Liver-Directed and Systemic Therapies for Colorectal Cancer Liver Metastases.
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ABSTRACT:
SUBMITTER: Kemeny N
PROVIDER: S-EPMC8583383 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15?years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible. However, trial-based evidence is sparse to support this concept. Peri-operative FOLFOX has demonstrated a progression-free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy-associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre-operative chemotherapy should not extend beyond 3?months. For patients with unresectable liver-only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin- or irinotecan-containing combinations represent the standard options, although single-agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K-ras mutations, anti-epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.
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Project description:Liver metastases are the most common site of metastatic spread in colorectal cancer. Current treatment approaches involve effective systemic therapies in combination with surgical and/or interventional strategies. Multimodal strategies greatly improved clinical outcomes of patients with metastatic colorectal cancer over the last decades. Identification of predictive and prognostic biomarkers helped to comprehensively refine individual targeted treatment approaches and resulted in median overall survival rates of 30 months or longer. Current guidelines, thus, recommend treatment selection according to patients' performance status, tumor localization and stage as well as the tumor's molecular and genetic status. Here, we outline the latest developments in molecular decision-making for patients with upfront resectable, potentially or initially unresectable and non/never-resectable colorectal cancer liver metastases.
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Project description:Patients presenting with synchronous or metachronous colorectal cancer liver metastases (CLM) should be evaluated for multimodal management with curative intent. Preoperative systemic chemotherapy shows beneficial impact on adjuvant progression-free survival and also borderline on overall survival, without significantly increasing initially R0 resectable patients postoperative complication rates. Postoperative chemotherapy recommended based on the perioperative trial experience for those patients achieving at least stable disease during preoperative chemotherapy, or based on the adjuvant trials for patients receiving upfront resection. 'Borderline' resectable CLM, preoperative chemotherapy plays an important role in both in achievement of a resectable status and improvement of prognosis. Recent 4 drug combinations demonstrated response rates up to 80% even for advanced disease and are thus promising regimens for further evaluation in patients with resectable or unresectable liver-limited (+/- lung) disease.
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Project description:Hepatic metastases, which are frequently seen in patients with neuroendocrine tumors (NETs), have a major adverse impact on the patient's quality of life and survival. Surgery is the treatment of choice for hepatic metastases but is possible in only a small percentage of patients. Systemic chemotherapy yields disappointing results. Somatostatin analogs are effective in controlling symptoms in many of these patients; however, the disease can become refractory to treatment. Transcatheter intra-arterial liver-directed therapies, such as hepatic artery embolization, chemoembolization, and radioembolization are frequently used in patients with NETs metastatic to the liver, especially in patients with refractory, unresectable, or recurrent disease. These treatments are effective in palliating the hormonal symptoms as well as achieving objective tumor responses. This review focuses on the technique, safety, and clinical efficacy of hepatic artery embolization, chemoembolization, and radioembolization in patients with metastatic NETs.
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Project description:Selection of the optimal surgical and interventional therapies for advanced colorectal cancer liver metastases (CRLM) requires multidisciplinary discussion of treatment strategies early in the trajectory of the individual patient's care. This paper reports on expert consensus on locoregional and interventional therapies for the treatment of advanced CRLM. Resection remains the reference treatment for patients with bilateral CRLM and synchronous presentation of primary and metastatic cancer. Patients with oligonodular bilateral CRLM may be candidates for one-stage multiple segmentectomies; two-stage resection with or without portal vein embolization may allow complete resection in patients with more advanced disease. After downsizing with preoperative systemic and/or regional therapy, curative-intent hepatectomy requires resection of all initial and currently known sites of disease; debulking procedures are not recommended. Many patients with synchronous primary disease and CRLM can safely undergo simultaneous resection of all disease. Staged resections should be considered for patients in whom the volume of the future liver remnant is anticipated to be marginal or inadequate, who have significant medical comorbid condition(s), or in whom extensive resections are required for the primary cancer and/or CRLM. Priority for liver-first or primary-first resection should depend on primary tumour-related symptoms or concern for the progression of marginally resectable CRLM during treatment of the primary disease. Chemotherapy delivered by hepatic arterial infusion represents a valid option in patients with liver-only disease, although it is best delivered in experienced centres. Ablation strategies are not recommended as first-line treatments for resectable CRLM alone or in combination with resection because of high local failure rates and limitations related to tumour size, multiplicity and intrahepatic location.
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Project description:Despite advances over the past 20 years in colorectal cancer (CRC) screening, diagnosis, and treatment, survival outcomes remain suboptimal. Five-year survival for patients with locally advanced CRC is 69%; 5-year survival drops to 12% for patients with metastatic disease. Novel, effective systemic therapies are needed to improve long-term outcomes. In this review, we describe currently available systemic therapies for the treatment of locally advanced and metastatic CRC and discuss emerging therapies, including encouraging advances in identifying novel targeted agents and exciting responses to immunotherapeutic agents.
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Project description:mRNA sequencing by Lexogen Quantseq 3 prime of colorectal liver metastases
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Project description:Colorectal cancer (CRC) is the third most common and second most deadly cancer worldwide. Treatments for metastatic CRC (mCRC) are still largely based on toxic chemotherapy regimens, but important insights into tumor biology enabled the development of targeted cancer therapies. Here, we describe a proteogenomic analysis of CRC liver metastases (metastatic CRC, mCRC), an ideal setting to analyze therapeutic resistance which occurs in a short time frame. We selected liver metastases from two CRC patients on both of which we performed deep proteome profiling and WES and RNAseq-directed database searches, identifying 10 predicted muttaions, one of which was KRAS G12V. finding we generated targeted parallel reaction monitoring (PRM) assays using stable isotope labelled standard (SIS) peptides to quantify the actual concentration (fmol per µg of total protein) of the mutated and canonical (wildtype) protein variants for 8 different mutations. We demonstrate on a total of 8 tumor and 6 paired healthy tissue samples (7 and 6 out of these KRASG12V) that PRM allows quantifying the actual mutation rate on the protein level from as little 10 µg of total protein starting amount and within a single 1 hour nano-LC-MS/MS run.
2019-12-04 | PXD014222 | Pride
Project description:Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour-liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (β [95% confidence interval, CI]: 24.57 [18.28-30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (β [95% CI]: 24.18 [18.70-29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (β [95% CI]: 23.29 [1.78-44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.
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