Biological Markers For Crlm
Based on current standard of care, KRAS and BRAF mutations are probably the most well studied in the context of CRC. KRAS mutant status has been associated with lower likelihood of having resectable CRLM. There is also higher risk of extrahepatic disease, adverse response to targeted anti-EGFR therapy as well as to oxaliplatin or irinotecan-based peri-operative chemotherapy . RAS mutation status has also been found to confer poorer survival for patients who underwent CRLM metastatectomy . Therefore, RAS mutation status is important in guiding decision-making before embarking on aggressive surgical therapies, e.g., 2-stage liver resections and those who are planning for liver resection after second-line chemotherapy . On the same note, BRAF mutation in CRC has been found to confer poorer survival and poorer response to biological therapies . The outcomes of patients with BRAF mutation status who underwent CRLM metastatectomy has also been shown to be poor .
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
Get A Second Opinion For Liver Metastases
Even if you were not treated at Roswell Park initially, we can arrange for a consultation with our specialized team for liver metastases. Our experienced surgeons are dedicated to making patients disease-free to extend survival and provide the best chance to successfully control and cure the disease. This special expertise, formally offered in a surgical opinion, is especially important for patients who have been told their liver metastases are unresectable or cannot be effectively removed. For patients who truly cannot have their cancer resected, we offer innovative treatments and therapies that can improve outcomes and potentially convert tumors from unresectable to resectable status.
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Taking Care Of Yourself
You go through a lot when you have cancer. Rest, exercise, and managing stress can help. It’s also important to eat well during your treatment. It may be harder now for your body to absorb nutrients from food. Work with a dietitian to make sure you get enough calories and nutrition. Ask your doctor for a referral.
Make sure you get the emotional support you need during this time, too. Friends, family members, social workers, and therapists can all be a big help. They may not be sure what to offer, so let them know what would be helpful. Ask them to listen when youâve had a tough day or to do something fun with you when you have the energy for it.
Colon Cancer Spread To Abdomen
Colorectal cancer may also spread to the space in the abdominal cavity, metastasizing to abdominal organs or the peritoneum, a membrane that lines the abdomen. Treatment for these metastases may involve both systemic chemotherapy, surgery and/or:
- Cytoreductive Surgery/Hyperthermic Intraperitoneal Chemotherapy . This highly specialized approach for abdominal metastases involves surgery to remove all visible tumor, a process called debulking. Then, the abdominal cavity is bathed with heated chemotherapy drugs to kill any remaining microscopic cancer cells. This is a very complex treatment that requires careful planning. However, it may be possible to combine with liver-directed therapy for some patients who have both liver and peritoneal metastases
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Treating Colon Cancer That Has Spread To The Liver: A Team Approach
Reviewed By:
Adrian Gerard Murphy, M.B. B.C.H. B.A.O., M.B.B.Ch., Ph.D.
If you or a loved one has a colon cancer diagnosis, there is also the chance that the cancer will spread to other organs, most commonly the liver. However, according to Dr. Richard Burkhart, a Johns Hopkins cancer surgeon and researcher, advancements in the treatment of liver tumors caused by colon cancer have improved survival rates drastically. In fact, 40-60 percent of patients treated for isolated colon cancer liver metastasis are still alive five years after treatment.
At Johns Hopkins, researchers such as Dr. Burkhart are conducting clinical trials to find ways to slow or prevent the spread of colon cancer. These trials, coupled with a multidisciplinary, or team, approach using molecular testing, surgical techniques, chemotherapy and radiation, have greatly improved life expectancy for patients in the last 10 years.
Radiation Based Therapies For Unresectable Crlm
In addition to chemotherapy in all its forms, unresectable CRLM may be treated by radiation either by selective internal radiotherapy or stereotactic body radiotherapy .
Selective internal radiation therapy: The blood supply of metastatic liver tumours is predominantly arterial, in contrast to that of hepatocytes which is mostly portal venous. This, together with significant arterial neovascularisation in the tumour bed, provides the physiological underpinning of SIRT, which achieves tumour destruction by delivery of radioactive microspheres via its arterial supply. Ytrium-90, which undergoes beta decay, is the most commonly used radionuclide used to label microspheres, on account of favourable penetration characteristics: Mean and maximal penetration are 2.5 and 10 mm respectively, thus delivering maximal irradiation to the tumour whilst sparing surrounding parenchyma. Currently glass and resin-based versions of the sphere are commercially available. A newer sphere which employs Holmium-166 rather than Ytrium-90 is also available and being evaluated.
In the context of colorectal liver metastases, interest in SIRT originated from studies done in patients with unresectable liver or liver dominant metastases who had proved refractory to conventional chemotherapy. These studies suggested response to SIRT in the face of prior chemo refractory status, and in some reports, significantly improved OS in patients who responded to SIRT.
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Dynamic Yap Activity Is Required For The Outgrowth Of Colorectal Cancer Organoids
To understand the origin of active YAP/TAZ signaling in growth-stagnated micro-organoids, we assessed the temporal expression patterns of micro-organoidârelated YAP genes during clonal organoid formation. As observed in mouse organoids , most YAP genes demonstrated highest expression levels during the earliest stage of outgrowth, which subsequently decreased over time , suggesting that the transcriptional state of micro-organoids mimics the earliest stages of organoid outgrowth prior to symmetry break.
To assess whether persistent YAP signaling is related to the homogeneous nature of micro-organoids, we measured SC activity upon perturbing YAP signaling activity. Inducible expression of YAP5SA, a constitutively active YAP mutant, led to transcriptional downregulation of intestinal SC markers in multiple lines, while overexpression of the inactive mutant YAPS94A had no effect . To confirm this on protein level, we chose flow cytometry analysis over Western blot, due to low expression levels of intestinal SC markers and a lack of proven antibodies. As expected, expressing YAP5SA for 48 hours in different colorectal cancer organoids prior to symmetry break induced a loss of STARhi CSCs, while STARlo cells became more frequent . Conversely, upon inducible expression of YAP inhibitor YTIP , the fraction of CSCs increased at the expense of the STARlo population .
Human Colorectal Cancer Liver Metastases
The collection and processing of human tissue from residual material of liver resection specimens was performed in accordance with the Declaration of Helsinki and approved by the Biobank Research Ethics Committee of the University Medical Center Utrecht . This tissue is classified as âresidual materialâ and the collection and processing of this biological material is in accordance with the âno objectionâ procedure defining the release of anonymized residual material without broad consent under strict conditions and approval under aforementioned Research Ethics Committee.
Liver tissue strips from patients with colorectal cancer measuring 5â10 cm à 2 cm and extending from a macrometastasis into healthy peripheral liver tissue were formalin-fixed paraffin embedded and consecutively cut. When no macrometastasis was available for diagnostic reasons, a liver tissue strip was obtained from a part of the liver unrelated to a macrometastasis.
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Mayo Clinic Minute: When Colon Cancer Spreads To The Liver
Colorectal cancer is a leading cancer among men and women around the world. Many colorectal cancers are likely to spread to other organs, with the most common site of metastases being the liver.
In this Mayo Clinic Minute, Dr. Sean Cleary, a hepatobiliary and pancreas surgeon at Mayo Clinic explains what this means to patients.
Journalists: Broadcast-quality video is in the downloads at the end of this post. Please courtesy: “Mayo Clinic News Network.” Read the script.
“Up to 30% of patients with colon cancer will develop a spot in their liver of metastasis at some point in their fight against colon cancer,” explains Dr. Cleary.
He says while the diagnosis is serious, recent advances in treatment have improved the outlook for patients.
“The best options are if we can combine chemotherapy and surgery to remove all of the metastasis from the liver. We can be quite aggressive with that. The liver is a wonderful organ in that it regenerates. So we can remove up to 70% almost 80% of someone’s liver and still have that 20% to 30% that we leave behind to regenerate and regrow so that patients can continue on with their lives,” says Dr. Cleary.
In these situations, applying individualized medicine is key to successful treatment.
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Ablation Techniques For Crlm
The observation of long term survival after resection of colorectal liver metastases, and evidence suggesting that locoregional resection is oncologically equivalent to major anatomical resection has prompted interest in minimally invasive ablative techniques which might achieve similar results to non-anatomical resection with less morbidity. Radiofrequency ablation and microwave ablation have been investigated in the context of a variety of liver tumours including colorectal liver metastases.
Radiofrequency ablation: RFA delivers alternating electrical current to cause ionic agitation, with the resulting heat generation causing denaturation and coagulation of the targeted tissue.
The benefit of radiofrequency ablation over systemic chemotherapy alone was suggested by the European Organisation for Research and Treatment of Cancer 40004 CLOCC trial comparing systemic chemotherapy alone to chemotherapy combined with RFA +/- resection for patients with inoperable CRLM, which showed a significantly improved progression-free survival for patients treated with RFA in the initial analysis and at 9.7 years of median follow up.
Meta-analyses have nevertheless assessed the efficacy of RFA in comparison to liver resection.
In terms of the efficacy of MWA in comparison to chemotherapy alone, no randomised studies have been carried out.
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Colorectal Cancer That Has Spread To The Liver: What You Should Know
In cases where a tumor is too large to be safely removed right away, treatments like hepatic arterial infusion chemotherapy can shrink the tumor enough to make a patient eligible for surgery.
We place a catheter into the artery and attach a subcutaneous pump in the abdomen so patients can get chemotherapy continuously to try to shrink the tumor, Castellanos said. It can help us get to a point where less liver needs to be removed during surgery.
External beam or other radiation techniques may also be used to treat tumors that cant be removed surgically.
Surveillance After Resection Of Crlm
Given that over half of patients undergoing liver resection for CRLM develop recurrence, that approximately half of these are hepatic only, and in the light of favourable outcomes after re-hepatectomy for intra hepatic recurrence, there is an intuitive and logical justification for surveillance following resection of CRLM. However, there is considerable heterogeneity in surveillance practice, and concerns have been raised regarding the implications of irradiation and health care costs.
Defining optimal surveillance requires a knowledge of when recurrence occurs, and how best to detect it. In a retrospective multi-institution cohort study of 2320 patients undergoing initial hepatectomy for CRLMs, Hallet et al reported that 89.1% of recurrences developed within 3 years. Recurrence was intrahepatic in 46.2%, extrahepatic in 31.8% and combined intra/extrahepatic in 22%.
Heterogeneity applies not only to length of surveillance but also to surveillance type, reflecting the lack of evidence in this area.
However, in a prospective study of 76 patients, Bhattacharjya et al reported that the use of CT or tumour markers CEA alone failed to demonstrate early recurrence in 12 and 18 patients respectively, and that the combination of tumour markers and CT detected significantly more recurrence than either modality alone, thus supporting the combination of CT and CEA in the follow-up of patients with resected colorectal liver metastases.
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Treatment Outcomes Vary Based On Your Specific Disease
According to Hopkins Medicine, 40% to 60% of people treated for isolated colon cancer liver metastasis are still alive five years after treatment. If there are multiple organs involved, outcomes are generally worse, Dr. Abrams says. If the liver has one solitary small lesion, its much better than if the whole liver is engulfed with cancer. For example, if you just have one liver lesion, your doctors may be able to remove it and in some cases cure you, says Dr. Abrams. In other cases with more extensive cancer in the liver, it can be considered incurable, although chemotherapy may help control the disease to some extent, he says.
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A fit and healthy father diagnosed with stage four cancer says he was left looking like the Nightmare on Elm Street after a horrific reaction to chemotherapy left him too embarrassed to go to his young sons cricket matches and is now hoping to save his life with a ground-breaking vaccine.
Geoffrey Seymour, 41, a procurement specialist, loved playing tennis, basketball and cricket and had always been healthy until just before his 41st birthday when he began experiencing blood in his stool.
Geoffrey was aware of this being a symptom for cancer from adverts on the television, so quickly went to his GP.
Geoffrey, who lives in Richmond, London, with his wife Santa, 44, and their son Marco, 10, was diagnosed with stage four colorectal cancer, which had spread from his colon to his liver a situation so severe and seemingly hopeless he likened it to being wrapped in a paper bag that is on fire.
He also had a bad reaction to chemotherapy severely blistering the skin on his face and, according to Geoffrey, making him look like Freddy Krueger from the 1984 horror film, Nightmare on Elm Street.
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Can Doctors Cure Advanced Cancer
Treatment for advanced bowel cancer can keep it under control, relieve symptoms and give you a good quality of life.
In a few people with advanced bowel cancer, treatment can control the cancer for a long time. And for a small number of these people, a cure might be possible.
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ESMO clinical practice guidelines for diagnosis, treatment and follow upE van Cutsem and othersAnnals of Oncology 2014 Vol 25 : iii1-iii9
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The National Institute for Health and Care Excellence , 2020. Updated December 2021
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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Key Molecules And Signaling Pathway Driving Liver Metastasis
Various signaling pathways and factors may be involved in the process of CRLM, including hepatocyte growth factor/cMet signaling pathway, phosphatase of regenerating liver , Notch pathway, TGF signaling, Tyrosine kinase c-MET signaling, tumor-associated calcium signal transducer 2 , L1 cell adhesion molecule , metastasis-related gene 1 , S100 family proteins and other pathways. There are multiple intersections between these molecular mechanisms driving CRLM.
HGF/c-Met signaling pathway
Fig. 4
The association between C-Met and CRC was even stronger due to c-MET being identified as a transcriptional target of colon cancer MACC1. MACC1 promotes proliferation, invasion, and HGF-induced scattering of CRC cells in cell culture and tumor growth and metastasis in mouse models. In advanced metastatic CRC patients, MACC1 and c-Met were both upregulated. MACC1, a new detectable biomarker in cancer, is also an independent prognostic factor for the recurrence after liver resection of CRC metastasis.
HGF/c-Met signaling promoted metastasis of cancer cells by regulating a diverse downstream prometastatic effector molecules, via Ras-MAPK/ERK, PI3K/AKT signaling, JAK2/STAT3 signaling. MACC1, KPNB1 and FOXC2 could transactivate the expression of c-MET.
CRLM and PRL3
Fig. 5
PRL3 promoted metastasis of cancer cells by regulating a diverse downstream prometastatic effector molecule, via NF-B pathway, AKT, STAT3, EGFR, IL-8 and CCL26.
CRLM and Notch pathway
Fig. 6
CRLM and TGF signaling
Sufficient Future Liver Remnant & Quality Of The Liver Parenchyma
It is imperative for the liver surgeon to study the images the liver scan to determine the location and size of the lesion with crucial surrounding structures. The relationship of the lesion to critical inflow pedicular structures such as bile duct, portal vein and hepatic artery as well as outflow structures such as hepatic veins has significant influence on how the surgery will be conducted.
Peripherally located tumours can be easily resected if the quality of the liver parenchyma allows so. In most circumstances, the liver parenchyma of patients with CRLM should be able to withstand liver resection, provided it is not exposed to excessive amount of systemic chemotherapy which may cause CALI liver as discussed above. Small wedge resection should be reasonably safe in most patients. If the tumours are located deep within the parenchyma of the liver and near to major hepatic veins, portal veins or biliary pedicles, major liver resection will be necessary in order to achieve R0 resection. In this circumstance, careful consideration must be given to the size of the FLR and the adequacy of liver function post resection. In most circumstances, up to 70% to 75% of non-cirrhotic liver could be resected as long as the remnant liver volume contributing to 25% to 30% of the total liver volume . The safety margin increases significantly in these patients with non-cirrhotic liver if a smaller resection is required.
Figure 4
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