Exploring microRNA patterns as biomarkers of FOLFOX chemotherapy-induced peripheral neuropathy in patients with colorectal cancer.

FOLFOX is a combination of chemotherapeutic agents (5-fluorouracil, leucovorin, and oxaliplatin) and is used to treat advanced colorectal cancer (CRC) but induces various side effects. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most critical side effects that compromise the quality of life of patients with CRC undergoing FOLFOX chemotherapy. This study aimed to evaluate circulating miRNA, cortisol and catecholamine as potential biomarkers that can predict FOLFOX-CIPN symptoms. High-throughput microRNA (miRNA) sequencing was performed on the RNA circulating in the plasma of eight patients with CRC who underwent FOLFOX chemotherapy. miRNA expression profiles were evaluated according to two groups: those who underwent ≤3 cycles and those who underwent ≥6 cycles of FOLFOX chemotherapy. The identified miRNAs were validated in 27 patients with CRC who underwent FOLFOX chemotherapy using quantitative reverse transcription polymerase chain reaction. Target genes were predicted using bioinformatics and functional analyses. Cortisol and catecholamine concentrations in peripheral plasma were measured using an enzyme-linked immunosorbent assay. miR-3184-5p was differentially expressed when miRNA expression was compared between the groups that underwent ≤3 and ≥6 cycles of FOLFOX chemotherapy. Cortisol levels were significantly higher in the group that underwent ≥6 cycles of FOLFOX chemotherapy than in the group that underwent ≤3 cycles. This study suggests that miR-3184-5p may be a potential marker for predicting CIPN.

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.

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.

Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild-type metastatic colorectal cancer: A phase II trial (HYBRID).

BACKGROUND: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. RESULTS: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. CONCLUSIONS: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.

Modified FOLFIRINOX (mFOLFIRINOX) as neoadjuvant therapy and 'salvage' in patients with high risk locally advanced rectal cancers - tolerance and early outcomes.

BACKGROUND: There is limited data with regard to the use of modified 5-fluoroural-leucovorin-irinotecan-oxaliplatin (mFOLFIRINOX) in terms of tolerance and enabling total mesorectal excision (TME) of locally advanced rectal adenocarcinomas (LARC) with high-risk characteristics (T4b status, signet ring histology etc) post standard neoadjuvant long course chemoradiation (NACTRT) or short course radiation (SCRT) and chemotherapy. MATERIALS AND METHODS: Patients with LARC from January 2018 to December 2020 receiving mFOLFIRINOX post NACTRT/SCRT to facilitate TME were evaluated. The primary endpoint was assessment of grade 3 and grade 4 treatment related toxicity and TME rates. Event free survival (EFS), where event was defined as disease progression or recurrence post resection after mFOLFIRINOX, was calculated by Kaplan Meier method. RESULTS: Forty-seven patients were evaluated with a median age of 33 years (Range:18-59), 45% T4b status, 96% radiological circumferential margin (CRM) involved (79% CRM positive post NACTRT/SCRT), 43% extramural venous invasion (n=33) and 36% signet ring histology. 62% had received prior NACTRT and 38% had received SCRT with chemotherapy before receiving mFOLFIRINOX. The most common grade 3 and grade 4 treatment related side effects included diarrhoea (7%), anaemia (4%) and infections (4%). Intended duration of mFOLFIRINOX or beyond was completed in 94% of patients. 60% of patients underwent curative local resection with R0 resection rates of 100% (n=28) and pathological complete response rates of 21%. The most common surgeries done were exenterations and abdominoperineal in 22% and 17% patients respectively. With a median follow up of 19 months, 24 patients had recurred or progressed for a median EFS of 20 months [95% confidence interval (CI): 15-24]. CONCLUSIONS: Locally advanced rectal cancers with high-risk characteristics are a niche group of cancers with less-than-optimal outcomes post standard neoadjuvant strategies. mFOLFIRINOX appears to be well tolerated and enables TME in a significant proportion of these patients.

Efficacy and Toxicity of Palliative Chemotherapy in Elderly Patients With Advanced Pancreatic Cancer.

OBJECTIVES: We aimed to compare the efficacy and toxicity of palliative chemotherapy in elderly patients with pancreatic ductal adenocarcinoma (PDAC) with those in younger patients. METHODS: A total of 60 patients with locally advanced or metastatic PDAC who received FOLFIRINOX or nab-paclitaxel plus gemcitabine at our institution from January 2014 to December 2021 were analyzed. Patients 70 years or older were classified into an elderly group. RESULTS: The elderly group included 16 patients (26.7%). In the elderly group, nab-paclitaxel plus gemcitabine was used more than FOLFIRINOX compared with the young group (75.0% and 25.0% vs 34.1% and 64.9%, respectively; P = 0.008). The overall survival was not significantly different between the 2 groups (15.6 vs 13.4 months, P = 0.259). However, the elderly group showed better progression-free survival (11.4 vs 7.4 months, P = 0.034). The incidence of adverse events including neutropenia (75.0% vs 81.8%, P = 0.716), thrombocytopenia (25.0% vs 31.3%, P = 0.743), and anemia (50.0% vs 43.2%, P = 0.771) was not different between the 2 groups. Peripheral neuropathy was more common in the elderly group (18.3% vs 2.3%, P = 0.054), though not statistically significant. CONCLUSION: The efficacy and toxicity of chemotherapy in elderly patients with advanced PDAC were comparable with those in younger patients.

Optimal duration of oxaliplatin-based adjuvant chemotherapy in patients with different risk factors for stage II-III colon cancer: a meta-analysis.

BACKGROUND: The duration of oxaliplatin-based chemotherapy in high-risk stage II, low-risk stage III, and high-risk stage III colon cancer (CC) patients is controversial. To reduce the risk of adverse events (AEs) without compromising efficacy while improving chemotherapy compliance is crucial. METHODS: The authors searched Cochrane, Embase, Pubmed, and Web of Science databases for articles from inception to August 8, 2023, the main outcomes were disease-free survival, overall survival, chemotherapy completion rates, and AE frequency. RESULTS: Six randomized controlled trials (RCTs) involving 10 332 patients were included. Disease-free survival analysis revealed that only the high-risk stage III CC patients experienced better results with the 6-month FOLFOX regimen when compared with the 3-month regimen [Hazard ratio (HR): 1.32, 95% CI: 1.15-1.51, P <0.0001). Overall survival (OS) analysis revealed that extending the use of FOLFOX and CAPEOX regimens did not provide survival benefits for stage III CC patients (HR: 1.16, 95% CI: 0.9-1.49, and HR: 0.89, 95% CI: 0.67-1.18, P =0.40). The completion rate of the 3-month oxaliplatin-based adjuvant chemotherapy regimen was significantly higher than that of the 6-month regimen [Relative risk (RR): 1.16, 95% CI: 1.06-1.27, P =0.002]. Moreover, the 3-month regimen had significantly lower AE rates than the 6-month regimen (RR: 0.62, 95% CI: 0.57-0.68, P <0.00001), with differences mainly concentrated in grade 3/4 neutropenia (RR: 0.70, 95% CI: 0.59-0.85, P =0.0002), peripheral sensory neuropathy at ≥grade 2 (RR: 0.45, 95% CI: 0.38-0.53, P <0.00001), and hand-foot syndrome at ≥grade 2 (RR: 0.36, 95% CI: 0.17-0.77, P =0.009). CONCLUSION: The 6-month FOLFOX regimen should only be recommended for high-risk stage III CC, while the 3-month regimen can be recommended for other stages. A 3-month CAPEOX regimen can be recommended for stage II-III CC.

Phase I trial of apatinib and paclitaxel+oxaliplatin+5-FU/levoleucovorin for treatment-naïve advanced gastric cancer.

Chinese guidelines recommend POF (paclitaxel, oxaliplatin, and 5-FU/levoleucovorin) as first-line treatment for advanced gastric cancer (AGC). Apatinib can augment the antitumor effect of paclitaxel, oxaliplatin, or fluorouracil in preclinical studies of AGC. A phase I clinical trial was conducted to evaluate the anticancer activity and maximum tolerated dose (MTD) of apatinib plus POF in treatment-naïve patients with AGC and to establish a recommended phase II dose. Participants received escalating doses of daily oral apatinib (250, 375, 500, 625, 750, and 850 mg) plus POF every 2 weeks using a conventional "3 + 3" study design. Among 21 treated patients, one experienced a dose-limiting toxicity (grade 3 skin ulceration at 850 mg). No MTD was reached. Apatinib 750 mg plus POF was recommended for phase II study. The most common grade 3-4 adverse events (AEs) were neutropenia (33.3%), mucositis (14.3%), and hand-foot syndrome (14.3%). Median progression-free and overall survival were 10.4 months (95% CI: 6.3, 14.6) and 18.4 months (95% CI: 9.8, 28.2), respectively. Apatinib up to 850 mg coadministered with POF was well tolerated with manageable AEs. The safety and anticancer activity of this regimen warrants its further investigation as first-line treatment for AGC in a larger study.

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.

Long-Term Follow-up Data of a Multi-Institutional Phase-2 Study of S-1/oxaliplatin and Bevacizumab Therapy in Patients with Advanced Colorectal Cancer: The HiSCO-02 Study.

Oral fluoropyrimidines (FUs) have certain advantages over intravenous FUs, such as longer intervals between outpatient visits, no requirement for central venous port (CVP) implantation, and lower incidence of neutropenia. We previously reported the efficacy of S-1/oxaliplatin (SOX) with bevacizumab therapy as a first-line treatment for advanced colorectal cancer (CRC) in a prospective phase-II multi-institutional clinical trial (HiSCO-02 study). However, our prognostic data at the time lacked a sufficient observation period. Herein, we analyze the longer-term follow-up data, focusing on the status of eventual CVP implantation via an open-label, non-randomized, multicenter study. This study enrolled 55 patients (mean age, 64 years), of whom 43 died (41 of primary cancer). The median overall survival was 22.7 months (95% CI: 20.1-34.7 months). Post-treatment regimens after failure of first-line treatment were initiated in 43 patients; CPT11-based regimens were selected in most cases, and other oral FU combinations in nine. CVP was implanted in 35 patients prior to first-line treatment; eleven of the remaining 20 patients did not require CVP implantation. In conclusion, we report here the final prognostic update of the Phase II clinical trial examining the efficacy of SOX plus bevacizumab therapy, the results of which confirm the clinical efficacy of this regimen.

Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study.

PURPOSE: The intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS: In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS: Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION: The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.

First-line Palliative Chemotherapy for Colorectal Cancer: a Population-based Analysis of Delivery and Outcomes in a Single-payer Health System.

AIMS: Clinical practice guidelines recommend palliative chemotherapy for most patients with metastatic colorectal cancer. However, outcomes observed in the real world compared with patients enrolled in clinical trials have not been sufficiently described. The objective of this study was to evaluate the delivery and outcomes of first-line palliative chemotherapy administered to patients with colorectal cancer in routine clinical practice compared with clinical trials. MATERIALS AND METHODS: Using linked health administrative data, we carried out a retrospective population-level cohort study on patients diagnosed with colorectal cancer in Ontario, Canada from 2010 to 2019. Patient, disease and treatment characteristics were summarised. The primary outcome was median overall survival, stratified by treatment prescribed and age. Demographics and outcomes in this real-world population were compared with those from pivotal clinical trials. A multivariable Cox regression model reporting hazard ratios and 95% confidence intervals was used to determine factors associated with survival in patients receiving systemic treatment. RESULTS: We identified 70 987 patients with a new diagnosis of colorectal cancer, of which 4613 received first-line chemotherapy for unresectable locally advanced or metastatic disease and formed the study cohort. Fifty-eight per cent were male and the mean age was 63 years. Most had colon cancer (69%), at least one comorbidity (73%) and lived in an urban location (79%). Less than half (47%) had surgery after diagnosis. The most common regimen prescribed was folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) with bevacizumab or epidermal growth factor receptor inhibitors (EGFRi; n = 2784, 60%). Among all treated patients, the median overall survival was 17.1 months, with survival difference by regimen [median overall survival 18.3 for FOLFIRI with bevacizumab or EGFRi, 19.6 for folinic acid, 5-fluorouracil and oxaliplatin (FOLFOX)/capecitabine, oxaliplatin (XELOX) with bevacizumab or EGFRi, 13.6 for FOLFIRI alone and 7.8 for 5-fluorouracil or capecitabine]. Patients aged >80 years were most likely to have received single-agent 5-fluorouracil or capecitabine, and had inferior overall survival compared with their younger counterparts. Compared with pivotal clinical trials, patients in the real world had inferior overall survival outcomes despite similar demographic characteristics (including age and sex). CONCLUSIONS: In this real-world population-based analysis of patients receiving first-line chemotherapy for unresectable locally advanced or metastatic colorectal cancer, survival outcomes were inferior to those reported in randomised trials despite similarities in age and sex. This information can be used when counselling patients in routine practice about expected outcomes.

Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.

BACKGROUND: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma. METHODS: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing. FINDINGS: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event. INTERPRETATION: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven. FUNDING: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants.

A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer.

PURPOSE: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). MATERIALS AND METHODS: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. RESULTS: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0). CONCLUSION: GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel for Resectable Esophagogastric Cancer: Interim Results From the Randomized, Multicenter, Phase II/III DANTE/IKF-s633 Trial.

PURPOSE: This trial evaluates the addition of the PD-L1 antibody atezolizumab (ATZ) to standard-of-care fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) as a perioperative treatment for patients with resectable esophagogastric adenocarcinoma (EGA). METHODS: DANTE started as multicenter, randomized phase II trial, which was subsequently converted to a phase III trial. Here, we present the results of the phase II proportion, focusing on surgical pathology and safety outcomes on an exploratory basis. Patients with resectable EGA (≥cT2 or cN+) were assigned to either four preoperative and postoperative cycles of FLOT combined with ATZ, followed by eight cycles of ATZ maintenance (arm A) or FLOT alone (arm B). RESULTS: Two hundred ninety-five patients were randomly assigned (A, 146; B, 149) with balanced baseline characteristics between arms. Twenty-three patients (8%) had tumors with microsatellite instability (MSI), and 58% patients had tumors with a PD-L1 combined positive score (CPS) of ≥1. Surgical morbidity (A, 45%; B, 42%) and 60-day mortality (A, 3%; B, 2%) were comparable between arms. Downstaging favored arm A versus arm B (ypT0, 23% v 15% [one-sided P = .044]; ypT0-T2, 61% v 48% [one-sided P = .015]; ypN0, 68% v 54% [one-sided P = .012]). Histopathologic complete regression rates (pathologic complete response or TRG1a) were higher after FLOT plus ATZ (A, 24%; B, 15%; one-sided P = .032), and the difference was more pronounced in the PD-L1 CPS ≥10 (A, 33%; B, 12%) and MSI (A, 63%; B, 27%) subpopulations. Complete margin-free (R0) resection rates were relatively high in both arms (A, 96%; B, 95%). The incidence and severity of adverse events were similar in both groups. CONCLUSION: Within the limitations of the exploratory nature of the data, the addition of ATZ to perioperative FLOT is safe and improved postoperative stage and histopathologic regression.

Oxaliplatin­induced changes in splenic volume and liver fibrosis indices: retrospective analyses of colon cancer patients receiving adjuvant chemotherapy.

The aim of our study was to evaluate the association between increased splenic volume (SV) and liver fibrosis indices in colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy. Patients who received adjuvant oxaliplatin-based regimens with the diagnosis of stage II and III colon cancer were evaluated. Splenic volume measurements, liver function tests, platelet count, and non-invasive liver fibrosis indices [NAFLD fibrosis score (NFS), AST to platelet ratio (APRI), and Fibrosis-4 (FIB-4)] were measured before and after treatment. A 30% increase in SV after chemotherapy compared to baseline was considered increased SV. The rate of increase in SV was 57.7% in the whole group. An increase in SV was shown at a higher rate in patients treated with capecitabine and oxaliplatin (CAPOX) than those treated with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) (66.3% vs. 36.8%, p = 0.002). Furthermore, the CAPOX regimen (OR: 2.831, 95% CI: 1.125-7.121; p = 0.027), and higher post-treatment FIB-4 score (OR: 3.779; 95% CI:1.537- 9.294, p = 0.004) were determined as independent risk factors for the increased SV. Our study revealed that increased SV had a significant association with higher FIB-4 score in patients treated with oxaliplatin-based chemotherapy.

Real-world tolerance and outcomes of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer-Does dose intensity matter?

INTRODUCTION: Fluoropyrimidine and oxaliplatin-based adjuvant chemotherapy delivered as 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), or capecitabine and oxaliplatin (CAPOX) is the standard of care for resected stage III colon cancer. Without randomized trial data, we compared real-world dose intensity, survival outcomes, and tolerability of these regimens. METHODS: Records of patients treated with FOLFOX or CAPOX in the adjuvant setting for stage III colon cancer across four institutions in Sydney during 2006-2016 were reviewed. The relative dose intensity (RDI) of fluoropyrimidine and oxaliplatin of each regimen, disease-free survival (DFS), overall survival (OS), and incidence of grade ≥2 toxicities were compared. RESULTS: Characteristics of patients receiving FOLFOX (n = 195) and CAPOX (n = 62) were evenly matched. FOLFOX patients had a higher mean RDI for both fluoropyrimidine (85% vs. 78%, p < 0.01) and oxaliplatin (72% vs. 66%, p = 0.06). In spite of a lower RDI, CAPOX patients trended toward a better 5-year DFS (84% vs. 78%, HR = 0.53, p = 0.068) and similar OS (89% vs. 89%, HR = 0.53, p = 0.21) compared to the FOLFOX group. This difference was most pronounced in the high-risk (T4 or N2) group where 5-year DFS was 78% versus 67% (HR = 0.41, p = 0.042). Patients receiving CAPOX experienced more grade ≥2 diarrhea (p = 0.017) and hand-foot syndrome (p < 0.001) but not peripheral neuropathy or myelosuppression. CONCLUSION: In a real-world setting, patients who received CAPOX had similar OS rates when compared to those receiving FOLFOX in the adjuvant setting in spite of lower RDI. In the high-risk population, CAPOX appears to demonstrate a superior 5-year DFS over FOLFOX.

A Real-World Retrospective Study to Evaluate the Reliability of Cetuximab plus Capecitabine versus Capecitabine as Maintenance Therapy in Patients with RAS and BRAF Wild-Type Metastatic Colorectal Cancer.

BACKGROUND: The optimal maintenance therapy for rat sarcoma (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) metastatic colorectal cancers (mCRCs) remains unclear. It is critical to evaluate the reliability of cetuximab-capecitabine (the observation group) relative to capecitabine alone (control group). PATIENTS AND METHODS: In this retrospective analysis, patients with RAS and BRAF mCRC admitted to Huizhou Municipal Central Hospital, between January 2016 and October 2020 were enrolled and treated with cetuximab plus 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as an initial therapy. Patients whose disease was controlled after at least six cycles of treatment were administered a maintenance therapy until disease progression. We also analyzed the prognosis of patients according to clinicopathological features. Altogether, 39 RAS and BRAF mCRC patients were recruited from January 2016 to October 2020, with 18 cases in the treatment group and 21 cases in the control group. The difference in baseline clinicopathological features between the two treatments is not obvious. RESULTS: The median progression-free survival after maintenance treatment in observation group (9.5 months [95% confidence interval (CI) = 6.4-12.6]), was significantly better than the control group (7.3 months [95% CI = 5.8-8.8]). During maintenance treatment, there were no deaths caused by treatment-related adverse events, and the overall incidence of rash acne was different between the observation and control groups (p < 0.05). Most adverse events were mild and easily controlled. Primary tumor site, baseline carcinoembryonic antigen levels, and microsatellite instability status were independent prognostic factors. CONCLUSION: Maintenance therapy using cetuximab plus capecitabine improved survival in patients with mCRC and was well tolerated by patients.

Impact of Folinic Acid Dosing on Efficacy and Toxicity of High-Dose Methotrexate in Central Nervous System Lymphoma.

INTRODUCTION: High-dose methotrexate (HDMTX)-based regimens are the treatment of choice in primary central nervous system lymphoma (PCNSL). Folinic acid (FA) rescue is used to mitigate the toxic effects of MTX on normal cells. However, the optimal dosing of FA in PCNSL remains uncertain. METHODS: We analyzed the relationship between FA dosing and treatment efficacy and toxicity in a cohort of 36 PCNSL patients treated at our institute between the years 2014 and 2022. A combination of univariate and multivariate analyses using known prognostic factors were used to determine the association between FA dosing and treatment outcomes. RESULTS: We found that higher per-treatment cumulative FA doses were associated with inferior progression-free survival (PFS), with a hazard ratio (HR) of 2.2 for each 100 mg/m2 increase in FA dose. We identified a threshold of 350 mg/m2/treatment, above which there was a significant reduction in PFS. Notably, lower FA doses did not result in increased toxicity. CONCLUSION: Our findings suggest that optimizing FA dosing to avoid very high rescue doses may improve treatment outcomes in PCNSL patients receiving HDMTX. Further prospective studies are warranted to validate these findings.

A phase-II study based on dose adjustment according to UGT1A1 polymorphism: is irinotecan underdosed in first-line FOLFIRI regimen for mCRC?

PURPOSE: Irinotecan has considerable importance in the treatment of metastatic colorectal cancer (mCRC). UDP-glucoronyltransferase (UGT) 1A1 is responsible for the inactivation of SN-38, a metabolite of irinotecan. Depending on UGT1A1 polymorphism, the activity of the UGT enzyme can be reduced leading to more frequent occurrence of adverse events related to irinotecan. The present study aimed to assess the safety and efficacy of different doses of irinotecan adjusted according to UGT1A1 polymorphism. METHODS: Thirty-four patients treated with FOLFIRI as first-line treatment for mCRC were included in this study. The irinotecan dosage was adapted on the basis of UGT1A1 polymorphisms: *1/*1 (370 mg/m2); *1/*28 (310 mg/m2), and *28/*28 (180 mg/m2). The incidence of grades 3 and 4 toxicities (neutropenia, febrile neutropenia, and diarrhoea) was recorded. Response was assessed according to the RECIST 1.1 criteria. RESULTS: On the basis of UGT1A1 genotyping, 20 patients were *1/*1 (58.8%), 12 were *1/*28 (35.3%) and 2 were *28/*28 (5.9%). Seven patients experienced at least one severe toxicity, i.e., 21% of the population, amounting to eleven adverse events. Concerning the response rate, 15 patients (44%) had partial or complete response. CONCLUSION: This study demonstrates that mCRC patients treated with FOLFIRI can tolerate a higher dose of irinotecan than the standard dose, i.e., > 180 mg/m2, on the basis of their UGT1A1 genotype, without increased toxicities. TRIAL REGISTRATION: NCT01963182 (registered on 16/10/2013, Clermont-Ferrand, France).