Fluoropyrimidine Research Articles

The Optimal Duration of Adjuvant Chemotherapy in Colon Cancer.

Simple SummaryThis review provides an overview of adjuvant chemotherapy in colon cancer over the last 30 years. Key questions address choice of regimen, treatment duration, treatment-dependent toxicity and possible prognostic/predictive factors. Thus, main focus is on the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration which was founded to investigate whether a shortened (3 months) of adjuvant therapy containing a fluoropyrimidine and oxaliplatin is comparable to the current/former standard of care (duration of 6 months). Results of this collaboration will be discussed and evaluated in the context of achieving the best efficacy possible while reducing severe toxicities, and future prognostic/predictive factors.Adjuvant chemotherapy for colon cancer (UICC stage II and III) has been under investigation over the last 30 years, regarding treatment duration and regimens. In this review, choice of regimen, its duration, possible limitations and future perspectives are discussed. Monotherapy with 5-fluorouracil was followed by addition of oxaliplatin, resulting in improved 3-yr disease free survival (DFS) and overall survival (OS) rates, but also increased peripheral sensory neurotoxicity (PSN). The International Duration Evaluation of Adjuvant therapy (IDEA) collaboration demonstrated less toxicity, especially PSN, when shortening treatment duration to 3 months. However, formally, the anticipated non-inferiority of 3 months with fluoropyrimidine (FP)/oxaliplatin over 6 months (at 3-yr DFS) was not met for all patients groups, although subgroup analyses showed non-inferiority with capecitabine/oxaliplatin (CAPOX) rather than with FOLFOX, and also in relation to the prognostic information (e.g., clinical low-risk group, pT1-3 N0). In addition, first data of newer parameters like Immunoscore® and ctDNA show promising results as stratification parameters. Further investigations to better define clinical risk groups and prognostic factors are mandatory. Besides this, individual decision-making of treatment intensity (FP or FP/oxaliplatin) and duration should always consider patient characteristics and preferences, also given the absolute relatively small differences and their clinical relevance.

448P Predictive factor of cardiotoxicity in fluoropyrimidine-treated colorectal cancer patients: Interim analysis of the prospective observational CHECKPOINT trial

Cardiotoxicity represents an unexpected and potentially life-threatening toxicity in colorectal (CRC) patients (pts) treated with fluoropyrimidines (FP). Currently, there are no predictive factors of FP-induced cardiotoxicity (FIC), moreover the correlation between FIC and known cardiovascular (CV) risk factors remains controversial. CRC FP naïve pts have been enrolled at Candiolo Cancer Institute from January 2016 to February 2020. Before the start of FP-based chemotherapy (CT), all patients were screened for CV comorbidities and potential risk factors with an optimization of the cardiological treatment if needed. During the first 3 CT cycles, pts were monitored with CV symptoms collection, serial electrocardiograms and brain natriuretic peptide (BNP) measurement, as well plasma samples were obtained. Primary objective was the incidence rate of FIC. Secondary objectives comprised the study of risk factors for FIC including BNP baseline levels and the validation of circulating microRNAs (c-miRNAs) as potential biomarkers of FIC. A total of 135 pts (60.7% men, median age 66 years) were included in the interim analysis, of whom 48.7% presented CV risk factors. During the treatment period 20 pts (15%) experienced FIC: 1 acute coronary syndrome, 1 coronary vasospasm, 1 paroxysmal supraventricular tachycardia, 1 complete left bundle branch block, 3 syncope, 4 typical chest pain, 6 sudden dyspnea and 3 sudden palpitations. A higher incidence of FIC in women (p. 0.048) was highlighted. No correlation between age (</> 75 years), cardiovascular risk (high/low), type of FP (5-fluorouracil/capecitabine) and disease status (adjuvant/metastatic) was observed. Among symptomatic pts 10 (50%) had CV comorbidities and/or CV risk factors. A decreasing trend in BNP values was observed in pts treated with capecitabine who experienced FIC, but this result did not reach statistical significance yet. Although FIC was observed in a not negligible percentage of patients, no relationship with CV comorbidities or risk factors was found. A more precise correlation of cardiac events with c-miRNAs will be available at completed recruitment (200 pts).

404MO Clinical relevance of MIR27A rs895819 polymorphism and its interaction with DPYD variants for predicting grade 4-5 fluoropyrimidine (FP) toxicity (tox) in the FUSAFE individual patient data meta-analysis (IPD-MA)

404MO Clinical relevance of MIR27A rs895819 polymorphism and its interaction with DPYD variants for predicting grade 4-5 fluoropyrimidine (FP) toxicity (tox) in the FUSAFE individual patient data meta-analysis (IPD-MA)

Impact of age on efficacy and early mortality of initial sequential treatment versus upfront combination chemotherapy in patients with metastatic colorectal cancer: a subgroup analysis of a phase III trial (AIO KRK0110, XELAVIRI study)

IntroductionThe XELAVIRI study compared application of fluoropyrimidine (FP) and bevacizumab (Bev) followed by sequential escalation to irinotecan (Iri), FP and Bev (arm A) to upfront combination therapy with FP, Iri and Bev (arm B) in patients with metastatic colorectal cancer (mCRC). To elucidate the impact of age on survival, we evaluated efficacy and early mortality in the underlying trial. MethodsPatients were stratified for age in three cohorts (<65 years, 65–74 years and ≥75 years). Survival end-points were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. Objective response and 60-day mortality were evaluated by chi-square testing. ResultsThe efficacy analyses suggest more substantial benefit from upfront combination chemotherapy in younger patients with mCRC. Elderly patients (≥75 years) derived limited benefit from upfront combination chemotherapy, particularly in terms of overall survival. Of 421 randomised patients, 13 patients (3.1%) died within 60 days after treatment initiation with the highest prevalence in elderly patients (1.6% < 65 years, 2.8% 65–74 years and 5.2% ≥ 75 years, p = 0.26). The frequency of 60-day mortality was significantly associated with age (with a maximum of 8.7% in patients aged ≥75 years) in patients undergoing upfront combination therapy (p = 0.027) but not in patients receiving sequential treatment (p = 0.63). ConclusionCombination therapy with FP, Iri and Bev does not substantially improve the outcome of patients aged ≥75 years as compared with sequential treatment algorithm. These patients appear to be at a relevant risk for 60-day mortality under Iri-based combination chemotherapy plus Bev.

Impact of DPYD, DPYS, and UPB1 gene variations on severe drug-related toxicity in patients with cancer.

Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS, and UPB1 genes. Genotype‐guided dose individualization of FP therapy has been proposed in western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP‐related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intron regions of their DPYD, DPYS, and UPB1 genes. In total, 24 single nucleotide variants (15 in DPYD, 7 in DPYS and 2 in UPB1) were identified including 3 novel variants in DPYD and 1 novel variant in DPYS. We did not find a significant association between FP‐related high toxicity and each of these individual variants, although a certain trend toward significance was observed for p.Arg181Trp and p.Gln334Arg in DPYS (P = .0813 and .087). When we focused on 7 DPYD rare variants (p.Ser199Asn, p.IIe245Phe, p.Thr305Lys, p.Glu386Ter, p.Ser556Arg, p.Ala571Asp, p.Trp621Cys) which have an allele frequency of less than 0.01% in the Japanese population and are predicted to be loss‐of‐function mutations by in silico analysis, the group of patients who were heterozygous carriers of at least one these rare variants showed a strong association with FP‐related high toxicity (P = .003). Although the availability of screening of these rare loss‐of‐function variants is still unknown, our data provide useful information that may help to alleviate FP‐related toxicity in Japanese patients with cancer.

Comparison of 4 Screening Methods for Detecting Fluoropyrimidine Toxicity Risk: Identification of the Most Effective, Cost-Efficient Method to Save Lives.

Background:Fluoropyrimidines (FPs) carry around 20% risk of G3-5 toxicity and 0.2-1% risk of death, due to dihydropyrimidine dehydrogenase (DPD) deficiency. Several screening approaches exist for predicting toxicity, however there is ongoing debate over which method is best. This study compares 4 screening approaches.Method:472 patients treated for colorectal, head-and-neck, breast, or pancreatic cancers, who had not been tested pre-treatment for FP toxicity risk, were screened using: DPYD genotyping (G); phenotyping via plasma Uracil (U); phenotyping via plasma-dihydrouracil/uracil ratio (UH2/U); and a Multi-Parametric Method (MPM) using genotype, phenotype, and epigenetic data. Performance was compared, particularly the inability to detect at-risk patients (false negatives).Results:False negative rates for detecting G5 toxicity risk were 51.2%, 19.5%, 9.8% and 2.4%, for G, U, UH2/U and MPM, respectively. False negative rates for detecting G4-5 toxicity risk were 59.8%, 36.1%, 21.3% and 4.7%, respectively. MPM demonstrated significantly (p < 0.001) better prediction performance.Conclusion:MPM is the most effective method for limiting G4-5 toxicity. Its systematic implementation is cost-effective and significantly improves the risk-benefit ratio of FP-treatment. The use of MPM, rather than G or U testing, would avoid nearly 8,000 FP-related deaths per year globally (500 in France), and spare hundreds of thousands from G4 toxicity.

Feasibility of switching to S-1 after other fluoropyrimidine-related cardiotoxicity during chemotherapy for solid tumors.

7037 Background: Fluoropyrimidines (FP) are the cornerstone of chemotherapy in many solid tumors and linked to cardiotoxicity (CarTx) in about 5% (Polk, Cancer Treat Rev 2013), often leading to FP discontinuation. CarTx may be less common with S-1 and successful switch from other FP has been reported (Kwakman, EJC 2017). Methods: This 6-country, 12-center, cohort study included patients with solid tumors (ICD10 C15-C21, C24-25, C50, C80) who experienced FP-related CarTx. Primary endpoint was recurrent (R) CarTx during S-1 therapy after switch from any other FP. Results: CarTx during capecitabine (n = 124), continuous (n = 13) or bolus 5-fluorouracil (n = 4) was reported for 141 patients who switched to S-1 therapy. CarTx was chest pain including vasospasm without cardiac findings (55%), acute coronary syndrome or myocardial infarction (32%), atrial fibrillation (4%), heart failure/cardiomyopathy (4%), tachy-/bradycardia (3%), and/or other (15%). CarTx was grade 3-4 in 55%, appeared on cycle 1-2 in 89%, and at median 4 days (range 0-466) from FP initiation (Table). Causality was judged related in 26%, probable in 60%, and possible in 14%. Action with FP causing CarTx was permanent discontinuation in 91%. Treatment intent was curative in 70%. Cumulative incidence of RCarTx with S-1 was 3.5% (CI95%, 1.2-8.4%) and median time to R-CarTx was 11 (range 6-195) days. Four (out of 141) had grade 1 and one grade 2 R-CarTx. Three were judged possibly related to S-1 and 2 not related. S-1 was discontinued in one patient and continued in 4 (for 63-252 days) without action (n = 2), with dose reduction (n = 1), or delay (n = 1). There were no differences in demographic or risk factors regarding R-CarTx on S-1 (Table). Conclusions: FP-related CarTx is often severe, occurs early, and leads to permanent FP discontinuation. Switching to S-1-based therapy is safe, with, at the most, grade 1-2 R-CarTx in only 3.5%, and rarely leads to treatment discontinuation (0.7%), allowing patients to continue on an FP-based regimen. Clinical trial information: NCT04260269 . [Table: see text]

FOLFIRINOX de-escalation in advanced pancreatic cancer (aPC): A multicenter real-life study.

4639 Background: FOLFIRINOX (5FU, irinotecan, and oxaliplatin) is a reference first line (L1) of chemotherapy (CT) in fit patients (Pts) with advanced pancreatic cancer (aPC). Limiting toxicities (in particular, neuropathy) are frequent and maintaining quality of life without a lack of efficacy is a crucial need. Modalities and efficacy of maintenance strategy in aPC remain scarcely studied. Our study describes the French practices of a FOLFIRINOX de-escalation and maintenance in a real-life multicentric cohort. Methods: We performed a retrospective multicentric study in 5 French centers. Pts receiving FOLFIRINOX L1 for aPC were recruited between January 2011 and December 2018. FOLFIRINOX de-escalation was defined as stopping oxaliplatin and/or irinotecan in patients without tumor progression, after at least 4 cycles of FOLFIRINOX. Maintenance schedules were oral capecitabine or intravenous (IV) 5FU, FOLFOX or FOLFIRI. Primary endpoint was overall survival (OS). Secondary endpoints were first progression-free survival (PFS1) and, in case of reintroduction of FOLFIRINOX, second progression free survival (PFS2). OS and PFS were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Among the 321 patients included, 147 (46%) received a maintenance therapy. Median age was 60.0 (53-66), 35 (24%) had locally advanced PC and 91 (62%) had metastatic PC. The median number of cycles of FOLFIRINOX was 9.0 (6.0-11.0). Median OS was 16.1 months (95%CI=13.7-20.3). Median PFS1 was 9.4 months (95%CI=8.5-10.4). The preferred maintenance regimen was FOLFIRI in 66 (45%), vs fluoropyrimidine (FP) in 52 (35%) and FOLFOX in 25 (17%). Among 118 Pts who received a maintenance CT with FP or FOLFIRI, there was no difference in PFS1 (median: 10.1 vs 9.0, respectively, p=0.33) or OS (median: 16.6 versus 18.7, p=0.86) between the 2 maintenance regimens. After progression under maintenance CT with FOLFIRI or FP, reintroduction of FOLFIRINOX was performed in 20.2% of Pts, with a median PFS2 of 2.8 months (95%CI=2.0-22.3). The rates of G3-4 toxicity were significantly higher during FOLFIRI maintenance CT than with FP (41% vs 22%, p=0.03), especially neuropathy (73% vs 9%). Conclusions: FOLFIRINOX de-escalation in aPC is largely used in France. Fluoropyrimidine maintenance chemotherapy appears to be as effective as FOLFIRI.

Neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer (LARC) with or without oxaliplatin (OX): Individual patient data (IPD) meta-analysis of three randomized controlled trials (RCTs) with subgroup analyses of age cohorts.

4074 Background: Neoadjuvant CRT with fluoropyrimidine (FP) is standard treatment for LARC, which is increasing in younger patients (pts). RCTs examining the addition of OX are still controversial. A post hoc analysis of the CAO/ARO/AIO-04 trial showed significant benefit in pts &lt; 60y. We hypothesised that younger pts with LARC might have improved outcomes with OX-CRT. Methods: Systematic review and IPD meta-analysis were performed. Data from 3 RCTs (CAO/ARO/AIO-04, ACCORD-12, PETACC-6) testing the addition of OX to standard FP-based CRT in LARC were available (of 9 RCTs identified). Primary endpoint: disease-free survival (DFS), secondary endpoints: pathologic complete response (pCR), overall survival (OS). Analyses were by intention to treat (ITT), stratified by trial. Age cut-offs were 60y and 50y. Given the focus on young age a multivariate analysis evaluating all possible confounders was not intended in the current work. Results: IPD from 2914 pts were included (48.5% of available literature). Median age was 63; 70% were male; 79% had a performance status = 0; 72% were stage ≥III. In ITT (Hazard Ratio [HR] 0.88, 95%CI 0.77-1.01, p = 0.06), DFS was not significantly improved by the addition of OX (Table). In &lt; 60y (n = 1166, 40% total), DFS was significantly improved by OX (HR 0.77, 95%CI 0.62-0.96, p = 0.02). In &lt; 50y (n = 350, 12% total) there was a numerically better DFS, although not significant (HR 0.73, 95%CI 0.49-1.08, p = 0.12). Interaction test between age and DFS was non-significant (60y p = 0.11; 50y p = 0.44). In ITT, OX increased pCR from 13% to 16% (Odds Ratio [OR] 1.28, 95%CI 1.04-1.57, p = 0.024 [stratified by trial]), without significant interaction with age (60y p = 0.11, 50y p = 0.74). No OS benefit was demonstrated (HR 0.97, 95%CI 0.82-1.15, p = 0.75). Conclusions: This first IPD meta-analysis of three RCTs evaluating the addition of OX to CRT did not show significant interaction of OX with age. However, we confirm a signal for DFS benefit in pts &lt; 60y and a non-significant increment in DFS in &lt; 50 y although this analysis may be underpowered. Stage-stratified analyses and feasibility/toxicity data in age cohorts will be presented. [Table: see text]

Perineural Invasion and Postoperative Adjuvant Chemotherapy Efficacy in Patients With Gastric Cancer.

Purpose: There is currently a lack of validated predictors for adjuvant chemotherapy efficacy in patients with gastric cancer (GC). Perineural invasion (PNI) is the process of neoplastic invasion of the nerves, accompanied by tumor microenvironment (TME) changes. TME can determine treatment outcome while the impact of PNI on chemotherapy efficacy remains unknown in GC. We investigated the association between PNI and the efficacy of postoperative adjuvant chemotherapy in patients with resected GC.Methods: Patients who underwent radical resection of stage IB-III GC with or without fluoropyrimidine (FU)-based adjuvant chemotherapy were retrospectively selected from two separate patient cohorts. PNI was confirmed with S100 immunohistochemistry (IHC). Tumor hypoxia and activity of selected pathways were quantified by mRNA-based signature scoring based on publicly available data. A hypoxia biomarker, ERO1A, and a FU resistance biomarker, thymidylate synthase (TS), were assessed by IHC, respectively.Results: Two cohorts included 223 and 599 patients, respectively. Adjuvant chemotherapy significantly improved overall survival (OS) and disease-free survival (DFS) in PNI-positive but not in PNI-negative patients, which was not impacted by stages. Multivariate models showed that adjuvant chemotherapy was an independent predictor for OS and DFS in PNI-positive patients in both cohorts. For TME, PNI-negative tumors were more hypoxic than were PNI-positive tumors, and displayed relative up-regulation of signaling along the pathways that are important in FU metabolism or resistance. Expressions of ERO1A and TS significantly decreased in PNI-positive compared to PNI-negative tumors.Conclusions: PNI might help predict adjuvant chemotherapy benefit in patients with resected GC. Validation in prospective studies is required. Novel treatment strategies need to be developed in PNI-negative patients.

Feasibility of Switching Fluoropyrimidine Due to Cardiotoxicity Study

Feasibility of Switching Fluoropyrimidine Due to Cardiotoxicity Study

Prospective DPYD testing and dose adjustment in colorectal cancer patients prior to fluoropyrimidine-based chemotherapy: Experience in a regional cancer center.

93 Background: The fluoropyrimidines (FP), 5-Fluorouracil (5-FU) and capecitabine are a mainstay of colorectal cancer (CRC) treatment. Dihydropyrimidine dehydrogenase (DPYD), an enzyme encoded by the DPYD gene, is the initial and rate-limiting step in pyrimidine catabolism, deactivating over 80% of 5-FU. Approximately 5% of the population are deficient in DPYD and can develop severe or fatal FP toxicities. Currently, few national guidelines recommend routine prospective DPYD testing. In July 2019, we commenced a 6 month prospective pilot, testing DPYD status of all CRC patients undergoing first FP treatment in a large regional cancer centre. Methods: All CRC patients eligible for first exposure to FP are tested using a rapid molecular assay screening for five SNPs (detects 70% of DPYD mutations) and we will present data on prevalence of each. We will use electronic chemotherapy prescribing records (July 19-Jan 20) to collect information on dose modifications and toxicities. Once the pilot is completed we will perform a cost-effectiveness analysis. Results: Data from the first 3 months of this pilot have been reviewed and 201 patients have been tested with 15 heterozygotes identified, of which 2 had more than one mutation. No homozygotes were found. All heterozygote patients are started with a dose reduction (or have alternative therapy). One patient treated at 50% dose was hospitalised with several grade 3 toxicities despite dose reduction. Two patients have had subsequent dose escalation (by 25%). Nine patients have received one dose reduced cycle without complication. Three patients are due to start dose-reduced treatment. Conclusions: Routine prospective testing of DPYD status in a large regional cancer centre is feasible and with a sufficiently swift result turnaround to permit up-front dose modification. Detailed toxicity analysis and cost-effectiveness data will be presented.

RECIST and iRECIST criteria for the evaluation of nivolumab + ipilimumab combination in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC): Results of the GERCOR NIPICOL phase II study.

101 Background: Immune checkpoint inhibitors (ICKi) are highly effective for MSI/dMMR mCRC pts. RECIST1.1 criteria are reported to underestimate response to ICKi. The GERCOR NIPICOL phase II study aimed to evaluate disease control rate (DCR) using RECIST1.1 and iRECIST for MSI/dMMR mCRC pts treated with nivolumab (NIVO) and ipilimumab (IPI). Methods: MSI/dMMR mCRC pts previously treated with fluoropyrimidines (FP), oxaliplatin (OX) and irinotecan (IRI) ± targeted therapies received NIVO 3 mg/kg + IPI 1 mg/kg Q3W for 4 cycles then NIVO 3 mg/kg Q2W until progression or a maximum of 20 cycles. CT-scan tumor assessments were done every 6 weeks during 24 weeks and then every 12 weeks. Primary objective was DCR at 12 weeks (12wDCR) according to RECIST1.1 and iRECIST by central review. Response rates and progression-free survival (PFS) by central review were secondary objectives. A one-stage Fleming design was used with a targeted improvement of 12wDCR from 70% to 85%. Results: Of 57 pts included between Dec 2017 and Nov 2018, 43.9% had received ≥ 3 prior lines including FP (100%), OX (100%), IRI (95.5%), antiangiogenics (57.9%) and anti-EGFRs (45.6%). 17.5% of pts had BRAF mutation and 27.5% Lynch syndrome. Grade 3-4 treatment-related adverse events were reported in 49.1% of pts, mainly hepatitis (12.3%). 12wDCR was 86.0% and 87.7% using RECIST1.1 and iRECIST respectively, with only 1 pseudo-progression (1.8%) observed during the first 12 weeks, and one later. Kappa coefficient between RECIST and iRECIST 12wDCR was 0.92 (95%CI 0.77-1.0). Best observed responses with RECIST1.1/iRECIST were: 2/2 complete responses (3.5/3.5%), 19/19 partial responses (33.3/33.3%), 30/31 stable diseases (52.6/54.4%) and 3/2 disease progressions (5.3/3.5%), with 3 pts not evaluable (cancer-related deaths before first evaluation). Conclusions: Combination of NIVO and IPI in MSI/dMMR mCRC is associated with a low frequency of pseudo-progression and high DCR rate. PFS will be evaluated in Dec 2019, with all pts having completed the predefined 1-year of ICKi therapy. Clinical trial information: NCT033501260.

DPD Testing Before Treatment With Fluoropyrimidines in the Amsterdam UMCs: An Evaluation of Current Pharmacogenetic Practice.

IntroductionThe fluoropyrimidines (FP) (5-Fluorouracil, capecitabine, and tegafur) are commonly used anti-cancer drugs, but lead to moderate to severe toxicity in about 10–40% of patients. DPD testing [either the enzyme activity of dihydropyrimidine dehydrogenase (DPD) or the DPYD genotype] identifies patients at higher risk for toxicity who may be treated more safely with a lower drug dose. The Netherland's National guideline for colon carcinoma was updated in 2017 to recommend DPYD genotyping before treatment with FP. Pretreatment DPYD genotyping identifies approximately 50% of the patients that will develop severe FP toxicity. The aim of the study was to assess the uptake of DPD testing in the Amsterdam University Medical Centers over time and to evaluate stakeholder experiences to indicate barriers and facilitators of implementation in routine clinical care.Materials and MethodsWe used a mixed-method approach involving electronic patient records of 753 unique patients and pharmacy information systems analyses and fifteen semi-structured interviews with oncologists, pharmacists, and patients. The constellation perspective was used to identify barriers and facilitators at the level of practice, culture and structure. The proportion of FP users who were DPD tested pretreatment showed an increase from 1% (1/86) in Q2-2017 up to 87% (73/84) in Q4-2018. Unlike a landmark paper published in 2015, the National guideline for colorectal carcinoma followed by meetings to achieve local consensus led to this steep increase in the proportion of patients tested.ResultsFacilitating factors for stakeholders to implement testing included the existence of clear protocols, (anecdotal) evidence of the utility, being aware that peers are adhering to standard practice and clear and simple procedures for ordering and reporting. Main barriers included the lack of clear divisions of responsibilities, the lack of consensus on a test approach, long turn-around times and non-user-friendly IT-infrastructures. More professional education on the utility and limitations of pharmacogenetic testing was desired by most stakeholders.ConclusionWhile the evidence for DPD testing was sufficient, only after the update of a National guideline and local consensus meetings the proportion of FP users that were DPD tested pretreatment rose to 87%. The implementation of personalized medicine requires stakeholders involved to attune practice, culture and structure.

The Role of Maintenance Strategies in Metastatic Colorectal Cancer

In metastatic colorectal cancer, induction combination chemotherapy with a targeted agent is considered the mainstay of treatment. Multiple randomized clinical trials have examined different strategies of continuing cytotoxic therapy until progression compared with a period of either observation or the use of various maintenance agents. However, those randomized clinical trials have shown inconsistent efficacy results that make it challenging to draw any conclusion on which strategy is preferred. Therefore, a network meta-analysis is helpful to compare different agents across randomized clinical trials. To evaluate the comparative effectiveness of different treatment strategies for patients with metastatic colorectal cancer. MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for randomized clinical trials evaluating different strategies for patients with previously untreated metastatic colorectal cancer. Trials of interest included those including patients with metastatic colorectal cancer who were treated with an initial period of cytotoxic chemotherapy (with or without a biologic) and then switched to one of the following strategies: observation; maintenance with bevacizumab (Bev), fluoropyrimidine (FP), or both (FP + Bev); or continuing the induction regimen until progression. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian and Laird random-effects model. Network meta-analysis was conducted using a random-effects consistency model to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Initial analysis was performed on December 18, 2018. An updated search was performed in April 2019, and no additional studies were added. Twelve trials at low risk of bias (5540 patients; age range, 23-85 years; 64.4 % male) were included. Network meta-analysis showed no benefit of continuing full cytotoxic chemotherapy until progression vs observation in terms of PFS (hazard ratio, 0.71; 95% CI, 0.46-1.09) and OS (hazard ratio, 0.95; 95% CI, 0.85-1.07). Compared with observation, maintenance therapy showed a PFS benefit (hazard ratio, 0.58; 95% CI, 0.43-0.77) but not an OS benefit (hazard ratio, 0.91; 95% CI, 0.83-1.01). All maintenance strategies (FP, FP + Bev, and Bev) showed significant improvement in PFS vs observation. On SUCRA analysis, maintenance treatment (FP or FP + Bev) had the highest likelihood of achieving improved PFS (67.1% for FP, 99.8% for FP + Bev, and 36.5% for Bev) and OS (81.3% for FP, 73.2% for FP + Bev, and 32.6% for Bev). For patients with metastatic colorectal cancer, there is no benefit to continuing the full induction regimen until progression, without a period of either observation or maintenance treatment. A maintenance strategy with a fluoropyrimidine, with or without the addition of bevacizumab, is preferred. However, given the lack of a clear OS benefit, shared decision-making should include observation as an acceptable alternative.

Revisiting oral fluoropyrimidine with cetuximab in metastatic colorectal cancer: Real-world data in Chinese population.

BACKGROUNDCetuximab in combination with oral fluoropyrimidine (FP) remains controversial in metastatic colorectal cancer (mCRC). In view of the regional variation in the tolerability of FP, we conducted a retrospective analysis to compare oral FP with infusional FP in combination with cetuximab in Chinese population.AIMTo compare the efficacy and safety profile of cetuximab in combination with oral FP and infusional FP in Chinese population in the real-world setting.METHODSA retrospective cohort study was done to analyse consecutive patients with Kras wild-type mCRC who received first-line treatment with cetuximab and FP-based chemotherapy in our unit from January 2010 to December 2015. Ninety-five eligible patients were included. The median follow-up of our cohort was 65.0 mo.RESULTSThe median progression-free survival (mPFS) and median overall survival (mOS) of the entire cohort were 9.66 mo (95%CI: 7.72–12.5) and 25.8 mo (95%CI: 18.7–35.6), respectively. Between oral FP and infusional FP, there was no statistical significant difference in the mPFS [9.79 mo (95%CI: 7.49–12.7) vs 9.63 mo (95%CI: 6.34–13.4); P = 0.72] and mOS [25.8 mo (95%CI: 15.2–35.6) vs 26.3 mo (95%CI: 18.7–41.2); P = 0.63]. Grade 3 or above adverse events were reported in 28.4% of patients, being similar with oral and infusional FP, and included 10.5% of neutropenia and 2.1% of diarrhoea events.CONCLUSIONThe current analysis demonstrates comparable efficacy and safety profiles of cetuximab in combination with oral and infusional FP in Chinese population. The results expand treatment options for Chinese patients and invite revision of existing treatment guidelines to incorporate oral FP-based chemotherapy plus cetuximab.

Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France

AimsDespite fluoropyrimidines (FPs) constituting the main component of the chemotherapy combination protocols in 50% of chemotherapies for solid tumour treatments, incidence data for FP-related toxicity are poorly documented in real life. This study evaluated the number of patients receiving FP-based chemotherapies in France, along with the true incidence of FP-related serious adverse effects (SAEs) before the recent mandatory dihydropyrimidine dehydrogenase (DPD)-screening was introduced by French health authorities, DPD being the rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. MethodsExhaustive data on the number of patients treated with FP-based chemotherapy in 2013–2014 were collected in the Centre-Val de Loire region of France. True incidence of SAEs was extracted from a cohort of 513 patients with incident solid tumours receiving first-line FP-based chemotherapy. ResultsAfter extrapolation at national level, we estimated that 76,200 patients are currently treated annually with 5FU (53,100 patients, 62% digestive system-related versus 26% breast cancers versus 12% head and neck cancers) or capecitabine (23,100 patients, 45% digestive system-related versus 37% breast cancers versus 18% non-documented). Earlier (in the first two cycles) the SAE incidence rate was 19.3% (95% confidence interval (CI) 16–23%) including one toxic death (0.2%, 95%CI 0–1%). SAE incidence rate was 32.2% (95%CI 28–36%) over the first 6 months of treatment. Incidence of death, life-threatening prognosis or incapacity/disability was 1.4% (95%CI 0.4–2.4%) and 1.6% (95%CI 0.5–2.6%) during first two cycles and first 6 months, respectively. ConclusionThese data highlight the significant public health issue related to FP toxicity, with around 1200 patients developing FP-related life-threatening prognosis or incapacity/disability annually in France, including 150 toxic deaths. It is hoped that DPD-deficiency screening will reduce such iatrogenic events and eradicate toxic deaths.

Clinical impact of first-line bevacizumab plus chemotherapy in metastatic colorectal cancer of mucinous histology: a multicenter, retrospective analysis on 685 patients.

In metastatic colorectal cancer (MCRC), mucinous histology has been associated with poor response rate and prognosis. We investigated whether bevacizumab combined with different chemotherapy regimens may have an impact on clinical outcomes of MCRC patients with mucinous histology. 685 MCRC patients were classified in mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (NMC) and were treated with first-line bevacizumab plus fluoropyrimidine (FP)-based, oxaliplatin (OXA)-based, irinotecan (IRI)-based, or FOLFOXIRI. Ninety-four (13.7%) patients had MC. With a median follow-up of 50months, MC patients had a median overall survival (OS) of 28.2months compared with 27.7months for the NMC group [hazard ratio (HR) = 0.92; 95% confidence interval (CI) 0.70-1.19, P = 0.530]. The overall response rates for MC and NMC were 41.5% (95% CI 31.5-51.4) and 62.4% (95% CI 58.4-66.3), respectively (Chi-square test, P <0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, age, resection of the primary tumour, and number of metastatic sites were found to be associated with poorer OS, but not mucinous histology. Compared with NMC, MCRC patients with mucinous histology treated with bevacizumab plus chemotherapy had comparable OS despite lower overall response rate.

569P - FUSAFE individual patient data meta-analysis (MA) to assess the performance of dihydropyrimidine dehydrogenase (DPD) gene polymorphisms for predicting grade 4-5 fluoropyrimidine (FP) toxicity

BackgroundDespite decades of research, performance of DPYD genotyping to predict FP toxicity (tox) is poorly documented. GPCO-UNICANCER and RNPGx groups initiated the FUSAFE MA on individual patient data (IPD) to assess the prognostic value of consensual deleterious DPYD variants on grade (G) 4-5 FP tox. MethodsEligibility criteria included unbiased recruitment of Caucasian patients (pts) without FP dose adjustment based on DPD status. Main endpoint was 12 weeks hematological or digestive G4-5 tox. Age, sex, body mass index (BMI), advanced stage (M- vs M+), FP drug (5FU vs capecitabine), FP administration (bolus±continuous vs continuous alone or p.o.) and associated anticancer drugs (AAD) were collected. Multivariable logistic models were applied. Performance was assessed by AUC and diagnostic indices maximizing Youden index. ResultsFrom the 18 identified eligible studies (10230 pts), 14 were included (9030 pts), with complete IPD collected for 6403 pts (84% colorectal, 16% M+, 66% 5FU, 80% AAD). G4-5 tox prevalence was 8% (518 events). DPYD variants *2A, D949V, *13 and HapB3 were carried by 0.9%, 1.2%, 0.2% and 3.9% of pts, respectively. The clinical model (M1) retained age, sex, BMI, FP-administration, AAD. Adding variants *2A/D949V/*13 (at least one mutated allele) significantly (p<.0001) improved the model (M2). Further adding HapB3 did not improve the model (p=.24, M3). M3-adjusted OR (95%CI) was 10.0 (6.9-14.7) for the 3 variants *2A/D949V/*13 and 2.1 (1.4-3.0) for HapB3. Similar results were observed on colorectal pts only, or when excluding bolus administration alone.Table569PTableModelAUC (area under the curve)SensitivitySpecificityPositive predictive valueNegative predictive valueM10.72569.7%65.4%15.1%96.1%M20.75075.5%62.8%15.2%96.7%M30.75276.4%61.9%15.0%96.8% ConclusionsThis is the largest MA on DPYD genotyping and toxicity. It shows the relevance of clinical variables and of the 3 consensual DPYD variants. Despite its association with tox, HapB3 does not improve the discriminant ability to identify pts at risk of G4-5 toxicity. Legal entity responsible for the studyCentre Antoine Lacassagne, Nice, France (Dr Marie-Christine Etienne-Grimaldi, coordinator). FundingFrench Cancer Institute (INCa) funding (PHRC-K 14-193 FUSAFE) and French Ligue Nationale Contre le Cancer. DisclosureV. Boige: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Prestizia; Advisory / Consultancy: Eisai; Travel / Accommodation / Expenses: Sanofi. J. Taieb: Advisory / Consultancy: Amgen; Advisory / Consultancy: Lily; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Servier; Advisory / Consultancy: Sirtex; Advisory / Consultancy: Pierre Fabre. D. Meulendijks: Full / Part-time employment: AstraZeneca UK. C. Palles: Advisory / Consultancy: Oxford Cancer Biomarkers. U. Zanger: Licensing / Royalties: Robert Bosch GmbH. M. Boisdron-Celle: Speaker Bureau / Expert testimony, Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: ODPM. A. Marinaki: Full / Part-time employment: Viapath. E. Gross: Licensing / Royalties: Klinikum Rechts der Isar der Technischen Universitat Munchen. All other authors have declared no conflicts of interest.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictive and prognostic markers in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation

BackgroundA standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC.MethodsWe reviewed patients with LARC undergoing nCRT followed by surgery from 2005 to 2013 across 8 Canadian cancer centres. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for associations between baseline hematologic variables and outcomes.ResultsOf 1527 identified patients, 1237 (81%) were included in the DFS/OS analysis. Median age was 62 (range 23–88), 69% were male, and 80% had performance status (PS) 0–1. Twenty-six percent had elevated NLR (≥ 4), and 66% had elevated PLR (≥ 150). Ninety-seven percent of patients received FP-based nCRT, with 96% receiving ≥44 Gy. 81% completed neoadjuvant chemotherapy and 95% completed neoadjuvant radiotherapy, with a pCR rate of 18%. After a median follow-up time of 71 months, 8% developed local recurrence, 22% developed distant recurrence and 24% died. 5-year DFS and OS were 69% (95% CI 66–72%) and 79% (95% CI 77–82%), respectively. In multivariate analyses, elevated baseline NLR and PLR were neither prognostic for DFS and OS nor predictive of pCR.ConclusionsNLR and PLR were not found to be independently prognostic for DFS or OS and did not predict for pCR in patients with LARC undergoing nCRT followed by surgery.