Unresectable Metastatic Colorectal Cancer Research Articles

Tolerability on Serious Adverse Events of First-Line Bevacizumab and Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

Proper medication management is crucial in metastatic colorectal cancer because of its substantially low survival rate. There has been advancing evidence on the efficacy of the two most prescribed targeted agents (bevacizumab and cetuximab); however, comprehensive analyses on their safety are limited. This study aims to comprehensively assess the clinical safety of first-line bevacizumab and cetuximab-based chemotherapy in unresectable RAS wild-type metastatic colorectal cancer patients and to provide guidance on the selection of appropriate targeted therapeutic agents. Keyword searches of MEDLINE, Cochrane Library, and ClinicalKey were conducted per PRISMA guidelines. We performed pooled analysis on safety outcomes from six studies which administered FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) as backbone chemotherapy. Thirty different adverse events from six categories were compared. First-line bevacizumab-based chemotherapy substantially lowered the risks of adverse events related to the dermatological (RR 0.24, 95% CI: 0.11–0.53, p < 0.00001) and renal systems (RR 0.57, 95% CI: 0.37–0.86, p = 0.007), while significantly increasing the incidence of cardiovascular adverse events (RR 4.65, 95% CI: 1.83–11.78, p = 0.001). Thus, first-line cetuximab-based chemotherapy increases patient susceptibility to dermatological and renal adverse events, especially with rash and electrolyte disorders, whereas bevacizumab-based chemotherapy increases cardiovascular risks such as hypertension and arrhythmia.

Longitudinal High-Throughput Sequencing of the T-Cell Receptor Repertoire Reveals Dynamic Change and Prognostic Significance of Peripheral Blood TCR Diversity in Metastatic Colorectal Cancer During Chemotherapy.

Colorectal cancer (CRC) is a major cause of cancer mortality and morbidity. Despite advances in chemotherapy and targeted therapy, unsustainable clinical benefit was noted due to recurrence and therapy resistance. The immune status of the cancer patient may affect the effectiveness of disease treatments. The dynamic change in the T-cell receptor (TCR) repertoire might be a clinical parameter for monitoring treatment responses. In this study, we aimed to determine the characteristics and clinical significance of the TCR repertoire in patients with unresectable metastatic colorectal cancer (mCRC). Herein, we comprehensively profile 103 peripheral blood samples from 20 healthy controls and 16 CRC patients with a follow-up of 98 to 452 days to identify hypervariable rearrangements of the TCRα and TCRβ repertoires using high-throughput sequencing. We found that TCRα repertoires, TCRβ repertoires, and CDR3 clonotypes were altered in mCRC patients compared with healthy controls. The diversity of TCR repertoires and CDR3 clonotypes decreased in most mCRC patients after therapy. Furthermore, compared with baseline TCR diversity, patients whose TCR diversity dropped considerably during therapy had better treatment responses, including lower CEA and CA19-9 levels and smaller tumor sizes. TCR baseline diversity was also significantly associated with partial response (PR) status (odds ratio: 5.29, p = 0.04). In conclusion, the present study demonstrated the association between dynamic changes in TCR diversity during chemotherapy and clinical outcomes as well as the potential utility of the TCR repertoire in predicting the prognosis of cancer treatment.

Long-term Survival, Tolerability, and Safety of First-Line Bevacizumab and FOLFIRI in Combination With Ginsenoside-Modified Nanostructured Lipid Carrier Containing Curcumin in Patients With Unresectable Metastatic Colorectal Cancer.

Background:Colorectal cancer is the third most common malignant disease and the second leading cause of death worldwide. Previous studies showed improved bioavailability and cytotoxicity of ginsenoside-modified nanostructured lipid carrier containing curcumin (G-NLC) in human colon cancer cell lines. This study aimed to evaluate the safety and tolerability with long-term survival rates in patients with colorectal cancer with unresectable metastases after treatment with first-line bevacizumab/FOLFIRI (folinic acid, bolus/continuous fluorouracil, and irinotecan) in combination with a dietary supplement of G-NLC.Methods:This study was a prospective, observational, single-group analysis. The enrolled patients had colorectal cancer with unresectable metastases and were administered bevacizumab and FOLFIRI in combination with daily oral G-NLC as first-line treatment. Overall survival, progression-free survival, tumor response, and adverse events were evaluated.Results:A total of 44 patients were enrolled between 2015 and 2019. The median age was 65 (range 45-81) years and the sex ratio was 31:13 (male:female). The primary tumor locations were the colon (31 patients) and rectum (13 patients). The metastatic sites included, liver only (n = 20), lung only (n = 6), both liver and lung (n = 12), and others (n = 6). The median duration of curcumin supply was 7.9 (range 0.9-16.6) months. The most common grade 3 or higher adverse events were neutropenia (n = 15, 34.1%), followed by nausea (n = 4, 9.1%) and vomiting (n = 4, 9.1%). Within the median follow-up period of 22.8 months, the median overall survival was 30.7 months, and the median progression-free survival was 12.8 months. None of the patients achieved complete response (CR); however, 9 patients showed partial response (PR), and 3 patients underwent conversion surgery.Conclusions:Bevacizumab/FOLFIRI with G-NLC as first-line chemotherapy in patients with colorectal cancer with unresectable metastases presented comparable long-term survival outcomes with acceptable toxicity outcomes. Additional randomized controlled studies are needed to establish definitive conclusions regarding this new regimen for metastatic colorectal cancer.

Upfront primary tumour resection and survival in synchronous metastatic colorectal cancer according to primary tumour location and RAS status: Pooled analysis of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)

IntroductionRetrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy. Patients and methodsSurvival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling. ResultsOf 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15–1.48; p < 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13–1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00–1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05–1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21–1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13–1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08–1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS. ConclusionConsidering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.

Contribution of "complete response to treatment" to survival in patients with unresectable metastatic colorectal cancer: A retrospective analysis.

The aim of the study is to reveal the contribution of complete response (CR) to treatment to overall survival (OS) in patients with unresectable metastatic colorectal cancer. In addition, to evaluate progression-free survival (PFS) in patients who attained CR to treatment and to examine the clinicopathologic features of the patient group with CR. This article is a retrospective chart review. Patients diagnosed with metastatic colorectal cancer were divided into two groups. The systemic treatment was compared with the patients who received a full response according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1) and those who did not attain CR (progression partial response and stable response) in terms of both PFS and OS data, and the effect of attaining CR to treatment on prognosis was evaluated. A total of 222 patients were included in the study. 202 of 222 patients could be evaluated in terms of complete response. All data from their files were tabulated and analyzed retrospectively. The mean age of diagnosis of the study group was 60.13 ± 12.52 years. The total number of patients who attained CR to treatment was 31 (15.3%); 171 (84.6%) patients did not attain CR. Patients who had a CR had longer median PFS times than patients who did not have a CR (15.2 vs. 7.4 months, P<0.001). Patients who had CR had longer median survival times than patients who did not have a CR (39.2 vs. 16.9 months, P<0.001). In subgroup patients who underwent primary surgery, the number of patients who attained CR was statistically higher compared with the number of patients who did not attain CR (p<0.001). Complete response was less common in the presence of liver metastasis and bone metastasis (p = 0.041 and p = 0.046, respectively), had a negative prognostic effect. In other words, 89.1% of patients with liver metastasis, 100.0% of patients with bone metastasis, and 88.7% of those who died did not have a CR to the treatment. According to multivariate analysis, CR to treatment, primary surgery, first-line chemotherapy (combination compared with fluoropyrimidine), and no bone metastasis were found to be predictors for OS. Providing CR with systemic treatment in patients with unresectable metastatic colorectal cancer (mCRC) contributes to prognosis. The primary resection in our secondary acquisitions from the study, the number of metastatic regions and the combination therapy regimens also contributed to the prognosis.

Lymphocyte-to-C-Reactive Protein Ratio Is the Most Sensitive Inflammation-Based Prognostic Score in Patients With Unresectable Metastatic Colorectal Cancer.

Systemic inflammation contributes to the progression of malignancies. The preoperative lymphocyte-to-C-reactive protein ratio has recently been shown to predict survival of patients with colorectal cancer who undergo surgery, but its prognostic value remains unclear in patients with unresectable metastatic colorectal cancer. This study aimed to examine the prognostic values of inflammation-based prognostic scores in patients with metastatic colorectal cancer, focusing on the lymphocyte-to-C-reactive protein ratio. This is a retrospective study from a prospectively collected database. This study was conducted at a high-volume multidisciplinary tertiary cancer center in Japan. The subjects were 756 consecutive patients with unresectable metastatic colorectal cancer who received systemic chemotherapy from 2000 to 2015. The prognostic value of the lymphocyte-to-C-reactive protein ratio was evaluated by univariable and multivariable analyses. Time-dependent receiver operating characteristics curve analysis was conducted to compare the prognostic impact of the lymphocyte-to-C-reactive protein ratio with the impact of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, or the modified Glasgow Prognostic Score. The primary outcomes measured were the correlations of prognostic scores with overall survival. Median survival times of patients with high, intermediate, and low lymphocyte-to-C-reactive protein ratios were 29.4, 19.3, and 13.1 months (p < 0.001). In all subgroups according to key prognostic factors (performance status, use of targeted agents, pretreatment CEA levels, tumor sidedness, M category, and primary tumor resection), patient prognosis could be clearly stratified into 3 groups by the lymphocyte-to-C-reactive protein ratio. Multivariable analysis revealed that decreased lymphocyte-to-C-reactive protein ratio was independently associated with reduced survival (low vs high: HR 1.96, p < 0.001; intermediate vs high: HR 1.44, p < 0.001). The time-dependent receiver operating characteristics curve analysis revealed that the lymphocyte-to-C-reactive protein ratio was the most sensitive predictor of survival among all inflammation-based prognostic scores on a continuous basis. This study was retrospective in nature. The lymphocyte-to-C-reactive protein ratio is a useful prognostic biomarker for unresectable metastatic colorectal cancer and could contribute to accurate prognostication and therapeutic decision making. See Video Abstract at http://links.lww.com/DCR/B600. ANTECEDENTES:La inflamación sistémica contribuye en la progresión de neoplasias malignas. Recientemente se ha demostrado que la proporción preoperatoria de linfocitos -proteína C reactiva predice la supervivencia de los pacientes con cáncer colorrectal que se sometieron a cirugía, pero su valor pronóstico sigue sin estar claro en pacientes con cáncer colorrectal metastásico irresecable.OBJETIVO:Evaluar el valor pronostico de los scores inflamtorios centrandose en linfocito- proteina c reactiva en pacientes con cáncer colorrectal metastásico.DISEÑO:Estudio retrospective evaluando una base de datos.AJUSTE:Este estudio se llevó a cabo en un centro oncológico terciario multidisciplinario de gran volumen en Japón.PACIENTES:Se incluyeron 756 pacientes consecutivos todos con cáncer colorrectal metastásico irresecable que recibieron quimioterapia sistémica de 2000 a 2015. El valor pronóstico de la proteína C reactiva se evaluó mediante análisis univariables y multivariables. Se realizó análisis de la curva de características operativas del receptor dependiente del tiempo para comparar el impacto pronóstico de la proteína linfocito-C-reactiva con el de la proporción de neutrófilos a linfocitos, la proporción de plaquetas a linfocitos, la proporción de linfocitos a monocitos o la proporción de puntuación pronóstica segun escala de Glasgow modificada.PRINCIPALES MEDIDAS DE RESULTADO:Correlacion de las puntuaciones pronósticas con la supervivencia global.RESULTADOS:La mediana de supervivencia de los pacientes con niveles altos, intermedios y bajos de proteína C reactiva de linfocitos fue de 29,4, 19,3 y 13,1 meses, respectivamente (p <0,001). En todos los subgrupos de acuerdo con los factores pronósticos clave (estado funcional, uso de agentes dirigidos, niveles de antígeno carcinoembrionario antes del tratamiento, lado del tumor, categoría M y resección del tumor primario), el pronóstico del paciente podría estratificarse claramente en tres grupos por linfocito a C- proteína reactiva. El análisis multivariable reveló que la disminución de linfocitos a proteína C reactiva se asoció de forma independiente con una supervivencia reducida (baja frente a alta: cociente de riesgo 1,96, p <0,001; intermedio frente a alto: cociente de riesgo 1,44, p <0,001). El análisis de la curva de características operativas del receptor dependiente del tiempo reveló que de linfocito a proteína C reactiva era el predictor de supervivencia más sensible entre todas las puntuaciones de pronóstico basadas en inflamación de forma continua.LIMITACIONES:Este estudio fue de naturaleza retrospectiva.CONCLUSIONES:La proteína C reactiva de linfocitos a C es un biomarcador pronóstico útil para el cáncer colorrectal metastásico irresecable y podría contribuir a un pronóstico preciso y a la toma de decisiones terapéuticas. Consulte Video Resumen en http://links.lww.com/DCR/B600.

Improved Survival over Time After Resection of Colorectal Liver Metastases and Clinical Impact of Multigene Alteration Testing in Patients with Metastatic Colorectal Cancer

BackgroundThe past 20 years have seen advances in colorectal cancer management. We sought to determine whether survival in patients undergoing resection of colorectal liver metastases (CLM) has improved in association with three landmark advances: introduction of irinotecan- and/or oxaliplatin-containing regimens, molecular targeted therapy, and multigene alteration testing. MethodsPatients undergoing CLM resection during 1998–2014 were identified and grouped by resection year. The influence of alterations in RAS, TP53, and SMAD4 was evaluated and validated in an external cohort including patients with unresectable metastatic colorectal cancer. ResultsOf 1961 patients, 1599 met the inclusion criteria. Irinotecan- and/or oxaliplatin-containing regimens and molecular targeted therapy were used for more than 50% of patients starting in 2001 and starting in 2006, respectively, so patients were grouped as undergoing resection during 1998–2000, 2001–2005, or 2006–2014. Liver resectability indications expanded over time. The 5-year overall survival (OS) rate was significantly better in 2006–2014, vs. 2001–2005 (56.5% vs. 44.1%, P < 0.001). RAS alteration was associated with worse 5-year OS than RAS wild-type (44.8% vs. 63.3%, P < 0.001). However, OS did not differ significantly between patients with RAS alteration and wild-type TP53 and SMAD4 and patients with RAS wild-type in our cohort (P = 0.899) or the external cohort (P = 0.932). Of 312 patients with genetic sequencing data, 178 (57.1%) had clinically actionable alterations. ConclusionOS after CLM resection has improved with advances in medical therapy and surgical technique. Multigene alteration testing is useful for prognostication and identification of potential therapeutic targets.

Genomic temporal heterogeneity of circulating tumour DNA in unresectable metastatic colorectal cancer under first-line treatment

ObjectiveCirculating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical...

The Impact of Tumor-associated Macrophages on Chemoresistance via Angiogenesis in Colorectal Cancer

The tumor microenvironment plays an important role in tumor progression. Tumor-associated macrophages (TAMs) have been reported to promote proliferation, invasion, metastasis, angiogenesis, and immunosuppression. Furthermore, angiogenesis has been reported to induce chemoresistance due to the inefficient distribution of drugs to cancer cells. However, the impact of TAMs on chemoresistance via angiogenesis in colorectal cancer (CRC) remains unclear. The aim of the study was to evaluate the impact of TAMs on the chemotherapeutic outcome in CRC. We enrolled 54 patients who underwent chemotherapy for unresectable metastatic CRC after resection of the primary tumor. We evaluated the density of TAMs and the degree of angiogenesis by immunohistochemistry and then explored the correlation between the density of TAMs and chemotherapeutic outcome. Furthermore, we assessed any correlation between the density of TAMs and that of neovascularity. The high-TAMs group had a significantly worse progression-free survival (p=0.0006) and a poorer response rate (p=0.0274) than the low-TAMs group. In addition, a positive correlation was observed between the density of TAMs and the degree of neovascularity (r=0.665, p=0.0004). TAMs were shown to promote chemoresistance via angiogenesis in CRC.

503P Mutational landscape in synchronous unresectable metastatic colorectal cancer (mCRC) according to upfront primary tumour resection (UPTR)

Most retrospective data suggest that UPTR confers a survival benefit in patients with unresectable synchronous asymptomatic mCRC. The possible mechanisms that could explain the different outcomes based on UPTR or not are not known.

LBA20 FOLFOXIRI plus bevacizumab (bev) plus atezolizumab (atezo) versus FOLFOXIRI plus bev as first-line treatment of unresectable metastatic colorectal cancer (mCRC) patients: Results of the phase II randomized AtezoTRIBE study by GONO

FOLFOXIRI/bev is an upfront therapeutic option for selected mCRC pts. Immune checkpoint inhibitors (ICIs) reported remarkable achievements in dMMR but not in pMMR mCRC. The association of cytotoxics and bev may promote the sensitivity to ICIs increasing the exposure of neoantigens, inducing immunogenic cell death, and increasing the immune infiltration in tumor microenvironment while reducing the activity of Tregs.

420P A single-arm, multicenter, phase II study of anlotinib combined with CAPEOX as first-line treatment in RAS/BRAF wild-type unresectable metastatic colorectal cancer (ALTER-C002)

Anlotinib is an oral multi-target tyrosine kinase inhibitor, mainly targets VEGFR1-3, FGFR 1-4, PDGFR α/β and c-kit. Previous trial has demonstrated that anlotinib monotherapy was effective and safe in advanced colorectal cancer following the failure of standard treatment. ALTER-C002 trial was designed to evaluate the efficacy and safety of anlotinib plus CAPEOX as first-line therapy in patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer (mCRC). Preliminary results demonstrated significant antitumor activity and manageable toxicity.

Lactate Dehydrogenase Is a Useful Marker for Predicting the Efficacy of Bevacizumab-containing Chemotherapy in Patients With Metastatic Colorectal Cancer.

No biomarkers that predict the benefit from anti-vascular endothelial growth factor (VEGF) antibodies have been identified. It is necessary to discover biomarkers that can identify patients who are more likely to benefit from bevacizumab-containing treatment, especially those who are more likely to benefit from treatment with bevacizumab beyond progression (BBP). Levels of serum lactate dehydrogenase (LDH), reported to be an indirect marker of hypoxia and angiogenesis, may be a useful marker for monitoring the efficacy of suppression of angiogenesis. The clinical data of 91 patients with unresectable metastatic colorectal cancer who were treated with bevacizumab-containing chemotherapy as first-line treatment were collected and studied. In the second-line treatment, the bevacizumab plus chemotherapy group showed significantly better progression-free survival (PFS) in comparison to the chemotherapy-alone group in patients with low post-first-line-treatment serum LDH levels. On the other hand, no significant differences in the PFS rate were observed between the two groups in patients with high post-first-line-treatment serum LDH levels. The post-first-line-treatment serum LDH levels may, therefore, be useful marker for predicting the efficacy of treatment with BBP.

Genomic Sequencing and Insight into Clinical Heterogeneity and Prognostic Pathway Genes in Patients with Metastatic Colorectal Cancer

An understanding of signaling pathways has not been fully incorporated into prognostication and therapeutic options. We evaluated the hypothesis that information about cancer-related signaling pathways can improve prognostic stratification and explain some of the clinical heterogeneity in patients with metastatic colorectal cancer. We analyzed prognostic relevance of signaling pathways in patients undergoing resection of colorectal liver metastases (CLM) from 2004-2017, and clinical actionability of gene alterations in 7 signaling pathways: p53, Wnt, RTK-RAS, PI3K, TGFβ, Notch, and cell cycle. To assess the wide applicability, the results were validated in an external retrospective cohort including patients with unresectable metastatic colorectal cancer. Of 579 patients, the numbers of patients with pathway alterations were as follows: p53, n=420 (72.5%); Wnt, 340 (58.7%); RTK-RAS, 333 (57.5%); PI3K, 110 (19.0%); TGFβ, 65 (11.2%); Notch, 41 (7.1%); and cell cycle, 15 (2.6%). More than 80% of alterations in each pathway occurred in a single predominant gene TP53, APC, KRAS, PIK3CA, FBXW7, and RB1 in p53, Wnt, RTK-RAS, PI3K, Notch, and cell cycle pathways, respectively. Alterations of 4 pathways (p53, RTK-RAS, TGFβ, and Notch) and corresponding predominant genes (TP53, RAS/BRAF, SMAD4, and FBXW7) were significantly associated with worse overall survival (OS), and alterations of Wnt pathway (APC) were associated with better OS in the median follow-up duration of 3.8 years. Similarly, in the external cohort, alterations of p53 (TP53) and RTK-RAS (RAS/BRAF) were significantly associated with worse OS, whereas alteration of Wnt (APC) was associated with better OS in the median follow-up duration of 2.6 years. Genomic sequencing provides insights into clinical heterogeneity and permits finer prognostic stratification in patients with metastatic colorectal cancer.

A retrospective study of local hepatic artery infusion chemotherapy combined with regorafenib in the treatment of advanced colorectal cancer with predominant liver metastases.

e15563 Background: The hepatic arterial infusion chemotherapy (HAIC) as a second/third-line therapy has resulted in promising clinical outcomes for unresectable liver metastatic colorectal cancer (CRC). HAIC combined with regorafenib has not been reported for advanced CRC patients with predominant liver metastases. This retrospective study explored the benefits and tolerability in advanced hepatic metastatic CRC patients who received HAIC combined with regorafenib after failure of standard systemic chemotherapy. Methods: This retrospective study collected and analyzed 47 patients treated with HAIC in combination with regorafenib after standard systemic oxaliplatin and/or irinotecan in combination with Bevacizumab or Cetuximab between Jan 2017 and Jun 2020 at the Beijing cancer hospitals in China. Regorafenib was taken for 3 weeks every 4-week cycles and mostly taken 5-7 days before or after the first HAIC. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were observed. Results: Among these 47 patients, 32(68%) were males. The median age was 61 (range: 29-75) . The median follow-up was 22.2 months (range:3.7-50.7 months). Before receiving HAIC in combination with regorafenib, 34 (72.3%) patients had previously received ≥ 2 prior lines of systemic therapy and 37 (78.7%) patients had previously received targeted biological treatment (anti-VEGF or anti-EGFR, or both).These patients underwent HAIC for a median of 4 sessions (range2--8,). The starting doses of regorafenib were 40 mg/d (n = 1, 2.13%), 80 mg/d (n = 11, 23.43%), 120 mg/d (n = 2, 4.26%), and 160 mg/d (n = 23, 48.94%). The median OS was 22.2 months. The median PFS was 10.8 (95% CI: 9.0-13.7) months. The ORR was 51.3% and DCR was 100% among 39 patients whose tumor responses were evaluated in the liver. The ORR was 13.8% and DCR was 48.3% among 29 patients whose tumor responses were evaluated outside the liver. Toxicity profile of regorafenib was as expected, with common AE were hand-foot skin reaction (12.77%), fatigue (6.38%), vomiting (6.38%), and decreased appetite (6.38%). The most common grade 3 and 4 adverse events were hand-foot skin reaction (4.26%), hypertension (2.13%), diarrhea (2.13%), and stomachache (2.13%). Only 2 patients stopped regorafenib due to AEs. Conclusions: This real-world study demonstrated that regorafenib combined with HAIC was beneficial and tolerable in advanced CRC patients with liver metastases whose disease had progressed after standard systemic therapy. It also indicated a new promising treatment strategy for late stage CRC. Additional prospective and large-scale studies are required for further confirmation. Key words: hepatic artery infusion chemotherapy; regorafenib; colorectal cancer

Updated results of ALTER-C002: Anlotinib combined with CAPEOX in first-line treatment of patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer.

e15564 Background: Antiangiogenic therapy plus chemotherapy is one of the standard treatments in mCRC. Anlotinib, an oral small multi-targeted tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR α/β and c-kit, has demonstrated prolonged PFS in refractory mCRC. This trial was conducted to evaluate the efficacy and safety of anlotinib combined with CAPEOX as first-line treatment for unresectable RAS/BRAF wild-type mCRC. Methods: Patients aged 18-75, with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment and ECOG status ≤ 1were enrolled in 3 hospitals in Zhejiang, China. Enrolled patients received capecitabine (850 mg/m2 p.o., bid, on day 1-14 every 3 weeks), oxaliplatin (130 mg/m2 i.v., on day 1 every 3 weeks) and anlotinib (12 mg p.o. qd, on day1-14 every 3 weeks) as inducing therapy. After 6 cycles of combined therapy, patients who achieve complete response (CR)/ partial response (PR)/ stable disease (SD) would receive capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint is objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: From November, 2019 to February, 2021, 31 patients had been enrolled. 1 patient was excluded for refused treatment. By now, 27 patients received at least 2 cycles of treatment and were available for efficacy evaluation: 22 patients had partial response (PR), 5 patients had stable disease (SD). The ORR was 81.5% (95% CI: 61.9–93.7%), and DCR was 100% (95% CI: 87.2–100%).1 patient received radical surgery after 6 cycles of treatment. The median PFS has not been reached yet. The most common grade≥3 AEs included hypertension (45.2%), neutropenia (25.8%) and diarrhea (12.9%). No treatment-related deaths occurred. Conclusions: The combination of anlotinib and CAPEOX showed promising antitumor activity and manageable toxicity in unresectable RAS/BRAF wild-type mCRC. Furthermore, we are launching a phase 3, multicenter, double-blind trial to further assess the efficacy of this regimen. Clinical trial information: NCT04080843. [Table: see text]

FOLFIRINOX-R study design: a phase I/II trial of FOLFIRINOX plus regorafenib as first line therapy in patients with unresectable RAS-mutated metastatic colorectal cancer

BackgroundThe chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX – a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer.MethodsFOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1–2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, β = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150–180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle.DiscussionFOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer.Trial registrationEudraCT: 2018-003541-42; ClinicalTrials.gov: NCT03828799.

Trial Questions Role of Resection of the Primary Tumor in Metastatic Colorectal Cancer

For patients with unresectable metastatic colorectal cancer and an asymptomatic primary tumor, retrospective studies have suggested improved survival

Rate of Curative Surgery in Real-world Patients with Unresectable Metastatic Colorectal Cancer Treated with FOLFOXIRI ± Bevacizumab: A Western Canadian Province Experience.

Recent evidence from randomized trials suggests that FOLFOXIRI (fluorouracil, oxaliplatin, and irinotecan) ± bevacizumab is associated with higher response rates, with the potential for conversion of unresectable to resectable disease in metastatic colorectal cancer (mCRC). However, limited evidence is available on the efficacy and safety of this regimen in real-world patients with mCRC. The current study aims to evaluate the conversion rate and safety of FOLFOXIRI ± bevacizumab in real-world patients with unresectable mCRC. In this retrospective multicenter population-based cohort study, patients who were diagnosed with unresectable mCRC between January 2015 and December 2018 in Saskatchewan and received FOLFOXIRI ± bevacizumab were assessed. Kaplan-Meier survival methods and the log-rank test were performed. A total of 28 eligible patients with a median age of 51years (interquartile range 39-60) and a male:female ratio of 11:17 were identified; 39% had rectal cancer, 46% had extrahepatic disease, and 46% had bilobar liver metastases. Overall, 63% of the patients had a positive response to FOLFOXIRI ± bevacizumab and 53% underwent metastasectomy. Of all patients 60% had grade 3/4 toxicity and 32% required hospital admission. No treatment-related mortality was noted. After 4years, 50% of the patients were alive. Median progression-free survival of patients who underwent surgery was 18months (95% CI 11.3-24.7) versus 11months (4-18.1) without surgery (p=0.28). Median overall survival of patients with surgery was 33months (17.5-48.5) versus 16months (8.3-23.7) without surgery (p=0.03). The current study suggests that FOLFOXIRI ± bevacizumab therapy in real-world patients with mCRC is associated with a high rate of conversion from unresectable to resectable metastatic disease. Patients with metastasectomy had better survival.

Change in the neutrophil-to-lymphocyte ratio during chemotherapy may predict prognosis in patients with advanced or metastatic colorectal cancer.

The neutrophil-to-lymphocyte ratio (NLR) has been reported to be an independent prognostic factor of unresectable advanced or metastatic colorectal cancer (uCRC). However, few studies have documented changes in NLR during chemotherapy. The current study analyzed whether a change in NLR during chemotherapy in patients with uCRC could be used as a prognostic biomarker. The present retrospective study enrolled 71 patients who received first-line chemotherapy for uCRC between April 2012 and April 2019. The exclusion criteria were as follows: Acute infection or systemic inflammatory disease, duration of first-line chemotherapy <3 months, curative resection after chemotherapy and treatment with granulocyte-colony stimulating factor within 1 month. NLR, Lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), lactate dehydrogenase, alkaline phosphatase (ALP), albumin, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were calculated before chemotherapy and at 3 months after chemotherapy. Among these laboratory data, NLR, PLR, ALP, CEA and CA19-9 levels were significantly decreased during chemotherapy. For Cox univariate analyses, these five data makers were divided into two groups: Decreased and increased (comparing before and at 3 months after chemotherapy). Only the change in NLR was significantly associated with overall survival (P=0.0002). Furthermore, the overall survival (P<0.0001) and progression-free survival (P=0.0041) of patients with decreased NLR was increased compared with patients with increased NLR. The change in NLR from pre-chemotherapy to 3 months following chemotherapy was determined to be a predictor of prognosis in patients with uCRC. The ability to predict prognosis at an early phase of chemotherapy may provide useful information for the selection of subsequent treatment and may improve the quality of patient life.