A thought-provoking installment of Clinical Quandaries is presented by Alejandro Gabutti, MD; and Tommaso Cascella, MD, of a 36-year-old patient with hepatitis C virus-related cirrhosis and a subsequent diagnosis of hepatocellular carcinoma.
A 6-cm liver tumor in segment 8 was found in a woman, aged 36 years, with hepatitis C virus (HCV)–related cirrhosis. The tumor was initially noticed in a screening ultrasound and further characterization was done with a multiphase CT scan. The tumor showed arterial enhancement and venous washout, and hepatocellular carcinoma (HCC) was definitively diagnosed.
For final staging, a chest CT and bone scintigraphy were performed. There was no evidence of extrahepatic disease or vascular invasion. At diagnosis, liver function was well compensated (Child-Pugh A5) and MELD (Model for End-Stage Liver Disease) score was 12. Alfa-fetoprotein plasma level was 7 ng/ml (within normal limits). Also, imaging studies revealed spleen enlargement and collateral venous circulation due to portal hypertension. The patient was classified as stage B according to the Barcelona criteria.
The patient’s relevant clinical history included sofosbuvir/velpatasvir (Epclusa) as treatment for HCV, which had been successfully completed 15 months before the HCC diagnosis. A sustained viral response was achieved.
Two weeks after diagnosis, the patient underwent a conventional transarterial chemoembolization (ethiodized oil [Lipiodol] plus doxorubicin, and polyvinyl alcohol [PVA] particles as embolic agent). The first follow-up was done with a multiphase CT 1 month after transarterial chemoembolization. No arterial enhancement was noticed, but there was a 2-cm area of absent ethiodized oil uptake within the tumor. Because of a high suspicion of tumor persistence, MRI was immediately performed, which showed a 1.8-cm viable residual tumor. A bland embolization with PVA particles was performed because of a doxorubicin shortage. Stable disease was documented. Due to residual tumor size and lack of response to transarterial embolization, a percutaneous ablation was performed. Because of the proximity of the tumor to the diaphragm, chemical ablation with ethanol was employed. Four weeks post treatment, an MRI showed a complete response.
What posttreatment follow-up should be done after achieving complete response?
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major global health concern.1 Its incidence has been rising over the last 20 years and is expected to increase until 2030.2 Diagnosis, treatment, and follow-up rely mainly on imaging. Thorough radiological assessment is critical in terms of satisfactory patient management.
HCC treatment must be decided by a multidisciplinary liver tumor board. Medical oncologists play an essential role, especially in patients with intermediate- or advanced-stage disease. Oncologists view the disease as a systemic issue, and along with clinical evaluation, radiological evaluations are probably the most important tools to promote the best outcomes.
The therapeutic armamentarium for HCC is broad and heterogeneous and can be divided into treatments with curative and noncurative intent.3 Curative treatments include liver transplantation, resection, and ablation. Noncurative treatments include transarterial chemoembolization (TACE) and variants, transarterial radioembolization (TARE), stereotactic body radiation therapy (SBRT), and systemic therapies.
HCC treatments are under continuous development and evolution. New therapeutic strategies, including novel antiangiogenic agents, immunomodulators, and combinations with locoregional therapies (LRTs), are currently in the spotlight.4 An interesting example is the evolution of TARE. Technical improvements have transformed it to a potentially curative therapy when was it was previously considered a palliative treatment.5
How should we assess the response of HCC to treatment? This is a matter of constant debate and discussion.6
The radiological evaluation protocols after treatment are heterogeneous and may vary by institution and therapeutical strategy.7 The follow-up protocol strength relies on 3 essential points: timing, imaging method, and the chosen radiological response criteria. It is not the aim of this article to deeply review the imaging findings after locoregional or systemic therapies, but rather to review the evidence of when and how to assess response.
The accepted timing for performing the first imaging study after treatment (LRT or systemic) is 4 to 6 weeks.7-9 An exception is when the patient has been treated with TARE or SBRT. The first imaging evaluation after a radiation-based LRT, unlike other LRTs, is 3 months.10 This is because radiation-induced tumor necrosis is often delayed.10-12 Once 4 to 6 weeks have elapsed, most of the inflammatory changes related to LRTs have resolved. However, inflammation and tumor persistence may be challenging to distinguish with imaging, as both usually appear as areas of arterial hyperenhancement on multiphase CT or MRI.13,14
The first imaging surveillance has 2 main objectives: to identify tumoral viability and early complications.8,15 If viable tumor is detected on the first imaging assessment after treatment, it is classified as residual disease.16 Large areas of residual tumor will be easily seen on the first imaging surveillance. Viable tumor shows the characteristic radiological appearance of HCC, especially arterial enhancement.17 However, this is not always obvious in small foci of residual tumor, and in such cases diagnosis can be challenging. Not uncommonly, a final diagnosis of tumor viability is made only on further follow-up.
If equivocal findings of residual tumor are detected initially, the imaging evaluation should be repeated no longer than 3 months after treatment (2 months after the first assessment) until a final diagnosis is established.12,18 The identification of viable tumor within the first follow-up must lead to a case reevaluation to guide further therapy.13,18,19
Other than detecting tumoral persistence, the first imaging evaluation is also important for early recognition of treatment-related complications, including necrosis infection, biloma formation, bile duct stricture, vascular injuries, or nontarget treatment effects.8,19 While the rate of complications after LRTs is low, typically less than 5%,20 early management of any that are detected is essential to avoid delay in future treatments.
The first radiological assessment can be focused just on local tumor response. Whole-body imaging is not necessary, unless metastatic disease was present at diagnosis. Once there is no evidence of tumor viability, an active surveillance protocol should be begun. Beyond this point, tumoral viability detected within a treated tumor is classified as recurrence.16
In early-stage HCC, when a curative-intent treatment (ablation or resection) was employed, patients can be monitored every 3 to 4 months during the first 2 years, with surveillance every 6 months thereafter.1,2,7 European Association for the Study of the Liver (EASL) guidelines emphasize particularly close follow-up of patients who also had successfully completed hepatitis C virus treatment with direct-acting antivirals.1
The every-6-months monitoring schedule should continue indefinitely. The majority of HCC cases develop in the context of cirrhosis. Therefore, the surveillance aim is not only the detection of late-onset recurrence, but also to recognize neohepatocarcinogenesis.
For patients with intermediate-stage disease, who are usually treated with embolotherapies, follow-up can be every 3 months.2 For patients with advanced-stage disease treated with systemic agents, a radiological evaluation every 2 to 3 months is suggested.7 Both schedules aim to monitor for tumor progression to guide future therapeutic decisions.2,7 The follow-up protocol should continue indefinitely or until there is a major management change, eg, successfully downstaging with subsequent liver transplantation as the final therapy.
Two questions may arise in assessing response: First, in which situations should extraabdominal imaging studies be performed? And second, what is the best imaging method for evaluating local response after treatment? While there is lack of consensus or precise recommendations about these issues, certain facts support our recommendations, we believe.
Some clues in answering both questions are provided by the initial disease staging. The HCC work-up typically includes state-of-the-art liver imaging (multiphase CT or MRI), chest CT, and a bone scan.1,2 However, the usefulness of bone scan with technetium-99m methyl diphosphonate is controversial. Some authors suggest that in early-stage HCC (within Milan criteria), it is not cost-effective and should not be done.21,22
Even when the disease is radiologically limited to the liver, high tumor burden (index tumor > 5 cm), elevated levels of alpha-fetoprotein (> 400 ng/ml), and vascular invasion are considered major risk factors for extrahepatic disease.23 Identifying patients with increased risk of metastasis can influence the follow-up protocol. In this particularly high-risk population, it is advisable to consider thoracoabdominal scans in order to detect systemic disease early, as the diagnosis of metastatic disease has a major impact on a patient’s management and prognosis.23,24
The treatment goal in early-stage HCC is local tumor eradication, utilizing liver-directed therapies. In this scenario, in patients with low risk of systemic disease, follow-up is focused on the liver, especially after ablation or surgical resection. Also, the option of surgical resection has been explored in patients without portal hypertension and absence of radiological vascular invasion, but with preserved hepatic function, regardless of tumor size.25,26 Because the frequency of micrometastases and vascular invasion rises with tumor size, it is advisable to use a thoracoabdominal radiological follow-up in this uncommon subgroup of patients.
In advanced-stage disease, systemic therapy plays the main role. Beyond treatment with tyrosine kinase inhibitors, immunotherapy is currently gaining acceptance and showing promising results.4 Also, several therapy combinations are actively under investigation, constantly changing the way HCC is treated. In this scenario, thoracoabdominal imaging follow-up is mandatory.
Intermediate-stage HCC represents a very heterogeneous group of disease scenarios, making decisions difficult to generalize. Patients within intermediate-stage HCC are still candidates for local tumor control with LRTs. However, a sustained complete response is not commonly achieved; therefore, the treatment is most often considered palliative. Patients treated with LRT without curative intent may benefit from a follow-up protocol similar to the one followed by those with advanced-stage disease.
For systemic and local therapies, the only 2 recommended imaging techniques for response assessment are multiphase CT and MRI.1,2 They have comparable diagnostic performance, especially for HCCs larger than 2 cm.27 Below this size cutoff, MRI is considered superior.1,27 There is a trend favoring MRI as the posttreatment imaging of choice, especially after LRTs.28
Tumor ablation and resection are curative-intent therapies employed in early-stage HCC.1,2 The principle of the most popular ablative techniques is tumor destruction, utilizing a thermal or chemical modality.29,30 Ablation techniques that are less widely used include irreversible electroporation and laser ablation.
All of the above-mentioned techniques must achieve complete tumor destruction, including a disease-free margin of at least 0.5 cm to 1 cm.31 Viable tumor is often characterized by areas of arterial enhancement in the ablation/resection margin with venous washout.12
Both CT and MRI can be used to assess the effectiveness of curative-intent therapies. A recurrent or persistent tumor after resection or ablation is often small in size. Because MRI has a better diagnostic performance for small tumor foci detection than CT, it may be the preferred imaging method to evaluate a curative-intent therapy.27 In addition, the use of hepatospecific contrast media improves the diagnostic performance of MRI in this scenario.32
Embolotherapies include a wide variety of techniques that are conventionally considered palliative. They rely on the selective arterial delivery of an embolizing agent, with or without local chemotherapy. Therefore, tumor destruction is mediated by ischemia and the cytotoxic effect of chemotherapy.33
The tumor size and the imaging technique employed for diagnosis are essential factors in considering correct posttreatment follow-up. Transarterial therapies are usually employed in large tumors that are not suitable for ablation/resection. However, in daily practice, small tumors can be treated by embolotherapies when a curative-intent treatment is not technically feasible.34 Conventional TACE (cTACE) is the technique that is most often used and studied. A chemotherapeutic drug is mixed with ethiodized oil resulting in micelles formation. The micelles carry the drug into the tumor and release it selectively over a long time period. This technique ensures a high drug concentration within the tumor, with minimal systemic effect.35
Ethiodized oil contains high amounts of iodine, which makes it intrinsically hyperdense on CT. As such, areas of arterial enhancement could be subtly obscured, limiting the accuracy of an evaluation of response.12 However, the presence of ethiodized oil only minimally affects an MRI signal, so MRI use is advised to evaluate cTACE effectiveness.12 The ethiodized oil-free embolotherapies, such as transarterial embolization and drug-eluting beads–TACE (DEB-TACE), can be evaluated equally with CT or MRI,1,2 as there is no tumoral staining with hyperdense agents.
Care must be taken with the intrinsically radiopaque DEBs that are commercially available (eg LUMI). These particular beads contain iodine within their structure.36 When a high intra- or peritumoral concentration is achieved, a ethiodized oil-like effect can be expected on CT images, so here, too, an MRI assessment may be advisable.
Selective internal radiation therapy (SIRT), also known as TARE, consists of selective intraarterial administration of yttrium-90–coated particles. Its tumoricidal effect relies on direct cell destruction mediated by beta particles that have a penetration range of 2.6 mm to 11 mm.10 The embolic effect of SIRT is minimal, especially when glass spheres are employed, resulting in nonsignificant hypoxia,12 whereas the hallmarks of acute tumor necrosis due to ischemia are often absent after TARE.
TARE is well tolerated by patients with benign or malignant portal thrombosis.37 Arterial embolization in the setting of portal occlusion may lead to severe liver ischemia and necrosis. Also, a TARE variant known as radiation segmentectomy can be performed as a curative-intent treatment for early-stage HCC.5,38
Response assessment after SIRT can be challenging. Radiation-induced tumoral and peritumoral changes are highly heterogeneous and can show different enhancement patterns.12 Tumoral arterial enhancement may not immediately disappear after treatment and may persist for months, even if the tumor was completely treated.39 Therefore, when arterial enhancement persists, progressive tumor shrinkage is the main hallmark of adequate response to TARE.12
Perfusional changes in the radiated liver parenchyma are characterized by arterial enhancement.12 They usually resolve within 6 months but may persist even longer. Therefore, they can be potentially confused with tumoral infiltration. The lack of venous washout and no signal abnormalities on T2 weighted/diffusion images are useful MRI features to distinguish tumoral infiltration from benign post-TARE findings.12
MRI and CT can both be used to assess response. For challenging cases, especially when arterial enhancement persists for longer than expected, MRI may provide more accurate information about tumor viability.12
SBRT uses multiple focused radiation beams to treat HCC. SBRT and SIRT share several posttreatment radiological features, especially the initial minimal effect on arterial enhancement and size.12 In fact, 75% of HCC cases treated with SBRT exhibit persistent arterial enhancement for 3 to 6 months.40,41 Consequently, assessment of SBRT response can be accomplished using the same recommendations as those for SIRT.
No less important is the patient’s compatibility and safety with the selected imaging technique. Patients with an implanted electronic or metallic device should always be checked for compatibility with MRI. Also, metallic artifacts near the liver may degrade image quality, impairing the diagnostic performance of either MRI or CT. The use of contrast media is mandatory for the posttreatment imaging follow-up. Therefore, renal function must always be evaluated before the employment of any gadolinium- or iodine-based contrast media to avoid complications.
Other imaging modalities include contrast-enhanced ultrasound and PET-CT. Both have been extensively studied and are also suggested as valid resources for response assessment.9 However, guidelines currently include only CT and MRI as valid tools in this setting.1,2
For years, the therapeutic armamentarium for advanced-stage HCC was limited to a single drug, sorafenib (Nexavar). Recently, though, new agents, including immunotherapy, have been approved for the treatment of HCC,4 and with this therapeutical evolution comes new challenges in response evaluation.
In contrast to LRTs, in which necrosis is induced by a direct insult focused on the tumor, systemic agents cause tumoral death with multiple mechanisms that create microvasculature changes and immune activation.4 The functional data obtained with CT, MRI, and nuclear medicine can be applied as biomarkers of tumor viability. Tumoral biomarkers, such as metabolism, perfusion, and cellularity, in combination with morphologic changes, may in the future be the new standard of response evaluation.6
Systemic therapy is currently reserved for advanced-stage HCC.42 However, its efficacy in combination with LRT in intermediate-stage disease is being explored in multiple clinical trials.43
Beyond the use of tumor burden in response assessment, a patient’s performance status and liver function are vitally important to consider. Patients with Child-Pugh stage C are unlikely to derive clinical benefit from systemic therapy, and best supportive care should be considered when the patient is not a candidate for liver transplantation.1
Systemic therapy response assessment is not straightforward. It should always be done with multiphase abdominal CT or MRI, plus thoracic imaging. Therefore, CT can be logistically more efficient than MRI. CT, however, can include both the multiphase abdominopelvic exam and a thoracic evaluation. Thoracic MRI is not recommended for oncologic surveillance and abdominal evaluation; it is usually limited to the hepatic area. However, high-quality liver imaging should always be the priority; as such, a CT-MRI combination is feasible and useful.
The multiparametric nature of MRI can accurately depict tumoral necrosis. An MRI “second look” is advisable when CT evaluation is not conclusive. The detection of true necrosis is of main importance, especially when antiangiogenic drugs are used. Changes in the tumoral microvasculature may be represented as the loss of the characteristic arterial enhancement in a viable tumor on CT or MRI.6,44 Rather than a true antitumoral effect, this phenomenon can be explained by a reduction of vascular permeability to contrast agents.44 Despite this, a decrease in arterial enhancement and tumor necrosis are equally accepted indicators of adequate response after systemic therapy.9
Imaging also plays an important role in the surveillance of drug adverse effects, especially when immunotherapy is employed. Bone scintigraphy is not included in the imaging follow-up protocol after systemic therapy.
Once timing and imaging technique are established, selecting the imaging response criteria (RC) is the final step in completing the assessment. RC were first created to be used in clinical trials in which tumor response was the primary end point.1,45 Today, RC are commonly employed in daily practice and heavily influence management decisions.46
A multidisciplinary team should make the selection of the RC to be employed. Every health professional involved in the management of HCC must clearly understand how to assess and how to classify response.
Further, imaging RC can be divided into 2 main groups: those based on morphologic tumor burden, and those based on the viability of the tumor burden.6 The main characteristic of tumor viability is arterial enhancement.
Conventional cytotoxic agents induce rapid tumor shrinkage, but adequate response to HCC-specific therapies is not accurately represented by tumor size changes.6,47 Also, posttreatment transient tumoral enlargement is a well-known phenomenon; it should not automatically be considered tumor progression because it could actually be inflammation-mediated.9,45,48
Figure 2 resumes the current and more frequently used response criteria employed for HCC response assessment.
Current viability-based response criteria, such as mRECIST and EASL, were designed specifically for HCC, mainly to assess response after LRTs, although they are also employed for systemic therapy evaluation.49 Metastatic disease is assessed with conventional response criteria, with size and not viability the principal characteristic.45
American College of Radiology Liver Imaging Reporting and Data System (LI-RADS) treatment response criteria (LR-TR) have been introduced into clinical practice and have gained wide acceptance. LI-RADS classifies posttreatment results (LR-TR) into 3 groups: nonviable, viable, and equivocal. However, importantly, LR-TR cannot be used to assess systemic therapy response.18 Unlike mRECIST, the LI-RADS treatment response categories are assigned on a lesion-by-lesion basis and are not assigned to the whole liver or patient.18
An HCC that has been completely treated with a radiation-based modality can retain arterial enhancement, which can be misinterpreted as viable disease by mRECIST and EASL.12 If the LI-RADS response algorithm is employed, a persistent arterial enhancement is best classified as LR-TR equivocal or LR-TR not viable as long as the treated tumor is decreasing in size.12
Inflammation secondary to immunotherapy can cause initial tumoral enlargement. HCC-designed RC may misclassify this phenomena as progression, leading to unnecessary changes or cessation of therapy. iRECIST was developed to assess response on immunotherapy and precisely defines this phenomena as pseudoprogression. It is characterized by an initial increase in the size of lesions, or the visualization of new lesions followed by a response.48
mRECIST is the most studied response system and is frequently compared with RECIST in clinical trials. In several studies, mRECIST has demonstrated an improved prediction of treatment response and overall survival.50-52
The Organ Procurement and Transplantation Network (OPTN) system is employed to allocate patients on the waiting list for liver transplantation in the HCC setting in the United States.53 OPTN class 5 indicates that a liver tumor meets radiological criteria for HCC (analogous to LI-RADS 5). OPTN has a special category to assess response of previously treated HCCs with locoregional therapy. A class OPTN 5T is given to treated HCCs with any residual viable tumor or perfusion defect, corresponding to LI-RADS TR viable or equivocal.54 As in LI-RADS, the OPTN 5T category cannot be applied to assess response to systemic agents.
Response assessment for HCC relies mainly on imaging, and it should take into account 3 essential aspects: timing, imaging technique, and response criteria to be employed.
The first imaging assessment after LR and systemic therapies is usually done after 4 weeks.
After a complete response is achieved, a follow-up schedule based on 3-month intervals is advisable. Mutiphase CT and MRI are the only 2 imaging techniques recommended for HCC response assessment. Contrast-enhanced ultrasound and PET-CT are currently being evaluated for this purpose. MRI diagnostic performance is superior to CT for small tumors (< 2 cm) and those that have been treated with cTACE. HCC that has been treated with radiation-based therapies may show a delayed response, which is characterized by the persistence of arterial enhancement. For accepted radiological response criteria, arterial enhancement is the hallmark of tumor viability. Systemic therapies are continuously evolving; immunotherapies have shown promising results and their response evaluation should include special imaging considerations.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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