Home  -  About us  -  Editorial board  -  Search  -  Ahead of print  -  Current issue  -  Archives  -  Instructions  -  Subscribe  -  Contacts  -  Advertise - Login 
 
 
     

 Table of Contents  
ORIGINAL ARTICLE - RETROSPECTIVE STUDY
Year : 2021  |  Volume : 11  |  Issue : 1  |  Page : 86-90

Cancer chemotherapy-induced oral adverse events: Oral dysesthesia and toothache - A retrospective study


1 Department of Oral and Maxillofacial Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan
2 Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital, Okayama, Japan
3 Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan

Date of Submission22-Apr-2020
Date of Decision19-Jan-2021
Date of Acceptance03-Feb-2021
Date of Web Publication24-Jul-2021

Correspondence Address:
Dr. Shunsuke Hino
Department of Oral and Maxillofacial Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550
Japan
Login to access the Email id


DOI: 10.4103/ams.ams_136_20

Rights and Permissions
  Abstract 

Introduction: Due to the development of newly developed anticancer drugs, oral dysesthesia and toothache other than conventional oral mucositis, dry mouth, and dysgeusia are increasing among oral adverse events. The objective of this study was to assess the characteristics of chemotherapy-induced oral dysesthesia and toothache. Materials and Methods: Subjects were patients referred to the oral surgery clinic for oral adverse events related to cancer chemotherapy and with an observation period of more than 1 month after the last course of chemotherapy. Oral adverse events were divided according to the categories of the National Cancer Institute Common Terminology Criteria for Adverse Events, v5.0. Statistical comparison was made using the binomial test. Results: A total of 180 patients were referred to the oral surgery clinic. Oral dysesthesia and/or toothache was found in 15 cases, which included 13 with oral dysesthesia, 4 with toothache, and 2 with both oral dysesthesia and toothache. Of these 15 cases, 13 had concomitant occurrence of peripheral neuropathy (PN) (86.7%, P = 0.0037) and 12 cases had dysgeusia (80.0%, P = 0.0176). Symptoms of oral dysesthesia and/or toothache continued after chemotherapy in 10 of 15 cases with the continuation of accompanied PN (66.7%) and/or dysgeusia and persisted for more than 6 months in 5 cases (33.3%). Discussion: Although oral dysesthesia and toothache are low-grade chemotherapy-induced adverse events, it is suggested that they may be nervous system disorders rather than gastrointestinal disorders. Clinicians should understand that they potentially persist for a long period after the end of chemotherapy.

Keywords: Adverse events, chemotherapy, oral dysesthesia, toothache


How to cite this article:
Hino S, Yamada M, Iijima Y, Fujita Y, Sano M, Kaneko T, Horie N. Cancer chemotherapy-induced oral adverse events: Oral dysesthesia and toothache - A retrospective study. Ann Maxillofac Surg 2021;11:86-90

How to cite this URL:
Hino S, Yamada M, Iijima Y, Fujita Y, Sano M, Kaneko T, Horie N. Cancer chemotherapy-induced oral adverse events: Oral dysesthesia and toothache - A retrospective study. Ann Maxillofac Surg [serial online] 2021 [cited 2021 Dec 2];11:86-90. Available from: https://www.amsjournal.com/text.asp?2021/11/1/86/322232


  Introduction Top


The number of cancer patients has increased in recent years, and chemotherapeutic agents have contributed to the treatment of various types of cancer, including both solid and hematopoietic types.[1] At the same time, adverse events from chemotherapy have also been increasing.[2] The adverse events are various and are described precisely in the list of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), v5.0.[3] Among these, various oral adverse events can be found in the categories of gastrointestinal disorders and nervous system disorders. The common oral adverse events include oral mucositis, dry mouth, and dysgeusia.[4] Patients suffering from mucosal discomfort without mucosal change and tooth hypersensitivity are more frequently seen at present, probably because of newly developed chemotherapeutic agents.[5] These mucosal and tooth complications are divided into oral dysesthesia and toothache, respectively, in the CTCAE v5.0.[3] Oral dysesthesia and toothache, which are classified as gastrointestinal disorders, are relatively low-grade adverse events, but it is unclear whether it is appropriate to classify them as gastrointestinal disorders even though they include perceptual complications. Among oral adverse events, the clinical characteristics and treatment strategies for oral mucositis and dry mouth have been well described.[5] However, studies into oral dysesthesia and toothache are rare.[4],[5],[6] As chemotherapy-induced oral dysesthesia and toothache are expected to become more common with the development of biological targeted therapies and immune checkpoint inhibitors, it is worthwhile to improve our understanding of oral dysesthesia and toothache.[4],[5] The objective of this study was to assess the characteristics of cancer chemotherapy-induced oral dysesthesia and toothache and describe the association between nervous system disorders and oral dysesthesia and toothache.


  Materials and Methods Top


The Ethics Review Board at the University approved the protocol of the study (approval number: 2018-1878), which proceeded in accordance with the Declaration of Helsinki. Patients referred to the oral and maxillofacial surgery clinic for oral adverse events related to cancer chemotherapy from other clinics from April 1, 2016 to September 30, 2018 were searched. Data on these patients were obtained from their clinical records, and they were analyzed retrospectively. In these, patients who had an observation period of more than 1 month after the last course of chemotherapy were included as subjects in the study. Patients were excluded if they did not have complete medical records. In addition, patients receiving palliative care were excluded because these patients had various oral complications not related to chemotherapy, and patients with head and neck cancer were excluded because tumour progress and/or radiotherapy cause oral complications. Oral adverse events in patients were divided according to the categories of CTCAE v5.0.[3] As some oral events described in CTCAE v5.0 are broad and difficult to classify clinically into one event, in this study, “oral pain” and “oral dysesthesia,” both of which are defined as events with no change in the mucosa, were classified under the term “oral dysesthesia”. In addition, bisphosphonate and denosumab are used to treat cancer, but this “oral dysesthesia” does not include early symptoms of medication-related osteonecrosis of the jaw. As there are no eligible criteria that describe hypersensitivity and dysesthesia of teeth except for “toothache”, “toothache” was used as the term for hypersensitivity and dysesthesia of teeth. In addition, this “toothache” is not caused by an odontogenic cause such as dental caries, impacted teeth, and any other pathologies.

In this study, patients with oral dysesthesia and/or toothache were subsequently compiled and their chemotherapy and adverse events data were analyzed. Data were statistically analyzed by the binomial test using Origin Pro 2016 software (Lightstone Corp., Tokyo, Japan). The level of significance for all tests was set at 5% (P < 0.05).


  Results Top


A total of 188 patients were referred to the oral surgery clinic. Two patients were excluded from this study due to the absence of precise medical records, and six patients were excluded because the observation period was shorter than 1 month after the last course of chemotherapy. As a result, 180 patients were enrolled in this study. Among these, there were 15 cases of oral dysesthesia and/or toothache, in which oral dysesthesia was found in 13 cases and toothache was found in 4 cases. Two cases showed both oral dysesthesia and toothache. The details of patients with oral dysesthesia and/or toothache are shown in [Table 1]. There were 8 men and 7 women, whose ages ranged from 36 to 80 (60.3 ± 13.9) years. Thirteen cases had concomitant peripheral neuropathy (PN) (86.7%, P = 0.0037) and 12 cases had dysgeusia (80.0%, P = 0.0176). Drugs that are known to cause PN were used in 12 cases; 4 used taxanes (2 each of docetaxel and paclitaxel), 4 used oxaliplatin, 3 used vincristine, and 1 used cytarabine. The most common symptom of oral dysesthesia was tingling of the tongue (8/13) (61.5%, P = 0.5000) and all 4 cases of toothache showed hypersensitivity to cold stimulation (100.0%). The onset of oral dysesthesia and/or toothache was at the same time of PN in 4 cases (30.8%) and later than that of PN in 9 cases (69.2%). Symptoms of oral dysesthesia and/or toothache continued after chemotherapy in 10 of 15 cases with the continuation of accompanying PN and/or dysgeusia (66.7%) (P = 0.1509) and persisted for more than 6 months in 5 cases (33.3%).
Table 1: Characteristics of patients with oral dysesthesia and/or toothache

Click here to view



  Discussion Top


In this study, the characteristics of cancer chemotherapy-induced oral dysesthesia and toothache were described, and the association between nervous system disorders and oral dysesthesia and toothache was discussed.

Adverse events, including oral events, can vary based on the chemotherapy regimen. The most common oral adverse events are oral mucositis, dysgeusia, and dry mouth,[4],[7],[8] while the occurrence of oral dysesthesia and toothache is somewhat less common. A recent study noted that 12% of patients who were treated with vascular endothelial growth factor receptor-directed multitargeted tyrosine kinase inhibitor therapies had oral dysesthesia.[4] In this study, oral dysesthesia and toothache were found in 7.2% (13/181) and 2.2% (4/181), respectively.[4]

Oral dysesthesia is a gastrointestinal disorder and is characterized by a burning or tingling sensation on the lips, tongue, or the entire mouth (CTCAE v5.0).[3] In CTCAE v5.0, oral pain, which is defined as a disorder characterized by a sensation of marked discomfort in the mouth, tongue, or lips, presents as a complication of the oral mucosa, similarly to oral dysesthesia. It is difficult to distinguish these two events clinically; thus, in this study, the term “oral dysesthesia” was used to describe mucosal discomfort without mucosal change. Toothache is also a gastrointestinal disorder and is characterized by a sensation of marked discomfort in the tooth (CTCAE v5.0). There are no criteria that describe tooth hypersensitivity and discomfort other than “toothache” in CTCAE v5.0. The precise study of oral dysesthesia and toothache is rare.[4],[5],[6]

Recently, an association between PN and oral dysesthesia was suggested.[4],[9] PN is classified as a nervous system disorder in CTCAE v5.0 and is a common adverse event of chemotherapy.[3] PN includes both motor and sensory neuropathy and can be characterized by inflammation or degeneration of peripheral motor or sensory nerves (CTCAE v5.0). The pathophysiological processes of PN are multifactorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration, and membrane remodeling, as well as immune processes and neuroinflammation.[10],[11],[12] PN is characterized by predominantly sensory axonal PN with longer axons affected first, such as in the feet and hands.[13],[14] The histopathological changes associated with PN commonly involve large myelinated fibers,[15] and the symptoms include numbness, tingling, paresthesia, and dysesthesia induced by touch, warm or cool temperatures, impaired vibration, and altered touch sensations.[16] Platinum-based agents (oxaliplatin and cisplatin), vinca alkaloids (vincristine and vinblastine), epothilones (ixabepilone), diterpenes (taxanes; paclitaxel and docetaxel), antimetabolites (cytarabine), proteasome inhibitors (bortezomib), and immunomodulatory drugs (thalidomide) are known to induce PN.[12]

In this study, 13 of 15 oral dysesthesia and/or toothache cases had concomitant PN (86.7%, P = 0.0037), and there were various oral dysesthesia and/or toothache-inducing drugs, but 12 of the 15 cases used oxaliplatin, paclitaxel, docetaxel, vincristine or cytarabine, which are known to cause PN. In addition, 12 of the 15 oral dysesthesia and/or toothache cases concomitantly developed dysgeusia (80.0%, P = 0.0176), which is a nervous system disorder. These results suggest that oral dysesthesia and/or toothache is closely associated with PN and dysgeusia, although oral dysesthesia and toothache are considered to be gastrointestinal disorders, not nervous system disorders, in CTCAE v5.0.

In this study, the most frequently affected site for oral dysesthesia was the tongue, particularly the apex of the tongue, irrespective of the drugs administered. The oral mucosa appeared to be largely intact, except in cases with mucositis. The major symptom of oral dysesthesia in almost all cases was tingling of the tongue (8/13) (61.5%), not severe pain, and this finding was consistent with previous reports.[6] All toothache cases showed hypersensitivity to cold stimulation on vital teeth. In all cases, the affected teeth were not random, but were concentrated in one block; for example, the left side of the maxilla.

PN is a dose-dependent adverse effect, and so may be oral dysesthesia and/or toothache. In this study, there were no cases in which oral dysesthesia and/or toothache occurred before PN. The occurrence of oral dysesthesia and/or toothache may require greater dose accumulation than PN. In 10 of 15 cases (66.7%), symptoms of oral dysesthesia and/or toothache continued after the end of chemotherapy with the continuation of accompanied PN and/or dysgeusia, and 5 cases (33.3%) persisted for more than 6 months. Oral dysesthesia and/or toothache is a low-grade adverse event, but may also be a long-term persistent event.

Burning mouth syndrome (BMS) is a lesion that shows similar symptoms as chemotherapy-induced oral dysesthesia. BMS is defined as a chronic condition characterized by a burning sensation in the oral mucosa for which no cause can be found. The etiology of BMS and pathogenesis is uncertain, but both psychogenic factors and peripheral and central neuropathies appear to be involved.[17] BMS frequently occurs in the tongue, and occurrence in other sites is rare.[18] In contrast to chemotherapy-induced oral dysesthesia, it is rare that BMS accompanies other chronic neuropathic pain disorders.[17] It is explained that the reason why BMS is frequent in the tongue is that the lingual mucosa, as compared to other sites in the oral mucosa, exhibits a decreased number of small diameter nerve fibers and that the remaining small-diameter nerve fibers show upregulation of the transient receptor potential subfamily member V 1 (TRPV1) ion channel, and upregulation of P2 × 3 receptors and nerve growth factor.[17],[19] The tongue mucosa seems to be a neurologically sensitive site. The causes of oral dysesthesia and BMS are different, but the mechanical process of chemotherapy-induced oral dysesthesia and BMS may be closely associated.

In clinical settings, as oral dysesthesia is a low-grade adverse event (≤grade 3), almost all cases of oral dysesthesia have been removed from the object of treatment. As a practical matter, however, there have been no established regimens to prevent or reduce oral dysesthesia. It is recommended to avoid irritating foods.[5] In cases of PN, analgesic medications including anticonvulsants (pregabalin, gabapentin, carbamazepine, oxcarbazepine, lamotrigine, and topiramate) and antidepressants (amitriptyline, nortriptyline, venlafaxine, and duloxetine) are used. However, their effects are limited.[12] Accordingly, current treatment strategies for severe PN are predominantly based on dose reduction, changes to less effective chemotherapeutic agents, or even cessation of therapy.[12],[20] In this study, cases with persistent PN were given one or more of these analgesic medications, and in severe PN cases, dose reduction was performed. There have been some reports of analgesic medications for PN being used for oral dysesthesia, but their effectiveness has not been verified.[5] In this study, patients with PN reported that concomitant oral complications were improved to some degree. Local application of capsaicin, which can bind to TRPV1 ion channels, is reported to be effective for the treatment of BMS, but there has been no study into capsaicin being used for chemotherapy-induced oral dysesthesia.[21]

Good oral hygiene is a basic and important means of preventing and reducing the severity of oral mucositis. It has also been noted that oral hygiene is an essential treatment for other oral adverse events, such as oral dysesthesia and dysgeusia,[5] probably because it prevents local secondary inflammation and irritation.

Toothache can be reduced by dental treatments such as application of antihypersensitive agents and/or covering of the tooth surface with dental cement.[22] However, the effects are limited when the sensitive area is large. Splints that cover the tooth surface may be effective for hypersensitivity in multiple teeth. In addition, the differentiation of chemotherapy-induced toothache from dental caries and tooth hypersensitivity is important.[23],[24]

Some limitations of the present study should be considered. First, the data were collected retrospectively. Second, the relatively small number of participants means that the more accurate statistical analysis was difficult, and additional studies with larger cohorts were therefore required.


  Conclusion Top


Although oral dysesthesia and toothache are low-grade chemotherapy-induced adverse events, it is suggested that they may be nervous system disorders rather than gastrointestinal disorders. Clinicians should understand that they potentially persist without effective treatment for a long period after the end of chemotherapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends--an update. Cancer Epidemiol Biomarkers Prev 2016;25:16-27.  Back to cited text no. 1
    
2.
Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: Systematic review and meta-analysis. BMJ 2018;360:k793.  Back to cited text no. 2
    
3.
National Cancer Institute NIoH, U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. United States: National Cancer Institute NIoH, U.S; 2017.  Back to cited text no. 3
    
4.
Yuan A, Kurtz SL, Barysauskas CM, Pilotte AP, Wagner AJ, Treister NS. Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors. Oral Oncol 2015;51:1026-33.  Back to cited text no. 4
    
5.
Vigarios E, Epstein JB, Sibaud V. Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Support Care Cancer 2017;25:1713-39.  Back to cited text no. 5
    
6.
Kollmannsberger C, Bjarnason G, Burnett P, Creel P, Davis M, Dawson N, et al. Sunitinib in metastatic renal cell carcinoma: Recommendations for management of noncardiovascular toxicities. Oncologist 2011;16:543-53.  Back to cited text no. 6
    
7.
Cheng Y, Qin SK, Chen YP, Dong LH, Sun XD, Yu SY, et al. Local analgesic effect of a bioadhesive barrier-forming oral liquid in cancer patients with oral mucositis caused by chemotherapy and/or radiotherapy: A randomized multicenter, single-use, positive-controlled, open-label study. Onco Targets Ther 2018;11:8555-64.  Back to cited text no. 7
    
8.
Lacouture M, Sibaud V. Toxic side effects of targeted therapies and immunotherapies affecting the skin, oral mucosa, hair, and nails. Am J Clin Dermatol 2018;19:31-9.  Back to cited text no. 8
    
9.
Iijima Y, Yamada M, Endo M, Sano M, Hino S, Kaneko T, et al. Dysgeusia in patients with cancer undergoing chemotherapy. J Oral Maxillofac Surg Med Pathol 2019;31:214-7.  Back to cited text no. 9
    
10.
Peters CM, Jimenez-Andrade JM, Kuskowski MA, Ghilardi JR, Mantyh PW. An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. Brain Res 2007;1168:46-59.  Back to cited text no. 10
    
11.
Sittl R, Lampert A, Huth T, Schuy ET, Link AS, Fleckenstein J, et al. Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current. Proc Natl Acad Sci U S A 2012;109:6704-9.  Back to cited text no. 11
    
12.
Starobova H, Vetter I. Pathophysiology of chemotherapy-induced peripheral neuropathy. Front Mol Neurosci 2017;10:174.  Back to cited text no. 12
    
13.
Han Y, Smith MT. Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN). Front Pharmacol 2013;4:156.  Back to cited text no. 13
    
14.
Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 2002;249:9-17.  Back to cited text no. 14
    
15.
Gutierrez-Gutierrez G, Sereno M, Miralles A, Casado-Saenz E, Gutierrez-Rivas E. Chemotherapy-induced peripheral neuropathy: Clinical features, diagnosis, prevention and treatment strategies. Clin Transl Oncol 2010;12:81-91.  Back to cited text no. 15
    
16.
Bernhardson BM, Tishelman C, Rutqvist LE. Chemosensory changes experienced by patients undergoing cancer chemotherapy: A qualitative interview study. J Pain Symptom Manage 2007;34:403-12.  Back to cited text no. 16
    
17.
Feller L, Fourie J, Bouckaert M, Khammissa RA, Ballyram R, Lemmer J. Burning mouth syndrome: Aetiopathogenesis and principles of management. Pain Res Manag 2017;2017:1926269.  Back to cited text no. 17
    
18.
Coculescu EC, Radu A, Coculescu BI. Burning mouth syndrome: A review on diagnosis and treatment. J Med Life 2014;7:512-5.  Back to cited text no. 18
    
19.
Yilmaz Z, Renton T, Yiangou Y, Zakrzewska J, Chessell IP, Bountra C, et al. Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci 2007;14:864-71.  Back to cited text no. 19
    
20.
Areti A, Yerra VG, Naidu V, Kumar A. Oxidative stress and nerve damage: Role in chemotherapy induced peripheral neuropathy. Redox Biol 2014;2:289-95.  Back to cited text no. 20
    
21.
de Moraes M, do Amaral Bezerra BA, da Rocha Neto PC, de Oliveira Soares AC, Pinto LP, de Lisboa Lopes Costa A. Randomized trials for the treatment of burning mouth syndrome: An evidence-based review of the literature. J Oral Pathol Med 2012;41:281-7.  Back to cited text no. 21
    
22.
Clark D, Levin L. Tooth hypersensitivity treatment trends among dental professionals. Quintessence Int 2018;49:147-51.  Back to cited text no. 22
    
23.
Hong CH, Hu S, Haverman T, Stokman M, Napeñas JJ, Braber JB, et al. A systematic review of dental disease management in cancer patients. Support Care Cancer 2018;26:155-74.  Back to cited text no. 23
    
24.
Olczak-Kowalczyk D, Krasuska-Sławińska E, Brożyna A, Turska-Szybka A, Dembowska-Bagińska B. Dental caries in children and adolescents during and after antineoplastic chemotherapy. J Clin Pediatr Dent 2018;42:225-30.  Back to cited text no. 24
    



 
 
    Tables

  [Table 1]



 

Top
 
 
Search
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)  

 
  In this article
   Abstract
  Introduction
   Materials and Me...
  Results
  Discussion
  Conclusion
   References
   Article Tables

 Article Access Statistics
    Viewed280    
    Printed4    
    Emailed0    
    PDF Downloaded69    
    Comments [Add]    

Recommend this journal