Occurrence Of Hand-foot Syndrome Research Articles

P38 MAPK, NF-κB, and JAK-STAT3 Signaling Pathways Involved in Capecitabine-Induced Hand-Foot Syndrome via Interleukin 6 or Interleukin 8 Abnormal Expression.

Hand-foot syndrome (HFS) is a major adverse reaction to capecitabine (CAP). The exact pathogenesis of this disease remains unclear. In this study, metabolomics combined with cell RNA sequencing was used to study the mechanisms of CAP-induced HFS. The murine model of HFS was constructed by intragastric administration of CAP or its metabolites. Quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays were used to verify the mechanisms. Metabolomics showed the phosphatidylinositol signaling pathway and amino acid and fatty acid metabolism to be the major metabolic alterations related to the occurrence of HFS. Transcriptomics profiles further revealed that the cytokine-cytokine receptor interaction, IL17 signaling pathway, Toll-like receptor signaling pathway, arachidonic acid metabolism, MAPK signaling pathway, and JAK-STAT3 signaling pathway were the vital steps in skin toxicity induced by CAP or its metabolites. We also verified that the inflammation mechanisms were primarily mediated by the abnormal expression of interleukin (IL) 6 or IL8 and not exclusively by COX-2 overexpression. Finally, the P38 MAPK, NF-κB, and JAK-STAT3 signaling pathways, which mediate high levels of expression of IL6 or IL8, were identified as potential pathways underlying CAP-induced HFS.

Evaluation of the Preventive Effect of Regional Cooling Nursing on Hand Foot Syndrome Caused by Doxorubicin Hydrochloride Liposome

Purpose: To explore the preventive effect of Regional cooling comprehensive nursing on hand foot syndrome caused by pegylated liposomal doxorubicin (PLD). Method: Adopt overall sampling method. Patients who used the same adjuvant drugs from January to December 2020 were randomly divided into an intervention group and a control group. The patients in the two groups received routine nursing guidance and drug prevention for the use of amygdalin. The patients in the intervention group were required to take protective measures of Regional cooling during chemotherapy. The occurrence of hand foot syndrome during adriamycin liposome administration was compared between the two groups. Results: By comparing the adverse reactions of cases during Adriamycin Administration, the incidence rates of grade I, II and III hand foot syndrome in the control group were 28.8%, 7.6% and 27.5% respectively, and the incidence rates of grade I, II and III hand foot syndrome in the intervention group were 42.1%, 12.3% and 7.0% respectively, with statistical significance (P < 0.05). Conclusion: Regional cooling nursing and preventive behavior guidance can effectively reduce the severity of hand foot syndrome caused by adriamycin.

High dose and hepatobiliary dysfunction are associated with hand-foot syndrome in patients with lymphoma using pegylated liposomal doxorubicin: a retrospective study

PurposeIn clinical practice, the risk factors for pegylated liposomal doxorubicin-related hand-foot syndrome remain unclear. The purpose of this study was to determine the risk factors associated with hand-foot syndrome in patients with lymphoma using pegylated liposomal doxorubicin.MethodsThis retrospective descriptive analysis included patients with lymphoma who received PLD treatment (≥ 2 cycles of chemotherapy) at our cancer centre and had complete follow-up data from January 2016 to February 2020. Clinical, laboratory data, as well as the occurrence of hand-foot syndrome (incidence, location, severity, impact on follow-up chemotherapy) were obtained. The primary end point was the incidence of hand-foot syndrome, which was classified according to the “Common Terminology Criteria for Adverse Events” (Version 4.0). A multivariate logistic regression analysis was used to identify risk factors for hand-foot syndrome in patients with lymphoma using doxorubicin liposomes.FindingsA total of 167 patients met the inclusion criteria. 58 developed HFS, of which 45 occurred after the second course of chemotherapy. The multivariate logistic regression analysis revealed that a dose increase of pegylated liposomal doxorubicin and hepatobiliary dysfunction were significantly associated with an increased risk for hand-foot syndrome(dose intensity, OR = 6.479; 95% CI, 1.431–29.331 [P = 0.015]; history of gallstones, OR = 14.144, 95% CI, 1.512–132.346 [P = 0.020]; alanine aminotransferase, OR = 1.194, 95% CI, 1.056–1.350 [P = 0.005]; aspartate aminotransferase, OR = 1.162, 95% CI, 1.010–1.336 [P = 0.035]; and glutamine transpeptidase, OR = 1.092, 95% CI, 1.016–1.174 [P = 0.018]).ImplicationsThese findings contribute to the risk assessment of patients with lymphoma before using pegylated liposomal doxorubicin. For patients with the above risk factors, preventive measures should be taken in advance to reduce the incidence of HFS.

Henna Application in the Prevention of Capecitabine-Induced Hand-Foot Syndrome in Breast and Colorectal Cancer Patients.

AIMThis study investigates the prophylactic effect of henna on the occurrence of hand-foot syndrome (HFS) in patients receiving capecitabine for breast and colorectal cancer.METHODThis experimental study was carried out between May 2014 and May 2015. In this self-control experimental study, 52 patients with breast and colorectal cancer were included on the first day of capecitabine treatment and had a minimum follow-up of 3 cycles. One hand/foot of each patient constituted the study hand/foot, whereas the others constituted the control. Henna was administered to the study hand/foot on the first day of treatment and application renewed weekly. Development of grade 1–3 toxicity was set as the termination criterion for study.RESULTSPainful skin changes such as rawness, intumescence and bulla formation, blocking the daily activities or self-care were observed in 26.9% of the patients in the 3rd or 4th cycles of treatment. Development time and severity of skin changes over time did not differ significantly between the study and the control hand/foot.CONCLUSIONFurther studies with a larger sample size are needed to conclude on the prophylactic effect of henna in the management of the HFS.

SNPs in the COX-2/PGES/EP signaling pathway are associated with risk of severe capecitabine-induced hand-foot syndrome.

Capecitabine is a widely used 5-fluorouracil oral prodrug. Hand-foot syndrome (HFS), one of the most common adverse events of capecitabine, impacts patients' quality of life seriously. The pathogenesis of HFS remains unclear but was usually considered as a type of inflammation conducted by cyclooxygenase-2 (COX-2). The COX-2/PGES/EP signaling pathway plays an important role in the inflammatory reaction. We hypothesized that the single nucleotide polymorphisms (SNPs) in this pathway may be associated with the risk of HFS induced by capecitabine. Using DNA from blood samples of 225 patients, we genotyped 19 SNPs in 6 core genes (COX-2, PGES, EP1, EP2, EP3, and EP4). Common Terminology Criteria for Adverse Events version 3.0 was used to grade hand-foot syndrome. We used logistic regression analysis to evaluate the correlations between genotype variants and occurrence of HFS. The cumulative incidence of HFS was assessed by Kaplan-Meier analysis. Among the 225 participants, 58.6% (132/225) patients developed into HFS, including 41.3% (93/225) grade 1 HFS, 10.2% (23/225) grade 2 HFS and 7.1% (16/225) grade 3 HFS. Multivariate logistic regression analysis showed the AG/GG genotype of rs3810255 to be associated with a significantly higher risk of grade 2/3 HFS, while the AG/AA genotype of rs17131450 to be associated with a significantly lower risk of grade 2/3 HFS (OR = 3.646, P = 0.011; and OR = 0.266, P = 0.036; respectively). Our study showed that rs3810255 AG/GG genotypes and rs17131450 GG genotypes to be associated with high risk of capecitabine-induced HFS.

Effective prevention of sorafenib-induced hand-foot syndrome by dried-bonito broth.

BackgroundSorafenib (SOR) is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC). Therefore, the management of side effects is essential for the longer period of continuous medication. Among the various side effects, hand–foot syndrome (HFS) is the most common, occurring in 30%–50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms.Materials and methodsTo assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB), which was reported to improve peripheral blood flow, on the prevention of the symptom was examined by monitoring its occurrence and the peripheral blood flow.ResultsA total of 25 patients were enrolled in this study. In all, eight patients developed HFS, and all cases showed a significant decrease in the peripheral blood flow. DBB contributed to an increase in the flow (p = 0.009) and significantly decreased occurrence of HFS (p = 0.005) than control. Multivariable analysis showed that the ingestion of DBB is a significant independent contributor to HFS-free survival period (p = 0.035).ConclusionThe mechanism of SOR-induced HFS involves a decrease in the peripheral blood flow, and the ingestion of DBB effectively prevents the development of the syndrome by maintaining the flow.

MP16-01 CLINICAL IMPLICATIONS OF SUNITINIB AND N-DESETHYL-SUNITINIB PLASMA CONCENTRATIONS FOR TREATMENT OUTCOME IN METASTATIC RENAL CELL CARCINOMA PATIENTS

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II1 Apr 2017MP16-01 CLINICAL IMPLICATIONS OF SUNITINIB AND N-DESETHYL-SUNITINIB PLASMA CONCENTRATIONS FOR TREATMENT OUTCOME IN METASTATIC RENAL CELL CARCINOMA PATIENTS Kazuyuki Numakura, Nobuhiro Fujiyama, Makoto Takahashi, Hiroshi Tsuruta, Atsushi Maeno, Mitsuru Saito, Takamitsu Inoue, Shintaro Narita, Mingguo Huang, Shigeru Satoh, Takenori Niioka, Masatomo Miura, and Tomonori Habuchi Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Nobuhiro FujiyamaNobuhiro Fujiyama More articles by this author , Makoto TakahashiMakoto Takahashi More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Atsushi MaenoAtsushi Maeno More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Mingguo HuangMingguo Huang More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , Takenori NiiokaTakenori Niioka More articles by this author , Masatomo MiuraMasatomo Miura More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.507AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Therapeutic drug monitoring (TDM) has been recognized as a useful tool for optimizing the dosages of many drugs, even in molecular-targeted therapeutics. In this study, we examined the associations between the pharmacokinetics of sunitinib (SU) and its metabolite N-desethyl-sunitinib (DSU) and adverse events (AEs) and clinical outcomes in patients with metastatic renal cell carcinoma (mRCC). METHODS The pharmacokinetics of SU and DSU were examined in 26 patients (20 male and 6 female patients) with mRCC. Plasma SU and DSU levels were measured using high-performance liquid chromatography, and a pharmacokinetic study was performed on day 7 in the first cycle of SU. The associations between SU/DSU pharmacokinetics and the occurrence of AEs, best response rate, progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS) were investigated. RESULTS All patients were treated with 37.5 mg/day SU at the day of pharmacokinetics. The mean trough levels of SU and DSU were 76.7 and 16.8 ng/mL respectively. Occurrence of hand-foot syndrome and thrombocytopenia (P = 0.002 and 0.024 respectively by Mann-Whitney test) was associated with high trough levels of SU. Low trough levels of DSU were significantly associated with drug discontinuation due to disease progression and were associated with worse tumor response (P = 0.035 and 0.042 respectively by Mann-Whitney test, Figure 1). Patients with DSU trough levels of or higher than 15.0 ng/mL showed a tendency toward increased PFS, TTF, and OS than those with trough levels lower than 15.0 ng/mL (Figure 2). SU trough levels were not associated with prognosis. CONCLUSIONS TDM of SU and DSU in patients with mRCC may be useful to determine adequate dosages and prevent severe AEs. Further studies are required to establish the usefulness of TDM of SU and DSU for ensuring long-term clinical efficacy in patients with mRCC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e179 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kazuyuki Numakura More articles by this author Nobuhiro Fujiyama More articles by this author Makoto Takahashi More articles by this author Hiroshi Tsuruta More articles by this author Atsushi Maeno More articles by this author Mitsuru Saito More articles by this author Takamitsu Inoue More articles by this author Shintaro Narita More articles by this author Mingguo Huang More articles by this author Shigeru Satoh More articles by this author Takenori Niioka More articles by this author Masatomo Miura More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

卵巣がんに対するPegylated Liposomal Doxorubicin療法による手足症候群発現に及ぼす影響因子の解析

Pegylated liposomal doxorubicin (PLD) is a liposomal formulation of doxorubicin hydrochloride. It was approved for the treatment of ovarian cancer aggravated after chemotherapy. The occurrence of hand-foot syndrome (HFS) associated with the administration of PLD is considered one of the major adverse side effects. The development of Grade2 ≦ HFS (Serious HFS) during the course of PLD therapy calls for dose reduction or discontinuation of subsequent PLD administration. However, the factors that influence the development of HFS are unclear in Japan. Therefore, we focused on the factors influencing the development of HFS in patients receiving PLD therapy for ovarian cancer. The study population consisted of 36 patients. Twenty patients (55.6%) developed HFS while 10 patients (27.8%) developed serious HFS. The patients who did not develop stomatitis during PLD therapy, also never developed serious HFS. In contrast, 37.0% (10/27) of the patients who had developed stomatitis during PLD therapy were reported to have developed serious HFS (P = 0.0390). For the 10 patients with serious HFS, the median time for the occurrence of serious HFS and stomatitis after the initiation of PLD therapy was 3 cycles and 1 cycle, respectively. In conclusion, patients who developed stomatitis during the course of PLD therapy were more likely to develop serious HFS than those who did not. Additionally, stomatitis has been reported to develop prior to serious HFS. Therefore, the occurrence of stomatitis during PLD therapy can aid in the prediction of serious HFS development in future.

Abstract P3-06-10: Hand-foot-syndrome (HFS) is a strong predictor for OS and PFS in HER2-negative metastatic breast cancer (mBC) treated with first-line capecitabine (CAP) + bevacizumab (BEV): Results of a subanalysis of the randomized phase III CECOG TURANDOT trial

Abstract Background: The randomized phase III TURANDOT trial performed by the Central European Cooperative Oncology Group (CECOG) compared first-line BEV + paclitaxel (PAC) vs BEV + CAP in HER2-negative mBC in a prospective randomized trial [Lang, Lancet Oncol 2013]. In this trial, HFS was the most common adverse drug reaction in the BEV + CAP arm. In the present subanalysis, we investigated whether the occurrence of HFS constituted a predictor for improved efficacy of BEV + CAP in the study population randomized to this treatment arm. Methods: In the TURANDOT trial, patients with HER2-negative mBC who had received no prior chemotherapy for mBC were randomized to either BEV-PAC (BEV 10 mg/kg d1 &amp; 15 + PAC 90 mg/m2 d1, 8, &amp; 15 q4w) or BEV-CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m2 bid d1-14 q3w). Only patients who were randomized to the BEV-CAP arm and received at least one dose of CAP were included in the present analysis. Cox proportional hazard models with time-dependent covariate "HFS of any grade" and "HFS grade" were used to analyze the association between HFS and OS or PFS. In addition, landmark (LM) analyses were performed analyzing the impact of HFS occurrence within the first 3 treatment months on PFS and OS. Results: Baseline characteristics of patients with HFS (n=154) versus no HFS (n=123) were well balanced and showed no significant differences. Table 1 shows that with the occurrence of HFS, the hazard for progression or death was reduced by &amp;gt; 40%, while the risk reduction (RR) was &amp;gt;55% for OS. Moreover, with increasing HFS-grade an increasing RR was observed for OS. In patients with and without HFS in the first 3 months, the median PFS after the 3 months LM were 10 and 6.2 months (logrank test p=0.0026), respectively, and the corresponding OS rates at 2 years after the 3 months LM were 63% and 44% (log rank test, p=0.0842), respectively. Updated OS results will be presented at the conference. Cox Proportional Hazards Models for PFS and OS with HFS as Time-dependent CovariateUnivariateMultivariate*EndpointTime depent variableHazard ratio (95%Cl)p-valueHazard ratio (95%Cl)p-valuePFSHFS(Yes vs No)0.577(0.431,0.772)0.00020.558(0.409,0.760)0.0002HFS Grade 10.639(0.440,0.927)0.01840.536(0.350,0.821)0.0042HFS Grade 20.481(0.321,0.720)0.00040.487(0.320,0.741)0.0008HFS Grade 30.641(0.411,0.999)0.04950.740(0.466,1.178)0.2043OSHFS(Yes vs No)0.417 (0.273, 0.637)&amp;lt;.00010.436 (0.285, 0.666)0.0001HFS Grade 10.568 (0.334, 0.968)0.03750.548 (0.322, 0.934)0.0270HFS Grade 20.417 (0.227, 0.765)0.00480.448 (0.243, 0.824)0.0098HFS Grade 30.220 (0.093, 0.520)0.00060.247 (0.104, 0.586)0.0015* Significant baseline factors in multivariate models: ECOG (0 vs 1-2) in all models, ER/PR status (Any positive vs Other) in both OS models. Conclusion: HFS is a strong predictor for prolonged PFS and OS in mBC patients receiving BEV + CAP first-line treatment. Early occurrence of HFS and HFS severity might be used for treatment modifications and patient motivation. Detection of biomarkers for HFS could strengthen this approach. Citation Format: Zielinski C Christoph, Lang Istvan, Beslija Semir, Kahan Zsuzsanna, Moshe J Inbar, Stemmer M Salomon, Anghel Rodica, Vrbanec Damir, Messinger Diethelm, Brodowicz Thomas. Hand-foot-syndrome (HFS) is a strong predictor for OS and PFS in HER2-negative metastatic breast cancer (mBC) treated with first-line capecitabine (CAP) + bevacizumab (BEV): Results of a subanalysis of the randomized phase III CECOG TURANDOT trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-10.

The effect of seasonal variation and secretion of sunitinib in sweat on the development of hand–foot syndrome

Hand-foot syndrome (HFS) is a side effect of sunitinib with considerable impact on quality of life. Seasonal variation and hyperhydrosis are possibly correlated to occurrence of HFS. Therefore, we proposed to study the prevalence of HFS in different seasons retrospectively and to study the relationship between sunitinib sweat secretion and HFS prospectively. A retrospective cohort of 19 patients treated with sunitinib was used to determine seasonal prevalence of HFS. In a prospective study, sunitinib and N-desethyl sunitinib levels in sweat patches of 25 patients treated with sunitinib were quantified and correlated to severity of HFS. In the retrospective cohort, the patients suffered from more severe HFS during summertime compared with the rest of the year. In the prospective study, the cumulative amounts of sunitinib plus metabolite measured in the patches of the on-treatment phase (median 129.4 ng/patch) were higher than the off-treatment phase (median 39.5 ng/patch). A tendency was observed towards increasing amounts of drug per patch with increasing severity of HFS. Patients experienced more HFS in summer time compared to other seasons. However, no statistically significant correlation between sunitinib sweat secretion and severity of HFS could be demonstrated within our patient cohort.

Outcomes of sunitinib therapy in patients (pts) with metastatic renal cell carcinoma (mRCC) with poor risk features.

476 Background: Temsirolimus is perceived as the standard of care in pts with mRCC with poor risk features. However, sunitinib (Su) is commonly used in this setting. In this study, we assessed the use of Su in an unselected mRCC population. Methods: Retrospective analysis of 51 pts with mRCC and ≥ 3 poor prognosis features, as determined in the Advanced Renal Cell Carcinoma (ARCC) trial, treated with Su between January 2006 and July 2012. Primary outcome was overall survival (OS). Clinical and laboratory parameters were evaluated, as well as Su-related adverse events (AE). Median time to treatment failure (mTTF) and OS were estimated by Kaplan–Meier methods. On exploratory grounds, univariate, and multivariate analysis using Cox regression model was performed to determine possible prognostic variables. Results: Median age was 60 years (26-89). Most had clear cell histology (98%), 19% prior systemic treatment, and 51% prior nephrectomy. 64%, 15%, and 4% had 4, 5, and 6 adverse prognosis factors respectively. 88% had diagnosis to treatment intervals &lt; 1 year and 45% had KPS scores of &lt; 80. A median of 2 cycles (0–12) were administered. 63% received standard regimen of Su (50 mg/d 4 wk on/2 wk off). Reasons for discontinuation were disease progression (63%) and adverse events (21%). Most grade ≥ 3 AE were fatigue (14%), neutropenia (8%), and stomatitis (8%). 17%, 25%, and 14% developed hypothyroidism, hand-foot syndrome (HFS), and hypertension, respectively. Two therapy-related deaths were observed (one febrile neutropenia and one intracranial hemorrhage). Estimated mTTF and mOS of this cohort were 2.4 and 6.6 months, respectively. Multivariate analysis revealed that in a model adjusted for type of Su regimen, KPS, presence of brain metastasis, and occurrence of HFS, only Su-associated hypothyroidism was significantly associated with survival (respectively, odds ratio [OR] = 0.23; 95% CI = 0.07-0.68). Conclusions: Pts with mRCC with poor risk features treated with Su have an OS, TTF and rates of therapy discontinuation due to AE comparable to clinical trial subsets of similar pts. Our data suggest that the development of hypothyroidism in this setting might be useful as a predictor of OS, and this finding should be further investigated.

PD-0021 Hand-Foot-Syndrome (HFS) is a Clinical Predictor of Survival in Capecitabine Treated Patients (PTS) with Colorectal Cancer

ABSTRACT Introduction HFS is a typical adverse event in capecitabine treated patients (pts). Post hoc analyses of the AIO KRK-0104 trial showed that HFS is associated with improved prognosis in capecitabine recipients in stage IV colorectal cancer. Here we evaluated the potential association of HFS and survival in a pooled analysis of pts with metastatic colorectal cancer and locally advanced rectal cancer (Mannheim rectal cancer trial). Methods Pts receiving capecitabine within the AIO KRK-0104 and Mannheim rectal cancer trials were analyzed. HFS was graded according to NCI-CTCAE. Occurrence and kinetics of occurrence per cycle were investigated defining “early HFS” as developing of any HFS during the fist two cycles. Groups (HFS versus non-HFS) were compared using Fisher’s exact test. Survival was compared using Kaplan-Meier estimation and logrank analysis. Overall survival (OS) and progression-free (PFS) or disease-free survival (DFS) were pooled. Results Of 374 pts a total of 29.3% developed HFS. The frequency of “early HFS” was 70.9%. Baseline characteristics were comparable between the HFS and the non-HFS groups. Multivariate analysis for age, gender, ECOG status and UICC stage on the occurrence of HFS was done but none of these factors had influence. The percentage of all-grade haematological toxicities did not differ between both groups. We observed in the HFS group a significantly higher rate of all grade (but not grade 3-4) diarrhoea, stomatitis/mucositis and fatigue (p Conclusion HFS as a sign of individual capecitabine metabolism is a clinical predictor of survival in colorectal cancer patients. Pts developing HFS had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with haematological toxicity was noticed.

Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy

This multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer. Patients were assigned to 24 weeks of capecitabine 1250 mg/m(2) twice daily on days 1-14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS). The intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77-1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74-1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥ 70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand-foot syndrome may be associated with better outcomes in capecitabine recipients. Oral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.

Investigation of hand-foot syndrome (HFS) observed in pazopanib (P)-treated patients (pts) with renal cell carcinoma (RCC).

3061 Background: HFS is an adverse-effect of several agents used to treat cancer, particularly the VEGF TKIs. HFS can be debilitating for patients, affecting their physical, mental, and social well-being. This study sought to explore demographic, pharmacokinetic (PK) and pharmacogenetic (PGx) factors which may contribute to pazopanib-related HFS in pts with RCC. Methods: Week (wk) 4 plasma P trough concentrations (Cmin) were determined for 204 out of 225 pts with advanced RCC from a phase II study (VEG102616). Logistic and ordinal regression analyses were used to evaluate the effect of demographic (gender, race, baseline weight and height) and wk 4 Cmin on occurrence and severity of HFS, respectively. For the PGx analyses, DNA samples were collected from consenting pts with advanced RCC from three P clinical studies; VEG102616 (phase II), VEG105192 (phase III), and VEG107769. Pts were defined as HFS cases (NCI-CTCv3 grade ≥ 1, n=33) or controls (grade = 0 with treatment duration >28 days, n=321). A total of 3012 SNPs in 89 candidate genes were evaluated. The penalized maximum likelihood logistic regression was used to evaluate the effect of genotypes on the HFS case-control status. Results: While the overall incidence was low (7.7%), a high proportion of east and south-east Asians exhibited HFS (21/71, 30%) compared to Caucasians (22/489, 4%). Wk4 Cmin (P = 0.0005) and race (P = 0.03) were significantly associated with occurrence of HFS by logistic regression. A similar correlation was observed between maximal HFS grades (CTC v3) and wk4 Cmin (P < 0.0001) and race (P = 0.0045). None of the genetic markers were significantly associated with HFS after correction for multiple comparisions. Five SNPs in ABCG2, PDGFRA, GZMB and TPCN2 genes showed suggestive association with HFS at a nominal significance level P<0.01 and with a plausible genetic model. Conclusions: Both race (Asian vs. Caucasian) and wk4 P Cmin concentrations are significant predictors of HFS. Candidate gene analyses revealed that some genetic markers may be associated with P- related HFS. However, as none of the markers passed the significance level of multiple testing corrections, further evaluation in independent data sets is required to confirm or refute these findings.

P.1.1: PREDICTIVE FACTORS FOR TUMOR CONTROL AMONG HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH SORAFENIB

Background and aim: Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, the predictive factors of outcome among treated patients have not been fully investigated. Aim of this study was to identify factors predictive for tumor control among patients with advanced HCC treated with sorafenib. Material and methods: All consecutive HCC patients treated with sorafenib at our Unit from October 2008 to October 2010 were evaluated. All patients received 800 mg/day of sorafenib until progression or unacceptable toxicities. Overall survival (OS) and time to progression (TTP) were estimated by using Kaplan-Meier curves. TTP was considered as a marker of tumor control. Univariate analysis included age, gender, etiology, AFP, Child-Pugh class, MELD, alanine aminotransferase (ALT), alkaline phosphatase, bilirubin, albumin, ascites, metastasis, portal vein thrombosis, oesophageal varices, effects related to VEGF inhibition: rash, arterial hypertension, bleeding, and hand-foot syndrome (HFS). To detect factors independently related to TTP, multivariate analysis by Cox’s model was done. Results: We treated 101 patients (median age 67 years; 81 males; 98 cirrhotics; Child A/B: 79/19; 55 macrovascular invasion; 39 extrahepatic spread). Median therapy duration was 4 (range 1-16) months. Median OS was 10 (95% CI 4.5-15.5) months. TTP was 9 (95%CI 3.7-14.3) months. Complete/partial response occurred in 21% of patients and stable disease in 19%. At univariate analysis, the variables significantly related to TTP were: female sex (14 months vs 6 months, p=.05), no portal thrombosis (13 months vs 6 months, p=.04), ALT =60UI (15 months vs 6 months, p=.02), no ascites (11 months vs 2 months, p=.003), and occurrence of HFS (16 months vs 5 months, p<0.000). At multivariate analysis, no ascites (p=.02; HR 2.7, 95%CI 1.2-6.0) and occurrence of HFS (p<.000; HR 8.9, 95%CI 3.3-23.8) were independently related to TTP. Conclusions: In sorafenib treated patients, the absence of ascites and the occurrence of HFS are predictive factors for longer TTP. HFS was the only symptom related to inhibition of VEGF predicting tumor control.

P.1.2: THE PERSISTENCE OF HCV REPLICATION IS ASSOCIATED WITH AN INCREASED MORTALITY RATE IN HCV RECURRENT TRANSPLANT PATIENTS: RESULTS FROM THE AISF-RECOLT-C GROUP

Background and aim: Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, the predictive factors of outcome among treated patients have not been fully investigated. Aim of this study was to identify factors predictive for tumor control among patients with advanced HCC treated with sorafenib. Material and methods: All consecutive HCC patients treated with sorafenib at our Unit from October 2008 to October 2010 were evaluated. All patients received 800 mg/day of sorafenib until progression or unacceptable toxicities. Overall survival (OS) and time to progression (TTP) were estimated by using Kaplan-Meier curves. TTP was considered as a marker of tumor control. Univariate analysis included age, gender, etiology, AFP, Child-Pugh class, MELD, alanine aminotransferase (ALT), alkaline phosphatase, bilirubin, albumin, ascites, metastasis, portal vein thrombosis, oesophageal varices, effects related to VEGF inhibition: rash, arterial hypertension, bleeding, and hand-foot syndrome (HFS). To detect factors independently related to TTP, multivariate analysis by Cox’s model was done. Results: We treated 101 patients (median age 67 years; 81 males; 98 cirrhotics; Child A/B: 79/19; 55 macrovascular invasion; 39 extrahepatic spread). Median therapy duration was 4 (range 1-16) months. Median OS was 10 (95% CI 4.5-15.5) months. TTP was 9 (95%CI 3.7-14.3) months. Complete/partial response occurred in 21% of patients and stable disease in 19%. At univariate analysis, the variables significantly related to TTP were: female sex (14 months vs 6 months, p=.05), no portal thrombosis (13 months vs 6 months, p=.04), ALT =60UI (15 months vs 6 months, p=.02), no ascites (11 months vs 2 months, p=.003), and occurrence of HFS (16 months vs 5 months, p<0.000). At multivariate analysis, no ascites (p=.02; HR 2.7, 95%CI 1.2-6.0) and occurrence of HFS (p<.000; HR 8.9, 95%CI 3.3-23.8) were independently related to TTP. Conclusions: In sorafenib treated patients, the absence of ascites and the occurrence of HFS are predictive factors for longer TTP. HFS was the only symptom related to inhibition of VEGF predicting tumor control.

Candidate mechanisms for capecitabine‐related hand–foot syndrome

The oral fluoropyrimidine prodrug capecitabine is widely used in oncology. Capecitabine was designed to generate 5FU via the thymidine phosphorylase (TP) enzyme, preferentially expressed in tumoral tissues. Hand-foot syndrome (HFS) is a limiting toxicity of capecitabine. A pilot study on healthy volunteers was conducted in order to test the hypothesis that the occurrence of HFS could be related to tissue-specific expression of drug-metabolizing enzymes in the skin of the palm and sole. To this end, the expression of TP (activating pathway), dihydropyrimidine dehydrogenase (DPD, catabolic pathway) and cell proliferation (Ki67) were measured in the skin of the palm (target tissue for HFS) and of the lower back (control area). Two paired 4-mm diameter punch biopsy specimens (palm and back) were taken in 12 healthy volunteers. Immunohistochemical analyses were performed on frozen tissues. Proliferation rate (Ki67 staining) was significantly higher in epidermal basal cells of the palm compared with the back (P = 0.008). Also, TP and DPD expression were significantly greater in the palm relative to the back (P = 0.039 and 0.012, respectively). TP and Ki67 expression were positively and significantly correlated in the palm. The high proliferation rate of epidermal basal cells in the palm could make them more sensitive to the local action of cytotoxic drugs. TP-facilitated local production of 5FU in the palm during capecitabine treatment could explain the occurrence of HFS. This observation may support future strategies to limit the occurrence of HFS during capecitabine therapy.

Hand-foot syndrome (HFS) in patients treated with capecitabine (CAP) and the role of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD)

8615 Background: HFS is the most common toxicity of CAP. Preclinical studies have shown that radiation (XRT) up-regulates TP, which may in turn increase efficacy of CAP. CAP is degraded by DPD, and a deficiency in this enzyme may increase toxicity of CAP. However, effect of XRT on frequency of HFS and association with TP and DPD has not been fully characterized. Methods: Toxicity data were collected from pts with LA pancreatic cancer enrolled in 3 clinical trials conducted at UAB between Apr 2001 and Jul 2005. Overall results of these trials have been reported elsewhere. Pts received XRT (50.4 Gy) with CAP (1,200–1,600 mg/m2 BID M-F) followed CAP (2,000 mg/m2 BID x 14 days). Pts were classified into 2 groups to evaluate HFS: CAP-XRT and CAP. Roche grading was used to assess HFS. Dose modifications were according to drug insert. Pts received prophylactic udder cream and pyridoxine. Tumor specimens were procured in 36 pts by EUS-FNA 1 wk pre- and 2 wks post XRT to evaluate TP and DPD. Age, race, sex, and PS were evaluated as prognostic factors. Results: Median duration of CAP was 6 wks (range: 3–6) for CAP-XRT and 2.5 cycles (range: 0–17) for CAP. Among 58 pts, 14 developed HFS (24%). CAP group had a higher incidence of HFS than CAP-XRT (17.2 % vs. 10.3 %; P = 0.12). Grade 2/3 HFS was observed in 15.5 % of CAP and 1.7 % of CAP-XRT (P = 0.0078). Median cumulative dose of CAP for first development of HFS was 235,000 mg/m2 in CAP-XRT group and 3,185,000 mg/m2 in CAP, with relative frequency of an event occurring in CAP-XRT vs. CAP of 0.59. HFS occurred at a median of 5 wks in CAP-XRT and 6 wks in CAP. Log-rank test showed neither age, sex, ECOG PS, or race was associated with development of HFS. There was no difference in tumor responses of pts with vs. without HFS. Mean tumor TP was higher among pts with vs. without HFS (275.77 vs. 215.29; P = 0.32). Mean tumor DPD was lower among pts with vs. without HFS (55.18 vs. 63.58; P = 0.49). Mean TP:DPD ratio was higher among pts with vs. without HFS (10.29 vs. 3.04; P = 0.31). Conclusions: This study suggests that incidence, severity, and time to occurrence of HFS with CAP-XRT &lt; CAP, indicating no effect of XRT. No significant association of HFS with higher tumor TP or lower tumor DPD was found. Pharmacological basis for HFS with CAP needs to be explored. [Table: see text]

Up-regulation of thymidine phosphorylase (TP) by radiotherapy (RT): a phase I study of capecitabine (CAP) with concurrent RT for pts with locally advanced (LA) pancreatic cancer (Pan Ca)

4104 Introduction: Concurrent 5-FU-RT is the standard Rx for LA Pan Ca. CAP is metabolized by TP to its metabolite, 5-FU. Preclinical studies suggest that RT prior to CAP leads to synergistic cytotoxicity and better antitumor effects than 5-FU-RT due to up-regulation of TP. Objective: This is a hypothesis-driven phase I study which examines the effect of RT on TP and TNF-alpha expression, defines MTD of CAP with RT and determines if there is a correlation between pt response and intra-tumor TP/DPD ratio. Patients and Methods: During Part A (CAP-RT) pts received concurrent RT (50.4 Gy) with escalating doses of CAP (600mg/m2 PO BID; 800mg/m2 PO BID; 1000mg/m2 PO BID) on days 1–5, 8–12, 15–19, 22–26, 29–33, and 36–40 in consecutive cohorts of 3–6 pts till MTD is achieved. After finishing Part A, pts were assessed for tumor response and resectability. During Part B (CAP), stable, responding and resected pts were treated with CAP 1000mg/m2 PO BID for 14d q 3 wks until disease progression. Re-staging asessment was performed q 3 cycles. Tumor specimens procured by EUS pre- and post-therapy (wk 2) were evaluated for TP, TNF-alpha and DPD mRNA levels by RT-Q-PCR. Results: From April to Dec 2003, 11 pts (4M/ 7F; Median age: 63 yrs; PS ECOG: 0–2) were enrolled. Toxicities are summarized in Table 1. DLT [Grade 3 diarrhea] was observed at 1000mg/m2 BID, and a total of 6 pts will be enrolled at this level to define MTD and DLT. No occurrence of Hand-Foot syndrome (HFS) was seen during Part A, and Grade 2 HFS was observed in 2 pts during Part B. With 5 pts still on study, 24 cycles have been administered, with a median of 3. Three pts responded to Rx (2 PR: 54% and 43%; 1 SD; 1 PD; 3 off-study due to delay > 2 wks). Intra-tumor expression of TP, TNF-alpha, and DPD are pending and will be available at the meeting. Conclusions: CAP-RT appears to be well tolerated and active in LA Pan Ca. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche; Sanofi Roche Pharmaceuticals

Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial

Gemcitabine is an active antitumor agent in the treatment of advanced pancreatic cancer, and has shown potential synergistic activity with the oral fluoropyrimidine capecitabine in previous phase I/II trials. Based on this background and in order to define the therapeutic potential and tolerance of this combination more precisely, the present randomized multicenter phase II trial was initiated. We prospectively randomized 83 patients to treatment with biweekly gemcitabine 2,200 mg/m(2) given as a 30 min intravenous infusion on day 1, or the same treatment plus oral capecitabine 2,500 mg/m(2) given from days 1 to 7. In both arms, chemotherapy was administered for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of the two treatment arms was evaluated according to standard criteria, i.e. objective response, progression-free survival (PFS) and overall survival (OS), as well as by analysis of clinical benefit response. The overall objective response rate among the 42 patients treated with gemcitabine alone was 14% compared with 7/41 (17%) among those treated with the combination arm. Similar to response rates, there was no apparent difference between the two groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus 9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients with tumor-related symptoms, who were considered evaluable for clinical benefit response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in both arms with only four versus six patients experiencing WHO grade 3 symptoms. Apart from the occurrence of hand-foot syndrome in 10 patients, no major increase in incidence and/or degree of adverse reactions was noted in the combination arm. Results of this trial suggest a fairly good therapeutic index for the combination of biweekly high-dose gemcitabine and capecitabine for the treatment of advanced pancreatic cancer. Despite a somewhat superior clinical benefit response rate, no advantage over single-agent gemcitabine, however, was noted in terms of objective efficacy parameters.