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Different acneiform rashes linked to multikinase inhibitor treatment

Definition: papulopustular rash is also referred to as acneiform rash, acne-like rash or folliculitis.1 This kind of skin eruption is much more common with EGFR inhibitors and rare with MKIs. It is more or less confined to the seborrheic areas (areas rich in sebaceous glands): the face (especially the nose, the cheeks, the forehead and the chin), the scalp, the neck and retroauricular area, the shoulders and the upper trunk (typically V-shaped reflecting the density of the sebaceous glands in that skin area). Sometimes the lower parts of the back, the abdomen, the buttocks and even the arms and legs can be involved as well, whereas the palms of hands and soles of feet (containing no hair follicles) are spared.1-3

Incidence: Rash, which includes both papulopustular and maculopapular rash, is reported to be a very common skin toxicity occurring in over 10% of patients receiving treatment with all the multikinase inhibitors discussed on this website.4-15

Grading and lesion characteristics: According to the CTCAEv5.0,16 papulopustular rash is defined as, “A disorder characterised by a rash consisting of papules (a small, raised pimple) and pustules (a small pus filled blister), typically appearing in face, scalp, and upper chest and back. Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions.” However, grading of papulopustular rash according to the CTCAEv5.0 criteria is problematic as the proportion of the affected area needs to be expressed as a percentage of the whole body surface area (BSA).

Table 2: Grading of Papulopustular (acneiform) Rash according to the CTCAEv5.016

Grade

Description

1

Papules and/or pustules covering <10% BSA, which may or may not be associated with symptoms of pruritus or tenderness

2

Papules and/or pustules covering 10-30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL; papules and/or pustules covering > 30% BSA with or without mild symptoms 

3

Papules and/or pustules covering >30% BSA with moderate or severe symptom; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated

4

Life-threatening consequences; Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness & are associated with extensive superinfection with IV antibiotics indicated;

ADL: Activities of Daily Living, BSA: Body Surface Area

An alternate option for grading papulopustular rash is provided by the Multinational Association of Supportive Care in Cancer (MASCC) EGFR Inhibitor Skin Toxicity Tool (MESTT),17 which allows for more detailed reporting of rash.

Table 3: Grading of papulopustular eruption according to MESTT17

Grading individually for face, scalp, chest or back

Grade

Description

1

1A Papules or pustules < 5; OR area of erythema or oedema < 1cm in size;

1B Papules or pustules > 5; OR area of erythema or oedema <1cm in size AND mild pain or pruritus

2

2A Papules or pustules 6-20; OR more than 1 area of erythema or oedema <1cm in size;

2B Papules or pustules 6-20; OR more than 1 area of erythema or oedema <1cm in size; AND pain, pruritus, or effect on emotions or functioning

3

3A Papules or pustules >20; OR more than 5 areas of erythema or oedema <1cm in size;

3B Papules or pustules >30; OR more than 5 areas of erythema or oedema <1cm in size; AND pain, pruritus, or effect on emotions or functioning; 

Pathological features: Papulopustular skin lesions have an early infiltration with T-lymphocytes, followed by a hyperkeratotic, ectatic appearance of the follicular infundibula and a florid, neutrophilic suppurative infiltrate.3 As a result, the most common picture is that of perifolliculitis and neutrophilic folliculitis. The pustules are notably sterile with negative cultures or staining for bacteria, fungi, yeasts (including Malassezia furfur) or Demodex mites.3 Papulopustular acneiform is typically seen with EGFR-inhibitors. In that sense, multikinase inhibitors that also inhibit EGFR may exhibit papulopustular reactions, but multikinase inhibitors with this feature are more the exception than the rule. Vandetanib is an example. 

Onset: Multikinase inhibitor-associated rash is reported to start within 1-2 weeks following treatment initiation and gradually subsides over a few months18. 

Resolution: The incidence of rash is reduced over months. Also see Prophylaxis and treatment - reactive management - Papulopustular rash.

Grade 1 (mild) rash

The NCI-CTCAE v5.0 definition for ‘grade 1 Acneiform rash’ states: Papules and/or Pustules covering <10% BSA, which may or may not be associated with symptoms of Pruritus or tenderness.

Grade 2 (moderate) rash

The corresponding NCI-CTCAE v5.0 definition for ‘grade 2 Acneiform rash’ reads: Papules and/or Pustules covering 10-30% BSA, which may or may not be associated with symptoms of Pruritus or tenderness; associated with psychosocial impact; limiting instrumental activities of daily living (ADL: refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money etc.). The example shown demonstrates how the rash in this patient could be perceived to be grade 1 rash according to CTCAEv5.0 criteria based on the extent of the rash on the face; however, the extent of the rash on the whole body needs to be considered which in this example warrants allocation of a grade 2 rash.

Grade 3/4 (Severe) rash

The NCI-CTCAE v5.0 definition for ‘grade 3 Acneiform rash’ reads: Papules and/or Pustules covering >30% BSA, which may or may not be associated with symptoms of Pruritus or tenderness; limiting self-care ADL (refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not confined to bed); associated with local superinfection with oral antibiotics indicated.

The NCI-CTCAE v5.0 definition for the extremely rare ‘grade 4 Acneiform rash’ reads: Papules and/or Pustules covering any % BSA, which may or may not be associated with symptoms of Pruritus or tenderness and are associated with extensive superinfection with intravenous (IV) antibiotics indicated; life-threatening consequences.

Related Links

References

  1. Widakowich C. Oncologist. 2007;12;1443-1455.
  2. Lacouture ME. Support Care Cancer. 2011;19:1079–1095.
  3. Segaert S, et alEur J Cancer. 2009;45:295-308. 
  4. European Medicines Agency. Stivarga (regorafenib) Summary of Product Characteristics 2018.
  5. European Medicines Agency. Nexavar (sorafenib) Summary of Product Characteristics 2018.
  6. European Medicines Agency. Caprelsa (vandetanib) Summary of Product Characteristics 2019.
  7. European Medicines Agency. Sutent (sunitinib) Summary of Product Characteristics 2019.
  8. European Medicines Agency. Glivec (imatinib) Summary of Product Characteristics 2019.
  9. European Medicines Agency. Cabometyx (cabozantinib) Summary of Product Characteristics 2019.
  10. European Medicines Agency. Cometriq (cabozantinib) Summary of Product Characteristics 2019.
  11. European Medicines Agency. Kisplyx (lenvatinib) Summary of Product Characteristics 2019.
  12. European Medicines Agency. Lenvima (lenvatinib) Summary of Product Characteristics 2019.
  13. European Medicines Agency. Sprycel (dasatinib) Summary of Product Characteristics 2019.
  14. European Medicines Agency. Votrient (pazopanib) Summary of Product Characteristics 2018.
  15. European Medicines Agency. Rydapt (midostaurin) Summary of Product Characteristics 2018.
  16. 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).
  17. MASCC EGFR Inhibitor Skin Toxicity Tool (MESTT). (Accessed 15 April 2019).
  18. Cignola S, et al. Eur J Oncol Nurs. 2016; 20:133-139.

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