Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Implementation of perioperative FLOT compared to ECX/EOX chemotherapy regimens in resectable esophagogastric adenocarcinomas: an analysis of real-world data.

BACKGROUND AND PURPOSE: Perioperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) is recommended in resectable esophagogastric adenocarcinoma based on randomised trials. However, the effectiveness of FLOT in routine clinical practice remains unknown as randomised trials are subject to selection bias limiting their generalisability. The aim of this study was to evaluate the implementation of FLOT in real-world patients. METHODS: Retrospectively collected data were analysed in consecutive patients treated before or after the implementation of FLOT. The primary endpoint was complete pathological response (pCR) and secondary endpoints were margin-free resection (R0), overall survival (OS), relapse-free survival (RFS) tolerability of chemotherapy and surgical complications. RESULTS: Mean follow-up time for patients treated with FLOT (n = 205) was 37.7 versus 47.0 months for epirubicin, cis- or oxaliplatin, and capecitabine (ECX/EOX, n = 186). Surgical resection was performed in 88.0% versus 92.0%; pCR were observed in 3.8% versus 2.4%; and R0 resections were achieved in 78.0% versus 86.0% (p = 0.03) in the ECX/EOX and FLOT cohorts, respectively. Survival analysis indicated no significant difference in RFS (p = 0.17) or OS (p = 0.37) between the cohorts with a trend towards increased OS in performance status 0 (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.50-1.04). More patients treated with ECX/EOX completed chemotherapy (39% vs. 28%, p = 0.02). Febrile neutropenia was more common in the FLOT cohort (3.8% vs. 11%, p = 0.0086). 90-days mortality (1.2% vs. 0%) and frequency of anastomotic leakage (8% vs. 6%) were equal and low. INTERPRETATION: Patients receiving FLOT did not demonstrate improved pCR, RFS or OS. However, R0 rate was improved and patients in good PS trended towards improved OS.

Medication error with methotrexate. / Feildosering av metotreksat.

Background: A woman in her seventies presented to the accident and emergency department (A&E) with shortness of breath that had increased over a period of three weeks. She had a history of COPD, hypertension and polymyalgia rheumatica. A medication error involving methotrexate, used for autoimmune diseases, was discovered during her medical history review. Case presentation: The patient arrived with stable vital signs, including 94 % oxygen saturation and a respiratory rate of 20 breaths/min. She had been taking 2.5 mg of methotrexate daily for the past three weeks instead of the prescribed weekly dose of 15 mg. Other examinations revealed no alarming findings, except for a slightly elevated D-dimer level. Interpretation: Considering her medical history and exclusion of other differential diagnoses, methotrexate toxicity was suspected. The patient was admitted to the hospital and intravenous folinic acid was initiated as an antidote treatment. Five days later, the patient was discharged with an improvement in the shortness of breath. This case underscores the importance of effective communication in health care, particularly in complex cases like this, where understanding dosages and administration is crucial. Medical history, clinical examinations and medication reviews, often involving clinical pharmacists, are vital in the A&E to reveal medication errors.

Efficacy and safety of hepatic arterial infusion chemotherapy combined with lenvatinib and PD-1 inhibitors for advanced hepatocellular carcinoma with macrovascular invasion.

BACKGROUND AND AIMS: The prognosis of hepatocellular carcinoma (HCC) with macrovascular invasion(MaVI)is poor, and the treatment is limited. This study aims to explore the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC), combined with lenvatinib and programmed cell death-1(PD-1) inhibitor in the first-line treatment of HCC with MaVI. METHODS: From July 2020 to February 2022, we retrospectively analyzed consecutive patients with HCC with MaVI who received hepatic arterial infusion FOLFOX(oxaliplatin, 5-fluorouracil, and leucovorin)combined with lenvatinib and PD-1 inhibitor. The efficacy was evaluated by RECIST 1.1. Kaplan-Meier was used to explore the overall survival and progression-free survival (PFS), and the COX regression model was used to analyze the risk factors of PFS. Adverse events (AEs) were evaluated according to CTCAE5.0. RESULTS: Thirty-two patients with HCC complicated with MaVI were recruited from the Second Affiliated Hospital of Nanchang University. Among the patients treated with HAIC combined with lenvatinib and PD-1 inhibitor, ten patients (31.25%) got partial response, eighteen patients (56.25%) maintained stable disease and four patients (12.50%) suffered progressive disease during follow-up; and objective response rate was 31.25%, and disease control rate was 87.5%. The median PFS was 179 days. Univariate and multivariate Cox analysis showed that the extrahepatic metastases and Child-Pugh score were independent prognostic factors of PFS. Twenty-two (68.75%) patients suffered adverse reactions. The main AEs were elevated transaminase (46.87%), thrombocytopenia (40.63%), hypoalbuminemia (28.13%), nausea and vomiting (21.88%), leukopenia (18.76%), abdominal pain (15.63%), hypertension (15.63%) and fever (15.63%). There were seven cases (21.88%) that had grade 3 or above AEs; Among them, two cases with elevated transaminase (6.25%), leukopenia, thrombocytopenia, nausea and vomiting, abdominal pain, and diarrhea occurred in one case respectively. Moreover, no treatment-related death was observed. CONCLUSIONS: Hepatic arterial infusion of FOLFOX combined with lenvatinib and PD-1 inhibitor as the first-line treatment for HCC complicated with MaVI is effective, and adverse reactions are tolerable.

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma.

BACKGROUND: The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated. AIM: To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC. METHODS: We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen. RESULTS: The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs). CONCLUSION: The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.

Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D.

BACKGROUND: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. RESULTS: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. CONCLUSION: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. GOV IDENTIFIER: ClinicalTrials.gov; NCT03374254.

Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma.

Background: The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Materials and methods: Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). Results: A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7-30.1) and the median PFS was 11.9 months (95% CI, 6.7-17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Conclusion: Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.

A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer.

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.

Which Treatment for Which Patient: Rectal Cancer Management After PROSPECT Trial.

Determining treatment options for patients with locally advanced rectal cancer after the PROSPECT trial data readout adds an important level to the decision-making process.

A preliminary study of optimal treatment response rates in patients undergoing hepatic arterial infusion chemotherapy combined with molecular targeting and immunotherapy.

Objectives: This study aimed to examine the effectiveness of the best response rate (BRR) as a surrogate for overall survival (OS), using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), in patients with unresectable hepatocellular carcinoma (HCC) undergoing hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) combined with molecular targeting and immunotherapy. Methods: This study enrolled 111 consecutive patients who had complete imaging data. The median age of patients was 58 years (IQR 50.5-65.0). Among the patients, those with Barcelona Clinic Liver Cancer (BCLC) stage A, BCLC stage B, and BCLC stage C comprised 6.4%, 19.1%, and 73.6%, respectively. The optimal threshold of BRR can be determined using restricted cubic splines (RCS) and the rank sum statistics of maximum selection. Survival curves of patients in the high rating and low rating groups were plotted. We then used the change-in-estimate (CIE) method to filter out confounders and the inverse probability of treatment weighting (IPTW) to balance confounders between the two groups to assess the robustness of the results. Results: The median frequency of the combination treatment regimens administered in the overall population was 3 times (IQR 2.0-3.0). The optimal BRR truncation value calculated was -0.2. Based on this value, 77 patients were categorized as the low rating group and 34 as the high rating group. The differences in the OS between the high and low rating groups were statistically significant (7 months [95%CI 6.0-14.0] vs. 30 months [95%CI 30.0-]; p< 0.001). Using the absolute 10% cut-off value, the CIE method was used to screen out the following confounding factors affecting prognosis: successful conversion surgery, baseline tumor size, BCLC stage, serum total bilirubin level, number of interventional treatments, alpha-fetoprotein level, presence of inferior vena cava tumor thrombus, and partial thrombin activation time. The survival curve was then plotted again using IPTW for confounding factors, and it was found that the low rating group continued to have better OS than the high rating group. Finally, the relationship between BRR and baseline factors was analyzed, and inferior vena cava tumor thrombus and baseline tumor size correlated significantly with BRR. Conclusions: BRR can be used as a surrogate endpoint for OS in unresectable HCC patients undergoing FOLFOX-HAIC in combination with molecular targeting and immunotherapy. Thus, by calculating the BRR, the prognosis of HCC patients after combination therapy can be predicted. Inferior vena cava tumor thrombus and baseline tumor size were closely associated with the BRR.

Hepatic arterial infusion chemotherapy, lenvatinib plus programmed cell death protein-1 inhibitors: A promising treatment approach for high-burden hepatocellular carcinoma.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has demonstrated remarkable local therapeutic efficacy in treating patients with large unresectable hepatocellular carcinoma (HCC). Additionally, the combination of lenvatinib and programmed cell death protein-1 (PD-1) inhibitors has demonstrated promising antitumor effects in unresectable HCC. Therefore, we conducted a retrospective analysis to evaluate the efficacy and safety of combining HAIC with lenvatinib and PD-1 inhibitors as a first-line therapeutic approach in high-burden HCC patients. METHODS: We conducted a retrospective analysis on patients diagnosed with high-burden HCC who had major portal vein tumor thrombosis (Vp3 and Vp4) or tumor occupancy exceeding 50% of the liver. These patients received a first-line treatment consisting of HAIC with a combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), along with lenvatinib and PD-1 inhibitors between November 2020 and June 2023. The primary endpoints of this study included progression-free survival (PFS) and overall survival (OS), while the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). RESULTS: Ninety-one patients were enrolled in this study, with a median PFS of 8.8 months (95% confidence interval [CI]: 5.75-11.78) and a median OS of 14.3 months (95% CI: 11.23-17.31). According to RECIST 1.1 criteria, the ORR was 52.7%, and DCR was 95.6%. According to the mRECIST criteria, the ORR was 72.5%, and the DCR was 96.5%. Among all patients, 86 (94.5%) experienced TRAEs, and there were no instances of treatment-related deaths. CONCLUSION: The combination of HAIC-FOLFOX with lenvatinib and PD-1 inhibitors as a first-line therapy has exhibited notable therapeutic efficacy and well-tolerated adverse events among patients with high-burden HCC.

Hepatic artery infusion chemotherapy combined with the FOLFOX regimen for the treatment of hepatocellular carcinoma: recent advances and literature review.

INTRODUCTION: The incidence of primary liver cancer (PLC) has experienced a significant global increase, primarily attributed to the rise in hepatocellular carcinoma (HCC). Unfortunately, HCC is often diagnosed in advanced stages, leaving patients with limited treatment options. Therefore, transformation therapy is a crucial approach for long-term survival and radical resection in patients with advanced HCC. Conversion therapy has demonstrated promise in the treatment of advanced HCC. When integrated with the FOLFOX regimen, hepatic artery infusion chemotherapy (HAIC) can significantly improve tumor response efficiency, leading to high conversion and resection rates. AREAS COVERED: We reviewed landmark trials of HAIC in combination with different drugs or means for the treatment of HCC to determine the clinical value of HAIC-centric translational therapies in HCC treatment. Furthermore, we specifically emphasize the advantages associated with employing FOLFOX-HAIC in the treatment of advanced HCC. EXPERT OPINION: The combination of HAIC with the FOLFOX regimen can help prevent the low intratumoral accumulation and high adverse reaction rate caused by the FOLFOX alone, holding significant potential in the comprehensive treatment of future HCC patients.

Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.

BACKGROUND: Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC. METHODS: SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models. RESULTS: Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95). CONCLUSIONS: Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.

Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E.

BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary. RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E. CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.

[An update on total neoadjuvant treatment of adenocarcinoma of the rectum]. / Actualisation des données sur le traitement néoadjuvant total de l'adénocarcinome du rectum.

A major advance has been made in the management of rectal cancer, with the emergence in 2021 of total neoadjuvant treatment. The main publications from the RAPIDO and PRODIGE-23 trials reported a significant improvement in progression-free survival and the pathological complete response rate. The aim of this review is to synthesize recent data on neoadjuvant treatment of rectal cancer, to explain the long-term results of the RAPIDO and PRODIGE-23 trials, and to put them into perspective, considering current advances in de-escalation strategies. The update of the 5-year survival data from the RAPIDO trial highlights an increased risk of loco-regional relapse, with 11.7% of relapses in the experimental group and 8.1% in the control group, while the update of the PRODIGE-23 trial confirms the benefits of this treatment regimen, with a significant improvement in overall survival. In addition, the results of the OPRA and PROPSPECT trials confirm the benefit of total neoadjuvant treatment with induction chemotherapy, as well as the possibility of surgical de-escalation in the OPRA trial and radiotherapy in the PROSPECT trial. The challenge for the future is to identify patients who require total neoadjuvant treatment with the aim of curative surgery to obtain a cure without local or distant relapse, and those for whom therapeutic de-escalation can be envisaged.

Bone loss over time and risk of osteoporosis in advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer has a high risk of developing osteoporosis. However, the impact of osteoporosis has not been well-studied. This study aimed to evaluate bone loss over time and risk of osteoporosis in patients with advanced pancreatic cancer. METHODS: We retrospectively examined consecutive patients with unresectable pancreatic cancer who had evaluable computed tomography before treatment and at 1-year follow-up. Bone mineral density at the first lumbar vertebra was measured on computed tomography, and osteoporosis was defined as bone mineral density < 135 Hounsfield units. The prevalence and risk factors for osteoporosis, changes in bone mineral density over time and incidence of bone fractures were analyzed. RESULTS: Three hundred eighty patients were included. Osteoporosis was associated with older age, female sex, low body mass index and poor performance status at baseline. A consistent decrease in bone mineral density was observed over time regardless of age, sex or disease status, resulting in an increase in the prevalence of osteoporosis over time (47% at baseline, 79% at 1 year, 88% at 2 years, 89% at 3 years, 95% at 4 years and 100% at 5 years). Changes in bone mineral density from baseline were greater in patients with locally-advanced pancreatic cancer, in those who received modified FOLFIRINOX or S-IROX for more than 3 months, and in those who received radiation therapy. Incident fractures developed in 45 patients (12%) during follow-up. CONCLUSIONS: Osteoporosis and osteoporotic fractures were highly prevalent in patients with advanced pancreatic cancer. This study highlights the importance of screening for osteoporosis in such patients.

Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial.

BACKGROUND: Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer. PATIENTS AND METHODS: This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS). RESULTS: Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms. CONCLUSIONS: Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.

Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer.

PURPOSE: A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects. METHODS: We trained a new machine learning model, referred to as the colon oxaliplatin signature (COLOXIS) model, for predicting response to oxaliplatin-containing regimens. We examined whether COLOXIS was predictive of oxaliplatin benefits in the CC adjuvant setting among 1,065 patients treated with 5-fluorouracil plus leucovorin (FULV; n = 421) or FULV + oxaliplatin (FOLFOX; n = 644) from NSABP C-07 and C-08 phase III trials. The COLOXIS model dichotomizes patients into COLOXIS+ (oxaliplatin responder) and COLOXIS- (nonresponder) groups. Eight-year recurrence-free survival was used to evaluate oxaliplatin benefits within each of the groups, and the predictive value of the COLOXIS model was assessed using the P value associated with the interaction term (int P) between the model prediction and the treatment effect. RESULTS: Among 1,065 patients, 526 were predicted as COLOXIS+ and 539 as COLOXIS-. The COLOXIS+ prediction was associated with prognosis for FULV-treated patients (hazard ratio [HR], 1.52 [95% CI, 1.07 to 2.15]; P = .017). The model was predictive of oxaliplatin benefits: COLOXIS+ patients benefited from oxaliplatin (HR, 0.65 [95% CI, 0.48 to 0.89]; P = .0065; int P = .03), but COLOXIS- patients did not (COLOXIS- HR, 1.08 [95% CI, 0.77 to 1.52]; P = .65). CONCLUSION: The COLOXIS model is predictive of oxaliplatin benefits in the CC adjuvant setting. The results provide evidence supporting a change in CC adjuvant therapy: reserve oxaliplatin only for COLOXIS+ patients, but further investigation is warranted.

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.