Neoadjuvant Immuno-Chemotherapy Versus Neoadjuvant Chemoradiotherapy in Locally Advanced Oesophageal Squamous Cell Carcinoma.

Background Neoadjuvant chemoradiotherapy (NACRT) using the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) protocol has improved esophageal cancer outcomes. This study reports the real-world experience of the CROSS regimen for esophageal squamous cell carcinoma (ESCC) regarding its feasibility, safety, and predictors of treatment completion from an Indian tertiary center. Methodology A retrospective review was conducted for patients with ESCC receiving CROSS (radiation dose: 41.4 Gy) or a modified CROSS (mCROSS; radiation dose: 45 Gy) protocol NACRT between 2015 and 2022. We studied the treatment tolerability, factors predicting NACRT completion, and the effect of completion of its chemotherapy component on the pathological outcomes. Results Of the109 patients (68.8% males; mean age, 56 ± 9 years; Charlson's comorbidity index [CCI] >2, 19.3%; stage III–IVA, 58%; mean tumor length, 5.5 ± 2.1cm; CROSS, 70.6%; mCROSS, 29.4%), all except 4 completed radiotherapy but only 58 (53.2%) patients completed ≥4 cycles of chemotherapy. Forty-nine patients belonged to the “extended” CROSS trial inclusion criteria. Among the 60 patients who fulfilled the CROSS inclusion criteria, only 51.7% were able to complete ≥4 chemotherapy cycles. The commonest reason for noncompletion of chemotherapy was the occurrence of neutropenia (60.8%). Pretreatment hemoglobin (≥12 vs. <12 g%; odds ratio [OR]: 2.76; 95% confidence interval [CI]: 1.10–6.96; p = 0.031), a low CCI (≤2 vs. >2; OR: 2.98; 95% CI: 1.02–8.73; p = 0.047), and radiation therapy techniques (conformal vs. conventional; OR: 3.29; 95% CI: 1.14–9.50; p = 0.028) were associated with completion of chemotherapy (≥4 cycles). Although there was a trend toward improved R0 resection (95.7 vs. 91.4%), reduced node positivity (17.0 vs. 31.4%), and a high pCR (57.4 vs. 48.6%) in patients completing chemotherapy (≥4 cycles) compared with those not completing chemotherapy (<4 cycles), these differences were statistically nonsignificant. Conclusion In this study, ESCC patients receiving the CROSS protocol NACRT could complete their radiotherapy component, but a significant proportion exhibited poor chemotherapy tolerance. Neutropenia was a major factor limiting chemotherapy delivery, but anemia, high CCI, and conventional radiation techniques were also associated with noncompletion of chemotherapy. The omission of a few chemotherapy cycles had no significant effect on the pathological response; however, its impact on cancer survival requires further evaluation.

Background and aim 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.

After the ESOPEC trial showed a survival benefit for fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT)-treated adenocarcinomas of the esophagus (EAC) and the gastroesophageal junction (GEJ) compared with Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS), a European, high-volume center study for stage cT2cN0 EAC and GEJ was undertaken, as it has been published that a third of these patients are understaged and could benefit from a multimodal approach PATIENTS AND METHODS: Retrospective analysis of prospective databases from ten high-volume European centers was performed. Inclusion criteria were GEJ Siewert type I/II or EAC with cT2cN0 status at diagnosis undergoing multimodal treatment with FLOT or CROSS. Primary endpoint was overall survival (OS) RESULTS: Between 2012 and 2023, 133 patients met the inclusion criteria, of whom 73 (54.9%) received CROSS and 60 (45.1%) underwent treatment with FLOT. In both groups, patients were mainly male (p = 0.08), older than 70 years (p = 0.24), and had American Society of Anesthesiologists (ASA) II classification (p = 0.45). Regarding surgical treatment, more patients underwent gastrectomy in the FLOT than in the CROSS cohort (23.3% versus 6.8%, p = 0.007). There were no differences regarding pT, pN, and pM category (p > 0.05). Median survival was not reached, while mean survival was 74.6 months (95% CI 60.5-88.7 months) for CROSS versus 100.8 months (95% CI 72.5-94.5 months, p = 0.028) for FLOT. The 3-year survival was 87% in the FLOT group versus 59% in the CROSS group. In multivariable analyses, FLOT was independent factor for survival (p < 0.001) CONCLUSIONS: For cT2cN0 staged EAC and GEJ type I /II patients FLOT chemotherapy showed a survival benefit and should be the preferred treatment in a multimodal approach.

Introduction: Treatment of oesophageal (OC), gastro-oesophageal junction (GOJ), and gastric cancer (GC) includes either neoadjuvant Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) for OC or GOJ or perioperative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for OC, GOJ, and GC adenocarcinomas. This study aims to describe the real-world outcomes of patients with GC, GOJ, and OC treated with FLOT or CROSS and identify variables associated with efficacy through exploratory analysis. We also aimed to evaluate the comparison of FLOT and CROSS for the treatment of OC and GOJ adenocarcinomas. Methods: This is a retrospective observational study of patients with locally advanced OC, GOJ, or GC treated with FLOT or CROSS between January 2015 and June 2021 in 5 cancer centres across Sydney, Australia. Long-rank test was used to compare survival estimated between subgroups. Hazard ratios for univariate and multivariate analyses were estimated with Cox proportional regression. Results: The study included 168 patients. The 24-month relapse-free survival (RFS) and overall survival (OS) for FLOT were 59% and 69%, respectively. The median RFS was 29.6 months and median OS was not reached. For CROSS, the 24-month RFS and OS were 55% and 63% with a median RFS and OS of 28.5 and 40.2 months, respectively. There was no difference in OS and RFS between the treatments. FLOT was less tolerable than CROSS with more dose reductions, treatment discontinuation, and clinically relevant grade 3 and 4 toxicity. Neutrophil lymphocyte ratio was associated with survival for both treatments. Conclusion: Similar efficacy outcomes were seen in this real-world population compared to the clinical trials for FLOT and CROSS.

BackgroundPatients with curable esophageal cancer (EC) who proceed beyond the original Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) eligibility criteria are also treated with neoadjuvant chemoradiotherapy (nCRT). This study assessed the effect that extending the CROSS eligibility criteria for nCRT has on treatment-related toxicity and overall survival (OS) in EC.MethodsThe study enrolled 161 patients with locally advanced EC (T1N1-3/T2-4aN0-3/M0) treated with the CROSS schedule followed by esophagectomy. Group 1 consisted of 89 patients who met the CROSS criteria, and group 2 consisted of 72 patients who met the extended eligibility criteria, i.e. a tumor length greater than 8 cm (n = 24), more than 10% weight loss (n = 35), more than 2–4 cm extension in the stomach (n = 21), celiac lymph node metastasis (n = 13), and/or age over 75 years (n = 2). The study assessed the differences in nCRT-associated toxicity [National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3] and 90-day postoperative mortality. Moreover, the prognostic value for OS was assessed with multivariate Cox regression analysis.ResultsNo difference was found in nCRT-associated toxicity (P = 0.117), postoperative complications (P = 0.783), and 90-day mortality (P = 0.492). The OS differed significantly (P = 0.004), with a median of 37.3 months [95% confidence interval (CI), 10.4–64.2 months] for group 1 and 17.2 months (95% CI 13.8–20.7 months) for group 2. Pathologic N stage (P = 0.023), pathologic T stage (P = 0.043), and group 2 (P = 0.008) were independent prognostic factors for OS.ConclusionsExtension of the CROSS study eligibility criteria for nCRT did not affect nCRT-associated toxicity, postoperative complications, and postoperative mortality, but was prognostic for OS.

In their correspondence, Beatty and Laking recognized the statistically significant added survival benefit of preoperative chemoradiotherapy compared with strict surgical resection makes it the treatment of choice in patients who are suitable candidates for surgery, as reported in the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS). The study did not aim to analyze cost-effectiveness, nor did it include economic end points, and therefore the claim to deny CROSS its landmark findings because of the cost of radiation therapy is irrelevant. This study did not address a third arm of preoperative chemotherapy alone; therefore, drawing conclusions across other clinical trials is to be absolutely avoided. Previously, the Radiation Therapy Oncology Group (RTOG) study 85-01 demonstrated that definitive chemoradiotherapy was superior to radiation therapy alone with improved median and overall survival. For medically fit patients, with tumors invading at least the submucosa or with involved lymph nodes, the most common approach, which until now remained investigational, is multimodality preoperative chemoradiotherapy. The prospective CROSS trial, the largest in its class, demonstratedalmostdoublingofmediansurvivalwhenchemoradiotherapywas delivered before surgery. We do recognize that, on the basis of patients’ morbidityandavailablehealthresources,othermodalitiesmaybeacceptable. Future identification of molecular predictors might shed more light on identifying patients who are suitable for each modality.

BackgroundA standard of care for nonmetastatic esophageal cancer is trimodality therapy consisting of neoadjuvant chemoradiation and esophagectomy, with evidence for improved overall survival versus surgery alone in the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial. Patients who receive treatment with curative intent but are poor candidates for or decline surgery receive definitive bimodality therapy. Literature characterizing patients who receive bimodality therapy compared to trimodality therapy, and their relative outcomes, is sparse, especially among patients who are too old or too frail to qualify for clinical trials. In this study, we assess a single-institution real-world dataset of patients receiving bimodality and trimodality management.MethodsPatients treated for clinically resectable, nonmetastatic esophageal cancer between 2009 and 2019 who received bimodality or trimodality therapy were reviewed, generating a dataset of 95 patients. Clinical variables and patient characteristics were assessed for association with modality on multivariable logistic regression. Overall, relapse-free, and disease-free survival were assessed with Kaplan-Meier analyses and Cox proportional modeling. For patients nonadherent to planned esophagectomy, reasons for nonadherence were recorded.ResultsBimodality therapy was associated with greater age-adjusted comorbidity index, worse performance status, higher N-stage, presenting symptom other than dysphagia, and held chemotherapy cycles on multivariable analysis. Compared to bimodality therapy, trimodality therapy was associated with higher overall (3-year: 62% vs. 18%, P<0.001), relapse-free (3-year: 71% vs. 18%, P<0.001), and disease-free (3-year: 58% vs. 12%, P<0.001) survival. Similar results were observed among patients who did not meet CROSS trial qualifying criteria. Only treatment modality was associated with overall survival after adjusting for covariates (HR 0.37, P<0.001, reference group: bimodality). Patient choice accounted for 40% of surgery nonadherence in our population.ConclusionsPatients receiving trimodality therapy were observed to have superior overall survival compared to bimodality therapy. Patient preference for organ-preserving therapies appears to impact resection rate; further characterization of patient decision-making may be helpful. Our results suggest patients who wish to prioritize overall survival should be encouraged to pursue trimodality therapy and obtain early consultation with surgery. Development of evidence-based interventions to physiologically prepare patients before and during neoadjuvant therapy as well as efforts to optimize the tolerability of the chemoradiation plan are warranted.

For many years, oncologists have held the view that “radiation improves local control, but not survival.” Although this perspective is fairly common, it is not always accurate and does not recognize a more nuanced interplay between local control, systemic control, and cure. Solid tumors cannot be cured without achieving local control of the primary malignancy, and thus local control is a critical component of tumor cure. A more nuanced statement that could be true might be the following: “When surgery provides good local control, the local control advantage provided by radiation may not lead to a statistically significant survival advantage if the competing risk of distant metastases is very high or very low.” Radiation therapy also might not improve survival if systemic chemotherapy improved local control without radiation, or if salvage surgery were effective and local recurrence did not increase the risk of distant metastases. It is worth considering the relationship between local control and survival in several solid tumors. The initial randomized trials demonstrating the benefit of radiation in breast cancer suggested that irradiating the breast after lumpectomy, or the chest wall after mastectomy, improved local control but did not affect survival. The lack of a survival benefit, however, may have been attributable to a relatively small number of deaths in these studies. In fact, meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group suggest that improved local control does lead to improved cancer-specific and overall survival. In gastric cancer, the North American standard of care was established by Intergroup-0116, in which patients were randomly assigned to surgery alone versus surgery followed by adjuvant chemotherapy and radiation. In this study, the reduction in local and regional recurrences, from 47% to 24%, correlated closely with the improvement in overall survival, and the rate of distant metastases was similar in both arms. In fact, the observation that improved survival appeared attributable mainly to improved local control was the impetus for the successor Intergroup trial, CALGB 80101, which sought to further improve survival by more aggressively addressing the risk of distant metastases. Rectal cancer is a disease in which we frequently hear that radiation improves local control without affecting survival. Although there certainly are data that are consistent with this view, the totality of the data is more ambiguous. The results of NSABP R-02, for example, do support the hypothesis that radiation can improve local control without a survival benefit. In this trial, patients who underwent surgery for locally advanced rectal cancer were randomly assigned to postoperative chemotherapy or postoperative chemoradiotherapy. Patients who received radiation had a statistically significant improvement in local control without an improvement in disease-free or overall survival. However, not all rectal cancer studies have come to the same conclusion. The Swedish Rectal Cancer trial, in which patients were randomly assigned to surgery alone versus preoperative short course radiation, showed statistically significant improvements in local control, cancer-specific survival, and overall survival in the irradiated patients. Conversely, EORTC 22921, a 1,000-patient study using a 2 2 design testing both preand postoperative chemotherapy and radiation, failed to demonstrate a statistically significant survival benefit in patients who received adjuvant chemotherapy. Perhaps most significant is GITSG 7175, a four-arm trial in which patients were randomly assigned to surgery alone, adjuvant chemotherapy, adjuvant radiation therapy, or adjuvant chemotherapy and radiation. This trial established the benefit of adjuvant therapy for rectal cancer and was thus the last large US phase III trial to contain a surgery-alone arm. In this study, both radiation and chemotherapy provided similar magnitude, nonsignificant benefits in disease-free survival, whereas only the combined chemoradiation arm resulted in a statistically significant improvement compared with surgery alone. The mechanisms behind the synergistic effect of combining chemotherapy and radiation have been well documented, as reviewed by Seiwert et al. Clinical trials in many types of solid tumors have confirmed that concurrent administration of chemotherapy and radiation leads to a better outcome than sequential administration, or using either modality alone. Examples include non–small-cell lung cancer, cervical cancer, head and neck cancer, and anal cancer. Thus, understanding the patterns of failure can help us understand ways in which we can both improve tumor control and decrease morbidity. In esophageal cancer, the trials comparing neoadjuvant chemoradiotherapy with surgery alone have had mixed results. Although some demonstrated a benefit, most showed a nonsignificant trend in favor of neoadjuvant therapy, though recent meta-analyses have consistently favored the use of neoadjuvant therapy. Most recently, the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) demonstrated that preoperative carboplatin and paclitaxel with concurrent radiation is an extremely well-tolerated regimen with a higher rate of R0 resections (92% v 69%) and improved JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 5 FEBRUARY 1

Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent (P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.

Trimodality therapy using the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial protocol is an accepted standard of care for locally advanced oesophageal and gastroesophageal junction cancers. For medically inoperable patients, chemoradiotherapy (CRT) has been a therapeutic option. This single institution review aimed to assess the real-world application of the CROSS trial protocol. This is a retrospective review of 83 patients who underwent CRT with carboplatin and paclitaxel with trimodality or definitive intent between June 2012 and June 2018. Sixty-five patients underwent neoadjuvant CRT (NCRT); 40 had surgery, 18 had definitive CRT (DCRT). Patients' demographics, clinical, pathological, treatment and surgical characteristics were assessed. The data were analysed in exploratory analyses and Kaplan-Meier curves. For 83 patients, the following median values were seen: radiotherapy dose, 50.4 Gy; chemotherapy doses, 5; and time from CRT to surgery, 62 days. Twenty-three percent NCRT and 72% DCRT patients were aged ≥75 years, and 49% and 33% of these respectively had no interruptions to CRT. Patients aged ≥75 years were more likely to have DCRT (P = 0.001). Patients who underwent surgery were younger (P = 0.04). For NCRT and surgery, NCRT only and DCRT respectively, median overall survival was 35.5, 12.1 and 17.1 months (log rank P = 0.008); progression-free survival was 32.2, 10 and 9.6 months (log rank P = 0.001). Despite broadening of the CROSS trial eligibility criteria in our real-world data, there appears to be a survival benefit with trimodality therapy. The use of carboplatin and paclitaxel in DCRT may be of value and requires further study.

1232P CROSS protocol for esophageal cancer in India: Reality or pipe dream?

Trimodal therapy consisting of neoadjuvant chemoradiation followed by esophagectomy has become the standard of care in North America for locally advanced esophageal cancer. While cisplatin/5-fluorouracil has been a common concurrent chemotherapy regimen since the 1980s, its utilization has declined in recent years as the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) trial regimen of carboplatin/paclitaxel has become widely adopted. The efficacy of the CROSS regimen compared to alternate chemotherapy choices, however, has rarely been evaluated when each is used as a component of a trimodal treatment approach. The aim of this study is to report our institutional experience with these two concurrent chemotherapy regimens at a specialized esophageal cancer center.We performed an Institutional Review Board-approved retrospective review of a prospectively maintained institutional foregut registry from a single National Cancer Institute-designated cancer center. Esophageal cancer patients who completed trimodal therapy with a chemotherapy regimen of either carboplatin/paclitaxel or cisplatin/5-fluorouracil were identified and divided into groups based on their chemotherapy regimens. Multivariable logistic regression was used to analyze pathologic complete response rates, while the Kaplan-Meier and Cox proportional hazards models were utilized to evaluate recurrence-free and overall survival. Analytical models were adjusted for age, clinical stage, radiation dose, histologic subtype (adenocarcinoma vs. squamous cell carcinoma), and time interval from completion of neoadjuvant therapy to surgery.One hundred and forty-two patients treated between January of 2000 and July of 2015 were identified as meeting inclusion criteria. Of this group, 87 had received the CROSS regimen of carboplatin/paclitaxel, while 55 had completed cisplatin/5-fluorouracil. Multivariable analysis demonstrated that the cisplatin/5-fluorouracil.group had an increased odds of pathologic complete response (odds ratio = 2.68, 95% confidence interval, P = 0.032), as well as significantly improved recurrence-free survival (hazard ratio = 0.39, 95% confidence interval 0.21-0.73, P = 0.003) and overall survival (hazard ratio = 0.46, 95% confidence interval 0.24-0.87, P = 0.016), compared to the carboplatin/paclitaxel group.Concurrent chemotherapy with cisplatin/5-fluorouracil in locally advanced esophageal cancer is associated with higher rates of pathologic complete response and improved recurrence-free and overall survival compared to the CROSS regimen of carboplatin/paclitaxel. This suggests that, for select patients, alternate neoadjuvant chemotherapy approaches, such as cisplatin/5-fluorouracil, merit reconsideration as potential primary treatment choices in the management of this highly morbid disease.

Despite improvement in surgical results after esophagectomy, the long-term prognosis of patients with esophageal carcinoma remains suboptimal. With emergence of multimodality treatment strategies in recent decades, various regimens of neoadjuvant therapy have become commonplace. The Dutch Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) trial was first published in 2012 and recently updated with its long-term results. It was a randomized controlled trial that involved 368 patients including both adenocarcinoma and squamous cell carcinoma of the esophagus and gastroesophageal junction. Patients were randomized into either surgery alone group (188 patients) or chemoradiotherapy (weekly administration of carboplatin and paclitaxel with concurrent radiotherapy 41.4 Gy) followed by surgery (171 patients).

Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial

Oesophageal adenocarcinomas may show different histopathological patterns, including excessive acellular mucin pools, signet‐ring cells (SRCs), and poorly cohesive cells (PCCs). These components have been suggested to correlate with poor outcomes after neoadjuvant chemoradiotherapy (nCRT), which might influence patient management. However, these factors have not been studied independently of each other with adjustment for tumour differentiation grade (i.e. the presence of well‐formed glands), which is a possible confounder. We studied the pre‐ and post‐treatment presence of extracellular mucin, SRCs, and/or PCCs in relation to pathological response and prognosis after nCRT in patients with oesophageal or oesophagogastric junction adenocarcinoma. A total of 325 patients were retrospectively identified from institutional databases of two university hospitals. All patients were scheduled for ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) nCRT and oesophagectomy between 2001 and 2019. Percentages of well‐formed glands, extracellular mucin, SRCs, and PCCs were scored in pre‐treatment biopsies and post‐treatment resection specimens. The association between histopathological factors (≥1 and >10%) and tumour regression grade 3–4 (i.e. >10% residual tumour), overall survival, and disease‐free survival (DFS) was evaluated, adjusted for tumour differentiation grade amongst other clinicopathological variables. In pre‐treatment biopsies, ≥1% extracellular mucin was present in 66 of 325 patients (20%); ≥1% SRCs in 43 of 325 (13%), and ≥1% PCCs in 126 of 325 (39%). We show that pre‐treatment histopathological factors were unrelated to tumour regression grade. Pre‐treatment presence of >10% PCCs was associated with lower DFS (hazard ratio [HR] 1.73, 95% CI 1.19–2.53). Patients with post‐treatment presence of ≥1% SRCs had higher risk of death (HR 1.81, 95% CI 1.10–2.99). In conclusion, pre‐treatment presence of extracellular mucin, SRCs, and/or PCCs is unrelated to pathological response. The presence of these factors should not be an argument to refrain from CROSS. At least 10% PCCs pre‐treatment and any SRCs post‐treatment, irrespective of the tumour differentiation grade, seem indicative of inferior prognosis, but require further validation in larger cohorts.