Management of rectal cancer in the era of total neoadjuvant therapy and watch and wait: A multidisciplinary team discussion at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting 2022.

Rectal cancer is a common malignancy. The management of rectal cancer has recently evolved and has undergone a paradigm shift with the advent of treatment approaches such as total neoadjuvant therapy and the watch-and-wait approach. However, despite the recently available evidence, there is no consensus on the optimal management approach in the setting of locally advanced rectal cancer. To address some of the controversies, a joint multidisciplinary panel discussion was conducted at the Australasian Gastro-Intestinal Trials Group (AGITG) Annual Scientific Meeting in November 2022. Members from different subspecialties formed two panels and discussed three clinical cases in a debate format. Each case represented some of the complex issues faced by clinicians in this setting. The discussion is now presented in this manuscript, which depicts the different available management approaches and reiterates the importance of a multidisciplinary approach.

Pathologic Lymph Node Regression After Neoadjuvant Chemotherapy Predicts Recurrence and Survival in Esophageal Adenocarcinoma: A Multicenter Study in the United Kingdom.

PURPOSE: There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma. METHODS: Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index. RESULTS: In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). CONCLUSION: Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.

Emerging targets in gastroesophageal adenocarcinoma: what the future looks like.

Gastroesophageal adenocarcinoma (GEA) is a heterogeneous disease with a poor prognosis. Chemotherapy has been the cornerstone in treating metastatic diseases. Recently, the introduction of immunotherapy demonstrated improved survival outcomes in localized and metastatic diseases. Beyond immunotherapy, several attempts were made to improve patient survival by understanding the molecular mechanisms of GEA and several molecular classifications were published. In this narrative review, we will discuss emerging targets in GEA, including fibroblast growth factor receptor and Claudin 18.2, as well as the accompanying drugs. In addition, novel agents directed against well-known targets, such as HER2 and angiogenesis, will be discussed, as well as cellular therapies like CAR-T and SPEAR-T cells.

Study protocol for the OligoMetastatic Esophagogastric Cancer (OMEC) project: A multidisciplinary European consensus project on the definition and treatment for oligometastatic esophagogastric cancer.

BACKGROUND: A uniform definition and treatment for oligometastatic esophagogastric cancer is currently lacking. However, a comprehensive definition of oligometastatic esophagogastric cancer is necessary to initiate studies on local treatment strategies (e.g. metastasectomy or stereotactic radiotherapy) and new systemic therapy agents in this group of patients. For this purpose, the OligoMetastatic Esophagogastric Cancer (OMEC) project was established. The OMEC-project aims to develop a multidisciplinary European consensus statement on the definition, diagnosis, and treatment for oligometastatic esophagogastric cancer and provide a framework for prospective studies to improve outcomes of these patients. METHODS: The OMEC-project consists of five studies, including 1) a systematic review on definitions and outcomes of oligometastatic esophagogastric cancer; 2) real-life clinical scenario discussions in multidisciplinary expert teams to determine the variation in the definition and treatment strategies; 3) Delphi consensus process through a starting meeting, two Delphi questionnaire rounds, and a consensus meeting; 4) publication of a multidisciplinary European consensus statement; and 5) a prospective clinical trial in patients with oligometastatic esophagogastric cancer. DISCUSSION: The OMEC project aims to establish a multidisciplinary European consensus statement for oligometastatic esophagogastric cancer and aims to initiate a prospective clinical trial to improve outcomes for these patients. Recommendations from OMEC can be used to update the relevant guidelines on treatment for patients with (oligometastatic) esophagogastric cancer.

Imaging standardisation in metastatic colorectal cancer: A joint EORTC-ESOI-ESGAR expert consensus recommendation.

BACKGROUND: Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on reporting and interpretation of imaging findings yet offer no guidance on a standardised imaging protocol tailored to patients with mCRC. Imaging protocol heterogeneity remains a challenge for the reproducibility of conventional imaging end-points and is an obstacle for research on novel imaging end-points. PATIENTS AND METHODS: Acknowledging the recently highlighted potential of radiomics and artificial intelligence tools as decision support for patient care in mCRC, a multidisciplinary, international and expert panel of imaging specialists was formed to find consensus on mCRC imaging protocols using the Delphi method. RESULTS: Under the guidance of the European Organisation for Research and Treatment of Cancer (EORTC) Imaging and Gastrointestinal Tract Cancer Groups, the European Society of Oncologic Imaging (ESOI) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the EORTC-ESOI-ESGAR core imaging protocol was identified. CONCLUSION: This consensus protocol attempts to promote standardisation and to diminish variations in patient preparation, scan acquisition and scan reconstruction. We anticipate that this standardisation will increase reproducibility of radiomics and artificial intelligence studies and serve as a catalyst for future research on imaging end-points. For ongoing and future mCRC trials, we encourage principal investigators to support the dissemination of these imaging standards across recruiting centres.

Mind the target: programmed death ligand 1 in oesophagogastric cancers.

PURPOSE OF REVIEW: Metastatic oesophagogastric cancers carry a prognosis of generally less than 2 years despite current treatment. There has been recent excitement in the field focused on immune checkpoint inhibition though anti-PD-1 antibodies. In this article, we review recent phase 3 clinical trials evaluating first line PD-L1 inhibition in metastatic HER-2-negative oesophagogastric cancers and discuss future questions and challenges in the field. RECENT FINDINGS: Prior studies have shown promise using PD-L1 inhibition as third and fourth line treatment but recent phase 3 clinical trials have shown clear benefit to overall survival as first line treatment. PD-L1 inhibition as monotherapy demonstrated earlier death rates but there are a subset of patients with a long-term durable benefit when compared with chemotherapy. PD-L1 inhibition when combined with chemotherapy showed benefit in overall survival and progression-free survival and is enhanced in subsets of patients with increased PD-L1 expression. SUMMARY: Although there are still open questions how best to assess PD-L1 status, these studies provide clear evidence for use of PD-L1 inhibition combined with cytotoxic chemotherapy as first-line treatment in metastatic or unresectable oesophagogastric cancers that express PD-L1. In addition, they lay the groundwork for future studies evaluating PD-1 inhibition in earlier stages of disease.

A systematic review and meta-analysis assessing the impact of body mass index on long-term survival outcomes after surgery for colorectal cancer.

BACKGROUND: The impact of body mass index (BMI) on long-term survival outcomes after colorectal cancer surgery is debated. DESIGN: A systematic literature review and meta-analysis was performed to compare long-term survival outcomes of patients of different BMI categories after colorectal cancer surgery. RESULTS: Of the 2588 articles screened, 56 articles met the inclusion criteria, reporting on 72,582 participants. Patients with BMI <18.5 had significantly worse overall survival [hazard ratio (HR) 1.91; P < 0.0001], cancer-specific survival (HR = 1.91; P < 0.0001), disease-free survival (HR = 1.50; P < 0.0001) and recurrence-free survival (HR = 1.13; P = 0.007) compared to patients with a BMI of 18.5-25. There was no significant difference between those with BMI 25-30 and 18.5-25 in overall survival, cancer-specific survival, disease-free survival and recurrence-free survival, except for the subgroup of patients with colon cancer where patients with BMI 25-30 had significantly improved overall survival (HR = 0.90; P = 0.05) and disease-free survival (HR = 0.90; P = 0.04). Patients with BMI >30 had significantly worse disease-free survival (HR = 1.05; P = 0.03) compared to patients with a BMI of 18.5-25, but no significant difference in overall survival, cancer-specific survival and recurrence-free survival. Patients with BMI >35 compared to 18.5-25 had significantly worse overall survival (HR = 1.24; P = 0.02), cancer-specific survival (HR = 1.36; P = 0.01), disease-free survival (HR = 1.15; P = 0.03) and recurrence-free survival for colon (HR = 1.11; P = 0.04) and rectal (HR = 4.10; P = 0.04) cancer. CONCLUSIONS: Being underweight (BMI < 18.5) or class II/III obese (BMI > 35) at the time of colorectal cancer surgery may result in worse long-term survival outcomes, whereas being overweight (BMI 25-30) may improve survival in a subgroup of patients with colon cancer. Optimising BMI may preoperatively improve long-term survival after surgery for colorectal cancer.

Immunotherapy for Squamous Esophageal Cancer: A Review.

Esophageal squamous cell carcinoma (ESCC) is a rare gastrointestinal tumour with high mortality. A multimodality treatment based on chemoradiotherapy followed by surgery is the standard of care in the case of non-metastatic disease; chemotherapy has historically been the gold standard in the metastatic setting. However, the rate of relapse after curative treatment is high and the prognosis of ESCC is poor. In this context, immunotherapy is a novel and intriguing chance to improve survival. Therefore, in this narrative review, we depict the current scenario in the field of immunotherapy for ESCC according to the stage of disease and alongside the discussion of promising biomarkers and future perspectives. The Checkmate-577 trial showed that nivolumab is the best option as adjuvant treatment in patients with non-metastatic ESCC and residual disease after a multimodality approach. In the metastatic setting, nivolumab, pembrolizumab, camrelizumab, sintilimab and toripalimab improved survival outcomes as a first-line treatment in addition to chemotherapy. In the second-line, nivolumab, pembrolizumab, camrelizumab and tislelizumab showed positive results, with differences according to the subgroups, agents and study population included in the trials. Then, the finding of valid molecular biomarkers is crucial in selecting patients for immunotherapy.

Combination immune checkpoint blockade in advanced untreated gastroesophageal adenocarcinoma: Seeking biomarkers for durable benefit.

The CheckMate 649 trial, recently published in Nature, established chemotherapy plus nivolumab as a standard in advanced, treatment-naive gastroesophageal adenocarcinoma, with best results seen in patients with high PD-L1 expression and microsatellite unstable tumors. In contrast, nivolumab plus ipilimumab, compared with chemotherapy, showed early progression and no overall survival benefit.

Immunotherapy in Gastro-Oesophageal Cancer: Current Practice and the Future of Personalised Therapy.

Initial studies of immune checkpoint inhibitors in biomarker unselected gastro-oesophageal cancer yielded limited improvement in survival. However, emerging data from recent clinical trials suggest immunotherapies may offer a meaningful clinical benefit within selected populations. Gastro-oesophageal cancer is a heterogeneous disease with respect to histopathological and molecular features; hypermutation and the biology of immune checkpoint pathways are key to appropriate selection of populations most likely to benefit from immune checkpoint inhibitors. Programmed death-ligand 1 expression, typically measured using the combined positive score, is an important biomarker in determining which patients may benefit from immunotherapy agents. However, combined positive score thresholds are not standardised across trials and the benefit in programmed death-ligand 1-negative cohorts is uncertain. Data suggest that patients with tumours with microsatellite instability, high tumour mutational burden and Epstein-Barr Virus positivity are more likely to benefit from immunotherapy, which may be of importance within programmed death-ligand 1-negative populations. Here, we describe the current evidence base for the use of checkpoint inhibitors in the treatment of advanced gastro-oesophageal cancer and adjuvant treatment of high-risk oesophageal cancer, as well as the ongoing studies of immunotherapy in the treatment of patients with gastro-oesophageal cancers across an increasing range of clinical settings.

Low Programmed Death-Ligand 1-Expressing Subgroup Outcomes of First-Line Immune Checkpoint Inhibitors in Gastric or Esophageal Adenocarcinoma.

PURPOSE: The US Food and Drug Administration has granted regulatory approval for the use of nivolumab-an immune checkpoint inhibitor (ICI)-in the first-line treatment of advanced gastric or esophageal adenocarcinoma (GEAC), regardless of programmed death-ligand 1 (PD-L1) expression. However, the efficacy of ICIs in low PD-L1-expressing tumors remains unclear. MATERIALS AND METHODS: This study aims to reconstruct unreported Kaplan-Meier (KM) plots of PD-L1 combined positive score (CPS) subgroups of randomized phase III trials comparing the addition of ICIs with conventional chemotherapy in the first-line treatment of GEAC. A graphical reconstructive algorithm was adopted to estimate time-to-event outcomes from reported overall survival and progression-free survival (OS and PFS) KM plots describing overall or subgroup cohorts. Using reconstructed time-to-event outcomes, KMSubtraction conducts bipartite matching of patients from the reported subgroup among the overall cohort. By excluding matched patients, KM plots and survival analyses of the unreported subgroups were retrieved. RESULTS: CheckMate-649, KEYNOTE-062, and KEYNOTE-590 were included. Two PD-L1 subgroups were identified with data unreported in the primary manuscripts: PD-L1 CPS 1-4 from CheckMate-649 and PD-L1 CPS 1-9 from KEYNOTE-062. No significant differences in OS and PFS were demonstrated in ICI-chemotherapy combinations when compared with chemotherapy among CheckMate-649 PD-L1 CPS 1-4 (OS: hazard ratio [HR] = 0.950, 95% CI, 0.747 to 1.209, P = .678; PFS: HR = 0.958, 95% CI, 0.743 to 1.236, P = .743) and KEYNOTE-062 PD-L1 CPS 1-9 subgroups. In the KEYNOTE-062 PD-L1 CPS 1-9 subgroup, patients treated with pembrolizumab had an increased hazard of tumor progression (HR = 2.092, 95% CI, 1.661 to 2.635, P < .001). CONCLUSION: Using KMSubtraction, data of PD-L1 subgroups previously unreported by primary manuscripts of pivotal clinical trials were retrieved. These data suggest the lack of benefit in the addition of ICI to chemotherapy in low PD-L1-expressing GEAC tumors.

Early-Onset Colorectal Adenocarcinoma in the IDEA Database: Treatment Adherence, Toxicities, and Outcomes With 3 and 6 Months of Adjuvant Fluoropyrimidine and Oxaliplatin.

PURPOSE: Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years). MATERIALS AND METHODS: Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non-cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered. RESULTS: Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% v 80%, P < .01), similar T stage (% T1-3/T4: 76/24 v 77/23, P = .97), higher N2 disease rate (24% v 22%, P < .01), more likely to complete the planned treatment duration (83.2% v 78.2%, P < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% v 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; P value < .001) and higher 5-year cancer-specific mortality rate (24% v 20%; HR 1.21; 95% CI, 1.00 to 1.47; P value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% v 56%; HR 0.97; 95% CI, 0.73 to 1.29; P value = .85). CONCLUSION: Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology.