Optimizing the biomarker combination to be analyzed in liquid biopsies should improve personalized medicine. We developed a method to purify circulating cell-free mRNAs from plasma samples and to ...quantify them by RT-qPCR. We selected three candidate colorectal cancer biomarkers (B2M, TIMP-1, and CLU). Their mRNA levels were significantly higher in plasma of patients with metastatic colorectal cancer patients (mCRC) (n = 107) than in healthy individuals (HI) (n = 53). To increase the discriminating performance of our method, we analyzed the sum of the three mRNA levels (BTC index). The area under the ROC curve (AUC) to estimate the BTC index capacity to discriminate between mCRC and HI plasma was 0.903. We also determined the optimal BTC index cut-off to distinguish between plasma samples, with 82% of sensitivity and 93% of specificity. By using mRNA as a novel liquid biopsy analytical parameter, our method has the potential to facilitate rapid screening of CRCm.
Objective: The prognosis of pancreatic cancer after curative surgery is burdened by frequent recurrence. The aim of this study was to evaluate the impact of dysplasia in the surgical specimen on ...disease-free survival (DFS). Methods: A post-hoc analysis of the phase III PRODIGE 24-CCTG PA 6 trial was performed. From April 2012 to October 2016, 493 patients were included in the primary study. Assessment for dysplasia in the surgical specimens was secondarily performed. Dysplasia was defined based on presence and grade of three most common pre-malignant lesions (intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN) and pancreatic intraepithelial neoplasia (PanIN). The primary endpoint was DFS validated through multivariate analysis. Results: Two hundred twenty-six patients (45.9%) had a preneoplastic lesion. PanIN lesions were found in 193 patients (39.2%), including 100 high-grade lesions (20.6%); 43 patients had IPMN lesions (8.7%), including high-grade lesions in 32 (6.5%). Three MCN were described (0.6%). In bivariate analysis, the presence of dysplasia was not associated with poorer DFS (HR = 0.82, 95% CI 0.66; 1.03). In multivariate analysis, risk factors for poorer DFS were poorly differentiated/undifferentiated tumor, N1 status, R1 surgical margins and perineural invasion. Conclusions: The presence of dysplasia in the surgical specimen after pancreatic cancer surgery does not worsen DFS.
The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French ...patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5-7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.
Objective: This study investigated the correlation between positive resection margins and outcomes in patients with pancreatic ductal adenocarcinoma who underwent surgery and adjuvant chemotherapy ...according to the pivotal trial PRODIGE 24-CCTG PA-6. Background: The primary focus is on elucidating the prognostic significance of specific resection margins, including those associated with the superior-mesenteric vein (SMV), medial, and posterior pancreas. Methods: The analysis involved 400 patients across multiple centers in France and Canada. Surgical resection and subsequent adjuvant chemotherapy were core interventions. This study assessed the prognostic impact of resection margins, highlighting the significance of standardized pathology assessments. Additionally, the influence of chemotherapy regimen choice, comparing gemcitabine to mFOLFIRINOX, on the implications of positive resection margins was examined. Results: Only three margins, SMV (HR=1.48 95% CI 1.11;1.96, P <.001), medial (HR=1.92 95% CI 1.36;2.73, P <.001) and posterior (HR=1.65 95% CI 1.21;2.24, P =.002), had a significant prognostic impact on disease-free survival and were sufficient compared with the seven recommended margins (Kappa=0.90 95% CI 0.87; 0.94). R1 status was significant independent prognostic factor for poorer survival in gemcitabine-treasted patients (HR=1.97 95% CI 1.23;3.16, P =.005) but lost its significance with mFOLFIRINOX (HR=1.46 95% CI 0.91;2.35, P =.114). Conclusions: All efforts should be made to evaluate the three margins of the highest prognostic value, with the others being secondary. A key finding of this study is the likely effect of mFOLFIRINOX on local invasion in operated patients, which seems to correct the impairment related to margin involvement, probably explaining the improvements in DFS and OS.
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Background: Pancreatic adenocarcinoma (PDAC) has a poor prognosis. Only 10-15% of patients present with resectable tumors upfront, and most patients develop recurrence and die prematurely. The ...data are incongruous when considering R1 status, direct invasion is not consistently a significant prognostic factor. It is recommended that 7 margins be identified for surgery: the bile duct, pancreatic neck, proximal and distal duodenum, superior mesenteric vein (SMV), superior mesenteric artery (SMA), and posterior pancreas. By analyzing data from the PRODIGE 24-CCTG PA-6 trial that validated the mFOLFIRINOX regimen in adjuvant setting, our main objective was to analyze the prognostic value of margin involvement on disease-free survival (DFS). Methods: The protocol recommended that the surgeon inked the resection margins. R1 was defined as direct tumor margin infiltration within 1 mm of one or more resection margins. All patient data were re-evaluated centrally by an external review committee including pathologists, surgeons, and medical oncologists to verify key prognostic factors, including inking and filling of resection margins. Results: Among the 400 patients included in the study, the median number of documented margins was 6, IQR (5-7). In 214 patients (53.5%), fewer than 7 margins were reported. The most common margin involvement was on the SMV groove (28.3%), posterior margin (21%), SMA (14.5%), and pancreatic neck transection (5.3%). Margin inking was performed in 64.9% of cases. Misclassification of the R1 status concerned 24.1% of the files after centralized review. When positive, only 3 margins (SMV groove, median and posterior) were significant prognostic factors in unifactorial analysis (all p < 0.01). When combined, one R1 margin among these three had independent prognostic value in multivariable analysis. In multivariate analysis, DFS was significantly different by quality of resection margins in the gemcitabine arm (HR 95% CI 1.97 1.23;3.16; p = .005) but not in the mFOLFIRINOX arm (HR 95% CI 1.46 0.91;2.35; p = .114). Conclusions: Few studies have examined the prognostic implications of each margin. We consider that every effort should be made to evaluate the 3 best prognostic margins. One finding of this work is the likely effect of mFOLFIRINOX on local invasion in operated patients. It seems that this chemotherapy regimen (unlike gemcitabine) corrects the alteration related to margin involvement, probably explaining all or part of the improved survival. Therefore, the value of additional therapies, such as cloture radiotherapy, should be evaluated in patients with unknown marginal status or in those who did not benefit from mFOLFIRINOX chemotherapy. A patient who received mFOLFIRINOX as adjuvant therapy is more likely to recur with distant metastasis (80%) and with a better survival of 28 months. Clinical trial information: NCT01526135 .
Early results at 3 years from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial showed survival benefits with adjuvant treatment with modified FOLFIRINOX vs gemcitabine in ...patients with resected pancreatic ductal adenocarcinoma; mature data are now available.
To report 5-year outcomes and explore prognostic factors for overall survival.
This open-label, phase 3 randomized clinical trial was conducted at 77 hospitals in France and Canada and included patients aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who had undergone complete macroscopic (R0/R1) resection within 3 to 12 weeks before randomization. Patients were included from April 16, 2012, through October 3, 2016. The cutoff date for this analysis was June 28, 2021.
A total of 493 patients were randomized (1:1) to receive treatment with modified FOLFIRINOX (oxaliplatin, 85 mg/m2 of body surface area; irinotecan, 150-180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 2400 mg/m2, every 2 weeks) or gemcitabine (1000 mg/m2, days 1, 8, and 15, every 4 weeks) as adjuvant therapy for 24 weeks.
Primary end point was disease-free survival. Secondary end points included overall survival, metastasis-free survival, and cancer-specific survival. Prognostic factors for overall survival were determined.
Of the 493 patients, 216 (43.8%) were women, and the mean (SD) age was 62.0 (8.9) years. At a median of 69.7 months' follow-up, 367 disease-free survival events were observed. In patients receiving chemotherapy with modified FOLFIRINOX vs gemcitabine, median disease-free survival was 21.4 months (95% CI, 17.5-26.7) vs 12.8 months (95% CI, 11.6-15.2) (hazard ratio HR, 0.66; 95% CI, 0.54-0.82; P < .001) and 5-year disease-free survival was 26.1% vs 19.0%; median overall survival was 53.5 months (95% CI, 43.5-58.4) vs 35.5 months (95% CI, 30.1-40.3) (HR, 0.68; 95% CI, 0.54-0.85; P = .001), and 5-year overall survival was 43.2% vs 31.4%; median metastasis-free survival was 29.4 months (95% CI, 21.4-40.1) vs 17.7 months (95% CI, 14.0-21.2) (HR, 0.64; 95% CI, 0.52-0.80; P < .001); and median cancer-specific survival was 54.7 months (95% CI, 45.8-68.4) vs 36.3 months (95% CI, 30.5-43.9) (HR, 0.65; 95% CI, 0.51-0.82; P < .001). Multivariable analysis identified modified FOLFIRINOX, age, tumor grade, tumor staging, and larger-volume center as significant favorable prognostic factors for overall survival. Shorter relapse delay was an adverse prognostic factor.
The final 5-year results from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial indicate that adjuvant treatment with modified FOLFIRINOX yields significantly longer survival than gemcitabine in patients with resected pancreatic ductal adenocarcinoma.
EudraCT: 2011-002026-52; ClinicalTrials.gov Identifier: NCT01526135.
GemPred, a transcriptomic signature predictive of the efficacy of adjuvant gemcitabine (GEM), was developed from cell lines and organoids and validated retrospectively. The phase III PRODIGE-24/CCTG ...PA6 trial has demonstrated the superiority of modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX) over GEM as adjuvant therapy in patients with resected pancreatic ductal adenocarcinoma at the expense of higher toxicity. We evaluated the potential predictive value of GemPred in this population.
Routine formalin-fixed paraffin-embedded surgical specimens of 350 patients were retrieved for RNA sequencing and GemPred prediction (167 in the GEM arm and 183 in the mFOLFIRINOX mFFX arm). Survival analyses were stratified by resection margins, lymph node status, and cancer antigen 19-9 level.
Eighty-nine patients' tumors (25.5%) were GemPred+ and were thus predicted to be gemcitabine-sensitive. In the GEM arm, GemPred+ patients (n = 50, 30%) had a significantly longer disease-free survival (DFS) than GemPred- patients (n = 117, 70%; median 27.3
10.2 months, hazard ratio HR, 0.43 95% CI, 0.29 to 0.65;
< .001) and cancer-specific survival (CSS; median 68.4
28.6 months, HR, 0.42 95% CI, 0.27 to 0.66;
< .001). GemPred had no prognostic value in the mFFX arm. DFS and CSS were similar in GemPred+ patients who received adjuvant GEM and mFFX (median 27.3
24.0 months, and 68.4
51.4 months, respectively). The statistical interaction between GEM and GemPred+ status was significant for DFS (
= .008) and CSS (
= .004). GemPred+ patients had significantly more adverse events of grade ≥3 in the mFFX arm (76%) compared with those in the GEM arm (40%;
= .001).
This ancillary study of a phase III randomized trial demonstrates that among the quarter of patients with a GemPred-positive transcriptomic signature, survival was comparable with that of mFOLFIRINOX, whereas those receiving adjuvant gemcitabine had fewer adverse events.
This multi-cohort trial explored the efficacy and safety of regorafenib for patients with advanced sarcomas of bone origin; this report details the cohort of patients with metastatic or locally ...advanced chondrosarcoma (CS), progressing after prior chemotherapy.
Patients with CS, progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progressive disease. The primary endpoint was progression-free rate (PFR) at 12 weeks. With one-sided α of 0.05, and 80% power, at least 16/24 progression-free patients at 12 weeks were needed for success (P0 = 50%, P1 = 75%).
From September 2014 to February 2019, 46 patients were included in the CS cohort, and 40 patients were evaluable for efficacy: 16 on placebo and 24 on regorafenib. Thirteen patients (54.2%; 95% CI 35.8%-) were non-progressive at 12 weeks on regorafenib versus 5 (31.3%; 95% CI 13.2%-);) on placebo. Median PFS was 19.9 weeks on regorafenib, and 8.0 on placebo. Fourteen placebo patients crossed over to regorafenib after progression. The most common grade ≥3 treatment-related adverse events on regorafenib included hypertension (12%), asthenia (8%), thrombocytopenia (8%) and diarrhoea (8%). One episode of fatal liver dysfunction occurred on regorafenib.
Although the primary endpoint was not met statistically in this small randomised cohort, there is modest evidence to suggest that regorafenib might slow disease progression in patients with metastatic CS after the failure of prior chemotherapy.
The trial is registered at ClinicalTrials.gov (NCT02389244).
•Progression-free rate at 12 weeks was 54% on regorafenib and 31% on placebo.•Median PFS was 19.9 weeks on regorafenib, and 8.0 weeks on placebo.•PFS rate at 24 weeks was 43% for patients on regorafenib and 25% on placebo.•The safety of regorafenib was as expected despite one fatal case of hepatic toxicity.•These results suggest modest activity of regorafenib in metastatic chondrosarcoma.
Although gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, ...possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies.
We performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan–Meier curves and a Cox regression model stratified on the trial.
Two hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio HR = 0.91 95% confidence interval CI 0.71–1.16; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%–47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%–43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 95%CI: 0.78–1.35; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%–57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%–56.5%) for observation.
With 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.
•The role of gemcitabine-based adjuvant treatment in biliary tract cancer is uncertain.•The role of gemcitabine-based adjuvant treatment in biliary tract cancer is unproven.•We performed a combined analysis (n = 419) of the two recent trials BCAT and PRODIGE 12.•The analysis does not show benefit in recurrence-free survival or overall survival.•Gemcitabine-based adjuvant chemotherapy should not be used in biliary tract cancers.
The REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort.
Patients with relapsed ES ...progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success.
From September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI 37.5%-)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI 0.4%-) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%).
Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.
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