Hand Foot Skin Reaction is Associated with the Clinical Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Sorafenib

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1 Original Article Japanese Journal of Clinical Oncology Advance Access published August 15, 2013 Jpn J Clin Oncol doi: /jjco/hyt110 Hand Foot Skin Reaction is Associated with the Clinical Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Sorafenib Kazuhiko Nakano *, Kenji Komatsu, Taro Kubo, Shinsuke Natsui, Akinori Nukui, Shinsuke Kurokawa, Minoru Kobayashi and Tatsuo Morita Department of Urology, Jichi Medical University, Tochigi, Japan *For reprints and all correspondence: Kazuhiko Nakano, Department of Urology, Jichi Medical University, Yakushiji , Shimotsuke city, Tochigi , Japan. nknkzhk@jichi.ac.jp Received April 17, 2013; accepted July 15, 2013 Background: To elucidate whether Hand Foot skin reaction could become a biomarker of clinical outcome in patients with metastatic renal cell carcinoma treated with sorafenib, we retrospectively examined the association between the Hand Foot skin reaction and the clinical outcome in metastatic renal cell carcinoma patients treated with sorafenib. Methods: Thirty-six Japanese metastatic renal cell carcinoma patients treated with sorafenib were enrolled and divided into the groups with or without Hand Foot skin reaction. Patient characteristics, best tumor response, progression-free survival and adverse events were investigated and compared between these two groups. Results: A sorafenib-induced Hand Foot skin reaction in metastatic renal cell carcinoma patients was observed at a significantly higher rate in patients in the favorable-risk group in the Memorial Sloan-Kettering Cancer Center risk classification, and with Eastern Cooperative Oncology Group Performance Status of one or less, prior nephrectomy, higher hemoglobin, lower lactate dehydrogenase and lower C-reactive protein. The mean best tumor response was significantly better in the group with Hand Foot skin reaction (216.7%) than that in the group without it (17.9%; P, 0.001). The median progression-free survival was significantly longer in the group with Hand Foot skin reaction (4.6 months) than that in the group without it (1.5 months; P ¼ 0.002). In multivariate analysis, only Hand Foot skin reaction was shown to be a predictive factor of progression-free survival (hazard ratio 0.312, P ¼ 0.010). Conclusions: A sorafenib-induced Hand Foot skin reaction in metastatic renal cell carcinoma patients emerged at a significantly higher rate in patients in the favorable-risk group in the Memorial Sloan-Kettering Cancer Center risk classification and was significantly associated with best tumor response and progression-free survival, suggesting that Hand Foot skin reaction might be an independent predictive factor for clinical outcome in metastatic renal cell carcinoma patients treated with sorafenib. Key words: Hand Foot skin reaction renal cell carcinoma sorafenib tyrosine kinase inhibitor INTRODUCTION Severe adverse events of Grades 3 and 4 have been shown to be associated with survival in patients with metastatic renal cell carcinoma (mrcc) treated with sunitinib and sorafenib, categorized as multitargeted tyrosine kinase inhibitors (1). In particular, hypertension (HT), which is one of the common adverse events associated with sunitinib, was shown to be associated with the clinical outcome in patients with mrcc treated with this drug (2). This probably occurred because the inhibition of the vascular endothelial growth factor (VEGF) by sunitinib caused sensitivity of normal blood vessels, resulting in HT, and sensitivity of tumor blood vessels, producing # The Author Published by Oxford University Press. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Page 2 of 7 Sorafenib-induced HFSR in mrcc an antitumor effect. However, the detailed mechanisms are unclear. Hand foot skin reaction (HFSR) is one of the common adverse events in patients with mrcc treated with sorafenib (3). The HFSR often necessitates discontinuation or dose reduction of sorafenib, even if sorafenib has a marked effect on the cancer lesion, making it a dose-limiting factor of sorafenib. Although the detailed mechanisms underlying a sorafenib-induced HFSR are unknown, vascular endothelial growth factor receptor (VEGFR) was reported to be primarily responsible for this side effect (4 7). Among patients with other solid tumors (8) and advanced hepatocellular carcinoma (HCC) (9) treated with sorafenib, the time to progression was significantly prolonged in patients with HFSR compared with that in those without it. Without considering adverse events as predictive factors, some reported studies identified factors predictive of clinical outcomes in patients with mrcc treated with sorafenib (10,11). However, there have been no studies that investigated the association between HFSRs and clinical outcomes in patients with mrcc treated with sorafenib. The purpose of the present study was thus to elucidate whether the HFSR, usually understood as an adverse event, could become a biomarker of clinical outcome in patients with mrcc treated with sorafenib in the same way as HT in patients with mrcc treated with sunitinib. We retrospectively examined the clinical characteristics of patients developing HFSRs and the association between HFSRs and clinical outcomes in patients with mrcc treated with sorafenib. PATIENTS AND METHODS PATIENTS In this study, 36 Japanese patients who were diagnosed with mrcc by histological or radiological examination and treated with sorafenib at our institution between May 2008 and February 2012 were enrolled. The criteria for the initiation of treatment with sorafenib were a patient age of 18 years, the presence of at least one measurable lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI), Eastern Cooperative Oncology Group Performance Status (ECOG PS) of two or less, life expectancy of 12 weeks, the provision of written informed consent and fulfillment of certain criteria related to tests on the following variables: hemoglobin, white blood cell (WBC) count, platelets, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, lipase, creatinine, prothrombin time (PT) and activated partial thormboplastin time (APTT). However, brain metastasis, prior nephrectomy and Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification were not included in the criteria. DESIGN Patients received 400 mg of sorafenib orally, twice daily, on a continuous dosing schedule. Treatment was continued until disease progression, unacceptable toxicity or upon a patient s request for its cessation. Dose reduction was allowed for unacceptable toxicities at the discretion of attending physicians. If dose reduction was required, sorafenib was reduced to 400 mg and then to 200 mg once daily. If adverse events improved to Grade 1 or less, sorafenib could be increased back up to the dose before reduction. Recommendations were made to all subjects on how to prevent HFSR, such as the avoidance of friction and trauma and the wearing of thick cotton gloves and socks to protect the hands and feet, especially during the first 2 4 weeks of treatment. If HFSR developed during sorafenib treatment, agents that prevent symptom progression, including 20 40% urea cream and steroid ointments, were used aggressively (12). Patients were administered sorafenib as either first- or second-line treatment of mrcc. HFSR attributed to sorafenib treatment was determined according to the classification of the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3. Because HFSR is defined as Grades 1 3 by NCI-CTCAE, 36 mrcc patients administered sorafenib were divided into the following two groups: a group with HFSR, consisting of 23 patients in whom HFSR Grades 1 3 appeared, and a group without HFSR, consisting of 13 patients in whom HFSR was not observed, which meant Grade 0. To investigate the relationship between HFSR and antitumor efficacy, this retrospective analysis assessed best tumor response, progression-free survival (PFS), patient characteristics and adverse events between the groups with and without HFSR. The best tumor response was evaluated at least every 12 weeks by imaging techniques such as CT and MRI. Assessment was made using the Response Evaluation Criteria in Solid Tumors (RECIST). PFS was defined as the time from the initiation of sorafenib treatment to disease progression. Adverse events including skin toxicity, such as HFSR, were recorded according to NCI-CTCAE version 3. To confirm the association between HFSR and other adverse events, they were also divided into Grades 0 and 1 4 and compared for the groups with and without HFSR. At the initiation of treatment and at least once every 4 weeks, recording of medical history, physical examination, PS evaluation and hematological examination were performed. Patients were hospitalized until at least Day 28 and examined for the presence and the degree of development of HFSR by observing the skin of the whole body, focusing particularly on the hands and feet, every day. This study was approved by the institutional review board of Jichi Medical University, and a written informed consent to participate in this study was obtained from all patients. STATISTICAL ANALYSIS The Mann Whitney U test or x 2 test was used for comparing clinical and pathological data, best tumor response and adverse events between the groups with and without HFSR. PFS was obtained by the Kaplan Meier method and subjected to comparison using a log-rank test. Multivariate analysis was

3 Jpn J Clin Oncol 2013 Page 3 of 7 performed using the Cox proportional-hazard model for identification of the factors predictive of PFS. P values of,0.05 were judged as statistically significant. RESULTS PATIENTS The patient characteristics by group are shown in Table 1.The median observation period was 13 months (range: 2 48 months). The mean period for sorafenib administration was 5.6 months (range: months). The median relative dose intensity (RDI) of sorafenib treatment was higher in the group without HFSR (0.70; range: ) than in the group with it (0.62; range: ), although there was no statistically significant difference. However, there were statistically significant differences in the MSKCC risk classification, ECOG PS, prior nephrectomy, hemoglobin, LDH and C-reactive protein (CRP) between the groups with and without HFSR. A total of 29 (81%) patients required reduction in the dose of sorafenib. A total of 33 (92%) patients discontinued sorafenib treatment: of whom, 16 (44%), 15 (42%), 1 (3%) and 1 (3%) patients discontinued sorafenib treatment due to disease progression, unacceptable toxicity, death and the patient s own request, respectively. The remaining three patients are still undergoing sorafenib treatment. SAFETY A total of 35 (97%) patients experienced at least one adverse event. The most common severe adverse events (Grade 3) among all patients were HFSR (52%), HT (11%), AST (11%), ALT (11%) and rash/desquamation (8%). The HFSR was observed to varying degrees in 23 patients (64%), who were classified into the group with HFSR. The development of a sorafenib-induced HFSR was not associated with other adverse events, except HT, diarrhea and lipase (Table 2). In multivariate analysis, which included the parameters of the four most common non-hematological adverse events (HFSR, rash/desquamation, diarrhea and HT), only the HFSR was identified as a factor predictive of PFS [hazard ratio (HR) 0.342, 95% confidence interval (CI) , P ¼ 0.020, Table 3A]. Unacceptable toxicity caused the discontinuation of sorafenib treatment in 15 (42%) patients, in whom HFSR, rash/ desquamation, AST/ALT and gastrointestinal hemorrhage were shown in 6 (40%), 6 (40%), 2 (13%) and 1 (7%) patients, respectively. ASSOCIATION OF HFSR WITH THE CLINICAL OUTCOME Among the total of 36 patients, no patient had a complete response (CR), 5 patients (14%) had a partial response (PR), 21 patients (58%) had stable disease (SD), 6 patients (17%) had progressive disease (PD) and 4 patients (11%) could not be Table 1. Baseline patient characteristics according to the grade of HFSR in NCI-CTCAE version 3 HFSR P value Age (years) Gender Male 10 (77) 18 (78) Female 3 (23) 5 (22) BMI (kg/m 2 ) ECOG PS 0 4 (31) 15 (66) (38) 7 (30) 2 4 (31) 1 (4) Liver metastasis Yes 3 (23) 3 (13) No 10 (77) 20 (87) No. of disease sites 1 2 (15) 8 (35) (85) 15 (65) Histology Clear cell 5 (38) 17 (74) Other 1 (8) 3 (13) Unknown 7 (54) 3 (13) Prior nephrectomy Yes 6 (46) 20 (87) No 7 (54) 3 (13) Prior systemic treatment First line 3 (23) 7 (30) Second line 10 (77) 16 (70) MSKCC risk classification Favorable 0 (0) 7 (30) Intermediate 7 (54) 14 (61) Poor 6 (46) 1 (4) Hemoglobin (g/dl) LDH (U/l) CRP (mg/dl) Neutrophil (cells/ml) Platelet (10 4 ml) Corrected calcium (mg/dl) RDI HFSR, Hand Foot skin reaction; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; MSKCC, Memorial Sloan-Kettering Cancer Center; LDH, lactate dehydrogenase; CRP, C-reactive protein; RDI, relative dose intensity. All continuous data are shown as mean values.

4 Page 4 of 7 Sorafenib-induced HFSR in mrcc Table 2. Incidence of sorafenib-induced adverse events according to the grade of HFSR in NCI-CTCAE version 3 Table 2. Continued HFSR P value a HFSR P value a Any event Grade 0 1 (8) 0 (0) Grades (92) 23 (100) Rash/desquamation Grade 0 8 (62) 13 (57) Grades (38) 10 (43) Alopecia Grade 0 12 (92) 18 (78) Grades 1 and 2 1 (8) 5 (22) Allergic reaction Grade 0 12 (92) 20 (87) Grades (8) 3 (13) Hypertension Grade 0 11 (85) 11 (48) Grades (15) 12 (52) Stomatitis Grade 0 12 (92) 20 (87) Grades (8) 3 (13) diarrhea Grade 0 11 (85) 10 (43) Grades (15) 13 (57) Anorexia Grade 0 11 (85) 18 (78) Grades (15) 5 (22) Fatigue Grade 0 12 (92) 18 (78) Grades (8) 5 (22) Proteinuria Grade 0 13 (100) 21 (91) Grades (0) 2 (9) AST increase Grade 0 7 (54) 11 (48) Grades (46) 12 (52) ALT increase Grade 0 9 (69) 12 (52) Grades (31) 11 (48) ALP increase Grade 0 10 (77) 20 (87) Grades (23) 3 (13) Continued Lipase increase Grade 0 12 (92) 14 (61) Grades (8) 9 (39) Amylase increase Grade 0 12 (92) 18 (78) Grades (8) 5 (22) HT, hypertension; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase. a x 2 test. evaluated. The disease control rate reached 53%. Fifteen patients (47%) among the 32 who had evaluable lesions had some decrease in the size of measurable lesions. The median PFS was 4.6 months (95% CI months) on the basis of 28 events. The best tumor response by RECIST showed that the group with HFSR had a tendency to be judged significantly better than the group without it (P ¼ 0.004, Table 4). A waterfall plot of the best tumor response showed that 17 of 23 patients (74%) in the group with HFSR had some decrease in the size of measurable lesions, while the figure was 2 of 13 patients (15%) in the group without HFSR (Fig. 1). The mean reduction in tumor size for measurable lesions by RECIST was better in the group with HFSR (216.7%; 95% CI to 27.7%) than in the group without it (17.9%; 95% CI 20.9 to 36.7%) (P, 0.001). The median PFS was longer in the group with HFSR (4.6 months; 95% CI months) than in the group without it (1.5 months; 95% CI months) (P ¼ 0.002, Fig. 2). In multivariate analysis, which included the major parameters of the baseline patient characteristics associated with the incidence of HFSR (ECOG PS, MSKCC risk classification and LDH), only HFSR was identified as a factor predictive of PFS (HR 0.312, 95% CI , P ¼ 0.010, Table 3B). DISCUSSION The present study was carried out to clarify whether the adverse event of HFSR is a useful biomarker of clinical outcome in patients with mrcc treated with sorafenib. The following two findings were made. First, a sorafenib-induced HFSR in mrcc patients emerged at a significantly higher rate in patients in the favorable-risk group in the MSKCC risk classification. Second, the best tumor response and PFS were

5 Jpn J Clin Oncol 2013 Page 5 of 7 Table 3. Univariate and multivariate analyses of the most common non-hematological sorafenib-induced adverse events (A) and major patient characteristics (B) as a predictive factor for progression-free survival Parameter Category n mpfs Univariate Multivariate HR 95% CI P value a HR 95% CI P value b (A) HFSR Grade Grades Rash/desquamation Grade Grades Diarrhea Grade Grades HT Grade Grades (B) HFSR Grade Grades ECOG PS 0, MSKCC risk classification Favorable, intermediate Poor LDH,200 (U/l) (U/l) mpfs, median progression-free survival; HR, hazard ratio; CI, confidence interval. a Log-rank test. b Cox proportional-hazards model. Table 4. Best tumor response by RECIST according to the grade of HFSR in NCI-CTCAE version 3 HFSR* Complete response 0 (0) 0 (0) Partial response 0 (0) 5 (22) Stable disease 6 (46) 15 (65) Progressive disease 5 (38) 1 (4) Not evaluated 2 (15) 2 (9) RECIST, Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. *P ¼ 0.004; x 2 test for linear trend toward better evaluation of best tumor response with grade of HFSR. significantly better in patients with HFSR than in those without it, suggesting that HFSR might be an independent predictive factor in patients with mrcc treated with sorafenib. Figure 1. Waterfall plot of best tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) according to the grade of Hand Foot skin reaction (HFSR) in National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) version 3. A prediction index for HFSR treated with sorafenib was developed in a previous study (13), in which the final variables retained as significant predictors of sorafenib-induced HFSR were female gender, ECOG PS of one or less, no lung metastasis, liver metastasis, two or more organs involved,

6 Page 6 of 7 Sorafenib-induced HFSR in mrcc Figure 2. Kaplan Meier estimates of progression-free survival (PFS) according to the grade of HFSR in NCI-CTCAE version 3. baseline WBC count cells/l and duration from the initiation of sorafenib therapy. This suggested that HFSR tended to appear at significantly higher frequency in patients with better ECOG PS contained within the favorable-risk group in the MSKCC risk classification. Upon administering sorafenib, attention needs to be paid to the potential emergence of HFSR, especially in patients in the favorable-risk group in the MSKCC risk classification. Despite a report stating that HFSR often coincided with other adverse skinrelated events (6), this was not replicated in the present study. Multivariate analysis assessing the association between PFS and adverse events in the present study revealed that HFSR was the only independent predictive factor, while other common adverse events including HT and diarrhea were not. To eliminate the confounding influence among the factors of baseline patient characteristics associated with the incidence of HFSR, multivariate analysis using four factors (HFSR, ECOG PS, MSKCC risk classification and LDH) as the parameters was performed, which also showed HFSR as an independent predictive factor. As in other solid tumors (8,9), the HFSR was identified as a possible predictive factor in patients with mrcc treated with sorafenib. Acne-like rash, as an adverse event of the skin, was previously associated with a better clinical outcome in patients treated with epidermal growth factor receptor (EGFR) inhibitors, including erlotinib against non-small-cell lung cancer (14,15) and cetuximab against colon cancer (16,17). Furthermore, it was confirmed that the development of other adverse events like HT (2,18), interstitial pneumonia (19) and a particular range of adverse events (1) was associated with the clinical outcome upon treatment with other molecular-targeted drugs. Although a variety of factors predictive of the clinical outcome upon treatment with sorafenib have been presented (10,11,20,21), all of these studies only focused on the variable of tumor grade. However, the combination of tumor-related factors and host-related factors represented by adverse events can be expected to enable more accurate estimation of the clinical outcome of sorafenib. The detailed mechanisms behind the development of HFSR are imperfectly understood, although it often develops upon administration of sorafenib and sunitinib. The intracellular signaling spectrum shows that the use of these drugs inhibits VEGFR, platelet-derived growth factor receptor (PDGFR), c-kit and FLT-3 (22), which might play a role in HFSR development (4 7). Meanwhile, in the skin, especially in pressure lesions, there is repeated damage and repair of subcutaneous blood capillaries caused by subclinical trauma associated with skin compression, suggesting that blockade of the vascular-repair pathways by sorafenib might lead to HFSR (23). It is expected that patients with good ECOG PS, such as those in the favorable-risk group in the MSKCC risk classification, would exhibit more intense activities of daily living than those with poor ECOG PS, even during sorafenib therapy. As a result, blockade of the vascular-repair pathways by sorafenib might have a greater effect and cause a high incidence of HFSR in the favorable-risk group in the MSKCC risk classification. However, further investigation is necessary to elucidate the mechanisms behind HFSR. The present study had the following limitations: a limited number of cases, the retrospective nature of the study, the fact that measurement bias between raters is likely to have occurred, especially when assessing adverse events and the possibility that the judgment and evaluation of adverse events as a biomarker would change depending on the presence or the absence of prevention. These limitations have also been mentioned in reports describing the association between HT and sunitinib (2) and between acne-like rash and HER1/EGFR inhibitors (15). Forty-two percent of the patients in this study discontinued sorafenib treatment due to adverse events, in which skin adverse events accounted for 80%. This is a much higher incidence than in other reports (24,25). This might be because sorafenib treatment was discontinued even when lowgrade skin adverse events were noted, since we were not familiar with the management of skin adverse events at that time. Furthermore, a conflicting report has been published which described that the occurrence of diarrhea, but not HFSR, was associated with PFS in 46 patients with advanced hepatocellular carcinoma treated with sorafenib (26). The discrepancy between that report and ours might be ascribed to differences in the target populations, such as in terms of ethnicity. In fact, the profile of adverse events of sorafenib has been shown to differ between Caucasians (3) and Japanese (25). The frequencies of adverse events of any grade/grades 3 and 4 in Caucasians and Japanese were 43%/2% and 34%/1% for diarrhea and 30%/6% and 55%/9% for HFSR, respectively. In conclusion, the present study showed that a sorafenibinduced HFSR in mrcc patients emerged at a significantly higher rate in patients in the favorable-risk group in the MSKCC risk classification. Upon administering sorafenib, attention should be paid to the potential emergence of HFSR, especially in patients in the favorable-risk group in the MSKCC risk classification. In terms of best tumor response

7 Jpn J Clin Oncol 2013 Page 7 of 7 and PFS, significantly better results were seen in patients with HFSR than in those without it, suggesting that HFSR might be an independent predictive factor in patients with mrcc treated with sorafenib. However, further studies with a large number of patients are necessary to confirm this point. Conflict of interest statement None declared. References 1. Di Fiore F, Rigal O, Menager C, Michel P, Pfister C. Severe clinical toxicities are correlated with survival in patients with advanced renal cell carcinoma treated with sunitinib and sorafenib. Br J Cancer 2011;105: Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011;103: Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356: Lacouture ME, Reilly LM, Gerami P, Guitart J. Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol 2008;19: Chu D, Lacouture ME, Fillos T, Wu S. Risk of Hand Foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 2008;47: Lee WJ, Lee JL, Chang SE, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol 2009;161: Zhang L, Zhou Q, Ma L, Wu Z, Wang Y. Meta-analysis of dermatological toxicities associated with sorafenib. Clin Exp Dermatol 2011;36: Strumberg D, Awada A, Hirte H, et al. Pooled safety analysis of BAY (sorafenib) monotherapy in patients with advanced solid tumours: is rash associated with treatment outcome? Eur J Cancer 2006;42: 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: Choueiri TK, Garcia JA, Elson P, et al. Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. Cancer 2007;110: Tanigawa G, Kawashima A, Yamaguchi S, et al. Clinical outcome and prognostic factors of sorafenib in Japanese patients with advanced renal cell carcinoma in general clinical practice. Jpn J Clin Oncol 2011;41: Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of Hand Foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 2008;13: Dranitsaris G, Vincent MD, Yu J, Huang L, Fang F, Lacouture ME. Development and validation of a prediction index for Hand Foot skin reaction in cancer patients receiving sorafenib. Ann Oncol 2012;23: Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004;22: Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/ EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005;23: Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351: Park SR, Kook MC, Choi IJ, et al. Predictive factors for the efficacy of cetuximab plus chemotherapy as salvage therapy in metastatic gastric cancer patients. Cancer Chemother Pharmacol 2010;65: Scartozzi M, Galizia E, Chiorrini S, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 2009;20: Dabydeen DA, Jagannathan JP, Ramaiya N, et al. Pneumonitis associated with mtor inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer 2012;48: Zurita AJ, Jonasch E, Wang X, et al. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol 2012;23: Kusuda Y, Miyake H, Behnsawy HM, Fukuhara T, Inoue TA, Fujisawa M. Prognostic prediction in patients with metastatic renal cell carcinoma treated with sorafenib based on expression levels of potential molecular markers in radical nephrectomy specimens. Urol Oncol 2011;13: Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6: Jain L, Gardner ER, Figg WD, Chernick MS, Kong HH. Lack of association between excretion of sorafenib in sweat and Hand Foot skin. Pharmacotherapy 2010;30: Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27: Akaza H, Tsukamoto T, Murai M, Nakajima K, Naito S. Phase II study to investigate the efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma. Jpn J Clin Oncol 2007;37: Koschny R, Gotthardt D, Koehler C, Jaeger D, Stremmel W, Ganten TM. Diarrhea is a positive outcome predictor for sorafenib treatment of advanced hepatocellular carcinoma. Oncology 2013;84:6 13.