Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies

Background: Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest. Patients and methods: This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged greater than 65, greater than or equal to 65, and greater than or equal to 70 years. Results were compared using unstratified hazard ratios (HRs). Grade 3-5 adverse events were also assessed. Results: Bevacizumab statistically significantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49-0.68] and OS (HR 0.85; 95% CI 0.74-0.97) in patients aged greater than or equal to 65 years; patients aged greater than or equal to 70 years had similar improvements. Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged greater than or equal to 65 and greater than or equal to 70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3-5 adverse events were observed. Conclusions: In medically fit older patients, bevacizumab provides similar PFS and OS benefits as in younger patients

I need more knowledge : Qualitative Analysis of Oncology Providers\u27 Experiences with Sexual and Gender Minority Patients

Background: While societal acceptance for sexual and gender minority (SGM) individuals is increasing, this group continues to face barriers to quality healthcare. Little is known about clinicians\u27 experiences with SGM patients in the oncology setting. To address this, a mixed method survey was administered to members of the ECOG-ACRIN Cancer Research Group. Materials and methods: We report results from the open-ended portion of the survey. Four questions asked clinicians to describe experiences with SGM patients, reservations in caring for them, suggestions for improvement in SGM cancer care, and additional comments. Data were analyzed using content analysis and the constant comparison method. Results: The majority of respondents noted they had no or little familiarity with SGM patients. A minority of respondents noted experience with gay and lesbian patients, but not transgender patients; many who reported experience with transgender patients also noted difficulty navigating the correct use of pronouns. Many respondents also highlighted positive experiences with SGM patients. Suggestions for improvement in SGM cancer care included providing widespread training, attending to unique end-of-life care issues among SGM patients, and engaging in efforts to build trust. Conclusion: Clinicians have minimal experiences with SGM patients with cancer but desire training. Training the entire workforce may improve trust with, outreach efforts to, and cancer care delivery to the SGM community

Carbonic anhydrase 9 is a predictive marker of survival benefit from lower dose of bevacizumab in patients with previously treated metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Carbonic anhydrase 9 (CA9) is a marker for hypoxia and acidosis, which is linked to a poor prognosis in human tumors. The purpose of this comparative analysis was to evaluate whether CA9 and VEGF expression are associated with survival outcomes in patients with metastatic colorectal cancer (mCRC) after treatment with bevacizumab as second or later line treatment.</p> <p>Methods</p> <p>Thirty-one mCRC patients who were treated with bevacizumab-containing chemotherapy as second or later line treatment and who had analyzable tumor paraffin blocks were selected for this study. The planned dose of bevacizumab was 5 mg/kg/2-week. Immunohistochemical (IHC) staining of CA9 and VEGF was performed and their expression was scored by the intensity multiplied by percentage of stained area.</p> <p>Results</p> <p>The overall response rate was 19.4% and the disease control rate (DCR) was 61.3% with 6 partial responses and 13 cases of stable disease. The DCR was significantly higher in patients with a lower CA9 expression score compared to those with a higher score (80.0% vs. 27.3%, respectively, P = 0.004). The patients with a low CA9 expression score also showed better outcomes with regard to the median progression-free survival (P = 0.028) and overall survival (P = 0.026). However, VEGF expression was not associated with the DCR and survival.</p> <p>Conclusion</p> <p>Lower degree of CA9 expression was associated with better clinical outcomes in patients with mCRC treated with lower dose bevacizumab-based chemotherapy. Prospective studies are now needed to determine the correlation between CA9 expression and clinical outcomes after bevacizumab treatment, at different doses and in varied settings.</p

Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial

BACKGROUND: Complete resection of metastases can result in cure for selected patients with metastatic colorectal cancer. METHODS: First BEAT evaluated the safety of bevacizumab with first-line chemotherapy in 1914 patients. Prospectively collected data from 225 patients who underwent curative-intent surgery were analysed, including an exploratory comparison of resection rate in patients treated with different regimens. NO16966 compared efficacy of oxaliplatin-based chemotherapy plus bevacizumab or placebo in 1400 patients. A retrospective analysis of resection rate was undertaken. RESULTS: In First BEAT, 225 out of 1914 patients (11.8%) underwent curative-intent surgery at median 64 days ( range 42-100) after the last dose of bevacizumab. R0 resection was achieved in 173 out of 225 patients (76.9%). There were no surgery-related deaths and serious post-operative complications were uncommon, with grade 3/4 bleeding and wound-healing events reported in 0.4% and 1.8%, respectively. Resection rates were highest in patients receiving oxaliplatin-based combination chemotherapy (P=0.002), possibly confounded by patient selection. In NO16966, 44 out of 699 patients treated with bevacizumab (6.3%) and 34 out of 701 patients treated with placebo (4.9%) underwent R0 metastasectomy (P=0.24). CONCLUSIONS: The rate of serious post-operative complications in First BEAT was comparable to historical controls without bevacizumab. In NO16966, there were no statistically significant differences in resection rates or overall survival in patients treated with bevacizumab vs placebo

The management of cancer in the elderly: targeted therapies in oncology

Cancer is universally considered a disease of ageing. Today the management of elderly cancer patients poses many specific problems and it should be revisited in the light of the most recent advances in both diagnosis and treatment of human malignancies. In particular, the potential use of novel therapeutic options, based on therapeutic agents raised against molecular targets (the so called targeted therapy), appears to be promising in this clinical settings especially in view of the limited side-effects. The mainstays of cancer treatment during the twentieth century were surgery, radiation and chemotherapy. However, surgery is not curative in metastatic disease, radiation and chemotherapy are limited by side effects because they can't discriminate between healthy and cancerous cells. When key molecular changes responsible for malignant transformation were identified (e.g. growth factors and their receptors), it was hoped that new targeted agents, by inhibiting cancer-specific pathways, would spare normal cells and thereby offer improved safety benefits and a higher therapeutic index over standard chemotherapeutics. The most common targeted therapies used in clinical practice, i.e. monoclonal antibodies and small molecules, are described

Safety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours

The aim of this open-label phase 1b study was to assess the safety and pharmacokinetics of motesanib in combination with gemcitabine in patients with advanced solid tumours. Eligible patients with histologically or cytologically documented solid tumours or lymphoma were enroled in three sequential, dose-escalating cohorts to receive motesanib 50 mg once daily (QD), 75 mg two times daily (BID), or 125 mg QD in combination with gemcitabine (1000 mg m−2). The primary end point was the incidence of dose-limiting toxicities (DLTs). Twenty-six patients were enroled and received motesanib and gemcitabine. No DLTs occurred. The 75 mg BID cohort was discontinued early; therefore, 125 mg QD was the maximum target dose. Sixteen patients (62%) experienced motesanib-related adverse events, most commonly lethargy (n=6), diarrhoea (n=4), fatigue (n=3), headache (n=3), and nausea (n=3). The pharmacokinetics of motesanib and of gemcitabine were not markedly affected after combination therapy. The objective response rate was 4% (1 of 26), and 27% (7 of 26) of patients achieved stable disease. In conclusion, treatment with motesanib plus gemcitabine was well tolerated, with adverse event and pharmacokinetic profiles similar to that observed in monotherapy studies

Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation

Chemotherapy plus bevacizumab is currently considered as the standard 1st line treatment of advanced colorectal cancer (ACC). Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported. We identified 18 patients with ACC who participated in a phase III multicentre trial which included chemotherapy and bevacizumab, who developed a GI ulcer (n = 6), perforation (n = 8) or both (n = 4). The risk of developing a symptomatic GI ulcer or perforation was 1.3% and 1.6%, respectively. Central review of the histology specimens showed ulceration and/or granulation tissue with neovascularisation. The majority (89%) of events developed early during treatment. Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation

Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases

Background:This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin-and irinotecan-based systemic chemotherapy regimens.Methods:Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9-2.2).Results:Of 50 eligible patients, 38 (76%) had received 654 lines of chemotherapy. Most presented with synchronous disease (72%), <4 hepatic metastases (58%), 25-50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (<48 h) WHO G1-2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0-18.3); 2-year survival was 19.6%.Conclusion: Radioembolisation produced meaningful response and disease stabilisation in patients with advanced, unresectable and chemorefractory mCRC. \ua9 2010 Cancer Research UK All rights reserved

A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment

<p>Abstract</p> <p>Background</p> <p>About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX.</p> <p>Methods/design</p> <p>The Hepatica study is a two-arm, multicenter, randomized, comparative efficacy and safety study. Patients are assessed no more than 8 weeks before surgery with CEA measurement and CT scanning of the chest and abdomen. Patients will be randomized after resection or resection combined with RFA to receive CAPOX and Bevacizumab or CAPOX alone. Adjuvant treatment will be initiated between 4 and 8 weeks after metastasectomy or resection in combination with RFA. In both arms patients will be assessed for recurrence/new occurrence of colorectal cancer by chest CT, abdominal CT and CEA measurement. Patients will be assessed after surgery but before randomization, thereafter every three months after surgery in the first two years and every 6 months until 5 years after surgery. In case of a confirmed recurrence/appearance of new colorectal cancer, patients can be treated with surgery or any subsequent line of chemotherapy and will be followed for survival until the end of study follow up period as well. The primary endpoint is disease free survival. Secondary endpoints are overall survival, safety and quality of life.</p> <p>Conclusion</p> <p>The HEPATICA study is designed to demonstrate a disease free survival benefit by adding bevacizumab to an adjuvant regime of CAPOX in patients with colorectal liver metastases undergoing a radical resection or resection in combination with RFA.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier NCT00394992</p

Zeolite structures loading with an anticancer compound as drug delivery systems

The authors are thankful to Dr. A. S. Azevedo for collecting the powder diffraction data.Two different structures of zeolites, faujasite (FAU) and Linde type A (LTA), were studied to investigate their suitability for drug delivery systems (DDS). The zeolites in the sodium form (NaY and NaA) were used as hosts for encapsulation of α-cyano-4- hydroxycinnamic acid (CHC). CHC, an experimental anticancer drug, was encapsulated in both zeolites by diffusion in liquid phase. These new drug delivery systems, CHC@zeolite, were characterized by spectroscopic techniques (FTIR, 1H NMR, 13C and 27Al solidstate MAS NMR, and UV−vis), chemical analysis, powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). The effect of the zeolites and CHC@zeolite drug deliveries on HCT-15 human colon carcinoma cell line viability was evaluated. Both zeolites alone revealed no toxicity to HCT-15 cancer cells. Importantly, CHC@zeolite exhibit an inhibition of cell viability up to 585-fold, when compared to the non-encapsulated drug. These results indicate the potential of the zeolites for drug loading and delivery into cancer cells to induce cell deathO.M. and R.A. are recipients of fellowships (SFRH/BD/36463/2007, SFRH/BI/51118/2010) from Fundação para a Ciência e a Tecnologia (FCT, Portugal). This work was supported by the FCT projects refs PEst-C/ QUI/UI0686/2011, PEst-C/CTM/LA0011/2011, and PTDC/ SAU-FCF/104347/2008, under the scope of “Programa Operacional Temático Factores de Competitividade” (COMPETE) of “Quadro Comunitário de Apoio III” and cofinanced by Fundo Comunitário Europeu FEDER, and the Centre of Chemistry and Life and Health Sciences Research Institute (University of Minho, Portugal)