TOXICAN: a guide for grading dermatological adverse events of cancer treatments.

PURPOSE: The dermatological toxicity of cancer treatments is frequent and sometimes debilitating. Its reference classification, the NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events), is sometimes difficult to use and does not include yet the newest toxicities. Our objective was to create a guide, TOXICAN, based on the CTCAE, which is easy to use in everyday practice and which facilitates the recognition and grading of these dermatological toxicities. METHODS: This guide was developed by a working group ("GESTIM") comprising oncodermatologists, allergists, pathologists, and researchers from Nantes University Hospital. It was based on the dermatological toxicities found in the CTCAE and adapted to daily practice. These toxicities were grouped into categories and associated with photographs of typical cases to aid recognition. A simplified grading scale derived from the CTCAE was also created. This booklet was validated by means of user evaluation, and then the Delphi consensus method. RESULTS: We selected 32 dermatological toxicities, including 12 created by our group, sorted into 7 categories: skin rash, dry skin/pruritus, hyperkeratotic papules, palmoplantar changes, hair and nail changes, mucosal changes, and others. Our simplified grading scale only differed from the CTCAE for one item, urticaria. Three items were modified after evaluation by the user group and 11 after application of the Delphi method. CONCLUSION: The objective of our practical guide is to facilitate the use of the CTCAE for recognizing and grading dermatological toxicity of cancer treatments in order to provide optimal guidance for therapeutic adaptations. Its impact on clinical practice remains to be evaluated.

Development of brain metastases in patients with metastatic melanoma while receiving ipilimumab.

UNLABELLED: Ipilimumab is a monoclonal antibody blocking the inhibitory molecule CTLA4 expressed by activated T lympocytes, used for the treatment of metastatic melanoma. Recent studies have shown its potential efficacy on brain metastases. OBJECTIVES: To assess the development of brain metastases under ipilimumab and identify clinical, histological or evolving criteria related to the appearance of these metastases. A retrospective study was conducted in 52 patients treated with 4 cycles of ipilimumab 3 mg/kg every 3 weeks for unresectable stage III or stage IV melanoma between January 2011 and July 2013 in a Department of Dermato-Oncology. As no data has been find in the literature, the results were compared to our other cohort of patients treated with vemurafenib during the same period. Ten patients (21.7 %) developed brain metastases under ipilimumab in a median time of 6.58 months after treatment initiation. The multivariate analysis showed a lower rate of brain metastases in patients with acral lentiginous melanoma and melanoma of unknown primary site. The median survival after diagnosis of brain metastases was of 2.5 months. There was no significant difference with vemurafenib-treated patients in terms of incidence rate of brain metastasis, time of development and survival after diagnosis of cerebral metastases. This was the first study focused on the development of brain metastases under treatment with ipilimumab 3 mg/kg. Although ipilimumab is used for the treatment of brain metastases, it paradoxically did not seem to reduce the risk of developing brain metastases.

Profile of vemurafenib-induced severe skin toxicities.

BACKGROUND: Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown. OBJECTIVE: To determine the rate of permanent vemurafenib discontinuation due to grade 3-4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival. METHODS: Retrospective cohort study of 131 patients treated with vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias. RESULTS: Among the 131 vemurafenib-treated patients, 26% developed grade 3-4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3-4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash. CONCLUSION: In this study, vemurafenib was continued in 56% of patients with grade 3-4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and cutaneous carcinoma, treatment adjustment is usually not needed.

Development of squamous cell carcinoma into basal cell carcinoma under treatment with Vismodegib.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in humans. Vismodegib, a Hedgehog pathway inhibitor, has proved its effectiveness in treating non-resectable advanced BCC. AIM: However, its action on squamous cell carcinoma (SCC) is unknown. We present three SCC cases developed into BCC in vismodegib-treated patients. MATERIAL AND METHODS: We have described three cases of patients developing SCC during treatment by vismodegib for BCC. RESULTS: Patient 1 was treated with vismodegib for five facial BCC. Due to the progression of one of the lesions at month 3 (M3), a biopsy was performed and showed SCC. Patient 2 was treated with vismodegib for a large facial BCC. A biopsy was performed at M2 on a BCC area not responding to treatment and showed SCC. Patient 3 was treated with vismodegib for a BCC on the nose. Due to vismodegib ineffectiveness, a biopsy was performed and showed SCC. DISCUSSION: Two similar cases have been described in the literature. This could be due to the appearance of the squamous contingent of a metatypical BCC or to the squamous differentiation of stem cells through inhibition of the hedgehog pathway. CONCLUSION: In practice, any dissociated response of a BCC to vismodegib should be biopsied.

Incidence and characteristics of melanoma brain metastases developing during treatment with vemurafenib.

Vemurafenib is indicated for the treatment of patients with BRAF (V600)-mutant metastatic melanoma. We studied for the first time the characteristics of brain metastases developed during treatment with vemurafenib in real-life conditions. We included all patients treated over 3 years with vemurafenib in our department for metastatic melanoma without initial brain involvement. Our primary endpoint was to assess the incidence of brain metastases in these patients. Our secondary endpoints were to identify the risk factors for metastases occurrence and their characteristics and course. In our retrospective cohort of 86 patients, 20% had developed brain metastases on average 5.3 months after vemurafenib initiation. The median follow-up was 9 months (1-26 months). Radiological examinations revealed multiple brain metastases in 41% of patients. The only risk factor for metastasis occurrence identified was a high number of metastatic sites when initiating vemurafenib (p = 0.045). Metastasis development was associated with a trend toward a decrease in overall survival from 12.8 to 8.5 months (p = 0.07) and a significant decrease in progression-free survival from 7 to 5 months (p = 0.04). Among the patients who developed brain metastases, 82% died, of whom 64% within 3 months, versus 58% of patients without brain metastases over the same period. The extra-cerebral disease was well controlled in 59% of patients during brain progression. In vemurafenib-treated melanoma patients, brain metastases are frequent and associated with a particularly poor prognosis. Because of their high frequency in patients with controlled extra-cerebral disease, brain explorations should be systematically performed during treatment.

Melanoma and rituximab: an incidental association?

Rituximab is an anti-CD20 monoclonal antibody increasingly used in haematology and rheumatology, but also in internal medicine and dermatology. It has a good tolerance profile without known increased risk of cancer. We report a case of nodular melanoma with a 4.8 mm Breslow thickness that appeared after 2 years of rituximab in a 45-year-old patient with non-Hodgkin lymphoma. Fifteen additional rituximab-associated melanoma cases in 13 patients have been identified in the literature and in the EudraVigilance database. These patients were treated for various indications and had melanomas, often aggressive, initially diagnosed at a metastatic stage in 31% of cases. Our work raises the question of rituximab accountability in melanoma onset in these immunosuppressed patients. A dermatological monitoring seems necessary in patients treated with rituximab, especially in case of risk factors for melanoma. In case of individual melanoma history, the benefit/risk ratio of initiating rituximab therapy should be carefully assessed.

Survey on the management of skin toxicity associated with EGFR inhibitors amongst French physicians.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are part of the therapeutic arsenal available for advanced cancer. However, they are frequently associated with cutaneous side-effects, which can hamper compliance, lead to treatment refusal and impair quality of life. OBJECTIVE: To know the attitudes of French oncologists who deal with this skin toxicity. This work is one of the steps to build a therapeutic algorithm of side-effects induced by EGFR inhibitors taking both evidence-based medicine and standard practices into account. METHODS: Physicians completed a questionnaire as part of regional meetings, before any discussion. Questions concerned the management of 11 clinical situations in the context of EGFR inhibitor prescription. RESULTS: Sixty-seven questionnaires were analysed. The collaboration with dermatologists was especially planned for persisting or worsening lesions beyond 2 weeks, but never considered at the time of the introduction of targeted therapy. The results demonstrated the difficulties encountered in diagnosing and grading skin lesions. Attitudes of oncologists were uniform for preventive care and management of mild lesions for which moisturizing and cyclines were widely prescribed. Significant differences appeared in the treatment of less typical cases such as the involvement of skin appendages, secondary infections of folliculitis or cases associated with radiodermatitis. Discrepancies existed also for what to do in relation with maintenance or interruption of EGFR inhibitor mainly if they were responsible for severe lesions. CONCLUSION: This original survey emphasizes the interest of greater multidisciplinary collaboration and the necessity to harmonize practice.

Semiology of skin toxicity associated with epidermal growth factor receptor (EGFR) inhibitors.

PURPOSE: Advances in the understanding of the mechanisms involved in oncogenesis have led to the development of so-called targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors, which take on an increasingly important role in the management of cancer. These treatments have the advantage not to trigger the adverse effects traditionally encountered with chemotherapy, such as nausea, vomiting or haematological toxicity. However, they do cause new forms of toxicity: the most common one is skin toxicity. It is important to be aware of it because it can be debilitating, adversely impacting patients' quality of life and altering treatment compliance, although it appears to be correlated with treatment response in certain series. Non-specialists can have difficulty in recognising this unusual skin toxicity. METHODS: The dermatologic side effects most frequently triggered by EGFR inhibitors are discussed in this article. RESULTS: They are divided into three categories depending on their target: inflammation of the pilo-sebaceous follicle, represented by EGFR inhibitor-associated folliculitis, which occurs at an early stage and is frequent; alteration in the skin barrier, primarily responsible for xerosis, fissures and pruritus, which are frequent and delayed; and lesions of the skin appendages (paronychia, pyogenic granuloma, hair changes), which are delayed and less frequent. CONCLUSION: It is essential for all practitioners concerned to know about these dermatologic side effects in order to ensure better global management of patients, particularly in terms of quality of life.

Management of cutaneous adverse events induced by anti-EGFR (epidermal growth factor receptor): a French interdisciplinary therapeutic algorithm.

PURPOSE: Cutaneous adverse events induced by epidermal growth factor receptor (EGFR) inhibitors can hamper the patients' quality of life. The aim of our work was to draft an algorithm for the optimised management of this skin toxicity. METHODS: This algorithm was built in three steps under the responsibility of a steering committee. Step I: a systematic literature analysis (SLA) has been performed. Step II: the collection of information about practices was performed through a questionnaire.These questions were asked during regional meetings to which oncologists, gastro-enterologists, radiotherapists, and dermatologists were invited. Step III: a final meeting was organised involving the bibliography group and the steering committee and regional scientific committees for proposing a final algorithm. RESULTS: Step I: 14 publications were selected to evaluate the use of cyclines as curative or prophylactic treatment of the folliculitis induced by EGFR inhibitors. Nineteen publications were retained for the topical treatment of the folliculitis. Forty-six articles were selected for the management of the cutaneous lesions in link with appendages and 12 for xerosis and pruritus. Step II: 96 delegates attended the seven regional meetings and 67 questionnaires were analysed. Step III: a final algorithm was proposed on the basis of the conclusions of the first two steps and expert opinions present at this final meeting. The different propositions were unanimously approved by the 14 experts who voted. CONCLUSIONS: This multidisciplinary study summarising published data and current practices produced a therapeutic algorithm, which should facilitate the standardised, optimised management of skin toxicity associated with EGFR inhibitors in France.

Onychopathy induced by temsirolimus, a mammalian target of rapamycin inhibitor.

Temsirolimus belongs to the mammalian target of rapamycin (mTOR) inhibitors, targeted therapies for which indications are booming in oncology. While their tolerance is usually good, mucocutaneous toxicity is the most common, including stomatitis, rashes, edemas, pruritus, dry skin and nail disorders. The latter are common in clinical practice but have not yet been well characterized. We report 2 cases of patients who developed, after 6-7 months with temsirolimus, a dystrophy of the 20 nails with fragility, distal onycholysis, yellow discoloration, associated in 1 case with painful paronychia. Topical steroids improved the paronychia, without changing the nail dystrophy. To our knowledge, the occurrence of yellow nail discoloration with temsirolimus has never been reported before. We review the cutaneous and mucosal toxicities induced by temsirolimus and everolimus, two mTOR inhibitors used as anticancer agents and by their parent molecule sirolimus.

Is primary melanoma ulceration a factor of good response to adoptive immunotherapy?

BACKGROUND: Primary melanoma ulceration is a factor of poor prognosis at the local and regional stage. The physiopathological mechanisms which explain its prognostic impact are still little known. However, two recent studies suggest that it could be a predictive factor of good response to a non-specific immunotherapy (interferon-alpha) and to an active immunotherapy (vaccine). OBJECTIVE: The aim of this study was to determine whether ulceration could be a factor of good prognosis in the context of an adoptive immunotherapy with tumour infiltrating lymphocytes (TIL) in stage III regional lymph node metastatic melanoma (sixth American Joint Committee on Cancer staging system) and whether it was associated with an improvement in the effectiveness of this treatment compared with the control group. METHODS: We have included all the patients treated in open prospective randomized TIL vs. control protocols in our unit from 1997 to 2009. Clinical data were derived retrospectively from patient files. Statistical analysis was performed using log-rank tests, Cox models and tests for interaction. RESULTS: A total of 144 patients were included. In the group of 80 patients treated with TIL, primary melanoma ulceration remained a pejorative factor for relapse-free and overall survival in univariate and multivariate analysis. The presence of ulceration did not change the effectiveness of TIL treatment in comparison with the control group with regards to relapse-free and overall survival. CONCLUSION: Our study demonstrates that primary melanoma ulceration does not have any impact on the response to TIL adoptive immunotherapy and thus does not confirm its positive prognostic value suggested by two other immunotherapy approaches.

[Lymphomatoid granulomatosis revealed by cutaneous lesions]. / Granulomatose lymphomatoïde de révélation cutanée.

BACKGROUND: Lymphomatoid granulomatosis is a rare Epstein Barr virus (EBV)-related lymphoproliferative disorder. It most frequently involves the lungs, skin and central nervous system and arises preferentially in patients with immune disorders. Here we report a case revealed by cutaneous lesions in an immunocompetent patient. CASE REPORT: A 56-year-old man consulted for erythematous nodules of the trunk associated with malaise and marked weight loss (14kg). In a few days the nodules became necrotic. Two weeks later a cough appeared and the chest computerized tomography showed multiple poorly defined nodular opacities with a peribronchovascular distribution. Cutaneous and pulmonary biopsies showed an infiltrate composed of medium-sized atypical lymphocytes T and B. EBV was present in the infiltrate (in situ hybridization) with a high EBV load in plasma. All of these data helped confirm the diagnosis of lymphoid granulomatosis. Despite aggressive treatment with polychemotherapy, the patient died after 2 months. DISCUSSION: Lymphomatoid granulomatosis represents a diagnostic challenge. In most cases, the presenting symptoms are not specific: malaise, weight loss, fever and cough. Moreover histology is difficult because of the T-cell-rich background. It is essential to consider this diagnosis in cases of cutaneous and pulmonary symptoms.