Multikinase Inhibitor-Induced Hand–Foot Skin Reaction: A Review of Clinical Presentation, Pathogenesis, and Management

Chanprapaph, Kumutnart; Rutnin, Suthinee; Vachiramon, Vasanop

doi:10.1007/s40257-016-0197-1

Cited by 39 publications

(39 citation statements)

References 98 publications

(165 reference statements)

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“…HFSR was the most common ADR, which is consistent with the findings of other trials. HFSR is a known AE associated with MKIs such as sorafenib , and Asian patients seem to be more susceptible . However, it is unknown whether specific genetic polymorphisms are associated with the development of HFSR.…”

Section: Discussionmentioning

confidence: 99%

Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting

et al. 2019

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Background Regorafenib improved the overall survival (OS) of patients with metastatic colorectal cancer (mCRC) who progress after standard therapies in two phase III trials. The present large‐scale prospective observational study evaluated the safety and effectiveness of regorafenib administered to Japanese patients with mCRC in real‐life setting. Materials and Methods Patients with mCRC were prospectively registered and initially received ≤160 mg oral regorafenib daily, at the investigator's discretion, for weeks 1–3 of each 4‐week cycle. The study's primary aim was to assess safety, particularly unexpected clinically significant adverse drug reactions (ADRs). A Cox's proportional hazards model was used to evaluate the association between OS, hand‐foot skin reaction (HFSR), and baseline characteristics. Results We evaluated 1,227 of 1,301 patients (enrolled from March 2013 to May 2015). ADRs occurred in 89.3% of patients (mostly within the first 4 weeks) and were a major reason for discontinuing treatment. The most frequent ADRs were HFSR, liver injury, and hypertension. The cumulative incidence of HFSR and liver injury was higher in patients who initially received 160 mg than in those who received ≤120 mg. The incidence of hypertension and fatigue was similar between groups. Median OS was 6.9 months (95% confidential interval, 6.4–7.4). OS was associated with early onset of HFSR and good performance status (PS) but not with the initial dose. Conclusion The outcomes of this study were consistent with those of clinical trials. There were no new safety concerns. Regorafenib treatment would not be recommended for patients with higher PS. Implications for Practice Previous clinical trials demonstrated regorafenib improved overall survival in patients with metastatic colorectal cancer who progress after standard chemotherapies. Because the eligibility criteria of the trials were restricted compared with a real‐world setting, the data from the trials may not fully represent the profiles of regorafenib in clinical practice. This large‐scale observational study showed that the safety and effectiveness of regorafenib in clinical practice were generally consistent with previous trials. The majority of patients reported adverse drug reactions within the first 4 weeks, most commonly hand‐foot skin reaction. Regorafenib treatment would not be recommended for patients with higher performance status.

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Section: Discussionmentioning

confidence: 99%

Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting

et al. 2019

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“… 46 These drugs often cause notorious hand–foot skin reactions and other skin eruptions, such as maculopapular eruptions, stomatitis, and genital erosions. 47 – 49 Among these medications, higher frequency of cutaneous toxicity has been found in patients using sorafenib. 1 Hand–foot skin reactions are severe, painful edematous erythema lesions on the palms and soles, and even progression with blistering or hyperkeratotic plaques.…”

Section: Stevens-johnson Syndrome/toxic Epidermal Necrolysismentioning

confidence: 99%

Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies

Chen¹,

Wu²,

Ng³

et al. 2018

CMAR

115

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With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5–91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management.

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“…In contrast, TKI-induced hand-foot syndrome manifests with hyperkeratotic lesions on the palms and soles that are more severe at pressure points. Although this too is a dose-dependent reaction, the pathogenic mechanism has not been fully explained [27]. The hand-foot syndrome caused by multikinase inhibitors shows no significant association with other cutaneous eruptions.…”

Section: Differences Between Acral Erythema Caused By Targeted Therapmentioning

confidence: 98%

“…Hand-foot syndrome is the most common of the cutaneous adverse events caused by TKIs. Table 4 lists the drugs most often responsible for hand-foot syndrome [27][28][29][30].…”

Section: Epidemiologymentioning

confidence: 99%

“…This is a dose-dependent reaction that occurs in the first 2-4 weeks of therapy and increases in severity towards the second and third months of therapy. The clinical features usually tend to abate gradually as treatment continues [27,30]. The lesions are located at pressure points on the palms and soles, although they can affect other areas subjected to friction, such as the knuckles or the sides of the feet.…”

Section: Clinical Featuresmentioning

confidence: 99%

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Clinical management of cutaneous adverse events in patients on targeted anticancer therapies and immunotherapies: a national consensus statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology

et al. 2018

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Progress in the understanding of many tumors has enabled the development of new therapies, such as those targeted at specific molecules involved in cell growth (targeted therapies) or intended to modulate the immune system (immunotherapy). However, along with the clinical benefit provided by these new treatments, new adverse effects have also appeared. Dermatological toxicities such as papulopustular eruptions, xerosis, and pruritus are common with EGFR inhibitors. Other adverse effects have also been described with PDGFR, BCR-ABL, and MAPK tyrosine kinase inhibitors, antiangiogenic drugs, and inhibitors at immune checkpoints such as CTLA-4 and PD-1/PD-L1. Onset of these adverse effects often causes dose reductions and/or delays in administering the prescribed therapy, which can affect patient survival and quality of life. It is, therefore, important to prevent the occurrence of these adverse effects, or to treat unavoidable ones as soon as possible. This requires cooperation between medical oncologists and dermatologists. This article reviews the various dermatological toxicities associated with targeted therapies and immunotherapies, along with their diagnosis and therapeutic management.

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Multikinase Inhibitor-Induced Hand–Foot Skin Reaction: A Review of Clinical Presentation, Pathogenesis, and Management

Cited by 39 publications

References 98 publications

Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting

Large-Scale, Prospective Observational Study of Regorafenib in Japanese Patients with Metastatic Colorectal Cancer in a Real-World Clinical Setting

Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies

Clinical management of cutaneous adverse events in patients on targeted anticancer therapies and immunotherapies: a national consensus statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology

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