Publications by authors named "Tiuri E Kroese"

6 Publications

  • Page 1 of 1

Severe lymphopenia acquired during chemoradiotherapy for esophageal cancer: Incidence and external validation of a prediction model.

Radiother Oncol 2021 Aug 25;163:192-198. Epub 2021 Aug 25.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: The incidence of grade 4 lymphopenia in patients treated with chemoradiotherapy (CRT) according to Chemoradiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) regimen is unclear. The primary aim was to determine the incidence of grade 4 lymphopenia during CROSS for esophageal cancer. Secondary aims were to externally validate a prediction model for grade 4 lymphopenia and compare overall survival between patients with and without grade 4 lymphopenia.

Methods: Patients who underwent CRT for esophageal cancer between 2014 and 2019 were eligible for inclusion. Patients with a planned radiation dose of 41.4 Gy (CROSS) or 50.4 Gy ("extended-CROSS") and concurrent carboplatin and paclitaxel were included. The primary outcome was the incidence of grade 4 lymphopenia during CRT defined according to Common Terminology Criteria for Adverse Events version 5.0 (i.e. lymphocyte count nadir < 0.2 µL). The secondary outcome measures were the prediction model's external performance (i.e. discrimination and calibration). Overall survival for patients with versus without grade 4 lymphopenia was compared using Kaplan-Meier analysis.

Results: A total of 219 patients were included of whom 176 patients (80%) underwent CROSS and 43 patients (20%) extended-CROSS. The incidence of grade 4 lymphopenia was 11% in CROSS and 33% in extended-CROSS (p < 0.001). External discrimination yielded a c-statistic of 0.80 (95% confidence interval: 0.70-0.89). External calibration of the model was poor in CROSS but fair in extended-CROSS. Adjusted calibration using intercept correction (adjusted for the lower a-priori risk for grade 4 lymphopenia in CROSS) showed fair agreement between the observed and predicted risk for grade 4 lymphopenia. Median overall survival in patients with versus without grade 4 lymphopenia was 12.7 versus 42.5 months (p = 0.045).

Conclusion: The incidence of grade 4 lymphopenia is significantly higher in esophageal cancer patients receiving extended-CROSS compared to those receiving CROSS. The prediction model demonstrated good external performance in the setting of the CROSS-regimen and could be used to identify patients at high-risk for grade 4 lymphopenia who might be eligible for lymphopenia-mitigating strategies.
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August 2021

The Influence of Severe Radiation-Induced Lymphopenia on Overall Survival in Solid Tumors: A Systematic Review and Meta-Analysis.

Int J Radiat Oncol Biol Phys 2021 Jul 28. Epub 2021 Jul 28.

Departments of Radiation Oncology.

Purpose: Emerging evidence suggests a detrimental prognostic association between radiation-induced lymphopenia (RIL) and pathologic response, progression-free survival, and overall survival (OS) in patients who undergo radiation therapy for cancer. The aim of this study was to systematically review and meta-analyze the prognostic impact of RIL on OS in patients with solid tumors.

Methods And Materials: PubMed/MEDLINE and Embase were systematically searched. The analysis included intervention and prognostic studies that reported on the prognostic relationship between RIL and survival in patients with solid tumors. An overall pooled adjusted hazard ratio (aHR) was calculated using a random-effects model. Subgroup analyses for different patient-, tumor-, treatment-, and study-related characteristics were performed using meta-regression.

Results: Pooling of 21 cohorts within 20 eligible studies demonstrated a statistically significant association between OS and grade ≥3 versus grade 0-2 RIL (n = 16; pooled aHR, 1.65; 95% confidence interval [CI], 1.43-1.90) and grade 4 RIL versus grade 0-3 (n = 5; aHR, 1.53; 95% CI, 1.24-1.90). Moderate heterogeneity among aHRs was observed, mostly attributable to overestimated aHRs in 7 studies likely subject to model-overfitting. Subgroup analysis showed significant prognostic impact of grade ≥3 RIL in 4 brain tumor (aHR, 1.63; 95% CI, 1.06-2.51), 4 lung cancer (aHR, 1.52; 95% CI, 1.01-2.29), and 3 pancreatic cancer (aHR, 1.92; 95% CI, 1.10-3.36) cohorts.

Conclusions: This meta-analysis demonstrates a significant detrimental prognostic association between grade ≥3 lymphopenia and OS in patients receiving radiation therapy for solid tumors. This finding appears consistent for tumors of the brain, thorax, and upper abdomen and provides an imperative to further elucidate the potential survival benefit of lymphopenia-mitigating strategies.
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July 2021

Prognosis of Interval Distant Metastases After Neoadjuvant Chemoradiotherapy for Esophageal Cancer.

Ann Thorac Surg 2021 Feb 18. Epub 2021 Feb 18.

Department of Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. Electronic address:

Background: In esophageal cancer patients, distant metastases develop between the start of neoadjuvant chemoradiotherapy and planned surgery, so-called interval metastases. The primary aim of this study was to assess management, overall survival (OS), and prognostic factors for OS in these patients. A secondary aim was to compare OS with synchronous metastatic patients.

Methods: Esophageal cancer patients with interval distant metastases were identified from the Netherlands Cancer Registry (2010 to 2017). Management was categorized into metastasis-directed therapy (MDT), primary tumor resection, or best supportive care (BSC). The OS was calculated from the diagnosis of the primary tumor. Prognostic factors affecting OS were studied using Cox proportional hazard models. Propensity score-matching (1:3) generated matched cases with synchronous distant metastases.

Results: In all, 208 patients with interval metastases were identified: in 87 patients (42%) MDT was initiated; in 10%, primary tumor resection only; in 7%, primary tumor resection plus MDT; and in 41%, BSC. Median OS was 10 months (interquartile range, 8.6 to 11.1). Compared with BSC, superior OS was independently associated with MDT (hazard ratio [HR] 0.36; 95% confidence interval [CI], 0.26 to 0.49), primary tumor resection (HR 0.55; 95% CI, 0.33 to 0.94), and primary tumor resection plus MDT (HR 0.20; 95% CI, 0.10 to 0.38). Worse OS was independently associated with signet ring cell carcinoma (HR 1.92; 95% CI, 1.12 to 3.28) and poor differentiation grade (HR 1.96; 95% CI, 1.35 to 2.83). The OS was comparable between matched patients with interval and synchronous distant metastases (10.2 versus 9.4 months, P = .760).

Conclusions: In esophageal cancer patients treated with neoadjuvant chemoradiotherapy with interval distant metastases, the OS was poor and comparable to that of synchronous metastatic patients.
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February 2021

Impact of Obesity on Treatment Approach for Resectable Esophageal Cancer.

Ann Thorac Surg 2021 10 17;112(4):1059-1066. Epub 2020 Dec 17.

Division of Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: With the prevalence of obesity and its known association with esophageal cancer, there is increasing need to understand how obesity affects treatment.

Methods: Using The Society of Thoracic Surgeons General Thoracic Surgery Database, we retrospectively evaluated all patients who underwent esophagectomy with gastric conduit reconstruction between 2012 and 2016. Patients were categorized into five body mass index groups. Associations between body mass index and surgical technique, resection, lymphadenectomy, staging, and neoadjuvant treatment were evaluated using multivariable logistic regression models.

Results: In all, 8547 patients were included in the analysis. Obese and morbidly obese patients were more likely to undergo open procedures compared with normal-weight patients (odds ratio [OR] 1.18, P = .016; and OR 1.45, P = .007), with longer operative times. Morbidly obese patients had a higher rate of intraoperative conversion from minimally invasive to open approaches (OR 3.75, P = .001). There were no differences in R0 resection or lymphadenectomy, and staging workup was similar. Obese patients were less likely to receive neoadjuvant therapy (OR 0.75, P = .048), and overweight and obese patients were less likely to receive preoperative radiation (OR 0.75, P = .017; and OR 0.71, P = .010). Analyzing by stage, overweight and obese patients with cT2N0 disease were less likely to receive neoadjuvant treatment (OR 0.54, P = .016; and OR 0.37, P < .001). There were no differences in neoadjuvant therapy for cT3 or node-positive disease.

Conclusions: Higher body mass index is associated with increased use of open versus minimally invasive esophagectomy and intraoperative conversion. Whereas staging workup and oncologic outcomes of surgery are similar, overweight and obese patients with cT2N0 disease are less likely to undergo neoadjuvant treatments.
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October 2021

Routine intraoperative jejunostomy placement and minimally invasive oesophagectomy: an unnecessary step?†.

Eur J Cardiothorac Surg 2019 Oct;56(4):746-753

Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.

Objectives: Adequate nutrition is challenging after oesophagectomy. A jejunostomy is commonly placed during oesophagectomy for nutritional support. However, some patients develop jejunostomy-related complications and the benefit over oral nutrition alone is unclear. This study aims to assess jejunostomy-related complications and the impact of intraoperative jejunostomy placement on weight loss and perioperative outcomes in patients with oesophageal cancer treated with minimally invasive Ivor Lewis oesophagectomy (MIE).

Methods: From a prospectively maintained database, patients were identified who underwent MIE with gastric reconstruction. Between 2007 and 2016, a jejunostomy was routinely placed during MIE. After 2016, a jejunostomy was not utilized. Postoperative feeding was performed according to a standardized protocol and similar for both groups. The primary outcomes were jejunostomy-related complications, relative weight loss at 3 and 6 months postoperative and perioperative outcomes, including anastomotic leak, pneumonia and length of stay, respectively.

Results: A total of 188 patients were included, of whom 135 patients (72%) received a jejunostomy. Ten patients (7.4%) developed jejunostomy-related complications, of whom 30% developed more than 1 complication. There was no significant difference in weight loss between groups at 3 months (P = 0.73) and 6 months postoperatively (P = 0.68) and in perioperative outcomes (P-value >0.999, P = 0.591 and P = 0.513, respectively).

Conclusions: The use of a routine intraoperative jejunostomy appears to be an unnecessary step in patients undergoing MIE. Intraoperative jejunostomy placement is associated with complications without improving weight loss or perioperative outcomes. Its use should be tailored to individual patient characteristics. Early oral nutrition allows patients to maintain an adequate nutritional status.
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October 2019

Systematic Review on the Trial Period for Bone Conduction Devices in Single-Sided Deafness: Rates and Reasons for Rejection.

Otol Neurotol 2017 06;38(5):632-641

*Department of Otorhinolaryngology - Head and Neck Surgery †Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: To systematically review the literature to evaluate the trial period of bone conduction devices (BCDs) for adult patients with single-sided deafness (SSD).

Data Sources: The PubMed, Embase, and Cochrane Library databases were searched from their inception up to August 15, 2016 for SSD, BCD, and their synonyms.

Study Selection: In total, 523 articles were retrieved, of which 12 satisfied the eligibility quality criteria. Our outcomes of interest were: 1) the BCD implantation rejection percentage, 2) reasons to reject BCD implantation, and 3) possible prognostic factors predicting the trial outcome.

Data Extraction And Synthesis: At critical appraisal, six studies (n = 471 patients) scored a moderate to high directness of evidence and a medium or low risk of bias and were selected for data extraction. Due to heterogeneity between studies, pooling of data for meta-analysis was not feasible. Therefore, results of studies were summarized per outcome: 1) after the BCD trial, 32.0 to 69.6% of SSD patients rejected BCD implantation, 2) the three main reasons for rejection were experiencing limited benefit from the device, patients fearing or being unfit for surgery and cosmetic aspects, 3) no clear prognostic factors predicting the trial outcome could be identified.

Conclusion: Roughly half of patients rejected BCD implantation after a trial period. From the current literature it is unclear which patients could benefit most from BCD implantation. High level of evidence studies should be conducted to investigate possible prognostic factors that predict the BCD trial outcome.
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June 2017