Background: Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is a standard treatment for potentially curable esophageal cancer. Active surveillance in patients with a clinically complete response (cCR) 12 weeks after nCRT is regarded as possible alternative to standard surgery. The aim of this study is to monitor the safety, adherence and effectiveness of active surveillance in patients outside a randomized trial. Methods: This nationwide prospective cohort study aims to accrue operable patients with non-metastatic histologically proven adenocarcinoma or squamous cell carcinoma of the esophagus or esophagogastric junction. Patients receive nCRT and response evaluation consists of upper endoscopy with bite-on-bite biopsies, endoscopic ultrasonography plus fine-needle aspiration of suspicious lymph nodes and ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography scan. When residue or regrowth of tumor in the absence of distant metastases is detected, surgical resection is advised. Patients with cCR after nCRT are suitable to undergo active surveillance. Patients can consult an independent physician or psychologist to support decision-making. Primary endpoint is the number and severity of adverse events in patients with cCR undergoing active surveillance, defined as complications from response evaluations, delayed surgery and the development of distant metastases. Secondary endpoints include timing and quality of diagnostic modalities, overall survival, progression-free survival, fear of cancer recurrence and decisional regret. Discussion: Active surveillance after nCRT may be an alternative to standard surgery in patients with esophageal cancer. Similar to organ-sparing approaches applied in other cancer types, the safety and efficacy of active surveillance needs monitoring before data from randomized trials are available. Trial registration: The SANO-2 study has been registered at ClinicalTrials.gov as NCT04886635 (May 14, 2021) – Retrospectively registered.

Background: Overall survival (OS) is the standard endpoint for oncological treatment efficacy, but requires long follow-up. The aim of this study was to evaluate pCR as a surrogate for OS in oesophageal cancer. Methods: An integrated analysis of individual patient data (IPD) from phase III trials comparing perioperative therapies for resectable oesophageal and gastro-oesophageal junction cancer was conducted. Individual-level surrogacy between pCR and OS was assessed using Kendall’s rank correlation coefficient (τ). A τ of 0.8 was considered a threshold for a good surrogate. As no method estimating τ between an ordinal endpoint and OS has been reported, a new method was proposed using the inverse-probability-of-censoring weighted estimator adjusted for tied data. Results: Of 22 eligible trials, 10 provided IPD for 1641 patients, including 624 who received neoadjuvant chemotherapy (NAC; 45 (7.2%) achieved pCR) and 1017 who received neoadjuvant chemoradiotherapy (NACRT; 299 (29.4%) achieved pCR). In the NAC subgroup, patients with pCR had an HR for OS of 0.12 (95% c.i. 0.05 to 0.33), the C-index was 0.54 (95% c.i. 0.52 to 0.56), and τ was 0.256. In the NACRT subgroup, the HR was 0.57 (95% c.i. 0.47 to 0.70), the C-index was 0.56 (95% c.i. 0.54 to 0.58), and τ was 0.174. Hypothetical data suggested that achieving strong surrogacy (τ of 0.8) required an HR of 0.09 (95% c.i. 0.07 to 0.11). Conclusion: Although pCR was correlated with OS, no evidence of individual-level surrogacy with OS was demonstrated, making it inappropriate to consider pCR as a surrogate endpoint for OS in resectable oesophageal cancer.

Definitive chemoradiotherapy (dCRT) is a potentially curative therapy for esophageal cancer. As indications for dCRT differ widely, it is challenging to draw conclusions on outcomes and survival. The aim of this study was to evaluate overall survival (OS) and recurrence patterns according to indications for treatment. Patients who underwent dCRT (50.4 Gy concomitant with carboplatin/paclitaxel) for esophageal cancer between 2012 and 2022 were identified. Indications for dCRT were: cervical tumor, irresectable disease, unfit for surgery, and patient and/or physician preference. The primary endpoint was OS calculated with the Kaplan–Meier method. Secondary endpoints included the proportion of patients that completed the dCRT regimen, 30- and 90-day mortality, and disease recurrence. One hundred and fifty-seven patients were included (72.6% esophageal squamous cell carcinoma) with a median follow-up of 20 months (IQR 10.0–43.9). The full dCRT regimen was completed by 116 patients (73.9%). Thirty- and 90-day mortality were 2.5% and 8.3%, respectively. Median and 5-year OS for all patients were 22.9 months (95% CI 18.0–27.9) and 31.4%, respectively. The median OS per indication was 23.7 months (95% CI 6.5–40.8) for patients with cervical tumors, 10.9 months (95% 0.0–23.2) for irresectable disease, 28.2 months (95% CI 12.3–44.0) for unfit patients, and 22.9 months (95% CI 15.4–30.5) for patients’ preference for dCRT (P = 0.11). Disease recurrence was observed in 74 patients (46%), located locoregionally (46%), distant (19%), or combined (35%). Patients who underwent dCRT had a 5-year OS of 31.4%, but OS differed according to indications for treatment with patients who had irresectable disease having the worst prognosis.

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.

FLOT and CROSS are effective neoadjuvant regimens for esophageal cancer patients. Chemotherapy (FLOT) is aimed to have merely a systemic effect whereas neoadjuvant chemoradiotherapy (CROSS) achieves good locoregional response with clinically complete response (cCR) rates up to 33% [1]. The aim of the present study is to assess safety and feasibility of dual therapy (FLOT-CROSS) in patients with oligometastases. This phase-II single-center, single-arm, intervention study includes patients with oligometastatic adenocarcinoma of the esophagus or esophagogastric junction. Patients will be treated with four biweekly cycles of FLOT, consisting of intravenous fluorouracil (2600 mg/m²), leucovorin (200 mg/m²), oxaliplatin (85 mg/m²) and docetaxel (50 mg/m²). Response evaluation by CT-scan will be performed 4–6 weeks after completion of FLOT. In case of regression or stable disease according to RECIST criteria (v.1.1), patients will receive additional CROSS, consisting of five weekly cycles of intravenous carboplatin (AUC 2) and paclitaxel (50 mg/m²), with concurrent 41.4 Gy radiotherapy, in 23 daily fractions of 1.8 Gy [2]. Response evaluation by endoscopy with biopsies, endoscopic ultrasonography and CT-scan will be performed 4–6 weeks after completion of CROSS. Primary endpoint is tolerability of FLOT-CROSS, defined as the proportion of patients who complete the full regimen. Secondary endpoints include disease control rate, objective response rate, overall survival and progression-free survival. In total, 20 patients will be included. If patients are able to complete and tolerate FLOT-CROSS, this regimen should be tested in a phase-III trial and as neoadjuvant treatment in patients with locally advanced non-metastatic esophageal or junctional adenocarcinoma.

Background: Although several oesophageal squamous cell carcinoma (OSCC) studies have reported no definitive overall survival (OS) differences between neoadjuvant chemoradiotherapy (NACRT) and neoadjuvant chemotherapy (NAC), the higher pCR rate with NACRT has been viewed as a potential advantage. Beyond ongoing concerns about the validity of pCR as a surrogate endpoint, it remains uncertain whether survival differs between these modalities among patients with OSCC who achieve pCR. Methods: An integrated analysis of individual patient data (IPD) from phase III trials evaluating perioperative therapies for resectable OSCC was conducted, emphasizing prognostic differences between NAC and NACRT, particularly among patients who achieved pCR. Results: IPD from seven phase III RCTs across six countries included data for 1044 patients with OSCC (83.5% male; mean age of 62.3 years). Of these patients, 605 (58.0%) received NAC and 439 (42.0%) received NACRT, with R0 resection rates of 89.6% versus 84.7% and pCR rates of 6.9% versus 34.2% respectively. Among patients who achieved pCR (192 patients), 5-year OS was 97.5% in the NAC group and 70.4% in the NACRT group, while 5-year recurrence-free survival was 80.8% and 63.7% respectively. Multivariable analysis demonstrated a significant survival advantage for NAC among patients who achieved pCR. Conclusion: Among patients who achieved pCR, postoperative outcomes varied considerably by neoadjuvant treatment modality. The markedly favourable prognosis associated with pCR after NAC suggests that these patients may represent an optimal candidate cohort for future evaluation of surgery-avoidance and watch-and-wait strategies.