Association between pazopanib exposure and safety in Japanese patients with renal cell carcinoma or soft tissue sarcoma.

The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough concentrations with soft tissue sarcoma (STS) are limited. This study investigated the relationship between plasma trough concentrations and pazopanib safety in 45 Japanese patients with RCC or STS. Among the 33 patients included, the median pazopanib trough concentration was 37.5 (range, 12.1-67.6) µg/mL, which was not significantly different between Japanese RCC and STS patients. The plasma trough concentrations showed significant and positive correlations with aspartate aminotransferase and alanine aminotransferase values in blood samples taken for pharmacokinetic measurements after the administration. The incidence of pazopanib treatment discontinuation were significantly higher in RCC patients (p = 0.027). The primary reason for treatment discontinuation was hepatic dysfunction (5/6, 83.3%). Furthermore, this study revealed that pazopanib trough concentration was affected significantly by proton pump inhibitors but not by histamine 2-receptor blockers. In conclusion, the observed pazopanib trough levels and their safety in the Japanese RCC and STS populations in this study were similar to those of the global population. This is the first study to correlate the hepatotoxicity and pharmacokinetic property of pazopanib plasma trough levels by comparing Japanese patients with RCC or STS.

Fast and Ultrasensitive Glycoform Analysis by Supercritical Fluid Chromatography-Tandem Mass Spectrometry.

The glycoform of a therapeutic monoclonal antibody (mAb) has a significant impact on its effector function as well as its safety and pharmacokinetics. Glycoform heterogeneity is influenced by various factors, including the producing cells and cell culture processes. Therefore, accurate glycoform characterization is essential for drug design, process optimization, manufacturing, and quality control of therapeutic mAbs. In this study, we developed a fast, quantitative, and highly sensitive analytical platform for glycan profiling by supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) and applied the technique to the glycan structural analysis of mAbs. To achieve both the highest sensitivity and the most comprehensive glycan profiling, we integrated our energy-resolved oxonium ion monitoring (Erexim) method with SFC-MS to construct a new SFC-Erexim technology. An 8 min analysis of bevacizumab, nivolumab, ramucirumab, rituximab, and trastuzumab by SFC-Erexim detected a total of 102 glycoforms, with a detection limit of 5 attomoles. The dynamic range of glycan abundance was over 6 orders of magnitude for bevacizumab analysis by SFC-Erexim compared to 3 orders of magnitude for conventional fluorescence HPLC analysis. This method revealed the glycan profile characteristics and lot-to-lot heterogeneity of various therapeutic mAbs. We were also able to detect a series of structural variations in pharmacologically important glycan structures. The SFC-MS-based glycoform profiling method will provide an ideal platform for the in-depth analysis of precise glycan structure and abundance.

[Evaluation of Neutropenia and Usages of Antihypertensive Drugs in Patients Treated with Ramucirumab plus Paclitaxel Therapy].

Hypertension is one of the main side effects of ramucirumab(RAM)plus paclitaxel(PTX)therapy. Although dihydropyridine calcium channel blockers(D-CCBs)are considered to cause drug-drug interactions with PTX based on the inhibition of cytochrome P450, D-CCBs are often administered to patients receiving RAM plus PTX therapy in clinical practice. We retrospectively studied the actual usage of antihypertensive drugs in 133 advanced or recurrent gastric cancer patients who received RAM plus PTX therapy. Antihypertensive drugs were administered to 34(25.6%)patients. Among them, 13 (38.2%)received antihypertensive drugs during the first course, and 19(55.9%)received D-CCBs. We also investigated whether D-CCBs affect the expression of Grade 3 or higher neutropenia caused by PTX. Results of multivariate analysis indicated that D-CCBs did not increase the risk of neutropenia caused by PTX.

Safety evaluation of fixed-dose nivolumab in patients with gastric cancer.

Background and Aims: This study aimed to examine the safety of fixed-dose nivolumab. Methods: We retrospectively reviewed the medical records of 113 Japanese patients with gastric cancer who were previously treated with cytotoxic chemotherapy and initiated nivolumab. The endpoints were the incidence of Grade 2 or higher immune-related adverse events (irAEs) in the conventional dose (3 mg/kg) and fixed-dose groups (240 mg). Results: The incidence rates of irAEs in the conventional-dose and fixed-dose groups were 29.9% and 19.4%, respectively, and the rates of Grade 2 or higher irAEs were 23.3% and 19.4%, respectively, with no significant difference between the two groups, suggesting that nivolumab at 240 mg is as safe as the 3 mg/kg dose. Conclusion: This is the first report on the safety of nivolumab at 240 mg in Japanese patients.

Occurrence of Infusion-Related Reactions due to Obinutuzumab Therapy for Follicular Lymphoma.

BACKGROUND: Obinutuzumab is used to treat follicular lymphoma in Japan. Its characteristic adverse event is infusion- related reactions(IRRs). Although interruption of administration improves many IRRs, serious symptoms can occur; thus, timing the interruption to correspond with the onset of these symptoms is necessary. However, the specific symptoms and timing of IRRs caused by obinutuzumab remain unclear. Therefore, the purpose of this study was to clarify the specific symptoms and timing of the onset of IRRs with obinutuzumab treatment. METHODS: Thirty patients were administered obinutuzumab for one year from October 2018 to September 2019. The frequency of IRRs, expression time, severity, symptoms, and correspondence were investigated. RESULTS: IRRs occurred in 13 patients(43.3%), and all occurred after the first dosing. In 9 of 13 cases(69.2%), IRRs occurred within 90 min of the first dosage. Grade 3 symptoms were expressed in 1 of 13 cases (7.7%). The symptoms of IRRs were throat discomfort, breathing difficulty, skin rash, chills, and fever. CONCLUSIONS: Most IRRs due to obinutuzumab occurred within 90 min of the first dosage. They were mostly Grade 2 or lower, and the frequency of serious IRRs was low. Thus, careful observation of symptoms during treatment with obinutuzumab is necessary.

Association Between Regorafenib Dose and Efficacy Against Metastatic Colorectal Cancer in a Real-World Setting.

The association between regorafenib dosage in the treatment of metastatic colorectal cancer (mCRC) and efficacy is currently not well established. It was previously reported that the regorafenib dose as prescribed is associated with efficacy, but doses in actual clinical settings have not been analyzed. We retrospectively analyzed patients with mCRC who had received regorafenib as third-line or later chemotherapy between May 2013 and June 2018. Patients who were not treated in the Pharmaceutical Outpatient Clinic for compliance assessment were excluded. Overall survival was calculated using the Kaplan-Meier method. Prognostic factors, including baseline demographics and adverse events, were evaluated using Cox proportional hazard models. A total of 176 patients were enrolled. By multivariate analysis, total dose until the second cycle < 3180 mg (HR = 1.71, 95% CI, 1.20-2.44, P = .003) was one of independent negative predictors of overall survival. Median survival times of the lower-dose group (< 3180 mg) and higher-dose group (≥ 3180 mg) were 5.8 and 7.6 months, respectively (P = .045). The cumulative dose of regorafenib until the second cycle in patients with mCRC was associated with survival. It is important to individualize regorafenib dose in mCRC patients.

The Combined Use of 5 or More Drugs Is a Factor Related to Lower Adherence to S-1 in S-1 and Oxaliplatin Treatment for Advanced Gastric Cancer.

S-1 plus oxaliplatin (SOX) is an established treatment for advanced gastric cancer. S-1 adherence is the key to successful SOX treatment. This study focused on S-1 adherence by evaluating real-world adherence to S-1 and investigating factors related to decreased S-1 adherence. This study included cases treated between August 1, 2014 and October 12, 2016 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The S-1 adherence rate per cycle was defined as the number of times a patient took S-1/28. In this study, adherence to S-1 was assessed through pill counts and by asking the patient about the reason for non-adherence at a pharmaceutical outpatient clinic. Univariate and multivariate analyses were performed to investigate factors influencing lower adherence. This analysis included 116 patients evaluated for adherence to S-1 on SOX treatment. The median rate of adherence to S-1 was 92.8% in the first cycle and 90.5% in the seventh cycle. The median relative dose intensity of S-1 was 84.6%. In terms of reasons for nonadherence, patients most commonly cited nausea/vomiting (43.7%), diarrhea (20.8%), missed dose (11.8%), and fever (8.1%). Logistic regression analysis was performed using the most appropriate regression equation, and a significant association was detected with 1 factor, number of combined drugs ≥5 (odds ratio (OR) = 2.50; 95% confidence interval (CI), 1.04-6.03, p = 0.04). Eliminating unnecessary concomitant medications helps maintain proper adherence to S-1 in SOX treatment.

Risk factors for severe neutropenia in pancreatic cancer patients treated with gemcitabine/nab-paclitaxel combination therapy.

AIM: Combination therapy with gemcitabine and nanoparticle albumin-bound paclitaxel (nab-paclitaxel), known as GnP therapy, significantly prolongs the survival of pancreatic cancer patients compared with gemcitabine monotherapy. However, it may cause severe neutropenia, requiring discontinuation of treatment. This study aimed to clarify the risk factors for Grade 3/4 neutropenia during GnP therapy. METHODS: Clinical data of pancreatic cancer patients who underwent GnP therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from December 2014 to December 2016 were retrospectively collected. The relationship of Grade 3/4 neutropenia onset to laboratory values and patient background factors was investigated by multivariate logistic regression analysis. RESULTS: Clinical data of 222 patients were analyzed. Grade 3/4 neutropenia occurred in 118 patients (53.2%) in the first cycle of GnP therapy. Multivariate analysis identified low absolute neutrophil count (ANC), high total bilirubin (T-Bil), and low C-reactive protein (CRP) as risk factors for Grade 3/4 neutropenia. Age was not a risk factor. The incidence of neutropenia was 85.7% in patients with all three risk factors, but only 27.7% in patients with none of them. CONCLUSION: Low ANC, high T-Bil, and low CRP may be risk factors for Grade 3/4 neutropenia in patients receiving GnP therapy, even if these laboratory values are within normal reference ranges. Patients with these risk factors should be carefully monitored for adverse events.

Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers.

PURPOSE: The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. METHODS: The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. RESULTS: We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035). CONCLUSION: This study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.

[Effect of the Antiemetic Drug Olanzapine on Blood Sugar Levels in Patients Treated with Adjuvant or Neoadjuvant Chemotherapy for Breast Cancer].

This retrospective study aimed to evaluate the effect of the antiemetic drug olanzapine(OLZ)on blood sugar levels in patients treated with adjuvant or neoadjuvant chemotherapy(AC: doxorubicin plus cyclophosphamide or CEF: cyclophosphamide plus epirubicin plus fluorouracil) for breast cancer. Here, we evaluated the frequency of diabetes(postprandial blood sugar: PBS≥200 mg/dL)and the change in PBS in 149 patients who were prescribed OLZ between September 2016 and August 2017 at our hospital. No diabetic patients were identified during the observation period(median: 3 cycles of chemotherapy). Among the 95 patients with more than 2 PBS readings, no difference was observed in the incidence of increased PBS, regardless of the diabetic risk, before and after OLZ administration. This study therefore found that the short term use of OLZ as an antiemetic had little effect on PBS, suggesting that it can be used safely during treatment with AC or CEF.

Association Between Immune-related Adverse Events and Clinical Outcome Following Nivolumab Treatment in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: Immune-related adverse events (irAEs) are associated with the efficacy of immune-checkpoint inhibitors in patients with melanoma and non-small cell lung cancer. We therefore evaluated the relationship between irAEs and nivolumab efficacy against metastatic renal cell carcinoma. PATIENTS AND METHODS: The medical records of 53 consecutive patients were reviewed and analyzed. RESULTS: Median overall survival was significantly better in patients who showed irAEs at any time compared to patients without irAEs (p=0.013). We identified irAEs in 24 of 53 patients (45.3%), including four patients (7.5%) with grade 3 events. Multivariate analysis also revealed that risk factors for the onset of irAEs were positively associated with a platelet-to-lymphocyte ratio <156 before nivolumab treatment (p=0.006). CONCLUSION: Development of irAEs was associated with survival outcomes of nivolumab treated patients with metastatic renal cell carcinoma.

Impact of Primary Pegfilgrastim Prophylaxis on Relative Dose Intensity in Neoadjuvant/Adjuvant FEC-100 Chemotherapy.

BACKGROUND/AIM: This study aimed was to clarify the impact of pegfilgrastim (PEG) 3.6 mg primary prophylaxis of febrile neutropenia (FN) on the average relative dose intensity (ARDI) of neoadjuvant/adjuvant FEC-100 for breast cancer. MATERIALS AND METHODS: This retrospective, single-centre cohort study including 296 patients who received FEC-100 compared PEG and non-PEG groups. The PEG group received PEG 3.6 mg as a single subcutaneous injection in each study cycle. The primary endpoint was the ARDI of FEC-100. The secondary endpoints were patient percentage of ARDI≥85%, factors associated with ARDI≥85%, and reasons for reduced ARDI. RESULTS: The PEG group showed significantly higher mean ARDI (95.6% versus 90.7%, p<0.001) and patient percentage of ARDI≥85% (93.0% versus 79.9%, p=0.001). PEG was significantly associated with ARDI≥85% (p=0.009). Neutropenia and FN, the main reasons for reduced ARDI, were significantly lower in the PEG group (p<0.05). CONCLUSION: Primary PEG 3.6 mg prophylaxis increased the ARDI of FEC-100.

Comparison of cisplatin-induced nephrotoxicity when using conventional versus short hydration in gastric cancer-a retrospective study.

Although a short hydration protocol for cisplatin has been recently developed for use in lung cancer, this has yet to be established for gastric cancer. This study reviewed medical records of patients with gastric cancer who received XPT(capecitabine/cisplatin/trastuzumab) therapy containing cisplatin. Patients received either the conventional or short hydration regimen. Nephrotoxicity was compared between these two regimens by monitoring the serum creatinine. Out of the 26 total patients, 19 received the conventional regimen while 7 received the short hydration regimen. There was a higher nephrotoxicity was observed in the group receiving the conventional regimen (42.1%, 8/19) as compared to the short hydration regimen (0%, 0/7). There was a statistically significant difference in nephrotoxicity between the regimens (P = 0.039). Study results suggest that short hydration may be a feasible regimen for XPT therapy in gastric cancer patients.

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma.

PURPOSE: Immune-related adverse events (irAEs) have been associated with the efficacy of programmed cell death protein 1 (PD-1) inhibitors in patients with urothelial cancer. We therefore evaluated the relationship between irAEs and pembrolizumab efficacy in urothelial cancer patients. METHODS: Patients with urothelial cancer who were treated with pembrolizumab in a second-line setting or later between January 2018 and December 2018 were identified by reviewing their medical records from the Cancer Institute Hospital, Japanese Foundation for Cancer Research. Data were updated as of December 31, 2018. Kaplan-Meier curves for overall survival (OS) and time to treatment failure (TTF) according to irAE grade were evaluated using the log-rank test. Risk factors for exacerbation of irAEs were also evaluated with multivariate analysis. RESULTS: In this retrospective study, 43 patients received pembrolizumab. We identified irAEs in 22 of the 43 patients (51.2%), including 11 patients (25.6%) with grade 2 or 3 events. In patients with irAE grade 0 or 1, median TTF was 127 days, and median OS was 160 days according to the Kaplan-Meier method. On the other hand, in patients with irAE grade ≥2, median TTF and OS were not reached. Multivariate analysis also revealed that risk factors for exacerbation of irAEs (to grade ≥2) were positively associated with lymphocyte count at baseline (>2,000/µL) before pembrolizumab treatment (p = 0.021). CONCLUSIONS: Development of irAEs was associated with survival outcome of pembrolizumab treatment in patients with advanced urothelial cancer.

Identification of risk factors for venous thromboembolism and evaluation of Khorana venous thromboembolism risk assessment in Japanese lung cancer patients.

BACKGROUND: The reported incidence of venous thromboembolism (VTE) in cancer patients is 4-20%. The Khorana VTE risk score (KRS) and the Vienna VTE risk score (VRS) have been proposed as scoring models for evaluation of cancer-associated VTE. However, the risk factors of VTE in Japanese lung cancer patients have not been clarified. METHODS: This retrospective study included 682 hospitalized Japanese patients with newly diagnosed lung cancer who were examined for VTE on admission between January 2014 and December 2016. RESULTS: Seventy-one (10.4%) of the 682 patients were diagnosed with VTE. Multivariate logistic regression analysis showed that body mass index (BMI) ≥25 kg/m2 (OR, 2.02; 95% CI, 1.06-3.72), white blood cell (WBC) count >11 × 109/L (OR, 2.31; 95% CI, 1.11-4.61), pre-chemotherapy serum D-dimer concentration ≥1.44 µg/mL (OR, 2.73; 95% CI, 1.49-4.99), and non-small cell lung cancer (OR, 3.13; 95% CI, 1.32-9.23) were significantly associated with VTE in these patients. The cut-off values for BMI, WBC count, and D-dimer concentration determined using receiver operating characteristic curves were 25.4 kg/m2, 11.2 × 109/L, and 1.95 µg/mL, respectively. CONCLUSIONS: In this study, we were able to identify four independent risk factors for cancer-associated VTE in Japanese lung cancer patients for the first time. Moreover, we showed that a cut-off level of ≥25 kg/m2 for BMI was a risk factor for VTE in this cohort.

[Effects of Seven Tyrosine Kinase Inhibitors on the Anticoagulation Activity of Warfarin].

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.

Factors Associated With Regorafenib Adherence With Metastatic Colorectal Cancer.

INTRODUCTION: Regorafenib is an oral multikinase inhibitor for the treatment of metastatic colorectal cancer (mCRC). The clinical factors that may affect adherence to regorafenib remain unclear. The aim of this study was to evaluate adherence to regorafenib with mCRC and to identify factors that might affect adherence to regorafenib. METHODS: A total of 108 consecutively enrolled Japanese patients with mCRC received regorafenib. Adherence was measured by pharmacists using pill counts and a self-reported treatment diary for patients at a pharmaceutical outpatient clinic. The median relative dose intensities of regorafenib and the factors adversely affecting adherence were retrospectively surveyed. Logistic regression analysis was then performed using patient socio-demographic factors and clinical factors. RESULTS: A total of 96 patients were included in the analysis. The median adherence rate was 61.7% in the first cycle. The median relative dose intensity was 57.1%. The most common reason for non-adherence was a hand-foot-skin reaction (35.6%). On multivariate analysis, increased non-adherence to regorafenib was significantly associated with sex (female) [odds ratio (OR) = 4.36; 95% confidence interval (CI): 1.43-13.22, p = 0.01]. DISCUSSION: Hand-foot-skin reactions and female sex were associated with lower adherence to regorafenib. Since these factors could be associated with lower adherence to regorafenib, it would be useful to consider these factors when assessing adherence.

[Effects of Tyrosine Kinase Inhibitors on Control of PT-INR in Patients Receiving Warfarin].

Few studies have evaluated the influence of anticancer drugs on the anticoagulation response to warfarin(WF). This retrospective, single-center, observationalstudy evaluated the changes in prothrombin time-internationalnormal ized ratio (PT-INR)in patients receiving a combination of WF and anticancer drugs. We compared(a)PT-INR changes between groups receiving WF and concomitantly started on either tyrosine kinase inhibitors(TKI)(WF+TKI group: n=14)or anticancer drugs other than TKI(WF+non-TKI group: n=20)and(b)PT-INR changes between groups that were started on WF concomitantly while receiving either TKI(TKI+WF group: n=16)or anticancer drugs other than TKI(non-TKI+WF group: n=13). (a)PT-INR changes were significantly larger in the WF+TKI group than in the WF+non-TKI group(2.23 vs 0.42, p<0.001). In the WF+TKI group, the WF dose was reduced after all 14 patients(100.0%)showed increased PT-INR.(b)PT-INR changes during the WF induction period were significantly larger in the TKI+WF group than in the non-TKI+WF group(2.18 vs 0.68, p<0.001). In the TKI+WF group, the WF dose was reduced after 12 patients(75.0%)showed increased PT-INR. It might be necessary to consider a reduction in WF dose when WF is administered in combination with TKIs.

Association of Hand-Foot Skin Reaction with Regorafenib Efficacy in the Treatment of Metastatic Colorectal Cancer.

PURPOSE: Hand-foot skin reaction (HFSR) can deteriorate quality of life in patients receiving regorafenib. Cutaneous toxicity is a main adverse effect of multikinase inhibitors and has also been associated with clinical outcome. This study assessed the association between the antitumor efficacy of regorafenib and HFSR in patients with metastatic colorectal cancer (mCRC). METHODS: Patients who received regorafenib at 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they developed HFSR between May 2013 and October 2015. Estimates of overall survival and progression-free survival were calculated using the Kaplan-Meier method. RESULTS: Ninety-seven patients received at least one dose of regorafenib in this retrospective study. Of these patients, 81.4% (n = 79) experienced HFSR of any grade, and 34.0% (n = 33) had grade 3 HFSR. Among those patients with HFSR at any time during the study, 68.0% (n = 66) underwent the first HFSR event (any grade) during cycle 1. Both overall survival and progression-free survival were improved in patients who had HFSR grade ≥2 at any time compared with those who had HFSR grade ≤1. Multivariate logistic regression analysis revealed a history of HFSR grade ≥2 induced by capecitabine as a significant risk factor for severe HFSR (grade ≥2). CONCLUSIONS: Patients with mCRC treated using regorafenib who experienced severe HFSR showed better overall survival than patients without severe HFSR. Severe HFSR may offer an early surrogate marker for the efficacy of regorafenib in patients with mCRC.

Regorafenib-Induced Hand-Foot Skin Reaction Is More Severe on the Feet Than on the Hands.

Regorafenib is a multikinase inhibitor for the treatment of metastatic colorectal cancer. Regorafenib-induced hand-foot skin reaction (HFSR) is a common side effect during treatment. The reported frequency of HFSR was 80% (grade 3: 28%) in the Japanese subpopulation in the CORRECT trial; however, more detailed data regarding HFSR in terms of onset and sites of susceptibility are unclear. Additionally, the risk factors for regorafenib-induced severe HFSR are unknown. The aim of this study was to compare HFSR between the hands and feet and identify preexisting risk factors for severe HFSR in Japanese patients receiving regorafenib. We retrospectively examined the onset and severity of HFSR on the hands and feet of patients with metastatic colorectal cancer treated with regorafenib from May 2013 to October 2015 in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. In addition, we examined the possible association between preexisting clinical factors and severe HFSR. Our results showed that no significant difference in the incidence of HFSR of any grade was observed between the hands (71%) and feet (74%) (p = 0.63). The incidence of grade 3 HFSR was more frequent on the feet (33%) than on the hands (8%) (p < 0.01). The onset of grade 3 HFSR was earlier on the feet than on the hands (p < 0.001). No preexisting risk factor was identified. Our findings indicate that severe HFSR was more prevalent on the feet than on the hands, suggesting the need for appropriate screening for early detection and treatment of regorafenib-induced HSFR.