Oral complications and management strategies for patients undergoing cancer therapy.

1. Introduction

Cancer, from its initial diagnosis to the completion of its treatment, is a heart-rending experience for many. It is a period of great pressure and stress for not only the patients themselves but also their families and friends. According to the United States Cancer Statistics 2009, the National Program of Cancer Registries, the ten ranking cancers by site in the American population (per 100,000 persons) are prostate (137.7), breast (123.1), lung and bronchus (64.3), colon and rectum (42.5), corpus and uterus, NOS (25.1), urinary bladder (20.5), melanomas of the skin (19.4), non-Hodgkin's lymphoma (18.9), kidney and renal pelvis (15.7), and thyroid (13.2) [ 1 ]. The American Cancer Society has estimated that there will be approximately 1,660,290 new cancer cases being diagnosed in 2013. As the second leading cause of death in the United States, preceded only by heart disease, cancer is expected to take the lives of 580,350 Americans in the year of 2013, that is, about 1600 deaths per day [ 2 , 3 ]. Though the survival statistics can vary significantly with the stage at which the cancer is diagnosed as well as the cancer type itself, survival rates continued to climb over the past years. In fact, the 5-year relative survival rate for all cancers diagnosed from 2002 to 2008 is 68%, compared to 49% in 1975–1977 [ 3 ]. Coupled with the ongoing advances in cancer detection and treatment modalities, the future trend would entail increased likelihood for dentists to encounter patients who are currently, or have previously been, under cancer therapy.

Contemporary cancer treatment modalities commonly include surgical resection, chemotherapy, radiotherapy, and hematopoietic stem cell transplantation (HSCT), a form of immunotherapy, either administered alone or used in combination. Although the effectiveness of cancer treatment has continued to improve over the past decades, collateral damage to the head and neck structures is frequently encountered as an unwanted consequence. Radio- and chemotherapy can cause direct harm to the soft and hard tissue of the oral structures, whereas their systemic toxicity can give rise to indirect damages. These oral complications, be they acute or chronic, may arise throughout and after cancer treatment and often encompass mucositis, dysgeusia, and infectious diseases [ 4 ]. Although literature has shown that the oral health status in most cancer patients mirrors those of the general population, poorly restored dentition, moderate to advanced periodontal disease, and other pathologies associated with negligence of oral health care, the many oral complications as sequelae of aggressive cancer treatment can greatly hamper patients' quality of life; this necessitates optimal oral health care [ 5 ]. Maintaining oral health is essential in the preservation of daily functions, such as eating, verbal and nonverbal communications, and the prevention of infectious diseases.

While the necessity of dental clearance is debatable and empirical guidelines vary from center to center, assessment, treatment, and prevention of any preexisting pathological condition make up an important aspect of the overall treatment outcome in cancer patients [ 6 , 7 ]. Unfortunately, priority is often given to the more “life-threatening” condition that is cancer, and administering oral care has become an activity frequently neglected [ 8 , 9 ]. Yet, it is the ethical and medical/legal responsibility of all health care practitioners, including professionals in the field of dentistry, to ensure that the oral health status of patients undergoing cancer therapy is thoroughly evaluated. Thus, it is the aim of this paper to paint a detailed picture for dental professionals on the topic of oncology related oral care. Cancer treatment modalities will be introduced first and oral complications of cancer therapy will be discussed. Some therapeutic alternatives that may help to alleviate the painful and debilitating adverse effects will also be presented.

2. Management of Malignancy

Treatment of malignancy is complex and often involves a multidisciplinary approach. It is beyond the scope of this paper to give an in-depth review of different types of cancer therapy. Brief comments on cancer treatment modalities, including surgery, chemotherapy, radiotherapy, and HSCT, will be made to give a general picture of contemporary mainstream cancer therapies.

Surgery has come a long way in the treatment of malignancy and is still one of the most common methods in managing primary solid tumors today [ 10 ]. In dentistry, the impacts of surgical resection on patients' lives are particularly evident in the cases of oral and oropharyngeal cancers. Over the past decades, advances in surgery have resulted in major changes in surgical approaches to the mandibular areas and cervical lymph nodes [ 11 ]. In addition, safer anesthesia, tumor ablation via radiofrequency, and radiosurgery have opened up many more options and alternatives for the professionals in the effective management of the disease [ 12 ]. Combined with advances in various reconstruction techniques, the functional and aesthetic outcomes have been greatly improved in cancer patients. Nowadays, survivors of head and neck cancers no longer have to live with severe functional disabilities or aesthetic impairments that compromise their quality of life [ 11 ].

Chemotherapeutic agents are drugs designed to have a selective toxicity towards the tumor cells. Current chemotherapeutic agents are often cytostatic or cytotoxic in nature to prevent the rapid division of the malignant cells and/or destroy them in the process [ 13 ]. Unlike surgery and radiation therapy, whose usages are limited to cancers confined to specific areas of the body, the major advantage offered by chemotherapy is the ability to target widespread or metastatic cancer [ 14 ]. Yet, even the most modern chemotherapeutic agents are not without their shortcomings. Ironically, while exploiting the tumor cells' characteristic feature of shortened cell cycle and having a selective toxicity design in mind, these anticancer agents are not so “specific” as they also act upon normal cells with a high turnover rate (accelerated cell cycle) such as bone marrow cells, hair follicle cells, and the epithelial cells of the gastrointestinal tract [ 13 , 15 ]. Some common drugs used in chemotherapy for oral cancer include 5-fluorouracil, bleomycin, cisplatin, cyclophosphamide, methotrexate, and vinblastine [ 16 ].

As one of the most effective forms of cancer treatment, radiation therapy plays an indispensable role in the management of many head and neck cancers as well as lymphomas. The dose of ionizing radiation administered often depends on factors such as the location of the malignancy, the type of the malignancy, the sensitivity of the surrounding normal tissues, and whether radiation is used as the sole treatment option [ 17 , 18 ]. Typically, for most head and neck cancer patients, a dose of 2 Gy per fraction is delivered once a day, five days per week, over a five-to-seven-week period with a total dosage of 64–70 Gy [ 19 ]. The amount of radiation used to treat malignant lymphomas is usually lower [ 17 ]. Although the main aim of radiotherapy is to deliver a concentrated and lethal dose of radiation to the solid tumor while at the same time minimizing the exposure of the surrounding tissues, the salivary glands, oral mucosa, and jaws are inevitably covered in the blast radius, resulting in a variety of problems within the area [ 20 ].

HSCT, also known as bone marrow transplant, has formed an important part of the treatment modalities for many malignant diseases, acute and chronic leukemia, myelodysplastic syndromes, myeloproliferative disorders, multiple myeloma, and non-Hodgkin's lymphomas, as well as a number of other nonmalignant diseases such as aplastic anemia [ 21 , 22 ]. For patients to undergo the HSCT procedure, they are required to partake in preoperative conditioning which often involves the use of cyclophosphamide and total body irradiation (TBI). The objective is to eradicate the cancer and induce an immunosuppressive environment that permits engraftments. Although HSCT can result in more cures and remissions compared to alternative treatment, it also tends to cause greater morbidity and mortality with the mortality rates of less than 2% and 10% for some autologous and allogeneic transplantations, respectively. With as much as 40% of the advanced cancer patients dying from complications related to transplantation, further research is warranted to determine the best ablative regimens for specific conditions and reduce the toxicity of the preparative regimens [ 21 ].

3. Oral Complications of Cancer Therapy

3.1. General Considerations and Overview

Despite the encouraging evolvement in cancer management over the past decades, one should bear in mind that current treatment modalities do have the potential to result in debilitating and sometimes life-threatening adverse effects that not only decrease the patients' quality of life but also increase their morbidity and mortality.

Oral complications associated with cancer therapy encompass diseases such as stomatitis, infection, bleeding, mucositis, pain, loss of function, and xerostomia [ 23 ]. The mucosa, the periodontium, and the teeth are the three anatomical sites most commonly associated with these complications [ 24 ]. Oral complications associated with specific oncological therapy will be discussed in the following sections.

3.2. Complications Associated with Surgery

The long-term complications associated with the surgical treatment of oral cancers are many; they range from functional limitations on speech, mastication and swallowing, damages to the cranial nerves and the resultant neurological problems, chronic fistulas, and healing issues to aesthetic considerations such as severe disfigurement and prosthetic rehabilitation; taking these functional and aesthetic impairments, together with their psychological implications, the patients' long-term quality of life could be hampered [ 25 ].

Surgical resection of cancers in the oral cavity can negatively impact speech, mastication, and swallowing in a very significant way. In general, surgical ablation that involves the most anterior region of the tongue is often associated with significant speech alteration, whereas ablation that incorporates the posterior tongue affects swallowing [ 26 – 29 ]. With tumor ablation and the subsequent loss of a significant portion of the tongue, the manipulation and formation of the bolus (the oral preparatory phase) and the transfer of bolus from the anterior oral cavity to the posterior tonsillar area (the initiation of the swallowing reflex) are severely restricted [ 30 ]. The situation could be further complicated where surgical management also involves the floor of mouth, maxilla, and mandible with the adjacent tissues ( Figure 1(a) ); those are vital structures for mastication. Resection of the maxilla or the mandible could prove problematic for the patient during grinding as the stable and reproducible stomatognathic system relationships or tooth-to-tooth contact is lost, resulting in diminished biting force [ 30 , 31 ]. Furthermore, combined with soft tissue bulk and sensation loss, the ability of the patient to manipulate food bolus to and fro from occlusal table and its consolidation before deglutition are impaired. Thus, the overall masticatory efficiency, which encompasses manipulation, trituration, and consolidation, being the result of synchronous interaction of both hard and soft tissues, is drastically reduced [ 32 ].

Trismus, that is, limited mouth opening, is a common complaint after oral cancer surgery ( Figure 1(b) ). Postoperative healing, including fibrosis and scar contraction, often results in restricted interocclusal opening of less than 35 mm between the maxillary and mandibular incisors. Procedures that may lead to trismus commonly include maxillary surgery involving the origin of medial and lateral pterygoid muscles from the pterygoid plates and mandibulectomy involving any of the muscles of mastication (the temporalis insertion to the coronoid process, the masseter insertion to the angle and ramus, and the pterygoid insertions to the medial ramus and condylar neck) [ 30 ]. Note that trismus could be exacerbated by the fibrotic changes due to combination radiotherapy.

Additionally, the resection of primary tumor and lymph nodes has put several cranial nerves at risk: spinal accessory nerve, phrenic nerve, hypoglossal nerve, lingual nerve, vagus nerve, sympathetic trunk, and marginal mandibular branch of the facial nerve. The size of the tumor and its location and the extent of the neck pathology often require the nerves involved or in close association to be sacrificed. The issue with access and certainty of satisfactory tumor removal can compromise the integrity of the cranial nerves within the area [ 30 ].

Fistula is another complication often associated with oral oncologic surgeries. The risk of fistulas being developed often depends on the general physical and nutritional status of the patient, the incision design, and the tumor type and stage. Its management is particularly difficult where radiation therapy is also involved, as surgical wound closure is delayed due to low oxygen tensions, vasculitis, endothelial fibrosis, and reduced blood supply [ 25 ]. Fistulas generally occur 3-4 weeks after surgery, but they can also develop as early as 1 week. Persistent or chronic fistulas are those that remain present 1 month after the surgery. In addition, patients may present with low grade fever, inflammation, and induration of the skin flap under the area of dependant drainage. Prevention is often the best treatment, but surgical excision and closure of the mucosa and skin are indicated where the problem persists [ 25 , 33 ].

The complex anatomy of the bone and associated muscle attachments often require careful planning and placement of plates and screws to stabilize bone segments and secure bone flaps in mandibular osteotomies and/or resection. Any abusing of the reconstruction principles and overmanipulation of the material, along with unbalanced masticatory force, can result in hardware failure ranging from fracturing of the plates, loosening of the screws, and mobility of the mandibular segments to exposure of the material through the overlying soft tissue and secondary infection [ 25 ]. Although early treatment of the problem is preferred, surgical intervention may be delayed due to adjunctive radiation therapy which can compromise the wound healing; in which case, hyperbaric oxygen treatments may improve the healing abilities of the soft tissue overlying the hardware replacement [ 33 – 35 ].

Appropriate prosthetic and functional rehabilitation, which entails the reestablishment of a functional maxillomandibular complex providing for an adequate dentition for mastication with underlying bone support for facial features and soft tissue for the restoration of speech and swallowing, served as the desired endpoint for many patients. However, such a feat may not always be feasible as many factors play into this prosthetic problem. As noted by Kolokythas, the issue is a multidisciplinary one; it may not always be possible to convene all members of the treatment team to discuss the treatment plan of the oral cancer patient prior to resection. Thus, the plans for reconstruction may often have to be formed postoperatively and may not be ideal. Furthermore, the extent of the resection, several postsurgical and radiation associated complications, may not allow for the ideal rehabilitation. The patient's compliance and financial background may also be a barrier to reaching the final restorative goal [ 25 ].

3.3. Complications Associated with Chemotherapy

Chemotherapeutic agents have gained a notorious reputation in damaging not only the malignant cells but also the normal tissue in the patient's body. The level and the type of toxicity of the treatment greatly depend on the overall immune status of the patient prior to and during chemotherapy, the regimen itself, the frequency and the dosage of the treatment, the route of administration, and the type of tumor. In many patients, these drugs can cause a number of oral complications including mucositis, pain, infection, hemorrhage, xerostomia, and neurologic and nutritional problems [ 14 ].

Oral mucositis (OM) is an iatrogenic condition of erythematous inflammatory changes which tends to occur on buccal and labial surfaces, the ventral surface of the tongue, the floor of the mouth, and the soft palate of patients receiving chemotherapy [ 36 ]. Its severity ranges from localized ( Figure 2 ) to generalized erythema ( Figure 3 ) to frank ulceration and hemorrhage [ 37 ]. The initial condition is often described as a burning or tingling sensation making the mouth hypersensitive to foods. And as the condition progresses, eating, swallowing, and talking become increasingly difficult [ 38 ]. In the more severe cases, OM can compromise the airway leading to anoxia-induced brain injury and even death [ 39 – 41 ]. As a form of iatrogenic stomatitis, mucositis usually starts off with aplasia 7–14 days after the initiation of chemotherapy. Clinically, the earliest sign may be characterized by leukoedema, appearing as a diffuse, poorly defined area of milky-white opalescence most noticeable on the buccal mucosa, which will disappear upon stretching [ 14 ]. In the following 1-2 weeks, a loss of epithelial structure and integrity is observed, and severe ulceration develops [ 42 ]. In general, OM can be assessed both clinically and with subjective input from the patient. The World Health Organization (WHO) has also provided a useful grading scale that combines both objective and subjective elements ( Table 1 ) [ 43 ]. Current literature's reported incidence of OM is highly variable, ranging from 75% to 99% [ 44 , 45 ]. The current working biophysical model of OM as proposed by Sonis [ 40 ] involves 5 phases: initiation, upregulation and message generation, amplification and signaling, ulceration, and healing. Initiation involves direct irreversible and reversible DNA damages and the generation of reactive oxygen species via the chemotherapeutic agents. In the upregulation and message generation phase, transcription factors (e.g., NF- κ B) are activated, resulting in the production of messaging and effector proteins including the proinflammatory cytokines and enzymes. Positive feedback loops in phase III increase cytokine production and thus signal amplification; apoptosis and tissue injury ensue. In the ulcerative stage, clinically evident erosions are detected; bacterial colonization and additional proinflammatory cytokine secretions are also involved. In due course, spontaneous healing occurs where epithelial cells migrate to cover the ulcerations [ 40 ]. Several chemotherapy agents have been associated with OM [ 46 , 47 ]. A summary of these drugs is given in Table 2 .

Chemotherapy-related oral infections, which account for 25–50% of the total infections, contribute significantly to the morbidity and mortality in these patients [ 48 ]. Susceptible areas include teeth, gingiva, salivary glands, and mucosa. It should be noted that in the myelosuppressed patient the cardinal signs of infection such as erythema and swelling are not always present. Therefore, the more reliable indicators such as fever, pain, and the appearance of lesions should be used to closely monitor all suspected infections [ 14 ]. Common oral flora and opportunistic microorganisms include coagulase-negative Staphylococci and Streptococci , Klebsiella pneumonia, Pseudomonas aeruginosa, and Escherichia coli [ 48 – 51 ]. It has been shown that pathogenic microorganisms found subgingivally or in periradicular area may cause acute exacerbations of preexisting periodontal or periradicular infections when the granulocyte count dips below 1000/mm 3 [ 49 , 52 ].

Perhaps, the most dangerous complication in the realm of infections comes from fungal species, most notably Candida species [ 48 , 49 ]. The mortality rate from systemic fungal infections is much higher compared to other infections, with the majority believed to have originated from the oral cavity [ 49 ]. Clinically, fungal infections in the oral cavity can manifest in several forms, with erythematous or pseudomembranous candidiasis being the most common. Erythematous candidiasis presents itself as patchy or diffuse areas of erythema, often occurring on the palate. Pseudomembranous candidiasis appears as curd-like or patchy white lesions, which can be rubbed off but will produce bleeding and erosion in the tissue underneath. Also worth mentioning is hyperplastic candidiasis, which resembles leukoplakia as elevated white plaques that cannot be wiped off [ 53 , 54 ]. Particularly troublesome is the chronic atrophic candidiasis, which is often accompanied by angular cheilitis and denture stomatitis. Angular cheilitis, an infection at the corner of the mouth, may sometimes involve Staphylococcus species. Ill-fitting denture bases, usually of the maxilla, can be a source of chronic irritation and a reservoir for Candida albicans [ 14 ].

Viral infections frequently seen in patients undergoing chemotherapy include the herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) [ 14 ]. Viral reactivity is not uncommon during periods of myeloimmunosuppression, particularly with HSV infections. With incidence of recurrent infection reported up to 48%, HSV infected patients often report severe, painful, and prolonged ulcerations atypical of those discovered in immunocompetent hosts [ 55 – 57 ]. HSV recurrence typically appears 7–14 days after chemotherapy, and lesions can often be seen on lips and keratinized mucosa as small cluster of vesicles that rapidly ulcerate and coalesce [ 55 , 58 ]. Fortunately, it is self-limiting and resolves in 2 weeks. VZV infections, also known as herpes zoster/shingles, can occur within the trigeminal dermatome. Lesions can be seen on the face or intraorally with the characteristic feature of halting abruptly at the midline on the side of the respective trigeminal divisions involved. Similar to HSV, VSV recurrence is confined to keratinized mucosa and is shown to manifest several weeks after the completion of chemotherapy, with widespread, painful lesions lasting up to several weeks. Intraorally, CMV infections may be seen as irregular pseudomembranous ulcerations, coupled with common clinical manifestations such as esophagitis, gastritis, colitis, hepatitis, pneumonia, and retinitis. Furthermore, a fever may also be involved but often resolves in 3–5 days. Dissemination of CMV in immunosuppressed patients is often fatal [ 14 ].

Intraoral bleeding is another complication associated with chemotherapy. The bleeding can be spontaneous, traumatically induced, or effect from existing pathology [ 59 , 60 ]. It can also be the result of thrombocytopenia secondary to hematopoietic tissues suppression. Laboratory tests should be used to assess bleeding potential. Thrombocyte count and bleeding time can give the dentist a decent picture of the quantity, quality, and function of platelets.

3.4. Complications Associated with Radiotherapy

Orofacial tissues that may be influenced by head and neck radiotherapy include salivary glands, taste buds, mucous membranes, bone and teeth, the temporomandibular joint (TMJ), and related musculatures. In general, complications from radiation therapy are categorized into acute and chronic/late types. The acute effects usually develop early in the radiation treatment period and persist 2-3 weeks after completion of treatment, whereas the late effects may become evident at any time after treatment completion, ranging from weeks to years [ 61 ]. In fact, it is shown that in 90% to 100% of the patients whose radiation therapy covers the oral cavity some degree of oral complication will always develop [ 62 ].

Xerostomia is perhaps the most commonly reported oral sequela among patients receiving radiotherapy for head and neck cancers. The effects of radiation on salivary glands have been well documented. Ionizing radiation may cause irreversible damage to glandular tissue and loss of salivary fluid secretion; the gross architecture of the gland is slowly replaced by ductal remnants and fibrous tissues with lymphocytes and plasma cells infiltration [ 63 , 64 ]. The progressive glandular atrophy and fibrosis and the reduction in salivary outflow occur shortly after the initial exposure to radiation and intensify thereafter [ 65 ]. Mantle, unilateral, and bilateral fields of radiation are associated with a reduction of salivary flow by 30% to 40%, 50% to 60%, and 80%, respectively. For patients whose major salivary glands are in the radiation fields, the prevalence of xerostomia is shown to range from 94% to 100% [ 66 – 68 ]. Clinically, the condition becomes apparent as saliva becomes “scant, sticky, and viscous.” The patient may experience oral discomfort and pain. Furthermore, dryness of the mucosa may put the patient at risk of oral infections and can lead to difficulties in speech, chewing, and swallowing, which significantly affects their quality of life [ 69 , 70 ]. Reduced salivary outflow can also increase the susceptibility to dental caries and compromise the mucosal integrity [ 7 ]. It has been shown that xerostomia is associated with as little as two or three doses of 2 Gy each, whereas doses greater than 30 Gy can usually result in permanent or semipermanent xerostomia [ 71 , 72 ]. It is interesting to note that a “compensatory” hypertrophy of the unirradiated salivary gland may occur after a few months and up to 1 year after therapy which may alleviate the condition; yet, if all the major salivary glands are included in the field of radiation, salivary function is expected to fall as much as 50–60% within the first week [ 73 , 74 ]. Thus, it is suggested that, if irradiation of salivary tissues can be spared by patient positioning or shielding, the resultant salivary gland dysfunction may be reduced [ 75 ].

As taste is associated with salivary functions, it is not uncommon to hear complaints of taste loss in relation to xerostomia as a result of head and neck radiotherapy. Dysgeusia can occur at a rapid rate and be exacerbated at up to an accumulated dose of 30 Gy, then the progress of taste deterioration would slow down as perception for all four tastes, that is, salty, sweet, sour, and bitter, approaches zero [ 75 ]. In addition, microvilli damages brought about by the radiation may cause secondary taste loss [ 75 ]. Fortunately, the condition seems to be reversible. In the majority of the cases, taste acuity is reported to be partially restored and fully restored 20–60 days and 2–4 months after radiation therapy, respectively [ 76 ]. However, there were reports of subjective residual hypogeusia [ 75 ].

Perhaps, the most alarming and worrisome acute reaction for patients receiving radiotherapy is the radiation-induced mucositis. The high turnover rate and low radiation resistance of the mucosal cells within the oral cavity, pharynx, and larynx make them susceptible to destruction from head and neck fractionated external beam irradiation. In fact, the literature shows that mucosal erythema could develop within 1 week of fractionated doses of, each, 2 Gy per day [ 77 ]. The condition will intensify with continued treatment by daily regimen doses of greater than 2 Gy and large treatment volumes such that almost all patients would develop confluent mucositis by the third week [ 77 ]. Initially, the erythema is the result of epithelium thinning and vascular dilation, inflammation, and oedema of the submucosa [ 78 ]. As the therapy continues, however, the mucosa will become denuded, ulcerated, and covered with a fibrinous exudate [ 78 ]. There may also be bleeding. The patient is often accompanied by symptoms of intense pain, dysphagia, and odynophagia, which, in many cases, prevent oral intake and necessitate the use of parenteral analgesics; as a result, not only the patients' quality of life but also the implementation of the therapy itself is greatly affected [ 79 ]. Radiation-induced mucositis usually persists 2-3 weeks after completion of radiotherapy [ 77 , 80 ]. About 90% to 95% of the patients would show complete resolution by the 4th week [ 77 ].

It is now widely accepted that, through the generation of free radicals, ionizing radiation can cause alteration of the vascular elements in the bone within the irradiated fields. Overtime, the irradiated area will show endothelial cell death, hyalinization, thrombosis, and obliteration of vessels; consequently, the periosteum and marrow spaces will become fibrotic while the osteoblasts and osteocytes will necrose [ 75 ]. The end result is an area described as being hypovascular, hypocellular, and hypoxic, with minimal ability to withstand trauma (e.g., dental extraction, alveoloplasty) or to be repaired [ 81 – 83 ]. However, it should be noted that the degree, progression, and irreversibility of these changes are thought to be dose related [ 75 ]. In fact, osteoradionecrosis (ORN) is not a common complication of radiotherapy, and the incidence in the literature has been reported to range from 1% to 37.5% [ 61 ]. A representative 30-year retrospective study of 830 patients showed a collective rate of only 8.2% [ 84 ]. There has also been report that the incidence of ORN is on a decline over the past 20 years, which may be explained by the advent of high-energy radiation sources [ 75 , 85 ]. The ORN contains a wide range of clinical presentations which vary from a small stable asymptomatic region of exposed bone to a full-scale ORN that is accompanied by severe pain, foul-smelling necrotic bone of green-grey color, and suppuration [ 61 ]. In general, elective oral surgical procedures such as extractions or soft tissue surgeries are contraindicated within the irradiated field [ 7 ].

Currently, there is little data on the effects of ionizing radiation on teeth. Results from literature appear to be conflicting as to the differential decalcification rates between irradiated and nonirradiated teeth. However, it is widely agreed that the dental pulp of patients who received radiotherapy will demonstrate reduced vascularity, accompanied by fibrosis and atrophy [ 86 ]. Pulpal response to trauma, dental procedures, and bacterial assaults maybe compromised, but tolerance to pain seems to increase. The secretory mechanism of odontoblasts may also be affected as excessive osteodentine formation was observed in irradiated rats [ 87 , 88 ]. With regard to tooth development, the timing of exposure is crucial; tooth bud may be destroyed if irradiation occurs before significant calcification, while growth may be retarded and enamel and dentine irregularities result if exposure happens during a later stage of development [ 86 ].

Under direct assault of the ionizing radiation, the TMJ and the muscles of mastication may ultimately undergo fibrosis and contracture resulting in trismus [ 89 ]. According to the literature, about 5% to 38% of the patients develop trismus after receiving radiation therapy for head and neck cancer [ 90 , 91 ]. Clinically, trismus manifests as the gradual inability to open the mouth for normal functions; the onset of reduced interincisal opening is generally noted at 9 weeks after radiotherapy. A rate of 2.4% loss per month was observed in the following 9 months, and a 32% reduction in the mean interincisal opening was observed after 4 years [ 92 ]. Although speech articulation is not adversely affected, this painless condition could make mastication and oral intake of food particularly problematic. The implication is significantly more profound in the case of denture wearers as they may be unable to insert their prostheses and new ones cannot be satisfactorily made due to restricted access and range of jaw motions [ 75 ]. Oral hygiene is also severely compromised.

3.5. Complications Associated with HSCT

HSCT, once viewed as experimental decades ago, has since advanced as a customary treatment protocol for a variety of malignancies. HSCT can be categorized into allogenic and autologous: the former is where bone marrow is harvested from a histocompatible donor while the latter is from the patient's own; both are now regularly performed and considered standard of care for selected malignancies [ 93 ]. The risk of oral complications from HSCT is comparable to that of conventional chemotherapeutic treatment; patients receiving autologous transplant exhibit possibly slightly higher risk while those undergoing allogeneic graft may face cumbersome complications due to the infusion of donor's stem cells [ 94 – 96 ]. In general, patients undergoing HSCT are at high risk of bacterial (including those of periodontal origin), fungal (particularly Candida ), and viral (e.g., HSV, VZV, and CMV) infections [ 97 – 106 ]. Also, there has been report of hairy leukoplakia in human-immunodeficiency-virus- (HIV-) negative HSCT patients [ 107 ]. Potentially life-threatening complications from preexisting periodontitis have also been implicated from cultures of atypical pathogenic organisms isolated from disease sites; the importance of establishing healthy periodontal status before cancer therapy could not have been emphasized more [ 108 – 110 ].

Perhaps, of particular concern is the graft versus host disease (GVHD). GVHD is the most important complication of allogeneic transplantation. It occurs via an immunological reaction where the transplanted “graft” cells (donor lymphocytes) recognize the tissues of the “host” (the recipient) as foreign. GVHD can be acute or chronic [ 111 ]. Acute form of GVHD usually occurs within a few weeks of the transplantation. It damages the skin, gut, and liver. Typical signs and symptoms may include nausea, vomiting, abdominal pain, diarrhea, bloody stool, and jaundice [ 21 ]. The main risk factor is the major histocompatibility antigens (HLA) mismatch; it has been shown that, if prophylaxis is not provided, acute GVHD can affect almost every recipient [ 112 ]. Chronic GVHD may immediately follow the acute stage or may occur several months later. It is associated with loss of self-tolerance and symptomatically resembles scleroderma or Sjögren's syndrome [ 113 ]. Chronic GVHD is characterized by bronchiolitis, keratoconjunctivitis sicca, esophageal stricture, malabsorption, cholestasis, hematocytopenia, and generalized immunosuppression [ 21 ]. The oral manifestation of GVHD varies with the severity of the condition and is associated with a spectrum of presentations. In general, clinical or subclinical chronic GVHD exhibits features that include mild oral mucosal erythema, desquamative gingivitis, loss of lingual papillae, lichenoid hyperkeratosis, and xerostomia ( Figure 4 ), whereas acute GVHD patients may encounter painful desquamation and ulcerative-pseudomembranous reactions. Erythema, angular cheilitis, and lichenoid-like changes have also been observed [ 111 ].

4. Present Practice and Therapeutic Options

Although priority is often given to the treatment of the malignancy itself, focus should also be directed at prevention and amelioration of complications that may occur as a result of the disease and/or its treatment. A thorough head and neck evaluation, oral soft and hard tissue examination, and the associated intraoral radiographs are all essential parts of the initial dental visit for cancer patients. The goal of such visit is to remove and document any preexisting acute and chronic pathological conditions, for example, periodontal and periapical pathology, residual cysts, and impacted or partially erupted teeth. Through consultation with the patient's primary-care physician and revision of his/her medical status, oral surgery, intermediate or definitive restorations, and oral prophylaxis procedures may be performed safely, and if required, under intravenous sedation and/or local/general anesthesia [ 7 ]. It should be noted that evaluation, treatment, and prevention of any preexisting oral and dental pathology contribute significantly to the overall favourable treatment outcome for cancer patients; for this reason, the patient's oral health status should be stabilized/optimized for minimally predictable complications [ 7 , 114 ].

In the following section, some therapeutic options for the management of common oral complications of cancer treatment are presented. Through this general guide, the author of this paper sincerely hopes that general dental practitioners can benefit from it and may find it useful in ameliorating some of the painful oral complications of cancer therapy.

4.1. Mucositis

Presently, there is no medication proven to be able to successfully eliminate mucositis [ 4 ]. However, painful symptoms can still be managed and oral discomfort alleviated so as to improve the patient's quality of life. The current approach focuses on the management of pain and the encouragement of eating, especially in chemotherapy-induced mucositis [ 115 ]. One strategy on pain relief pertains to the use of an oral solution mixture known as “Magic Mouthwash;” it is composed of diphenhydramine, viscous lidocaine, bismuth, subsalicylate, and corticosteroids [ 116 ]. It is said to relieve acute pain and reduce inflammation, making oral consumption of food much easier. Yet, high-grade mucositis pain is commonly relieved with potent analgesic medications such as opioids [ 117 ]. Alternatively, a number of recent studies have investigated the potential of newer therapeutic interventions, in particular, concerning the efficacy of growth factors and cytokines in curtailing the development of high-grade mucositis and reducing the duration of the lesions. Palifermin (Kepivance; Amgen, Thousand Oaks, CA, USA), a recombinant human keratinocyte growth factor vigorously researched, shows much promise in reducing the frequency of high-grade (WHO grade 3 or 4) mucositis [ 118 ]. Furthermore, palifermin has been demonstrated to decrease the duration of mucositis, thereby lessening the use of parenteral nutrition and entailing higher scores for physical and functional well-being [ 118 ]. In a separate study, the beneficial effect of palifermin as preventive therapy for mucositis has been confirmed [ 119 ]. Nevertheless, the drug is not without its side effect; taste alteration in patients treated with palifermin has been reported [ 120 ].

Other practical therapies for mucositis are also showing promises, though evidence and data from the literature are limited. One method widely used among oncologists is the application of ice chips to the mouth every 30 minutes for prevention and treatment of oral mucositis in patients undergoing chemotherapy. The rationale of oral cryotherapy is that, through vasoconstriction, the release of chemotherapeutic drugs to the mucosal epithelium is reduced [ 121 ]. Perhaps, an effective preventive measure of recent interest is the use of low level laser therapy (LLLT). Various studies have demonstrated the potential benefits of LLLT in its ability to reduce the rates of WHO severe grade mucositis [ 121 , 122 ]. Other novel methods and experimental approaches include a formulation containing the amino acid L-glutamine and the hormone, leptin; both have been shown to have a positive impact on the development of mucositis [ 123 – 126 ].

4.2. Oral Infections

Often, cancer treatments can negatively affect the patient's immune system. With his/her immune response suppressed, opportunistic infections can contribute to significant morbidity and mortality.

4.2.1. Bacterial Infections

Normal oral flora comprises of a variety of bacteria, some of which may become pathogenic with immunosuppression. According to Rautemaa and colleagues, sepsis of unknown origin may possibly be the result of oral infections (e.g., Viridans Streptococcus , Prevotella species, Fusobacterium , Actinobacillus actinomycetemcomitans , and Actinomyces species) [ 127 ]. Nonetheless, the infections are usually localized to oral mucosa and can be treated with a combination of penicillin and metronidazole, followed by routine dental procedures if necessary [ 4 ]. Given the patient's condition, meticulous oral hygiene practice is paramount. Bacteria may be removed from the teeth by gentle brushing with a soft bristle tooth brush and flossing. One may consider using an antimicrobial mouthwash as an adjunct. In the case where brushing becomes difficult (e.g., mucosal damage), a chlorhexidine-containing mouthwash is generally recommended [ 6 ].

4.2.2. Candidiasis

According to Lalla and colleagues, the prevalence of oral fungal infection from all forms of cancer therapy was about 7.5% before treatment, 40% during treatment, and 30% after treatment [ 128 ]. Yet, a Cochrane meta-analysis has concluded that there is currently insufficient evidence from the literature to make a recommendation for or against the treatment of oral candidiasis with antifungal agents in patients undergoing cancer treatment [ 129 ]. Nevertheless, it is the responsibility of the general dental practitioner to ease the patient's suffering, and that entails morbidity reduction and systemic infection prevention. It should be noted that although topical antifungal agents are commonly prescribed for their lower risk of side effects and drug interactions, literature support of their efficacy is inconsistent [ 128 ]. According to the guidelines provided by the Infectious Disease Society of America (IDSA), clotrimazole troches and nystatin pastilles are the first line drugs for mild oropharyngeal candidiasis [ 130 ]. However, they may be difficult to apply in situations such as hyposalivation and/or mucositis in which the experience can be traumatic; thus, an alternate solution is to use nystatin rinses [ 128 ]. With the high relapse rate of topical agents, one may also consider systemic antifungal agents [ 131 ]. In fact, the IDSA guidelines recommend the use of systemic fluconazole (100–200 mg/day for 2 weeks) (Diflucan; Pfizer Labs, New York, NY, USA) for the management of moderate to severe infections [ 130 ]. In fluconazole resistant cases, itraconazole capsules (200 mg/day for 2–4 weeks) or itraconazole oral solution (200 mg/day for 2 weeks) may also be considered [ 128 ]. As a second line drug, posaconazole (Noxafil; Merck & CO., Whitehouse Station, NJ, USA) is suggested by the IDSA [ 130 ]. In situations where the disease becomes refractory, a broader spectrum drug of a more potent nature such as voriconazole (Vfend; Pfizer Labs, New York, NY, USA), caspofungin (Cancidas; Merck & CO., Whitehouse Station, NJ, USA), and amphotericin B (Fungizone; Bristol-Myers Squibb Co., Princeton, NJ, USA) is suggested. Note that voriconazole has been reported to be associated with severe photosensitivity, and possibly an increased risk of skin cancer, whereas amphotericin B is known for its systemic side effects, for example, high fever [ 128 , 130 , 132 ].

Whereas the aforementioned modalities are all aimed at treating oral candidiasis, the potential benefits of prophylaxis should not be ignored, particularly in severely immunosuppressed and/or neutropenic patients. From a Cochrane review, there is reasonably good evidence from randomized controlled trials that drugs absorbed from the GI tract prevent candidiasis in cancer patients [ 129 ]. A number of studies have demonstrated the efficacy of prophylactic use of fluconazole, itraconazole, posaconazole, and intravenous micafungin (Mycamine; Astellas Pharma US, Inc., Deerfield, IL, USA) in reducing the prevalence of all clinical fungal infections during cancer therapy [ 128 , 133 – 137 ]. Interestingly, however, there has been little evidence from the literature on the relative cost effectiveness of systemic versus topical prophylaxis for oral fungal infections [ 129 ].

4.2.3. Viral Infections

HSV is quite prevalent in the general population. In the majority of the cases, HSV infection stems from latent viral reactivation. Current literature suggests that immunosuppression due to chemotherapy is the main contributive factor, with prevalence approaching 40%. Neutropenic patients with hematological malignancies are at the greatest risk, that is, 50%, during treatment [ 138 ]. Presently, acyclovir (Zovirax; GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC, USA) and valacyclovir (Valtrex; GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC, USA) have both been shown to be equally efficacious in prevention and treatment of HSV [ 139 ]. Oral prophylaxis can be accomplished with acyclovir at the dose of 200–800 mg thrice a day or valacyclovir at the dose of 500 mg twice a day [ 139 – 141 ]. During treatment, acyclovir may be used intravenously at the dose of 5 mg/kg every 8 hours or perorally 200–400 mg 3–5 times a day; on the other hand, the unavailability of intravenous valacyclovir limits its use to the oral dosing regimen of 500–1000 twice a day [ 139 ]. An alternative is famciclovir (Famvir; Novartis Pharmaceuticals Corp., East Hanover, NJ, USA). In case of drug resistance, intravenous foscarnet (Foscavir; AstraZeneca, Wilmington, NC, USA) and cidofovir (Vistide; Gilead Sciences, Inc., Foster City, CA, USA) may be used [ 142 ].

Of particular concern is oral hairy leukoplakia (OHL), a result of Epstein-Barr virus infection, commonly seen in HIV infected individuals. However, OHL can also manifest in immunocompromised patients (e.g., patients under cancer treatment) who are HIV negative. Reports have shown that OHL can occur in patients under chemotherapy for acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma, as well as in patients under corticosteroid regimen for gastrointestinal stromal tumor [ 143 – 147 ]. At present, there is no universal therapy for the management of OHL; however, high dose oral valacyclovir may be used safely and effectively [ 148 ]. Alternatively, topical treatment, that is, 25% podophyllin resin alone or in combination with 5% topical acyclovir, and gentian violet could be considered [ 149 – 151 ].

4.3. Xerostomia

Patients who have undergone head and neck cancer radiotherapy tend to have long-term side effects which are xerostomia and hyposalivation, resulting in further complications such as increased caries incidence and loss of taste [ 5 ]. It is advisable for the patient who has dry mouth to take frequent sips of water (every 10 minutes) and melt ice chips in mouth for comfort. Additionally, one may consider the use of artificial saliva spray (e.g., Xerotin, Moi-Stir, Salivart, Xero-Lube, Saliva Orthana) and mouth moisturizing gel (e.g., Biotène Oral Balance). The lips may well be lubricated with petroleum jelly or a lanolin-containing preparation (e.g., BioXtra moisturizing gel). Patients should be cautioned against coffee, tea, soft drinks with caffeine, and commercial mouth rinses with alcohol as they can dehydrate the mouth. Alcohol-free mouth rinses (e.g., BioXtra alcohol-free mouthrinse, Biotène mouthwash, and OralSeven moisturising mouthwash) are recommended. Residual salivary gland activity and salivary flow rate may be increased by saliva stimulating tablets (SST) and medications like pilocarpine (Salagen, 5 mg, thrice a day), respectively. Finally, patients are recommended to use sorbitol- or xylitol-based chewing gum for salivary flow stimulation and caries arresting.

4.4. Dysgeusia

It is estimated that about 50% to 75% of the cancer patients receiving chemotherapy, radiotherapy, or both will suffer from distorted or impaired ability to taste [ 152 , 153 ]. While patients under radiation treatment tend to suffer most from dysgeusia, its severity is highly correlated to the cumulative radiation dose. Mild dysgeusia is generally well tolerated; nevertheless, impaired ability to taste, which affects appetite, reduces caloric intake, induces weight loss, and hampers nutritional status, can exert great impact on the patient's quality of life [ 5 ]. At present, several strategies have been proposed for the management of dysgeusia. Although clinical efficacy of zinc supplementation has been quite variable, its use has been suggested by several studies to ameliorate the debilitating effects of dysgeusia [ 154 ]. The rationale is such that zinc element may be structurally important in the proteins responsible for regulating the taste bud pores [ 5 ]. Additionally, one may also consider supplementing diet with vitamin D as it was reported that patients suffering from dysgeusia made improvement from it [ 155 ]. Sometimes, dietary counselling may have more impact on long-term dysgeusia and improve patient outcome [ 156 , 157 ]. Several simple methods have been utilized by nutritionists for symptomatic patients [ 153 ]. Patients are advised to drink plenty of fluids during meal, as such would enable the dissolution of taste components in the food and facilitate their translocation to taste buds. Food should be chewed slowly and thoroughly to release more flavours and stimulate saliva production; this is especially crucial if the patient is also suffering from dry mouth where saliva is important to taste. Patients should also switch foods during meals to prevent adaptation of taste receptors while taking care to maintain a balanced diet at the same time [ 152 ].

Acknowledgment

This work was supported by the Committee on Research and Conference Grants, The University of Hong Kong (Project no. 10401084).

Conflict of Interests

The author declares that there is no conflict of interests regarding the publication of this paper.

1 Centers for Disease Controland Prevention Ttop ten cancers 2009, http://apps.nccd.cdc.gov/uscs/toptencancers.aspx

2 Siegel R Naishadham D Jemal A Cancer statistics, 2012 CA—A Cancer Journal for Clinicians 2012 62 1 10 29 2-s2.0-84855792427 22237781 10.3322/caac.20138

3 American Cancer Society Cancer Facts & Figures 2013, http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf

4 Mosel DD Bauer RL Lynch DP Hwang ST Oral complications in the treatment of cancer patients Oral Diseases 2011 17 6 550 559 2-s2.0-79960700200 21306481 10.1111/j.1601-0825.2011.01788.x

5 Joshi VK Dental treatment planning and management for the mouth cancer patient Oral Oncology 2010 46 6 475 479 2-s2.0-77952744761 20400359 10.1016/j.oraloncology.2010.03.010

6 Hong CHL Napeñas JJ Hodgson BD A systematic review of dental disease in patients undergoing cancer therapy Supportive Care in Cancer 2010 18 8 1007 1021 2-s2.0-77956455496 20449756 10.1007/s00520-010-0873-2 PMC2914291

7 Chambers MS Toth BB Martin JW Fleming TJ Lemon JC Oral and dental management of the cancer patient: prevention and treatment of complications Supportive Care in Cancer 1995 3 3 168 175 2-s2.0-0029302951 7655777 10.1007/BF00368886

8 Miller M Kearney N Oral care for patients with cancer: a review of the literature Cancer Nursing 2001 24 4 241 254 2-s2.0-0034907291 11502032 10.1097/00002820-200108000-00001

9 Barker GJ Epstein JB Williams KB Gorsky M Raber-Durlacher JE Current practice and knowledge of oral care for cancer patients: a survey of supportive health care providers Supportive Care in Cancer 2005 13 1 32 41 2-s2.0-13244253894 15549427 10.1007/s00520-004-0691-5

10 Al-Dakkak I The association between cancer treatments and oral diseases Evidence-Based Dentistry 2011 12 1 15 16 2-s2.0-79953228895 21436858 10.1038/sj.ebd.6400775

11 Kolokythas A Long-term surgical complications in the oral cancer patient: a comprehensive review. Part I Journal of Oral & Maxillofacial Research 2010 1 3, article e1 10.5037/jomr.2010.1301 PMC3886056 24421971

12 Carreca I Balducci L Extermann M Cancer in the older person Cancer Treatment Reviews 2005 31 5 380 402 2-s2.0-26444533513 15967582 10.1016/j.ctrv.2005.04.012

13 López BC Esteve CG Pérez MGS Dental treatment considerations in the chemotherapy patient Journal of Clinical and Experimental Dentistry 2011 3 e31 e42

14 Toscano N Holtzclaw D Hargitai IA Oral implications of cancer chemotherapy The Journal of Implant & Advanced Clinical Dentistry 2009 1 51 69

15 López Galindo MP Bagán JV Jiménez Soriano Y Alpiste F Camps C Clinical evaluation of dental and periodontal status in a group of oncological patients before chemotherapy Medicina Oral, Patologia Oral y Cirugia Bucal 2006 11 1 17 21 2-s2.0-33644805753 16388287

16 Caribé Gomes F Chimenos Küstner E López López J Finestres Zubeldia F Guix Melcior B Dental management of the complications of radio and chemotherapy in oral cancer Medicina Oral 2003 8 3 178 187 2-s2.0-0037676275 12730652

17 Vissink A Jansma J Spijkervet FKL Burlage FR Coppes RP Oral sequelae of head and neck radiotherapy Critical Reviews in Oral Biology and Medicine 2003 14 3 199 212 2-s2.0-0037867773 12799323 10.1177/154411130301400305

18 Begg AC Stewart FA Vens C Strategies to improve radiotherapy with targeted drugs Nature Reviews Cancer 2011 11 4 239 253 2-s2.0-79953054421 21430696 10.1038/nrc3007

19 Bourhis J Etessami A Lusinchi A New trends in radiotherapy for head and neck cancer Annals of Oncology 2005 16 2 ii255 ii257 2-s2.0-21344436657 15958468 10.1093/annonc/mdi736

20 Kielbassa AM Hinkelbein W Hellwig E Meyer-Lückel H Radiation-related damage to dentition The Lancet Oncology 2006 7 4 326 335 2-s2.0-33645767660 16574548 10.1016/S1470-2045(06)70658-1

21 Copelan EA Hematopoietic stem-cell transplantation The New England Journal of Medicine 2006 354 17 1813 1826 2-s2.0-33646119401 16641398 10.1056/NEJMra052638

22 Yamagata K Onizawa K Yanagawa T A prospective study to evaluate a new dental management protocol before hematopoietic stem cell transplantation Bone Marrow Transplantation 2006 38 3 237 242 2-s2.0-33746314545 16850033 10.1038/sj.bmt.1705429

23 Toth B Fleming TJ Oral care for the patient with cancer Highlights Antineoplastic Drugs 1990 8 27 35

24 Toth B Martin JW Fleming TJ Oral and dental care associated with cancer therapy Cancer Bulletin 1991 43 397 402

25 Kolokythas A Long-term surgical complications in the oral cancer patient: a comprehensive review. part II Journal of Oral & Maxillofacial Research 2010 1, article e2 10.5037/jomr.2010.1302 PMC3886053 24421972

26 LaBlance GR Kraus K Steckol KF Rehabilitation of swallowing and communication following glossectomy Rehabilitation Nursing 1991 16 5 266 270 2-s2.0-0026230158 1891651 10.1002/j.2048-7940.1991.tb01231.x

27 Massengill R Jr. Maxwell S Pickrell K An analysis of articulation following partial and total glossectomy Journal of Speech and Hearing Disorders 1970 35 2 170 173 2-s2.0-0014788509 5442338 10.1044/jshd.3502.170

28 Pauloski BR Logemann JA Colangelo LA Surgical variables affecting speech in treated patients with oral and oropharyngeal cancer Laryngoscope 1998 108 6 908 916 2-s2.0-0031837422 9628509 10.1097/00005537-199806000-00022

29 Roa Pauloski B Logemann JA Rademaker AW Speech and swallowing function after anterior tongue and floor of mouth resection with distal flap reconstruction Journal of Speech and Hearing Research 1993 36 2 267 276 2-s2.0-0027210412 8487519 10.1044/jshr.3602.267

30 Kolokythas A Long-term surgical complications in the oral cancer patient: a comprehensive review. Part I Journal of Oral and Maxillofacial Surgery 2010 1, article e1 10.5037/jomr.2010.1301 PMC3886056 24421971

31 Urken ML Buchbinder D Weinberg H Functional evaluation following microvascular oromandibular reconstruction of the oral cancer patient: a comparative study of reconstructed and nonreconstructed patients Laryngoscope 1991 101 9 935 950 2-s2.0-0026006301 1886442 10.1288/00005537-199109000-00004

32 Curtis DA Plesh O Miller AJ A comparison of masticatory function in patients with or without reconstruction of the mandible Head and Neck 1997 19 4 287 296 2-s2.0-0030916250 9213107 10.1002/(sici)1097-0347(199707)19:4<287::aid-hed7>3.0.co;2-x

33 Kerawala CJ Complications of head and neck cancer surgery—prevention and management Oral Oncology 2010 46 6 433 435 2-s2.0-77952746287 20435509 10.1016/j.oraloncology.2010.03.013

34 Kim DD Ord RA Complications in the treatment of head and neck cancer Oral and Maxillofacial Surgery Clinics of North America 2003 15 2 213 227 2-s2.0-0038281305 18088676 10.1016/S1042-3699(02)00100-0

35 Neovius EB Lind MG Lind FG Hyperbaric oxygen therapy for wound complications after surgery in the irradiated head and neck: a review of the literature and a report of 15 consecutive patients Head and Neck 1997 19 4 315 322 2-s2.0-0030964302 9213110 10.1002/(sici)1097-0347(199707)19:4<315::aid-hed10>3.0.co;2-8

36 Treister N Sonis S Mucositis: biology and management Current Opinion in Otolaryngology and Head and Neck Surgery 2007 15 2 123 129 2-s2.0-34247109492 17413415 10.1097/MOO.0b013e3280523ad6

37 Hong CH daFonseca M Considerations in the pediatric population with cancer Dental Clinics of North America 2008 52 1 155 181 2-s2.0-37249085580 18154869 10.1016/j.cden.2007.10.001

38 Borbasi S Cameron K Quested B Olver I To B Evans D More than a sore mouth: patients’ experience of oral mucositis Oncology Nursing Forum 2002 29 7 1051 1057 2-s2.0-0036673455 12183754 10.1188/02.ONF.1051-1057

39 Murray JC Chiu JKH Dorfman SR Ogden AK Epiglottitis following preparation for allogeneic bone marrow transplantation Bone Marrow Transplantation 1995 15 6 997 998 2-s2.0-0029003116 7581105

40 Sonis ST A biological approach to mucositis Journal of Supportive Oncology 2004 2 1 21 32 2-s2.0-5144229908 15330370

41 Chaimberg KH Cravero JP Mucositis and airway obstruction in a pediatric patient Anesthesia and Analgesia 2004 99 1 59 61 2-s2.0-3042615684 15281504 10.1213/01.ANE.0000121309.01069.0A

42 Fadda G Campus G Lugliè P Risk factors for oral mucositis in paediatric oncology patients receiving alkylant chemotherapy BMC Oral Health 2006 6, article 13 2-s2.0-33750560463 10.1186/1472-6831-6-13 PMC1629008 17049085

43 World Health Organization Handbook For Reporting Results of Cancer Treatment 1979 Geneva, Switzerland World Health Organization

44 Sonis ST Elting LS Keefe D Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients Cancer 2004 100 9 1995 2025 2-s2.0-11144356545 15108222 10.1002/cncr.20162

45 Rubenstein EB Peterson DE Schubert M Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 2004 100 2026 2046 15108223 10.1002/cncr.20163

46 Köstler WJ Hejna M Wenzel C Zielinski CC Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention and treatment CA—A Cancer Journal for Clinicians 2001 51 5 290 315 2-s2.0-0035570382 11577493 10.3322/canjclin.51.5.290

47 Saadeh CE Chemotherapy- and radiotherapy-induced oral mucositis: review of preventive strategies and treatment Pharmacotherapy 2005 25 4 540 554 2-s2.0-16344389534 15977916 10.1592/phco.25.4.540.61035

48 Karthaus M Rosenthal C Ganser A Prophylaxis and treatment of chemo- and radiotherapy-induced oral mucositis—are there new strategies? Bone Marrow Transplantation 1999 24 10 1095 1108 2-s2.0-0032710875 10578160 10.1038/sj.bmt.1702024

49 Huber MA Terezhalmy GT The medical oncology patient Quintessence International 2005 36 5 383 402 2-s2.0-17444395908 15892536

50 Epstein JB Schubert MM Oropharyngeal mucositis in cancer therapy:Review of pathogenesis, diagnosis, and management Oncology 2003 17 12 1767 1779 2-s2.0-2442517228 14723014

51 Crawford J Dale DC Lyman GH Chemotherapy-induced neutropenia, risks, consequences, and new directions for their management Cancer 2004 100 228 237 14716755 10.1002/cncr.11882

52 Heimdahl A Prevention and management of oral infections in cancer patients Supportive Care in Cancer 1999 7 4 224 228 2-s2.0-0033046495 10423047 10.1007/s005200050253 PMC7102151

53 Epstein JB Chow AW Oral complications associated with immunosuppression and cancer therapies Infectious Disease Clinics of North America 1999 13 4 901 923 2-s2.0-0032705444 10579115 10.1016/s0891-5520(05)70115-x

54 Glick M Siegel MA Viral and fungal infections of the oral cavity in immunocompetent patients Infectious Disease Clinics of North America 1999 13 4 817 831 2-s2.0-0032725752 10579110 10.1016/s0891-5520(05)70110-0

55 Montgomery MT Redding SW LeMaistre CF The incidence of oral herpes simplex virus infection in patients undergoing cancer chemotherapy Oral Surgery Oral Medicine and Oral Pathology 1986 61 3 238 242 2-s2.0-0022619916 10.1016/0030-4220(86)90368-3 3010211

56 Tang IT-L Shepp DH Herpes simplex virus infection in cancer patients: prevention and treatment Oncology 1992 6 7 101 109 2-s2.0-0026749302 1322152

57 Epstein JB Sherlock C Page JL Spinelli J Phillips G Clinical study of herpes simplex virus infection in leukemia Oral Surgery Oral Medicine and Oral Pathology 1990 70 1 38 43 2-s2.0-0025289607 10.1016/0030-4220(90)90175-r 2164654

58 Reusser P Current concepts and challenges in the prevention and treatment of viral infections in immunocompromised cancer patients Supportive Care in Cancer 1998 6 1 39 45 2-s2.0-0031953152 9458535 10.1007/s005200050130

59 Lockhart PB Sonis ST Relationship of oral complications to peripheral blood leukocyte and platelet counts in patients receiving cancer chemotherapy Oral Surgery Oral Medicine and Oral Pathology 1979 48 1 21 28 2-s2.0-0018593776 10.1016/0030-4220(79)90230-5 313547

60 Caprini JA Sener SF Altered coagulability in cancer patients CA—A Cancer Journal for Clinicians 1982 32 3 162 172 2-s2.0-0019929750 6804035 10.3322/canjclin.32.3.162

61 Sciubba JJ Goldenberg D Oral complications of radiotherapy The Lancet Oncology 2006 7 2 175 183 2-s2.0-31544436908 16455482 10.1016/S1470-2045(06)70580-0

62 Herrstedt J Prevention and management of mucositis in patients with cancer International Journal of Antimicrobial Agents 2000 16 2 161 163 2-s2.0-0033780559 11053801 10.1016/s0924-8579(00)00232-6

63 Mossman KL Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy Radiation Research 1983 95 2 392 398 2-s2.0-0020634652 6611856

64 Mossman K Shatzman A Chencharick J Long-term effects of radiotherapy on taste and salivary function in man International Journal of Radiation Oncology Biology Physics 1982 8 6 991 997 2-s2.0-0019988877 10.1016/0360-3016(82)90166-3 7107441

65 Kaplan P Mantle irradiation of the major salivary glands The Journal of Prosthetic Dentistry 1985 54 5 681 686 2-s2.0-0022151476 3863944 10.1016/0022-3913(85)90250-1

66 Hughes PJ Scott PM Kew J Dysphagia in treated nasopharyngeal cancer Head & Neck 2000 22 4 393 397 10862024 10.1002/1097-0347(200007)22:4<393::aid-hed13>3.0.co;2-2

67 Ramirez-Amador V Silverman S Jr. Mayer P Tyler M Quivey J Candidal colonization and oral candidiasis in patients undergoing oral and pharyngeal radiation therapy Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 1997 84 2 149 153 2-s2.0-0031202310 10.1016/s1079-2104(97)90061-5 9269016

68 Kies MS Haraf DJ Rosen F Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer Journal of Clinical Oncology 2001 19 7 1961 1969 2-s2.0-0035300759 11283128 10.1200/JCO.2001.19.7.1961

69 Schweiger JW Oral complications following radiation therapy: a five-year retrospective report The Journal of Prosthetic Dentistry 1987 58 1 78 82 2-s2.0-0023371815 3475463 10.1016/s0022-3913(87)80148-8

70 Mandel ID The role of saliva in maintaining oral homeostasis The Journal of the American Dental Association 1989 119 2 298 304 2-s2.0-0024710202 2671090 10.14219/jada.archive.1989.0211

71 Eisbruch A Kim HM Terrell JE Marsh LH Dawson LA Ship JA Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer International Journal of Radiation Oncology Biology Physics 2001 50 3 695 704 2-s2.0-0035400492 10.1016/s0360-3016(01)01512-7 11395238

72 Roesink JM Konings AWT Terhaard CHJ Battermann JJ Kampinga HH Coppes RP Preservation of the rat parotid gland function after radiation by prophylactic pilocarpine treatment: radiation dose dependency and compensatory mechanisms International Journal of Radiation Oncology Biology Physics 1999 45 2 483 489 2-s2.0-0032817960 10.1016/s0360-3016(99)00185-6 10487575

73 Porter SR Scully C Hegarty AM An update of the etiology and management of xerostomia Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 2004 97 1 28 46 2-s2.0-0347949726 10.1016/j.tripleo.2003.07.010 14716254

74 Chambers MS Garden AS Kies MS Martin JW Radiation-induced xerostomia in patients with head and neck cancer: pathogenesis, impact on quality of life, and management Head and Neck 2004 26 9 796 807 2-s2.0-4344691765 15350026 10.1002/hed.20045

75 Andrews N Griffiths C Dental complications of head and neck radiotherapy: Part 1 Australian Dental Journal 2001 46 2 88 94 2-s2.0-0035377792 11491236 10.1111/j.1834-7819.2001.tb00562.x

76 Conger AD Loss and recovery of taste acuity in patients irradiated to the oral cavity Radiation Research 1973 53 2 338 347 2-s2.0-0015581565 4695231

77 Million RR Cassisi NJ The effect of radiation on normal tissues of the head and neck Management of Head and Neck Cancer: a Multidisciplinary Approach 1984 Philadelphia, Pa, USA J. P. Lippincott

78 Brown LR Dreizen S Handler S Johnston DA Effect of radiation induced xerostomia on human oral microflora Journal of Dental Research 1975 54 4 740 750 2-s2.0-0016712073 1099136 10.1177/00220345750540040801

79 Scully C Epstein J Sonis S Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy. Part 2: diagnosis and management of mucositis Head and Neck 2004 26 1 77 84 2-s2.0-0346102609 14724910 10.1002/hed.10326

80 Dreizen S Description and incidence of oral complications NCI Monographs 1990 9 11 15 2-s2.0-0025071179 2188148

81 Marx RE Osteoradionecrosis: a new concept of its pathophysiology Journal of Oral and Maxillofacial Surgery 1983 41 5 283 288 2-s2.0-0020530740 6572704 10.1016/0278-2391(83)90294-x

82 Beumer J III Silverman S Jr. Benak SB Jr. Hard and soft tissue necroses following radiation therapy for oral cancer The Journal of Prosthetic Dentistry 1972 27 6 640 644 2-s2.0-0015351076 4503890 10.1016/0022-3913(72)90311-3

83 Epstein JB Rea G Wong FLW Spinelli J Stevenson-Moore P Osteonecrosis: study of the relationship of dental extractions in patients receiving radiotherapy Head and Neck Surgery 1987 10 1 48 54 2-s2.0-0023530688 3130334 10.1002/hed.2890100108

84 Reuther T Schuster T Mende U Kübler AC Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients—a report of a thirty year retrospective review International Journal of Oral and Maxillofacial Surgery 2003 32 3 289 295 2-s2.0-0038201995 12767877 10.1054/ijom.2002.0332

85 Studer G Grätz KW Glanzmann C Osteoradionecrosis of the Mandibula in Patients Treated with Different Fractionations Strahlentherapie und Onkologie 2004 180 4 233 240 2-s2.0-1842765543 15057434 10.1007/s00066-004-1171-z

86 Beumer J III Curtis T Harrison RE Radiation therapy of the oral cavity: sequelae and management, Part I Head and Neck Surgery 1979 1 4 301 312 2-s2.0-0018749529 500366 10.1002/hed.2890010404

87 Collett WK Thonard JC The effect of fractional radiation on dentinogenesis in the rat Journal of Dental Research 1965 44 84 90 2-s2.0-0042448424 14245501 10.1177/00220345650440013501

88 Koppang HS Studies on the radiosensitivity of the rat incisor Odontologisk Tidskrift 1967 75 5 413 450 2-s2.0-0014217171 5234968

89 Vissink A Jansma J Spijkervet FKL Burlage FR Coppes RP Oral sequelae of head and neck radiotherapy Critical Reviews in Oral Biology and Medicine 2003 14 3 199 212 2-s2.0-0037867773 12799323 10.1177/154411130301400305

90 Thomas F Ozanne F Mamelle G Wibault P Eschwege F Radiotherapy alone for oropharyngeal carcinomas: the role of fraction size (2 Gy vs 2.5 Gy) on local control and early and late complications International Journal of Radiation Oncology Biology Physics 1988 15 5 1097 1102 2-s2.0-0023796742 10.1016/0360-3016(88)90190-3 3182341

91 Steelman R Sokol J Quantification of trismus following irradiation of the temporomandibular joint Missouri Dental Journal 1986 66 6 21 23 2-s2.0-0022814832 3465988

92 Wang C-J Huang E-Y Hsu H-C Chen H-C Fang F-M Hsiung C-Y The degree and time-course assessment of radiation-induced trismus occurring after radiotherapy for nasopharyngeal cancer Laryngoscope 2005 115 8 1458 1460 2-s2.0-23344440062 16094124 10.1097/01.mlg.0000171019.80351.46

93 Eisen D Essell J Broun ER Oral cavity complications of bone marrow transplantation Seminars in Cutaneous Medicine and Surgery 1997 16 4 265 272 2-s2.0-0031471072 9421217 10.1016/s1085-5629(97)80015-6

94 Barasch A Safford MM Management of oral pain in patients with malignant diseases Compendium 1993 14 11 1376 1386 2-s2.0-0027703962 8620375

95 Collins R Miller GW Fay JW Autologous bone marrow transplantation: a review BUMC Proceedings 1991 4 2 3 12

96 Maxymiw WG Wood RE The role of dentistry in patients undergoing bone marrow transplantation British Dental Journal 1989 167 7 229 234 2-s2.0-0024964074 2528979 10.1038/sj.bdj.4806974

97 Barrett AP Schifter M Antibiotic strategy in orofacial/head and neck infections in severe neutropenia Oral Surgery, Oral Medicine, Oral Pathology 1994 77 4 350 355 2-s2.0-0028415289 10.1016/0030-4220(94)90196-1 8015798

98 Mattsson T Heimdahl A Dahllof G Lonnquist B Ringden O Oral and nutritional status in allogeneic marrow recipients treated with T-cell depletion or cyclosporine combined with methotrexate to prevent graft- versus-host disease Oral Surgery Oral Medicine and Oral Pathology 1992 74 1 34 40 2-s2.0-0026689092 10.1016/0030-4220(92)90212-9 1508507

99 Toth BB Martin JW Chambers MS Robinson KA Andersson BS Oral candidiasis: a morbid sequela of anticancer therapy Texas Dental Journal 1998 115 6 24 29 2-s2.0-0032087397 9667209

100 Brown AT Shupe JA Sims RE In vitro effect of chlorhexidine and amikacin on oral gram-negative bacilli from bone marrow transplant recipients Oral Surgery Oral Medicine and Oral Pathology 1990 70 6 715 719 2-s2.0-0025669889 10.1016/0030-4220(90)90006-e 2263328

101 Birek C Patterson B Maximiw WC Minden MD EBV and HSV infections in a patient who had undergone bone marrow transplantation: oral manifestations and diagnosis by in situ nucleic acid hybridization Oral Surgery Oral Medicine and Oral Pathology 1989 68 5 612 617 2-s2.0-0024443753 10.1016/0030-4220(89)90249-1 2554231

102 LeVeque FG Ratanatharathorn V Dan ME Orville B Coleman DN Turner S Oral cytomegalovirus infection in an unrelated bone marrow transplantation with possible mediation by graft-versus-host disease and the use of cyclosporin-A Oral Surgery, Oral Medicine, Oral Pathology 1994 77 3 248 253 2-s2.0-0028391196 10.1016/0030-4220(94)90293-3 8170655

103 Schubert MM Peterson DE Flournoy N Meyers JD Truelove EL Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection Oral Surgery Oral Medicine and Oral Pathology 1990 70 3 286 293 2-s2.0-0025076681 10.1016/0030-4220(90)90142-f 2170891

104 Schuchter LM Wingard JR Piantadosi S Burns WH Santos GW Saral R Herpes zoster infection after autologous bone marrow transplantation Blood 1989 74 4 1424 1427 2-s2.0-0024414777 2548641

105 Vose JM Kennedy BC Bierman PJ Kessinger A Armitage JO Long-term sequelae of autologous bone marrow or peripheral stem cell transplantation for lymphoid malignancies Cancer 1992 69 3 784 789 2-s2.0-0026555169 1730128 10.1002/1097-0142(19920201)69:3<784::aid-cncr2820690328>3.0.co;2-m

106 Schubert MM Epstein JB Lloid ME Cooney E Oral infections due to Cytomegalovirus in immunocompromised patients Journal of Oral Pathology and Medicine 1993 22 6 268 273 2-s2.0-0027200826 8394928 10.1111/j.1600-0714.1993.tb01069.x

107 Epstein JB Sherlock CH Wolber RA Hairy leukoplakia after bone marrow transplantation Oral Surgery Oral Medicine and Oral Pathology 1993 75 6 690 695 2-s2.0-0027308990 10.1016/0030-4220(93)90424-3 8390632

108 Toth BB Chambers MS Fleming TJ Lemon JC Martin JW Minimizing oral complications of cancer treatment Oncology 1995 9 9 851 866 2-s2.0-0029364924 8562326

109 Toth BB Chambers MS Fleming TC Prevention and management of oral complications associated with cancer therapies: radiotherapy/chemotherapy Texas Dental Journal 1996 113 6 23 29 2-s2.0-0030153917 9518843

110 Peterson DE Pretreatment strategies for infection prevention in chemotherapy patients NCI Monographs 1990 9 61 71 2-s2.0-0025125190 2111469

111 Fayle SA Duggal MS Williams SA Oral problems and the dentist’s role in the management of paediatric oncology patients Dental Update 1992 19 4 152 158 2-s2.0-0026864715 1289155

112 Sullivan KM Deeg HJ Sanders J Hyperacute graft-v-host disease in patients not given immunosuppression after allogeneic marrow transplantation Blood 1986 67 4 1172 1175 2-s2.0-0022647626 3513869

113 Tivol E Komorowski R Drobyski WR Emergent autoimmunity in graft-versus-host disease Blood 2005 105 12 4885 4891 2-s2.0-20444362731 15746077 10.1182/blood-2004-12-4980 PMC1894995

114 Chang AE Hayes DF Pass HI Oncology: an Evidence-Based Approach 2006 New York, NY, USA Springer

115 Cheng KK-F Oral mucositis, dysfunction, and distress in patients undergoing cancer therapy Journal of Clinical Nursing 2007 16 11 2114 2121 2-s2.0-34250209833 17313536 10.1111/j.1365-2702.2006.01618.x

116 Chan A Ignoffo RJ Survey of topical oral solutions for the treatment of chemo-induced oral mucositis Journal of Oncology Pharmacy Practice 2005 11 4 139 143 2-s2.0-33646165102 16595065 10.1191/1078155205jp166oa

117 Keefe DM Schubert MM Elting LS Updated clinical practice guidelines for the prevention and treatment of mucositis Cancer 2007 109 5 820 831 2-s2.0-33847389418 17236223 10.1002/cncr.22484

118 Spielberger R Stiff P Bensinger W Palifermin for oral mucositis after intensive therapy for hematologic cancers The New England Journal of Medicine 2004 351 25 2590 2598 2-s2.0-10344242939 15602019 10.1056/NEJMoa040125

119 Schmidt E Thoennissen NH Rudat A Use of palifermin for the prevention of high-dose methotrexate-induced oral mucositis Annals of Oncology 2008 19 9 1644 1649 2-s2.0-50849122647 18453519 10.1093/annonc/mdn179

120 Vadhan-Raj S Trent J Patel S Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial Annals of Internal Medicine 2010 153 6 358 367 2-s2.0-77957343771 20855800 10.7326/0003-4819-153-6-201009210-00003

121 Lalla RV Sonis ST Peterson DE Management of Oral Mucositis in Patients Who Have Cancer Dental Clinics of North America 2008 52 1 61 77 2-s2.0-37249093932 18154865 10.1016/j.cden.2007.10.002 PMC2266835

122 Silva GBL Mendonça EF Bariani C Antunes HS Silva MAG The prevention of induced oral mucositis with low-level laser therapy in bone marrow transplantation patients: a randomized clinical trial Photomedicine and Laser Surgery 2011 29 1 27 31 2-s2.0-78651276280 20969443 10.1089/pho.2009.2699

123 Noé JE L-glutamine use in the treatment and prevention of mucositis and cachexia: a naturopathic perspective Integrative Cancer Therapies 2009 8 4 409 415 2-s2.0-77949388240 19942578 10.1177/1534735409348865

124 Peterson DE Jones JB Petit RG II Randomized, placebo-controlled trial of saforis for prevention and treatment of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy Cancer 2007 109 2 322 331 2-s2.0-33846213104 17154160 10.1002/cncr.22384

125 Sukhotnik I Mogilner JG Karry R Effect of oral glutamine on enterocyte turnover during methotrexate-induced mucositis in rats Digestion 2009 79 1 5 13 2-s2.0-58149386730 19142037 10.1159/000191209

126 Sukhotnik I Mogilner JG Shteinberg D Leptin accelerates enterocyte turnover during methotrexate-induced intestinal mucositis in a rat Cancer Biology and Therapy 2009 8 10 899 906 2-s2.0-68049137586 19276673 10.4161/cbt.8.10.8128

127 Rautemaa R Lauhio A Cullinan MP Seymour GJ Oral infections and systemic disease—an emerging problem in medicine Clinical Microbiology and Infection 2007 13 11 1041 1047 2-s2.0-35148869655 17714525 10.1111/j.1469-0691.2007.01802.x

128 Lalla RV Latortue MC Hong CH A systematic review of oral fungal infections in patients receiving cancer therapy Supportive Care in Cancer 2010 18 8 985 992 2-s2.0-77956458554 20449755 10.1007/s00520-010-0892-z PMC2914797

129 Worthington HV Clarkson JE Khalid T Meyer S McCabe M Interventions for treating oral candidiasis for patients with cancer receiving treatment Cochrane Database of Systematic Reviews) 2010 7 p. CD001972 2-s2.0-77955484032 10.1002/14651858.CD001972.pub4 PMC7063978 20614427

130 Pappas PG Kauffman CA Andes D Clinical practice guidelines for the management of candidiasis: 2009 Update by the Infectious Diseases Society of America Clinical Infectious Diseases 2009 48 5 503 535 2-s2.0-60549098868 19191635 10.1086/596757 PMC7294538

131 Meis JFGM Verweij PE Current management of fungal infections Drugs 2001 61 1 13 25 2-s2.0-0035137216 11219547 10.2165/00003495-200161001-00002

132 Vazquez JA Invasive oesophageal candidiasis: current and developing treatment options Drugs 2003 63 10 971 989 2-s2.0-0038706040 12699400 10.2165/00003495-200363100-00004

133 Collins CD Ellis JJ Kaul DR Comparative cost-effectiveness of posaconazole versus fluconazole or itraconazole prophylaxis in patients with prolonged neutropenia American Journal of Health-System Pharmacy 2008 65 23 2237 2243 2-s2.0-57149096710 19020192 10.2146/ajhp070588

134 Schonfeld W Wang Cheng J Tong KB Seifeldin R Cost-effectiveness analysis of antifungal prophylaxis in patients undergoing hematopoietic stem cell transplantation Clinical Therapeutics 2008 30 5 964 973 2-s2.0-44849129213 18555943 10.1016/j.clinthera.2008.04.020

135 Stam WB O’Sullivan AK Rijnders B Economic evaluation of posaconazole vs. standard azole prophylaxis in high risk neutropenic patients in the Netherlands European Journal of Haematology 2008 81 6 467 474 2-s2.0-56649109482 18754857 10.1111/j.1600-0609.2008.01141.x

136 Sohn HS Lee T-J Kim J Kim D Cost-effectiveness analysis of micafungin versus fluconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplantation in Korea Clinical Therapeutics 2009 31 5 1105 1115 2-s2.0-66949167401 19539111 10.1016/j.clinthera.2009.05.011

137 De La Cámara R Jarque I Sanz MA Economic evaluation of posaconazole vs fluconazole in the prevention of invasive fungal infections in patients with GVHD following haematopoietic SCT Bone Marrow Transplantation 2010 45 5 925 932 2-s2.0-77952423334 19802030 10.1038/bmt.2009.272

138 Elad S Zadik Y Hewson I A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea Supportive Care in Cancer 2010 18 8 993 1006 2-s2.0-77956483923 20544224 10.1007/s00520-010-0900-3

139 Glenny A-M Fernandez Mauleffinch LM Pavitt S Walsh T Interventions for the prevention and treatment of herpes simplex virus in patients being treated for cancer Cochrane Database of Systematic Reviews 2009 1 CD006706 2-s2.0-62449219622 10.1002/14651858.CD006706.pub2 19160295

140 Reusser P Management of viral infections in immunocompromised cancer patients Swiss Medical Weekly 2002 132 27-28 374 378 2-s2.0-0037072213 12428191 10.4414/smw.2002.09875

141 Arduino PG Porter SR Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management Oral Diseases 2006 12 3 254 270 2-s2.0-33646688452 16700734 10.1111/j.1601-0825.2006.01202.x

142 Chilukuri S Rosen T Management of acyclovir-resistant herpes simplex virus Dermatologic Clinics 2003 21 2 311 320 2-s2.0-0037733109 12757254 10.1016/s0733-8635(02)00093-1

143 Syrjanen S Laine P Niemela M Happonen R-P Oral hairy leukoplakia is not a specific sign of HIV-infection but related to immunosuppression in general Journal of Oral Pathology and Medicine 1989 18 1 28 31 2-s2.0-0024321340 2545869 10.1111/j.1600-0714.1989.tb00728.x

144 Cho H-H Kim S-H Seo S-H Oral hairy leukoplakia which occurred as a presenting sign of acute myeloid leukemia in a child Annals of Dermatology 2010 22 1 73 76 2-s2.0-77953503644 20548888 10.5021/ad.2010.22.1.73 PMC2883404

145 Blomgren J Bäck H Oral hairy leukoplakia in a patient with multiple myeloma Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 1996 82 4 408 410 2-s2.0-0030254644 10.1016/s1079-2104(96)80305-2 8899778

146 Nicolatou O Nikolatos G Fisfis M Oral hairy leukoplakia in a patient with acute lymphocytic leukemia Oral Diseases 1999 5 1 76 79 2-s2.0-0032890768 10218045 10.1111/j.1601-0825.1999.tb00067.x

147 Piperi E Omlie J Koutlas IG Pambuccian S Oral hairy leukoplakia in HIV-negative patients: report of 10 cases International Journal of Surgical Pathology 2010 18 3 177 183 2-s2.0-77952249368 19033322 10.1177/1066896908327865

148 Walling DM Flaitz CM Nichols CM Epstein-Barr virus replication in oral hairy leukoplakia: response, persistence, and resistance to treatment with valacyclovir Journal of Infectious Diseases 2003 188 6 883 890 2-s2.0-0141729383 12964120 10.1086/378072

149 Moura MDG Guimarães TRM Fonseca LMS de Almeida Pordeus I Mesquita RA A random clinical trial study to assess the efficiency of topical applications of podophyllin resin (25%) versus podophyllin resin (25%) together with acyclovir cream (5%) in the treatment of oral hairy leukoplakia Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 2007 103 1 64 71 2-s2.0-33845515878 10.1016/j.tripleo.2006.02.016 17178496

150 Moura MDG Haddad JPA Senna MIB Ferreira E Ferreira E Mesquita RA A new topical treatment protocol for oral hairy leukoplakia Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology 2010 110 5 611 617 2-s2.0-77958101215 10.1016/j.tripleo.2010.05.015 20813564

151 Bhandarkar SS MacKelfresh J Fried L Arbiser JL Targeted therapy of oral hairy leukoplakia with gentian violet Journal of the American Academy of Dermatology 2008 58 4 711 712 2-s2.0-40649101196 18342722 10.1016/j.jaad.2007.11.017

152 Cowart BJ Taste dysfunction: a practical guide for oral medicine Oral Diseases 2011 17 1 2 6 2-s2.0-78650140583 20796233 10.1111/j.1601-0825.2010.01719.x

153 Hovan AJ Williams PM Stevenson-Moore P A systematic review of dysgeusia induced by cancer therapies Supportive Care in Cancer 2010 18 8 1081 1087 2-s2.0-77956466515 20495984 10.1007/s00520-010-0902-1

154 Halyard MY Taste and smell alterations in cancer patients—real problems with few solutions Journal of Supportive Oncology 2009 7 2 68 69 2-s2.0-67649551441 19408460

155 Fink M Vitamin D deficiency is a cofactor of chemotherapy-induced mucocutaneous toxicity and dysgeusia Journal of Clinical Oncology 2011 29 4 e81 e82 2-s2.0-79952095508 21060025 10.1200/JCO.2010.31.5317

156 Ravasco P Monteiro-Grillo I Vidal PM Camilo ME Impact of nutrition on outcome: a prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy Head and Neck 2005 27 8 659 668 2-s2.0-23444450540 15920748 10.1002/hed.20221

157 Ravasco P Monteiro-Grillo I Vidal PM Camilo ME Dietary counseling improves patient outcomes: a prospective, randomized, controlled trial in colorectal cancer patients undergoing radiotherapy Journal of Clinical Oncology 2005 23 7 1431 1438 2-s2.0-14944339251 15684319 10.1200/JCO.2005.02.054