10.1 The role of topical treatments in the treatment of keratinocyte cancer

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Background

Topical treatments for keratinocyte cancer (KC) used in Australia include:

  • imiquimod 5% cream
  • diclofenac 3% gel
  • 5-fluorouracil 5% cream
  • ingenol mebutate gel.

Imiquimod 5% cream

The mechanism of action of topical imiquimod 5% cream involves a complex array of molecular events that result in the stimulation of both the innate and cell-mediated immune responses to tumour antigens.

The main effects of imiquimod are induced by the stimulation of toll like receptors (TLR7 and TLR8) on immune cells, primarily monocytes/macrophages and dendritic cells, which help in the recognition of pathogen-associated molecular patterns. This results in the activation of nuclear factor kappa B subunit 1 (NFKB1), which induces the expression of various cytokines: interferon alpha 1 (IFNA1), tumour necrosis factor (TNF), interleukins (IL2, IL6, IL8 and IL12), chemokines and other inflammatory mediators. These factors promote apoptosis and also inhibit angiogenesis.

Imiquimod 5% cream is approved by the Australian Therapeutic Goods Administration (TGA) for the primary treatment of confirmed superficial basal cell carcinoma (BCC) where surgery is considered inappropriate, and for the treatment of actinic (solar) keratosis (AK) on the face and scalp.[1]

Imiquimod is available in sachets or a pump pack delivery system.

For the treatment of AK, application can be cyclical (3 nonconsecutive days per week in 4-week cycles until clearance is achieved), or continuous (3 nonconsecutive days per week for up to 16 weeks). For BCC, recommended application is 5 consecutive days per week for 6 weeks.[1]

Local reactions are common among patients treated for AK. These include severe erythema (24%), severe scabbing and crusting (20%), itching (14%) and burning (5%).[1] Skin infections have also been observed.[1] Among patients treated for BCC, common local reactions include severe erythema (31%), severe erosions (13%), and severe scabbing and crusting (19%).[1]

Diclofenac 3% gel

The mechanism of action of 3% diclofenac gel is not yet fully understood. Diclofenac inhibits the cyclo-oxygenase and lipo-oxygenase enzymes, resulting in a decrease in the downstream by-products of arachidonic acid metabolism. These metabolites have been shown to play a pivotal role in promoting epithelial tumour growth. Diclofenac induces apoptosis, inhibits cell proliferation, and suppresses angiogenesis.[2][3]

Hyaluronic acid is believed to enhance the partitioning of diclofenac into human skin and its retention and localisation in the epidermis (forming a depot effect).

Topical 3% diclofenac gel is approved by the Australian TGA for the treatment of AK.[4]

Twice-daily application for 90 days is recommended. The product is administered by the patient and is generally well tolerated. This field treatment can be combined with liquid nitrogen cryotherapy for more hypertrophic or resistant AK.

Local reactions are relatively common and include: irritation, inflammation, blistering, contact dermatitis, erythema, exfoliation, and skin ulcer.[4]

5-fluorouracil 5% cream

Fluorouracil is an antimetabolite that blocks thymidine synthesis inducing cell-cycle arrest and apoptosis. Topical 5-fluorouracil cream 5% has been used for many years to treat AK and Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC).

5-fluorouracil 5% cream is approved by the Australian TGA for the treatment of AK and Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC).

Treatment of AK involves application (once or) twice daily for 2–4 weeks on the head and neck. Erythema, irritation, inflammation, pain, burning, vesiculation, crusting, dyspigmentation, photosensitivity, ulceration and other local adverse effects are common.

Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC) is treated with 5-fluorouracil 5% cream twice a day for between 4–8 weeks.

Local reactions are relatively common and include: local pain/pruritus, hyperpigmentation, burning, crusting, contact dermatitis, erosions, erythema, irritation, photosensitivity, ulceration, and infections including herpes simplex.[5]

Ingenol mebutate gel

The mechanism of action of ingenol mebutate is not fully understood.[6] Its effects are thought to be due to local cell death and a local inflammatory response characterised by production of proinflammatory cytokines, chemokines and infiltration of immunocompetent cells, which induce epidermal necrosis.[6]

Topical ingenol mebutate gel is approved by the Australian TGA for the treatment of AK.[6] Two formulations are available:

  • 0.015% for AK on the face and scalp (applied daily for 3 consecutive days)
  • 0.05% for AK on the trunk and extremities (applied daily for 2 consecutive days)

Each tube contains enough gel to cover an area of approximately 25cm2.

Ingenol mebutate is not TGA-approved for the treatment of Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC), BCC or cutaneous squamous cell carcinoma (cSCC).

Local reactions are relatively common and include: application site pain, pruritus, irritation, infection, erythema, flaking, scaling, crusting, swelling, vesiculation, pustulation, erosion, ulceration, headache, and application site pigmentation change.[6]
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Systematic review evidence

What role does ingenol mebutate gel have in the treatment and management of basal cell carcinoma and/or cutaneous squamous cell carcinoma?

A systematic review was undertaken to evaluate the effectiveness of ingenol mebutate gel in the treatment of KCs.

The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.

Two randomised clinical trials (RCTs) that met inclusion criteria reported outcomes in patients treated with BCC or cSCC in situ treated with ingenol mebutate.[7][8]

An Australian multicentre Phase IIa RCT[7] with a low risk of bias compared ingenol mebutate 0.0025%, 0.01% and 0.05% gel and matching vehicle gel, administered as two applications (on 2 consecutive days or 1 week apart) in 60 patients each with a single histologically confirmed BCC on the arm, shoulder, chest, face, neck, abdomen, back, leg or scalp considered suitable for surgical excision (maximum diameter of 4–15mm and maximum thickness of 4mm). Among those who received treatment on 2 consecutive days, 0.05% ingenol mebutate gel was associated with histological clearance at 85 days post treatment in 5 of 8 participants (65%), compared with 0 of 6 participants in the control (vehicle gel) group. Adverse events included mild-to-moderate erythema extending beyond the treatment site (n=2), mild application-site pain (n=2), and mild-to-moderate headache (n=2).[7] Most local effects resolved completely within 1 week, and the remainder resolved within the study period.[7] Severe treatment-related events included vesicles (n=4), flaking/scaling/dryness (n=2), oedema (n=1), erosion/ulceration (n=1), and erythema and scabbing/crusting (n=1).

Another Australian RCT[8] with an unclear risk of bias compared ingenol mebutate 0.05% gel with no treatment (lesions randomised to full occlusion, partial occlusion or no occlusion) in 75 patients with histologically confirmed superficial BCC (4–15mm in diameter and <1mm thick) on the trunk or extremities. Complete clinical clearance rates and complete histological clearance rates were 70.4% and 74.1%, respectively, for full occlusion, 37.5% and 75.0% for semi-occlusion, and 54.2% and 75.0% for no occlusion (statistical analysis not reported).[8] A total of 15 treatment-related adverse events were reported, of which 11 were in the full occlusion group. All were resolved or resolving by the end of the trial period. Adverse effects included application-site pain, hypopigmentation and scarring.[8]

Evidence summary and recommendations

Evidence summary Level References
Ingenol mebutate is well tolerated in the treatment and management of BCC, with only mild to moderate adverse events reported. II [7], [8]
Response rates (histological and clinical clearance rates) to ingenol mebutate in the treatment of superficial BCC were highest after treatment with 0.05% gel (versus 0.0025% and 0.01%) and after treatment on two consecutive days (versus treatment one week apart).

Complete clinical clearance rates after treatment of superficial BCC with 0.5% ingenol mebutate were similar with full occlusion, semi-occlusion and no occlusion, but the complete histological clearance rate was higher with full occlusion.

II [7], [8]
There is a lack of evidence on recurrence rates following the treatment and management of BCC with ingenol mebutate gel. II [7], [8]
Key point(s)

All prescribers should discuss the relative harms and benefits of ingenol mebutate gel with patients offered this treatment option.

Notes on the evidence

At present there is inadequate evidence to inform patient selection for treatment of BCC and cSCC with ingenol mebutate gel as an alternative to established treatment options. Were more clinical trial data to become available supporting its use, its role is likely to be restricted to the treatment of BCC or cSCC in patients who are unable to undergo surgical excision or destructive therapies, and in whom other topical therapies are less suitable.

Although adverse effects of ingenol mebutate gel may not evolve until after the completion of a course of 2 or 3 consecutive days of treatment, prescribers should clearly advise patients to discontinue use if they experience severe adverse effects during treatment. Further use (completion of the interrupted course or a future course of treatment) should be discouraged unless adverse effects were only mild or moderately severe.

Overview of evidence (non-systematic literature review)

Note: no systematic reviews were undertaken for evidence on topical treatments other than ingenol mebutate (see: Systematic review evidence).

Imiquimod 5% cream

Actinic keratoses

The short-term efficacy of topical Imiquimod 5% cream in patients with AK has been assessed in five large, double-blind placebo-controlled RCTs.[9][10][11][12][13]

Complete clearance rates varied between 45% and 57%.[9][10][11][12][13] Clearance rates of more than 75% of lesions were achieved in up to 72% of patients.[13]

No data on recurrence and progression rates for follow-up beyond 1 year are available.

Imiquimod is applied once daily, three times per week, for up to 16 weeks, or alternatively applied up to three times per week for two 4-week cycles.

Care should be used if applications are used to areas greater than 25cm2.

The cycle may be repeated after a month (off therapy) if necessary to increase efficacy. Rest periods (i.e., missed applications) are advised if the inflammatory reaction becomes excessive.

Bowen's disease

A randomised double-blind vehicle-controlled trial has investigated the use of topical imiquimod 5% cream in the treatment of patients with Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC).[14] The cream was applied daily for 16 weeks and allowances were made for rest periods.

Complete clearance was observed in 73% of 15 patients who received imiquimod 5%, compared with 0% of those who received placebo. No recurrence was seen at 6-months follow-up. In clinical practice, most practitioners treat areas of Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC) for 4–6 weeks with applications three to five times per week. Clinical review during treatment may be required because of the development of excessive inflammation in some patients. Rest periods may be required in some patients during treatment.

Superficial basal cell carcinoma

Phase III studies[15] demonstrate that the recommended imiquimod regimen for primary superficial BCC (application five times per week for 6 weeks) results in a histological clearance rate of 82%.

Skin biopsy to confirm the diagnosis is highly recommended. Histological confirmation of the diagnosis before treatment is a requirement for Pharmaceutical Benefits Scheme (PBS) reimbursement.

Imiquimod cream is applied to the tumour and a 5mm margin of surrounding normal skin. The area of application should not be increased even if inflammation extends beyond the initial area.

Efficacy assessments are made clinically at three months post therapy. Regular clinical follow up is recommended for 3 years post treatment.

The inflammatory response to treatment may vary significantly between patients and between lesions at different sites on the same patient. During treatment the inflammatory reaction may become excessive and the patient may require rest periods during which the cream is not applied. The cream application regimen is recommenced when the excessive inflammation has resolved.

Diclofenac 3% gel

A double-blind placebo-controlled RCT in 96 patients, with five or more AK each, reported that twice-daily application for 90 days (the standard recommended protocol) resulted in complete clearance of baseline AK in 50% of patients, compared with 20% of the placebo group (p<0.001).[16]

5-fluorouracil 5% cream

Twice daily application for 2–4 weeks on the head and neck results in significant inflammation that settles within 1–2 weeks of ceasing therapy. Published evidence for 5-fluorouracil efficacy is scant.[17] A recent study reported that the probability of tumour-free survival, 5 years after treatment, was 70.0% for 5-fluorouracil (95% CI = 62.9-76.0).[18]

Actinic keratoses

A RCT comparing topical 5-fluorouracil 5% cream (applied twice daily for 4 weeks), topical imiquimod and cryosurgery in the treatment of AK, reported sustained complete field clearance at 12-month follow-up in 33% of the 5-fluorouracil 5% group, compared with 73% of the imiquimod group (p<0.01).[19]

Another recent RCT comparing common field-directed treatments for AKs on the hand reported that the cumulative probability of remaining free from treatment failure 12 months after treatment was significantly higher among patients who received 5-fluorouracil (74.7%; 95% confidence interval [CI] 66.8–81.0) than among those who received imiquimod (53.9%; 95% CI 45.4 to 61.6), ingenol mebutate (28.9%; 95% CI 21.8–36.3) or methyl aminolevulinate-photodynamic therapy (MAL-PDT) (37.7%; 95% CI 30.0–45.3.[20]

Bowen's disease

Studies evaluating 5-fluorouracil cream twice a day for between 4–8 weeks in the treatment of Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC) have demonstrated cure rates ranging between 87% and 92%.[21] A European multicentre RCT in 225 patients with histologically confirmed cSCC in situ (6–40mm) reported a 12-month sustained complete response of 69% and a good or excellent cosmetic response in 76% of patients following treatment with 5-fluorouracil 5% cream, (compared with 80% and 94%, respectively, in patients treated with MAL-PDT; difference statistically nonsignificant).[22][23]

Ingenol mebutate

In a pooled analysis of two multicentre RCTs investigating ingenol mebutate 0.015% in the treatment of AK on the face and scalp,[12] the rate of complete clearance of AK was higher with ingenol mebutate than with placebo (42.2% versus 3.7%, p<0.001).

In a pooled analysis of two multicentre RCTs investigating ingenol mebutate 0.05% in the treatment of AK on the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% versus 4.7%, p<0.001).[12] Adverse events were generally mild to moderate in intensity and resolved without sequelae.[12]
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Practice Point

Practice pointQuestion mark transparent.png

PP 10.1.1. Skin biopsy is highly recommended before treatment of superficial basal cell carcinoma with imiquimod 5% cream (and is required for PBS-reimbursed prescription).

Key point(s)
  • Imiquimod 5% cream, a topical cytokine- and interferon-inducer, can be considered for the treatment of actinic keratoses and primary basal cell carcinomas where surgery or other therapies are inappropriate or contraindicated.
  • Skin biopsy is not required when treating actinic keratoses with imiquimod 5% cream.
  • Imiquimod 5% cream is contraindicated for sclerosingscar-like (morphoeic), infiltrative and micronodular basal cell carcinoma subtypes.
  • Long-term follow-up is essential after treatment of basal cell carcinoma with imiquimod 5% cream.
  • The use of 5-fluorouracil 5% cream can be considered for the treatment of actinic keratoses and Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC).
  • Supervision of 5-fluorouracil 5% cream therapy in first-time users is essential.
  • Whilst they are effective as spot treatments, the principal role of topical therapies is field therapy for multiple actinic keratoses or for superficial keratinocyte carcinomas (Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC) and superficial basal cell carcinoma).
Note: Follow-up of patients after treatment is individually tailored according to patient factors, tumour factors, anatomic site and the perceived adequacy of treatment.


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Appendices

Jutta's magnifying glass icon.pngPICO question OT1 View Evidence statement form OT 1Evidence statement form OT1

View Systematic review report OT 1Systematic review report OT1

References

  1. 1.01.11.21.31.4 iNova Pharmaceuticals (Australia) Pty Ltd. Aldara™ Cream 5% (Imiquimod) Consumer Medicine Information. [homepage on the internet] Sydney, Australia: Therapeutic Goods Administration (Australian Government); 2017 Nov [cited 2018 Dec]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-CMI-06168-3&d=201901081016933.
  2. Fecker LF, Stockfleth E, Nindl I, Ulrich C, Forschner T, Eberle J. The role of apoptosis in therapy and prophylaxis of epithelial tumours by nonsteroidal anti-inflammatory drugs (NSAIDs). Br J Dermatol 2007 May;156 Suppl 3:25-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17488403.
  3. Seed MP, Brown JR, Freemantle CN, Papworth JL, Colville-Nash PR, Willis D, et al. The inhibition of colon-26 adenocarcinoma development and angiogenesis by topical diclofenac in 2.5% hyaluronan. Cancer Res 1997 May 1;57(9):1625-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9134996.
  4. 4.04.1 Menarini Australia. Solareze 3% gel (diclofenac sodium). Therapeutic Goods Administration, Australian Government Department of Health; 2015 Jan 19 Available from: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01713-1.
  5. iNova Pharmaceuticals. Australian PI – Efudix (fluorouracil cream). Therapeutic Goods Administration, Australian Government Department of Health.; 2019 Jan 15 Available from: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01673-1.
  6. 6.06.16.26.3 Leo Pharma. Australian PI – Picato (ingenol mebutate) gel. Therapeutic Goods Administration, Australian Government Department of Health; 2019 Jan 15 Available from: www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-02798-1.
  7. 7.07.17.27.37.47.57.6 Siller G, Rosen R, Freeman M, Welburn P, Katsamas J, Ogbourne SM. PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase IIa trial. Australas J Dermatol 2010 May;51(2):99-105 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20546215.
  8. 8.08.18.28.38.48.58.6 Spelman L, Rosen R, Knudsen KM, Zibert JR, Freeman M. Ingenol mebutate 0.05% gel under occlusion is efficacious in treating superficial basal cell carcinoma. B J Dermatol. 2014;171(Suppl. 4):58–9.
  9. 9.09.1 Alomar A, Bichel J, McRae S. Vehicle-controlled, randomized, double-blind study to assess safety and efficacy of imiquimod 5% cream applied once daily 3 days per week in one or two courses of treatment of actinic keratoses on the head. Br J Dermatol 2007 Jul;157(1):133-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17501955.
  10. 10.010.1 Jorizzo J, Dinehart S, Matheson R, Moore JK, Ling M, Fox TL, et al. Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head. J Am Acad Dermatol 2007 Aug;57(2):265-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17512087.
  11. 11.011.1 Korman N, Moy R, Ling M, Matheson R, Smith S, McKane S, et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 2005 Apr;141(4):467-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15837864.
  12. 12.012.112.212.312.4 Lebwohl M, Dinehart S, Whiting D, Lee PK, Tawfik N, Jorizzo J, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol 2004 May;50(5):714-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15097955.
  13. 13.013.113.2 Szeimies RM, Gerritsen MJ, Gupta G, Ortonne JP, Serresi S, Bichel J, et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J Am Acad Dermatol 2004 Oct;51(4):547-55 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15389189.
  14. Patel GK, Goodwin R, Chawla M, Laidler P, Price PE, Finlay AY, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen's disease): a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 2006 Jun;54(6):1025-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16713457.
  15. Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004 May;50(5):722-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15097956.
  16. Wolf JE Jr, Taylor JR, Tschen E, Kang S. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol 2001 Nov;40(11):709-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11737438.
  17. Dillaha CJ, Jansen GT, Honeycutt WM, Holt GA. Further studies with topical 5-fluorouracil. Arch Dermatol 1965 Oct;92(4):410-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/5835333.
  18. Jansen MHE, Mosterd K, Arits AHMM, Roozeboom MH, Sommer A, Essers BAB, et al. Five-Year Results of a Randomized Controlled Trial Comparing Effectiveness of Photodynamic Therapy, Topical Imiquimod, and Topical 5-Fluorouracil in Patients with Superficial Basal Cell Carcinoma. J Invest Dermatol 2018 Mar;138(3):527-533 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/29045820.
  19. Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, Stockfleth E. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol 2007 Dec;157 Suppl 2:34-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18067630.
  20. Jansen MHE, Kessels JPHM, Nelemans PJ, Kouloubis N, Arits AHMM, van Pelt HPA, et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med 2019 Mar 7;380(10):935-946 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/30855743.
  21. Moreno G, Chia AL, Lim A, Shumack S. Therapeutic options for Bowen's disease. Australas J Dermatol 2007 Feb;48(1):1-8; quiz 9-10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17222293.
  22. Morton C, Campbell S, Gupta G, Keohane S, Lear J, Zaki I, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 2006 Nov;155(5):1029-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17034536.
  23. Morton C, Horn M, Leman J, Tack B, Bedane C, Tjioe M, et al. Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or Fluorouracil for treatment of squamous cell carcinoma in situ: Results of a multicenter randomized trial. Arch Dermatol 2006 Jun;142(6):729-35 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16785375.


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