Complete pathological response after chemotherapy or immune checkpoint inhibitors in deficient MMR metastatic colorectal cancer: Results of a retrospective multicenter study.

About 5% of the patients with metastatic colorectal cancers (mCRC) present microsatellite instability (MSI)/deficient mismatch repair system (dMMR). While metastasectomy is known to improve overall and progression-free survival in mCRC, specific results in selected patients with dMMR/MSI mCRC are lacking. Our study aimed to describe metastasectomy results, characterize histological response and evaluate pathological complete response (pCR) rate in patients with dMMR/MSI mCRC. We retrospectively reviewed data from all consecutive patients with dMMR/MSI mCRC who underwent surgical metastasectomy between January 2010 and June 2021 in 17 French centers. Primary outcome was to assess the pCR rate defined by tumor regression grade (TRG) 0. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), and explored TRG as predictive factor for RFS and OS. Among the 88 patients operated, 109 metastasectomies were performed in 81 patients after neoadjuvant treatment [chemotherapy ± targeted therapy (CTT): 69, 85.2%; immunotherapy (ICI): 12, 14.8%], and pCR was achieved in 13 (16.1%) patients. Among the latter, pCR rate were 10.2% in the patients having received CTT (N = 7) and 50.0% in the patients treated with ICI (N = 6). Radiological response did not predict TRG. With a median follow-up of 57.9 (IQR 34.2-81.6) months, median RFS was 20.2 (15.4-not reached) months, median OS was not reached. Major pathological responses (TRG0 + TRG1) were significantly associated with longer RFS (HR 0.12, 95% CI 0.03-0.55; P = .006). The pCR rate of 16.1% achieved with neoadjuvant treatment in patients with dMMR/MSI mCRC is consistent with previously reported rates in pMMR/MSS mCRC. Immunotherapy showed better pCR rate than chemotherapy ± targeted therapy. Further prospective trials are needed to validate immunotherapy as neoadjuvant treatment in resectable/potentially resectable dMMR/MSI mCRC and identify predictive factors for pCR.

Daily practices in chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma: METESTOMAC French prospective cohort.

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.

Prognosis and chemosensitivity of non-colorectal alimentary tract cancers with microsatellite instability.

BACKGROUND: Data on outcomes of microsatellite instable and/or mismatch repair deficient (dMMR/MSI) digestive non-colorectal tumors are limited. AIMS: To evaluate overall survival (OS) of patients with dMMR/MSI digestive non-colorectal tumor. METHODS: All consecutive patients with a dMMR/MSI digestive non-colorectal tumor were included in this French retrospective multicenter study. RESULTS: One hundred and sixteen patients were included with a mean age of 63.6 years and 32.6% with a Lynch syndrome. Most tumors were oesophago-gastric (54.3%) or small bowel (32.8%) adenocarcinomas and at a localized stage at diagnosis (86.7%). In patients with localized tumors and R0 resection, median OS was 134.0 ± 64.2 months. Median disease-free survival (DFS) was 100.3 ± 65.7 months. Considering oesophago-gastric tumors, median DFS was improved when chemotherapy was added to surgery (not reached versus 22.8 ± 10.0 months, p = 0.03). In patients with advanced tumors treated by chemotherapy, median OS was 14.2 ± 1.9 months and median progression-free survival was 7.4 ± 1.6 months. CONCLUSION: dMMR/MSI digestive non-colorectal tumors are mostly diagnosed at a non-metastatic stage with a good prognosis. Advanced dMMR/MSI digestive non-colorectal tumors have a poor prognosis with standard chemotherapy.

FOLFIRI plus BEvacizumab or aFLIbercept after FOLFOX-bevacizumab failure for COlorectal cancer (BEFLICO): An AGEO multicenter study.

After failure of first line FOLFOX-bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second-line FOLFIRI increases survival compared to FOLFIRI alone. In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI-aflibercept or FOLFIRI-bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), disease control rate (DCR: CR + PR + SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2 years and 45.2% of patients were men. Most patients had RAS-mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2 months, median OS was 13.0 months (95% CI: 11.3-14.7) and 10.4 months (95% CI: 8.8-11.4) in the bevacizumab and aflibercept groups, respectively (P < .0001). Median PFS was 6.0 months (95% CI: 5.4-6.5) and 5.1 months (95% CI: 4.3-5.6) (P < .0001). After adjustment on age, PS, PFS of first line, primary tumor resection, metastasis location and RAS/BRAF status, bevacizumab was still associated with better OS (HR: 0.71, 95% CI: 0.59-0.86, P = .0003). FOLFIRI-bevacizumab combination was associated with longer OS and PFS, and a better tolerability, as compared to FOLFIRI-aflibercept after progression on FOLFOX-bevacizumab.

Prevalence and prognosis of microsatellite instability in oesogastric adenocarcinoma, NORDICAP 16-01.

BACKGROUND: The prevalence and prognosis association of microsatellite instability (MSI) in oesogastric junction and gastric adenocarcinoma (OGC) have been reported with conflicting results. METHODS: Patients with OGC from 2010 to 2015 were enrolled in this retrospective multicenter study. MSI was determined by genotyping. MLH1 promoter methylation and BRAFV600E mutation were screened in the MSI tumors. RESULTS: Among 315 tumors analyzed, 39 (12.4%) were of the MSI phenotype. Compared to MSS tumors, MSI tumors were more frequent in patients >70 years (17% vs 9%, p=0.048) and in gastric antral primary (20% versus 5% in junction tumor and 12% in fundus tumor. Among 29 MSI tumors analyzed, 28 had a loss of MLH1 protein expression and 27 had MLH1 promotor hypermethylation. None had a BRAF V600E mutation. The 4-year cumulative incidence of recurrence for patients with resected tumor was significantly lower in dMMR tumors versus pMMR tumors (17% versus 47%, p=0.01). For the patients with unresectable tumor the median overall survival was 11 months in MSS group and 14 months in MSI group (p=0.24). CONCLUSION: MSI prevalence in OGC was 12.4%, associated with antral localization and advanced age. Patients with MSI tumors had a lower cumulative incidence of recurrence after surgery. MSI phenotype was mainly associated with loss of MLH1 protein expression, MLH1 promotor hypermethylation and had no BRAFV600E mutation.

Does neoadjuvant FOLFOX chemotherapy improve the prognosis of high-risk Stage II and III colon cancers? Three years' follow-up results of the PRODIGE 22 phase II randomized multicentre trial.

AIM: Neoadjuvant chemotherapy has proven valuable in locally advanced resectable colon cancer (CC) but its effect on oncological outcomes is uncertain. The aim of the present paper was to report 3-year oncological outcomes, representing the secondary endpoints of the PRODIGE 22 trial. METHOD: PRODIGE 22 was a randomized multicentre phase II trial in high-risk T3, T4 and/or N2 CC patients on CT scan. Patients were randomized between 6 months of adjuvant FOLFOX (upfront surgery) or perioperative FOLFOX (four cycles before surgery and eight cycles after; FOLFOX perioperative). In wild-type RAS patients, a third arm testing perioperative FOLFOX-cetuximab was added. The primary endpoint was the tumour regression grade. Secondary endpoints were 3-year overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and time to recurrence (TTR). RESULTS: Overall, 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients represented our intention-to-treat population. In the perioperative group, 96% received the scheduled four neoadjuvant cycles and all but one had adjuvant FOLFOX for eight cycles. In the control arm, 38 (73%) patients received adjuvant FOLFOX. The median follow-up was 54.3 months. Three-year OS was 90.4% in both arms [hazard ratio (HR) = 0.85], 3-year DFS, RFS and TTR were, respectively, 76.8% and 69.2% (HR=0.94), 73% and 69.2% (HR = 0.86) and 82% and 72% (HR = 0.67) in the perioperative and control arms, respectively. Forest plots did not show any subgroup with significant difference for survival outcomes. No benefit from adding cetuximab was observed. CONCLUSION: Perioperative FOLFOX has no detrimental effect on long-term oncological outcomes and may be an option for some patients with locally advanced CC.

Impact of tobacco smoking on the patient's outcome after (chemo)radiotherapy for anal cancer.

PURPOSE: Anal squamous cell carcinoma is associated with multiple risk factors, including infection with human papillomavirus and human immunodeficiency virus, immunosuppression, multiple sex partners, receptive anal sex and tobacco smoking. The aim of our study was to identify prognostic factors associated with poor outcomes after radiotherapy for anal cancer. METHODS: We analysed retrospectively the medical records of 171 patients treated by (chemo)radiotherapy for non-metastatic anal cancer in our institution from 2000 to 2015. Patients and tumour characteristics, treatments (chemotherapy, radiotherapy [RT] and surgery) and outcomes were reported. Colostomy-free survival (CRF), disease-free survival and overall survival (OS) at 5 years were studied. Univariate and multivariate analyses were performed by logistic regression to determine factors associated with poor progression-free survival (PFS). RESULTS: Patients' characteristics were as follows: median age, 62 years (range = 36-89); gender, 45 men (26%) and 126 women (74%); HIV serology, positive: 21 patients (12%); tobacco smoking, 86 patients (50%), among whom 28 patients and 58 patients were current and former smokers, respectively. Tumours were classified as locally limited (T1-2, N0, M0) for 86 patients (50%) and locally advanced (T3-4 or N+, M0) for 85 patients (50%). The median total dose was 64.4 Gy (range = 54-76.6), and 146 patients were treated by concurrent chemoradiotherapy. Factors associated with poor PFS in univariate analysis were as follows: tumour size >4 cm, lymph node involvement, tobacco smoking, no initial surgical excision and anal warts at diagnosis. In multivariate analysis, only tobacco smoking status was significantly associated with poor PFS (hazard ratio = 2.85, 95% confidence interval [1.25-6.50], p = 0.013). Five-year PFS for non-smokers, former smokers and current smokers was 88.1%, 76.7% and 73.8%, respectively (p = 0.038). Tobacco smoking was also associated with poor overall survival (p = 0.03), locoregional relapse-free survival (LRFS; p = 0.05) and CFS (p = 0.02). CONCLUSIONS: Tobacco smoking status is associated with poor OS, LRFS, PFS and CFS in patients treated for anal cancer by high RT dose ± chemotherapy.

Low phospholipid-associated cholelithiasis syndrome: A rare cause of acute pancreatitis that should not be neglected.

BACKGROUND: Low phospholipid-associated cholelithiasis (LPAC) syndrome is a very particular form of biliary lithiasis with no excess of cholesterol secretion into bile, but a decrease in phosphatidylcholine secretion, which is responsible for stones forming not only in the gallbladder, but also in the liver. LPAC syndrome may be underreported due to a lack of testing resulting from insufficient awareness among clinicians. AIM: To describe the clinical and radiological characteristics of patients with LPAC syndrome to better identify and diagnose the disease. METHODS: We prospectively evaluated all patients aged over 18 years old who were consulted or hospitalized in two hospitals in Paris, France (Bichat University Hospital and Croix-Saint-Simon Hospital) between January 1, 2017 and August 31, 2018. All patients whose profiles led to a clinical suspicion of LPAC syndrome underwent a liver ultrasound examination performed by an experienced radiologist to confirm the diagnosis of LPAC syndrome. Twenty-four patients were selected. Data about the patients' general characteristics, their medical history, their symptoms, and their blood tests results were collected during both their initial hospitalization and follow-up. Cytolysis and cholestasis were expressed compared to the normal values (N) of serum aspartate and alanine transaminase activities, and to the normal value of alkaline phosphatase level, respectively. The subjects were systematically reevaluated and asked about their symptoms 6 mo after inclusion in the study through an in-person medical appointment or phone call. Genetic testing was not performed systematically, but according to the decision of each physician. RESULTS: Most patients were young (median age of 37 years), male (58%), and not overweight (median body mass index was 24). Many had a personal history of acute pancreatitis (54%) or cholecystectomy (42%), and a family history of gallstones in first-degree relatives (30%). LPAC syndrome was identified primarily in patients with recurring biliary pain (88%) or after a new episode of acute pancreatitis (38%). When present, cytolysis and cholestasis were not severe (2.8N and 1.7N, respectively) and disappeared quickly. Interestingly, four patients from the same family were diagnosed with LPAC syndrome. At ultrasound examination, the most frequent findings in intrahepatic bile ducts were comet-tail artifacts (96%), microlithiasis (83%), and acoustic shadows (71%). Computed tomography scans and magnetic resonance imaging were performed on 15 and three patients, respectively, but microlithiasis was not detected. Complications of LPAC syndrome required hospitalizing 18 patients (75%) in a conventional care unit for a mean duration of 6.8 d. None of them died. Treatment with ursodeoxycholic acid (UDCA) was effective and well-tolerated in almost all patients (94%) with a rapid onset of action (3.4 wk). Twelve patients' (67%) adherence to UDCA treatment was considered "good." Five patients (36%) underwent cholecystectomy (three of them were treated both by UDCA and cholecystectomy). Despite UDCA efficacy, biliary pain recurred in five patients (28%), three of whom adhered well to treatment guidelines. CONCLUSION: LPAC syndrome is easy to diagnose and treat; therefore, it should no longer be overlooked. To increase its detection rate, all patients who experience recurrent biliary symptoms following an episode of acute pancreatitis should undergo an ultrasound examination performed by a radiologist with knowledge of the disease.

Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study).

BACKGROUND: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting. MATERIALS AND METHODS: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR). RESULTS: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007). CONCLUSION: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF. IMPLICATIONS FOR PRACTICE: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study.

Mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI) colorectal cancers (CRC) represent about 5% of metastatic CRC (mCRC). Prognosis and chemosensitivity of dMMR/MSI mCRC remain unclear. This multicenter study included consecutive patients with dMMR/MSI mCRC from 2007 to 2017. The primary endpoint was the progression-free survival (PFS) in a population receiving first-line chemotherapy. Associations between chemotherapy regimen and survival were evaluated using a Cox regression model and inverse of probability of treatment weighting (IPTW) methodology in order to limit potential biases. Overall, 342 patients with dMMR/MSI mCRC were included. Median PFS and overall survival (OS) on first-line chemotherapy were 6.0 and 26.3 months, respectively. For second-line chemotherapy, median PFS and OS were 4.4 and 21.6 months. Longer PFS (8.1 vs. 5.4 months, p = 0.0405) and OS (35.1 vs. 24.4 months, p = 0.0747) were observed for irinotecan-based chemotherapy compared to oxaliplatin-based chemotherapy. The association was no longer statistically significant using IPTW methodology. In multivariable analysis, anti-VEGF as compared to anti-EGFR was associated with a trend to longer OS (HR = 1.78, 95% CI 1.00-3.19, p = 0.0518), whatever the backbone chemotherapy used. Our study shows that dMMR/MSI mCRC patients experienced short PFS with first-line chemotherapy with or without targeted therapy. OS was not different according to the chemotherapy regimen used, but a trend to better OS was observed with anti-VEGF. Our study provides some historical results concerning chemotherapy in dMMR/MSI mCRC in light of the recent nonrandomized trials with immune checkpoint inhibitors.

Efficacy of modern chemotherapy and prognostic factors in patients with ovarian metastases from gastric cancer: A retrospective AGEO multicentre study.

BACKGROUND: Ovarian metastases from gastrointestinal tumours frequently lead to locoregional complications and undermine quality of life. The chemosensitivity of ovarian metastases from gastric cancer is unknown. AIM: To evaluate the efficacy of modern chemotherapy regimens in first-line treatment for patients with ovarian metastases from gastric cancer. METHODS: All consecutive patients with ovarian metastases from gastric cancer who received at least one cycle of chemotherapy were included in this retrospective study. RESULTS: Thirty-five patients were included (median age, 50.5 years; synchronous ovarian metastases, 60%). Seventeen patients (48.6%) underwent oophorectomy. Patients were treated with first-line chemotherapy based on platinum (n=14), irinotecan (n=8), taxane plus platinum (n=4) or epirubicin plus platinum (n=9). The median PFS and OS were 6.8 and 18.8 months, respectively. The objective response rate (ORR) for extra-ovarian (13.6%) and ovarian (20.9%) metastatic sites was not significantly different (p=0.55). There was no significant difference in terms of ORR on ovarian metastatic site according to the first-line chemotherapy (p=0.21). In multivariate analysis, oophorectomy was an independent prognostic factor for OS (p<0.01). CONCLUSIONS: This study suggests that ovarian metastases from gastric cancer are not more resistant than extra-ovarian metastases, and that oophorectomy is an independent prognostic factor significantly linked to OS. Prospective studies are needed to confirm these results.