**5. Clinical assessment and management of the oral environment in a child patient receiving cancer treatment**

#### **5.1 The impact of cancer therapies on the oral cavity**

The likelihood is high that aggressive cancer treatment will have toxic effects on normal cells as well as cancer cells. The gastrointestinal tract, including the mouth, is particularly prone to damage. This is true whether the treatment is radiation or chemotherapy. Most patients being treated for head and neck cancer will experience some oral complications, and while most of these are manageable, complications can sometimes become severe enough that treatment must be completely stopped. In addition, surgical solutions to tumor removal may lead to oral and nutritional problems as well. The most common oral problems occurring after radiation and chemotherapy are *mucositis* (an inflammation of the mucous membranes in the mouth), *infection, pain,* and *bleeding*. Other possible complications might include dehydration and malnutrition, commonly brought on by difficulties in swallowing (dysphagia). Radiation therapy to the head and neck may injure the glands that produce saliva (xerostomia), or damage the muscles and joints of the jaw and neck (trismus). These treatments may also cause hypovascularization (reduction in blood vessels and blood supply) of the bones of the maxilla or mandible (the bones of the mouth). In addition, treatments may affect other forms of dental disease (caries, or soft tissue complications), or even cause bone death (osteonecrosis). By identifying patients at risk for oral complications, health care providers are able to start preventive measures before cancer therapy begins,

What is the Role of Pediatricians on Oral Health? 155

regimen: high-dose melphalan (HDM) regimens exceed busulphan, busulphan– cyclophosphamide, cyclophosphamide–TBI, cyclophosphamide–carmustine (BCNU) and

Diagnosis of mucositis is clinical and based on the use of known stomatotoxic therapy, and the appearance, timing and location of oral lesions. Chemotherapy-induced mucositis occurs on the movable mucosae, rarely affecting the dorsum of the tongue, the hard palate or the gingiva. Radiation-induced mucositis also affects the movable mucosae and may involve the hard palate, albeit rarely. Infections and graft-versus-host disease (GVHD) are the most common differential diagnoses. Viral infections differ clinically from mucositis in that they are typically croppy, localized and involve keratinized mucosa of the hard palate, gingival and dorsal tongue and their onset often coincides with fever. Culture or exfoliative cytology at the time of lesion presentation is prudent. Graft-vs-host disease is limited to patients who have received allogeneic HSCT and develops following haematologic recovery (beyond 21 days after transplant) and typically results in dramatic oral lesions that are often lichenoid in character, sometimes also with xerostomia (Woo et al., 1997). Neutropenia, induced by

The early clinical sign of mucositis is erythema presenting about 4–5 days following chemotherapy infusion or at cumulative doses of head and neck radiation of about 10 Gy. Patients also often complain of burning and intolerance of spicey foods at this stage. Seven to 10 days after chemotherapy or at cumulative radiation doses of 30 Gy, ulcers develop, resulting in marked discomfort, often requiring opioid intervention and in many cases causing patients to alter their diet. In the case of chemotherapy-induced mucositis, lesions are seen mostly on the movable mucosae of the buccal mucosae and lateral and ventral surfaces of the tongue. The hard palate and gingiva appear not susceptible to chemotherapy-induced mucositis. In contrast, radiation-induced mucositis may involve any radiation-exposed area, including the hard palate, albeit rarely. Chemotherapy-induced mucositis lasts approximately 1 week and generally heals spontaneously by 21 days after infusion. Radiation-induced mucositis stays at a peak for at least 2 weeks following the completion of radiotherapy (typically 60–70 Gy). As a result, it is not uncommon for patients receiving radiotherapy for cancers of the mouth and contiguous areas, to have severe ulcerative oral mucositis persisting for 5–7 weeks. Chronic mucositis following radiation therapy does occur, but rarely. A large number of mucositis scoring systems have been devised (summarized by Sonis et al, 2004) but most lack standardization or validation. The two most commonly used scoring tools to describe toxicity are the WHO and the National

Cancer Institute (NCI) common terminology criteria for adverse events (Table 4).

3 Ulcers but requires liquid diet 4 Oral alimentation not possible

2 Erythema, ulcers but able to eat solids

Grade Clinical features

1 Soreness/erythema

0 -

Table 4. WHO Mucositis scale (WHO, 1979).

cyclophosphamide–etoposide–carmustine (Wardley et al., 2000).

chemotherapy, may be associated with necrotizing gingivitis.

**5.2.2 Clinical diagnosis** 

reducing the occurrence of problems brought about by different treatment modalities. *The most important risk factors leading to problems are oral or dental disease that already exists, and poor oral care during cancer therapy.* Other risk factors include the type of cancer, the chemotherapy type and schedule used, the area irradiated and how much radiation is given, how low blood counts are decreased and for how long, the patient's age, and the general condition of the patient's health pre-treatment. Pre-existing oral conditions may increase the risk of infection or other problems. Problems such as caries, calculus and tartar on the teeth, broken (fractured) teeth, the condition and quality of existing dental repairs such as crowns or fillings, periodontal disease, and appliances such as removable fixtures, or orthodontic brackets can make therapy more difficult later on. Bacteria and fungi can live in the mouth, and may develop into an infection when the immune system is not working well, or when white blood cell counts are low. Both of these factors can be caused by the treatment methods used. Where the gums (gingiva) or other soft tissues are irritated, tissues can thin and waste away, causing sores in the mouth. These complications can result in a significant reduction in the quality of life for the patient.

#### **5.2 Oral mucositis**

#### **5.2.1 What is oral mucositis?**

Mucositis is a common toxicity associated with both chemotherapy, and head and neck radiation used for the treatment of cancer (Scully et al., 2003, 2004). It is characterized by ulceration in the oro-oesophageal and gastrointestinal mucosae that results in pain, dysphagia, diarrhoea and dysfunction depending on the tissue affected (Sonis & Fey, 2002). Oral mucositis results in severe discomfort and impairs patients' ability to eat, swallow and talk. Concomitant therapy-induced myelosuppression places patients at significant risk of bacteraemia and sepsis from oral microorganisms resulting in increased days of fever, antibiotic use and hospitalization (Donnelly et al., 1995). Historically, mucositis has been associated with particular high-risk groups such as patients being irradiated for cancers of the head and neck, individuals receiving conditioning regimens for stem cell transplant that include total body irradiation or high dose melphalan and patients receiving specific induction protocols for acute leukaemia. Mucositis has been consistently reported to occur in at least 75% of treated patients in these groups. Radiation-induced mucositis occurs in almost all patients who are treated for cancers of the mouth, oropharynx and nasopharynx, and in approximately two-thirds of those treated for cancers of the hypopharynx or larynx. Mucositis risk and severity are determined by the treatment dose, radiation field size and fractionation schedules prescribed for individual patients. Hyperfractionated schedules and combination of radiation with chemotherapy increase the prevalence, severity and duration of mucositis. In patients receiving cancer chemotherapy, the frequency and severity of mucositis is mainly determined by the type(s) and dose of cancer chemotherapeutic agents used. five-fluorouracil (5-FU), cisplatin, etoposide and melphalan are particularly stomatotoxic (Chi et al., 1995; Pico et al., 1998) and mucositis is common with doxorubicin, vinblastine, taxanes and methotrexate, but uncommon with asparaginase and carmustine (Symonds, 1998). Finally, mucositis is seen in 75–99% of patients receiving conditioning regimens for haemopoietic stem cell transplantation (HSCT) particularly in those that combine total body irradiation (TBI) and chemotherapy (Blijlevens et al, 2000). Mucositis is the most common symptom and distressing complication of HSCT (Bellm et al., 2000), and some 30–50% of patients with HSCT complain that mucositis is their most significant toxicity. The only independent risk factor identified for mucositis is the conditioning regimen: high-dose melphalan (HDM) regimens exceed busulphan, busulphan– cyclophosphamide, cyclophosphamide–TBI, cyclophosphamide–carmustine (BCNU) and cyclophosphamide–etoposide–carmustine (Wardley et al., 2000).

#### **5.2.2 Clinical diagnosis**

154 Complementary Pediatrics

reducing the occurrence of problems brought about by different treatment modalities. *The most important risk factors leading to problems are oral or dental disease that already exists, and poor oral care during cancer therapy.* Other risk factors include the type of cancer, the chemotherapy type and schedule used, the area irradiated and how much radiation is given, how low blood counts are decreased and for how long, the patient's age, and the general condition of the patient's health pre-treatment. Pre-existing oral conditions may increase the risk of infection or other problems. Problems such as caries, calculus and tartar on the teeth, broken (fractured) teeth, the condition and quality of existing dental repairs such as crowns or fillings, periodontal disease, and appliances such as removable fixtures, or orthodontic brackets can make therapy more difficult later on. Bacteria and fungi can live in the mouth, and may develop into an infection when the immune system is not working well, or when white blood cell counts are low. Both of these factors can be caused by the treatment methods used. Where the gums (gingiva) or other soft tissues are irritated, tissues can thin and waste away, causing sores in the mouth. These complications can result in a significant

Mucositis is a common toxicity associated with both chemotherapy, and head and neck radiation used for the treatment of cancer (Scully et al., 2003, 2004). It is characterized by ulceration in the oro-oesophageal and gastrointestinal mucosae that results in pain, dysphagia, diarrhoea and dysfunction depending on the tissue affected (Sonis & Fey, 2002). Oral mucositis results in severe discomfort and impairs patients' ability to eat, swallow and talk. Concomitant therapy-induced myelosuppression places patients at significant risk of bacteraemia and sepsis from oral microorganisms resulting in increased days of fever, antibiotic use and hospitalization (Donnelly et al., 1995). Historically, mucositis has been associated with particular high-risk groups such as patients being irradiated for cancers of the head and neck, individuals receiving conditioning regimens for stem cell transplant that include total body irradiation or high dose melphalan and patients receiving specific induction protocols for acute leukaemia. Mucositis has been consistently reported to occur in at least 75% of treated patients in these groups. Radiation-induced mucositis occurs in almost all patients who are treated for cancers of the mouth, oropharynx and nasopharynx, and in approximately two-thirds of those treated for cancers of the hypopharynx or larynx. Mucositis risk and severity are determined by the treatment dose, radiation field size and fractionation schedules prescribed for individual patients. Hyperfractionated schedules and combination of radiation with chemotherapy increase the prevalence, severity and duration of mucositis. In patients receiving cancer chemotherapy, the frequency and severity of mucositis is mainly determined by the type(s) and dose of cancer chemotherapeutic agents used. five-fluorouracil (5-FU), cisplatin, etoposide and melphalan are particularly stomatotoxic (Chi et al., 1995; Pico et al., 1998) and mucositis is common with doxorubicin, vinblastine, taxanes and methotrexate, but uncommon with asparaginase and carmustine (Symonds, 1998). Finally, mucositis is seen in 75–99% of patients receiving conditioning regimens for haemopoietic stem cell transplantation (HSCT) particularly in those that combine total body irradiation (TBI) and chemotherapy (Blijlevens et al, 2000). Mucositis is the most common symptom and distressing complication of HSCT (Bellm et al., 2000), and some 30–50% of patients with HSCT complain that mucositis is their most significant toxicity. The only independent risk factor identified for mucositis is the conditioning

reduction in the quality of life for the patient.

**5.2 Oral mucositis** 

**5.2.1 What is oral mucositis?** 

Diagnosis of mucositis is clinical and based on the use of known stomatotoxic therapy, and the appearance, timing and location of oral lesions. Chemotherapy-induced mucositis occurs on the movable mucosae, rarely affecting the dorsum of the tongue, the hard palate or the gingiva. Radiation-induced mucositis also affects the movable mucosae and may involve the hard palate, albeit rarely. Infections and graft-versus-host disease (GVHD) are the most common differential diagnoses. Viral infections differ clinically from mucositis in that they are typically croppy, localized and involve keratinized mucosa of the hard palate, gingival and dorsal tongue and their onset often coincides with fever. Culture or exfoliative cytology at the time of lesion presentation is prudent. Graft-vs-host disease is limited to patients who have received allogeneic HSCT and develops following haematologic recovery (beyond 21 days after transplant) and typically results in dramatic oral lesions that are often lichenoid in character, sometimes also with xerostomia (Woo et al., 1997). Neutropenia, induced by chemotherapy, may be associated with necrotizing gingivitis.

The early clinical sign of mucositis is erythema presenting about 4–5 days following chemotherapy infusion or at cumulative doses of head and neck radiation of about 10 Gy. Patients also often complain of burning and intolerance of spicey foods at this stage. Seven to 10 days after chemotherapy or at cumulative radiation doses of 30 Gy, ulcers develop, resulting in marked discomfort, often requiring opioid intervention and in many cases causing patients to alter their diet. In the case of chemotherapy-induced mucositis, lesions are seen mostly on the movable mucosae of the buccal mucosae and lateral and ventral surfaces of the tongue. The hard palate and gingiva appear not susceptible to chemotherapy-induced mucositis. In contrast, radiation-induced mucositis may involve any radiation-exposed area, including the hard palate, albeit rarely. Chemotherapy-induced mucositis lasts approximately 1 week and generally heals spontaneously by 21 days after infusion. Radiation-induced mucositis stays at a peak for at least 2 weeks following the completion of radiotherapy (typically 60–70 Gy). As a result, it is not uncommon for patients receiving radiotherapy for cancers of the mouth and contiguous areas, to have severe ulcerative oral mucositis persisting for 5–7 weeks. Chronic mucositis following radiation therapy does occur, but rarely. A large number of mucositis scoring systems have been devised (summarized by Sonis et al, 2004) but most lack standardization or validation. The two most commonly used scoring tools to describe toxicity are the WHO and the National Cancer Institute (NCI) common terminology criteria for adverse events (Table 4).


Table 4. WHO Mucositis scale (WHO, 1979).

What is the Role of Pediatricians on Oral Health? 157

al., 1995). Cubukcu & Sevinir (2007) used debridement technique to promote healing of established mucositis and to alleviate symptom clusters in a group of children who were on induction chemotherapy. They concluded that debridement promoted resolution and decreased the severity of oral mucositis significantly. Thus, the subjects had less oral discomfort, pain, and nutritional difficulties. *In general, mucositis should be treated conservatively to avoid further tissue irritation and damaging the remaining cells from which the epithelium will regenerate. Plaque control and oral hygiene should be maintained with careful tooth brushing* (Borowski et al, 1994)*. The potential benefit of prophylactic rinses with chlorhexidine may be to control plaque levels, gingivitis, reduce caries risk and oropharyngeal candidosis, rather than any direct effect upon oral mucositis. The patient should be advised to take a soft bland diet, avoiding* 

Tooth caries (decay) remains a substantial problem in young children and is made worse by existing barriers that prevent them from obtaining dental care. Because most children are exposed to medical care but not dental care at an early age, pediatricians have the opportunity to play an important role in helping children and their families gain access to dental care. Instructional efforts to increase pediatricians' dental knowledge or opinions of the importance of oral diseases are unlikely to be effective in increasing dental referral unless they include methods to increase confidence in providers' ability to identify and appropriately refer children with disease. Pediatricians can provide oral health promotion and disease prevention activities, thereby eliminating or delaying dental disease and the

Aas JA, Griffen AL, Dardis SR, Lee AM, Olsen I (2008). Bacteria of dental caries in primary

Adamietz IA, Rahn R, Bottcher HD, Schafer V, Reimer K, Fleischer W (1998). Prophylaxis

Ahola AJ, Yli-Knuuttila H, Suomalainen T, Poussa T, Ahlström A, Meurman JH, Korpela R

Alaluusa S, Kiviranta H, Leppanilmi A (2002). Natal and neonatal teeth in relation to environmental toxicants. *Pediatr Res* 52, 5 (Nov 2002), 652-655, ISSN 0031-3998. Almonaitiene R, Balciuniene I, Tutkuviene J (2010). Factors influencing permanent teeth eruption. Part One-general factors. *Stomatologija* 12, 3, 67-72, ISSN 1392-8589. AlQahtani SJ, Hector MP, Liversidge HM (2010). Brief communication: The London atlas of

American Academy of Pediatric Dentistry (2003b). Clinical guidelines on infant oral

http://www.aapd.org/media/Policies\_Guidelines/G\_InfantOralHealthCare.pdf.

*Support Care Cancer* 6, 4 (Jul 1998), 373-377, ISSN 0941-4355.

and permanent teeth in children and young adults. *J Clin Microbiol* 46, 4 (Jan 2008),

with povidone-iodine against induction of oral mucositis by radiochemotherapy.

(2002). Short-term consumption of probiotic-containing cheese and its effect on dental caries risk factors. *Arch Oral Biol* 47, 11 (Nov 2002), 799-804, ISSN 0003-9969.

human dental development and eruption. *Am J Phys Anthropol* 142, 3 (Jul 2010),

*irritants such as tobacco, alcohol or spices. Nutrition should be maintained.* 

**6. Conclusion** 

**7. References** 

need for treatment at a very young age.

1407-1417, ISSN 0095-1137.

481-490, ISSN 0002-9483.

healthcare, accessed 3/29/2010, avaliable from:

#### **5.2.3 Prevention and treatment options**

There are a number of strategies adopted by oncologists to minimize the adverse effects of cancer therapy such as dose reduction, and other preventive treatment options. For example, leucovorin has been used for years to minimize the mucositis resulting from use of 5-FU (Lalla and Peterson, 2005). These are the province of oncologists and are not discussed further here. There has been a range of interventions developed for prophylaxis of oral mucositis but a more rational approach may be warranted. Indeed, there are very few randomized controlled double-blind trials (RCTs) assessing most of the interventions. A recent Cochrane review (Worthington, 2011) concluded that *cryotherapy (ice chips) and Keratinocyte Growth Factor (Palifermin ®) have shown some evidence of benefit in the prevention of mucositis. There is weaker less reliable evidence of a benefit associated with aloe vera, amifostine, intravenous glutamine supplementation, granulocyte-colony stimulating factor, honey, laser, polymixin/tobramycin/amphotericin (PTA) lozenges and sucralfate. There is no evidence that chlorhexidine is more effective that placebo and this intervention should not be used in the preventionofmucositis.*

The outcomes from studies testing GM-CSF, benzydamine hydrochloride or amifostine are mixed. (Mascarin et al, 1999; Tejedor et al, 2000). *Benzydamine HCl has been shown in single centre studies and in a multicentre double blind randomized placebo controlled trial in radiation therapy to reduce the intensity and duration of mucosal damage as well as to delay the need to use systemic pain-relievers including opioids* (Epstein et al., 1989, 2001)*.* Benzydamine was not effective however, in patients receiving accelerated radiotherapy doses of more than 220 cGy. A preliminary study indicated that the severity of oral mucositis, both objective and subjective, in HSCT patients may be reduced by 0.1% topical tretinoin cream which has antiinflammatory activity, administered daily from the beginning of the HCST conditioning until marrow engraftment (Cohen et al., 1997). Local antimicrobials containing amphotericin, polymixin and tobramycin may have some activity (Bondi et al., 1997). *Small single centre trials show that the incidence, severity and duration of radiochemotherapy-induced mucositis can be significantly reduced by oral rinsing with povidone iodine performed in addition to the standard prophylaxis scheme* (Adamietz et al. 1998). Mixed results have been seen with oral glutamine, which is involved in protein and nucleic acid synthesis: one group showed a decrease in the severity and duration of oropharyngeal mucositis in autologous HSCT patients but not in allogeneic HSCT patients. It is possibly because of interaction with methotrexate (Anderson et al., 1998a,b). While similar results were shown in a trial of intravenous glutamine in HSCT (MacBurney et al., 1994), and from an uptake-enhanced glutamine suspension used orally (Peterson, 2006), others have found no benefit (Schloerb & Skikne, 1999). Mucositis invariably requires systemic analgesics, adjunctive medications, physical therapy and psychologic therapy in addition to oral care. A recent Cochrane review (Worthington, 2004) concluded that there was *no evidence that patient controlled analgesia (PCA) is better than continuous infusion method for controlling pain, but less opiate was used per hour, and duration of pain was shorter, for PCA.* Only weak and unreliable evidence that allopurinol mouthwash, vitamin E, immunoglobulin or human placental extract improve or eradicate mucositis.

Pain from established mucositis can be reduced by systemic analgesics with non-steroidal agents and othernon-opiods used first, combined with opioids such as morphine and hydromorphone when pain is severe. In the in-patient setting, PCA provides the most effective pain control with lower total doses of opioid. Topical analgesics may combat pain and dysphagia when used prior to meals. Capsaicin may also provide analgesia (Berger et al., 1995). Cubukcu & Sevinir (2007) used debridement technique to promote healing of established mucositis and to alleviate symptom clusters in a group of children who were on induction chemotherapy. They concluded that debridement promoted resolution and decreased the severity of oral mucositis significantly. Thus, the subjects had less oral discomfort, pain, and nutritional difficulties. *In general, mucositis should be treated conservatively to avoid further tissue irritation and damaging the remaining cells from which the epithelium will regenerate. Plaque control and oral hygiene should be maintained with careful tooth brushing* (Borowski et al, 1994)*. The potential benefit of prophylactic rinses with chlorhexidine may be to control plaque levels, gingivitis, reduce caries risk and oropharyngeal candidosis, rather than any direct effect upon oral mucositis. The patient should be advised to take a soft bland diet, avoiding irritants such as tobacco, alcohol or spices. Nutrition should be maintained.* 
