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Role of current strategies for preventing xerostomia in oropharyngeal cancer patients

A literature review

Nazeer, Muhammad R; Jamal, Shizrah; Aziz, Surhan; Ghafoor, Robia

doi: 10.4103/ijssr.ijssr_10_18
Review Article

Xerostomia occurring as sequelae of radiation therapy results in oral complications, i.e., acid erosion, dysphagia, dysgeusia, periodontal diseases, taste disturbance, and dental caries. The best strategy should be to prevent damage of any salivary acini during the course of radiotherapy; therefore, we planned to look for all the strategies for its prevention. We searched PubMed, Google Scholar, and Oral and Dentistry database thoroughly and included all the relevant articles published in the past 12 years (2005–2017). We found the following strategies for the prevention of xerostomia during radiation therapy: amifostine, pilocarpine, Vitamin C, and Vitamin E, acupuncture, bethanechol, botulism toxin, histamine, insulin growth factor, submandibular gland transfer, intensity-modulated radiation therapy, radiation stents, stem cell transplantation, intravenous injection of adipose stem cells, lasers, and lidocaine HCL. These preventive methods not only maintain the morphology and function of salivary glands but also reduces the need for saliva-enhancing therapies later.

Postgraduate Resident, Aga Khan University Hospital, Karachi, Pakistan

Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan

Postgraduate Resident, Aga Khan University Hospital, Karachi, Pakistan

Assistant Professor From the Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan

Address for correspondence:Robia Ghafoor, Assistant Professor From the Department of Surgery, Aga Khan University Hospital, Karachi, Pakistan

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The incidence rate of oropharyngeal cancer is progressively increasing worldwide and is reported to be 11.2%. 1 The management of oropharyngeal cancer generally includes surgery, radiotherapy, and/or chemotherapy. 2 Radiotherapy utilizes a high energy X-ray beam to slow growth of a tumor or destroy its cells. 2 However, like all other treatment modalities, oral complications are reported by patients undergoing radiotherapy of head-and-neck region. These complications include xerostomia, mucositis, candidiasis, taste alterations, trismus, and oral ulcers. 2

Xerostomia can be defined as “subjective complain of dryness of mouth” which occurs either due to decrease in secretion of saliva by salivary gland (hyposalivation) or sometimes the flow rates remain normal, yet the patient is complaining of dryness. 3 The reported prevalence of xerostomia is in the range of 0.9%–64.8%. 4 The cause of xerostomia is multifactorial; 2 , 3 , 4 however, the most common is mentioned in /1.{Table 1}

Xerostomia occurring as a sequelae of radiation therapy adversely affects patient's health and quality of life. 4 Average radiation dose required in cases of oropharyngeal tumor is 70 Gy or more, with a routine fraction of approximately 2 Gy. 4 The total radiation dose given is directly related to the extent of damage to sensitive organs (for example, salivary glands) in oral and pharyngeal region. The parenchymal component of a salivary gland is usually most sensitive to these ionizing radiations, as a result they are likely to get damage during a radiotherapy. The reversible damage usually occurs when the radiation dose is limited to 20–30 Gy. 5 However, when it exceeds up to 50 Gy, irreversible damage can occur within a salivary gland, resulting in degenerative changes in ductal epithelium and connective tissue fibrosis. Serous acini are more sensitive than mucous ones, resulting in thick ropy saliva in patients underwent radiotherapy. 2 , 6

Saliva is the most essential and physiological fluid of human body. It performs certain vital functions such as lubrication, swallowing, speech, taste, protection of mucous membrane and also provides antimicrobial and buffering property. 6 As a result, a hyposalivation following radiotherapy, an individual is prone to health-related risks. 2 As saliva contains certain antimicrobial agents, so host defense is compromise causing an increase in the incidence of dental caries and superinfections such as candidiasis in xerostomic patients. 2 , 6 Xerostomia could lead to increased prevalence of cariogenic microbial flora which includes Streptococcus mutans, Lactobacillus, Actinomyces, Fusobacterium, and Streptococcus sanguinis. 2 Lack of salivary flow is followed by certain complications in oral cavity which include acid erosion, dysphagia, dysgeusia, periodontal diseases, taste disturbance, and most commonly, dental caries. 2 , 4 These difficulties eventually reduce patient's appetite and alter choice of food, resulting in compromised nutrition and health, hence distress general health and quality of life of the patient. 2 , 6

The management of xerostomia in patients underwent radiotherapy is usually palliative, i.e., symptomatic treatment and preventing occurrence of further complications. 2 Hence, a patient after radiotherapy face certain difficulties before consulting a clinician for cure. However, the best strategy should be to prevent damage of any salivary acini during the phase of radiotherapy. Different strategies can be employed to prevent salivary gland damage. 6 These strategies are summarized in /1. Details of each preventive modality are as follows:{Table 2}

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Amifostine is an adjuvant drug that can be given for prevention of xerostomia in patients undergoing radiotherapy. 7 Amifostine (cysteamine analog) is a prodrug of aminothiol group which is metabolize at the tissue site by alkaline phosphatase to its active form, i.e., WR-1065 by the process of phosphorylation. The resultant metabolite (WR-1065) is a free thiol molecule that is then taken up by cells. 7 There are two mechanisms by which amifostine protect normal cells from being damaged by the radiotherapy. Lack of alkaline phosphates and acidic medium in tumor cells prevent the action of amifostine in these tissues selectively. 8 Second, the active metabolite in the normal tissues acts as a strong scavenger for oxygen-free radicals and hence provides cytoprotection during radiotherapy. 8

Wasserman et al. reported that when amifostine is injected (intravenous), before each session of radiotherapy results in improvement in xerostomia up to 57%. 9 A systematic review concluded that the administration of amifostine not only reduces xerostomia but also certain other side effects of radiotherapy such as mucositis and dysphagia in oropharyngeal cancer patients. 10 Subcutaneous administration of amifostine has been proven to be safe and easy method when compared to IV administration for preventing xerostomia. 11

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Pilocarpine is a parasympathomimetic agent that causes stimulation of muscarinic/cholinergic receptors of salivary gland acinar cells. 12 A number of randomized control trials proved the effectiveness of pilocarpine in preventing xerostomia during the course of radiotherapy. The recommended dose is 5–10 mg daily for three times a day. 13 , 14 However, some studies reported that the continued use of pilocarpine is not beneficial in most patients. 15 , 16

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Vitamin C and E

Vitamin C and E are natural antioxidants that can also provide protection to salivary glands during the course of radiotherapy. If they are administered at an appropriate time, in effective dosage, it protects the cellular membrane of a gland from oxidative damage by free radicals. 17 , 18 Chung et al. reported that the daily ingestion 1000 mg of Vitamin C and 200 IU of Vitamin E during the phase of radiotherapy preserves the function of the major salivary glands. 17 Several randomized controlled trials demonstrate that vitamins with antioxidant action such as alpha-tocopherol and beta-carotene reduce the negative effects of radiotherapy on the mucosal cells of the larynx, pharynx, and esophagus. 19 , 20

Animal studies revealed that the use of antioxidants may reduce radiation-induced side effects by specially protecting normal cells from oxidative damage. However, the supraphysiological amounts may compromise the efficacy of radiotherapy by protecting tumor cells through nonselective scavenging. 21 , 22 A study endorses Vitamin E to be an important radioprotective agent for salivary gland function, but further research is needed in the future for its application in human beings. 23

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Acupuncture is a relatively new treatment modality that is in practice for several years for managing diverse health-related complains such as pain, neurologic disease, and several musculoskeletal disorders. 24 It causes an increased concentration of a neuropeptide (calcitonin gene-related peptide) and a hormone (vasoactive intestinal polypeptide) in the saliva. Hence, the secretion of saliva is improved in xerostomic patients. 25 Various studies have shown convincing results regarding its use in xerostomic patients. 24 , 26 Meng et al. carried out a randomized controlled trial to prove that acupuncture can reduce xerostomia in patients with the history of radiation therapy. 27 Zhuang et al. concluded that the procedure of acupuncture requires further investigation in terms of total treatment sessions need, manipulation protocol, and the precise combination of acupoints to achieve the best outcome. 24 Therefore, substantial investigation is required before endorsing acupuncture for the treatment of radiation-induced xerostomia.

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It is the product of b-methylcholine which acts on muscarinic-receptor and stimulates gland secretion. 28 Jham et al. concluded that when bethanechol is used prophylactically before radiation therapy, the unstimulated saliva is significantly higher. 28 Therefore, bethanechol causes significant improvement in xerostomia in patients with a history of radiation therapy. Jaguar et al. in his study supported the use of bethanechol during radiotherapy for improving salivary secretion, but at the same time, the study fails to determine long-term effectiveness of bethanechol. 29

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Botulism Toxin

Apart from its use in various neurologic disorders, botulinum toxin (BoNT) is now progressively used for the management of salivary gland pathologies such as sialorrhea. 30 An in vitro study done on rats found that when BoNT is injected intraglandular prior radiotherapy, it causes atrophy of a gland and reduction in acinar cells during the period of irradiation. As it makes glandular acini less sensitive to radiations, hence radiation-induced damage can be minimized. 30 Human studies failed to provide enough evidence to support the use of BoNT. Therefore, it requires more evaluation in clinical trials before considering it as a preventive treatment modality. 31

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Histamine is an amine analog which performs several physiological and pathological activities. 44 Medina et al. demonstrated that histamine preserves a salivary gland from radiation damage by preventing alterations in morphology and histology of a gland. Moreover, histamine partially prevents reduction in submandibular gland proliferation caused by the radiation. 32 Another study showed that when histamine was given in rats, it results in significant reduction in acinar and ductal cell apoptosis. Hence, histamine can be radioprotective. 45 However, future studies are required to establish the efficacy and safety of histamine.

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Insulin Growth Factor

An experimental study conducted in mice reported that, when a single dose recombinant insulin growth factor-1 (IGF-1) is injected, it results in improved salivary rates following radiotherapy. IGF-1 activates a signaling pathway (by release of endogenous Akt) which reduces apoptosis in irradiated tissues. 33 Pretreatment with IGF-1 injection arrests cell cycle in tissues during radiotherapy, hence allowing cellular repair afterward maintaining stimulated salivary flow rates. 34

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Submandibular Gland Transfer

Submandibular salivary gland can be prevented from the destructive ionizing radiations by transferring it into the submental space behind the digastric muscle. 35 , 46 By this method, a gland can be shielded from radiations' signification and absorb only approximately 5% of the total radiation dose. 46 The effectiveness of submandibular salivary gland transfer was studied in a systematic review. 47 The study concluded that it preserves the baseline stimulated and unstimulated salivary flow rates for up to 3–6 months following radiotherapy. 47 Several studies have reported favorable outcomes with this method, i.e., improvement in salivary flow rates postoperatively. 46 , 47 , 48

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Intensity-Modulated Radiation Therapy

Intensity-modulated radiation therapy (IMRT) also abbreviated as IMRT is an advanced imaging technique in which a specific area or whole tumor is focused during radiotherapy sparing the normal tissues. The radiotherapy is under the control of computerized linear accelerators. 36 The advantage of IMRT is that an effective and high precision radiation can safely be given to the tumor. Hence, the major side effect of radiotherapy such as xerostomia is greatly reduced. 36

The efficacy of IMRT in the management of oropharyngeal cancer is mentioned by multiple studies. 36 , 37 Wang and Eisbruch reported that postoperative complication such as xerostomia and dysphagia is reduced in patients receiving IMRT. 36 The quality of life after IMRT is much improved as compared to the conventional radiotherapy without compromising the radiation dose to the tumor. 37 The treatment site should be carefully planned using magnetic resonance imaging or computed tomography before IMRT to determine the precise location of the tumor. 49 Su et al. concluded that the conventional radiotherapy should replace IMRT because of less postoperative complications and better outcomes. 50

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Radiation Stents

Radiation stents are customized devices used to protect or shield the normal tissues so that the radiotherapy can be safely administered to the affected area only. As in IMRT, stents reduce the exposure of normal tissues to radiations; therefore, postoperative morbidity associated with radiotherapy is minimal in these patients. 38 Various materials used for the fabrication of stent are heat cure acrylic and alloys (Cerrobend and Lipowitz). 38

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Stem Cell Transplantation

Studies have shown that when stem cells are transplanted into a salivary gland, it results in restoration of morphology and function of a gland. Certain stem cells (c-kit stem cells) when injected into the submandibular gland of mice results in normal function. 39 , 40

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Intravenous Transplantation of Adipose Stem Cells

Li et al. stated that when adipose tissue-derived stem cells (ADSCs) were immediately injected systemically in mice after the radiation dose, results in preservation of salivary gland function as well as morphology. 41 ADSC protects a salivary gland by enhancing cell proliferation, inhibiting apoptosis, and promoting angiogenesis so that it remains unaffected during the radiation course. 41

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Gonnelli et al. reported that when low level laser therapy (InGaAlP laser) is delivered during radio and chemotherapy, results in prevention of hyposalivation postoperatively. Therefore, health-related quality of life can be significantly improved afterward. 42 However, the preventive therapy required more investigation in clinical trials.

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Hakim et al. conducted a Phase I clinical trials among rabbits and concluded that administration of lidocaine hydrochloride (10 and 12 mg/kg) before radiotherapy results in signification protection of salivary gland function afterward. The recommended dose is 10–12 mg/kg. 43 Hence, the radiation-related damage to a salivary gland can be avoided. 43 However, the modality requires Phase II trials before considering it as a recommended preventive therapy.

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Salivary gland damage due to ionizing radiations adversely affects health-related quality of life. Therefore, preservation of normal salivary gland function is very important in patients undergoing radiotherapy for oropharyngeal cancers. It is very important for a clinician to employ preventive strategies during the phase of radiotherapy to reduce postoperative morbidity. These preventive methods not only maintain the morphology and function of a salivary glands but also reduce the need for salivary enhancing therapies later. By preventing occurrence of xerostomia in these patients, other oral complications such as dental caries, alterations in taste, and dysphasia are also significantly improved.

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Conflicts of interest

There are no conflicts of interest

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51. . .;:

    Head and neck cancer; hyposalivation; oropharyngeal cancer; radiation therapy; xerostomia

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