Els Visser

Prognosis and Treatment After Diagnosis of Recurrent Esophageal Carcinoma Following Esophagectomy with Curative Intent

BackgroundStrategies for the treatment of recurrence after initial curative esophagectomy are increasingly being recognized. The aim of this study was to identify prognostic factors that affect survival in patients with recurrence and to evaluate treatment strategies.MethodsA prospective database (2003–2013) was used to collect consecutive patients with esophageal carcinoma treated with initial curative esophagectomy. Locations, symptoms, and treatment of recurrence were registered. Post-recurrence survival was defined as the time between the first recurrence and death or last follow-up.ResultsOf the 335 selected patients, 171 (51xa0%) developed recurrence. Multivariable analysis identified distant recurrence as opposed to locoregional recurrence [hazard ratio (HR) 2.15, 95xa0% confidence interval (CI) 1.27–3.65; pxa0=xa00.005], more than three recurrent locations (HR 2.42, 95xa0% CI 1.34–4.34; pxa0=xa00.003), and treatment (HR 0.29, 95xa0% CI 0.20–0.44; pxa0<xa00.001) as independent prognostic factors associated with post-recurrence survival. Primary tumor characteristics, including neoadjuvant therapy, histological type, pTN stage, and radicality, did not independently influence post-recurrence survival. Treatment was initiated in 62 patients (37xa0%) and included chemotherapy, radiotherapy, and/or surgery. Median post-recurrence survival of all patients was 3.0xa0months (range 0–112). In total, six patients (4xa0%) were still disease-free following treatment, indicating cure.ConclusionsIn patients treated for esophageal cancer at curative intent, distant recurrence and more than three recurrent locations were independent prognostic factors associated with worse post-recurrence survival, irrespective of primary tumor characteristics. Although survival after recurrence was poor, treatment can prolong survival and can even lead to cure in selected patients.

Waiting Time from Diagnosis to Treatment has no Impact on Survival in Patients with Esophageal Cancer

BackgroundWaiting time from diagnosis to treatment has emerged as an important quality indicator in cancer care. This study was designed to determine the impact of waiting time on long-term outcome of patients with esophageal cancer who are treated with neoadjuvant therapy followed by surgery or primary surgery.MethodsPatients who underwent esophagectomy for esophageal cancer at the University Medical Center Utrecht between 2003 and 2014 were included. Patients treated with neoadjuvant therapy followed by surgery and treated with primary surgery were separately analyzed. The influence of waiting time on survival was analyzed using Cox proportional hazard analyses. Kaplan–Meier curves for short (<8xa0weeks) and long (≥8xa0weeks) waiting times were constructed.ResultsA total of 351 patients were included; 214 received neoadjuvant treatment, and 137 underwent primary surgery. In the neoadjuvant group, the waiting time had no impact on disease-free survival (DFS) [hazard ratio (HR) 0.96, 95xa0% confidence interval (CI) 0.88–1.04; pxa0=xa00.312] or overall survival (OS) (HR 0.96, 95xa0% CI 0.88–1.05; pxa0=xa00.372). Accordingly, no differences were found between neoadjuvantly treated patients with waiting times of <8 and ≥8xa0weeks in terms of DFS (pxa0=xa00.506) and OS (pxa0=xa00.693). In the primary surgery group, the waiting time had no impact on DFS (HR 1.03, 95xa0% CI 0.95–1.12; pxa0=xa00.443) or OS (HR 1.06, 95xa0% CI 0.99–1.13; pxa0=xa00.108). Waiting times of <8xa0weeks versus ≥8xa0weeks did not result in differences regarding DFS (pxa0=xa00.884) or OS (pxa0=xa00.374).ConclusionsIn esophageal cancer patients treated with curative intent by either neoadjuvant therapy followed by surgery or primary surgery, waiting time from diagnosis to treatment has no impact on long-term outcome.

Prognostic gene expression profiling in esophageal cancer: a systematic review

Background Individual variability in prognosis of esophageal cancer highlights the need for advances in personalized therapy. This systematic review aimed at elucidating the prognostic role of gene expression profiles and at identifying gene signatures to predict clinical outcome. Methods A systematic search of the Medline, Embase and the Cochrane library databases (2000-2015) was performed. Articles associating gene expression profiles in patients with esophageal adenocarcinoma or squamous cell carcinoma to survival, response to chemo(radio)therapy and/or lymph node metastasis were identified. Differentially expressed genes and gene signatures were extracted from each study and combined to construct a list of prognostic genes per outcome and histological tumor type. Results This review includes a total of 22 studies. Gene expression profiles were related to survival in 9 studies, to response to chemo(radio)therapy in 7 studies, and to lymph node metastasis in 9 studies. The studies proposed many differentially expressed genes. However, the findings were heterogeneous and only 12 (ALDH1A3, ATR, BIN1, CSPG2, DOK1, IFIT1, IFIT3, MAL, PCP4, PHB, SPP1) of the 1.112 reported genes were identified in more than 1 study. Overall, 16 studies reported a prognostic gene signature, which was externally validated in 10 studies. Conclusion This systematic review shows heterogeneous findings in associating gene expression with clinical outcome in esophageal cancer. Larger validated studies employing RNA next-generation sequencing are required to establish gene expression profiles to predict clinical outcome and to select optimal personalized therapy.

Impact of Lymph Node Yield on Overall Survival in Patients Treated With Neoadjuvant Chemoradiotherapy Followed by Esophagectomy for Cancer: A Population-based Cohort Study in the Netherlands

Objective: To evaluate the impact of lymph node yield (LNY) on survival in patients treated with neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for cancer. Background: The value of an extended lymphadenectomy after nCRT for esophageal cancer is debated. Recent reports demonstrate no association between LNY and survival. This association has not yet been evaluated in larger cohorts. Methods: All patients who underwent nCRT followed by esophagectomy between 2005 and 2014 were identified from the Netherlands Cancer Registry. The association between LNY and overall survival was analyzed using multivariable Cox regression analyses, adjusting for diagnosis year, referral, hospital volume, age, sex, malignancy history, tumor location, histology, cTN-stage, surgical approach, radicality, and ypTN-stage. Analyses were performed with LNY as categorized predictor (<15 vs ≥15 nodes) and continuous predictor (per 10 additionally nodes). Results: A total of 2698 patients were included with a median overall survival of 34 months (range 4–143). A higher LNY was significantly associated with improved overall survival, both as categorized predictor (hazard ratio 0.77, 95% confidence interval 0.68–0.86) and as continuous predictor (hazard ratio 0.84, 95% confidence interval 0.78–0.90). Furthermore, a higher LNY was associated with favorable hazard ratios across subgroups, including both squamous cell carcinoma and adenocarcinoma, both cN0 and cN+, both transthoracic and transhiatal approaches, and both ypN0 and ypN+. Conclusions: This large population-based cohort study demonstrates an association between LNY and overall survival, indicating a therapeutic value of extended lymphadenectomy during esophagectomy. Therefore, an extended lymphadenectomy should be the standard of care after nCRT.

Impact of Weekday of Esophagectomy on Short-term and Long-term Oncological Outcomes: A Nationwide Population-based Cohort Study in the Netherlands.

Objective: The aim of this study was to determine whether weekday of esophagectomy impacts 30-day mortality, and short- and long-term oncologic outcomes in esophageal cancer. Summary of background data: Recent literature suggests a relationship between the weekday of esophagectomy and overall survival. This finding could impact clinical practice, but has not yet been validated in other studies. Methods: The Netherlands Cancer Registry database (2005–2013) identified all patients who underwent esophagectomy for esophageal cancer. The impact of weekday on 30-day mortality, the total number of resected lymph nodes, and R0 resection rates was evaluated with multivariable logistic regression analyses and for overall survival with Cox regression analyses. Results: In total, 3840 patients were included. Weekday was not significantly associated with 30-day mortality (P > 0.05), nor the total number of resected lymph nodes (P > 0.05), nor with R0 resection rates (P > 0.05). Also, weekday did not significantly influence overall survival using weekday as discrete variable [Monday–Friday, hazard ratio (HR) 0.98, P = 0.140), as 2 weekday categories (Wednesday–Friday vs Monday–Tuesday, HR 0.97, P = 0.434), or with separate weekday categories (Tuesday vs Monday, HR 0.99, P = 0.826; Wednesday vs Monday, HR 1.06, P = 0.430; Thursday vs Monday, HR 0.92, P = 0.206; Friday vs Monday, HR 0.91, P = 0.140). Conclusions: This large population-based cohort study in the Netherlands refutes the finding from a previous report that suggests that the weekday of esophagectomy in patients diagnosed with potentially curable esophageal cancer impacts overall survival. In addition, this study demonstrates that weekday of esophagectomy does not influence other outcomes including the 30-day mortality, total number of resected lymph nodes, and R0 resection rates.

Missed low-grade infection in suspected aseptic loosening has no consequences for the survival of total hip arthroplasty

Background and purpose — Aseptic loosening and infection are 2 of the most common causes of revision of hip implants. Antibiotic prophylaxis reduces not only the rate of revision due to infection but also the rate of revision due to aseptic loosening. This suggests under-diagnosis of infections in patients with presumed aseptic loosening and indicates that current diagnostic tools are suboptimal. In a previous multicenter study on 176 patients undergoing revision of a total hip arthroplasty due to presumed aseptic loosening, optimized diagnostics revealed that 4–13% of the patients had a low-grade infection. These infections were not treated as such, and in the current follow-up study the effect on mid- to long-term implant survival was investigated. Patients and methods — Patients were sent a 2-part questionnaire. Part A requested information about possible re-revisions of their total hip arthroplasty. Part B consisted of 3 patient-related outcome measure questionnaires (EQ5D, Oxford hip score, and visual analog scale for pain). Additional information was retrieved from the medical records. The group of patients found to have a low-grade infection was compared to those with aseptic loosening. Results — 173 of 176 patients from the original study were included. In the follow-up time between the revision surgery and the current study (mean 7.5 years), 31 patients had died. No statistically significant difference in the number of re-revisions was found between the infection group (2 out of 21) and the aseptic loosening group (13 out of 152); nor was there any significant difference in the time to re-revision. Quality of life, function, and pain were similar between the groups, but only 99 (57%) of the patients returned part B. Interpretation — Under-diagnosis of low-grade infection in conjunction with presumed aseptic revision of total hip arthroplasty may not affect implant survival.

Association Between Waiting Time from Diagnosis to Treatment and Survival in Patients with Curable Gastric Cancer : A Population-Based Study in the Netherlands

BackgroundIn the Netherlands, a maximum waiting time from diagnosis to treatment (WT) of 5xa0weeks is recommended for curative cancer treatment. This study aimed to evaluate the association between WT and overall survival (OS) in patients undergoing gastrectomy for cancer.MethodsThis nationwide study included data from patients diagnosed with curable gastric adenocarcinoma between 2005 and 2014 from the Netherlands Cancer Registry. Patients were divided into two groups: patients who received neoadjuvant therapy followed by gastrectomy, or patients who underwent gastrectomy as primary surgery. WT was analyzed as a categorical (≤5xa0weeks [Reference], 5–8xa0weeks, >8xa0weeks) and as a discrete variable. Multivariable Cox regression analysis was used to assess the influence of WT on OS.ResultsAmong 3778 patients, 1701 received neoadjuvant chemotherapy followed by gastrectomy, and 2077 underwent primary gastrectomy. In the neoadjuvant group, median WT to neoadjuvant treatment was 4.6xa0weeks (interquartile range [IQR] 3.4–6.0), and median OS was 32xa0months. In the surgery group, median WT to surgery was 6.0xa0weeks (IQR 4.3–8.4), and median OS was 25xa0months. For both groups, WT did not influence OS (neoadjuvant: 5–8xa0weeks, hazard ratio [HR] 0.82, pxa0=xa00.068; >8xa0weeks, HR 0.85, pxa0=xa00.354; each additional week WT, HR 0.96, pxa0=xa00.078; surgery: 5–8xa0weeks, HR 0.91, pxa0=xa00.175; >8xa0weeks, HR 0.92, pxa0=xa00.314; each additional week WT, HR 0.99, pxa0=xa00.264).ConclusionsLonger WT until the start of curative treatment for gastric cancer is not associated with worse OS. These results could help to put WT into perspective as indicator of quality of care and reassure patients with gastric cancer.

Impact of diagnosis-to-treatment waiting time on survival in esophageal cancer patients – A population-based study in The Netherlands

BACKGROUNDnThe aim of this study was to determine whether the waiting time from diagnosis to treatment with curative intent for esophageal cancer impacts oncologic outcomes.nnnPATIENTS AND METHODSnAll patients treated by esophagectomy for esophageal carcinoma in 2005-2013 were identified from the Netherlands Cancer Registry. Patients who underwent multimodality treatment and patients treated with surgery only were analyzed separately. Multivariable logistic regression analyses were performed to evaluate the impact of diagnosis-to-treatment waiting time on pT-status, pN-status, and R0 resection rates. Cox regression was applied to estimate the influence of waiting time on overall survival. Analyses were performed with the original scale and in three categorized groups of waiting time (≤5 weeks, 5-8 weeks, and >8 weeks) based on guidelines and previous studies.nnnRESULTSnOf 3839 patients, 2589 underwent multimodality treatment and 1250 were treated with surgery only. In both groups, pT-status, pN-status, and R0 resection rates were not significantly influenced by waiting time (p-values >0.05). Also, waiting time was not significantly associated with overall survival in the multimodality treatment group (5-8 weeks vs. ≤5 weeks, hazard ratio [HR] 1.12, pxa0=xa00.171; and >8 weeks vs. ≤5 weeks, HR 1.21, pxa0=xa00.167), nor in the surgery only group (5-8 weeks vs. ≤5 weeks, HR 0.92, pxa0=xa00.432; and >8 weeks vs. ≤5 weeks, HR 1.00, pxa0=xa00.973).nnnCONCLUSIONnThis large population-based cohort study demonstrates that longer waiting time from diagnosis to treatment in patients treated for esophageal cancer with curative intent does not negatively impact pT-status, pN-status, R0 resection rates, and overall survival.

Postoperative pain management after esophagectomy: a systematic review and meta-analysis

Effective pain management after esophagectomy is essential for patient comfort, early recovery, low surgical morbidity, and short hospitalization. This systematic review and meta-analysis aims to determine the best pain management modality focusing on the balance between benefits and risks. Medline, Embase, and the Cochrane library were systematically searched to identify all studies investigating different pain management modalities after esophagectomy in relation to primary outcomes (postoperative pain scores at 24 and 48 hours, technical failure, and opioid consumption), and secondary outcomes (pulmonary complications, nausea and vomiting, hypotension, urinary retention, and length of hospital stay). Ten studies investigating systemic, epidural, intrathecal, intrapleural and paravertebral analgesia involving 891 patients following esophagectomy were included. No significant differences were found in postoperative pain scores between systemic and epidural analgesia at 24 (mean difference (MD) 0.89; 95% confidence interval (CI) -0.47-2.24) and 48 hours (MD 0.15; 95%CI -0.60-0.91), nor described for systemic and other regional analgesia. Also, no significant differences in pulmonary complication rates were identified between systemic and epidural analgesia (relative risk (RR) 1.69; 95%CI 0.86-3.29), or between systemic and paravertebral analgesia (RR 1.49; 95%CI 0.31-7.12). Technical failure ranged from 17% to 22% for epidural analgesia. Sample sizes were too small to draw inferences on opioid consumption, the risk of nausea and vomiting, hypotension, urinary retention, and length of hospital stay when comparing the different pain management modalities including systemic, epidural, intrathecal, intrapleural, and paravertebral analgesia. This systematic review and meta-analysis shows no differences in postoperative pain scores or pulmonary complications after esophagectomy between systemic and epidural analgesia, and between systemic and paravertebral analgesia. Further randomized controlled trails are warranted to determine the optimal pain management modality after esophagectomy.

Timing of postoperative chemotherapy in patients undergoing perioperative chemotherapy and gastrectomy for gastric cancer

BACKGROUNDnFor patients who qualify for perioperative chemotherapy and gastrectomy for gastric cancer, the optimal timing of the postoperative chemotherapy (PC) seems equivocal. The aim of this study was to evaluate the influence of timing of PC on overall survival (OS) in patients receiving perioperative chemotherapy.nnnMETHODSnPatients undergoing perioperative chemotherapy and gastrectomy with curative intent (2010-2014) were extracted from the nationwide population-based Netherlands Cancer Registry. Timing of PC was analyzed as a linear and categorical variable (<6 weeks, 6-8 weeks, and >8 weeks). Risk factors for a late start of PC (≥6 weeks), and the association between timing of PC and OS were assessed by multivariable regression analyses.nnnRESULTSnAmong 1066 patients who underwent perioperative chemotherapy and gastrectomy, 463 (43%) patients started PC. PC was administered within 6 weeks in 208 (45%) patients, within 6-8 weeks in 155 (33%) patients, and after 8 weeks in 100 (22%) patients. A total of 419 (91%) and 351 (76%) patients finished all cycles of preoperative and PC, respectively. A late start of PC was associated with a longer hospital stay (+1 hospital day: OR 1.15, 95% CI [1.08-1.23], pxa0<xa00.001). Timing of PC was not associated with OS (6-8 weeks vs. <6 weeks, HR 1.14, 95% CI [0.79-1.65], pu202f=u202f0.471; >8 weeks vs. <6 weeks, HR 1.04, 95% CI [0.79-1.65], pu202f=u202f0.872).nnnCONCLUSIONnTiming of postoperative chemotherapy does not influence survival in patients receiving perioperative chemotherapy for gastric cancer. The results suggest that the early postoperative period may be safely used for recovery and optimizing patients for the start of PC.