Chemotherapy For Advanced Colorectal Cancer Research Articles

DOSAGE study: protocol for a phase III non-inferiority randomised trial investigating dose-reduced chemotherapy for advanced colorectal cancer in older patients

IntroductionTreating older adults with chemotherapy remains a challenge, given their under-representation in clinical trials and the lack of robust treatment guidelines for this population. Moreover, older patients, especially those with...

Abstract B017: Clinical utility of next generation sequencing in advanced colorectal cancer: The earlier the better

Abstract Background. Since next generation sequencing (NGS) was approved in solid tumor in Korea, it has been usually performed when patients were progressed on standard chemotherapy in advanced colorectal cancer (CRC). Recently, new targeted agents have been developed rapidly, so the NGS is recommended as early as possible. In this study, we analyzed NGS results and investigated clinical benefit in advanced CRC. Patient and method. Between October 2018 to December 2022, NGS data in 85 advanced CRC patients in St. Vincent’s Hospital, Suwon, Korea were retrospectively analyzed. Results. Seven patients had metachronous, and others had synchronous metastasis. The median age was 58 (34-84), and 59 (69.4%) were male. Fourteen (16.5%) were right-side, 40 (47.1%) were left-side colon, and 30 (35.3%) were rectum. The median time from diagnosis of advanced CRC to NGS was 13 (0-81) months, and median time to death after NGS was 8 (0.3-43.0) months. NGS platform were ‘Oncomine comprehensive assay Plus’ in 71 (83.5%), and the others were various platforms in K-master project. NGS analyses revealed new therapeutic target in 17 (20%): high tumor mutational burden (n = 2), KRAS G12C (n = 4), KRAS (n = 1) or BRAF (n = 2) mutation not routinely screened at initial, BRAF class II mutation (n = 2), Her2/3 mutation (n = 2), and NTRK fusion (n = 1). Among those, two patients with KRAS G12C mutation enrolled in clinical trial of KRAS G12 inhibitor, and one patient with NTRK fusion received NTRK inhibitor (3.5% of total). Among RAS wild type population (n=30), we identified hyperselected patients (n = 18, [60%], absence of either KRAS, NRAS, PTEN, and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET or NTRK1 fusions by PARADIGM trial), which showed longer survival in cetuximab-treated population (p<0.001). Specific mutation including KRAS, NRAS, BRAF, TP53, or APC did not impact on prognosis. High TMB (≥10Mut/Mb) were associated with longer survival (p = 0.020). For patients with oligometastasis, hyperselected patients (p = 0.062) showed good prognosis. Conclusion. The NGS results provided additional predictive or prognostic information in advanced CRC patients. Application of NGS as early as possible might help to make a clinical decision. Citation Format: Ho Jung An, Hyunho Kim, Hyung Soon Park, Hyeon-Min Cho, Bong-Hyeon Kye, Ri Na Yoo, Ji-Yeon Moon, Sung Hwan Kim, Jonghoon Lee, Hyo Chun Lee. Clinical utility of next generation sequencing in advanced colorectal cancer: The earlier the better [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B017.

The Role of Cyanidin-3-O-glucoside in Modulating Oxaliplatin Resistance by Reversing Mesenchymal Phenotype in Colorectal Cancer.

Epithelial-mesenchymal transition (EMT) plays an important role in the biological and biochemical processes of cells, and it is a critical process in the malignant transformation, and mobility of cancer. Additionally, EMT is one of the main mechanisms contributing to chemoresistance. Resistance to oxaliplatin (OXA) poses a momentous challenge in the chemotherapy of advanced colorectal cancer (CRC) patients, highlighting the need to reverse drug resistance and improve patient survival. In this study, we explored the response of cyanidin-3-O-glucoside (C3G), the most abundant anthocyanin in plants, on the mechanisms of drug resistance in cancer, with the purpose of overcoming acquired OXA resistance in CRC cell lines. We generated an acquired OXA-resistant cell line, named HCT-116-ROx, by gradually exposing parental HCT-116 cells to increasing concentrations of OXA. To characterize the resistance, we performed cytotoxicity assays and shape factor analyses. The apoptotic rate of both resistant and parental cells was determined using Hoechst 33342/Propidium Iodide (PI) fluorescence staining. Migration capacity was evaluated using a wound-healing assay. The mesenchymal phenotype was assessed through qRT-PCR and immunofluorescence staining, employing E-cadherin, N-cadherin, and Vimentin markers. Resistance characterization announced decreased OXA sensitivity in resistant cells compared to parental cells. Moreover, the resistant cells exhibited a spindle cell morphology, indicative of the mesenchymal phenotype. Combined treatment of C3G and OXA resulted in an augmented apoptotic rate in the resistant cells. The migration capacity of resistant cells was higher than parental cells, while treatment with C3G decreased the migration rate of HCT-116-ROx cells. Analysis of EMT markers showed that HCT-116-ROx cells exhibited loss of the epithelial phenotype (E-cadherin) and gain of the mesenchymal phenotype (N-cadherin and Vimentin) compared to HCT-116 cells. However, treatment of resistant cells with C3G reversed the mesenchymal phenotype. The morphological observations of cells acquiring oxaliplatin resistance indicated the loss of the epithelial phenotype and the acquisition of the mesenchymal phenotype. These findings suggest that EMT may contribute to acquired OXA resistance in CRC. Furthermore, C3G decreased the mobility of resistant cells, and reversed the EMT process, indicating its potential to overcome acquired OXA resistance.

Analysis the effect of cytokine-induced killer cells combined with mFOLFOX6 regimen in chemotherapy for advanced colorectal cancer

Objective: To investigate the effect of cytokine-induced killer cells (CIK) combined with mFOLFOX6 regimen (fluorouracil+oxaliplatin+calcium folinate) on advanced colorectal cancer. Methods: 161 patients with advanced colon cancer admitted to the Fourth Clinical College of Xinxiang Medical College, Xinxiang Central Hospital of Henan Province from 2019 to 2021 were selected and divided into the study group (mFOLFOX6 regimen chemotherapy+CIK therapy) with 80 cases and the control group (mFOLFOX6 regimen chemotherapy) with 81 cases. The KPS score, median survival time, progression-free survival time, the proportion of Treg in peripheral blood mononuclear cells, the levels of CD4+, CD4+/CD8+, the expression levels of Foxp3 and CD127 mRNA, the quality-of-life score and the occurrence of toxic and side effects were compared between the two groups before and after chemotherapy. Results: The ages of patients in the study group and the control group were (64.8±7.5) and (66.1±7.0) years old, respectively, and the proportions of males were 62.5% (50 cases) and 50.6% (41 cases), respectively (both P values>0.05). After 2 cycles of chemotherapy and at the end of chemotherapy, the proportions of Treg, Foxp3 and CD127 mRNA in the study group were lower than those in the control group [2 cycles of chemotherapy: (4.33±0.86)% vs (4.89±1.20)%, (0.61±0.22) vs (0.73±0.20), (0.58±0.13) vs (0.70±0.15); after chemotherapy: (2.66±0.70)% vs (3.31±0.84)%, (0.43±0.18) vs (0.51±0.16), (0.41±0.10) vs (0.50±0.13)] (all P values<0.05). The KPS scores of the study group were higher than those of the control group [2 cycles of chemotherapy: (68.41±5.41) points vs (65.38±5.11) points; after chemotherapy: (72.08±5.94) points vs (67.95±5.51) points] (all P values<0.05). The median survival time of the study group was (16.8±2.2) months, which was higher than that of the control group [(11.2±1.8) months]. The progression-free survival time of the study group was also higher than that of the control group [(9.5±1.1) months vs (6.4±1.2) months], and the mortality rate was lower than that of the control group [11.3% (9 cases) vs 31.3% (25 cases)] (all P values<0.001). After chemotherapy, the scores of physical function, emotional function and role function in the study group were higher than those in the control group, and the scores of pains, fatigue and insomnia in the study group were lower than those in the control group (all P values<0.05). Conclusions: CIK combined with mFOLFOX6 regimen for advanced colorectal cancer can improve and regulate the immune function of patients, prolong the survival time of patients, and enhance the quality of life of patients.

Different doses of bevacizumab in combination with chemotherapy for advanced colorectal cancer: a meta-analysis and Bayesian analysis.

The aim of the present study was to explore the incremental benefit of bevacizumab (Bev) in the treatment of advanced colorectal cancer (CRC) with different doses. A literature search of eight electronic databases (China National Knowledge Infrastructure, Wanfang databases, Chinese Biomedical Database, VIP medicine information, Cochrane Library, MEDLINE, PubMed, and EMBASE) was conducted from database creation to December 2022. Randomized controlled trials (RCTs) that compared Bev at various dosages + chemotherapy (CT) versus placebo (or blank control) + CT were selected. The overall survival (OS), progression-free survival (PFS), overall response rate (ORR; complete response [CR] + partial response [PR]), and grade ≥ 3 adverse events (AEs) were integrated first by pooled analysis. The likelihood of ideal dosage of Bev was then ranked using random effects within Bayesian analysis. Twenty-six RCTs involving 18,261 patients met the inclusion criteria. OS increased significantly after using 5mg (HR: 0.87, 95% CI 0.75 to 1.00) and 10mg dosages of Bev (HR: 0.75, 95% CI 0.66 to 0.85) with CT, but statistical significance was not attained for the 7.5mg dose (HR: 0.95, 95% CI 0.83 to 1.08). A significantly increased in PFS with doses of 5mg (HR: 0.69, 95% CI 0.58 to 0.83), 7.5mg (HR: 0.81, 95% CI 0.66 to 1.00), and 10mg (HR: 0.60, 95% CI 0.53 to 0.68). ORR distinctly increased after 5mg (RR: 1.34, 95% CI 1.15 to 1.55), 7.5mg (RR: 1.25, 95% CI 1.05 to 1.50), and10mg (RR: 2.27, 95% CI 1.82 to 2.84) doses were administered. Grade ≥ 3 AEs increased clearly in 5mg (RR: 1.11, 95% CI 1.04 to 1.20) compared to 7.5mg (RR: 1.05, 95% CI 0.82 to 1.35) and 10mg (RR: 1.15, 95% CI 0.98 to 1.36). Bayesian analysis demonstrated that 10mg Bev obtained the maximum time of OS (HR: 0.75, 95% CrI 0.58 to 0.97; probability rank = 0.05) indirectly compared to 5mg and 7.5mg Bev. Compared with 5mg and 7.5mg Bev, 10mg Bev also holds the longest duration for PFS (HR: 0.59, 95% CrI 0.43 to 0.82; probability rank = 0.00). In terms of ORR, 10mg Bev holds the maximum frequency (RR: 2.02, 95% CrI 1.52 to 2.66; probability rank = 0.98) in comparison to 5mg and 7.5mg Bev clearly. For grade ≥ 3 AEs, 10mg Bev has the maximum incidence (RR: 1.15, 95% CrI 0.95 to 1.40, probability rank = 0.67) in comparison to other doses of Bev. The study suggests that 10mg dose Bev could be more effective in treating advanced CRC in efficacy, but 5mg Bev could be more safer in terms of safety.

Chronomodulated Administration of Chemotherapy in Advanced Colorectal Cancer: A Systematic Review and Meta-Analysis.

In this systematic review, the efficacy and safety of chronomodulated chemotherapy, defined as the delivery of chemotherapy timed according to the human circadian rhythm, were assessed and compared to continuous infusion chemotherapy for patients with advanced colorectal cancer. Electronic English-language studies published until October 2020 were searched. Randomised controlled trials (RCTs) comparing chronomodulated chemotherapy with non-chronomodulated (conventional) chemotherapy for the management of advanced colorectal cancer were included. The main outcomes were the objective response rate (ORR) and system-specific and overall toxicity related to chemotherapy. Electronic databases including Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Review were searched. In total, seven RCTs including 1,137 patients were analysed. Males represented 684 (60%) of the study population. The median age was 60.5 (range = 47.2-64) years.There was no significant difference between chronomodulated and conventional chemotherapy in ORR (risk ratio (RR) = 1.15; 95% confidence interval (CI) = 0.87-1.53). Similarly, there was no significant difference in gastrointestinal toxicity under the random effect model (RR = 1.02; 95% CI = 0.68-1.51). No significant difference was found regarding neurological and skin toxicities (RR = 0.64, 95% CI = 0.32-1.270 and RR = 2.11, 95% CI = 0.33-13.32, respectively). However, patients who received chronomodulated chemotherapy had less haematological toxicity (RR = 0.36, 95% CI = 0.27-0.48). In conclusion, there was no overall difference in ORR or haematologic toxicity between chronomodulated and non-chronomodulated chemotherapy used for patients with advanced colorectal cancer. Chronomodulated chemotherapy can be considered in patients at high risk of haematological toxicities.

Abstract 1250: Impact of homologous recombination repair or mismatch repair gene alteration on first-line FOLFOX chemotherapy in advanced colorectal cancer patients: K-MASTER project

Abstract Purpose: Homologous recombination repair (HRR) and mismatch repair (MMR) alteration is known to have a good response to platinum-based chemotherapy in both breast and ovarian cancer. However, HRR/MMR alteration and response for 1L FOLFOX chemotherapy in advanced colorectal cancer (CRC) is not fully understood. Methods: From 2017 to 2021, a number of 1,225 advanced CRC patients with available HRR/MRR alteration data were registered in K-MASTER project. After excluding missing data, adjuvant chemotherapy alone, other chemotherapeutic regimen, 390 patients who received 1L FOLFOX chemotherapy were finally analyzed. Targeted sequencing was conducted using Cancer Scan panel, FIRST panel, and K-MASTER Cancer (v1.0 or v1.1) panel for tumor tissue. If tumor tissue was not available, liquid biopsy was performed. HRR gene defined as follow; ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, FANCD2, FANCG, PALB2, RAD50, RAD51. MMR gene defined as below; MLH1, MSH2, PMS2, MSH6, POLE, ARID1A. Results: Among 340 patients, 79 patients harbored HRR/MMR alteration. The median progression free survival (PFS) was 5.6 months vs 5.7 months in HRR/MMR alteration and wild-type group, respectively (hazard ratio (HR)=1.19, p-value=0.21). The median overall survival (OS) was comparable between two group (40.6 months vs 34.5 months, respectively; HR=0.71, p-value=0.17). Multivariate cox-proportional hazard model also showed HRR/MRR alteration status was not an independent factor for both PFS and OS (Both p-value&amp;gt;0.05). Conclusions: Patients harbored HRR/MRR alteration may not be sensitive for 1L oxaliplatin-based chemotherapy than wild-type. The effective treatment targeting high genomic instability populations warrants further investigation in CRC. Table 1. Baseline clinical characteristics and survival outcomes HRR/MMR alteration (n = 79) HRR/MMR wild-type (n = 261) P-value Age, year 58.5 ± 12.4 59.1 ± 12.8 0.710 Primary tumor resection, n (%) 70 (88.6%) 241 (92.3%) 0.298 Prior neoadjuvant or adjuvant chemotherapy, n (%) 10 (12.7%) 27 (10.3%) 0.212 Clinical stage IV, n (%) 71 (91.0%) 240 (92.7%) 0.855 Combined target agents, n (%) 54 (68.4%) 183 (70.1%) 0.811 HRR/MMR variants, n (%) N/A HRR mutation alone 38 (48.1%) - MMR mutation alone 30 (38.0%) - HRR+MMR mutation 11 (13.9%) - Median PFS (95% CI), months 5.6 (4.9-6.3) 5.7 (5.5-5.9) 0.215 Median OS (95% CI), months 40.6 (39.5-41.8) 34.5 (29.3-39.8) 0.175 Citation Format: Myung Han Hyun, Jwa Hoon Kim, Ah Reum Lim, Jae Sook Sung, Hee-Joon Chung, Yeul Hong Kim, Soohyeon Lee. Impact of homologous recombination repair or mismatch repair gene alteration on first-line FOLFOX chemotherapy in advanced colorectal cancer patients: K-MASTER project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1250.

Patient-Derived Organoid Serves as a Platform for Personalized Chemotherapy in Advanced Colorectal Cancer Patients.

BackgroundAddition of oxaliplatin to adjuvant 5-FU has significantly improved the disease-free survival and served as the first line adjuvant chemotherapy in advanced colorectal cancer (CRC) patients. However, a fraction of patients remains refractory to oxaliplatin-based treatment. It is urgent to establish a preclinical platform to predict the responsiveness toward oxaliplatin in CRC patients as well as to improve the efficacy in the resistant patients.MethodsA living biobank of organoid lines were established from advanced CRC patients. Oxaliplatin sensitivity was assessed in patient-derived tumor organoids (PDOs) in vitro and in PDO-xenografted tumors in mice. Based on in vitro oxaliplatin IC50 values, PDOs were classified into either oxaliplatin-resistant (OR) or oxaliplatin-sensitive (OS) PDOs. The outcomes of patients undergone oxaliplatin-based treatment was followed. RNA-sequencing and bioinformatics tools were performed for molecular profiling of OR and OS PDOs. Oxaliplatin response signatures were submitted to Connectivity Map algorithm to identify perturbagens that may antagonize oxaliplatin resistance.ResultsOxaliplatin sensitivity in PDOs was shown to correlate to oxaliplatin-mediated inhibition on PDO xenograft tumors in mice, and parallelled clinical outcomes of CRC patients who received FOLFOX treatment. Molecular profiling of transcriptomes revealed oxaliplatin-resistant and -sensitive PDOs as two separate entities, each being characterized with distinct hallmarks and gene sets. Using Leave-One-Out Cross Validation algorithm and Logistic Regression model, 18 gene signatures were identified as predictive biomarkers for oxaliplatin response. Candidate drugs identified by oxaliplatin response signature-based strategies, including inhibitors targeting c-ABL and Notch pathway, DNA/RNA synthesis inhibitors, and HDAC inhibitors, were demonstrated to potently and effectively increase oxaliplatin sensitivity in the resistant PDOs.ConclusionsPDOs are useful in informing decision-making on oxaliplatin-based chemotherapy and in designing personalized chemotherapy in CRC patients.

Blood transfusion has an adverse impact on the prognosis of patients receiving chemotherapy for advanced colorectal cancer: experience from a single institution with a patient blood management program.

Perioperative blood transfusion in early stage cancer patients had a negative effect on the prognosis of patients, but the prognostic impact of transfusion in advanced cancer patients remains unclear. To minimize and guide rational transfusion, an institutional patient blood management (PBM) program was launched, and we evaluated the new program that has changed the practice and impacted on the prognosis of advanced cancer patients. We investigated the medical records of colorectal cancer patients who received chemotherapy from 2015 to 2020. The amount and frequency of transfusion, iron replacement and laboratory findings, and overall survival were compared before and after implementation of PBM. The rate of transfusion in colorectal cancer patients was significantly decreased from 23.5/100 person-quarter in 2015 to 1.2/100 person-quarter in 2020, but iron supplementation therapy was frequently used, and the proportion of patients who received transfusion under hemoglobin 7 g/dL significantly increased from 15.9% in 2015 to 55.3% in 2020. Multivariate analysis revealed that transfusion was a significant risk factor affecting the overall survival of patients (HR 2.70, 95% CI: 1.93-3.78, p<0.001). Kaplan-Meier analysis revealed that overall survival was significantly longer in non-transfused patients than in transfused patients (11.0 versus 22.4 months; HR 0.69, 95% CI: 0.56-0.86, p<0.001). This study shows that minimized transfusion through an institutional PBM can positively affect the prognosis of patients who are receiving chemotherapy for advanced colorectal cancer.

CHFR-Promoter-Methylation Status Is Predictive of Response to Irinotecan-based Systemic Chemotherapy in Advanced Colorectal Cancer.

We investigated whether promoter methylation of the checkpoint-with-forkhead-and-ring-finger-domains (CHFR) gene is a predictor of the efficacy of irinotecan-based systemic chemotherapy for advanced colorectal cancer (CRC) patients. CHFR-promoter methylation was measured by quantitative methylation-specific PCR (qMSP). The histoculture drug response assay (HDRA) was used in vitro to analyze the correlation between CHFR-promoter methylation and the efficacy of the irinotecan-active-metabolite SN38 in colorectal-cancer tissues from 44 CRC patients. CHFR promoter-methylation was also analyzed for its correlation with clinical response to irinotecan-based systemic chemotherapy of 49 CRC patients. CHFR-promoter methylation significantly-positively correlated with inhibition of colon cancer by SN38 in the HDRA (p=0.002). CHFR-promoter methylation also significantly-positively correlated with clinical response to irinotecan-based systemic chemotherapy (p=0.04 for disease control). CHFR-promoter methylation also significantly-positively correlated (p=0.01) with increased progression-free survival for patients treated with irinotecan-containing FLOFIRI in combination with bevacizumab, the most-frequent regimen in the cohort. Sensitivity of advanced CRC patients to irinotecan-based systemic chemotherapy can be predicted by the extent of CHFR-promoter methylation.

Endoscopic Stenting and Palliative Chemotherapy in Advanced Colorectal Cancer: Friends or Foes? An Analysis of the Current Literature

Chemotherapy offers a clear benefit in terms of survival rates of stage IV metastatic colorectal cancer (CRC) patients, but this advantage might be mitigated by the theoretical risks of short- and mid-term complications in the cases of contextual self-expandable metal stent (SEMS) positioning, which might also affect survival rates. We reviewed all available literature from Medline and Scopus databases to study the role of chemotherapy with or without the simultaneous administration of targeted therapy in increasing the risk of the complications after SEMS positioning and, eventually, in affecting the survival rates. Thirteen retrospective studies and 1 randomized controlled trial (RCT) were eligible for the present analysis. The study group consisted of a total of 682 patients. A total of 305 patients were treated with conventional chemotherapy, 212 with conventional chemotherapy also containing targeted therapy, and 165 with no chemotherapy administration. Chemotherapy administration did not increase the rate of SEMS-related complications and these complications did not affect the overall survival rates. Chemotherapy administration is not associated with a higher risk of SEMS-related complications and a reduction in the survival rates.

Abstract 346: Tumoral expression of folate-associated genes is associated with progression-free survival of patients with advanced colorectal cancer

Abstract Background - 5-fluorouracil (5-FU) in combination with the folate leucovorin (LV) has formed the backbone of chemotherapy for advanced colorectal cancer for several decades. A number of genes encode proteins that participate in transportation of LV into the cells, as well as in subsequent metabolic action. We previously reported that high tumoral expression of genes involved in folate transport, polyglutamation, and metabolism was associated with decreased risk of recurrent disease in patients with stage III colorectal cancer treated with 5-FU + LV (FLV) alone, or in combination with oxaliplatin (FLOX) according to the Nordic bolus regimen. The aim of the present study was to determine the association between expression of the folate-associated genes ABCC3, MTHFD2, SLC19A1, SLC25A32, SLC46A1, and TYMS and outcome of patients with metastatic colorectal cancer subjected to palliative chemotherapy. Patients and Methods - A total of 290 patients treated with FLV (n = 113), FLOX (n = 102) or FLV + irinotecan (FLIRI, n = 75) were included. Relative gene expression (ΔCt) was determined in primary tumors by quantitative PCR and analyzed in relation to clinical benefit, based on RECIST criteria and 3-year progression-free survival (PFS). Analyses were conducted on the whole study group, and on subgroups based on tumor stage at primary surgery (subgroup 1, stage I-III; subgroup 2, stage IV). An ANOVA test was used to assess the relationship between expression and clinical benefit. A multivariate Cox proportional hazard model was applied to assess potential associations between genetic markers, clinical variables and PFS. A Stepwise model selection was used to identify a minimal set of variables associated with PFS. Results - Low expression of TYMS and MTHFD2, and high expression of ABCC3 was significantly associated with a clinical benefit in the whole group (p&amp;lt;0.0001, p=0.017, and p=0.028, respectively). The association between TYMS expression and clinical benefit was seen in both sub-groups, whereas ABCC3 expression was significant in subgroup 2 (p=0.041). Multivariate models showed that low TYMS and high SLC25A32 expression in subgroup 1 and high ABCC3 expression in subgroup 2 correlated significantly with better PFS (Hazard Ratio (HR) = 0.75 (95% CI = 0.57-1.0), HR = 2.21 (95% CI = 1.37-3.6), and HR = 1.34 (95% CI = 1.08 -1.7), respectively). Conclusion - Expression of TYMS, the target enzyme of 5-FU, was strongly associated with clinical benefit in the whole group, whereas expression of TYMS and the folate transporters SLC25A32, and ABCC3 was associated with PFS in the subgroups (stage I-III and stage IV), respectively. The prospective global phase III study AGENT is presently conducted on patients with advanced colorectal cancer, to determine whether expression of these genes can predict response to 5-FU-based chemotherapy that includes LV or the novel folate arfolitixorin. Citation Format: Yvonne Wettergren, Elisabeth Odin, Göran Carlsson, Pushpa Saksena, Anders Edsjö, Alessandro Di Cara, Roger Tell, Bengt Gustavsson. Tumoral expression of folate-associated genes is associated with progression-free survival of patients with advanced colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 346.

Abstract 2522: Exploring the prognostic and predictive value of circulating tumor DNA in patients with advanced colorectal cancer and chemotherapy

Abstract Background: Chemotherapy improves the survival of advanced colorectal cancer (CRC) patients but recurrences do happen frequently. Early indicators of reccurence/relapse post-chemotherapy are essential for optimal clinical decision. Circulating tumor DNA (ctDNA) are cancer-specific DNA fragments in plasma. They have been considered as predictive biomarkers of early stage CRC. However, the predictive value of ctDNA in advanced CRC is still undetermined. Here, we evaluate the applicability of early changes in ctDNA as a marker that might predict clinical course in advanced CRC patients after chemotherapy. Methods: 122 patients with CRC were enrolled and their ctDNA fingerprints, designed based on individual patient's top somatic mutated genes, were determined and monitored over time (~ 3-6 months interval). The patients were classified into high- and low-ctDNA groups divided by the median concentration of ctDNA. We subsequently analyzed the correlation between overall survival (OS) and ctDNA levels in patients with or without chemotherapy. The dynamics of ctDNA were used to assess the prognosis and OS. Results: In the 122 patients, higher ctDNA levels (above median) were associated with shorter OS (HR, 2.89; CI 95% 1.45-5.79, P=0.0027). The conclusion upheld in a subset of 48 who had advanced CRC (stage IV) and received chemotherapy (HR, 1.601, CI 95% 0.61-4.17, p=0.037). Moreover, changes of ctDNA were detected early during the chemotherapy treatment course. In the same 48 patients with advanced CRC and chemotherapy, those who had undetectable and decreased ctDNA had longer OS overall, suggesting that ctDNA dynamics is predictive of clinic change in chemotherapy in advanced CRC. Finally, compared with clinical imaging diagnosis, we found that approximately 52.9% (18/34) patients belonged to a “consistent” group, in which patients with decreased/undetectable ctDNA had relieved clinical diagnosis and patients with increased ctDNA had elevated diagnosis. However, 14.7% (5/34) patients had inconsistent results between imaging diagnosis and ctDNA monitoring, and 32.4% (11/34) patients were uncertain due to unstable ctDNA levels. Conclusion: This study confirms the association between baseline levels of ctDNA and survival times of CRC patients. Additionally, it also suggests the use of early change of ctDNA as a potential biomarker of therapeutic efficacy in CRC chemotherapy. Oncologists may be able to use ctDNA fingerprints to guide treatment decisions and predict individual patient's prognosis. Citation Format: Xiu Liu, Xuan Zhang, Kai Ou, Chelong Lu, Dong Zheng, Jun Liu, Qiang Xu, Lin Yang. Exploring the prognostic and predictive value of circulating tumor DNA in patients with advanced colorectal cancer and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2522.

Clinical Validation of a Machine-learning-derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer.

FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC. A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOXai. Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints. A 67-gene signature was cross-validated in a training cohort (N = 105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; P = 0.04 and FOLFOXIRI HR, 0.483; P = 0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma. Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.

Effectiveness and Safety of Chinese Herbal Injections Combined with Fluoropyrimidine and Oxaliplatin-based Chemotherapy for Advanced Colorectal Cancer: A Systematic Review and Meta-analysis of 63 Randomized Controlled Trials.

Purpose: To investigate effectiveness and safety of Chinese herbal injections (CHIs) in conjunction with fluoropyrimidine and oxaliplatin-based chemotherapy (FOBC) for advanced colorectal cancer (CRC).Methods: A comprehensive search was conducted in 7 electronic databases for related randomized controlled trials (RCTs) from inception to April 30, 2021. The quality of each trial was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions, the differences in effectiveness and safety outcomes between two groups were evaluated, and the results were expressed as the risk ratios (RRs) and 95% confidence interval (CI). Subgroup analyses were performed according to the types of CHIs, and Review Manager 5 was used to statistically analyze the outcomes.Results: 63 studies involving 9 CHIs and 4733 patients were included in this review. The meta-analysis results suggested that compared with FOBC therapy, CHIs plus FOBC therapy showed significant improvements in objective response rate (ORR) (RR=1.34, 95% CI: 1.27-1.42, P<0.00001), disease control rate (DCR) (RR=1.09, 95%CI: 1.06-1.11, P<0.00001), 1-year survival rate (RR=2.27, 95% CI: 1.23-4.18, P=0.009) and quality of life (QoL) (RR=1.21, 95% CI: 1.14-1.28, P<0.00001), and decreases in the incidence of chemotherapy-induced leukopenia (RR=0.64, 95% CI: 0.50-0.82, P<0.0005), nausea and vomiting (RR=0.65, 95% CI: 0.51-0.83, P=0.0005) and diarrhea (RR=0.34, 95% CI: 0.20-0.58, P<0.0001).Conclusion: From the evidence available, CHIs could increase ORR, DCR and 1-year survival rate, improve QoL and relieve chemotherapy-induced leukopenia, nausea and vomiting and diarrhea when combined with FOBC in advanced CRC treatment, Nevertheless, on account of the limitations, more rigorous RCTs with high-quality methodology were needed to further confirm the results.

Efficacy of Chinese herbal injections combined with fluoropyrimidine and oxaliplatin-based chemotherapy for advanced colorectal cancer: A protocol for systematic review and meta-analysis of randomized controlled trials.

Background:Fluoropyrimidine combined with oxaliplatin-based chemotherapy have become the first-line treatment for advanced colorectal cancer (CRC). Chinese herbal injections (CHIs), as an important part of TCM, have been widely applied as adjunctive treatments to chemotherapy in patients with advanced CRC. However, the efficacy of this combination therapy has not been evaluated comprehensively.Methods:We will conduct this systematic review and meta-analysis in accordance with the Preferred Reported Items for Systematic Review and Meta-analysis (PRISMA) guidelines. 7 databases will be searched for related randomized controlled trials (RCTs) from their inception to August 31, 2020: PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals (VIP), SinoMED and Wanfang Database. Two researchers will perform study selection, data extraction, and assessment of risk of bias independently. The primary outcomes are the disease control rate (DCR) and the objective response rate (ORR), the secondary outcomes are progression-free survival (PFS), survival rate, quality of life (QoL) and adverse effects. Cochrane Review Manager (RevMan 5.3) software will be used to analyze the outcomes.Results and Conclusion:This systematic review will evaluate the efficacy of CHIs and fluoropyrimidine and oxaliplatin-based chemotherapy for advanced CRC so as to provide valuable evidence to the application of CHIs in advanced CRC.Systematic review registration:INPLASY registration number: INPLASY2020100050.

Enhanced Detection of Treatment Effects on Metastatic Colorectal Cancer with Volumetric CT Measurements for Tumor Burden Growth Rate Evaluation.

Mathematical models combined with new imaging technologies could improve clinical oncology studies. To improve detection of therapeutic effect in patients with cancer, we assessed volumetric measurement of target lesions to estimate the rates of exponential tumor growth and regression as treatment is administered. Two completed phase III trials were studied (988 patients) of aflibercept or panitumumab added to standard chemotherapy for advanced colorectal cancer. Retrospectively, radiologists performed semiautomated measurements of all metastatic lesions on CT images. Using exponential growth modeling, tumor regression (d) and growth (g) rates were estimated for each patient's unidimensional and volumetric measurements. Exponential growth modeling of volumetric measurements detected different empiric mechanisms of effect for each drug: panitumumab marginally augmented the decay rate [tumor half-life; d [IQR]: 36.5 days (56.3, 29.0)] of chemotherapy [d: 44.5 days (67.2, 32.1), two-sided Wilcoxon P = 0.016], whereas aflibercept more significantly slowed the growth rate [doubling time; g = 300.8 days (154.0, 572.3)] compared with chemotherapy alone [g = 155.9 days (82.2, 347.0), P ≤ 0.0001]. An association of g with overall survival (OS) was observed. Simulating clinical trials using volumetric or unidimensional tumor measurements, fewer patients were required to detect a treatment effect using a volumetric measurement-based strategy (32-60 patients) than for unidimensional measurement-based strategies (124-184 patients). Combined tumor volume measurement and estimation of tumor regression and growth rate has potential to enhance assessment of treatment effects in clinical studies of colorectal cancer that would not be achieved with conventional, RECIST-based unidimensional measurements.

Risk factors of chemotherapy-induced nausea and vomiting in patients with metastatic colorectal cancer: a prospective cohort study (YCOG1301).

Although the effectiveness of antiemetic therapy for colorectal cancer chemotherapy has improved with further drug development, some patients still suffer from chemotherapy-induced nausea and vomiting (CINV) even with only 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The present study investigated the risk factors of CINV in patients who received chemotherapy for colorectal cancer and clarified which patients need additional neurokinin 1 receptor antagonist. Patients with colorectal cancer receiving moderate-emetic-risk chemotherapy (MEC) were enrolled in this prospective single-arm study with intravenous palonosetron 0.75 mg and dexamethasone 9.9 mg before chemotherapy and with paroral dexamethasone 8 mg on days 2 and 3. The primary endpoint was the complete response (CR) rate for delayed-phase CINV. A total of 179 patients were eligible for this study. The delayed CR rate was 84.9% (152/179). There were no significant differences in any risk factors, but women with a low body mass index (BMI) (a combination of "female sex" and "BMI < 20") showed a significantly lower rate of CC (complete control) (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.17-1.13; p = 0.039), and young patients with a low BMI (combination of "age < 65" and "BMI < 20") showed a significantly lower rate of CR (OR = 0.34, 95% CI = 0.13-0.88; p = 0.022) than the other patients. This study failed to identify any single risk factors associated with delayed CINV in patients who received chemotherapy for advanced colorectal cancer. However, combinations of "thin and women" or "young and thin patients" might be possible predictive conditions, thus, candidates for NK1 receptor antagonist administration in MEC. Further investigations are required to develop criteria for the supplementation of NK1 receptor antagonist.

Sequential versus combination chemotherapy for advanced colorectal cancer

Sequential versus combination chemotherapy for advanced colorectal cancer

Skin Toxicities During Colorectal Cancer Chemotherapy: Incidence and Pearls of Treatment in Our Experience

IntroductionMedical treatment of advanced colorectal cancer is effective in prolonging the survival of patients. The aim of this study was to describe the most common skin toxicities that occur in those patients, analyzing the association between the type of reaction and the different chemotherapeutic drugs; and to evaluate the importance of an outpatient dermatologic service to improve quality of life. Patients and MethodsSeventy-two patients with skin reactions from advanced colorectal cancer chemotherapy were included. Each patient underwent physical examination and digital photographic imaging, and completed a quality-of-life questionnaire (Dermatology Life Quality Index [DLQI]). ResultsPapulopustular rash was the most common side effect observed. It was statistically associated with EGFRi + irinotecan, EGFRi + FOLFOX, and EGFRi. Xerosis occurred in 50% of patients during EGFRi therapy. Periungual pyogenic granuloma-like lesions occurred in 30% of patients during EGFRi therapy. Our data underline a statistically significant association between capecitabine, FOLFOX + EGFRi, FOLFIFI + EGFRi, and hand–foot syndrome (P < .001). Because none of patients treated with EGFRi alone developed this kind of reaction, we suppose that it is associated with the use of 5-fluorouracil. Fifty percent of patients receiving anti–epidermal growth factor receptor (EGFR) therapy developed trichomegaly. These data underline a statistically significant association between these reactions and this specific drug. ConclusionA dermatologic visit is useful, both for the correct diagnosis of and for the adequate therapy of chemotherapy side effects. The prevention and treatment of these toxicities are important, not only to improve quality of life but also to avoid unnecessary dose reduction or interruption, which can have a negative effect on treatment outcome.