Impact of treatment on elder-relevant physical function and quality of life outcomes in older adults with metastatic castration-resistant prostate cancer.

INTRODUCTION: Understanding physical function (PF) and quality of life (QoL) treatment effects are important in treatment decision-making for older adults with cancer. However, data are limited for older men with metastatic castration-resistant prostate cancer (mCRPC). We evaluated the effects of treatment on PF and QoL in older men with mCRPC. MATERIALS AND METHODS: Men aged 65+ with mCRPC were enrolled in this multicenter prospective observational study. PF measures included instrumental activities of daily living, grip strength, chair stands, and gait speed. QoL measures included fatigue, pain, mood, and Functional Assessment of Cancer Therapy (FACT)-General total and sub-scale scores. Outcomes were collected at baseline, three, and six months. Linear mixed effects regression models were used to examine PF and QoL differences over time across various treatment cohorts. RESULTS: We enrolled 198 men starting chemotherapy (n = 71), abiraterone (n = 37), enzalutamide (n = 67), or radium-223 (n = 23). At baseline, men starting chemotherapy had worse measures of PF, QoL, pain, and mood than the other groups. Over time, all PF measures remained stable, pain improved, but functional wellbeing (FWB) and mood worsened significantly for all cohorts. However, change over time in all outcomes was not appreciably different between treatment cohorts. Worst-case sensitivity analyses identified attrition (ranging from 22 to 42% by six months) as a major limitation of our study, particularly for the radium-223 cohort. DISCUSSION: FWB and mood were most prone to deterioration over time, whereas pain improved with treatment. Although patients initiating chemotherapy had worse baseline PF and QoL, chemotherapy was not associated with significantly greater worsening over time compared to other common therapies for mCRPC. These findings may assist in treatment discussions with patients. However, given the modest sample size, attrition, and timeframe of follow-up, the impact of treatment on PF and QoL outcomes in this setting requires further study, particularly for radium-223.

The role of frailty in modifying physical function and quality of life over time in older men with metastatic castration-resistant prostate cancer.

INTRODUCTION: As treatment options for metastatic castration-resistant prostate cancer (mCRPC) expand and its patient population ages, consideration of frailty is increasingly relevant. Using a novel frailty index (FI) and two common frailty screening tools, we examined quality of life (QoL) and physical function (PF) in frail versus non-frail men receiving treatment for mCRPC. MATERIALS AND METHODS: Men aged 65+ starting docetaxel chemotherapy, abiraterone, or enzalutamide for mCRPC were enrolled in a multicenter prospective cohort study. QoL, fatigue, pain, and mood were measured with the Functional Assessment of Cancer Therapy-General scale, the Edmonton Symptom Assessment System tiredness and pain subscales, and the Patient Health Questionnaire-9. PF was evaluated with grip strength, four-meter gait speed, five times Sit-to-Stand Test, and instrumental activities of daily living. Frailty was determined using the Vulnerable Elders Survey (VES-13), the Geriatric 8 (G8), and an FI constructed from 36 variables spanning laboratory abnormalities, geriatric syndromes, functional status, social support, as well as emotional, cognitive, and physical deficits. We categorized patients as non-frail (FI ≤ 0.2, VES < 3, G8 > 14), pre-frail (FI > 0.20, ≤0.35), or frail (FI > 0.35, VES ≥ 3, G8 ≤ 14); assessed correlation between the three tools; and performed linear mixed-effects regression analyses to examine longitudinal differences in outcomes (0, 3, 6 months) by frailty status. A sensitivity analysis with worst-case imputation was conducted to explore attrition. RESULTS: We enrolled 175 men (mean age 74.9 years) starting docetaxel (n = 71), abiraterone (n = 37), or enzalutamide (n = 67). Our FI demonstrated moderate correlation with the VES-13 (r = 0.607, p < 0.001) and the G8 (r = -0.520, p < 0.001). Baseline FI score was associated with worse QoL (p < 0.001), fatigue (p < 0.001), pain (p < 0.001), mood (p < 0.001), PF (p < 0.001), and higher attrition (p < 0.01). Over time, most outcomes remained stable, although pain improved, on average, regardless of frailty status (p = 0.007), while fatigue (p = 0.045) and mood (p = 0.015) improved in frail patients alone. DISCUSSION: Among older men receiving care for mCRPC, frailty may be associated with worse baseline QoL and PF, but over time, frail patients may experience largely similar trends in QoL and PF as their non-frail counterparts. Further study with larger sample size and longer follow-up may help elucidate how best to incorporate frailty into treatment decision-making for mCRPC.

Association of Chemotherapy, Enzalutamide, Abiraterone, and Radium 223 With Cognitive Function in Older Men With Metastatic Castration-Resistant Prostate Cancer.

Importance: Older adults are at greater risk of cognitive decline with various oncologic therapies. Some commonly used therapies for advanced prostate cancer, such as enzalutamide, have been linked to cognitive impairment, but published data are scarce, come from single-group studies, or focus on self-reported cognition. Objective: To longitudinally examine the association between cognitive function and docetaxel (chemotherapy), abiraterone, enzalutamide, and radium Ra 223 dichloride (radium 223) in older men with metastatic castration-resistant prostate cancer. Design, Setting, and Participants: A multicenter, prospective, observational cohort study was conducted across 4 academic cancer centers in Ontario, Canada. A consecutive sample of 155 men age 65 years or older with metastatic castration-resistant prostate cancer starting any treatment with docetaxel, abiraterone acetate, enzalutamide, or radium Ra 223 dichloride (radium 223) were enrolled between July 1, 2015, and December 31, 2019. Exposures: First-line chemotherapy (docetaxel), abiraterone, enzalutamide, or radium 223. Main Outcomes and Measures: Cognitive function was measured at baseline and end of treatment using the Montreal Cognitive Assessment, the Trail Making Test part A, and the Trail Making Test part B to assess global cognition, attention, and executive function, respectively. Absolute changes in scores over time were analyzed using univariate and multivariable linear regression, and the percentages of individuals with a decline of 1.5 SDs in each domain were calculated. Results: A total of 155 men starting treatment with docetaxel (n = 51) (mean [SD] age, 73.5 [6.2] years; 34 [66.7%] with some postsecondary education), abiraterone (n = 29) (mean [SD] age, 76.2 [7.2] years; 18 [62.1%] with some postsecondary education), enzalutamide (n = 54) (mean [SD] age, 75.7 [7.4] years; 33 [61.1%] with some postsecondary education), and radium 223 (n = 21) (mean [SD] age, 76.4 [7.2] years; 17 [81.0%] with some postsecondary education) were included. Most patients had stable cognition or slight improvements during treatment. A cognitive decline of 1.5 SDs or more was observed in 0% to 6.5% of patients on each measure of cognitive function (eg, 3 of 46 patients [6.5%; 95% CI, 2.2%-17.5%] in the group receiving chemotherapy [docetaxel] had a decline of 1.5 SDs for Trails A and Trails B). Although patients taking enzalutamide had numerically larger declines than those taking abiraterone, differences were small and clinically unimportant. Conclusions and Relevance: These findings suggest that most older men do not experience significant cognitive decline in attention, executive function, and global cognition while undergoing treatment for advanced prostate cancer regardless of the treatment used.

Examining the ability of the Cancer and Aging Research Group tool to predict toxicity in older men receiving chemotherapy or androgen-receptor-targeted therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: Because multiple treatments are available for metastatic castrate-resistant prostate cancer (mCRPC) and most patients are elderly, the prediction of toxicity risk is important. The Cancer and Aging Research Group (CARG) tool predicts chemotherapy toxicity in older adults with mixed solid tumors, but has not been validated in mCRPC. In this study, its ability to predict toxicity risk with docetaxel chemotherapy (CHEMO) was validated, and its utility was examined in predicting toxicity risk with abiraterone or enzalutamide (A/E) among older adults with mCRPC. METHODS: Men aged 65+ years were enrolled in a prospective observational study at 4 Canadian academic cancer centers. All clinically relevant grade 2 to 5 toxicities over the course of treatment were documented via structured interviews and chart review. Logistic regression was used to identify predictors of toxicity. RESULTS: Seventy-one men starting CHEMO (mean age, 73 years) and 104 men starting A/E (mean age, 76 years) were included. Clinically relevant grade 3+ toxicities occurred in 56% and 37% of CHEMO and A/E patients, respectively. The CARG tool was predictive of grade 3+ toxicities with CHEMO, which occurred in 36%, 67%, and 91% of low, moderate, and high-risk groups (P = .003). Similarly, grade 3+ toxicities occurred among A/E users in 23%, 48%, and 86% with low, moderate, and high CARG risk (P < .001). However, it was not predictive of grade 2 toxicities with either treatment. CONCLUSIONS: There is external validation of the CARG tool in predicting grade 3+ toxicity in older men with mCRPC undergoing CHEMO and demonstrated utility during A/E therapy. This may aid with treatment decision-making.

Outcomes of Multi-disciplinary Management of Metastatic Renal Cell Carcinoma.

Metastatic renal cell carcinoma (mRCC) is associated with a poor prognosis. It is traditionally a treatment-resistant disease necessitating multi-modal treatment and close follow-up. We herein report a case of mRCC in a patient who was managed closely by a multi-disciplinary team and still retained a very good performance status and treatment response three years after diagnosis. We highlight the importance of close monitoring, switching systemic therapies at progression, early palliative radiotherapy, and patient education in controlling disease burden and maintaining quality of life in patients with mRCC.

Improving Timeliness of Oncology Assessment and Cancer Treatment Through Implementation of a Multidisciplinary Lung Cancer Clinic.

PURPOSE: Timely lung cancer care has been associated with improved clinical outcomes and patient satisfaction. We identified improvement opportunities in lung cancer management pathways at Kingston Health Sciences Centre. Quality improvement strategies led to the implementation of a multidisciplinary lung cancer clinic (MDC). METHODS: We set an outcome measure of decreasing the time from diagnosis to first cancer treatment by 10 days within 6 months of clinic implementation. We implemented a weekly MDC that involved respirologists, medical oncologists, and radiation oncologists at which patients with new lung cancer diagnoses were offered concurrent oncology consultation. We used Plan-Do-Study-Act cycles to guide our improvement initiatives. A total of five Plan-Do-Study-Act cycles spanned 14 months and consisted of an MDC pilot clinic, large-scale MDC launching, debriefing meetings, and clinic expansion. Pre-MDC data were analyzed retrospectively to establish baseline and prospectively for improvement. Statistical Process Control XmR(i) charts were used to report data. RESULTS: Since MDC initiation, 128 patients have been seen in 34 MDC clinics (3.8 patients per clinic). Mean days from diagnosis to first oncology assessment decreased from 12.4 days to 3.9 days, and mean days from diagnosis to first cancer treatment decreased from 39.5 to 15.0 days, both of which demonstrated special cause variation. Time to assessment and treatment improved for patients with every stage of lung cancer and for both small-cell and non-small-cell subtypes. CONCLUSION: MDC shortens the time from lung cancer diagnosis to oncology assessment and treatment. Time to treatment improved more than time to oncology assessment, which suggests the improvement is related to benefits beyond faster oncology assessment.

Perioperative chemotherapy for urothelial carcinoma of the upper urinary tract: A systematic review and meta-analysis.

INTRODUCTION: Upper tract urothelial carcinomas are rare malignancies with differences in anatomy and biology requiring therapeutic strategies that differ from bladder cancer. The role of perioperative systemic therapy in this disease remains uncertain with limited data to support its use. A systematic review of the literature and meta-analysis was therefore undertaken to provide more information and guide clinical practice. METHODS: A literature search was performed using Embase and Medline databases with additional searches performed manually using terms associated with upper tract urothelial malignancies. Data was extracted from studies of patients that underwent nephrouretectomy for the management of upper tract urothelial carcinoma and received either neoadjuvant or adjuvant systemic therapy. Overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were summated and analyzed using Cochrane Revman software Version 5.3. RESULTS: There were 13 comparative studies and no randomized studies identified for data extraction; 11 adjuvant and 2 neoadjuvant with 1170 patients receiving perioperative systemic therapy and 3472 controls that did not. Perioperative chemotherapy was associated with improved OS (HR 0.75, 95%CI 0.57-0.99), DFS (HR 0.54, 95%CI 0.32-0.92), and CSS (HR 0.69, 95%CI 0.42-1.15). CONCLUSIONS: The available data suggests that perioperative systemic therapy is associated with improved survival in patients with upper tract urothelial cancer.

Canadian Cancer Trials Group (CCTG) IND211: A randomized trial of pelareorep (Reolysin) in patients with previously treated advanced or metastatic non-small cell lung cancer receiving standard salvage therapy.

OBJECTIVES: Pelareorep (reolysin), a Dearing strain of reovirus serotype 3, has demonstrated oncolytic activity as single agent and synergy with chemotherapy. We evaluated pelareorep, combined with standard second-line chemotherapy in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This randomized phase II trial enrolled patients with advanced or metastatic NSCLC after first line chemotherapy. After a safety run-in, patients were randomized 1:1 to chemotherapy (pemetrexed [500 mg/m2, non-squamous], or docetaxel [75 mg/m2], day 1 every 21 days]) +/- pelareorep (4.5 × 1010 TCID50, days 1-3 every 21 days), stratified by EGFR mutation status. The primary outcome was progression free survival (PFS) of patients randomized to chemotherapy + pelareorep vs. chemotherapy alone. Secondary outcomes included overall survival, objective response rate and exploratory translational analyses. RESULTS: Between October 2012 and August 2015, 166 patients were enrolled (14 to the safety run in). Pelareorep did not improve the PFS vs. single agent chemotherapy (median PFS 3.0 months, 95% confidence interval [CI] 2.6-4.1) vs. 2.8 months (95% CI 2.5-4.0), hazard ratio (HR) 0.90 (95% CI 0.65-1.25), P = 0.53). Neither KRAS or EGFR mutation was associated with improved PFS, but STK11 mutations did appear to have an association with improved PFS (HR 0.29 [0.12-0.67); as did PIK3CA mutation (HR 0.45 [0.22-0.93]). The combination was tolerable, although associated with increased rates of neutropenic fever. CONCLUSION: The addition of pelareorep to second-line chemotherapy did not improve the PFS of patients with NSCLC. The three-day pelareorep schedule was tolerable. Further research is needed to evaluate the potential benefit in molecular subtypes of NSCLC.

A randomized phase II study of pelareorep and docetaxel or docetaxel alone in men with metastatic castration resistant prostate cancer: CCTG study IND 209.

BACKGROUND: Pelareorep is an oncolytic virus with activity in many cancers including prostate. It has in vitro synergism with microtubule-targeted agents. We undertook a clinical trial evaluating pelareorep in mCRPC patients receiving docetaxel. PATIENTS AND METHODS: In this randomized, open-label phase II study, patients received docetaxel 75mg/m2 on day 1 of a 21-day cycle and prednisone 5mg twice daily, in combination with pelareorep (arm A) or alone (arm B). The primary endpoint was 12 weeks lack of disease progression rate (LPD). RESULTS: Eighty-five pts were randomized. Median age was 69, ECOG performance status was 0/1/2 in 31%/66%/3% of patients. Bone/regional lymph node/liver metastases were present in 98%/24%/6%. The median prognostic score was slightly higher in Arm A (144 vs. 129 p= 0.005). Adverse events were as expected but more prevalent in arm A. The 12-week LPD rate was 61% and 52.4% in arms A/B (p=0.51). Median survival was 19.1 on Arm A and 21.1 months on Arm B (HR 1.83; 95% CI 0.96 to 3.52; p=0.06). No survival benefit of pelareorep was found. CONCLUSION: Pelareorep with docetaxel was tolerable with comparable LPD in both arms but response and survival were inferior and so this combination does not merit further study.

Randomized trial of oral versus intravenous acetaminophen for postoperative pain control.

PURPOSE: Results of a study comparing pain control outcomes with preoperative oral versus intraoperative i.v. acetaminophen use in adults undergoing total hip or knee arthroplasty are reported. METHODS: A single-center, randomized, placebo-controlled, equivalence trial was conducted. Patients were assigned (1:1) to receive 2 500-mg capsules of acetaminophen before surgery, with an i.v. placebo infusion during surgery (the oral group), or 2 oral placebo capsules followed by an i.v. infusion of acetaminophen 1,000 mg/100 mL (the i.v. group). Patients were followed after postanesthesia care unit (PACU) admission up to 24 hours postoperatively. RESULTS: Among 486 patients included in a modified intention-to-treat analysis (mean ± S.D. age, 66.3 ± 9.4 years), there were no significant differences in preoperative and intraoperative use of pain medication between the oral and i.v. groups. Postoperative opioid use in morphine milligram equivalents (MMEs) was equivalent in the oral and i.v. groups (i.e., the mean difference in median MME values was within the prespecified equivalence margin), with no significant between-group differences in mean pain scores over 24 hours. CONCLUSION: In patients undergoing hip or knee arthroplasty, oral acetaminophen given preoperatively was equivalent to i.v. acetaminophen administered in the operating suite in controlling pain in the immediate postoperative period. I.V. acetaminophen was not superior to oral acetaminophen in reducing postoperative nausea and vomiting, time to ambulation, time to first dose of as-needed pain medication, length of PACU stay, or total length of hospital stay.

Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis: A randomized controlled trial.

BACKGROUND: Liver X receptors (LXRs) are involved in maintaining epidermal barrier and suppressing inflammatory responses in model systems. The LXR agonist VTP-38543 showed promising results in improving barrier function and inflammatory responses in model systems. OBJECTIVE: To assess the safety, tolerability, cellular and molecular changes, and clinical efficacy of the topical VTP-38543 in adults with mild to moderate atopic dermatitis (AD). METHODS: A total of 104 ambulatory patients with mild to moderate AD were enrolled in this randomized, double-blind, vehicle-controlled trial between December 2015 and September 2016. VTP-38543 cream in 3 concentrations (0.05%, 0.15%, and 1.0%) or placebo was applied twice daily for 28 days. Pretreatment and posttreatment skin biopsy specimens were obtained from a subset of 33 patients. Changes in SCORing of Atopic Dermatitis, Eczema Area and Severity Index, Investigator's Global Assessment, and tissue biomarkers (by real-time polymerase chain reaction and immunostaining) were evaluated. RESULTS: Topical VTP-38543 was safe and well tolerated. VTP-38543 significantly increased messenger RNA (mRNA) expression of epidermal barrier differentiation (loricrin and filaggrin, P = .02) and lipid (adenosine triphosphate-binding cassette subfamily G member 1 and sterol regulatory element binding protein 1c, P < .01) measures and reduced epidermal hyperplasia markers (thickness, keratin 16 mRNA). VTP-38543 nonsignificantly suppressed cellular infiltrates and down-regulated mRNA expression of several TH17/TH22-related (phosphatidylinositol 3, S100 calcium-binding protein A12) and innate immunity (interleukin 6) markers. CONCLUSION: Topical VTP-38543 is safe and well tolerated. Its application led to improvement in barrier differentiation and lipids. Longer-term studies are needed to clarify whether a barrier-based approach can induce meaningful suppression of immune abnormalities. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02655679.

Symptom and Quality of Life Improvement in LUX-Lung 8, an Open-Label Phase III Study of Second-Line Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung After First-Line Platinum-Based Chemotherapy.

INTRODUCTION: In the phase III LUX-Lung 8 trial, afatinib significantly improved progression-free survival (PFS) and overall survival (OS) versus erlotinib in patients with squamous cell carcinoma (SCC) of the lung progressing during or after platinum-based chemotherapy. Patient-reported outcomes (PROs) and health-related quality of life (QoL) in these patients are presented. PATIENTS AND METHODS: Patients (n = 795) were randomized 1:1 to oral afatinib (40 mg/d) or erlotinib (150 mg/d). PROs were collected (baseline, every 28 days until progression, 28 days after discontinuation) using the European Organization for Research and Treatment of Cancer QoL questionnaire and lung cancer-specific module. The percentage of patients improved during therapy, time to deterioration (TTD), and changes over time were analyzed for prespecified lung cancer-related symptoms and global health status (GHS)/QoL. RESULTS: Questionnaire compliance was 77.3% to 99.0% and 68.7% to 99.0% with afatinib and erlotinib, respectively. Significantly more patients who received afatinib versus erlotinib experienced improved scores for GHS/QoL (36% vs. 28%; P = .041) and cough (43% vs. 35%; P = .029). Afatinib significantly delayed TTD in dyspnea (P = .008) versus erlotinib, but not cough (P = .256) or pain (P = .869). Changes in mean scores favored afatinib for cough (P = .0022), dyspnea (P = .0007), pain (P = .0224), GHS/QoL (P = .0320), and all functional scales. Differences in adverse events between afatinib and erlotinib, specifically diarrhea, did not affect GHS/QoL. CONCLUSION: In patients with SCC of the lung, second-line afatinib was associated with improved prespecified disease-related symptoms and GHS/QoL versus erlotinib, complementing PFS and OS benefits with afatinib.

The Use of Systemic Treatment in the Maintenance of Patients with Non-Small Cell Lung Cancer: A Systematic Review.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is often diagnosed at later stages when treatment options are limited. Maintenance therapy may prolong the time to disease progression and potentially increase overall survival. Secondarily, it may increase the proportion of patients eligible for second-line therapy at the time of progression. The objective of this systematic review was to examine the use of systemic treatment in the maintenance of patients with NSCLC. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched for phase III randomized controlled trials comparing maintenance systemic treatment against another systemic treatment or placebo in patients with stage IIIB or IV NSCLC who had received a minimum of four prior cycles of platinum-based chemotherapy. Meta-analyses were conducted with clinically homogenous trials. RESULTS: Fourteen randomized controlled trials with 22 publications were included. The overall survival benefit was strongest for maintenance therapy with pemetrexed for patients with nonsquamous NSCLC (hazard ratio = 0.74, 95% confidence interval: 0.64-0.86) but not significant for patients with squamous NSCLC. There was also an overall survival benefit with maintenance therapy with epidermal growth factor receptor tyrosine kinase inhibitors, but the magnitude of the benefit was smaller than with pemetrexed (hazard ratio = 0.84, 95% confidence interval: 0.75-0.94). Docetaxel or gemcitabine as maintenance chemotherapies did not have an impact on overall survival. CONCLUSION: For patients with advanced, stable stage IIIB/IV NSCLC whose disease has not progressed after four to six cycles of platinum-based chemotherapy, the overall survival benefits were strongest for pemetrexed maintenance therapy followed by epidermal growth factor receptor tyrosine kinase inhibitor maintenance therapy.

Impact of the addition of chemotherapy to radiotherapy for oropharyngeal cancer in 2003-2004: Population-based study from the Province of Ontario, Canada.

BACKGROUND: Concurrent chemoradiotherapy (CRT) became the standard of care for locoregionally advanced head and neck cancers based on clinical trials but its effectiveness at the community level is not reported. METHODS: We conducted a population-based comparative effectiveness study of all 571 patients with oropharyngeal cancer in Ontario Canada (2003-2004) that describes the patients and the treatments and compares concurrent CRT to radiotherapy (RT) alone. RESULTS: When comparing the outcomes (CRT vs RT) for all patients or patients eligible for either treatment, for patients of centers with the "higher use" of CRT to patients of the 'lower use' centers and comparing all centers, we found no overall or disease-specific advantage to CRT over RT alone. There was also no difference in recurrence-free survival, pattern of recurrences, or distant control. CONCLUSION: In Ontario (2003-2004), in daily clinical practice, the addition of concurrent CRT to RT had little impact on survival in patients with oropharyngeal carcinoma.

A phase II study of GW786034 (pazopanib) with or without bicalutamide in patients with castration-resistant prostate cancer.

INTRODUCTION: Pazopanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. In this randomized, open label phase II study, pazopanib alone or in combination with bicalutamide was evaluated in patients with chemotherapy-naive castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Patients received either pazopanib 800 mg daily (arm A) or pazopanib 800 mg plus bicalutamide 50 mg daily (arm B). A 2-stage study design was used, and the primary endpoint was prostate-specific antigen (PSA) response rate (defined as a confirmed ≥ 50% decline from baseline). RESULTS: A total of 23 patients (arm A, 10; arm B, 13) were accrued. The main grade 3+ toxicities were hypertension, fatigue, decreased lymphocytes, and increased alanine transaminase. Owing to significant toxicity, the protocol was amended after the first 11 patients and the pazopanib starting dose was reduced to 600 mg daily. In arm A, of 9 evaluable patients, there was 1 patient (11%) with a PSA response, 3 (33%) with stable PSA, and 5 (56%) with PSA progression; in arm B, of 12 evaluable patients, there were 2 patients (17%) with PSA responses, 6 (50%) with stable PSA, and 4 (33%) with PSA progression. Median progression-free survival was similar in both arms at 7.3 months (95% CI, 2.5 months to not reached). Long-term stable disease was seen in 4 patients who remained on treatment for 18 months (arm A), 26 months (arm A), 35 months (arm B), and 52 months (arm B). CONCLUSION: In this unselected patient population, pazopanib either alone or in combination with bicalutamide failed to show sufficient activity to warrant further evaluation. However, 4 patients had long-term benefit, suggesting that targeting the VEGFR pathway may still be relevant in selected patients and emphasizing the need for improved predictive markers for patients with CRPC.

Alternative agents versus prophylactic platelet transfusion for preventing bleeding in patients with haematological disorders after chemotherapy or stem cell transplantation.

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine whether alternative agents (e.g. artificial platelet substitutes, platelet-poor plasma, fibrinogen, rFVIIa, thrombopoietin mimetics) are as effective and safe as the use of platelet transfusions for the prevention of bleeding (prophylactic platelet transfusion) in patients with haematological disorders who are undergoing myelosuppressive chemotherapy or stem cell transplantation. Antifibrinolytics (lysine analogues) will not be included in this review because they have been the focus of another Cochrane review (Wardrop 2013).

A multicenter phase II clinical trial of lapatinib (GW572016) in hormonally untreated advanced prostate cancer.

OBJECTIVES: Lapatinib (GW572016) is a selective and potent dual tyrosine kinase inhibitor of the epidermal growth factor 1 (EGFR) and 2 (HER2), approved in the treatment of HER2 positive breast cancer. Since EGFR and HER2 overexpression has also been seen in prostate cancer and appears to correlate with a worse clinical outcome, Lapatinib may represent a novel therapeutic strategy in prostate cancer. This Phase II multicenter clinical trial is the first to evaluate Lapatinib in early stage, hormonally untreated recurrent or metastatic prostate cancer. METHODS: Eligible patients received lapatinib 1500 mg PO daily until progression. The primary end point was prostate specific antigen (PSA) response. Archival tumor tissue was collected for EGFR and HER2 analysis. RESULTS: A total of 23 patients, median age 67, ECOG PS 0-2, mean baseline PSA 7.5, were evaluable for response. In total, 125 cycles were administered. The most frequent adverse events were lymphopenia, fatigue, rash, dyspepsia, and diarrhea. Grade 3+ increased alanine aminotransferase (ALT) was reported in 2 patients, and grade 4 blurry vision in 1 patient. No PSA responses were seen. Median time to progression (TTP) was 4.6 months and 6 months progression-free estimate was 44.5%. CONCLUSIONS: Lapatinib was well tolerated but like other EGFR- and HER2-targeted agents in advanced HRPC failed to show significant antitumor activity even in this very early stage hormonally untreated population.

The management of thymoma: a systematic review and practice guideline.

INTRODUCTION: Thymoma is a rare tumor for which there is little randomized evidence to guide treatment. Because of the lack of high-quality evidence, a formal consensus-based approach was used to develop recommendations on treatment. METHODS: A systematic refview of the literature was performed. Recommendations were formed from available evidence and developed through a two-round modified Delphi consensus approach. RESULTS: The treatment recommendations are summarized as follows: Stage I--complete resection of the entire thymus without neoadjuvant or adjuvant therapy. Stage II--complete resection of the entire thymus with consideration of adjuvant radiation for high-risk tumors. Stage IIIA--surgery either initially or after neoadjuvant therapy, or surgery followed by adjuvant therapy. Stage IIIB--treatment may include a combination of chemotherapy, radiation, and/or surgery, or if technically possible, surgery in combination with chemoradiotherapy (concurrent cisplatin based). For bulky tumors, consideration should be given to sequential chemotherapy followed by radiation. Stage IVA--as per stage III, with surgery only if metastases can be resected. Stage IVB--treatment on an individual case basis (no generic recommendations). Recurrent disease--consider surgery, radiation, and/or chemoradiation. Chemoradiation should be considered in all medically inoperable and technically inoperable patients. CONCLUSION: Consensus was achieved on these recommendations, which serve to provide practical guidance to the physician treating this rare disease.

Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20.

PURPOSE: This double-blind randomized phase II trial examined whether vandetanib, an inhibitor of vascular endothelial and epidermal growth factor receptors, could prolong progression-free survival in responding patients with small-cell lung cancer. PATIENTS AND METHODS: Eligible patients with complete response (CR) or partial response (PR) to combination chemotherapy (+/- thoracic or prophylactic cranial radiation) received oral vandetanib 300 mg/d or matched placebo. With 100 patients and 77 events, the study had 80% power to detect an improvement in median progression-free survival from 4 to 6.5 months (one-sided, 10%-level test). RESULTS: Between May 2003 and March 2006, 107 patients were accrued; 46 had limited disease and 61 extensive disease. There were fewer patients with a performance status of 0 (n = 11 v 20), and fewer had CR to initial therapy (n = 4 v 8) in the vandetanib arm. Vandetanib patients had more toxicity and required more dose modifications for gastrointestinal toxicity and rash. Asymptomatic Corrected QT interval (QTC) prolongation was observed in eight vandetanib patients. Median progression-free survival for vandetanib and placebo was 2.7 and 2.8 months, respectively (hazard ratio [HR], 1.01; 80% CI, 0.75 to 1.36; one-sided P = .51). Overall survival for vandetanib was 10.6 versus 11.9 months for placebo (HR, 1.43; 80% CI, 1.00 to 2.05; one-sided P = 0.9). In planned subgroup analyses, a significant interaction was noted (P = .01): limited-stage vandetanib patients had longer overall survival (HR, 0.45; one-sided P = .07) and extensive-stage vandetanib patients shorter survival compared with placebo (HR, 2.27; one-sided P = .996). CONCLUSION: Vandetanib failed to demonstrate efficacy as maintenance therapy for small-cell lung cancer.