Neuroendocrine Neoplasms (NENs) present complex challenges to diagnosis and treatment. Even in metastatic cases spreading to the liver, there are some important differences compared to the more common types of gastrointestinal tumours and pancreatic adenocarcinomas, e.g. their sometimes indolent nature and their ability to oversecrete hormones causing distinct clinical syndromes. Also, the tumours are known to be highly vascular which is a feature where growth inhibition and symptom relief may be achieved by specific ‘blocking’ agents – this is particularly the case with liver metastases in well-differentiated Neuroendocrine Tumours (NETs).
Spread to the liver may occur from NETs of the foregut, midgut as well as hindgut. NET metastases are usually multiple and of varying size. In most cases, both liver lobes are affected, but widespread (miliary) seeding throughout the liver is seen only occasionally according to my research. Midgut NETs are the most type causing liver metastases, especially when of small intestine origin. Appendix NETs unusually give rise to hepatic spread and hindgut, particularly rectal less than 2 cm rarely metastasise to the liver. Many NET patients will have been initially diagnosed via liver biopsy indicating late diagnoses are pretty common. Pancreatic NETs vary in malignant potential and frequency of liver metastases, most are non-functional, but these can often spread silently to the liver. Functional pancreatic NETs can announce themselves earlier and some remain fairly indolent rarely spreading (e.g. insulinomas). Many of these factors statistically guide clues during the diagnostic period as doctors look to tie down primary locations and syndromic connections – it can, however, often be looking for a needle in a haystack. Please note that when NETs spread, they often spread to the liver. That does not mean you have liver cancer. Liver metastases are simply clones of the primary tumour, even when they cannot find that primary tumour.
Surgery remains the only curative option for NETs but it’s true to say this mainly applies to localised tumours at the lower grades. For many the declaration of liver metastasis means that the cancer is now at an advanced stage and is therefore incurable. However, it is treatable. I’ve discussed surgery in many articles, including the dilemma for doctors and patients in deciding to cut or not to cut. And I have written about my own liver treatment here. For this article, I wanted to focus on the types of liver-directed therapy excluding surgery.
If you can see them, you can treat them
Finding the liver metastases can often be easier than finding the primary, however, some scans or combinations of scans may be necessary to determine the best picture to plan for therapeutic intervention. Many people will have had an ultrasound-guided liver biopsy which is good enough for that purpose but that scan type has a low mean sensitivity in detecting every liver deposit. NET liver metastases are hypervascular so they may look different from normal liver abnormalities if contrast infusion is used during CT. However, to take advantage of their hypervascular nature, scanning using both arterial and portal phases make it less likely that metastases will be missed. Most texts say CT has a sensitivity of around 85% for NET liver metastases. MRI is at least as good as CT for NET liver metastases. Often, somatostatin receptor nuclear scans such as the Octreotide scan or Ga68 PET, can at best confirm the staging or enhance it by finding further and/or smaller deposits.
Clearly, systemic treatment covers the liver too, but liver-directed therapy does what it says on the tin – it directly targets cancer in the liver and is often used to treat NETs that have spread to the liver for a number of reasons including:
- control symptoms caused by too many hormones released by the tumour, especially if somatostatin analogues have stopped working.
- relieve or control the symptoms of advanced neuroendocrine cancer (palliative therapy).
- slow down and control the growth of cancer.
- shrink one or more tumours before surgery/clean up after surgery.
The following liver-directed therapies may be used to treat NETs in the liver. You may have other treatments before or after liver-directed therapy.
As stated above, NETs are known to be highly vascular, that is they live on blood supply. Tumour embolization is a procedure to shrink a liver tumour by cutting off its blood supply. The doctors put a thin, flexible tube, called a catheter, into an artery near your groin or in your arm. He or she guides the catheter into the liver artery (the hepatic artery) that supplies blood to the tumour. So, the theory is if you block the blood supply to a tumour, the tumour will reduce or die. It’s a procedure carried out in the UK by a person known as an interventional radiologist – it’s very much image-guided. Other countries may use other appropriately trained personnel and they may have different names.
There are essentially 3 types of liver embolization:
Often known as Hepatic Arterial Embolization (HAE) or TransArterial Embolization (TAE). Basically, the technique is described above.
Chemo – Trans Arterial Chemo Embolization (TACE)
As per the bland type but they add some chemo (normally Fluorouracil (5-FU) but could be different depending on where you are). There is currently some debate about the actual advantages of that over bland.
Radioembolization – Trans Arterial Radio Embilization (TARE)
Also often called selective internal radiotherapy (SIRT), uses tiny radioactive beads (microspheres). It damages the blood vessels to the tumour so that it can’t get the nutrients it needs, and the radiation given off by the SIRT beads damages the cancer cells and hopefully stops them from growing. The radiation used is mostly always Yttrium 90 or Y90. (Should not be confused with the Y90 version of Peptide Receptor Radio Therapy (PRRT) which is a different type of treatment for the whole body).
Side Effects and Rest
Common side effects of hepatic arterial embolization are a group of symptoms called postembolization syndrome. These side effects include pain in the abdomen, fever, nausea, abnormal liver function tests, and in extreme cases, hormonal crisis.
I had a bland embolization prior to major surgery with the aim of ‘softening up’ some of my tumours in preparation. I was admitted the evening before the procedure and given octreotide IV to de-risk the chances of a hormonal crisis (carcinoid crisis) as I was syndromic at this point. The procedure itself is fairly straightforward, I had a mild sedative but I was aware of everything going on. There is some discomfort after as you need to lie still for a few hours as the puncture wound used to insert and retract the catheter heals. I remained in hospital overnight and was discharged with pain killers the following day. I had a week off work to rest. I had minor pain and discomfort for around 5 or 6 days. Your treating doctor (normally an Interventional Radiologist) should explain the procedure in more detail. I was scheduled to get a TACE after my liver surgery, but it was aborted (…long story).
Radiofrequency ablation (RFA) and microwave ablation (MWA) use heat to destroy cancer cells or tumours (more than just the liver). The heat is supplied by electrical currents passed through a special needle placed directly into the liver. Side effects will depend mainly on how much of the liver is treated. RFA/MWA is undertaken by doctors with special experience, and it may not be available at all treatment centres. You can hear about this in the videos below. There are several other ablation techniques used worldwide including Interstitial laser ablation (e.g. Nanoknife), high-intensity focused ultrasound (HIFU), cryoablation, and irreversible electroporation.
Interest point: Trans Arterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis
Liver-directed hepatic arterial therapies are associated with improved survival and effective symptom control for patients with unresectable neuroendocrine liver metastases (NELM). Whether trans arterial chemoembolization (TACE) or trans arterial radioembolization (TARE) with yttrium-90 (y-90) are associated with improved short- or long-term outcomes is unknown.
A retrospective review was performed of all patients with NELM undergoing trans arterial therapies, from 2000 to 2018, at 2 academic medical centers. Postoperative morbidity, radiographic response according to response evaluation criteria in solid tumors (RECIST) criteria, and long-term outcomes were compared among patients who underwent TACE vs TARE.
Among 248 patients with NELM, 197 (79%) received TACE and 51 (21%) received TARE. While patients who underwent TACE were more likely to have carcinoid syndrome, larger tumors, and higher chromogranin A levels, there was no difference in tumor differentiation, primary site, bilobar disease, or synchronous presentation. Nearly all TARE treatments (92%) were performed as outpatient procedures, while 99% of TACE patients spent at least 1 night in the hospital. There were no differences in overall morbidity (TARE 13.7% vs TACE 22.6%, p = 0.17), grade III/IV complication (5.9% vs 9.2%, p = 0.58), or 90-day mortality. The disease control rate (DCR) on first post-treatment imaging (RECIST partial/complete response or stable disease) was greater for TACE compared with TARE (96% vs 83%, p < 0.01). However, there was no difference in median overall survival (OS, 35.9 months vs 50.1 months, p = 0.3) or progression-free survival (PFS, 15.9 months vs 19.9 months, p = 0.37).
In this retrospective multi-institutional analysis, both TACE and TARE with Y-90 were safe and effective liver-directed therapies for unresectable NELM. Although TARE was associated with a shorter length of hospital stay, TACE demonstrated improved short-term DCR, and both resulted in comparable long-term outcomes.
Credit: Trans Arterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis
Egger, Michael E. et al. Journal of the American College of Surgeons, Volume 230, Issue 4, 363 – 370
Interest point: Clinical Trials for Liver Directed Therapy
Lu177 Based. There’s a clinical trial looking at the use of Lu177 in a liver-directed modality. Based in Netherlands, you can read about the Intra-arterial Lu177 (PRRT) for Neuroendocrine Cancer liver metastases (LUTIA) trial here.
Ablative Immunotherapy Based. A Phase 1 Study of PV-10 (Rose Bengal) ablation of Neuroendocrine Tumours (NET) Metastatic to the Liver – read more here.
Histotripsy: A new technique which destroys cancer using soundwaves (now in Clinical Trials) – read more here.
1. NET Research Foundation patient information video (University of Chicago) (10-12 minutes) – click here – focused on interventional radiology for liver directed therapy.
2. Royal Free London NET Team patient information video – click here – longer than above but more detailed, link starts 10 minutes in at the start of the interventional radiology talk – mainly liver based but does include some interesting stuff they also do which will be of interest to some NET Patients – apologies for use of ancient ‘carcinoid’ terminology.
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General Clinical Trials Disclaimer
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact.
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