Tips for APPs on using TACE, TAE for hepatocellular carcinoma
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Hepatocellular carcinoma, the sixth most common cancer, accounts for 90% of primary liver cancers worldwide. Its incidence has tripled since the 1980s.
The prognosis is very poor for liver cancer, which is the second most common cause of cancer death around the world. The highest rates of the disease occur in Middle and Western Africa and in East and Southeast Asia.
Incidence of HCC is increasing due to a growing prevalence of its risk factors, which include cirrhosis, hepatitis B virus, hepatitis C virus, coinfection with HBV and HVC, high alcohol use, smoking, nonalcoholic fatty liver disease, autoimmune hepatitis, schistosomiasis and cryptogenic liver cirrhosis. Eighty percent of HCC is secondary to liver cirrhosis, and men are more likely to develop HCC.
In the United States, incidence of HCC is expected to continue to rise over the next 15 years. Ten percent to 15% of patients with HCC have curative options at the time of diagnosis, and only 5% survive 5 years.
The Barcelona Clinic Liver Cancer (BCLC) staging system is the most commonly used staging system for HCC, placing patients into stages 0 to D (See Table).
Intermediate-stage HCC (BCLC stage B) has good ECOG status and preserved liver function but is not curable due to a high tumor burden. Transarterial chemoembolization (TACE) is the standard of care for this stage of disease. Ideal candidates are those with limited multifocal disease or solitary tumors.
TACE vs. TAE
The goal of TACE is to improve quality of life, prolong survival and downstage the tumor for surgical resection.
Normal liver perfusion occurs via the portal vein and hepatic artery. HCC is supplied by the hepatic artery.
TACE, performed by accessing the femoral artery, is accomplished through injection of a chemotherapeutic agent selectively into the artery feeding the targeted tumors. Many different agents may be utilized in TACE, including mitomycin, cisplatin and doxorubicin. No chemotherapeutic agent to date has proved superior. A single treatment with TACE is usually insufficient and, therefore, multiple-staged procedures are utilized to be super-selective and preserve liver function.
In a meta-analysis by Maluccio and colleagues that included 322 patients with HCC, TACE significantly improved OS compared with best supportive care (HR = 0.7; 95% CI, 0.5-0.99).
However, other trials have not repeated this survival benefit, likely due to variety in patient selection and a lack of standardization of the procedure. There also is selection bias in who receives TACE or transarterial embolization (TAE) based on who will likely be able to tolerate the procedure with existing comorbidities.
For some, decompensated cirrhosis is considered a contraindication to TACE, whereas others consider it an option in cases of impaired portal flow, usually due to thrombus. Other contraindications include, infection, leukopenia, renal insufficiency, decompensated heart failure, hepatic encephalopathy and biliary obstruction.
TAE utilizes intravascular delivery of embolic microspheres to cause tumor cell ischemia without the delivery of chemotherapeutic agents. Controversies remain regarding TAE, because it is not clearly established whether embolization confers a comparable survival advantage to that of chemoembolization. It is thought that some patients may tolerate TAE because no chemoembolization is involved.
However, studies have not shown a difference in 1-year survival rates between patients who underwent TACE vs. TAE. For instance, in a study published in Journal of Clinical Oncology, Brown and colleagues compared data of 51 patients who underwent embolization with microspheres alone (TAE) with that of 50 patients who received embolization with 150 mg doxorubicin (TACE). Researchers reported similar median PFS (6.2 months vs. 2.8 months; HR = 1.36; 95% CI, 0.91-2.05) and median OS (19.6 months vs. 20.8 months; HR = 1.11; 95% CI, 0.71-1.76) for the TAE and TACE groups.
Still, TACE is preferable in the treatment of HCC, and many institutions only offer TACE.
Treatment effect
The variation in outcomes with TACE is due to lack of its standardization. It also is important to note that although TACE is effective, the results are often impacted by case selection bias.
There are no guidelines that specify when to repeat the procedure. Current practice relies on expert opinions that suggest “on-demand” TACE. Chemotherapy should be administered every 3 weeks to fit the cell cycle, but no superior chemotherapy has been identified and patients, still recovering from the procedure, would not be able to tolerate another TACE.
Repeating TACE that frequently also would increase the risk for adverse events. Selective TACE utilizes embolic particles in the segmental or subsegmental branches feeding the tumors and is associated with higher levels of necrosis.
HCC tumors are hypervascular, which allows embolic particles to create tumor hypoxia and necrosis. The addition of chemotherapy has not been studied as a known effect of tumor necrosis.
TACE assumes the HCC is chemosensitive to improve survival over and above TAE.
Despite TAE or TACE, patients often relapse at the treated sites, new hepatic sites or in extrahepatic locations. Randomized phase 2 trials continue to accrue patients to study the use of TACE/TAE and concurrent anti-VEGFR and anti-PDGFR agents to prevent angiogenesis and tumor regrowth.
Controversy also exists regarding concurrent systemic treatment, especially given the availability of new immunotherapy agents.
Sorafenib (Nexavar, Bayer), a tyrosine kinase inhibitor, has been the standard systemic treatment option for locally advanced HCC. In intermediate-stage HCC, sorafenib is utilized in conjunction with locoregional therapies.
Nivolumab (Opdivo, Bristol-Myers Squibb), an anti-PD-1 immunotherapy, also has been FDA approved for systemic treatment of HCC. The agent is well-tolerated compared with sorafenib. However, PD-1 antibodies administered as a monotherapy have response rates of only 10% to 20%, and the identification of biomarkers for prediction of treatment response is needed. Currently, there are no clinical trials with multimodal therapy combining immunotherapy and locoregional treatment to prove efficacy.
APP’s role in TACE/TAE care
APPs play a pivotal role in the care of patients in preparation for and following the TACE/TAE procedure and should be aware of potential toxic effects.
At our institution, APPs follow the patient from before to after the procedure. On admission, APPs perform a history and physical, noting anything that would contradict the procedure, such as hepatorenal syndrome. We also perform a thorough evaluation of laboratory values. Due to coagulopathies in the HCC population, fresh frozen plasma or platelets may need to be given prior to the procedure. We transfuse for international normalized ratio greater than 1.5 and platelets less than 50 x 109/L.
On the day of the procedure, antibiotic prophylaxis is used for cholangitis prevention. Several doses also are administered after the procedure.
Immediately after the procedure, the affected limb should remain straight with a closure device for 2 hours, and the puncture site should be monitored for hematoma or pseudoaneurysm and checked every 2 hours for 8 hours. For patients with closure devices placed post-procedure, patients are instructed to keep the affected extremity straight and to lie flat for 4 hours.
Patients often stay overnight for monitoring and pain control. Patients are hydrated with IV fluids during this time, as they may vomit and require hydration. In order to be discharged, patients must be able to drink 4 ounces of fluid without vomiting. Narcotics and antiemetics are ordered by the APP during this time.
Post-embolization syndrome occurs in the first 24 to 72 hours after TACE/TAE among up to 90% of patients and can last up to a week. This is thought to be due to an anti-inflammatory response to tissue necrosis and chemotherapy. Post-embolization syndrome includes transient fever, abdominal pain, elevated transaminases, nausea and vomiting, and is treated with narcotics and antiemetics.
At our institution, hepatic liver function is monitored and if a normal elevation occurs in response to therapy, patients are discharged the next day knowing that they will continue to have pain, nausea and vomiting. If the APP notes transaminases above 1,000 IU/L, the patient is at high risk for liver failure. Patients are monitored with daily liver function tests and will be discharged when the transaminases downtrend.
Liver failure can occur in about 7.5% of patients after TACE/TAE, with greater risk among patients with portal vein thrombosis and those with high tumor burden. Imaging studies should be ordered to assess for liver abscess among patients with a persistently elevated white blood cell count, prolonged pain and fevers greater than 102.5°F for 5 days.
Extrahepatic embolization can occur with embolic and chemotherapeutic agents in procedures that are not super-selective. Damage also can occur to the gastrointestinal mucosa, gallbladder, diaphragm and the skin. This damage is treated as necessary.
Post-embolization follow-up will include serial CT scans to assess response of the tumor to TACE or TAE. Tumor necrosis will be considered a positive response. HCC tumors always recur.
Patients are also monitored for their ability to resume a diet and previous activity.
Conclusion
TACE or TAE is considered the standard of care for patients with BCLC stage B HCC. The data do not favor TACE or TAE as superior. Ongoing clinical trials are accruing patients to try to address this issue. Currently, it is up to the provider to decide which procedure to use for the patient with HCC, creating selection bias.
The addition of chemotherapy to the embolizing particles does not show improved patient outcomes. Locoregional therapies continue to evolve, with use of chemotherapy and immunotherapies. Providers need to be aware of symptoms after the procedure for delivery of quality patient care.
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