Radionuclide Therapy of Tumors of the Liver and Biliary Tract
The liver represents a frequent site for both primary cancer and metastatic disease, In these circumstances, liver-directed therapies as cytoreduction via surgery or in situ ablative techniques may influence the natural history of the disease progression and improve clinical outcomes.
Radioembolization (RE) is a selective internal radiotherapy technique in which 131I-lipiodol or 90Y microspheres are infused through the hepatic arteries. It is based on the fact that primary and secondary hepatic tumors are vascularized mostly by arterial blood flow whereas the normal liver perfusion is mostly from the portal network. This enables high radiation doses to be delivered, sparing the surrounding non-malignant liver parenchyma.
Although there are some clinical evidences that RE may play an important role in the management of hepatocellular carcinoma of intermediate or advanced stage and in liver-dominant metastatic colorectal cancer and metastatic neuroendocrine tumors, further randomised clinical trials are mandatory to better assess the potential beneficial and harmful outcomes of trans-arterial radioembolisation either as a monotherapy or in combination with other systemic or locoregional therapies.
In this chapter we discuss some technical aspects, patient selection, current clinical evidence, and future directions of radioembolisation for primary and secondary liver cancer.
KeywordsHepatocellular carcinoma Selective internalradiation therapy Radioembolization Liver Neoplasm Metastasis
5-Fluorouracil, a chemotherapy agent
99mTc-human serum albumin
Alpha-fetoprotein, a circulating serum marker of hepatocellular carcinoma (and of testicular germ-cell cancer as well)
Body surface area
- CA 19–9
Carbohydrate antigen 19–9, a tumor-associated serum marker
Contrast-enhanced x-ray computed tomography
X-ray computed tomography
European Association for the Study of the Liver
Eastern Cooperative Oncology Group
Giga-Becquerel (109 Becquerel)
Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)
4-Hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol, a chelating agent
Kiloelectron volt (103 eV)
Lung shunt fraction
Mega-Becquerel (106 Becquerel)
Megaelectron volt (106 eV)
Maximum intensity projection
Medical Internal Radiation Dose
Magnetic resonance imaging
Positron emission tomography
Positron emission tomography/computed tomography
Portal vein thrombosis
Response evaluation criteria in solid tumors
Radiation-induced liver diseases
Region of interest
Selective internal radiation therapy
Single-photon emission computed tomography/computed tomography
Standardized uptake value
Standardized uptake value at point of maximum
Transcatheter arterial chemoembolization
Neuroendocrine tumor producing vasoactive intestinal peptide
World Health Organization
Both primary tumors and metastatic malignancies can arise in the liver. Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, and its incidence is rising . In addition, the liver is one of the most common sites for hematogenous metastases from different solid tumors primarily arising in other tissues/organs, most importantly colorectal cancer (CRC). About 15–25% of all CRCs may present synchronous hepatic metastases or develop metachronous metastatic involvement of the liver disease during the course of the disease .
Although significant survival benefit can be achieved with curative resection or liver transplantation in selected cases , less than 15% of the patients with newly diagnosed HCC are candidates for surgical procedures with curative intents. Although various treatments have been proposed for the remaining patients, definite agreement has not been reached on which option offers the greatest survival benefit associated with the least toxicity.
External beam radiation therapy has a limited role in the treatment of HCC due to the relatively high radiosensitivity of normal hepatic tissue . In fact, exposure of the liver to radiation doses greater than 40 Gy may result in a clinical syndrome called “radiation-induced liver disease ” (RILD) or radiation hepatitis. This syndrome, which occurs weeks to months following therapy, includes elevated liver enzymes, anicteric hepatomegaly, and ascites [4, 5].
Minimally invasive, percutaneous ablative treatments include radiofrequency ablation (RFA), microwave ablation, cryoablation, and irreversible electroporation (IRE) that have become widely accepted as potentially curative therapies for either HCC or metastatic liver disease . In particular, these ablative techniques are useful for treating patients who do not meet the criteria for surgery but in whom curative treatment is desired.
Transcatheter arterial chemoembolization (TACE) is the mainstay of catheter-based locoregional therapies for unresectable primary liver cancer; its use is expanding and includes liver metastatic disease from other malignancies . Conventional TACE typically involves the injection of chemotherapeutic agents mixed with lipiodol and embolic particles into the branch of the hepatic artery that feeds the tumor . TACE with drug-eluting beads (DEB) involves the injection of DEBs into the tumor-feeding artery, offering simultaneous delivery of chemotherapy and embolization with sustained and controlled drug release over time . Both TACE and DEB-TACE are effective as palliative treatments for primary and metastatic liver cancers [10, 11].
There are substantial differences in the treatment strategies for primary or metastatic malignancies of the liver. While locoregional treatments are a mainstay in primary liver cancers , transcatheter techniques such TACE or DEB-TACE are not commonly used for patients with metastatic liver disease.
The recent successful development of trans-arterial radioembolization (TARE) with 90Y-labeled particles has revived interest in an approach to locoregional treatment of liver tumors with radionuclides that had been introduced earlier with the use of lipiodol containing 131I but had shown little benefit for long-term survival (see further below). This technique is also defined as “selective internal radiation therapy ” (SIRT); therefore, the acronyms TARE and SIRT can be employed in an interchangeable manner.
Rationale of Radioembolization Therapy for Liver Tumors
In order to deliver the highest possible therapeutic doses to the tumor while sparing normal liver parenchyma, techniques based on minimally invasive intra-arterial administration of therapeutic radionuclides have been developed, an approach that takes advantage of the dual blood supply to the liver. Normal hepatic tissue derives greater than 70% of its blood supply from the portal system, whereas blood to malignant tissue is preferentially supplied by the arterial system. High tumoricidal doses can thus be selectively delivered to the tumor lesions (more than 70 Gy, usually 200–300 Gy) through locoregional administration of agents emitting β− particles (labeled with either 131I, 90Y, 188Re, or 166Ho), with low levels of associated damage for the non-affected liver and therefore a minimal risk of inducing RILD [13, 14, 15, 16, 17].
Upon injection into the hepatic artery of patients with HCC, the iodinated oil 131I-lipiodol (a suspension of lipidic particles) follows the preferential blood flow toward the tumor; the radiolabeled micellae are then retained by pinocytosis both in the tumor cells and in the endothelial cells of the arteries feeding the tumor . Following this route of administration (which is performed under angiographic monitoring), more than 75% of the injected 131I-lipiodol remains in the liver, while the remainder distributes mainly to the lungs. Release of free radioiodine results in some accumulation of radioactivity in the thyroid gland. Dose to the thyroid galnd can be minimized by pretreatment with sodium iodide. Tumor/non-tumor uptake ratios in the liver are generally higher than 5, and more than 10% of the injected radioactivity remains within the tumor with an effective half-life greater than 6 days, longer than in the normal liver tissue [14, 15, 19]. Administered activity can be either a fixed amount of 2.4 GBq (65 mCi) or defined on the basis of patient-specific dosimetric estimates. Due to the long half-life of 131I-lipiodol in the tumor, current legislation in some countries requires hospitalization for about 1 week, for the purpose of radioprotection of the general population.
Treatment is in general well tolerated, and serious adverse effects are very rare, while generic asthenia is commonly reported; hematologic toxicity is exceptionally rare, although blood cell counts may be altered due to the cirrhosis-related hypersplenism often present in these patients. Interstitial pneumopathy due to trapping and retention of the radiolabeled particle suspension is reported as the main risk of this treatment .
Both retrospective studies [21, 22, 23] and prospective trials [21, 24, 25] have demonstrated the safety of 131I-lipiodol therapy, while the objective response rate is reported in the 40–50% range. In particular, a randomized controlled trial comparing 131I-lipiodol therapy versus best supportive care in a group of 27 HCC patients with portal thrombosis demonstrated that survival at 3 months was 71% in the treatment arm versus 10% in the best supportive care arm (with median overall survivals of 26 weeks and 10 weeks, respectively) .
In the adjuvant setting, the efficacy of 131I-lipiodol therapy was tested in a phase II study involving 28 patients . Median time to recurrence was 28 months (range 12–62 months) in the 16 patients who were apparently disease-free at follow-up; overall survival in the responding patients was 86% at 3 years and 65% at 5 years. In a recently published phase III study, 21 patients without evidence of residual disease after potentially curative resection for HCC received 1,850 MBq of 131I-lipiodol intra-arterially as adjuvant therapy, while 22 patients treated with surgery alone served as the control group . The recurrence rate in the patients treated with surgery alone was 63.6%, while it was 47.6% in those receiving adjuvant radioembolization. The 5-year, 7-year, and 10-year disease-free survivals were 61.9%, 52.4%, and 47.6%, respectively, in the adjuvant therapy group, significantly higher than the values in the corresponding control group (31.8% with P = 0.0397, 31.8% with P = 0.0224, and 27.3% with P = 0.0892, respectively). Also, overall survivals in the treated group (66.7% at both 5 and 7 years, 52.4% at 10 years) were higher than in the control group (36.4% with P = 0.0433 at 5 years, 31.8% with P = 0.0243 at 7 years, and 27.3% with P = 0.0905 at 10 years, respectively). When compared with chemoembolization, embolization with 131I-lipiodol has yielded similar results in terms of efficacy but better tolerance .
More recently lipiodol labeled with 188Re using 4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD) as the chelating agent  was shown to be a promising agent for radioembolization in patients with inoperable large and/or multifocal HCCs. 188Re has potentially favorable physical characteristics, such as a shorter half-life than 131I (16.9 h versus 8 days), a β− emission of high energy with ensuing good tumoricidal effect (E max = 2.1 MeV), and a 155-keV γ emission favorable for gamma-camera imaging (for the purpose of dosimetric estimates). Furthermore, the relatively short-lived 188Re can be obtained through a generator system based on its parent radionuclide (188W) that has a physical half-life of 69 days, suitable for distribution logistics.
Therapy of HCC with 188Re-HDD-lipiodol results in higher tumor-killing efficacy than 131I-lipiodol, yet combined with lower toxicity. The 188Re-labeled agent represents therefore an excellent alternative to the 131I-labeled agent .
Promising results of both safety and clinical response following therapy with 188Re-HDD-lipiodol were obtained in a multicenter study performed in 93 patients with inoperable HCC . Treatment was well tolerated, and an objective response (including either tumor regression of some degree or stabilization of disease that was in progression prior to therapy) was observed in 66/93 patients (71%); out of these 66 objective responses, there were 5 cases with complete ablation of the tumor mass, 17 cases of partial response, and 23 cases with stabilization of disease.
Intra-arterial radioembolization with 90Y-labeled particles was approved in 2002 for the treatment of liver tumors, both primary malignancies and metastatic lesions originated by other tumors . 90Y is a pure β− emitter that decays to stable 90Zr and has a physical half-life of 64.2 h. The average energy of β− emission is 0.936 MeV, with a mean tissue penetration of 2.5 mm and a maximum tissue range of 10 mm. The physical properties of 90Y allow the delivery of high-radiation doses to hepatic malignancies, when administered with this technique, while minimally affecting the non-affected surrounding liver parenchyma.
Two types of microspheres labeled with 90Y are currently available, made, respectively, of glass (TheraSphere®, MDS Nordion, Ottawa, Ontario, Canada) and of resin (SIR-Spheres®, Sirtex Medical, Sydney, Australia). These two preparations differ in some important respects . TheraSphere® consists of particles 20–30 μm in diameter, each one carrying 2,500 Bq of 90Y (high specific activity); about 1.2 million microspheres is injected intra-arterially for a single treatment, corresponding to a total administered activity of about 3 GBq (81 mCi). SIR-Spheres® consists instead of particles 20–60 μm in diameter, each one carrying 50 Bq of 90Y (low specific activity); 40–80 million microspheres are injected for a single treatment to achieve a similar total administered activity of 3 GBq .
After the diagnosis of inoperable liver tumor has been made on the basis of proper imaging and biopsy, the pretreatment functional status of the liver is evaluated by routine blood chemistry workup. Patients with an ECOG performance status of greater than two are not considered ideal candidates for this treatment.
An inadequate liver function reserve with total bilirubin >2.0 mg/dL and serum albumin <3 g/dL is considered a contraindication to treatment with 90Y-microspheres. In case of concomitant renal failure, care must be taken to avoid or minimize the use of iodinated contrast medium during angiography (see further below).
Pretreatment evaluation for TARE/SIRT with 90Y-microspheres is based on cross-sectional imaging and arteriograms in the individual patient, with the fundamental prerequisite that the patient has liver-dominant unresectable disease. The workup should include CT or MR imaging of the liver for assessment of tumoral and non-tumoral volume, portal vein patency, and extent of extrahepatic disease. Distribution of the tumor disease is typically characterized as unilobar or bilobar; however, the correlation of tumor lesions with hepatic arterial supply is variable and can only be ascertained through arteriography. Ascites indicates poor hepatic reserve or peritoneal metastasis, both of which bear poor prognosis.
The final decision-making about treatment with 90Y-microsphere TARE/SIRT for each individual patient should be achieved after careful consideration of all functional and anatomic parameters within a multidisciplinary team involving interventional radiologists, surgical oncologists, medical oncologists, nuclear medicine physicians, radiation oncologists, medical physicists, and radiation safety experts.
Assessment of Arterial Anatomy
Pretreatment angiography (an essential requisite for the therapeutic procedure) is performed to assess the vascular anatomy of the liver, patency of the portal vein, and presence of artero-portal shunting and/or shunting to extrahepatic territories, the most important of which is the liver-to-lung shunt (see further below). Abnormal blood flow spreading the radiolabeled microspheres outside the liver vasculature is prevented by prophylactic embolization of some vessels identified during angiography, such as the gastroduodenal artery and the right gastric artery . This is a safe and effective procedure to minimize the risks of hepato-enteric flow. Mesenteric angiography is necessary to ensure that blood supply to the lesions has been adequately identified, as incomplete/inaccurate definition of the pattern of blood supply to the tumor may lead to incomplete/ineffective targeting of the tumor lesion.
Pretreatment Imaging with 99mTc-MAA
It is crucial to correlate the 99mTc-MAA scintigraphic images to the angiography pattern, as topographic proximity of the duodenum and stomach to the liver may decrease the ability to identify extrahepatic shunting by scintigraphy alone, especially if based solely on planar imaging. Based on ROI technique, the lung shunt fraction (LSF) is calculated and employed to estimate the radiation dose delivered to the lungs for any given amount of radioactivity, so that appropriate adjustments in the administered activity can be made to minimize the risk of radiation pneumonitis (see further below).
The choice of the most appropriate 90Y activity to be delivered into the tumor target and to the normal liver parenchyma requires adequate knowledge of many factors, mainly the liver function and reserve, that are frequently influenced by concomitant pathologies (i.e., cirrhosis) or by prior chemotherapy and/or external beam radiation therapy.
The main complications possibly linked to 90Y-microsphere radioembolization are caused by excessive irradiation of nontarget tissue. In this regard, the key limiting factor is the lower tolerance to radiation of normal liver parenchyma relative to the dose required to destroy the tumor target. The maximum external beam acceptable cumulative dose to the whole liver is 35 Gy (based on prior experience with external beam radiation therapy) , while the estimated dose to destroy a solid tumor is more than 70 Gy. Above the 35 Gy threshold radiation dose to the liver parenchyma, the risk of liver failure rises sharply.
The other absolute and relative contraindications for the procedure are related to the possible flow/reflux of part of the 90Y-microspheres to arteries feeding the wall of the gastrointestinal tract and to excessive lung radiation due to a high hepato-pulmonary shunt, frequently observed in HCC as well as in metastatic disease with a large tumor burden. In this case, the administration of therapeutic amounts of 90Y-microspheres increases the risk of clinically relevant radiation pneumonitis.
To warrant the safety of the procedure, it is crucial to quantify the lung shunt fraction (LSF) as detected in the pretreatment evaluation with the 99mTc-MAA scan, in order to calculate the expected radiation dose to the lungs. Previous data extrapolated from the large body of experience accumulated with external beam radiation therapy indicate that the highest tolerable dose to the lungs is 30 Gy for a single administration and less than 50 Gy as the cumulative dose for multiple treatments .
Different models have been proposed and can be employed to calculate the 90Y activity to be administered that would allow delivery of the highest dose to the tumor while sparing normal liver tissue. The so-called partition model (based on the MIRD approach) takes into account three different compartments for radiation dose estimates, i.e., the liver tumor, the non-tumoral liver, and the lungs . The basic assumption is that the LSF and the relative distribution of 99mTc-MAAs in the tumor and non-tumor liver compartments (expressed as T/N ratio) reliably predicts distribution of the 90Y-microspheres that will be administered during another interventional radiology procedure performed a few days later by the same radiologist trying to replicate exactly the same position of the intra-arterial catheter as during 99mTc-MAA administration. The activity of 90Y-microspheres to be administered can be estimated using the LSF derived from the 99mTc-MAA scintigraphic images. This approach is adopted routinely when administering the glass 90Y-microspheres and has been shown to yield safe and reproducible estimates regarding expected toxicity and clinical outcomes.
When using the resin 90Y-microspheres, two additional methods can be employed to estimate the activity to be administered, i.e., empiric method and the body surface area (BSA) method. The empiric method is based on the volume of the liver occupied by the tumor tissue expressed as a fraction of the overall liver volume, as estimated by cross-sectional imaging (either CT or MRI). A 90Y-microsphere activity of 2 GBq is recommended for a tumor/liver fraction <0.25, increasing to 2.5 GBq for tumor fractions between 0.25 and 0.5 and increasing further to 3 GBq for tumor fractions >0.5 (keeping in mind that a value above 0.7 constitutes per se an absolute contraindication to treatment).
Although these two methods based on clinically derived data of intraoperative activity calculations are routinely used in some centers, they are not optimal in certain situations, in particular when the target is well identified and the total volume of the three compartments is accurately known. Moreover, it has been demonstrated that both the BSA method and the empiric method frequently overestimate the activity to be administered to the patient [38, 39]. Therefore, the use of the MIRD partition model should be recommended when administering the resin 90Y-microspheres.
Patient-specific dosimetry requires accurate evaluation of the liver and tumor mass (usually derived from anatomic imaging such as CT) and of 99mTc-MAA biodistribution based on scintigraphic imaging. However, the predictive value of 99mTc-MAA scintigraphy as to the distribution of 90Y-microspheres in the liver is still a matter of debate [40, 41, 42]. Parameters that may induce some discordance between the distribution of 99mTc-MAAs and that of the 90Y-microspheres include interval differences in catheter position during injection in the two separate occasions, physiologic changes in hepatic blood flow, tumor histopathology, and tumor load, size, and morphology differences between the 99mTc-MAA particles and the 90Y-microspheres . These factors may all limit the concordance between 99mTc-MAA distribution as assessed in the pretreatment procedure and actual distribution of the 90Y-microspheres administered for therapy .
Although the ability of 99mTc-MAA to predict radiation dosimetry expected from 90Y-microsphere administration is far from ideal, most of the retrospective studies based on 99mTc-MAA scintigraphy for these estimates have shown a definite dose-response correlation with a threshold value from 120 to 205 Gy [43, 44] and even up to 500 Gy . However, no prospective studies have confirmed these observations, and no single cutoff value that ensures tumor response has been identified as yet.
The dosimetry-based methods utilized to calculate the activity to be administered during radioembolization are described in detail in Chap. 13 of this book (“Radiobiology and Radiation Dosimetry in Nuclear Medicine”).
During the radioembolization session, the vessel perfusing the tumor is reached under fluoroscopic guidance, and the 90Y-microsphere suspension is injected into the artery feeding the target lesion. A delivery system that allows the administration in a step-by-step manner is useful to avoid early full embolization of the vasculature that prevents infusion of the total estimated activity. The infusion is usually done with alternating injections of iodinated contrast medium and sterile water/glucose solution when using the resin 90Y-microspheres or of saline solution during infusion of the glass 90Y-microspheres. Continuous fluoroscopy monitoring ensures that no stasis occurs during infusion and also serves to confirm that the flow of microspheres is similar to that observed during the prior angiographic workup.
According to topography of the tumor, treatment can be either selective (i.e., directed to one liver lobe) or super-selective (directed to one liver segment).
Early posttreatment assessment of the pattern of 90Y-microsphere deposition by high-quality imaging is necessary to exclude radioactivity accumulation in gastrointestinal tract and to evaluate the radiation-absorbed dose delivered to the tumor.
A post-therapy planar and SPECT/CT scan based on the bremsstrahlung emission generated by the high-energy β− particles of 90Y helps to confirm correct deposition of the radiolabeled microspheres in the tumor lesions . However, the low-resolution and poor-quality imaging obtained from the bremsstrahlung emission does not allow an accurate quantification of microsphere distribution, especially when dealing with small lesions.
Radioembolization with 90Y-microspheres can be performed as an outpatient procedure, and the patient can be discharged from the hospital on the same day of treatment or on the following day.
Patient Follow-Up and Assessment of Response to Therapy
Tumor response to radioembolization is monitored both clinically and radiologically. Routine follow-up includes blood chemistry to monitor possible toxicity due to treatment; in the case of HCC, measurement of the serum levels of the tumor-associated marker AFP serves to assess evolution of the malignant disease. Contrast CT is performed at 1 month posttreatment, while additional CT scans are performed every 3 months to assess response to treatment or progression of disease. Although tumor response to therapy can be assessed by classical RECIST criteria, specific criteria set by the World Health Organization (WHO) and by the European Association for the Study of the Liver (EASL) based on size parameters and on necrosis parameters, respectively, are employed to assess response in the target lesions [13, 52].
90Y-Microsphere Radioembolization Combined with Other Therapies
Radioembolization with 90Y-microspheres is a valid therapeutic option per se, preferably in patients with early stage inoperable liver-predominant malignancies. Nevertheless, it can be used also in combination with systemic molecular/chemotherapies in patients presenting with an intermediate or even advanced stage of HCC  or with unresectable liver-predominant metastases from colorectal cancer. Moreover, thanks to its ability to downsize/downgrade the disease, SIRT/TARE may be used as neoadjuvant therapy also in patients with HCC not meeting the criteria for resection, percutaneous ablation, or transplantation.
Before planned resection or transplantation , radioembolization may be considered as a neoadjuvant treatment to reduce the tumor burden and simplify surgery or to stop/slow down tumor progression in order to keep patients on the transplant waiting list or to improve the long-term outcome – even achieving in some cases downstaging of the disease . In selected clinical situations where the non-tumoral liver is too small in terms of functional reserve (thus hindering any type of resection), lobar or segmental selective radioembolization may lead to ipsilateral lobar of segmental parenchymal hypotrophy and contra-lobar hypertrophy (ranging from 21% to 35%) allowing subsequent surgery .
As an alternative option when other ablative treatments cannot be applied. 90Y-microsphere radioembolization as well trans-arterial chemoembolization may improve the survival in patients with poor prognosis with portal vein occlusion, who are often excluded from a targeted therapy .
In combination with systemic therapies. Although preliminary data suggest a synergistic beneficial effect of 90Y-microsphere radioembolization when combined with sorafenib (with associated tolerable toxicity) [67, 68, 69, 70], large-scale multicenter trials are still ongoing to confirm these data and to define the safety profile and the impact of the combination on survival of this combination regimen.
In patients with unresectable liver-predominant metastases from colorectal cancer, preliminary results of the SIRFLOX study indicate that radioembolization combined with systemic therapy as first-line treatment can lead to downstaging of the disease in a significant proportion of cases and to improved PFS for the liver lesions (but not overall PFS, while the follow-up phase is ongoing for overall survival) .
As a second-line treatment and in the salvage setting for liver-predominant metastatic colorectal cancer, there are clinical evidences that combination of radioembolization and systemic chemotherapy using radiosensitizing drugs (i.e., oxaliplatin, 5-FU, and irinotecan) is safe, with preliminary results indicating a 79% response rate .
Radioembolization with 90Y-microspheres has shown to be an effective procedure with significant impact on survival of patients with either primary or secondary liver malignancies.
Primary Liver Tumors
Radioembolization as a treatment option has been extensively investigated for the most common primary liver malignancy, i.e., HCC, especially after Geschwind and coworkers published their landmark comprehensive analysis on the use of 90Y-microspheres for HCC. Besides demonstrating overall clinical safety and benefit of this therapy, the study also indicated better survival as treatment was employed earlier in the course of disease, i.e., in Okuda stage I (63% for 1-year survival and 628-day median survival) rather than in Okuda stage II patients (51% for 1-year survival and 384-day median survival, with P = 0.02) .
The response rates to radioembolization with 90Y-microspheres may vary widely not only because of variable tumor biology but also because of differences in evaluation times or in treatment intensity. Tumor shrinkage after therapy may take months to occur, with a median time to response of approximately 6 months according to WHO criteria . Nevertheless, response in tumor size is not an adequate parameter to define all the antitumor effects of therapy. When combining different response criteria, such as tumor size and arterial contrast enhancement with the EASL response criteria, the overall tumor response rates vary between 40% and 90%, with a disease control rate in targeted lesion of 80–100%. According to changes in vascular enhancement, time to response occurs in the treated tumor lesions earlier than response in tumor size, around 2 months after 90Y-microsphere radioembolization .
Surgery is the optimal standard of care with curative intents for patients with HCC; however, resection is possible only for lesions limited in size and number and if the liver function is well preserved; the latter is not a frequent condition considering that most HCCs originate in patients with liver cirrhosis. On the other hand, patients with a single lesion <5 cm in diameter, or with ≤3 lesions, all <3 cm without extrahepatic metastases or portal vein thrombosis (PVT), are eligible for liver transplantation. Nevertheless, orthotopic liver transplantation has had a limited role in the management of patients with HCC due both to limited availability of donor organs and to dropout of patients because of tumor progression. Since radioembolization has been shown to slow the progression of HCC, this procedure may allow patients more time to wait for donor organs and thus increases their chance of undergoing liver transplant [75, 76, 77].
Patients whose disease is too advanced to meet transplant criteria, but do not have malignant PVT or metastatic HCC, are good candidates for radioembolization. In fact, radioembolization has been shown to downstage the disease so that 56% of the patients who were initially stratified as non-eligible for transplant according to Milan criteria then become eligible for transplant after therapy; 8 out of 34 downstaged patients actually underwent subsequent liver transplantation, with 84%, 54%, and 27% overall survivals, respectively, at 1, 2, and 3 years. In addition to downstaging, radioembolization also prolongs overall survival of these patients [75, 76, 77].
Survival benefit following radioembolization has been observed also in patients with malignant vascular involvement, with a 70% response rate according to EASL criteria . The presence of distant metastases contraindicates treatment, as a survival benefit has not been demonstrated for this subset of patients.
Resection has a modest survival benefit in patients who have resectable intrahepatic cholangiocarcinoma (ICC). Some improvement in survival has been observed after trans-arterial chemoembolization, but toxicity associated with this treatment remains high. On the other hand, while radioembolization has been shown to be an effective treatment for HCC, its role in the management of ICC patients has not been extensively investigated. Nevertheless, a pilot study in 24 patients with biopsy-proven ICC has shown favorable tumor response and favorable survival outcomes following therapy with 90Y-microspheres, especially for patients with better ECOG performance status .
A recent systematic review on the use of TARE in the treatment of ICC identified 12 studies including a total of 73 patients. PR and SD at 3 months were reported in 28% and 54% of patients, respectively. In a pooled analysis, the overall weighed median survival was 15.5 months, and downstaging to surgery was achieved in seven patients . The combination of TARE and chemotherapy as a strategy for downstaging ICC to achieve resectability has recently been proposed, with encouraging initial data . However, when comparing different locoregional treatments for ICC, TARE may not be the most effective approach. In a comparative analysis, TARE performed second in terms of tumor response to intra-arterial chemotherapy but was more effective than TACE or DEB-TACE both in terms of tumor response and in terms of overall survival. In fact, overall survival was 22.8 months for intra-arterial chemotherapy, 13.9 months for TARE, 12.4 months for TACE, and 12.3 months for DEB-TACE. Nevertheless, intra-arterial chemotherapy had the highest toxicity . Despite the lack of randomized controlled trials, locoregional treatments appear to be somewhat more effective than the current standard chemotherapy regimens with oxaliplatin and gemcitabine . For patients with unresectable ICC, trans-arterial radioembolization with 90Y-microspheres seems to be best suited for patients who are not eligible for intra-arterial chemotherapy.
[18F]FDG-PET is the best independent predictor for patient outcome after radioembolization treatment, based on reduction in the metabolically active tumor volume at 3 months after therapy .
Metastatic Liver Tumors
Extrahepatic metastasis and comorbidities limit the role of surgical resection in patients with secondary liver tumors . The use of radioembolization in these patients has been extensively investigated, either as a single treatment or in adjunct to systemic chemotherapy.
Metastatic Colorectal Carcinoma
Liver metastases from colorectal carcinoma (CRC) are resectable in less than 10% of the patients . Radioembolization has been shown to be effective in the treatment of metastatic CRC to the liver. Candidates for radioembolization are those patients who have unresectable liver metastases and are on systemic chemotherapy or have failed to respond to first- or second-line chemotherapy. In these patients, [18F]FDG-PET has been shown to be more sensitive than CT for assessing tumor response to radioembolization [54, 85]. Furthermore, reduction of the hepatic metastatic load can be assessed quantitatively by [18F]FDG-PET, by evaluating the percent change of total liver SUV after treatment [53, 54].
Most of the studies on 90Y-microsphere TARE reported so far have been conducted in patients with chemorefractory liver-predominant metastatic CRC. A systematic review of 20 studies including a total of 979 patients treated with resin 90Y-microspheres has demonstrated the overall safety and efficacy of TARE for unresectable, chemorefractory metastatic CRC, with a median time to intrahepatic progression of 9 months and overall survival of 12 months .
In a randomized controlled clinical trial involving 74 patients, the combination of systemic therapy with radioembolization resulted in significantly better tumor response (44% objective response versus 17.6% in the control group), longer time to progression, and longer survival than systemic chemotherapy alone ; furthermore, the safety profile of the combined regimen was acceptable , and dose escalation studies have shown improved tumor response with increasing doses .
Several prospective trials have investigated the efficacy of TARE in combination with systemic chemotherapy versus systemic chemotherapy alone. In an early study, TARE combined with systemic 5-fluorouracil (5-FU) induced better objective response rates than 5-FU alone: 73% versus 0%, with time to progression of 18.6 months versus 3.6 months and overall survival of 29.4 months versus 12.8 months . More recent prospective studies have evaluated chemotherapy regimen more up-to-date than 5-FU. In a first-line setting, TARE combined with FOLFOX4 achieved a 90% PR rate , while TARE with irinotecan in a second-line setting after failure of previous chemotherapy reported an overall 87% response rate, with 48% PR and 39% SD . In the SIRFLOX study, a randomized clinical trial including 530 patients, the results of mFOLFOX 6 with or without bevacizumab were compared with TARE + mFOLFOX 6 with or without bevacizumab. While there was no difference in progression-free survival, there was a significant difference in progression-free survival in the liver, favoring the combination with TARE (20.5 months) over chemotherapy alone (12.6 months, with P = 0.002). Objective response rates were somewhat better with the combination therapy than with chemotherapy alone (76.4% versus 68.1%, but without reaching statistical significance, with P = 0.113) .
Also the recently published results obtained by Hong and coworkers show that radioembolization is safe and effective as a salvage therapy in the management of metastatic CRC when compared with chemoembolization .
A recent systematic review on TARE in unresectable, chemorefractory metastatic CRC includes 20 studies for a total of 979 patients enrolled after failure of two to five lines of chemotherapy. TARE achieved CR, PR, and SD in 0% (range 0–6%), 31% (range 0–73%), and 40.5% (range 17–76%) of patients, respectively. The median time to intrahepatic progression was 9 months (range 6–16), and median overall survival was 12 months (range 8.3–36) . In a large multicenter trial, overall survival was strongly dependent on previous treatments; in particular, median survival after 90Y-microsphere radioembolization was 13 months (95% CI 10.5–14.6) when TARE was performed as second-line treatment, 9 months (95% CI 7.8–11.0) for third-line treatment, and 8.1 months (95% CI 6.4–9.3) for fourth-line treatment and over, respectively, with P < 0.001 .
Metastatic Neuroendocrine Tumors
Several neuroendocrine tumors , such as carcinoids, VIPomas, gastrinomas, and somatostatinomas, metastasize to the liver. These lesions are often well arterialized and represent a target for trans-arterial therapies, similarly to patients with HCC. The goals of treatment in these patients are both control of symptoms and survival. Systemic chemotherapy and ablative procedures have all been shown to produce modest benefit in these patients. Patients with unresectable disease are considered candidates for radioembolization. The results obtained in a multicenter study including 148 patients have shown that radioembolization of metastatic neuroendocrine tumors to the liver is safe and effective, with very high response rates: any response in 95.1% of patients and progressive disease in only 4.9% of the patients. Response rates were even longer than 2 years, especially in non-pancreatic NETs [96, 97].
Absolute and Relative Contraindications
Two absolute contraindications exist for therapy with 90Y-microspheres intra-arterially. The main contraindication is represented by a pretreatment 99mTc-MAA scan demonstrating significant hepato-pulmonary shunting. This occurrence would in fact result in the delivery of a radiation dose to the lungs greater than 30 Gy with a single infusion or as much as 50 Gy for multiple infusions. The second contraindication is the inability to prevent deposition of the radiolabeled microspheres in the gastrointestinal tract. Relative contraindications include reduced pulmonary function, inadequate functional liver reserve, serum creatinine >2.0 mg/dL, and platelet count <75 × 109/L. When such relative contraindications exist, clinical judgment should be exercised for determining whether or not a patient is appropriate to undergo the procedure, taking into consideration either 90Y-microspheres or 131I-lipiodol .
Early and Late Toxicities
The most common clinical toxicity observed with 90Y-microsphere therapy is a mild post-embolic syndrome. Similarly as observed with other embolic treatments such as trans-arterial chemoembolization, this syndrome includes fatigue, vague abdominal discomfort, pain, and fever [99, 100]. Other toxicities that can occur as a result of nontarget radiation (and should therefore be avoided by adequate pre-therapy procedures and by accurate treatment planning) include the following: cholecystitis, gastric ulceration, gastroduodenitis, pancreatitis, radiation pneumonitis, and RILD [75, 78, 79, 101]. By adopting meticulous planning, careful selection of patients, and proper techniques, the majority of these toxicities can be mitigated. Finally, a common hematologic toxicity observed in the immediate post-radioembolization period is represented by lymphopenia, not an unexpected finding considering the sensitivity of lymphocytes to radiation. Despite this possible occurrence, no infectious complications have been reported [13, 33, 52, 53, 54, 99, 100, 101, 102].
Perspectives on Radioembolization for Primary and Metastatic Liver Tumors
A growing body of evidence supports the use of TARE with 90Y-microspheres as an effective monotherapy in patients with HCC. Future avenues to be explored concern the scenario of combination therapies with systemic and locoregional agents, specifically sorafenib and TARE, in the adjuvant or neoadjuvant setting. Although the mechanisms of action for the two therapeutic approaches can in principle be considered as complementary one to the other from the pathophysiologic point of view, there are currently scarce data confirming the actual clinical benefit of regimens based on this combination.
In the only prospective study so far reported for combination therapy of TARE with sorafenib, the rate of objective responses was 25%, somewhat disappointing with respect to that expected on the basis of the underlying rationale. Moreover, 39% of the patients could not complete the prescribed dose of sorafenib due to important side effects . On the other hand, initial safety results in the first 40 patients enrolled in a randomized controlled clinical trial comparing TARE with resin 90Y-microspheres followed by sorafenib with sorafenib only indicate a similar tolerance for the two treatment arms . Long-term outcome data from ongoing randomized controlled clinical trials such as SORAMIC, SARAH, or SIRveNIB (based on the use of resin 90Y-microspheres) or STOP-HCC (using glass 90Y-microspheres) have not been published yet.
Regarding treatment of metastatic disease, there is the need of randomized controlled clinical trials comparing TARE with up-to-date chemotherapy regimens, since the few data so far available have been obtained in studies comparing the efficacy of therapy with resin 90Y-microspheres versus chemotherapeutic regimen that are now obsolete or the studies lack survival data. An ongoing randomized controlled clinical phase III trial evaluates treatment with glass 90Y-microspheres and second-line chemotherapy after failure of first-line chemotherapy in comparison to second-line chemotherapy alone for metastatic CRC; 360 patients have been enrolled in this trial, and the first results of the analysis are expected to be released soon.
The FOXFIRE global is an international phase III study assessing the value of additional resin 90Y-microspheres in the setting of first-line treatment with FOLFOX6m (NCT01721954). Enrollment of 530 patients has been completed, and the preliminary results are encouraging, with significantly prolonged PFS in the liver by competing risk analysis, from a median of 12.6 months for control patients to 20.5 months (P = 0.002) for patients receiving resin 90Y-microspheres; this translates into a 31% reduction in the risk of disease progression in the liver. Pooling the data of studies with similar designs (SIRFLOX, FOXFIRE, and FOXFIRE global) from over 1,100 patients will provide sufficient statistical power to assess the survival benefit derived from the addition of resin 90Y-microspheres to current chemotherapy regimens. Survival data from the three combined studies are expected to be released in 2017.
Further ongoing studies evaluate the role of TARE in uveal melanoma with liver metastasis (SIRUM trial, NCT01473004) or the combination of TARE and pasireotide and everolimus in liver metastatic neuroendocrine tumors (NCT01469572) .
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