Mucosal Changes - Stomatitis

Definition

Stomatitis is a general term for inflammation of the oral mucosa which encompasses mucositis, dry mouth, dysgeusia, dysphagia and oral dysesthesia.1-4 Oral mucositis describes inflammation of the oral mucosa.4 Dry mouth is characterised by reduced salivary flow in the oral cavity.4 Dysgeusia is characterised by abnormal sensory experience with the taste of foodstuffs, and can be related to a decrease in the sense of smell.4 Dysphagia is characterised by difficulty in swallowing.4 Finally, oral dysesthesia is characterised by burning or tingling sensation on the lips, tongue or entire mouth.4

Incidence

Overall incidence of stomatitis varies amongst patients treated with sorafenib, sunitinib, and imatinib, ranging from 5% to 29%.5-9 The incidence of dry mouth, one of the symptoms of stomatitis, in patients treated regorafenib, vandetanib, and sunitinib is reported to be between 5% to 10%.10-14 Dysgeusia, another symptom of stomatitis, has been reported in 28% of patients treated with sunitinib in clinical trials.10

Grading

A NCI-CTCAE V4.034 grading for stomatitis is lacking, however, stomatitis can be allocated under the term “Gastrointestinal disorders -Other, specify”. The specific symptoms, such as dysphagia, dry mouth, oral dysesthesia, oral pain and lip pain, can be reported separately.

On the other hand according to the MESTT,15 stomatitis can be reported as mucositis –oral, since this grading tool is developed specifically for targeted therapies. In addition, “Dry mouth/Hyposalivation” and “Dysgeusia” can be recorded separately. No definitions are included in MESTT grading.

Grade 1 (mild) Mucosal Changes

Mucositis Oral

  • The NCI-CTCAE V4.03 definition of grade 1 mucositis oral reads: Asymptomatic or mild symptoms; intervention not indicated

Dysphagia

  • The NCI-CTCAE V4.03 definition of grade 1 dysphagia reads: Symptomatic, able to eat regular solid diet

Dry Mouth

  • The NCI-CTCAE V4.03 definition of grade 1 dry mouth reads: Symptomatic (e.g., dry or thick saliva) without significant dietary alteration; unstimulated saliva flow >0.2 ml/min
  • The MESTT definition of grade 1 dry mouth/hyposalivation reads: Can eat but requires liquids, no effect on speech

Oral Dysesthesia

  • The NCI-CTCAE V4.03 definition of grade 1 oral dysesthesia reads: Mild discomfort; not interfering with oral intake

Oral Pain

  • The NCI-CTCAE V4.03 definition of grade 1 oral pain reads: Mild pain

Lip Pain

  • The NCI-CTCAE V4.03 definition of grade 1 lip pain reads: Mild pain

Mucositis

  • The MESTT definition of grade 1 mucositis (oral or anal) reads: Mild erythema, oedema, no pain

Dysgeusia

  • The MESTT definition of grade 1 dysgeusia reads: Altered or reduced taste; no impact on oral intake

Grade 2 (moderate) Mucosal Changes

Mucositis Oral

  • The NCI-CTCAE V4.03 definition of grade 2 mucositis oral reads: Moderate pain; not interfering with oral intake; modified diet indicated

Dysphagia

  • The NCI-CTCAE V4.03 definition of grade 2 dysphagia reads: Symptomatic & altered eating/swallowing

Dry Mouth

  • The NCI-CTCAE V4.03 definition of grade 2 dry mouth reads: Moderate symptoms; oral intake alterations (e.g., copious water, other lubricants, diet limited to purees and/or soft, moist foods); unstimulated saliva 0.1 to 0.2 ml/min
  • The MESTT definition of grade 2 dry mouth/hyposalivation reads: Moderate/thickened saliva: cannot eat dry foods, mild speech impairment (sticky tongue, lips, affecting speech)

Oral Dysesthesia

  • The NCI-CTCAE V4.03 definition of grade 2 oral dysesthesia reads: Moderate pain; interfering with oral intake

Oral Pain

  • The NCI-CTCAE V4.03 definition of grade 2 oral pain reads: Moderate pain; limiting instrumental ADL

Lip Pain

  • The NCI-CTCAE V4.03 definition of grade 2 lip pain reads: Moderate pain; limiting instrumental ADL

Mucositis

  • The MESTT definition of grade 2A mucositis (oral or anal) reads: Symptomatic (mild pain, opioid not required): erythema or limited ulceration, can eat solid foods and take oral medication (oral mucositis only)
  • The MESTT definition of grade 2B mucositis (oral or anal) reads: Pain requiring opioid analgesic; erythema and ulceration, cannot eat solids, can swallow liquids (oral mucositis only)

Dysgeusia

  • The MESTT definition of grade 2 dysgeusia reads: Altered or reduced taste affecting interest & ability to eat no intervention required

Grade 3 (severe) Mucosal Changes

Mucositis Oral

  • The NCI-CTCAE V4.03 definition of grade 3 mucositis oral reads: Severe pain; interfering with oral intake

Dysphagia

  • The NCI-CTCAE V4.03 definition of grade 3 dysphagia reads: Severely altered eating/swallowing; tube feeding or TPN or hospitalisation indicated

Dry Mouth

  • The NCI-CTCAE V4.03 definition of grade 3 dry mouth reads: Inability to adequately aliment orally; tube feeding or TPN indicated; unstimulated saliva <0.1 ml/min
  • The MESTT definition of grade 3 dry mouth/hyposalivation reads: No saliva, unable to speak without water, no oral intake without water

Oral Dysesthesia

  • The NCI-CTCAE V4.03 definition of grade 3 oral dysesthesia reads: Disabling pain; tube feeding or TPN indicated

Oral Pain

  • The NCI-CTCAE V4.03 definition of grade 3 oral pain reads: Severe pain; limiting self-care ADL

Lip Pain

  • The NCI-CTCAE V4.03 definition of grade 3 lip pain reads: Severe pain; limiting self-care ADL

Mucositis

  • The MESTT definition of grade 3 mucositis (oral or anal) reads: Erythema and ulceration, cannot tolerate p.o. intake; require tube feeding or hospitalisation (oral mucositis only)

Dysgeusia

  • The MESTT definition of grade 3 dysgeusia reads: Taste abnormalities, requires intervention

Grade 4 (life-threatening) Mucosal Changes

Mucositis Oral

  • The NCI-CTCAE V4.03 definition of grade 4 mucositis oral reads: Life-threatening consequences; urgent intervention indicated

Dysphagia

  • The NCI-CTCAE V4.03 definition of grade 4 dysphagia reads: Life-threatening consequences; urgent intervention indicated

Note: Grade 4 not applicable for other mucosal changes mentioned above.

Onset

There are very little reported data on the onset of stomatitis, dry mouth, and dysgeusia with multikinase inhibitors. It is reported that regorafenib-associated stomatitis occurs between 5 and 14 days after the start of a treatment cycle resolves during drug holidays and reappears every cycle of treatment.1

Resolution

There are no apparent published data on the resolution of stomatitis and related events occurring with multikinase inhibitor therapy. Also see management of Stomatitis.

References

1De Wit M, et al. Prevention and management of adverse events related to regorafenib. Support Care Cancer. 2014;22:837–846.
2Boers-Doets CB, et al. Mammalian target of rapamycin inhibitor-associated stomatitis. Future Oncol. 2013;9:1883–1892.
3Boers-Doets CB, et al. Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. The Oncologist. 2012;17:135–144.
4National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events and Common Toxicity Criteria [v4.0]. 15-12-2010. (accessed 22 August 2014)
5European Medicines Agency. Nexavar® (sorafenib) Summary of Product Characteristics 2014.
6Food and Drug Administration. Nexavar® (sorafenib) Prescribing Information 2013.
7European Medicines Agency. Glivec® (imatinib) Summary of Product Characteristics 2014.
8Food and Drug Administration. Gleevec® (imatinib) Prescribing Information 2013.
9European Medicines Agency. Sutent® (sunitinib) Summary of Product Characteristics 2014.
10European Medicines Agency. Stivarga® (regorafenib) Summary of Product Characteristics 2013.
11Food and Drug Administration. Stivarga® (regorafenib) Prescribing Information 2013.
12Food and Drug Administration. Caprelsa® (vandetanib) Prescribing Information 2014.
13European Medicines Agency. Caprelsa® (vandetanib) Summary of Product Characteristics 2014.
14European Medicines Agency. Sutent® (sunitinib) Summary of Product Characteristics 2014.
15Multinational Association of Supportive Care in Cancer (MASCC) EGFR Inhibitor Skin Toxicity Tool (MESTT)

Last update: 26 August 2014