Substantial changes have occurred in the epidemiology of esophageal adenocarcinoma. We examined trends in incidence in a large national population.
All esophageal adenocarcinomas registered in ...England and Wales over a 31-year period (1971-2001) were included. Incidence rates were calculated by age, sex, and socio-economic category, by 5-year period, and by birth cohort.
A total of 43,753 esophageal adenocarcinomas were analyzed. Age-standardized (world) incidence rates rose rapidly, by an average of 39.6% (95% CI 38.6-40.6) every 5 years in men, and 37.5% (35.8-39.2) every 5 years in women. Incidence has increased about three-fold in men and women since 1971. Incidence has risen in all deprivation categories since 1986, especially in the most affluent groups. The cumulative risk of esophageal adenocarcinoma over the age range 15-74 years in men rose ten-fold, from 0.1% for those born in 1900 to 1.1% for those born in 1940. The cumulative risk rose five-fold in women.
The incidence of esophageal adenocarcinoma has increased sharply over the past few decades, both by period and birth cohort. Etiological studies are required to explain the rapid increase of this lethal cancer.
The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for ...refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understanding its potential prognostic implications.
We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned to each tumor and cell line a combination of up to three CMS subtypes with a threshold above 20%.
Over 55% of tumors corresponded to mixtures of at least two CMSs, demonstrating pervasive ITH in colon cancer. Of note, ITH was associated with shorter disease-free survival (DFS) and overall survival, HR, 1.34; 95% confidence interval (CI; 1.12-1.59), 1.40, 95% CI (1.14-1.71), respectively. Moreover, we uncovered specific combinations of CMS associated with dismal prognosis. In multivariate analysis, ITH represents the third parameter explaining DFS variance, after T and N stages. At a cellular level, combined WISP and single-cell transcriptomic analysis revealed that most colon cancer cell lines are a mixture of cells falling into different CMSs, indicating that ITH may correspond to distinct functional statuses of colon cancer cells.
This study shows that CMS-based transcriptomic ITH is frequent in colon cancer and impacts its prognosis. CMS-based transcriptomic ITH may correspond to distinct functional statuses of colon cancer cells, suggesting plasticity between CMS-related cell populations. Transcriptomic ITH deserves further assessment in the context of personalized medicine.
Background
Around 50% of gastric cancers are diagnosed at an advanced stage. Several chemotherapy regimens are now internationally validated. Few data are available on the routine daily management of ...advanced gastric or gastroesophageal junction cancers. We aimed to describe chemotherapy practices, tolerance, and efficacy overall survival (OS) and Progression free survival (PFS) in a prospective French cohort.
Methods
Patients starting palliative chemotherapy were prospectively enrolled in 49 French centres. The primary objective was to report and describe patients' characteristics and treatment strategies. Secondary objectives were OS, PFS, objective response rate, adverse events rate, performance status deterioration during the chemotherapy.
Results
A total of 182 patients were included; 179 were analysed. Most patients received platinium‐based chemotherapy as the first treatment and FOLFIRI as second; 62.0% of patients received a second line, and 32.4% a third line. More than two thirds of Her2‐positive patients were first treated with trastuzumab. The FOLFIRI regimen was the most frequently used second‐line therapy. Median OS was 13.3 months, similar whatever the chemotherapy or combinations used in the first line. One‐ and 2‐year OS increased with the number of chemotherapy lines received, from respectively 24.7% and 5.7% (1 line), to 46.9% and 12.4% (2 lines) and 88.1% and 29.9% (3 or more lines) (p < 0.0001).
Conclusion
Our study showed that treatment strategies in France are based on a succession of doublets, making it possible to offer a second and third line of treatment more often. This treatment strategy must be taken into account for future trials with immunotherapy combinations.
Flow chart of the multicenter prospective METESTOMAC cohort.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background The use of oxaliplatin in digestive tract cancers could induce severe peripheral neuropathy (OIPN) decreasing the quality of life of patients and survivors. There is currently, no univocal ...treatment for these peripheral neuropathies. Donepezil, a reversible inhibitor of cholinesterase, used to treat Alzheimer's disease and dementia, is reported to have a good safety profile in humans, and preclinical data have provided initial evidence of its effectiveness in diminishing neuropathic symptoms and related comorbidities in OIPN animal models. Methods The DONEPEZOX trial will be a proof-of-concept, randomised, triple-blinded, and multicentre study. It will be the first clinical trial evaluating the efficacy and safety of donepezil for the management of OIPN. Adult cancer survivors with OIPN that report sensory neuropathy according to QLQ-CIPN20 sensory score (equivalence of a grade greater than or equai to 2), at least 6 months after the end of an oxaliplatin-based chemotherapy will be included. Eighty patients will be randomly assigned to receive either donepezil or placebo over 16 weeks of treatment. The primary endpoint will be the rate of responders (neuropathic grade decreases according to the QLQ-CIPN20 sensory score) in the donepezil arm. The severity of OIPN will be assessed by the QLQ-CIPN20 sensory scale before and after 16 weeks of treatment. The comparison versus the placebo arm will be a secondary objective. The other secondary endpoints will be tolerance to donepezil, the severity and features of OIPN in each arm before and after treatment, related-comorbidities and quality of life. Fleming's one-stage design will be used for sample size estimation. This design yields a type I error rate of 0.0417 and power of 91% for a responder rate of at least 30% in donepezil arm. A total of 80 randomized patients is planned. Discussion This study will allow, in the case of positive results, to initiate a phase 3 randomized and placebo-controlled (primary endpoint) clinical study to assess the therapeutic interest of donepezil to treat OIPN. Trial registration NCT05254639, clincialtrials.gov, Registered 24 February 2022. Keywords: Pain, Chemotherapy-induced peripheral neuropathy, Anticholinesterase, Donepezil, Oxaliplatin, Study protocol
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Small intestinal bacterial overgrowth (SIBO) is a common complication of bariatric surgery. Digestive decontamination treatments with oral antibiotic therapy vary and are not codified. ...This retrospective study was conducted to analyse the characteristics of bariatric surgery patients who underwent a glucose breath test (GBT) and to analyse the effectiveness of the antibiotic decontamination therapy.
Materials and Methods
A total of 101 operated patients (Roux-en-Y bypass (RYB), omega bypass (ΩB) and sleeve gastrectomy (SG)) who underwent a GBT (75 g/250 mL) were included. Anthropometric data, symptoms of SIBO, type of surgery, use of proton pump inhibitors (PPIs) and antibiotic therapy were analysed. The effectiveness of the antibiotic treatment, defined by improvement of the symptoms, was evaluated during the follow-up.
Results
Of the 85 women and 16 men included (48.5 ± 3.6 years old), 63 underwent RYB, 31 underwent ΩB and 7 underwent SG. The GBT was positive in 83% of the patients. A positive test was associated with age (
p
< 0.001), female sex (
p
< 0.01) and PPI use (
p
< 0.01), but there was no significant difference according to the type of surgery. Sixty-one percent of patients treated with gentamicin/metronidazole sequential antibiotic therapy and 58% of patients treated with metronidazole alone achieved treatment efficacy (with no significant difference in efficacy between these treatments).
Conclusion
SIBO should be systematically considered in the context of abdominal symptoms in bariatric surgery patients, regardless the type of surgery, particularly in patients who are older or female and after PPI treatment. Digestive decontamination appears to be similar between gentamycin/metronidazole and metronidazole treatments.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from ...colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection.
In the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session.
Fifty-seven patients were enrolled. Grade 3-5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8-65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7-45.8), and median PFS 10.8 months (95% CI, 8.2-12.3).
Front-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal.
NCT01839877.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Efficacy of immune checkpoint inhibitors (ICI) as monotherapy in 2nd line treatment for gastric or gastro-oesophageal junction (GEJ) adenocarcinoma is low, with no evaluation of efficacy and safety ...of ICI combined with chemotherapy. The DURIGAST PRODIGE 59 study is a randomised, multicentre, phase II study designed to assess the efficacy and safety of the combination of FOLFIRI + Durvalumab +/- Tremelimumab as 2nd line treatment of patients with advanced gastric/GEJ adenocarcinoma. Here, we report data from the safety run-in phase with FOLFIRI Durvalumab (arm A) or FOLFIRI Durvalumab and Tremelimumab (arm B). Among the 11 patients included, 63.6% experienced at least one grade 3-4 adverse events (AEs) related to the treatment, most frequently neutropenia (36.4%). There was only one immune-related AE (grade 2 hyperthyroidism). Ten serious AEs were described among six patients, but only two were related to the treatment, due to the chemotherapy. One seizure epilepsy related to a brain metastasis was observed, but was not related by the investigator to the treatment. However, the Independent Data Monitoring Committee recommended brain imaging at inclusion. This safety run-in phase demonstrates an expected safety profile of FOLFIRI with Durvalumab +/- Tremelimumab combination allowing the randomised phase II.
Population-based studies on colorectal malignant polyps (MPs) are scarce. The aim of this study was to describe time trends in the incidence of colorectal MPs before and after the introduction of a ...colorectal mass-screening programmein 2003 and to assess outcomes (survival and recurrence) after endoscopic or surgical resection in patients with MPs.
We included 411 patients with MPs diagnosed between 1982 and 2011 in a well-defined population. Age-standardised incidence rates were calculated. Univariate and multivariate 5-year recurrence and net survival analyses were performed according to gross morphology.
Age-standardised incidence of MPs in patients aged 50-74 years doubled from 5.4 in 1982-2002 to 10.9 per 100 000 in 2003-2011. Pedunculated MPs were more frequently resected endoscopically (38.2%) than were sessile MPs (19.1%;
<0.001). For patients with pedunculated MPs and a pathological margin ≥1 mm, the 5 -year cumulative recurrence rate did not differ significantly between surgical and endoscopic resection (8.2% and 2.4%, respectively). For patients with sessile MPs, it was 3.0% after first-line or second-line surgical resection, 8.6% after endoscopic resection and 17.9% after transanal resection (p=0.016). The recurrence rate decreased dramatically for patients with sessile MPs from 11.3% (1982-2002) to 1.2% (2003-2009) (p=0.010) and remained stable for pedunculated MPs at 4.6% and 6.7%, respectively. Five-year net survival was 81.0% when pathological margins were <1 mm and 95.6% when ≥1 mm (p=0.024).
Outcomes following polypectomy in patients with a pathological margin ≥1 mm are similar to those following surgery in the general population. Endoscopic resection needs to be completed by surgery if pathological margins are less than 1 mm.
There is no standard second-line treatment after platinum–etoposide chemotherapy for gastroenteropancreatic neuroendocrine carcinoma. We aimed to evaluate the efficacy of FOLFIRI plus bevacizumab, ...and FOLFIRI alone, in this setting.
We did a randomised, non-comparative, open-label, phase 2 trial (PRODIGE 41-BEVANEC) at 26 hospitals in France. We included patients aged 18 years or older with locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinoma or neuroendocrine carcinoma of unknown primary origin, documented progressive disease during or after first-line platinum–etoposide chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1; block size of three), without stratification, to receive FOLFIRI (irinotecan 180 mg/m2, calcium folinate 400 mg/m2 or levofolinate 200 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) plus bevacizumab 5 mg/kg or FOLFIRI alone, intravenously, every 2 weeks until disease progression or unacceptable toxicity. Neither patients nor investigators were masked to group assignment. The primary outcome was overall survival at 6 months after randomisation, evaluated in the modified intention-to-treat population (all enrolled and randomly assigned patients who received at least one cycle of FOLFIRI). This study is now complete and is registered with ClinicalTrials.gov, NCT02820857.
Between Sept 5, 2017, and Feb 8, 2022, 150 patients were assessed for eligibility and 133 were enrolled and randomly assigned: 65 to the FOLFIRI plus bevacizumab group and 68 to the FOLFIRI group. 126 patients (59 in the FOLFIRI plus bevacizumab group and 67 in the FOLFIRI group) received at least one cycle of FOLFIRI and were included in the modified intention-to-treat population, 83 (66%) of whom were male and 43 (34%) were female, and the median age of the patients was 67 years (IQR 58–73). The primary tumour location was colorectal in 38 (30%) of 126 patients, pancreatic in 34 (27%), gastro-oesophageal in 22 (17%), and unknown in 23 (18%). After a median follow-up of 25·7 months (95% CI 22·0–38·2), 6-month overall survival was 53% (80% CI 43–61) in the FOLFIRI plus bevacizumab group and 60% (51–68) in the FOLFIRI group. Grade 3–4 adverse events that occurred in at least 5% of patients were neutropenia (eight 14% patients), diarrhoea (six 10%), and asthenia (five 8%) in the FOLFIRI plus bevacizumab group, and neutropenia (seven 10%) in the FOLFIRI group. One treatment-related death (ischaemic stroke) occurred in the FOLFIRI plus bevacizumab group.
The addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma.
French Ministry of Health and Roche SAS.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
