Hepatic Metastasis Of Colorectal Cancer

Maximizing Regional Treatment Of Colorectal Cancer Liver Metastasis To Decrease Intrahepatic Recurrence

The role of hepatic arterial infusion for patients with resected CRLM initially was tested without concurrent systemic therapy, which at the time of the initial trials did not include modern systemic agents such as oxaliplatin and irinotecan. To date, there have been no prospective randomized controlled trials comparing adjuvant HAI with modern systemic therapy vs modern systemic therapy alone in patients with resected CRLM. In 2016, Kemeny et al reported on an analysis of 4 consecutive HAI adjuvant trials for patients with resected CRLM from 1991 to 2009 . The patients were divided into 2 groups: those treated before and after 2003, corresponding to the incorporation of modern systemic oxaliplatin or irinotecan-containing regimens. With a median follow-up period of 11 years, the investigators reported that patients treated after 2003 had a 5- and 10-year OS of 78% and 61%, respectively, with the median survival not being reached. Patients treated before 2003 had a 3- and 5-year DFS of 42% and 41%, respectively. Taken together, these data support that properly selected patients with CRLM can have hepatic resection of their disease followed by adjuvant systemic therapy plus HAI and achieve a 5-year survival as high as 78%. However, similar to toxicity associated with systemic therapy, treatment with HAI has risks, including biliary sclerosis in less than 5% of patients, that needs to be balanced with the anticipated benefit of treatment.

How We Care For You

The symptoms of liver metastases are often vague and hard to identify yourself. If you have any concerns, contact your doctor. Memorial Sloan Kettering has a team of specialists who are very experienced in diagnosing and treating the condition.

• Our goal is to provide treatment options that give you the very best possible quality of life and survival rate.
• MSK surgeons work closely with interventional radiologists in using powerful imaging tests such as CT, ultrasound, or MRI to guide treatments directly to where your tumor is located. We can often destroy tumors with minimally invasive techniques, such as ablation and embolization.
• Through genetic testing of tumors, we learn about the molecular blueprint of your particular cancer and customize a treatment plan for you. Another option is to combine surgery with hepatic arterial chemotherapy, which delivers the drug directly to the liver.

We also offer a range of support programs that can help you and your loved ones manage the challenges and stress of life during and after treatment for liver cancer.

Additional File : Table S1

The influence of primary tumour location on survival in liver metastatic colorectal cancer, stratified by stage. Cox regression model adjusted for: age, sex, synchronous versus metachronous, size of largest liver metastasis , number of liver metastases, liver resection, lung metastases and stratified by stage.

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Calculation Of Fibrosis Score

To assess the presence of fibrosis in fatty liver, the aspartate aminotransferase and alanine aminotransferase ratio was calculated in patients with hepatic steatosis . The serum level of aspartate aminotransferase and alanine aminotransferase was obtained before treatment of liver metastasis. And the cutoff of AAR was obtained by the maxstat package using R version 3.6.1 . Patients with AAR > 1.08 were defined as fibrotic liver.

Building A Family Tree For Metastatic Colorectal Cancer

There has been a longstanding debate about when metastasis occurs, Dr. Curtis said. Studying the metastatic process in humans is challenging because researchers cant observe the process directly, she noted.

Colorectal cancer is a good model for studying the genetic changes in human tumors over time because the genetic changes that initiate colorectal cancer development, known as driver mutations, are well known, Dr. Curtis and her coauthors wrote.

To gain insights into the genetic changes involved in metastasis, the team first compared the patterns of genetic mutations between the primary tumors of 21 patients with metastatic colorectal cancer and metastatic tumors in the liver or brain from the same patients.

The researchers used the mutation patterns to create a family tree showing the genetic relatedness between the primary tumor and the metastatic tumor for each patient, Dr. Curtis explained. In 17 of 21 patients , the primary tumor appeared to give rise to the metastatic tumor very early in the disease process.

In those 17 patients, the team found few driver mutations that were unique to the metastasis. Rather, the driver mutations found in the metastatic tumors were already present in the primary tumor, Dr. Curtis said. Moreover, most of these mutations were present throughout different regions of the primary tumor and in the majority of cells, suggesting that they arose early during tumor development.

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Systemic Therapy For Treatment Of Crlm

Advances in systemic chemotherapy as well as biologic agents have significantly improved the OS of patients with CRLM and other metastatic disease in CRC treatment. Based on current evidence, possible first line chemotherapy for treating CRC with CRLM include: fluorouracil, leucovorin and oxaliplatin , fluorouracil, leucovorin, irinotecan , capecitabine plus oxaliplatin and fluorouracil, leucovorin, oxaliplatin and irinotecan . They can also be complimented with biological agents such as bevacizumab or cetuximab in the course of treatments. The RAS and BRAF status are crucial in deciding if these biologic agents will be useful in the treatment strategies as discussed above. Fakih summarised very nicely the recommendations based on the RAS and BRAF mutation status. FOLFOXFIRI with or without bevacizumab, FOLFOX or FOLFIRI with anti-EGFR are favoured for downstaging for resection. However, bevacizumab must be avoided in patients with high risk of bowel perforation or thrombotic events. These regimens have been shown to have good response rate of > 50% with improvement of OS by around 30 months .

Expert Review And References

• Alexander HR Jr, Berlin J, Moeslein F. Metastatic cancer to the liver. DeVita VT Jr, Lawrence TS, Rosenberg SA. Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins 2011: 149:2177-2191.
• BC Cancer Agency . Cancer Management Guidelines: Secondary Neoplasms of the Liver. BC Cancer Agency 2006: .

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What Is A Relative Survival Rate

A relative survival rate shows how long someone with a specific condition may live after their diagnosis compared with someone without the condition. For example, a 5-year relative survival rate of 70% means that 70 out of 100 people diagnosed with a condition are still living at least 5 years from the time of diagnosis.

Its most important to remember that figures are estimates, and everyone is different. Talk with your doctor about your specific condition.

Role Of Systemic Therapy

These patients could be defined as those with multiple and bilobar disease, which prevents obtaining a R0 resection by maintaining adequate FLR. Due to the increasing efficacy of systemic therapy, patients with CRClm only must be considered definitively unresectable after receiving 24 months of optimal treatment.

The choice of a systemic treatment strategy is based on patient-related factors, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs .

The chemotherapy options for the treatment of patients with metastatic CRC are typically a cytotoxic doublet such as FOLFOX, CAPOX or FOLFIRI or, in selected patients, the triplet FOLFOXIRI or fluoropyrimidine monotherapy in unfit patients.

All patients considered for systemic therapy should be stratified according to RAS and BRAF mutations .

RAS mutant Bevacizumab has demonstrated its effectiveness independent of the state of RAS therefore, the treatment of choice in these patients is the combination of chemotherapy plus bevacizumab in those who can tolerate an intensive treatment .

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Gene And Potential Drugs Interaction

Protein expression level in different stages of CRC was curated from the Clinical Proteomic Tumor Analysis Consortium by UALCAN. The immunohistochemical images of the hub genes in advance and early stages were also identified using Human Protein Atlas . The Drug Gene Interaction Database was used to predict the potential drugs targeting hub genes . Drugs with combined value of query score and interaction score > 10 were selected for docking. Homologous structures of gene-encoded protein were downloaded from the Protein Data Bank and three-dimension structures of drug from PubChem . Autodock software was used to preprocess and define the proteins and drugs to receptors and ligands, respectively . The docking grid box was set to envelop the whole receptors docking parameters was set as genetic algorithm with short maximum number of evaluations. The docking results were ranked by energy, and the first model was exported to Pymol for visualization .

Liver Transplantation In Crl Liver Metastasis

While hepatocellular carcinoma has become the standard indication for liver transplantation in the recent decades, there is more evidence in the past few years showing acceptable survival benefits of liver transplantation in unresectable CRLM as demonstrated in the SECA I trial by the Norwegian group in Oslo . The key considerations in using liver transplantation as the treatment for CRLM are as follows:

• Oncologically sound-survival outcomes comparable to other standard indications of liver transplantation
• Interaction between immunosuppressants, systemic chemotherapy and tumour recurrence
• Availability of organs for liver transplantation-competing with existing indications
• Technically sound-LDLT vs. DDLT.

The initial enthusiasm of transplanting patients with unresectable CRLM died down rapidly due to the unsatisfactory initial results. The key reasons were attributed to poor patient selection with no standardised protocol, learning curve of surgical expertise in LT and the absence of standardized immunosuppression protocols. Indeed, in many initial experiences, the postoperative mortality after LT was high . Furthermore, the systemic options of chemotherapy for CRC towards the end of the last century were not associated with good outcomes . Following that, liver transplant community accepted that unresectable CRLM should not be treated with liver transplantation as it is associated with poor 5-year survival and a high recurrence rate.

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When Surgery Isnt Possible

If surgery isnt recommended, there are other potential treatments that may be used either alone or in combination. These include:

• Ablation: Ablation involves using an ultrasound to place a needlelike probe into the tumor. Then, radio waves can be used to heat the probe, killing the surrounding cancer cells.
• Radiation therapy:Stereotactic radiosurgery can be used to deliver a large amount of radiation to a small, specific area of the liver. Whole liver radiation is less common and is mostly used as a part of palliative care.
• Chemotherapy:Chemotherapy uses drugs that target the growth and division of cancer cells. It may be given orally or by an IV and can help to kill the cancer cells or slow down their growth.
• Targeted therapy: Targeted therapy hones in on specific markers on cancer cells. Targeted therapy, either alone or with chemotherapy, may be used to treat CRC liver metastases. Some examples of targeted therapy drugs that may be used are:

Overall, the outlook can depend on many factors, including the specific characteristics of the cancer, how much of the liver is affected, and whether it has spread to other places. Your age and overall health also play a role.

Epidemiology Of Colorectal Cancer

Colorectal cancer is among the leading malignant tumours both by incidence and by death rate . Globally, in the year 2012, it was the 3rd most frequent cancer in men and the 2nd in women . The incidence and mortality is higher in males . The highest incidence rates are found in Australia and New Zealand, Europe and North America contrasting with low incidence in Africa and South Central Asia. As shown in Table 2, the incidence is generally higher in more developed countries . The decrease in colorectal cancer incidence in USA reflects successful screening and removal of colorectal adenomas. The incidence growth, recently observed in Western Asia and Eastern Europe , reflects increased prevalence of risk factors as diet, obesity and smoking.

Global incidence and mortality attributable to colorectal cancer by Globocan data

1 Among all cancers.

ASR, age-standardised ratio per 100,000.

Incidence and mortality caused by colorectal cancer by regional welfare

1Includes Europe, North America, Australia, New Zealand and Japan.

2Includes Africa, Asia , Latin America, Melanesia, Micronesia and Polynesia.

ASR, age-standardised ratio per 100,000.

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Questions For Your Doctor

When you’re diagnosed with any kind of cancer, you’re bound to have a lot of questions for your doctor, such as:

• What treatments will work best for me? Whatâs involved?
• For how long will I need treatment?
• What’s my outlook?
• Should I consider a clinical trial?
• Should I get a second opinion? Will you recommend someone?
• How often should I see you for follow-ups?

Echography And Diagnostic Laparoscopy

Echography is a low-cost test utilized as first line in the diagnostic evaluation ofhepatic metastases, and it has the ability of identifying small parenchymatous lesions,and the size and grade of hepatic affection.12 The use of echography in the transoperative period can detect occultcolorectal metastasis that was not visualized by CT, with 96% global sensitivity. It isalso useful for demonstrating hepatic segmental anatomy, acquiring relevance when thetumor is in close proximity to the blood vessels. The value of the intraoperativeechography is operator-dependent, but in expert hands, it has been demonstrated that italters the surgical plan in 20% of patients.3

The diagnostic laparoscopy is useful prior to hepatic resection, aiding in theidentification of lesions not observed during preoperative imaging. Carrying out thelaparoscopy in terms of time, expenses, and morbidity has not demonstrated its performanceas suggested in generalized practice. A high clinical risk score has been developed toclarify the performance of laparos-copy prior to the resection, including variables, suchas the carcinoembryonic-antigen level, status of the primary-tumor lymphatic ganglion, thedisease lapse , and the number andsize of the hepatic tumors. This preoperative index is helpful for staging patients with ahigh risk of earlier recurrence and can aid in determining patients who requireneoadjuvant therapy. Also, it can determine disease extension prior to an aggressivesurgical approach.3

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Hepatic Metastasis From Colorectal Cancer

Alfred Wei Chieh Kow1,2

1Division of Hepatopancreaticobiliary Surgery and Liver Transplantation, Department of Surgery, National University Health System, Singapore, Singapore 2Department of Surgery, National University of Singapore, Singapore, Singapore

Correspondence to:

Keywords: Colorectal liver metastasis systemic chemotherapy liver resection liver transplantation liver targeted therapy

Submitted Jul 21, 2019. Accepted for publication Aug 14, 2019.

doi: 10.21037/jgo.2019.08.06

How Do Doctors Diagnose Colorectal Cancer That Has Spread To The Liver

If you have symptoms that suggest CRC has spread to your liver, there are tests that your doctor can do to see if metastasis has occurred.

Imaging plays a big role in diagnosing cancer spread. It can help your doctor get a view of your liver to check for the presence of one or more tumors.

Some of the preferred imaging methods to use include CT scans and MRIs. Its also possible your doctor may use an ultrasound or positron emission tomography scan.

Blood tests may be ordered as well, including:

• metabolic panel
• tumor markers, such as CEA and CA19-9

If you have not been diagnosed with CRC, but your doctor suspects CRC with liver metastasis, tests to diagnose CRC may also be done. In addition to whats mentioned above, this can involve a diagnostic colonoscopy with biopsy.

Its also possible that the liver may be evaluated during surgical treatment for CRC. If suspicious areas are present on or around the liver, your surgeon will collect a sample for analysis.

The main treatment for CRC thats spread to the liver is surgery. However, its important that surgery doesnt negatively affect the function of your liver.

When deciding if surgery is a treatment option, your healthcare team will take several factors into account:

• the number of tumors present
• the location of the tumors
• the size of the tumors
• your overall health, which includes whether or not you already have existing liver disease

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Hepatic Steatosis Is A Predictor Of Overall And Hepatic Rfs Of Crlm Patients

The terminal event of our follow-up was cancer recurrence, regardless of organs, and the median follow-up period for participants included was 7.0 months . Recurrence of any organ was observed in 153 of 195 patients. There were 124 patients with hepatic recurrence, among which 88 had liver-only recurrence, and the other 36 had multiple organ recurrences. In patients with hepatic steatosis, hepatic recurrence was observed in 82.05% of patients , while the recurrence rate was 58.97% in patients without steatosis. As shown in Figure 2, patients with hepatic steatosis had a significantly worse overall RFS and hepatic RFS . For extrahepatic RFS, no significant difference was found in these two groups . Besides, Cox regression analyses confirmed the role of hepatic steatosis in prediction of overall RFS and hepatic RFS in CRLM patients. In addition to hepatic steatosis, number of liver metastasis, preoperative chemotherapy, and KRAS mutation were also identified as significant predictors of hepatic RFS .

Figure 2. Hepatic steatosis is a predictor of overall and hepatic RFS of CRLM. Patients with steatosis had a significantly worse overall RFS and hepatic RFS than Patients without steatosis .

Some Colorectal Tumors Are Born To Be Bad

To get a better handle on the timing of metastasis, the team developed a computer model to simulate the evolution of millions of virtual tumors under different conditions.

We could then compare the simulated data with the observed patient data using various statistical techniques, Dr. Curtis explained.

The modeling data indicated that metastasis begins very early during tumor developmentwhen the primary tumor is smaller than the tip of a sharpened pencil.

In other words, Dr. Curtis said, some tumors may be “born to be bad.

The team next investigated whether the results from their small set of paired samples of primary and metastatic tumors from patients could be extended to a larger number of patients.

They analyzed publicly available data from 938 people with metastatic colorectal cancer and 1,813 people with early-stage, nonmetastatic colorectal cancer whose medical histories were known. The primary tumors of these patients had been profiled to identify genetic changes in known cancer-associated genes.

This analysis showed that certain genetic changes tend to occur together, and that specific combinations of three to five mutations were more common in patients with metastatic cancer than in those with nonmetastatic disease, suggesting that specific combinations of early genetic changes confer the potential for tumor cells to spread.

If confirmed in future studies, this information could potentially be used to guide treatment decisions, she said.

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