Chemotherapy For Metastatic Colorectal Cancer Research Articles

Triplet chemotherapy in metastatic colorectal cancer: which patients, when, how and with which targeted therapies?

Triplet chemotherapy in metastatic colorectal cancer: which patients, when, how and with which targeted therapies?

Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer.

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

Economic evaluation of personalized vs. standard dosing of 5-fluorouracil in first-line chemotherapy for metastatic colorectal cancer in Australia.

Using pharmacokinetics (PK)-guided 5-fluorouracil (5-FU) for metastatic colorectal cancer (mCRC) improves overall survival (OS) and decreases toxicity, yet its value for money in the Australian setting is unknown. Our study assesses the cost-effectiveness of PK vs. body surface area (BSA) dosing of 5-FU for patients with mCRC. We developed a semi-Markov model with four health states to compare PK-guided dosing within a FOLFOX regimen vs. BSA-guided dosing for mCRC patients from an Australian healthcare system perspective. Transition probabilities were derived from fitted survival models, with utility values obtained directly from published studies. We calculated direct healthcare costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs), and included both one-way and probabilistic sensitivity analyses. BSA-guided FOLFOX provided 1.291 QALYs at a cost of $36 379, compared with PK-guided FOLFOX which delivered 1.751 QALYs at a cost of $32 564. Therefore, PK-guided dosing emerges as the dominant strategy offering both better health outcomes and lower costs. The variables that had the greatest impact on the overall ICER were the adverse event rates in the BSA and PK groups, model time horizon, utility of progression-free survival and PREDICT assay cost. Our univariate and multivariate sensitivity analysis confirmed that the ICER for PK FOLFOX consistently remained below $50 000 per QALY across all tested variables. PK dose management of 5-FU-based chemotherapy in mCRC patients appears to be a cost-saving strategy in Australia. However, our model estimates are drawn from limited, low-quality evidence. Further evidence from randomized controlled trials (RCTs), directly comparing PK-based to BSA-based dosing across a variety of current regimens, is needed to address our model's uncertainties.

Serum angiopoietin-like protein 2 level in patients who received bevacizumab-containing chemotherapy for metastatic colorectal cancer.

209 Background: Anti-angiogenic agents are important for treating patients with advanced colorectal adenocarcinoma, however, their efficacy is not long-lasting and survival benefits are modest. Reliable biomarkers and novel targets for angiogenesis are still required in this era. Angiopoietin-like protein 2 (AGLP-2) is an emerging biomarker for angiogenesis in cardiovascular disease, but its role in the oncology area is yet to be elucidated. Methods: Serum samples from patients with advanced colorectal carcinoma treated with bevacizumab-containing chemotherapy were retrospectively studied. Blood samples at baseline and at disease progression of the first line systemic therapy were selected. Serum angiopoietin-like protein 2 (AGLP-2) concentrations were measured using ELISA kit, serial changes, and the relationship with progression-free survival and overall survival on the systemic therapy were statistically analyzed. Results: 68 patients were enrolled. Their median age was 66 years old (range, 38-82), and 14 (20.6%) patients had metastatic lesions at 3 or 4 organs. The median serum AGLP-2 levels at baseline and at disease progression (PD) were 41,618 pg/ml (95% confidence interval (CI) 34,560-40,713), and 49,706 pg/ml (95% CI 39,853-49,017), respectively. There was a tendency of difference between AGLP-2 levels at baseline and at PD ( p=0.057). Patients whose baseline serum AGLP-2 levels with 40,000 pg/ml or above showed relatively shorter overall survival (median 31.4 months with 95% CI, 14.4-38.6) compared with patients with serum AGLP-2 level below 40,000 pg/ml at baseline (median 38.6 months with 95% CI, 23.6-127.3), but not statistically significant ( p=0.0946). There was no survival difference observed according to serum AGLP-2 levels at disease progression on the first line bevacizumab-containing chemotherapy. Conclusions: Serum angiopoietin-like protein-2 has potential as a new target for novel anti-angiogenic therapy in metastatic colorectal cancer.

MFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer (FROST trial): Study protocol for an open label, multicenter, randomized, phase II study.

TPS230 Background: Patients with high-risk stage III colon cancer have a significantly poorer prognosis than those with stage II or low-risk stage III colon cancer. Despite this distinction, most guidelines recommend similar adjuvant treatment approaches for all stages, and there is a dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis through more intensive adjuvant treatment. Given the proven efficacy of triplet chemotherapy in metastatic colorectal cancer, this study aims to assess the effectiveness and toxicity of modified 5-fluoropyrimidine (5-FU)/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) in comparison with the current standard of care—modified oxaliplatin and 5-FU (mFOLFOX-6)—as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer. Methods: This multicenter, randomized (1:1), open-label, phase II trial aims to compare the adjuvant treatment efficacy of mFOLFIRINOX and mFOLFOX-6 in patients with high-risk stage III colon cancer. The trial aimed to enroll 312 eligible patients aged between 20 and 70 years with an Eastern Cooperative Oncology Group performance status of 0-2, or between 70 and 75 years with an Eastern Cooperative Oncology Group performance status of 0. All patients underwent radical resection and were randomized into two arms: Arm A experimental arm, received 12 cycles of mFOLFIRINOX every 2 weeks, while arm B, the reference arm, received 12 cycles of mFOLFOX 6 every 2 weeks. The primary endpoint of this study was the 3-year disease-free survival, whereas the secondary endpoints included assessing the 3-year overall survival and treatment toxicity. Discussion: The Frost trial is expected to elucidate the safety and oncologic efficacy of mFOLFIRINOX compared to mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancers, and provide evidence about this treatment, and contribute to improve the prognoses ultimately. Clinical trial information: NCT05179889 .

Reclassification of RAS/BRAF allele mutations predicts the survival benefit of triplet chemotherapy in metastatic colorectal cancer.

Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial. Between March 2017 and September 2022, the patients diagnosed as stages I-IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan-Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models. A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS/BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36-5.12; p = 0.0091). In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.

Delta tocotrienol as a supplement to FOLFOXIRI in first-line treatment of metastatic colorectal cancer. A randomized, double-blind, placebo-controlled phase II study

Purpose Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether δ-tocotrienol, a vitamin E analogue, with possible neuroprotective and anti-inflammatory effects, reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo-controlled trial in mCRC patients receiving first-line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). Material and Methods Seventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either δ-tocotrienol or placebo at the Department of Oncology, Vejle Hospital, Denmark. Eligibility criteria were adenocarcinoma in the colon or rectum, age 18–75 years and ECOG performance status 0–1. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. δ-tocotrienol 300 mg or placebo × 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy. Results Median time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and was NR in the δ-tocotrienol group (95% CI 1.87-NR) with a hazard ratio of 0.70 (95% CI 0.36–1.36). Grade 3–4 toxicities were uncommon in both groups, except for neutropenia, which occurred in 19 patients (58%) in the placebo group and 17 patients (50%) in the δ-tocotrienol group. There were no grade 3 or 4 peripheral sensory neuropathy. In the placebo group, 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the δ-tocotrienol group (p = 0.047). Conclusion The addition of δ-tocotrienol to FOLFOXIRI did not statistically significant prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of δ-tocotrienol.

Overall Survival, BRAF, RAS, and MSI Status in Patients Who Underwent Cetuximab After Refractory Chemotherapy for Metastatic Colorectal Cancer.

Evaluate overall survival (OS), RAS, BRAF, and MSI frequencies in patients with metastatic colorectal cancer (mCRC), refractory to chemotherapy, and finally treated with cetuximab. A retrospective cohort study to evaluate 211 mCRC patients with wild-type KRAS treated with cetuximab. BRAF V600E, KRAS, NRAS gene mutations, and MSI status were identified using PCR techniques in a population of pre-treated patients who were refractory to fluoropyrimidines, oxaliplatin, and irinotecan. In addition, we evaluated the mutation frequency of the BRAF and NRAS genes and the MSI status of this population. Uni- and multivariate analyses were performed for independent prognostic factors of OS. The median OS was 10.4months, 6.6months for patients with right and 11.5months for left colon cancers (p = 0.02). The frequencies of mutations were BRAF at 3.9% (median OS of 4.9months), NRAS at 3.38% (median OS of 6.9months), and MSI-High status at 3.3% (median OS of 4.6months). The OS, NRAS, and MSI frequencies were similar to those found in other studies that evaluated cetuximab in poly-treated patients and were associated with lower survival rates in univariate analyses. The frequency of BRAF mutations was lower than that found in previous studies. The only variable that remained significant for OS in the multivariate model was tumour laterality, with patients with right colon cancer presenting a worse prognosis (HR = 2.81). Although BRAF, NRAS mutations, and MSI-High status were associated with shorter OS in univariate analyses, only tumour laterality remained an independent prognostic factor in the multivariate analysis.

Clinical outcomes of intensive versus less intensive first-line chemotherapy for metastatic colorectal cancer.

Aims: Physicians determine the treatment regimen for metastatic colorectal cancer on a case-by-case bases, according to the individual disease characteristics. We retrospectively compared the baseline characteristics and efficacies of first-line treatment among patients with metastatic colorectal cancer who received intensive therapy involving fluoropyrimidine plus oxaliplatin and/or irinotecan, potentially with molecularly targeted agents as well, versus less intensive fluoropyrimidine and/or bevacizumab therapy. Materials & methods: Data were collected from a medical claims database. The efficacy outcomes were: time to treatment failure, time to first subsequent therapy and overall survival. Results: The less intensive therapy group (n=633) had higher median age, lower daily activity levels and shorter time to treatment failure, time to first subsequent therapy and overall survival than the intensive therapy group (n=3829). Combination therapy with molecularly targeted agents and bevacizumab improved treatment efficacy outcomes in the intensive and less intensive groups, respectively. Conclusion: Patient age and daily activity levels were important factors for determining treatment intensity.

Targeted Therapy in the Palliative Setting of Colorectal Cancer-Survival and Medical Costs.

(1) Background: Targeted therapy is used alone or together with chemotherapy in metastatic colorectal cancer. The aim of this study was to assess overall survival and medical costs in a cohort of patients with metastatic colorectal cancer. (2) Methods: Demographic and clinical characteristics of 337 patients and pathological data of colorectal tumors were retrospectively collected in this population-based study. The overall survival and medical costs for patients receiving chemotherapy plus targeted therapy were compared with those for patients receiving chemotherapy only. (3) Results: Patients administered chemotherapy plus targeted therapy were less frail and had more often RAS wild-type tumors but had higher CEA levels than patients receiving chemotherapy only. No prolonged overall survival could be observed in patients receiving palliative targeted therapy. The medical costs for patients undergoing treatment with targeted therapy were significantly higher than for patients treated only with chemotherapy; they were especially higher in the group receiving targeted therapy early than late in the palliative setting. (4) Conclusions: The use of targeted therapy in metastatic colorectal cancer leads to significantly higher medical costs when used early in the palliative setting. No positive effects of the use of targeted therapy could be observed in this study; therefore, we suggest that targeted therapy be used in later lines of palliative therapy in metastatic colorectal cancer.

Impact of genetic variants involved in the lipid metabolism pathway on progression free survival in patients receiving bevacizumab-based chemotherapy in metastatic colorectal cancer: a retrospective analysis of FIRE-3 and MAVERICC trials.

Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches glucose-dependent to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer (CRC). Therefore, we hypothesised that genetic variants in the lipid metabolism pathway may predict clinical outcomes [overall response rate (ORR), overall survival (OS) and progression-free survival (PFS)] in metastatic CRC (mCRC) patients receiving bevacizumab-based first-line treatment. Genomic DNA from blood samples of patients enrolled in FIRE-3 (a global, randomised, open-label, phase 3 trial, between 2007-6-23 and 2012-9-19, discovery cohort: FOLFIRI/bevacizumab arm, n=107; control cohort: FOLFIRI/cetuximab arm, n=129) and MAVERICC (a global, randomised, open-label, phase II study, between 2011-8 and 2015-7, in United States, Canada, Estonia, Ireland, Switzerland, Norway, and Portugal. Validation cohort: FOLFIRI/bevacizumab arm, n=163) trials, was genotyped using the OncoArray-500K beadchip panel. The impact on OS and PFS of 17 selected SNPs in 7 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1/2, CPT1A, FASN, ACACA) was analysed using Kaplan-Meier curves, the log-rank test for univariate analyses and likelihood ratio tests of Cox proportional hazards regression parameters for multivariable analyses. ORR and SNP associations were evaluated using Chi-square or Fisher's exact tests. In the discovery cohort, patients with FASN rs4485435 any C allele (n=21) showed significantly shorter PFS (median PFS: 8.69 vs 13.48 months) compared to carriers of G/G (n=62) in multivariable (HR=2.87; 95%CI 1.4-5.9; p=0.00675) analysis. These data were confirmed in the validation cohort in multivariable analysis (HR=2.07, 95%CI: 1.15-3.74; p=0.02), but no association was observed in the cetuximab cohort of FIRE-3. In the comparison of bevacizumab vs cetuximab arm in FIRE-3, a significant interaction was shown with FASN rs4485435 (p=0.017) on PFS. Our study demonstrates for the first time, to our knowledge, that FASN polymorphisms may predict outcome of bevacizumab-based treatment in patients with mCRC. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF treatment. This work was supported by the National Cancer Institute [P30CA 014089 to H.-J.L.], Gloria Borges WunderGlo Foundation, Dhont Family Foundation, Victoria and Philip Wilson Research Fund, San Pedro Peninsula Cancer Guild, Ming Hsieh Research Fund, Eddie Mahoney Memorial Research Fund, Shanghai Sailing Program (22YF1407000), China National Postdoctoral Program for Innovative Talents (BX20220084), China Postdoctoral Science Foundation (2022M710768), National Natural Science Foundation of China (82202892).

Bleeding and thrombotic events in patients with colorectal cancer treated with bevacizumab and receiving novel oral anticoagulants and antiplatelet medications.

104 Background: Bevacizumab is a humanized monoclonal VEGF antibody given in combination with fluorouracil-based chemotherapy for metastatic colorectal cancer (mCRC). Many patients with mCRC also have cardiovascular comorbidities requiring anticoagulation or antiplatelet therapy. The bleeding and thrombotic event rates in the setting of concurrent novel oral anticoagulants (NOACs) and bevacizumab treatment in patients with mCRC remain unclear. Methods: 462 patients with mCRC at Barnes-Jewish Hospital were identified between December 1, 2016 and December 1, 2021 and screened for concurrent treatment with bevacizumab and anticoagulant or antiplatelet therapy. Demographic and clinical information was extracted by electronic chart review. Results: 21 patients were identified who received bevacizumab and either apixaban or rivaroxaban for mCRC treatment. Aspirin was prescribed in some of these patients within 3 years of starting apixaban or rivaroxaban. Of the 13 patients who had no history of aspirin prescription, 9 were given apixaban, and 4 were given rivaroxaban while on bevacizumab. 44.4% of the patients who received apixaban experienced bleeding. All these events were epistaxis, and only 25% of the cases resulted in any treatment discontinuation. 75% of the patients who received rivaroxaban experienced bleeding events, which 33.3% of the time resulted in discontinuation of either rivaroxaban or bevacizumab. We also looked at 8 patients who had received aspirin in the last three years: 7 patients were on apixaban, and one was on rivaroxaban while on concomitant aspirin and bevacizumab. 28.6% of the patients who received apixaban with bevacizumab and aspirin experienced an adverse bleeding event that resulted in some form of treatment discontinuation. Meanwhile, the patient who received rivaroxaban with bevacizumab and aspirin experienced a bleeding event that resulted in discontinuation of a medication. No patient experienced any adverse thrombotic events. Conclusions: Patients with mCRC treated with bevacizumab and apixaban with no history of prior aspirin use within three years have a relatively low risk of developing bleeding events that warrant treatment discontinuation. The addition of NOAC to bevacizumab therapy does not appear to increase the risk of adverse thrombotic events.

Intra-arterial chemotherapy in metastatic colorectal cancer: a review of the literature and a clinical case

Intra-arterial chemotherapy in metastatic colorectal cancer: a review of the literature and a clinical case

Cost-effectiveness analysis of pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer

The aim of this study was to assess the cost-effectiveness of pembrolizumab versus chemotherapy for metastatic colorectal cancer (mCRC) patients with mismatch-repair deficiency or microsatellite instability-high (dMMR/MSI-H) in China. A partitioned survival model was constructed to determine the costs and effects of pembrolizumab and chemotherapy based on KEYNOTE-177 trial outcomes data. Health outcomes were measured in quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). The Chinese health service system perspective was considered. A willing-to-pay threshold was set at 35,832 USD/QALY, which was three times the gross domestic product (GDP) per capita of China in 2021. We examined the robustness of the model in the one-way and probabilistic sensitivity analysis. Pembrolizumab was associated with better health outcomes than chemotherapy (5.30 vs 3.37 QALYs). Compared with chemotherapy, the pembrolizumab strategy yielded an incremental cost of $16 032.57, which resulted in an ICER of $8285 per QALY. The cost of pembrolizumab and chemotherapy had the largest impact on the ICER. The parameters with less influence on the ICER were utility values of the Post-PFS state. Compared to chemotherapy, pembrolizumab had the economic advantage as the first-line treatment of mCRC patients with dMMR/MSI-H in China.

Efficacy and Safety of Xelox in Comparison with Folfox in Metastatic Colorectal Cancer

Background: The study aimed to evaluate efficacy and safety of Xelox in comparison to Folfox chemotherapy for metastatic colorectal cancer. Methods: A quasi experimental study was undertaken at the Department of Oncology, Jinnah Postgraduate Medical Center between April 2022 to November 2022. All the patients coming to oncology department JPMC with confirmed diagnosis of metastatic colorectal cancer of age 18 years and above were included. All data were recorded in a predefined proforma by the researchers. Patients’ age, gender, and comorbidity, family history, and clinical characteristics were noted. The primary endpoints were the overall response rates and the frequency of adverse effects. Results: A total of 200 patients were enrolled with a mean age of 40 ± 14.38 years. There were 100 participants in the Xelox group while 100 participants in the Folfox group. About 45 (45%) in the Xelox group and 62 (62%) in the Folfox group reported adverse effects of the chemotherapy (p=0.015). The rate of neutropenia grade III/IV was greater in the Folfox category than the Xelox. Hand foot syndrome was significantly more frequently reported in the Xelox group than the Folfox group 22 (48.89%) and 18 (29.03%); p=0.036, respectively. Oral mucositis was also more frequently reported in patients taking Xelox than Folfox [20 (44.44%) vs. 15 (24.19%); p=0.023]. There was no significant statistical difference between Xelox and Folfox in terms of patient overall response rates. Conclusion: According to the study, there are no appreciable differences between Xelox and Folfox chemotherapy in terms of overall response rates among patients with colorectal cancer. However, overall, patients taking Folfox reported significantly higher rates of adverse effects with the exception of hand foot syndrome and oral mucositis which was more frequent in the Xelox group. Keywords: colorectal carcinoma, chemotherapy, xelox, folfox, Capecitabine, Oxaliplatin, fluorouracil

LBA23 Avelumab versus standard second-line treatment chemotherapy in metastatic colorectal cancer (mCRC) patients with microsatellite instability (MSI): The SAMCO-PRODIGE 54 randomised phase II trial

Immune checkpoint inhibitors have failed in treating mCRC patients (pts) except those with MSI/dMMR tumours. However, in pts with MSI/dMMR mCRC, only one randomized trial in the first-line setting, showed the superiority of an anti-programmed death 1 (anti–PD-1) antibody over standard treatment. The SAMCO-PRODIGE 54 trial aimed to evaluate efficacy and safety of an anti-programmed death ligand-1 (anti–PD-L1) antibody compared with a standard treatment in the second-line setting in pts with MSI/dMMR mCRC.

Prognostic factors for renal function deterioration during palliative first-line chemotherapy for metastatic colorectal cancer: a retrospective study.

PurposeFirst-line choice of therapy is critical as it affects treatment decisions in later lines in patients with metastatic colorectal cancer (mCRC). We assessed changes in renal function for 1 year among patients diagnosed with mCRC who received first-line chemotherapy. We aimed to analyze the prognostic factors and effect of each chemotherapy regimen on the renal function of the patients.MethodsWe retrospectively investigated patients with mCRC who were treated with a standard triplet regimen (FOLFOX/FOLFIRI with bevacizumab/cetuximab) in the first-line setting at Korea University Anam Hospital from 2015 to 2020. We checked renal function at 3-month intervals for 12 months. We calculated changes in eGFR (△eGFR, estimated glomerular filtration rate) and compared them with clinical factors such as age, sex, chronic disease, body mass index (BMI), disease status, baseline proteinuria, and first-line chemotherapy regimen.ResultsAmong 472 patients with mCRC, the median eGFR at baseline was 90.9 mL/min/1.73 m2; it was significantly lower (80.1 mL/min/1.73 m2, p < 0.001) at 12 months after chemotherapy initiation. Particularly, the eGFR of patients treated with FOLFIRI + bevacizumab was 74.9 mL/min/1.73 m2. The 1-year incidence rate of acute kidney injury (AKI) was 9.1%, with the lowest occurrence in patients receiving FOLFOX/cetuximab (2.1%) and the highest in those receiving FOLFIRI + bevacizumab (19.2%). Renal dysfunction was more frequent with FOLFIRI + bevacizumab as compared to the other regimens. Additionally, old age, low BMI, and proteinuria at baseline were also associated with a decreased eGFR.ConclusionsThese findings can serve as important factors when selecting the first-line chemotherapy regimen for patients with mCRC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00520-022-07249-2.

PNA-Modified Liposomes Improve the Delivery Efficacy of CAPIRI for the Synergistic Treatment of Colorectal Cancer.

Tumor-associated antigen mucin 1 (MUC1) is highly expressed in colorectal cancer and is positively correlated with advanced stage at diagnosis and poor patient outcomes. The combination of irinotecan and capecitabine is standard chemotherapy for metastatic colorectal cancer and is known as XELIRI or CAPIRI, which significantly prolongs the progression-free survival and overall survival of colorectal cancer patients compared to a single drug alone. We previously reported that peanut agglutinin (PNA)-conjugated liposomes showed enhanced drug delivery efficiency to MUC1-positive liver cancer cells. In this study, we prepared irinotecan hydrochloride (IRI) and capecitabine (CAP)-coloaded liposomes modified by peanut agglutinin (IRI/CAP-PNA-Lips) to target MUC1-positive colorectal cancer. The results showed that IRI/CAP-PNA-Lips showed an enhanced ability to target MUC1-positive colorectal cancer cells compared to unmodified liposomes. Treatment with IRI/CAP-PNA-Lips also increased the proportion of apoptotic cells and inhibited the proliferation of colorectal cancer cells. The targeting specificity for tumor cells and the antitumor effects of PNA-modified liposomes were significantly increased in tumor-bearing mice with no severe cytotoxicity to normal tissues. These results suggest that PNA-modified liposomes could provide a new delivery strategy for the synergistic treatment of colorectal cancer with clinical chemotherapeutic agents.

Abstract 6112: Clinical relevance of intra-tumoral density of regulatory T cells as a predictive factor for chemotherapy response in metastatic colorectal cancer

Abstract Background: Within the tumor microenvironment, regulatory T cells (Tregs) are potent facilitators of immune tolerance, and in most solid tumors a higher proportion of Tregs compared to cytotoxic T cells predicts a worse outcome. However, the role of Tregs in colorectal cancer (CRC) is more controversial, possibly due in part to the effect of the gut microbiome on colorectal tumors. We explore the association between colorectal cancer (CRC) Treg density, cancer biology, and clinical outcome. The aim of the study is to investigate the clinical relevance of the fraction of Tregs within the colorectal cancer TME using xCell score with mRNA expression data across several CRC cohorts. Methods: We used xCell to estimate intra-tumoral Tregs in 898 CRC patients in the Cancer Genome Atlas (TCGA) and GCE39582 cohorts. into two groups based on high versus low proportions of Tregs. We studied the correlation between intra-tumoral Treg density and cancer biology including host immune response, ICM expression, and the tumor microbiome by comparing gene ex-pression between the two groups. We further examined two CRC cohorts which contained data on response to neoadjuvant chemotherapy using mFOLFOX6 and bevacizumab, in order to explore the association between Treg infiltration and response to treatment. Results: High-Treg CRCs enriched immune response-related gene sets; inflammatory response, IFN-γ and IFN-α response, IL2/IL6 signaling, and allograft rejection, and had significantly high infiltration of CD8, CD4, M1/M2 macrophage, and dendritic cells in both cohorts. While high-Treg CRCs enriched multiple pro-cancer signaling pathways compared to low-Treg CRCs, such as Epithelial Mesenchymal Transition, K-ras, Hypoxia, TGF-β, TNF-α, and angiogenesis, Treg infiltration was surprisingly associated with earlier CRC stage in TCGA. Metastatic CRCs with more Tregs showed a significantly better response to mFOLFOX6 versus low-Treg CRC metastases (88.9% response vs. 16.7%, p &amp;lt; 0.001). Finally, high-Treg CRCs were associated with increased expression of immune check-point molecules PD-L1/PD-L2, CTLA4, TIGIT and BTLA, implying susceptibility to immunotherapy. Conclusion: We show that unlike in other cancers, Tregs in CRC are not necessarily a marker of poor prognosis. High-Treg CRC enriched not only cancer aggravating gene sets, such as EMT, KRAS, TGF-β and angiogenesis, but also immune response-related gene sets, which is consistent with high infiltration of anti-cancerous immune cells. High Treg density was a predictor of response to chemotherapy in metastatic CRC. Citation Format: Masanori Oshi, Joy Sarkar, Rongrong Wu, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Clinical relevance of intra-tumoral density of regulatory T cells as a predictive factor for chemotherapy response in metastatic colorectal cancer [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 6112.

A single center phase 2 study of anti-PD-1 antibody plus bevacizumab and FOLFIRI as second-line treatment for patients with MSI-H metastatic colorectal cancer.

e15541 Background: The therapeutic efficacy of second-line chemotherapy for metastatic colorectal cancer (mCRC) is low. Immunotherapy is suitable for MSI-H mCRC, but the efficacy of single-drug immunotherapy is still unsatisfactory. We investigated to combine immunotherapy with bevacizumab and FOLFIRI as second-line treatment for these patients. Methods: This single center exploratory phase 2 study enrolled adults patient with histologically confirmed metastatic colorecal adenocarcinoma, who were failure of oxaliplatin-based chemotherapy as first-line therapy. Patients receive FOLFIRI (iritecan 180mg/m2, leucovorin 400mg/m2, fluorouracil 400mg/m2 bolus, fluorouracil 2400mg/m2 46-48 hours), anti-PD-1 antibody (Nivolumab 240mg, or Pembromab 200mg, or Terriprizumab 240mg), and bevacizumab (5mg/kg). Maintenance therapy was allowed using PD-1, bevacizumab and/or fluorouracil. An-PD-1 antibody is given for up to 24 months. Results: Between November 29,2018 and January 15, 2021, a tolal of 8 patients were enrolled in our study. There were 3 femles and 5 males, and the median age was 39.5 years old. Among 8 patients who were evaluated, complete resonse (CR) was obtained in 3 cases, partial response (PR) was observed in 3 cases, and stable disease (SD) in 2 cases. Objective response rate was 75%, and disease control rate was 100%. The median PFS and the median overal survival have not yet been reached. The most common adverse events (AE) were alopecia (87.5%), nausea (75%), vomit (50%), hypothyroidism (50%), leukopenia (37.5%), hypertension (25%) and proteinuria (25%). Most of the AEs were grade 1 or 2, and the most common grade 3 or 4 treatment-related AE was hypertension (25%). Conclusions: Anti-PD-1 antibody plus bevacizumab and FOLFIRI demonstrated promising activity as second-line treatment for patients with MSI-H metastatic colorectal cancer. Clinical trial information: NCT05035381.