Transarterial Chemoembolization of Liver Metastases from Uveal ...

Cardiovasc Intervent Radiol (2015) 38:1532–1541 DOI 10.1007/s00270-015-1093-4

CLINICAL INVESTIGATION

INTERVENTIONAL ONCOLOGY

Transarterial Chemoembolization of Liver Metastases from Uveal Melanoma Using Irinotecan-Loaded Beads: Treatment Response and Complications Ulrik Carling1 • Eric J. Dorenberg1 • Sven-Petter Haugvik2 • Nils Andreas Eide3 Dag Tallak Berntzen1 • Bjørn Edwin4 • Svein Dueland5 • Ba˚rd Røsok2

•

Received: 21 October 2014 / Accepted: 15 March 2015 / Published online: 2 April 2015 Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2015

Abstract Purpose The purpose of this study was to evaluate treatment response and complications of transarterial chemoembolization using drug-eluting beads loaded with irinotecan (DEBIRI) in patients with liver metastases from uveal melanoma (UM). Materials and Methods Patients treated with DEBIRI (n = 14) were retrospectively analyzed regarding overall survival, compared to patients (n = 14) treated with intravenous dacarbazine (DTIC). Median overall survival was calculated from time of diagnosis of metastatic disease (OS1) and start of treatment (OS2). Radiological response for DEBIRI was assessed according to RECIST 1.1 on contrast-enhanced computed tomography (CT), obtained 1.5 months (range 1.2–3.7) post treatment. Major complications of DEBIRI were defined according to the Society of Interventional Radiology classification for complications by outcome.

Results In the DEBIRI group, OS1 was 14.8 months (range 3.9–47.5), and OS2 was 9.4 months (range 1.7–39). Further, 11/13 (84.6 %) of these patients had progressive disease on first follow-up CT and new lesions were seen in nine. There were 12 major complications in nine patients, possibly including one case of mortality due to disseminated intravascular coagulation (DIC). Conclusion For patients with liver metastases from UM, the effect on overall survival of DEBIRI alone is questionable. Compared to previous reports, the response rate of DEBIRI was poor, with new liver lesions observed in the majority of patients. Major complications possibly included one case of DIC. Keywords Transarterial chemoembolization Uveal melanoma Liver metastases DEBIRI Irinotecan Drug-eluting beads

& Ulrik Carling [email protected]; [email protected] Eric J. Dorenberg [email protected] Sven-Petter Haugvik [email protected] Nils Andreas Eide [email protected] Dag Tallak Berntzen [email protected] Bjørn Edwin [email protected] Svein Dueland [email protected]

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Ba˚rd Røsok [email protected] 1

Department of Radiology and Nuclear Medicine, Oslo University Hospital, Postbox 4950, 0424 Oslo, Norway

2

Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Postbox 4950, 0424 Oslo, Norway

3

Department of Ophthalmology, Oslo University Hospital, Postbox 4950, 0424 Oslo, Norway

4

The Intervention Centre, Oslo University Hospital, Postbox 4950, 0424 Oslo, Norway

5

Department of Oncology, Oslo University Hospital, Postbox 4950, 0424 Oslo, Norway

U. Carling et al.: Transarterial Chemoembolization of Liver Metastases from Uveal Melanoma…

Introduction Uveal melanoma (UM) is the most common primary intraocular malignancy [1]. The incidence in Europe is highest in the Nordic countries with 6.1–8.6 cases per million [2], whereas the incidence in the United States is around five cases per million [1]. About half of the patients develop metastatic disease with the liver as the predominant metastatic site [3]. The traditional oncologic treatment for metastatic UM includes systemic palliative chemotherapy with dacarbazine (DTIC), which is associated with an overall survival of 5 months [4]. Hepatic tumor burden is a major prognostic factor [5] and several methods for locoregional treatment of liver metastases from UM have been investigated. Conventional transarterial chemoembolization (cTACE) has been performed for over 20 years, with reported overall survival ranging from 5 to 21 months [6–11]. In cTACE, different chemotherapeutic and embolic agents have been used in a non-standardized way. The Society of Interventional Radiology (SIR) states, in their current guidelines, that the benefit of chemoembolization is uncertain for this patient group [12]. Transarterial immunoembolization is an alternative, with a reported overall survival of 20.4 months [13]. Recently, radioembolization has been studied as a therapeutic tool for patients with liver metastases from UM, with reports on overall survival of 10–12 months [14, 15]. Hepatic perfusion with melphalan has recently spurred significant interest. This treatment can be performed either through a percutaneous [16, 17] or a surgical approach [18, 19], with a reported overall survival of up to 24 months [19]. The transarterial and perfusion techniques are under continuous development, and there exists no consensus on selection of type and timing of treatment for patients with liver metastases from UM. TACE with the use of drug-eluting beads (DEB) loaded with chemotherapeutic drugs, has been investigated in different clinical settings including both primary and metastatic liver tumors [20]. DEBs are non-resorbable hydrogel microspheres that are available in various sizes. These beads are loaded with a chemotherapeutic drug to promote intrahepatic release in a controlled and sustained fashion. In addition to the ischemic effect on the tumor itself, embolization with DEBs allows for sustainable high concentrations of therapeutic agents in tumors, while keeping systemic concentrations low [21, 22]. Chemoembolization with DEBs is a more standardized method than cTACE [21]. Currently, DEBs are loaded either with doxorubicin (DEBDOX) or irinotecan (DEBIRI). Neither doxorubicin nor irinotecan is routinely used in systemic treatment of metastatic uveal melanoma; however, in 2009,

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Fiorentini et al. [23] reported a 100 % radiological response rate according to RECIST 1.1 in patients with liver metastases from UM treated with DEBIRI. The findings were partly supported by Venturini et al. [24] in a later study; however, none of the two studies presented sufficient data on overall survival. Just recently, Valpione et al. [25] published an overall survival of 15.5 months following DEBIRI in a retrospective comparison of DEBIRI and different systemic chemotherapeutic regimes. A clinical trial was completed in 2013 (clinical trials: NCT01010984) where DEBDOX was used in melanoma patients (all types). The final results from this trial have not yet been published, and currently there is no evidence for superiority of one chemotherapeutic agent over the other in DEB TACE treatment in patients with liver metastases from UM. Due to the anticipated benefits of a standardized method for TACE and promising reports on the use of irinotecan-loaded beads, we have offered DEBIRI TACE as a palliative treatment for patients with liver metastases from UM at our institution. In this retrospective study, our primary aim was to evaluate the overall survival in patients with liver metastases from UM treated with DEBIRI TACE, and to compare this to historical control patients treated with standard palliative chemotherapy, DTIC. Our secondary aim was to report radiological response, and major complications related to DEBIRI TACE.

Materials and Methods The retrospective collection of data was approved by the data protection official for research at our institution. Patients Fourteen patients diagnosed with liver metastases from UM were treated with DEBIRI TACE, from June 2010 until October 2013, at our institution. Medical records, laboratory tests, and radiological exams were analyzed retrospectively. DEBIRI was offered following a multidisciplinary tumor board consensus in patients not eligible to surgical resection or percutaneous ablation. All patients were diagnosed with liver metastases on annual contrast-enhanced ultrasound. Subsequently, contrast-enhanced computed tomography (CT; n = 14), contrast-enhanced magnetic resonance imaging (MRI; n = 8), and 18F-FDG-positron emission tomography (PET; n = 14) were performed for assessment of liver involvement and detection of extra-hepatic disease. Two patients were defined as liver dominant (with [80 % of metastatic disease located in the liver) and the rest as liver only. All patients had a patent portal vein, and an Eastern Cooperative Oncology Group (ECOG) grade of 0 or 1.

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As a control group, 14 patients were identified from an institutional database. These patients had consecutively been diagnosed with liver metastases from UM, and were treated with intravenous DTIC before DEBIRI was introduced in our institution, receiving the first dose between May 2005 and December 2009. Pretreatment imaging examinations, including PET (n = 4) and CT (n = 13), were analyzed retrospectively in the same manner as in the DEBIRI group. Two of the 14 patients in the control group had liver dominant disease, and the rest were considered to have liver-only disease. Patient characteristics for both groups are shown in Table 1. Treatment Protocol The treatment was performed using DC beads 100–300 lm (DC-BeadsTM, Biocompatibles UK Ltd, Farnham, United Kingdom). According to the manufacturer’s recommendation, in patients with bilobar (n = 13) disease, one treatment consisted of two procedures per lobe, with a total of four procedures. In each procedure beads loaded with 100 mg irinotecan were administered, thus a maximum total dose of 400 mg of irinotecan. The procedures were scheduled every second week, alternating between the lobes. In the patient with unilobar disease, the lobe was treated with 4 weeks interval. In 14 patients, a total of 57 procedures were performed. See Table 2 for an overview of number of treatments. In all procedures, arterial femoral access with either a 4F or a 6F sheet (Avanti?, Cordis Johnson and Johnson, Miami FL, USA) was used. Initial angiographic series were performed in both the celiac trunk and the superior mesenteric artery for evaluation of hepatic artery anatomy. Selective catheter position for lobar administration of beads was achieved using microcatheters (ProgreatTM, Terumo Medical Corporation, Somerset NJ, USA), and beads were injected distally to the cystic artery when

possible. To achieve a safe and complete lobar treatment, segmental catheterizations were necessary in some cases due to anatomic variants. In each procedure, beads loaded with irinotecan were mixed with 10–15 ml iodine contrast and injected slowly, following 1–3 ml of intra-arterial lidocaine (10 mg/ml). The endpoint was complete drug administration, unless arterial blood flow ceased before the whole dose had been injected, in which case the procedure would be stopped. An overview angiogram was performed at the end of the procedure. Experienced interventional radiologists performed the procedures, and complete drug administration (100 mg of irinotecan) was achieved in 50/57 (88 %) procedures. Patients routinely had an intravenous pump to administer 1 mg ketobemidone every eight minutes during the procedure. Other applied periprocedural drugs included intravenous diazepam and metoclopramide. Antibiotic agents were not routinely administered. The postprocedural median hospitalization was one day (range 1–4). Laboratory tests were performed within 3 days before each procedure and at least once during the hospitalization after each procedure. Tests included hemoglobin, white blood count, blood platelet count, albumin, international normalized ratio (INR), and liver function tests (LFTs) including alanine aminotransferase (ALT), serum aspartate (AST), gamma-glutamyl transferase (cGT), alkaline phosphatase (ALP), and lactate dehydrogenase (LD). Standard DTIC dose in the control group was 1000 mg/ m2 every 3 weeks. The median number of DTIC-rounds was 3 (range 1–22). Clinical and Radiological Analyses Overall survival was calculated from time of diagnosis of metastatic disease (OS1), and time of start of oncologic treatment (OS2).

Table 1 Patient characteristics in the two groups receiving transarterial chemoembolization (TACE) with DEBIRI or intravenous dacarbazine (DTIC) DEBIRI TACE

DTIC

Age; median years (range)

64 (39–74)

64 (24–84)

Gender—male

6/14 (43 %)

8/14 (57 %)

Primary tumor stage IIB–IIIA (%)

71

79

Time from primary tumor to metastases; years (range)

2.6 (0.3–9.6)

4.1 (1.8–7.5)*

Time to treatment from metastatic diagnosis; median months (range)

4.1 (1.2–12.7)

2.5 (0.6–4.7)*

Total liver volume; median liters (range)

1.6 (1.1–2.4)

2.3 (1.2–6.1)*

Liver tumor burden [ 20 % Pre-TACE systemic treatment

1/14 (7 %) 2/14 (14 %)

5/14 (36 %) Not available

Post-TACE systemic treatment

5/14 (36 %)

Not available

Pretreatment lactate dehydrogenase level; IU/l (range)

261 (177–1134)

487 (148–2581)*

* p value \0.05

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Table 2 Treatment dose and pre/post-TACE treatment in 14 patients treated with DEBIRI TACE Patient

Total irinotecan dose (mg)

No of procedures

Reason for not maximum dose

Pre-TACE treatment

Post-TACE treatment

1

310

4

Pain

Ablation, resection

Resection

2

400

4

–

–

Bland embolization, liver txe Repeat TACE

3

400 ? 400

4?4

–

–

4

300

3

SMAa dissection

Dacarbazine

–

5

370

4

Flow reduction

–

Dacarbazine

6

400

4

–

–

Dacarbazine

7 8

400 100

4 1

– Comorbidityb

– –

– –

9

400

4

–

–

Dacarbazine, ipilimumab

10

400

4

–

Temozolomide/ lomustine ? selumetinib

–

11

370

4

Flow reduction

–

Ipilimumab

12

230 ? 125

3?2

Unilobarc ? Bilobard

–

Repeat TACE

13

400

4

–

–

Dacarbazine

14

370

4

Flow reduction

–

–

a d

Superior mesenteric artery, b pelvic bleeding and deteriorating performance status, c three unilobar procedures due to difficult anatomy, repeat TACE treatment was discontinued due to rapid disease progression, e liver transplant 4.7 months after TACE

Total liver volume measurements for both groups were performed manually on CT images, measuring slice area and multiplying with slice thickness. Tumor volume measurements were performed in the same manner for larger tumors ([2 cm). Smaller tumors were calculated from diameter measurements, assuming spherical shapes. Liver tumor burden (LTB) was calculated by dividing tumor volume and total liver volume. In the DEBIRI TACE group, number of metastases and short diameter of the largest lesion at diagnosis were registered. Radiological response rate was assessed according to RECIST 1.1, using two-phase contrast-enhanced CT (CECT) obtained on first follow-up at median 1.5 months (range 1.2–3.7) after the last procedure. The radiological analyses were performed by co-authoring board certified radiologists. Major complications in the DEBIRI TACE group were registered according to the Society of Interventional Radiology (SIR) classification for complications by outcome [26]. Statistical Analyses All statistical analyses were performed in IBM SPSS 21.0 (IBM Corporation, Armonk NY, USA), confidence intervals were set to 95 %, and a p value \0.05 was defined as statistically significant. Survival data were analyzed using the Kaplan–Meier method with the Log rank test for comparison. Laboratory and radiological data were analyzed for potential correlation with survival. The data were non-normal distributed, and non-parametric methods were

used (e.g. Spearman’s test for correlation and Mann– Whitney U test for comparison between groups). Regression analyses were not performed due to the small number of patients.

Results Overall Survival for DEBIRI TACE Versus DTIC In the DEBIRI group, two patients were still alive while the others had died due to metastatic disease. The median OS1 in this group was 14.8 months (range 3.9–47.5), compared to 7.4 (range 2.2–33.3) in the DTIC group (p = 0.13). Median OS2 was 9.4 months (range 1.7–39) in the DEBIRI group, compared to 4.6 months (range 0.5–29.7) in the DTIC group (p = 0.23). Kaplan–Meier survival plots are shown in Fig. 1. Patients in the DEBIRI group with LD levels above 250 IU/l (n = 7) had significantly shorter overall survival compared to the patients with levels below 250 IU/l (n = 7; 3.5 versus 14.3 months, p = 0.001), as shown in Fig. 2. Correlation analyses indicated that survival in the DEBIRI group was correlated to the pretreatment levels of cGT and LD, and level of LD changes after first procedure. Liver tumor burden (LTB) and total liver volume change also indicated a correlation with survival, as seen in Table 3. Also, a correlation between liver volume change and LD elevation after first treatment was observed (R2 = 0.58, p = 0.002).

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A

0,8

Cum Survival

Cum Survival

250 U/l 250-censored

DTIC DEBIRI-TACE DTIC-censored DEBIRI-TACEcensored

0,8

Log Rank p=0.13

0,6

0,4

0,6

0,2

0,0

0,0 10,00

20,00

30,00

40,00

Log Rank p=0.001

0,4

0,2

,00

LD250GROUP

1,0

GROUP

1,0

,0

50,00

10,0

20,0

B 1,0

GROUP DTIC DEBIRI-TACE DTIC-censored DEBIRI-TACE-censored

0,8

Cum Survival

30,0

40,0

OS2 (months)

OS1 (months)

Fig. 2 Overall survival plot for DEBIRI patients with lactate dehydrogenase (LD) levels below (n = 7) or above (n = 7) 250 IU/ l. X-axis in months. Median 14.3 versus, 3.5 months, log rank p = 0.001 Table 3 Bivariate correlations (R) for overall survival from diagnosis of metastatic disease (OS1), and treatment start (OS2) in the DEBIRI-TACE group

0,6

Log Rank p=0.23

OS1 No. of metastases

0,4

Liver tumor burden 0,2

Liver volume change 0,0 ,00

10,00

20,00

30,00

40,00

OS2 (months)

Fig. 1 Kaplan–Meier survival plot for patients receiving DEBIRI TACE or dacarbazine (DTIC), with overall survival from time of diagnosis of metastatic disease (OS1) in A, and time of treatment start (OS2) in B. X-axis in months. A Median OS1 DTIC 5.4 months, DEBIRI 15.8 months (two patients alive at 21.6, and 22.3 months). B Median OS2 DTIC 4.6 months, DEBIRI 9.4 months (two patients alive at 18.6, and 19.3 months)

LDa pretreatment

LDa change first procedure

2

cGT pretreatment

OS2

R

-0.58

-0.50

p value

0.03

0.07

N R

14 -0.90

14 -0.84

p value

0.00

0.00

N

14

14

R

-0.65

-0.62

p value

0.02

0.03

N

13

13

R

-0.74

-0.72

p value

0.00

0.00

N

14

14

R

-0.80

-0.76

p value

0.00

0.00

N

14

14

R

-0.73

-0.61

p value

0.00

0.02

N

14

14

Response Rate for DEBIRI TACE

a

Radiological response rate according to RECIST 1.1 was assessed for 13/14 (92.8 %) patients. These patients had a median of 12 lesions (range 2–102), and the median short diameter length of the largest tumor was 28 mm (range

15–124 mm). The correlation of number of metastases with survival was weaker than for liver tumor burden, see Table 3. On first follow-up imaging, none of the patients obtained a

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LD lactate dehydrogenase,

b

cGT gamma-glutamyl transferase


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Fig. 3 Pretreatment and first follow-up contrast-enhanced CT in a patient treated with DEBIRI, showing progressive disease due to new lesion. A Pretreatment left, posttreatment right. Treatment response in tumor in segment 2 of left liver lobe, arrows decrease in size,

devascularization, and delineation. B Pretreatment left, posttreatment right. In the same patient as in A, a small new lesion is detected adjacent to hepatic vein in segment 4, arrow

complete or partial response. Two patients had stable disease on first follow-up, but progressive disease on CT obtained at 8.9 and 10.4 months, respectively, after the last procedure. One of these patients had an OS2 of 39 months. The other patient was still alive at 18.6 months after treatment start, and had received a second DEBIRI treatment. In all, 11/13 (84.6 %) had progressive disease on first follow-up CT. Nine patients (69.2 %) had one or more new lesions in the liver, whereas two patients had 53 and 28 % target lesion growth, respectively. There were cases where target lesions were delineated and had decreased contrast enhancement, indicative

of successful treatment, while at the same time new lesions had come, as illustrated in Fig. 3. Complications Related to DEBIRI TACE Major complications related to DEBIRI TACE are listed in Table 4. Four patients had a total liver volume increasing between 62.5 and 311 % post treatment on the follow-up CT. The volume increase was not interpreted as due to progressive disease, as shown in Fig. 4. These patients also had deteriorating LFTs.

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Table 4 Major complications related to DEBIRI TACE according to the Society of Interventional Radiology (SIR) classification Major complications Pain, post-embolization syndrome

Number 4

SIR classification

variant anatomy, it is possible that the DIC was related to the DEBIRI treatment. A follow-up CT of the liver was not performed.

1C, 3D

Dissection superior mesenteric artery

1

D

Pulmonary embolism

1

C

Sepsis

1

D

Liver dysfunction/failure

4

4E

Mortality \ 30 days

1

F

Total Number of patients

12 9

– –

One patient died 10 days after the fourth procedure, due to disseminated intravascular coagulation (DIC) and multiple cerebral infarctions. This patient had 6 months earlier been treated with systemic temozolomide/lomustine and a mitogen-activated protein kinase (MEK) inhibitor. The patient had 11 liver lesions, with the largest short diameter length of 33 mm, and LTB of \5 %. The patient had a LD elevation from 414 to 1900 IU/l between the first and the fourth procedure, deteriorating LFTs (AST 23–303, ALT 15–199, ALP 82–307, cGT 17–271 IU/l), but normal bilirubin, albumin, and INR. Further, this patient had a variant liver anatomy, with a single segment 5 arterial feeder from the superior mesenteric artery, and the rest of the arterial circulation from the proper hepatic artery. These two systems were treated separately. On the last control angiogram after the fourth procedure, there was a shunt between these separate arterial systems, and there had possibly been an overlap of treatments. At discharge, the day after the procedure, the patient was in habitual status; however 5 days later the patient was admitted to the local hospital with malaise, and laboratory findings indicating DIC. The patient then developed multiple cerebral infarctions, partly hemorrhagic, and died 4 days later. Due to the development in LD and LFTs, with relatively limited radiological disease at treatment start, and a complicated

Discussion In our study on patients with liver metastases from UM, the overall survival from start of DEBIRI TACE treatment was 9.4 months. This suggests no significantly different impact on overall survival compared to other chemoembolization strategies, as the overall survival in earlier series using other chemoembolization strategies is around 10 months [12], and ranging from 5 to 21 months in a review on nine publications [27]. Patients in the DTIC group that are used for comparison had an overall survival of 4.6 months, which is coherent with earlier published data [4]. Correlation analyses indicated that patients in the DEBIRI TACE group with more advanced disease, e.g. higher LTB, high cGT, and LD before start of treatment, as well as higher LD rise after first procedure, were at risk for shorter survival. Specifically, there was a significant shorter overall survival in patients with LD [ 250 IU/l. LFTs, including LD, are known predictors of survival in this patient group [28]. Survival was more strongly correlated to relative tumor burden than to the number of metastases. A phase II study on chemoembolization in 24 patients by Patel et al. [7] presented significant differences in overall survival based on metastatic burden. Patients with LTB \ 20 % had 19 months of survival, compared to 5.4 months in patients with LTB 20–50 %. In our study, the LTB was higher in the DTIC group, as well as the total liver volume. Also the pretreatment LD was higher as shown in Table 1. Valpione et al. [25] just recently published an overall survival of 15.5 months using DEBIRI in 58 patients, where 38 % of the patients were still alive with a median

Fig. 4 CT images pre- (left) and posttreatment (right) in a patient treated with DEBIRI, showing a 149 % increase in total liver volume, and ascites 1 month after treatment

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follow-up of 11.4 months. Also, 84 % of the patients were given systemic treatment, fotemustine, after first DEBIRI procedure. Valpione et al. did not report the doses of DEBIRI. The control group, receiving different systemic regimes, had an overall survival of 11.5 months, which was longer than for the two groups in our study. The DEBIRI patients in our study with LD levels below 250 IU/l had comparable overall survival to the DEBIRI patients in the study of Valpione et al. This indicates that patient selection can be an important factor for differences in survival in different studies. Difference in overall survival between the groups in our study did not reach statistical significance. This may be due to the small number of patients in both groups; however, several patients in the DEBIRI group received systemic treatment after DEBIRI, which favors this group. Also, the biomarkers indicate that the difference in overall survival may be related to significant differences in disease burden, and the effect of DEBIRI alone on overall survival is questionable. Response Rate for DEBIRI TACE Our findings with progressive disease in 85 % of the cases 1.5 months after the last procedure are incoherent with the findings published by Fiorentini et al. in 2009 [23], where an overall response of 100 % was reported. A second publication [24] on DEBIRI treatment in patients with liver metastases from UM reported a progressive disease rate of 20 %, and Valpione et al. [25] reported no progressive disease. One explanation for this could be that these publications report the response rate on imaging studies obtained 1 month after treatment, while we obtained the first CECT follow-up slightly later. In our study, we saw cases where treated lesions were delineated and had decreased contrast enhancement on CT as signs of treatment response, while small new lesions were detected as an indication of progressive disease according to RECIST 1.1. These findings support suggestions by other authors to combine intra-arterial treatment with systemic treatment [25, 29]. Since new lesions were observed in 9/11 patients with progressive disease, differences regarding time for follow-up CT could be an important factor for explaining the differences in response rate. Further, this implies that use of classification systems differentiating response due to changes of attenuation or contrast enhancement, such as presented by Choi [30] or the modified RECIST criteria [31], would not have had significant influence on the progression rate in our study.

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complication in our study, as reported for DEBIRI TACE by other authors [23, 32–37]. The four patients in our study with major liver enlargements, as well as progressive deterioration of the LFTs post treatment, had relatively high elevation of LD after the first procedure. On review of the follow-up CT, the enlargement was not interpreted as due to progressive metastatic disease. It is, therefore, suspected that this was related to treatment toxicity. Hepatitis and liver failure are known potential complications of chemoembolization, often being transient [36]. The study by Fiorentini et al. [23] reported two cases of non-icteric hepatitis out of 10 cases. There are no other reports on toxicity of DEBIRI treatment for patients with UM. However, several publications on treatment of colorectal liver metastases have been published [33–35]. In a study by Martin et al. including 109 patients receiving DEBIRI, 21(19 %) cases of liver dysfunction were reported [32]. Most patients with liver metastases from UM die from liver dysfunction due to metastatic burden. It is possible that both the treatment and the disease itself caused the liver dysfunction and enlargement in our study, due to a synergistic effect. Metastatic burden of [50 % has often been described as a relative cut-off for the indication of chemoembolization [12], and this was also found to be predictive of adverse events in the study of Martin et al. [32]. As earlier mentioned, the patients receiving DEBIRI in our study were all well below this limit. The patient who died 10 days after the fourth procedure due to disseminated intravascular coagulation (DIC) is described above. There is a possibility that DIC was related to DEBIRI, and a possible over-treatment of segments due to the described variant anatomy with shunting. In retrospect, a CT should have been performed after the second procedure due to the elevation of LD and LFTs, before deciding on a third and fourth procedure. To the best of our knowledge, there are no previous reports on DIC as a complication to DEBIRI TACE. Our study has certain limitations as it was done retrospectively and includes a limited number of patients. The pretreatment imaging protocols were not standardized. There were differences in level of disease between the groups, and also differences in time to treatment start. However, as there are only a small number of publications on DEBIRI TACE for liver metastases from uveal melanoma, we consider the results from this retrospective study to be important.

Conclusion Complications Related to DEBIRI TACE Peri- and postinterventional upper abdominal pain as part of the post-embolization syndrome was a common major

For patients with liver metastases from UM, the effect on overall survival of DEBIRI alone is questionable. Compared to previous reports, the response rate of DEBIRI was

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poor, with new liver lesions observed in the majority of patients. Major complications possibly included one case of DIC. Conflict of Interest of interest.

14.

All authors declare that they have no conflicts 15.

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