•This ESMO Clinical Practice Guideline provides key recommendations for managing oesophageal cancer.•The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment ...and follow-up.•Algorithms for the management of locoregional and advanced/metastatic disease are provided.•The author group encompasses a multidisciplinary group of experts from different institutions in Europe and Australia.•Recommendations are based on available scientific data and the authors’ collective expert opinion.
•MSI-H has been associated with favorable survival outcomes in gastroesophageal cancer.•In gastroesophageal cancer, MSI-H tumors show resistance to specific cytotoxic drugs.•MSI-H tumors show ...remarkable and often durable responses to immunotherapy in gastroesophageal cancer.
Gastroesophageal cancers are a major cause of death worldwide and treatment outcomes remain poor. Adequate predictive biomarkers have not been identified.
Microsatellite instability (MSI) as a result of mismatch repair deficiency is present in four to twenty percent of gastroesophageal cancers and has been associated with favorable survival outcomes compared to microsatellite stable tumors. This prognostic advantage may be related to immunosurveillance, which may also explain the favorable response to immune checkpoint inhibition observed in MSI high (MSI-H) tumors. The value of conventional cytotoxic treatment in MSI-H tumors is unclear and results on its efficacy range from detrimental to beneficial effects.
Here the recent data on MSI as a predictive factor for outcome of gastroesophageal cancer treatment is reviewed.
The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy ...(CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial.
The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib–Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival.
Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios.
After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).
•Overall survival remained not significantly different between post-operative CT and CRT in the updated ITT analysis.•Post-operative compliance was poor; about 60% of the patients started the allocated post-operative treatment.•In the per-protocol analysis, the CT group had a better 5-year overall survival.•More peritoneal metastases were observed in the CRT group.
Background
In the era of individualized gastric cancer (GC) treatment, accurate determination of histological subtype becomes increasingly relevant. As yet, it is unclear whether preoperative ...chemotherapy may affect the histological subtype. The aim of this study was to assess concordance in histological subtype between pretreatment biopsies and surgical resection specimens before and after the introduction of perioperative treatment.
Methods
Histological subtype was centrally determined in paired GC biopsies and surgical resection specimens of patients treated with either surgery alone (SA) in the Dutch D1/D2 study or with preoperative chemotherapy (CT) in the CRITICS trial. The histological subtype as determined in the resection specimen was considered the gold standard. Concordance rates and sensitivity and specificity of intestinal, diffuse, mixed, and “other” subtypes of GC were analyzed.
Results
In total, 105 and 515 pairs of GC biopsies and resection specimens of patients treated in the SA and CT cohorts, respectively, were included. Overall concordance in the histological subtype was 72% in the SA and 74% in the CT cohort and substantially higher in the diffuse subtype (83% and 86%) compared to the intestinal (70% and 74%), mixed (21% and 33%) and “other” subtypes (54% and 54%). In the SA cohort, sensitivities and specificities were 0.88 and 0.71 in the intestinal, 0.67 and 0.93 in the diffuse, 0.20 and 0.98 in the mixed, and 0.50 and 0.93 in the “other” subtypes, respectively.
Conclusion
Our results suggest that accurate determination of histological subtype on gastric cancer biopsies is suboptimal but that the impact of preoperative chemotherapy on histological subtype is negligible.
Background
In 2011, the Dutch Upper Gastrointestinal Cancer Audit (DUCA) group began nationwide registration of all patients undergoing surgery with the intention of resection for oesophageal or ...gastric cancer. The aim of this study was to describe the initiation and implementation of this process along with an overview of the results.
Methods
The DUCA is part of the Dutch Institute for Clinical Auditing. The audit provides (surgical) teams with reliable, weekly updated, benchmarked information on process and (case mix‐adjusted) outcome measures. To accomplish this, a web‐based registration was designed, based on a set of predefined quality measures.
Results
Between 2011 and 2014, a total of 2786 patients with oesophageal cancer and 1887 with gastric cancer were registered. Case ascertainment approached 100 per cent for patients registered in 2013. The percentage of patients with oesophageal cancer starting treatment within 5 weeks of diagnosis increased significantly over time from 32·5 per cent in 2011 to 41·0 per cent in 2014 (P < 0·001). The percentage of patients with a minimum of 15 examined lymph nodes in the resected specimen also increased significantly for both oesophageal cancer (from 50·3 per cent in 2011 to 73·0 per cent in 2014; P < 0·001) and gastric cancer (from 47·5 per cent in 2011 to 73·6 per cent in 2014; P < 0·001). Postoperative mortality remained stable (around 4·0 per cent) for patients with oesophageal cancer, and decreased for patients with gastric cancer (from 8·0 per cent in 2011 to 4·0 per cent in 2014; P = 0·031).
Conclusion
Nationwide implementation of the DUCA has been successful. The results indicate a positive trend for various process and outcome measures.
High‐quality national audit when properly resourced
Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been ...associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2–3 mutation status was assessed in 143 stage II (n = 85) and III (n = 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer‐specific (CSS) and overall survival (OS) was analyzed using Kaplan–Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n = 73) and KRAS mutations in 16% of cases (n = 23). Patients with double wild‐type cancers (dWT; i.e., BRAF and KRAS wild‐type) had a highly favourable survival with 5‐year CSS of 93% (95% CI 84–100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5‐year CSS of 76% (95% CI 67–85%). In the subgroup of stage II patients with dWT cancers no cancer‐specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.
What's new?
Mutations in the BRAF and KRAS genes are widely studied in patients with colorectal carcinomas (CRC), but their prognostic impact in cancers characterized by microsatellite instability due to impaired DNA mismatch repair remains unclear. Here the authors show that both mutations are associated with poor survival in patients afflicted with these genetically hypermutatable tumors as compared to patients carrying tumors with wildtype BRAF and KRAS genes, underscoring the prognostic value of determining combined or single mutations in these genes in this subset of CRC patients.
Purpose
One-third of patients with
RAS
wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We ...evaluated cetuximab tumor accumulation on
89
ZrZr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy.
Patients and methods
PET/CT imaging of
89
ZrZr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m
2
≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent
89
ZrZr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks.
Results
Visual tumor uptake on
89
ZrZr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative,
P
= 0.16), progression-free survival (3.6 versus 5.7 months,
P
= 0.15), or overall survival (7.1 versus 9.4 months,
P
= 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750–1250 mg/m
2
) was applied, potentially influencing outcome in this group. None of the second
89
ZrZr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making
89
ZrZr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUV
peak
did not correlate to changes in tumor size on CT (
P
= 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit.
BRAF
mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab.
Conclusion
Tumor uptake on
89
ZrZr-cetuximab PET/CT failed to predict treatment benefit in patients with
RAS
wild-type mCRC receiving cetuximab monotherapy.
BRAF
mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, ...cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD.
In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families.
Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas.
We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.
The aim of this study is to clarify the prognostic importance of several well‐known but still debated pathological variables related to the survival of colon cancer patients. The study focuses on the ...definition and survival carried by the pT4 category and stage II where the presence of high‐risk variables may determine whether or not adjuvant chemotherapy is administered. A retrospective nationwide study was carried out including all colon cancer patients that underwent resection in Iceland between 1990 and 2004 (n = 889). All histopathology was reassessed. Cancer‐specific survival (CSS) and overall survival were analysed using Kaplan‐Meier and Cox regression analysis. In stage II, the five‐year CSS for pT4 was 50% (95% CI, 32–69%), which was the lowest survival observed in that stage. In stage III the five‐year CSS was 30% (95% CI, 18–41%) and 37% (95% CI, 26–48%) for pT4 and pN2 tumors, respectively. Lymphatic invasion and differentiation had no prognostic value in stage II. The survival associated with pT4a versus pT4b depends on how these categories are defined with regard to Shepherd's local peritoneal involvement (LPI). In the present series, pT4 is a major indicator of poor prognosis in patients with stage II and III colon carcinoma. Four‐tiered TNM or Dukes staging systems are insufficient by not taking this variable into account. Only Shepherd's LPI4 and a subgroup of LPI3 (i.e., borderline LPI3/LPI4) should qualify for the pT4a subcategory. The results do not support lymphatic invasion or poor differentiation as high‐risk stage II variables.
What's new?
Lymph node status is considered to be the single most important determinant of prognosis in colon cancer, supporting the standard four‐tiered TNM and Dukes staging systems. This study indicates, however, that pT4, the most advanced category for local invasion, is equally as important as positive lymph nodes in determining colon cancer prognosis. The findings suggest that the survival impact of pT4a versus pT4b depends on how the categories are defined and that lymphatic invasion and poor differentiation are not useful as high‐risk stage II variables.
Background
Studies investigating the association between hospital volume and quality of gastric cancer surgery are lacking. In the present study, the effect of hospital volume on quality of gastric ...cancer surgery was evaluated by analysing data from the CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial.
Methods
Patients who underwent gastrectomy with curative intent in the Netherlands were selected from the CRITICS trial database. Annual hospital volume of participating centres was derived from the Netherlands Cancer Registry. Hospital volume was categorized into very low (1–10 gastrectomies per year per institution), low (11–20), medium (21–30) and high (31 or more), and linked to the CRITICS database. Quality of surgery was analysed by surgicopathological compliance (removal of at least 15 lymph nodes), surgical compliance (removal of indicated lymph node stations) and the Maruyama Index. Postoperative morbidity and mortality were also compared between hospital categories.
Results
Between 2007 and 2015, 788 patients were included in the CRITICS study, of whom 494 were analysed. Surgicopathological compliance was higher (86·7 versus 50·4 per cent; P < 0·001), surgical compliance was greater (52·9 versus 19·8 per cent; P < 0·001) and median Maruyama Index was lower (0 versus 6; P = 0·006) in high‐volume hospitals compared with very low‐volume hospitals. There was no statistically significant difference in postoperative complications or mortality between the hospital volume categories.
Conclusion
Surgery performed in high‐volume hospitals was associated with better surgical quality than surgery carried out in lower‐volume hospitals.
High volume better quality
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