Symptoms and grading

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Adverse mucosal changes associated with multikinase inhibitor treatment

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 characterized by burning or tingling sensation on the lips, tongue or entire mouth.4

Incidence: Overall incidence of stomatitis is reported as being a common (≥1/100 to <1/10) or very common (≥1/10) adverse reaction in patients treated with cabozantinib, imatinib, lenvatinib, sunitinib, sorafenib, dasatinib, pazopanib or midostaurin. 5-23 The incidence of dry mouth, one of the symptoms of stomatitis, in patients treated with cabozantinib, imatinib, lenvatinib, sunitinib, pazopanib, regorafenib or vandetanib is also reported to be common or very common. 5-15, 20, 21, 24-27 Dysphagia occurrence is also common or very common under treatment with cabozantinib, sunitinib, sorafenib, and vandetanib.5-8, 14-17, 26,27 Similarly, for oral pain under treatment with cabozantinib, lenvatinib and sunitinib. 5-8, 11-15

Dysgeusia, another symptom of stomatitis, has been reported as commonly or very commonly occurring in patients treated with all of the multikinase inhibitors except midostaurin. 5-27

Grading: A CTCAEv5.04 grading for stomatitis is lacking, however, stomatitis can be assigned under the MedDRA System Organ Class (SOC) of “Gastrointestinal disorders -Other, specify”. The specific symptoms, such as dysphagia, dry mouth, oral dysesthesia, oral pain and lip pain, can be reported separately.

According to the MESTT, 28 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 the MESTT grading.

Table 16: Grading of Gastrointestinal disorders - Other, specify according to CTCAEv5.0

Grade Description
1 Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL
3 Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of existing hospitalisation indicated; disabling; limiting self-care ADL
4 Life-threatening consequences; urgent intervention indicated

 ADL = Activities of Daily Living

Table 17: Grading of Dry mouth according to CTCAEv5.0

Grade Description
1 Symptomatic (e.g., dry or thick saliva) without significant dietary alteration; unstimulated saliva flow >0.2 ml/min
2 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
3 Inability to adequately aliment orally; tube feeding or Total Parenteral Nutrition (TPN) indicated; unstimulated saliva <0.1 ml/min

Table 18: Grading of Oral pain according to CTCAEv5.0

Grade Description
1 Mild pain
2 Moderate pain; limiting instrumental ADL
3 Severe pain; limiting self-care ADL

Table 19: Grading of Lip pain according to CTCAEv5.0

Grade Description
1 Mild pain
2 Moderate pain; limiting instrumental ADL
3 Severe pain; limiting self-care ADL

ADL = Activities of Daily Living

Table 20: Grading of Dysgeusia according to CTCAEv5.0

Grade Description
1 Altered taste but no change in diet
2 Altered taste with change in diet (e.g., oral supplements); noxious or unpleasant taste; loss of taste
3 -

Table 21: Grading of Dysphagia according to CTCAEv5.0

Grade Description
1 Symptomatic, able to eat regular diet
2 Symptomatic & altered eating/swallowing
3 Severely altered eating/swallowing; tube feeding or TPN or hospitalisation indicated
4 Life-threatening consequences; urgent intervention indicated

Table 22: Grading of Oral dysesthesia according to CTCAEv5.0

Grade Description
1 Mild discomfort; not interfering with oral intake
2 Moderate pain; interfering with oral intake
3 Disabling pain; tube feeding or TPN indicated 

Table 23: Grading of Mucositis (-Oral or -Anal) according to MESTT

Grade Description
1 Mild erythema, oedema
2 Symptomatic (mild pain, opioid not required): erythema or limited ulceration, can eat solid foods and take oral medication (Oral mucositis only)
3 Pain requiring opioid analgesic; erythema and ulceration, cannot eat solids, can swallow liquids (Oral mucositis only)
4 Erythema and ulceration, cannot tolerate PO intake; require tube feeding or hospitalisation (Oral mucositis only)

Table 24: Grading of Hyposalivation according to MESTT

Grade Description
1 Can eat but requires liquids, no effect on speech
2 Moderate/thickened saliva: cannot eat dry foods, mild speech impairment (sticky tongue, lips, affecting speech)
3 No saliva, unable to speak without water, no oral intake without water

Table 25: Grading of Dysgeusia according to MESTT

Grade Description
1 Altered or reduced taste; no impact on oral intake
2 Altered or reduced taste affecting interest & ability to eat, no intervention required
3 Taste abnormalities, requires intervention

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 may reappear after subsequent cycles 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 Prophylaxis and treatment - reactive management – Stomatitis.

Related Links

References

  1. De Wit M, et al. Support Care Cancer. 2014;22:837–846.
  2. Boers-Doets C, et al. Future Oncol. 2013;9:1883–1892.
  3. Boers-Doets C, et al. The Oncologist. 2012;17:135–144.
  4. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events and Common Toxicity Criteria [v5.0]. 27 November 2017. (Accessed 15 April 2019).
  5. European Medicines Agency. Cabometyx (cabozantinib) Summary of Product Characteristics 2019.
  6. Food and Drug Administration. Cabometyx (cabozantinib) Prescribing Information 2019.
  7. European Medicines Agency. Cometriq (cabozantinib) Summary of Product Characteristics 2019.
  8. Food and Drug Administration. Cometriq (cabozantinib) Prescribing Information 2018.
  9. European Medicines Agency. Glivec (imatinib) Summary of Product Characteristics 2019.
  10. Food and Drug Administration. Gleevec (imatinib) Prescribing Information 2018.
  11. European Medicines Agency. Kisplyx (lenvatinib) Summary of Product Characteristics 2019.
  12. European Medicines Agency. Lenvima (lenvatinib) Summary of Product Characteristics 2019.
  13. Food and Drug Administration.  Lenvima (lenvatinib) Prescribing Information 2018.
  14. European Medicines Agency. Sutent (sunitinib) Summary of Product Characteristics 2019.
  15. Food and Drug Administration. Sutent (sunitinib) Prescribing Information 2019.
  16. European Medicines Agency. Nexavar (sorafenib) Summary of Product Characteristics 2018.
  17. Food and Drug Administration. Nexavar (sorafenib) Prescribing Information 2018.
  18. European Medicines Agency. Sprycel (dasatinib) Summary of Product Characteristics 2019.
  19. Food and Drug Administration. Sprycel (dasatinib) Prescribing Information 2018.
  20. European Medicines Agency. Votrient (pazopanib) Summary of Product Characteristics 2018.
  21. Food and Drug Administration. Votrient (pazopanib) Prescribing Information 2017.
  22. European Medicines Agency. Rydapt (midostaurin) Summary of Product Characteristics 2018.
  23. Food and Drug Administration. Rydapt (midostaurin) Prescribing Information 2018.
  24. European Medicines Agency. Stivarga (regorafenib) Summary of Product Characteristics 2018.
  25. Food and Drug Administration. Stivarga (regorafenib) Prescribing Information 2019.
  26. European Medicines Agency. Caprelsa (vandetanib) Summary of Product Characteristics 2019.
  27. Food and Drug Administration. Caprelsa (vandetanib) Prescribing Information 2018.
  28. MASCC EGFR Inhibitor Skin Toxicity Tool (MESTT). (Accessed 15 April 2019).
Last update: 13 September 2019