Taking it in the chin: vitamin K1 for the prevention of acneiform rash

In this issue of Annals of Oncology, Hofheinz et al. study the efficacy of a topical formulation of vitamin K1 in the prevention of a disfiguring toxicity resulting from epidermal growth factor receptor (EGFR) inhibitors [1]. An acneiform rash on the face and upper body develops in the majority of patients treated with EGFR inhibitors [2]. In addition to its psychosocial impact [3], it is associated with symptoms of pruritus and pain, may result in secondary infections [4], all of which may lead to inconsistencies in the dosing of causal anticancer agents [5]. Since the rash has been correlated with antitumor efficacy across most solid tumors in which it has been employed [6], mitigating this untoward event has been the subject of research for the past 15 years.

Based on the prototypical lesions present in the rash (i.e. papules and pustules), therapies used against acne and rosacea have been studied in randomized trials, including the semisynthetic tetracyclines minocycline and doxycycline. These orally administered agents have shown a reduction by >50% in the number of lesions [7] and grade ≥2 rash [8], respectively, establishing these agents as primary prevention and treatment tools in guidelines, based on their robust efficacy. Conversely, the effect of topical antibiotics has been modest, with only improvements in quality of life [9], or number of lesions [10, 11] not reaching statistical significance. In addition to the clinical benefits, it is noteworthy that prophylactic therapies and consequent lower incidence of grade ≥2 rash did not affect antitumor efficacy of EGFR inhibitors as there were no differences in survival [8, 9].

Antibiotic therapies are believed to interfere in the latter stages of the pathogenic cascade involved in rash development, through their microbicidal and anti-inflammatory effects [2]. Therefore, a rational therapy would act earlier, by preventing the inhibition of the EGFR pathway in epidermal keratinocytes. Exposure to the vitamin K intermediate menadione (vitamin K3) has been shown to activate the EGFR and to counteract the inhibitory effect of cetuximab on the EGF pathway in keratinocytes [12]. Based on these findings, uncontrolled studies have revealed that vitamin K1 [13] may decrease the incidence and severity of rash in humans.

Hofheinz et al. [1] conducted a double-blind, randomized, placebo-controlled study with prophylactic vitamin K1 0.1% cream in addition to docycyline in patients with mCRC receiving first line cetuximab. Patients were treated during the first 8 weeks of cetuximab, during which the acneiform rash is expected to be at its most severe. The primary objective of this study was to assess the effect on grade ≥2 rash as graded with the Common Terminology Criteria for Adverse Events v4.0. Secondary objectives included grading using a more granular scale (WoMo), effects on other skin toxicities, the efficacy of anticancer therapy, and the impact on quality of life. The incidence of CTCAE grade ≥ 2 rash was no different between the two groups (63.3% with vehicle and 73.3.% with vitamin K1; P = 0.28). No differences in QoL questionnaires were observed between the two arms. Similarly, no differences were observed when the WoMo score was used to measure rash severity, with the exception of the WoMO score component (C) of rash severity from weeks 5 through 8. A benefit was observed in skin fissures in patients treated with the vitamin K1 (14% reduction) when compared with controls (3% reduction) (OR 0.22; 95% CI 0.05, 1.06).

Although the primary end point of this study was not met, several important lessons command attention. First, even more than a decade after the introduction of the first EGFR inhibitors, both patients and physicians find this adverse event as a continued problem worthy of research and care, despite important advances being made in its prevention, with the use of oral antibiotics. The lack of reduction in CTCAE grade ≥ 2 rash could also have been due to all patients being on prophylactic doxycycline, which has been shown and is most likely the most effective agent for this toxicity, therefore additional differences in severity would be more difficult to capture. The 68.3% incidence of grade ≥2 rash is higher than what would be expected with prophylactic doxycycline, so it is possible that these patients had a more severe rash that made them unresponsive to therapy with vitamin K1.

The differences observed with the more granular WoMo scale C (which comprises a semiquantitative description of five items of information on the nature of the rash considering the most severely affected region of the body) [14] are consistent with previous reports showing that CTCAE grading, although enormously valuable in AE reporting and detection, may not be the most sensitive tool in supportive care studies [15]. The difference in WoMo scale towards the end of treatment (week 8) suggests that this agent may have an effect towards a more rapid recovery from the acneiform rash in the setting of doxycycline-treated patients. It is plausible that vitamin K1 could be investigated as single agent with other EGFR inhibitors that have a lower incidence of severe rash. The finding that fissures were reduced in the vitamin K1-treated patients compared with controls (14% versus 3%, OR 0.22; 95% CI 0.05, 1.06) may represent a signal that merits further study to treat this event in patients with agents known to cause xerosis, manifested as fissures in the fingertips and soles of the feet.

Possibly the most important lesson is that this represents a rational attempt to target a dermatologic toxicity with a mechanism-based intervention, based on the known effects of Vitamin K3 (menadione) on EGFR activation. However, such inferences must be done with caution-the agent used in the study was vitamin K1, not the byproduct menadione (vitamin K3) known to have an effect in vitro. Therefore, in vitro data of the effects of vitamin K1 would be important, or correlative analyses in skin samples should be integrated in future studies. Taken as whole, this elegant study raises a signal for vitamin K1 in the resolution phase of EGFR inhibitor-induced acneiform rash and the prevention of skin fissures, and opens the door to targeting skin toxicities resulting from targeted therapies.

Funding

MEL is supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748.

Disclosure

MEL: Berg, Veloce, US Biotest, Galderma, Jannsen, Boehringer Ingelheim, Debio, Legacy, Helsinn, Novocure, Novartis, Merck, Celldex, Adgero, ADCT, Johnson and Johnson, AbbVie, Menlo.