Fibrolamellar treatment options

Tucker Davis, one day after surgery

After patients are diagnosed with fibrolamellar carcinoma (FLC), they and their medical teams will begin exploring different treatment options. (Our Find A Doctor application can be a valuable resource for newly diagnosed patients who have not yet found a medical team.)

Surgery to remove the tumor is the only treatment that has been statistically proven to extend life. When the tumor cannot be removed completely, systemic therapies, such as chemotherapy, targeted therapy and immunotherapy, as well as other local therapies, including radiation therapy and interventional radiology techniques are often used as treatments. Systemic treatments refers to drugs or therapies that can affect the entire body, reaching tumors or cancer cells wherever they are located. Local treatments address the cancer in a specific location.

Beyond surgery, there is currently no clinically-proven “standard of care” for the disease, so non-surgical therapies can vary considerably from patient-to-patient and institution-to-institution. Because FLC is so rare, it has been difficult for investigators to complete the clinical studies that are necessary to document the benefit of different systemic treatments. Nevertheless, due to rapid developments in targeted therapy and immunotherapy, and increased FLC research efforts, treatment options for FLC patients have been expanding. The search for new curative therapies is actively underway.

There are many approaches currently being used to treat fibrolamellar carcinoma. Each person’s treatment plan is unique, depending on the size, number and location of tumors; the general condition of their health; their age; plus whether the goals for the treatment are to cure the disease, extend life or alleviate symptoms. It’s important that patients have confidence in the treatment plans their doctors suggest, so patients should feel free to get a second – even a third – opinion before proceeding with treatment.

Treatment options for FLC include:

Overview

A common treatment for fibrolamellar carcinoma (FLC) is surgical removal (resection) of the tumor. Doctors sometimes use the term resectable to describe cancers they believe can be removed by surgery and unresectable to describe those they think are too difficult to be entirely removed by surgery. Surgical treatments for FLC include both curative surgery and palliative surgery. Curative surgery removes all visible traces of cancer from the body. Palliative surgery means the goal is to “debulk” the tumor, improve symptoms, lessen pain or provide better quality of life, even when all visible tumor can’t be removed.

In this excerpt from the January 2021 Virtual Open House at the University of Washington, Dr. Kim Riehle discusses the diagnosis and surgical treatment of FLC

Surgery is the only treatment for FLC that is proven to be potentially curative. As a result, many patients will go to great lengths to make sure surgery is a viable option for their treatment, including:

  • consulting with multiple surgeons about whether or not their disease can be completely resected
  • working with their surgical and oncology teams to identify systemic treatments or interventional radiology treatments that could potentially shrink the disease enough to make them a candidate for surgery.

Because the liver is the only organ which can regenerate itself, it can grow to compensate for the removed portions after surgery. This can allow surgeons to resect up to 70-80% of the liver in exceptional cases. After liver surgery, liver function typically returns to normal within 2 to 3 weeks of resection surgery and liver size returns to normal within 3 to 6 months.

Surgical approaches for FLC

Two main types of surgery are used to treat FLC that has not spread beyond the liver. These include:

Liver resection is the surgical removal of a portion of the liver.  A wedge resection (also called a segmentectomy) involves removing the area of the liver where the tumor is located; a lobectomy involves removing the whole lobe (section) of the liver that contains the tumor(s). Both are complicated operations and require an experienced team of surgeons and assistants. If the amount of liver tissue removed is not too great, the liver will function normally because its tissue has the ability to grow back.

In this video from MedStar Georgetown University Hospital, Dr. Jason Hawksworth, a transplant and hepatobiliary surgeon, explains how he performs a liver resection, why a patient might need one, and the risks of having this type of surgery.

If a patient is a candidate for surgery, their surgeon will likely discuss resection margins when planning treatment. Because tumor cells left behind after surgery can potentially re-grow, removing both the tumor and wide margins of healthy tissue surrounding it will lower the risk of the tumor coming back after surgery. A wide resection margin is the best outcome, if possible. However, the location of tumors near important structures like critical blood vessels sometimes makes wide resection margins impossible to achieve.

In some cases, a patient’s medical team may prescribe a course of chemotherapy or other systemic therapy before surgery in order to shrink the tumor to make it easier to remove.  In addition, some doctors prescribe chemotherapy after surgery to reduce the chances of stray tumor cells causing a recurrence of the disease.

After liver resection surgery, most patients can expect to be in the hospital anywhere from five to seven days, depending on their prior health and the size of the incision. Patients generally should be out of bed the day after surgery, and able to eat a limited diet and walk before they are discharged. Patients that are still in pain at discharge will be given a prescription for pain medication.  Doctors generally advise that recovering resection patients slowly increase the amount of walking they do and perform regular, moderate tasks every day to help with leg swelling and fatigue. However, patients should avoid lifting anything over five pounds for eight weeks, and need to wait for a doctor’s go-ahead before safely driving a car.

Source: Johns Hopkins University

Total hepatectomy (removal of the entire liver) followed by a liver transplant is possible when cancer has not metastasized, or spread beyond the liver.  This surgery offers a high survival rate, but it is a more involved surgery that can take up to 12 hours and requires a long recuperation time.

This video from NewYork-Presbyterian Hospital describes the importance of living donation in liver transplantation

Traditionally, patients needing a liver transplant had to wait until a suitable liver from a recently deceased person became available.  In recent years, doctors have been able to successfully transplant a portion of a liver taken from a healthy living donor. (The donor’s liver will regenerate, or grow back, over time.) The donor must go through an evaluation to be sure his/her liver is healthy and suitable, but he/she does not need to be a family member of the recipient. Living donor liver transplantation has the benefit of increasing the availability of organs, and transplants can be scheduled in advance. However, the majority of liver transplants are still from deceased donors.

Source: Cleveland Clinic

Patients with fibrolamellar who are awaiting a liver transplant from a deceased donor will be put on a “waiting list” managed by UNOS, the United Network for Organ Sharing. Priority on the UNOS list depends on a patient’s MELD score (model of end stage liver disease), with the sickest patients moving to the top of the list. 

There are many requirements for liver transplant surgery, many of which are specified by the patient’s surgical hospital of choice. In general, before a patient can begin the liver transplant evaluation process, they must be free of:

  • Cancer outside the liver
  • Substance abuse
  • Active infections
  • Disabling psychiatric conditions
  • A documented history of not following medical instructions
  • Other diseases or conditions.

Most institutions also want to be sure that the patient is willing and able to make the lifestyle changes to support the gift of life that a liver transplant provides.

After a liver transplant, most patients are able to resume normal daily activities after a couple of months, although full recuperation can take as long as six months.  Transplant patients also need to take anti-rejection medication for the rest of their lives. Since the anti-rejection medication weakens the immune system, they may need to take additional medications to prevent infections as well.

In addition, although a transplant can be potentially curative, it could prevent a patient from trying new immunotherapy treatments in the future. Because of the increased risk of organ rejection after a transplant, immunotherapy may not be an option if a transplant patient experiences a recurrence of the disease.

For more details on liver transplants, see https://www.mayoclinic.org/tests-procedures/liver-transplant/about/pac-20384842

For more details on living donor transplants, see
https://my.clevelandclinic.org/health/treatments/21083-living-donor-liver-transplant


Tumor recurrence

It is possible for tumors to recur (return) even when resection and/or transplantation has been considered successful. Different studies have shown that between 43 percent and 65 percent of all patients with liver tumors (including, but not exclusive to those with fibrolamellar) have recurrences within two years of a liver resection.

For that reason, patients are typically monitored with regular checkups and CT and/or MRI scans at regular intervals to watch for signs of recurrence. Most recurring tumors tend to appear within a few years of surgery, but patients are typically monitored for 10 years or more to be on the safe side. Depending on where they show up, recurring tumors are frequently treated with another surgery.

Overview

Chemotherapy – the use of powerful drugs to kill dividing cancer cells and prevent them from growing – is commonly used in treating fibrolamellar. Because it is a systemic treatment, chemotherapy can reach cells almost anywhere in the body. Most chemotherapies are cytotoxic chemicals, meaning that they kill cells. Chemotherapy is used as a treatment because rapidly growing and dividing cancer cells are generally more susceptible to damage by the chemo agents than normal cells.

This video from the Canadian Cancer Society gives an overview of how chemotherapy works

Chemotherapy is used in three ways:

  • to kill or shrink tumors when surgery is not possible, sometimes in the hope of enabling surgery after sufficient tumor shrinkage
  • to kill cancer cells that have spread beyond the liver, or
  • as an adjuvant therapy in combination with surgery and/or radiation
    • to enhance the response of a tumor to radiation therapy
    • to destroy residual cancer cells that could be left behind after surgery.

Chemotherapies used in liver cancer and FLC

There are many chemotherapy drugs that doctors can choose from. Oncologists generally choose which drug to use based on a standard protocol for a disease (the drugs with the history of the best outcomes), the stage of the cancer, as well as the health and age of the patient. Because of the rarity of cases of FLC and the lack of systematic studies to establish a clear “standard of care”, many oncologists prescribe chemotherapies for FLC based on treatments that have been shown to be effective in HCC, plus their best judgement. In light of the limited evidence supporting the use of any particular treatment in FLC, a wide variety of treatments are currently prescribed.

Because FLC tumors can be resistant to many chemotherapy drugs, oncologists often use a combination of 2 or 3 of these drugs to achieve the best results. (See rationale for combination therapies in the targeted therapy section.) The response rate to chemotherapy drugs with FLC is roughly 25 percent.1

Chemotherapies that are used to treat fibrolamellar patients include:

  • 5-fluorouracil (5-FU)
  • Capecitabine (Xeloda) – Capecitabine is closely related to 5-FU. Instead of being an infused drug, capecitabine comes in a pill form. It is metabolized by the body into 5-FU.
  • 5-FU plus interferon
  • FOLFOX (5-FU, oxaliplatin and leucovorin)
  • Gemcitabine (Gemzar)
  • GEMOX (gemcitabine plus oxaliplatin)
  • Oxaliplatin (Eloxatin)
  • Doxorubicin (pegylated liposomal doxorubicin)
  • Cisplatin
  • Mitoxantrone (Novantrone).

Chemotherapy administration

Chemotherapy port placement

Chemotherapy is often administered by injection or infusion, though some can be administered in pill or capsule form, which can be taken at home. Since many chemotherapies are strong medications, they can potentially cause damage if repeatedly injected into a peripheral vein in a patient’s arm. Consequently, doctors will often insert a port, a nickel-sized device with an attached catheter (tube) that ends close to the heart. This position allows infused agents to be spread throughout the body quickly and efficiently, and the port allows medication to be injected into it rather than through frequent needle stick injections. The port is usually implanted under the skin in a patient’s upper chest, and can remain in place as long as necessary. Insertion of the port is done in an operating room using local anesthesia while the patient is sedated, but awake.

This video from Moffitt Cancer Center describes what a port is, what it is used for, and how it is inserted

Doctors give chemotherapy in cycles, with each period of treatment followed by a rest period to give the body time to recover. The treatment schedule varies with the patient and the drugs used.

Other methods of administering chemotherapy that are sometimes used in FLC include:

  • Transarterial chemoembolization (TACE) – with TACE, a catheter is inserted in the groin and guided into the artery that supplies the cancerous tumor. Chemotherapy drugs are delivered straight to that artery, with the goal of disrupting the tumor’s blood supply while trapping the chemotherapy inside the tumor. (See the interventional radiology section for more information)
  • Percutaneous hepatic perfusion (PHP) – In PHP, the liver’s blood supply is temporarily disconnected from the body’s circulation and chemotherapy drugs are circulated through the liver for a short time. Unlike traditional chemotherapy, in which medications circulate throughout the entire body, PHP targets the liver only. As a result, oncologists can treat tumors with higher doses of chemotherapy using PHP than are possible when the chemo is given systemically.

Both TACE and PHP are minimally invasive surgeries that can be used in conjunction with other treatments, such as surgery, radiation or ablation.

Side Effects

Everyone reacts to chemotherapy drugs differently, but many side effects are common. Most chemotherapy drugs work by attacking cells in your body that are dividing quickly. Cancer cells form new cells more rapidly than normal cells. However, other cells in your body also divide quickly, like those in the bone marrow, the lining of the mouth and intestines, and hair follicles. As a result, these cells can also be affected by the chemotherapy drugs, which can lead to side effects. While the exact side effects of chemotherapy depend on the specific drug, dosage and length of time they are taken, typical side effects include:

  • hair loss
  • nausea
  • diarrhea
  • infertility
  • extreme fatigue (due to low red blood cell counts)
  • increased risk of infection (due to low white blood cell counts)
  • neuropathy (tingling, burning or numbness, most often in the fingers and feet).

While all of these side effects are unpleasant, not all are serious. Talking to the treatment team about them is important, as adjustments can sometimes be made when a side effect is particularly debilitating.


1https://emedicine.medscape.com/article/278354-treatment

Overview

Targeted therapy is a newer type of cancer treatment that uses drugs or other substances to more precisely identify and attack certain types of cancer cells. Targeted drugs block the growth and spread of cancer by interfering with specific biochemical pathways in tumor cells that are important to their growth or survival. By targeting specific molecules involved in those pathways, the drugs can inhibit the growth of the tumor while limiting damage to normal cells. Targeted therapy is sometimes called “molecular targeted therapy” or “precision medicine”.

In this video from Cancer.net, Dr. Jyoti Patel describes how targeted therapies work and how it differs from other systemic approaches

Targeted therapies differ from traditional chemotherapy in that targeted therapies try to alter how the cancer cells work. To do that, they focus on part of the cancer cell that makes it different from a healthy cell. In contrast, most standard chemotherapies kill rapidly dividing cancerous and normal cells. Like chemotherapy, targeted therapy drugs enter the bloodstream and reach most areas of the body, which makes them potentially useful against cancers that have spread. Because standard chemo is not very effective in most patients with liver cancer, doctors are focusing more on using targeted therapies.

Types of targeted therapy

There are many different types of targeted cancer drugs. They include both

  • small molecule drugs that are are small enough to enter a cancer cell and target a specific substance inside the cell, and
  • large molecule drugs that can’t fit inside a cell, but work by weakening or destroying proteins or enzymes on the cancer cell’s surface.

Most of these targeted therapy drugs work by one of the following mechanisms:

  • Slowing or stopping the development of new blood vessels that feed the cancer cell (This type of drug is called an angiogenesis inhibitor)
  • Blocking signals that tell a cancer cell to grow or divide
  • Triggering the immune system to attack the cancer cell
  • Changing specific proteins within a cancer cell, so the cell dies
  • Carrying other types of treatments (like chemotherapy) directly to a cancer cell to kill it, while leaving normal cells alone (These are often called antibody-drug conjugates or ADCs).

Targeted therapies used in liver cancer and FLC

FLC patients are often treated with the following targeted therapies. All are approved treatments for HCC:

Protein kinases are enzymes on or near the surface of a cell that send growth signals. Kinase inhibitors and tyrosine kinase inhibitors are small molecules that block these chemical messengers. Blocking these proteins can often help stop a cell from growing and dividing and can slow the formation of new blood vessels. The growth factor receptors most commonly targeted by TKIs are vascular endothelial growth factor receptor (VEGFR), basic fibroblast growth factor receptor (bFGFR), platelet-derived growth factor receptor (PDGFR), and epidermal growth factor receptor (EGFR).

How Tyrosine Kinase Inhibitors work
Source: Cancer Research UK

Specific kinase inhibitors that are currently being used to treat fibrolamellar include:

  • Sorafenib (Nexavar) – a targeted therapy that blocks the growth of blood vessels and cancer cells. In 2007, sorafenib became the first targeted drug approved by the FDA to treat patients with HCC.
  • Regorafenib (Stivarga) – blocks the growth of blood vessels and inhibits tumor growth. In 2017, regorafenib was approved as a treatment for HCC in patients who have already been treated with sorafenib.
  • Lenvatinib (Lenvima) – another drug that blocks blood vessel growth. In 2018, lenvatinib was also approved to treat HCC.
  • Cabozantinib (Cabometyx) – blocks blood vessel growth and some of the processes involved in tumor invasiveness and metastasis. In 2019, cabozantinib was approved for use in patients with HCC who have already been treated with sorafenib.

To try to overcome resistance, these targeted therapy drugs are frequently used in combination with other drugs, including:

  • traditional chemotherapy drugs (e.g. GemOx plus lenvatinib; lenvatinib plus capecitabine), or
  • immune checkpoint inhibitors (e.g. nivolumab plus lenvatinib).

Please see the discussion of combination therapies below and in the immunotherapy section.

mTOR is another type of kinase protein that causes cells to produce chemicals that trigger cell growth or initiate the development of new blood vessels. mTOR is involved in the control of cell growth and aging. By blocking mTOR, mTOR inhibitors can stop the growth of some types of cancer. 

Monoclonal antibodies are man-made versions of immune system antibodies that attach to a specific target. They work by recognizing and finding specific proteins on cancer cells. Each MAB recognizes one particular protein. Depending on that protein, they can work in different ways to kill cancer cells or stop them from growing.

This brief video from the National Cancer Institute discusses some of the ways monoclonal antibodies are used to fight cancer

MABs that are sometimes used in fibrolamellar treatment include:

  • Bevacizumab (Avastin) – a monoclonal antibody that targets vascular endothelial growth factor (VEGF), a protein that helps new blood vessels to form. This drug is currently used with the immunotherapy drug atezolizumab (Tecentriq) as the first treatment for HCC that cannot be treated by surgery or that has spread to other organs.
  • Ramucirumab (Cyramza) – a monoclonal antibody that targets a VEGF receptor (VEGFR) protein on cells, which can help stop the formation of new blood vessels. This drug can be used to treat advanced liver cancer, typically after another treatment stops working.


Rationale for combination therapies

As with any systemic therapy, cancer cells can become resistant to targeted therapy drugs, causing the drugs to become ineffective over time. This resistance can occur if the tumor cells mutate so the drug no longer interacts well with the cell targets, or if the tumor finds a new pathway to grow that does not depend on the drug’s target. To help avoid this problem, targeted therapies are frequently delivered in combination with other drugs, rather than alone.

For many cancers like fibrolamellar, it is believed that combinations of drugs – a “one-two punch” of treatment – can achieve many benefits. Potential benefits include:

  • Reducing tumor resistance to the treatment. By using drug combinations, the risk that a tumor is resistant to the drug decreases.
  • Attacking multiple targets at once. The use of drug combinations allows doctors to target several factors driving a cancer’s growth simultaneously. Theoretically, working on multiple molecular targets at the same time should raise the chances of killing cancer cells and eliminating a tumor.
  • Taking advantage of drug synergies. Sometimes a combination of drugs can be synergistic, meaning the impact of the combination is bigger than sum of the individual effects of each drug. For example, one drug could sensitize a tumor cell to another drug, making the combination much more effective than either drug alone.

However, combination therapies also have some risks or disadvantages, including:

  • Increased side effects could be experienced because more than one drug is used
  • The drugs could potentially interact in ways that cause additional new side effects.

Because patients with fibrolamellar carcinoma tend to be young and (aside from the cancer) usually have no underlying liver disease, many believe the benefits of drug combinations outweigh their risks. Consequently, there is a lot of activity, from early research to clinical trials, focused on investigating the use of different combination therapies in liver cancer and FLC.


Role of genomic profiling tests

Genomic profiling provides information about the specific genetic makeup of an individual patient’s cancer cells. To get this information, a sample of tumor tissue from a recent surgery or biopsy is analyzed to identify changes in the DNA (and sometimes the RNA) of the cancer cells. These tests generally do not perform a complete genomic analysis of the patient’s tissue. Instead they often look for specific mutations for which a drug treatment is already available, or under development.

This “Mutations Matter” video from the Cholangiocarcinoma Foundation provides an overview of the value of molecular profiling in cancer treatment

For some patients, an “actionable target” is found. This means that the test discovered a particular mutation in a patient’s tumor that can be attacked by an existing drug.

Unlike many other cancers, FLC tumors tend to have few genetic mutations other than the DNAJB1PRKACA fusion gene. As a result, many FLC patients do not receive actionable results from these tests. Nevertheless, many FLC patients opt to pursue the testing, hoping to find and potentially benefit from new emerging targeted cancer treatments.

Many major medical centers offer this type of testing to their patients. In addition, many commercial laboratories (including Caris, Foundation Medicine, Guardant, Molecular Health, and Paradigm) also offer tumor profiling tests. If interested, patients should speak with their medical teams about the costs and potential benefits of genomic or molecular testing.

Overview

While chemotherapy works directly on tumors to kill cancer cells, immunotherapy works by “revving up” a patient’s own immune system to attack the cancer. It is another relatively new treatment that strives to improve the immune system’s ability to identify and destroy cancer cells. Immunotherapy has been used in many different types of cancer, including liver cancer.

In this video from a 2019 Cancer Research Institute Immunotherapy Patient Summit, Dr. Elizabeth Jaffee, deputy director of the Sidney Kimmel Comprehensive Cancer Center (and member of the FCF Medical & Scientific Advisory Board), gives an overview of the emerging role of immunotherapy in cancer treatment

There are several different types of immunotherapies that are being developed for many different diseases. These include:

  • Checkpoint inhibitors – drugs that block proteins that stop the immune system from recognizing and attacking the cancer cells
  • Adoptive cell transfer therapy – a treatment that engineers a patient’s own immune cells to better recognize the cancer, grows them in a lab, and reinserts them in the body to attack the cancer. One type of adoptive cell therapy that has already made strong progress in certain types of blood cancers is CAR-T (chimeric antigen receptor T cell) therapy.
  • Monoclonal antibodies (MABs) – immune system proteins created in the lab that are designed to bind to specific targets on cancer cells. While some MABs are considered “targeted therapy”, some can be used to mark cancer cells so that they will be better seen and destroyed by the immune system.
  • Treatment vaccines – vaccines which cause a person’s immune system to attack cancer cells.
  • Immune system modulators – naturally occurring proteins that enhance the body’s immune response against cancer.

Immunotherapies used as treatment for FLC

Of those five types of immunotherapy, three are currently being used to treat FLC, including checkpoint inhibitors, monoclonal antibodies and immune system modulators. In each of these immunotherapy categories, patient treatment with at least one drug is already underway.

An important function of a person’s immune system is keeping their immune cells from attacking normal cells in the body. T cells (a main type of immune cell that kill virus-infected cells and cancer cells) have proteins on them that are used to turn on or off an immune response. These are called checkpoints. Cancer cells can sometimes use these checkpoints to avoid being attacked by the immune system. Drugs that block these checkpoint proteins are called checkpoint inhibitors.

This video from the National Cancer Institute give a general overview of how immune checkpoint inhibitors work

PD-1 is one type of checkpoint protein on T cells. When PD-1 attaches to PD-L1, a protein on other cells in the body, it acts as an “off switch” that tells the T cell to leave the other cell alone. If cancer cells contain large amounts of PD-L1, they can essentially remain hidden from T cells. Drugs that can block the binding of PD-L1 and PD-1 can therefore boost an immune response against cancer cells.

Several checkpoint inhibitors are currently being used to treat liver cancer and FLC. These include:

  • Nivolumab (Opdivo) – a checkpoint inhibitor that targets the PD-1/PD-L1 pathway. In 2017, nivolumab was approved by the FDA for patients with advanced liver cancer. In 2020, the combination with ipilimumab was also approved for patients with HCC that were previously treated with sorafenib. (See the combination therapy discussion below.)
  • Pembrolizumab (Keytruda) – a checkpoint inhibitor that targets the PD-1/PD-L1 pathway. In 2018, pembrolizumab was approved for patients with advanced liver cancer who were previously treated with sorafenib. (See the clinical trials page for more information about a pediatric clinical trial using pembrolizumab).
  • Atezolizumab (Tecentriq) – a checkpoint inhibitor that targets the PD-L1 pathway. In 2020, atezolizumab plus bevacizumab (Avastin), was approved as a first-line treatment for some patients with advanced liver cancer.
  • Ipilimumab (Yervoy) – a checkpoint inhibitor that, unlike the previously listed drugs, targets a different checkpoint – the CTLA-4 pathway. Ipilimumab in combination with nivolumab, was approved in 2020 for patients with advanced, previously treated liver cancer.

Many immune system modulator drugs are based on cytokines – proteins made by white blood cells. One in particular, interferon alfa is sometimes used in the treatment of fibrolamellar. Interferon alfa can enhance a patient’s immune response to cancer cells by causing some white blood cells to become active and to attack the cancer. It can also encourage cancer cells to send out chemicals that attract immune system cells to them.

For many years, interferon alfa has been administered to patients in conjunction with the chemotherapy drug, 5-FU. Interferon alpha-2B is also part of the newer “triple therapy” – nivolumab/5-FU/interferon alfa-2b – that has been given to some FLC patients. This “triple therapy” is currently being used as a treatment at some institutions and is currently the subject of a clinical trial (see the clinical trials page for more information).

Therapeutic cancer vaccines work by stimulating the immune system to attack tumor cells. They are made from cancer cells, parts of cancer cells, or proteins from the surface of cancer cells and are designed to help the body to recognize the disease and fight it.

In this video, Dr. Mark Yarchoan from Johns Hopkins describes the use of therapeutic vaccines to treat cancer

Research in this area is at an early stage and vaccines are only available today as part of a clinical trial. There is currently a clinical trial underway to assess the effectiveness of a peptide vaccine that targets the unique fusion protein in FLC. In this trial, the peptide vaccine is used in combination with Opdivo and Yervoy. Please see the clinical trials page for more information.


Combination therapies including immunotherapy

Across many cancers, there has been a lot of research conducted investigating the benefit of combining immunotherapy treatments (especially checkpoint inhibitors) with other therapies, including chemotherapy, targeted therapy and radiation therapy. It is thought that the breakdown of tumor cells by other drugs and localized treatments could help immune cells recognize a cancer as foreign, and therefore improve the effectiveness of the immunotherapy. Alternatively, the additional treatments could potentially drive additional immune cells to penetrate the tumor and therefore enhance the impact of the immunotherapy treatment.

Notable immunotherapy combination treatments under investigation for FLC include:

  • Nivolumab, plus 5-fluorouracil (5-FU) and interferon alpha-2b. Many fibrolamellar patients have already been prescribed this “triple therapy” at some institutions. See the clinical trials page for more information about a clinical trial that is trying to understand the interactions of this combination and the value of sequencing the drugs.
  • Ipilimumab plus nivolumab (approved in 2020 for the treatment of HCC).
  • Atezolizumab plus bevacizumab (approved in 2020 for the treatment of HCC).
  • Nivolumab plus lenvatinib.

Overview

Interventional radiology (IR) can be used to locally treat FLC tumors without major surgery.

In this video from Roswell Park Comprehensive Cancer Center, Michael Petroziello, MD gives an overview of interventional radiology

Interventional radiologists can reach virtually every organ in the body by inserting small needles, wires or catheters through tiny incisions in the skin. IR doctors use medical imaging techniques, such as ultrasound, CT and MRI, to guide their instruments to the precise location of a tumor. As a result, doctors can complete a procedure or give treatment right where a patient needs it. Some of the benefits of interventional radiology include a reduction in the cost, recovery time, pain, and risk to patients who would otherwise need traditional open surgery.

IR techniques used in FLC

Interventional radiologists use a variety of techniques to treat cancers like FLC. These include:

Ablation is sometimes used to treat specific tumors or alleviate symptoms. Liver ablation is often done when the tumor can’t be removed surgically, when the patient is too sick for surgery, or to buy time while the patient is awaiting a transplant.

This video from oncolex describes how radiofrequency ablation is used to treat liver tumors

In liver ablation, a tumor (generally under 3 cm, or just over one inch) is destroyed without being removed.  There are several ablation techniques used to destroy the tumor, including

  • Radiofrequency ablation – the use of high-energy radio waves to heat the tumor
  • Microwave ablation – the use of electromagnetic waves to heat the tumor
  • Cryoablation– freezing  the tumor
  • Ethanol ablation – also called percutaneous ethanol injection (PEI). In this procedure, concentrated alcohol is injected directly into the tumor to damage the cancer cells.

During ablation therapy, heat or cold is transmitted from a special machine through a needle-shaped probe placed into the tumor. With the guidance of an ultrasound or a CT scan, the doctor inserts the probe through the skin and into the liver and the tumor. Imaging is also used throughout the procedure to monitor the treatment and determine whether the approach is helping to destroy the tumor tissue.

Because ablation often destroys some of the normal tissue around the tumor, it might not be a good choice for treating tumors near major blood vessels, the diaphragm, or major bile ducts.

Ablation is not a major surgery, although general anesthesia may be used.

Embolization can also be used as a treatment option when FLC can’t be removed by surgery. Embolization is a procedure that cuts off the blood supply to a tumor by injecting particles directly into the blood vessels feeding the tumors. Since blood carries oxygen and nutrients that are necessary for tumor growth, restricting the blood flow can significantly slow down or stop tumor growth.

In liver embolization, small particles or beads are injected into the hepatic artery. During the procedure, a doctor places a catheter into an artery in the thigh and threads it up into the hepatic artery, using imaging techniques to guide the catheter to the appropriate location. Once the catheter is in the correct place, the doctor injects the beads to block the artery.

Embolization is often used to administer chemotherapy or radiation. The principal types of embolization that are used as FLC treatments include:

This video from Stanford Hospital outlines the use of chemoembolization for liver cancers
  • Transarterial Chemoembolization (TACE). In TACE or chemoembolization procedures, a high dose of cancer-killing drug (chemotherapy) is delivered directly to tumor while depriving the tumor of its blood supply by blocking the arteries that feed it. In these procedures, the chemotherapy is delivered to the tumor either by direct injecting the drug through the catheter, using a gelatin sponge soaked in the drug, or using special drug-eluting beads that already have the chemotherapy in them. This type of treatment can allow a higher amount of the drug to reach the tumor with fewer side effect than systemic chemotherapy. This is because the beads or embolizing agents keep the chemotherapy drug contained in the tumor by blocking the flow to other parts of the body. Consequently, a higher dose of chemotherapy drug can be used, because less of the drug is able to circulate to the healthy cells in the body.
This overview of SIRT produced by SIRTeX, a supplier of Y-90 radioactive beads, gives a useful overview of the procedure for liver cancer patients
  • Transarterial radioembolization (TARE), also called selective internal radiotherapy (SIRT). This form of treatment is a type of brachytherapy, or internal beam radiation. It has the advantage of delivering a high dose of radiation to a very targeted area. This method is very similar to chemoembolization, but instead of using chemotherapy drugs, it uses radioactive glass beads. In TARE, tiny microspheres containing yttrium 90 (Y-90), a radioactive isotope that kills cancer cells, are injected into the artery supplying the tumor. After being infused, the beads lodge in the blood vessels near the tumor, where they emit small amounts of radiation to the tumor site over several days. Because the radiation travels only a short distance, its effects are mainly limited to the tumor.

In general, embolization has relatively few side effects because the anticancer agents are contained near the tumor and don’t travel throughout the body.

Irreversible electroporation (IRE) is a new technology that destroys tumors with short electrical pulses without thermal heat. The principal advantage of IRE is that it can potentially be used on tumors that are near critical structures, such as arteries, veins, and bile ducts, without doing damage to the healthy tissue.

This video from Inova Health System describes how the NanoKnife, a type of irreversible electroporation system, can be used to destroy liver tumors

In IRE, doctors insert one or more thin probes into the tumor and deliver short electrical pulses into the tumor. This creates small holes within the cancer cell membranes, which can lead to tumor cell death. IRE is sometimes used along with surgery to increase the margins for resectable tumors. When tumors are located near major blood vessels, there can be a risk of impacting healthy body parts located along the edges or margins of the tumor. By using IRE before performing surgery, it may be easier to remove the tumor without damaging the healthy tissue.

IRE procedures are sometimes referred to as “NanoKnife” procedures, after the brand name of an IRE-based ablation system.

Overview

Radiation is the use of high-energy electromagnetic rays to disrupt the DNA that causes cancer. Radiation can kill the cancer cells and/or stop new cells from being created. A radiation oncologist plans and directs radiation treatment in cancer patients, working with a team that may include a radiation oncology nurse, technicians, and therapists.

In this video from Cancer.net, Dr. Karen Winkfield gives an overview of the types of radiation therapy and potential side effects

In some cases, radiation is used in combination with other treatments, such as surgery and/or chemotherapy. For example, radiation may be used to shrink tumors before surgery, or may be used in conjunction with chemotherapy to treat recurring tumors. Radiation can also be used to shrink tumors, make the patient more comfortable, and prolong life when surgery is not possible. Radiation is also sometimes used to treat fibrolamellar metastases outside of the liver1.

Use of radiation therapy in FLC

For cancers like FLC, radiation therapy is typically given in two ways:

External beam radiation therapy (EBRT) can help control the growth of liver metastases. This approach is most often used when the cancer can’t be removed surgically, and the liver tumors are too large for treatment with ablation, a type of interventional radiology.

With EBRT, a machine delivers radiation following imaging scans taken of the tumors. As with any form of radiation, the goal is to deliver a targeted dose of radiation directly to a tumor, with as little radiation as possible hitting healthy organs. For that reason, a patient’s abdomen may be tattooed with tiny dots to help the technician pinpoint the exact location of the disease.

Before the start of radiation treatment, the patient is also usually fitted for a mold – a foam device that will hold the body in place during treatment and ensure that the patient will be in exactly the same position for all the radiation treatments.

Sometimes other drugs, like 5-FU, are used alongside radiation therapy as radiosensitizers, to make the tumor more susceptible to damage by the radiation treatment.

Types of EBRT

There are several ways of delivering the external radiation:

  • Stereotactic body radiation therapy (SBRT) is an intense radiation dose (delivered in one to several sessions). The major downside of SBRT is the possibility of damaging neighboring organs.
  • Intensity-modulated radiation therapy (IMRT) involves targeting the tumor with small beams of radiation of varying strengths, which has the advantage of limiting exposure to adjacent organs.
  • Three-dimensional conformal radiation therapy (3D-CRT) uses a three dimensional image of the tumor, then employs beams of radiation matched to the tumor’s size and shape. Because of its precision, it is often used when tumors are close to vital organs. This form of radiation usually requires multiple sessions over many weeks.
  • Proton beam therapy (PBT) aims proton beams (positively-charged particles that create energy to destroy cancer cells) at the tumor. PBT has the advantage of being highly targeted and can be done over just a few sessions. However, there are very few treatment centers that offer PBT, and it is much more expensive than other treatments.

In many clinics and hospitals, the radiation technology is sometimes called by the brand name of the company that made the machine. Brands of commonly-used machines that move around to target the tumor from many different angles include CyberKnife, X-Knife, Clinac, Novalis, and TrueBeam. Gamma Knife is another brand of machine that uses about 200 separate small beams of radiation at one time, creating a very large dose focused on the tumor.

Coping with Side Effects

A session of radiation typically takes about 15 minutes, and is painless. However, many people do experience side effects after several sessions. Some of the most common side effects with abdominal radiation include itchy, dry or blistering skin at the site of the radiation, fatigue, loss of appetite, nausea, diarrhea and cramping. 

A patient’s radiology team will suggest ways to cope with most of these side effects. For example, there are medications to prevent vomiting, lotions to soothe the skin, and dietary changes that can help with digestive issues. The good news is that many of these side effects are temporary and go away shortly after radiation treatments have ended.

With internal beam radiation, an interventional radiologist inserts radioactive material inside or near the tumor to kill cancer cells and shrink the tumor.  This form of treatment is often called brachytherapy. It has the advantage of delivering a high dose of radiation to a very targeted area. Radioembolization is the most common form of brachytherapy used in FLC and other liver cancers. (See radioembolization under interventional radiology.)


For more information about radiation therapy, please visit:
https://www.cancer.net/navigating-cancer-care/how-cancer-treated/radiation-therapy/understanding-radiation-therapy


1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804803/

Overview

Any treatment that is done to relieve the symptoms of cancer or the negative effects of cancer treatment is considered palliative care. Palliative care is not curative; rather, the idea is to make patients more comfortable and improve their quality of life while undergoing treatments. Studies have shown that palliative care can greatly enhance a patient’s quality of life during this very difficult time, especially if begun early in treatment. 1

This patient education video from ASCO introduces palliative care and discusses its importance to cancer care

Palliative care is usually provided by a specially-trained team of doctors, nurses and other specialists who work together with a patient’s doctors to provide an extra layer of support. Sometimes called “supportive care”, palliative care is driven by the unique needs of the individual patient, not on the patient’s prognosis. Palliative care is appropriate at any stage of a serious illness, and it can be provided along with the patient’s regular treatments.

While pain management is certainly a large part of palliative care, it’s not the only concern. Besides their physical needs, cancer patients have emotional and often spiritual needs as well. All major cancer centers have palliative care teams, including a therapist and spiritual advisor, to address those needs. There’s often also a dietitian to address nausea, weight loss, and loss of appetite, and a financial advisor to help the patient and family through the maze of bills and insurance claims.

Differences between palliative care and hospice care

It is important to make the distinction between palliative care and hospice care. The two are often confused because they overlap. However, while palliative care can and should be practiced during all stages of cancer treatment, hospice care is focused on making the patient feel cared for and comfortable in what is thought to be the last six months of life. (Therefore, hospice care includes palliative care, but palliative care is not necessarily hospice care.)

Find out more

To find out more about palliative care, talk to your oncologist or someone on your oncology care team. They can refer you to the appropriate specialists.

Click here to learn more about hospice care.


1 https://meetinglibrary.asco.org/record/136346/abstract

Please note: The Fibrolamellar Cancer Foundation does not provide medical advice or recommend any specific organizations or services.  We provide website users with information to help them better understand their health conditions and current approaches to the diagnosis and treatment of FLC. Always seek the advice of your physician or other qualified healthcare provider.