Geke A P Hospers

University of Groningen, Groningen, Groningen, Netherlands

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Publications (126)565.55 Total impact


  • No preview · Article · Feb 2016 · Journal of Nuclear Medicine
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    ABSTRACT: Background and purpose: Neoadjuvant chemoradiotherapy (nCRT) improves survival in esophageal cancer (EC) patients, but the response to treatment is heterogeneous and little is known regarding prognostic and predictive markers in these patients. CD44, SOX2 and SHH have been implicated in resistance to CRT, possibly through an association with a cancer stem cell phenotype. Material and methods: 101 EC patients treated with nCRT and surgery were included. Sufficient pre-treatment biopsy material was present in 71 patients, of which 53 patients were non-complete responders on nCRT (nCR). Protein expression was examined using immunohistochemistry (IHC). Prognostic factors were determined using Cox regression analysis for disease free survival (DFS) and cause specific survival (CSS) in the complete cohort, the pre-treatment biopsies group and post-treatment nCR group. Results: Low CD44 expression in the nCR group was an independent prognostic factor for both DFS and CSS (DFS HR 2.81, p=0.002 and CSS HR 3.48, p=0.002). Absent SOX2 expression in pretreatment biopsies was related to systemic recurrence (p=0.029) while low SHH in pretreatment biopsies was an independent prognostic factor for a poor DFS (HR 2.27, p=0.036). No relation between marker expression and response to nCRT was observed. Conclusions: Low expression of CD44 and SHH are associated with a poor survival outcome in EC patients treated with nCRT.
    Full-text · Article · Sep 2015 · Radiotherapy and Oncology
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    ABSTRACT: Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years.
    No preview · Article · Aug 2015 · The Lancet Oncology
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    ABSTRACT: Due to differences in anatomy, primary rectal and colon cancer require different staging procedures, different neo-adjuvant treatment and different surgical approaches. For example, neoadjuvant radiotherapy or chemoradiotherapy is administered solely for rectal cancer. Neoadjuvant therapy and total mesorectal excision for rectal cancer might be responsible in part for the differing effect of adjuvant systemic treatment on overall survival, which is more evident in colon cancer than in rectal cancer. Apart from anatomic divergences, rectal and colon cancer also differ in their embryological origin and metastatic patterns. Moreover, they harbor a different composition of drug targets, such as v-raf murine sarcoma viral oncogene homolog B (BRAF), which is preferentially mutated in proximal colon cancers, and the epidermal growth factor receptor (EGFR), which is prevalently amplified or overexpressed in distal colorectal cancers. Despite their differences in metastatic pattern, composition of drug targets and earlier local treatment, metastatic rectal and colon cancer are, however, commonly regarded as one entity and are treated alike. In this review, we focused on rectal cancer and its biological and clinical differences and similarities relative to colon cancer. These aspects are crucial because they influence the current staging and treatment of these cancers, and might influence the design of future trials with targeted drugs. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jun 2015 · Cancer Treatment Reviews
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    ABSTRACT: Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Up-regulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16α-[(18)F]fluoro-17β-oestradiol ((18)F-FES) as potential marker to select breast cancer patients for oestradiol therapy. Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after ≥2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent (18)F-FES-PET/CT imaging at baseline. Tumour (18)F-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUVmax). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression ≥24 weeks. (18)F-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value (PPV/NPV) of (18)F-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUVmax >1.5. (18)F-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy.
    Preview · Article · Jun 2015 · European Journal of Nuclear Medicine
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    ABSTRACT: The aim of this study was to evaluate the effect on the number of performed biopsies and costs associated with implementing positron emission tomography (PET) and computed tomography (PET/CT) with 16α-[(18)F]fluoro-17β-oestradiol (FES) or 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) as an upfront imaging test for diagnosing metastatic breast cancer (MBC) in comparison with the standard work-up in oestrogen receptor-positive women with symptoms. A published computer simulation model was adapted and validated. Three follow-up strategies were evaluated in a simulated cohort of women with primary breast cancer over a 5-year-time horizon: (1) the standard work-up, (2) upfront FES-PET/CT and (3) upfront FDG-PET/CT. The main outcome was the number of avoided biopsies to assess MBC. The costs for all three strategies were calculated based on the number of imaging tests and biopsies. The incremental cost-effectiveness ratio (ICER) to avoid a biopsy was calculated only based on the costs of initial imaging and staging tests. The FES-PET/CT strategy decreased the number of biopsies by 39±9%, while upfront FDG-PET/CT increased the number of biopsies by 38±15% when compared with the standard work-up. Both PET/CT strategies reduced the number of imaging tests and false positives when compared with the standard work-up. The number of false negatives decreased only in the FES-PET/CT strategy. The ICER in the FES-PET/CT strategy per avoided biopsy was 12.1±3.4 thousand Euro. In the FDG-PET/CT strategy, the costs were higher and there were no avoided biopsies as compared with the standard work-up, hence this was an inferior strategy in terms of cost effectiveness. The number of performed biopsies was lower in the FES-PET/CT strategy at an ICER of 12.1±3.4 thousand Euro per biopsy avoided, whereas the application of the FDG-PET/CT did not reduce the number of biopsies and was more expensive. Whether the FES-PET/CT strategy has additional benefits for patients in terms of therapy management has to be evaluated in clinical studies.British Journal of Cancer advance online publication 16 April 2015. doi:10.1038/bjc.2015.138 www.bjcancer.com.
    No preview · Article · Apr 2015 · British Journal of Cancer
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    ABSTRACT: Metastatic rectal cancer patients could benefit from novel therapeutic approaches. The signaling network formed by chemokines and their receptors can promote metastasis and resistance to current anticancer treatments. This study assessed the expression of chemokine receptor 4 (CXCR4) and its ligand CXCL12 immuhistochemically in stage IV rectal tumors. Paraffin-embedded primary tumor collected before and after local radiotherapy and systemic treatment with bevacizumab, oxaliplatin and capecitabine was analyzed. Receptor and ligand expression was assessed in the cytoplasm and nucleus of tumor, stromal and normal rectal crypt cells. Baseline expression of CXCR4 and CXCL12 was correlated with patients' pathologic response to treatment. At diagnosis (n=46), 89% of the rectal tumors expressed cytoplasmic CXCR4 and 81% CXCL12. Nuclear CXCR4 expression in tumor cells was present in 30% and nuclear CXCL12 expression in 35% of the tumors. After radiochemotherapy and bevacizumab, nuclear CXCL12 expression was present in 79% of residual tumors, as compared to 31% of the paired tumor samples expressing nuclear CXCL12 before treatment (P=0.001). There were no differences in CXCR4 or CXCL12 expression at baseline between the patients that had (n=9) and did not have (n=30) a pathologic complete response. Our results show that CXCR4 and CXCL12 are extensively expressed in primary rectal tumors of patients presenting with metastatic disease, while radiochemotherapy and bevacizumab further upregulate CXCL12 expression. These data indicate the importance of the CXCR4/CXCL12 axis in rectal tumor biology, and may suggest the CXCR4/CXCL12 receptor-ligand pair as a potential therapeutic target in metastatic rectal cancer.
    No preview · Article · Jan 2015 · Current pharmaceutical design

  • No preview · Article · Dec 2014 · Radiotherapy and Oncology
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    ABSTRACT: The estrogen receptor (ER) α is expressed in ~70% of ovarian cancer tumors. Positron emission tomography (PET) of tumor ERα expression with the tracer 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of (18)F-FES-PET to determine tumor ERα expression non-invasively in epithelial ovarian cancer patients. (18)F-FES-PET/CT was performed shortly before cytoreductive surgery. Tumor (18)F-FES uptake was quantified for all lesions ≥10 mm on CT and expressed as maximum standardized uptake value (SUVmax). (18)F-FES-PET/CT findings were compared to histology and immunohistochemistry for ERα, ERβ, and progesterone receptor (PR). Receptor expression was scored semi-quantitatively using H-scores (percentage of positive tumor cells x staining intensity). The optimum threshold to discriminate ER-positive and negative lesions was determined by receiver operating characteristic analysis. In the 15 included patients with suspected ovarian cancer, 32 measurable lesions >10 mm were present on CT. Tumor (18)F-FES uptake could be quantified for 28 lesions (88%), four lesions were visible but non-quantifiable due to high uptake in adjacent tissue. During surgery, histology was obtained of 23 out of 28 quantified lesions (82%). Quantitative (18)F-FES uptake correlated with the semi-quantitative immunoscore for ERα (ρ = 0.65, P < 0.01), weakly with PR expression (ρ = 0.46, P = 0.03) and was not associated with ERβ expression (ρ = 0.21, P = 0.33). The optimal threshold to discriminate ERα-positive and ERα-negative lesions was a SUVmax >1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% CI 0.70-1.00). In two of seven patients with cytology/histology available at primary diagnosis and at debulking surgery immunohistochemical ERα expression had changed over time. (18)F-FES-PET was in accordance with histology at debulking surgery, but not at primary diagnosis, indicating that (18)F-FES-PET can provide reliable information about current tumor ERα status. (18)F-FES-PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases non-invasively. Evaluation of the predictive value of (18)F-FES-PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    No preview · Article · Dec 2014 · Journal of Nuclear Medicine
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    ABSTRACT: The aim of this prospective study was to determine the proportion of locoregional recurrences (LRRs) that could have been prevented if radiotherapy treatment planning for oesophageal cancer was based on PET/CT instead of CT. Ninety oesophageal cancer patients, eligible for high dose (neo-adjuvant) (chemo)radiotherapy, were included. All patients underwent a planning FDG-PET/CT-scan. Radiotherapy target volumes (TVs) were delineated on CT and patients were treated according to the CT-based treatment plans. The PET images remained blinded. After treatment, TVs were adjusted based on PET/CT, when appropriate. Follow up included CT-thorax/abdomen every 6months. If LRR was suspected, a PET/CT was conducted and the site of recurrence was compared to the original TVs. If the LRR was located outside the CT-based clinical TV (CTV) and inside the PET/CT-based CTV, we considered this LRR possibly preventable. Based on PET/CT, the gross tumour volume (GTV) was larger in 23% and smaller in 27% of the cases. In 32 patients (36%), >5% of the PET/CT-based GTV would be missed if the treatment planning was based on CT. The median follow up was 29months. LRRs were seen in 10 patients (11%). There were 3 in-field recurrences, 4 regional recurrences outside both CT-based and PET/CT-based CTV and 3 recurrences at the anastomosis without changes in TV by PET/CT; none of these recurrences were considered preventable by PET/CT. No LRR was found after CT-based radiotherapy that could have been prevented by PET/CT. The value of PET/CT for radiotherapy seems limited. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    No preview · Article · Nov 2014 · Radiotherapy and Oncology
  • Frederik H E Schagen · Rob C Hoeben · Geke A.P. Hospers
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    ABSTRACT: Abstract Recently, the first human medicine containing a genetically modified organism (GMO medicine) was authorized for use in the European market. Just as any medicinal product, the market authorization for a GMO medicine contains a precise description of the therapeutic use for which the medicinal product is intended. Within this use, the application of the GMO medicine is permitted, without the need for the institution to obtain a specific permit. In practice, however, medicinal products are also frequently prescribed for treatment outside the registered therapeutic use, a practice that is referred to as "off-label use." While off-label use of conventional medicines is permitted and has been very useful, the off-label use of GMO medicines is not covered in the European Union (EU) legislation or guidelines and falls under each member state's national environmental legislation. This implies that in the Netherlands and most other EU member states, an environmental permit will be required for any institution that uses the GMO medicine outside the registered application(s). In the Netherlands, this permit is identical to the permits required for the execution of clinical trials involving nonregistered GMOs. The application procedure for such permit is time-consuming. This process can therefore limit the therapeutic options for medical professionals. As a consequence, desired treatment regimens could be withheld for certain patient (groups). To make future off-label use of GMO medicines permissible in a way that is acceptable for all stakeholders, regulators should adopt a proactive attitude and formulate transparent legislative procedures for this. Only then the field can maintain the public acceptance of GMO medicines, while maintaining the freedom to operate of medical professionals.
    No preview · Article · Oct 2014 · Human Gene Therapy
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    ABSTRACT: Background: Locally advanced rectal cancer is customarily treated with neoadjuvant chemoradiotherapy (CRT) followed by a total mesorectal excision. During the course of CRT, previously non-detectable distant metastases can appear. Therefore, a restaging CT scan of the chest and abdomen was performed prior to surgery. The aim of this study was to determine the frequency of a change in treatment strategy after this restaging CT scan. Methods: Patients treated with neoadjuvant CRT for locally advanced rectal cancer between January 2003 and July 2013 were included retrospectively. To determine the value of the restaging CT scan, the surgical treatment as planned before CRT was compared with the treatment ultimately received. Results: A total of 153 patients (91 male) were eligible, and median age was 62 (32-82) years. The restaging CT scan revealed the presence of distant metastases in 19 patients (12.4, 95 % confidence interval [CI] 7.0-17.8). In 17 patients (11.1, 95 % CI 6.1-16.1), a change in treatment strategy occurred due to the detection of metastases with a restaging CT scan. Conclusion: A restaging CT scan after completion of neoadjuvant CRT may detect newly developed metastases and consequently alter the initial treatment strategy. This study demonstrated the added value of the restaging CT scan prior to surgery.
    Full-text · Article · Aug 2014 · Annals of Surgical Oncology
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    ABSTRACT: Background Neoadjuvant chemoradiotherapy (CRT) in esophageal cancer (EC) patients may increase the formation of thromboembolic events (TEE’s). We analyzed the incidence and impact of TEE’s in EC patients treated with platinum-based CRT. Patient and methods A total of 336 patients with EC underwent an esophagectomy of which 110 patients received neoadjuvant CRT (41.4Gy with concurrent Carboplatin/Paclitaxel). Patients were matched based on pre- and perioperative characteristics. Results Preoperatively, 9 (8.2%) patients with neoadjuvant CRT (p=0.004) were diagnosed with TEE’s. Despite delay until surgery (p=0.021), the postoperative course did not differ. In multivariate analysis, a history of DVT (p=0.005) and neoadjuvant CRT (p=0.004) were identified as risk factors. Postoperatively, there was no differences in TEE’s (p=0.560) observed. In multivariate analysis, a history of pulmonary embolism (p=0.012) was identified as risk factor for postoperative TEE’s. Conclusion Preoperatively, EC patients treated with neoadjuvant CRT have an increased risk to develop a TEE, especially those with a previous history of TEE. After surgery no increased incidence was observed. We recommend secondary prophylaxis during neoadjuvant treatment in this high-risk group.
    No preview · Article · Aug 2014 · American journal of surgery
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    ABSTRACT: Objectives: This study was initiated to investigate the feasibility and efficacy of preoperative radiotherapy with weekly paclitaxel and carboplatin in locally advanced gastric cancer. Methods: In a prospective study, patients with locally advanced gastric cancer stage IB-IV(M0) were treated with chemoradiotherapy followed by surgery 4-6 weeks after the last irradiation. Chemoradiotherapy consisted of radiation to a total dose of 45 Gy given in 25 fractions of 1.8 Gy, combined with concurrent weekly carboplatin and paclitaxel. Results: Between December 2007 and January 2012, 25 patients with cT3 (64%) or cT4 (36%) gastric cancer were included. One patient discontinued concurrent chemotherapy in the 4th week due to toxicity, but completed radiotherapy. Another patient discontinued chemoradiotherapy after the 3rd week due to progressive disease. Grade III adverse events of chemoradiotherapy were: gastrointestinal 12%, haematological 12% and other 8%. All patients, except one who developed progressive disease, were operated. Surgical complications were: general/infectious 48%, anastomotic leakage 12%, and bowel perforation 8%. Postoperative mortality was 4%. Microscopically radical resection rate was 72%. Pathological complete response rate was 16% and near complete response rate 24%. Conclusions: In this study, preoperative chemoradiotherapy for patients with locally advanced gastric cancer was associated with manageable toxicity and encouraging pathological response rates.
    No preview · Article · May 2014 · Radiotherapy and Oncology

  • No preview · Article · May 2014 · Oncology (Williston Park, N.Y.)
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    Preview · Article · Apr 2014 · Journal of Clinical Oncology
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    ABSTRACT: Methods Patients with advanced cutaneous melanoma were treated in the netherlands (nl) and the United King-dom (UK) with ipilimumab at 3 mg/kg. Baseline charac-teristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. Results a total of 166 patients were treated in the neth-erlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (lDH) was demonstrated to be the strongest predictive factor for OS. Abstract Introduction Ipilimumab, a cytotoxic t lymphocyte-associated antigen-4 blocking antibody, has improved over-all survival (OS) in metastatic melanoma in phase III tri-als. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit.
    No preview · Dataset · Mar 2014
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    ABSTRACT: Ipilimumab, a cytotoxic T lymphocyte-associated antigen-4 blocking antibody, has improved overall survival (OS) in metastatic melanoma in phase III trials. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit. Patients with advanced cutaneous melanoma were treated in the Netherlands (NL) and the United Kingdom (UK) with ipilimumab at 3 mg/kg. Baseline characteristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. A total of 166 patients were treated in the Netherlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (LDH) was demonstrated to be the strongest predictive factor for OS. These findings were validated in an independent cohort of 64 patients from the UK. In both the NL and UK cohorts, long-term benefit of ipilimumab treatment was unlikely for patients with baseline serum LDH greater than twice the upper limit of normal. In the absence of prospective data, clinicians treating melanoma may wish to consider the data presented here to guide patient selection for ipilimumab therapy.
    Full-text · Article · Mar 2014 · Cancer Immunology and Immunotherapy
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    ABSTRACT: Methods Patients with advanced cutaneous melanoma were treated in the netherlands (nl) and the United King-dom (UK) with ipilimumab at 3 mg/kg. Baseline charac-teristics and peripheral blood parameters were assessed, and patients were monitored for the occurrence of adverse events and outcomes. Results a total of 166 patients were treated in the neth-erlands. Best overall response and disease control rates were 17 and 35 %, respectively. Median follow-up was 17.9 months, with a median progression-free survival of 2.9 months. Median OS was 7.5 months, and OS at 1 year was 37.8 % and at 2 years was 22.9 %. In a multivariate model, baseline serum lactate dehydrogenase (lDH) was demonstrated to be the strongest predictive factor for OS. Abstract Introduction Ipilimumab, a cytotoxic t lymphocyte-associated antigen-4 blocking antibody, has improved over-all survival (OS) in metastatic melanoma in phase III tri-als. However, about 80 % of patients fail to respond, and no predictive markers for benefit from therapy have been identified. We analysed a 'real world' population of patients treated with ipilimumab to identify markers for treatment benefit.
    Full-text · Dataset · Mar 2014
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    ABSTRACT: The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options. In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively). Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. F Hoffmann-La Roche.
    Full-text · Article · Feb 2014 · The Lancet Oncology

Publication Stats

3k Citations
565.55 Total Impact Points

Institutions

  • 1989-2015
    • University of Groningen
      • • Department of Medical Oncology
      • • Department of Internal Medicine
      Groningen, Groningen, Netherlands
  • 1988-2014
    • Universitair Medisch Centrum Groningen
      • • Department of Nuclear Medicine and Molecular Imaging
      • • Department of Internal Medicine
      Groningen, Groningen, Netherlands
  • 2005
    • Bethesda Hospital
      Hoogeveen, Drenthe, Netherlands
  • 2000
    • GGD Groningen
      Groningen, Groningen, Netherlands