Perioperative Chemotherapy for Gastro-Esophageal or Gastric Cancer: Anthracyclin Triplets versus FLOT.

Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes of perioperative FLOT to anthracyclin triplets in a real-world Dutch gastric cancer population. Methods: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) gastric or gastro-esophageal junction carcinoma between 2015-2021 who received neoadjuvant FLOT or anthracyclin triplets were selected from the Netherlands Cancer Registry. The primary outcome was overall survival (OS), analyzed through multivariable Cox regression. Secondary outcomes included pathological complete response (pCR), neoadjuvant chemotherapy cycle completion, surgical resection rates, and adjuvant therapy. Results: Adjusted OS showed no significant survival benefit (HR = 0.88, 95% CI 0.77-1.01, p = 0.07), even though the median OS was numerically improved by 8 months with FLOT compared to anthracyclin triplets (48.1 vs. 39.9 months, p = 0.16). FLOT patients were more likely to undergo diagnostic staging laparoscopies (74.2% vs. 44.1%, p < 0.001), had higher rates of completing neoadjuvant chemotherapy (OR = 1.35, 95% CI 1.09-1.68, p = 0.007), receiving adjuvant therapy (OR = 1.34, 95% CI 1.08-1.66, p = 0.08), and achieving pCR (OR = 1.52, 95% CI 1.05-2.20, p = 0.03). No significant differences were observed in (radical) resection rates. Conclusion(s): Real-world data showed no significant OS improvement for FLOT-treated patients compared to anthracyclin triplets, despite more staging laparoscopies. However, FLOT patients demonstrated higher rates of neoadjuvant therapy completion, proceeding to adjuvant therapy, and increased pCR rates. Therefore, we recommend the continued use of neoadjuvant FLOT therapy in the current clinical setting.

Staging laparoscopy in gastric cancer patients: From a Dutch nationwide Delphi consensus towards a standardized protocol.

BACKGROUND: Staging laparoscopy is a common diagnostic tool in gastric cancer, but its performance varies widely. The aim of this study was to gain Dutch nationwide consensus regarding the indications for and execution of staging laparoscopy in patients with gastric cancer. METHODS: All surgeons in the Netherlands specialized in gastric cancer surgery (n = 52) were asked to participate in a Delphi consensus study. The study involved an initial questionnaire with a 3-point Likert scale, an online consensus meeting, and a second questionnaire using a 2-point Likert scale (agree/disagree). Consensus was defined as 70% or more agreement among participants. RESULTS: In total, 45 experts completed both questionnaires (87% response rate). Consensus was reached on the indication to perform staging laparoscopy in cT3-4 or cN + or diffuse-type gastric cancer, including Siewert type III oesophagogastric junctional cancer. The experts agreed that if preoperative scans suggest infiltration of surrounding organs (cT4), the tumour's resectability should explicitly be investigated. Consensus was also reached for a systematic peritoneal cavity inspection according to Sugarbaker's Peritoneal Cancer Index (PCI) score. All regions should be inspected routinely, although the omental bursa may be inspected on indication. Aspiration of ascites or peritoneal washing should be performed for cytology. The experts agreed that restaging laparoscopy should be performed before resection in case of progressive disease on preoperative imaging. Without progression, global inspection was considered sufficient. CONCLUSIONS: The results of this Dutch nationwide Delphi consensus study exposed the variability of performing staging laparoscopy in patients with gastric cancer and provided the concept for a standardized protocol.

Impact of 18FFDG-PET/CT and Laparoscopy in Staging of Locally Advanced Gastric Cancer: A Cost Analysis in the Prospective Multicenter PLASTIC-Study.

BACKGROUND: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging. MATERIALS AND METHODS: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18FFDG-PET/CT first, then SL, (2) SL only, (3) 18FFDG-PET/CT only, and (4) neither SL nor 18FFDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18FFDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18FFDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations). RESULTS: 18FFDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18FFDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis. CONCLUSIONS: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18FFDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs. TRIAL REGISTRATION: NCT03208621. This trial was registered prospectively on 30-06-2017.

Intraoperative Music to Promote Patient Outcome (IMPROMPTU): A Double-Blind Randomized Controlled Trial.

INTRODUCTION: Perioperative music can have beneficial effects on postoperative pain, anxiety, opioid requirement, and the physiological stress response to surgery. The aim was to assess the effects of intraoperative music during general anesthesia in patients undergoing surgery for esophagogastric cancer. MATERIALS AND METHODS: The IMPROMPTU study was a double-blind, placebo-controlled, randomized multicenter trial. Adult patients undergoing surgery for stage II-III esophagogastric cancer were eligible. Exclusion criteria were a hearing impairment, insufficient Dutch language knowledge, corticosteroids use, or objection to hearing unknown music. Patients wore active noise-cancelling headphones intraoperatively with preselected instrumental classical music (intervention) or no music (control). Computerized randomization with centralized allocation, stratified according to surgical procedure using variable block sizes, was employed. Primary endpoint was postoperative pain on the first postoperative day. Secondary endpoints were postoperative pain during the first postoperative week, postoperative opioid requirement, intraoperative medication requirement, the stress response to surgery, postoperative complication rate, length of stay, and mortality, with follow-up lasting 30 d. RESULTS: From November 2018 to September 2020, 145 patients were assessed and 83 randomized. Seventy patients (music n = 31, control n = 39) were analyzed. Median age was 70 [IQR 63-70], and 48 patients (69%) were male. Music did not reduce postoperative pain (numeric rating scale 1.8 (SD0.94) versus 2.0 (1.0), mean difference -0.28 [95% CI -0.76-0.19], P = 0.236). No statistically significant differences were seen in medication requirement, stress response, complication rate, or length of stay. CONCLUSIONS: Intraoperative, preselected, classical music during esophagogastric cancer surgery did not significantly improve postoperative outcome and recovery when compared to no music using noise-cancelling headphones.

Outcomes after Surgical Treatment of Oesophagogastric Cancer with Synchronous Liver Metastases: A Multicentre Retrospective Cohort Study.

Approximately 10-12% of patients with oesophageal or gastric cancer (OGC) present with oligometastatic disease at diagnosis. It remains unclear if there is a role for radical surgery in these patients. We aimed to assess the outcomes of OGC patients who underwent simultaneous treatment for the primary tumour and synchronous liver metastases. Patients with OGC who underwent surgical treatment between 2008 and 2020 for the primary tumour and up to five synchronous liver metastases aiming for complete tumour removal or ablation (i.e., no residual tumour) were identified from four institutional databases. The primary outcome was overall survival (OS), calculated with the Kaplan-Meier method. Secondary outcomes were disease-free survival and postoperative outcomes. Thirty-one patients were included, with complete follow-up data for 30 patients. Twenty-six patients (84%) received neoadjuvant therapy followed by response evaluation. Median OS was 21 months [IQR 9-36] with 2- and 5-year survival rates of 43% and 30%, respectively. While disease recurred in 80% of patients (20 of 25 patients) after radical resection, patients with a solitary liver metastasis had a median OS of 34 months. The number of liver metastases was a prognostic factor for OS (solitary metastasis aHR 0.330; p-value = 0.025). Thirty-day mortality was zero and complications occurred in 55% of patients. Long-term survival can be achieved in well-selected patients who undergo surgical resection of the primary tumour and local treatment of synchronous liver metastases. In particular, patients with a solitary liver metastasis seem to have a favourable prognosis.

Induction chemotherapy followed by response evaluation and esophagectomy for advanced esophageal cancer.

INTRODUCTION: Patients with limited metastatic/advanced esophageal cancer not amenable for neoadjuvant therapy plus surgery have a poor prognosis and often receive palliative care. Alternatively, induction chemotherapy with response evaluation can be considered and in some patients surgery with curative intent may become feasible. The aim of this study was to evaluate the outcomes of patients treated with induction chemotherapy and to identify patient and/or tumor characteristics associated with survival. MATERIAL AND METHODS: Patients with esophageal or junctional cancer who underwent induction chemotherapy between 2005 and 2021 were identified from an institutional database of a tertiary referral center. Response to therapy was assessed by (18F-FDG PET)/CT. Response to therapy and treatment options, including surgery or palliation, were discussed in the multidisciplinary tumor board. Overall survival (OS) was calculated using the Kaplan Meier method. Uni- and multivariable analyses were performed to identify prognostic factors for survival. RESULTS: 238 patients were identified. The majority had esophageal adenocarcinoma (68.9 %) and were treated with a taxane/platinum-based chemotherapy (79.4 %). Response evaluation was performed in 233 patients and 154 of 238 patients (64.7 %) underwent surgical exploration. Resection was performed in 127 patients (53.4 %) resulting in a median and 5-year OS of 26.3 months (95 % CI 18.8-33.8) and 29.6 %, respectively. Presence of T4b (HR = 2.01, 95 % CI 1.02-3.92) and poorly differentiated tumor (HR = 1.45, 95 % CI 1.02-2.10) was associated with worse survival (p = 0.04). CONCLUSION: In carefully selected patients with advanced disease not amenable for standard curative treatment, induction chemotherapy followed by esophagectomy may result in a 5-year overall survival of approximately 30 %.

Tumor-positive peritoneal cytology in patients with gastric cancer is associated with poor outcome: A nationwide study.

BACKGROUND: The clinical significance of tumor-positive peritoneal cytology (CYT+) in gastric cancer (GC) patients is unclear. This nationwide cohort study aimed to i) assess the frequency of cytological analysis at staging laparoscopy; ii) determine the prevalence of CYT+GC; and iii) compare overall survival (OS) in CYT+ patients versus those with (PM+) and those without (PM-) macroscopic peritoneal disease. METHODS: All patients diagnosed with cT1-4, cN0-2 and M0 or synchronous PM GC between 2016-2021 were identified in the Netherlands Cancer Registry database and linked to the nationwide pathology database. RESULTS: A total of 4397 patients was included, of which 40 % underwent cytological assessment following staging laparoscopy (863/1745). The prevalence of CYT+ was 8 %. A total of 69 patients had CYT+(1.6 %), 789 (17.9 %) had PM+ and 3539 (80.5 %) had PM- disease. Hazard ratio for OS in CYT+ versus PM+ was 0.86 (95 %CI 0.64-1.17, p-value=0.338), and in PM- versus PM+0.43 (95 %CI 0.38-0.49, p-value<0.001). No survival difference was found between systemic chemotherapy versus surgical resection in CYT+ patients. DISCUSSION: In this nationwide study, OS for gastric cancer patients with CYT+ was equally unfavorable as for those with PM+ and significantly worse as compared to those with PM-. The optimal treatment strategy has yet to be established.

Fasciocutaneous and jejunal free flaps for circumferential hypopharyngeal defect reconstruction: A 22-year multicenter cohort study.

BACKGROUND: It remains unclear whether a tubed fasciocutaneous or jejunal free flap (FCFF and JFF) is preferable for reconstruction of circumferential pharyngolaryngoesophageal defects. METHODS: All consecutive patients with circumferential pharyngolaryngoesophageal defects reconstructed with an FCFF or JFF between 2000 and 2022 were included. Outcomes of interest were rates of fistulas, strictures, and donor-site complications. RESULTS: In total, 112 patients were included (35 FCFFs and 77 JFFs). Fistula and stricture rates were significantly lower following JFF compared to FCFF reconstructions, with 12% versus 34% (p = 0.008) and 29% versus 49% (p = 0.04), respectively. Severe donor-site complications leading to surgical intervention or ICU admittance only occurred after JFF reconstructions (18%, p = 0.007). CONCLUSIONS: The high fistula and stricture rates in FCFF reconstructions and the rate of severe abdominal complications in JFF reconstructions illustrate inherent procedure-specific advantages and disadvantages. Relative pros and cons should be carefully weighed when tailoring treatments to the individual needs of patients.

18 F-FDG PET/MRI for restaging esophageal cancer after neoadjuvant chemoradiotherapy.

PURPOSE: The purpose of this study was to investigate whether 18F-fluorodeoxyglucose ( 18 F-FDG) PET/MRI may potentially improve tumor detection after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. METHODS: This was a prospective, single-center feasibility study. At 6-12 weeks after nCRT, patients underwent standard 18 F-FDG PET/computed tomography (CT) followed by PET/MRI, and completed a questionnaire to evaluate burden. Two teams of readers either assessed the 18 F-FDG PET/CT or the 18 F-FDG PET/MRI first; the other scan was assessed 1 month later. Maximum standardized uptake value corrected for lean body mass (SUL max ) and mean apparent diffusion coefficient (ADC mean ) were measured at the primary tumor location. Histopathology of the surgical resection specimen served as the reference standard for diagnostic accuracy calculations. When patients had a clinically complete response and continued active surveillance, response evaluations until 9 months after nCRT served as a proxy for ypT and ypN (i.e. 'ycT' and 'ycN'). RESULTS: In the 21 included patients [median age 70 (IQR 62-75), 16 males], disease recurrence was found in the primary tumor in 14 (67%) patients (of whom one ypM+, detected on both scans) and in locoregional lymph nodes in six patients (29%). Accuracy (team 1/team 2) to detect yp/ycT+ with 18 F-FDG PET/MRI vs. 18 F-FDG PET/CT was 38/57% vs. 76/61%. For ypN+, accuracy was 63/53% vs. 63/42%, resp. Neither SUL max (both scans) nor ADC mean were discriminatory for yp/ycT+ . Fourteen of 21 (67%) patients were willing to undergo a similar 18 F-FDG PET/MRI examination in the future. CONCLUSION: 18 F-FDG PET/MRI currently performs comparably to 18 F-FDG PET/CT. Improvements in the scanning protocol, increasing reader experience and performing serial scans might contribute to enhancing the accuracy of tumor detection after nCRT using 18 F-FDG PET/MRI. TRIAL REGISTRATION: Netherlands Trial Register NL9352.

Evolution in Laparoscopic Gastrectomy From a Randomized Controlled Trial Through National Clinical Practice.

OBJECTIVE: To examine the influence of the LOGICA RCT (randomized controlled trial) upon the practice and outcomes of laparoscopic gastrectomy within the Netherlands. BACKGROUND: Following RCTs the dissemination of complex interventions has been poorly studied. The LOGICA RCT included 10 Dutch centers and compared laparoscopic to open gastrectomy. METHODS: Data were obtained from the Dutch Upper Gastrointestinal Cancer Audit (DUCA) on all gastrectomies performed in the Netherlands (2012-2021), and the LOGICA RCT from 2015 to 2018. Multilevel multivariable logistic regression analyses were performed to assess the effect of laparoscopic versus open gastrectomy upon clinical outcomes before, during, and after the LOGICA RCT. RESULTS: Two hundred eleven patients from the LOGICA RCT (105 open vs 106 laparoscopic) and 4131 patients from the DUCA data set (1884 open vs 2247 laparoscopic) were included. In 2012, laparoscopic gastrectomy was performed in 6% of patients, increasing to 82% in 2021. No significant effect of laparoscopic gastrectomy on postoperative clinical outcomes was observed within the LOGICA RCT. Nationally within DUCA, a shift toward a beneficial effect of laparoscopic gastrectomy upon complications was observed, reaching a significant reduction in overall [adjusted odds ratio (aOR):0.62; 95% CI: 0.46-0.82], severe (aOR: 0.64; 95% CI: 0.46-0.90) and cardiac complications (aOR: 0.51; 95% CI: 0.30-0.89) after the LOGICA trial. CONCLUSIONS: The wider benefits of the LOGICA trial included the safe dissemination of laparoscopic gastrectomy across the Netherlands. The robust surgical quality assurance program in the design of the LOGICA RCT was crucial to facilitate the national dissemination of the technique following the trial and reducing potential patient harm during surgeons learning curve.

Patients' Preferences Towards Decision Counseling for Active Surveillance After Neoadjuvant Chemoradiotherapy for Esophageal Cancer.

BACKGROUND: Decision counseling (DC) is offered to enable patients to reflect on their treatment preferences and to think through the consequences of alternative treatment options. However, the timing of DC is debatable. In this study, patients who underwent DC at different times were interviewed about their experiences, specifically focusing on the timing of DC. METHODS: Patients with locally advanced esophageal cancer eligible for participation in a prospective cohort study on active surveillance (SANO-2 study) were offered DC either before or after neoadjuvant chemoradiotherapy (nCRT). Structured interviews were conducted by phone 1 week after DC, and responses were analyzed using frequency counts for the answers to set response categories. The primary outcome was the preferred time to receive DC, while the secondary outcome was the overall experience of patients with DC. RESULTS: Overall, 40 patients were offered DC between 2021 and 2023. Patients who had counseling before the start of nCRT (n = 20) were satisfied with the timing of DC. Of the 20 patients who had DC after nCRT, 6 would have preferred counseling at an earlier time point. Patients who had DC both before or after the completion of nCRT reflected positively on DC. CONCLUSION: It is recommended to introduce the option of DC as early as possible and discuss with the patient at which moment during the decision-making process they prefer to discuss all treatment options more extensively.

Collaborative multidisciplinary management and expertise of cT2-3 locally advanced operable esophageal squamous cell carcinoma: a report of two cases.

Background: The accurate clinical staging of esophageal squamous cell carcinoma (ESCC) is pivotal for guiding treatment strategies. However, the current precision in staging for clinical T (cT)2 and cT3 stages remains unsatisfactory. This article discusses the role of multidisciplinary teams (MDTs) in the clinical staging and formulation of neoadjuvant treatment strategies for locally advanced operable ESCC. These challenges underscore the importance of precise staging in the decision-making process for appropriate therapeutic interventions. Case Description: Through the lens of two patient case studies with locally advanced resectable ESCC, the article showcases the intricate process of treatment planning undertaken by MDTs. It captures a range of expert perspectives from Japan, China, Hong Kong (China), Korea, the USA, and Europe, focusing on the challenges of differentiating between cT2 and cT3 stages of the disease, which is a critical determinant in the management and therapeutic approach for patients. Conclusions: The article concludes that the accurate staging of ESCC is a cornerstone in determining the most suitable treatment strategies. It underscores the vital role that MDTs play in both clinical staging and the decision-making process for treatment. Highlighting the limitations in current diagnostic methods, the article emphasizes the urgent need for advanced research and the refinement of diagnostic tools to improve the precision of staging, particularly between the cT2 and cT3 stages. It suggests that future research should consider whether a reclassification of these stages could be warranted to enhance treatment planning and outcomes for patients with ESCC.

The association between hospital variation in curative treatment for esophagogastric cancer and health-related quality of life and survival.

BACKGROUND: As previous studies showed significant hospital variation in curative treatment of esophagogastric cancer, this study assesses the association between this variation and overall, cancer-specific and recurrence-free survival, and Health-Related Quality of Life (HRQoL). METHODS: Patients diagnosed with potentially curable esophageal or gastric cancer between 2015 and 2018 as registered in the Netherlands Cancer Registry were included. Data on overall survival was available for all patients, data on cancer-specific and recurrence-free survival and HRQoL was available for subgroups. Patients were classified according to diagnosis in hospitals with low, medium or high probability of treatment with curative intent (LP, MP or HP). Multivariable models were used to assess the association between LP, MP and HP hospitals and HRQoL and survival. RESULTS: This study includes 7,199 patients with esophageal, and 2,407 with gastric cancer. Overall and cancer-specific survival was better for patients diagnosed in HP versus LP hospitals for both esophageal (HR = 0.82, 95%CI:0.77-0.88 and HR = 0.82, 95%CI:0.75-0.91, respectively), and gastric cancer (HR = 0.82, 95%CI:0.73-0.92 and HR = 0.74, 95%CI:0.64-0.87, respectively). These differences disappeared after adjustments for treatment. Recurrence-free survival was worse for gastric cancer patients diagnosed in HP hospitals (HR = 1.50, 95%CI:1.14-1.96), which disappeared after adjustment for radicality of surgery. Minor, but no clinically relevant, differences in HRQoL were observed. CONCLUSIONS: Patients diagnosed in hospitals with a high probability of treatment with curative intent have a better overall and cancer-specific but not recurrence-free survival, while minor differences in HRQoL were observed.

2 days versus 5 days of Postoperative Antibiotics for Complex Appendicitis: Cost Analysis of a Randomized, Non-inferiority Trial.

OBJECTIVE: To compare costs for 2 days versus 5 days of postoperative antibiotics within the Antibiotics following aPPendectomy In Complex appendicitis (APPIC) trial.Summary Background Data:Recent studies suggest that restrictive antibiotic use leads to a significant reduction in hospital stay without compromising patient safety. Its potential effect on societal costs remains underexplored. METHODS: This was a pragmatic, open-label, multicenter clinical trial powered for non-inferiority. Patients with complex appendicitis (age ≥ 8 y) were randomly allocated to 2 days or 5 days of intravenous antibiotics after appendectomy. Patient inclusion lasted from June 2017 to June 2021 in 15 Dutch hospitals. Final follow-up was on September 1, 2021. The primary trial endpoint was a composite endpoint of infectious complications and mortality within 90 days. In the present study, main outcome measures were overall societal costs (comprising direct healthcare costs and costs related to productivity loss) and cost-effectiveness. Direct healthcare costs were recorded based on data in the electronic patient files, complemented by a telephone follow-up at 90 days. In addition, data on loss of productivity were acquired through the validated Productivity-Cost-Questionnaire at four weeks after surgery. Cost estimates were based on prices for the year 2019. RESULTS: In total, 1005 patients were evaluated in the Intention-to-Treat analysis: 502 patients allocated to the 2-day group and 503 to the 5-day group. The mean difference in overall societal costs was - € 625 (95% confidence interval - € 958 to - € 278) to the advantage of the 2-day group. This difference was largely explained by reduced hospital stay. Productivity losses were similar between the study groups. Restricting postoperative antibiotics to two days was cost-effective, with estimated cost savings of € 31,117 per additional infectious complication. CONCLUSIONS: 2 days of postoperative antibiotics for complex appendicitis results in a statistically significant and relevant cost reduction, as compared with 5 days. Findings apply to laparoscopic appendectomy in a well-resourced healthcare setting. TRIAL REGISTRATION: Trialregister.nl number NL5946.