who are at risk for ONJ and for whom extraction/implant placements are not ideal treatment options (Fig. 1).