Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section A – Symptom Management and Palliative Care

Chapter 40 – Oral Complications

Kostandinos Sideras,Charles L. Loprinzi,
Robert L. Foote

SUMMARY OF KEY POINTS

Incidence

  

   

Mucositis is a major dose-limiting toxic effect of chemotherapy for solid tumors developing in 5% to 40% of patients.

  

   

Mucositis develops in 70% to 100% of patients receiving high doses of chemotherapy with bone marrow rescue.

  

   

Radiation therapy to the oral cavity frequently causes a host of oral complications, including mucositis, xerostomia, dental caries, tissue necrosis, and taste alterations.

Etiology of Complications

  

   

Cytotoxic chemotherapy and radiation therapy cause oxidative stress and injury to oral cavity tissues, leading to upregulation of inflammatory cytokines, additional signaling and amplification of inflammatory pathways, and subsequent ulceration and healing.

  

   

Treatment-induced myelosuppression may lead to secondary infections.

  

   

Graft-versus-host disease (GVHD) is a further complication.

Prophylactic Measures

  

   

The importance of instituting oral hygiene protocols in patients receiving chemotherapy is well established.

  

   

Cryotherapy is the most conventional and easy to use preventative method, at least for 5-FU-based bolus therapy and appears to have implications for other chemotherapeutic regimens as well, such as edatrexate and high-dose melphalan therapy.

  

   

The role of antibiotics, either topically or systemically, has not yet been established.

  

   

Glutamine supplementation in the form of AES-15 (Saforis) has recently shown promise as a potentially effective agent.

  

   

Palifermin, a keratinocyte growth factor preparation, has been approved by the FDA for use with high-dose chemotherapeutic regimens associated with high rates of mucositis and has shown promise in other settings as well

  

   

Low-level laser therapy has shown promise, but its use is limited to centers that are able to support its use.

  

   

Pretreatment dental care, good oral hygiene, and sophisticated treatment planning are recommended for patients receiving radiation therapy.

Treatment

  

   

There is an overall lack of evidence regarding the efficacy of various agents in promoting healing of the oral mucosa after mucositis is established.

  

   

Systemic analgesic therapy of mucositis pain with narcotic medications is well established and recommended.

  

   

Antibiotics and/or antifungal medications should be given to patients with evidence of infection.

  

   

In the palliative setting, various mouthwashes are widely used in clinical practice based on provider preference and experience. These mouthwashes most frequently contain combinations of diphenhydramine, viscous lidocaine, magnesium hydroxide/aluminum hydroxide, nystatin, and corticosteroids. The efficacy of these measures has not been adequately evaluated to date.

  

   

Baking soda mouth rinses appear to be the most economical solution, although efficacy has not been clearly established.

INTRODUCTION

The oral cavity is a common site for chemotherapy-induced and radiation-induced toxicity. Manifestations of this toxicity include alimentary tract mucositis; secondary infectious complications induced by bacteria, fungi, and viruses; and graft versus host disease in patients receiving allogeneic bone marrow transplants. Although alimentary tract mucositis can involve the entire gastrointestinal tract,[1] it is most frequently manifested in the oral cavity as ulceration, pain, and bleeding. Mucositis leads to significant patient morbidity and decline in quality of life and limits the use of additional chemotherapeutic treatment. Moreover, the economic burden of this frequent oncologic complication is also considerable. [2] [3] This chapter discusses the etiology, incidence, risk factors, prevention, and treatment of oral toxic effects of standard chemotherapy, intensive marrow-ablative chemotherapy, and radiation therapy. The prevention and treatment of graft-versus-host disease is beyond the scope of this chapter (seeChapter 32 ).

Pathophysiology of Mucosal Injury

It is currently accepted that the processes of mucosal injury and subsequent healing are not limited to the epithelium alone but involve all layers of the mucosa, including the extracellular matrix. A five-stage process has been postulated to explain the complex molecular, cellular, and histologic events that are associated with chemotherapy-induced mucosal injury[4] ( Fig. 40-1 ). Oxidative stress related to chemotherapy is thought to be responsible for the first phase of mucosal injury (initiation phase). The second phase involves the upregulation of transcription factors and the generation of messenger signals (upregulation and message generation phase). In this stage, upregulation of NF-κ beta is thought to play a central role in the subsequent upregulation of multiple proinflammatory cytokines, such as TNF-α, IL-1b, and IL-6. NF-κ beta is also thought to upregulate cyclooxygenese-2, which in turn is implicated in the upregulation of matrix metalloproteinase.[5] In addition to the sphyringomyelinase and ceramide pathways, fibronectin breakup and macrophage activation are other complex events that take place leading to further mucosal injury and apoptosis. The third phase of mucosal injury involves additional signaling and amplification of the previously discussed pathways, leading to the generation of additional proinflammatory cytokines (signaling and amplification phase). Up to this point, the biologically altered mucosa appears still to be anatomically intact. The fourth phase consists of the symptomatic phase of mucositis, involving mucosal ulceration, pain, and bleeding (ulceration phase). Bacterial superinfection and reduction in salivary gland function can complicate and amplify the mucosal injury at this stage. The fifth and final phase involves the healing of the mucosa, a process that depends on angiogenesis and on increased biological activity in the extracellular matrix (healing phase). In patients who are undergoing myeloablative chemotherapy, the healing phase might not begin until leukocyte recovery. It is important to understand that these phases do not necessarily follow a linear progression but may occur simultaneously at different locations.[4]

 
 

Figure 40-1  Phases in the development of oral mucositis.  (Adapted from Peterson DE: New strategies for management of oral mucositis in cancer patients. J Support Oncol 2006;4:9–13.)

 

 

 

Mucositis Assessment

Multiple mucositis scales exist in clinical practice, differing in the level of objective and subjective information used. However, it is known that patient-provided data lead to the same conclusions as do clinician-determined data.[6] The WHO and NCI-CTC scales are the most commonly used ones and combine information from both the patient's signs and symptoms and the patient's functional status and ability to eat.[4]

ORAL COMPLICATIONS FROM CHEMOTHERAPY INCLUDING MYELOABLATIVE CHEMOTHERAPY

Incidence and Risk Factors

The type of chemotherapeutic agents that are used, the specific dose, route, and frequency of administration, and whether the chemotherapy is given as monotherapy or in combination with other agents and modalities of treatment significantly affect the degree of injury ( Fig. 40-2 ).

 
 

Figure 40-2  Risk of mucositis according to type of cancer therapy.  (Adapted from Peterson DE: New strategies for management of oral mucositis in cancer patients. J Support Oncol 2006;4:9–13.)

 

 

 

Antimetabolites such as methotrexate and 5-FU, antitumor antibiotics such as doxorubicin, platinum agents such as cisplatin, purine analogs such as cytarabine, and topoisomerase inhibitors such as etoposide are most specifically associated with mucositis. Methotrexate and etoposide are secreted into the saliva thus enhancing mucosal toxicity. Irinotecan, although notorious for causing gastrointestinal mucositis in the form of diarrhea, has limited oral toxicity.

Regarding the time course of mucosal injury, 5-FU-induced mucositis is usually first noticed anywhere from 3 to 7 days after initiation of therapy. Incidence peaks at 7 to 12 days and diminishes by around 2 to 3 weeks ( Fig. 40-3 ). With myeloablative chemotherapy for hematologic malignancies, mucositis severity can peak up to 18 days following initiation of therapy.[7]

 
 

Figure 40-3  Percentages of patients with mucositis for 30 days after initiation of 5-fluorouracil-based chemotherapy. These data come from two sequential randomized trials: [32] [36] one that compared 30 minutes of oral cryotherapy (▴) with a control group (▵) and one that compared 30 minutes of cryotherapy (○) with 60 minutes of cryotherapy (&z.cirf;).

 

 

Chemotherapy for the treatment of solid tumors leads to the development of mucositis in 5% to 40% of patients (5% to 15% grade 3 to 4).[8] Many modern treatment approaches have not solved this problem and, owing to their aggressiveness, are frequently more toxic.[9] A vast experience exists with 5-FU, the most commonly used drug to treat gastrointestinal malignancies. Although there has long been the belief that continuous administration of 5-FU carries a higher risk of mucositis than does bolus administration of 5-FU, a meta-analysis of trials failed to support this association.[10]

When myeloablative chemotherapy is used, the incidence of mucositis increases to 70% to 100% (21% to 67% grade 3 to 4). [7] [11] This appears to be especially true for induction regimens that contain high-dose melphalan.[7] When chemotherapy is used in combination with radiation therapy to treat cancer of the head and neck, the rate of mucositis approaches 90% to 100% of patients (43% grade 3 to 4).[12]

The role of age and gender in the development of mucositis has not yet been clearly defined, owing to conflicting reports.[13] There is also conflicting evidence on whether the type of bone marrow transplant (autologous versus allogeneic) or the use of total body irradiation in the conditioning regimen is related to the risk of mucositis.[13] On the other hand, poor oral hygiene, dental caries, periodontal disease, and high titers of herpes simplex virus (HSV) and positive cultures for Candida tropicalis are generally accepted to be risk factors.[13]

Finally, interpersonal variability in the development of mucositis been observed for years and could be due to the differences in metabolism of the chemotherapeutic drugs from person to person. A prime example consists of the drug methotrexate, which results in much higher degrees of mucositis[14] in patients with an inability to metabolize this drug.

Prevention of Chemotherapy-Induced Oral Complications

Effective means of preventing chemotherapy-induced oral complications would allow for an improved quality of life for patients receiving chemotherapy as well as a reduction of the rate of life-threatening infections that are thought to be originating from the oral mucosa. Theoretically, it might also improve the effectiveness of antineoplastic therapy by preventing treatment modifications during subsequent cycles and permitting more dose-intensive therapies. Several different methods have been proposed for preventing chemotherapy-induced oral complications ( Box 40-1 ).

Box 40-1 

PREVENTION OF CHEMOTHERAPY-INDUCED ORAL MUCOSITIS

The importance of instituting oral hygiene protocols in patients receiving chemotherapy is well established. Cryotherapy is the most conventional and easy-to-use preventive method, at least for 5-FU-based bolus therapy, and appears to have implications for other chemotherapeutic regimens as well, such as edatrexate and high-dose melphalan therapy. The role of antibiotics, either topically or systemically, has not yet been established. Glutamine supplementation in the form of AES-15 (Saforis) has recently shown promise as a potentially effective agent. The FDA has approved palifermin, a keratinocyte growth factor preparation, for use with high-dose chemotherapeutic regimens associated with high rates of mucositis, and it has shown promise in other settings as well. Low-level laser therapy has shown promise, but it is limited to centers that are able to support its use.

Oral Hygiene

Although generally there is insufficient evidence to suggest any one approach, there is enough collective evidence to recommend the institution of a comprehensive oral care protocol for patients receiving chemotherapy for solid tumors.[15] Multiple oral care protocols have demonstrated feasibility and tolerability, and some have shown a reduction in the severity of mucositis and an improvement in the patient's ability to cope with symptoms.[15] Such oral care protocols are usually implemented by nursing staff and involve various degrees of patient education. They can include cavity screening and dental consultations; basic oral care with tooth brushing, flushing, and rinsing; regular inspection of the oral cavity; and avoidance of substances such as smoking, alcohol, and spices. [16] [17] The cross-study differences that are seen in two similar treatment arms illustrated in Figure 40-3 could be related to the use of nurse-directed oral care recommendations in the second study that were not used in the first study. Teeth extraction prior to chemotherapy for severe periodontal disease may also be reasonable to consider.[18]

Currently, there is a wide heterogeneity in the approach to mucositis prevention in the United States, and multiple different oral care protocols are available. The need for a more standardized approach is evident, including the institution of multidisciplinary teams. [19] [20]

Regarding the oral care of myeloablative chemotherapy candidates, guidelines drafted by the Centers for Disease Control, Infectious Disease Society of America, and American Society of Blood and Marrow Transplantation in 2000 recommend a formal dental evaluation, with appropriate subsequent treatment, prior to initiation of any conditioning regimen. This includes appropriate treatment of caries, proper fitting of any dental prosthesis, and extraction of teeth with significant periodontal disease. These interventions should ideally be performed 10 to 14 days prior to any conditioning therapy. During therapy, oral hygiene should be maintained with rinses four to six times a day using either sterile water, normal saline, or sodium bicarbonate solutions, and patients should brush their teeth at least twice daily with a soft or ultra-soft tooth brush or a toothette (i.e., foam swab on a stick). Use of toothpaste is optional, and daily dental flossing should be done only by patients who are experienced in the technique, if it can be done without trauma. Orthodontic appliances and space maintainers can be removed during therapy, although if good tissue integrity and satisfactory daily oral hygiene are maintained, their use can continue during the initial conditioning phase.[21]

Antimicrobial Agents

In the past, microorganisms were hypothesized to play a central role in the pathogenesis of mucositis. This no longer is thought to be true. This is partly because topical and systemic antibiotics, to date, have failed to significantly affect the incidence and severity of mucositis and, as a result, are currently not recommended for routine use.[22] One explanation might be the general failure to significantly eradicate microbes from the oral cavity[23] or the possibility that alterations in the microbial flora by antimicrobial agents might make no difference or cause more harm. [22] [24] Another explanation is that microorganisms might play a more complex and possibly a more minor role than was initially thought. It is currently suggested that instead of being involved in the initiation phase, they probably intensify the inflammatory process associated with the later phases of mucosal injury. [4] [22] Nevertheless, what appears to be true is the association between the severity of mucositis and the incidence of sepsis and other infections, suggesting that microbes use the already damaged gastrointestinal mucosa as a portal of entry, thus increasing the risk of infectious complications.

Of all the antiseptics, chlorhexidine has been most extensively studied in multiple randomized trials, and the results have been mixed. Therefore, its regular use is not recommended. [15] [25] [26] Isenagan, a naturally occurring peptide with a broad antimicrobial spectrum, has also failed to show benefit.[27] Although one small placebo-controlled randomized trial has shown benefit for the prophylactic use of topical povidone-iodine, further study is needed before this agent is accepted in clinical use.[25] Regarding systemic antibacterial prophylaxis, data are also not convincing, and systemic antimicrobials therefore are not recommended at this time for the prevention of mucositis. [22] [28] [29]

Reactivation of HSV can be a significant complication in patients receiving myeloablative chemotherapy and frequently presents with oral ulceration. Although high titers of HSV and positive cultures forC. tropicalis have been reported as significant risk factors for the development of mucositis, routine surveillance cultures of oral tissues is not recommended.[30] On the other hand, HSV infection should be suspected if mucositis persists or appears to worsen, 2 or more weeks following transplantation. The guidelines of the Centers for Disease Control, Infectious Disease Society of America (IDSA), and American Society of Blood Marrow Transplantation (ASBMT) recommend testing for serum anti-HSV IgG prior to bone marrow transplant. However, prophylactic treatment with acyclovir is recommended only for seropositive allogeneic stem cell recipients. In this situation, its use is recommended only until engraftment, until mucositis resolves, or up to 30 days after the start of treatment. Prolonged treatment can be considered in patients with frequent recurrent HSV infections. Autologous seropositive recipients can also be potentially treated if significant mucositis is expected from the conditioning regiment. Valacyclovir and Foscarnet are not recommended for this indication.[21] Despite these recommendations, HSV is thought to have a marginal role in causing frank oral mucositis.[15]

Although antifungal medications are currently not recommended for the prophylaxis of oral candidiasis in patients receiving chemotherapy, there is evidence to suggest that prophylactic gastrointestinally absorbable or partially absorbable antifungal medications reduce the rate of oral candidiasis.[31]

Cryotherapy

5-FU-BASED CHEMOTHERAPY.

Initially, a North Central Cancer Treatment Group randomized clinical trial demonstrated that oral cryotherapy can inhibit the development of bolus 5-FU-induced mucositis.[32] This has been independently validated by other investigators. [33] [34] [35] It is hypothesized that cryotherapy works by causing local vasoconstriction during periods of peak 5-FU blood concentration, thus decreasing the delivery of 5-FU to the oral mucosa. This therapy is administered by having the patient suck on crushed ice, starting 5 minutes prior to 5-FU administration and continuing for a total of 30 minutes. A longer duration of oral cryotherapy (60 minutes) does not appear to provide any additional benefit in this setting.[36]

EDATREXATE.

Four small nonrandomized phase I and II trials have used 20 to 30 minutes of oral cryotherapy for prevention of mucositis in patients receiving edatrexate, a methotrexate analog with improved preclinical antitumor activity. Three out of the four trials have shown good tolerability of edatrexate when it is used with oral cryotherapy, [37] [38] [39] while one study showed high toxicity despite this preventive strategy.[40] Current guidelines recommend cryotherapy as an attempt to decrease mucositis in patients who are treated with bolus edatrexate.[15]

HIGH-DOSE MELPHALAN.

At least five small prospective nonrandomized studies in patients receiving high-dose melphalan therapy have tested the efficacy of oral cryotherapy as compared to historical controls. Grade 3 mucositis developed in only 0% to 11% of patients treated with oral cryotherapy as compared to the incidence of mucositis in historical controls, which is observed in over 70% of patients. [41] [42] [43] [44] [45] In the only randomized placebo-controlled study, using room temperature normal saline as placebo, 40 patients were treated with cryotherapy or placebo for 30 minutes before and 6 hours after chemotherapy with high-dose melphalan. Grade 3 mucositis was experienced in 14% of patients receiving cryotherapy and in 74% of patients receiving normal saline.[46] Although the need for such prolonged administration of cryotherapy is questionable, owing to patient noncompliance and the probably equivalent efficacy of shorter administration, cryotherapy appears to be a promising strategy in lowering mucositis in patients receiving high-dose melphalan therapy, and it is currently recommended in this setting.[47] This evidence points to a possible role for cryotherapy in more diverse settings than was previously thought.

Antioxidants, Anticholinergics, and Coating Agents

In general, insufficient evidence exists regarding the effectiveness of antioxidant compounds such as tretinoin and vitamin E in preventing oral mucositis in patients receiving chemotherapy.[13] A small randomized trial of zinc sulfate reported a statistically significant benefit in preventing severe mucositis; more investigation is warranted before accepting this agent as standard practice.[48] There is also insufficient evidence to support the prophylactic use of Propantheline, an anticholinergic drug that is thought to reduce the amount of etoposide secreted in the saliva.[25] Mixed data exist on the role of sucralfate, a coating agent; therefore, sucralfate is not currently recommended for the prevention of oral mucositis. [25] [26]

Anti-inflammatory Agents

Since inflammatory mediators appear to play a central role in mucositis development, the use of anti-inflammatory agents has been proposed as a method for preventing mucositis. However, cytokine inhibitors and anti-inflammatory agents have not yet proven to be efficacious.

Pentoxifylline, a TNF-α and IL-2 inhibitor, is currently not recommended in either the standard chemotherapy or bone marrow transplant setting. [15] [25] Benzydamine mouthwash has been approved for radiation-induced mucositis in Europe and Canada and is currently being tested in the United States. [15] [49] However, evidence regarding its use in prevention of chemotherapy-induced mucositis is weak, and it is currently not recommended in this setting.[25]

Amino Acids

Glutamine is a nitrogen-rich nonessential amino acid with a critical role in nucleotide synthesis, muscle function, and overall metabolic homeostasis. However, during periods of stress, it becomes a conditionally essential amino acid, and its stores can be significantly depleted, as is the case in patients with cancer.[50] Multiple trials to date have attempted to investigate the beneficial potential of different glutamine preparations through both the parenteral and oral routes, with mixed results. [50] [51] Glutamine had been administered through the parenteral route, as part of total parenteral nutrition, or in intravenous infusions mixed with normal saline. It has also been administered as oral supplements and as swish and swallow mouthwash preparations. Overall, these trials have been small, and conclusions have been difficult to draw.

However, recent data have emerged regarding Saforis, an oral suspension form of L-glutamine with an enhanced delivery system. Three hundred and twenty-six breast cancer patients who developed grade ≥2 mucositis during the first cycle of treatment with an anthracycline-based regimen were treated with Saforis, 2.5 g/5 mL orally three times per day concurrent with their next chemotherapy dose, swished for 30 seconds and then swallowed, for at least 14 days, versus placebo. The results showed a reduction in the incidence of grade ≥2 mucositis in the subsequent cycle of chemotherapy by 11% (50% to 39%: P = 0.03), as well as a reduction in the subsequent severity of mucositis in the patients who were treated with Saforis.[52] In another trial, 197 patients undergoing bone marrow transplant and treated with glutamine via the swish and swallow method for 14 days had a significant reduction in the severity and duration of mucositis. This was true for the autologous transplant patients but not the patients receiving allogeneic transplants.[53] In summary, although glutamine is not yet officially recommended for the prevention of chemotherapy-induced oral mucositis, results of several studies are promising, and if subsequent data are confirmatory, recommendations could change.

Growth Factors

Growth factors, systemically or topically, are hypothesized to help prevent oral mucositis due to their potential to improve healing. Although the use of granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor (GM-CSF) has been associated with reduced mucositis in certain randomized trials, the data are inconclusive as yet (Cochrane).[25] A recent meta-analysis found a benefit for prophylactic treatment with systemic growth factors but not for topical preparations.[26] However, the results of the meta-analysis were largely dependent on one strongly positive study alone, and further evidence is needed.[54]

Topical keratinocyte growth factor, which is secreted by injured mucosal epithelium, may have a more localized healing effect in the oral cavity. The Food and Drug Administration (FDA) recently approved one such preparation, palifermin, for use in preventing mucositis induced by myeloablative chemotherapy. The recommendation was based on a study of 212 patients who were randomized to receive intravenous palifermin or placebo for three consecutive days immediately before the initiation of conditioning therapy. Grade 3 or 4 mucositis developed in 63 percent of patients in the palifermin group and 98 percent of patients in the placebo group.[55] Palifermin has shown benefit in at least two more trials. In a series of 59 patients undergoing hematopoietic stem cell transplantation 13% of patients receiving palifermin developed severe mucositis compared to 48% of patient who received standard care.[56] Palifermin was also tested in 64 patients with colorectal cancer who received 5-FU-based chemotherapy, and a significant reduction in severe mucositis score was seen, with 29% of patients receiving palifermin developing severe mucositis compared to 61% receiving placebo.[57]Although apparently effective, it constitutes an expensive option for mucositis prevention at this point. In addition, since in these studies, oral cryotherapy was not administered to either the patients who received 5-FU-based chemotherapy or the patients who received high-dose melphalan therapy, it would be interesting to examine how palifermin would fare in comparison to oral cryotherapy.

Low-Level Laser Therapy

Evidence is accumulating that low-level laser therapy might promote healing and reduction of pain in patients who are at risk for oral mucositis. [58] [59] However, the expense, the need for specialized training and equipment, and the difficulty in interpreting and comparing the results from the various trials limit the widespread applicability of this approach at this time. Although no guidelines regarding its use exist yet, further investigation with large phase III randomized placebo-controlled clinical trials is encouraged.[15] Moreover, for centers that are able to support the necessary technology and training, this approach is recommended in an attempt to reduce the oral mucositis associated with myeloablative chemotherapy. In fact, low-level laser therapy is considered standard in some centers.[59]

Other Interventions

A variety of protocols include the prophylactic use of oral rinses and mouthwashes, such as normal saline, sodium bicarbonate solutions, and other mixtures. Although there is insufficient evidence to support their use, they constitute parts of various standard oral care protocols. Evidence does exist, however, that rinses that contain alcohol tends to worsen the symptoms of mucositis and therefore should be avoided. In a double-blind controlled trial in patients undergoing bone marrow transplantation, a benefit has been suggested for a neutral supersaturated calcium phosphate rinse (Caphosol) given in conjunction with fluoride when compared to fluoride rinsing alone.[60] Allopurinol mouthwashes, despite constituting standard clinical practice at some institutions the early 1990s, are currently not recommended, since at least two randomized clinical trials have convincingly shown no benefit. [25] [61] [62] Traumeel S, a homeopathic remedy, was tested as a mouthwash in a randomized placebo-controlled trial of 32 pediatric patients undergoing stem cell transplantation, and a statistically significant reduction in the incidence and severity of mucositis was reported. However, the study is not conclusive, and further investigation is under way. Finally, a double-blind randomized placebo-controlled trial of chamomile mouthwash has also failed to show benefit. [25] [26]

Conclusion

The importance of instituting oral hygiene protocols in patients receiving chemotherapy is well established. Cryotherapy is the most conventional and easy-to-use preventive method, at least for 5-FU-based bolus therapy, and appears to have implications for other chemotherapeutic regimens as well, such as edatrexate and high-dose melphalan therapy. The role of antibiotics, either topically or systemically, has not yet been established. Glutamine supplementation in the form of AES-15 (Saforis) has recently shown promise as a potentially effective agent. The FDA has approved palifermin, a keratinocyte growth factor preparation, for use with high-dose chemotherapeutic regimens associated with high rates of mucositis, and it has shown promise in other settings as well. Low-level laser therapy has shown promise, but it is limited to centers that are able to support its use.

Treatment of Chemotherapy-Induced Oral Mucositis

Scant information is available regarding the effective treatment of chemotherapy-induced mucositis, despite a plethora of prescribed remedies ( Box 40-2 ). Hence, initial treatment of established mucositis varies significantly among institutions, and different providers often prescribe remedies based on their individual experience and preference.[19] Among these many proposed treatments are various mouthwashes, coating agents, topical anesthetics or analgesics, anti- inflammatory agents, systemic narcotics, and topical and systemic growth factors.[15] These treatments are aimed at promoting the healing of the injured oral mucosa and thus limiting the severity and duration of ulcerations, as well as palliating the symptoms of oral mucositis.

Box 40-2 

TREATMENT OF CHEMOTHERAPY-INDUCED ORAL MUCOSITIS

There is overall lack of evidence regarding the efficacy of various agents in promoting healing of the oral mucosa after mucositis is established. Systemic analgesic therapy of mucositis pain with narcotic medications is well established and recommended. Antibiotics and/or antifungal medications should be given to patients who have evidence of infection. In the palliative setting, various mouthwashes are widely used in clinical practice based on provider preference and experience. These mouthwashes most frequently contain combinations of diphenhydramine, viscous lidocaine, magnesium hydroxide/aluminum hydroxide, nystatin, and corticosteroids. The efficacy of these measures has not been adequately evaluated to date. Salt and baking soda mouth rinses appear to be the most economical solution, although efficacy has not been clearly established.

General recommendations that are frequently given to the patients with established mucositis include the avoidance of spicy, coarse, hot, cold, or acidic foods or juices or medications or beverages containing alcohol and the encouragement of rather soft, moist foods and nonalcoholic beverages. Moreover, the treating physician should take care not to lose sight of the other important means of support for the cancer patient presenting with mucositis such as proper hydration, nutrition, infectious surveillance, and psychological support, all of which can significantly affect the patient's well-being and quality of life.

Mouthwashes

For patients with established mucositis, one of the first therapeutic measures that is frequently used consists of having the patients rinse their mouths every 2 to 4 hours with a solution of salt and baking soda (1/2 teaspoon salt plus 1/2 teaspoon baking soda in an 8-ounce glass of warm water). This is often soothing and is thought to be cleansing. Some centers use baking soda alone, since the addition of salt is thought to be too drying to the mucosa. In one multicenter study, 200 patients receiving standard chemotherapy, who followed a carefully planed oral hygiene protocol (PRO-SELF), were randomized to one of three different mouthwashes: salt and soda, chlorhexidine, or “magic” mouthwash (lidocaine, Benadryl, and Maalox). No significant differences were observed in time to cessation of the signs and symptoms of mucositis among the three regiments; salt and soda was the least costly.[63]

Mouthwashes, often referred to as “magic” or “miracle mouthwash,” are usually topical preparations of analgesic, anesthetic, and coating agents, the composition of which varies across institutions. The most common ingredients are diphenhydramine, viscous lidocaine, magnesium hydroxide/aluminum hydroxide, nystatin, and corticosteroids.[64] Other ingredients include benzocaine, milk of magnesia, chlorhexidine, kaolin, and pectin.[15] Despite their widespread use, the general lack of evidence supporting their efficacy and tolerability does not allow presently any of these preparations to be included into formal guidelines.[15] Further study of these palliative mixtures however is strongly encouraged, given their overall availability, ease of administration, frequent use, and low cost.

Chlorhexidine mouthwashes are not recommended, since studies have failed to support the use of this agent for the treatment of established mucositis.[15] Coating agents, such as sucralfate, have also failed to show any benefit for the treatment of established chemotherapy-induced mucositis when tested in small randomized trials.[65]

Anti-inflammatory Agents

Anti-inflammatory agents in general have failed to find a role in the treatment of chemotherapy-induced mucositis.[66]

Growth Factors

It is hypothesized that GM-CSF, systemically or topically as a mouthwash, might stimulate proliferation of endothelial cells and promote keratinocyte growth, thus enhancing recovery of oral mucositis. However, studies have been limited and are of poor methodological quality. [65] [67]

Systemic Analgesics

Oral mucositis pain can be severe and can significantly interfere with the quality of life of patients receiving chemotherapy. Management should follow the same aggressive guidelines that are used to treat pain in patients with cancer in general.[68] The use of patient-controlled anesthesia is effective and well established for treating mucositis pain, especially in the hematopoietic stem cell transplantation setting.[15]

Conclusion

There is overall lack of evidence regarding the efficacy of various agents in promoting healing of the oral mucosa after mucositis is established. Systemic analgesic therapy of mucositis pain with narcotic medications is well established and recommended. Antibiotics and/or antifungal medications should be given to patients who have evidence of infection. In the palliative setting, various mouthwashes are widely used in clinical practice based on provider preference and experience. These mouthwashes most frequently contain combinations of diphenhydramine, viscous lidocaine, magnesium hydroxide/aluminum hydroxide, nystatin, and corticosteroids. The efficacy of these measures has not been adequately evaluated to date. Salt and baking soda mouth rinses appear to be the most economical solution, although efficacy has not been clearly established.

RADIATION THERAPY

Mucositis

Etiology

The most troublesome acute reaction for patients who are receiving radiation therapy to the oral cavity is radiation-induced mucositis. Acute mucositis results from the loss of squamous epithelial cells owing to the sterilization of mucosal stem cells and the inhibition of transit cell proliferation. This leads to a gradual linear decrease in epithelial cell numbers. As radiation therapy continues, a steady state between mucosal cell killing and mucosal cell regeneration may occur because of an increased cell production rate from the surviving cells. Usually, however, cell regeneration cannot keep up with cell killing, and partial or complete denudation develops. This presents as patchy or confluent pseudomembranous mucositis. Healing eventually occurs when cells regenerate from the surviving mucosal stem cells. The loss of the epithelial barrier exacerbates insults from physical, chemical, and microbial agents. It has been reported that the oropharyngeal flora may contribute to radiation therapy–induced mucositis. However, which flora is involved and which step in the mucositis process may be prevented by eliminating the offending flora remain unknown. One hypothesis is that endotoxins produced by gram-negative bacilli are potent mediators of the inflammatory process.

The oral cavity mucosa, having a relatively high turnover rate, change early during a course of fractionated external-beam radiation therapy. With 200-cGy fractions per day, 5 days per week, mucosal erythema is typically noted within the first week or two of treatment. By approximately 2 to 3 weeks, the erythematous mucosa develops small whitish yellow patches called patchy pseudomembranous mucositis. These pseudomembranes represent collections of dead surface epithelial cells, fibrin, and polymorphonuclear leukocytes on a moist background. This acute reaction is typically accompanied by oral discomfort. In many patients, the patchy mucositis becomes confluent by the third or fourth week of radiation therapy and can be associated with significant pain.

The severity of mucositis is related to the daily dose of radiation therapy, the total cumulative dose, the volume of irradiated tissue, and the use of concurrent radiation-sensitizing and/or mucositis-inducing chemotherapeutic agents. At fractions of 170 to 180 cGy daily, 5 days per week, the maximal reaction is typically intense erythema with occasional patchy mucositis. In this situation, the cell killing and repopulation of epithelial stem cells are in near equilibrium. If the daily dose is increased to 200 cGy or more, as in the case of altered fractionation schedules such as hyperfractionation (110 to 150 cGy twice a day) or accelerated fractionation (160 cGy two or three times a day or concomitant boost with 180 cGy in the morning and 150 cGy in the afternoon), and the treatment volume is large (the entire oral cavity), cell killing will exceed the proliferative capacity of the epithelial stem cells, and almost all patients will have confluent mucositis by the third week of radiation therapy. Mucositis first appears and is often most severe on the mucosa of the soft palate, tonsillar pillars, buccal mucosa, lateral border of the tongue, and pharyngeal walls. In contrast, mucositis less frequently involves the hard palate, gingival ridges, and dorsum of the tongue during a course of radiation therapy or, alternatively, only after very high doses or when administered with concurrent radiation-sensitizing chemotherapy. In patients with metallic dental restorations, a prominent mucositis frequently develops on the adjacent buccal mucosa and/or the lateral border of the adjacent tongue or both as a result of backscattering of low-energy electrons.

Symptoms of oral discomfort are usually maximal 3 to 4 weeks into the course of radiation therapy. Thereafter, symptoms usually plateau and may even diminish in patients who are treated with radiation therapy alone, even though treatment is continued. After external-beam radiation therapy, the mucous membranes normally heal within 4 to 6 weeks, although an occasional patient might require up to 12 weeks or even several months. The latter is particularly true of patients treated with concurrent radiation-sensitizing chemotherapy.

The mucositis that is produced by an interstitial radioactive implant typically appears 7 to 10 days after removal and is maximal approximately 2 weeks after removal. The mucositis generally heals by 6 weeks unless the implanted volume was large, in which case complete healing may require several months.

Radiation-induced oral mucositis can result in intense pain, which may substantially limit adequate hydration and nutrition, prevent proper oral hygiene, serve as a portal for infection, and affect speech. All these effects can significantly interfere with the general well-being of the patient and might tempt the treating physician to interrupt the course of treatment to permit resolution of the acute symptoms. At times, the treatment might be discontinued altogether before delivery of a potentially curative dose of radiation therapy.

Clinical and radiobiologic evidence shows that the protraction of overall treatment time adversely influences the radiocurability of certain human tumors, particularly squamous cell carcinomas of the head and neck region. The additional dose that is needed to compensate for a protracted course of radiation therapy has been attributed to an accelerated tumor clonogenic growth rate. Randomized clinical trials have demonstrated improved local control and survival when altered fractionation schemes that deliver conventional or higher doses of radiation therapy are used over a shorter-than-conventional period.[69] Therefore, a break in radiation therapy because of mucositis may lead to treatment failure.

Prevention and Treatment

In light of the serious deleterious effects that radiation-induced oral mucositis may have on a patient's well-being and the potential loss of tumor control that may result from an interruption or prolongation of treatment because of mucositis, measures for preventing mucositis are being investigated. Benzydamine hydrochloride 0.15% oral rinse, a nonsteroidal drug, that has analgesic, anesthetic, anti-inflammatory, and antimicrobial properties, is effective, safe, and well tolerated for prophylactic treatment of radiation-induced oral mucositis. [49] [70] Nonetheless, benzydamine is not approved for this use in the United States, as the data are not convincing regarding its benefit and as some of the studies looking at it used an alcohol-based control arm (which should cause toxicity in patients getting radiation therapy) instead of an inert placebo substance.

Several controlled clinical trials have evaluated the combination of relatively nonabsorbable antibiotics (tobramycin, polymyxin E, and amphotericin B or bacitracin, clotrimazole, and gentamicin or iseganan) for patients undergoing radiation therapy to the oral cavity. [49] [71] [72] [73] [74] [75] [76] [77] [78] [79] In total, these trials do not provide convincing data of sufficient clinical magnitude to recommend use of antimicrobial mouthwashes (chlorhexidine or benzydamine), antibiotic lozenges, or paste as part of standard practice. For a critical review, the reader is referred to an article by Sutherland and Browman.[80]

The inability to control mucositis-related pain can be frustrating for both the patient and the treating physician. Viscous lidocaine with 1% cocaine; dyclonine hydrochloride 1.0%; a mixture of kaolin-pectin solution, diphenhydramine, and saline; morphine; tricyclic antidepressants; a mucosa-adhesive water-soluble polymer film containing topical anesthetics and antibiotics; oral aloe vera; capsaicin lozenges; and a sodium-sucrose octasulfate oral rinse have all been evaluated, with mixed results. [81] [82] [83] [84] [85] [86] Janjan and colleagues[87] reported improved pain management in patients undergoing radiation therapy for head and neck cancer with daily nursing intervention consisting of instructions on the use of mouthwashes and a three-step analgesic protocol consisting of acetaminophen, acetaminophen with codeine suspension, and liquid morphine for relief of mild, moderate, and severe pain, respectively. The physician promptly changed the prescribed analgesic regimen when the patient's symptoms changed. Patients who had daily nursing intervention reported fewer days of moderate and severe pain; had less pain throughout the day; and noted less disturbance in sleep, eating, and energy level. Daily review of a symptom survey by a radiation oncology nurse combined with a well-defined strategy for mouth care and analgesics appeared to improve pain management of radiation-induced oropharyngeal mucositis because of prompt attention to patient needs. Many narcotic pain medications come in a liquid formulation that is relatively easy to swallow or can be administered through a feeding tube. Fentanyl patches are also very effective for patients who cannot swallow. A topical morphine mouthwash might be a more effective treatment for mucositis pain than a commonly utilized “magic mouthwash” (lidocaine, diphenhydramine, magnesium aluminum hydroxide).[88]

Additional interventions for preventing or minimizing radiation-induced mucositis have been evaluated. One such intervention involves the use of a sucralfate suspension, an agent that appears to provide a protective barrier and may also have a cytoprotective effect. The latter may be mediated through prostaglandin release, resulting in increased mucosal blood flow, increased mucus production, increased mitotic activity, and a surface migration of cells. However, results from small double-blind, placebo-controlled, randomized prospective trials are contradictory. [89] [90] [91] [92] [93] [94] [95] Thus, the randomized trials of sucralfate for therapy-induced mucositis do not establish a role for sucralfate in clinical practice.

In an evaluation of another intervention, Maciejewski and colleagues[96] reported that painting the buccal mucosa with a 2% silver nitrate solution for several days before radiation therapy stimulates normal mucosa repopulation during radiation therapy, producing a significantly less severe mucosal reaction and faster mucosal healing after completion of radiation therapy. Low-energy laser therapy might also activate epithelial healing. A phase III, randomized, placebo-controlled trial to evaluate the efficacy of low-energy helium-neon laser in the prevention of radiation-induced mucositis demonstrated significant reductions in severity and duration of oral mucositis associated with radiation therapy, even when combined with chemotherapy.[97] A double-blind, placebo-controlled, randomized trial of treatment with 40 mg of prednisone, beginning on day 8 of an accelerated course of radiation therapy, did not show a reduction in the intensity or duration of mucositis. However, there was a trend favoring prednisone in terms of shorter treatment interruptions and a significant reduction in overall treatment time.[98] Zinc sulfate, α-tocopherol, and intravenous L-alanyl-L-glutamine have been found to be effective in decreasing the severity of radiation-induced mucositis and oral discomfort in placebo-controlled prospective trials. [48] [99] [100] In an uncontrolled evaluation, orgotein, a Cu-Zn superoxide dismutase, demonstrated reduced acute toxicity associated with radiation therapy.[101] These unique approaches to the problem of acute mucositis deserve further study.

Other preliminary studies have investigated the direct application of a prostaglandin E2 gel,[102] the use of oral glutamine,[103] and daily use of subcutaneous GM-CSF.[104] Results of pilot studies suggested that GM-CSF might be quite effective in the prevention and treatment of radiation-induced oral mucositis. [105] [106] [107] [108] However, prospective randomized clinical trials have revealed no definite evidence that subcutaneously administered GM-CSF reduce the severity of radiation-induced mucositis. [109] [110] On the other hand, some early murine mucosal and human clinical data suggest that keratinocyte growth factor might be efficacious in the prevention and treatment of radiation-induced mucositis. [55] [111] [112] [113] This was previously reviewed in the section on prevention of chemotherapy-induced oral mucositis. A multicenter study of intravenous palifermin to reduce mucositis in patients with head and neck cancer receiving chemoradiotherapy is being conducted by the Radiation Therapy Oncology Group.

The radioprotector amifostine has been evaluated as a means of preventing radiation-induced acute mucositis. One small randomized clinical trial reported that amifostine reduced the severity of acute mucositis.[114] Unfortunately, larger randomized trials evaluating intravenous or subcutaneous amifostine in patients receiving radiation therapy alone or combined with chemotherapy have revealed conflicting results. [115] [116] [117] [118] [119] Nausea, vomiting, hypotension, and allergic and injection site reactions are common side effects of this drug. These side effects may be reduced by rapid intravenous push, optimal hydration of the patient, premedication with antiemetics, and subcutaneous administration. The questionable efficacy and significant toxicity are associated with remarkably increased costs.[120] In total, present data are insufficient to recommend amifostine at the current dose and schedules to prevent mucositis associated with radiation therapy.[121]

One should not forget the role that sophisticated radiation therapy treatment planning can have in limiting the volume of normal tissues that are irradiated and thereby reducing the severity of normal tissue reactions. Normal tissue reactions can be reduced in a substantial number of patients with head and neck cancer by the use of computed tomography-based target delineation, intensity-modulated radiation therapy and simple, custom-made, intraoral devices that are designed to exclude uninvolved tissues from the treatment portals or to provide shielding of tissues within the treatment area. [118] [122] [123]Patients with primary cancers of the oral cavity, oropharynx, paranasal sinuses, and salivary glands are the best candidates for the use of such devices. These intraoral stents can be very useful in excluding the mucosa of the tongue and the floor of the mouth when hard palate, nasal cavity, and paranasal sinus malignancies are being treated. These same stents can be useful in excluding the palate mucosa during treatment of the tongue or floor of the mouth. Shielding stents made with a lead alloy were found to be useful in treatment of well-lateralized tumors of the oral cavity, parotid gland, lip, and skin of the cheek. These shielding stents can decrease the amount of radiation that is delivered to the contralateral mucosa. More frequent use of electron-beam and/or sophisticated three-dimensional conformal, multibeam, wedged-pair, or oblique treatment plans will also help to exclude or minimize the radiation dose to uninvolved mucosa. Packing gauze between metallic dental restorations and mucosa of the lateral tongue and buccal area appears to be very beneficial in minimizing the dose from scattered radiation.

Given these data, what measures should be taken to prevent and treat mucositis in patients receiving radiation to the oral cavity? Standard practice often includes aggressive, good oral hygiene consisting of brushing teeth after each meal, using a soft toothbrush and baking soda toothpaste, and rinsing the mouth every 2 hours throughout the day with a half-strength hydrogen peroxide or alkaline solution. Patients should be instructed to avoid the use of irritating or abrasive substances such as commercial toothpastes and mouthwashes; tobacco; alcoholic beverages; extremely hot or cold drinks or foods; very spicy foods; acidic foods such as citrus fruits and their juices; and foods that are hard and coarse, such as pretzels, raw vegetables, potato chips, crackers, and hard bread. When discomfort develops, topical anesthetic agents can be used. As the pain progresses, use of systemic analgesics, including acetaminophen with codeine suspension or oral morphine sulfate elixir, might become necessary. Suspensions are preferred over elixirs because suspensions are formulated without alcohol. As Janjan and colleagues suggest,[87] daily intervention by a radiation therapy nurse or physician with prompt increases in doses of systemic analgesics appears to result in improved pain control, improved sense of well-being, and less weight loss.

The mucosa of patients undergoing radiation therapy to the oral cavity should be examined at least once a week, and antibiotic or antifungal medications should be prescribed as infections are documented. Clotrimazole troches, one dissolved in the mouth five times a day for 14 days, generally work well for oral candidiasis. However, if significant mucositis, altered taste, or xerostomia has developed, the troches might not be tolerated. In this situation, nystatin oral suspension or fluconazole in tablet or liquid form is often effective. Fluconazole is more effective than nystatin and might need to be given at a higher dose and/or for an extended period of time in patients who are receiving combined chemotherapy and radiation therapy due to infections with resistant species. [124] [125]

Xerostomia

Etiology

The major salivary glands (parotid, submandibular, and sublingual) produce most of the salivary secretion (up to 80%). The rest of the saliva is produced by minor glands scattered throughout the oral cavity. It is estimated that the sublingual glands contribute only 2% to 5% of the salivary flow rate. Submandibular glands seem to be as important as, or more important than, parotid glands in the resting state, although parotid glands become the main contributors under stimulation.

When radiation therapy treatment fields include the major salivary glands, many patients will experience dryness of the oral mucosa during the first 1 or 2 weeks of treatment. Not only is the quantity of saliva reduced, but its composition and physical properties are changed as well. Drastic reductions of baseline and reflex production of alkaline and watery secretions of serous acini often persist after the completion of radiation therapy. Without appropriate management, this problem can lead to progressive deterioration of the teeth, mucosa, gingiva, and mandible.

The acute radiation response of serous salivary glands has been shown to be due to interphase killing of serous cells. Chronic atrophy of these glands is attributed to the death of the reproductive stem cells and damage to the fibrovascular stroma. A progressive reduction in salivary flow rates, pH, and secretory immunoglobulin A (IgA) with increasing doses of radiation therapy has been demonstrated. In 90% of parotid glands that receive less than 1000 cGy, there will be continued secretion of measurable quantities of saliva after stimula tion. This is reduced to 50% after administration of 3000 cGy, 19% after 5000 cGy, and 0% after 7000 cGy. In 94% of patients receiving doses of less than 5200 cGy, there may be recovery of secretion beginning 2 months after treatment with continual improvement of the salivary flow for up to 18 months. Doses exceeding 6400 cGy cause irreversibly depressed parotid function in the majority of glands. Patients who receive doses of more than 6400 cGy to one gland might have only slight dryness; however, patients with both glands irradiated will have severe problems with salivary flow and discomfort of dryness. Exclusion of more than 50% of both parotid glands from the direct radiation beam can prevent severe dryness when the rest of the major salivary glands are included in the field. There is a linear correlation between postradiotherapy flow ratio and parotid gland dose (5% loss of function per 1 Gy of mean dose) and a strong parotid volume dependency.[126] There is no threshold dose. Therefore, in radiation treatment planning, attempts should be made to achieve as low a mean parotid dose as possible. A mean dose below 39 Gy has a complication probability of 50%. Recovery of parotid function can be demonstrated at 6 months, 12 months, and 5 years after radiation therapy. [127] [128]

Eisbruch and colleagues[129] and Blanco and colleagues[126] suggested that a mean parotid gland dose of ≤26 Gy should be a planning goal if substantial sparing of the gland function is desired. Using the Normal Tissue Complication Probability model, they found that the dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response/function relationships when the thresholds are reached, and a maximal volume dependence parameter. Chao and colleagues[130] observed a correlation between mean parotid dose and the fractional reduction of stimulated saliva output at 6 months after the completion of radiation therapy. They also noted that responses to quality-of-life questions on eating and speaking functions were significantly correlated with stimulated and unstimulated saliva flow at 6 months. Therefore, sparing of the parotid glands should translate into objective and subjective improvement of xerostomia and quality of life in patients with head and neck cancer receiving radiation therapy. Eisbruch and colleagues[129] found that the degree of xerostomia was related to the degree of preradiation therapy xerostomia, the time since radiation therapy, and the mean dose to the major salivary glands (most notably the submandibular gland) and to the oral cavity. This would suggest that sparing of the oral mucosa with its minor salivary glands is an important goal in treatment planning to reduce the severity of radiation-induced xerostomia.

Prevention and Treatment

Treatment of radiation-induced xerostomia includes the avoidance of any drugs that might also decrease the flow of saliva and contribute to the discomfort of xerostomia. These drugs may include anorectic agents, anticholinergics, antidepressants, antihistamines, antihypertensives, antipsychotics, antiparkinsonian agents, diuretics, caffeine, nicotine, hypnotics, and sedatives. Patients should be advised to take frequent sips of water and suck on ice chips. Because chewing stimulates the flow of saliva, patients with residual salivary function may be helped by eating foods such as carrots or celery or by chewing sugarless or xylitol-containing gum. Patients with xerostomia are highly susceptible to dental caries and should not use sugar-containing foods or acidic foods or beverages to stimulate salivary flow. Commercial nonprescription solutions that are used to lubricate the oral tissues might be the only effective treatment for patients without functioning salivary gland parenchyma or for those whose salivary glands do not respond to stimulation. Virtually all lubricants can provide some short-term relief for patients with xerostomia. Some studies have indicated that salivary substitutes that contain carboxymethylcellulose or hydroxymethyl cellulose are more effective in relieving dryness than are water- or glycerin-based solutions. Some patients prefer mucopolysaccharide solutions. Xialine, a xanthan gum–based saliva substitute, has been shown to be no better than placebo in decreasing the effects of xerostomia, although a trend was seen in favor of Xialine for improving problems with speech and senses.[131] Various reports have suggested that acupuncture can subjectively (patient-completed xerostomia inventories) and objectively (unstimulated and stimulated salivary flow rates) reduce symptoms of xerostomia and improve salivary flow rates. [132] [133] [134]

For the treatment of established radiation-induced xerostomia, the following are recommended ( Box 40-3 ):

  

   

Pilocarpine: 5.0 mg, given orally three to four times a day, up to 10 mg three times a day maximum

  

   

Artificial saliva (Mouthkote, Xerolube, Moistir, Salivert, Sage)

  

   

Biotene products (gum, toothpaste, mouthwash)

Box 40-3 

PREVENTION AND THERAPY OF RADIATION-INDUCED XEROSTOMIA

Prevention of radiation-induced xerostomia has been actively studied in the recent past. Results from the use of pilocarpine in this situation have been mixed, the largest placebo-controlled trial being negative. However, on the basis of results of clinical trials, the FDA has approved amifostine in the adjuvant setting as an agent that can attenuate the development of xerostomia. Nonetheless, the inconvenience and toxicity of this drug therapy limit its use in some practices. Intensity-modulated radiation therapy has been shown in a phase III trial to preserve salivary flow and improve quality of life in patients with early stage nasopharyngeal carcinoma.

Xerostomia primarily affects mastication and oral manipulation of dry, absorbent food material. Initiation and duration of the pharyngeal swallow do not appear to be affected. Patients with severe xerostomia may be helped by eating soft, bland foods, especially cool or cold foods with a high liquid content, such as ice cream, Popsicles, puddings, watermelon, and grapes. Solid foods can be made easier to swallow by adding gravies, sauces, melted butter, broth, mayonnaise, yogurt, or salad dressing. Dunking bread and other baked foods in milk or other liquids will make them easier to swallow. Some patients may find a pureed diet or a full-liquid diet easier to swallow than solid foods. Addition of a liquid high-protein supplement will help to ensure that patients are getting enough protein and calories. Hot, spicy, or acidic foods may be irritating and should be eaten with caution. Some patients find that a vaporizer or humidifier in the room or at the bedside helps to alleviate the discomfort of xerostomia. Frequent oral rinses with an alkaline solution may help to refresh the taste, moisten the mouth, and promote better hygiene.

Two large randomized, double-blind, placebo-controlled, multicenter clinical trials have documented the efficacy of oral pilocarpine (5.0 mg given orally three times a day) in relieving oral dryness; improving salivary flow, mouth comfort, and ability to speak; and reducing the need for oral comfort agents after head and neck irradiation. Adverse reactions are minimal, the most common being mild to moderate sweating, which is dose-related. Best results may require continuous treatment for more than 8 weeks. [135] [136] [137] Most patients report significant relief of symptoms of xerostomia and improvement in quality of life that do not appear to be dependent on previous radiotherapy dose/volume parameters, suggesting that oral pilocarpine acts primarily by stimulating ectopic salivary glands and can be of benefit for a whole range of patients with xerostomia of varying severity. Topical pilocarpine administration has shown results similar to those achieved with systemic treatment but with improved patient tolerance.[138]

One small retrospective trial and two small double-blind, placebo-controlled, randomized trials suggested that pilocarpine (5.0 mg given orally four times a day), started the day before or on the same day as radiation therapy, given concurrently with radiation therapy and for 3 months after radiation therapy, results in a lower frequency of oral symptoms and xerostomia during treatment and afterward. It might not be necessary to continue the use after 3 months to maintain the benefit. [139] [140] [141] Two large placebo-controlled clinical trials conducted by Princess Margaret Hospital and the Radiation Therapy Oncology Group nonetheless failed to confirm these initial findings and did not demonstrate any reduction in the incidence or severity of radiation-induced xerostomia with prophylactic use of pilocarpine 3 days before radiation therapy, during radiation therapy, and for 3 months after completion of radiation therapy. [142] [143]

Amifostine appears to protect the salivary glands from the effects of radiation therapy and might prove to be helpful in preventing or minimizing the effects of xerostomia and loss of taste. [114] [115] [116] [119] [144] [145] Buntzel and colleagues,[114] Brizel and colleagues,[116,] Wasserman and colleagues,[144] Antonadou and colleagues,[115] and Jellema and colleagues[145] have all reported significant reduction in the severity of acute and chronic radiation-induced xerostomia with prophylactic use of amifostine as determined by non-placebo-controlled clinical trials. There was no evidence that amifostine interfered with the antitumor effects of radiation therapy as measured by local or regional control and overall survival. Jellema and colleagues compared no amifostine to amifostine three times weekly and five times weekly amifostine. Grade 2 or greater late xerostomia differed significantly at 6 months (74% for no amifostine, 67% for three times weekly, and 52% for five times weekly) but not thereafter. Patient-rated xerostomia deteriorated more in the patients who received no amifostine. There was no difference between three times weekly and five times weekly administration of amifostine. Nausea and emesis were common side effects with 28% of patients discontinuing the amifostine before the end of radiotherapy.[145] Subcutaneous administration of amifostine may be as effective as intravenous administration with less severe nausea, vomiting, and hypotension but more frequent cutaneous toxicity.[146] It is of interest to note the continued reduction in the incidence of grade ≥2 xerostomia, and increased unstimulated and stimulated saliva production at 12, 18, and 24 months in the patients not receiving amifostine. In addition, while the mean overall scores for the patient benefit questionnaire are improved significantly by amifostine at 12 months, there are no significant differences at 18 or 24 months.[144] A placebo-controlled phase III trial failed to confirm the radioprotective benefit of amifostine on salivary function following chemoradiotherapy.[118] Patient self-reported xerostomia questionnaire scores are a more accurate reflection of the severity of xerostomia, since physician-assessed scores underestimate the severity of xerostomia.[147] A small randomized trial demonstrated that amifostine might prevent deterioration of dental health.[148] The use of amifostine may be considered to decrease the incidence of acute and late xerostomia in patients undergoing fractionated radiation therapy in the head and neck region that includes the salivary glands.[121] The Food and Drug Administration has approved amifostine for use in the postoperative adjuvant setting.

In selected patients with cancers in the oropharynx, hypopharynx, or larynx, it has been reported that surgical transfer of a submandibular gland into the submental space can be successfully accomplished.[149] If patients require postoperative radiation therapy, the submandibular gland can more readily be excluded from the irradiated volume, thus preserving some saliva production. This process requires validation by controlled clinical trials.

Three-dimensional conformal and intensity-modulated radiation therapy has been shown in prospective uncontrolled and controlled phase III clinical trials to preserve parotid salivary flow and improve quality of life by reducing the dose to the parotid glands. [117] [129] [130] [150] [151] Altered fractionation radiation therapy schedules may also help to preserve salivary function. Leslie and Dische[152]evaluated the function of parotid glands in patients treated with three different radiation therapy schedules 9 or more months after completion of treatment. Twelve parotid glands that had received conventionally fractionated radiotherapy to a dose of 60 to 66 Gy showed a mean percentage flow of 20% and a significant decrease in saliva pH. Six glands that had received continuous hyperfractionated accelerated radiation therapy showed mean percentage flows of 65% with only slight and nonsignificant decreases in saliva pH. These results were attributed to the lower dose per fraction used, with subsequent greater repair of sublethal damage between treatment fractions.

Dental Caries

Etiology

Patients undergoing radiation therapy to the oral cavity have an increased incidence of caries because of the lack of saliva to cleanse the teeth and changes in the quality of the saliva. This promotes oral cavity colonization with a more cariogenic flora. In addition, the discomfort associated with xerostomia and persistent mucositis may result in poor oral hygiene with infrequent brushing, flossing, and oral rinses. Some patients may also alter their diet to include sugar-containing drinks and soft foods to help alleviate the effects of xerostomia. Rampant caries can occur, involving all tooth surfaces (including the cervical portion) after just a few months of xerostomia.

Prevention and Treatment

To prevent the development of dental caries (which may result in the need for extraction, soft-tissue necrosis, bone exposure, and osteoradionecrosis) after a course of radiation therapy, all patients should undergo a thorough dental evaluation before treatment. Nonsalvageable teeth should be extracted, and an alveolotomy and primary wound closure should be performed, if indicated. A thorough dental prophylaxis should be performed, including scaling, root cleaning, curettage, and polishing. Restorative dental procedures, including surgical endodontics, should be performed for salvageable teeth. A preventive regimen should be initiated, including plaque removal with the use of dental floss and thorough instructions for correct toothbrushing. Custom-made fluoride carriers should be fabricated, and a neutral 1.1% sodium fluoride gel should be applied to the teeth after breakfast and before bedtime for a period of 2 weeks, beginning as soon as possible after the initiation of radiation therapy. This may be reduced to one bedtime application for 1 month and then twice-weekly fluoride applications indefinitely. Some patients may require twice-daily application throughout their lifetime. The dosage of the fluoride should be modified according to the patient's history of dental caries and oral hygiene performance. Patients should also use a calcium phosphate remineralizing rinse immediately after fluoride applications. Combined fluoride and calcium formulations are available.

Edentulous patients should have their dentures evaluated, and ill-fitting dentures should be corrected. Patients should be discouraged from wearing their dentures until the mucosa is completely healed from the acute effects of radiation therapy (usually about 3 months).

After radiation therapy, patients should be seen every 3 months for frequent dental checkups. There is no concern regarding the additional X-ray exposure of dental films, because the dose is insignificant in comparison with the therapeutic dose that is given for the cancer therapy. All routine dental procedures can be performed without unusual precautions after a course of radiation therapy except radical periodontal treatment and extractions, which may lead to osteoradionecrosis if not done with special care. When extractions are required after a course of radiation therapy, it is best to remove one tooth at a time with as little trauma to adjacent tissues as possible and to wait until healing is complete before proceeding to further extractions. Prophylactic antibiotic coverage should be started 1 day before extraction and be continued until the site is completely healed. Some institutions favor the use of hyperbaric oxygen before extraction.[153] Primary closure of the wound should be carried out over a smooth, bony surface so that no sharp spicules or ridges are left beneath the mucosa. Postradiation therapy tooth extractions carried out in this manner have a good chance of complete healing without the development of necrosis. When extreme root sensitivity occurs after radiation therapy, brushing fluoride onto the exposed root surface and using specially formulated commercially available toothpaste appears to decrease the sensitivity to some extent.

Soft-Tissue and Bone Necrosis

Etiology

The soft-tissue necrosis of oral cavity mucosa that occurs after high doses of radiation therapy may be attributed to the obliteration of small blood vessels or severe mucositis with ulceration. Irradiated epithelium is thinner than normal and appears pale and atrophic. It also has telangiectatic vessels. The irradiated mucosa is more susceptible to mechanical injury and to the noxious effects of alcohol and tobacco. Soft-tissue necrosis usually begins with breakdown of damaged mucosa, resulting in a small ulcer. Most soft-tissue necroses will occur within 2 years after radiation therapy. Occurrence after 2 years is generally preceded by mucosal trauma. The risk of soft-tissue necrosis is increased with larger fraction sizes, higher total doses, large volumes of irradiated mucosa, and the use of an interstitial implant.

Treatment

If recurrent cancer is not clinically suspected, biopsy should be avoided, because this may enlarge the area of necrosis. Topical anesthetics can relieve the discomfort associated with soft-tissue necrosis and allow the patient to eat normally. Antibiotics often provide pain relief, particularly when the ulceration is deep and infected. It is essential that the patient discontinue the use of alcohol and tobacco. If the area of necrosis is traumatized by dentures, the dentures should not be worn until healing is complete.

More than 90% of soft-tissue necroses will heal with conservative treatment, although in some instances, it might take many months. A small trial (consisting of 12 patients with 15 sites of late radiation necrosis of the soft tissues) has been conducted to evaluate the effect of pentoxifylline on healing radiation necrosis. The average duration of nonhealing before treatment with pentoxifylline was 30.5 weeks. With the institution of pentoxifylline (400 mg given orally three times a day), 13 of 15 necroses healed completely, and one partially healed an average of 9 weeks after treatment was started. All patients had pain relief.[154] Additional case reports and small clinical trials have suggested that the combination of pentoxifylline, tocopherol, and clodronate may be beneficial in preventing and healing severe osteoradionecrosis, radiation-induced trismus, radiation-induced ulcerated fibrosis, soft-tissue necrosis, and mucosal necrosis. [155] [156] [157] [158] [159] [160] [161] [162] These results support further study of pentoxifylline in patients in whom soft-tissue necrosis develops after a course of radiation therapy.

The mandible and maxilla will tolerate rather high doses of radiation therapy without serious problems, as long as the tissues overlying the bone remain intact. If soft-tissue necrosis develops in the mucosa overlying the mandible or maxilla, the underlying bone may become exposed. This can lead to serious injury, resulting in bone necrosis (osteoradionecrosis). Compared with the maxilla, the gingiva of the mandible has a rather tenuous blood supply, placing the mandible at greater risk of exposure and necrosis. Most bone exposures will heal spontaneously after conservative treatment. Small areas of bone exposure (<1 cm) generally heal spontaneously after a period of weeks to months. Larger areas of bone exposure may persist for a long period and may lead to bone necrosis, followed by sequestration. If exposed, necrotic bone may become infected. The necrotic process may then extend to involve adjacent bone for a considerable distance. Severe necrosis can then develop and lead to orocutaneous fistulae and pathologic fractures.

If the bone is rough or protrudes above the level of the gingiva, an oral surgeon may remove it to promote healing. Local debridement of moderate-size necrosis can be performed by an oral surgeon if indicated. If the patient wears a denture, it should be withheld from use or relieved over the site of exposure. Pain is not a common symptom; if present, it can usually be controlled with analgesics. A local anesthetic can be applied with a cotton-tipped applicator if needed for pain control. Antibiotics frequently reduce infection and discomfort within a few days but should be continued for 2 to 3 weeks. Hyperbaric oxygen along with antibiotic therapy and local debridement may help promote healing. Mandibular resection should be reserved as the last resort for the patient with intractable pain, recurrence of severe infections, fracture, or trismus.

Most bone problems develop within 3 to 12 months after radiation therapy, but some risk persists for many years, especially if the patient undergoes dental extractions. Necrosis is most likely to occur after extraction of mandibular teeth, although this is infrequent if special precautions are taken. The edentulous patient has a lower overall risk for bone necrosis compared with the dentulous patient.

Patients who are at highest risk for osteoradionecrosis appear to be those with tumors involving the gingiva or bone; those who continue to smoke or drink or both after radiation therapy; and those who receive high doses of radiation therapy, large treatment volumes, large fraction sizes, and/or interstitial implants.

Taste Alterations

Loss of taste occurs rapidly early in the course of radiation therapy to the oral cavity. Most patients report that the sense of taste is essentially nonexistent by the third or fourth week of treatment. After the completion of radiation therapy, most patients report some taste improvement within 1 to 2 months. Full recovery of taste usually requires 2 to 4 months. In some patients, taste never returns to normal, at least in part because of xerostomia. Although some studies have suggested that zinc therapy may be useful in improving taste acuity, a randomized clinical trial did not show any benefit for zinc over a placebo.[163] Amifostine may protect against taste loss caused by irradiation. [114] [116]

Trismus

Etiology

Trismus may be caused by fibrosis of the muscles of mastication after high-dose radiation therapy to the oral cavity or oropharynx, surgical scarring, and/or advanced carcinomas involving the pterygoid and/or masseter musculature. The temporomandibular joint itself is relatively resistant to ankylosis caused by radiation therapy, but the risk of injury increases if the joint is invaded by tumor. The use of large daily treatment fractions also appears to increase the risk of trismus.

Prevention and Treatment

High-energy x-ray beams and sophisticated multiple-field techniques should be used whenever possible to reduce the dose of radiation therapy to the temporomandibular joint and to the muscles of mastication. Patients who are treated with both surgery and radiation therapy have a greater risk for trismus than do patients who are treated with either modality alone. Patients who are at high risk for trismus and those in whom trismus has developed before treatment should perform jaw-stretching exercises daily in an attempt to increase the interarch or interincisor distance. A number of techniques are used, including commercially available jaw-stretching tools and less expensive stacked tongue blades, tapered corks, or clothespins. These devices are inserted between the teeth to increase the interincisor distance until slight pain is encountered. The exercises should be done for about 30 seconds every 2 hours. Additional tongue blades can be added, or a thicker aspect of the cork can be placed between the teeth every few days to increase the interincisor distance and stretch the muscles of mastication.

Malignancy

The carcinogenic effect of ionizing radiation has long been recognized. The latent interval between radiation therapy and the development of cancer varies from several to many years. Kogelnik and colleagues[164] reviewed charts of 1163 patients treated for head and neck cancer at the M.D. Anderson Cancer Center who had survived a minimum of 5 years after treatment without having recurrent cancer. Follow-up for these patients ranged from 7.5 to 25.5 years. Patients were treated with surgery alone (337 patients) or radiation therapy with or without surgery (826 patients). The incidence of new cancers in the primary tumor site (1.8% versus 2.7%), within the immediate vicinity of the primary tumor (4.2% versus 3.1%), or at sites remote from the primary tumor but still within the oral cavity or pharynx (4.7% versus 5.7%) was very similar for patients treated with surgery alone and patients treated with irradiation with or without surgery, respectively. It was concluded that moderate or high-dose radiation therapy did not produce any new squamous cell carcinomas of the mucous membranes. Similar findings were reported from the Fox Chase Cancer Center[165] and the University of California, Los Angeles.[166]

The rarity of radiation-induced sarcomas, the long latent period before their development, and the difficulty in obtaining reliable long-term follow-up data make the task of estimating the true risk of this problem difficult. However, most series include one or two cases of radiation-induced bone sarcoma per 1000 5-year survivors. If one were to assume malignant induction in 1 patient of every 500 long-term survivors, then with an estimated 5-year survival rate of 40% for all patients with head and neck cancer who received radiation therapy, it is calculated that 1 case would be induced per 1250 patients treated. A review of the Mayo Clinic experience showed no difference in survival between patients with radiation-induced sarcomas of the mandible or maxilla and non-radiation-induced sarcomas of the same site (45% 5-year overall survival).

Because some patients with radiation-induced osteogenic sarcomas of the mandible or maxilla can be cured, the risk of dying from a radiation-induced sarcoma after a course of radiation therapy is minimal and is very similar to the risk of death that a patient accepts when undergoing chemotherapy, general anesthesia, general surgery, or major head and neck cancer surgery.

An association has also been noted between radiation therapy and thyroid tumors. The latent period is usually 10 to 30 years. Almost all reported cases have followed low doses of radiation therapy (<6 to 1500 cGy), well below the doses that are used for squamous cell carcinomas of the head and neck. Doses greater than 2000 to 3000 cGy are associated with a very low risk of induction of thyroid neoplasia compared with lower doses. This is likely because higher doses of radiation therapy either completely destroy follicular cells or at least render the surviving cells incapable of division. Not all thyroid neoplasms that develop after radiation therapy are malignant, and many of the malignant neoplasms that do develop (papillary and follicular carcinomas) are readily curable with surgery. Thus, the risk of radiation-induced carcinoma should not be a major factor in determining treatment approaches for the typical patient with head and neck cancer.

Implementation of Prevention and Treatment of Radiation-Induced Oral Complications

Jansma and colleagues[167] surveyed all Dutch radiation therapy centers in which irradiation of patients with head and neck cancer is performed to determine which prevention and treatment regimens are used for oral sequelae resulting from head and neck radiotherapy. Survey questions included queries about screening, care before irradiation, care during radiation therapy, care during postradiation therapy, and the composition of the dental team who evaluated and treated the patients undergoing radiation therapy. Unfortunately, these investigators found a great diversity in the preventive approach to treatment of patients with head and neck cancer at Dutch radiotherapy institutes. Disturbing findings included a lack of well-defined guidelines in many centers, absence of a dental team at some centers, absence of an oral hygienist on some dental teams, and the observation that many patients were not referred to the dental team in a timely manner. The investigators recommend the development of a general protocol for the prevention of oral complications applicable at all head and neck cancer radiation therapy centers.[168] Similar deficiencies are probably present at the head and neck cancer radiotherapy centers within the United States. It is strongly recommended that dedicated teams be assembled to administer aggressive care to patients receiving radiation therapy to the oral mucosa. These teams should institute preventive measures and treat symptoms early in their course.

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