Janus kinase inhibitors and the changing landscape of vitiligo management: a scoping review.

Vitiligo is a chronic skin condition caused by an autoimmune response that results in the progressive loss of melanocytes and recent studies have suggested that Janus kinase inhibitors (JAKi) are emerging as a promising new treatment modality. Therefore, to assess and understand the extent of knowledge in the emerging field of JAKi use in vitiligo, a scoping review of the literature was undertaken. The reviewed articles explored a wide variety of JAKi administered either orally or topically for vitiligo. There were no injectable JAKi studied. Tofacitinib was the most commonly studied oral JAKi in 16 of the 35 studies selected for review, followed by baricitinib (n = 3), and one study each with ritlecitinib, ruxolitinib, and upadacitinib. Ruxolitinib (n = 6) and tofacitinib (n = 6) were the most often studied topical JAKi, followed by delgocitinib (n = 1). Potential benefits may vary between JAKi based on their receptor selectivity profile and coexistent autoimmune diseases. A topical JAKi would be advantageous in limited body area involvement and in adolescents. Concurrent use of JAKi with phototherapy or sun exposure appears beneficial. Most studies permitted the use of other topical agents. Acne-related events, though frequent yet mild, were reported with both oral and topical JAKi. Nasopharyngitis, upper respiratory tract infections, and headaches were the most common adverse effects seen in the larger trials with JAKi. No serious or clinically meaningful hematology or thromboembolic events were detected. Treatment of vitiligo with oral or topical JAKi seems to be promising and the growing evidence shows a favorable risk-benefit profile.

Association Between Vonoprazan and the Risk of Gastric Cancer After Helicobacter pylori Eradication.

BACKGROUND & AIMS: Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs are associated with an increased risk of gastric cancer (GC) after Helicobacter pylori (Hp) eradication, it is uncertain whether PCABs carry the same risk. METHODS: Using a population-based claims database in Japan, we identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018. Patients who failed this regimen and those diagnosed with GC before or within 1 year after Hp eradication were excluded. We compared GC incidence between PCAB users and histamine type-2 receptor antagonist (H2RA) users, matching them on the basis of propensity scores calculated with considerations for age, sex, smoking, alcohol consumption, comorbidities, and co-administered medications. PCABs included only vonoprazan in this study. RESULTS: Among 54,055 patients, 568 (1.05%) developed GC during the follow-up period (mean, 3.65 years). The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in PCAB users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. The use of PCABs was associated with a higher GC risk (matched hazard ratio, 1.92; 95% confidence interval, 1.13-3.25; P = .016). Longer PCAB use and high-dose PCAB use were significantly associated with higher incidence of GC. Sensitivity analyses showed the risk of GC incidence among PCAB users was comparable with that of PPI users. CONCLUSIONS: The use of PCABs was associated with an increased risk of GC among Hp-eradicated patients, with duration/dose response effects.

Comparison of the efficacy and safety of Shanhuang Jiangzhi tablets and atorvastatin in the treatment of patients with hyperlipidaemia.

OBJECTIVES: To compare the efficacy and safety of Shanhuang Jiangzhi tablets and atorvastatin in reducing blood lipid levels. METHODS: Patients with hyperlipidaemia admitted to the cardiac centre between January 2019 and December 2020 were included in the study. A total of 1063 patients with hyperlipidaemia took either Shanhuang Jiangzhi tablets (n = 372) or atorvastatin (n = 691) and met the inclusion and exclusion criteria. Clinical data, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, were retrospectively evaluated after propensity score matching (PSM) analysis. The adverse events were also recorded during the therapy process. RESULTS: Following PSM analysis, both groups were well matched across all parameters. Compared with the baseline, Shanhuang Jiangzhi tablets had greater effects on TC, TG and LDL-C, and the difference was statistically significant (p < 0.001). Furthermore, the results showed that Shanhuang Jiangzhi tablets are similar to atorvastatin in reducing TC and LDL-C, and all p-values were > 0.05. However, the decrease of TG was greater in the Shanhuang Jiangzhi group (p < 0.001). Clinical adverse reactions of Shanhuang Jiangzhi tablets are rare and have no statistical significance compared with atorvastatin (p = 0.682). CONCLUSIONS: Shanhuang Jiangzhi tablets have a higher hypotriglyceridaemic performance than atorvastatin and an equivalent ability to lower TC and LDL-C. In addition, Shanhuang Jiangzhi tablets are a low-risk option for lowering blood lipids.

Short-term safety and efficacy of escalating doses of atorvastatin for dyslipidemia in children with predialysis chronic kidney disease stage 2-5.

BACKGROUND: Dyslipidemia is a potentially modifiable risk factor in patients with chronic kidney disease (CKD). Information on the safety and efficacy of statins in pediatric CKD is limited. METHODS: Patients with CKD stage 2-5 and aged 5-18 years with low-density lipoprotein cholesterol (LDL-C) > 130 mg/dL and/or non-high-density lipoprotein cholesterol (non-HDL-C) > 145 mg/dL were enrolled from September 2019 to February 2021. All patients were administered atorvastatin 10 mg/day, which was escalated to 20 mg/day if LDL-C remained > 100 mg/dL and/or non-HDL-C > 120 mg/dL at 12 weeks. Proportion of patients achieving target lipid levels (LDL-C ≤ 100 mg/dL and non-HDL-C ≤ 120 mg/dL) and adverse events were assessed at 24 weeks. RESULTS: Of 31 patients enrolled, target lipid levels were achieved in 45.2% (95% CI 27.8-63.7%) at 24 weeks; 22 patients required dose escalation to 20 mg at 12 weeks. There was no difference in median lipid level reduction with 10 (n = 9) versus 20 mg/day (n = 22, P = 0.3). Higher baseline LDL-C (OR 1.06, 95% CI 1.00-1.11) and older age (OR 36.5, 95% CI 2.57-519.14) were independent predictors of failure to achieve target lipid levels with 10 mg/day atorvastatin. None had persistent rise in AST/ALT > 3 times upper normal limit (UNL) or CPK > 10 times UNL. No differences were noted in adverse events due to atorvastatin 10 or 20 mg/day. CONCLUSION: Atorvastatin (10-20 mg/day) administered for 24 weeks was safe and effectively reduced LDL-C and non-HDL-C in children with CKD stages 2-5. Patients with higher baseline LDL-C required higher doses to achieve the target. A higher resolution version of the Graphical abstract is available as Supplementary information.

Severe Liver Injury Associated With High-Dose Atorvastatin Therapy.

Statins are recommended for first-line management of elevated cholesterol in the primary and secondary prevention of atherosclerotic cardiovascular disease. Statins may occasionally be associated with mild transaminase elevations but can also result in life-threatening liver injury. Atorvastatin is the most common cause of clinically significant liver injury in this drug class. We report a case of severe, asymptomatic liver injury in a hepatocellular pattern in a 71-year-old man occurring within 3 months of switching from simvastatin to high-intensity atorvastatin therapy. Hepatitis improved rapidly with cessation of atorvastatin and did not recur after resuming simvastatin.

Maneuvering Clinical Pathways for Ulcerative Colitis.

PURPOSE OF REVIEW: Recent years have brought about several advances in the treatment of patients with ulcerative colitis (UC). Here, we discuss salient recommendations of recent treatment guidelines; review the efficacy, safety, and real-world data of vedolizumab and tofacitinib; appraise their place vis-à-vis established agents; and consider the newly proposed approaches of risk-stratified and treat-to-target therapy. RECENT FINDINGS: Once daily oral mesalamine dosing is equivalent to split dosing in mild-moderate UC. Real-world data are accumulating on the effectiveness and safety of vedolizumab for moderate to severe UC, while there are few such data on the most recently approved agent, tofacitinib. High-dose infliximab is being investigated for severe UC. New approaches are challenging the established paradigm of selecting therapy based on current disease activity. The risk-stratified approach incorporates long-term risk as well as the current burden of inflammation. The treat-to-target approach aims at improved long-term outcomes by adjusting therapy to resolve intestinal inflammation. The therapeutic options for UC are continually expanding. Risk-stratified therapy and the treat-to-target approach represent paradigm shifts in UC management. Optimal disease control requires an individualized approach that takes into consideration current inflammatory burden, long-term risk, patient preferences, and ongoing assessment of response to treatment.

Oral small molecules for the treatment of atopic dermatitis: a systematic review.

Introduction: Atopic dermatitis (AD) is a chronic, inflammatory skin disease. Conventional treatments include topical emollients, corticosteroids, calcineurin inhibitors, phototherapy, and systemic immunomodulatory agents, however, these medications have limitations in the treatment of moderate to severe AD. Current literature demonstrates that oral small molecules may be an effective modality to treat AD. Method: Using PubMed/MEDLINE, Embase, Cochrane Skin databases and clinicaltrials.gov a search with terms 'atopic dermatitis or atopic eczema' and 'name of the oral small molecule' was conducted resulting in 1197 articles. Inclusion criteria were studies involving human subjects treated with oral small molecule medication for AD and written in English. Randomized clinical trials, open-label prospective trials, and case reports/series were reviewed. Results: Seven articles, with a total of 250 patients, were included for review. Oral small molecules studied include: apremilast, baricitinib, JNJ-39758979, and tofacitinib. Small molecules demonstrate improvement in AD disease scores, patient-reported outcomes, and quality of life. Conclusion: Preliminary results demonstrate that oral small molecules are an effective treatment option in AD with minimal side effects. Additional randomized studies with larger sample sizes are needed to determine the efficacy and long-term side effects of these novel therapies.

[Comparison of efficacy between sorafenib and sunitinib as first-line therapy for metastatic renal cell carcinoma and analyze prognostic factors for survival].

Objective: To investigate the efficacy and drug related adverse reactions of sorafenib and sunitinib as first-line tyrosine-kinase inhibitors (TKIs) for patients with metastatic renal cell carcinoma (mRCC) and analyze the clinical prognostic factor for survival. Methods: The data of 271 patients with metastatic renal cell carcinoma who had complete clinicopathological data were retrospectively analyzed, including 174 cases in sorafenib group and 97 cases in sunitinib group, to access patients' overall survival (OS) and progression-free survival (PFS). Prognostic values of all characteristics were determined by using univariate and multivariate Cox regression models. Results: The objective response rates (ORR) of the sorafenib and sunitinib groups were 14.9% and 19.6%, respectively, and the disease control rates (DCR) were 85.1% and 88.6%, respectively. No significant difference was found between the sorafenib and sunitinib group in ORR (P=0.325) or DCR (P=0.408). The most common grade 3 to 4 adverse events in the sorafenib group were hand-foot syndrome (6.7%), diarrhea (2.3%), and rash (2.3%). The most common grade 3 to 4 adverse events in the sunitinib group were neutropenia (6.2%), hand-foot syndrome (6.2%), and thrombocytopenia (4.6%). During the follow-up, 97 cases death occurred and 81 cases disease progression occurred in sorafenib group. The median PFS was 12 months (95% CI: 9-15 months), and the median OS was 25 months (95% CI: 21-29 months) in sorafenib group. While 74 cases death occurred and 40 cases disease progression occurred in sunitinib group, the median PFS was 12 months (95% CI: 10-12 months) and the median OS was 23 months (95% CI: 20-32 months) in sunitinib group. No significant difference was found between the sorafenib and the sunitinib group in PFS (P=0.771) or OS (P=0.548). Multivariate analysis showed Fuhrman grades (HR=1.358, 95%CI: 1.004-1.835), number of metastatic sites (HR=1.550, 95%CI: 1.143-2.101) and MSKCC risk grade (Intermediate risk group: HR=1.621, 95%CI: 1.117-2.232; Poor risk group: HR=2.890, 95%CI: 1.942-4.298) were independent prognostic factors for PFS. Fuhrman grades (HR=2.135, 95%CI: 1.533-2.974), number of metastatic sites (HR=1.774, 95%CI: 1.279-2.461) and MSKCC risk grade (Intermediate risk group: HR=1.415, 95%CI: 1.002-1.998; Poor risk group: HR=3.161, 95%CI: 2.065-4.838) were independent prognostic factors for OS. Conclusions: The results of this study indicate that sorafenib and sunitinib are both effective as the first-line TKIs for mRCC patients and sorafenib has comparable efficacy to sunitinib. But they have differences in the incidence of adverse effects. Fuhrman grades, number of metastatic sites and MSKCC risk grade are independent prognostic factors for mRCC patients.

Effects of Toceranib Phosphate on the Hypothalamic-Pituitary-Thyroid Axis in Tumor-Bearing Dogs.

BACKGROUND: Thyroid dysfunction is associated with the use of tyrosine kinase inhibitors (TKI) in people. HYPOTHESIS/OBJECTIVES: To determine whether dysfunction in the hypothalamic-pituitary-thyroid axis occurs in dogs receiving the TKI, toceranib phosphate. ANIMALS: Forty-three client-owned dogs with cancer. METHODS: Prospective, observational study. Concentrations of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), and thyroid-stimulating hormone (TSH) were evaluated on day 0, 30, and 90. Dogs also were evaluated for the presence of thyroglobulin autoantibodies. RESULTS: The proportion of dogs with low TT4, low FT4, low TT3, high TSH, or primary hypothyroidism (increased TSH and decreased TT4, FT4 or both) did not change over 90 days. Hormone concentrations remained within laboratory reference intervals, but FT4 (P = 0.0032) and TSH (P < 0.0001) changed over time. Mean FT4 was 1.22 ng/dL (95% confidence interval [CI], 1.10-1.34) on day 0 and 1.00 ng/dL (95% CI, 0.86-1.16) on day 90. Mean TSH was 0.17 ng/mL (95% CI, 0.13-0.23) on day 0 and 0.34 ng/mL (95% CI, 0.24-0.48) on day 90. Furthermore, TT4/TT3 ratio also changed over time (P = 0.0086). Mean TT4/TT3 ratio was 2.57 (95% CI, 2.26-2.88) on day 0 and 2.02 on day 90 (95% CI, 1.61-2.44). Thyroglobulin autoantibodies were not detected in any dog. CONCLUSIONS AND CLINICAL IMPORTANCE: Toceranib phosphate can disrupt the hypothalamic-pituitary-thyroid axis in dogs. Periodic evaluation of TT4, FT4, TT3, and TSH should be carried out in dogs receiving long-term treatment with this medication.

Design, Synthesis and Evaluation of Novel 2-Hydroxypyrrolobenzodiazepine-5,11-dione Analogues as Potent Angiotensin Converting Enzyme (ACE) Inhibitors.

Under the guidance of combination of traditional Chinese medicine chemistry (CTCMC), this study describes the preparation of a phenolic acid/dipeptide/borneol hybrid consisting of phenolic acid and a bornyl moiety connected to the dipeptide N-terminal and C-terminal respectively. It also evaluates their angiotensin converting enzyme (ACE) inhibitory and synergistic antihypertensive activities. Briefly, a series of novel 2-hydroxypyrrolobenzodiazepine-5,11-dione analogues were prepared and investigated for their ability to inhibit ACE. The influence of the phenolic acid and bornyl moiety on subsite selectivity is also demonstrated. Among all the new compounds, two compounds-7a and 7g-reveal good inhibition potency in in vitro ACE-inhibitory tests. Interestingly, favorable binding results in molecular docking studies also supported the in vitro results. Additionally, the bioassay showed that oral administration of the two compounds displayed high and long-lasting antihypertensive activity both in acute antihypertensive tests and in therapeutic antihypertensive tests by non-invasive blood pressure measurements in spontaneously hypertensive rats.

[Systemic treatment of vitiligo : Balance and current developments]. / Systemtherapie der Vitiligo : Bilanz und aktuelle Entwicklungen.

Systemic drug treatment of vitiligo is currently limited to predominantly adjuvant measures for increasing the effectiveness of UV light therapy. We here present new approaches for the systemic treatment of vitiligo currently under clinical investigation. These include the α­MSH-analogue afamelatonide and oral immunosuppressants such as the Janus kinase (JAK) inhibitors which target interferon-α-dependent autotoxic inflammatory reactions. In 2015 the first publications on the successful systemic use of Janus kinase (JAK) inhibitors in vitiligo appeared. The effectiveness was experimentally supported by animal models of vitiligo and by the characterization of new biomarkers in the serum of vitiligo patients. This may significantly expand the range of treatment options for vitiligo. Topical antiinflammatory and UV therapies are still the main components of vitiligo treatment, often in combination. The main outcome parameters include the extent and duration of repigmentation, cessation of spreading, avoidance of side effects and improvement in the quality of life of patients.

Comparison of efficacy, safety, and quality of life between sorafenib and sunitinib as first-line therapy for Chinese patients with metastatic renal cell carcinoma.

BACKGROUND: Sorafenib and sunitinib are widely used as first-line targeted therapy for metastatic renal cell carcinoma (mRCC) in China. This study aimed to compare the efficacy, safety, and quality of life (QoL) in Chinese mRCC patients treated with sorafenib and sunitinib as first-line therapy. METHODS: Clinical data of patients with mRCC who received sorafenib (400 mg twice daily; 4 weeks) or sunitinib (50 mg twice daily; on a schedule of 4 weeks on treatment followed by 2 weeks off) were retrieved. Primary outcomes were overall survival (OS), progression-free survival (PFS), adverse events (AEs), and QoL (SF-36 scores), and secondary outcomes were associations of clinical characteristics with QoL. RESULTS: Medical records of 184 patients (110 in the sorafenib group and 74 in the sunitinib group) were reviewed. PFS and OS were comparable between the sorafenib and sunitinib groups (both P > 0.05). The occurrence rates of leukocytopenia, thrombocytopenia, and hypothyroidism were higher in the sunitinib group (36.5% vs. 10.9%, P < 0.001; 40.5% vs. 10.9%, P < 0.001; 17.6% vs. 3.6%, P = 0.001), and that of diarrhea was higher in the sorafenib group (62.7% vs. 35.2%, P < 0.001). There was no significant difference in SF-36 scores between the two groups. Multivariate analysis indicated that role-physical and bodily pain scores were associated with the occurrence rate of grade 3 or 4 AEs (P = 0.017 and 0.005). CONCLUSIONS: Sorafenib has comparable efficacy and lower toxicity profile than sunitinib as first-line therapy for mRCC. Both agents showed no significant impact on QoL of patients.

Association of post-treatment hypoalbuminemia and survival in Chinese patients with metastatic renal cell carcinoma.

BACKGROUND: Hypoalbuminemia adversely affects the clinical outcomes of various cancers. The purpose of this study was to estimate the prognostic value of hypoalbuminemia 3-5 weeks after treatment in patients with metastatic renal cell carcinoma (mRCC) who received sorafenib or sunitinib as first-line treatment. METHODS: In this single-center, retrospective study, we assessed the progression-free survival (PFS) and overall survival (OS) of 184 mRCC patients who received first-line sorafenib or sunitinib treatment. PFS and OS were compared between patients with post-treatment hypoalbuminemia (post-treatment albumin level <36.4 g/L) and those with normal post-treatment albumin level (albumin level ≥36.4 g/L). The Memorial Sloan Kettering Cancer Center (MSKCC) risk model stratified mRCC patients into three risk categories. Prognostic values of all patient characteristics including MSKCC risk category were determined by using univariate and multivariate Cox regression models. Prognostic value was further determined using the Harrell concordance index and receiver operating characteristic curve analysis. RESULTS: The median PFS and OS of the 184 patients were 11 months (95% confidence interval [CI] 9-12 months) and 23 months (95% CI 19-33 months), respectively. Patients with post-treatment hypoalbuminemia had significantly shorter median PFS (6 months [95% CI 5-7 months]) and OS (11 months [95% CI 9-15 months]) than patients who had normal post-treatment albumin levels (PFS: 12 months [95% CI 11-16 months], P < 0.001; OS: 31 months [95% CI 24-42 months], P < 0.001), respectively. Multivariate analysis showed that post-treatment hypoalbuminemia was an independent predictor of PFS (hazard ratio [HR], 2.113; 95% CI 1.390-3.212; P < 0.001) and OS (HR, 2.388; 95% CI 1.591-3.585; P < 0.001). Post-treatment hypoalbuminemia could also be combined with the MSKCC risk category for better prediction about OS. The model that included post-treatment hypoalbuminemia and MSKCC risk category improved the predictive accuracy for PFS and OS (c-index: 0.68 and 0.73, respectively) compared with the basic MSKCC risk model (c-index: 0.67 and 0.70, respectively). The prognostic values for PFS and OS of the integrated MSKCC risk model involving post-treatment hypoalbuminemia were significantly more accurate than the basic MSKCC risk model using likelihood ratio analysis (both P < 0.001). CONCLUSIONS: Post-treatment hypoalbuminemia can be considered an independent prognostic factor for patients with mRCC who undergo first-line treatment with tyrosine kinase inhibitors. Additionally, integrating post-treatment serum albumin level into the basic MSKCC risk model can improve the accuracy of this model in predicting patient overall survival and progression-free survival.

Small Molecules for Psoriasis.

Acitretin is an older, oral, non-immunosuppressive medication for the treatment of psoriasis. Tofacitinib is an oral Janus kinase inhibitor that has been studied for use in psoriasis. Each offers efficacy in certain settings and patient types but carries substantial safety risks.

Sunitinib treatment in patients with advanced renal cell cancer: the Brazilian National Cancer Institute (INCA) experience.

PURPOSE: The aim of this study was to assess the impact of sunitinib treatment in a non-screened group of patients with metastatic renal cell cancer (mRCC) treated by the Brazilian Unified Health System (SUS) at a single reference institution. MATERIAL AND METHODS: Retrospective cohort study, which evaluated patients with mRCC who received sunitinib between May 2010 and December 2013. RESULTS: Fifty-eight patients were eligible. Most patients were male 41 (71%), with a median age of 58 years. Nephrectomy was performed in 41 (71%) patients with a median interval of 16 months between the surgery and initiation of sunitinib. The most prevalent histological subtype was clear cell carcinoma, present in 52 (91.2%) patients. In 50 patients (86%), sunitinib was the first line of systemic treatment. The main adverse effects were fatigue (57%), hypothyroidism (43%), mucositis (33%) and diarrhea (29%). Grade 3 and 4 adverse effects were infrequent: fatigue (12%), hypertension (12%), thrombocytopenia (7%), neutropenia (5%) and hand-foot syndrome (5%). Forty percent of patients achieved a partial response and 35% stable disease, with a disease control rate of 75%. Median progression free survival was 7.6 months and median overall survival was 14.1 months. CONCLUSION: Sunitinib treatment was active in the majority of patients, especially those with low and intermediate risk by MSKCC score, with manageable toxicity. Survival rates were inferior in this non-screened population with mRCC treated in the SUS.

Sunitinib treatment in patients with advanced renal cell cancer: the Brazilian National Cancer Institute (INCA) experience

ABSTRACT Purpose: The aim of this study was to assess the impact of sunitinib treatment in a non-screened group of patients with metastatic renal cell cancer (mRCC) treated by the Brazilian Unified Health System (SUS) at a single reference institution. Material and Methods: Retrospective cohort study, which evaluated patients with mRCC who received sunitinib between May 2010 and December 2013. Results: Fifty-eight patients were eligible. Most patients were male 41 (71%), with a median age of 58 years. Nephrectomy was performed in 41 (71%) patients with a median interval of 16 months between the surgery and initiation of sunitinib. The most prevalent histological subtype was clear cell carcinoma, present in 52 (91.2%) patients. In 50 patients (86%), sunitinib was the first line of systemic treatment. The main adverse effects were fatigue (57%), hypothyroidism (43%), mucositis (33%) and diarrhea (29%). Grade 3 and 4 adverse effects were infrequent: fatigue (12%), hypertension (12%), thrombocytopenia (7%), neutropenia (5%) and hand-foot syndrome (5%). Forty percent of patients achieved a partial response and 35% stable disease, with a disease control rate of 75%. Median progression free survival was 7.6 months and median overall survival was 14.1 months. Conclusion: Sunitinib treatment was active in the majority of patients, especially those with low and intermediate risk by MSKCC score, with manageable toxicity. Survival rates were inferior in this non-screened population with mRCC treated in the SUS.

[Early detection of cancer therapeutics-related cardiac dysfunction]. / Stratégie de dépistage précoce de la toxicité cardiaque secondaire aux anthracyclines et thérapies moléculaires ciblées.

Anthracyclines and molecular targeted agents have improved prognosis of patients undergoing chemotherapeutics for malignancy. However, the use of these therapies is limited because of risk of cardiac toxicity. The severity of the cardiomyopathy can range from an asymptomatic left ventricular (LV) dysfunction to a severe congestive heart failure. Cardiomyopathy can be reversible or irreversible according to the type of chemotherapy, modality of administration and patient's characteristics. Several studies aimed to early detection and the evaluation of tools to characterize patients at risk to develop cardiac side effects in order to prevent severe LV dysfunction. According to this literature, it is recommended that initial assessment and follow-up of patients undergoing these chemotherapies be performed using troponin dosage, assessment of left ventricle ejection fraction and evaluation of LV myocardial deformation assessing LV global longitudinal strain.

Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network.

PURPOSE: To quantify the hepatic safety of pazopanib and comparator anti-vascular endothelial growth factor (VEGF) therapies in clinical practice among renal cell carcinoma (RCC) patients. METHODS: A population-based cohort study of new anti-VEGF users was conducted in two US healthcare databases, Department of Veterans Affairs (VA) and an oncology practice network (Altos), and the PHARMO Database Network in The Netherlands. A common protocol was used to collect liver chemistry (LC) data from anti-VEGF initiation through 4 years of follow-up. In the VA population, suspected drug-induced liver injury (DILI) outcomes were investigated via chart review, with adjudication by hepatologists. RESULTS: In Altos and VA, respectively, the total RCC patients were: pazopanib (156, 243), bevacizumab (122, 99), sorafenib (82, 249) and sunitinib (285, 751). PHARMO contained too few patients to be included. Few cases of alanine aminotransferase (ALT) ≥8× the upper limit of normal were seen across the anti-VEGF cohorts; incidence rates (per 100 person-years) ranged from 0 (sunitinib) to 8.2 (pazopanib) in Altos and from 0 (bevacizumab and sorafenib) to 2.1 (pazopanib) among VA patients. No cases of Hy's law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; one case was observed in those treated with sorafenib, and two cases were found among sunitinib users. One case of adjudicated DILI was observed in a sunitinib-treated patient; none were found among patients treated with pazopanib, bevacizumab or sorafenib. CONCLUSIONS: Severe liver injury occurred infrequently during exposure to pazopanib and other anti-VEGF therapies in a population-based setting.

Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial.

BACKGROUND: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib followed by sunitinib and regorafenib is the standard sequence of treatment for advanced disease. Pazopanib is effective in soft tissue sarcomas but has never been assessed in advanced GIST in a randomised trial. We aimed to assess the efficacy and safety of pazopanib in patients with previously treated advanced GIST. METHODS: In this randomised, open-label phase 2 study, we enrolled adults (aged ≥18 years) with advanced GIST resistant to imatinib and sunitinib from 12 comprehensive cancer centres or university hospitals in France and randomly assigned them 1:1 using an interactive web-based centralised platform to 800 mg oral pazopanib once daily in 4-week cycles plus best supportive care or best supportive care alone. Randomisation was stratified by the number of previous treatment regimens (2 vs ≥3); no-one was masked to treatment group allocation. Upon disease progression, patients in the best supportive care group were allowed to switch to pazopanib as compassionate treatment. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat. All randomised participants who received at least one dose of pazopanib were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01323400. FINDINGS: Between April 12, 2011, and Dec 9, 2013, 81 patients were enrolled and randomly assigned to pazopanib plus best supportive care (n=40) or best supportive care alone (n=41). The median follow-up was 26·4 months (IQR 22·0-37·8) in the pazopanib plus best supportive care group and 28·9 months (22·0-35·2) in the best supportive care group. 4-month investigator-assessed progression-free survival was 45·2% (95% CI 29·1-60·0) in the pazopanib plus best supportive care group versus 17·6% (7·8-30·8) in the best supportive care group (hazard ratio [HR] 0·59, 95% CI 0·37-0·96; p=0·029). Median progression-free survival was 3·4 months (95% CI 2·4-5·6) with pazopanib plus best supportive care and 2·3 months (2·1-3·3) with best supportive care alone (HR 0·59 [0·37-0·96], p=0·03). 36 (88%) of the patients originally assigned to the best supportive care group switched to pazopanib following investigator-assessed disease progression; these patients had a median progression-free survival from pazopanib initiation of 3·5 months (95% CI 2·2-5·2). 55 (72%) of the 76 pazopanib-treated patients had pazopanib-related grade 3 or worse adverse events, the most common of which was hypertension (15 [38%] in the pazopanib plus best supportive care group and 13 [36%] in the best supportive care group). 20 (26%) patients had pazopanib-related serious adverse events (14 [35%] in the pazopanib plus best supportive care group and six [17%] in the best supportive care group), including pulmonary embolism in eight (9%) patients (five [13%] in the pazopanib plus best supportive care group and three [7%] in the best supportive care group). Three pazopanib-related deaths occurred (two pulmonary embolisms [one in each group] and one hepatic cytolysis [in the best supportive care group]). Three adverse event-related but not pazopanib-related deaths occurred in the best supportive care group after switch to pazopanib; these deaths were from hyperammonaemic encephalopathy, pneumopathy, and respiratory failure. INTERPRETATION: Pazopanib plus best supportive care improves progression-free survival compared with best supportive care alone in patients with advanced GIST resistant to imatinib and sunitinib, with a toxicity profile similar to that reported for other sarcomas. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for these patients. FUNDING: GlaxoSmithKline, French National Cancer Institute, EuroSARC (FP7-278742), Centre Léon Bérard.

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS: In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.