A multicenter study evaluating efficacy of immune checkpoint inhibitors in advanced non-colorectal digestive cancers with microsatellite instability.

BACKGROUND: One randomized phase III trial comparing chemotherapy (CT) with immune checkpoint inhibitors (ICI) has demonstrated significant efficacy of ICI in deficient DNA mismatch repair system/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer. However, few studies have compared ICI with CT in other advanced dMMR/MSI-H digestive tumors. METHODS: In this multicenter study, we included patients with advanced dMMR/MSI-H non-colorectal digestive tumors treated with chemotherapy and/or ICIs. Patients were divided retrospectively into two groups, a CT group and an immunotherapy (IO) group. The primary endpoint was progression-free survival (PFS). A propensity score approach using the inverse probability of treatment weighting (IPTW) method was applied to deal with potential differences between the two groups. RESULTS: 133 patients (45.1/27.1/27.8% with gastric/small bowel/other carcinomas) were included. The majority of patients received ICI in 1st (29.1%) or 2nd line (44.4%). The 24-month PFS rates were 7.9% in the CT group and 71.2% in the IO group. Using the IPTW method, IO treatment was associated with better PFS (HR=0.227; 95% CI 0.147-0.351; p < 0.0001). The overall response rate was 26.3% in the CT group versus 60.7% in the IO group (p < 0.001) with prolonged duration of disease control in the IO group (p < 0.001). In multivariable analysis, predictive factors of PFS for patients treated with IO were good performance status, absence of liver metastasis and prior primary tumor resection, whereas no association was found for the site of the primary tumor. CONCLUSIONS: In the absence of randomized trials, our study highlights the superior efficacy of ICI compared with standard-of-care therapy in patients with unresectable or metastatic dMMR/MSI-H non-colorectal digestive cancer, regardless of tumor type, with acceptable toxicity.

Echoendoscopic ultrasound pancreatic adenocarcinoma diagnosis and theranostic approach: should KRAS mutation research be recommended in everyday practice?

Background: The impact of KRAS mutation testing on pancreatic ductal adenocarcinoma (PDAC) samples by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for reducing the need to repeat EUS-FNA has been demonstrated. Such testing however is not part of standard practice for endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). Objectives: We aim to analyse the proportion of non-contributive samples by EUS-FNB and to evaluate the impact of KRAS mutation testing on the diagnosis, theranostics and survival. Design: In this retrospective study, the impact on diagnosis and survival of KRAS testing for contributive and non-contributive samples by EUS-FNB was analysed. Methods: The EUS-FNB samples, combined with KRAS testing using the Idylla® technique on liquid-based cytology from patients with PDAC between February 2019 and May 2023, were retrospectively reviewed. The cytology results were classified according to the guidelines of the World Health Organization System for Reporting Pancreaticobiliary Cytopathology (WHOSRPC). Results: A total of 85 EUS-FNB specimens were reviewed. In all, 25 EUS-FNB samples did not lead to a formal diagnosis of PDAC according to the WHOSRPC (30.2%). Out of these 25, 11 (44%) could have been considered positive for a PDAC diagnosis thanks to the KRAS mutation test without carrying out further diagnosis procedures. The sensitivity of KRAS mutation testing using the Idylla technique was 98.6%. According to the available data, survival rates were not statistically different depending on the type of mutation. Conclusion: KRAS mutation testing on liquid-based cytology using the Idylla or equivalent technique, combined with the PDAC EUS-FNB sample, should become a standard for diagnosis to avoid delaying treatment by doing another biopsy. Furthermore, knowledge of the KRAS status from treatment initiation could be used to isolate mutations requiring targeted treatments or inclusion in clinical research trials, especially for wild-type KRAS PDAC.

Diagnostic and theranostic interest of searching for a KRAS mutation in echoendoscopic ultrasound biopsies of pancreatic adenocarcinomas The echoendoscopic ultrasound diagnostic of pancreatic adenocarcinomas sometimes remains difficult due to the nature of these tumors with a particular microenvironment. For more than 30 years, several authors have underlined the importance of searching for a KRAS mutation on samples taken by echoendoscopic ultrasound to improve diagnostic performance. However, this research is not common practice. Our retrospective study made it possible to review the files of 85 patients with pancreatic adenocarcinoma in whom an echoendoscopic ultrasound biopsy was performed with a search for the KRAS mutation (with second-generation fine needle biopsy). Forty-four percent could have been considered positive for the diagnosis of PDAC thanks to the search for the KRAS mutation without repeating new samples. Furthermore, knowledge of the KRAS mutation type from diagnosis would make it possible to isolate mutations justifying possible targeted treatments.

Primary resistance to immunotherapy in patients with a dMMR/MSI metastatic gastrointestinal cancer: who is at risk? An AGEO real-world study.

BACKGROUND: The outstanding efficacy of immunotherapy in metastatic dMMR/MSI gastro-intestinal (GI) cancers has led to a rapid increase in the number of patients treated. However, 20-30% of patients experience primary resistance to immune checkpoint inhibitors (ICIPR) and need better characterization. METHODS: This AGEO real-world study retrospectively analyzed the efficacy and safety of ICIs and identified clinical variables associated with ICIPR in patients with metastatic dMMR/MSI GI cancers treated with immunotherapy between 2015 and 2022. RESULTS: 399 patients were included, 284 with colorectal cancer (CRC) and 115 with non-CRC, mostly treated by an anti-PD(L)1 (88.0%). PFS at 24 months was 55.8% (95CI [50.8-61.2]) and OS at 48 months was 59.1% (95CI [53.0-65.9]). ORR was 51.0%, and 25.1% of patients were ICIPR. There was no statistical difference in ORR, DCR, PFS, or OS between CRC and non-CRC groups. In multivariable analysis, ICIPR was associated with ECOG-PS ≥ 2 (OR = 3.36), liver metastases (OR = 2.19), peritoneal metastases (OR = 2.00), ≥1 previous line of treatment (OR = 1.83), and age≤50 years old (OR = 1.76). CONCLUSION: These five clinical factors associated with primary resistance to ICIs should be considered by physicians to guide treatment choice in GI dMMR/MSI metastatic cancer patients.

Adjuvant chemotherapy benefit according to T and N stage in small bowel adenocarcinoma: a large retrospective multicenter study.

BACKGROUND: Small bowel adenocarcinoma is a rare cancer, and the role of adjuvant chemotherapy for localized disease is still debated. METHODS: This retrospective multicenter study included all consecutive patients who underwent curative surgical resection for localized small bowel adenocarcinoma between 1996 and 2019 from 3 French cohort studies. Prognostic and predictive factors of adjuvant chemotherapy efficacy were analyzed for disease-free survival and overall survival. The inverse probability of treatment weighting method was applied in the Cox regression model using the propensity score derived from multivariable logistic regression. RESULTS: A total of 354 patients were included: median age, 63.5 years; duodenum location, 53.5%; and tumor stage I, II, and III in 31 (8.7%), 144 (40.7%), and 179 (50.6%) patients, respectively. The adjuvant chemotherapy was administered in 0 (0%), 66 (48.5%), and 143 (80.3%) patients with stage I, II, and III, respectively (P < .0001). In the subgroup analysis by inverse probability of treatment weighting method, a statistically significant disease-free survival and overall survival benefit in favor of adjuvant chemotherapy was observed in high-risk stage II (T4 and/or <8 lymph nodes examined) and III (T4 and/or N2) but not for low-risk stage II (T3 and ≥8 lymph nodes examined) and III (T1-3/N1) tumors (Pinteraction < .05). Furthermore, tumor location in jejunum and ileum was also a statistically significant predictive factor of response to adjuvant chemotherapy in stage II and III tumors (Pinteraction < .05). CONCLUSION: In localized small bowel adenocarcinoma, adjuvant chemotherapy seems to provide a statistically significant survival benefit for high-risk stage II and III tumors and for jejunum and ileum tumor locations.

DCF versus doublet chemotherapy as first-line treatment of advanced squamous anal cell carcinoma: a multicenter propensity score-matching study.

Triplet DCF (docetaxel, cisplatin and 5-flurouracil) and doublet CP/CF (carboplatin and paclitaxel/cisplatin and 5-fluorouracil) regimens were prospectively evaluated in advanced squamous anal cell carcinoma (SCCA), and validated as standard treatments. Even though the high efficacy and good tolerance of DCF regimen were confirmed in 3 independent prospective trials, doublet CP regimen is still recommended in several guidelines based in its better safety profile with similar efficacy compared to CF regimen. We performed a propensity score-adjusted method with inverse probability of treatment weighted (IPTW) and matched case control (MCC) comparison among patients with metastatic or non-resectable locally advanced recurrent SCCA, treated with chemotherapy as first line regimen. The primary endpoint was the overall survival (OS), and the secondary endpoint was the progression-free survival (PFS). 247 patients were included for analysis. 154 patients received DCF and 93 patients received a doublet regimen. The median OS was 32.3 months with DCF and 18.3 months with doublet regimens (HR 0.53, 95%CI 0.38-0.74; p = 0.0001), and the median PFS was 11.2 months with DCF versus 7.6 months with doublet regimens (HR 0.53, 95%CI 0.39-0.73; p < 0.0001). The hazard ratios by IPTW and MCC analyses were 0.411 (95% CI, 0.324-0.521; p < 0.0001) and 0.406 (95% CI, 0.261-0.632; p < 0.0001) for OS, and 0.466 (95% CI, 0.376-0.576; p < 0.0001) and 0.438 (95% CI, 0.298-0.644; P < 0.0001) for PFS. The triplet DCF regimen provides a high and significant benefit in OS and PFS over doublet regimens, and should be considered as upfront treatment for eligible patients with advanced SCCA.

One-Year Follow-Up of Seroprevalence of SARS-CoV-2 Infection and Anxiety among Health Workers of a French Cancer Center: The PRO-SERO-COV Study.

Infection of SARS-CoV-2 among health workers (HWs) in contact with cancer patients has been a major issue since the beginning of the pandemic. We aimed to assess the serological immune status of SARS-CoV-2 infection among these HWs. A prospective cohort study was initiated in the comprehensive cancer center of the Nouvelle-Aquitaine region (NA, France). Volunteer HWs working on March 2020 without active infection or symptoms of COVID-19 completed a self-questionnaire and had a blood test at inclusion, at 3 and 12 months. Positive serological status of SARS-CoV-2 infection was defined by anti-nucleocapsid antibodies and/or IgG anti-spike antibodies, except at 12 months due to vaccine. Half of the HWs were included (N = 517) and 89% were followed for three months (N = 500) and one year (N = 462). Seroprevalence of SARS-CoV-2 infection was 3.5% (95% CI: 1.9-5.1), 6.2% (95% CI: 4.1-8.3), and 10% (95% CI: 7.2-12.7) on June-September 2020, September 2020-January 2021, and June-October 2021, respectively. At 12 months, 93.3% had detectable antibodies with 80% vaccinated in the first three months of vaccine availability. The COVID-19-free policy of the institution, respect for barrier gestures, high and early vaccination of HWs, and low prevalence of SARS-CoV-2 in NA may explain the low rate of seropositivity among the HWs of the Institut Bergonié.

Reprogramming immune cells activity by furin-like enzymes as emerging strategy for enhanced immunotherapy in cancer.

Immunotherapy is becoming an advanced clinical management for various cancers. Rebuilding of aberrant immune surveillance on cancers has achieved notable progress in the past years by either in vivo or ex vivo engineering of efficient immune cells. Immune cells can be programmed with several strategies that improves their therapeutic influence and specificity. It has become noticeable that effective immunotherapy must consider the complete complexity of the immune cell function. However, today, almost all immune cells can be transiently or stably reprogrammed against various cancer cells. As a consequence, investigations have interrogated strategies to improve the efficacy of cancer immunotherapies by enhancing T-cell infiltration into tumour tissues. Here, we review the emerging role of furin-like enzymes work related to T-cell reprogramming, their tumour infiltration and cytotoxic function.

Chemotherapy in advanced pancreatic adenosquamous carcinoma: A retrospective multicenter AGEO study.

Pancreatic adenosquamous carcinoma (PASC) account for <5% of pancreatic malignancies. The efficacy of modern chemotherapy regimens in patients with advanced PASC is unknown. Patients with advanced PASC from 2008 to 2021 were consecutively included in this retrospective multicenter study. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Ninety-four PASC from 16 French centers were included (median age, 67.3 years; males, 56.4%; metastatic disease, 85.1%). The first-line treatment was chemotherapy for 79 patients (84.0%) (37 FOLFIRINOX (FX), 7 Gemcitabine-nab paclitaxel (GN) and 35 for all other regimen) or best supportive care (BSC) alone for 15 patients (16.0%). No significant difference was observed between FX and GN in terms of PFS (P = .67) or OS (P = .5). Modern regimens pooled together (FX and GN) as compared to all others chemotherapy regimens showed an improvement of overall response rate (39.5% and 9.7%, P = .002), PFS (median, 7.8 vs 4.7 months, P = .02) and OS (median, 12.7 vs 9.2 months, P = .35). This large study evaluating first-line treatment regimens in advanced PASC suggests that modern regimens as FX or GN may be preferable to all other chemotherapy regimens. These results deserve confirmation in prospective studies.

[Oesogastric cancer - new therapeutic targets]. / Adénocarcinome œsogastrique ­ nouvelles cibles thérapeutiques.

The median overall survival of metastatic esophagogastric adenocarcinoma is approximately twelve months. In fifteen years, major breakthrough have been the targeting of HER2 overexpression and more recently immunotherapy in patients with CPS≥5. Recent advances in molecular biology have identified some molecular alterations in esophageal adenocarcinoma, interesting to target. FGFR2 is overexpressed in one third of patients, and its targeting with a specific monoclonal antibody bemarituzumab showed a significant improvement in survival. Claudin 18.2 (CLDN 18.2) is overexpressed in at least a third of esophagogastric adenocarcinomas. The combination of zolbetuximab and chemotherapy provides a survival benefit, correlated with the intensity of CLDN 18.2 expression. The potential interest of targeting other pathways is under investigation in several trials with some encouraging preliminary data, and early trials in these indications, justifying considering large molecular screening in patients who might be candidate for early phase trial. Finally, with the recent advent of immunotherapy, one of the future challenges will be to optimize it through combination strategies with targeted therapies. The combination of anti-angiogenic and immunotherapy seems promising in gastric cancer.

Sulconazole inhibits PD-1 expression in immune cells and cancer cells malignant phenotype through NF-κB and calcium activity repression.

The overexpression of the immunoinhibitory receptor programmed death-1 (PD1) on T-cells is involved in immune evasion in cancer. The use of anti-PD-1/PDL-1 strategy has deeply changed the therapies of cancers and patient survival. However, their efficacy diverges greatly along with tumor type and patient populations. Thereby, novel treatments are needed to interfere with the anti-tumoral immune responses and propose an adjunct therapy. In the current study, we found that the antifungal drug Sulconazole (SCZ) inhibits PD-1 expression on activated PBMCs and T cells at the RNA and protein levels. SCZ repressed NF-κB and calcium signaling, both, involved in the induction of PD-1. Further analysis revealed cancer cells treatment with SCZ inhibited their proliferation, and migration and ability to mediate tumor growth in zebrafish embryos. SCZ found also to inhibit calcium mobilization in cancer cells. These results suggest the SCZ therapeutic potential used alone or as adjunct strategy to prevent T-cell exhaustion and promotes cancer cell malignant phenotype repression in order to improve tumor eradication.

Hepatic Arterial Infusion Chemotherapy With Folfirinox or Oxaliplatin Alone in Metastatic Colorectal Cancer.

Background: Hepatic arterial infusion (HAI) of chemotherapy is an option for the treatment of patients with liver metastases from colorectal cancer (LMCRC). Though HAI with oxaliplatin (HAI-Ox) is generally used, intravenous (IV) 5-fluoro-uracil (5FU)-oxaliplatin-irinotecan HAI (HAI-Folfirinox) is feasible and leads to curative-intent surgery in 30% of pretreated patients. We compared the efficacy and safety of HAI-Ox and HAI-Folfirinox. Methods: Patients who underwent HAI chemotherapy for LMCRC were retrospectively included from 2008 to 2019 from six French expert centers. Results: Data were collected from 273 previously treated patients with LMCRC. Patients received HAI-Folfirinox (n = 52) or HAI-Ox (n = 221) combined with IV chemotherapy. The objective response rate (ORR) was 43.2% in patients with HAI-Folfirinox and 45.9% (ns) in patients with HAI-Ox. Median overall survival (OS) was 17 months (95% CI: 15-32.3) with HAI-Folfirinox and 26.2 months (95% CI: 19.4-34.4; p = 0.1) with HAI-Ox. Median progression-free survival (PFS) was 7.9 months (95% CI: 4.9-10.3) with HAI-Folfirinox and 6.4 months (95% CI: 6.0-7.7; p = 0.6) with HAI-Ox. The secondary liver resection rate was 35.6% with HAI-Folfirinox and 16.7% with HAI-Ox (p = 0.007). Grade 2 and above toxicities were significantly more frequent with HAI-Folfirinox. In the global population, only 2 factors were prognostic for OS in multivariable analyses: liver-only disease [hazard ratio (HR): 0.4; 95% CI 0.20-0.83; p = 0.013] and local complications of the catheter (HR: 3.8; 95% CI 1.6-9.0; p = 0.002). Conclusion: Hepatic arterial infusion results in high response rates, secondary resections, and long survival in pretreated patients with LMCRC.

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.

The Give-and-Take Interaction Between the Tumor Microenvironment and Immune Cells Regulating Tumor Progression and Repression.

A fundamental concern of the majority of cancer scientists is related to the identification of mechanisms involved in the evolution of neoplastic cells at the cellular and molecular level and how these processes are able to control cancer cells appearance and death. In addition to the genome contribution, such mechanisms involve reciprocal interactions between tumor cells and stromal cells within the tumor microenvironment (TME). Indeed, tumor cells survival and growth rely on dynamic properties controlling pro and anti-tumorigenic processes. The anti-tumorigenic function of the TME is mainly regulated by immune cells such as dendritic cells, natural killer cells, cytotoxic T cells and macrophages and normal fibroblasts. The pro-tumorigenic function is also mediated by other immune cells such as myeloid-derived suppressor cells, M2-tumor-associated macrophages (TAMs) and regulatory T (Treg) cells, as well as carcinoma-associated fibroblasts (CAFs), adipocytes (CAA) and endothelial cells. Several of these cells can show both, pro- and antitumorigenic activity. Here we highlight the importance of the reciprocal interactions between tumor cells and stromal cells in the self-centered behavior of cancer cells and how these complex cellular interactions control tumor progression and repression.

FFCD 1709-SIRTCI phase II trial: Selective internal radiation therapy plus Xelox, Bevacizumab and Atezolizumab in liver-dominant metastatic colorectal cancer.

Immune checkpoint inhibitors (ICI) have high efficacy in metastatic colorectal cancer (mCRC) with microsatellite instability (MSI) but not in microsatellite stable (MSS) tumour due to the low tumour mutational burden. Selective internal radiation therapy (SIRT) could enhance neoantigen production thus triggering systemic anti-tumoral immune response (abscopal effect). In addition, Oxalipatin can induce immunogenic cell death and Bevacizumab can decrease the exhaustion of tumour infiltrating lymphocyte. In combination, these treatments could act synergistically to sensitize MSS mCRCs to ICI SIRTCI is a prospective, multicentre, open-label, phase II, non-comparative single-arm study evaluating the efficacy and safety of SIRT plus Xelox, Bevacizumab and Atezolizumab (anti-programmed death-ligand 1) in patients with liver-dominant MSS mCRC. The primary objective is progression-free survival at 9 months. The main inclusion criteria are patients with MSS mCRC with liver-dominant disease, initially unresectable disease and with no prior oncologic treatment for metastatic disease. The trial started in November 2020 and has included 10 out of the 52 planned patients.

Role of Furin in Colon Cancer Stem Cells Malignant Phenotype and Expression of LGR5 and NANOG in KRAS and BRAF-Mutated Colon Tumors.

Proprotein convertases or PCs are known to regulate the malignant phenotype of colon cancer cells by different mechanisms, but their effects on cancer stem cells (CSCs) have been less widely investigated. Here, we report that PCs expression is altered in colon CSCs, and the inhibition of their activity reduced colon CSCs growth, survival, and invasion in three-dimensional spheroid cultures. In vivo, repression of PCs activity by the general PC inhibitors α1-PDX, Spn4A, or decanoyl-RVKR-chloromethylketone (CMK) significantly reduced tumor expression levels of the stem cell markers LGR5 and NANOG that are associated with reduced tumor xenografts. Further analysis revealed that reduced tumor growth mediated by specific silencing of the convertase Furin in KRAS or BRAF mutated-induced colon tumors was associated with reduced expression of LGR5 and NANOG compared to wild-type KRAS and BRAF tumors. Analysis of various calcium regulator molecules revealed that while the calcium-transporting ATPase 4 (ATP2B4) is downregulated in all the Furin-silenced colon cancer cells, the Ca2+-mobilizing P2Y receptors, was specifically repressed in BRAF mutated cells and ORAI1 and CACNA1H in KRAS mutated cells. Taken together, our findings indicate that PCs play an important role in the malignant phenotype of colon CSCs and stem cell markers' expression and highlight PCs repression, particularly of Furin, to target colon tumors with KRAS or BRAF mutation.

Diagnostic accuracy and clinical impact of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in Positron Emission Tomography - Computed Tomography (PET-CT)-positive mediastinal lymphadenopathies in patients with thoracic or extra-thoracic malignancies.

BACKGROUND: The high sensitivity of PET-CT can identify hypermetabolic mediastinal adenopathies during cancer management, but specificity is low and a biopsy is sometimes required to eliminate benign adenopathies. METHODS: This prospective diagnostic accuracy study included patients with hypermetabolic mediastinal lymphadenopathies revealed on PET-CT during either the initial management of a cancer, treatment evaluation, or monitoring. All patients underwent EUS-FNA. Diagnoses of malignancy based on cytological analysis following EUS-FNA were compared with clinical and radiological follow-up information. The treatment strategy decided before the results of the EUS-FNA pathology reports (Multidisciplinary Team Meeting [MTM-1]) was recorded and compared to the treatment strategy decided once pathological data from EUS-FNA were available (MTM-2). MAIN FINDINGS: Between 2013 and 2018, 75 patients were included with 47 eligible and evaluable patients. Sensitivity, specificity, and positive and negative predictive values of EUS-FNA were 93%, 100%, 100% and 90%, respectively. The concordance value between the therapeutic strategies determined for MTM-1 and MTM-2 was 44.7%. There were no significant differences in the intensity of fixation on PET-CT between malignant and benign lesions. CONCLUSION: The diagnostic accuracy of the minimally invasive EUS-FNA procedure is sufficiently robust to avoid the need for diagnostic surgery. The combination of PET-CT and EUS-FNA may alter the therapeutic strategy that would be considered after PET-CT alone. REGISTRATION: NCT01892501.

Phase III randomized trial comparing systemic versus intra-arterial oxaliplatin, combined with LV5FU2 +/- irinotecan and a targeted therapy, in the first-line treatment of metastatic colorectal cancer restricted to the liver (OSCAR): PRODIGE 49.

INTRODUCTION: In patients with unresectable liver metastases from colorectal cancer (CRCLM), systemic doublet or triplet chemotherapy and targeted therapy is considered a standard first-line treatment. Hepatic arterial infusion of oxaliplatin (HAI-ox) generates a high response rate, but this still needs to be confirmed in a randomized trial. We incorporated HAI-ox in doublet or triplet + targeted therapy to validate its efficacy. AIM: The OSCAR study is an ongoing randomized phase III trial comparing FOLFOX + targeted therapy according to RAS status, or FOLFOXIRI + bevacizumab in patients eligible for triplet therapy, with the same regimen but with HAI-ox instead of IV-ox as the first-line treatment for CRCLM. MATERIALS AND METHODS: Main eligibility criteria are colorectal cancer, unresectable liver metastasis, no extra-hepatic metastases except pulmonary nodules if ≤3 and <10 mm, ECOG performance status 0 or 1. ENDPOINT: The primary endpoint is progression-free survival (PFS). A difference of 4 months for the median PFS in favor of HAI-ox is expected (HR = 0.73). Secondary endpoints include overall survival, overall response rate, secondary liver resection, safety, and quality of life. CONCLUSION: This study is planned to include 348 patients to demonstrate the superiority of HAI-ox over systemic oxaliplatin in first-line CRCLM treatment (NCT02885753).

Gemcitabine + Nab-paclitaxel or Gemcitabine alone after FOLFIRINOX failure in patients with metastatic pancreatic adenocarcinoma: a real-world AGEO study.

BACKGROUND: Gemcitabine (Gem) alone or with Nab-paclitaxel (Gem-Nab) is used as second-line treatment for metastatic pancreatic adenocarcinoma (mPA) after FOLFIRINOX (FFX) failure; however, no comparative data exist. This study evaluates the efficacy and safety of adding Nab-paclitaxel to Gem for mPA after FFX failure. METHODS: In this retrospective real-world multicenter study, from 2011 to 2019, patients with mPA receiving Gem-Nab (Gem 1000 mg/m² + Nab 125 mg/m², 3 out of 4 weeks) or Gem alone were included after progression on FFX. RESULTS: A total of 427 patients were included. Patients receiving Gem-Nab had more metastatic sites, peritoneal disease and less PS 2 (24% vs. 35%). After median follow-up of 22 months, Gem-Nab was associated with better disease control rate (DCR) (56% vs. 32%; P < 0.001), progression-free survival (PFS) (3.5 vs. 2.3 months; 95% CI: 0.43-0.65) and overall survival (OS) (7.1 vs. 4.7 months; 95% CI: 0.53-0.86). After multivariate analysis, Gem-Nab and PS 0/1 were associated with better OS and PFS. Grade 3/4 toxicity was more frequent with Gem-Nab (44% vs. 29%). CONCLUSION: In this study, Gem-Nab was associated with better DCR, PFS and OS compared with Gem alone in patients with mPA after FFX failure, at the cost of higher toxicity.

Second-line treatment after docetaxel, cisplatin and 5-fluorouracil in metastatic squamous cell carcinomas of the anus. Pooled analysis of prospective Epitopes-HPV01 and Epitopes-HPV02 studies.

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is a rare disease often diagnosed at a localised stage. For locally advanced recurrence or metastatic disease, DCF (docetaxel, cisplatin, 5-fluorouracil) demonstrated high efficacy and became one of the standard regimens. However, there is no standard of care in the second line. PATIENTS AND METHODS: In the Epitopes-HPV01 and Epitopes-HPV02 prospective trials, 115 patients with advanced SCCA were treated with a DCF regimen in the first line. In these studies, second-line data were registered per protocol. RESULTS: After a median follow-up of >40 months, at progression, 73 patients received a second-line (L2) treatment. In this L2 population, median overall survival (mOS) was 13.5 months (95%CI 9.4-19.8), and median progression-free survival (mPFS) was 5.7 months (3.4-7.3) in L2. Fourteen patients presented an oligometastatic progression and were treated with an ablative treatment (surgery or radiotherapy); mOS was 48.3 months (NE-NE), and mPFS was 31.3 months (23.2-NE). Fifty-nine patients received a systemic treatment (chemotherapy or immunotherapy); mOS was 11 months (8.4-15.4) and mPFS was 4.9 months (3.3-7). The most frequent chemotherapy regimens were the reintroduction of DCF, paclitaxel, FOLFIRI and mitomycin plus fluoropyrimidine. No significant difference was observed between regimens (p = 0.26). Six patients received anti-PD1/L1-based immunotherapy. CONCLUSION: Second-line treatments are effective in patients with SCCA. Ablative treatment is feasible and is probably the best option for patients with oligometastatic progression. If this is not possible, systemic therapy by an anti-PD1/L1 immunotherapy or chemotherapy can be recommended. Reintroduction of DCF, paclitaxel, FOLFIRI or mitomycin-C plus fluoropyrimidine are possible options.