Post-surgery sequelae unrelated to disease progression and chemotherapy revealed in follow-up of patients with stage III colon cancer.

BACKGROUND: We studied the poorly-known dynamics of circulating DNA (cir-nDNA), as monitored prospectively over an extended post-surgery period, in patients with cancer. METHODS: On patients with stage III colon cancer (N = 120), using personalised molecular tags we carried out the prospective, multicenter, blinded cohort study of the post-surgery serial analysis of cir-nDNA concentration. 74 patients were included and 357 plasma samples tested. FINDINGS: During post-operative follow-up, the patients' median cir-nDNA concentration was greater (P < 0.0001 in the [43-364 days range]) than both the median value in healthy individuals and the pre-surgery value. These cir-nDNA levels were highly associated with NETs markers (P-value associating MPO and cir-nDNA, and NE and cir-nDNA are 6.6 x 10-17, and 1.9 x 10-7), in accordance with previous reports which indicate that cir-nDNA are NETs by-products. Unexpectedly, in 34 out of 50 patients we found that NETs continued to be formed for an extended duration post-surgery, even in patients without disease progression. Given that this phenomenon was observed in patients without adjuvant CT, and in patients >18 months post-surgery, the data suggest that the persistence of NETs formation is not due to the adjuvant CT. INTERPRETATION: (1), Given the inter-patient heterogeneity, the post-surgery cir-nDNA level cannot be considered a reliable value, and caution must be exercised when determining mutation allele frequency or the mutation status; and (2), specific studies must be undertaken to investigate the possible clinical impact of the persistent, low-grade inflammation resulting from elevated NETs levels, such as observed in these post-surgery patients, given that such levels are known to potentially induce adverse cardiovascular or thrombotic events. FUNDING: This work was supported by the H2020 European ERA-NET grant on Translational Cancer Research (TRANSCAN-2).

Preoperative Chemoradiotherapy vs Chemotherapy for Adenocarcinoma of the Esophagogastric Junction: A Network Meta-Analysis.

Importance: The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone. Objective: To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes. Data Sources: Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023. Study Selection: Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach. Main Outcomes and Measures: Overall and disease-free survival, postoperative morbidity, and mortality. Results: The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]). Conclusions and Relevance: In this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.

Regorafenib plus FOLFIRINOX as first-line treatment for patients with RAS-mutant metastatic colorectal cancer (FOLFIRINOX-R trial): a dose-escalation study.

PURPOSE: The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC. METHODS: The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180 mg/m²). Regorafenib (120 or 160 mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC. RESULTS: Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs. CONCLUSION: The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov : NCT03828799.

Triplet chemotherapy plus cetuximab as first-line treatment in extended RAS wild-type metastatic colorectal cancer patients.

BACKGROUND: Triplet chemotherapy plus cetuximab showed promising results in phase II trials in unsystematically selected RAS population. We evaluated FOLFIRINOX+cetuximab efficacy as first-line treatment in extended RAS wild-type metastatic colorectal cancer (mCRC) patients. METHODS: We retrospectively analyzed patients treated with FOLFIRINOX+cetuximab, using data from clinical trials and real-life practice. Extended mutation analysis was performed when RAS/BRAF status was unavailable. The primary endpoint was progression-free survival (PFS). RESULTS: Seventy patients (61.4 % male, median age 58.7 years) were analyzed. Eighty percent had left-sided mCRC and 97.1 % had liver metastases. Median PFS and overall survival (OS) were 13.3 and 48.5 months, respectively. The objective response rate was 85.7 %, with 20 % complete response. Primary tumor location did not affect OS and PFS. BRAF wild-type patients (n = 65) had longer PFS (13.3 vs. 6.0 months; p = 0.005) and OS (50.1 vs. 21.2 months; p = 0.007) than BRAF mutated patients (n = 5, including four BRAFV600E). Median OS was significantly longer in resected patients (n = 39, 55.1 vs. 30.7 months; p = 0.030). Main toxicities were diarrhea (31.4 %) and neutropenia (21.4 %). CONCLUSION: FOLFIRINOX+cetuximab provides good PFS, high response rate and prolonged disease control in initially unresectable extended RAS wild-type mCRC. This combination is particularly interesting for selected patients with liver-limited disease eligible to secondary resection.

A prospective registry study of stereotactic magnetic resonance guided radiotherapy (MRgRT) for primary liver tumors.

BACKGROUND AND PURPOSE: Stereotactic body radiation therapy (SBRT) has demonstrated safe and effective results for primary liver tumors. Magnetic Resonance guided Radiotherapy (MRgRT) is an innovative radiotherapy modality for abdominal tumors. The aim of this study is to report on acute and late toxicities and initial oncological results for primary liver tumors treated with MRgRT. MATERIALS AND METHODS: We prospectively included in our cohort all patients treated by MRgRT for a primary liver tumor at the Montpellier Cancer Institute. The primary endpoint was acute and late toxicities assessed according to CTCAE v 5.0. The mean prescribed dose was 50 Gy in 5 fractions. RESULTS: Between October 2019 and April 2022, MRgRT treated 56 patients for 72 primary liver lesions. No acute or late toxicities of CTCAE grade greater than 2 attributable to radiotherapy were noted during follow-up. No cases of radiation-induced liver disease (RILD), either classical or non-classical, occurred. After a median follow-up of 13.2 months (95% CI [8.8; 15.7]), overall survival was 85.1% (95% CI: [70.8; 92.7]) at 1 year and 74.2% at 18 months (95% CI [52.6; 87.0]). Local control was 98.1% (95% CI: [87.4; 99.7]) and 94.7% (95% CI: [79.5; 98.7]) at 12 and 18 months, respectively. Among the HCC subgroup, no local recurrences were observed. CONCLUSION: MRgRT for primary liver tumors is safe without severe adverse events and reach excellent local control. Numerous studies are underway to better assess the value of MRI guidance and adaptive process in these indications.

Individual Participant Data Network Meta-Analysis of Neoadjuvant Chemotherapy or Chemoradiotherapy in Esophageal or Gastroesophageal Junction Carcinoma.

PURPOSE: The optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data (IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups. PATIENTS AND METHODS: All, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158). RESULTS: IPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99), P = .03 and HR = 0.77 (0.68 to 0.87), P < .001 respectively. The NMA comparison of CRS versus CS for OS gave a HR of 0.90 (0.74 to 1.09), P = .27 (consistency P = .26, heterogeneity P = .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors (P = .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women (P = .003, .012, respectively). CONCLUSION: Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.

A straightforward method to quantify circulating mRNAs as biomarkers of colorectal cancer.

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.

Stereotactic MR-Guided Radiotherapy for Liver Metastases: First Results of the Montpellier Prospective Registry Study.

Liver stereotactic body radiotherapy (SBRT) is a local treatment that provides good local control and low toxicity. We present the first clinical results from our prospective registry of stereotactic MR-guided radiotherapy (MRgRT) for liver metastases. All patients treated for liver metastases were included in this prospective registry study. Stereotactic MRgRT indication was confirmed by multidisciplinary specialized tumor boards. The primary endpoints were acute and late toxicities. The secondary endpoints were survival outcomes (local control, overall survival (OS), disease-free survival, intrahepatic relapse-free survival). Twenty-six consecutive patients were treated for thirty-one liver metastases between October 2019 and April 2022. The median prescribed dose was 50 Gy (40-60) in 5 fractions. No severe acute MRgRT-related toxicity was noted. Acute and late gastrointestinal and liver toxicities were low and mostly unrelated to MRgRT. Only 5 lesions (16.1%) required daily adaptation because of the proximity of organs at risk (OAR). With a median follow-up time of 17.3 months since MRgRT completion, the median OS, 1-year OS and 2-year OS rates were 21.7 months, 83.1% (95% CI: 55.3-94.4%) and 41.6% (95% CI: 13.5-68.1%), respectively, from MRgRT completion. The local control at 6 months, 1 year and 2 years was 90.9% (95% CI: 68.3-97.7%). To our knowledge, we report the largest series of stereotactic MRgRT for liver metastases. The treatment was well-tolerated and achieved a high LC rate. Distant relapse remains a challenge in this population.

Tumor Growth Rate Informs Treatment Efficacy in Metastatic Pancreatic Adenocarcinoma: Application of a Growth and Regression Model to Pivotal Trial and Real-World Data.

BACKGROUND: Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. METHODS: We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. RESULTS: g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. CONCLUSIONS: Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.

The landscape of cancer-associated fibroblasts in colorectal cancer liver metastases.

Rationale: Patients with colorectal cancer die mainly due to liver metastases (CRC-LM). Although the tumor microenvironment (TME) plays an important role in tumor development and therapeutic response, our understanding of the individual TME components, especially cancer-associated fibroblasts (CAFs), remains limited. Methods: We analyzed CRC-LM CAFs and cancer cells by single-cell transcriptomics and used bioinformatics for data analysis and integration with related available single-cell and bulk transcriptomic datasets. We validated key findings by RT-qPCR, western blotting, and immunofluorescence. Results: By single-cell transcriptomic analysis of 4,397 CAFs from six CRC-LM samples, we identified two main CAF populations, contractile CAFs and extracellular matrix (ECM)-remodeling/pro-angiogenic CAFs, and four subpopulations with distinct phenotypes. We found that ECM-remodeling/pro-angiogenic CAFs derive from portal resident fibroblasts. They associate with areas of strong desmoplastic reaction and Wnt signaling in low-proliferating tumor cells engulfed in a stiff extracellular matrix. By integrating public single-cell primary liver tumor data, we propose a model to explain how different liver malignancies recruit CAFs of different origins to this organ. Lastly, we found that LTBP2 plays an important role in modulating collagen biosynthesis, ECM organization, and adhesion pathways. We developed fully human antibodies against LTBP2 that depleted LTBP2+ CAFs in vitro. Conclusion: This study complements recent reports on CRC-LM CAF heterogeneity at the single-cell resolution. The number of sequenced CAFs was more than one order of magnitude larger compared to existing data. LTBP2 targeting by antibodies might create opportunities to deplete ECM-remodeling CAFs in CRC-LMs. This might be combined with other therapies, e.g., anti-angiogenic compounds as already done in CRC. Moreover, we showed that in intrahepatic cholangiocarcinoma, in which ECM-remodeling CAF proportion is similar to that of CRC-LM, several genes expressed by ECM-remodeling CAFs, such as LTBP2, were associated with survival.

Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial.

Importance: 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. Objective: To report 5-year outcomes and explore prognostic factors for overall survival. Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: EudraCT: 2011-002026-52; ClinicalTrials.gov Identifier: NCT01526135.

The desmoplastic growth pattern is associated with second-stage completion and longer survival in 2-stage hepatectomy for colorectal cancer liver metastases.

BACKGROUND: Two-stage hepatectomy for bilobar colorectal cancer liver metastases is potentially curative for selected patients. Histological growth patterns of colorectal liver metastases (desmoplastic, replacement, and pushing) have prognostic value. Our aim was to evaluate their association with pathologic response to preoperative treatment, second-stage hepatectomy completion, and survival in patients treated with a curative-intent 2-stage hepatectomy. METHODS: In 67 patients planned for 2-stage hepatectomy, colorectal liver metastases resected from the first-stage hepatectomy were retrospectively evaluated for growth patterns and pathologic response according to Tumor Regression Grading, modified Tumor Regression Grading, and Blazer grading. Tumor Regression Grading 1 to 3, modified Tumor Regression Grading 1 to 3, and Blazer 0 and 1 defined good responders. RESULTS: Desmoplastic growth patterns (GP) were more frequent among good responders (P < .001). Second-stage hepatectomy completion was associated with desmoplastic growth patterns and pathologic response on univariate analysis and multivariable analyses (P = .017 and P = .041, respectively). Median follow-up was 84 months (95% confidence interval: 53.4 [not reached]). Nondesmoplastic GP patients and nonresponders had a poorer overall survival (hazard ratio = 3.86, 95% confidence interval: 2.11-7.07, P < .001 and hazard ratio = 2.14, 95% confidence interval: 1.19-3.83, P = .009, respectively) on univariate analysis. Nondesmoplastic growth pattern was the only factor associated with a poorer overall survival on multivariable analysis (hazard ratio = 4.17, 95% confidence interval: 1.79-9.74, P < .001). Nondesmoplastic GP was also associated with a poorer recurrence-free survival (hazard ratio = 2.05, 95% confidence interval: 1.13-3.70, P = .017). CONCLUSION: Desmoplastic GP could represent a useful morphological marker for early identification of patients who might benefit from 2-stage hepatectomy completion.

[hPG80 and cancer: A new blood biomarker in development for patient monitoring]. / hPG80 et cancer : un nouveau biomarqueur sanguin en développement pour le suivi des patients.

Recent technological advances coupled with our improved understanding of the molecular and cellular mechanisms associated with cancer development have enabled better overall patient care. Among the newly identified biomarkers such as circulating tumor DNA or circulating tumor cells, hPG80 (circulating progastrin) that is easy to detect and quantify by a simple ELISA assay has the potential to become a new routine clinical tool in oncology if on-going studies validated its utility. Indeed, on the one hand, hPG80 was found in the blood of patients with different tumors (colorectal, pancreatic, liver, lung, stomach, kidney cancers) at a significantly higher concentration than in healthy donors. Moreover, some studies suggested a potential association between hPG80 concentration changes and anti-cancer treatment efficacy in patients with gastro-intestinal and hepatocellular carcinomas. Finally, hPG80 might be a prognostic factor for overall survival in metastatic renal cell carcinoma cancer (mRCC) and in hepatocellular carcinoma (HCC). If these hypotheses were validated, hPG80 might help better stratify patients according to their prognosis, and also become a tool to monitor relapse and predict treatment response. Prospective validation studies are on-going.

Stereotactic MR-Guided Radiotherapy for Pancreatic Tumors: Dosimetric Benefit of Adaptation and First Clinical Results in a Prospective Registry Study.

Introduction: Stereotactic MR-guided adaptive radiotherapy (SMART) is an attractive modality of radiotherapy for pancreatic tumors. The objectives of this prospective registry study were to report the dosimetric benefits of daily adaptation of SMART and the first clinical results in pancreatic tumors. Materials and Methods: All patients treated in our center with SMART for a pancreatic tumor were included. Patients were planned for five daily-adapted fractions on consecutive days. Endpoints were acute toxicities, late toxicities, impact of adaptive treatment on target volume coverage and organs at risk (OAR) sparing, local control (LC) rate, distant metastasis-free survival (DMFS), and overall survival (OS). Results: Thirty consecutive patients were included between October 2019 and April 2021. The median dose prescription was 50 Gy. No patient presented grade > 2 acute toxicities. The most frequent grade 1-2 toxicities were asthenia (40%), abdominal pain (40%), and nausea (43%). Daily adaptation significantly improved planning target volume (PTV) and gross tumor volume (GTV) coverage and OAR sparing. With a median follow-up of 9.7 months, the median OS, 6-month OS, and 1-year OS were 14.1 months, 89% (95% CI: 70%-96%), and 75% (95% CI: 51%-88%), respectively, from SMART completion. LC at 6 months and 1 year was respectively 97% (95% CI: 79-99.5%) and 86% (95% CI: 61%-95%). There were no grade > 2 late toxicities. With a median follow-up of 10.64 months, locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC) patients (22 patients) had a median OS, 6-month OS, and 1-year OS from SMART completion of 14.1 months, 76% (95% CI: 51%-89%), and 70% (95% CI: 45%-85%), respectively. Nine patients underwent surgical resection (42.1% of patients with initial LAPC and 33.3% of patients with BRPC), with negative margins (R0). Resected patients had a significantly better OS as compared to unresected patients (p = 0.0219, hazard ratio (HR) = 5.78 (95% CI: 1.29-25.9)). Conclusion: SMART for pancreatic tumors is feasible without limiting toxicities. Daily adaptation demonstrated a benefit for tumor coverage and OAR sparing. The severity of observed acute and late toxicities was low. OS and LC rates were promising. SMART achieved a high secondary resection rate in LAPC patients. Surgery after SMART seemed to be feasible and might increase OS in these patients.

Association of neutrophil extracellular traps with the production of circulating DNA in patients with colorectal cancer.

We postulate that a significant part of circulating DNA (cirDNA) originates in the degradation of neutrophil extracellular traps (NETs). In this study, we examined the plasma level of two markers of NETs (myeloperoxidase (MPO) and neutrophil elastase (NE)), as well as cirDNA levels in 219 patients with a metastatic colorectal cancer (mCRC), and in 114 healthy individuals (HI). We found that in patients with mCRC the content of these analytes was (i) highly correlated, and (ii) all statistically different (p < 0.0001) than in HI (N = 114). These three NETs markers may readily distinguish between patients with mCRC from HI, (0.88, 0.86, 0.84, and 0.95 AUC values for NE, MPO, cirDNA, and NE + MPO + cirDNA, respectively). Concomitant analysis of anti-phospholipid (anti-cardiolipin), NE, MPO, and cirDNA plasma concentrations in patients with mCRC might have value for thrombosis prevention, and suggested that NETosis may be a critical factor in the immunological response/phenomena linked to tumor progression.

Chemotherapy (doublet or triplet) plus targeted therapy by RAS status as conversion therapy in colorectal cancer patients with initially unresectable liver-only metastases. The UNICANCER PRODIGE-14 randomised clinical trial.

BACKGROUND: Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting. METHODS: PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx. RESULTS: Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48-66) with the 3-CTx versus 48.4% (95% CI: 39-57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx. CONCLUSION: We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

Perioperative FOLFOX in Patients With Locally Advanced Oesogastric Adenocarcinoma.

BACKGROUND: We hypothesized that perioperative FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) might be used as an alternative to standard FLOT (docetaxel, 5-fluorouracil, leucovorin, and oxaliplatin) in patients with locally advanced oesogastric adenocarcinomas (OGA), particularly those with frailties. PATIENTS AND METHODS: We reviewed the charts of 61 consecutives patients treated with FOLFOX for resectable OGA to estimate overall survival, recurrence-free survival, and safety. RESULTS: The median follow-up was 69.7 (range=3.6-97.9) months. Few patients experienced grade 3 adverse events during the preoperative (n=6; 10%) and postoperative (n=6; 16%) phases. One patient experienced a fatal grade 5 adverse events (cardiogenic shock). Median overall survival was 51.7 months [95% confidence interval (CI)=31.6-93.2 months] and the 5-year survival rate was 44.4% (95% CI=30.3%-57.5%). CONCLUSION: Regarding its comparable efficacy and its favourable toxicity profile, perioperative FOLFOX is a reasonable alternative to FLOT for frail patients with resectable OGA.

Stereotactic MR-Guided Adaptive Radiotherapy for Pancreatic Tumors: Updated Results of the Montpellier Prospective Registry Study.

Introduction: Stereotactic MR-guided Adaptive RadioTherapy (SMART) is a novel process to treat pancreatic tumors. We present an update of the data from our prospective registry of SMART for pancreatic tumors. Materials and methods: After the establishment of the SMART indication in a multidisciplinary board, we included all patients treated for pancreatic tumors. Primary endpoints were acute and late toxicities. Secondary endpoints were survival outcomes (local control, overall survival, distant metastasis free survival) and dosimetric advantages of adaptive process on targets volumes and OAR. Results: We included seventy consecutive patients in our cohort between October 2019 and April 2022. The prescribed dose was 50 Gy in 5 consecutive fractions. No severe acute SMART related toxicity was noted. Acute and late Grade ≤ 2 gastro intestinal were low. Daily adaptation significantly improved PTV and GTV coverage as well as OAR sparing. With a median follow-up of 10.8 months since SMART completion, the median OS, 6-months OS, and 1-year OS were 20.9 months, 86.7% (95% CI: (75−93%), and 68.6% (95% CI: (53−80%), respectively, from SMART completion. Local control at 6 months, 1 year, and 2 years were, respectively, 96.8 % (95% CI: 88−99%), 86.5 (95% CI: 68−95%), and 80.7% (95% CI: 59−92%). There was no grade > 2 late toxicities. Locally Advanced Pancreatic Cancers (LAPC) and Borderline Resectable Pancreatic Cancers (BRPC) patients (52 patients) had a median OS, 6-months OS, and 1-year OS from SMART completion of 15.2 months, 84.4% (95% CI: (70−92%)), and 60.5% (95% CI: (42−75%)), respectively. The median OS, 1-year OS, and 2-year OS from initiation of induction chemotherapy were 22.3 months, 91% (95% CI: (78−97%)), and 45.8% (95% CI: (27−63%)), respectively. Twenty patients underwent surgical resection (38.7 % of patients with initially LAPC) with negative margins (R0). Conclusion: To our knowledge, this is the largest series of SMART for pancreatic tumors. The treatment was well tolerated with only low-grade toxicities. Long-term OS and LC rates were achieved. SMART achieved high secondary resection rates in LAPC patients.

Determinants of Distinct Trajectories of Fatigue in Patients Undergoing Chemotherapy for a Metastatic Colorectal Cancer: 6-Month Follow-up Using Growth Mixture Modeling.

OBJECTIVES: This longitudinal prospective and observational study was designed to identify fatigue trajectories during a 6-month period of chemotherapy in patients with metastatic colorectal cancer, and examine the psychosocial factors predicting these trajectories. Associations between fatigue and survival were also investigated. METHODS: A total of 169 patients (Mage = 64.36 years, SD = 10.5) reported their fatigue levels every 2 weeks for 6 months. Psychological variables (anxiety, depression, internal control, and coping) were assessed at baseline. A Growth Mixture Model was used to identify latent trajectories of fatigue, and a multinomial logistic regression tested covariate predictors of patients' trajectories. RESULTS: Four clinically distinct fatigue trajectories were identified: intense fatigue (6.51%), moderate fatigue (48.52%), no fatigue (33%), and increasing fatigue (11.83%). Fatigue severity was directly associated with overall survival. High depression levels were associated with fatigue severity over time for intense (OR = 1.80 [1.32-2.47]) and for moderate (OR = 1.58 [1.25-2.00]) fatigue, compared to patients reporting no fatigue. Patients who did not report fatigue were better adjusted, and had more resources, such as better internal control over the disease and less emotion-focused coping (guilt and avoidance), than those who reported intense (ORcontrol = 0.77 [0.65-0.92]) or moderate (ORcontrol = 0.89 [0.79-0.99] and ORcoping = 1.13 [1.02-1.24]) fatigue. CONCLUSION: Fatigue trajectories differed considerably across patients with metastatic colorectal cancer. This first longitudinal study on colorectal cancer patients involving transactional variables suggests that psychosocial interventions should target these specific outcomes, in order to help patients manage their fatigue.

Image-Guided Liver Stereotactic Body Radiotherapy Using VMAT and Real-Time Adaptive Tumor Gating: Evaluation of the Efficacy and Toxicity for Hepatocellular Carcinoma.

Liver SBRT is a therapeutic option for the treatment of HCC in patients not eligible for other local therapies. We retrospectively report the outcomes of a cohort of consecutive patients treated with SBRT for HCC at the Montpellier Cancer Institute. Between March 2013 and December 2018, 66 patients were treated with image-guided liver SBRT using VMAT and real-time adaptive tumor gating in our institute. The main endpoints considered in this study were local control, disease-free survival, overall survival, and toxicity. The median follow-up was 16.8 months. About 66.7% had prior liver treatment. Most patients received 50 Gy in five fractions of 10 Gy. No patient had local recurrence. Overall survival and disease-free survival were, respectively, 83.9% and 46.7% at one year. In multivariate analysis, the diameter of the lesions was a significant prognostic factor associated with disease-free survival (HR = 2.57 (1.19-5.53) p = 0.02). Regarding overall survival, the volume of PTV was associated with lower overall survival (HR = 2.84 (1.14-7.08) p = 0.025). No grade 3 toxicity was observed. One patient developed a grade 4 gastric ulcer, despite the dose constraints being respected. Image-guided liver SBRT with VMAT is an effective and safe treatment in patients with inoperable HCC, even in heavily pre-treated patients. Further prospective evaluation will help to clarify the role of SBRT in the management of HCC patients.