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Motixafortide and Pembrolizumab Combined to Nanoliposomal Irinotecan, Fluorouracil, and Folinic Acid in Metastatic Pancreatic Cancer: The COMBAT/KEYNOTE-202 Trial.
Bockorny, B, Macarulla, T, Semenisty, V, Borazanci, E, Feliu, J, Ponz-Sarvise, M, Abad, DG, Oberstein, P, Alistar, A, Muñoz, A, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(18):5020-5027
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. PATIENTS AND METHODS Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability. RESULTS A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen. CONCLUSIONS Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.
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S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation.
Mosca, L, Pagano, M, Borzacchiello, L, Mele, L, Russo, A, Russo, G, Cacciapuoti, G, Porcelli, M
International journal of molecular sciences. 2021;(17)
Abstract
Colorectal cancer (CRC) is the second deadliest cancer worldwide despite significant advances in both diagnosis and therapy. The high incidence of CRC and its poor prognosis, partially attributed to multi-drug resistance and antiapoptotic activity of cancer cells, arouse strong interest in the identification and development of new treatments. S-Adenosylmethionine (AdoMet), a natural compound and a nutritional supplement, is well known for its antiproliferative and proapoptotic effects as well as for its potential in overcoming drug resistance in many kinds of human tumors. Here, we report that AdoMet enhanced the antitumor activity of 5-Fluorouracil (5-FU) in HCT 116p53+/+ and in LoVo CRC cells through the inhibition of autophagy, induced by 5-FU as a cell defense mechanism to escape the drug cytotoxicity. Multiple drug resistance is mainly due to the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp). We demonstrate here that AdoMet was able to revert the 5-FU-induced upregulation of P-gp expression and to decrease levels of acetylated NF-κB, the activated form of NF-κB, the major antiapoptotic factor involved in P-gp-related chemoresistance. Overall, our data show that AdoMet, was able to overcome 5-FU chemoresistance in CRC cells by targeting multiple pathways such as autophagy, P-gp expression, and NF-κB signaling activation and provided important implications for the development of new adjuvant therapies to improve CRC treatment and patient outcomes.
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PNN and KCNQ1OT1 Can Predict the Efficacy of Adjuvant Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer Patients.
Lapucci, A, Perrone, G, Di Paolo, A, Napoli, C, Landini, I, Roviello, G, Calosi, L, Naccarato, AG, Falcone, A, Bani, D, et al
Oncology research. 2021;(6):631-644
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Abstract
The benefit of adjuvant chemotherapy in the early stages of colorectal cancer (CRC) is still disappointing and the prediction of treatment outcome quite difficult. Recently, through a transcriptomic approach, we evidenced a role of PNN and KCNQ1OT1 gene expression in predicting response to fluoropyrimidine-based adjuvant chemotherapy in stage III CRC patients. Thus, the aim of this study was to validate in an independent cohort of stages IIIII CRC patients our previous findings. PNN and KCNQ1OT1 mRNA expression levels were evaluated in 74 formalin-fixed paraffin-embedded tumor and matched normal mucosa samples obtained by stages IIIII CRC patients treated with fluoropyrimidine-based adjuvant chemotherapy. PININ, the protein encoded by PNN, was immunohistochemically evaluated in 15 tumor and corresponding normal mucosa samples, selected on the basis of a low, medium, or high mRNA expression tumor/mucosa ratio. PNN and KCNQ1OT1 mRNA mean expression levels were significantly higher in tumor compared with normal tissues. Patients with high PNN or KCNQ1OT1 tumor mRNA levels according to ROC-based cutoffs showed a shorter disease-free survival (DFS) compared with patients with low tumor mRNA gene expression. Also, patients with tumor mRNA expression values of both genes below the identified cutoffs had a significantly longer DFS compared with patients with the expression of one or both genes above the cutoffs. In a representative large cohort of stages IIIII CRC untreated patients retrieved from GEO datasets, no difference in DFS was observed between patients with high and low PNN or KCNQ1OT1 gene expression levels. These data confirm our previous findings and underscore the relevance of PNN and KCNQ1OT1 expression in predicting DFS in early stages of CRC treated with fluoropyrimidine-based adjuvant chemotherapy. If further validated in a prospective case series, both biomarkers could be used to identify patients who benefit from this treatment and to offer alternative chemotherapy regimens to potential unresponsive patients. In relation to the suggested biological role of PNN and KCNQ1OT1 in CRC, they might also be exploited as potential therapeutic targets.
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Cross-talk between YAP and RAR-RXR Drives Expression of Stemness Genes to Promote 5-FU Resistance and Self-Renewal in Colorectal Cancer Cells.
Bauzone, M, Souidi, M, Dessein, AF, Wisztorski, M, Vincent, A, Gimeno, JP, Monté, D, Van Seuningen, I, Gespach, C, Huet, G
Molecular cancer research : MCR. 2021;(4):612-622
Abstract
The mechanisms whereby the Hippo pathway effector YAP regulates cancer cell stemness, plasticity, and chemoresistance are not fully understood. We previously showed that in 5-fluorouracil (5-FU)-resistant colorectal cancer cells, the transcriptional coactivator YAP is differentially regulated at critical transitions connected with reversible quiescence/dormancy to promote metastasis. Here, we found that experimental YAP activation in 5-FU-sensitive and 5-FU-resistant HT29 colorectal cancer cells enhanced nuclear YAP localization and the transcript levels of the retinoic acid (RA) receptors RARα/γ and RAR target genes CYP26A1, ALDH1A3, and LGR5 through RA Response Elements (RARE). In these two cell models, constitutive YAP activation reinforced the expression of the stemness biomarkers and regulators ALDH1A3, LGR5, and OCT4. Conversely, YAP silencing, RAR/RXR inhibition by the pan-RAR antagonist BMS493, and vitamin A depletion downregulated stemness traits and self-renewal. Regarding the mechanisms engaged, proximity-dependent labeling, nuclear YAP pulldown coupled with mass spectrometry, and chromatin immunoprecipitation (ChIP)/re-ChIP experiments revealed: (i) the nuclear colocalization/interaction of YAP with RARγ and RXRs; and (ii) combined genomic co-occupancy of YAP, RARα/γ, and RXRα interactomes at proximal RAREs of LGR5 and ALDH1A3 promoters. Moreover, activation of the YAP/RAR-RXR cross-talk in colorectal cancer cells promoted RAR self-activation loops via vitamin A metabolism, RA, and active RAR ligands generated by ALDH1A3. Together, our data identify YAP as a bona fide RAR-RXR transcriptional coactivator that acts through RARE-activated stemness genes. IMPLICATIONS Targeting the newly identified YAP/RAR-RXR cross-talk implicated in cancer cell stemness maintenance may lead to multitarget combination therapies for patients with colorectal cancer.
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Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study.
Yoo, C, Kim, KP, Jeong, JH, Kim, I, Kang, MJ, Cheon, J, Kang, BW, Ryu, H, Lee, JS, Kim, KW, et al
The Lancet. Oncology. 2021;(11):1560-1572
Abstract
BACKGROUND The prognosis of patients with advanced biliary tract cancer who have progressed on gemcitabine plus cisplatin is dismal. We aimed to investigate the efficacy and safety of second-line liposomal irinotecan plus fluorouracil and leucovorin in patients with metastatic biliary tract cancer that has progressed on gemcitabine plus cisplatin. METHODS This multicentre, open-label, randomised, phase 2b (NIFTY) study was done at five academic institutions in South Korea and included patients aged 19 years or older with histologically or cytologically confirmed metastatic biliary tract cancer that had progressed on first-line gemcitabine plus cisplatin and an Eastern Cooperative Oncology Group performance status of 0 or 1. By use of an interactive web-based response system integrated with an electronic data capture system, patients were randomly assigned (1:1) using permuted blocks (block size 4) to receive either intravenous liposomal irinotecan (70 mg/m2 for 90 min) plus intravenous leucovorin (400 mg/m2 for 30 min) and intravenous fluorouracil (2400 mg/m2 for 46 h) every 2 weeks or leucovorin and fluorouracil only every 2 weeks, and were stratified by primary tumour site, previous surgery with curative intent, and participating centre. Study treatment was continued until the patient had disease progression or unacceptable toxicities, or withdrew consent. The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival. The primary endpoint and safety were assessed in the full analysis set and the safety analysis set, respectively, both of which comprised all randomly assigned patients who received at least one dose of the study treatment. This trial is registered with ClinicalTrials.gov, NCT03524508, and enrolment is complete. FINDINGS Between Sept 5, 2018, and Feb 18, 2020, 193 patients were screened for eligibility, of whom 174 (88 in the liposomal irinotecan plus fluorouracil and leucovorin group and 86 in the fluorouracil plus leucovorin group) were enrolled and included in the full analysis and safety analysis sets. At a median follow-up of 11·8 months (IQR 7·7-18·7), the median BICR-assessed progression-free survival was significantly longer in the liposomal irinotecan plus fluorouracil and leucovorin group (7·1 months, 95% CI 3·6-8·8) than in the fluorouracil and leucovorin group (1·4 months, 1·2-1·5; hazard ratio 0·56, 95% CI 0·39-0·81; p=0·0019). The most common grade 3-4 adverse events were neutropenia (21 [24%] of 88 in the liposomal irinotecan plus fluorouracil and leucovorin group vs one [1%] of 86 in the fluorouracil and leucovorin group) and fatigue or asthenia (11 [13%] vs three [3%]). Serious adverse events occurred in 37 (42%) patients receiving liposomal irinotecan plus fluorouracil and leucovorin and 21 (24%) patients receiving fluorouracil and leucovorin. There were no treatment-related deaths. INTERPRETATION Adding liposomal irinotecan to fluorouracil and leucovorin significantly improved BICR-assessed progression-free survival in patients with advanced biliary tract cancer. Liposomal irinotecan plus fluorouracil and leucovorin could be considered a standard-of-care second-line therapy for advanced biliary tract cancer. FUNDING Servier and HK inno. N TRANSLATION For the Korean translation of the abstract see Supplementary Materials section.
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Dose-dense TPF induction chemotherapy for locally advanced head and neck cancer: a phase II study.
Hsieh, CY, Lein, MY, Yang, SN, Wang, YC, Lin, YJ, Lin, CY, Hua, CH, Tsai, MH, Lin, CC
BMC cancer. 2020;(1):832
Abstract
BACKGROUND Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck (SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN. METHODS In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer. Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50 mg/m2 on day 1, leucovorin 250 mg/m2 on day1, followed by 48-h continuous infusion of 2500 mg/m2 of 5-fluorouracil on day 1 and 2, every 2 weeks for 6 cycles followed by radiotherapy. The primary endpoint was the response rate (RR) after ICT. RESULTS Fifty-eight patients were enrolled from June 2014 to September 2015. Overall RR after ICT was 89.6% [complete response (CR), 31%; partial response (PR), 58.6%]. Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively. 94.8% of patients completed all treatment courses of ICT without dose reduction. The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%). Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS. CONCLUSIONS Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN. The presence of CR after ICT predicted long-term survival. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04397341 , May 21, 2020, retrospectively registered.
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Maintenance treatment with fluoropyrimidine plus bevacizumab versus fluoropyrimidine alone after induction chemotherapy for metastatic colorectal cancer: The BEVAMAINT - PRODIGE 71 - (FFCD 1710) phase III study.
Manfredi, S, Turpin, A, Malka, D, Barbier, E, Laurent-Puig, P, Zaanan, A, Dahan, L, Lièvre, A, Phelip, JM, Michel, P, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2020;(10):1143-1147
Abstract
BACKGROUND Maintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens. METHODS BEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) - but remains unresectable - after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.
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Neoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer.
Sah, BK, Zhang, B, Zhang, H, Li, J, Yuan, F, Ma, T, Shi, M, Xu, W, Zhu, Z, Liu, W, et al
Nature communications. 2020;(1):6093
Abstract
Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT regimen) has shown promising results in terms of pathological response and survival rate in patients with locally advanced resectable gastric cancer (LAGC). However, tegafur gimeracil oteracil potassium capsule (S-1) plus oxaliplatin (SOX regimen) is the preferred chemotherapy regimen in Eastern countries. Here, we conduct an open label, two-arm, phase II randomized interventional clinical trial (Dragon III; ClinicalTrials.gov: NCT03636893) to evaluate the safety and efficacy of both regimens. Patients with LAGC are randomly assigned to receive either 4 cycles of the neoadjuvant FLOT regimen (40 patients) or 3 cycles of the SOX regimen (34 patients) before gastrectomy. The primary endpoint is the comparison of complete (TRG1a) or subtotal (TRG1b) tumor regression grading in the primary tumor. There are no significant differences in adverse effects or postoperative morbidity and mortality between the two groups. No significant differences in the proportion of tumor regression grading between the FLOT group and the SOX group are found. Complete or subtotal TRG is 20.0% in the FLOT group versus 32.4% in the SOX group. Therefore, our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer.
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A Phase II Study of Modified FOLFOX6 for Advanced Gastric Cancer Refractory to Standard Therapies.
Mitani, S, Kadowaki, S, Komori, A, Kondoh, C, Oze, I, Kato, K, Masuishi, T, Honda, K, Narita, Y, Taniguchi, H, et al
Advances in therapy. 2020;(6):2853-2864
Abstract
INTRODUCTION In patients with advanced gastric cancer refractory to chemotherapy, the treatment options are limited. Via this phase II study, we aimed to assess the efficacy and safety of oxaliplatin in combination with 5-fluorouracil and l-leucovorin (modified FOLFOX6). METHODS Patients who had histologically confirmed metastatic gastric cancer refractory to ≥ two previous chemotherapy regimens were included. The primary endpoint was the overall response rate (ORR) by an independent central review. According to an assumption of a threshold ORR of 10% and expected ORR of 25%, with α = 0.05 and β = 0.20, at least 33 patients were required. The secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life measured by EQ-5D, and safety. RESULTS Among the 35 enrolled patients, 33 were included in the primary analysis. All patients previously received fluoropyrimidines, cisplatin, and taxanes, and 24 (73%) were pretreated with irinotecan. The confirmed ORR was 27% [95% confidence interval (CI) 13-46]. The median PFS and OS were 2.2 (95% CI 1.2-3.2) and 5.6 (95% CI 4.1-7.0) months, respectively. In the multivariate analyses, immunotherapy within 90 days and a Glasgow Prognostic Score of 0 were associated with better treatment outcomes. The most common grade ≥ 3 adverse event was neutropenia (36%), and no febrile neutropenia was observed. The median EQ-5D scores did not change from baseline at 2, 4, and 8 weeks (p value = 0.38, 0.79, and 0.98, respectively). CONCLUSION Modified FOLFOX6 (mFOLFOX6) showed substantial activity and acceptable toxicity for chemotherapy-refractory advanced gastric cancer. TRIAL REGISTRATION UMIN Clinical Trial Registry (UMIN000016416).
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Consumption of Lactose, Other FODMAPs and Diarrhoea during Adjuvant 5-Fluorouracil Chemotherapy for Colorectal Cancer.
Holma, R, Laatikainen, R, Orell, H, Joensuu, H, Peuhkuri, K, Poussa, T, Korpela, R, Österlund, P
Nutrients. 2020;(2)
Abstract
Chemotherapy-induced mucosal injury of the small intestine may interfere with the enzymes and transporters responsible for the hydrolysis and absorption of dietary carbohydrates causing diarrhoea, abdominal discomfort and pain. The aim of this study was to investigate the association between the consumption of foods rich in FODMAPs (fermentable oligo-, di- and monosaccharides and polyols) and gastrointestinal symptoms in patients receiving adjuvant therapy for colorectal cancer. The patients (n = 52) filled in a 4-day food diary at baseline and during therapy and kept a symptom diary. The intakes of FODMAP-rich foods were calculated as portions and the intakes were divided into two consumption categories. Patients with high consumption of FODMAP-rich foods had diarrhoea more frequently than those with low consumption (for lactose-rich foods the odds ratio (OR) was 2.63, P = 0.03; and for other FODMAP-rich foods 1.82, P = 0.20). Patients with high consumption of both lactose-rich and other FODMAP-rich foods had an over 4-fold risk of developing diarrhoea as compared to those with low consumption of both (OR, 4.18; P = 0.02). These results were confirmed in multivariate models. Conclusion: Consumption of lactose-rich foods results in an increased risk of diarrhoea during adjuvant therapy for colorectal cancer, especially when the consumption of other FODMAP-rich foods is also high.