Henk Boot

Netherlands Cancer Institute, Amsterdamo, North Holland, Netherlands

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Publications (156)980.5 Total impact

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    ABSTRACT: Purpose: Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing. Patients and methods: Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses. Results: A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs. Conclusion: DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving.
    Journal of Clinical Oncology 11/2015; DOI:10.1200/JCO.2015.63.1325 · 18.43 Impact Factor
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    ABSTRACT: The process of preparing endoscopic esophageal adenocarcinoma samples for next-generation DNA/RNA sequencing is poorly described. Therefore, we assessed the feasibility and pitfalls of preparing esophageal adenocarcinoma endoscopic biopsies toward DNA/RNA samples suitable for next-generation sequencing. In this prospective study, four tumor biopsy samples were collected from consecutive esophageal cancer patients during esophagogastroduodenoscopy and fresh-frozen in liquid nitrogen. DNA and RNA were isolated from samples with a tumor percentage of at least 50%. For next-generation sequencing, double-stranded DNA (dsDNA) is required and high-quality RNA preferred. The quantity dsDNA and RNA quantity and quality were assessed with the Nanodrop 2000 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) and Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA). Biopsy samples of 69 consecutive patients with esophageal adenocarcinoma were included. In five patients (7%), the tumor percentage was less than 50% in all four biopsies. Using a protocol allowing simultaneous DNA and RNA isolation, the median dsDNA yield was 2.4 μg (range 0.1-12.0 μg) and the median RNA yield was 0.5 μg (range 0.01-2.05 μg). The median RNA integrity number of samples that were fresh-frozen within 30 minutes after sampling was 6.7 (range 4.2-8.9) compared with 2.5 (1.8-4.5) for samples that were fresh-frozen after 2 hours. The results from this study show that obtaining dsDNA and RNA for next-generation sequencing from endoscopic esophageal adenocarcinoma samples is feasible. Tumor percentage and dsDNA/RNA yield and quality emphasize the need for sampling multiple biopsies and minimizing the delay before fresh-freezing.
    Diseases of the Esophagus 11/2015; DOI:10.1111/dote.12430 · 1.78 Impact Factor
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    ABSTRACT: Purpose: The prognosis of gastroesophageal cancer is poor, and current regimens are associated with limited efficacy. The purpose of this study was to explore the safety and preliminary efficacy of docetaxel, oxaliplatin plus capecitabine for advanced cancer of the stomach or the gastroesophageal junction (GEJ). Secondary objectives included pharmacokinetic and pharmacogenetic analyses. Methods: Patients were treated in escalating dose levels with docetaxel and oxaliplatin (both on day 1), plus capecitabine b.i.d. on days 1-14 every 3 weeks, to determine the dose-limiting toxicity and maximum tolerated dose (MTD). An expansion cohort was treated at the MTD. A total of ten polymorphisms in pharmacokinetic and pharmacodynamic candidate genes were analyzed and tested for association with treatment outcome. Results: A total of 34 evaluable patients were enrolled. The MTD was docetaxel 50 mg/m(2), oxaliplatin 100 mg/m(2) plus capecitabine 850 mg/m(2) b.i.d. The median number of treatment cycles was 6 (range 2-8). Grade ≥ 3 toxicities included neutropenia (24 %), leukocytopenia (15 %), febrile neutropenia (12 %), fatigue (9 %) and diarrhea (6 %). The overall response rate was 45 %; two patients achieved a complete response. Median progression-free survival and overall survival were 6.5 months (95 % CI 5.4-7.6) and 11.0 months (95 % CI 7.9-14.1), respectively. The polymorphisms ERCC1 354C>T, TYMS 1053C>T and rs2612091 in ENOSF1 were associated with severe toxicity; ERCC1 354C>T and ERCC2 2251A>C were associated with poor progression-free survival. Conclusion: Docetaxel, oxaliplatin plus capecitabine are a well-tolerable, safe and effective treatment regimen for patients with advanced cancer of the stomach or GEJ. Pharmacogenetic markers in pharmacokinetic and pharmacodynamic candidate genes may be predictive for treatment outcome.
    Cancer Chemotherapy and Pharmacology 10/2015; 76(6). DOI:10.1007/s00280-015-2872-y · 2.77 Impact Factor
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    ABSTRACT: Abdominal (chemo-)radiotherapy is associated with dose-limiting toxicity of various normal structures. The purpose of this retrospective study was to investigate radiation-induced changes of the spleen and their clinical consequences. In gastric cancer patients treated with postoperative chemoradiotherapy, the spleen size and its functions were assessed at follow-up by spleen volume on CT-scan, serum leucocytes/thrombocytes, and the occurrence of infectious events consisting of pneumonia and fatal sepsis. To evaluate the effect of radiation dose, mixed effects and Cox regression models were used. Forty-six out of 90 consecutive patients treated from 2006 to 2011 were evaluable. All patients received 45Gy in 25 fractions with concurrent capecitabine (n=8), and capecitabine/cisplatin (n=38). Median Dmean to the spleen was 40Gy (range 32-46). Mean relative spleen volume reduced to 37% (95% CI 32-42%) at 4-year follow-up, which was most strongly associated to the V44 (p<0.001). Median follow-up time was 67 (95% CI 57-78) months. Eleven patients had 13 pneumonias and 3 fatal sepsis. No association with dosimetric parameters was observed. In postoperative chemoradiotherapy for gastric cancer, the spleen received a high radiation dose. This resulted in a progressive, radiation dose-dependent reduction of spleen volume. Pneumonia and fatal sepsis occurred frequently, possibly as a result of functional hyposplenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Radiotherapy and Oncology 08/2015; DOI:10.1016/j.radonc.2015.07.036 · 4.36 Impact Factor
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    ABSTRACT: Several studies have shown the potential benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients. At present the most effective chemotherapeutic regime in HIPEC for gastric cancer is unknown. The aim of this review was to provide a comprehensive overview of chemotherapeutic agents used for HIPEC in gastric cancer. A literature search was conducted using the PubMed database to identify studies on chemotherapy used for HIPEC in gastric cancer patients. The chemotherapeutic regime of choice in HIPEC for gastric cancer has yet to be determined. The wide variety in studies and study parameters, such as chemotherapeutic agents, dosage, patient characteristics, temperature of perfusate, duration of perfusion, carrier solutions, intraperitoneal pressure and open or closed perfusion techniques, warrant more experimental and clinical studies to determine the optimal treatment schedule. A combination of drugs probably results in a more effective treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Critical reviews in oncology/hematology 04/2015; 95(3). DOI:10.1016/j.critrevonc.2015.04.004 · 4.03 Impact Factor
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    ABSTRACT: In recent years, evidence supporting multimodality treatment for oesophageal, oesophagogastric junction (OGJ), and gastric cancer has accumulated. This population-based cohort-study investigates trends and predictors of utilisation of multimodality treatment for oesophagogastric cancer in the Netherlands. Data were obtained from the Netherlands Cancer Registry regarding patients with oesophageal (n = 5450), OGJ (n = 2168) and gastric cancer (n = 6683) without distant metastases who had undergone R0 or R1 surgery diagnosed between 2000 and 2012. Follow-up was completed until February 2014. Preoperative/postoperative chemotherapy and/or radiotherapy combined with surgery were considered multimodality treatment. Logistic regression analysis was performed to analyse the association of age, gender, socioeconomic status, clinical T and N classification, hospital type, comprehensive cancer centre network region, and year of diagnosis, with multimodality treatment receipt. Additional analyses were performed to explore differences in trends of utilisation of multimodality treatment between academic and non-academic hospitals. Multimodality treatment utilisation for oesophageal, OGJ and gastric cancer increased significantly to 90%, 85% and 56% in 2012, respectively. In oesophageal and OGJ cancer patients, preoperative chemoradiotherapy was most frequently administered (85% and 47% in 2012, respectively), and in gastric cancer patients preoperative chemotherapy (47% in 2012). Lower age, higher clinical T and N classification, and diagnosis in more recent years were significantly associated with more frequent multimodality treatment receipt. The adoption of most types of multimodality treatment in academic hospitals preceded non-academic hospitals by a year. In the Netherlands, the utilisation of multimodality treatment for oesophagogastric cancer has significantly increased during the past decade, especially in oesophageal and OGJ cancer. Multimodality treatment utilisation was especially dependent on patient and tumour characteristics and year of diagnosis, but multimodality treatment trends seem to be related to the publication of landmark studies, participation in nationally running clinical trials, and hospital type, preceding national guidelines.
    Acta oncologica (Stockholm, Sweden) 03/2015; DOI:10.3109/0284186X.2015.1009638 · 3.00 Impact Factor
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    Radiotherapy and Oncology 03/2015; 114(3):420. DOI:10.1016/j.radonc.2015.03.008 · 4.36 Impact Factor
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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; 75(4). DOI:10.1007/s00280-015-2698-7 · 2.77 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; 136(3). DOI:10.1016/j.ygyno.2014.12.037 · 3.77 Impact Factor
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    ABSTRACT: Background and study aims: A new esophageal stent with two anti-migration features was developed to minimize migration. The aim of this study was to evaluate the clinical efficacy and safety of this stent in patients with malignant dysphagia. Patients and methods: A total of 40 patients with dysphagia due to a malignant obstruction of the esophagus were prospectively enrolled in this cohort study. Results: Stent placement was technically successful in 39 patients (98 %). The median dysphagia-free time after stent placement was 220 days (95 % confidence interval 94 - 345 days). Nine patients (23 %) experienced recurrent dysphagia due to tissue overgrowth (n = 2), stent fracture (n = 1), and partial (n = 5) or complete (n = 1) stent migration. A total of 16 serious adverse events occurred in 14 patients (36 %), with hemorrhage (n = 3) and severe nausea or vomiting (n = 3) being the most common causes. Conclusions: This new stent design was effective for the palliation of malignant dysphagia and had a low rate of recurrent dysphagia. However, despite the anti-migration features, stent migration was still a major cause of recurrent dysphagia. Furthermore, treatment was associated with a high adverse event rate. Dutch Trial Registration (NTR 3313).
    Endoscopy 09/2014; 46(12). DOI:10.1055/s-0034-1377632 · 5.05 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; 112(2). DOI:10.1016/j.radonc.2014.08.039 · 4.36 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
    Annals of Surgical Oncology 08/2014; 22(2). DOI:10.1245/s10434-014-4032-8 · 3.93 Impact Factor
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    ABSTRACT: Aim: 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. Patients and methods: In this retrospective study, all esophageal cancer patients for whom CRT followed by surgery was planned between January 2008 and April 2013 and in whom an FDG PET/CT was performed before and after CRT were included. For the response analyses, both FDG PET/CT scans had to be made on a similar scanner. Metabolic response of the primary tumor was assessed using the SUVmax, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). These parameters were correlated with the pathologic response using the tumor regression grade (TRG) scale according to Mandard et al (Cancer. 1994;73:2680-2686). Results: In 6 (8%) of 76 consecutively treated patients, new distant metastases were detected on FDG PET/CT after neoadjuvant CRT; these patients therefore did not undergo operation. Forty-eight (63%) of 76 patients were eligible for response analysis. The relative change in SUVmax, MTV, and TLG was significantly different between patients with a major (TRG, 1-2) and a minor response (TRG, 3-5) but not between patients with and without a pathologic complete response. The area under the curve of the receiver operating characteristic for predicting a major response was 0.70 (95% confidence interval, 0.65-0.92) for a relative decrease in SUVmax, compared with 0.73 (95% confidence interval, 0.58-0.88) both for MTV and TLG. A relative decrease in SUVmax of 60% or more had the highest positive predictive value (75%). Conclusions: Futile surgery was prevented in 8% of our esophageal cancer patients because interval metastases were detected on an FDG PET/CT after neoadjuvant CRT. The accuracy for predicting a complete or major pathologic response was limited and does not support the use of FDG PET/CT for refraining from surgical treatment.
    Clinical Nuclear Medicine 08/2014; 39(10). DOI:10.1097/RLU.0000000000000517 · 3.93 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 · 3.01 Impact Factor
  • W. Meinhardt · A. Metha · V. Verwaal · H. Boot ·
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    ABSTRACT: De literatuur over urachuscarcinomen bestaat uit casusbeschrijvingen en kleinere series.
    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 · 7.04 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 · 2.35 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; 84(3). DOI:10.1016/j.ijrobp.2013.11.213 · 4.26 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 · 3.93 Impact Factor

Publication Stats

4k Citations
980.50 Total Impact Points


  • 1995-2015
    • Netherlands Cancer Institute
      • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 2010
    • Leiden University Medical Centre
      • Department of Surgery
      Leiden, South Holland, Netherlands
  • 2001
    • Leiden University
      Leyden, South Holland, Netherlands