Original StudyPilot Clinical Trial on the Efficacy of Prophylactic Use of Vitamin K1–Based Cream (Vigorskin) to Prevent Cetuximab-Induced Skin Rash in Patients With Metastatic Colorectal Cancer
Introduction
The efficacy of cetuximab (Erbitux) in K-ras wild-type metastatic colorectal cancer (mCRC) is unfortunately associated with a significant risk of skin toxicity, prevalently acneiform skin rash but also xerosis, hair changes, paronychia, nail pitting, nail discoloration, and onycholysis. In fact the majority of patients treated with cetuximab develop an acneiform rash, and it is of severe grade (grade 3 or more) in 10% to 20% of patients (Table 1).1, 2, 3, 4, 5, 6, 7, 8, 9 The percentage of moderate (grade 2) rash is not always available in large registration trials; however, in the National Cancer Institute (NCI) CO17 trial, it was reported to be 37.2%.4
Cetuximab-induced acneiform skin rash (CISR) is one of the major causes of treatment delay7 and the cause of dose reduction in 3.5% to 4.4% of the patients4, 5, 9; it also has an effect on the quality of life (QoL), both physical and psychosocial.10, 11, 12, 13 However, recent data from the CRYSTAL trial found no effect of cetuximab on global health status and QoL.14
Incidence and severity of CISR are usually dose-related, although with long-term treatment, rash can decrease.15 Predictive factors of skin rash are male sex, age younger than 50 years,16 and colorectal cancer compared with other neoplasms treated with cetuximab.17 The maintenance of dose intensity through effective skin rash management is fundamental, and there are data indicating a possible association between rash and good prognosis; however, dose-to-rash strategies have not led to improved patient survival.2, 4, 6, 7, 18, 19
According to recent recommendations by Pinto et al,20 the treatment of CISR depends primarily on its grade, with an escalation of measures ranging from educational counseling to topical and systemic antibiotics and short courses of steroids. In grade 3 highly symptomatic or nonresponder/grade 4 rash, the treatment must also include retinoids and antihistamines. Cetuximab interruption is necessary in grade 3 CISR and must be followed by dose titration, and after grade 4 rash (eg, interfering with activities of daily living and necessitating intravenous antibiotics), cetuximab must be definitively discontinued.20
Currently the prophylaxis of skin rash remains controversial.21 Different strategies to prevent rash have been proposed.22, 23, 24
Causes of inadequate control of acneiform rash can be the concomitant use of other drugs capable of inducing it, such as immunomodulatory drugs, corticosteroids, neuropsychotherapeutic drugs, and antitubercular drugs.25
At the same time, the drugs used in the management of CISR, such as topical and systemic corticosteroids and antibiotics, are probably not directed against the real causative pathway of the rash, whose mechanisms are not completely understood. There is, however, evidence of a multiple-factor causative pathway involving both skin inflammation with cetuximab-driven leukocyte chemotaxis and follicular plugging due to skin desquamation and overinfection. A cause of keratinocyte desquamation is epidermal growth factor receptor (EGFR) inhibition in basal keratinocytes that increases the expression of the negative cell-cycle regulator p27, determining cell death.26 At the same time, a decrease of skin antimicrobial defenses can play an important role, because the EGFR signaling pathway is essential for the induction of expression of Toll-like receptors.27 Moreover, as an immunoglobulin G1 antibody, cetuximab may exert its antitumor efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity; finally, antibody-driven receptor internalization can also be a cause of skin rash.12
For this reason, the importance of effective mechanism-based therapies is increasing, with the most interesting results coming from vitamin K derivatives.12, 28
Phytomenadione (vitamin K1) is the major form of dietary vitamin K, and it is metabolized to menaquinones (vitamin K2), the active forms, especially menaquinone 4, through a menadione (vitamin K3) intermediate; menadione is a phosphatase inhibitor.29
The majority of preclinical data come from menadione (vitamin K3), and clinical data on phytomenadione (vitamin K1) are sparse. Vitamin K3 is a potent phosphatase inhibitor, and it has been found to be a potent EGFR activator and protector against erlotinib and cetuximab compared with vitamins K1 and K2 in malignant and normal keratinocytes in vitro.30 This effect can be mediated both by reactive oxygen species generation and by phosphatase inhibition at nontoxic concentrations.31 Other data indicated that menadione reduces erlotinib-induced keratinocyte cytotoxicity more than hydrocortisone, cyclosporine A, minocycline, and diphenhydramine.32
These studies suggested the rationale for the use of vitamin K–based preparations in vivo for both treatment and prevention of EGFR-inhibitor-induced skin toxicities. Currently only a few trials are available (Table 2).
Section snippets
Patients and Methods
From September 2010 to July 2012, vitamin K1–based cream (Vigorskin) was distributed at San Giovanni Battista Hospital, Turin, Italy, by one of the authors to all patients before starting cetuximab with or without chemotherapy for mCRC. Patients' demographic data, degree of disease extension and occurrence, and degree of CISR, with special attention to the degree of CISR at weeks 4 and 8 of treatment, were then collected. The study was conducted according to the provisions of the Declaration of
Results
Forty-one patients undergoing a cetuximab-based regimen for mCRC received vitamin K1–based cream as prophylaxis for CISR. Thirty-four patients received this therapy for at least 12 weeks; 7 patients interrupted within the 12th week: 2 for the execution of radiofrequency thermal ablation, 2 for unacceptable gastroenteric toxicity, 1 for progressive disease, 1 for the occurrence of another neoplasm (follicular lymphoma), and 1 for unacceptable skin toxicity. Only 1 patient had relevant skin
Discussion
There is no standard available in the prevention of acneiform rash induced by EGFR inhibitors such as cetuximab. In the population of patients affected by mCRC, a moderate-to-severe acneiform rash occurs in about 50% to 60% of patients, with a dose reduction, in registrative trials, in 4% of patients (see Table 1) and a possibly substantial effect on the QoL.10, 11, 12, 13, 14 To the present authors' knowledge, no effective strategy to prevent EGFR inhibitor-induced skin rash is available.21, 22
Conclusion
Globally, this study found a lower proportion of grade 2 rash (25%) and grade 3 rash corresponding to the lower limit reported in the literature on the use of prophylactic vitamin K1–based cream in patients with mCRC treated with cetuximab. The treatment was well tolerated. These data confirm previously published studies suggesting a possible benefit in this population.
Disclosure
Vigorskin cream has been furnished free from Merck Serono SpA, an affiliate of Merck KGaA. All authors have no other conflict of interest.
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2021, European Journal of Oncology NursingCitation Excerpt :However, the results in Eriksen's study were independent from the use of systemic tetracycline and thus this study was not excluded from this systematic review. In addition, from the study of Pinta et al., (2014) we preserved solely the results for Grade 0 and Grade 1 rash because the study initiated patients on antibiotic or steroid treatment when they experienced Grade 2 and Grade 3 EGFRIr. The number of cases excluded from our review was small, as only 6 patients out of 41 advanced to Grade 3 rash and required minocycline and corticosteroids.
Ester derivatives of phyllohydroquinone effectively deliver the active form of vitamin K<inf>1</inf> topically, owing to their non-photosensitivity
2020, European Journal of Pharmaceutical SciencesDermatologic conditions in women receiving systemic cancer therapy[Formula presented]
2019, International Journal of Women's DermatologyCitation Excerpt :Topical menadione (vitamin K3) has been investigated for the prevention of acneiform rash but did not show efficacy in a Phase 1 trial (Eriksen et al., 2017). In a single-center study, topical phytomenadione (vitamin K1) applied prophylactically did reduce the incidence of rash (Pinta et al., 2014; Tomková et al., 2013), but larger, controlled studies are needed to validate this finding. Treatment of the papulopustular rash depends on the grade (Table 3).
Dermatologic Toxicity Occurring During Anti-EGFR Monoclonal Inhibitor Therapy in Patients With Metastatic Colorectal Cancer: A Systematic Review
2018, Clinical Colorectal CancerCitation Excerpt :No signs of toxicity or intolerance were observed after the topical application, and no changes in blood coagulation occurred.71 Another study (n = 41) found the application of phytomenadione cream twice daily resulted in a low proportion of patients with grade 2 (25%) and grade 3 (15%) rash.72 Furthermore, a recent study (n = 60) found that applying the cream 3 times daily on the day of anti-EGFR administration improved the skin itch and dry skin symptoms for patients with mCRC.73
Taking it in the chin: Vitamin K1 for the prevention of acneiform rash
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F.P. and A.P. contributed equally to this work as first authors.