This study aimed to identify the most effective first-line treatment for patients with metastatic colorectal cancer based on overall survival, identify the most commonly used treatment, and generate a meaningful ranking among all available treatments based on their relative effectiveness. Researchers used the ANOVA parametrization method to fit the second-order fractional polynomial network meta-analysis with a random-effect model. Using a non-proportional hazards network meta-analysis, 46 treatments were compared by considering a combination of direct and indirect evidence extracted from clinical trial studies. Included in the review were 46 trials involving 21350 patients. Between January 2000 and January 2023, researchers conducted a thorough search through Embase, PubMed/Medline, and Scopus. To undertake a secondary analysis of this data, we recreate individual patient data from published Kaplan-Meier (K-M) survival curves and assess the accuracy of that reconstruction. A random-effects model was used to evaluate the pooled overall survival and hazard ratio with a 95 percent confidence interval. The predicted survival curves for the network meta-analysis showed that GOLFIG and FOLFOX + Cetuximab treatments have higher survival, respectively. Our results provide moderate quality evidence and comparative effective estimates for various available first-line treatments for metastasis colorectal cancer based on network meta-analysis.

To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis.

The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens.

A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs.

In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity.

Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC).

Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants.

FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

Colorectal cancer is the third most common type of cancer worldwide and has become one of the major human disease burdens. In clinical practice, the treatment of colorectal cancer has been closely related to the use of irinotecan. Irinotecan combines with many other anticancer drugs and has a broader range of drug combinations. Combination therapy is one of the most important means of improving anti-tumor efficacy and overcoming drug resistance. Reasonable combination therapy can lead to better patient treatment options, and inappropriate combination therapy will increase patient risk. For the colorectal therapeutic field, the significance of combination therapy is to improve the efficacy, reduce the adverse effects, and improve the ease of treatment. Therefore, we explored the clinical advantages of its combination therapy based on mechanism or metabolism and reviewed the rationale basis and its limitations in conducting exploratory clinical trials on irinotecan combination therapy, including the results of clinical trials on the combination potentiation of cytotoxic drugs, targeted agents, and herbal medicine. We hope that these can evoke more efforts to conduct irinotecan in the laboratory for further studies and evaluations, as well as the possibility of more in-depth development in future clinical trials.

Aim: The key purposes of the treatment of metastatic malignancies are to extend survival and maintain the quality of life. Recently it has been emphasized in the scientific literature that the maintenance of maximal dose intensity is not always beneficial. Method: We examined the effectiveness of first-line mFOLFIRI-based treatments used in mCRC indication in 515 patients, treated between 1 January 2013 and 31 December 2018 at the Department of Oncotherapy of the University of Pécs, on a basis of real-world retrospective data analysis. We studied the effect of decreased dose intensity treatment modifications on patient survival. Results: 45% of all patients achieved the optimal relative dose intensity (RDI) of 85%, and the median progression-free and overall survival (mPFS, mOS) were 199 and 578 days, compared to 322 and 743 days, (mPFS p < 0.0002, 1 y (year) PFS OR (odds ratio) 0.39 (95% CI: 0.26−0.56) and mOS p = 0.0781, 2 yrs OS OR 0.58 (95% CI: 0.39−0.85), respectively) in the group of patients not achieving the RDI of 85%. Conclusions: Decreased dose intensity did not reduce the effectiveness of treatment; in fact, there was a significant improvement in most of the analyzed parameters. The option of reduced dose intensity, which shows the same or even better results with less toxicity, should definitely be considered in the future palliative treatment of mCRC patients.

Intra-arterial hepatic (IAH) treatment has shown promising results in the management of patients with unresectable colorectal liver metastases (CRLM) the prognosis of which is poor. Bevacizumab adjunction to standard chemotherapy has been shown to improve survival of this patient population. This prospective study was conducted to assess the efficacy and safety of IAH bevacizumab combined to systemic chemotherapy after first-line treatment failure in patients with CRLM.

Included patients had dominant or isolated unresectable CRLM progressing after standard first-line treatment for metastases of colorectal cancer. Three patients had less than 30% liver invasion, three patients between 30 and 50%, two more than 50% and data was missing in two patients. An intra-hepatic catheter was implanted surgically or percutaneously. Bevacizumab 7.5 mg/kg was administered once every 3 weeks in combination with capecitabine 2000 mg/m² per day for 2 weeks and oxaliplatin 130 mg/m² or irinotecan 200 mg/m² once every 3 weeks. The primary end-point was the objective response rate.

Between June 2013 and February 2015, 10 patients were included. The trial was prematurely closed because of the lack of financial support and poor accrual. The patients had a median of 6 [1-9] cycles of treatment. Partial response was achieved in 2 patients (20%) and a R0 liver metastases resection in one another. All patients died of disease progression. The median overall and progression-free survival rates were respectively 14.0 (95% IC [4.8 - 25.8] and 5.4 months (95% IC [1.6 - 6.2]). Four patients had severe side effects but no toxic death occurred.

IAH bevacizumab combined to systemic chemotherapy is feasible and safe in patients with unresectable isolated or dominant CRLM progressing after a first-line systemic treatment. Based on the low number of patients included in our study, our results suggest that this treatment does not increase dramatically the response rate versus an adapted systemic treatment. However, considering the safety data provided in this study, arterial infusion of bevacizumab in adjunction to chemotherapeutic agents could be evaluated in the future.

The treatment and management of hepatic malignancies can be complex because it encompasses a variety of primary and metastatic malignancies and an assortment of local and systemic treatment options. When to use each of these treatments is critical to ensure the most appropriate care for patients. Interventional radiologists have a key role to play in the delivery of a variety of liver directed treatments including percutaneous ablation, transarterial embolization with bland embolic particles alone, transarterial chemoembolization (TACE) with injection of a chemotherapeutic emulsion, and transarterial radioembolization (TARE). Based on 9 clinical variants, the appropriateness of each treatment is described in this document. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Systemic treatments, namely, either monotherapy or combination therapy, are commonly administered to patients with advanced or metastatic colorectal cancer (CRC). This study aimed to provide the complete efficacy and safety profiles and ranking of systemic therapies for the treatment of unresectable advanced or metastatic CRC.

We searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception until June 30, 2021, and also the bibliographies of relevant studies. Randomized controlled trials comparing two or more treatments, namely, at least capecitabine, 5-fluorouracil, leucovorin, irinotecan, bevacizumab, cetuximab, oxaliplatin, or panitumumab were investigated. A network meta-analysis using the Bayesian approach was performed to compare the efficacy and safety of treatments. The surface under the cumulative ranking curve (SUCRA) was calculated for the probability of each treatment as the most effective. The overall response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), adverse events (AEs) grade ≥3, and serious adverse events (SAEs) were evaluated.

One hundred two publications with 36,147 participants were assigned to 39 different treatments. Among 11 treatments with full information on six outcomes, FOLFIRI/FOLFOX/FOLFOXIRI + bevacizumab significantly improved both the ORR and DCR, compared to FOLFIRI. Although FOLFOX and FOLFIRI/FOLFOX + cetuximab significantly prolonged both OS and PFS, treatments were comparable in terms of AEs grade ≥3 and SAEs. The top highest SUCRA values were observed in the FOLFOXIRI + panitumumab group for ORR (96%) and DCR (99%), FOLFIRI + bevacizumab + panitumumab group for OS (62%) and PFS (54%), and FOLFOXIRI + bevacizumab group for AEs grade ≥3 (59%) and SAEs (59%) outcomes.

These findings suggest an available range of systemic treatment therapies with different efficacy and safety profiles with patients. Further investigations of the side effects and mutation status are required to confirm our findings.

https://www.crd.york.ac.uk/prospero/, identifier CRD42019127772.

Irinotecan, a topoisomerase inhibitor, is a common cytotoxic agent prescribed for metastatic colorectal cancer (mCRC) patients. Diarrhea is the most common adverse event (AE). The underlying mechanism of irinotecan-induced diarrhea is intestinal mucosal damage caused by SN-38 (active metabolite of irinotecan) hydrolyzed from SN-38G (inactive metabolite) by bacterial -glucuronidase (G). According to an animal study, silymarin reduces the activity of bacterial G without impairing antitumor efficacy. We conducted a prospective open-label pilot study to evaluate the effect of silymarin as supplementation in reducing toxicities of mCRC patients undergoing irinotecan-based chemotherapy. We enrolled and randomized 70 mCRC patients receiving first-line FOLFIRI (5-fluorouracil/leucovorin/irinotecan) plus bevacizumab. In each treatment cycle, the study group was administered silymarin capsules (150 mg) three times daily for 7 days. The study group experienced less AEs in diarrhea (5.7% vs. 14.6%, p=0.002) and nausea (27.0% vs. 40.2%, p=0.005) in comparison with the control group, but no significant differences in hepatic toxicities were observed. In conclusion, simultaneous administration of silymarin is a potential effective supplementation for reducing toxicities in mCRC patients undergoing first-line FOLFIRI plus bevacizumab, especially in diarrhea and nausea.

The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis.

In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017.

With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P < 0.0001 for non-inferiority). In patients with left-sided RAS wild-type tumours, median PFS durations were 11.4 and 16.9 months in the control and experimental groups, respectively (HR: 0.68, 95% CI: 0.48-0.96, P = 0.028).

S-1 and irinotecan plus bevacizumab resulted in comparable OS and non-inferior PFS with that of mFOLFOX6/CapeOX plus bevacizumab treatment as first-line chemotherapy for patients with mCRC. We recommend the use of S-1 and irinotecan plus bevacizumab as a standard first-line regimen independent of tumour sidedness or RAS status in mCRC.

UMIN-CTR: 000007834.

Intravenous administration of fluoropyrimidine-based chemotherapy has been the backbone of treatment in colorectal cancer (CRC) for decades. The availability of oral capecitabine has improved the tolerability and simplified combination schedules. In addition to capecitabine, several other oral drugs have proven efficacy, particularly in palliative treatment lines. Clinical guidelines describe several available third-line treatment options for metastatic CRC (mCRC), but few insights are provided to guide the selection and sequence. In this review, we describe the available evidence and most recent data concerning oral drugs with proven efficacy in CRC, including antiangiogenetic tyrosine kinase inhibitors (VEGFR TKIs), inhibitors blocking EGFR/Raf/MEK/ERK signaling pathway and modified fluoropyrimidine, and share recommendations and insights on selecting third-line oral therapies for mCRC in China. In general, third-line treatment options for mCRC are mainly regorafenib, fruquintinib, and chemo/targeted therapy reintroduction, while FTD/TPI was rarely used in China probably due to poor accessibility. Fruquintinib is preferred in patients with poor performance status (PS), elder age, and severe organ dysfunction, compared to regorafenib. New drugs of clinical trials were more recommended for the patients with BRAF mutant tumor, and those with good previous treatment efficacy tended to be recommended for chemo/targeted therapy reintroduction. The management of mCRC is evolving, and it must be emphasized that the consideration and recommendations presented here reflect current treatment practices in China and thus might change according to new clinical data as well as the availability of new oral drugs.

To assess the relative efficacy and safety of first-line systemic therapies in patients with metastatic colorectal cancer.

A comprehensive literature review was conducted including MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase II or III randomized controlled trials (RCTs) published up to and including July 15, 2019. We included RCTs in which at least 1 intervention was either chemotherapeutic agents (such as fluorouracil, irinotecan, or oxaliplatin) or antibodies targeting angiogenesis (such as bevacizumab) or agents that act on the epidermal growth factor receptor pathway (such as cetuximab and panitumumab) or studies reported at least one of the following outcomes: overall survival (OS), progression-free survival (PFS), and/or Grade 3 + adverse events (AEs). Using a random effect model, we performed a Bayesian network meta-analysis to analyze the probability of optimal therapeutic regime obtained from direct comparisons with indirect evidences. We estimated hazard ratios for OS and PFS.

A total of 30 RCTs comprising 12,146 mCRC patients with 25 different treatment strategies were included. The triple combination FOLFOXIRI [fluorouracil, leucovorin, oxaliplatin, and irinotecan] plus bevacizumab provided significant survival benefits with improved OS over all other treatments. The network meta-analysis also indicated a significant advantage of using FOLFOXIRI plus bevacizumab in comparison to other treatment strategies for PFS. Besides, FOLFOXIRI plus bevacizumab was associated with the well-tolerated adverse events.

Our study supported the use of FOLFOXIRI plus bevacizumab as the best first-line regimen and potentially effective and safe strategy for the management of patients with mCRC.

Distant metastasis is the main cause of death in patients with colon-adenocarcinoma(COAD). Due to the lack of effective molecular markers and treatment, the prognosis of patients with metastatic colon cancer is still rather poor.

Metastatic related signature (MRS) of stage I and stage IV in colon cancer were identified from different cohorts. Univariate cox regression is used to analyze the relationship between MRS and the overall survival. L1000FWD and DGIdb databases are used to identify molecular drugs. Expression and functional experimental validation of the hub MRS were carried out.

16 MRS were identified, of which 14 MRS was significantly correlated with overall survival. Further functional enrichment analysis showed that MRS was significantly involved with important biological functions such as cell migration, and apoptosis. As important metastatic related genes, GSR, FAS and CYP1B1 have significant interaction with drug molecules. Further studies have confirmed that the expression of FAS and GSR is low, and inhibition of its expression can promote the metastasis of COAD. CYP1B1 expression is highly expressed, and inhibition of its expression can attenuate the malignant biological behavior of colon cancer.

Our research could increase the understanding of the mechanism of colon cancer metastasis and provide theoretical basis for the treatment of metastatic colon cancer.

This document is a summary of the French intergroup guidelines regarding the management of metastatic colorectal cancer (mCRC) published in January 2019, and available on the French Society of Gastroenterology website (SNFGE) (www.tncd.org).

This collaborative work was realized by all French medical and surgical societies involved in the management of mCRC. Recommendations are graded in three categories (A, B and C), according to the level of evidence found in the literature, up until December 2018.

The management of metastatic colorectal cancer has become complex because of increasing available medical, radiological and surgical treatments alone or in combination. The therapeutic strategy should be defined before the first-line treatment, mostly depending on the presentation of the disease (resectability of the metastases, symptomatic and/or threatening disease), of the patient's condition (ECOG PS, comorbidities), and tumor biology (RAS, BRAF, MSI). The sequence of targeted therapies also seems to have an impact on the outcome (angiogenesis inhibition beyond progression). Surgical resection of metastases was the only curative intent treatment to date, joined recently by percutaneous tumor ablation tools (radiofrequency, microwave). Localized therapies such as hepatic intra-arterial infusion, radioembolization and hyperthermic intraperitoneal chemotherapy, also have seen their indications specified (liver-dominant disease and resectable peritoneal carcinomatosis). New treatments have been developed in heavily pretreated patients, increasing overall survival and preserving quality of life (regorafenib and trifluridine/tipiracil). Finally, immune checkpoint inhibitors have demonstrated high efficacy in MSI mCRC.

French guidelines for mCRC management are put together to help offer the best personalized therapeutic strategy in daily clinical practice, as the mCRC therapeutic landscape is complexifying. These recommendations are permanently being reviewed and updated. Each individual case must be discussed within a multidisciplinary team (MDT).

Studies over the past 10 years strongly support an association between skeletal muscle mass (SMM) depletion and outcome in metastatic colorectal cancer (mCRC). Factors influencing SMM changes over time are, however, poorly studied. We analyzed the impact of SMM on overall survival and chemotherapy toxicities in mCRC patients treated with first-line chemotherapy. Changes in weight and body composition were evaluated during follow-up.

Patients enrolled in the randomized phase II ACCORD trial comparing two chemotherapy regimens were screened. Body composition parameters (SMM, adipose tissue) were assessed prospectively with computed tomography (CT) imaging, and toxicities were recorded. Mixed models were used to assess weight and BC changes during 4 months of treatment follow-up.

Among 145 patients included in ACCORD, 76 had available baseline CT scans and were included in the current study. Mean age was 60.6 ± 10.0 years, 50% were women, 82% had colon cancer, and 62% had two or more metastatic sites. At baseline, 49% had lost at least 5% of their initial weight, including 26% who had lost more than 10%; 53% had SMM depletion. In this homogenous cohort, there were no statistically significant associations between SMM depletion and overall survival, progression-free survival or chemotherapy toxicity. There were no decreases in weight or SMM during follow-up. Weight and SMM changes were not influenced by diarrhea either grade 3-4 or any grade (reported in 74% of patients). For patients with weight loss ≥10% at baseline, SMM increased significantly after 4 months of follow-up and after disease stabilization following chemotherapy (P = 0.008).

In a homogenous mCRC cohort, SMM depletion was not associated with survival or chemotherapy toxicity. Despite most patient experiencing diarrhea, no changes in weight or SMM were found during 4 months of follow-up. However, hypotheses deriving from our exploratory study have to be tested in further larger sample size studies.

Clinicaltrials.gov NCT00423696 (2011).

Response Evaluation Criteria in Solid Tumors (RECIST) are used to assess tumour shrinkage after cytotoxic chemotherapy, but may be inadequate for efficacy evaluation of anti-angiogenic therapies.

This study aimed to identify novel radiologic tumour response criteria based on early changes in tumour size and density, observed on computed tomography (CT), in patients with colorectal liver metastases (CRLM) treated with bevacizumab-containing chemotherapy.

CT of 71 and 68 CRLM patients treated with bevacizumab and non-bevacizumab-based regimens, respectively, were retrospectively reviewed. Tumour size, tumour density, and tumour-to-liver density (TTLD) ratio were determined at baseline and at first restaging. We tested their correlation with progression-free (PFS) and overall survival (OS) using the log-rank test.

In the bevacizumab group, neither RECIST response nor tumour density variation was correlated with PFS or OS. In contrast, PFS and OS were significantly longer in patients with tumour size reduction ≥15% (RECIST_-15%) and/or decrease in TTLD ratio not exceeding -10% (TTLD_-10%) than in patients who did not reach any of those criteria, in univariate and multivariate analysis. Only size-response criteria predicted clinical outcome in the non-bevacizumab group.

This study highlights new quantitative CT criteria that may early predict the efficacy of bevacizumab in CRLM patients.

Tumor radiologic response after systemic chemotherapy has been used as endpoint of trials of patients with metastatic colorectal cancer (mCRC), which can report the best overall response rate (ORR) and the disease control rate (DCR) by RECIST criteria as well as the early tumor shrinkage (ETS). The present study perform a trial-level analysis to verify whether such response-related endpoints are predictive of overall survival (OS).

After a systematic search, randomized clinical trials (RCTs) were selected each time they evaluated the three response endpoints and progression-free survival (PFS). Two arms per trial were selected, and the correlation between the difference in each endpoint and the difference in OS was calculated. The analysis then evaluated the effects of treatment on ∆ORR, or ∆DCR, ∆ETS, ∆PFS, and on ∆OS, using separate linear regressions for each of them, and the proportion of variability explained (R²_trial) on OS for each of the four endpoints was calculated.

The systematic review of the literature led to the selection of 12 RCTs, 7 phase-3 and 5 phase-2. ETS reported a different performance in the entire sample compared to phase-3 trials (R²_trial = 0.172 vs. 0.842), differently from DCR (R²_trial = 0.541 vs. 0.816) and ORR (R²_trial = 0.349 vs. 0.740). Surprisingly, PFS predicted OS with a weak correlation, which was not significant in the subgroup of phase-3 studies (R²_trial = 0.455 vs. 0.466).

The results of the present trial-level analysis report a good performance of two response-related endpoints, DCR and ETS, and suggest that they could be differently used depending on the setting of disease and the type of medical treatment.

The treatment of metastatic colorectal cancer has evolved over the last two decades with the FDA approval of several cytotoxic, biological, and targeted agents. In this paper, we review the impact of sidedness, RAS, BRAF, HER-2, and other immune biomarkers on metastatic colorectal cancer treatment selection and sequencing in both the palliative and curative intent settings.

Early tumor shrinkage (ETS) is a response-related endpoint of clinical trials of chemotherapy (CHT) of patients with metastatic colorectal cancer (mCRC). It identifies a dimensional reduction of tumor size by at least 20-30% after 6-8 weeks of CHT.

A literature search of randomized trials of systemic treatment including CHT with or without antiangiogenics or anti-EGFR inhibitors in patients with mCRC has been conducted, and studies reporting the results of the relationship of ETS with overall survival (OS) and progression-free survival (PFS) were selected.

Twelve trials, including 3117 patients, have been included; all data were retrospective and only 72% of the enrolled patients have been evaluated for ETS. Two meta-analyses, each including 20 study cohorts from the selected 12 trials, reported a strong relationship of ETS with OS (HR 0.62; CIs 0.55-0.69) and of ETS with PFS (HR 0.66; CIs 0.60-0.73). However, both meta-analyses displayed a high level of heterogeneity. Among nine possible moderators, three variables (median age, surgery of metastases, and publication year) were able to explain at least a part of this heterogeneity.

ETS is a simple and interesting intermediate endpoint for clinical practice and future trials of medical treatments of patients with mCRC, but a large prospective analysis and validation are mandatory.

Nowadays, systemic chemotherapy with intravenous (IV) 5-fluorouracil (5-FU) remains the most commonly prescribed treatment for metastatic colorectal cancers (CRC), in combination with other cytotoxic drugs. 5-FU can be administered through a bolus injection or continuous infusion (cIV), with the latter becoming the preferred administration method and standard of care in recent years. Oral fluoropyrimidines were developed to overcome challenges associated with the IV administration of 5-FU, among which capecitabine has become the most widely used one. However, although capecitabine and other oral fluoropyrimidine-based regimens are more convenient to administer, their efficacy and safety in comparison with IV 5-FU are not well understood. Results from recent randomized controlled trials, observational studies, and meta-analyses have been inconsistent. Safety, in particular, remains controversial. Our review, a first comprehensive meta-analysis comparing the efficacy and safety of cIV 5-FU with capecitabine, the two most widely used fluorouracil modalities in CRC, showed that cIV 5-FU-based regimens are associated with greater response rates compared with capecitabine-based regimens, with no difference in progression-free survival, time to treatment failure, overall survival, or disease-free survival between the two. Furthermore, cIV 5-FU-based regimens showed an improved safety profile compared with capecitabine-based regimens. Our findings suggest that cIV 5-FU remains a more effective and safer modality of fluorouracil administration than capecitabine, thus providing supporting evidence to guide clinical practice in the management of colorectal cancer.

The aim of this randomized, multicenter, noncomparative, phase II trial was to investigate the efficacy and safety of two potential first-line treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with metastatic colorectal cancer (mCRC).

Patients with untreated mCRC were randomly assigned to receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m² on day 1 and oral capecitabine 2,000 mg/m² on days 1-14, every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg and irinotecan 200 mg/m² on day 1 and capecitabine 1,600 mg/m² on days 1-14, every 3 weeks). The primary endpoint was overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

A total of 107 patients were enrolled. The intent-to-treat population comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm, respectively. The frequencies of hematological and nonhematological adverse events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in the CapIRI/BEV arm, respectively.

CapOX plus bevacizumab and CapIRI plus bevacizumab are equally effective and feasible as the first-line treatments in Japanese patients with mCRC.

The CCOG-1201 study was designed to evaluate the efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and capecitabine and irinotecan plus bevacizumab as a first-line treatment in Japanese patients with metastatic colorectal cancer. This article reports on the trial and efforts to define the role of these regimens, including the effect of KRAS status and UGT1A1 polymorphisms in metastatic colorectal cancer.

Chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer; however, the optimal chemotherapy sequence to administer simultaneously with radiotherapy remains unclear. We conducted a phase I/II study to test a new regimen, TEGAFIRI (combination tegafur, uracil [UFT], leucovorin [LV], irinotecan), for patients with locally advanced rectal cancer.

A total of 22 patients with locally advanced lower rectal adenocarcinoma were enrolled in the present study. The radiation dose was 50.4 Gy in 28 fractions. UFT (300 mg/m²/d) and LV (75 mg/body weight/d) were administered orally 3 times daily. Irinotecan was administered as an intravenous infusion at 3 escalating dose levels. The initial dose was 50 mg/m² (level 1; n = 7), the intermediate was 70 mg/m² (level 2; n = 8), and the maximum was 80 mg/m² (level 3; n = 7). The drug was administered on days 1, 15, 29, and 43.

Dose-limiting toxicity was not observed at any dosing level. The most frequent adverse event was leukopenia (50%), followed by diarrhea (45.5%), anal pain (31.8%), and neutropenia (27.3%). All were well-managed with the appropriate drugs. The total pathologic complete response rate was 22.7%, and the proportion of good responders was 28.6%, 50%, and 71.4% at levels 1, 2, and 3, respectively. None of the patients experienced local recurrence. The 5-year relapse-free and overall survival rates were 80.4% and 80.8%, respectively.

TEGAFIRI is a promising CRT regimen that results in marked tumor regression and good local control. Moreover, its adverse events are well-tolerated.

Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study proposed to improve the spatial uniformity of the antivascular effect and drug penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12 ± 0.08 μm, mean ± standard deviation) were used to perform USMD. The efficiency of the antivascular effect was evaluated by intravital imaging to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the antivascular effect and liposomal-doxorubicin (5 mg/kg) penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11 ± 3, 14 ± 5, 19 ± 7, and 23 ± 10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p < 0.05). The effective treatment time of USMD (at 2 × 10⁷ microbubbles/mouse, 7 MPa, and three cycles) was 60-120 min, which resulted in the disruption of 21-44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous antivascular effects and drug penetration within tumors and thereby improve the efficacy of combination therapies.

Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux^®, Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix^®, Amgen UK Ltd, Cambridge, UK).

To investigate the clinical effectiveness and cost-effectiveness of panitumumab in combination with chemotherapy and cetuximab in combination with chemotherapy for rat sarcoma (RAS) wild-type (WT) patients for the first-line treatment of metastatic colorectal cancer.

The assessment included a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions, and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted up to 27 April 2015 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library.

Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab or panitumumab in participants with previously untreated metastatic colorectal cancer with RAS WT status. All steps in the review were performed by one reviewer and checked independently by a second. Narrative synthesis and network meta-analyses (NMAs) were conducted for outcomes of interest. An economic model was developed focusing on first-line treatment and using a 30-year time horizon to capture costs and benefits. Costs and benefits were discounted at 3.5% per annum. Scenario analyses and probabilistic and univariate deterministic sensitivity analyses were performed.

The searches identified 2811 titles and abstracts, of which five clinical trials were included. Additional data from these trials were provided by the manufacturers. No data were available for panitumumab plus irinotecan-based chemotherapy (folinic acid + 5-fluorouracil + irinotecan) (FOLFIRI) in previously untreated patients. Studies reported results for RAS WT subgroups. First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who are RAS WT. For the independent economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) for RAS WT patients for cetuximab plus oxaliplatin-based chemotherapy (folinic acid + 5-fluorouracil + oxaliplatin) (FOLFOX) compared with FOLFOX was £104,205 per quality-adjusted life-year (QALY) gained; for panitumumab plus FOLFOX compared with FOLFOX was £204,103 per QALY gained; and for cetuximab plus FOLFIRI compared with FOLFIRI was £122,554 per QALY gained. The ICERs were sensitive to treatment duration, progression-free survival, overall survival (resected patients only) and resection rates.

The trials included RAS WT populations only as subgroups. No evidence was available for panitumumab plus FOLFIRI. Two networks were used for the NMA and model, based on the different chemotherapies (FOLFOX and FOLFIRI), as insufficient evidence was available to the assessment group to connect these networks.

Although cetuximab and panitumumab in combination with chemotherapy appear to be clinically beneficial for RAS WT patients compared with chemotherapy alone, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT in patients with RAS WT.

This study is registered as PROSPERO CRD42015016111.

The National Institute for Health Research Health Technology Assessment programme.

Studies of a modified XELIRI (mXELIRI; capecitabine plus irinotecan) regimen suggest promising efficacy and tolerability profiles in the first-line and second-line settings. Therefore, we aimed to compare the efficacy and safety of the mXELIRI regimen with that of standard FOLFIRI (leucovorin, fluorouracil, and irinotecan), with or without bevacizumab in both regimens, as a second-line therapy for metastatic colorectal cancer.

We did a multicentre, open-label, randomised, non-inferiority, phase 3 trial. We enrolled patients from 98 hospitals in Japan, China, and South Korea who were aged 20 years or older with histologically confirmed and unresectable colorectal adenocarcinoma, and who had withdrawn from first-line chemotherapy for metastatic colorectal cancer. We randomly assigned patients (1:1) to receive either mXELIRI with or without bevacizumab (irinotecan 200 mg/m² intravenously on day 1 plus oral capecitabine 800 mg/m² twice daily on days 1-14, repeated every 21 days, with or without bevacizumab 7·5 mg/kg intravenously on day 1) or FOLFIRI with or without bevacizumab (irinotecan 180 mg/m² intravenously on day 1, leucovorin 200 mg/m² intravenously on day 1, fluorouracil 400 mg/m² intravenously on day 1, and a 46-h continuous intravenous infusion of fluorouracil [2400 mg/m²], repeated every 14 days, with or without the addition of bevacizumab 5 mg/kg intravenously on day 1) via a centralised electronic system. We used the minimisation method to stratify randomisation by country, Eastern Cooperative Oncology Group performance status, number of metastatic sites, previous oxaliplatin treatment, and concomitant bevacizumab treatment. Patients and clinicians were not masked to the allocated treatment. The primary endpoint was overall survival analysed on an intention-to-treat basis with a non-inferiority upper margin of 1·30 for the hazard ratio (HR). This study is registered with ClinicalTrials.gov, number NCT01996306, and is ongoing but no longer recruiting participants.

Between Dec 2, 2013, and Aug 13, 2015, 650 patients were enrolled and randomly assigned to receive mXELIRI with or without bevacizumab (n=326) or FOLFIRI with or without bevacizumab (n=324). After a median follow-up of 15·8 months (IQR 8·7-24·9), a total of 490 patients had died (242 in the mXELIRI with or without bevacizumab group and 248 in the FOLFIRI with or without bevacizumab group) and the median overall survival was 16·8 months (95% CI 15·3-19·1) in the mXELIRI group and 15·4 months (13·0-17·7) in the FOLFIRI group (HR 0·85, 95% CI 0·71-1·02; p_{non-inferiority}<0·0001). In the per-protocol safety population, the most common grade 3-4 adverse event was neutropenia (affecting 52 [17%] of 310 patients in the mXELIRI group and 133 [43%] of 310 in the FOLFIRI group). Incidences of grade 3-4 diarrhoea were higher in the mXELIRI group (22 [7%]) than in the FOLFIRI group (ten [3%]). Serious adverse events were reported in 46 (15%) of 310 patients in the mXELIRI group and 63 (20%) of 310 in the FOLFIRI group. Two treatment-related deaths (one pneumonitis and one lung infection) were observed in the mXELIRI group and there was one treatment-related death (lung infection) in the FOLFIRI group.

mXELIRI with or without bevacizumab is well tolerated and non-inferior to FOLFIRI with or without bevacizumab in terms of overall survival. mXELIRI could be an alternative to FOLFIRI as a standard second-line backbone treatment for metastatic colorectal cancer, at least for Asian patient populations.

Chugai Pharmaceutical and F Hoffmann-La Roche.

In 2016, the third version of guidelines for the diagnosis and treatment of neuroendocrine tumors (NETs) has been published by the European Neuroendocrine Tumor Society (ENETS). These guidelines reflect the progress in treatment of NETs, and by comparing the newest guidelines with the first guidelines of 2001, this progress can be clearly recognized. Diagnostic accuracy has been increased by the introduction of PET-CT with Ga-labelled somatostatin analogs, and multiple new treatments and treatment schedules have been developed, like peptide receptor radiotherapy with radiolabeled somatostatin analogs, or targeted therapies. Evidence and indications for these therapies are discussed in the ENETS guidelines. In this review, we aim to show the progress in NET diagnosis and treatment on the basis of the advances in the guidelines, but also to discuss the unsolved questions and unmet needs which still remain.

5-Fluorouracil (5-Fu) is one of the most commonly prescribed antineoplastic agents against gastric and colorectal cancers. Continuous infusion would be the optimal way of its administration, however, may usually cause thrombosis, infection, and prolonged hospital stay. Oral fluoropyrimidines would be an attractive alternative, but their efficiency and toxicities for the treatment of gastric and colorectal cancer are still obscure as compared with infusion 5-Fu.

Literature retrieval, trials selection and assessment, data collection, and statistic analysis were performed according to the Cochrane Handbook. The outcome measures were tumor response rate, progression-free survival, overall survival, and adverse effects.

Twenty-nine randomized controlled trials, comprising totally 15 154 patients, were included. Meta-analysis showed similar overall outcome in terms of response rate (1.01; 95% confidence interval [CI], 0.92-1.12), progression-free survival (hazard ratio 1.00; 95%CI, 0.94-1.06), and overall survival (hazard ratio 0.96; 95%CI, 0.92-1.01) between oral fluoropyrimidine-based and intravenous 5-Fu-based regimens in gastric and colorectal cancer patients. The risk of grade 3/4 neutropenia, thrombocytopenia, and stomatitis was more prominent in intravenous 5-Fu-based regimens; while more frequent grade 3/4 hand-foot syndrome, diarrhea, and anorexia were detected in oral fluoropyrimidine-based regimens.

Oral-fluoropyrimidines showed equivalent response and similar survival outcomes, but different toxicity profiles, as compared with intravenous 5-Fu. Thus, it would be a more convenient and adjustable alternative in treatment of advanced gastric and colorectal cancer.

Over the past 20 years, substantial advances have been made in the treatment of patients with metastatic colorectal cancer (mCRC). In particular, there is now a wide range of options for the front-line treatment of mCRC. Sophisticated molecular technologies have been developed to identify novel prognostic and predictive biomarkers for CRC. DNA sequencing technology has made remarkable advances in recent years, primarily as a result of the development of next-generation sequencing and whole exome sequencing, which are powerful new tools for the discovery of predictive molecular biomarkers to facilitate the delivery of personalized medicine. In addition to tumor tissue, recent efforts have focused on analyzing circulating tumor DNA in peripheral blood. Herein, we review the evolution of standard chemotherapy and targeted therapy strategies for the treatment of mCRC in the front-line setting, the molecular technologies that are presently being used to facilitate our ability to practice individualized medicine, and the practical aspects of applying molecular biomarkers to everyday clinical practice.

In the past decade, significant advances have been made in the treatment of advanced colorectal cancer. Multiple cytotoxic agents and targeted therapies have been approved for management of metastatic colorectal cancer, leading to improvement of median overall survival in clinical trials to more than 30 months. Of note, before the introduction of biologics into treatment algorithms for metastatic colorectal cancer, median survival in phase III trials never exceeded 24 months. In 2016, the most common treatment approach in first line is a combination of chemotherapy with a biologic agent. The choice of therapy is influenced by patient factors (eg, age, comorbidities), tumor characteristics (eg, overall tumor burden, pattern of metastatic spread, mutation signature), potential adverse effects of therapy, and goals of treatment. The choice between irinotecan- or oxaliplatin-based cytotoxic chemotherapy regimen is primarily based on differential toxicity profile because they have similar efficacy. Currently, three biologic agents-bevacizumab, cetuximab, and panitumumab-are approved for first-line treatment of metastatic colorectal cancer. For patients with mutant RAS and likely mutant BRAF V600E tumors, bevacizumab is the only biologic agent that can be used in conjunction with cytotoxic chemotherapy. The choice of anti-epidermal growth factor antibody or anti-vascular endothelial growth factor antibody in RAS wild-type tumors is based on the specific clinical scenario. Recently, some clinical and molecular biomarkers have emerged that may help in decision making. In this review, we discuss the role of biologics in the management of first-line treatment of metastatic colorectal cancer.

Transmembrane tumor necrosis factor-α (tmTNF-α) is known to induce the activation of NF-κB to protect tumor cells. Upregulation of tmTNF-α leads to resistance to apoptosis and induces drug resistance in breast cancer. However, the expression of tmTNF-α in colorectal cancer (CRC) and its association with clinical outcome in CRC have remained unclear. In this study, we examined the tmTNF-α expression in CRC by immunohistochemistry and western blotting, assessed the prognostic value of tmTNF-α related to the recurrence/metastasis and survival of stage II/III CRC by the Kaplan-Meier survival curve and Cox regression model, and also explored the role of tmTNF-α expression on the chemotherapeutic efficacy of 5-Fluorouracil by flow cytometry assay and cell counting kit-8 (CCK-8) in vitro. Overall, we found that 77 (78.6%) out of 98 patients exhibited higher tmTNF-α expression in the CRC tissues comparing with the adjacent tissues. The tmTNF-α expression was correlated with Differentiation (P = 0.019), TNM stage (P = 0.039), Lymph nodes metastasis (P = 0.024) and Lymphovascular invasion (P = 0.027) but not related with Age (P = 0.617), Gender (P = 0.625), Tumor location (P = 0.138), Perforation/Obstruction (P = 1.000), Depth of invasion (P = 0.327), and microsatellite instability status (P = 0.150). The prognostic analyses showed that high tmTNF-α expression patients was significantly associated with decreased Disease-Free Survival (P = 0.0209) and Overall Survival (P = 0.0163). CCK-8 results suggested that the tmTNF-α influenced the chemotherapeutic effect of 5-Fluorouracil on colon cancer cells. Altogether, these data indicated the stageII/III CRC patients with high tmTNF-α expression were more likely to have a worse prognosis than patients with low tmTNF-α expression and tmTNF-α may influence the chemotherapeutic effect of 5-Fluorouracil. The mechanism for these observations warrants further study.

Treatment of metastatic colorectal cancer (mCRC) has been modified since the launching of targeted therapies. Colorectal cancer (CRC) is common in elderly patients; their representation in randomized controlled trials (RCTs) is thus crucial. This study aimed to evaluate and quantify the inclusion of elderly/frail patients in RCTs of targeted therapies in mCRC. A systematic review using Medline, Scopus, Cochrane Database and ISI Web of Science was performed to identify all phase II/III RCTs of bevacizumab, cetuximab, panitumumab, regorafenib and aflibercept in mCRC until January 2015. Two reviewers independently performed studies selection, and data extraction. The protocol was registered in Prospero (CRD42015016163). Among 1,369, identified publications, 54 RCTs were selected. Nine RCTs (17%) excluded elderly patients; median age of the included population was <65years old in 50 RCTs (93%). Twenty RCTs (37%) excluded frail patients, and many RCTs excluded patients with uncontrolled hypertension or heart failure, patients treated with specific drugs (mainly anticoagulants), and patients with inadequate creatinine clearance. Elderly/frail patients are underrepresented in RCTs studying targeted therapies in mCRC, and those elderly patients included in RCTs do not reflect well the general elderly population with mCRC because of the exclusion criteria. RCTs results concerning targeted therapies can be inferred only to relatively healthy elderly subjects.

Patients prefer oral to intravenous (IV) palliative chemotherapy, provided that oral therapy is not less effective. We compared the efficacy and safety of oral and IV fluoropyrimidines for treatment of colorectal cancer (CRC).

To compare the effects of oral and IV fluoropyrimidine chemotherapy in patients treated with curative or palliative intent for CRC.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 5), along with OVID MEDLINE, OVID Embase, and Web of Science databases, in June 2016. We also searched five clinical trials registers, several conference proceedings, and reference lists from study reports and systematic reviews. We contacted pharmaceutical companies to identify additional studies.

We included randomised controlled trials (RCTs) comparing oral and IV fluoropyrimidine chemotherapy in patients treated with curative or palliative intent for CRC.

Three review authors extracted data and assessed risk of bias independently. We assessed the seven domains in the Cochrane 'Risk of bias' tool and three additional domains: schedules of outcome assessment and/or follow-up; use of intention-to-treat analysis; and baseline comparability of treatment arms.

We included nine RCTs (total of 10,918 participants) that examined treatment with curative intent for CRC with neoadjuvant and/or adjuvant chemotherapy. We included 35 RCTs (total of 12,592 participants) that examined treatment with palliative intent for inoperable advanced or metastatic CRC with chemotherapy (31 first-line studies, two second-line studies, and two studies of first- or second-line chemotherapy). All studies included male and female participants, and no studies included participants younger than 18 years of age. Patients treated with curative intent for CRC with neoadjuvant and/or adjuvant chemotherapy • Disease-free survival (DFS): DFS did not differ between participants treated with oral versus IV fluoropyrimidines (hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.87 to 1.00; seven studies, 8903 participants; moderate-quality evidence).• Overall survival (OS): OS did not differ between participants treated with oral versus IV fluoropyrimidines (HR 0.92, 95% CI 0.84 to 1.00; seven studies, 8902 participants analysed; high-quality evidence).• Grade ≥ 3 adverse events (AEs): Participants treated with oral fluoropyrimidines experienced less grade ≥ 3 neutropenia/granulocytopenia (odds ratio (OR) 0.14, 95% CI 0.11 to 0.16; seven studies, 8087 participants; moderate-quality evidence), stomatitis (OR 0.21, 95% CI 0.14 to 0.30; five studies, 4212 participants; low-quality evidence), and any grade ≥ 3 AEs (OR 0.82, 95% CI 0.74 to 0.90; five studies, 7741 participants; low-quality evidence). There was more grade ≥ 3 hand foot syndrome (OR 4.59, 95% CI 2.97 to 7.10; five studies, 5731 participants; low-quality evidence) in patients treated with oral fluoropyrimidines. There were no differences between participants treated with oral versus IV fluoropyrimidines in occurrence of grade ≥ 3 diarrhoea (OR 1.12, 95% CI 0.99 to 1.25; nine studies, 9551 participants; very low-quality evidence), febrile neutropenia (OR 0.59, 95% CI 0.18 to 1.90; four studies, 2925 participants; low-quality evidence), vomiting (OR 1.05, 95% CI 0.83 to 1.34; eight studies, 9385 participants; low-quality evidence), nausea (OR 1.21, 95% CI 0.97 to 1.51; seven studies, 9233 participants; low-quality evidence), mucositis (OR 0.64, 95% CI 0.25 to 1.62; four studies, 2233 participants; very low-quality evidence), and hyperbilirubinaemia (OR 1.67, 95% CI 0.52 to 5.38; three studies, 2757 participants; very low-quality evidence). Patients treated with palliative intent for inoperable advanced or metastatic CRC with chemotherapy • Progression-free survival (PFS): Overall, PFS was inferior in participants treated with oral versus IV fluoropyrimidines (HR 1.06, 95% CI 1.02 to 1.11; 23 studies, 9927 participants; moderate-quality evidence). Whilst PFS was worse in participants treated with oral compared with IV fluoropyrimidines when UFT/Ftorafur or eniluracil with oral 5-fluorouracil (5-FU) was used, PFS did not differ between individuals treated with oral versus IV fluoropyrimidines when capecitabine, doxifluridine, or S-1 was used.• OS: Overall, OS did not differ between participants treated with oral versus IV fluoropyrimidines (HR 1.02, 95% CI 0.99 to 1.05; 29 studies, 12,079 participants; high-quality evidence). OS was inferior in participants treated with oral versus IV fluoropyrimidines when eniluracil with oral 5-fluorouracil (5-FU) was used.• Time to progression (TTP): TTP was inferior in participants treated with oral versus IV fluoropyrimidines (HR 1.07, 95% CI 1.01 to 1.14; six studies, 1970 participants; moderate-quality evidence).• Objective response rate (ORR): ORR did not differ between participants treated with oral versus IV fluoropyrimidines (OR 0.98, 95% CI 0.90 to 1.06; 32 studies, 11,115 participants; moderate-quality evidence).• Grade ≥ 3 AEs: Participants treated with oral fluoropyrimidines experienced less grade ≥ 3 neutropenia/granulocytopenia (OR 0.17, 95% CI 0.15 to 0.18; 29 studies, 11,794 participants; low-quality evidence), febrile neutropenia (OR 0.27, 95% CI 0.21 to 0.36; 19 studies, 9407 participants; moderate-quality evidence), stomatitis (OR 0.26, 95% CI 0.20 to 0.33; 21 studies, 8718 participants; low-quality evidence), mucositis (OR 0.17, 95% CI 0.12 to 0.24; 12 studies, 4962 participants; low-quality evidence), and any grade ≥ 3 AEs (OR 0.83, 95% CI 0.74 to 0.94; 14 studies, 5436 participants; low-quality evidence). There was more grade ≥ 3 diarrhoea (OR 1.66, 95% CI 1.50 to 1.84; 30 studies, 11,997 participants; low-quality evidence) and hand foot syndrome (OR 3.92, 95% CI 2.84 to 5.43; 18 studies, 6481 participants; moderate-quality evidence) in the oral fluoropyrimidine arm. There were no differences between oral and IV fluoropyrimidine arms in terms of grade ≥ 3 vomiting (OR 1.18, 95% CI 1.00 to 1.40; 23 studies, 9528 participants; low-quality evidence), nausea (OR 1.16, 95% CI 0.99 to 1.36; 25 studies, 9796 participants; low-quality evidence), and hyperbilirubinaemia (OR 1.62, 95% CI 0.99 to 2.64; nine studies, 2699 participants; low-quality evidence).

Results of this review should provide confidence that treatment for CRC with most of the oral fluoropyrimidines commonly used in current clinical practice is similarly efficacious to treatment with IV fluoropyrimidines. Treatment with eniluracil with oral 5-FU was associated with inferior PFS and OS among participants treated with palliative intent for CRC, and eniluracil is no longer being developed. Oral and IV fluoropyrimidines have different patterns of side effects; future research may focus on determining the basis for these differences.

Sequential administration of the chemotherapy regimes capecitabine and oxaliplatin (XELOX) and capecitabine and irinotecan (XELIRI) in the first- to second-line treatment setting would allow patients to be managed more easily in an outpatient unit. However, a small number of studies have raised concerns of cumulative adverse events as a consequence of the continuous use of capecitabine. To investigate this, the present study conducted a retrospective review of 81 consecutive metastatic colorectal cancer (mCRC) patients treated with the oxaliplatin, fluorouracil and leucovorin-irinotecan, fluorouracil and leucovorin (FOLFOX-FOFIRI/F-F) regimen (n=40) or the XELOX-XELIRI (X-X) regimen (n=41) in first- to second-line chemotherapy in Saitama Medical Center between 2006 and 2012. The disease control rate (DCR), the progression free survival (PFS), the overall survival (OS) and the time to failure of strategy (TFS) from first to second-line chemotherapy, as well as adverse events, were assessed and compared between patients receiving X-X or F-F. A total of 10 and 20 patients were additionally treated with bevacizumab in the F-F and X-X regimens, respectively, during first or second-line chemotherapy. There was no significant difference in DCR and the median PFS between the two regimens for first or second-line chemotherapy. There was no significant difference in the median OS and TFS between the two regimens (OS=24.5 and TFS=14 months in the F-F vs. 23.2 and 12.0 months in the X-X). Regarding adverse events, 45.0% of patients (18/40) exhibited grade 3-4 neutropenia throughout treatment with F-F. Whilst, 15.0% of patients (6/41) exhibited grade 3 hypertension throughout treatment with X-X, which was effectively controlled by a single antihypertensive drug. The results show that sequential administration of X-X is as effective and feasible as F-F treatment, while additionally reducing the frequency of infusion visits and eliminating the need for a central venous access device or home infusion pump, thereby offering a more convenient treatment option to patients with mCRC.

Transition metals have been successfully applied to catalyze non-natural chemical transformations within living cells, with the highly efficient labeling of subcellular components and the activation of prodrugs. In vivo applications, however, have been scarce, with a need for the specific cellular targeting of the active transition metals. Here, we show the design and application of cancer-targeting palladium catalysts, with their specific uptake in brain cancer (glioblastoma) cells, while maintaining their catalytic activity. In these cells, for the first time, two different anticancer agents were synthesized simultaneously intracellularly, by two totally different mechanisms (in situ synthesis and decaging), enhancing the therapeutic effect of the drugs. Tumor specificity of the catalysts together with their ability to perform simultaneous multiple bioorthogonal transformations will empower the application of in vivo transition metals for drug activation strategies.

It has been reported that many patients with lung metastasis of colorectal cancer (CRC) underwent chemotherapy with fluorouracil, folinic acid, oxaliplatin, irinotecan, or capecitabine. There is a small number of reports about the capecitabine and irinotecan (XELIRI) plus bevacizumab (BV) therapy for patients with metastatic CRC in Japan. We report a case of successful BV+XELIRI therapy for rectal cancer with multiple lung metastases as first-line chemotherapy. A 53-year-old female presented with advanced rectal cancer and metastatic lung tumors. Following surgery, the patient was treated with XELIRI+BV. After 6 courses, a computed tomography scan showed complete response of the lung metastases. No recurrence has occurred for 3 years after chemotherapy was stopped.

Indocyanine green (ICG) is increasingly being used in digestive oncology. In colorectal cancer, ICG can be used to detect lymph node metastasis and hepatic metastasis on the surface of the liver. In peritoneal carcinomatosis, it was previously suspected that the diffusion of ICG in the tumor mass was due to the enhanced permeability and retention effect; however, this phenomenon has not been clearly demonstrated. Using bevacizumab, an antibody directed against vascular endothelial growth factor that consequently inhibits neoangiogenesis, we sought to confirm the mode of ICG diffusion. We compared the fluorescence of peritoneal carcinomatosis nodules from patients who had previously received bevacizumab during their oncologic treatment with those who did not receive this therapy. The sensitivity of the carcinomatosis nodule fluorescence was higher in the patients who did not receive bevacizumab compared with those who received the drug (76.3% and 65.0%, respectively). The rate of false-negative results was higher in the bevacizumab group than in the group that did not receive the drug (53.8% and 42.9%, respectively). Using bevacizumab, we demonstrate that the enhanced permeability and retention effect causes ICG accumulation in peritoneal carcinomatosis resulting from colorectal cancer.

Capecitabine and irinotecan combination therapy (XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer (mCRC). Recently, in the Association of Medical Oncology of the German Cancer Society (AIO) 0604 trial, tri-weekly XELIRI plus bevacizumab, with reduced doses of irinotecan (200 mg/m2 on day 1) and capecitabine (1600 mg/m2 on days 1-14), repeated every 3 weeks, has shown favorable tolerability and efficacy which were comparable to those of capecitabine and oxaliplatin (XELOX) plus bevacizumab. The doses of capecitabine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab (BIX) as second-line chemotherapy was well tolerated and had promising efficacy in Japanese patients.

The Asian XELIRI ProjecT (AXEPT) is an East Asian collaborative, open-labelled, randomized, phase III clinical trial which was designed to demonstrate the non-inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI (5-fluorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second-line chemotherapy for patients with mCRC. Patients with 20 years of age or older, histologically confirmed mCRC, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and disease progression or intolerance of the first-line regimen will be eligible. Patients will be randomized (1:1) to receive standard FOLFIRI with or without bevacizumab (5 mg/kg on day 1), repeated every 2 weeks (FOLIRI arm) or XELIRI with or without bevacizumab (7.5 mg/kg on day 1), repeated every 3 weeks (XELIRI arm). A total of 464 events were estimated as necessary to show non-inferiority with a power of 80% at a one-sided α of 0.025, requiring a target sample size of 600 patients. The 95% confidence interval (CI) upper limit of the hazard ratio was pre-specified as less than 1.3.

The Asian XELIRI ProjecT is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second-line treatment option of mCRC. Trial registration ClinicalTrials.gov NCT01996306. UMIN000012263.