What is liver cancer?
Liver cancer is defined by an abnormal and uncontrolled growth of cells within the liver. These altered cells progressively substitute the normal cells, collapsing the normal function of the liver, and invading other organs. These events irremediably lead to the death of the patients affected from this disease. We should distinguish liver cancer from benign tumors, that are also the result of an altered cellular growth, but they lack the invasiveness capacities of the malignant tumors (cancer). Therefore, the prognosis of benign tumors is excellent and in the majority of cases there is no need of treating them.
A relative has been diagnosed with liver metastases. Is it liver cancer?
Briefly, there are two main types of liver cancer: Primary liver cancer, which appear from the cells that are normally located in the liver, and secondary liver cancer (also known as metastases), that is a cancer originated in other part of the body (in the lungs, breasts or in the colon, for instance) that sends the diseased cells to the liver, where are implanted. The treatment of this secondary liver cancer depends on the type of primary cancer from which is originated, and is mainly based in the use of pharmaceutical drugs commonly known as chemotherapy. We will focus our information on the primary liver cancer. There are several types of primary liver cancer according to the type of cells that are altered. The most frequent, by far, is the hepatocellular carcinoma (HCC), which is a cancer derived from the main cell of the liver called hepatocyte. There are other types of primary liver cancer such as intrahepatic cholangiocarcinoma (derived from the biliary cells), sarcomas, etc., that should also be taken into account.
Is primary liver cancer frequent?
Primary liver cancer is a very common cancer worldwide. Recent studies ranked the primary liver cancer as the sixth most frequent and it is particularly common in the Eastern and Sub-Saharian Africa. Therefore, this cancer is a priority for the Health institutions and scientific communities.
Is there any risk factor for its appearance? How can we prevent it?
HCC appears mainly in patients with a chronic liver disease, particularly when this liver disease is advanced and causes cirrhosis. There are several causes of liver disease, but the most important are the alcohol abuse and the chronic infection by hepatic virus (mainly by hepatitis B and C viruses). Accordingly, the most effective way to prevent the development of HCC is avoiding those agents that are able to damage the liver (for instance, universal vaccination for preventing the infection by hepatitis B virus, avoiding excessive alcohol consumption, etc.), or treating them eagerly before the liver develops cirrhosis (for instance, antiviral therapies if the liver is chronically infected by an hepatic virus).
Which kind of symptoms is associated with the development of HCC?
HCC produces symptoms when it is too advanced and at that point, usually there are no effective therapies. The most frequent symptoms are tiredness, weight lost, appetite decrease, and signs of liver failure such as jaundice, fluid retention, intestinal bleeding, etc.
If HCC is usually asymptomatic at the beginning, how can we detect it at early stages?
As we have pointed out, the presence of cirrhosis is the most important risk factor for HCC development. For that reason, all the scientific societies recommend performing a periodical abdominal ultrasound (every 6-12 months) in those cirrhotic patients in whom any treatment could be applied if an HCC is detected. The aim of this surveillance program is detecting the disease at early stages, when treatment is feasible and effective.
How can HCC be diagnosed?
Once a suspicious liver nodule is detected by ultrasound, it is recommended to perform a dynamic imaging technique (computed tomography or magnetic resonance) for further characterization. If this nodule displays a specific vascular profile through the different phases of the dynamic study, the HCC diagnosis can be confidently done without the need of a biopsy. Contrarily, if the vascular pattern is not the typical, the only way to confirm the diagnosis of HCC is by obtaining a biopsy. There is an active research in tumor markers that could help physicians to diagnose the disease at a very early stage, when imaging techniques and pathological assessment are unable to confidently perform the HCC diagnosis.
I have heard that the hepatocellular carcinoma is a cancer with a very bad prognosis. Is that true?
The prognosis of HCC is very variable and depends on several factors. First, the number, size and extension of the tumor. In that regard, the presence of tumor within a vessel or outside the liver indicates an advanced stage and poor prognosis; at that point only palliative therapies are available. Contrarily, small solitary tumors can be successfully treated in most cases and long-term survivals are possible. Second, we have to keep in mind that in most cases HCC appears within an underlying chronic liver disease. Therefore, the degree of liver function reserve determines not only the treatment options, but also the outcome. Finally, the presence of symptoms indicates an advanced disease and limits the tolerance and success of several treatment approaches. As a summary, the prognosis of this cancer is very wide and your physician can inform you about the expectation and treatment possibilities.
Is surgery useful for HCC?
As stated previously, there are several treatment options, but the decision of which is the best is based mainly on the tumor stage and the degree of liver function impairment. In the case of HCC, the first option is surgical resection. However, this approach is contraindicated in those patients with decompensated cirrhosis and the best outcome is obtained in those patients with solitary tumors and well-preserved liver function. If surgical resection is not feasible, the next option to be considered is liver transplantation. This approach not only allows to completely remove the tumor, but also the impaired liver. Lamentably, the scarcity of donors and the potential risk of tumor recurrence after liver transplantation determine that only those candidates with the best-expected outcome should be enlisted. In that regard, liver transplantation is contraindicated in those cases with vascular invasion or extrahepatic spread and in most centers there are a pre-established limits according to the size and number of nodules. In addition, advanced age and associated diseases may also constitute a contraindication for liver transplantation.
If surgery is not indicated, are there any other effective options?
Definitively, yes. There are several locoregional approaches that are designed for efficiently destroying the tumor without affecting the surrounding liver parenchyma. These treatments are potentially curative and allow increasing the survival. One modality is the percutaneus ablation. It is based in the injection of substances (for instance, ethanol or acetic acid) or the change of the intratumoral temperature (for instance, delivering heat by radiofrequency or freezing the tumor by cryotherapy) using a device introduced through the skin by the guidance of an imaging technique, usually ultrasonography. This treatment modality is recommended in patients with small tumors in whom surgical treatments are not feasible or during the waiting time for liver transplantation. Regrettably, these treatments are not effective in large tumors or with multiple foci. Another strategy is the transarterial procedures. These treatments are based on the almost exclusive arterial vascularization of the HCC compared to the mixed (arterial and venous) of the normal liver. These procedures allow delivering chemotherapy or radiotherapy at high doses directly into the tumor and also to selectively block the vascular feeding. The most frequently transarterial therapy used worldwide is the transarterial chemoembolization (also known as TACE) and is habitually used in large tumors and/or multifocal. In the last years, there has been an active research in the field of locoregional therapies and they have become a cornerstone treatment modality for this disease.
Is chemotherapy useful in HCC?
Several chemotherapeutical agents, alone or in combination, have been evaluated in HCC. Regrettably, all these studies have shown a limited efficacy and an inadmissible rate of side effects, mainly due to the frequent association between HCC and cirrhosis. Accordingly, standard chemotherapy is not recommended for HCC. Luckily, in the last years, great advancements have been done in the knowledge of the disrupted molecular pathways associated with the cancer initiation and progression. These findings have allowed to design new agents that specifically and selectively block the altered pathways, minimizing the frequent side effects associated with conventional therapies. Among them, the only one that up to date has shown benefits in term of survival is sorafenib, an oral available multikinase inhibitor that acts mainly inhibiting the tumor proliferation and the formation of new vessels, freezing the tumor growth. The positive results obtained with sorafenib in several clinical trials have justified that this agent has become the standard therapy in patients with advanced HCC. There are other molecular targeted therapies under investigation in HCC, and in some of them, promising preliminary results have been obtained. Accordingly, it is highly recommended to participate in clinical trials that evaluate these novel agents. Undoubtedly, in the next years further treatment advancements will be in place, allowing to increase the survival and the quality of life of patients affected with HCC.
What is cholangiocarcinoma?
The liver contains several different types of cells. The cells present in the greatest concentration are the liver cells also known as hepatocytes. These carry out most of the functions of the liver and make up the bulk of liver tissue. Bile is made in the liver and is drained from the liver by the bile ducts. Bile ducts drain the left and right sides of the liver separately. These right and left ducts meet just outside the liver substance, are joined by a duct from the gall bladder (the cystic duct) and drain into the intestine. Bile ducts are lined by cells that are different from the hepatocytes, called cholangiocytes. In addition, the liver also contains cells of the immune system, cells that help the liver repair itself after damage, and other types as well. Each of these different types of cells can give rise to a cancer. Cholangiocarcinoma arises from the cells that line the bile ducts.
Cholangiocarcinoma is the second most common liver cancer after cancers arising from liver cells (hepatocellular carcinoma), but it is still relatively infrequent. About 10-15% of all cancers that first arise in the liver are cholangiocarcinoma. Depending on where the tumour arises the treatment and outcomes may be different. One form of cholangiocarcinoma is the intrahepatic cholangiocarcinoma which arises from the small bile ducts within the substance of the liver. A second form arises in the main bile ducts draining the liver. These are called extra-hepatic cholangiocarcinoma. The third form arises in the gallbladder, and finally there is a form that arises at the junction of the bile duct and the small intestine.
Extra-hepatic cholangiocarcinomas are further subclassified, depending on their location, into tumors which are located at or near the junction of the ducts draining the right and left lobes of the liver (see the graphic). This is termed perihilar cholangiocarcinoma; previously referred to as Klatskin tumor, Tumors located beyond the junction of the bile duct and the duct draining the gallbladder (cystic duct) are called distal cholangiocarcinoma. Gallbladder cancer and cancer of the junction of the bile duct and the small intestine (ampulla of Vater) are distinct separate entities. Among the subtypes of cholangiocarcinoma, the perihilar form is the most common, accounting for 50-60% of cases, followed by the distal cholangiocarcinoma (20-30%) and lastly intrahepatic cholangiocarcinoma (10-20%).
The different types of liver cancer
How common is cholangiocarcinoma?
The incidence rates of cholangiocarcinoma vary by geographic region. In most regions (including Australia, Europe, Japan and USA), cholangiocarcinoma is classified as an uncommon to rare disease with incidence rates below 6 cases per 100,000 population/year. In contrast, cholangiocarcinoma incidence is much higher in regions such as South East Asia and Thailand with incidence rates of 85 cases per 100,000 population. Over time, intrahepatic and extrahepatic cholangiocarcinoma have shown divergent trends in incidence rates, with an increasing trend in the intrahepatic cholangiocarcinoma incidence rate, whereas the incidence of extrahepatic cholangiocarcinoma has decreased in recent decades.
What are the risk factors of cholangiocarcinoma?
The risk factors of cholangiocarcinoma also vary by geographic location. For example, liver fluke infection by the parasites Opisthorchis viverrini or Clonorchis sinesis is associated with a high risk of the development of cholangiocarcinoma. Liver fluke infections are found almost exclusively in certain regions of Asia with more than 9% of the total population in North East Thailand infected with Clonorchis sinesis. This explains the high incidence rate of cholangiocarcinoma in this region. In contrast, primary sclerosing cholangitis (PSC) is the most prevalent risk factor for cholangiocarcinoma in the Western world with a reported 400-fold increased risk compared to those who do not have PSC. However, PSC itself is a very uncommon disease so that overall the risk of developing cholangiocarcinoma in the Western world is not high. There are other even less common risk factors such as a rare inherited conditions such as choledochal cyst or Caroli’s disease. Other important risk factors include excessive alcohol consumption, cirrhosis, stones in the bile ducts, (choledocholithiasis), stones in the gall bladder (cholecystolithiasis), hepatitis B virus infection, hepatitis C virus infection, inflammatory bowel disease, smoking, and type 2 diabetes. Other causes may include exposure to environmental factors such as, asbestos, aromatic toxins and aflatoxin B1, although the relationship with these factors is less certain. Though many potential causal factors have been identified, the fact is that a majority of cholangiocarcinoma cases have with no clear underlying risk factors (i.e., occur sporadically).
What is the main molecular pathogenesis of cholangiocarcinoma?
Cancer is a multi-step process that develops over long time, but in cholangiocarcinoma the progressive stages are still relative poorly characterized. While different etiologies engage diverse mechanisms to promote cellular transformation of the normal biliary epithelium into precursor lesions, one likely common feature in the neoplastic path to establish biliary tumors is inflammation.
Recurrently mutated genes among biliary tumors include the oncogene KRAS Proto-Oncogene GTPase (KRAS), resulting in constitutive activation of Ras/MAPK signaling; the tumor suppressor, Tumor Protein P53 (TP53), compromising its tumor suppressive function in DNA damage response; Isocitrate Dehydrogenase 1 and 2 (IDH1/2), causing altered metabolism and cellular dedifferentiation. Additionally, a distinct subgroup of patients with cholangiocarcinoma have been identified with recurrent fusions in the Fibroblast Growth Factor Receptor 2 (FGFR2), whereby the kinase-containing domain of FGFR2 becomes fused to diverse partner genes, which increases proliferation of fusion-positive cells. However, the frequency of these mutations significantly varies dependent on the anatomical location of the tumor, the etiology and geographical region of the world, from which the patient comes. Research is underway on implied genes in order to have biomarkers for diagnosis and treatment.
How to diagnose cholangiocarcinoma?
Depending on where the cholangiocarcinoma is located the way it comes to medical attention may be different. For example, if it arises at the junction of the left and right bile ducts or lower down the bile duct it will block the flow of bile early in its course and cause jaundice. If it arises in either the left or right ducts or within the substance of the liver it will not initially cause jaundice, but may be associated with other symptoms such as weight loss. Jaundice then is only a late feature. Once a cancer is suspected the first step is imaging by either CT scan or MRI. MRI is probably the preferred method. The cancer will show as a mass in the liver or in the bile ducts and may also show that the bile ducts up-stream of the tumour are dilated. Because there are conditions other than cholangiocarcinoma that can cause this appearance additional testing is needed. These will include tests to assess the state of the liver (liver function tests), tests to see if a cause can be found, and a test called CA19-9, which is a tumour marker. A CA19-9 level which is high increases the likelihood that the mass seen on the CT or MRI is cholangiocarcinoma, but this is not 100% predictive. In many instances, a tumour biopsy will be required to confirm the diagnosis. Sometimes a diagnosis can be confirmed by samples taken during a procedure called ERCP (endoscopic retrograde cholangiopancreatography). In this procedure a tube is inserted through the mouth into the stomach and beyond to where the bile duct drains into the intestine. A smaller tube is inserted into the bile duct and samples of the bile taken and examined for tumour cells. This is also not 100% predictive. If the tumour is blocking a bile duct a narrow plastic tube can be pushed through the blocked duct to re-establish drainage. This is done at the same procedure.
What is a multidisciplinary team for the management of cholangiocarcinoma ?
Cholangiocarcinoma is a complex disease in terms of management, that requires doctors from various specialties in order to discuss the best treatment planning approach and provide individualized clinical care for each patient. This discussion between different experts is also called “multidisciplinary tumour board”. The multidisciplinary team includes, at least, a hepato-gastroenterologist, a medical oncologist, a radiation oncologist, surgeons, an interventional radiologist and nurses.
What is the role of surgery in the treatment of cholangiocarcinoma?
Surgery is the only curative treatment for cholangiocarcinoma. However, only a small proportion of patients (30-40%) are surgical candidates at the time of diagnosis. Surgical treatment usually consists of the removal of part of your liver. How much is removed will depend on where the cancer is located. Up to 60-70% of your liver can be safely removed. The liver will regenerate back to its original volume. If the tumour is at the junction of the left and right bile ducts the bile ducts will need to be removed together with the liver and a connection made between the remaining bile duct above the cancer and the intestine to allow bile to drain properly. Similarly, for distal cholangiocarcinoma the involved bile duct will need to be removed and the bile drained into the intestine in the same manner.
The 5-year survival after surgical resection for cholangiocarcinoma is around 30% depending on whether the tumour has spread to local lymph nodes, in which case the survival is less. (A 30% 5-year survival are means that after 5 years 30% of patients who have this procedure are still alive, although not necessarily cured). In some cases, an oral adjuvant chemotherapy (adjuvant means in addition to anatomical removal of the tumour, given in order to decrease the risk of tumor recurrence). Capecitabine is the most commonly used drug, usually given for 6 months after resection. In selected cases were the tumour is confined to the liver and cannot be removed with surgical resection, liver transplantation may constitute a treatment option. However, this is mainly done in specialized centers within very strict protocols and in very carefully selected patients, i.e., those who ae most likely to benefit.
What is the role of loco-regional treatment in the management of cholangiocarcinoma?
Loco-regional treatments are based on the local destruction of the tumor preserving the surrounding liver tissue. There are two main types of loco-regional therapies for cholangiocarcinoma: thermal ablation and intra-arterial procedures. Thermal ablation relies on the destruction of tumour tissue by heating or freezing the tumour tissue using special needles inserted into the tumor under guidance from CT scan or ultrasound. The two most frequently used techniques to heat the tissue are by radio waves or microwaves. These waves are generated by the needles and the waves cause the water molecules in the cells to heat up so much that the tumour is essentially cooked. Thermal ablation can be only performed in small tumors (smaller than 5 cm) and its effectiveness depends on the tumor localization and physician’s technical expertise. In very small tumors (solitary lesions smaller than 2 cm), thermal ablation may offer high chance of local control and even complete tumor elimination.
Intra-arterial procedures (trans-arterial chemoembolization or radioembolization) are based on the fact that the tumour has predominately arterial tumor blood supply compared with the mixed arterial and venous blood supply of the liver. This anatomical peculiarity allows to us to selectively deliver treatment to the tumour through the hepatic artery. This is usually in the form of chemotherapy, which may be accompanied by an attempt to block the supply of blood to the tumour or treatment may be by delivery of radioactive particles to the tumour. The ability of these techniques to effectively kill the tumour is not yet established. Both techniques kill some tumour tissue, but whether this leads to cure and an improvement in survival is still under investigation.
Has systemic treatment any place in the management of cholangiocarcinoma?
If you have a tumor in the liver that cannot be safely removed by surgery or by loco-regional therapies, or if the tumor has been grown beyond the liver and involves other organs (metastasis), the best treatment option is chemotherapy. This is treatment that destroys rapidly dividing cells such as cancer cells, which grow much more quickly than most other cells in the body (except mainly blood cells). Until very recently, the only systemic therapy that was able to demonstrate survival benefit was the combination of cisplatin and gemcitabine. Both agents are relatively well-tolerated, and they are administered in 3-weekly schedule (“cycle”). Both drugs are given on the first day (Day 1) and on Day 8 of each cycle and days 9 to 21 are rest days. A blood test before each treatment will check if the blood counts are high enough for next cycle of chemotherapy to be safely given. Kidney function will also be checked before any injection because injury to the kidney sometimes occurs. After the chemotherapy is given there may be symptoms of nausea and vomiting. These are treated with anti-nausea medications. More rarely the chemotherapy drugs may injure some nerves leading to decreased sensation and tingling in the feet. Hair loss is possible.
If the disease progresses despite this therapy, there are other chemotherapy agents used as “second-line” therapy, i.e., after the usual therapy has failed. Very recently, the combination of folinic acid (also called leucovorin or calcium folinate), fluorouracil (5FU) and oxaliplatin (FOLFOX) has demonstrated survival benefit in second line (after tumor increase in size under cisplatin and gemcitabine). FOLFOX is given every 14 days. On the first day of your treatment, oxaliplatin, folinic acid and a dose of 5FU are administered for 2 hours and afterwards, 5FU is continued through an infusion pump for 46 hours. This is similar to the way that some diabetics get their insulin. A needle is inserted under the skin and a tube placed. This is connected to a pump that delivers the medication. This is a wearable device. After the infusion is complete there is a rest period of 12 days with no treatment. This completes your first cycle of FOLFOX. The main adverse events of FOLFOX are fatigue, low blood counts, peripheral neuropathy (numbness and tingling of the extremities) and nausea and vomiting.
The systemic therapy in cholangiocarcinoma has evolved in the last years. This tumor is very heterogeneous. Different tumours may have a different genetic background. A new approach is to analyze the different genetic changes in the tumor and tailor treatment based on these changes since different medications target different metabolic processes (personalized medicine). For instance, a drug called ivosedinib has shown promising results for cancer that carry a specific mutation called IDH1. There are also several clinical trials evaluating promising drugs in patients with abnormalities of a gene called FGFR2.
What is the role of caregivers and family?
Patients undergoing treatment for cancer require a good deal of physical and emotional support. This can be provided by family members or friends or by a paid caregiver. Chemotherapy is hard on the body. Patients may feel exhausted, they may have nausea and vomiting, and may need to have special precautions to reduce the risk of infection. In addition, there is the fear of the effects of the cancer and its treatment as well as concerns around the possibility of dying. All of these require emotional support, but also help in the form of preparing meals that are palatable and if the patient is bedridden, taking care of toileting needs.
Patients who are mobile need to be taken to and from the treatment center. There may be symptoms after the treatment session that limit the ability to drive or to take public transport. The caregiver will therefore also have to be responsible for transport. Patients may not be able to shop for themselves and this would need to be done by the caregiver. All of this places a heavy burden on family members and it is best to try and share the load between family members, or if possible, a paid caregiver.
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