Inoperable Metastatic Colorectal Cancer Research Articles

First-Line LV5FU2 with or without Aflibercept in Patients with Non-Resectable Metastatic Colorectal Cancer: A Randomized Phase II Trial (PRODIGE 25-FFCD-FOLFA).

Fluropyrimidine monotherapy is an option for some patients with inoperable metastatic colorectal cancer. Unlike bevacizumab, the addition of aflibercept, an antibody acting as an anti-angiogenic agent, has never been evaluated in this context. The aim of the study was to determine whether aflibercept could increase the efficacy of fluoropyrimidine monotherapy without increasing toxicity. This multicenter phase II non-comparative trial evaluated the addition of aflibercept to infusional 5-fluorouracil/folinic acid (LV5FU2 regimen) as first-line treatment in patients unfit to receive doublet cytotoxic chemotherapy. The primary endpoint was 6-month progression-free survival (PFS). The clinical hypotheses expected a PFS rate at 6 months of over 40% (60% expected). A total of 117 patients, with a median age of 81 years, were included: 59 in arm A (LV5FU2-aflibercept) and 58 in arm B (LV5FU2 alone). Six-month PFS was 54.7% in both arms (90% CI 42.5-66.5 in both). Median overall survival was 21.8 months (arm A) and 25.1 months (arm B). Overall toxicity was more common in arm A: grade ≥ 3 toxicity in 82% versus 58.2%. Given the 6-month PFS, the study can be considered positive. However, the toxicity of aflibercept in this population was high, and continuation of the trial into phase III is not envisaged.

Vertical level of blood cell division cycle 42 predicts response and survival benefits to PD-1 inhibitor-based regimen in metastatic colorectal cancer patients

Cell division cycle 42 (CDC42) regulates the development of colorectal cancer (CRC) by modulating cancer malignant behaviors and facilitating immune escape. Hence, this study aimed to explore the correlation of blood CDC42 with treatment response and survival benefit to programmed cell death-1 (PD-1) inhibitor-based regimens in inoperable metastatic CRC (mCRC) patients. Fifty-seven inoperable mCRC patients who received PD-1 inhibitor-based regimens were recruited. The CDC42 in peripheral blood mononuclear cell (PBMC) was detected using RT-qPCR in inoperable mCRC patients at baseline and after 2-cycle treatment. Besides, PBMC CDC42 in 20 healthy controls (HCs) was also detected. CDC42 was higher in inoperable mCRC patients compared to HCs (p < 0.001). Elevated CDC42 was related to a higher performance status score (p = 0.034), multiple metastatic sites (p = 0.028), and the presence of liver metastasis (p = 0.035) in inoperable mCRC patients. During the 2-cycle treatment, CDC42 was reduced (p < 0.001). Higher CDC42 at baseline (p = 0.016) and after 2-cycle treatment (p = 0.002) were both linked with decreased objective response rate. CDC42 high at baseline was related to shorter progression-free survival (PFS) (p = 0.015) and overall survival (OS) (p = 0.050). Moreover, CDC42 high after 2-cycle treatment was also related to unfavorable PFS (p < 0.001) and OS (p = 0.001). After adjustment using multivariate Cox’s analyses, CDC42 high after 2-cycle treatment independently related to shorter PFS (hazard ratio (HR): 4.129, p < 0.001), and CDC42 reduction ≤230% also independently correlated with shorter OS (HR: 4.038, p < 0.001). The longitudinal change of blood CDC42 during PD-1 inhibitor-based regimen estimates treatment response and survival in inoperable mCRC patients.

439TiP A phase II (ph2), randomized study of magrolimab with bevacizumab and FOLFIRI in previously treated patients with advanced inoperable metastatic colorectal cancer (mCRC)

For patients (pts) with mCRC who are ineligible/unable to derive benefit from novel targeted therapies or immunotherapies, standard of care (SOC) doublet or triplet chemotherapy-based regimens associated with toxicity and limited responses are the only available treatment options. Magrolimab is an antibody blocking CD47, a “don’t eat me” signal on cancer cells, resulting in tumor phagocytosis by macrophages and nonclinical activity in hematologic and solid tumor malignancies. Chemotherapeutic agents can enhance prophagocytic signals on tumor cells, leading to the potential for synergistic antitumor activity with magrolimab. This study is evaluating the safety, tolerability, and efficacy of magrolimab with bevacizumab + FOLFIRI in advanced inoperable mCRC. This ph2, randomized, open-label study consists of safety run-in and ph2 cohorts. Eligible pts (≥18 y) progressed on or after 1 prior systemic therapy with chemotherapy based on 5-FU with oxaliplatin and bevacizumab. Magrolimab is administered intravenously with an initial 1-mg/kg priming dose to mitigate on-target anemia, followed by a 30-mg/kg dose during cycle 1 (28-day cycles) in the safety run-in to determine a recommended ph2 dose (RP2D) and evaluate pharmacokinetics and immunogenicity. In ph2, pts will be randomized 2:1 to magrolimab in combination with bevacizumab + FOLFIRI vs bevacizumab + FOLFIRI. After the magrolimab priming dose on day (D)1, the RP2D will be administered weekly starting on D8 for the next 6 doses, followed by every other week. Bevacizumab is administered at 5 mg/kg on D1 and D15 each cycle. FOLFIRI is administered per SOC on D1, D2, D15, and D16 of each cycle. Pts may continue treatment until unacceptable toxicity, progressive disease by RECIST 1.1, or pt/investigator choice. Primary endpoints include incidence of dose-limiting toxicities and adverse events (safety run-in) and PFS by investigator (ph2). Secondary endpoints include magrolimab concentration vs time, antidrug antibodies (safety run-in), objective response rate, PFS by independent central review, duration of response, and overall survival (ph2). NCT05330429. Gilead Sciences Inc.

Survival and prognostic association in stage IV colorectal cancer patients treated with chemotherapy in Bangladesh.

Prognostic factors in colorectal cancer have lesser been evaluated in developing countries. This study aims to determine overall survival and prognostic factors for metastatic colorectal cancer patients who were non-operable and received chemotherapy. The study retrospectively investigated 67 inoperable metastatic colorectal cancer patients at Square Hospital, Bangladesh. The primary endpoint was overall survival, and the secondary endpoints were prognostic association with factors. Survival probabilities were calculated by non-parametric Kaplan-Meier method and compared by log-rank test. Univariate and multivariable Cox proportional hazard models were implemented to assess the prognostic association. Median survival of the entire cohort was 14months (95% confidence interval: 11-25). In multivariable analysis, two prognostic factors were independently associated with survival: Karnofsky performance status and carcinoembryonic antigen. Patients with Karnofsky performance status <70 had significant higher risk of death than those with Karnofsky performance status ≥70 (adjusted hazard ratio 4.25, 95% confidence interval: 2.15-8.39). Higher risk of death was found to be associated with higher carcinoembryonic antigen: adjusted hazard ratio was 1.72 (95% confidence interval: 0.81-3.68) and 2.96 (95% confidence interval: 1.25-7.01) for patients with carcinoembryonic antigen 10-100 and >100ng/ml, respectively, while comparing with carcinoembryonic antigen <10ng/ml. The presence of peritoneal metastasis and grade-III tumour significantly worsened the survival in univariate analysis (hazard ratio 2.46, 95% confidence interval: 1.32-4.57 and hazard ratio 1.74, 95% confidence interval: 1.01-3.03, respectively) but not in multivariable analysis (adjusted hazard ratio 1.92, 95% confidence interval: 0.88-4.18 and adjusted hazard ratio 1.25, 95% confidence interval: 0.66-2.36, respectively). The study reported survival of stage IV colorectal cancer patients undergo chemotherapy and identified that Karnofsky performance status and carcinoembryonic antigen are the poor prognostic factors to this cohort adjusting for other factors.

First-line therapy for metastatic colorectal cancer: Current perspectives and future directions.

The prognosis for patients with newly diagnosed inoperable metastatic colorectal cancer has steadily improved over the past two decades as new agents have been introduced into clinical practice and many new biomarkers have been discovered. In parallel with this progress, clinicians face increasingly complex treatment decisions. This review summarizes recent progress, with a historical perspective, which should help guide the clinician in decision making and optimal therapy selection. This review not only focuses on important and readily identifiable subsets, including primary tumor side and v-RAF murine sarcoma viral oncogene homologue B (BRAF) mutations, but also discusses rarer molecular subgroups that may be important for determining treatment in the future.

MVA-5T4 immunotherapy and low-dose cyclophosphamide for advanced colorectal cancer (TaCTiCC): An open-label, randomized phase I/II trial.

154 Background: Current immunotherapies including checkpoint inhibitors and vaccines for advanced colorectal cancer (CRC) have been largely ineffective. We hypothesized that combining an MVA-based vaccine targeting the tumor-associated antigen 5T4 (TroVax) with low-dose cyclophosphamide to deplete Foxp3+regulatory T-cells (Tregs), could improve immunological responses and patient outcomes. Methods: In this open-label phase I/II clinical trial, TaCTiCC (TroVax and Cyclophosphamide Treatment in Colorectal Cancer) 53 patients with inoperable metastatic CRC were randomized to receive either no treatment (group 1, n=8), metronomic low-dose CPM (50mg B.D. during treatment weeks 1&amp;3; group 2, n=9), TroVax only (6 i.m. injections weeks 4 to 16, group 3, n=18), or low-dose CPM followed by TroVax (group 4, n=18). The primary endpoint was boosted anti-5T4 responses at week 7, as measured by increased T-cell and antibody responses; secondary endpoints included progression-free (PFS)/overall survival (OS), and anti-5T4 responses over the trial period. Results: CPM depleted Tregs in 21/27 patients during treatment week 3 (p=0.0045), resulting in significantly prolonged PFS amongst groups 2&amp;4 over group 1 (5.0 vs. 2.5 months, HR=0.17 95% CI 0.048-0.62, p=0.0072). TroVax induced a &gt;2-fold increase in anti-5T4 immune responses in 15/36 group 3&amp;4 patients; these patients experienced significantly prolonged median PFS (6.5 vs. 2.4 months, HR 0.31 95% CI 0.14-0.65, p=0.0022) and OS (20 vs. 12 months, HR=0.37 95% CI 0.17-0.82, p=0.014). Combination of CPM &amp; TroVax was not significantly superior. The primary endpoint at a single timepoint was not met since CPM-induced responses declined by week 7, and TroVax-induced responses were greatest at weeks 10-16. No serious adverse events were reported. Conclusions: Both CPM and TroVax induced highly beneficial anti-tumor immune responses resulting in significantly prolonged survival of end-stage CRC patients without toxicity. This is the first study to show a clear benefit of immunotherapy in advanced CRC, and suggests this approach may be superior (and less toxic) to continuous palliative chemotherapy in these patients. Clinical trial information: 54669986.

Maintenance strategy in metastatic colorectal cancer: A systematic review.

Colorectal cancer is the third most common cancer in men and second in women, estimated to cause 694,000 deaths worldwide in 2012. Although 5-year survival rate of CRC has increased, inoperable metastatic colorectal cancer (mCRC) is almost always fatal. The aim of this systematic review is to outline the maintenance strategies that increase the chance and duration of survival with less toxicity and sustained quality of life. Literature search in PubMed, in American Society of Clinical Oncology (ASCO) Annual Meetings and in ASCO Gastrointestinal Symposia and European Society for Medical Oncology (ESMO) Congresses was performed. Studies conducted in adult patients were written in English language and were published in peer-reviewed journals as phase II or III randomized controlled trials (RCTs) comparing continuous chemotherapy to intermittent chemotherapy, each with or without maintenance therapy was included along with at least one of the outcomes of interest. Twenty randomized controlled trials and systematic reviews were included from Medline search, together with 4 abstracts from ASCO meetings and 2 abstracts from ESMO meetings. Existing evidence-based data show that prolonged progression free survival (PFS) can be achieved with less toxic regimens compared to complete drug holidays or continued treatment. However, the impact of maintenance on overall survival is less clear. The specific data for maintenance with biological agents are evolving, while in general fluoropyrimidine based maintenance with bevacizumab is better than Bev alone or observation for PFS. Data regarding Cetuximab maintenance are less pronounced than that of Bev maintenance. Preliminary data show that erlotinib-Bev combination may be of benefit as maintenance. Although maintenance may provide significant clinical benefit in clinical studies, the optimal strategy should still be individualized.

2144 High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab

2144 High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab

High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab.

To assess the levels of D-dimer baseline levels in inoperable metastatic colorectal cancer (mCRC) patients treated with bevacizumab and its relationship with prognosis. From June 1, 2011 to December 31, 2013, a total of 121 patients with mCRC received beacizumab combined with chemotherapy and 74 of them were included in the present study. A nonparametric statistical test was performed to analyze the relationship between plasma D-dimer levels and clinical pathological factors. The Cox proportional model was used to analyze the effects of D-dimer on progression-free survival (PFS) time and overall survival (OS). Of the 74 cases, 40 were men and 34 women (aged 31-74 years), with a median age of 55.5 years. The median of PFS and OS were 6.3 and 17.8 months respectively. High levels of baseline plasma D-dimer were correlated with high scoring of Eastern Cooperative Oncology Group-Performance Status (P = 0.001), IV phase of disease at the first visit (P = 0.001), unremoval primary focal (P = 0.006), the number of metastatic organs ≥ 2 (P = 0.034), abdominal cavity effusion (P = 0.004) and no history of adjuvant chemotherapy (P = 0.003). It was found by single factor analysis that plasma baseline D-dimer levels ≥ 1.9 μg/mL were closely related with a short PFS (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.04-4.40, P = 0.038) and OS (HR 5.22, 95% CI 2.05-13.28, P = 0.001). After adjustment for other factors, plasma baseline D-dimer levels ≥ 1.9 μg/mL were still closely correlated with a short OS (HR 3.52, 95% CI 1.28-9.67, P = 0.015). High levels of plasma baseline D-dimer correlated with high tumor load, advanced disease status and poor prognosis of inoperable mCRC patients treated with bevacizumab. However, clinical research on a much larger cohort of patients will be required to verify these findings.

P-0243 - A Single Centre Experience of Bevacizumab in Combination with Chemotherapy for First Line Treatment of Inoperable Metastatic Colorectal Cancer

P-0243 - A Single Centre Experience of Bevacizumab in Combination with Chemotherapy for First Line Treatment of Inoperable Metastatic Colorectal Cancer

FOLFOX-4 Regimen as a First-line Therapy for Cuban Patients with Metastatic Colorectal Cancer

Introduction In Cuba, colorectal cancer (CRC) is the malignant neoplasm with the fourth-highest incidence and third-highest mortality. Over one-third of CRC patients exhibit metastatic disease at the time of diagnosis. Standard treatment for metastatic CRC is a 5-fluorouracil (5-FU) + Folinic Acid (FA) continuous infusion regimen. International studies have shown, however, that systemic therapy using oxaliplatin combined with 5-FU and FA (FOLFOX-4) improves results in terms of both tumor response and survival in patients with inoperable metastatic CRC. Objective Evaluate the FOLFOX-4 regimen as a first-line therapy for patients with inoperable metastatic CRC in Cuba. Methods FOLFOX-4 therapy was administered to 56 patients with metastatic CRC, in a treatment cycle repeated every 2 weeks for 6-8 cycles. Patients were followed up for a period of 2 years. Results Objective response was attained in 44.6% of patients, and complete response in 12.5%. Median duration of response and of progression-free survival was 9.6 and 8.9 months, respectively. Estimated survival at 2 years was 17% (95% CI: 6.89-26.8). The most frequent adverse events were nausea, vomiting, diarrhea and neutropenia, the majority grade 1-2, according to Common Terminology Criteria for Adverse Events (CTCAE) classification. Conclusions In patients studied, the FOLFOX-4 combination was shown to be an effective and well-tolerated therapeutic option for treating inoperable metastatic colorectal cancer.

Metro-FOLFIRI as first line chemotherapy in metastatic colorectal cancer (MCRC). Preliminary report of a phase II trial

3722 Background: FOLFIRI regimen is standard therapy in MCRC. Angiogenesis is a critical step in the metastatic process of colorectal cancer. New agents with antiangiogenic effect showed to be active in MCRC. In preclinical studies irinotecan demonstrated to have at metronomic dose (1/6 standard dose) antiangiogenic activity. For these reasons we carried out this pilot study in order to evaluate the safety and the activity of metronomic FOLFIRI regimen as first line chemotherapy in inoperable MCRC. Methods: From 10/03 to 10/04 we treated 26 pts (14M 12F), median age 66 years (range 41–77) with this mixed FOLFIRI schedule: CPT-11 10 mg/mq days 1, 7, 10 and CPT-11 150 mg/mq day 2, Folinic Acid 100 mg/mq days 2 and 3, 5-FU 400 mg/mq bolus days 2 and 3 and 5-FU 600 mg/mq 44 hours c.i. days 2 and 3 every two weeks for a maximum of 12 cycles. Results: All pts are evaluable for toxicity and 22 for activity. The chemotherapy was well tolerated; no toxic deaths occurred, no therapy ended for toxicity. 3 pts had 25% reduction dose for diarrhea G4 after the first cycle. The main toxicities recorded on a total of 173 cycles (cy) delivered were: diarrhea G4 1.7% and G3 2.3% of the cy. Neutropenia G3 5.8% and vomiting G3 0.5% of the cy. Anemia G2 was recorded in 7 pts. All pts suffered from partial alopecia and half of the pts from mild oral mucositis. As regard activity we registered 3 CR (13.6%), 9 PR (40.9%), 7 SD (31.8%) and 3 PD (13.6%). Before start therapy and after 4th, 8th and 12th cycle we collected blood samples of the pts in order to evaluate sVEGF modifications in relation to objective response. These data will be presented. Conclusions: Metro-FOLFIRI regimen appears to be safe and active in MCRC. No significant financial relationships to disclose.

Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741

Fluorouracil (5-FU), oxaliplatin and irinotecan combinations improve time to tumor progression (TTP), objective response and overall survival (OS) in patients with metastatic colorectal cancer (MCRC). Here we identify and describe patients treated on Intergroup study N9741 who initially had inoperable MCRC, but who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease. Patient research records in study arms (A) irinotecan/5-FU/leucovorin (LV) (IFL, n = 264), (F) oxaliplatin/5-FU/LV (FOLFOX4, n = 267) and (G) oxaliplatin/irinotecan (IROX, n = 265) were reviewed. TTP and median OS were calculated. Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection [hepatectomy, 16; radiofrequency-ablation (RFA), six; lung resection, two]. Twenty-two out of 24 (92%) resected patients received an oxaliplatin-based regimen (FOLFOX4, 11; IROX, 11). Seven patients (29.2%) remain disease-free; relapses occurred mainly in the resected organ. Median OS in resected patients is 42.4 months, and median TTP is 18.4 months. All six patients treated with RFA have recurred. Four out of five (80%) patients who received chemotherapy following resection are disease-free. Resection of metastatic disease after chemotherapy is possible in a small but important subset of patients with MCRC, particularly after receiving an oxaliplatin-based chemotherapy regimen, with encouraging OS and TTP observed in these highly selected patients.

Intravenous Weekly High-Dose Infusion of 5-Fluorouracil and Folinic Acid in Pretreated Patients with Metastatic Colorectal Cancer

<i>Background: </i>Effective second-line treatments of inoperable metastatic colorectal cancer are rare. Therefore, the efficacy and toxicity of weekly intravenous high-dose infusions of 5-fluoro-uracil (5-FU) and folinic acid (FA) in pretreated patients with metastatic colorectal cancer were evaluated. <i>Patients and Methods: </i>In 32 patients, 580 applications of an intravenous high-dose infusion of 5-FU/FA were administered. All patients had been pretreated. Thirty patients had received hepatic arterial (n = 8) or intravenous infusions (n = 22) of 5-FU/FA and 2 patients, hepatic arterial infusions of 5-fluorodeoxyuridine (FUdR). The high-dose chemotherapy regimen consisted of a weekly intravenous infusion of FA (500 mg/m²) over 1 h, immediately followed by a continuous intravenous infusion of 5-FU over 24 h. The starting dose of 5-FU was 2,400 mg/m². One course consisted of 12 weekly applications, interrupted by 1 week after 6 applications and by 4 weeks after 12 applications. <i>Results: </i>Diarrhea, nausea, and vomiting were the most frequent manifestations of toxicity. Two patients experienced WHO grade IV diarrhea, 15 patients experienced one episode of WHO grade III diarrhea. Hematological toxicity was never observed. Partial remission was observed in 11/32 patients (34%) and disease stabilization in 9/32 patients (28%), while the disease progressed in 12/32 patients (38%) under intravenous high-dose 5-FU with FA. The median overall survival was 22 months after start of first-line treatment and 12 months after initiation of 24-hour high-dose treatment. <i>Conclusion: </i>5-FU given as an intravenous 24-hour high-dose infusion with FA is well tolerated and produced a further response in progressive patients who were refractory to regional or conventional intravenous 5-FU/FA treatment. Therefore, we recommend that this treatment should be further studied in patients with metastatic colorectal cancer whose disease progressed under conventional pretreatment.