Case and Research Letters
Hand-Foot Skin Reaction to Regorafenib
Reacción cutánea mano-pie por regorafenib
a Servicio de Dermatología, Unidad de Oncodermatología, Consulta de efectos adversos por antineoplásicos, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain
b Servicio de Oncología Médica, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain
c Servicio de Dermatología, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain
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Espinosa Lara, C. Bueno Muiño, B. Doger de Spéville, J. Jiménez Reyes" "autores" => array:4 [ 0 => array:4 [ "nombre" => "P. Espinosa" "apellidos" => "Lara" "email" => array:1 [ 0 => "pablo.e.lara@outlook.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "C. Bueno" "apellidos" => "Muiño" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "B. Doger de" "apellidos" => "Spéville" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "J. Jiménez" "apellidos" => "Reyes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Dermatología, Unidad de Oncodermatología, Consulta de efectos adversos por antineoplásicos, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Oncología Médica, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital Universitario Infanta Cristina, Parla, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Reacción cutánea mano-pie por regorafenib" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 574 "Ancho" => 990 "Tamanyo" => 103824 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Erythema and mild desquamation on the palms.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In recent years, the appearance of targeted drugs has revolutionized treatment in the field of oncology. With these drugs, the profile of systemic side effects is different than in conventional chemotherapy and the need for dosage suspension is smaller, but skin reactions are more frequent and often have an effect on adherence. Among these drugs is regorafenib, a multikinase inhibitor that was recently approved for the treatment of metastatic colorectal cancer. The hand-foot skin reaction is one of the most common toxicities of this drug.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the case of a 69-year-old man diagnosed in 2012 with stage <span class="elsevierStyleSmallCaps">IV</span> rectal adenocarcinoma with liver and lung metastases and wild-type K-RAS, for which he had received chemotherapy according to the XELOX-Avastin treatment regimen (capecitabine, oxaliplatin, and bevacizumab), with progression in the liver after 13 cycles of treatment. He subsequently received treatment with FOLFIRI-Erbitux (irinotecan, 5-fluorouracil, and cetuximab), with progression in the liver and lungs after 12 cycles. Grade 2 palmar-plantar erythrodysesthesia occurred as a side effect and was initially attributed to the capecitabine treatment. When only residual erythema remained on the palms and soles, the lesions reappeared after the introduction of 5-fluorouracil. The patient also had grade 2 neuropathy, secondary to the oxaliplatin treatment, which persisted at grade 1 at the start of the regorafenib treatment. Two months later, in light of the progression of the disease with FOLFIRI-Erbitux treatment, treatment with regorafenib was started at a dose of 160<span class="elsevierStyleHsp" style=""></span>mg/d. At 2 weeks, the patient reported an increase in erythema on the palms and soles and the appearance of keratotic lesions on the weight-bearing surfaces of both feet (<a class="elsevierStyleCrossRefs" href="#fig0005">Figs. 1 and 2</a>). Physical examination revealed poorly defined areas of erythema on the palms, with more intense involvement of the thenar and hypothenar eminences (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), and erythema with diffuse desquamation that covered practically the entire surface of both soles, with keratotic papules that were mildly painful to the touch in the weight-bearing areas of the balls of the feet, distributed symmetrically and bilaterally (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). After diagnosis of regorafenib-induced hand-foot skin reaction, treatment was prescribed with emollients on the palms and soles, as well as curettage and the application of 30% urea to the keratotic regions. Clinical course was good and the pain disappeared, although the erythema persisted. To date, the patient has received 2 cycles of regorafenib, with optimal doses and no need for delays or suspension of treatment.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals) is a new oral multikinase inhibitor<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> that targets cell-signaling pathways involved in angiogenesis (VEGFR1–3, TIE2), oncogenesis (KIT, RET, RAF), and the maintenance of the tumor microenvironment (PDGFR and FGFR).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> It is indicated for the treatment of metastatic colorectal cancer in adult patients who have previously received treatment or are not candidates for other lines of chemotherapy, and in patients with gastrointestinal stromal tumors (GISTs) who are not candidates for surgery and who have not responded to other treatments (imatinib, sunitinib). Regorafenib is also being investigated for use in other types of cancer.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2,3</span></a> The recommended dosage is a single dose of 160<span class="elsevierStyleHsp" style=""></span>mg each day for 3 weeks, followed by 1 week off. Each 4-week period is considered a treatment cycle. Treatment continues as long as it obtains therapeutic benefits or until unacceptable toxicity appears.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Regorafenib was approved for the treatment of metastatic colorectal adenocarcinoma following the publication of the results of a phase <span class="elsevierStyleSmallCaps">iii</span> clinical trial named CORRECT, which compared regorafenib to placebo in patients with colorectal adenocarcinoma whose disease had progressed despite having received the standard antineoplastic therapy. In that study, the most common cutaneous side effect was the hand-foot skin reaction, which affected 46.6% of the 760 randomized patients (16.6% of whom had a grade 3 reaction)<span class="elsevierStyleSup">4</span>–higher rates than those seen with other multikinase inhibitors such as sorefenib.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> Other common side effects were asthenia (47.7% of patients, 9.2% grade 3), hypertension (27.8%), and diarrhea (33.8%).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In a 2013 meta-analysis by Belum et al<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> that included 1078 patients with colorectal adenocarcinoma, GISTs, renal cell carcinoma, and hepatocellular carcinoma who received treatment with regorafenib, the overall incidence of the hand-foot skin reaction was 60.5% (range in the various studies, 46.6%-84.8%). The lowest incidence (46.6%) was observed in a multicenter phase <span class="elsevierStyleSmallCaps">iii</span> trial with 500 patients with metastatic renal carcinoma, and the highest incidence (84.8%) was reported in a multicenter phase <span class="elsevierStyleSmallCaps">ii</span> trial with 33 patients with GISTs.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The precise molecular mechanism by which the hand-foot skin reaction is caused by multikinase inhibitors such as sorafenib–or, in our case, regorafenib–is unknown. According to one hypothesis, a class effect could be caused by direct cytotoxicity of the drug and a defect in cell repair caused by inhibition of PDGFR.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,6</span></a> This effect would manifest as very painful and incapacitating hyperkeratotic lesions on pressure or friction points on the palms and soles and would be exacerbated by trauma. The effect is dose-dependent and can be associated with the appearance of edema and blisters (grades 2 and 3). Histopathologic findings that have been described include epidermal parakeratosis and dyskeratosis with vacuolar degeneration of the keratinocytes, the presence of intracytoplasmic eosinophilic bodies, and blister formation in the Malpighian layer.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5,6</span></a> A dense superficial and perivascular lymphocytic inflammatory infiltrate with some degree of nonleukocytoclastic vasculitis is observed in the dermis.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a> Treatment consists of keratolytic agents (30%-40% urea, salicylic acid) plus prophylactic measures (preventive offloading with adapted orthopedic insoles, podiatric care, etc.), and analgesia. Early introduction of these measures can help make it possible to maintain antineoplastic therapy at optimal doses and prevent delays or withdrawal of treatment.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">It is important to differentiate this effect from hand-foot syndrome, also known as palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> This syndrome appears in patients who receive conventional chemotherapy such as liposomal doxorubicin, capecitabine, or cytarabine and is associated with erythema, variable desquamation and edema, and even fissuring and blistering. Both entities are dose-dependent, and in both cases cytotoxicity is the most likely pathophysiological mechanism. In the hand-foot skin reaction, however, hyperkeratosis is more frequent, appears earlier, is patchier, and can be the only manifestation.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6,10</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">This is the first case of hand-foot skin reaction secondary to regorafenib to be reported in the Spanish medical literature. Dermatologists should be aware of this entity and be able to diagnose it as part of the multidisciplinary management of the cutaneous side effects of new antineoplastic drugs, because managing these effects is important to ensuring adherence to treatment and optimizing the clinical response to therapy.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Lara PE, Muiño CB, Spéville BDd, Reyes JJ. Reacción cutánea mano-pie por regorafenib. Actas Dermosifiliogr. 2016;107:70–72.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 574 "Ancho" => 990 "Tamanyo" => 103824 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Erythema and mild desquamation on the palms.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1072 "Ancho" => 990 "Tamanyo" => 227897 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Hyperkeratotic papules on weight-bearing surfaces of the balls of the feet.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Adapted from V. Sanz Motilva.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a>" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Hand-Foot Syndrome \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Hand-Foot Skin Reaction \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Causative agents \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Conventional chemotherapy (5-fluorouracil and derivatives, cytarabine, liposomal doxorubicin, etc.). \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Multikinase inhibitors (sorafenib, sunitinib, vemurafenib, dabrafenib, regorafenib, etc.). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clinical manifestations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diffuse erythema and edema, fissures, desquamation, and blisters. Symmetrical. Worsens over time. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Erythematous papules and plaques with a peripheral halo in areas of pressure or friction. Marked hyperkeratosis. Improves over time. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dose dependence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Histopathology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Interface dermatitis.<br>Variable edema.<br>Epidermal detachment.<br>Epidermal dysmaturation.<br>Necrotic keratinocytes<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>eccrine squamous syringometaplasia.<br>Mild inflammatory infiltrate. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Epidermal hyperplasia.<br>Acanthosis, hyperkeratosis, and focal parakeratosis.<br>Intraepidermal edema.<br>Necrotic keratinocytes.<br>Interface dermatitis. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1396707.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Hand-Foot Syndrome vs Hand-Foot Skin Reaction.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.M. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 13 | 23 |
| 2024 October | 85 | 55 | 140 |
| 2024 September | 99 | 35 | 134 |
| 2024 August | 128 | 91 | 219 |
| 2024 July | 94 | 47 | 141 |
| 2024 June | 92 | 56 | 148 |
| 2024 May | 85 | 39 | 124 |
| 2024 April | 110 | 33 | 143 |
| 2024 March | 116 | 22 | 138 |
| 2024 February | 107 | 32 | 139 |
| 2024 January | 105 | 31 | 136 |
| 2023 December | 90 | 37 | 127 |
| 2023 November | 118 | 38 | 156 |
| 2023 October | 123 | 45 | 168 |
| 2023 September | 109 | 29 | 138 |
| 2023 August | 71 | 17 | 88 |
| 2023 July | 112 | 48 | 160 |
| 2023 June | 74 | 30 | 104 |
| 2023 May | 75 | 26 | 101 |
| 2023 April | 90 | 32 | 122 |
| 2023 March | 83 | 29 | 112 |
| 2023 February | 65 | 32 | 97 |
| 2023 January | 53 | 35 | 88 |
| 2022 December | 80 | 56 | 136 |
| 2022 November | 49 | 30 | 79 |
| 2022 October | 42 | 22 | 64 |
| 2022 September | 47 | 55 | 102 |
| 2022 August | 29 | 52 | 81 |
| 2022 July | 39 | 45 | 84 |
| 2022 June | 46 | 41 | 87 |
| 2022 May | 67 | 36 | 103 |
| 2022 April | 59 | 37 | 96 |
| 2022 March | 71 | 49 | 120 |
| 2022 February | 53 | 42 | 95 |
| 2022 January | 55 | 38 | 93 |
| 2021 December | 47 | 35 | 82 |
| 2021 November | 80 | 53 | 133 |
| 2021 October | 65 | 51 | 116 |
| 2021 September | 72 | 37 | 109 |
| 2021 August | 58 | 26 | 84 |
| 2021 July | 45 | 33 | 78 |
| 2021 June | 53 | 32 | 85 |
| 2021 May | 66 | 33 | 99 |
| 2021 April | 98 | 26 | 124 |
| 2021 March | 75 | 24 | 99 |
| 2021 February | 69 | 34 | 103 |
| 2021 January | 44 | 27 | 71 |
| 2020 December | 36 | 21 | 57 |
| 2020 November | 68 | 18 | 86 |
| 2020 October | 72 | 14 | 86 |
| 2020 September | 40 | 14 | 54 |
| 2020 August | 30 | 23 | 53 |
| 2020 July | 20 | 21 | 41 |
| 2020 June | 42 | 27 | 69 |
| 2020 May | 41 | 26 | 67 |
| 2020 April | 34 | 16 | 50 |
| 2020 March | 29 | 23 | 52 |
| 2020 February | 2 | 3 | 5 |
| 2020 January | 0 | 1 | 1 |
| 2019 December | 0 | 1 | 1 |
| 2019 October | 0 | 3 | 3 |
| 2019 May | 2 | 2 | 4 |
| 2019 April | 0 | 3 | 3 |
| 2019 March | 0 | 5 | 5 |
| 2018 December | 3 | 3 | 6 |
| 2018 November | 3 | 0 | 3 |
| 2018 October | 4 | 0 | 4 |
| 2018 September | 7 | 2 | 9 |
| 2018 August | 0 | 5 | 5 |
| 2018 July | 0 | 3 | 3 |
| 2018 June | 0 | 1 | 1 |
| 2018 May | 0 | 3 | 3 |
| 2018 March | 1 | 1 | 2 |
| 2018 February | 40 | 6 | 46 |
| 2018 January | 32 | 5 | 37 |
| 2017 December | 47 | 12 | 59 |
| 2017 November | 39 | 13 | 52 |
| 2017 October | 32 | 19 | 51 |
| 2017 September | 29 | 10 | 39 |
| 2017 August | 30 | 9 | 39 |
| 2017 July | 21 | 15 | 36 |
| 2017 June | 40 | 11 | 51 |
| 2017 May | 41 | 8 | 49 |
| 2017 April | 34 | 11 | 45 |
| 2017 March | 21 | 17 | 38 |
| 2017 February | 37 | 8 | 45 |
| 2017 January | 33 | 21 | 54 |
| 2016 December | 39 | 33 | 72 |
| 2016 November | 41 | 32 | 73 |
| 2016 October | 34 | 31 | 65 |
| 2016 September | 0 | 10 | 10 |
| 2016 August | 0 | 8 | 8 |
| 2016 July | 1 | 4 | 5 |
| 2016 June | 0 | 3 | 3 |
| 2016 May | 0 | 1 | 1 |
| 2016 April | 0 | 3 | 3 |
| 2016 March | 0 | 3 | 3 |
| 2016 February | 0 | 11 | 11 |
| 2016 January | 0 | 6 | 6 |
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