From twilight to starlight? Debating the role of chemoradiotherapy in gastric cancer in the D2 dissection era.

Patients affected by resectable locally advanced gastric cancer (GC) should receive perioperative chemotherapy as a standard of care. However, an additional benefit of adjuvant chemoradiation (CRT) has been negated by modern trials in the era of extended surgical dissection, and CRT is currently only considered on an individual basis in case of suboptimal resection. However, the dismal prognosis of GC and the modest treatment completion rates of perioperative chemotherapy have pushed to reconsider CRT, particularly as a preoperative treatment, in light of modern treatment techniques, advances in the understanding of the immune landscape and development of targeted agents. The aim of this review is to critically assess the historical role of CRT, the limitations of current evidence and to debate its potential role in an integrated neoadjuvant strategy for patients with resectable GC.

Histopathological response to chemotherapy and survival of mucinous type gastric cancer.

BACKGROUND: Data on the clinicopathological characteristics of mucinous gastric cancer (muc-GC) are limited. This study compares the clinical outcome and response to chemotherapy between patients with resectable muc-GC, intestinal (int-GC) and diffuse (dif-GC) gastric cancer. METHODS: Patients from the D1/D2 study or the CRITICS trial were included in exploratory surgery-alone (SAtest) or chemotherapy test (CTtest) cohorts. Real-world data from the Netherlands Cancer Registry on patients treated between with surgery-alone (SAvalidation), and receiving preoperative chemotherapy with or without postoperative treatment (CTvalidation) were used for validation. Histopathological subtypes were extracted from pathology reports filed in the Dutch Pathology Registry and correlated with tumor regression grade (TRG) and relative survival (RS). RESULTS: In SAtest (n = 549) and SAvalidation (n = 8062) cohorts, muc-GC patients had a five-year RS of 39% and 31%, similar to or slightly better than dif-GC (43% and 29%, p = .52 and p = .011), but worse than int-GC (55% and 42%, p = .11 and p < .001). In CTtest (n = 651) and CTvalidation (n = 2889) cohorts, muc-GC showed favorable TRG (38% and 44% (near-)complete response) compared to int-GC (26% and 35%) and dif-GC (10% and 28%, p < .001 and p = .005). The 5-year RS in CTtest and CTvalidation cohorts for muc-GC (53% and 48%) and int-GC (58% and 59%) was significantly better compared to dif-GC (35% and 38%, p = .004 and p < .001). CONCLUSION: Recognizing and incorporating muc-GC into treatment decision-making of resectable GC can lead to more personalized and effective approaches, given its favorable response to preoperative chemotherapy in relation to int-GC and dif-GC and its favorable prognostic outcomes in relation to dif-GC.

Using a modified Delphi procedure to select a PRO-CTCAE-based subset for patient-reported symptomatic toxicity monitoring in rectal cancer patients.

PURPOSE: Standardized patient-reported outcomes (PRO) monitoring during and after rectal cancer treatment provides insight into treatment-related toxicities patients experience and improves health-related quality-of-life as well as overall survival. We aimed to select a subset of the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for standardized monitoring of treatment-related symptomatic toxicities in rectal cancer. METHODS: We used a mixed methods approach including a literature review, and semi-structured interviews with health care providers (HCPs) involved in rectal cancer care and rectal cancer patients. Results from literature and interviews were summarized and used in a modified Delphi procedure to select a PRO-CTCAE subset specific for rectal cancer. RESULTS: Twenty-six PRO-CTCAE symptomatic toxicities were identified from literature. Fifteen HCPs from multiple disciplines (medical, radiation and surgical oncology), and a heterogeneous group of fifteen rectal cancer patients treated with chemotherapy and/or radiotherapy and/or surgery, participated in semi-structured interviews. Ten HCPs (67%) and nine patients (90%) participated in the first Delphi round. The final selected PRO-CTCAE core-subset contained 16 symptomatic toxicities: 'diarrhea', 'fecal incontinence', 'constipation','bloating of the abdomen', 'pain in the abdomen', 'vomiting', 'decreased libido', 'pain during vaginal sex', 'ability to achieve and maintain erection', 'fatigue', 'anxiety', 'feeling that nothing could cheer you up', 'urinary incontinence', 'painful urination', 'general pain', and 'hand-foot syndrome'. CONCLUSION: Based on a comprehensive mixed methods study, a PRO-CTCAE subset for standardized treatment-related symptomatic toxicity monitoring in rectal cancer was identified. Assessment of the effectiveness and compliance of symptomatic toxicity monitoring using this subset is recommended.

European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4)

The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

TRIP12 governs DNA Polymerase ß involvement in DNA damage response and repair.

The multitude of DNA lesion types, and the nuclear dynamic context in which they occur, present a challenge for genome integrity maintenance as this requires the engagement of different DNA repair pathways. Specific 'repair controllers' that facilitate DNA repair pathway crosstalk between double strand break (DSB) repair and base excision repair (BER), and regulate BER protein trafficking at lesion sites, have yet to be identified. We find that DNA polymerase ß (Polß), crucial for BER, is ubiquitylated in a BER complex-dependent manner by TRIP12, an E3 ligase that partners with UBR5 and restrains DSB repair signaling. Here we find that, TRIP12, but not UBR5, controls cellular levels and chromatin loading of Polß. Required for Polß foci formation, TRIP12 regulates Polß involvement after DNA damage. Notably, excessive TRIP12-mediated shuttling of Polß affects DSB formation and radiation sensitivity, underscoring its precedence for BER. We conclude that the herein discovered trafficking function at the nexus of DNA repair signaling pathways, towards Polß-directed BER, optimizes DNA repair pathway choice at complex lesion sites.

European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4).

INTRODUCTION: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). METHODS: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. RESULTS: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DISCUSSION: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

The impact of sex on treatment and outcome in relation to histological subtype in patients with resectable gastric cancer: Results from the randomized CRITICS trial.

BACKGROUND AND OBJECTIVE: This study aims to investigate the impact of sex on outcome measures stratified by histological subtype in patients with resectable gastric cancer (GC). METHODS: A post-hoc analysis of the CRITICS-trial, in which patients with resectable GC were treated with perioperative therapy, was performed. Histopathological characteristics and survival were evaluated for males and females stratified for histological subtype (intestinal/diffuse). Additionally, therapy-related toxicity and compliance were compared. RESULTS: Data from 781 patients (523 males) were available for analyses. Female sex was associated with a distal tumor localization in intestinal (p = 0.014) and diffuse tumors (p < 0.001), and younger age in diffuse GC (p = 0.035). In diffuse GC, tumor-positive resection margins were also more common in females than males (21% vs. 10%; p = 0.020), specifically at the duodenal margin. During preoperative chemotherapy, severe toxicity occurred in 327 (63%) males and 184 (71%) females (p = 0.015). Notwithstanding this, relative dose intensities were not significantly different between sexes. CONCLUSIONS: Positive distal margin rates were higher in females with diffuse GC, predominantly at the duodenal site. Females also experience more toxicity, but this neither impacts dose intensities nor surgical resection rates. Clinicians should be aware of these different surgical outcomes when treating males and females with GC.

Nationwide evaluation of pancreatic cancer networks ten years after the centralization of pancreatic surgery.

BACKGROUND: Due to centralization of pancreatic surgery, patients with pancreatic cancer are treated in pancreatic cancer networks, composed of referring hospitals (Spokes) and an expert center (Hub). This study aimed to investigate I) how pancreatic cancer networks are organized and II) evaluated by involved clinicians. METHODS: Two online surveys were sent out between January-May 2022. Part I was sent out to the surgical network directors of all hospitals of the Dutch Pancreatic Cancer Group (DPCG). Part II was sent out to all involved clinicians in the Hubs-and-Spokes networks. RESULTS: There was a large variety between the 15 networks concerning number of affiliated Spokes (1-7), annual pancreatoduodenectomies (20-129), and use of a service level agreement (SLA) (40%). More Spoke clinicians considered the Spoke the best location for diagnostic workup (74% vs 36%, P < 0.001). Only 30% of Spoke clinicians attended the Hubs multidisciplinary team meeting frequently. More Hub clinicians thought that exchange of patient information should be improved (37% vs 51%, P = 0.005). CONCLUSION: A large variety in Dutch pancreatic cancer networks was observed concerning number of affiliated Spokes, use of SLAs, and logistic aspects of network care. Improvement of network care concern agreements on diagnostic workup, use of SLA, Spoke participation in the MDT, and patient information exchange.

Incidence, Stage, Treatment, and Survival of Noncardia Gastric Cancer.

Importance: Gastric cancer is the fifth most common cancer worldwide, and investigating its incidence, characteristics, treatment, and outcomes over the past decades can help in selecting clinical strategies and future research directions. Objective: To analyze the trends in incidence, staging, and treatment of gastric cancer. Design, Setting, and Participants: This nationwide, population-based cohort study included patients diagnosed with noncardia gastric cancer (NCGC) between 1989 and 2021 in the Netherlands. Main Outcomes and Measures: Differences in tumor characteristics, treatment, and survival were analyzed per fixed time periods (1989-1993, 1994-1998, 1999-2003, 2004-2008, 2009-2013, 2014-2018, and 2019-2021). Results: In total, 47 014 patients (median [IQR] age, 73 [64-80] years; 28 032 [60%] male patients) were identified with mostly adenocarcinomas of the antrum region (when location was known). Age-standardized incidence decreased from 20.3 to 6.1 per 100 000 person-years between 1989 and 2021. During the study period, unknown T and N stages were recorded less frequently, and metastatic disease was diagnosed more frequently (1989-1993: 2633 of 9493 patients [28%]; 2019-2021: 1503 of 3200 patients [47%] in 2019-2021). Over time, fewer patients with metastatic disease underwent surgery with or without other treatment modalities (68% in 1989-1993 vs 64% in 2019-2021), and palliative chemotherapy in metastatic NCGC increased from 9% to 40%. For patients with nonmetastatic disease, 5-year relative survival improved from 28% (95% CI, 26.5%-29.2%) to 36% (95% CI, 33.5%-37.6%) between 1989 and 2021. For patients with nonmetastatic disease undergoing a resection, 5-year survival increased from 40% (95% CI, 38.3%-41.8%) to 51% (95% CI, 47.9%-53.3%). For patients with metastatic disease, 1-year relative survival increased from 10% (95% CI, 8.7%-11.1%) to 19% (95% CI, 17.2%-21.6%), but 3-year relative survival remained poor at 5% (95% CI, 3.6%-7.5%). Conclusions and Relevance: In this nationwide cohort study involving 47 014 patients diagnosed with NCGC (1989-2021), the results showed a decrease in incidence, more accurate staging, a shift in treatment modalities, and improved patient survival.

The impact of the COVID-19 pandemic on the diagnosis, stage, and treatment of esophagogastric cancer.

BACKGROUND: The COVID-19 pandemic has affected the entire global healthcare system, including oncological care. This study investigated the effects of the COVID-19 pandemic on the diagnosis, stage, and treatment of esophagogastric cancer in the Netherlands. METHODS: Patients diagnosed in 2020 were divided into 5 periods, based on the severity of the COVID-19 pandemic in the Netherlands, and compared to patients diagnosed in the same period in the years 2017-2019. Patient characteristics and treatments were evaluated for esophageal cancer (EC) and gastric cancer (GC) separately. RESULTS: The number of esophagogastric cancer diagnoses decreased prominently during the first 2 months of the COVID-19 pandemic. During this period, a significantly higher percentage of GC patients was diagnosed with incurable disease (52.5% in 2017-2019 and 67.7% in 2020, p = 0.011). We observed a significant reduction in the percentage of patients with potentially curable EC treated with resection and neoadjuvant chemoradiotherapy (from 35.0% in 2017-2019 to 27.3% in 2020, p < 0.001). Also, patients diagnosed with incurable GC were treated less frequently with a resection (from 4.6% in 2017-2019 to 1.5% in 2020, p = 0.009) in the second half of 2020. CONCLUSIONS: Compared to previous years, the number of esophagogastric cancer diagnoses decreased in the first 2 months of the COVID-19 pandemic, while an increased percentage of patients was diagnosed with incurable disease. Both in the curative and palliative setting, patients were less likely to be treated with a surgical resection.

[18F]FDG-PET-Based Personalized Radiotherapy Dose Prescription.

PET imaging with 2'-deoxy-2'-[18F]fluoro-D-glucose ([18F]FDG) has become one of the pillars in the management of malignant diseases. It has proven value in diagnostic workup, treatment policy, follow-up, and as prognosticator for outcome. [18F]FDG is widely available and standards have been developed for PET acquisition protocols and quantitative analyses. More recently, [18F]FDG-PET is also starting to be appreciated as a decision aid for treatment personalization. This review focuses on the potential of [18F]FDG-PET for individualized radiotherapy dose prescription. This includes dose painting, gradient dose prescription, and [18F]FDG-PET guided response-adapted dose prescription. The current status, progress, and future expectations of these developments for various tumor types are discussed.

Dose coverage and breath-hold analysis of breast cancer patients treated with surface-guided radiotherapy.

BACKGROUND: Surface-guided radiotherapy (SGRT) is used to ensure a reproducible patient set-up and for intra-fraction motion monitoring. The arm position of breast cancer patients is important, since this is related to the position of the surrounding lymph nodes. The aim of the study was to investigate the set-up accuracy of the arm of patients positioned using SGRT. Moreover, the actual delivered dose was investigated and an extensive breath-hold analysis was performed. METHODS: 84 patients who received local or locoregional breast radiation therapy were positioned and monitored using SGRT. The accuracy of the arm position, represented by the clavicle position, was studied on the anterior-posterior kV-image. To investigate the effect of changes in anatomy and patient set-up, the actual delivered dose was calculated on cone-beam CT-scans (CBCT). A deformable registration of the CT to the CBCT was applied to deform the structures of the CT onto the CBCT. The minimum dose in percentage of the prescribed dose that was received by 98% of different CTV volumes (D98) was determined. An extensive breath-hold analysis was performed and definitions for relevant parameters were given. RESULTS: The arm position of 77 out of 84 patients in total was successful, based on the clavicle rotation. The mean clavicle rotation was 0.4° (± 2.0°). For 89.8% of the patients who were irradiated on the whole-breast D98 was larger than 95% of the prescribed dose (D98 > 95%). D98 > 95% applied for 70.8% of the patients irradiated on the chest wall. Concerning the lymph node CTVs, D98 > 95% for at least 95% of the patients. The breath-hold analysis showed a mean residual setup error of - 0.015 (± 0.90), - 0.18 (± 0.82), - 0.58 (± 1.1) mm in vertical, lateral, and longitudinal direction, respectively. The reproducibility and stability of the breath-hold was good, with median 0.60 mm (95% confidence interval (CI) [0.66-0.71] mm) and 0.20 mm (95% CI 0.21-0.23] mm), respectively. CONCLUSIONS: Using SGRT we were able to position breast cancer patients successfully, with focus on the arm position. The actual delivered dose calculated on the CBCT was adequate and no relation between clavicle rotation and actual delivered dose was found. Moreover, breath-hold analysis showed a good reproducibility and stability of the breath-hold. Trial registration CCMO register NL69214.028.19.

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe.

BACKGROUND: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. METHODS: In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%). RESULTS: A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). CONCLUSION: The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Locally Recurrent Rectal Cancer: Toward a Second Chance at Cure? A Population-Based, Retrospective Cohort Study.

BACKGROUND: In current practice, rates of locally recurrent rectal cancer (LRRC) are low due to the use of the total mesorectal excision (TME) in combination with various neoadjuvant treatment strategies. However, the literature on LRRC mainly consists of single- and multicenter retrospective cohort studies, which are prone to selection bias. The aim of this study is to provide a nationwide, population-based overview of LRRC after TME in the Netherlands. PATIENTS AND METHODS: In total, 1431 patients with nonmetastasized primary rectal cancer diagnosed in the first six months of 2015 and treated with TME were included from the nationwide, population-based Netherlands Cancer Registry. Data on disease recurrence were collected for patients diagnosed in these 6 months only. Competing risk cumulative incidence, competing risk regression, and Kaplan-Meier analyses were performed to assess incidence, risk factors, treatment, and overall survival (OS) of LRRC. RESULTS: Three-year cumulative incidence of LRRC was 6.4%; synchronous distant metastases (LRRC-M1) were present in 44.9% of patients with LRRC. Distal localization, R1-2 margin, (y)pT3-4, and (y)pN1-2 were associated with an increased LRRC rate. No differences in LRRC treatment and OS were found between patients who had been treated with or without prior n(C)RT. Curative-intent treatment was given to 42.9% of patients with LRRC, and 3-year OS thereafter was 70%. CONCLUSIONS: Nationwide LRRC incidence was low. A high proportion of patients with LRRC underwent curative-intent treatment, and OS of this group was high in comparison with previous studies. Additionally, n(C)RT for primary rectal cancer was not associated with differences in treatment and OS of LRRC.

Microsatellite instability and sex differences in resectable gastric cancer - A pooled analysis of three European cohorts.

OBJECTIVE: Biological sex differences in cancer are increasingly acknowledged. Here, we examined these differences in clinicopathological characteristics and survival in microsatellite instability (MSI)-high and microsatellite stable (MSS) gastric cancer (GC). DESIGN: We analysed MSI status by polymerase chain reaction (PCR) and/or mismatch repair (MMR) status by immunohistochemistry in a pooled analysis of individual patient data from one retrospective cohort from Cologne, and the randomised phase III clinical trials D1/D2 and CRITICS. All patients had resectable adenocarcinoma of the stomach and/or gastro-oesophageal junction. Patients were treated with either surgery only or perioperative chemo(radio)therapy. RESULTS: MSI and/or MMR analyses on 1307 tumours resulted in 1192 (91.2%) MSS and/or MMR proficient (MMRP) [median age, 65 years; 759 males (63.7%); 619 treated with surgery only (51.9%)], and 115 (8.8%) MSI-high [median age, 69 years; 67 males (58.3%); 76 treated with surgery only (66.1%)] GC cases. Males had shorter overall survival (OS) than female MSI-high GC (5-year OS 34.7% vs. 69.7%; hazard ratio (HR) 2.68, 95%CI 1.60 to 4.49; p < 0.001). Females with MSI-high had longer OS than those with MSS/MMRP GC (HR 0.61, 95%CI 0.41 to 0.92; p = 0.02). Males with MSI-high did not have longer OS than those with MSS/MMRP GC (HR 1.26, 95%CI 0.94 to 1.69; p = 0.12). CONCLUSIONS: MSI-high GC males had a significantly worse prognosis compared to their female counterparts in three independent cohorts. In addition, the favourable prognostic value of MSI was only seen in females and not in males. These observations emphasise the need to consider sex differences in prognosis and treatment effects in oncology. CLINICAL TRIAL REGISTRATION: The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02.

Triplet Chemotherapy with Cisplatin versus Oxaliplatin in the CRITICS Trial: Treatment Compliance, Toxicity, Outcomes and Quality of Life in Patients with Resectable Gastric Cancer.

(1) Background: Perioperative chemotherapy is the current standard treatment for patients with resectable gastric cancer. Based on studies in patients with metastatic gastric cancer, oxaliplatin has replaced cisplatin in the curative setting as well. However, evidence to prefer oxaliplatin over cisplatin in the curative setting is limited. (2) Methods: We compared patient-related and tumor-related outcomes for cisplatin versus oxaliplatin in patients with resectable gastric cancer treated with perioperative chemotherapy in the CRITICS trial. (3) Results: Preoperatively, 632 patients received cisplatin and 149 patients received oxaliplatin. Preoperative severe toxicity was encountered in 422 (67%) patients who received cisplatin versus 89 (60%) patients who received oxaliplatin (p = 0.105). Severe neuropathy was observed in 5 (1%) versus 6 (4%; p = 0.009) patients, respectively. Postoperative severe toxicity occurred in 109 (60%) versus 26 (51%) (p = 0.266) patients; severe neuropathy in 2 (1%) versus 2 (4%; p = 0.209) for patients who received cisplatin or oxaliplatin, respectively. Diarrhea impacted the quality of life more frequently in patients who received oxaliplatin compared to cisplatin. Complete or near-complete pathological response was achieved in 94 (21%) versus 16 (15%; p = 0.126) patients who received cisplatin or oxaliplatin, respectively. Overall survival was not significantly different in both groups (p = 0.300). (4) Conclusions: Both cisplatin and oxaliplatin are legitimate options as part of systemic treatment in patients with resectable gastric cancer.

Quality of Life Is Associated With Survival in Patients With Gastric Cancer: Results From the Randomized CRITICS Trial.

BACKGROUND: The evaluation of health-related quality of life (HRQoL) in clinical trials has become increasingly important because it addresses the impact of treatment from the patient's perspective. The primary aim of this study was to investigate the effect of postoperative chemotherapy and chemoradiotherapy (CRT) after neoadjuvant chemotherapy and surgery with extended (D2) lymphadenectomy on HRQoL in the CRITICS trial. Second, we investigated the potential prognostic value of pretreatment HRQoL on event-free survival (EFS) and overall survival (OS). PATIENTS AND METHODS: Patients in the CRITICS trial were asked to complete HRQoL questionnaires (EORTC Quality-of-Life Questionnaire-Core 30 and Quality-of-Life Questionnaire gastric cancer-specific module) at baseline, after preoperative chemotherapy, after surgery, after postoperative chemotherapy or CRT, and at 12 months follow-up. Patients with at least 1 evaluable questionnaire (645 of 788 randomized patients) were included in the HRQoL analyses. The predefined endpoints included dysphagia, pain, physical functioning, fatigue, and Quality-of-Life Questionnaire-Core 30 summary score. Linear mixed modeling was used to assess differences over time and at each time point. Associations of baseline HRQoL with EFS and OS were investigated using multivariate Cox proportional hazards analyses. RESULTS: At completion of postoperative chemo(radio)therapy, the chemotherapy group had significantly better physical functioning (P=.02; Cohen's effect size = 0.42) and less dysphagia (P=.01; Cohen's effect size = 0.38) compared with the CRT group. At baseline, worse social functioning (hazard ratio [HR], 2.20; 95% CI, 1.36-3.55; P=.001), nausea (HR, 1.89; 95% CI, 1.39-2.56; P<.001), worse WHO performance status (HR, 1.55; 95% CI, 1.13-2.13; P=.007), and histologic subtype (diffuse vs intestinal: HR, 1.94; 95% CI, 1.42-2.67; P<.001; mixed vs intestinal: HR, 2.35; 95% CI, 1.35-4.12; P=.003) were significantly associated with worse EFS and OS. CONCLUSIONS: In the CRITICS trial, the chemotherapy group had significantly better physical functioning and less dysphagia after postoperative treatment. HRQoL scales at baseline were significantly associated with EFS and OS.

Age-specific incidence, treatment, and survival trends in esophageal cancer: a Dutch population-based cohort study.

BACKGROUND: Data on the age-specific incidence of esophageal cancer are lacking. Our aim was to investigate the age-stratified incidence, treatment, and survival trends of esophageal cancer in the Netherlands, with a focus on adults <50 years. MATERIAL AND METHODS: Patients diagnosed with esophageal cancer were included from the nationwide Netherlands Cancer Registry (1989-2018). Follow-up data were available until 31 December 2018. Annual percentage changes of incidence were analyzed according to age group (<50, 50-74, and ≥75 years) and histology type: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). Treatment trends and relative survival rates (RSR) were estimated by age and stage grouping. RESULTS: A total 59,584 patients were included. In adults <50 years, EAC incidence tripled (mean increase per year: males 1.5%, females 3%), while the incidence of ESCC decreased (mean decrease per year: males -5.3%, females -4.3%). Patients <50 years more often presented with advanced disease stages compared to older patients and were more likely to receive multimodality treatments. Most patients <50 years with potentially curable disease were treated with neoadjuvant chemoradiotherapy followed by surgery compared to patients 50-74 and ≥75 years (74% vs. 55% vs. 15%, respectively; p < .001), and received more frequent systemic therapy once staged with palliative disease (72% vs. 54% vs. 19%, respectively; p < .001). The largest RSR improvement was seen in patients <50 years with early-stage (five years: +47%), potentially curable (five years: +22%), and palliative disease (one year: +11%). Over time, a trend of increasing survival difference was seen between patients <50 and ≥75 years with potentially curable (five-year difference: 17% to 27%) and palliative disease (one-year difference: 11% to 20%). CONCLUSION: The incidence of EAC is increasing in adults <50 years in the Netherlands. Differences in the use of multimodality treatments with curative or life-prolonging intent in different age categories may account for increasing survival gaps.

Response to neoadjuvant chemotherapy and survival in molecular subtypes of resectable gastric cancer: a post hoc analysis of the D1/D2 and CRITICS trials.

BACKGROUND: Epstein-Barr virus positivity (EBV+) and microsatellite instability (MSI-high) are positive prognostic factors for survival in resectable gastric cancer (GC). However, benefit of perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcomes of patients with EBV+, MSI-high, and EBV-/MSS GCs who received either surgery only or perioperative treatment. METHODS: EBV and MSI status were determined on tumor samples collected from 447 patients treated with surgery only in the D1/D2 trial, and from 451 patients treated perioperatively in the CRITICS trial. Results were correlated to histopathological response, morphological tumor characteristics, and survival. RESULTS: In the D1/D2 trial, 5-year cancer-related survival was 65.2% in 47 patients with EBV+, 56.7% in 47 patients with MSI-high, and 47.6% in 353 patients with EBV-/MSS tumors. In the CRITICS trial, 5-year cancer-related survival was 69.8% in 25 patients with EBV+, 51.7% in 27 patients with MSI-high, and 38.6% in 402 patients with EBV-/MSS tumors. Interestingly, all three MSI-high tumors with moderate to complete histopathological response (3/27, 11.1%) had substantial mucinous differentiation. No EBV+ tumors had a mucinous phenotype. 115/402 (28.6%) of EBV-/MSS tumors had moderate to complete histopathological response, of which 23/115 (20.0%) had a mucinous phenotype. CONCLUSIONS: In resectable GC, MSI-high had favorable outcome compared to EBV-/MSS, both in patients treated with surgery only, and in those treated with perioperative chemo(radio)therapy. Substantial histopathological response was restricted to mucinous MSI-high tumors. The mucinous phenotype might be a relevant parameter in future clinical trials for MSI-high patients.