Abstract
Objective:
To evaluate the feasibility, efficacy and safety of transcatheter arterial chemoembolization (TACE) with HepaSphere for patients with pulmonary or mediastinal metastases from hepatocellular carcinoma (HCC).
Methods:
Between June 2009 and January 2018, 14 patients with pulmonary or mediastinal metastases from HCC were treated with TACE with a combination of 1–3 chemotherapeutic drugs followed by HepaSphere embolization. As first end point, local tumor response and adverse events were evaluated after the first session of TACE, with Response Evaluation Criteria In Solid Tumors v. 1.1 and Common Terminology Criteria for Adverse Events v. 4 criteria, respectively. Overall survival was evaluated as secondary end point. TACE was repeated on-demand.
Results:
TACE with HepaSphere was well tolerated with acceptable safety profile and no 30 day mortality. 1 month objective response and disease control rate were calculated to be 7.1 and 100%, respectively. Mean tumor size reduction rate was 15.6±9.5% at the first month. Two Grade 3 cytopenia events were seen (14.3 %), however none of the Grade 2 or more post-embolization syndrome was observed. The median overall survival time was 15.0 months and the 1 year, 3 year and 5 year survival rate were, 57.1%, 28.6%, 19.1%, respectively.
Conclusion:
Early experience showed that the transarterial treatment with HepaSphere is safe and effective treatment for patients with pulmonary or mediastinal metastases from HCC.
Advances in knowledge:
Currently, the effects of molecular targeted drugs on HCC metastases are limited and side-effects are relatively frequent. In the present study, transarterial treatment might be a promising treatment for HCC metastasis.
Introduction
The most frequent organ of distant metastases from hepatocellular carcinoma (HCC) is the lung or mediastinum. 1–3 It is reported that 47% of extrahepatic metastases are lung or mediastinum. 4 The pulmonary or mediastinal metastases are usually found in the final stage of clinical course. Further extension of patients’ life seems difficult. The median survival time (MST) and 1 year survival rate for the HCC patients with extrahepatic metastases were 4.6 months and 20.3%, respectively. 5 Surgical resection could improve the patient’s survival if the tumor is solitary in the lung field. 1 Even if the tumors were multiple, resection may contribute to get longer survival in a specific situation. 2,3 However, metastatic lesions in lung are usually multiple and may adjacent to the mediastinum, surgical resection is generally not indicated for these cases. Systemic chemotherapy is widely adopted for metastatic HCC to lung or mediastinum, however, the prognosis is still poor. When cancer progress, patients with pulmonary metastasis usually present with severe respiratory symptoms including cough, dyspnea and pain. Effective local tumor control and palliative symptomatic relieve are required. Recent advance in catheterization, imaging techniques and embolic materials allow transbronchial arterial chemoembolization technically feasible for the treatment of pulmonary or mediastinal metastases. A recent study also demonstrated the feasibility of transarterial chemoembolization (TACE) in pulmonary or mediastinal metastases from breast cancer with promising clinical outcomes. 6 To our knowledge, technical feasibility and efficacy of TACE have not been studied for pulmonary or mediastinal metastases from HCC. The present study was retrospectively undertaken to illustrate the safety profiles of TACE for pulmonary or mediastinal metastasis from HCC.
Methods and materials
Patients and tumor characteristics
The present study was approved by the institutional review board and included consecutive patients who underwent TACE with HepaSphere for pulmonary and/or mediastinal metastases from HCC between June 2009 and January 2018. Informed consent was obtained from all patients.
Retrospective review of all electronic medical records was performed within study period. The indication criteria for TACE was defined as follows: (i) life-threatening case such as a bronchial infiltration or superior vena cava syndrome, (ii) contraindication for radical treatment such as surgery or radiofrequency ablation, (iii) refractory or inpatient for systemic chemotherapy as standard treatment, (iv) relatively good general condition (performance status one or two), (v) neither infection nor bleeding tendency, (vi) no other serious comorbidity. A total of 17 patients with pulmonary or mediastinal metastases from HCC were treated by TACE therapy in Image guided therapy (IGT) clinic, in Osaka, and among them, 14 patients who were followed-up by CT, labo datas and clinical examination longer than a month were enrolled for proper treatment feasibility, efficacy and safety evaluations. Patient characteristics are shown in Table 1. The median age was 61 years old (range, 23–72 years) including 12 males and 2 females. All patients underwent primary HCC treatments before enrolling this study, of which eight patients had complete remission and six patients had recurrent HCC, including four multiple hepatic lesions and two single lesion as per baseline CT study. Some treatment was undertaken for pulmonary or mediastinal lesions in all patients. 4 patients underwent partial peumonectomy, 5 patients underwent radiotherapy, and 11 patients underwent systemic chemotherapy. However, pulmonary or mediastinal metastases were not adequately controlled. Additional metastatic lesions were found in the bone in two cases, brain in one and adrenal gland in one case.
Table 1.
Patient characteristics
| No. of patients | 14 |
|---|---|
| Median age (years) | 61.0 (23–72) |
| Males:Females | 12:2 |
| Median size of tumors (mm) | 27.5 (12–52) |
| Previous treatment for primary HCC: | |
| Surgery | 12a |
| RFA | 4a |
| TACE | 11a |
| Proton beam therapy | 1a |
| Any of the above | 14 |
| Previous treatment for lung or mediastinal metastases: | |
| Surgery | 4a |
| Radiation therapy | 5a |
| Systemic chemotherapy | 11a |
| Any of the above | 14 |
| Previous treatment as a systemic chemotherapy: | |
| Sorafenib | 9a |
| S-1 | 2a |
| UFT | 1a |
| Any of the above | 11 |
| Reason for discontinuation of Sorafenib: | |
| PD | 5 |
| PD +Intolerance | 4 |
| Residual tumor in the liver: | |
| Yes | 6 |
| No (CR) | 8 |
| Metastasis to other organs: | |
| Brain | 1 |
| Bone | 1 |
| Adrenal gland | 1 |
CR, complete remission;HCC, hepatocellular carcinoma; PD, progressive disease; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; TAE, transcatheter arterial embolization; UFT, Uracil/ Tegafur.
These items are overlapping.
In this study, a maximum of 3 tumors was identified as target tumors, and a total of 33 target tumors were evaluated. In brief, 12 patients had lymph node (LN) metastases, 10 patients had pulmonary metastases with 7 bilateral and 3 unilateral involvement. Three patients had extrathoracic tumors. Tumor characteristics are described in Table 2 including tumor location, number of target tumors and size.
Table 2.
Tumor characteristics
| Patient no.a | Distribution of tumors in the thoracic region | Target tumor number | Target tumor location | Tumor size (mm) | |
|---|---|---|---|---|---|
| Before TACE | After TACE | ||||
| 1 | 19 lesions in bilateral lungs and 1 LN metastasis | 1 2 3 |
RSL #11R RIL |
36 37 29 |
32 23 21 |
| 2 | 1 lesion in right lung and 7 LN metastases | 4 5 |
#10L #5 |
26 26 |
23 21 |
| 3 | 3 lesions in right lung (pleura) and 4 LN metastases | 6 7 8 |
RSL RIL #7 |
24 27 39 |
21 24 34 |
| 4 | 31 lesions in bilateral lungs and no LN metastases | 9 10 11 |
RML RML RIL |
20 17 27 |
13 13 27 |
| 5 | 9 lesions in bilateral lungs and 2 LN metastases | 12 13 |
RSD LSD |
37 40 |
32 36 |
| 6 | More than 60 lesions in bilateral lungs and 11 LN metastases | 14 15 16 |
#4L #4R LLL |
23 38 30 |
22 29 32 |
| 7 | 4 lesions in bilateral lung and 2 LN metastasis | 17 18 19 |
#7 #12L LIL |
27 32 51 |
27 28 49 |
| 8 | No lung lesions and 5 LN metastases | 20 21 |
#10R RML |
26 30 |
26 29 |
| 9 | Multiple lesions in bilateral lungs and no LN metastasis | 22 23 24 |
RSL #10R RIL |
17 12 13 |
9 4 11 |
| 10 | 5 lesions in bilateral lungs and 6 LN metastases, | 25 26 27 |
#7 #4R #11R |
52 26 26 |
48 19 25 |
| 11 | 1 lesion in the right lung and 1 LN metastasis | 28 29 |
RML #4R |
31 35 |
20 33 |
| 12 | No lung lesions and 1 LN metastasis | 30 | #5 | 29 | 24 |
| 13 | No lung lesions and 1 LN metastasis | 31 | #10R | 24 | 21 |
| 14 | 16 bilateral lung lesions and 1 LN metastasis | 32 33 |
#10R RML |
33 16 |
29 12 |
LIL, left inferior lobe; LLL, left lingular lobe;LN, lymph node; LSD, left supradiaphragmatic; RIL, right inferior lobe; RML, right inferior lobe; RSD, right supradiaphragmatic; RSL, right left superior lobe; RSL, right superior lobe;TACE, transcatheter arterial chemoembolization.
Patient numbers do not match those of Figure 4.
Treatment procedure
All procedures were done under local anesthesia. Catheterization was performed with 4 F guiding catheter (cobra, shepherd hook, head hunter type, Terumo, Tokyo, Japan) for vascular mapping followed by catheterization of feeding arteries using a 1.9–2.4-F preshaped microcatheter (Terumo, JMS, or Toray, Tokyo, Japan). The bronchial arteries (BAs) and non-bronchial systemic arteries, such as branches of subclavian artery, and inferior phrenic arteries, were interrogated until the feeding arteries were detected. Enhancement of the tumor in the mediastinum and pulmonary field were both confirmed on CT scan (Toshiba Medical Systems, Tochigi, Japan) during the selective angiography. After confirmation of blood supply, 1–3 antineoplastic agents including cisplatin (CDDP; 10–30 mg), fluorouracil (5-FU; 250–500 mg), epirubicin (EPI; 10–20 mg), and mitomycin C (MMC; 4 mg) were selectively infused to feeding arteries. The treatment regimens and embolic materials used for TACE were summarized in Table 3. The amount of antineoplastic drug administered was based on area ratio of each tumor. Chemoinfusion was performed very slowly (3–5 mL/min) under free flow to avoid back flow, followed by embolization with HepaSphere (Merit Medical Systems, Inc, South Jordan, Utah). The diameter of the HepaSphere used in this were 30–60, 50–100, or 100–150 µm in the dry state. The reduced expansion technique was used to control the expansion of HepaSphere and allow distal embolization and to avoid the embolization of proximal arteries, which would result in the redistribution of the collateral arteries. In brief, 25 mg of HepaSphere was prepared with an aqueous solution containing 1 ml of 10% sodium chloride and 4 ml of contrast material. 7 HepaSphere was injected under free flow at 1–3 mL/min under fluoroscopy to avoid reflux and non-target embolization. The end point of embolization was near stasis with disappearance of the tumor stain. No other embolic materials was combined with HepaSphere. Follow-up visit including contrast-enhanced (CE) CT and clinical examination were performed 1 month after the first session of TACE to analyze tumor response, adverse events and clinical symptoms.
Table 3.
Treatment outcomes of each patient
| Patient no.a | Age (years) |
Regimen and embolic material | Tumor size (mm) | Regression rate (%) | Progression rate | Complications | |
|---|---|---|---|---|---|---|---|
| Before TACE | After TACE | ||||||
| 1 | 23 | b CDDP [25 mg]+5 FU [250 mg]+EPI [20 mg], CDDP-HepaSphere (50–100 µm) [ 12.0 mg] | 102 | 76 | 25.5 | SD | Nausea (Grade 1), |
| 2 | 49 | CDDP [75 mg]+5 FU [400 mg], 5-FU-HepaSphere (50–100 µm) [2.75 mg] | 52 | 44 | 15.4 | SD | Nausea (Grade 1) |
| 3 | 43 | CDDP [25 mg]+5 FU [250 mg], CDDP-HepaSphere (30–60 µm) [10.5 mg] | 90 | 79 | 12.2 | SD | − |
| 4 | 59 | CDDP [30 mg]+5 FU [250 mg], CDDP-HepaSphere (50–100 µm) [0.25 mg] | 64 | 53 | 17.2 | SD | − |
| 5 | 72 | CDDP [25 mg]+5 FU [250 mg]+MMC [4 mg], CDDP-HepaSphere (50–100 µm) [5.0 mg] | 77 | 68 | 11.7 | SD | WBC and platelet decreased (Grade 3) |
| 6 | 68 | CDDP [25 mg]+5 FU [500 mg]+EPI [10 mg], CDDP-HepaSphere (50–100 µm) [21.0 mg] | 91 | 83 | 8.8 | SD | − |
| 7 | 41 | CDDP [50 mg], B.HepaSphere (100–150 µm) [4.75 mg] | 110 | 104 | 5.5 | SD | Pain (Grade 1) |
| 8 | 67 | CDDP [50 mg]+5 FU [500 mg], B.HepaSphere (50–100 µm) [6.5 mg] | 56 | 55 | 1.8 | SD | − |
| 9 | 63 | b* CDDP [50 mg], B.HepaSphere (50–100 µm) [5.5 mg] | 42 | 24 | 42.9 | PR | Anaemia (Grade 3) |
| 10 | 38 | CDDP [100 mg]+5 FU [500 mg], B.HepaSphere (100–150 µm) [23.0 mg] | 104 | 92 | 11.5 | SD | Pain (Grade 1) |
| 11 | 57 | CDDP [50 mg]+5 FU [500 mg], B.HepaSphere (50–100 µm) [1.5 mg] | 66 | 53 | 19.7 | SD | Nausea
(Grade 1) Pain (Grade 1) |
| 12 | 68 | CDDP [50 mg]+5 FU [500 mg], B.HepaSphere (100–150 µm) [2.5 mg] | 29 | 24 | 17.2 | SD | − |
| 13 | 68 | CDDP [20 mg]+5 FU [250 mg] , B.HepaSphere (50–100 µm) [0.5 mg] | 24 | 21 | 12.5 | SD | − |
| 14 | 63 | cCDDP [50 mg]+5 FU [500 mg], B.HepaSphere (100–150 µm) [2.5 mg] | 49 | 41 | 16.3 | SD | − |
B.HepaSphere, bland HepaSphere microspheres;CDDP, cisplatin; CDDP-HepaSphere, cisplatin-loaded HepaSphere microspheres; EPI, epirubicin; 5-FU, fluorouracil; 5-FU-HepaSphere, 5-FU-loaded HepaSphere microspheres; MMC, mitomycin C;TACE, transcatheter arterial chemoembolization.
For patients with multiple tumors, tumor size was calculated as the sum of the tumor diameters.
Patient numbers do not match those of Figure 4.
Seventy % of the anticancer drug and 7 mg of HepaSphere was targeted to primary HCC; therefore, the actual dose administered to the lung was CDDP [7.5 mg]+5 FU [75 mg]+EPI [6 mg], CDDP-HepaSphere (50–100 µm) [ 5.0 mg].
A half of the anticancer drug and 3.5 mg of HepaSphere was targeted to primary HCC; therefore, the actual dose administered to the lung was CDDP [25 mg], B.HepaSphere (50–100 µm) [2.0 mg].
Retreatments and discontinuation
Indications for a repeated TACE were to control target tumor progression or to reduce patients’ respiratory symptoms. TACE was repeated on-demand. Contraindications for a repeated TACE were the detection of brain metastasis or a performance status of 3 or greater. In case of a repeated treatment, same regimen was adopted unless target tumor progression was detected. If target tumor was obviously progressed, the other drugs was selected or added to, such as Bevacizumab (100–200 mg) or as mentioned above.
End point and statistical evaluation
The primary end points were technical feasibility, local tumor response, safety profile and symptom improvement rate. Technical success was defined as devascularization of BA and non-BA to the tumor feeding arteries. The follow-up CECT examination was carried out in 1 month. A total of 33 nodules were measured pre- and post-TACE treatment. Tumor characteristics are described in Table 2. The regression rate was analyzed for each patient after the first session of TACE according to the RECIST v. 1.1 and the treatment outcomes are described in Table 3. Adverse events were evaluated according to the CTCAE v. 4. The level of α-fetoprotein was not evaluated because only six patients had residual tumors in the liver and three patients had metastatic lesions in the other organs. In principle, patients with symptoms were treated, but electronic medical chart did not provide symptomatic information in 3 out of 14 patients. The remaining 11 patients were evaluated.
The secondary end points were overall survival (OS). The OS was evaluated using the BellCurve for Excel (Social Survey Research Information Co., Ltd., Tokyo, Japan). The survival time was calculated from the beginning of pulmonary or mediastinal treatments in our institution until census.
Results
Primary endpoint
The technical success rate was 100% without intraprocedural complication. Mean hospital stay was 4.4 days. The median HepaSphere dose were 3.75 mg (range, 0.25–23.00 mg). Bland embolization with HepaSphere was performed in eight patients; while cisplatin-loaded HepaSphere was used in five patients and fluorouracil-loaded HepaSphere was used in one patient. Treatment regimens and the outcomes of the primary end point are shown in Table 3 and Figure 1. A total of 33 target lesions in pulmonary field or mediastinum were evaluated. Partial remission and stable disease were observed in 1 (7.1%) and 13 patients (92.9%), respectively, yielding the objective response (OR) of 7.1% and disease control rate (DCR) of 100%. The regression rate was 15.6±9.5% after the first session of TACE.
Figure 1.
Progression rate after first session of TACE. Blue area represents stable disease. Partial remission and stable disease were observed in 1 and 13 patients, respectively. Disease control rate was 100%. TACE, transcatheterarterial chemoembolization.
There was no 30 day morality nor severe adverse event in the study patients. Adverse events of each patient are listed in Table 3. A Grade 3 of both white blood cell and platelet decreased was reported in one patient (7.1%). A Grade 3 anemia was observed in one patient (7.1%). Three Grade 1 nausea events and three Grade 1 events in pain were reported, which were both considered as post-embolization syndrome (PES). No patients were found to have a toxicity of Grade 2 or more in the elevation of aspartate aminotransferase, alanine aminotransferase, blood bilirubin, creatinine, and non-hematological toxicity. 11 patients with adequate description of the medical records on the respiratory symptoms were evaluated. Before TACE treatment, seven patients (63.6%) reported to have symptoms of sever cough, respiratory distress and hemoptysis, and the remaining four patients (36.4%) had little symptom. Improvements of these symptoms were observed in five patients (45.4%) after the first session of treatment. Symptoms of other two patients (18.2%) were not improved.
Two typical but impressive cases would be presented (Figures 2 and 3).
Figure 2.
Case presentation 1: A 23 y/o female with refractory to sorafenib treatment. A 23 y/o female with hepatitis B developed HCC 4 years ago. Several sessions of conventional TACE using lipiodol, hepatectomy, RFA and sorafenib treatments had been done. However, she consulted us complaining of severe cough, hemoptysis and general fatigue due to massive lung metastases. Right bronchial arteriography showed tumor stain in the right hilum (a). CT angiography from this artery demonstrated selective enhancement of tumor invading right main bronchus (b). Infusion of anticancer drug (CDDP; 7.5 mg +5 FU; 75 mg +EPI; 6 mg) followed by embolization with HepaSphere (50–100 µm); 5.0 mg from the same artery was performed. The tumor staining was reduced after chemoinfusion and embolization (c). No complication but a marked improvement of symptom was found. CT follow-up in a month showed marked reduction of tumor in size and disappearance of tumor in the right main bronchus (d). Repetition of treatment was introduced for six sessions and the tumor in the mediastinum and lung has well been controlled in 10 months. Although the patient could undergo total 13 sessions of TACE in 23 months, she died of hemoptysis from lung metastases. CDDP, cisplatin; FU, fluorouracil; HCC, hepato cellular carcinoma; RFA, radio frequency ablation; TACE, transcatheter arterial chemoembolization.
Figure 3.
Case presentation 2: A 72 y/o male with intolerance to sorafenib treatment. 72 y/o male with HCC caused by hepatitis C. Although the hepatic lesions had become completely necrotic by TACE and sorafenib, both sides of the supradiaphragmatic lymph node metastases continuously developed without symptoms. CT angiography from both sides of internal thoracic artery showed the enhancement of the lymph nodes (a). Both sides of internal thoracic arterial infusion of anticancer drugs (CDDP;20 mg, 5-FU;250 mg, and MMC;4 mg) followed by CDDP loaded HepaSphere;5.0 mg. 6 months after 2 sessions of transarterial infusion and embolization, reduction of both lymph node metastases was confirmed (b). At that time, however, lung metastasis in the right basal lung field was newly observed (c). The bronchial arterial infusion (CDDP; 16.7 mg, 5-FU; 167 mg and MMC; 2.67 mg) with embolization (CDDP loaded HepaSphere; 7.0 mg) was carried out. CT examination after a month (d) showed marked shrinkage of lung metastases. However, 15 months after the first session of TACE, he died of hemorrhage from brain metastases. CDDP, cisplatin; FU, fluorouracil; HCC, hepato cellular carcinoma; RFA, radio frequency ablation; TACE, transcatheter arterial chemoembolization.
Secondary end points
The follow-up data and prognosis for each patient are shown in Table 4. With a median follow-up time of 11.5 month (range, 1–100 months). A total of 66 sessions of TACE were performed. Two patients with residual HCC were treated in the same TACE session of their pulmonary or mediastinal treatment. After the first session, a mean of 4.7 subsequent sessions (range: 1–13) were repeated on demand for each patient. During the follow-up period, two patients remained alive, eight patients died, and four patients were unknown. The causes of death included progression of lung metastasis in three patients, progression of brain metastasis in one patient, progression of primary HCC in one patient, pneumonia in one patient and unknown in two patients. The MST after the first treatment session was 15.0 months. The 1 year, 3 year, and 5 year survival rate were 57.1%, 28.6%, and 19.1%, respectively (Figure 4).
Table 4.
Follow-up of patients in this study
| Patient no.a | Follow-up term (months) | No. of TACE sessions | No. of regimen changes | Dead/Alive | Reason of death |
|---|---|---|---|---|---|
| 1 | 23 | 13 | 1 | Dead | Progression of lung metastasis |
| 2 | 40 | 8 | 3 | Dead | Progression of lung metastasis |
| 3 | 9 | 6 | 3 | Dead | Unknown |
| 4 | 11 | 2 | 0 | Dead | Progression of lung metastasis |
| 5 | 15 | 4 | 0 | Dead | Progression of brain metastasis |
| 6 | 1 | 2 | 0 | Dead | Unknown |
| 7 | 48 | 7 | 2 | Alive | − |
| 8 | 34 | 3 | 1 | Dead | Pneumonia |
| 9 | 1 | 1 | - | Unknown | - |
| 10 | 12 | 9 | 1 | Dead | Progression of primary HCC |
| 11 | 2 | 3 | 0 | Unknown | − |
| 12 | 2 | 1 | - | Unknown | − |
| 13 | 100 | 5 | 0 | Alive | − |
| 14 | 1 | 2 | 1 | Unknown | − |
HCC, hepatocellular carcinoma.
Patient numbers do not match those of Figure 4.
Figure 4.
Overall survival curve of 14 patients after total 66 sessions of TACE. The median survival time was 15 months and 1 year, 3 year and 5 year survival rate was, 57.1%, 28.6% , 19.1%, respectively. Six patients (42.9 %) survived more than 1 year. The longest survival time was 100 months.
Discussion
In 1969, Neyazaki et al 8 firstly reported the use of BA infusion for lung tumors with good results and described that blood supply to the primary lung cancer and to metastatic pulmonary malignancies through BA making the technique feasible for lung cancer treatment. BA anatomically also supplies the mediastinal and hilar lymph nodes, which allow lung metastases treatment possible. 9 This discovery has been demonstrated in several studies and BA infusion for lung cancer was reported to be effective. 10–12 The BA embolization (BAE) also could be safely done to control hemoptysis caused by chronic inflammatory diseases. 13
TACE for tumors feeding by BA or non-BA systemic arteries could also safely be done using HepaSphere/ drug-eluting HepaSphere to control tumor growth. 6 This technique is a favorable treatment to patients with pulmonary or mediastinal metastasis because it does not require open surgery like thoracotomy and can be done repeatedly whenever necessary. Also, tumors from other region could be treated together in the same session like in this study, two patients with residual HCC were treated together with their pulmonary or mediastinal lesion. Hori et al reported the effectiveness of this procedure without major complication such as BA or non-BA systemic artery damages, 6 and the recent advancement of imaging techniques and microsphere technology makes it possible to perform embolotherapy in a more precise manner to identify feeding arteries with minimal complications. Recent three-dimensional images of the thoracic aorta reconstructed from the dynamic CT scan is reliable to recognize the branching of bronchial arteries. 14 The combination use of angiomachine and CT scan (hybrid CT/ angiography system) provides price images to estimate the territory of specific artery taking the CT during infusion of contrast to the selected artery. 15 The end point of this procedure is symptom relief. When patients who have already had hemoptysis undergo TACE, the goal is to stop bleeding, such as BAE procedure, however it may be desirable to be performed TACE for the purpose of hemoptysis prevention. The most different from BAE is that chemo is retained around the tumor tissue and anticancer effect could be expected. The following tumors are considered good indications. (i) Tumors located in the mediastinum and/or hilar region. (ii) The size of the tumor is larger than about 2 cm. Because they often cause bronchial infiltration and / or vascular invasion, and BA and non-bronchial systemic arteries tend to feed the mediastinal and hilar tumors compare with tumors in the lung field. The larger the size, the more clearly the feeding arteries can be found. Even if the tumor is temporarily controlled by performing some session of TACE, follow-up study as short a span as possible was required, every month or every other month. Repeated TACE is needed because this procedure is palliative treatment like a systemic chemotherapy.
The main advantage of using HepaSphere or drug-eluting HepaSphere TACE lies in its retreatment potential without major vessel damage. In our series, damage of BA or non-BA systemic artery was documented at repeat embolization as 0%, which is quite low as compared to those using conventional TACE (cTACE) in hepatic artery. 16,17 Vessel damage using drug-eluting HepaSphere was 4.4% and consistently low in hepatic artery. 18 This might be due to conformity of HepaSphere to vessel wall allowing good vessel occlusion and preventing wash-out. Infusion of lipiodol the anticancer drugs followed by embolization using gelatin sponge is standard embolotherapy for HCC treatment, however, in cases of extrahepatic lesions, the same manner of embolization makes it difficult to do the repletion of treatment because of the intimal damage. The combination of embolic materials is not recommended because of lack of the evidence of safety for the other organs. Also, arterial damages caused by spherical embolic material are smaller than those caused by the other agents. 6,19,20 Retreatment could safely be done using microspheres. In addition, drug-eluting HepaSphere has shown to have superior safety profile with minimal complications as compared to cTACE in HCC therapy. 21 The incidence of complications in this study is very small. Most complications were low grade PES. These findings are consistent with the previous reports 19,22 and might be due to the features of control-release of chemotherapeutic drugs from HepaSphere and the conformity to vessel wall to prevent wash-out.
The sizes of HepaSphere used in this study were 30–60, 50–100, and 100–150 μm. The actual sizes were controlled to be double, and the final size were 60–120, 100–200, 200–300 μm using hyperosmoral contrast material. 7 The tumor vasculature represented on DSA images is effectively occluded by HepaSphere in these sizes without occlusion of tumor feeding arteries themselves. The possible risk of this technique is non-target embolization especially in cases of the presence of shunting between bronchial circulation and the pulmonary vein. Hybrid CT/angiography system is preferable to identify such risked arteries. With using it, in this series, no case of non-target embolization nor shunting to the pulmonary vein was identified. HepaSphere has to be slowly injected under free flow state until reduction of antegrade arterial flow to avoid back flow of embolic material from the target artery. Extensive vessel mapping to avoid occlusion of spinal circulation arising from intercostal arteries is needed, and spinal cord damage was not reported. Complications caused by mucosal damage of bronchus or esophagus were not experienced.
In our series, the optimal chemotherapeutic drug dose and regimens were not standardized and varied among patients. The reason why the regimens vary despite the identical primary tumor type in all patients is because each patient has a different chemotherapeutic history. The anticancer drugs were selected for each case with reference to it. The key chemotherapeutic drugs used were CDDP, 5-FU, MMC and Epirubicin and the selection of regimen was based on patients’ prior medical history and efficacy in systemic chemotherapy. 70% of nodules showed higher than 10% of tumor reduction and 87.9% lesions showed shrinkage at the first month. The reduction rate was 15.6% in average after the single session of treatment. Repetition of TACE provided father shrinkage of tumor and consequently resulted in release of air way compression. OR and DCR after the first session of HepaSphere and drug-eluting TACE were reported to be 7.1 and 100%, respectively. The tumor response rate in our study was slightly lower than previous study in HepaSphere/drug-eluting HepaSphere TACE for pulmonary or mediastinal metastases from breast tumor, which was 28.6%. 6 Both studies included patients with refractory/intolerance pulmonary or mediastinal metastases, and PD was 0% showing sufficient local disease control in the lung using this treatment method. Improvement rate of clinical symptoms was 5 patients 71.4% (5 out of 7 symptomatic patients) after the procedure. It might be due to effective local tumor control in pulmonary field and mediastinum.
In our study, the MST and 1 year survival rates were 15 months and 57.1%, respectively, which was much longer than those of systemic chemotherapy for HCC distant metastases (MST; 4.6, 1 year survival rate; 20%), as described above. 5 Administration of Sorafenib in combination with hepatic TACE and bronchial arterial chemoinfusion in the treatment of HCC with pulmonary metastases was reported that MST was 12 months. 23 Excellent result was reported that 5 year survival rate was 40.9% in patients who could get surgical resection, 24 but only limited patients could be surgical candidates and therefore be benefited. All patients in our series were not surgical candidates because of the number of lesion or the location of metastases and they were refractory/intolerance to systemic treatments/ radiotherapy. Transarterial treatment through bronchial arteries and mediastinal circulations can be performed for the unresectable patients with pulmonary and/or mediastinal metastases even in advanced situation, and therefore HepaSphere/drug-eluting HepaSphere still play an important role for promising results.
There are several limitations in this study. It is a single arm, single center retrospective study and does not offer comparison with other treatment modalities, e.g. cTACE and another drug eluting microsphere. The patient number was small with diverse patient backgrounds in the long recruitment period which may be leaded to restrictive inclusion criteria. Also, a combination of chemotherapeutic drugs was adopted depending on patients’ medical history and the treatment regimens were not standardize, which might impose different effects to treatment response. In addition, not every patient had comprehensive medical history concerning the pulmonary symptoms, which might preclude systematic evaluation on symptom improvement.
Conclusions
In summary, TACE for pulmonary and/or mediastinal metastases from HCC is a feasible with promising efficacy and minimal complications. Further study with longer follow-up and larger patient number should be planned.
Footnotes
Acknowledgment: The authors thank to Takafumi Goto, Miho Matsumoto and Pansy Tse for their efforts in data analysis and proofreading.
Contributor Information
Atsushi Hori, Email: horiat@igtc.jp, Department of Radiology, IGT Clinic, Image Guided Therapy, Osaka, Japan .
Ryosuke Ohira, Email: ohiraryosuke@gmail.com, Department of Radiology, Kansai Rosai Hospital, Osaka, Japan .
Tomoyuki Nakamura, Email: t1001g13@gmail.com, Department of Radiology, Tominaga Hospital, Osaka, Japan .
Yasushi Kimura, Email: y-kimura@radiol.med.osaka-u.ac.jp, Department of Diagnostic and Interventional Radiology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan .
Shota Ueda, Email: sht.1210.tenten@gmail.com, Department of Radiology, IGT Clinic, Image Guided Therapy, Osaka, Japan .
Masahiro Torii, Email: kanazono_491_7369@yahoo.co.jp, Department of Radiology, IGT Clinic, Image Guided Therapy, Osaka, Japan .
Norifumi Kennoki, Email: norifken@yahoo.co.jp, Department of Radiology, IGT Clinic, Image Guided Therapy, Osaka, Japan .
Shinichi Hori, Email: horishin@igtc.jp, Department of Radiology, IGT Clinic, Image Guided Therapy, Osaka, Japan .
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