H Boot

Netherlands Cancer Institute, Amsterdamo, North Holland, Netherlands

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Publications (139)777.86 Total impact

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    ABSTRACT: This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies. We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24 h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. Patients with a low clearance of 5FU were at increased risk of neutropenia (P < 0.05) and hand-foot syndrome (P = 0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P < 0.05) and HFS (P < 0.02), and IVS14+1G>A additionally with diarrhea (P < 0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR = 2.0, P < 0.01) and GEC group (HR = 5.4, P < 0.001) and worse OS in the GEC group (HR = 4.7, P < 0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR = 0.55, P = 0.001) and OS (HR = 0.60, P = 0.002) in the CRC group. Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.
    Cancer Chemotherapy and Pharmacology 02/2015; DOI:10.1007/s00280-015-2698-7 · 2.80 Impact Factor
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    ABSTRACT: About 5-15% of all malignant ovarian tumors are metastases from other malignancies such as gastrointestinal tumors, breast cancer or melanoma. Also other gynecological tumors can metastasize to the ovaries. It is crucial to differentiate between primary epithelial ovarian cancer (EOC) and ovarian metastases because different treatment is required. The clinical value of Human Epididymal secretory protein 4 (HE4) as a serum biomarker in primary ovarian cancer has been established. The use of HE4 in the differentiation between primary ovarian cancer and ovarian metastases from other malignancies has never been investigated. HE4, CA125 and CEA were measured in 192 patients with EOC (n=147) or ovarian metastases (n=40). Univariate and multivariate logistic regression analyses were done. Sensitivity, specificity and area under the curve (AUC) were calculated for all markers and ratios hereof using receiver operating characteristics methodology. Median serum HE4 concentration was significantly higher in patients with EOC compared to patients with ovarian metastases (431 pmol/L vs 68 pmol/L, p<0.001). HE4 and CEA were independent factors in differentiating between EOC and ovarian metastases (both p<0.001) while CA125 was not (p=0.33). The HE4(2.5)/CEA ratio demonstrated the highest discriminative value (ROC-AUC 0.94) compared to HE4, CEA, CA125 or CA125/CEA ratio (0.88, 0.78, 0.80 and 0.89 respectively) and showed a specificity of 82.5% at set sensitivity of 90% in discriminating EOC from ovarian metastases. HE4 can be used in combination with CEA to make the distinction between EOC and ovarian metastases from gastrointestinal origin. Copyright © 2014. Published by Elsevier Inc.
    Gynecologic Oncology 01/2015; DOI:10.1016/j.ygyno.2014.12.037 · 3.69 Impact Factor
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    ABSTRACT: Objective This observational study compares the effect of different radiotherapy techniques on late nephrotoxicity after postoperative chemoradiotherapy for gastric cancer. Patients and methods Dosimetric parameters were compared between AP–PA, 3D-conformal and IMRT techniques. Renal function was measured by 99mTc-MAG-3 renography, glomerular filtration rate (GFR) and the development of hypertension. Mixed effects models were used to compare renal function over time. Results Eighty-seven patients treated between 2002 and 2010 were included, AP–PA (n = 31), 3D-conformal (n = 25) and IMRT (n = 31), all 45 Gy in 25 fractions. Concurrent chemotherapy: 5FU/leucovorin (n = 4), capecitabine (n = 37), and capecitabine/cisplatin (n = 46). Median follow-up time was 4.7 years (range 0.2–8). With IMRT, the mean dose to the left kidney was significantly lower. Left kidney function decreased progressively in the total study population, however with IMRT this occurred at a lower rate. A dose–effect relationship was present between mean dose to the left kidney and the left kidney function. GFR decreased only moderately in time, which was not different between techniques. Six patients developed hypertension, of whom none in the IMRT group. Conclusions This study confirms progressive late nephrotoxicity in patients treated with postoperative chemoradiotherapy by different techniques for gastric cancer. Nephrotoxicity was less severe with IMRT and should be considered the preferred technique.
    Radiotherapy and Oncology 09/2014; DOI:10.1016/j.radonc.2014.08.039 · 4.86 Impact Factor
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    ABSTRACT: Objective The aim of this study was to investigate the impact of adjuvant chemoradiotherapy (CRT) on survival of non-metastatic gastric cancer patients who had undergone an R1 resection. Methods We compared the survival of patients after an R1 gastric cancer resection from the population-based Netherlands Cancer Registry who did not receive adjuvant CRT (no-CRT group) with the survival of resected patients who had been treated with adjuvant CRT (CRT group) at our institute. Patients who had a resection between 2002 and 2011 were included. CRT consisted of radiotherapy (45 Gy) combined with concurrent cisplatin- or 5-fluorouracil-based chemotherapy. The impact of CRT treatment on overall survival was assessed using multivariable Cox regression and stratified propensity score analysis. Results A series of 409 gastric cancer patients who had undergone an R1 resection were studied (no-CRT, N = 369; CRT, N = 40). In the no-CRT group, median age was higher (70 vs. 57 years; p p p = 0.003). In a multivariable analysis, adjuvant CRT was an independent prognostic factor for improved overall survival (hazard ratio 0.54; 95 % confidence interval 0.35–0.84). This effect of CRT was further supported by propensity score analysis. Conclusions Adjuvant CRT was associated with an improved survival in patients who had undergone an R1 resection for gastric cancer.
    Annals of Surgical Oncology 08/2014; 22(2). DOI:10.1245/s10434-014-4032-8 · 3.94 Impact Factor
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    ABSTRACT: The aim of this study is to evaluate the potential of FDG PET/CT for the detection of interval distant metastases after neoadjuvant chemoradiotherapy (CRT) and the prediction of the pathologic response to CRT in esophageal cancer patients.
    Clinical Nuclear Medicine 08/2014; DOI:10.1097/RLU.0000000000000517 · 2.86 Impact Factor
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    ABSTRACT: Aim To compare the outcome of women with ovarian metastasis who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) to outcome of women without ovarian metastasis who underwent CRS-HIPEC. Methods A prospective CRS-HIPEC database was searched to identify women with surgically treated colorectal carcinoma between 2000 and 2012. Patients with ovarian metastasis were identified and patients with peritoneal carcinomatosis but without ovarian metastasis were included as control cases. Results 75 patients with macroscopic ovarian metastasis underwent CRS-HIPEC with curative intent, while 50 female patients without ovarian metastasis were identified who underwent CRS-HIPEC. Patients with ovarian metastasis more often had a primary appendiceal tumour and had a more extensive intra-abdominal tumour load compared to patients without ovarian metastases. Median follow-up time was 45 months (95% CI: 37–53 months). Overall survival (OS) did not differ significantly between the two groups with a median OS in the ovarian metastasis group of 40 months (95% confidence interval (CI) 26–54) compared to 64 months (95% CI 17–111, P = 0.478) in the non-ovarian metastasis group. Recurrence patterns did not differ significantly between groups (p = 0.183). Conclusions Patients with ovarian metastasis of colorectal and appendiceal origin who underwent CRS-HIPEC had similar outcome compared to patients without ovarian metastasis. Given the findings of high coincidence of peritoneal metastases with ovarian metastases and ovarian metastases not being an independent factor for survival after CRS-HIPEC, this procedure should be recommended for patients with peritoneal metastases and ovarian metastases of colorectal and appendiceal carcinoma.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 08/2014; 40(8). DOI:10.1016/j.ejso.2014.02.238 · 2.56 Impact Factor
  • 05/2014; 4(3):90-91. DOI:10.1007/s13629-014-0055-y
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    ABSTRACT: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the preferred treatment of peritoneal carcinomatosis (PC) of colorectal carcinoma. Patients with positive lymph node status have worse survival after CRS-HIPEC, which is probably due to higher rates of systemic failure. In this study, we analysed the effect of administration and timing of systemic chemotherapy on the outcome of lymph node positive colorectal carcinoma patients treated with CRS-HIPEC. A prospective database was reviewed to identify lymph node positive patients with PC treated with CRS-HIPEC within 1 year after primary tumour diagnosis between 2004 and 2012. Medical history of the patients was studied for the administration of perioperative systemic chemotherapy and follow-up. Outcome parameters were progression-free survival (PFS), overall survival (OS) and pattern of recurrence. Seventy-three patients treated with CRS-HIPEC for PC from lymph node positive colorectal carcinoma were identified. Fourteen patients received pre-CRS-HIPEC chemotherapy only, 32 patients underwent post-CRS-HIPEC chemotherapy only, 9 patients received chemotherapy both pre- and post-CRS-HIPEC and 16 patients did not receive any systemic chemotherapy. Of the 47 patients who did not receive pre-CRS-HIPEC chemotherapy, 11 (23%) did not receive any chemotherapy due to major postoperative complications. PFS and OS were significantly higher in patients who received systemic chemotherapy (PFS: median 15 versus 4 months, P = 0.024; OS: median 30 versus 14 months, P = 0.015), although this difference was attenuated after adjustment for major complications. Different chemotherapy timings did not differ significantly in either survival or recurrence patterns. In patients with PC from lymph node positive colorectal carcinoma, perioperative systemic chemotherapy is associated with increased OS and PFS, although this difference may be partly explained by the occurrence of major postoperative complication; with no evidence of difference in PFS, OS and systemic recurrence rate by timing of systemic chemotherapy.
    Annals of Oncology 04/2014; 25(4):864-9. DOI:10.1093/annonc/mdu031 · 6.58 Impact Factor
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    ABSTRACT: 12-13% of patients with colorectal cancer(CRC) develop peritoneal carcinomatosis (PC), of whom the majority presents with unresectable disease. This study aimed to document the actual response rate and response characteristics of pre-operative modern systemic chemotherapy in this patient group. Patients underwent a PET/CT scan, laparoscopy and peritoneal biopsy to document unresectable PC. After four courses of pre-operative chemotherapy [capecitabine/oxaliplatin +/- bevacizumab], the extent of PC was re-evaluated by PET/CT(or CT), laparoscopy and peritoneal biopsy (if considered safe). Ten patients (M/F=7/3) with good performance status of median age 60.3 [45.6-72.8] years were studied. The first laparoscopy, documented unresectable PC. One patient was excluded because of systemic metastases on PET/CT. Nine proceeded to follow the trial protocol. Of these one developed early progressive disease, two had macroscopically stable disease and five had progressive disease at second laparoscopy. One patient developed a small bowel perforation at first laparoscopy and received palliative chemotherapy outside the protocol, after which progressive disease was found at an explorative laparotomy. Thus, 78% of patients with unresectable PC from CRC developed progressive disease under neo-adjuvant chemotherapy and 22% remained stable. No clear macroscopic response to chemotherapy could be demonstrated. Unresectable PC from CRC does not respond well to systemic chemotherapy. This article is protected by copyright. All rights reserved.
    Colorectal Disease 01/2014; 16(8). DOI:10.1111/codi.12560 · 2.02 Impact Factor
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    ABSTRACT: The internationally validated Memorial Sloan-Kettering Cancer Center (MSKCC) gastric carcinoma nomogram was based on patients who underwent curative (R0) gastrectomy, without any other therapy. The purpose of the current study was to assess the performance of this gastric cancer nomogram in patients who received chemoradiation therapy after an R0 resection for gastric cancer. In a combined dataset of 76 patients from the Netherlands Cancer Institute (NKI), and 63 patients from MSKCC, who received postoperative chemoradiation therapy (CRT) after an R0 gastrectomy, the nomogram was validated by means of the concordance index (CI) and a calibration plot. The concordance index for the nomogram was 0.64, which was lower than the CI of the nomogram for patients who received no adjuvant therapy (0.80). In the calibration plot, observed survival was approximately 20% higher than the nomogram-predicted survival for patients receiving postoperative CRT. The MSKCC gastric carcinoma nomogram significantly underpredicted survival for patients in the current study, suggesting an impact of postoperative CRT on survival in patients who underwent an R0 resection for gastric cancer, which has been demonstrated by randomized controlled trials. This analysis stresses the need for updating nomograms with the incorporation of multimodal strategies.
    International journal of radiation oncology, biology, physics 01/2014; DOI:10.1016/j.ijrobp.2013.11.213 · 4.59 Impact Factor
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    ABSTRACT: A microscopically irradical (R1) resection is a well-known adverse prognostic factor after gastric cancer surgery. However, the prognostic significance of an R1 resection in gastric cancer patients who are treated with chemoradiotherapy (CRT) after the operation has been poorly studied. Therefore, the aim of this study was to evaluate the effect of an R1 resection on (recurrence-free) survival in gastric cancer patients who were treated with CRT after surgery. Gastric cancer patients who had undergone a resection with curative intent followed by adjuvant CRT at our institute between 2001 and 2011 were included. CRT consisted of radiotherapy (45 Gy/25 fractions) combined with concurrent capecitabine (with or without cisplatin) or 5-fluorouracil/leucovorin. A consecutive series of 110 patients was studied, including 80 (73 %) patients who had undergone an R0 resection and 30 (27 %) patients with an R1 resection. Pathologic T-classification (p = 0.26), N-classification (p = 0.77), and histologic subtype according to Laurén (p = 0.071) were not significantly different between these groups. Three-year recurrence-free survival (45 vs. 35 %, p = 0.34) and overall survival (47 vs. 48 %, p = 0.58) did not significantly differ between patients who had undergone an R0 or R1 resection. In a multivariate analysis, pathologic T-classification and N-classification were independent prognostic factors for survival. A R1 resection was not an adverse prognostic factor in gastric cancer patients who had undergone CRT after the operation.
    Annals of Surgical Oncology 12/2013; 21(4). DOI:10.1245/s10434-013-3397-4 · 3.94 Impact Factor
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    ABSTRACT: Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses. Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.8 Gy to the primary tumor and macroscopically involved lymph nodes and 33 fractions of 1.5 Gy electively to the bilateral iliac and inguinal lymph node areas. Patients received a sequential radiation boost dose of 3 × 1.8 Gy on macroscopic residual tumor if this was still present in week 5 of treatment. Mitomycin C 10 mg/m(2) (maximum 15 mg) was administered intravenously on day 1, and capecitabine was given orally in a dose-escalated fashion (500-825 mg/m(2) b.i.d.) on irradiation days, until dose-limiting toxicity emerged in ≥2 of maximally 6 patients. An additional 8 patients were treated at the maximum tolerated dose (MTD). A total of 18 patients were included. The MTD of capecitabine was determined to be 825 mg/m(2) b.i.d. The predominant acute grade ≥3 toxicities included radiation dermatitis (50%), fatigue (22%), and pain (6%). Fifteen patients (83% [95%-CI: 66%-101%]) achieved a complete response, and 3 (17%) patients a partial response. With a median follow-up of 28 months, none of the complete responders, and 2 partial responders had relapsed. SIB-IMRT with concomitant single dose mitomycin C and capecitabine 825 mg/m(2) b.i.d. on irradiation days resulted in an acceptable safety profile, and proved to be a tolerable and effective treatment regimen for locally advanced anal cancer.
    International journal of radiation oncology, biology, physics 04/2013; 85(5):e201-7. DOI:10.1016/j.ijrobp.2012.12.008 · 4.59 Impact Factor
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    ABSTRACT: AIM: To study the outcome of patients who were surgically treated for primary gastric cancer with specific attention to differences in treatment results for intestinal and diffuse type tumours. METHODS: All patients who underwent a potentially curative gastric resection between 1995 and 2011 in our institute were included. Patient, tumour and treatment characteristics were obtained retrospectively. Binary logistic and Cox regression models were used for multivariate analysis. RESULTS: A consecutive series of 132 patients was included. Median follow-up was 53 months. There were no significant differences between patients with intestinal (N = 62) versus diffuse type (N = 70) gastric cancer with regard to the proportion of patients who underwent (neo)adjuvant treatment. Postoperative mortality was 2%. Pathological T- and N-stage were significantly more advanced for patients with diffuse type tumours. There was a significant difference in the percentage of microscopically irradical resections (2% versus 24%, p < 0.001) and median overall survival (129 versus 17 months, p < 0.001) between patients with intestinal type tumours and those with diffuse type tumours. On multivariate analysis, diffuse type histology was the only factor significantly associated with an R1 resection. In a multivariate Cox regression model, diffuse type histology was a significant adverse prognostic factor for overall survival. CONCLUSIONS: Striking differences were found between patients with diffuse type tumours and those with intestinal type tumours. These differences call for a differentiated approach in the potentially curative treatment of these two tumour types.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 03/2013; 39(7). DOI:10.1016/j.ejso.2013.02.026 · 2.56 Impact Factor
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    ABSTRACT: AIM: To evaluate current literature on gene expression profiling in oesophageal cancer. METHODS: We performed a review of the literature (2000-2010) on prognostication and prediction using gene expression analysis in oesophageal cancer. RESULTS: Seventeen papers comprising 638 patients were included. Gene expression profiles studied in relation to survival, lymph node metastasis and response to neoadjuvant therapy. Most studies included a limited number of patients. Several prognostic and predictive gene signatures were identified with different accuracies. In only one study, the gene signature was validated in a large, independent patient cohort. CONCLUSION: Gene expression profiling has potential clinical applications in oesophageal cancer. Especially a signature which is predictive for response to neoadjuvant treatment could be of great clinical value. To date, most published studies suffer from an underpowered training cohort or lack adequate validation. Clinicians should put effort in the collection of high quality tissue samples and should participate in biobank initiatives, considering the increasing availability and possibilities of sequencing technology.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 07/2012; 39(1). DOI:10.1016/j.ejso.2012.07.008 · 2.56 Impact Factor
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    ABSTRACT: Self-expanding metal stents (SEMSs) provide effective palliation in patients with malignant dysphagia. However, although life expectancy is generally limited, reintervention rates because of stent dysfunction are significant. New SEMSs are being designed to overcome this drawback. To investigate whether the results of SEMS placement could be improved with a new SEMS design. Consecutive patients with dysphagia or leakage caused by malignant esophageal disease. In a multicenter randomized clinical trial, consecutive patients with dysphagia or leakage because of malignant esophageal disease were randomized to placement of a conventional stent or the new stent. Patients were followed up by scheduled telephone calls 1 and 3 months after SEMS insertion. A total of 80 patients (73% male; median age, 67 years [range, 40-92 years]) were included. One patient refused follow-up. Technical success was 100% in both groups. The reintervention rate was 15/40 (38%) for the conventional stent and 4/39 (10%) for the new stent (P = .004). Major complications, including aspiration pneumonia and bleeding, occurred more frequently with the conventional stent (10/40, 25%) than with the new stent (3/39, 8%, P = .04). There was no difference in overall survival between the 2 groups. Inclusion of patients with a perforation or fistula. The conventional stent and the new stent were equally effective in the relief of malignant dysphagia and sealing fistulae. The conventional stent was associated with more stent dysfunction and a significantly higher rate of major complications. Patients treated with the new stent also needed significantly fewer reinterventions than did those treated with a conventional stent. This sets the preference for the new stent over the conventional stent for patients with malignant esophageal disease.
    Gastrointestinal endoscopy 07/2012; 76(1):52-8. DOI:10.1016/j.gie.2012.02.050 · 4.90 Impact Factor
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    ABSTRACT: Surgical resection remains the essential part in the curative treatment of gastric cancer. However, with surgery only, long-term survival is poor (5-year survival <25 % in Europe). Randomized studies, which compared limited (D1) lymph node dissection with more extended (D2) resections in the Western world, failed to show a survival benefit for more extensive surgery. A substantial increase in survival was found with perioperative chemotherapy in the MAGIC study. In addition, the SWOG/Intergroup 0116 study showed that postoperative chemoradiotherapy (CRT) prolonged 5-year overall survival compared to surgery only. However, it has been argued that surgical undertreatment undermined survival in this trial. In a randomized Korean study, patients with advanced stage gastric cancer who received postoperative CRT had better outcome after a D2 dissection. At our institute phase I-II studies with adjuvant cisplatin and capecitabine-based CRT have been performed in over 120 patients with resected gastric cancer. Retrospective comparison of patients treated in these studies with those that had surgery only in the D1D2 study, demonstrated that postoperative CRT was associated with better outcome, especially after D1 or a R1 resection. For daily practice, it remains unclear whether patients after optimal (D2) gastric surgery will benefit from postoperative CRT. This is currently being tested in prospective randomized phase III trials (CRITICS; TOPGEAR).
    Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2012; 196:229-40. DOI:10.1007/978-3-642-31629-6_16
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    ABSTRACT: For unresectable peritoneal carcinomatosis (PC) median overall survival (OS) is 5-6 months. This article analyzes patients with PC from colorectal cancer (CRC) uneligible for debulking and hyperthermic intra-peritoneal chemotherapy, describing patient- and tumor-related factors possibly affecting survival. From 2005 to 2009, 43 patients presented with unresectable PC from CRC: male/female ratio was 29/14, median age was 57.1 years (range 34.8-76.8). "Unresectability" was defined as: six to seven abdominal regions affected by PC, involvement of mesentery or small bowel in the PC, presence of liver metastases, retroperitoneal lymph nodes, vascular invasion, and/or neural invasion. Median time interval between diagnosis of the primary tumor and diagnosis of PC was 7.2 months (range 0.0-102.3). Primary tumors were right-sided in >50% and had been previously resected in >58%, 74.4% of PC occurred synchronously. Ascites was present at primary diagnosis in 37.2%. In 70% of cases, six to seven abdominal regions were affected and in 58.1% PC involved small bowel/mesentery. Systemic disease was present in 16.3%. In 18.6% of patients, a palliative diversion or ostomy was constructed. Median OS was 6.3 months (range 0.4-33.1). Thirty-one patients (72.1%) received palliative chemotherapy. Median OS was 9.3 months (range 0.9-33.1) with versus 3.1 months (range 0.4-6.5) without chemotherapy (P = 0.000), with less favorable patient and tumor characteristics in the latter group. No other factors clearly influenced OS. Palliative chemotherapy results in better OS, but this is probably attributable to factors influencing the patient's general condition.
    Journal of Surgical Oncology 09/2011; 104(3):269-73. DOI:10.1002/jso.21937 · 2.84 Impact Factor
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    ABSTRACT: Gastric Helicobacter pylori (HP) positive extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) develops during chronic antigenic stimulation with specific T-cell help. Chemotherapy that acts both on the malignant B-cells and on T-cells in the microenvironment, i.e. nucleoside analogs, might therefore be an attractive treatment. In 14 patients with gastric MALT lymphoma treated with fludarabine, alterations in T-cell subsets were studied in subsequent peripheral blood samples and in gastric biopsies. Treatment with fludarabine resulted in a steep decrease in T-cell subsets in peripheral blood samples. By contrast no decrease in T-cell populations was observed in subsequent gastric biopsy samples and a moderate increase was observed in relative infiltration with CD3 +, CD4 + and CD8 + cells. In addition an increase in density of FOXP3 + cells (i.e. Tregs) was seen (p = 0.047). These alterations in different T-cell subsets were not observed in gastric biopsy samples of patients treated with HP-eradication only.
    Leukemia & lymphoma 08/2011; 52(12):2262-9. DOI:10.3109/10428194.2011.607527 · 2.61 Impact Factor
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    ABSTRACT: Radical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively. In this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate. Results of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer. clinicaltrials.gov NCT00407186.
    BMC Cancer 08/2011; 11:329. DOI:10.1186/1471-2407-11-329 · 3.32 Impact Factor
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    ABSTRACT: The aim of this study was to retrospectively evaluate toxicity and efficacy of 3 chemoradiation regimens. Between 1997 and 2007, 94 patients with esophageal cancer were treated with chemoradiation in our institute. Treatment consisted of radiotherapy to 50 Gy in 25 fractions with concurrent cisplatin and 5-fluorouracil (group A, n = 65), radiotherapy to 50.4 Gy in 28 fractions with concurrent carboplatin and paclitaxel (group B, n = 16) or radiotherapy to 66 Gy in 33 fractions with low-dose cisplatin (group C, n = 13). Toxicity was scored according to Common Terminology Criteria version 3.0. Chemoradiation was planned as neoadjuvant (n = 58) or definitive (n = 36) treatment. Grade 3/4 hematological toxicity occurred in 18 (19%) patients and grade 3 nonhematologic toxicity in 8 (9%) patients. During treatment, 2 patients died (1 from duodenal ulcer bleeding and 1 from stroke). Overall, 81 (86%) patients completed the planned treatment (86%, 94%, and 77% in groups A, B, and C, respectively). Clinically complete or partial response was observed in 28 of 92 (30%) patients (21%, 50%, and 54% in groups A, B, and C, respectively). After clinical and radiologic response evaluation, treatment plan was changed in 14 (15%) patients. A total of 45 patients underwent surgery. Pathologic complete response and downstaging were seen in 12 (27%) and 34 (76%) operated patients, respectively. With a median follow-up of 15 (range, 1-108) months, the 3-year survival was 41% for all patients. With individual treatment planning, different regimens of chemoradiation for esophageal cancer resulted in acceptable rates of toxicity and efficacy.
    American journal of clinical oncology 08/2011; 34(4):343-9. DOI:10.1097/COC.0b013e3181dbbafe · 2.21 Impact Factor

Publication Stats

3k Citations
777.86 Total Impact Points


  • 1995–2015
    • Netherlands Cancer Institute
      • • Department of Medical Oncology
      • • Department of Radiotherapy
      • • Division of Surgical Oncology
      • • Department of Surgery
      • • Department of Pathology
      Amsterdamo, North Holland, Netherlands
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 2010
    • Leiden University Medical Centre
      • Department of Surgery
      Leiden, South Holland, Netherlands
  • 2006–2007
    • Utrecht University
      Utrecht, Utrecht, Netherlands