Drug-Related Cutaneous Adverse Events in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Literature Review.

Since myeloproliferative neoplasms (MPN) pose a significant risk for vascular and thrombotic complications, cytoreductive therapies, such as hydroxyurea (HU), interferon (IFN) inhibitors, and Janus kinase (JAK) inhibitors are recommended for patients at high risk. However, these agents also place patients at increased risk for drug-related cutaneous adverse events. Herein, we review the literature on skin toxicity related to the use of drugs for the treatment of MPN. Overall, the cytoreductive agents used for MPN are generally well tolerated and considered to be safe, except IFN, for which dropout rates as high as 25% have been reported. While IFN is known to give rise to flu syndrome, it rarely leads to hematological alterations. The most common hematological side effects of HU are mild and include granulocytopenia, anemia, and thrombocytopenia. The JAK inhibitor ruxolitinib has been associated with cytopenia and a higher incidence of viral infections, as well as increased risk for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Based on the present analysis, it can be concluded that cutaneous toxicity is not a negligible complication of commonly used treatments for MPN. While further research is needed, patients on these agents, and especially those with a history of cutaneous malignancies, should undergo thorough skin examination before and during therapy. In addition, detailed history is critical since many patients who develop non-melanoma skin cancer have multiple preexisting risk factors for cutaneous carcinogenesis.

Inflamed actinic keratoses associated with pemetrexed and carboplatin therapy.

Eruptive actinic keratosis (AK) consequent to systemic chemotherapy can be confused with drug allergies. We present the first case of inflamed AKs in one patient after receiving combination therapy with pemetrexed and carboplatin.A 68-year-old woman with non-small cell lung adenocarcinoma (NSCLC) presented with numerous pruritic ill-defined, gritty, erythematous papules consistent with AKs on her upper chest, upper back, and arms two weeks after completing the first cycle of combination therapy with carboplatin and pemetrexed. The care team managed her with topical steroids and the lesions resolved within one month. The patient resumed the second cycle of chemotherapy and reported the occurrence of a similar but milder eruption.This case illustrates that eruptive AKs should be considered in the differential diagnosis of drug-related rashes, especially if the physical exam is suggestive. The mainstay of treatment should be directed at symptomatic improvement, and chemotherapy may be continued.

Inflamed Actinic Keratoses After Pemetrexed.

A 66-year-old man presented with a 1-day history of a mildly pruritic eruption on the face, chest, arms, and upper part of the back. The dermatitis began 3 weeks after receiving an initial infusion of pemetrexed (500 mg/m2) as induction chemotherapy for non-small cell lung cancer. Physical examination revealed numerous erythematous, scaly papules over the face, extensor surface of the arms, hands, and upper aspects of the chest and back, sparing sun-protected areas (Figure). He acknowledged that in the past he frequently went shirtless outdoors and rarely wore sunscreen or sun protective clothing during the many years he worked at construction sites. Results from a biopsy specimen from a typical lesion on the forearm revealed an inflamed actinic keratosis. Systemic chemotherapy was continued, and only emollients and mid-potency topical steroids were used to treat the skin eruption. At 2-week follow-up, the patient's eruption was greatly diminished with loss of significant erythema and scale, as well as absence of pruritus.

Cutaneous effects of BRAF inhibitor therapy: a case series.

BACKGROUND: The cutaneous effects of rapidly accelerated fibrosarcoma kinase B (BRAF) inhibitors are not well understood. Squamous cell carcinoma (SCC), keratoacanthoma, and photosensitivity have been described in patients taking BRAF inhibitors. PATIENTS AND METHODS: To characterize the timing and frequency of skin lesions in patients receiving BRAF inhibitor therapy, we utilized a retrospective case review of 53 patients undergoing treatment with BRAF inhibitors for 4-92 weeks of therapy. Patients were evaluated at baseline, and then followed at 4- to 12-week intervals. Charts were retrospectively reviewed, and the morphology and timing of cutaneous events were recorded. RESULTS: Thirty-three of the 53 charts met exclusion/inclusion criteria, 15 were treated with vemurafenib, and 18 were treated with GSK 2118436/GSK 1120212. Of 33 patients treated with BRAF inhibitor, 13 developed photosensitivity (39.4%), 10 developed actinic keratoses (30.3%), 10 developed warts (30.3%), and 6 developed SCC (18.2%). CONCLUSIONS: Multiple cutaneous findings were observed in the 33 patients taking BRAF inhibitors. The previously described association with SCC and photosensitivity was observed in these patients as well. Over half of the observed SCCs were invasive in nature. Photosensitivity continues to be frequent with BRAF inhibitors. Patients taking BRAF inhibitors should have regular full body skin exams. Further studies are necessary to better elucidate the rates of these adverse cutaneous effects.

Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN.

Hydroxyurea (Hydroxycarbamide; HU) is commonly used for the long-term treatment of patients with Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs). It is considered a first-choice agent for the treatment of these disorders as underlined by the European Leukemia Net Consensus Conference [1], although it is formally approved for this indication in some countries only. The drug is reportedly well tolerated in the large majority of subjects, although systemic and/or localized toxicities have been reported. Consensus criteria for definition of "intolerance" to HU have been described;patients who develop intolerance are candidate for second-line therapy and, more recently, for investigational drugs. However, no epidemiologic information about the occurrence of the most clinically significant HU-associated adverse events is yet available. In this study, the authors report on a multicenter series of 3,411 patients who were treated with HU among which 184, accounting for 5% of total, developed significant drug-related toxicities. These data provide an estimate of the frequency and a detailed characterization of clinically significant HU-related toxicities; these information have relevance for the management of MPN patients who require second-line therapy after developing HU-related intolerance.

Topical Pharmacotherapy for Actinic Keratoses in Older Adults.

Actinic keratosis is caused by excessive lifetime sun exposure. It must be treated, regardless of thickness, because it is the biologic precursor of invasive squamous cell carcinoma, a potentially deadly malignancy. Physical ablative techniques such as cryotherapy, lasers, and curettage are the most used treatments for isolated lesions. Multiple lesions are treated with topical drugs, chemical peelings, and physical techniques. Drug preparations containing diclofenac plus hyaluronate, aminolevulinic acid, and methyl aminolevulinate and different concentrations of imiquimod and 5-fluorouracil are approved for this clinical indication. All treatments have a good profile of efficacy and tolerability although there are relevant differences in the clearance rate, tolerability, and type and frequency of adverse effects. In addition, they have very different mechanisms of action and treatment protocols. No differences in the efficacy and tolerability were found in older patients compared with younger patients, therefore no dose adjustments are needed. That said, older patients often need to be motivated to treat actinic keratoses and a careful attention to expectations, needs, and preferences should be used to obtain the maximal adherence and prevent treatment failure. This goal can be achieved with a careful evaluation not only of published efficacy, toxicity, and tolerability data but also of practical topics such as the frequency of daily applications, the overall duration of therapy, and the need for a caregiver. Finally, particular attention must be paid in the case of frail patients and immunosuppressed patients.

Sunscreen use: controversies, challenges and regulatory aspects.

Mismatches between skin pigmentation and modern lifestyle continue to challenge our naked skin. One of our responses to these challenges is the development and use of sunscreens. The management of sunscreens has to balance their protective effect against erythema, photocarcinogenesis and photoageing owing to the potential toxicity of the ultraviolet (UV) filters for humans and the environment. The protection against UV radiation offered by sunscreens was recently standardized in the European Union (EU) based on international harmonization of measurement techniques. Four different categories of sun protection have been implemented along with recommendations on how to use sunscreen products in order to obtain the labelled protection. The UV filters in sunscreens have long been authorized for use by the EU authority on the basis of data from studies on acute toxicity, subchronic and chronic toxicity, reproductive toxicity, genotoxicity, photogenotoxicity, carcinogenicity, irritation, sensitization, phototoxicity and photosensitization as well as on environmental aspects. New challenges with respect to the safety of UV filters have arisen from the banning of animal experiments for the development of cosmetics. Future debates on sunscreens are likely to focus on nanoparticles and environmental issues, along with motivation campaigns to persuade consumers to protect their skin. However, more efficient sunscreen use will also continue to raise questions on the benefit in preventing vitamin D synthesis in the skin induced by sunlight.

Evaluation of the Use of Capecitabine for the Treatment and Prevention of Actinic Keratoses, Squamous Cell Carcinoma, and Basal Cell Carcinoma: A Systematic Review.

Importance: Certain patient groups, such as solid organ transplant recipients (SOTRs), have a significantly increased risk of developing skin cancers. The chemotherapeutic drug capecitabine has been used off label as a chemopreventive modality to suppress the development of precancerous skin lesions and squamous cell carcinomas (SCCs). Objective: To systematically review published studies on the use of capecitabine for the treatment and prevention of precancerous and cancerous skin lesions, with a focus on cutaneous SCC. Evidence Review: For this systematic review, a literature search was performed using the PubMed and Embase databases in December 2019 for all articles published between January 1, 1998, and December 31, 2019, using the search term capecitabine paired with each of the following terms: actinic keratosis, actinic keratoses, squamous cell carcinoma, and basal cell carcinoma. Articles on the use of capecitabine for the treatment and prevention of actinic keratoses (AKs), SCCs, and basal cell carcinomas (BCCs) were selected for inclusion. Findings: Sixteen publications met the criteria for inclusion, with 8 case reports describing the inflammation of AKs in patients with solid organ cancer treated with capecitabine (2 patients with breast cancer and 6 patients with colorectal cancer). One case report and 1 case series of 4 patients investigated the use of capecitabine for the treatment of advanced or widespread cutaneous SCCs. A total of 6 publications (3 case reports and 3 case series) described the use of capecitabine to prevent development of SCCs in SOTRs. Of these case series, 2 studies found a significant reduction in SCC incidence rate during treatment with capecitabine compared with before treatment. Adverse effects, such as fatigue, nausea, vomiting, diarrhea, elevated creatinine level, hand-foot syndrome, hyperuricemia, weight loss, anemia, and cardiomyopathy, limited the duration of chemoprevention in several patients. Conclusions and Relevance: Capecitabine treatment may be associated with a decrease in the incidence of SCCs in SOTRs. Capecitabine treatment may also be associated with a decrease in AK and BCC incidence. However, practitioners must weigh this benefit against the risk of adverse effects for each patient individually. Further investigation with a prospective clinical trial is warranted.

Cutaneous squamous cell carcinoma and inflammation of actinic keratoses associated with sorafenib.

BACKGROUND: Sorafenib-induced dermatologic toxicity is common and consists primarily of dry skin, maculopapular rash, hand-foot skin reaction, and alopecia. Cutaneous squamous cell carcinoma (SCC) and inflammation of actinic keratosis (AK) were reported in 2 patients treated with sorafenib (Lacouture et al), but the scope of this observation has not been evaluated. PATIENTS AND METHODS: We reviewed medical records of 131 patients with metastatic renal cell carcinoma treated with single-agent sorafenib at our institution from June 1, 2005, through April 4, 2007. RESULTS: We identified 7 cases of cutaneous SCC, 2 cases of SCC keratoacanthoma type, 2 cases of focal squamous atypia, and 3 cases of AKs. The time to development of SCC or AK from the start of sorafenib was 9.3 months (median, 6.5 months; range, 0.9-43 months). Ten of these 14 patients discontinued therapy with sorafenib: 7 patients as a result of disease progression, 2 patients as a result of nondermatologic toxicity, and 1 patient as a result of dermatologic toxicity. Four patients are continuing sorafenib therapy at reduced doses because of diarrhea and fatigue. One patient receiving sorafenib at a 25% dose reduction developed a second invasive SCC lesion on his forearm 6 months after the initial resection. CONCLUSION: These data suggest that there could be an association between sorafenib therapy and the development of cutaneous SCC and inflammation of AK. This adverse event has important therapeutic implications. Full appraisal of this observation in prospective studies is warranted.

Skin lesions in patients treated with imatinib mesylate: a 5-year prospective study.

Imatinib mesylate (IM) represents the first-line treatment of patients with chronic myeloid leukemia (CLM) or gastrointestinal stromal tumor (GIST). It presents several side effects. However, less than 10% are nonhematologic including nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions. The aim of our study was to identify data regarding IM cutaneous adverse effects (AEs) to improve the clinical diagnosis and management of the more frequent side effects. Skin examination should be done before and during IM treatment so that AEs can be diagnosed and treated early with less impact on chemotherapy treatments and on the quality of life of the patient.