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Sonic hedgehog pathway inhibitor Vismodegib is the first systemic treatment to be approved for metastatic or locally advanced basal cell carcinoma non-subsidiary of surgical treatment, and appears to be a promising treatment option for patients with nevoid basal cell carcinoma syndrome. In these patients, where repeated or prolonged treatment may be necessary, the psychological exhaustion caused by the chronicity of less severe adverse effects appears as the main limiting factor in the persistence of the drug in the long term and in the willingness of patients to take the drug again after its suspension. We report our experience with three cases where a drug holiday approach was effective in decreasing the intensity of adverse effects or improving the patient's subjective tolerance to the drug while maintaining clinical response., (© 2020 Wiley Periodicals LLC.)

Background: Medullary thyroid carcinoma (MTC) accounts for 1% to 2% of thyroid cancers in the United States. When identified early, total thyroidectomy is most often curative. However, in advanced disease, more aggressive treatment such as laryngectomy and esophagectomy may be indicated. Postsurgical fistula formation and leak is a potential complication in such cases. These fistulas are most likely to occur at the anastomotic site in cases of laryngectomy or esophagectomy. Concomitant chemotherapy and radiation increase this risk. Tyrosine kinase inhibitors (TKI) such as Cabozantinib are used as therapy for metastatic MTC. These drugs have previously been associated with dehiscence of anastomotic sites in the gastrointestinal tract. While previously identified in the bowel, this report represents the first documented case of gastropharyngeal anastomosis leak described in the context of TKI use for head and neck cancer., Case Presentation: We present the case of a 72-year-old male previously diagnosed with MTC. His gastropharyngeal anastomosis status-post laryngopharyngectomy and gastric pull up had been stable for 23 years. Over the past year, he developed back pain and was found to have spinal metastases of MTC. He was subsequently started on Cabozantinib to slow the progression of the disease. Within months of starting this TKI, a bleeding pharyngocutaneous fistula developed at the anastomosis site of the gastric pull up and pharynx. Upon discontinuation of Cabozantinib, the fistula healed with no further complications., Conclusions: To our knowledge, this is the first documented case of gastropharyngeal anastomotic leak related to TKI use. A causal relationship is highly plausible given the previously stable anastomosis and the suspicious advent of complications within months of initiation of this new drug. While previously limited to cases of intraabdominal bowel dehiscence, this report now suggests that wound dehiscence must be considered a known side effect of TKIs throughout the gastrointestinal tract, including the gastropharynx. As such, the risk of anastomotic dehiscence should be discussed with the patient prior to starting a TKI.

Aim: To provide an overview on the available treatments to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer., Methods: The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published and assessed the validity of the information on efficacy and treatment-related toxicity., Results: Eight randomized controlled trials and one meta-analysis were identified. Two randomized trials demonstrated that prophylactic radiation therapy (RT) using 1 × 10 Gy or 2 × 6 Gy significantly reduced the rate of gynecomastia but not breast pain, as compared to observation. A randomized dose-finding trial identified the daily dose of 20 mg tamoxifen (TMX) as the most effective prophylactic dose and another randomized trial described that daily TMX use was superior to weekly use. Another randomized trial showed that prophylactic daily TMX is more effective than TMX given at the onset of gynecomastia. Two other randomized trials described that TMX was clearly superior to anastrozole in reducing the risk for gynecomastia and/or breast pain. One comparative randomized trial between prophylactic RT using 1 × 12 Gy and TMX concluded that prophylactic TMX is more effective compared to prophylactic RT and furthermore that TMX appears to be more effective to treat gynecomastia and/or breast pain when symptoms are already present. A meta-analysis confirmed that both prophylactic RT and TMX can reduce the risk of gynecomastia and/or breast pain with TMX being more effective; however, the rate of side effects after TMX including dizziness and hot flushes might be higher than after RT and must be taken into account. Less is known regarding the comparative effectiveness of different radiation fractionation schedules and more modern RT techniques., Conclusions: Prophylactic RT as well as daily TMX can significantly reduce the incidence of gynecomastia and/or breast pain. TMX appears to be an effective alternative to RT also as a therapeutic treatment in the presence of gynecomastia but its side effects and off-label use must be considered.

Aim: To assess safety and efficacy of vismodegib in the Italian cohort from the SafeTy Events in VIsmodEgib study. Materials & methods: Data from Italian patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC were analyzed. Results: Among 182 Italian patients, adverse events occurred with similar incidence to the overall population. Overall response rate was 67.1% in laBCC, 20% in metastatic BCC; complete response rate was 33.1% overall and 37.4% in laBCC. Median time to response was 2 months in complete responders versus 3.6 months overall. Quality of life improved from baseline. Conclusion: In the Italian cohort of STEVIE, vismodegib showed a safety profile consistent with the whole population; older age did not affect safety or efficacy. ClinicalTrials.gov registration: NCT01367665.

Introduction: Despite first-line approval in metastatic renal cell carcinoma (mRCC), the tyrosine kinase inhibitor cabozantinib is associated with frequent treatment-limiting side effects. Dose reductions in published trials of the drug and in clinical practice are commonplace. We analyzed our institution's real-world experience with cabozantinib dosing in patients with mRCC to assess strategies to improve tolerability and patient outcomes., Objectives: The purpose of our study is to retrospectively analyze dose intensity, tolerability, and duration of exposure in mRCC patients who received cabozantinib at our institution., Methods: In this retrospective, single-center chart review, we identified 35 adult patients who received at least one cycle cabozantinib for mRCC during a two-year period. Dosing patterns were reviewed for each patient to allow calculation of median dose intensity and median duration of exposure., Results: The median dose intensity for cabozantinib was 55.4% and the median actual daily dose was 33.2 mg. Median duration of cabozantinib exposure was 10.4 months. Several alternative dosing strategies were employed with 60% of patients requiring at least one dose intervention to manage toxicities., Conclusions: Patients in this analysis received a median actual daily dose of 33.4 mg, less than the reported median doses in the METEOR and CABOSUN trials. However, our median duration of cabozantinib treatment was 10.4 months compared to 8.3 months and 6.5 months in these respective trials. Further investigation is warranted to determine if alternative dosing strategies and lower median actual daily doses produce survival results comparable to published clinical trials.

Background: No trials have compared cabozantinib and regorafenib for the second-line treatment of advanced hepatocellular carcinoma (HCC)., Objectives: Conduct a matching-adjusted indirect comparison (MAIC) of the efficacy and safety of second-line cabozantinib and regorafenib in patients with advanced HCC and disease progression after prior sorafenib., Methods: The CELESTIAL and RESORCE trials were used for indirect comparison of second-line cabozantinib and regorafenib in advanced HCC. Population-level data were available for RESORCE, individual patient data (IPD) for CELESTIAL. To align with RESORCE, the CELESTIAL population was limited to patients who received first-line sorafenib only. To minimize potential effect-modifying population differences, the CELESTIAL IPD were weighted to balance the distribution of clinically relevant baseline characteristics with those of RESORCE. Overall survival (OS) and progression-free survival (PFS) were evaluated for the matching-adjusted second-line CELESTIAL population and compared with those for RESORCE using weighted Kaplan-Meier curves and parametric modeling. Rates of grade 3/4 treatment-emergent adverse events (TEAEs) affecting > 5% of patients in any study arm were compared., Results: In the matching-adjusted second-line populations (CELESTIAL, effective sample size = 266; RESORCE, n = 573), median (95% confidence interval) OS was similar for cabozantinib and regorafenib (11.4 [8.9-17.0] versus 10.6 [9.1-12.1] months; p = 0.3474, log-rank test). Median PFS was longer for cabozantinib than regorafenib (5.6 [4.9-7.3] versus 3.1 [2.8-4.2] months; p = 0.0005, log-rank test). There was a trend for lower rates of some grade 3/4 TEAEs with regorafenib than with cabozantinib, which may reflect the exclusion of sorafenib-intolerant patients from RESORCE but not from CELESTIAL, a difference that the MAIC methods could not remove. Only diarrhea rates were statistically significantly lower for regorafenib (p  ≤ 0.001)., Conclusions: Cabozantinib may achieve similar OS and prolonged PFS compared with regorafenib in patients with progressive advanced HCC after prior sorafenib.

Background: Smoothened receptor inhibitor vismodegib is indicated to treat locally advanced basal cell carcinoma (laBCC) and lesions in nevoid basal cell carcinoma syndrome (NBCCS). Methods: We treated 11 patients - including four NBCCS and seven laBCC patients - with vismodegib at our department. Results: Complete remission was achieved in three cases, without relapse after discontinuation. Two of the aforementioned patients had NBCCS, in their cases further treatment might be needed. Two patients showed improvement, but later passed away due to unrelated conditions. Two patients with laBCC initially showed remission, then the treatment was suspended due to side effects. After re-administration of the drug, loss of efficacy was observed. We did not observe therapy resistance in our NBCCS group. The rest of the patients showed good response to therapy, but have not reached full remission yet. The main side effects of vismodegib were muscle cramps, dysgeusia, nausea and alopecia. The frequency of adverse events did not show significant differences between the patient groups. Conclusions : Our results show that vismodegib therapy is effective in the treatment of BCC; however, side effects are often severe. Since the suspension of treatment can lead to therapy resistance, the management of side effects is of great importance.

In this study, we aimed to compare changes in cavernosal tissues in rats with antiandrogen treatment and orchiectomy. A total of 42 Wistar albino rats were divided into four groups. Group I, control group, Group II, LH-RH was given for 1 month, Group III-LH-RH + Bicalutamide was given for 1 month, and Group IV was defined as orchiectomy and followed up for 1 month. Measurements of intracavernosal pressure with different electrical stimuli and pathological findings of smooth muscle collagen in cavernosal tissues were examined. While the cavernosal pressure response in all the different electrical stimuli given in the control group and in all other groups was significantly lower than that in the other groups, it was statistically significant at 7.5 and 10 V (p = .005, p < 0001). According to the pathologic evaluation, the density of tissue collagen increased significantly in the other groups according to the control group. In groups 3 and 4, the density of 4+ collagen was found to be increased according to Groups 1 and 2. In the LH-RH alone group, it appears that there are no 4+ colloid density and less damage. According to these findings, the negative effect of LH-RH treatment on cavernosal tissues appears to be less., (© 2020 Blackwell Verlag GmbH.)

Purpose: In a mouse model, degarelix generated the least metabolic consequences via low follicle-stimulating hormone (FSH) levels compared with orchiectomy and leuprolide after 4 months of androgen deprivation therapy (ADT). Here, we comparatively investigated the influence of ADT with degarelix or leuprolide on the development of metabolic syndrome in patients with prostate cancer (PCa)., Methods: Patients with hormone-naive PCa were recruited. Eligible patients were randomized (1:1) to monthly degarelix or monthly leuprolide for 6 months. Key trial variables were monitored monthly. The primary endpoint was changes in fasting blood sugar (FBS). Secondary endpoints were changes in body weight, abdominal circumference, lipid profiles, and hemoglobin A1c (HbA1c) and FSH levels. Computed tomography was performed to measure subcutaneous and visceral fat areas before and after 6 months of ADT. Data were analyzed using the χ 2 test, Student's t test, and analysis of variance., Results: From the 100 patients registered, 85 completed the trial (degarelix: 40 patients; leuprolide: 45 patients). Mean increases in FBS did not differ between the two arms. Similarly, there were no differences between the arms in mean increases in body weight, abdominal circumference, lipid profiles, HbA1c, or subcutaneous and visceral fat areas. Follicle-stimulating hormone levels were significantly lower in the degarelix arm than in the leuprolide arm (p < 0.05)., Conclusions: Lipid and glucose metabolism did not differ significantly between the arms, while FSH levels were significantly lower in the degarelix arm.

Introduction: Bicalutamide is widely used in the treatment of prostate cancer. Among its side effects, central nervous system disorders are relatively rare, and the information about bicalutamide-associated hallucinations is limited., Case Report: We report an uncommon case of a patient with metastatic prostate cancer, who had hallucinations due to the use of bicalutamide., Management and Outcome: The patient accepted to receive only hormonal therapy (bicalutamide and leuprolide acetate). But he developed hallucinations due to bicalutamide use. His hallucinations disappeared after discontinuation of bicalutamide. A good response was obtained with the use of luteinizing hormone-releasing hormone agonist monotherapy., Discussion: The pathophysiology of bicalutamide-induced hallucinations is unclear. We hypothesize that antiandrogens can indirectly cause hallucinations through changes in plasma testosterone and cerebral reelin expression. Additionally, luteinizing hormone-releasing hormone agonist monotherapy is a good option in metastatic prostate cancer patients who have intolerable side effects due to the use of antiandrogens.

Introduction and Objectives: Vismodegib (Erivedge ® ), a hedgehog pathway inhibitor, is approved to treat metastatic or locally advanced basal cell carcinoma (BCC) not suitable for surgery or radiotherapy. Our main objectives were to study the objective response rate (ORR) assessed by treating physicians and safety of vismodegib in a real-world practice setting in Argentina., Material and Methods: This is a prospective cohort study in real-world practice. We included consecutive adult patients treated in Argentina with locally advanced or metastatic BCC not suitable for surgery or radiotherapy. Patients were followed until the end of the study, death, or loss to follow-up, whichever occurred first. Patients received 150 mg vismodegib PO daily., Result: We included in the analysis 63 patients who received treatment. Locally advanced BCC was present in 57 (90.4%) and metastatic disease in two (3.2%). ORR was observed in 46 patients (73%; 95% CI: 60.3-83.4), with partial response in 36 (57%; 95% CI: 44-69.5) and complete response in 10 (16%; 95% CI: 7.8-27.2). As to safety, 48 (76.2%) patients had at least one adverse event (AE). The most frequently observed AEs were muscular spasms in 25 (39.6%); dysgeusia in 23 (36.5%); alopecia in nine (14.2%); weight loss in seven (11.1%); and ageusia in (9.5%) patients. Serious AEs were observed in 11 (17%) patients with one episode of deep vein thrombosis and pulmonary embolism resulting in death., Conclusion: Our study provides additional evidence of the efficacy and tolerability of vismodegib in patients with locally advanced or metastatic BCC in a real-world practice., (© 2020 The International Society of Dermatology.)

Background: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs., Methods: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants., Results: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m 2 ). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness., Conclusion: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment., Trial Registration: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

Background: Vismodegib demonstrated 60% response rates in the ERIVANCE trial. Basal cell carcinoma has various histopathologies. Their effect on response is unclear., Objective: The purpose of this study was to determine whether basal cell carcinoma histopathology affected vismodegib response., Methods: This phase 2b, single-center, prospective case series study compared the efficacy of vismodegib in infiltrative, nodular, and superficial basal cell carcinomas treated for 12 or 24 weeks in 27 patients. Patients had 1 target lesion and up to 3 nontarget lesions., Results: Twenty-seven patients were enrolled, with 65 tumors (27 target lesions/38 nontarget lesions). At 24 weeks, most basal cell carcinomas achieved histologic clearance, with positive biopsy results in 10.5% of target lesions, 30.4% of nontarget lesions, and 21.4% overall. No statistical differences were observed between histopathologic subtypes. One hundred percent of patients experienced an adverse event, 94% grade 1 or 2. The most common adverse events were dysgeusia/loss of taste (86%), muscle spasms (82%), and alopecia (71%). Clinically progressive disease during treatment was low (1.5%). Two patients had recurrence within 1 year of treatment., Limitations: Limitations included sample size of basal cell carcinoma histopathologic subtypes, sampling punch biopsies, and short follow-up., Conclusions: Basal cell histopathologic subtype did not significantly affect response to vismodegib. Each subtype was observed to completely respond at 12 weeks of therapy, 24 weeks, or both., (Copyright © 2019 American Academy of Dermatology, Inc. All rights reserved.)

Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug., Competing Interests: Declaration of Competing Interest Stefano Fogli reports no conflicts of interest; Camillo Porta: MSD, Eisai, EUSA Pharma, Janssen, General Electrics, BMS, Ipsen, Novartis, Pfizer (consulting relationship, scientific advisory board, member of the speaker’s bureau, travel expenses); Marzia Del Re: Ipsen, Novartis, Pfizer, Sanofi Genzyme, AstraZeneca, Pierre-Fabre, Janssen (scientific advisory board, consulting relationship), Ipsen, AstraZeneca, Sanofi Genzyme (travel, accommodation, expenses); Stefania Crucitta reports no conflicts of interest; Giulia Gianfilippo reports no conflicts of interest; Romano Danesi: Ipsen, Novartis, Pfizer, Sanofi Genzyme, AstraZeneca, Janssen, Gilead, Lilly, Gilead, EUSA Pharma (scientific advisory board, consulting relationship), Ipsen, Sanofi Genzyme (travel, accommodation, expenses); Brian I. Rini: Pfizer, GlaxoSmithKline, BMS (scientific advisory board, consulting relationship), Roche, BMS, Pfizer (research funding); Manuela Schmidinger: BMS, Eisai, EUSA Pharma, Exelixis, Ipsen, Novartis, Pfizer, Roche (scientific advisory board, consulting relationship), Roche (research funding), Pfizer, Roche (travel, accommodation, expenses)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We report a case of rapid evolution of polycystic liver disease in a 76-year-old patient with metastatic renal cell carcinoma who underwent treatment with numerous antineoplastic agents. The aim was to identify a causative etiology for these hepatic cysts of unclear origin. The cystic lesions of the patient were ultimately innumerable and developed rapidly, more than tripling the total liver volume from complete absence over the course of 24 months. The hepatic lesions continued to grow despite an otherwise moderate tumor response. Prior to patient death, the patient remained relatively asymptomatic from the cyst burden and was without signs of grossly metastatic disease. This rapid development of polycystic liver disease most likely represents a previously unseen medication side-effect of cabozantinib or pazopanib. It is important to identify adverse effects of novel antineoplastic agents in this time of oncological medical discovery., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In metastatic renal cell carcinoma (mRCC) patients, cardiac metastases are a rare and often a post-mortem finding. Clinical manifestations of cardiac metastases have a late onset and include pericardial effusions, heart failure and embolic phenomena. Treatment of cardiac metastasis is not yet standardized, and few data are available about the efficacy of TKI on treatment of cardiac metastases in mRCC patients. In this report, we describe the case of a 66-year-old male who presented with mRCC with lung and cardiac metastases treated with cabozantinib, a multikinase inhibitor that was administered in second line after disease progression with sunitinib. To date, there are no data about the safety and efficacy of cabozantinib in mRCC with cardiac metastasis. In a real word analysis, cabozantinib demonstrated to be associated to a modest risk of developing left ventricular heart failure. It is unknown if this risk is higher in mRCC population with cardiac metastases. We report the first evidence of efficacy and safety of cabozantinib in cardiac mRCC patients, probably due to its specific inhibition of several molecular intracellular pathways. Additional molecular and clinical studies are needed before well tolerated and efficacy of cabozantinib treatment for these patients can be fully understood.

Background: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling., Methods: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib)., Results: Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment., Conclusions: Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population., Trial Registration: ClinicalTrials.gov Identifier: NCT01088815.

Background: Cabozantinib improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy in the phase III METEOR trial (NCT01865747). Limited data are available on the use of targeted therapies in older patients with advanced RCC., Methods: Efficacy and safety in METEOR were retrospectively analysed for three age subgroups: <65 (n = 394), 65-74 (n = 201) and ≥75 years (n = 63)., Results: PFS, OS and ORR were improved with cabozantinib compared with everolimus in all age subgroups. The PFS hazard ratios (HRs) were 0.53 (95% confidence interval [CI]: 0.41-0.68), 0.53 (95% CI: 0.37-0.77) and 0.38 (95% CI: 0.18-0.79) for <65, 65-74 and ≥75 years, respectively, and the OS HRs were 0.72 (95% CI: 0.54-0.95), 0.66 (95% CI: 0.44-0.99) and 0.57 (95% CI: 0.28-1.14). The ORR for cabozantinib versus everolimus was 15% vs 5%, 21% vs 2% and 19% vs 0%, respectively. No significant differences were observed in PFS or OS with age as a categorical or continuous variable. Grade III/IV adverse events (AEs) were generally consistent across subgroups, although fatigue, hypertension and hyponatraemia occurred more frequently in older patients treated with cabozantinib. Dose reductions to manage AEs were more frequent in patients receiving cabozantinib than in those receiving everolimus. Dose reductions and treatment discontinuation due to AEs were more frequent in older patients in both treatment groups., Conclusions: Cabozantinib improved PFS, OS and ORR compared with everolimus in previously treated patients with advanced RCC, irrespective of age group, supporting use in all age categories. Proactive dose modification and supportive care may help to mitigate AEs in older patients while maintaining efficacy., Competing Interests: Conflict of interest statement F.D. certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g. employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony royalties or patents filed, received or pending), are the following: F.D. received research grant support from Pfizer, Novartis, Ipsen, and Health Research Foundation of Central Denmark Region, outside the submitted work. R.J.M. served in a consultancy or advisory role for Pfizer, Novartis, Merck, Genentech/Roche, Eisai and Exelixis and received research funding from Bristol-Myers Squibb, Pfizer, Genentech/Roche, Eisai, Exelixis and Novartis. K.C. received honoraria from Roche, served in a consultancy or advisory role for Roche and Novartis and received support for travel and accommodation from Roche and Amgen. S.N. received honoraria from Pfizer, Bristol-Myers Squibb, Novartis, Ipsen and Eusa Pharma, outside the submitted work. I.C. and A.C. are employees of Exelixis. B.E. received grant support and personal fees from Bristol-Myers Squibb, Pfizer, Novartis, Ipsen and Eusa. S.P. received honoraria from Astellas Pharma, Medivation and Novartis, served in a consultancy or advisory role for Aveo, Bristol-Myers Squibb, Exelixis, Genentech, Myriad Pharmaceuticals, Novartis and Pfizer and received research funding from Medivation. T.P. served in a consultancy or advisory role for AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck and Novartis, and received research funding from AstraZeneca/MedImmune and Roche/Genentech. T.K.C. served in a consultancy or advisory role for Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Laboratories, Corvus, Ipsen, UpToDate, NCCN and Analysis Group, received research funding (institutional and personal) from AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Laboratories, Corvus, Calithera, Analysis Group and Takeda, received honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Laboratories, Corvus, Ipsen, UpToDate, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OncLive and PER), Lpath, Kidney Cancer journal, Clinical Care Options, PlatformQ, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology and Heron Therapeutics and has received travel, accommodations and expenses in relation to consulting and advisory roles or honoraria; T.K.C.'s institution (Dana-Farber Cancer Institute) may have received additional independent funding or royalties from drug companies potentially involved in research around the subject matter. All other authors declare no conflict of interest., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Longitudinal-ordered categorical data, common in clinical trials, can be effectively analyzed with nonlinear mixed effect models. In this article, we systematically evaluated the performance of three different models in longitudinal muscle spasm adverse event (AE) data obtained from a clinical trial for vismodegib: a proportional odds (PO) model, a discrete-time Markov model, and a continuous-time Markov model. All models developed based on weekly spaced data can reasonably capture the proportion of AE grade over time; however, the PO model overpredicted the transition frequency between grades and the cumulative probability of AEs. The influence of data frequency (daily, weekly, or unevenly spaced) was also investigated. The PO model performance reduced with increased data frequency, and the discrete-time Markov model failed to describe unevenly spaced data, but the continuous-time Markov model performed consistently well. Clinical trial simulations were conducted to illustrate the muscle spasm resolution time profile during the 8-week dose interruption period after 12 weeks of continuous treatment., (© 2019 Genentech. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Purpose: To analyze the efficacy and tolerability of cabozantinib-a small molecule inhibitor of MET and VEGFR2-alone or with trastuzumab in patients with breast cancer brain metastases (BCBM)., Methods: This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective., Results: Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1-9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume., Conclusions: Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia., Trial Registration: Clinicaltrial.gov registration: NCT02260531.

Purpose: Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation., Methods: An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy., Results: One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; P = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%)., Conclusion: Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.

Cabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx ® ) dose is 60 mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure-response (ER) models were developed to characterize the relationship between predicted cabozantinib exposure and the likelihood of various efficacy and safety endpoints. The ER models were used to predict hazard ratios (HR) for efficacy and safety endpoints for starting doses of 60, 40, or 20 mg daily. Statistically significant relationships between cabozantinib exposure and efficacy and safety endpoints were observed. For efficacy endpoints, predicted HR were lower for OS and PFS at 40 and 60 mg relative to the 20 mg dose: HR for death (OS) are 0.84 (40 mg) and 0.70 (60 mg); HR for disease progression/death (PFS) are 0.73 (40 mg) and 0.62 (60 mg). For safety endpoints, predicted HR were lower for palmar-plantar erythrodysaesthesia (PPE), diarrhea, and hypertension at 20 or 40 mg relative to the 60 mg dose: HR for PPE are 0.31 (20 mg) and 0.66 (40 mg); HR for diarrhea are 0.61 (20 mg) and 0.86 (40 mg); HR for hypertension are 0.46 (20 mg) and 0.76 (40 mg). The rate of dose modifications was predicted to increase in patients with lower cabozantinib apparent clearance. OS and PFS showed the greatest benefit at the 60 mg dose. However, higher cabozantinib exposure was predicted to increase the likelihood of AE and subsequent dose reductions appeared to decrease these risks.

Aim: We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain., Material and Methods: Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded., Results: Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin., Conclusions: Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV., Competing Interests: José Manuel Sousa has received fees as speaker from AbbVie, MSD and Gilead. Mercedes Vergara has received fees as an advisory board member from Gilead and has given lectures for AbbVie, Intercept, MSD, Janssen-Cilag and Gilead. Federico Pulido has received fees as speaker and advisor from AbbVie, Gilead, Janssen and MSD. Gloria Sánchez-Antolín has acted as speaker for AbbVie, MSD, Gilead Science, Novartis and Astellas. Diego Rincón has given lectures for AbbVie and MSD. Javier Salmerón has received speaker fees and grant funding from AbbVie; he declares no further conflict of interest. Luisa García-Buey has received speaker fees and travel grants from Abbvie, MSD and Gilead. José A. Carrión has received speaker fees from Abbvie, Gilead and MSD and has received fees as Advisor for AbbVie. Manuel Hernández-Guerra has been a consultant to Gilead Sciences, Intercept Pharmaceuticals, Abbvie and Bayer; he has received grant funding from Gilead Sciences and Abbvie. Nuria Espinosa has participated in Clinical Trials managed by Gilead and ViiV Healthcare; she has received advisory board, conference and course fees as well as expenses for attending congresses from Janssen-Cilag, Gilead Sciences, ViiV Healthcare, MSD and Abbvie. Rosa Mª Morillas has acted as a speaker for Gilead, Merck, AbbVie and Intercept, and has participated in advisory boards for AbbVie, Gilead and Intercept. Raul J. Andrade: Advisor/Speaker Bureau: Abbvie, Gilead Sciences, Merck Sharp and Dohme, Bristol-Myers Squibb, Janssen; Research Grants: Willmar Schwabe GmbH & Co, Gedeon Richter/Preglem S.A. Manuel Delgado has received scientific advisor fees from Abbie, Gilead, MSD. José M Moreno-Planas has received speaker fees from AbbVie, MSD, Gilead and Bayer. Fernando Menéndez has received fees as advisor from Bayer. Luis Morano has acted as speaker, advisor and/or investigator for Abbvie, Gilead Sciences, Merck Sharp and Dohme, Bristol-Myers Squibb, Janssen, Boehringer Ingelheim, Novartis, and Roche Farma. Manuel Rodríguez consults for and is on the speaker’s bureau for Gilead and AbbVie. Sara Lorente has received lecture fees from Abbvie, Gilead Sciences and MSD. Miguel Ángel Von-Wichmann has received fees as speaker and advisor from Abbvie, BMS, Gilead, Janssen, MSD and VIIV. Amanda Manzanares is employee of AbbVie and may hold stock or options. Lander Hijona, Fernando Carnicer, Beatriz Mateos-Muñoz, Antoni Jou, Benjamín Polo-Lorduy, Ángel Rubín, Ana Escarda, Patricia Aguilar, Teresa Aldámiz-Echevarría, Sonia Chimeno-Hernández, Adolfo Gallego, Marta Magaz, Ángel Estébanez, Mikel Rico, Blanca Sampedro, Sonia Izquierdo, José Manuel Zozaya, Senador Morán-Sánchez, Ignacio Martín-Granizo, Marcial Delgado declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Basal cell carcinoma (BCC) is the most common malignancy in Caucasians, and its incidence is increasing. Most BCCs are treated surgically, nevertheless surgery is not an effective treatment for locally advanced or metastatic BCC. Alterations in hedgehog signaling pathway, a key regulator of cell growth and differentiation during development, are implicated in the pathogenesis of basal-cell carcinoma. Vismodegib is a small-molecule inhibitor of smoothened (SMO), a key component of the hedgehog (Hh) signaling pathway, administered in BCC patients, especially when surgery and radiotherapy treatments have failed. We report a series of eight elderly patients treated with vismodegib for advanced BCC and affected by concomitant multiple comorbidities. The efficacy and tolerability of vismodegib in patients with single and/or multiple comorbidities has been poorly studied. In our observation an overall high safety and tolerability has been observed over the course of treatment, with side effects of grade I and II and no changes in vital parameters, electrocardiography and echocardiogram. Vismodegib has been shown to be a safe and well tolerated treatment option for elderly patients affected by multiple comorbidities and advanced BCC., (© 2019 Wiley Periodicals, Inc.)

Background/aim: Radiotherapy (RT) with adjuvant hormone therapy (HT) improves prognosis in prostate cancer (PC) patients. Gonadotrophin-releasing hormone agonist (GnRHa) with luteinizing hormone-releasing hormone (LH-RH) analogues is the standard HT. High-dose antiandrogen therapy also improves survival in patients with locally advanced PC. The aim of this study was to compare the results of patients treated with RT plus GnRHa and patients treated with RT plus bicalutamide., Patients and Methods: Our institutional PC database was used to identify patients treated with definitive or postoperative RT +/- HT which were included in this study., Results: Three hundred and eighteen patients were retrospectively reviewed (median follow-up=56 months). Five-year biochemical relapse-free survival was 85.5% and 88.3% in patients treated with GnRHa and bicalutamide, respectively (p=0.712)., Conclusion: Bicalutamide may be offered as an adjuvant treatment to RT in patients who refuse GnRHa because of related side effects. Furthermore, our study justifies randomized trials comparing RT plus GnRHa and RT plus bicalutamide., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and Aims: New direct-acting antiviral drugs have become the corner-stone treatment for HCV infection: they show promising results with accepted side-effects and low dropout rates. One of the available regimens is paritaprevir/ombitasvir/ritonavir (PTV/OMV/RTV). Our aim was to study the efficacy and safety of this drug regimen among HCV-positive hemodialysis patients., Methods: This prospective single-center study was performed in the Urology and Nephrology Center, Mansoura University, Egypt. Ninety-six maintenance hemodialysis patients were screened for HCV antibodies. Positive results were found in 46 patients (47.9%). HCV PCR was assessed in all HCV-antibody-positive patients; positive results were found positive for 38 (82%); all patients were HCV genotype 4. Four patients were excluded due to advanced liver cirrhosis, liver malignancy, or metastatic breast cancer. Thirty-four patients were prescribed PTV/OMV/RTV for 3 months to treat HCV., Results: Mean age was 43.2 ± 11.9 years. Most patients were male (67.6%). There was a rapid response to treatment: HCV PCR became negative by 4 weeks after starting treatment. By 12 and 24 weeks post-DAA therapy, there was a sustained viral response (SVR 12, SVR 24) in 100% of patients with improved liver-enzyme levels., Conclusion: The PTV/OMV/RTV regimen was safe and effectively treated Egyptian HCV-positive genotype-4 hemodialysis patients.

Background: Cabozantinib showed efficacy and manageable toxicity in patients with metastatic renal cell carcinoma (mRCC). In this study we aimed to describe the safety and to collect evidence on the potential efficacy of cabozantinib in mRCC patients with brain metastases (BM) in a real-world experience., Materials and Methods: We retrospectively collected data of patients treated with cabozantinib within the Italian Managed Access Program. Patients were selected for the presence of BM before the start of treatment and for at least 1 previous tyrosine kinase inhibitor (TKI) treatment regimen for metastatic disease. Safety data were reported, and overall response rate (ORR), brain-specific response, progression-free survival (PFS), and median overall survival (OS) were analyzed., Results: Overall, 12 patients treated with cabozantinib were evaluated. Any grade adverse events (AEs) accounted for 92%, Grade 3/4 AEs rated at 36% with no major neurological side effects. The most common AEs included hypertension (33%), fatigue (24%), aminotransferase elevation (25%), hypothyroidism (16%), and gastrointestinal toxicity (16%). The ORR was 50% with a disease control rate of 75%. All 5 patients treated with a combined systemic and brain-directed approach obtained intracranial disease control, without increased toxicity. Median PFS and median OS were 5.8 and 8.8 months, respectively. Comparable safety and tolerability results for other TKI regimens were reported from the literature., Conclusion: Cabozantinib showed safety, acceptable tolerability, and promising antitumor activity in a population of mRCC patients with BM from a real-world experience. A combined modality approach for renal cell carcinoma with BM, whenever feasible, could be recommended to improve oncological outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Treatment options are limited for patients with advanced hepatocellular carcinoma (HCC) that progresses after treatment with sorafenib. Cabozantinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, recently showed improved overall survival (OS) compared with placebo in sorafenib-pretreated patients with advanced HCC in the CELESTIAL trial. This study assessed the cost-effectiveness of cabozantinib for second-line treatment of patients with advanced HCC from a US healthcare system perspective., Patients and Methods: Cost and utility data were extracted from the CELESTIAL trial and used to determine the cost-effectiveness of cabozantinib compared with placebo plus best supportive care. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained by using cabozantinib compared with placebo plus best supportive care in sorafenib-pretreated HCC., Results: In the base-case analysis using data from the CELESTIAL trial, the incremental QALY and ICER were 0.067 and $1,040,675 for cabozantinib compared with placebo and best supportive care. OS reported in the CELESTIAL trial (hazard ratio, 0.76; 95% CI, 0.63-0.92) had the strongest association with the ICER. In one-way sensitivity analyses, there were no scenarios in which cabozantinib was cost-effective. In a cost-threshold analysis, cabozantinib would have to be priced at least $50 per pill to be cost-effective considering a willingness to pay of $100,000 per QALY. Although the CELESTIAL trial demonstrated that cabozantinib improves OS compared with placebo in patients with HCC that progresses after treatment with sorafenib, our analysis shows that cabozantinib is not a cost-effective therapy in this scenario., Conclusions: At current costs, cabozantinib is not cost-effective for second-line therapy of HCC in the United States.

Background: Cabozantinib is an approved treatment for metastatic renal cell carcinoma (mRCC). This report presents an analysis of the safety profile and efficacy of cabozantinib in an unselected population from Poland., Patients and Methods: Patients with mRCC, who had been treated with at least 1 previous agent targeting the vascular endothelial growth factor pathway, were eligible to receive cabozantinib at a once-daily dose of 60 mg orally, according to the Managed Access Program (MAP). Data were collected in 4 Polish centers. Patients who had received ≥ 1 dose of cabozantinib were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0., Results: A total of 115 patients were enrolled between October 2016 and March 2018, including 50% with bone metastases, 10% with brain metastases and 4.3% with non-clear-cell RCC; 76% had received ≥ 2 lines of therapy. The median time of follow-up was 12.6 months (95% confidence interval [CI], 11.5-14.1 months). The most common grade 3 and 4 AEs were fatigue (23%), hand-foot syndrome (12%), and diarrhea (10%). Only 4% of patients discontinued treatment owing to AEs, and there were no treatment-related deaths. Partial response was observed in 19% of patients, whereas 56% had stable disease. The median progression-free survival was 12.5 months (95% CI, 9.2-14.2 months), with a 12-month overall survival rate of 70.4% (95% CI, 60.2%-78.5%)., Conclusions: Cabozantinib demonstrated acceptable tolerability and activity in a large unselected population of patients with mRCC under clinical conditions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Data regarding the cardiac toxicity of cabozantinib lacks. The aim of our study was to assess the risk of cabozantinib-related cardiotoxicity in mRCC patients., Methods: We performed a multicentre prospective study on mRCC patients treated with cabozantinib between October 2016 and November 2017. Transthoracic echocardiogram and plasma biomarkers assay were assessed at baseline, 3 and 6 months after cabozantinib initiation., Results: The study population included 22 mRCC patients. At baseline, 9.1% had a reduced left ventricular ejection fraction (LVEF), but none had a left ventricular systolic dysfunction. Patients with baseline reduced LVEF did not show further significant LVEF modification after 3 months. After 6 months, only 1 had an LVEF decline >10% compared to baseline, resulting in LV systolic dysfunction. At baseline, 64.7% and 27.3% of patients had elevated precursor brain natriuretic peptide (proBNP) and high-sensitivity troponin I (hsTnI), respectively. Among patients with basal normal proBNP and hsTnI, none had elevated values at 3 and 6 months. No correlation was found between basal elevated proBNP and basal reduced LVEF (P = .29), and between elevated proBNP and reduced LVEF after 6 months (P = .37). Similarly, we found no correlations between elevated hsTnI and reduced LVEF or elevated proBNP at baseline (P = .47; P = .38), at 3 (P = .059; P = .45) and after 6 months (P = .72; P = 1.0)., Conclusions: This prospective study revealed a modest risk of developing left ventricular systolic dysfunction related to cabozantinib. A lack of correlation between elevated cardiac biomarkers and reduced LVEF at different time-points was detected. Assessments of the cardiac function should be reserved at the occurrence of clinical symptoms., (© 2019 The British Pharmacological Society.)

Paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin shows favorable results in hepatitis C virus genotype 1 (HCV-1) patients in terms of safety and efficacy, but real-world data remain limited for those with advanced hepatic fibrosis (fibrosis 3, F3) or compensated cirrhosis (F4). A total of 941 patients treated in four hospitals (the Keelung, the Linkuo, the Chiayi and the Kaohsiung Chang Gung Memorial Hospital) through a nationwide government-funded program in Taiwan were enrolled. Patients with HCV and advanced hepatic fibrosis or compensated cirrhosis received 12 weeks of PrOD in HCV-1b and 12 or 24 weeks of PrOD plus ribavirin therapy in HCV-1a without or with cirrhosis. Advanced hepatic fibrosis or compensated cirrhosis was confirmed by either ultrasonography, fibrosis index based on 4 factors (FIB-4) test, or transient elastography/acoustic radiation force impulse (ARFI). The safety and efficacy (sustained virologic response 12 weeks off therapy, SVR 12 ) were evaluated. An SVR 12 was achieved in 887 of 898 (98.8%) patients based on the per-protocol analysis (subjects receiving ≥1 dose of any study medication and HCV RNA data available at post-treatment week 12). Child-Pugh A6 (odds ratio: 0.168; 95% confidence interval (CI): 0.043-0.659, p = 0.011) was the only significant factor of poor SVR 12 . Fifty-four (5.7%) patients were withdrawn early from the treatment because of hepatic decompensation (n = 18, 1.9%) and other adverse reactions. Multivariate analyses identified old age (odds ratio: 1.062; 95% CI: 1.008-1.119, p = 0.024) and Child-Pugh A6 (odds ratio: 4.957; 95% CI: 1.691-14.528, p = 0.004) were significantly associated with hepatic decompensation. In conclusion, this large real-world cohort proved PrOD with or without ribavirin to be highly effective in chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis. However, Child-Pugh A6 should be an exclusion criterion for first-line treatment in these patients.

Importance: Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting., Objective: To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease., Design, Setting, and Participants: This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used., Interventions: Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year)., Main Outcomes and Measures: The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life., Results: Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life., Conclusions and Relevance: Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease., Trial Registration: French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.

Multi-target anticancer drugs have a more comprehensive and extensive range of action,and there is an uncertain risk in the combination of two drugs.A case of acute toxicity induced by erlotinib combined with cabozantinib is reported in this article.