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Pieter van Hagen

Bio: Pieter van Hagen is an academic researcher from Erasmus University Rotterdam. The author has contributed to research in topics: Chemoradiotherapy & Esophagectomy. The author has an hindex of 14, co-authored 16 publications receiving 2238 citations. Previous affiliations of Pieter van Hagen include Erasmus University Medical Center.

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Journal ArticleDOI
TL;DR: Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy in patients with clinically resectable, locally advanced cancer of the oesophagus or Oesophagogastric junction and shows a significant increase in 5-year overall survival.
Abstract: Summary Background Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. Methods Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2–3N0–1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m 2 of body-surface area] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. Findings Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1–116·8, IQR 70·7–96·6), median overall survival was 48·6 months (95% CI 32·1–65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2–33·7) in the surgery alone group (HR 0·68 [95% CI 0·53–0·88]; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2–116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4–26·7) in the surgery alone group (HR 0·48 [95% CI 0·28–0·83]; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9–61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0–41·2) in the surgery alone group (HR 0·73 [95% CI 0·55–0·98]; log-rank p=0·038). Interpretation Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. Funding Dutch Cancer Foundation (KWF Kankerbestrijding).

1,703 citations

Journal ArticleDOI
TL;DR: Preoperative CRT in patients with esophageal cancer reduced locoregional recurrence and peritoneal carcinomatosis and there was a small but significant effect on hematogenous dissemination in favor of the CRT group.
Abstract: Purpose To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. Patients and Methods Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. Results Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 3...

377 citations

Journal ArticleDOI
TL;DR: Chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resusceptible cancer in this paper.
Abstract: PURPOSEPreoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced res...

199 citations

Journal ArticleDOI
TL;DR: The fact that the 7th edition performs better predominantly in patients with adenocarcinomas who underwent a transhiatal surgical approach, in addition to findings from earlier research in other cohorts, supports its generalizability for different esophageal cancer practices.
Abstract: Background The new 7th edition of the Union for International Cancer Control–American Joint Committee on Cancer (UICC-AJCC) tumor, node, metastasis (TNM) staging system is the ratification of data-driven recommendations from the Worldwide Esophageal Cancer Collaboration database. Generalizability remains questionable for single institutions. The present study serves as a validation of the 7th edition of the TNM system in a prospective cohort of patients with predominantly adenocarcinomas from a single institution.

140 citations

Journal ArticleDOI
TL;DR: The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial, and data question the indication for maximization of lymphadenectomy after nCRT.
Abstract: OBJECTIVES: We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. BACKGROUND: Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently "sterilize" regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. METHODS: Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. RESULTS: One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12-27) and 14 (9-21), with 2 (1-6) and 0 (0-1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P=0.007), but not in the multimodality arm (hazard ratio 1.00; P=0.98). CONCLUSIONS: The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

137 citations


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TL;DR: Substantial increases in the number of avoidable cancer deaths in England are to be expected as a result of diagnostic delays due to the COVID-19 pandemic, and urgent policy interventions are necessary.
Abstract: Summary Background Since a national lockdown was introduced across the UK in March, 2020, in response to the COVID-19 pandemic, cancer screening has been suspended, routine diagnostic work deferred, and only urgent symptomatic cases prioritised for diagnostic intervention. In this study, we estimated the impact of delays in diagnosis on cancer survival outcomes in four major tumour types. Methods In this national population-based modelling study, we used linked English National Health Service (NHS) cancer registration and hospital administrative datasets for patients aged 15–84 years, diagnosed with breast, colorectal, and oesophageal cancer between Jan 1, 2010, and Dec 31, 2010, with follow-up data until Dec 31, 2014, and diagnosed with lung cancer between Jan 1, 2012, and Dec 31, 2012, with follow-up data until Dec 31, 2015. We use a routes-to-diagnosis framework to estimate the impact of diagnostic delays over a 12-month period from the commencement of physical distancing measures, on March 16, 2020, up to 1, 3, and 5 years after diagnosis. To model the subsequent impact of diagnostic delays on survival, we reallocated patients who were on screening and routine referral pathways to urgent and emergency pathways that are associated with more advanced stage of disease at diagnosis. We considered three reallocation scenarios representing the best to worst case scenarios and reflect actual changes in the diagnostic pathway being seen in the NHS, as of March 16, 2020, and estimated the impact on net survival at 1, 3, and 5 years after diagnosis to calculate the additional deaths that can be attributed to cancer, and the total years of life lost (YLLs) compared with pre-pandemic data. Findings We collected data for 32 583 patients with breast cancer, 24 975 with colorectal cancer, 6744 with oesophageal cancer, and 29 305 with lung cancer. Across the three different scenarios, compared with pre-pandemic figures, we estimate a 7·9–9·6% increase in the number of deaths due to breast cancer up to year 5 after diagnosis, corresponding to between 281 (95% CI 266–295) and 344 (329–358) additional deaths. For colorectal cancer, we estimate 1445 (1392–1591) to 1563 (1534–1592) additional deaths, a 15·3–16·6% increase; for lung cancer, 1235 (1220–1254) to 1372 (1343–1401) additional deaths, a 4·8–5·3% increase; and for oesophageal cancer, 330 (324–335) to 342 (336–348) additional deaths, 5·8–6·0% increase up to 5 years after diagnosis. For these four tumour types, these data correspond with 3291–3621 additional deaths across the scenarios within 5 years. The total additional YLLs across these cancers is estimated to be 59 204–63 229 years. Interpretation Substantial increases in the number of avoidable cancer deaths in England are to be expected as a result of diagnostic delays due to the COVID-19 pandemic in the UK. Urgent policy interventions are necessary, particularly the need to manage the backlog within routine diagnostic services to mitigate the expected impact of the COVID-19 pandemic on patients with cancer. Funding UK Research and Innovation Economic and Social Research Council.

1,119 citations

Journal ArticleDOI
TL;DR: This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.
Abstract: Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

710 citations

Journal ArticleDOI
TL;DR: This is the first review encompassing many cancer types, and it is demonstrated that efforts to expedite the diagnosis of symptomatic cancer are likely to have benefits for patients in terms of improved survival, earlier-stage diagnosis and improved quality of life, although these benefits vary between cancers.
Abstract: It is unclear whether more timely cancer diagnosis brings favourable outcomes, with much of the previous evidence, in some cancers, being equivocal. We set out to determine whether there is an association between time to diagnosis, treatment and clinical outcomes, across all cancers for symptomatic presentations. Systematic review of the literature and narrative synthesis. We included 177 articles reporting 209 studies. These studies varied in study design, the time intervals assessed and the outcomes reported. Study quality was variable, with a small number of higher-quality studies. Heterogeneity precluded definitive findings. The cancers with more reports of an association between shorter times to diagnosis and more favourable outcomes were breast, colorectal, head and neck, testicular and melanoma. This is the first review encompassing many cancer types, and we have demonstrated those cancers in which more evidence of an association between shorter times to diagnosis and more favourable outcomes exists, and where it is lacking. We believe that it is reasonable to assume that efforts to expedite the diagnosis of symptomatic cancer are likely to have benefits for patients in terms of improved survival, earlier-stage diagnosis and improved quality of life, although these benefits vary between cancers.

657 citations

Journal ArticleDOI
TL;DR: This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.
Abstract: PurposeThe efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the surviva...

464 citations

Journal ArticleDOI
TL;DR: The 8th edition of the American Joint Committee on Cancer (AJCC) staging of epithelial cancers of the esophagus and esophagogastric junction presents separate classifications for clinical, pathologic, and postneoadjuvant stage groups, with the role of ypTNM classification in additional treatment decision-making currently limited.
Abstract: The 8th edition of the American Joint Committee on Cancer (AJCC) staging of epithelial cancers of the esophagus and esophagogastric junction (EGJ) presents separate classifications for clinical (cTNM), pathologic (pTNM), and postneoadjuvant (ypTNM) stage groups. Histopathologic cell type markedly affects survival of clinically and pathologically staged patients, requiring separate groupings for each cell type, but ypTNM groupings are identical for both cell types. Clinical categories, typically obtained by imaging with minimal histologic information, are limited by resolution of each method. Strengths and shortcomings of clinical staging methods should be recognized. Complementary cytology or histopathology findings may augment imaging and aid initial treatment decision-making. However, prognostication using clinical stage groups remains coarse and inaccurate compared with pTNM. Pathologic staging is losing its relevance for advanced-stage cancer as neoadjuvant therapy replaces esophagectomy alone. However, it remains relevant for early-stage cancers and as a staging and survival reference point. Although pathologic stage could facilitate decision-making, its use to direct postoperative adjuvant therapy awaits more effective treatment. Prognostication using pathologic stage groups is the most refined of all classifications. Postneoadjuvant staging (ypTNM) is introduced by the AJCC but not adopted by the Union for International Cancer Control (UICC). Drivers of this addition include absence of equivalent pathologic (pTNM) categories for categories peculiar to the postneoadjuvant state (ypT0N0-3M0 and ypTisN0-3M0), dissimilar stage group compositions, and markedly different survival profiles. Thus, prognostication is specific for patients undergoing neoadjuvant therapy. The role of ypTNM classification in additional treatment decision-making is currently limited. Precision cancer care advances are necessary for this information to be clinically useful.

407 citations