Cancer Microsphere Intervention (CMI)

What is CMI

Cancer microsphere intervention (CMI) means a strategy of transarterial infusion of microspheres into tumor.Transarterial chemoembolization (TACE) is a most used option of CMI.

TACE is a form of intra-arterial catheter-based chemotherapy that selectively delivers high doses of cytotoxic drug to the tumor bed combining with the effect of ischemic necrosis induced by arterial embolization. Chemoembolization and radioembolization are at the core of the treatment of liver hepatocellular carcinoma (HCC) patients who cannot receive potentially curative therapies such as transplantation, resection or percutaneous ablation. TACE for liver cancer has been proven to be useful in local tumor control, to prevent tumor progression, prolong patients' life and control patient symptoms.

Although being used for decades, Lipiodol(®) remains important as a tumor-seeking and radio-opaque drug delivery vector in interventional oncology. There have been efforts to improve the delivery of chemotherapeutic agents to tumors. Drug-eluting bead (DEB) is a relatively novel drug delivery embolization system which allows for fixed dosing and the ability to release the anticancer agents in a sustained manner. Three DEBs are available, i.e., Tandem(®) (CeloNova Biosciences Inc., USA), DC-Beads(®) (BTG, UK) and HepaSphere(®) (BioSphere Medical, Inc., USA), among which, HepaSphere is most commonly used.

Apart from liver cancer, the CMI is also used for malignant tumor of other solid organs and tissue, such as lungs, kidneys, overy, uterus, prostate, soft tissue.

What is the HepaSphere?

HepaSphere (Merit Medical, Rockland, MA, USA) is biocompatible, hydrophilic (absorbent), nonresorbable, and expandable microsphere. HepaSphere is conformable and swells upon exposure to aqueous solution. It was made with sodium acrylate and vinyl alcohol copolymer. The particle size is precisely calibrated in the dry state. The dry microsphere absorbs fluid and swells within several minutes when exposed to aqueous-based media. The swollen particle is soft, deformable, and easily delivered through the majority of the currently available microcatheters.

The dry HepaSphereare supplied in a range of sizes, namely, 30-60,50-100, 100-150 and 150-200 µm. In vitro studies demonstrated that particle diameters in ionic contrast media are approximately 2 and 3.5 times larger than the original diameters in the dry state and 4 times larger in human serum. The polymer contained within HepaSphere is anionic, which allows the sequestering of cationic drug molecule, such as doxorubicin or epirubicin by Coulomb charge attraction. This enables cationic chemotherapeutic agent to be carried within the microsphere. Moreover, these particles, because of the slightly larger expansion in human serum, are able to mold to the morphology of the vessel lumen.

HepaSphere had been approved by the FDA in 2006. It had been getting widely used instead of the traditonallipiodol embolization for HCC in Europe and US.

HepaSpherehas been evaluated in aclinical study which comprised of 50 patients in four centers. The microspheres were either loaded with doxorubicin (mean dose 43.6±8.7 mg) or with epirubicin (mean dose 41.7±14.6 mg). It has been shown that that TACE using HepaSphere is feasible, well-tolerated, and is associated with good tumor response. Repeated TACE procedures can be carried out without difficulties.

By radioimmunology, 24 hours, 3 days, and 14 days post treatment, the drugs keep releasing obviously, largely prolonging contacting time with tumor cells, and thus fully kill the tumor cells.

The safety and efficacy of HepaSphere

In 2014 Katerina Malagari had published Chemoembolization of Hepatocellular Carcinoma with HepaSphere 30–60 μm. Safety and Efficacy Study.(CardiovascInterventRadiol. 2014; 37(1): 165–175.)The study shows that TACE with HepaSphere was well tolerated with an acceptable safety profile and no 30-day mortality. Response rates were calculated on intention-to-treat basis with complete response (CR) in 17.8 % reaching 22.2 % for the target lesion. Overall partial response (PR) was seen in 51.1 %, stable disease in 20 %, and progressive disease in 11.1 % of patients. Overall objective response (CR + PR), including patients treated at all dosages of doxorubicin, was seen in 68.9 % of cases. After a median follow-up of 15.6 months, 1-year survival is 100 %. Doxorubicin AUC was significantly lower in patients with HepaSphere 30–60 μm(35,195 ± 27,873 ng × min/ml) than in patients with conventional TACE (103,960 ± 16,652 ng × min/ml; p = 0.009). Cmax was also significantly lower with HepaSphere30–60 μm (83.9 ± 32.1 ng/ml) compared with c-TACE (761.3 ± 58.8 ng/ml; p = 0.002).

CR was achieved in 17.8 % of cases overall, reaching 22.2 % for the target lesion according to mRECIST criteria. Overall PR was seen in 51.1 %, SD in 20 %, and PD in 11.1 % of cases. Overall objective response (CR + PR) was seen in 68.9 % of cases. After a median follow-up of 15.6 months, the 1-year survival rate was 100 %.

Rates of local response 1 month after the last chemoembolization session, including target and nontarget lesions and new lesions as required by mRECIST criteria.

AFP Level:

There was a statistically significant decrease in levels of AFP after embolization, indicating the good response of the tumors to the embolization material (p < 0.0001).

Plasma doxorubicin:

Plasma levels of doxorubicin measured immediately after embolization and at follow-up hours and days after the procedure. The blue line shows the levels after embolization with HepaSphere 30–60 μm loaded with doxorubicin at50 mg/vial, and the green line shows the levels of doxorubicin at the same time spots after c-TACE with the same amount of doxorubicin. The graph indicates that there is no doxorubicin loss in plasma when embolizing with HepaSphere 30-60μm, thus leading to less systemic toxicity.

Maximum Concentration:

Cmax for HepaSphere and c-TACE showing the increased values of doxorubicin concentrations with c-TACE to a statistically significant level (p = 0.002).CmaxHepaSphere: 83.9 ± 32.1 ng/ml (mean ± SD).Cmax c-TACE: 761±58.8 ng/ml (mean±SD). Shapiro-Wilk test: HepaSphere=0.451; c-TACE=0.680)≥p=0.002(Student t test).

Therefore HepaSphere 30–60 μm is a highly effective and safe embolic agent for intermediate-stage HCC with low systemic exposure to doxorubicin. Objective local response with an intended doxorubicin dosage of 50–100 mg reached 68.9 % without damage to adjacent healthy liver as evidenced by imaging and liver biochemistry.

A multicenter study followed 50 patients (36 males, 14 females, aged 54-80 years) with primary HCC and classified as Child-Pugh class A or B(92% Child-Pugh A). Patients were treated with HepaSphere Microspheres loaded with a dose of 50mg doxorubicin or epirubicin. Obejective tumor response was 77.4% at 6-month follow-up, as measured by mRECIST criteria. Grosso M, et al. Transarterial Chemoembolization for Hepatocellular Carcinoma with Drug-Eluting Microspheres: Preliminary Results from an Italian Multicentre Study. Cardiovascular Interventional Radiology 2008; 31(6):1141-49.

Compared with the traditional TACE, HepaSphere can protect the liver function as much as possible, which could ensure for the further continuous process, while reducing the maximum concentration in the whole blood circulation. In 2011, Prof. HannahvanMalenstein and his team had published their study on the comparasion of HepaSphere and traditional TACE. (Hannah van Malestein, et al. A Randomized Phase II Study of Drug-Eluting Beads versus Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma.Onkologie 2011;34:368–376). 30 patients with unresectable HCC were included. Of the 30 patients, 16 patients received SAP microsphere and 14 patients received conventional TACE.

In 29 patients, the pharmacokinetics of doxorubicin were ana­lyzed. Mean Cmax in control patients was 1,928.1 ± 560.8 ng/ml compared to 495.5 ± 293.9 ng/ml in SAP microsphere patients (p < 0.001).

Also, the cumulative dose represented by the AUC was significantly lower in the SAP microsphere patients (mean AUCcontrol 165 ± 32.3 ng/ml min vs. mean AUCSAP 69.7 ± 26.9 ng/ml/min; p < 0.001).

In the randomized comparison, it shows drug-eluting SAPHepaSpherehave a superior toxicity profile compared to conventional TACE.Their ability to slowly release the cytotoxic drug into the tumor in combination with direct embolization leads to lowsystemic concentrations of the chemotherapeutic agent, thus reducing adverse events.

Not only for the Hepatocellular Carcinoma, HepaSphere can also show its advantages for liver metastases. Magdalena Jarząbek, Tomasz Jargiełło, et al. Drug-eluting microspheres transarterial chemoembolization (DEM TACE) in patients with liver metastases. Pilot study. Pol J Radiol.2011 Jul-Sep; 76(3): 26–32.Total 15 patients with hepatic metastases, who had been rejected from consideration of radical resection and thermoablation were subjected to chemoembolization of the proper hepatic artery branches.The procedure was performed using HepaSphere 50–100 μm impregnated with 100 mg of Doxorubicine. The primary tumor sites included: colorectal ca, cholangiocarcinoma, gastrinoma, gallbladder ca, pancreatic ca, GIST, lung ca, kidney ca, breast ca and larynx ca. The evolution of the disease was monitored by MRI scanning, which was performed after a mean time of 7.6 weeks from the chemoembolization.

(A,C) Gadolinium contrast MRI done before the procedure in the same patient with breast cancer metastases (B,D) gadolinium contrast MRI control after DEM TACE, extraction of the vascularization of the tumor.

(A,C) CT of the patient with microcellular lung cancer metastases done before the procedure, (B,D) MRI control after 7 weeks from DEM TACE with regression of the lesions.

There were no severe complications after the procedure. The main adverse events registered in 80% of patients were: abdominal pain, nausea, vomiting and fever. The mean time of the procedure was 2 hours and the mean time of hospitalisation was 4,7 days.

The average patient’s survival from the first drug-eluting microspheres TACE was 5,8 months (ranged from 6 to 60 weeks) including patients who are currently alive. Two patients did not report to the MRI control. According to RECIST 1.1 criteria 26.7% of the patients had partial response (≥30% decrease in size of the lesion) and 33.4% had stable disease (≤30% decrease and ≤20% increase in size of the lesion) (Figure 4). 26,7% of patients suffered metastatic progression (≥20% increase in size of the target lesion). Tumors which well responded to the treatment were: gastrinoma, colorectal ca, microcellular lung ca, clear cell renal ca, breast ca and cholangiocarcinoma.

This pilot study showed that drug eluting microspheres chemoembolization is safe and promising palliative treatment in advanced tumour disease with liver metastatic disease.

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