Addition of bevacizumab to compensate for the negative influence of attenuated relative dose intensity of cytotoxic agents on the outcome in patients with metastatic colorectal cancer.

e14614 Background: We reported that relative dose intensity (RDI) of key cytotoxic agents, irinotecan (IRI) and oxaliplatin (OX), is a significant predictor of disease control in patients with metastatic colorectal cancer (mCRC). However, in concomitant therapy with bevacizumab (BEV), the influence of adding BEV on the relation between RDI of cytotoxic agents and outcomes are unclear. In this study, we evaluate the impact of BEV on RDI of IRI and OX-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into three prospective clinical trials, testing FOLFIRI (CCOG-0502), mFOLFOX6 (CCOG-0704), FOLFIRI plus BEV and mFOLFOX6 plus BEV (CCOG-0801), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In FOLFIRI therapy, higher RDI (IRI, >median: 80%) group achieved significant better RR, DCR and PFS than lower RDI (<median) group (RR: 65 vs. 6% [p=0.001], DCR: 100 vs. 41% [p=0.003] and PFS: 9.9 vs. 5.6 months [p=0.002]). The other hand, in FOLFIRI plus BEV therapy, there were no difference between higher and lower RDI (IRI, median: 76%) group in ORR, DCR and PFS (RR: 31 vs. 27% [p=0.779], DCR: 75 vs. 53% [p=0.208] and PFS: 6.2 vs. 7.3 months [p=0.903]). In mFOLFOX6 therapy, higher RDI (OX, >median: 79%) group achieved better disease control than lower RDI group (RR: 47 vs. 33% [p=0.456], DCR: 100 vs. 73% [p=0.032] and PFS: 8.5 vs. 6.2 months [p=0.064]). In addition of BEV, there were no difference between higher and lower RDI (OX, median: 76%) group in any outcomes (RR: 54 vs. 74% [p=0.159], DCR: 88 vs. 91% [p=0.672] and PFS: 11.6 vs. 11.7 months [p=0.797]). Conclusions: RDI of key cytotoxic agents is a significant predictor of disease control, especially in IRI-based regimen. Nevertheless, in concomitant therapy with BEV, there were no relations between RDI of cytotoxic agents and outcomes. These results suggest that BEV could have ‘covering effect’ to reduce the influence of dose modification of cytotoxic agents in mCRC patients.

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Impact of relative dose intensity on the outcome of metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.508 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 508-508 ◽

Cited By ~ 1

Author(s):

Goro Nakayama ◽

Takahiro Asada ◽

Naomi Hayashi ◽

Chie Tanaka ◽

Suguru Yamada ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Control ◽

Metastatic Colorectal Cancer ◽

Standard Dose ◽

Objective Response ◽

Dose Intensity ◽

Cytotoxic Agents ◽

Relative Dose Intensity ◽

Lower Group ◽

Delivered Dose

508 Background: Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. There is established evidence supporting the significance of RDI in patients with various cancer, however data in patients with metastatic colorectal cancer (mCRC) are limited. In this study, we evaluate the significance of RDI of irinotecan and oxaliplatin-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into two prospective clinical trials, testing FOLFIRI (CCOG-0502) and mFOLFOX6 (CCOG-0704), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Results: The median RDI of irinotecan in FOLFIRI and oxaliplatin in mFOLFOX6 were 80% and 79%. ORRs In higher RDI (>median) group and lower RDI (<median) group were 64.7% and 5.9% of irinotecan (p=0.001), and 46.7% and 33.3% of oxaliplatin (p=0.456). DCRs in higher and lower group were 100% and 41.2% in FOLFIRI (p=0.003), and 100 and 73.3% in mFOLFOX6 (p=0.032). PFS in higher and lower group were 9.9 and 5.6 months in FOLFIRI (p=0.002), and 8.5 and 6.2 months in mFOLFOX6 (p=0.064). Conclusions: RDI of key cytotoxic agents is a significant predictor of disease control in patients with mCRC, especially in irinotecan-based regimen. Dose reductions and treatment delays could be minimized to achieve an RDI of at least 80%.

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Survival and relative dose intensity of 5-fluorouracil, oxaliplatin and irinotecan in real-life treatment of metastatic colorectal cancer

Współczesna Onkologia ◽

10.5114/wo.2020.100222 ◽

2020 ◽

Vol 24 (3) ◽

pp. 150-156

Author(s):

Ilfad Blazevic ◽

Willy Vaillant ◽

Maud Basso ◽

Karine Salignon

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Real Life ◽

Dose Intensity ◽

Relative Dose Intensity

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The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

Cancers ◽

10.3390/cancers13010137 ◽

2021 ◽

Vol 13 (1) ◽

pp. 137

Author(s):

Gianluca Mauri ◽

Erica Bonazzina ◽

Alessio Amatu ◽

Federica Tosi ◽

Katia Bencardino ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Mapk Pathway ◽

Treatment Options ◽

Braf Inhibitor ◽

Current Treatment ◽

Cytotoxic Chemotherapy ◽

Cytotoxic Agents ◽

Poor Prognostic Factor

The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

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Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211017973 ◽

2021 ◽

pp. 107815522110179

Author(s):

Olivia R Court

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Dose Reduction ◽

Progression Free Survival ◽

Electronic Patient Records ◽

Free Survival ◽

Length Of Treatment ◽

Common Grade ◽

Grade 3 ◽

The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

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Colorectal Cancer Biomarkers in the Era of Personalized Medicine

Journal of Personalized Medicine ◽

10.3390/jpm9010003 ◽

2019 ◽

Vol 9 (1) ◽

pp. 3 ◽

Cited By ~ 9

Author(s):

Jai Patel ◽

Mei Fong ◽

Megan Jagosky

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Therapy Response ◽

Dose Intensity ◽

Cancer Biomarkers ◽

Clinical Implications ◽

Test Results ◽

First Line ◽

Genomic Markers ◽

Generation Sequencing

The 5-year survival probability for patients with metastatic colorectal cancer has not drastically changed over the last several years, nor has the backbone chemotherapy in first-line disease. Nevertheless, newer targeted therapies and immunotherapies have been approved primarily in the refractory setting, which appears to benefit a small proportion of patients. Until recently, rat sarcoma (RAS) mutations remained the only genomic biomarker to assist with therapy selection in metastatic colorectal cancer. Next generation sequencing has unveiled many more potentially powerful predictive genomic markers of therapy response. Importantly, there are also clinical and physiologic predictive or prognostic biomarkers, such as tumor sidedness. Variations in germline pharmacogenomic biomarkers have demonstrated usefulness in determining response or risk of toxicity, which can be critical in defining dose intensity. This review outlines such biomarkers and summarizes their clinical implications on the treatment of colorectal cancer. It is critical that clinicians understand which biomarkers are clinically validated for use in practice and how to act on such test results.

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Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

Gastroenterology Research and Practice ◽

10.1155/2016/9189483 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

R.-D. Hofheinz ◽

U. Ronellenfitsch ◽

S. Kubicka ◽

A. Falcone ◽

I. Burkholder ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Optimal Sequence ◽

Primary Endpoints ◽

Disease Stabilization ◽

Antiangiogenic Drugs ◽

The Impact

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis.Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression.Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58).Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

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Regorafenib plus PD-1 inhibitors in Chinese patients with microsatellite stable/mismatch repair proficient metastatic colorectal cancer: A real-world study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15585 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15585-e15585

Author(s):

Kaili Yang ◽

Lu Han ◽

Yun-Bo Zhao ◽

Yang Ge ◽

Qin LI ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Disease Control ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Real World ◽

Objective Response ◽

Disease Control Rate ◽

Chinese Patients ◽

Hand Foot Syndrome

e15585 Background: A previous phase 1b trial has shown encouraging efficacy of regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). We aimed to evaluate the efficacy and safety of this regimen in Chinese patients in the real world. Methods: We retrospectively identified patients with MSS/pMMR mCRC who received at least one dose of programmed cell death-1 (PD-1) inhibitors plus regorafenib from 5/2019 to 2/2021 in 10 Chinese medical centers. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the safety. Results: Fifty-two patients were identified. Liver metastases were presented in 35 patients (67%). A total of 48 patients (92%) received regorafenib plus a PD-1 inhibitor as the third or later line treatment. At the data cut-off, 11 patients (21%) were still on treatment. Other patients terminated treatment because of progressive disease (45%), treatment-related adverse events (TRAEs) (14%) or treatment-unrelated deaths (6%). The median treatment cycle was 3 (range, 1-18). At a median follow-up of 4.9 months, the median OS was 17.3 months (95% CI, 10.2-NR) and the median PFS was 3.1 months (95%CI, 2.5-6.0). Baseline liver metastases were associated with inferior PFS (2.7 versus 6.3 months, p <0.05), but not OS (17.3 months versus NR, p =0.6). Among 38 patients evaluable for response, two patients (5%) achieved partial response, and 17 patients (45%) experienced stable disease as the best response. The DCR was 50% (95%CI, 5.0-NR) and was similar among different PD-1 inhibitors (Table). TRAEs were observed in 30 patients (58%). Fatigue (21%), hand-foot syndrome (19%) and rash (13%) were the most common TRAEs. Eight patients (15%) experienced grade 3-4 TRAEs, including rash (n=3), hand-foot syndrome (n=2), hypertension (n=1), myocardial enzyme elevation (n=1) and visual field loss (n=1). No treatment-related death occurred. Conclusions: The combination of regorafenib plus PD-1 inhibitors was generally tolerated and exhibited potential benefit in terms of OS and DCR. The presence of baseline liver metastases was predictive for shorter PFS but requires further investigation. Disease control rate of different PD-1 inhibitors.[Table: see text]

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Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer

Cancers ◽

10.3390/cancers14020406 ◽

2022 ◽

Vol 14 (2) ◽

pp. 406

Author(s):

Quang Loc Bui ◽

Léo Mas ◽

Antoine Hollebecque ◽

David Tougeron ◽

Christelle de la Fouchardière ◽

...

Keyword(s):

Colorectal Cancer ◽

Disease Control ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Immune Checkpoints ◽

Repair Deficiency ◽

Improved Outcomes ◽

Number Of Patients ◽

Tumor Types

Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

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The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis

10.21203/rs.2.18346/v1 ◽

2019 ◽

Author(s):

Li-Na Zhou ◽

Li-Qiang Weng ◽

Chun-Xia Feng ◽

Yan Zhang ◽

Ping Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Platelet Count ◽

Liver Fibrosis ◽

Metastatic Colorectal Cancer ◽

Medical Records ◽

Chemotherapy Regimen ◽

Splenic Enlargement ◽

History Of ◽

Colorectal Cancer Patients ◽

The Impact

Abstract Background: People suffer from schistosomiasis, leading to liver fibrosis, splenomegaly and thrombocytopenia. The effects of bevacizumab plus oxaliplatin or irinotecan-based chemotherapy regimens on platelets are different, but have not been determined. We conducted a retrospective analysis in metastatic colorectal cancer (mCRC) patients evaluating the impact of bevacizumab on platelet, in order to find a more suitable plan for mCRC patients with a history of schistosomiasis.Methods: The medical records of all mCRC patients with a history of schistosomiasis who received FOLFOX or FOLFIRI with or without bevacizumab from September 1, 2017 to June 30, 2019 in Kunshan Hospital were reviewed. Platelet counts and spleen sizes were compared from the first cycle until completion of chemotherapy.Results: Evaluable splenic enlargement and thrombocytopenia results were obtained from 73 Bevacizumab-treated patients and 80 non-bevacizumab treated patients. In patients treated with oxaliplatin, the rates of splenic enlargement (19.5% vs. 66.7%, P=0.01) and thrombocytopenia (31.7% vs. 77.2%, P=0.02) were lower in the bevacizumab-treated cohort than that in the nonbevacizumab cohort. When stratified for irinotecan, there were no statistical differences of frequency of splenic enlargement between the two groups, however, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the nonbevacizumab cohort (59.4% vs. 8.7%, P=0.01 ).Conclusion: The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for mCRC patients with a history of schistosomiasis, especially for lower platelet count patients.

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