|Year : 2021 | Volume
| Issue : 3 | Page : 733-739
Short-term efficacy and safety of callispheres drug-loaded microsphere embolization in primary hepatocellular carcinoma
Jinpeng Li1, Nan Wang2, Congcong Shi3, Qingran Liu4, Jinlong Song1, Xin Ye2
1 Interventional Therapy Department Ward 1, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
2 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital; Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
3 Shandong Mental Health Center, Jinan, China
4 Department of Intervention, Binzhou People's Hospital, Binzhou, Shandong, China
|Date of Submission||22-Dec-2020|
|Date of Decision||20-Jan-2021|
|Date of Acceptance||14-Mar-2021|
|Date of Web Publication||9-Jul-2021|
Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong
Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong,; Shandong Lung Cancer Institute, Jinan, Shandong
Source of Support: None, Conflict of Interest: None
Background: Drug-eluting beads transarterial chemoembolization (DEB-TACE) is a newly developed local regional therapy for improving the efficacy and safety of conventional transarterial chemoembolization (cTACE), which is now universally used to treat patients with unresectable liver cancer.Cohort studies, clinical trials, and meta-analysis have shown DEB-TACE to be associated with favorable treatment responses, prolonged survival, and at least similar safety profile when compared with cTACE.
Aims and Objectives: This study was to evaluate the short term clinical efficacy, side effects, and risk factors affecting the clinical effectiveness of CalliSpheres drug loaded bead transcatheter arterial chemoembolization (DEB TACE) in the treatment of primary hepatocellular carcinoma (HCC).
Materials and Methods: A total of 172 consecutive patients with HCC undergoing DEB TACE (loaded with doxorubicin) from January 2017 to December 2018 were prospectively enrolled. Short term local tumor response was evaluated by the modified RECIST criteria. Postoperative complications and liver function disorders were analyzed based on examinations and clinical symptoms.
Results: The median follow up period was 310 days. Based on the modified response evaluation criteria in solid tumors criteria, objective response rates(complete response [CR] + partial response [PR]) were 78.7%, 71.6%, and 63.2%, and disease control rates(CR + PR + stable disease) were 95.3%, 92.1%, and 85.9% at 2, 4, and 6 months posttreatment, respectively. Multivariate logistic regression analysis showed that nodule number >3, high BCLC stage, no vascular leak, and previous conventional TACE treatment were associated with poor ORR (P < 0.05). Postoperation, liver function showed transient changes. Postoperative complications were tolerated and relieved by symptomatic treatment. The average interval of TACE before D TACE was 43 days, compared with 70 days for average interval of DEB TACE. The average hospital stay was 1.87 days.
Conclusion: DEB TACE has improved short term efficacy and lower incidence of complications in primary HCC and prolongs the interval of TACE. It significantly increases the ORR, especially in patients with no extra hepatic metastasis pretreatment. DEB usage actually improves treatment efficacy and provides more benefits to patients. KEY WORDS: Drug-loaded bead-transcatheter arterial chemoembolization, hepatocellular carcinoma, microsphere embolization
Keywords: Drug-loaded bead-transcatheter arterial chemoembolization, hepatocellular carcinoma, microsphere embolization
|How to cite this article:|
Li J, Wang N, Shi C, Liu Q, Song J, Ye X. Short-term efficacy and safety of callispheres drug-loaded microsphere embolization in primary hepatocellular carcinoma. J Can Res Ther 2021;17:733-9
|How to cite this URL:|
Li J, Wang N, Shi C, Liu Q, Song J, Ye X. Short-term efficacy and safety of callispheres drug-loaded microsphere embolization in primary hepatocellular carcinoma. J Can Res Ther [serial online] 2021 [cited 2021 Aug 5];17:733-9. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/733/321020
| > Introduction|| |
Hepatocellular carcinoma (HCC) is growing in incidence, constituting the second major cause of cancer-related death worldwide. Most patients are in middle and late stages at diagnosis, with 5-year survival rates of 50% and 8%, respectively. Transcatheter arterial chemoembolization (TACE) is the most effective first-line therapy and can prolong survival. However, conventional TACE (cTACE) uses lipiodol to load chemotherapeutics, and efficacy and safety are unsatisfactory. Especially for the treatment of medium, large and multiple tumors are more difficult. This may be related to the fact that tumors will be more aggressive after TACE.
Drug-eluting bead-TACE (DEB-TACE) is a novel chemoembolization technique which not only loads and slowly releases high amounts of chemotherapeutics locally to reduce systemic toxicity but also permanently embolizes supplying vessels of tumors. Multiple studies have demonstrated superior short-term efficacy and safety of DEB-TACE over cTACE. Due to economic limitations, drug-loaded microspheres have not been widely used in China. Few studies have evaluated the efficacy and safety of DEB-TACE in HCC, assessing benefits to patients. The objective of the present study was to investigate the short-term efficacy, safety, and factors of CalliSpheres drug-loaded microspheres for HCC, providing a basis for the development of this novel technique.
| > Materials and Methods|| |
Consecutive HCC patients in Shandong Cancer Hospital and Institute from August 2016 to June 2018 were enrolled into the present prospective study if they met the following criteria: (1) primary HCC diagnosed clinically or pathologically in accordance with the guidelines of the American Association for the Study of Liver Diseases; (2) aged over 18 years; (3) Eastern Collaborative Oncology Group (ECOG) score <2; (4) Child-Pugh A or B hepatic function, or expected survival time ≥3 m; and (5) DEB-TACE required by the patient's wish or clinical situation.
Exclusion criteria were (1) severe hepatic or renal failure; (2) allergy or contraindication for the chemoembolic agent; and (3) contraindication for hepatic arterial embolization including arteriovenous fistula, portal occlusion, severe coagulation disorders, and severe uncontrolled systemic complications such as infection and diabetes mellitus; (4) severe cardiocerebrovascular disease; (5) complication with other primary tumors; (6) pregnancy or lactation in women; and (7) cognitive impairment or inability to comprehend the present study. The study was approved by the Ethics Committee of Shandong Cancer Hospital (Ethical approval number: SDZLEC-2017-001-01). All subjects provided written informed consent.
A total of 172 patients were eligible, including 139 males and 33 females with an average age of 54.62 ± 11.25 years. Of these, 130 patients (75.6%) had type B hepatitis and 16 (9.3%) had type C hepatitis. The ECOG score was 0 in 116 patients and 1 in 56 individuals. Thirteen patients were in BCLC Stage A, with 89 in Stage B and 70 in Stage C. One-hundred and fifty-one patients were classified as Child-Pugh A and 21 as Child-Pugh B. Seventy-one patients had multiple foci and 101 had a single focus. Sixteen patients (9.3%) were treated previously surgically, six with targeted therapy, and eight with radiofrequency ablation. A total of 98 patients had received c-TACA once to twice, with a median of one time.
CalliSpheres drug-loading microspheres (Jiangsu Hengrui Medicine Co. Ltd., Jiangsu, China) were used (300–500 μm or 100–300 μm). Percutaneous right femoral artery puncture intubation with a modified Seldinger technique was performed. Then, a 5F-Yashiro or RH (Terumo, Japan) catheter was introduced through a 5-F vascular sheath into the common hepatic artery under DSA guidance for celiac angiography to assess hepatic arterial anatomy and the potential existence of variants, location, size, number and staining of tumors, as well as tumor thrombus in the portal vein and hepatic arteriovenous fistulas. In case arteries supplying the tumors were not developed, arteriography was continued of the superior mesenteric artery, bilateral inferior phrenic arteries, internal thoracic arteries, and the aortic suprarenal artery to confirm these arteries supplying the tumors. Then, a 2.7F micro-catheter (Terumo, Japan) was advanced superselectively to the supplying artery of the tumor. CalliSpheres beads were fully loaded Epirubicin at a dosage of 60–80 mg and mixed with Ioversol at a volume ratio of 1:1–1.2, followed by standing for 5 min. Before use, the sample was mixed and placed in a 1 ml injector. The bead diameter and injecting sequence depended on the tumor size and supplying vessels. Subsequently, the mixture was manually injected in a pulsed mode into the tumor-supplying artery at a rate of 1 ml/min under fluoroscopic monitoring until the developer was stable or approached stability. Angiography was repeated 5 min after embolization to assess whether embolization was complete. If there were still tumors, embolization was continued until tumor-supplying vessels slowed down and contrast agent disappeared after 2–5 heart beats. Imaging examinations were conducted every 4–6 weeks, and the next TACE treatment was based on imaging results. Postoperation, liver protection, and pain relief treatments were provided. If necessary, antibiotics were also administered to prevent infection.
Follow-up and imaging evaluation
All patients were followed up during hospitalization or by telephone. Based on modified response evaluation criteria in solid tumors (mRECIST), computed tomography (CT) and/or magnetic resonance imaging were performed 4–6 weeks after DEB-TACE to evaluate local response. The objective response rate (ORR) was defined as the proportion of patients gaining CR or PR, and the disease control rate (DCR) as that of patients showing complete response (CR), partial response (PR), and stable disease (SD) In case of PD even after two D-TACE procedures for the same tumor focus, the patient no longer received drug-loaded microsphere embolization. Treatment efficacy in months 2, 4, and 6 was evaluated as well as the associated factors. The tumor lesions were evaluated by two independent experienced (more than 5 years of working experience) abdominal radiologists in cooperation with our department.
Safety was evaluated by changes of liver function including albumin (ALB), total bilirubin (TBIL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), and the tumor marker α-fetoprotein (AFP) 1 week preoperation, and 1 week and 1 month postoperation. Adverse events such as pain, fever, nausea, and vomiting 1 month post-DEB-TACE were recorded according to common terminology criteria for adverse events (CTCAE) established by the National Cancer Institute.
SPSS22.0 (SPSS Statistics, Chicago, IL, USA) was used for statistical analysis. Measurement data were expressed as mean ± standard deviation and compared by the t-test. Qualitative data were expressed as proportion (%) and compared by the Chi-square test. Factors predicting ORR were analyzed by univariate and multivariate logistic regression analyses. P < 0.05 was considered statistically different.
| > Results|| |
Factors influencing treatment response and tumor relapse
All CalliSpheres drug-loaded microsphere treatments were successfully conducted, and the technical success rate was 100%. A total of 358 DEB-TACE treatment were performed in 172 patients. A typical case is shown in [Figure 1]. All 172 patients were followed up, and efficacy was evaluated with the mRECIST criteria [Table 1].
|Figure 1: Short-term local tumor response of a patient treated with CalliSpheres microspheres. (a and b) Computed tomography scan showed a classic imaging features of hepatocellular carcinoma; (c) In the interventional procedure, we used 100–300 μm CalliSpheres microspheres to embolize the feeding artery of tumor; (d) Postoperative angiography showed complete embolization of tumor feeding artery; (e) Enhanced computed tomography examination at 1 months after surgery showed the efficacy evaluation was partial response. (f) Enhanced computed tomography examination at 3 months, the efficacy evaluation was complete response|
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|Table 1: Follow-up results based on the modified response evaluation criteria in solid tumors criteria|
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No residual DEB-DSA was found in DAS after DEB-TACE. Of the 325 tumor nodules in all patients, 146 (44.9%) relapsed 1–4 months post-DEB-TACE [Table 1]. The median follow-up period of CT was 1.6 months (1–4 months). Univariate analysis showed that BCLC stage (P = 0.001), tumor number (P = 0.002), previous cTACE (P = 0.010), AFP (P = 0.009), tumor border (P = 0.005), and no vascular leak (P = 0.001) were significantly associated with tumor relapse (P < 0.05) [Table 2].
|Table 2: Univariate analysis of factors associated with local relapse postdrug-eluting bead transarterial chemoembolization|
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The six factors were further assessed by logistic regression analysis. The results showed that CLC stage (odds ratio [OR] = 3.46, 95% confidence interval [CI] 1.93–34.76, P = 0.004), tumor number (OR = 3.83, 95% CI: 1.14–14.9, P = 0.0038), previous cTACE (OR = 5.640, 95% CI: 1.160–27.415, P = 0.0032), and no vascular leak (OR = 7.713, 95% CI: 1.521–39.112, P = 0.014) were significantly associated with reduced ORR post-DEB-TACE [Table 3].
Treatment intervals and hospitalization durations
The average interval of D-TACE was 70 days (28–198 days) and that of TACE before D-TACE was 43 days (28–84 days). The average hospitalization stay after D-TACE was 1.87 days [Table 4]. The interval of TACE treatment was significantly prolonged after TACE.
|Table 4: Hospitalization durations of patients with primary hepatocellular carcinoma|
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Changes of hepatic function and laboratory parameters pre-and post-treatment
The CTCAE grades of ALB, TBIL, ALT, and AST pretreatment ranged from 0 to 2, with Grade 0 being most common [Table 5]. One week posttreatment, ALB was significantly decreased, while TBIL, ALT, and AST were significantly increased, as well as CTCAE grade (P < 0.001). All parameters returned to normal 1–3 weeks posttreatment (P = 0.852, P = 0.167, P = 0.228, and P = 0.422, respectively). AFT was significantly decreased posttreatment (P < 0.05).
|Table 5: Laboratory parameters pre- and post-drug-eluting bead transarterial chemoembolization|
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The most common treatment-related adverse events included abdominal pain, vomiting, fever, and myelosuppression. There were eighty patients with mild pain (50.00%), 14 with moderate pain (8.14%), 2 with severe pain (1.16%), and 70 with no pain (40.7%). A total of 85 patients experienced vomiting including 80 with Grade 1 (46.51%) and 5 with Grade 2 (2.91%). Only one patient (0.58%) reported cardiac toxicity. There were sixty patients with no fever (34.88%), 72 with low-grade fever (41.86%), 39 with moderate-grade fever (22.67%), and one with high-grade fever (9.1%) [Table 6].
|Table 6: Adverse events post drug-transcatheter arterial chemoembolization|
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| > Discussion|| |
TACE is the standard therapy for advanced HCC. However, chemotherapeutics and treatment intervals and number in TACE remain controversial., The cTACE treatment usually employs lipiodol to load chemotherapeutics to block supply arteries of the tumor, which increases the concentration of chemotherapeutics within the tumor and decreases toxicity to the normal liver parenchyma. However, it also has some disadvantages such as introducing chemotherapeutics into the systemic circulation, which increases the incidence of systemic adverse events, complications, and drug resistance, potentially decreasing the survival benefit., The cTACE treatment is associated with improved survival benefit but higher relapse compared with expectant treatment. Therefore, it generally believed that TACE alone cannot solve this problem. How to increase the efficacy of TACE in HCC is an urgent topic. The embolization efficacy of TACE is largely dependent on the embolization material. The optimal material can block supplying arteries of the tumor at high local concentrations and low systemic levels. Compared with lipiodol, drug-loaded microspheres not only block supplying vessels of the tumor but also prolong the time of chemotherapeutics acting on tumor cells. They can induce long-term and sustained release of chemotherapeutics to kill the tumor tissues and decrease the circulating levels. Reportedly, DEB-TACE prolongs the survival time and reduces chemotherapeutic embolization, being superior to cTACE. However, in clinical practice, some patients first select DEB-TACE and others receive multiple cTACEs before considering DEB-TACE. Whether DEB-TACE can lengthen the treatment interval and increase treatment efficacy in HCC patients has not been reported. For patients with multiple unsuccessful TACE treatments, DEB-TACE may be a potential key to improve long-term prognosis.
Multiple cohort studies, clinical trials, and meta-analyses have shown that DEB-TACE has better treatment response, survival, and safety compared with cTACE. A retrospective cohort study suggested that DEB-TACE can be an effective bridge therapy before liver transplantation in late-stage HCC with liver dysfunction. Although DEB-TACE is applicable in advanced HCC, only a few patients are actually treated by this method in clinical practice, and studies and evidences of DEB-TACE treating BCLC C stage HCC are limited.
According to the mRECIST criteria, ORRs (CR + PR) were 78.7%, 71.6%, and 63.2%, and DCRs (CR + PR + SD) were 95.3%, 92.1%, and 85.9% at 2, 4, and 6 months posttreatment, respectively. The 1-year survival was 92.6%. Subgroup analysis showed that the CR and ORR were reduced in patients with high BCLC stage and a previous history of cTACE. Logistic regression analysis showed that >3 nodules, high BCLC stage, and previous cTACE treatment may be associated with reduced ORR. Multifocal HCC is considered a risk factor for poor HCC prognosis., Nodule number >3 reflects poor survival postliver resection. These findings showed that nodule number has a good predictive value, consistent with the current study. Poor ORR in patients with a history of cTACE in the present study may be due to low sensitivity to DEB-TACE post-cTACE. Multiple cTACE treatments worsen vascular injury, hepatic fibrosis, and resistance to chemotherapeutics, affecting the efficacy of subsequent treatment and causing TACE resistance. Besides, TACE can cause local tumor hypoxia, increased vascular permeability, tumor antigen release, T lymphocyte infiltration and aggregation, and release or expression of cytokines, but generally the effect is weak and short. D-TACE decreases drug spreading into the peripheral system, increases local drug concentration, strengthens the anti-tumor effect of chemotherapeutics, and increases the ORR.
The present study suggested that D-TACE could significantly prolong the interval of TACE treatment, i.e., 112 days in fifty patients treated by D-TACE with no previous treatment compared with 69 days in those administered other treatments. After treatment with drug-loading microspheres, the interval of TACE was significantly prolonged, which is beneficial for hepatoprotection, life quality enhancement, and decreasing the social burden. In patients with HCC, protection of hepatic function is also important, except for tumor treatment, and even more important than tumor treatment in some circumstances. Hepatic function directly affects treatment choice, efficacy, and prognosis. Chemotherapeutics and embolic agents can damage hepatic function, and sufficient interval of TACE is required to guarantee recovery of hepatic function. Besides, patients experience varying degrees of adverse events, which decrease the quality of life, affects life and working, increases the nursing load of families, and the social burden. Therefore, prolonging the TACE interval is very helpful for hepatic function recovery, life quality increase, and familial and social burden decreases.
Usually, hepatic function rapidly worsens 1-week posttreatment and returns to normal within 1–3 months posttreatment. In the present study, hepatic injury was relatively mild, possibly owing to baseline hepatic function being different from other studies. The rapid alteration of hepatic function 1-week posttreatment may be induced by surgery; liver function recovery 1–3 months posttreatment may be associated with moderate baseline hepatic function, suggesting the self-repair ability of the liver. Previous findings indicate that DEB-TACE can be tolerated, similar to cTACE, with most adverse events being low grade. To some extent, tolerance is better for DEB-TACE compared with cTACE, since no azithromycin-related systemic toxicity in patients with DEB-TACE was previously reported. In a previous study, 7 of 51 patients (13.7%) had low incidence of TACE-related complications such as liver decompensation, hepatic vein thrombosis, pancreatitis, and postembolization syndrome.
Good hepatic function and fewer complications can not only be more acceptable by patients but also increase the chance of combination therapy. At present, the researches of HCC treatment are mainly combined therapy. Shen et al. and found that TACE combined with Apatinib is safe and significantly prolong the overall survival of HCC patients. Ni and Ye also report the safety and efficacy of Apatinib as an adjunct in the treatment of HCC. Besides, Li et al. report that locoregional treatment may induce antitumor immune response, which maybe a key point of immunotherapy. In the present study, the most common adverse events pre- and post-treatment included pain, vomiting, hypertension, and fever, most of which were mild to moderate, consistent with previous findings. All these results prove the excellent safety of DEB-TACE. This treatment was well tolerated, and no liver abscess or failure, or bile leakage was reported. In addition, Meng et al. and Li et al. elaborated the TATI modalities as a new perspective on the treatment of advanced HCC based on clinical studies., This paper suggests three key viewpoints. First, the new mode of treatment for HCC is effective and safe. Second, the role of targeted therapy and immunotherapy is established based on TACE and/or Ablation. Third, the four treatments are reinforced and interlinked mutually. As a result, it can be speculated that DEB-TACE treatment is able to inhibit tumor more thoroughly through embolizing tumor and continuous chemotherapy. This has led the increasingly effective reduction of tumor loading, promoted tumor antigen release, and thereby enhanced systemic immune effectiveness. If DEB-TACE is used to replace cTACE in the study, it can be predicated that a better efficacy and safety will be achieved.
The present study still had limitations. (1) The follow-up period was short. (2) This was a single-center study. t (3) The study enrolled 74.4% of patients with a treatment history, which affected the consistency of the research. (4) The sample size in this study was small, which may caused selection bias. A multi-institutional prospective clinical trial to confirm our findings was needed.
| > Conclusions|| |
In conclusion, CalliSpheres® DEB-TACE is effective and well tolerated in Chinese HCC patients. Drug-loading microsphere DEB-TACE should be used as early as possible to reduce treatment time and medical cost, prolonging the TACE interval. BCL stage, nodule number, and a history of cTACE might be associated with treatment efficacy.
Jinpeng Li and Nan Wang were responsible for performing the experiments and drafted the manuscript. Nan Wang and Qingran Liu were responsible for acquisition and analysis of data. Jinpeng Li and Congcong Shi provided and collected the clinical data. Xin Ye and Jinlong Song were responsible for designing the experiments and supervising the study. All authors read and approved the final manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]