Early detection, prevention and management of cutaneous adverse events due to sorafenib: Recommendations from the Sorafenib Working Group

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1 Critical Reviews in Oncology/Hematology 82 (2012) Early detection, prevention and management of cutaneous adverse events due to sorafenib: Recommendations from the Sorafenib Working Group Sergio Bracarda a,, Enzo Maria Ruggeri b, Marcello Monti c, Marco Merlano d, Alessandro D Angelo e, Francesco Ferraù e, Enrico Cortesi f, Armando Santoro g a Ospedale San Donato USL8, Medical Oncology, Department of Oncology, Arezzo, Italy b Ospedale Belcolle, Viterbo, Italy c Università degli Studi di Milano e Istituto Clinico Humanitas, Milano, Italy d ASO Santa Croce e Carle, Cuneo, Italy e Ospedale Civico San Vincenzo, Taormina (ME), Italy f Policlinico Umberto I, Roma, Italy g Istituto Clinico Humanitas, Milano, Italy Accepted 17 August 2011 Contents 1. Introduction Overview of Sorafenib Sorafenib-related cutaneous events Hand-foot skin reaction Erythema Itching Follicular rash Xerosis or skin dryness Keratocanthoma (KA) and squamous cell carcinoma (SCC) Recommendations for the prevention and management of sorafenib-related cutaneous reactions Hand-foot skin reaction Erythema Itching Follicular rash Xerosis or skin dryness KA and SCC Conclusions Authors contributions Conflict of interest statement Reviewers Acknowledgments Appendix Appendix References Biographies Corresponding author. Tel.: ; fax: address: sergio.bracarda@usl8.toscana.it (S. Bracarda) /$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 S. Bracarda et al. / Critical Reviews in Oncology/Hematology 82 (2012) Abstract Cutaneous adverse events commonly reported with tyrosine kinase inhibitors (TKIs) in the treatment of malignancies, represent an important clinical concern since they can limit the optimal use of these novel drugs. Although there are numerous reports in the literature of these events there are no practical guidelines on how they should be managed. The Sorafenib Working Group (SWG) was established with the objective of developing recommendations to allow the early detection, prevention and management of cutaneous adverse events in everyday clinical practice. The SWG was a multidisciplinary team made up of experts in the field who were closely involved in the sorafenib clinical development program. This review provides an overview of the nature and incidence of cutaneous adverse events which manifest with sorafenib treatment and provides recommendations for their early detection and effective management in clinical practice Elsevier Ireland Ltd. All rights reserved. Keywords: Sorafenib; Cutaneous adverse events; Hand-foot skin reaction; Prevention; Guidelines; Targeted therapy 1. Introduction Advances in the understanding of cell molecular biology, leading to the discovery and elucidation of signal transduction processes and specific cell receptors, prompted investigators to develop novel anticancer agents directed against cell-specific pathways at a molecular level, including gene expression, growth regulation, cell cycle control, apoptosis, and angiogenesis. In the clinical settings targeted agents have shown considerable efficacy levels in a range of tumor types, particularly in terms of progression-free survival (PFS) and overall survival (OS), as well as acceptable, albeit diverse, toxicity profiles [1,2]. Even so, the introduction into the clinical practice of these targeted agents has raised a number of issues not just regarding the correct assessment of their efficacy, but also how best to manage their diverse toxicity profiles mainly characterized by low-grade and potentially long-term events [3,4]. In terms of severity, frequency and type, toxicities caused by targeted agents differ substantially from those of conventional cytotoxic chemotherapeutic regimens [5]. Adverse events with these new targeted agents are not life-threatening events which require major supportive care and/or treatment discontinuation, but rather a series of less frequent inconveniences and disturbances which nevertheless can have a major negative effect on quality of life by limiting activities of daily living (ADL) [6]. Assessment of the impact of the disease and its treatment on health-related quality of life may not only influence the choice of treatment but also can sometimes prevent the administration of recommended optimal doses. In addition, it is important to be aware of the long-term effects of these new agents both on the type and incidence of adverse events as well as the effects of these events on patient compliance to treatment. Initially this caused uncertainty among physicians who were unaccustomed to managing these unusual adverse events and often meant that the therapeutic approach was suboptimal [5]. Of note, a recent paper by Bellmunt et al. has extensively discussed the management of adverse events associated with sorafenib treatment in patients with renal cell carcinoma (RCC) [7]. The aim of this paper is to provide practicing physicians with the specific information necessary to diagnose, prevent and manage the dermatological events related to the treatment with sorafenib, with particular reference to the hand-foot skin reaction (HFSR). Although there are numerous reports in the literature of these events and some practical guidelines have been published, a general consensus upon this topic has not been reached. This may be attributed, at least in part, to the lack of prospective trials investigating the management of these dermatological events. To address this, the Sorafenib Working Group (SWG) was established. This group is made up of eight Italian investigators: seven oncologists with experience in managing and treating cancer patients and one dermatologist with particular experience in the management of targeted therapy-related adverse events. The SWG aims to collect the experience of each clinician, in order to develop detailed practical guidelines for the prevention and the management of dermatological adverse events associated with sorafenib. Importantly, all eight specialists had previously participated in pivotal trials as part of the sorafenib clinical development program and had built up long-term experience on its use in everyday clinical practice. Based on this experience, management of cutaneous events was carried out using preparations with proven efficacy but employing the commonly used agents that can potentially lead to adverse skin events, with care [8]. 2. Overview of Sorafenib Sorafenib (Nexavar, Bayer HealthCare AG) is an oral multikinase inhibitor with antiangiogenic and proapoptotic activity. Preclinical in vitro and in vivo tumor models demonstrate that sorafenib is a potent inhibitor of the C-RAF and B-RAF kinases, as well as the RTKs VEGF receptor- 2 (VEGFR-2) and platelet-derived growth factor receptor- [9]. Inhibition of these kinases gives the drug a dual mechanism of action its anti-proliferative activity directly on tumor cell targets and indirectly through the inhibition of angiogenesis [10]. Sorafenib was approved by the FDA in 2005 for the treatment of advanced renal cell carcinoma (RCC) and subsequently results of a phase III randomized, placebo-controlled trial (SHARP trial) showing that sorafenib improved

3 380 S. Bracarda et al. / Critical Reviews in Oncology/Hematology 82 (2012) Fig. 1. Incidence of adverse events due to sorafenib over the time. Adapted with permission from Hutson et al. [12]. survival and time to radiologic progression in patients with hepatocellular carcinoma (HCC), led to its approval in the treatment of advanced HCC [1,9,11]. Clinical trial data on the use of sorafenib monotherapy in the clinical practice show that the drug is generally well tolerated with a manageable adverse event profile. However, as with other tyrosine kinase inhibitors (TKIs), sorafenib causes a range of side effects including: dermatological, constitutional (fatigue, weight loss), gastrointestinal (diarrhea, nausea, vomiting, constipation), cardiovascular (mainly hypertension), pain and pulmonary events [1,11]. In most cases adverse events are grade 1 2 severity and decrease over time [12] (Fig. 1). Interestingly, observations from clinical trials and clinical practice suggest that adverse events present early in the course of treatment and there is a lack of unexpected adverse events and cumulative toxicity with the long-term use of sorafenib [13]. However the precise mechanism for this effect remains to be elucidated. 3. Sorafenib-related cutaneous events Due to their higher frequency and negative impact on quality of life, dermatological events probably represent the main problem in the care of sorafenib-treated patients. Eruptions affecting the hands and feet, commonly referred to as the hand-foot skin reaction (HFSR), are frequently described with sorafenib. Successful management of the HFSR requires good prior knowledge of the phenomenon as well as a skilled therapeutic approach [13]. The incidence of cutaneous adverse events in phases I, II and III sorafenib clinical trials in RCC and HCC ranges from 8 to 66% (Table 1) [1,11,14 17]. Other targeted therapies have similar cutaneous side effects with differences in percentages and severity [18]. Dermatological reactions of varying types are ranked among the most common adverse events with the three VEGFR TKIs currently approved sunitinib, sorafenib, and pazopanib, including HFSR with sunitinib and sorafenib and a high frequency of rash/desquamation with sorafenib. The exact pathogenic mechanism of these dermatological events is still unclear, but a number of hypotheses have been proposed [1,19 22]. One initial theory suggested that tyrosin kinase inhibition may affect keratinocyte proliferation and differentiation. Keratinocytes are high proliferation cells in the epidermis that constitute an essential barrier against outside/environmental injuries and prevent water loss from the body. Histological specimens from patients with HFSR highlight keratinocyte damage, the presence of intracytoplasmic eosinophilic bodies and vacuolar degeneration eventually leading to necrosis [22,23]. TKIs such as sorafenib may therefore indirectly interfere with normal skin function. Another theory is based on the observation that the majority of cutaneous adverse events occur in areas of microtrauma such as the scalp, mouth, nails, hands and feet. By blocking vascular development through VEGF and PDGFR-, the microvessels in these areas may be altered in some way that the renewal process cannot function properly [19]. The impairment of homeostatic mechanism regulating skin inflammatory responses has also been investigated by Pastore et al. [24]. Epidermal growth factor receptor (EGFR)- dependent ERK1/2 activity in keratinocytes takes part in a homeostatic mechanism that regulates epidermal involvement in the inflammatory response and confirms the role of kinase inhibition as a potential target for manipulating inflammation in the skin. Because EGFR inhibition represents an effective antitumour treatment strategy the activity due to EGFR inhibition may also rely on a stronger recruitment of inflammatory cells and hence a more pronounced antitumour immune response. We present here a summary of existing evidence regarding the most common events for which a dermatological treatment is required. We did not include other skin side effects (for example alopecia) where dermatological treatment is not required/or is not appropriate Hand-foot skin reaction Hand-foot skin reaction (HFSR), the most frequent event occurring in up to 62% of patients, is that which requires the

4 S. Bracarda et al. / Critical Reviews in Oncology/Hematology 82 (2012) Table 1 Incidence of different cutaneous events induced by sorafenib. Type of event Description All grades (%) Grade 3 (%) Grade 4 (%) Hand-foot skin reaction (HFSR) Erythema or blisters on friction/pressure sites a Erythema Diffuse skin redness with or without itching Itching Itching particularly of the scalp Follicular rash Face and trunk papular-pustular folliculitis Xerosis Pathological skin dryness with or without itching Stomatitis Mouth inflammation From references [1,8,10,13,14,15,16]. Not applicable to HFSR. Table 2 Severity of hand-foot skin reaction (according to common terminology criteria for adverse events, CTCAE v3.0). Grade Description 1 Small skin alterations or dermatitis (e.g. erythema) without pain 2 Skin alterations (exfoliation, small blisters, bleeding, edema) or pain not interfering with normal functions 3 Ulcerative dermatitis or skin alterations with pain interfering with normal functions most care and attention by physicians. Although it is not lifethreatening HFSR, which occurs mainly in the early period of sorafenib treatment, considerably affects the quality of life of patients and reduces their ability to carry out everyday activities. Where possible steps should be taken to prevent it occurring and when it manifests it should be carefully managed to reduce pain, risk of infection, and patient discomfort (subjective or objective), while at the same time avoiding the need to discontinue/reduce the prescribed dosage. In patients treated with sorafenib, the overall incidence of HFSR (grades 1 3) ranges from 18 to 62%. Severe reactions occur less frequently with 4 13% classified as grade 3 (Table 2). These incidences are in line with those observed with other TKIs. HFSR usually occurs two weeks after treatment is started. The first signs are redness and edema, in some cases associated with a burning sensation in the palms of the hands, mainly in the folds between the phalanx joints. Some patients with untreated more severe reactions, develop blisters which can burst and discharge serous fluid. The blisters in HFSR appear characteristically in areas of pressure where reactive hyperkeratosis is present and as such differ from classic hand-foot syndrome (HFS). Classic HFS, also termed acral erythema or palmar-plantar erythrodysesthesia, occurs with various chemotherapeutic agents including cytarabine, capecitabine, doxorubicin hydrochloride, and fluorouracil, while sorafenib-induced HFSR, more frequently than classic HFS, is associated with palmar and/or plantar hyperkeratosis [25]. At the site of the blister, a rose-colored area surrounded by a dry horny layer remains. In rare cases this is accompanied by an intense burning sensation, the entire palm of the hand becomes red and the horny layer becomes detached (corneolysis). In patients with re-existing foot problems (flat feet, hallux valgus, tendinous retractions, osteoporosis, obesity), at areas of high pressure an excess of horny layer (hyperkeratosis) is produced which gives rise to a horny patch or callosity. The presence of the horny layer on the sole of the foot indicates the area where the subject concentrates his bodyweight. In patients with existing callosities, erythemas and blisters can develop following treatment with sorafenib. When the patient walks and puts pressure on this area binding between the horny layer and the epidermis becomes defective and blisters develop. If treatment is delayed superficial erosion can develop. Sub-corneous blisters occur as a result of desmosome impairment binding between keratocytes in the upper layers. Keratocytes of the superficial layers of the epidermis undergo an involutional process losing the bindings with the horny layer which then detaches. The fact that blisters occur only at sites under pressure suggests that such forces are responsible for the mechanical detachment of the horny layer [26]. Histology of the bulla frequently shows upper epidermis keratinocytes fluctuating in the serous medium without evidence of junctions and the horny layer detached from the epidermis (Fig. 2) Erythema Erythema is usually mild (grades 1 and 2) and accounts for 15% of cutaneous reactions (Table 2). It tends to occur from the second or third week of treatment as an erythematous exanthema without specific characteristics, very often confined to the face, trunk and at times is associated with mild itching. Fig. 2. Achantholytic keratinocytes and cleavage of horny layer. Photograph provided and reproduced with the kind permission of Professor Monti.

5 382 S. Bracarda et al. / Critical Reviews in Oncology/Hematology 82 (2012) Itching Two types of itching are observed: one dependent, one independent on skin dryness with an overall incidence of 8 19% for all grades and <1% for grades 3 and 4. Itching independent of skin dryness appears early in the course of treatment and occurs mainly on the scalp. It is thought to be due to excretion of drug metabolites through the sudoriparous glands which are highly diffuse in the scalp [23] Follicular rash The incidence of follicular rash ranges from 11 to 66% for all grades and from 0.7 to 2% for grades 3 and 4. The follicular rash seen with sorafenib treatment is similar to that seen with anti-egf receptor inhibitors and is caused by an acute inflammation of the pilosebaceous follicle. Follicular rash can be predominantly papular-erythematous or predominantly papular-pustular with the face, scalp and upper trunk the sites most involved. Follicular rash is very debilitating as it causes itching, burning and because it is difficult to hide prevents the patient from carrying out every day activities Xerosis or skin dryness The incidence of xerosis grades 1 and 2 ranges from 8 to 23% no grade 3 or 4 have been reported. It is in the main due to reduced water retention in the horny layer which causes desquamation sometimes resembling dandruff. Often skin dryness causes an unpleasant itching sensation Keratocanthoma (KA) and squamous cell carcinoma (SCC) The development of KA and SCC in patients treated with sorafenib has been reported by Arnault et al.: 13 patients developed rapidly growing cutaneous squamous cell proliferation, possibly due to an impairment of skin immunosurvelliance associated with sorafenib treatment, even without a clear cause effect relationship [27]. 4. Recommendations for the prevention and management of sorafenib-related cutaneous reactions Management of cutaneous events with sorafenib should be based on the expertise and practical knowledge of the entire mutlidiscipinary team including oncologists, dermatologists and nurses who are in a position to identify adverse events in a timely manner and to treat with systemic therapy as necessary Hand-foot skin reaction Effective prevention of HFSR begins with a complete evaluation of the patient. Details of the patient s occupation should be noted, for example, if the patient does manual Table 3 Prevention measures. Hand prevention 1. Carefully inform the patient about the hand-foot skin reaction 2. Avoid, whenever possible, carrying heavy loads 3. Keep skin moisturized, wash hands with non-foaming cleansing creams and avoid normal soap 4. After each wash, apply an emollient cream to soften the horny layer Feet prevention 1. Clearly inform the patient about the hand-foot skin reaction 2. Evaluate the crucial plantar pressure points usually corresponding to callosities 3. In the evening apply glycolicsalicylic peeling cream on the plantar hyperkeratotic areas to keep skin soft 4. Recommend the use of comfortable shoes which do not exert pressure on foot and if possible with a latex insole to reduce plantar pressure 5. Wash the foot with non foaming cleansing creams instead of normal soap to keep skin soft 6. After washing, apply zinc oxide and magnesium silicate lenitive cream without vaseline to absorb sweat and reduce the friction 7. Wear perspiring socks without seams if possible labor it is more likely that sub-horny blisters will develop. Likewise, the feet should be carefully examined for the presence of pre-existing horny callosities and/or abnormal plantar pressure areas (Table 3). If, in spite of preventive measures, HFSR grade 1 occurs the following are recommended: Hands at the first onset of redness/sensation of burning where possible manual labor should be stopped and a zinc oxide and magnesium silicate lenitive cream without vaseline should be applied. Feet at the first onset of redness/sensation of burning preventive measures 4, 5, 6, 7 outlined in Table 3 should be initiated. If grades 2 and 3 lesions occur despite preventative measures the following are recommended (Appendix 1): Fluid inside the blister should be aspirated (using a needle from a 10/20 ml disposable syringe) to prevent growth of bacteria/infection. Insert the needle into the blister and aspirate or, after making a small opening with the needle, squeeze the blister with gauze to remove fluid. The area should be disinfected with a 0.2% solution of benzalkonium chloride (Appendix 2). After the blister is burst, medicate with a PEG-based cicatrizing ointment it is not necessary to bandage. If the horny layer covering the blister is dry and becomes detached it can be removed by cutting the edges. The skin below regenerates the horny layer and heals within 1 2 weeks. Avoid antibiotics Erythema If no other signs of cutaneous or systemic toxicity are observed, specific safety measures are not necessary other

6 S. Bracarda et al. / Critical Reviews in Oncology/Hematology 82 (2012) than symptomatic medication. In general erythema does not itch and should be treated with zinc oxide and magnesium silicate lenitive cream without vaseline (Appendix 1). The use of corticosteroids should be restricted to severe cases as they can mask the progression of erythema and/or other adverse events. In addition, it should be remembered that the erythema may be caused by concomitant medications (e.g. paracetamol) Itching Treatment of itching is symptomatic. Normally it cannot be treated topically and systemic therapy is necessary. Although no scientific rationale exists oral anti-histamines are considered to be the drugs of first choice with the potential use of steroids in selected cases Follicular rash As follicular rash following sorafenib is very similar to that seen with anti-egf receptor inhibitors, treatment is the same in both cases a cold compress of potassium permanganate % solution as an astringent anti-inflammatory followed by application of 2% sulfo-salicylic cream without vaseline. This reduces the erythema/pruritus complex as well as reducing pigmentation. Currently the use of antibiotics is not recommended (Appendix 2) Xerosis or skin dryness Xerosis or skin dryness should be managed as follows: If possible take showers instead of baths and avoid rubbing the skin vigorously. Use non-foaming cleansing cream instead of soap or shower-gel. Apply polydecene-based highly emollient ointment after showering to restore water content in the horny layer (Appendix 2) KA and SCC Patients treated with sorafenib should be examined regularly because they carry an increased risk of KA and SCC proliferation. Lesions should be surgically removed without interrupting the treatment, and there is no evidence of relapse after the removal; in patients with multiple, unresecatble lesions, an interruption of sorafenib may be considered, as it may likely lead to a spontaneous resolution of the symptoms [27 29]. psychological distress to patients but can also have a negative effect on outcome as dose reductions or treatment discontinuations may be necessary. Although data from sorafenib pivotal comparative trials and from expanded access trials show no differences in the incidence and severity of cutaneous adverse events between younger and older patients, the SWG believes that particular attention should be paid to elderly patients treated with sorafenib [30 32]. In this patient group cutaneous adverse events may be complicated by the presence of comorbidities. In addition, these patients are often imunocompromised and may need to take a range of concomitant medications. Sorafenib represents an important advance in the treatment of RCC and HCC two neoplastic diseases until a few years ago considered unresponsive to conventional chemotherapy and in the near future other tumor types could benefit from this drug. The major challenge for physicians is to develop ways to detect, prevent and effectively manage the cutaneous treatment-related adverse events in order to: allow the recommended dose of sorafenib to be administered; avoid the need for dose reductions; preclude temporary/permanent treatment discontinuation. The recommendations set out in this report in terms of early diagnosis, prevention and patient care present a practical and easy-to-implement method for physicians to care for their patients receiving sorafenib. Our goal is to prevent (where possible), or to effectively treat sorafenib-related cutaneous events without the need for additional drugs thereby reducing patient discomfort and increasing compliance. It is now generally accepted that cutaneous events represent a necessary evil in cancer treatment and they have been compared with neutropenia caused by conventional chemotherapeutic regimens, which if not controlled can also lead to dose reduction/discontinuation [33]. As it seems that cutaneous events cannot be completely prevented, our recommendation is that they should be managed in the best possible way starting from a complete review of any predisposing factors of the patient, through to early detection of symptoms and the timely introduction of treatment according to the grade and duration of skin reactions. Interestingly, retrospective studies in patients treated with sorafenib [34] and erlotinib [35] suggest that there may be a correlation between the onset of skin rash and an improved clinical outcome. Prospective trials are needed to determine if cutaneous reactions can be indeed considered as a clinical surrogate marker for antitumor activity. 5. Conclusions Management of sorafenib-related cutaneous reactions, including HFSR represents a major challenge for physicians. These complications not only cause physical and Authors contributions Sergio Bracarda, Enzo Maria Ruggeri, Marcello Monti contributed in conception and design of the study. Sergio Bracarda, Enzo Maria Ruggeri, Marcello Monti, Marco

7 384 S. Bracarda et al. / Critical Reviews in Oncology/Hematology 82 (2012) Merlano, Alessandro D Angelo, Francesco Ferraù, Enrico Cortesi, Armando Santoro provided study materials. Sergio Bracarda, Enzo Maria Ruggeri, Marcello Monti, Marco Merlano, Alessandro D Angelo, Francesco Ferraù, Enrico Cortesi, Armando Santoro have collected and assembled the data. Data analysis and interpretation done by Sergio Bracarda, Enzo Maria Ruggeri, Marcello Monti, Marco Merlano, Alessandro D Angelo, Francesco Ferraù, Enrico Cortesi, Armando Santoro. Sergio Bracarda, Enzo Maria Ruggeri, Marcello Monti, Marco Merlano, Alessandro D Angelo, Francesco Ferraù, Enrico Cortesi, Armando Santoro prepared the manuscript. Final approval of manuscript given by Sergio Bracarda, Enzo Maria Ruggeri, Marcello Monti, Marco Merlano, Alessandro D Angelo, Francesco Ferraù, Enrico Cortesi, Armando Santoro. Conflict of interest statement Employment/leadership position: None. Intellectual property rights/inventor or patent holder: None. Consultant/advisory role: Sergio Bracarda, Bayer Healthcare, Pfizer, Novartis, GSK. Enzo Maria Ruggeri, Bayer Healthcare, GSK, Pfizer. Honoraria received directly from commercial interest or their agents: Sergio Bracarda, Novartis. Research funding/contracted research: None. Ownership interest: None. Expert testimony: None. Reviewers Dr. Giuseppe Procopio, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Dr. Jann Luebbe, Clinique de Genolier, Dermatology Department, Route du Muids, CH-1272 Genolier, Switzerland. Prof. Francesco Di Costanzo, Azienda Ospedaliero Universitaria Careggi, Department of Oncology, Via Pieraccini 17, Florence, Italy. Acknowledgments Editorial assistance was provided by Luca Giacomelli, PhD, of Content Ed Net; this assistance was funded by Bayer Italy. Appendix 1. Recommendations for the management of treatment with sorafenib. Skin toxicity criteria for drug-dose reductions and treatment discontinuation (any adverse event). Toxicity a Drug administration management For the current cycle For the next cycle Grade 1 Appearance No modifications No modifications Grade 2 1st appearance Discontinuation until improvement to grade 1 No modifications 2nd appearance Discontinuation until improvement to grade 1 Consider drug dose reduction 3rd appearance Discontinuation until improvement to grade 1 Consider drug dose reduction 4th appearance Treatment withdrawal Grade 3 1st appearance Discontinuation until improvement to grade 1 Consider drug dose reduction b 2nd appearance Discontinuation until improvement to grade 1 Consider drug dose reduction 3rd appearance Treatment withdrawal a Toxicity evaluations according to CTCAE v3.0 ( CTCAE = common terminology criteria for adverse events. b For patients needing drug-dose reduction following grade 3 rash or hand-foot skin reaction, drug dose can be increased again to the starting dose provided that after a complete cycle at reduced dose no grade 1 event has been observed. Suggested drug-dose modifications of sorafenib in case of hand-foot skin reaction. Toxicity a Drug-dose modification Grade 1 Any Start immediately with prevention/supporting measures and continue treatment Grade 2 1st appearance Immediately start with prevention/supporting measures and consider drug dose reduction to 400 mg/day for 28 days If after drug dose reduction toxicity decreases to grade 1, return to full dose If after drug dose reduction toxicity does not revert to grade 1, discontinue treatment for a minimum of 7 days until toxicity decreases to grade 0 1 If after discontinuation toxicity reverts to grade 1, start treatment again at the reduced dose of 400 mg/day for 28 days. If at the reduced dose grade 0 1 toxicity continues, return to full dose after 28 days 2nd/3rd appearance As for the 1st appearance, but start treatment again permanently at the reduced dose of 400 mg/day 4th appearance The decision about treatment withdrawal should be based on clinical evaluation and the patient s wishes

8 S. Bracarda et al. / Critical Reviews in Oncology/Hematology 82 (2012) (Continued ) Toxicity a Drug-dose modification Grade 3 1st appearance Start immediately with prevention/supporting measures and discontinue treatment for at least 7 days If after drug dose reduction toxicity decreases to grade 1, start treatment again at the reduced dose of 400 mg/day for 28 days If at the reduced dose grade 1 toxicity continues, return to full dose after 28 days 2nd appearance As for the 1st appearance, but start treatment again permanently at the reduced dose of 400 mg/day 3rd appearance The decision regarding treatment withdrawal should be based on clinical evaluation and the patient s wishes a Toxicity evaluations according to CTCAE v3.0 ( CTCAE = common terminology criteria for adverse events. Appendix 2. Suggested products for the treatment of skin reactions. 1. Non foaming cleansing cream containing taurate and sarcosinate detergents 2. Polydecene based highly emollient ointment 3. Glycolic salicylic peeling cream 4. Zinc oxide and magnesium silicate lenitive cream without vaseline 5. Benzalkonium chloride 0.2% aqueous solution 6. Cicatrizing PEG and allantoin ointment 7. Potassium permanganate (tablet 250 mg) a 8. Sulfosalicylic cream without vaseline For external use compress only. a To prepare the potassium permanganate solution, dissolve a 250 mg tablet in 2 L of boiling water, cool and keep it in a dark glass bottle. References [1] Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356: [2] Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356: [3] Di Lorenzo G, Porta C, Bellmunt J, et al. Toxicities of targeted therapy and their management in kidney cancer. Eur Urol January 14 [Epub ahead of print]. [4] Kirkali Z. Adverse events from targeted therapies in advanced renal cell carcinoma: the impact on long-term use. 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9 386 S. Bracarda et al. / Critical Reviews in Oncology/Hematology 82 (2012) [26] Cirillo N, Prime SS. Desmosomal interactome in keratinocytes: a systems biology approach leading to an understanding of the pathogenesis of skin disease. Cell Mol Life Sci 2009;66: [27] Arnault JP, Wechsler J, Escudier B, et al. Keratoacanthomas and squamous cell carcinomas in patients receiving sorafenib. J Clin Oncol 2009;27(August (23)):e [28] Kong HH, Cowen EW, Azad NS, et al. Keratoacanthomas associated with sorafenib therapy. J Am Acad Dermatol 2007;56(January (1)): [29] Jantzem H, Dupre-Goetghebeur D, Spindler P, Merrer J. Sorafenibinduced multiple eruptive keratoacanthomas. Ann Dermatol Venereol 2009;136(December (12)): [30] Eisen T, Oudard S, Szczylik C, et al. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst 2008;100(October (20)): [31] Bukowski RM, Stadler WM, McDermott DF, et al. Safety and efficacy of sorafenib in elderly patients treated in the North American advanced renal cell carcinoma sorafenib expanded access program. Oncology 2010;78(5-6): [32] Beck J, Procopio G, Bajetta E, et al. Final results of the European advanced renal cell carcinoma sorafenib (EU-ARCCS) expandedaccess study: a large open-label study in diverse community settings. Ann Oncol February 15 [Epub ahead of print]. [33] Di Maio M, Gridelli C, Gallo C, et al. Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of three randomised trials. Lancet Oncol 2005;6(September (9)): [34] Vincenzi B, Santini D, Russo A, et al. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist 2010;15: [35] Cobo M, Cardenal F, Insa A, et al. Skin as a surrogate marker of efficacy in patients with non-small cell lung cancer treated with erlotinib. J Clin Oncol 2007:7602 (ASCO Annual Meeting Proceedings Part I, vol. 25, No. 18s). Biographies Sergio Bracarda is currently the director of the medical oncology Unit, Department of Oncology, Ospedale San Donato, Azienda USL8, Arezzo. Previously he was a senior oncologist at the Medical Oncology Division, Santa Maria della Misericordia Hospital, Perugia, Italy, from where he was appointed section chief of Oncology-Urology Tumors, and contract professor for the Schools of Specialization in Oncology and Urology at the University of Perugia. His main research interest is genito-urinary oncology, and in particular prostate cancer and advanced renal cell carcinoma, CNS tumors, targeted anticancer therapies and treatment approaches that combine biological agents with traditional chemotherapy or immunotherapy. Dr. Bracarda specialized in medical oncology at the Sacred Heart Catholic University of Rome, Italy, and in urology at the University of Perugia and has published 52 publications in peer-reviewed medical journals, more than 600 abstracts, and a number of text book chapters. Enzo Maria Ruggeri is director of the Medical Oncology Division, Ospedale Belcolle, Viterbo, Italy. He specialized in medical oncology at the La Sapienza University, Rome. His main current research interests are genitor-urinary and head-neck oncology. Marcello Monti is the director of the Dermatology Division in the Istituto Clinico Humanitas (ICH) in Rozzano (Milan), Italy and lecturer in Dermatology at the Specialisation Schools of Geriatrics, Plastic Surgery and Dermatology. He specialized in dermatology and venereology and subsequently in infective and parasitic diseases at Milan University. Marco Merlano is head of the Translational Laboratory, Medical Oncology Units and Department of Clinical Oncology at Santa Croce General Hospital, Cuneo and contract professor at the post-graduate School of Medical Oncology in Turin, Italy. His current main research interests are head neck and genitor-urinary oncology. Alessandro D Angelo is junior oncologist of the Medical Oncology Division, Ospedale Civico San Vincenzo, Taormina (ME), Italy. His current research interest is genitorurinary oncology. Francesco Ferraù is director of the Medical Oncology Division, Ospedale Civico San Vincenzo, Taormina (ME), Italy. His main research interests are breast and genitorurinary oncology. Enrico Cortesi is director of the Oncology Unit, Policlinico Umberto I and Professor of Medical Oncology at La Sapienza University, Rome, Italy. His main research interests are supportive care and genito-urinary oncology. Armando Santoro is director of the Medical Oncology Division, Humanitas Cancer Center Istituto Clinico Humanitas (ICH), Rozzano (Milan), Italy. He specialized in Clinical and Laboratory Hematology at the University of Rome and in Oncology at the University of Genoa, Italy. Genitor-urinary oncology is among his current research interests.