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ISSN: 2637-6679

Research and Reviews on Healthcare: Open Access Journal

Letter to Editor(ISSN: 2637-6679)

Prevention of Anti-BRAF-Induced Phototoxicity: not Just a Question of Photoprotector Volume 3 - Issue 5

M Cormerais1, A Boisrobert2, H Dutartre2, A Khammari2 and B Dreno2*

  • 1 Service de Dermatologie, CHU Pontchaillou, France
  • 2 Service de Dermatologie, CHU de Nantes, France

Received:July 09, 2019;   Published: July 17, 2019;

Corresponding author: B Dreno, Service de Dermatologie, CHU de Nantes, Place Alexis Ricordeau 44093 Nantes, France

DOI: 10.32474/RRHOAJ.2019.03.000171

Abstract PDF

Letter to Editor

Targeted therapies changed the prognosis of metastatic melanoma. Flaherty & al. and the BRIM-II study found a response rate between 53-81% and a median progression-free survival of about seven months [1,2].  The BRIM-III study reported a median survival of 13.6 months and a 6-month survival rate of 84% with Vemurafenib versus 9.7 months and 64% with dacarbazine [3].  The UVA-phototoxicity induced by Vemurafenib through a decrease in minimal erythema dose [4,5], was found respectively in 16% (1), 52% (2) and 40% (3) of patients in these 3 studies.  Although the benefit of sunscreen has been mentioned (4), to our knowledge, no efficacy study with an anti- UVA sunscreen has been conducted. This study assesses the benefit of therapeutic education associated with a photoprotector in a real-life setting. Patients with unresectable stage IIIC or IV BRAFV600E-mutated melanoma, treated with Vemurafenib 960mg twice daily, were included in the Dermatology department of Nantes University Hospital. Patients received 30mn training session performed by a nurse on the sunscreen during which they received free SPF50+ anti UVA (⩽3) photoprotector.

Regular follow-up was as well organized. After 12 weeks, patients were asked to self-asses: average daily application, application areas, tolerance to the treatment, by looking at redness level, burning sensation and/or pruritus sensation (classified in absent, mild, moderate or severe). The nurse assessed compliance at each follow-up. Patients were classified in group 1 with no or mild phototoxicity and in group 2 with moderate or severe phototoxicity. Only patients who applied photoprotector at least twice daily were considered compliant. Twenty-seven patients with a mean age of 56.2 years (32-89 years) were included. Fifteen patients were classified in group 1 and 12 in group 2 based on their self-reporting, including 6 patients with moderate phototoxicity and 6 patients with severe phototoxicity. Fourteen patients were considered compliant. Nurse questioning revealed that patients did not evaluate their observance correctly, and that only 2 patients of the group 2 were actually observant. The 10 other patients confessed regular omissions. Therefore in 25 out of the 27 patients, no significant phototoxicity on sun protected areas was observed.

A non-significant increase in phototoxicity (group 2) was observed in non-compliant patients (OR=2.04, 95%CI (0.35; 12.89), p=0.45). There was a non-significant difference in phototoxicity according to the age (OR=0.63, 95%CI (0.10; 3.7), p=0.70) or to the gender (OR=0.80, 95%CI (0.130; 5.23), p=1).  Anti-BRAF, photosensitivity and sunscreen There was a non-significant trend toward a decreased phototoxicity in patients with skin phototype 3 (OR=0.2621, 95%CI (0.10; 3.7), p=0.70) and in women (OR=0.24, 95%CI (0.02; 1.76), p= 0.22). Despite a therapeutic education and a free photoprotector, only 55% of patients reported no or mild phototoxicity and 52% were observant Various factors could explain these results, including a possible over-reporting of phototoxicity; Indeed, the phototoxicity was self-assessed by patients themselves since the treatment was taken at home and in addition, a strict definition of phototoxicity was used. Sunscreen has to be applied several times a day and in a context of anti-cancer treatment, it could appear of secondary importance compared to anti-cancer treatment explaining the low observance. In addition, UVAs pass through clouds and windows [6].

Patients should understand that photoprotection is needed daily in any weather and in any place. The absence of refund could be an additional barrier. A sun protection kit with Vemurafenib could be interesting. Phototoxicity appeared only on under-treated areas, except in 2 patients of group 2. This emphasizes the link between efficacy and compliance with treatment and the importance of therapeutic education. Klaeger et al. [7] reported that Vemurafenib could inhibit ferro chelatase responsible for an accumulation of Protoporphyrin.  In analogy to Erythropoietic Protoporphyrin, light absorption induces a production of Reactive oxygen species and inflammatory process with complement activation and mast cell degranulation explaining vasodilation and edema described in phototoxic reactions [8]. Alfamelanotide, an analog of alpha-melanocyte-stimulating hormone approved in Erythropoietic Protoporphyrin, could theoretically be discussed in combination with Vemurafenib [9]. However, carcinogenic potential is unknown [10]. In conclusion, the systematic prescription of an anti-UVA/ UVB photoprotector is insufficient to protect against Vemurafenibinduced phototoxicity. It should be accompanied by therapeutic education repeated during treatment. Cutaneous prevention is not a central concern for patients with metastatic melanoma. In this context, protective clothing remains essential.

Acknowledgment

We thank La Roche Posay International laboratories for providing the photoprotector. There is no other conflict of interest to report for this study.

References

  1. Flaherty, Keith T, Igor Puzanov, Kevin B Kim, Antoni Ribas, et al. (2010) ‘Inhibition of Mutated, Activated BRAF in Metastatic Melanoma’. New England Journal of Medicine 363 (9): 809-819.
  2. Sosman, Jeffrey A, Kevin B Kim, Lynn Schuchter, Rene Gonzalez, et al. (2012) ‘Survival in BRAF V600-Mutant Advanced Melanoma Treated with Vemurafenib’. New England Journal of Medicine 366 (8): 707-714.
  3. McArthur, Grant A, Paul B Chapman, Caroline Robert, James Larkin, et al. (2014). ‘Safety and Efficacy of Vemurafenib in BRAFV600E and BRAFV600K Mutation-Positive Melanoma (BRIM-3): Extended Follow-up of a Phase 3, Randomised, Open-Label Study’. The Lancet Oncology 15 (3): 323-332.
  4.  Dummer, Reinhard, Jeannine Rinderknecht, Simone M Goldinger (2012) ‘Ultraviolet A and Photosensitivity during Vemurafenib Therapy’. New England Journal of Medicine 366 (5): 480-481. 
  5. Brugière C, A Stefan, C Morice, E Cornet, A Moreau, et al. (2014) ‘Vemurafenib Skin Phototoxicity Is Indirectly Linked to Ultraviolet A Minimal Erythema Dose Decrease’. British Journal of Dermatology 171(6): 1529-1532.
  6. Sinha R, K Edmonds, JA Newton Bishop, ME Gore, J Larkin, et al. (2012) ‘Cutaneous Adverse Events Associated with Vemurafenib in Patients with Metastatic Melanoma: Practical Advice on Diagnosis, Prevention and Management of the Main Treatment-Related Skin Toxicities Cutaneous Adverse Events with Vemurafenib: Practical Advice’. British Journal of Dermatology 167(5): 987-994.
  7. Klaeger, Susan, Bjoern Gohlke, Jessica Perrin, Vipul Gupta, et al. (2016) ‘Chemical Proteomics Reveals Ferrochelatase as a Common Off-Target of Kinase Inhibitors’. ACS Chemical Biology 11(5): 1245-54.
  8. Lecha, Mario, Hervé Puy, Jean Charles Deybach (2009) ‘Erythropoietic Protoporphyria’. Orphanet Journal of Rare Diseases 4: pp19.
  9. Biolcati G, E Marchesini, F Sorge, L Barbieri, X Schneider Yin, et al. (2015) ‘LongTermObservational Study of Afamelanotide in 115 Patients with Erythropoietic Protoporphyria’. British Journal of Dermatology 172 (6): 1601-1612.
  10. Kim, Esther S, Karly P Garnock Jones (2016) ‘Afamelanotide: A Review in Erythropoietic Protoporphyria’. American Journal of Clinical Dermatology 17(2): 179-85.
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