Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer.

PURPOSE: The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patients. METHODS: Patients with advanced adenocarcinoma of the pancreas were enrolled. Eligible patients had a WHO performance status 0-2 and adequate hepatic and renal functions. The treatment regimen consisted of capecitabine 1000 mg/m(2) BID day 1-14 and everolimus 10 mg daily (5 mg BID) in a continuous 21-day schedule. Tumor assessment was performed with CT-scan every three cycles. Primary endpoint was response rate (RR) according to RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and 1-year survival rate. RESULTS: In total, 31 patients were enrolled. Median (range) treatment duration with everolimus was 76 days (1-431). Principal grade 3/4 toxicities were hyperglycemia (45 %), hand-foot syndrome (16 %), diarrhea (6 %) and mucositis (3 %). Prominent grade 1/2 toxicities were anemia (81 %), rash (65 %), mucositis (58 %) and fatigue (55 %). RR was 6 %. Ten patients (32 %) had stable disease resulting in a disease control rate of 38 %. Median overall survival was 8.9 months (95 % CI 4.6-13.1). Progression-free survival was 3.6 months (95 % CI 1.9-5.3). CONCLUSIONS: The oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer, with an acceptable toxicity profile at the applied dose level.

Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies.

Most patients with pancreatic cancer present with advanced/metastatic disease and have a dismal prognosis. Despite the proven albeit modest benefits of gemcitabine demonstrated over a decade ago, subsequent advances have been slow, suggesting it may be time to take a different approach. It is thought that some key characteristics of pancreatic cancer, such as the desmoplasia, restricted vasculature and hypoxic environment, may prevent the delivery of chemotherapy to the tumour thereby explaining the limited benefits observed to-date. Moreover, there is evidence to suggest that the stroma is not only a mechanical barrier but also constitutes a dynamic compartment of pancreatic tumours that is critically involved in tumour formation, progression and metastasis. Thus, targeting the stroma and the tumour represents a promising therapeutic strategy. Currently, several stroma-targeting agents are entering clinical development. Among these, nab-paclitaxel appears promising since it combines cytotoxic therapy with targeted delivery via its proposed ability to bind SPARC on tumour and stromal cells. Preclinical data indicate that co-treatment with nab-paclitaxel and gemcitabine results in stromal depletion, increased tumour vascularization and intratumoural gemcitabine concentration, and increased tumour regression compared with either agent alone. Phase I/II study data also suggest that a high level of antitumor activity can be achieved with this combination in pancreatic cancer. This was recently confirmed in a Phase III study which showed that nab-paclitaxel plus gemcitabine significantly improved overall survival (HR 0.72) and progression-free survival (HR 0.69) versus gemcitabine alone for the first-line treatment of patients with metastatic pancreatic cancer.

Protease-activated receptor-2 induces migration of pancreatic cancer cells in an extracellular ATP-dependent manner.

BACKGROUND: Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor suggested to play an important role in the proliferation and migration of tumor cells of epithelial origin. However, the role of PAR-2 in the setting of pancreatic cancer remains largely unexplored. OBJECTIVES: To understand the importance of PAR-2 in pancreatic cancer cell migration. METHODS AND RESULTS: The present study shows that PAR-2 does not affect pancreatic cancer cell proliferation but significantly induces the migration of pancreatic cancer cells in scratch assays. Interestingly, PAR-2 does not affect migration in a trans-well setting. This apparent discrepancy depends on extracellular ATP release in the scratch assays and the addition of exogenous (ATP)-induced PAR-2-dependent migration in trans-well assays, whereas a specific P2Y11 receptor antagonist prevents PAR-2-driven migration in scratch assays. In the scratch assays, inhibitors of Src, Rac, protein kinase C, mitogen-activated protein kinase kinase, p38, and epidermal growth factor (EGF) receptor blocked PAR-2-driven migration, whereas they did not affect fetal calf serum-driven wound closure. CONCLUSION: Taken together, PAR-2 activation drives pancreatic cancer cell migration via an EGF-Src-Rac-p38/mitogen-activated protein kinase kinase/EGF1/2 signaling pathway, which is facilitated by extracellular ATP. Targeting the PAR-2/ATP-driven signaling pathway may therefore limit cell migration, which could inhibit pancreatic cancer metastasis.

Neoadjuvant chemoradiotherapy followed by esophagectomy does not increase morbidity in patients over 70.

Esophagectomy in elderly esophageal carcinoma patients is correlated with a high morbidity and even mortality. Studies on neoadjuvant chemoradiotherapy (NT) in elderly patients are scarce. The aim of this study was to evaluate the effect of advanced age in combination with NT in esophageal carcinoma patients who underwent an esophagectomy. Patients who underwent NT prior to esophagectomy between 1993 and 2010 were divided into three groups: <70, 70-74, and ≥75 years. Toxicity of NT and postoperative morbidity were compared between groups. Primary endpoints were toxicity, complication rate, and survival. Two hundred thirteen patients underwent NT during the study period, 26 were aged 70-74 years, and 17 were ≥70 years. Toxicity of NT was comparable for younger and elderly patients (46% vs. 54% vs. 47%, P = 0.263). Overall complications occurred in 62% of younger patients versus 73% and 71% among patients aged 70-74 years and ≥75 years, respectively (P = 0.836). Cardiac complications occurred in 14% of younger patients versus 27% and 41% of elderly patients (P = 0.021). Three-year survival rates were 59% versus 44% versus 31% among patients aged <70, 70-74, and ≥75 years, respectively (P = 0.237). Higher age (odds ratio 1.750, P < 0.001) was an independent risk factor for development of cardiac complications. Toxicity of NT and postoperative complications are comparable for patients aged <70, 70-74, and ≥75 years, with the exception of cardiac complications. Therefore, we consider NT followed by esophagectomy in elderly patients a safe treatment modality in our center.

Preoperative chemoradiotherapy for esophageal or junctional cancer.

BACKGROUND: The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS: We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS: From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003). CONCLUSIONS: Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.).

Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial.

BACKGROUND: The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. PATIENTS AND METHODS: Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF)≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. RESULTS: Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+C→T+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+H→T+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). CONCLUSION: PLD+C+H→T+H is feasible and results in lower early cardiotoxicity rates compared with A+C→T+H.

Accuracy and reproducibility of 3D-CT measurements for early response assessment of chemoradiotherapy in patients with oesophageal cancer.

BACKGROUND: Chemoradiotherapy is increasingly applied in patients with oesophageal cancer. The aim of the present study was to determine whether 3D-CT volumetry is able to differentiate between responding and non-responding oesophageal tumours early in the course of neoadjuvant chemoradiotherapy. PATIENTS AND METHODS: Serial CT before and after two weeks of neoadjuvant chemoradiotherapy was performed in the multimodality treatment arm of a randomised trial including patients with oesophageal carcinoma. CT response was measured with the change in tumour volume between baseline and after 14 days of neoadjuvant therapy. Receiver Operating Characteristic (ROC) analysis was used to evaluate the ability of 3D-CT as an early imaging marker of response. RESULTS: CT response analysis was performed in 39 patients, of whom 26 patients were histopathological responders. Median tumour volume increased between baseline and after 14 days of chemoradiotherapy in histopathological responders as well as in non-responders, though changes were not statistically significant. The area under the ROC curve was 0.71. CONCLUSION: Tumour volume changes after 14 days of neoadjuvant chemoradiotherapy as measured by 3D-CT were not associated with histopathological tumour response. CT volumetry should not be used for early response assessment in patients with potentially curable oesophageal cancer treated with neoadjuvant chemoradiotherapy.

Endogenous activated protein C is essential for immune-mediated cancer cell elimination from the circulation.

Fibrinogen and platelets play an important role in cancer cell survival in the circulation by protecting cancer cells from the immune system. Moreover, endogenous activated protein C (APC) limits cancer cell extravasation due to sphingosine-1-phosphate receptor-1 (S(1)P(1)) and VE-cadherin-dependent vascular barrier enhancement. We aimed to study the relative contribution of these two mechanisms in secondary tumor formation in vivo. We show that fibrinogen depletion limits pulmonary tumor foci formation in an experimental metastasis model in C57Bl/6 mice but not in NOD-SCID mice lacking a functional immune system. Moreover, we show that in the absence of endogenous APC, fibrinogen depletion does not prevent cancer cell dissemination and secondary tumor formation in immune-competent mice. Overall, we thus show that endogenous APC is essential for immune-mediated cancer cell elimination.

Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings.

BACKGROUND: The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study provided sorafenib to advanced renal cell carcinoma (RCC) patients in whom previous systemic therapy had failed. The study assessed the safety and use of sorafenib for the treatment of advanced RCC in a large community-based patient population across 11 countries in Europe. PATIENTS AND METHODS: EU-ARCCS was a single-arm, open-label trial of sorafenib in advanced RCC patients. End points included safety, time to progression, progression-free survival (PFS), and disease control rate (DCR). Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, histology, prior therapy, and number and sites of metastases. RESULTS: About 1159 advanced RCC patients were enrolled. Most patients (94%) experienced drug-related adverse events (AEs) of any grade, with the most common grade ≥3 AEs including hand-foot skin reaction (13%), diarrhea (7%), fatigue (7%), hypertension (6%), and rash/desquamation (5%). The incidence of AEs in the subgroups was similar to that in the overall population. Median PFS was 6.6 months; DCR at ≥8 and ≥12 weeks was 85% and 78%, respectively. CONCLUSIONS: The sorafenib safety profile in European community-based practice settings was similar to that reported in clinical trials. The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessment of sorafenib in important subpopulations of advanced RCC patients.

Improved survival of colon cancer due to improved treatment and detection: a nationwide population-based study in The Netherlands 1989-2006.

BACKGROUND: We described changes in treatment of colon cancer over time and the impact on survival in The Netherlands in the period 1989-2006. PATIENTS AND METHODS: All 103,744 patients with invasive colon cancer during 1989-2006 in The Netherlands were included. Data were extracted from The Netherlands Cancer Registry. Trends in treatment over time were analysed and multivariable relative survival analysis was carried out. RESULTS: The administration of adjuvant chemotherapy in stage III patients <75 years increased from 19% in 1989-1993 to 79% in 2004-2006 and from 1% to 19% in stage III patients ≥75 years. Among stage IV patients, resection rates of the primary tumour decreased from 72% to 63%, while chemotherapy administration increased from 23% to 64% in those <75 years. Survival increased from 52% to 58% in males and from 55% to 58% among females. Stage III patients with adjuvant chemotherapy exhibited a relative excess risk of 0.4 (95% confidence interval 0.4-0.4) compared with those without. Among stage IV patients, resection of primary tumour, palliative chemotherapy, and metastasectomy were important prognostic factors. CONCLUSIONS: There were substantial improvements in management and survival of colon cancer from 1989 to 2006. Stage III disease patients with colon cancer experienced the largest improvement in survival, most likely related to the increased administration of adjuvant chemotherapy.

Could recombinant insulin compounds contribute to adenocarcinoma progression by stimulating local angiogenesis?

AIMS/HYPOTHESIS: Negative effects on the progression of adenocarcinomas by hyperinsulinaemia and the insulin analogue glargine (A21Gly,B31Arg,B32Arg human insulin) have recently been suggested. Most actions of this insulin analogue have hitherto been explained by direct stimulation of growth potential of neoplastic cells and by its IGF-1 related properties. However, insulin-stimulated angiogenesis could be an additional factor involved in tumour progression and clinical outcomes associated with cancer. METHODS: Five types of human adenocarcinoma (breast, colon, pancreas, lung and kidney) were evaluated for the presence of insulin receptors (IRs) on angiogenic structures. In an in vitro angiogenesis assay, various commercially available insulin compounds were evaluated for their potential to increase capillary-like tube formation of human microvascular endothelial cells (hMVEC). Insulin compounds used were: human insulin, insulin lispro (B28Lys,B29Pro human insulin), insulin glargine and insulin detemir (B29Lys[e-tetradecanoyl],desB30 human insulin). RESULTS: Insulin receptors were found to be strongly expressed on the endothelium of microvessels in all evaluated adenocarcinomas, in addition to variable expression on tumour cells. Low or no detectable expression of IRs was seen on microvessels in extratumoral stroma. Incubation with commercially available insulin compounds increased capillary-like tube formation of hMVEC in vitro. CONCLUSIONS/INTERPRETATION: Our results suggest that all tested insulin compounds may stimulate tumour growth by enhancing local angiogenesis. Future studies need to confirm the association between insulin therapy in type 2 diabetes and tumour progression.

Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma.

BACKGROUND: Angiogenesis inhibition is a rational treatment strategy for high-grade glioma (HGG). Combined antiangiogenic therapy and chemotherapy could be beneficial, taking advantage of different mechanisms of antitumour activity of both therapies. We carried out a phase I-II clinical trial with the combination of bevacizumab and continuous dose-intense temozolomide (TMZ) for patients with a recurrent HGG after first- or second-line treatment. PATIENTS AND METHODS: Twenty-three HGG patients were treated with bevacizumab (10 mg/kg i.v. every 3 weeks) and TMZ (daily 50 mg/m(2)), until clinical or radiological progression. Conventional and dynamic magnetic resonance imaging (MRI) were carried out on days -4, 3 and 21 and until clinical or radiological progression. RESULTS: Overall response rate (20%), 6-month progression-free survival (PFS6) (17.4%), median progression-free survival (13.9 weeks) and median overall survival (OS) (17.1 weeks) were considerably lower compared with most other studies with bevacizumab-containing regimens. The dynamic MRI parameters contrast transfer coefficient and relative cerebral blood volume decreased rapidly during the early phases of treatment, reflecting changes in vascularisation and vessel permeability but not in tumour activity. In addition, >50% of patients showed oedema reduction and a reduced shift on T1 images. CONCLUSION: Treatment with bevacizumab and TMZ is feasible and well tolerated but did not improve PFS6 and median OS.

Preoperative chemoradiation combined with regional hyperthermia for patients with resectable esophageal cancer.

PURPOSE: To analyse the treatment results of neo-adjuvant chemoradiation combined with regional hyperthermia in patients with resectable esophageal cancer. PATIENTS AND METHODS: Between August 2003 and December 2004, 28 patients entered a phase II study combining chemoradiation over a 4.5-week period with five sessions of regional hyperthermia. Chemotherapy consisted of carboplatin (AUC = 2) and paclitaxel (50 mg/m(2)) and radiotherapy of 41.4 Gy in 1.8 Gy daily fractions. Locoregional hyperthermia was applied using the AMC phased array of four 70 MHz antennas, aiming at a stable tumor temperature of 41 degrees C for one hour. Carboplatin was infused during the hyperthermia session. Esophageal resection was planned at 6-8 weeks after the end of radiotherapy. The majority of the patients had a T3 tumor (86%) and were cN+ (64%). Median follow-up for survivors was 37 months (range 31-46). RESULTS: Twenty-five patients (89%) completed the planned neo-adjuvant treatment and acute toxicity was generally mild. Twenty-six patients were operated on. A pathologically CR, PRmic, PR and SD were seen in 19%, 27%, 31% and 23% respectively. All patients had a R0 resection. In-field locoregional control during follow up for the operated patients was 100%. Quality of life was good for patients without disease progression. Survival rates at one, two and three years were 79%, 57% and 54% respectively. CONCLUSION: Neo-adjuvant chemoradiation combined with regional hyperthermia followed by esophageal resection for patients with esophageal cancer resulted in good locoregional control and overall survival.

Circulating tumour cells during laparoscopic and open surgery for primary colonic cancer in portal and peripheral blood.

BACKGROUND: The objective of this study was to detect and quantify circulating tumour cells (CTC) in peripheral and portal blood of patients who had open or laparoscopic surgery for primary colonic cancer. METHODS: Patients in the laparoscopic-group were operated on in a medial to lateral approach ("vessels first"), in the open-group a lateral to medial approach was applied. The enumeration of CTC was performed with the CellSearch System. Intra-operative samples were taken paired-wise (from peripheral and portal circulation) directly after entering the abdominal cavity (T1), after mobilisation of the tumour baring segment (T2), and after tumour resection (T3). Ploidy of both the CTC and tissue of the primary tumour was determined for chromosome 1, 7, 8 and 17. RESULTS: Thirty-one patients were included; 18 patients had open surgery, 13 patients were operated on laparoscopically. The percentage of samples with CTC at T1 was 7% in peripheral blood and 54% in portal blood (p=0.002). At T2, 4% and 31% respectively (p=0.031). And at T3, 4% and 26% respectively (p=0.125). The cumulative percentage of samples with CTC was significantly higher during open surgery as compared to the laparoscopic approach. Both the CTC and tissue of the primary tumour were diploid for chromosome 1, 7, 8 and 17. CONCLUSION: The detection rate and quantity of CTC is significantly increased intra-operatively and is significantly higher in portal blood compared to peripheral blood. Significantly less CTC were detected during laparoscopic surgery probably as result of the medial to lateral approach.

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS).

BACKGROUND: A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial. METHODS/DESIGN: The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm.The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up. DISCUSSION: This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen. TRIAL REGISTRATION: ISRCTN80832026.

Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity.

Colon carcinoma is one of the leading causes of death from cancer and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, it was reported that a population of undifferentiated cells from a primary tumor, so-called cancer stem cells (CSC), can reconstitute the original tumor on xenotransplantation. Here, we show that spheroid cultures of these colon CSCs contain expression of CD133, CD166, CD44, CD29, CD24, Lgr5, and nuclear beta-catenin, which have all been suggested to mark the (cancer) stem cell population. More importantly, by using these spheroid cultures or freshly isolated tumor cells from multiple colon carcinomas, we now provide compelling evidence to indicate that the capacity to propagate a tumor with all differentiated progeny resides in a single CSC. Single-cell-cloned CSCs can form an adenocarcinoma on xenotransplantation but do not generate the stroma within these tumors. Moreover, they can self-renew and are capable of multilineage differentiation. Further analysis indicated that the lineage decision is dictated by phosphoinositide 3-kinase (PI3K) signaling in CSCs. These data support the hypothesis that tumor hierarchy can be traced back to a single CSC that contains multilineage differentiation capacity, and provides clues to the regulation of differentiation in colon cancers in vivo.

[Angiogenesis inhibitors for the systemic treatment of metastatic renal cell carcinoma: sunitinib, sorafenib, bevacizumab and temsirolimus]. / Angiogeneseremmers voor de systemische behandeling van gemetastaseerd niercelcarcinoom: sunitinib, sorafenib, bevacizumab en temsirolimus.

Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.

Met expression is an independent prognostic risk factor in patients with oesophageal adenocarcinoma.

Oesophageal adenocarcinoma is an aggressive malignancy with propensity for early lymphatic and haematogenous dissemination. Since conventional TNM staging does not provide accurate prognostic information, novel molecular prognostic markers and potential therapeutic targets are subject of intense research. The aim of the present study was to study the prognostic significance of Met, the hepatic growth factor (HGF) receptor and a possible target for therapy in comparison to cyclooxygenase-2 (COX-2). Tumour sections from 145 consecutive patients undergoing intentionally curative surgery for oesophageal adenocarcinoma were immunohistochemically analysed for Met and COX-2 expression. Clinicopathological data were prospectively collected for all patients. Patients with high Met expression had significantly reduced overall and disease-specific 5-year survival rates (P< or =0.001 and P< or =0.001, respectively) and were more likely to develop distant metastases (P=0.002) and local recurrences (P=0.004) compared to patients with low Met expression. High COX-2 expression tended to be correlated with poor long-term survival but this did not reach statistical significance. Expression of Met was recognised as a significant and independent prognostic factor by stage-specific analysis and multivariate analysis (relative risk=2.3; 95% CI=1.3-4.1). These findings support the importance of Met in oesophageal adenocarcinoma and support the concept of Met tyrosine kinase inhibition as (neo-) adjuvant treatment.

Local recurrence and distant metastasis of supratentorial primitive neuro-ectodermal tumor in an adult patient successfully treated with intensive induction chemotherapy and maintenance temozolomide.

Supratentorial primitive neuro-ectodermal tumors (PNET) in adults are very rare. Extraneural metastasis are unusual and the optimal palliative chemotherapy regimen is not established. We present a 26-year-old patient with local recurrence and distant metastasis of supratentorial PNET successfully treated with intensive induction chemotherapy and maintenance temozolomide.