Oral Complications of Nonsurgical Cancer Therapies

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Oral Complications of Nonsurgical Cancer Therapies

Siri Beier Jensen, DDS, PhD,

Douglas E. Peterson, DMD, PhD, FDS RCSEd

OVERVIEW

Oral complications from cancer therapies are commonly of significant morbidity to the patient and may cause disruption of cancer treatment compromising the prognosis and increase health care costs. A wide range of oral complications of cancer therapies often appear concurrently which may complicate diagnoses and management; for example, intense oral and pharyngeal pain induced by a combination of oral mucositis, oropharyngeal candidiasis, salivary gland hypofunction, and xerostomia frequently lead to dysphagia in cancer patients compromising nutritional intake.1 Thus, oral complications of cancer therapies may severely affect quality of life during cancer treatment or when manifest as late oral complications months or years following treatment.

Oral complications induced by cancer therapies result from a complex interplay among multiple factors and the recognition of the underlying mechanisms causing oral complications continues to develop. However, there are no effective agents or protocols to collectively prevent adverse effects from cancer therapies. Thus, the current approach to minimize incidence and severity of oral complications of cancer therapies is the elimination of pre‐existing dental, periodontal, and mucosal infections in coherence with regular oral assessment and implementation of basic oral care protocols and prompt diagnosis of emerging oral complications during and after cancer therapy with adequate alleviation and treatment.2

An interdisciplinary approach, including dental professionals, is required to work in close collaboration with the patient in order to regularly—and by validated outcome measures—evaluate, prevent, and treat oral complications of cancer therapies.

This chapter addresses oral complications of nonsurgical cancer therapies and evidence‐based clinical practice guidelines for management.

Types of Cancer Therapies

Design of cancer treatment protocols is based on a number of key considerations, beginning with histopathologic confirmation of the type of malignancy. Additional components include staging (solid tumors), age and performance status of the patient, projected efficacy in relation to toxicity, and patient preferences.

Patients with hematologic malignancy

Patients with hematologic disease (Figure 8‐1; Figure 8‐2) may be treated by moderate or high‐dose chemotherapy, with or without hematopoietic stem cell transplantation (HSCT). As with head and neck cancer patients, factors influencing incidence and severity of oral complications across patients with hematologic disease include extent of oral disease prior to cancer treatment, intensity of cancer therapy, genetically‐governed susceptibility to oral mucosal injury, and patient compliance with health professional Recommendations regarding oral hygiene, diet, smoking cessation, and related variables.

Photo depicts peripheral blood smear from a patient with newly diagnosed acute myelogenous in blast crisis. The high-dose induction chemotherapy regimen that will be used to treat this patient is profoundly myelosuppressive, and typically causes severe ulcerative oral mucositis for at least two weeks duration.

Figure 8‐1 Peripheral blood smear from a patient with newly diagnosed acute myelogenous leukemia in blast crisis. The high‐dose induction chemotherapy regimen that will be used to treat this patient is profoundly myelosuppressive, and typically causes severe ulcerative oral mucositis for at least two weeks duration. The interface of profound myelosuppression with disruption in integrity of the oral mucosal barrier can result in risk for life‐threatening bacteremia and/or sepsis.

Source: Quintessence 2019.69

HSCT‐related oral toxicities are additionally influenced by the degree of genetic disparity between donor and patient. Acute and/or chronic graft‐versus‐host disease (GVHD) that results from immune‐modulated injury to the patient’s tissues can cause clinically significant salivary gland and/or oral mucosal disease.

Photos depict acute leukemia can be considered naturally metastatic in that the neoplasm arises within the white blood cell progenitors produced in the bone marrow. Because of the inherent circulation of these cells the disease is widespread by time of diagnosis. (a) A Histopathology based on hepatic biopsy, demonstrating widespread infiltrate of the blast leukemic cells. (b) Gingival leukemic infiltrate in newly diagnosed acute myelogenous leukemia patient.

Figure 8‐2 Acute leukemia can be considered “naturally metastatic” in that the neoplasm arises within the white blood cell progenitors produced in the bone marrow. Because of the inherent circulation of these cells the disease is widespread by time of diagnosis. (A) Histopathology based on hepatic biopsy, demonstrating widespread infiltrate of the blast leukemic cells. (B) Gingival leukemic infiltrate in newly diagnosed acute myelogenous leukemia patient. Note the evidence of extensive gingival engorgement caused by the infiltrating leukemic cells. The resulting ischemia can contribute to develop of tissue necrosis as well as opportunistic infection such as pseudomembranous candidiasis.

Source: Quintessence 2019.69

Patients with Head and Neck Cancer

Depending upon these variables, cancer treatment for a patient with solid head and neck cancer (e.g., oral, oropharyngeal, or laryngeal tumor) can consist of:

  • Surgical excision with resultant cure (early stage solid tumor).
  • Head and neck radiation, administered in fractionated or hyperfractioned doses five times/week for 6–7 weeks for a total cumulative dose of approximately 60–70 Gy.
  • Multimodality treatments that incorporate chemotherapy based on the following schema:
    • Neoadjuvant chemotherapy:
    • Administered prior to surgery, for purposes of debulking tumor.
    • Adjuvant chemotherapy:
    • Administered after surgery and prior to head and neck radiation.
    • Concurrent/concomitant chemotherapy:
    • Administered in combination with head and neck radiation, typically on a weekly basis throughout the duration of the 6–7 weeks of radiation.

Factors influencing incidence and severity of oral complications across patients with head and neck cancer include extent of oral disease prior to cancer treatment, dose and anatomic location of radiation therapy, genetically‐governed susceptibility to oral mucosal injury, and patient compliance with health professional recommendations regarding oral hygiene, diet, smoking cessation, and related variables.

Patients Receiving Targeted Cancer Therapies

Use of targeted cancer therapies such as multitargeted tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors has increased in recent years.3,4 These biologics are directed to molecular pathways that are unique to tumor cells, versus normal cells. Despite their targeting, however, side effects such as oral mucosal and dermal lesions can occur.

Epidemiology of Oral Complications of Cancer Therapies

The types of oral complications vary in pattern, duration, and intensity for each individual patient and depending on the cancer therapy regimen and dose intensity: e.g. cancer chemotherapy, head and neck radiation therapy, targeted cancer therapies, and hematopoietic stem cell transplantation.58 The Oral Care Study Group and the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) have performed systematic reviews of the most common oral complications of cancer therapies and provided prevalence of oral mucositis,911 oral pain,12 oral fungal infection,13 oral viral infection,14,15 salivary gland hypofunction and xerostomia,16 dysgeusia,17 trismus,18 dental disease,19,20 osteoradionecrosis,21 and medication‐related osteonecrosis of the jaw22,23 in relation to various regimens of cancer therapy. The prevalence data presented in these systematic reviews highlight the multiple variables that translate into the degree to which a cancer patient experiences a given toxicity, including pre‐existing oral status, type and intensity of cancer treatment, the patient’s genetically governed response, and patient‐reported outcomes.

ORAL CARE PROTOCOLS FOR PATIENTS RECEIVING CHEMOTHERAPY AND HEAD AND NECK RADIATION

Oral Care, Precancer Treatment

Elimination or stabilization of selected oral disease prior to initiation of chemotherapy or head and neck radiation can prevent or mitigate subsequent acute oral toxicities such as infection of dental, dental pulpal or, periodontal origin. Decision‐making relative to this medically necessary oral care, precancer treatment is illustrated in Figure 8‐3.

Implementation of Systematic Basic Oral Care Protocols for Oncology Patients

Oral care interventions are pertinent to all cancer patients in order to prevent and reduce the incidence and severity of oral complications and promote oral comfort during and following cancer therapies.

Development and implementation of oral care protocols should be interdisciplinary (nurse, physician, dentist, dental hygienist, dietician, pharmacist, and others as relevant) and include education of the patient, family, and health care professionals. The protocols should be focused on: Regularly scheduled oral assessment and decontamination to reduce the risk of infection, oral moisturization to reduce the risk of friction and trauma‐induced oral mucosal injury, and pain management to promote oral comfort and avoid dose reduction and interruption of cancer treatment.

Evidence‐based patient care fact sheets are available with a multidisciplinary approach on how to care for your mouth before, during and after radiation for head and neck cancer as well as during active chemotherapy (isoo.world/patient‐education.html).25 The fact sheets are multilingual and available in 21 languages.

Oral Decontamination

Toothbrushing two to three times a day with a soft nylon‐bristled toothbrush (with regular replacement of the toothbrush) is recommended.2,24,25 The bristles can be softened in warm water if oral hygiene procedures become discomforting, or can be modified to an ultrasoft toothbrush to ensure continued mechanical oral decontamination for as long as possible during cancer treatment. Toothbrushing should be supplemented by dental flossing once daily with instruction on atraumatic technique. Fluoridated toothpaste should be used, supplemented by high concentration prescription fluoride regimens if the patient’s ability to perform oral care is compromised or if increased risk of dental caries due to salivary gland hypofunction (e.g., 5000 ppm fluoride toothpaste or 1% neutral sodium fluoride gel in a dental tray for 5 minutes before bedtime: the dental tray should overlap the gingival margins of the teeth and still avoid unnecessary contact with the gingiva). Toothpastes containing sodium dodecyl/laureth sulfate (surfactant) and mint flavor should be avoided if it causes soreness of the oral mucosa. Antiseptic mouthwashes such as 0.12% chlorhexidine gluconate may be administered as a supplement to toothbrushing depending on the manifestation of periodontal disease or if toothbrushing is no longer possible due to oral pain.2,24,25 Professional mechanical bacterial plaque removal should be performed before the patient begins rinsing with chlorhexidine gluconate.26

Schematic illustration of the process of oral care, precancer treatment.

Figure 8‐3 Oral care, precancer treatment.

Oral Hydration

Alleviation of xerostomia comprises gustatory, masticatory, or pharmacologic stimulation of residual salivary gland secretory capacity or regular and frequent sipping and topical application to the oral cavity of water, bland rinses, or saliva substitutes (e.g., mouthwash, spray, or gel).25,27,28 Lubrication of lips should be incorporated to prevent crusting and ulceration of the prolabium.

The use of bland rinses, for example 0.9% saline rinse or sodium bicarbonate solution (1 teaspoon salt, 1 teaspoon baking soda in 1 liter of water) is recommended in cancer therapy populations for decontamination, moisturization, neutralization of pH, and for promoting oral comfort.2,24,25 Saline and sodium bicarbonate rinses are considered harmless to the oral cavity, thus frequent rinsing without swallowing can be performed as needed.

Evidence‐based clinical practice guidelines for management of salivary gland hypofunction and xerostomia are described in detail in Chapter 9 “Salivary Gland Diseases.”

Integration of Tobacco Intervention in Oral Supportive Care in Cancer

Tobacco intervention is essential after the diagnosis of cancer to improve clinical outcomes and should be a multidisciplinary approach with screening carried out throughout the continuum of care with intervention services available at each point of care.29,30

ORAL TOXICITY MANIFEST IN PATIENTS BOTH DURING CHEMOTHERAPY AND HEAD AND NECK RADIATION

Cancer patients can be at high risk for oral complications secondary to their cancer treatment (Figure 8‐4). Incidence and severity are governed by a number of cancer treatment variables, as described below.

Schematic illustration of the process of clinical management of oral complications of nonsurgical cancer therapies.

Figure 8‐4 Clinical management of oral complications of nonsurgical cancer therapies.

Oral Mucositis

Oral mucositis can have significant clinical and economic consequence in oncology practice (Figure 8‐5). The pain associated with the lesion can be sufficiently severe as to cause hospitalization in order to support nutritional intake and other daily functions. The pain can also cause dose reduction in future cycles of chemotherapy, thus compromising optimal delivery of the chemotherapy regimen.

Despite the prominence of oral pain in the clinical setting, however, there has been limited investigative research into the neuropathology component of the lesion. Mucosal injury in the neutropenic cancer patient can be source of systemic infection, with resultant morbidity and, in selected patients, mortality. Oral mucositis can thus cause clinically and economically adverse impact.

The current five phase pathobiologic model of oral mucositis is complex, and involves both epithelium as well as submucosa (Figure 8‐6).3133 In addition, the potential role of the oral microbiome in relation to oral mucositis pathobiology has received increasing research attention as well. Incidence of moderate–severe oral mucositis in high‐dose chemotherapy patients is approximately 40%.34

Evidence‐based guidelines for management of oral mucositis are centered on supportive care.9,11

The evidence base for clinical practice guidelines for prevention and treatment of oral mucositis was reviewed in 2019 by the Mucositis Study Group, MASCC/ISOO. The results were incorporated into recommendations or suggestions at three levels: (i) in favor of interventions for oral mucositis; (ii) against interventions for oral mucositis; or (iii) no guideline possible due to insufficient or conflicting evidence.10,11 Conclusions from these 2019 mucositis guidelines include:

Photo depicts oral mucositis in breast cancer patient receiving high-dose chemotherapy.

Figure 8‐5 Oral mucositis in breast cancer patient receiving high‐dose chemotherapy. The extensive pseudomembranous lesions can signficiantly impair normal oral function, and represent a portal of entry for severe systemic infection.

Source: Quintessence 2019.69

  1. Of the growth factors and cytokines studied for the management of oral mucositis, the evidence supports a recommendation in favor of intravenous keratinocyte growth factor (KGF)‐1 for prevention of oral mucositis in patients with hematological cancer undergoing autologous HSCT with high‐dose chemotherapy and total body irradiation and a suggestion against granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) in certain clinical settings.35
  2. Numerous natural products and herbal remedies have been studied for the management of oral mucositis. Of the agents reviewed in the systematic review, a guideline in favor was made for honey (combined topical and systemic), while a guideline against was made for chewing gum.36
  3. Of the agents studied for the management of oral mucositis‐associated pain, the evidence supports a suggestion in favor of topical morphine 0.2% mouthwash in patients with head and neck cancer receiving radiation therapy and chemotherapy.37 Additional guidance has been provided in a 2019 review by Epstein and Miaskowski, as cited in section Oral Pain.38

    The evidence supports recommendations for the use of oral cryotherapy for the prevention of oral mucositis for either (i) patients undergoing autologous hematopoietic stem cell transplantation with high‐dose melphalan conditioning protocols or (ii) patients receiving bolus 5‐fluorouracil chemotherapy.39

  4. Regarding basic oral care, the evidence supports implementation of multiagent combination oral care protocols for prevention of oral mucositis (in chemotherapy, head and neck radiation therapy, and hematopoietic stem cell transplantation) defined as interventions carried out by the patients, lay caregivers, and/or nondental care professionals. The rationale for their implementation is to increase awareness of both patients and staff of the importance of good oral hygiene, which may indirectly lead to less frequent and less severe oral complications.
  5. Typically, the protocols included in the systematic review involved a multifaceted approach to oral hygiene, including recommendations with regard to timing, frequency, and products such as combination of varying types of bland mouth rinses, toothbrushes, and flossing procedures.2
  6. Chlorhexidine was suggested not to be used in basic oral care protocols to prevent oral mucositis in patients with head and neck cancer undergoing radiation therapy. However, it was emphasized by the systematic review panel that this recommendation is specific to the prevention of oral mucositis and this recommendation does not apply to other conditions where chlorhexidine is indicated; for example, oral infections.2
    Photo depicts the conceptual framework for oral mucositis pathobiology consists of five stages, ranging from initial injury with hours of exposure to high-dose cancer therapy to eventual healing approximately 2–4 weeks after cessation of that treatment.

    Figure 8‐6 The conceptual framework for oral mucositis pathobiology consists of five stages, ranging from initial injury with hours of exposure to high‐dose cancer therapy to eventual healing approximately 2–4 weeks after cessation of that treatment. Although the illustration depicts an orderly and sequential mechanistic process, the likely course of molecular and cellular events is more likely dysregulated and biologically confounded.

    Source: Sonis 2007.31

  7. For other empiric basic oral care measures, only limited data were available. Thus, expert opinion supplements the basic oral care guidelines in support of the use of professional oral care for oral mucositis prevention; that is, dental evaluation and treatment as indicated prior to cancer therapy to reduce the patient’s risk for local and systemic infections from odontogenic sources. It was also the panel’s opinion that educating patients over the benefits of basic oral care strategies may improve the patient’s self‐management and adherence to the recommended oral care protocol during cancer treatment.
  8. Despite the limited data available for oral bland rinses, the panel recommends saline and sodium bicarbonate mouth rinses that increase oral clearance which may be helpful for maintaining oral hygiene and improving patient comfort.2
  9. Of the anti‐inflammatory agents studied for oral mucositis, the evidence supports use of benzydamine mouthwash for prevention of oral mucositis in patients with head and neck cancer receiving radiation therapy and chemotherapy.40
  10. Of the vitamins, minerals, and nutritional supplements studied for the management of oral mucositis, the evidence supports a recommendation against parenteral glutamine in patients receiving HSCT and a suggestion in favor of oral glutamine for management of oral mucositis in patients with head and neck cancer.41
  11. The evidence supports the use of specific settings of photobiomodulation therapy for the prevention of oral mucositis in specific patient populations. Under these circumstances, photobiomodulation is recommended for the prevention of oral mucositis. The guidelines are subject to continuous update based on new published data.42
  12. There is only one US Food & Drug Administration‐approved biologic for prevention of oral mucositis (see the section Patients undergoing hematopoietic stem cell transplantation [HSCT]). Additional interventions, including pharmacologic and photobiomodulation, are also being studied.42,43

Oral Pain

Oral pain in cancer patients is likely due to both nociceptive and neuropathic pathways; treatment of both of these mechanistic processes is thus needed to achieve effective management.38 The level of oral pain should be scored on a systematic basis, utilizing a validated pain ladder.

Pain management by patient‐controlled analgesia with morphine in hematopoietic stem cell transplantation, topical 0.2% morphine mouthwash in head and neck radiation therapy, or 0.5% doxepin mouthwash (patient population not specified) have been recommended or suggested depending on the level of evidence as interventions to treat pain due to oral mucositis.37 Management of pain from oral mucositis during head and neck radiation begins with nonsteroidal anti‐inflammatory drugs (NSAIDs) since generally there is not an increased risk of hemorrhage and this can be combined with opioids as the severity of oral mucositis and pain increases.44

Depending on the severity of mucositis, topical anesthetic rinses can be used to allow for continuity of oral care and food intake with the precaution that the patient is carefully informed to avoid mechanical trauma and burns in the anesthetized mucosal areas.

Oral Hemorrhage

Compromised basic oral care increases the risk of oral infection (gingivitis, periodontitis, oral candidiasis) which increases the risk of oral hemorrhage. Hemorrhage may also be caused by cancer treatment‐induced thrombocytopenia in patients receiving high‐dose chemotherapy or undergoing hematopoietic stem cell transplantation.

Hemorrhage can be controlled with basic oral care and adequate periodontal and antifungal treatment. However, if prolonged hemorrhage occurs (> 2 min), periodontal treatment should be discontinued and the oncologist/hematologist consulted. Further management of oral hemorrhage includes the use of vasoconstrictors, clot‐forming agents, and tissue protectants.45

PATIENTS RECEIVING HIGH‐DOSE CHEMOTHERAPY

Chemotherapy can be used in a variety of primary or adjunctive oncology settings (Table 8‐1). In addition to oral mucositis, oral infection can occur in association with chemotherapy‐induced myelosuppression (Table 8‐2). Unlike the head and neck radiation patient, however, long‐term effects of high‐dose chemotherapy on the oral tissues are rare.

Table 8‐1 Single and multimodality cancer treatments fororal cancer.

Source: Reprinted with permission from Peterson DE. Quintessence 2014.68

Neoadjuvant: Sole use prior to surgery
(debulk) (e.g., 5 days 5‐fluorouracil: mucositis)
Adjuvant: Use after surgery/before radiation therapy
(curative) (e.g., 5 days 5‐fluorouracil: mucositis)
Concurrent/
Concomitant: Combination with radiation therapy
(synergistic) (e.g., head and neck radiation therapy +
weekly cisplatin)

Patients may develop pseudomembranous oral candidiasis during periods of bone marrow suppression (Table 8‐3). Contributing factors may also include difficulties with oral hygiene during periods of oral mucositis as well as salivary gland hypofunction induced by medications used to support the care of the patient (e.g., antiemetics). Clinical diagnosis can often be established based on history and examination, although the assessment may be confounded by the concurrent presentation of chemotherapy‐induced oral mucositis as noted above. Topical oral antifungal therapy with nystatin rinses or clotrimazole troches can be considered for management (Table 8‐4). Resolution of the lesion typically occurs in the setting of bone marrow recovery and re‐establishment of optimal oral care.

The periodontium may infrequently be a site of acute infectious flare during profound myelosuppression (Figure 8‐7). These lesions are rarely encountered in oncology practice. When they do occur, however, the infection may not be readily detectable due to the impaired inflammatory response in the setting of profound neutropenia. Treatment usually consists of topical oral antimicrobial rinses and gentle mechanical plaque removal. Supervision of this intervention by a health professional with experience in dental management is highly recommended. Broad‐spectrum antimicrobial therapy should be considered if the clinical presentation so indicates.

Table 8‐2 High risk oral lesions in the myelosuppressedcancer patient.

Source: Reprinted with permission from Peterson DE. Quintessence 2019.69

Advanced and/or symptomatic dental caries
Periapical pathoses symptomatic within past 90 days
Severe periodontal disease for which prognosis of dentition is poor
Mucosal lesions secondary to trauma from prosthetic or orthodontic appliances

Table 8‐3 Oral candidiasis.

Source: Reprinted with permission from Peterson DE. Quintessence 2019.69

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Risk factors:

  • Myelosuppression
  • Mucosal injury
  • Salivary compromise
  • Antibiotics
  • Steroids
  • Increased length of hospital stay

Nov 28, 2021 | Posted by in General Dentistry | Comments Off on Oral Complications of Nonsurgical Cancer Therapies
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