Liver Cancer Symptoms, Stages and Treatment
In this article
What Is Liver Cancer?
Liver cancer is a malignant disease that develops when liver cells multiply uncontrollably. The great majority of primary liver cancers in adults arise from the liver's main functional cells (hepatocytes) as hepatocellular carcinoma (HCC) tumors. One of the most important features of liver cancer is that most cases develop against a background of underlying chronic liver disease (most commonly cirrhosis) — treatment decisions therefore depend not only on the size of the tumor but also on the remaining functional capacity of the liver. In this guide, we discuss the causes, symptoms, diagnostic and staging methods, current treatment options, and the diagnostic and treatment process in Turkey for liver cancer (primarily hepatocellular carcinoma), comprehensively and based on current literature.
The liver, located in the upper right abdomen beneath the diaphragm, is the body's largest internal organ; it carries out vital functions such as digestion, metabolism, detoxification, and production of clotting factors. The term "liver cancer" refers to cancers originating in the liver (primary cancers); this differs from cancers that spread to the liver (metastatic cancers) from elsewhere in the body (such as the colon, breast, or lung) — metastatic liver tumors are classified as cancer of the organ in which they originated, and treatment is planned accordingly. This article concerns primary cancers originating in the liver.
How Common Is Liver Cancer? (Current Statistics)
According to the report published by IARC on 8 July 2026 in CA: A Cancer Journal for Clinicians containing estimates for 2024, GLOBOCAN 2024 approximately 843.045 new cases of liver cancer occur worldwide each year ( %4,1 of all cancers, the 7th most common cancer), and approximately 732.489 people die from liver cancer — accounting for %7,5 of cancer deaths and making liver cancer the world's 3rd deadliest cancer. Liver cancer is approximately 2,3 times more common in men than in women (age-standardized rate of 11,8 per 100.000 men and 4,3 per 100.000 women).
According to the Türkiye country fact sheet published by IARC in July 2026 as part of the same GLOBOCAN 2024 publication cycle, approximately 3.718 new liver cancer cases are reported (1,6% of all cancers, the 16th most common cancer), and approximately 3.534 people die from liver cancer (3,1% of cancer deaths, ranking 10th). As these figures show, although liver cancer ranks lower in Turkey in terms of incidence, it ranks much higher in terms of deaths — reflecting the fact that this is also an aggressive cancer generally diagnosed at an advanced stage in Turkey. The 5-year point prevalence (the number of people currently living with the disease) is reported as 4.867.
According to the American Cancer Society's "Cancer Statistics, 2026" report, published on 13 January 2026, the estimated number of new liver (and intrahepatic bile duct) cancer cases in the US for 2026 is 42.340 (27.790 men, 14.550 women), and the estimated number of deaths is 30.980 (19.650 men, 11.330 women). The current overall 5-year relative survival rate, based on the SEER database and the cohort of patients diagnosed between 2015-2021, is %22; this rate varies markedly by stage: for localized disease, %38, for regional spread, %13, and for distant metastases, %3. An important trend highlighted by the same report is that, although overall survival has risen from 7% in the middle of the 1990s to 22% today, incidence in women continues to increase.
Risk Factors
The great majority of hepatocellular carcinoma cases (approximately 80-90%) develop against a background of underlying chronic liver disease and cirrhosis . The most common causes of cirrhosis are also the main risk factors for liver cancer:
This is the most common cause worldwide, accounting for approximately 40-55% of HCC cases, depending on the source; this proportion may exceed 60% in East Asia and sub-Saharan Africa. An important feature is that HBV can directly cause liver cancer even without cirrhosis developing. Chronic HBV carriage in Turkey has declined markedly over the past 30 years due to the Ministry of Health's infant vaccination program (over 95% vaccination coverage since 2009): the HBV carriage rate in the population was approximately 5,3% in 1995-2002, fell to 3,1% in 2010-2015, and has dropped to approximately 2% in current estimates.
It is estimated to account for approximately 20-30% of HCC cases worldwide; it is a more prominent cause in regions such as North America, Western Europe, and Japan. HCV-related HCC almost always develops against a background of cirrhosis. The prevalence of HCV in the Turkish population is much lower than that of HBV (approximately 0,3-1,0%).
Long-term excessive alcohol consumption is an important cause of cirrhosis and associated HCC; it is estimated to account for approximately 15-20% of HCC cases, depending on the source and region.
This fatty liver disease, associated with obesity, type 2 diabetes, and metabolic syndrome, is emerging as the world's — as also reflected in its name change (from NAFLD/NASH to MASLD in 2023) — fastest-growing cause of HCC; the proportion of HCC cases developing against this background is rising rapidly, particularly in Western countries with high obesity rates. An important clinical point is that MASLD-related HCC can arise even before cirrhosis develops (that is, at an earlier stage of liver disease), compared with other causes.
Other risk factors include:
- Aflatoxin exposure: Foods such as peanuts and corn stored under unsuitable conditions can develop the Aspergillus mold. The aflatoxin B1 it produces synergistically increases HCC risk in combination with chronic HBV infection, particularly in sub-Saharan Africa and Southeast Asia.
- Other causes of cirrhosis: Cirrhosis caused by inherited metabolic diseases such as hemochromatosis (iron accumulation), alpha-1 antitrypsin deficiency, and Wilson disease also increases HCC risk.
- The combination of smoking and excessive alcohol use: Each of these factors increases risk on its own, and their effects may be amplified when they occur together.
Rarely, HCC can also develop without underlying cirrhosis (particularly with MASLD or HBV). In addition, a rare subtype of HCC called fibrolamellar carcinoma typically occurs in young patients with no history of cirrhosis and follows a different clinical course (discussed separately below).
Types of Liver Cancer
It accounts for the great majority of primary liver cancers and is the main subject of this guide. It arises from the liver's functional cells (hepatocytes) and is strongly associated with the background of chronic liver disease described above.
It arises from the cells lining the bile ducts within the liver. It is a different disease from HCC; its risk factors, diagnostic approach, and treatment (mainly chemotherapy and targeted therapies, including targetable alterations such as FGFR2 fusions and IDH1 mutations) differ markedly, and it is outside the scope of this article.
This subtype, which accounts for a small proportion of HCC cases (approximately less than 1%), has a markedly different clinical profile from classic HCC: it typically occurs in young patients with no history of cirrhosis (the average age at diagnosis is in the 20s), is associated with the DNAJB1-PRKACA gene fusion, and generally has a normal AFP level. When detected early and treatable with surgery, its prognosis may be relatively better than that of classic HCC, but its response to systemic treatment at an advanced stage is more limited than that of classic HCC.
What Are the Symptoms?
Early-stage liver cancer usually causes no symptoms; regular surveillance (discussed separately below) is therefore very important in patients with underlying cirrhosis. Symptoms and signs that may emerge as the disease progresses include:
- Pain or a feeling of fullness in the upper right abdomen
- Unexplained weight loss
- Loss of appetite, feeling full early
- Nausea and vomiting
- General weakness and fatigue
- Yellowing of the skin and eyes (jaundice/icterus)
- Fluid accumulation in the abdomen (ascites) and bloating
- Light-colored stools, dark urine
- Easy bruising or a tendency to bleed
- Palpable liver enlargement or an abdominal mass
Many of these symptoms can also result from the underlying cirrhosis itself and do not necessarily mean cancer. However, new or worsening symptoms in a person with known cirrhosis or chronic hepatitis B/C infection require prompt evaluation.
Surveillance in High-Risk Patients (Early Screening)
Current guidelines, particularly those from AASLD (American Association for the Study of Liver Diseases) and EASL (European Association for the Study of the Liver), recommend surveillance for all patients diagnosed with cirrhosis and certain subgroups without cirrhosis who are chronic hepatitis B carriers considered at high risk for HCC (for example, carriers with a family history of HCC or those in certain ethnic/age groups), using liver ultrasonography every 6 months (together with serum alpha-fetoprotein/AFP in some guidelines). The aim of this surveillance is to detect HCC while it is still small and curable with surgery or local treatment.
Turkey does not have a national invitation-based liver cancer screening program comparable to those for breast, cervical, and colorectal cancer. In patients with known cirrhosis or chronic viral hepatitis, ultrasonography (±AFP) every 6 months is carried out by the gastroenterology/hepatology or internal medicine specialist following the patient, in line with international guidelines. It is very important for people diagnosed with cirrhosis or chronic hepatitis not to miss this follow-up.
How Is the Diagnosis Made?
The diagnostic process in liver cancer differs from that of most other cancers: in the presence of cirrhosis, masses showing a typical contrast enhancement pattern on imaging can be diagnosed without a tissue diagnosis (biopsy).
- Imaging: Multiphase contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) plays a central role in diagnosing HCC. The typical imaging pattern specific to HCC consists of marked contrast uptake by the mass in the arterial phase and loss of contrast ("washout") in the portal venous/late phase.
- LI-RADS (Liver Imaging Reporting and Data System): In this system, which standardizes the classification of imaging findings in patients with underlying cirrhosis, a mass classified as LR-5 can be considered HCC directly and treatment planned without a biopsy — an important guideline-supported exception that permits diagnosis without biopsy.
- Biopsy: A tissue biopsy is required if the imaging pattern is atypical, there is no underlying cirrhosis, or the diagnosis is uncertain.
- Serum alpha-fetoprotein (AFP): It is a marker that supports diagnosis and can be used to monitor treatment response; however, because it can remain within normal limits in a substantial proportion of HCC cases (particularly at an early stage), it is not used alone to diagnose or exclude the disease.
- Assessment of liver reserve: In addition to tumor characteristics, assessing the liver's remaining functional capacity (using the Child-Pugh score described below) is essential for cancer staging and treatment selection.
Staging: the BCLC System and Child-Pugh Score
Unlike many other cancers, liver cancer staging is not based solely on the anatomical extent of the tumor (TNM). Treatment decisions largely use a framework that considers, in addition to tumor burden, the liver's remaining functional capacity and the patient's overall performance status: the BCLC (Barcelona Clinic Liver Cancer) staging system . This system combines staging and the recommended treatment approach for each stage within a single framework.
Child-Pugh Score: Measuring Liver Reserve
The Child-Pugh score combines 5 scored parameters — bilirubin, albumin, prothrombin time (INR), presence of ascites, and degree of hepatic encephalopathy (confusion due to liver failure) — to classify the liver's functional reserve as A (good), B (moderate), or C (poor) . This classification directly affects which treatments (surgery, ablation, TACE, systemic therapy) the patient can safely tolerate; for example, most advanced systemic therapies have been tested in trials and approved only in Child-Pugh A patients.
The Child-Pugh score has two practical weaknesses: two of its parameters (degree of ascites and encephalopathy) rely on subjective assessment ; and because the great majority of HCC patients (72-85%) already fall within the Child-Pugh A group, the score does not sufficiently distinguish patients receiving treatment from one another. Introduced in 2015, the ALBI score (Albumin-Bilirubin) grades liver reserve more precisely using only two objective blood measurements — albumin and bilirubin; the "mALBI" version added in 2017 sharpens this distinction further by splitting the largest group into 2a and 2b. This distinction has concrete practical implications: among patients receiving systemic treatment, median survival is approximately 11 months in the mALBI 2a group, falling to approximately 7 months in the 2b group. ALBI is widely used, particularly in Japan and in determining eligibility for TACE/TARE; however, it is a complementary tool that has not replaced Child-Pugh — the BCLC system still relies on Child-Pugh and performance status.
| BCLC Stage | Definition | General Treatment Approach |
|---|---|---|
| 0 (Very Early Stage) | Single tumor ≤2 cm; preserved liver function, good performance status | Surgical resection or ablation |
| A (Early Stage) | Single tumor (regardless of size) or ≤3 tumors (each ≤3 cm); preserved liver function | Resection, liver transplantation, or ablation |
| B (Intermediate Stage) | Multifocal tumor confined to the liver; preserved function, good performance status | Transarterial chemoembolization (TAKE/TACE) or radioembolization (TARE) |
| C (Advanced Stage) | Vascular spread (portal vein invasion) or spread outside the liver; preserved function, mildly impaired performance status | Systemic therapy (immunotherapy-based or targeted therapy) |
| D (End Stage) | Severe liver failure (Child-Pugh C) or poor performance status | Supportive/palliative care (liver transplantation may be considered in some selected patients) |
Yes; the AJCC/UICC TNM system is also defined for liver cancer and is used particularly for pathological staging after surgery and in research. However, in current clinical practice, treatment decisions are guided by the BCLC system, which also takes liver reserve into account; this guide therefore focuses on BCLC.
Treatment Approaches at Early/Intermediate Stages
Surgical Resection
In patients with a single, well-positioned tumor and adequate liver reserve (usually Child-Pugh A), surgical removal of the tumor (partial liver resection) is a curative option. In patients with underlying cirrhosis, whether the remaining liver can maintain adequate function after surgery must be assessed carefully.
Liver Transplantation
Because liver transplantation treats both the tumor and the underlying cirrhosis at the same time, it offers the highest chance of cure in suitable patients. Transplant eligibility is determined by the internationally accepted Milan Criteria : a single tumor ≤5 cm, or up to 3 tumors, each ≤3 cm, with no vascular invasion and no spread outside the liver. Long-term survival after transplantation is generally higher than after resection in patients meeting these criteria; however, waiting times for an organ and limited donor availability are important practical constraints.
The Milan criteria provide a safe but narrow framework; expanded criteria were developed when it became clear that some patients outside these criteria could also benefit from transplantation. UCSF criteria (a single tumor ≤6,5 cm, or up to 3 tumors — the largest ≤4,5 cm and total diameter ≤8 cm) have yielded a 5-year survival of approximately %81 , similar to that achieved with the Milan criteria.
Even more important is downstaging : a patient initially outside the Milan criteria first receives TACE, TARE, or ablation; if the tumor burden can be brought within Milan limits, the patient is placed on the transplant list. National policy in the US since 2017, the UNOS-DS protocol has defined entry limits (a single tumor 5,1-8 cm; or 2-3 tumors each ≤5 cm, total ≤8 cm; or 4-5 tumors each ≤3 cm, total ≤8 cm; provided there is no vascular invasion/spread outside the liver), and an AFP level above 1000 must fall below 500 ng/mL. The results are striking: downstaging succeeds in approximately two-thirds of treated patients, and in successful cases, post-transplant 5-year survival is approximately 80%, with a recurrence rate below 15% — almost the same as in patients within Milan criteria from the outset. This is because the tumor not only shrinks, but its response to downstaging also serves as a selection test showing that the tumor is biologically "well-behaved" .
The wait on a liver transplant list can be long, and the tumor can grow during this time, causing the patient to lose the chance of transplantation. Without any treatment, dropout rates reach approximately 25% at 6 months and 38% at 12 months. Therefore, if the wait is expected to exceed 6 months, "bridging" therapy is given to keep the tumor under control: ablation for small tumors, TACE/TARE for larger or multifocal disease, and increasingly SBRT for unsuitable locations. This approach is reported to reduce dropout rates markedly; however, to be candid, these data come from retrospective studies — there is no randomized trial comparing bridging therapy with no bridging therapy.
Ablation (Radiofrequency/Microwave)
In small tumors (usually ≤3 cm), particularly in patients unsuitable for surgery, image-guided radiofrequency ablation (RFA) or microwave ablation (MWA) can destroy tumor tissue with heat; outcomes comparable to surgery have been reported for very small tumors (≤2 cm).
Transarterial Chemoembolization (TAKE/TACE) and Radioembolization (TARE)
In BCLC B (intermediate-stage) patients with multifocal disease confined to the liver but unsuitable for surgery/ablation, the tumor is targeted by catheter delivery of chemotherapy (TACE) or radioactive microspheres (Y90 radioembolization, TARE) directly into its feeding vessels; these methods aim to concentrate on the tumor while largely sparing the healthy liver. In well-selected BCLC B patients, current median overall survival with TACE is approximately 20-30 months ; it can reach 40 months in patients with very good liver function and limited tumor burden, but can fall to 14-16 months in extensive disease.
One of the most common clinical mistakes is to repeat TACE again and again when it is not working. Each TACE session causes some damage to liver function; if the procedure is ineffective, this damage may accumulate and make the patient unsuitable for systemic therapy. Therefore, instead of persisting in patients who have become "TACE-refractory," switching to systemic therapy in a timely manner is increasingly strongly recommended; retrospective data suggest an additional 10-12 months of survival in patients who make this switch in time. Patients and their families should discuss this openly with their physicians: "let's try once more" is not always the right decision.
Randomized trials comparing these two methods are small, and none has shown a definitive overall survival advantage; TARE's consistent advantage is a markedly longer time to disease progression (more than 26 months versus approximately 7 months in the PREMIERE trial). Thus, while TACE remains the default option for multifocal intermediate-stage disease, TARE is preferred particularly in patients with portal vein thrombosis, disease limited to a lobe/segment, a need for bridging to transplantation or downstaging, or TACE-refractory disease . In addition, the "radiation segmentectomy" approach that has emerged in recent years — delivery of Y90 at a very high ablative dose to a single liver segment — has reported very high complete response rates (above 80%) in early-stage single tumors unsuitable for surgery or thermal ablation. However, these data come from single-arm studies; equivalence to ablation or surgery has not yet been demonstrated in a randomized trial.
Radiotherapy: SBRT and Proton Therapy
Because the liver is sensitive to radiation, radiotherapy was used only to a limited extent in HCC for a long time. However, modern stereotactic body radiotherapy (SBRT) has changed this picture, because it can deliver a high dose in a small number of sessions while largely sparing healthy liver tissue.
The NRG Oncology/RTOG 1112 trial (JAMA Oncology, 2025) tested adding SBRT to sorafenib in locally advanced HCC (74% of patients had vascular invasion). It is important to interpret the results correctly: for the primary endpoint of overall survival, the median was 15,8 months versus 12,3 months ; however, the threshold for statistical significance was narrowly missed (p=0,055). In the prespecified adjusted analysis, the difference was significant (HR 0,72; p=0,04) — a supportive finding, not definitive evidence. By contrast, the difference in progression-free survival was clearly significant (9,2 months versus 5,5 months; p<0,001), and there was no increase in serious side effects. An important limitation is that the comparator drug was sorafenib , which is no longer the first-line standard today; whether adding SBRT to current immunotherapy combinations provides a benefit is unknown.
Proton therapy has a theoretical advantage because it deposits its dose in the tumor while almost entirely avoiding irradiation of the healthy tissue behind it. Small randomized trials have reported equivalent local control compared with radiofrequency ablation and better local control compared with TACE; however, these trials are small, and a survival advantage of protons over conventional (photon) radiotherapy has not been established — use depends largely on what is available at the treatment center.
Management of Portal Vein Tumor Thrombus (Vascular Spread)
Direct growth of the tumor into the portal vein, the liver's main vein (portal vein tumor thrombus), is one of the most challenging clinical situations in HCC and automatically places the patient in BCLC stage C. The approach varies with how centrally the thrombus is located:
- Systemic therapy is the foundation for all suitable patients. In the IMbrave150 subgroup with vascular invasion, median overall survival was 14,2 months with atezolizumab+bevacizumab and 9,7 months with sorafenib (HR 0,68). However, one point requires caution: patients with main portal vein trunk (Vp4) thrombosis were excluded from most immunotherapy trials — evidence in this most severe group is therefore weak.
- Radiotherapy can be added to systemic therapy in patients with disease confined to the liver and vascular invasion; most of the RTOG 1112 population consisted of these patients. International radiation oncology guidelines conditionally recommend EBRT in this setting.
- TARE is a relatively safe option in these patients because its vessel-blocking (embolic) effect is much lower than that of TACE.
- TACE is not recommended in the presence of main trunk or main branch thrombosis — it can further reduce hepatic blood flow in an organ whose circulation is already restricted, leading to liver failure.
Hepatic Arterial Infusion Chemotherapy (HAIC)
This method, based on delivering chemotherapy directly and continuously through a catheter placed in the hepatic artery, is widely used in China, Japan, and Korea but is not included in Western guidelines. Randomized trials conducted in Asia have shown favorable results (for example, median survival of 23,1 months versus 16,1 months for FOLFOX-HAIC versus TACE; 13,4 months versus 7,1 months when HAIC was added to sorafenib in patients with portal vein invasion). However, all these trials were conducted in Asian populations dominated by hepatitis B, used sorafenib — now an outdated comparator — and have not been validated in the West. HAIC should therefore be described as "standard in some parts of Asia, investigational elsewhere."
Systemic Treatment at an Advanced Stage (BCLC C)
Patients with vascular invasion or metastases outside the liver, or who are unsuitable for local treatments, receive systemic drugs. Over the past 6 years, this field has undergone a fundamental change, with immunotherapy-based combinations replacing targeted drugs alone in the first-line setting.
First-Line Treatment
Tested against sorafenib, this combination improved median overall survival to 19,2 months versus 13,4 months — this was the first positive phase 3 trial to end sorafenib's approximately 10-year dominance in HCC. FDA approval: 29 May 2020. It is used in Child-Pugh A patients; screening for esophageal/gastric varices (endoscopy) before treatment is mandatory because of bevacizumab's bleeding risk (discussed separately below).
In this combination tested against sorafenib, median overall survival was reported as 16,4 months versus 13,8 months . The 5-year follow-up data published in 2025 showed that a significant survival difference persisted in the long term (with 5-year survival rates of approximately 20% versus 10%). FDA approval: 21 October 2022. An important advantage of this regimen is that it contains no antiangiogenic drug (such as bevacizumab) apart from the single dose of tremelimumab, so it may be considered a more suitable option for patients at high risk of variceal bleeding.
On 11 April 2025, the FDA approved nivolumab+ipilimumab as first-line treatment based on the CheckMate 9DW trial involving 668 patients. The trial compared nivolumab+ipilimumab with investigator-selected lenvatinib or sorafenib; median overall survival was 23,7 months versus 20,6 months (HR 0,79), the overall response rate was 36,1% versus 13,2%, and the 3-year overall survival rate was 38% versus 24%. This date has another significance: on the same day, the accelerated approval granted to nivolumab+ipilimumab on 10 March 2020 for second-line treatment was also converted to full approval — an accelerated approval thus became permanent five years later with confirmatory phase 3 data. As of the date this guide was written (August 2026), this is the field's latest drug approval; no new drug approval was granted in HCC during 2026.
For patients unsuitable for immunotherapy (for example, those with active autoimmune disease or receiving immunosuppression after organ transplantation), targeted drugs alone remain an option. Sorafenib, on 16 November 2007 received FDA approval and was the first drug to usher in the era of systemic therapy in HCC (SHARP trial: median overall survival of 10,7 months versus 7,9 months with placebo). Lenvatinib was tested against sorafenib in a noninferiority design and showed similar efficacy in median overall survival (REFLECT trial: median 13,6 months versus 12,3 months); its FDA approval was on 16 August 2018.
Second-Line and Later Treatments
| Drug / Trial | Conditions for Use | Main Result |
|---|---|---|
| Regorafenib (RESORCE) | Patients who tolerated sorafenib and experienced progression | Median overall survival 10,6 months versus 7,8 months (placebo), HR 0,63 |
| Cabozantinib (CELESTIAL) | Patients previously treated with sorafenib (second/third line) | Median overall survival 10,2 months versus 8,0 months (placebo), HR 0,76 |
| Ramucirumab (REACH-2) | Patients with progression after sorafenib and serum AFP ≥400 ng/mL | Median overall survival 8,5 months versus 7,3 months (placebo), HR 0,71 |
| Pembrolizumab (KEYNOTE-224/240/394) | Patients previously treated with systemic therapy — the current FDA indication has been narrowed (see the note below) | Overall response rate ~13-17%; KEYNOTE-240 failed to meet its endpoints, and approval was retained only with data from KEYNOTE-394 conducted in Asia |
Liver cancer may be the most instructive example of how the accelerated approval system works (and corrects itself when necessary). Three separate immunotherapy indications were approved based on response rates in single-arm trials, then met three different outcomes:
- Nivolumab alone received accelerated approval for second-line treatment on 22 September 2017; however, when the confirmatory phase 3 trial (CheckMate 459) failed to meet its overall survival endpoint, this indication was completely withdrawn on 23 July 2021.
- Pembrolizumab alone was approved on 9 November 2018; the confirmatory KEYNOTE-240 trial failed to meet its endpoints, but following the favorable results of KEYNOTE-394 conducted in Asia, approval was converted to full approval on 25 January 2024 — but the indication was markedly narrowed: it now covers only patients with hepatitis B-related HCC who previously received systemic therapy that did not include PD-1/PD-L1.
- Nivolumab + ipilimumab received accelerated approval for second-line treatment on 10 March 2020 and, as described above, on 11 April 2025, based on CheckMate 9DW data, was converted to full approval.
These three different outcomes show that the phrase "FDA-approved" alone is not sufficient information: whether approval is accelerated or full , the population it covers, and the result of the confirmatory trial determine its real meaning for the patient.
One of the most anticipated questions in recent years was whether combining TACE with systemic treatment would improve outcomes. Two large phase 3 trials tested this question, and both followed the same pattern — they delayed disease progression, but did not prolong life:
- EMERALD-1 (TACE + durvalumab + bevacizumab): showed a significant progression-free survival benefit (15,0 months versus 8,2 months; HR 0,77). However, the final overall survival analysis announced in 2026 was negative (29,9 months versus 33,3 months; HR 1,10) — there was no survival difference, and the control arm was even numerically better. In the US, this combination has not been submitted for approval.
- LEAP-012 (TACE + pembrolizumab + lenvatinib): also showed a progression-free survival benefit, but on 29 October 2025 the manufacturers announced that overall survival had not reached significance at the interim analysis and the trial had been terminated. The combination is approved only in China .
Together, these two results demonstrate an important lesson: a tumor remaining progression-free on imaging for longer does not mean the patient will live longer. Therefore, as of August 2026, routinely combining TACE with systemic therapy is not a standard approach.
The rivoceranib+camrelizumab combination, which reported promising results against sorafenib in CARES-310 (median overall survival 23,8 months versus 15,2 months, HR 0,64), has been rejected by the FDA with complete response letters (CRLs) three times in succession (17 May 2024, March 2025, and 10 July 2026) because of manufacturing facility issues — manufacturing/inspection problems, rather than efficacy data, have delayed approval. As of August 2026, this combination has not yet received FDA approval; its developers are reportedly planning to resubmit. It is therefore not currently an approved treatment option, but is being followed as a candidate that may come onto the agenda in the near future.
Adjuvant atezolizumab+bevacizumab was tested to reduce recurrence risk after resection or ablation (IMbrave050). However, in the updated overall survival analysis published in 2026 in Journal of Hepatology (median follow-up 35,1 months), the result was in favor of the surveillance arm (HR 1,26 — more deaths in the treatment arm); the initial favorable difference in disease-free survival also disappeared over time (33,2 months versus 36,0 months, HR 0,90). The trial's own conclusion explicitly states that these data do not support routine use of adjuvant atezolizumab+bevacizumab. Therefore, as of August 2026, routine adjuvant systemic therapy after resection or ablation is not standard practice; these patients continue with imaging-based surveillance as described above.
A Preventable Cancer: the Role of Antiviral Treatment
The most important feature distinguishing liver cancer from many other cancers is that most cases arise from a known and treatable cause (chronic viral hepatitis). This makes liver cancer truly preventable — and this section may have the greatest potential to save lives in this guide.
In chronic hepatitis B, suppression of the virus with drugs such as entecavir or tenofovir, which are nucleos(t)ide analogues , markedly reduces liver cancer risk. This is not an observational inference but a finding demonstrated in a randomized trial: in the landmark trial conducted in patients with advanced fibrosis/cirrhosis (Liaw, NEJM, 2004), HCC developed at a rate of %3,9 in the treatment arm versus %7,4 in the control arm, and the trial was stopped early. Subsequent large cohorts with current drugs have reported a risk reduction of 50-70% .
An equally important finding is that antiviral treatment also reduces recurrence after cancer treatment: in a meta-analysis of 6.350 patients, those who received antivirals after curative treatment (surgery/ablation) had a recurrence risk approximately %34 lower and a risk of death approximately %44 lower. Current guidelines therefore recommend starting antiviral treatment in all patients diagnosed with hepatitis B-related HCC, regardless of which cancer treatment is used.
Complete clearance of hepatitis C with direct-acting antivirals (DAAs) (sustained virological response, SVR) reduces liver cancer risk by approximately %71 . The concern raised a few years ago — "Do DAAs increase cancer risk?" — was refuted.
However, there is a vital nuance here that most patients do not know: even after the virus is cleared, risk does not disappear completely in a liver that has developed cirrhosis. In patients with cirrhosis, annual HCC incidence after SVR remains approximately %2,1-2,3 , and this increased risk may persist even 10 years after the virus has been cleared. Therefore, patients with cirrhosis must continue ultrasound follow-up every 6 months for life, even if hepatitis C has been treated and "cured." By contrast, in patients who have not developed cirrhosis (F3 and below), risk falls below the surveillance threshold, and individualized follow-up is increasingly accepted for this group.
The hepatitis B vaccine is one of two vaccines worldwide that can directly prevent a cancer (the other is the HPV vaccine). Thanks to Turkey's infant vaccination program, implemented since 1998 and achieving coverage above 95% since 2009, carriage in the population has fallen from approximately 5,3% to 2% — this will translate into a marked reduction in the liver cancer burden over the coming decades. In addition, stopping alcohol use, controlling obesity and type 2 diabetes (to reduce the MASLD background), and vaccination against hepatitis A/B are fundamental prevention steps for everyone with chronic liver disease.
There are many news reports on this subject, but the honest summary is: no drug has been shown to prevent liver cancer in a randomized trial. All available data are observational, and observational studies are susceptible to biases such as people taking the drug already being healthier or receiving more regular follow-up.
- Statins: This is where the strongest observational signal lies (approximately a halving of risk in an analysis involving 1,77 million people). However, randomized trials in cirrhosis were designed around liver failure outcomes rather than cancer and have not demonstrated a cancer-preventive effect. Dedicated trials are ongoing.
- Aspirin: A large Swedish registry study found 10-year HCC rates of 4,0% versus 8,3%; however, in a comprehensive meta-analysis, this association disappeared when statin and metformin use were taken into account. Variceal bleeding in cirrhosis also poses a genuine potential harm.
- Metformin: The association is statistically not significant; there is no basis for recommending it.
- Coffee: Observational studies report approximately 35% lower risk with 2 cups a day; however, the authors rated their own evidence as "very low" quality.
The practical summary of the guidelines: For the purpose of preventing liver cancer, statins, aspirin, or metformin should not be started; however, they should be used if already recommended for another reason, such as heart disease or diabetes. Drinking coffee is not harmful and is probably beneficial. Genuine prevention consists of the antiviral treatment, vaccination, and avoidance of alcohol described above.
Supportive Treatment: Managing Cirrhosis Is Part of Cancer Treatment
A substantial proportion of patients with liver cancer die not from the cancer itself but from complications of the underlying cirrhosis . Managing cirrhosis is therefore not an "extra service" but a component with equal priority to cancer treatment; keeping these complications under control also directly determines whether the patient remains eligible for cancer treatment.
| Problem | Management and Its Relationship to Cancer Treatment |
|---|---|
| Fluid accumulation in the abdomen (ascites) | Salt restriction (~5 g per day) and diuretics; drainage of fluid with albumin support when needed. New or uncontrolled ascites can make a patient unsuitable for TACE or systemic therapy. Calorie intake must not decline when salt is restricted. |
| Esophageal/gastric varices | Screening endoscopy and beta-blockers or banding when necessary. Endoscopic screening for varices is mandatory before starting bevacizumab-containing treatment (discussed separately below); if banding has been performed, waiting approximately 2 weeks before starting treatment is recommended. |
| Hepatic encephalopathy (confusion) | Lactulose and rifaximin when needed. An important misconception must be corrected: protein should not be restricted — normal/high protein intake does not trigger encephalopathy and may instead improve it. Encephalopathy is a common reason for patients losing eligibility for systemic therapy. |
| Malnutrition and muscle loss (sarcopenia) | It occurs in 40-70% of patients with cirrhosis and independently worsens outcomes from surgery, TACE, and systemic treatment. Target: 30-35 kcal/kg of energy and 1,2-1,5 g/kg of protein daily; 4-7 meals a day and, importantly, a late-evening snack. This last item is the highest-yield intervention: in cirrhosis, fasting overnight is metabolically equivalent to fasting for days. |
| Other | Complete avoidance of alcohol, vaccination against hepatitis A and B, correction of vitamin D deficiency (present in 64-92% of patients with cirrhosis), and regular physical activity. Introducing palliative care support early markedly improves quality of life. |
Treatment Side Effects and Their Management
Antiangiogenic Drugs (Sorafenib, Lenvatinib, Bevacizumab, Regorafenib, Cabozantinib, Ramucirumab)
Common side effects of this drug class include hypertension, hand-foot syndrome (particularly prominent with sorafenib and regorafenib), proteinuria, diarrhea and fatigue . Hypertension and proteinuria may be more frequent and more pronounced with lenvatinib in particular.
Esophageal/gastric varices, common in patients with underlying cirrhosis, carry a bleeding risk because of bevacizumab's antiangiogenic effect. Therefore, before starting atezolizumab+bevacizumab, screening for varices with upper gastrointestinal endoscopy and, if necessary, treating them before therapy using methods such as banding are mandatory. This is an HCC-specific safety precaution that differs from standard chemotherapy/immunotherapy protocols and must be followed.
Immunotherapy Drugs (Atezolizumab, Durvalumab, Tremelimumab, Nivolumab, Ipilimumab, Pembrolizumab)
"Immune-related adverse events" (irAEs), caused by excessive activation of the immune system, can include colitis, hepatitis (a side effect requiring particularly careful monitoring in this patient group because of underlying liver disease), pneumonitis, endocrine disorders, and skin reactions. Combinations containing ipilimumab or tremelimumab may cause these side effects more frequently and more severely than single agents. Management is based on severity grading: mild side effects are managed by continuing with close monitoring, while moderate-to-severe side effects require stopping the drug and starting corticosteroid treatment.
Global Approval and Evidence Timeline
The history of drug development in liver cancer is a story of rapid expansion after two long periods of silence. There was no approved systemic therapy until 2007; after sorafenib's approval, ten years passed without a new drug being added; approvals then followed in succession from 2017 onward. The timeline below summarizes this journey honestly — including withdrawn indications and unsuccessful combinations.
Approved based on SHARP (median overall survival 10,7 months versus 7,9 months with placebo). Until then, no drug had proven efficacy in advanced HCC; this approval ended the era when the disease was considered "untreatable."
During the ten years following sorafenib's approval, many drugs tested in the first- and second-line settings (sunitinib, brivanib, everolimus, linifanib, and others) in phase 3 trials failed. This period provides concrete evidence of why drug development in liver cancer is so challenging (patients' limited capacity to tolerate drug toxicity because of underlying cirrhosis).
Approved based on RESORCE in patients who tolerated sorafenib and experienced progression (10,6 months versus 7,8 months) — the first defined second-line treatment in HCC.
Received accelerated approval in the second-line setting. However, when the confirmatory phase 3 trial (CheckMate 459) failed to meet its overall survival endpoint, this indication was withdrawn on 23 July 2021 — an example of the accelerated approval system correcting itself.
Demonstrated noninferiority to sorafenib in REFLECT (13,6 months versus 12,3 months) — an option approved on the basis of equivalence rather than superiority. On 9 November 2018, pembrolizumab also received accelerated approval in the second-line setting.
Cabozantinib was approved based on CELESTIAL (10,2 months versus 8,0 months), followed by ramucirumab on 10 May 2019 based on REACH-2. Ramucirumab is additionally important as the first drug approved in HCC for patients selected by a biomarker (AFP ≥400 ng/mL) .
In IMbrave150, median overall survival increased from 13,4 months to 19,2 months — the first positive phase 3 trial to demonstrate superiority to sorafenib, ending 13 years of sorafenib dominance. In the same year, on 10 March 2020, nivolumab+ipilimumab had also received accelerated approval for second-line treatment.
Y90 glass microspheres, used within a limited scope since 1999, received full device approval (PMA) for inoperable HCC based on LEGACY. Resin microspheres (SIR-Spheres) gained their HCC indication only on 1 July 2025 .
Approved based on HIMALAYA (16,4 months versus 13,8 months). Containing no antiangiogenic drug, it provided an important alternative for patients at high risk of variceal bleeding; 5-year follow-up data demonstrated a sustained long-term benefit.
After KEYNOTE-240 failed, approval was retained and converted to full approval with data from KEYNOTE-394 conducted in Asia; however, the indication was restricted to patients with hepatitis B-related HCC who had previously received systemic therapy not containing PD-1/PD-L1 .
Approved in the first-line setting based on CheckMate 9DW (23,7 months versus 20,6 months; 3-year survival 38% versus 24%). On the same day, the second-line accelerated approval from 2020 was also converted to full approval. As of August 2026, this is the latest drug approval in HCC.
Three of the field's most anticipated questions were answered negatively during this period: adjuvant atezolizumab+bevacizumab after surgery/ablation (IMbrave050) showed no overall survival benefit and was never approved; LEAP-012 (29 October 2025) and EMERALD-1 (2026), combining TACE with immunotherapy, showed progression-free survival benefits but failed to meet their overall survival endpoints. Rivoceranib+camrelizumab was rejected for the third time because of manufacturing compliance rather than efficacy (10 July 2026).
Liver cancer is a field of oncology where progress does not come easily. The barren decade of 2007-2017 and the major negative trials in 2025-2026 show the fundamental reason: two diseases are being treated at once — cancer and cirrhosis. Even if a treatment shrinks the tumor, if it strains the liver, what is gained and lost may cancel each other out. The finding from TACE + immunotherapy trials — "it delayed disease progression but did not prolong life" — expresses exactly this. By contrast, the truly major gains come from prevention rather than drugs: the hepatitis B vaccine and antiviral treatments reduce the global burden of this disease far more than drugs do.
Diagnosis, Licensing, and Reimbursement in Turkey
Liver cancer diagnosis and treatment in Turkey are carried out in gastroenterology, hepatobiliary surgery, and oncology centers at university and training/research hospitals, in line with international guidelines. For drugs to be used in Turkey, TİTCK licensing is required first; for SGK coverage, a separate reimbursement decision under SUT is also necessary.
Sorafenib has been licensed and covered by SGK in Turkey for a long time (in Child-Pugh A patients, subject to the prerequisites specified in the guideline). Regorafenib is also licensed and covered by SGK (in Child-Pugh A patients with progression after sorafenib). Atezolizumab + bevacizumab was brought under SGK coverage by the SUT update of 10 July 2025 for patients with HCC who had not previously received systemic treatment, had an ECOG performance status of 0-1 and Child-Pugh A liver function, and had unresectable disease/were unsuitable for locoregional treatment.
According to our sources, lenvatinib is not licensed by the Ministry of Health in Turkey, despite being a widely used first-line option for HCC worldwide. Access within the country is through TİTCK's special/individual drug supply process (importing drugs from abroad), a route generally not covered by SGK and usually secured through legal action (a lawsuit). This is an important point our readers should know about HCC treatment.
According to our sources, durvalumab+tremelimumab (STRIDE), durvalumab alone, cabozantinib (although licensed for the HCC indication, its SGK coverage status has not been clearly verified), ramucirumab, pembrolizumab, nivolumab, and nivolumab+ipilimumab are not listed with an HCC indication in Turkish drug prescribing information (KÜB) and are therefore not covered by SGK for this indication. Tislelizumab has no licensing record in Turkey that we could find. An important contextual note about these two drugs: durvalumab alone and tislelizumab for the liver cancer indication are not approved in the US (by the FDA) either — these are therefore not access problems specific to Turkey, but treatments without approval for this indication globally.
Drug licensing and reimbursement status can change frequently with SUT updates (multiple updates were made in 2025-2026 alone). The information in this section is a general summary compiled as of the date this article was updated (August 2026); always confirm precise, current information about your own treatment and reimbursement with your treating physician and the latest SGK SUT text.
Frequently Asked Questions
- I have cirrhosis; how often should I be checked for liver cancer?
- Current international guidelines recommend liver ultrasonography every 6 months (with AFP in some situations) in patients diagnosed with cirrhosis. This follow-up should be planned by the hepatology/gastroenterology specialist caring for you.
- Is a biopsy always necessary to diagnose liver cancer?
- No. In patients with underlying cirrhosis, masses showing the typical HCC-specific contrast enhancement pattern (LI-RADS LR-5) on imaging (CT/MRI) can be diagnosed and treatment planned without a biopsy.
- Can every patient receive a liver transplant?
- No. Liver transplantation is considered in patients who meet the Milan Criteria (a single tumor ≤5 cm or up to 3 tumors, each ≤3 cm, with no vascular invasion/spread outside the liver); organ waiting times and general health are also determining factors.
- Can everyone receive immunotherapy-based treatment?
- No. These treatments have generally been studied and approved in Child-Pugh A patients (preserved liver function); use may also be restricted in situations such as a history of active autoimmune disease or, for bevacizumab, an uncontrolled risk of variceal bleeding. Eligibility must be assessed jointly by oncology and hepatology specialists.
- My hepatitis C was treated and the virus cleared. Do I still need follow-up?
- If you have developed cirrhosis, yes, follow-up must continue for life. Viral clearance reduces liver cancer risk by approximately 71% but does not eliminate it: in patients with cirrhosis, annual risk remains around 2%, and this increased risk can persist even 10 years after the virus is cleared. In patients without cirrhosis, risk falls below the surveillance threshold, so follow-up decisions are individualized. This is where the mistaken belief "my hepatitis is cured, so nothing can happen now" is most dangerous.
- I take hepatitis B medication; should I continue during cancer treatment?
- Absolutely yes. Antiviral treatment is not an alternative to cancer treatment but complements it: it has been shown to reduce recurrence risk after curative treatment by approximately one-third and the risk of death by approximately 44%. Viral reactivation is also a serious risk during treatments affecting immunity, such as chemotherapy and immunotherapy. Guidelines recommend antiviral treatment in all patients with hepatitis B-related liver cancer.
- How many times can TACE (chemoembolization) be repeated?
- There is no fixed number, but the principle "do not repeat it if it is not working" is very important. Each TACE session causes some damage to liver function; persisting when the procedure becomes ineffective may make the patient unsuitable for systemic therapy. In this situation, a timely switch to systemic therapy has been associated with longer survival. It is sensible to discuss this balance with your physician when deciding whether to repeat the procedure.
- I am outside the Milan criteria; is transplantation completely ruled out?
- No. In the approach called "downstaging," TACE, TARE, or ablation is first used to try to bring the tumor burden within Milan limits; if successful, the patient may be listed for transplantation. This can succeed in approximately two-thirds of treated patients, and in successful cases, 5-year survival after transplantation reaches approximately 80%. One reason is that response to downstaging also serves as a selection criterion indicating that the tumor is biologically less aggressive.
- Sung H, et al. "Global cancer statistics 2024." CA: A Cancer Journal for Clinicians, 2026. DOI: 10.3322/caac.70090
- IARC Global Cancer Observatory (GLOBOCAN 2024) — Liver Cancer Fact Sheet and Turkey Country Fact Sheet. gco.iarc.who.int
- Siegel RL, et al. "Cancer Statistics, 2026." CA: A Cancer Journal for Clinicians, 2026. DOI: 10.3322/caac.70043
- American Cancer Society. Global Cancer Facts & Figures, 5th edition, 2024 (HCC etiology data).
- Republic of Turkey Ministry of Health and GBD-based studies — hepatitis B seroprevalence and vaccination program data in Turkey, 2024.
- Llovet JM, et al. Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy update. Journal of Hepatology, 2022 and subsequent updates.
- Mazzaferro V, et al. Milan Criteria, liver transplantation. NEJM, 1996; subsequent validation studies.
- Llovet JM, et al. "Sorafenib in Advanced Hepatocellular Carcinoma" (SHARP). NEJM, 2008.
- Kudo M, et al. "Lenvatinib versus Sorafenib" (REFLECT). Lancet, 2018.
- Finn RS, et al. "Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma" (IMbrave150), final analysis. NEJM, 2020; J Clin Oncol, 2022.
- Abou-Alfa GK, et al. "Tremelimumab plus Durvalumab" (HIMALAYA/STRIDE). NEJM Evidence, 2022; 5-year follow-up, Journal of Hepatology, 2025.
- FDA approval announcement: Nivolumab + Ipilimumab, first-line HCC (CheckMate 9DW), 11 April 2025. fda.gov
- Bruix J, et al. "Regorafenib for Hepatocellular Carcinoma" (RESORCE). Lancet, 2017.
- Abou-Alfa GK, et al. "Cabozantinib in Hepatocellular Carcinoma" (CELESTIAL). NEJM, 2018.
- Zhu AX, et al. "Ramucirumab for HCC with Elevated AFP" (REACH-2). Lancet Oncology, 2019.
- Qin S, et al. "Adjuvant Atezolizumab plus Bevacizumab" (IMbrave050), updated overall survival analysis. Journal of Hepatology, 2026.
- Cancer Network, ASCO Post — rivoceranib+camrelizumab (CARES-310) FDA complete response letters, 2024-2026.
- Johnson PJ, et al. ALBI (Albumin-Bilirubin) grading. J Clin Oncol, 2015; modified ALBI (mALBI), Liver Cancer, 2017.
- Yao FY, et al. UCSF criteria and downstaging protocols; UNOS downstaging policy (2017) and MERITS-LT consortium results.
- Dawson LA, et al. NRG Oncology/RTOG 1112: Sorafenib ± stereotactic body radiotherapy. JAMA Oncology, 2025.
- Salem R, et al. PREMIERE trial (Y90 vs cTACE); TRACE trial (Y90 vs DEB-TACE), Radiology, 2022; RASER trial (radiation segmentectomy).
- Li QJ, et al. HAIC (FOLFOX) trials; SoraHAIC. JAMA Oncology, 2019; FOHAIC-1.
- Liaw YF, et al. "Lamivudine for Patients with Chronic Hepatitis B and Advanced Liver Disease." NEJM, 2004; meta-analysis of the effect of hepatitis B antiviral treatment on HCC recurrence (13 studies, 6.350 patients).
- Pooled analyses of HCC risk after sustained virological response (SVR) in hepatitis C and the continuing residual risk in cirrhosis.
- Simon TG, et al. "Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality." NEJM, 2020; meta-analyses of chemoprevention with statins/aspirin/metformin/coffee.
- FDA. Withdrawal of the nivolumab HCC indication, 23 July 2021; conversion to full approval and narrowing of the pembrolizumab HCC indication, 25 January 2024.
- Lencioni R, et al. EMERALD-1 (TACE + durvalumab ± bevacizumab). Lancet, 2025; final overall survival results, ESMO GI 2026. Merck/Eisai LEAP-012 trial update, 29 October 2025.
- FDA device approvals: TheraSphere (PMA P200029), 17 March 2021; SIR-Spheres HCC indication expansion, 1 July 2025.
- FDA approval announcements (2007-2026): sorafenib (16 November 2007), regorafenib (27 April 2017), nivolumab (22 September 2017; withdrawal 23 July 2021), lenvatinib (16 August 2018), pembrolizumab (9 November 2018; full approval 25 January 2024), cabozantinib (14 January 2019), ramucirumab (10 May 2019), second-line nivolumab+ipilimumab (10 March 2020), atezolizumab+bevacizumab (29 May 2020), durvalumab+tremelimumab (21 October 2022), first-line nivolumab+ipilimumab and conversion of the second-line indication to full approval (11 April 2025). fda.gov
- Communiqué Amending the Healthcare Implementation Communiqué, 10 July 2025 (SGK SUT update).
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