Mario E. Lacouture

Mechanisms of cutaneous toxicities to EGFR inhibitors

The increased target specificity of epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is associated with the reduction or abolition of nonspecific and haematopoietic side effects. However, coincident inhibition of receptor activity in tissues that depend on EGFR signalling for normal function has undesirable consequences. Because of the key role of EGFR signalling in skin, dermatological toxicities have frequently been described with EGFRIs. The resultant significant physical and psycho-social discomfort might lead to interruption or dose modification of anticancer agents. There is an urgent need for an improved understanding of these toxicities to develop adequate staging systems and mechanistically driven therapies, and to ensure quality of life and consistent antineoplastic therapy.

Skin Toxicity Evaluation Protocol With Panitumumab (STEPP), a Phase II, Open-Label, Randomized Trial Evaluating the Impact of a Pre-Emptive Skin Treatment Regimen on Skin Toxicities and Quality of Life in Patients With Metastatic Colorectal Cancer

PURPOSE Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is approved in the United States and Europe for the treatment of refractory metastatic colorectal cancer (mCRC). Skin toxicities are the most common adverse events with EGFR inhibitors. This is the first study designed to examine differences between pre-emptive and reactive skin treatment for specific skin toxicities in patients with mCRC for any EGFR inhibitor. PATIENTS AND METHODS Patients receiving panitumumab-containing therapy were randomly assigned 1:1 to pre-emptive or reactive treatment (after skin toxicity developed). Pre-emptive treatment included use of skin moisturizers, sunscreen, topical steroid, and doxycycline. The primary end point of the study was the incidence of protocol-specified >or= grade 2 skin toxicities during the 6-week skin treatment period. Quality of life (QOL) was assessed with the Dermatology Life Quality Index (DLQI). RESULTS Of 95 enrolled patients, 48 received pre-emptive treatment, and 47 received reactive treatment. The incidence of protocol-specified >or= grade 2 skin toxicities during the 6-week skin treatment period was 29% and 62% for the pre-emptive and reactive groups, respectively. Mean DLQI score change from baseline to week 3 was 1.3 points and 4.2 points in the pre-emptive and reactive groups, respectively. CONCLUSION The pre-emptive skin treatment regimen was well tolerated. The incidence of specific >or= grade 2 skin toxicities during the 6-week skin treatment period was reduced by more than 50% in the pre-emptive group compared with the reactive group. Patients in the pre-emptive group reported less QOL impairment than patients in the reactive group.

Evolving Strategies for the Management of Hand–Foot Skin Reaction Associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib

The multitargeted kinase inhibitors (MKIs) sorafenib and sunitinib have shown benefit in patients with renal cell carcinoma, hepatocellular carcinoma (sorafenib), and gastrointestinal stromal tumor (sunitinib). Their efficacy in other malignancies is currently being investigated because of their broad range of activity. The effectiveness of these drugs is somewhat diminished by the development of a variety of toxicities, most notably hand-foot skin reaction (HFSR). Although HFSR does not appear to directly affect survival, it can impact quality of life and lead to MKI dose modification or interruption, potentially limiting the antitumor effect. Currently, no standard guidelines exist for the prevention and management of MKI-associated HFSR. To address this issue, an international, interdisciplinary panel of experts gathered in January 2008 to discuss and evaluate the best-practice management of these reactions. Based on these proceedings, recommendations for the management of HFSR have been provided to offer patients the best possible quality of life while taking these drugs and to optimize the patient benefit associated with MKI therapy.

Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities

BackgroundEpidermal growth factor receptor inhibitors (EGFRI) produce various dermatologic side effects in the majority of patients, and guidelines are crucial for the prevention and treatment of these untoward events. The purpose of this panel was to develop evidence-based recommendations for EGFRI-associated dermatologic toxicities.MethodsA multinational, interdisciplinary panel of experts in supportive care in cancer reviewed pertinent studies using established criteria in order to develop first-generation recommendations for EGFRI-associated dermatologic toxicities.ResultsProphylactic and reactive recommendations for papulopustular (acneiform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis/fissures, and paronychia are presented, as well as general dermatologic recommendations when possible.ConclusionPrevention and management of EGFRI-related dermatologic toxicities is critical to maintain patients’ health-related quality of life and dose intensity of antineoplastic regimens. More rigorous investigation of these toxicities is warranted to improve preventive and treatment strategies.

Atypical Melanocytic Proliferations and New Primary Melanomas in Patients With Advanced Melanoma Undergoing Selective BRAF Inhibition

PURPOSE Selective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules. PATIENTS AND METHODS In all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment. RESULTS Twelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent. CONCLUSION Malignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy-induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted.

Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib

BACKGROUND This study examined clinicopathological findings and management of hand foot skin reaction (HFSR) to sorafenib and sunitinib in a dermatology referral center for cancer-related toxic effects. PATIENTS AND METHODS We identified 12 patients who developed HFSR in a 1-year period (2007). Medical records and histological specimens were investigated for clinicopathological data and results on management. RESULTS We identified 12 patients developing HFSR on treatment with sorafenib (83%) or sunitinib (17%). Majority presented with grade 3 (75%) HFSR and a median Skindex score of 43. Biopsies in seven patients showed horizontal layers of keratinocyte necrosis, which correlated to time of drug exposure: early (<30 days from initiation) leading to stratum granulosum-spinosum alterations and late (> or =30 days) resulting in stratum corneum pathology. Treatment with topical urea singly (n = 3), plus tazarotene (n = 7), or fluorouracil (n = 2) resulted in > or =2 grade improvement in the majority of patients (58%), with five patients (42%) improving one grade (P = 0.007). Median Skindex score at follow-up was 32 (P = 0.22). CONCLUSIONS There are unique clinicopathological characteristics of HFSR due to the multikinase inhibitors that correlate with time of agent initiation. Treatment with topical agents having keratolytic, antiproliferative, and anti-inflammatory properties showed benefit.

Risk of hand-foot skin reaction with sorafenib: A systematic review and meta-analysis

Background. Hand-foot skin reaction (HFSR) is a dose-limiting toxicity associated with sorafenib, an oral multi-kinase inhibitor with clinical activity against solid tumors. This study was conducted to determine the risk of developing HFSR among patients receiving sorafenib. Patients and Methods. Databases from Pubmed, Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through July, 2007 were searched to identify relevant studies. Eligible studies were prospective clinical trials using single agent sorafenib. The summary incidence rate and the relative risk (RR) were calculated using random-effects model. Results. A total of 4 883 patients in 11 trials with metastatic tumors were included for analysis. Among patients receiving sorafenib, the summary incidence of all-grade HFSR was 33.8% (95% CI: 24.5–44.7%) with significant difference between patients with RCC and non-RCC malignancy (RR 1.52, 95% CI: 1.32–1.75%, p<0.001). The incidence of high-grade HFSR was 8.9% (95% CI: 7.3–10.7%). In addition, sorafenib was associated with a significant increased risk of HFSR with RR of 6.6 (95% CI: 3.7 to 11.7, p<0.001) in comparison with controls. Conclusion. There is a significant risk of HFSR associated with sorafenib. Proper management and further study are recommended to reduce the risk.

Analysis of Dermatologic Events in Vemurafenib-Treated Patients With Melanoma

BACKGROUND Vemurafenib has been approved for the treatment of patients with advanced BRAF(V600E)-mutant melanoma. This report by the Vemurafenib Dermatology Working Group presents the characteristics of dermatologic adverse events (AEs) that occur in vemurafenib-treated patients, including cutaneous squamous cell carcinoma (cuSCC). METHODS Dermatologic AEs were assessed from three ongoing trials of BRAF(V600E) mutation-positive advanced melanoma. Histologic central review and genetic characterization were completed for a subset of cuSCC lesions. RESULTS A total of 520 patients received vemurafenib. The most commonly reported AEs were dermatologic AEs, occurring in 92%-95% of patients. Rash was the most common AE (64%-75% of patients), and the most common types were rash not otherwise specified, erythema, maculopapular rash, and folliculitis. Rash development did not appear to correlate with tumor response. Photosensitivity occurred in 35%-63% of patients, and palmar-plantar erythrodysesthesia (PPE) occurred in 8%-10% of patients. The severity of rash, photosensitivity, and PPE were mainly grade 1 or 2. In all, 19%-26% of patients developed cuSCC, mostly keratoacanthomas (KAs). The majority of patients with cuSCC continued therapy without dose reduction after resection. Genetic analysis of 29 cuSCC/KA samples demonstrated HRAS mutations in 41%. CONCLUSIONS Dermatologic AEs associated with vemurafenib treatment in patients with melanoma were generally manageable with supportive care measures. Dose interruptions and/or reductions were required in <10% of patients.

A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group

BackgroundAccurate grading of dermatologic adverse events (AE) due to epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is necessary for drug toxicity determinations, interagent comparisons, and supportive care trials. The most widely used severity grading scale, the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0), was not designed specifically for this class of agents and may result in underreporting and poor grading of distinctive adverse events. We believe a class-specific grading scale is needed to help standardize assessment and improve reporting of EGFRI-associated dermatologic AEs.MethodsThe Multinational Association of Supportive Care in Cancer (MASCC) Skin Toxicity Study Group conducted an international multidisciplinary meeting that included 20 clinicians and researchers from academic centers and government agencies. Experts from different disciplines presented current information specific to EGFRI-induced dermatologic toxicities: grading scale development, pharmacovigilance safety reporting, health-related quality of life, patient reporting, and pharmacology. Group discussions, literature reviews, and professional expertise established the theoretical foundation for the proposed grading scale.ResultsA new grading system is proposed for the most common events associated with EGFRI-induced dermatologic AEs: papulopustular reaction or acneiform rash, nail changes, erythema, pruritus, xerosis, hair changes, telangiectasias, hyperpigmentation, mucositis, flushing, radiation dermatitis, hyposalivation, and taste changes. The proposed scale maintains consistency with the grading principles and language of the existing CTCAE version 4.0 and MedDRA terminology and includes relevant patient-reported health-related quality of life factors.ConclusionsA grading scale specific to EGFR inhibitor dermatologic AEs is presented for formal integration into future versions of CTCAE and for validation in clinical trial settings. The study group designed this scale to detect and report EGFRI-related toxicities with greater sensitivity, specificity, and range than the scales currently used. This scale should serve as a foundation for efforts to perform objective interdrug comparisons and assessments of supportive care treatment strategies more effectively than with current methods.

Impact and Management of Skin Toxicity Associated with Anti-Epidermal Growth Factor Receptor Therapy: Survey Results

Biologic agents targeting the epidermal growth factor receptor (EGFR) have emerged as a robust treatment option for various solid tumors. Despite lower systemic side effects than conventional chemotherapy, the majority of patients treated with these agents experience cutaneous toxicities, including papulopustular rashes, hair and nail changes, xerosis and pruritus, which have a significant impact on health and quality of life. Currently no consensus or management guidelines exist for these untoward events. Therefore, a retrospective survey was carried out across 110 oncology practioners in the US that were administering EGFR inhibitors. Providers were queried on the impact and management of these untoward events in their practices. Responses suggest that combination therapies (topical and oral) were more effective than either therapy alone, and also lead to a more rapid resolution of the papulopustular rash. Providers also reported that patients frequently complained of physical symptoms associated with the rash (itching and pain), and that they had a positive perception when being treated for their cutaneous side effects. The survey results support that attentive cutaneous care is important in patients treated with EGFR inhibitors, and that proactive/combined interventions may enhance quality of life and optimize consistent drug administration.