Repeated Treatment with 90 Y-Microspheres in Intrahepatic Cholangiocarcinoma Relapsed After the First Radioembolization

Abstract

Background:

The aim of this study was to evaluate the safety and efficacy of repeated administration of ⁹⁰Y-microspheres in intrahepatic cholangiocarcinoma (ICC) relapsed after the first radioembolization (RE).

Methods:

Nine patients with ICC relapsed after the first ⁹⁰Y-RE were enrolled. Six patients presented recurrence in the right hepatic lobe, 3 in the left lobe. All subjects underwent a second administration of ⁹⁰Y-resin microspheres. Toxicity was assessed according to Common Terminology Criteria for Adverse Events (CTCAE, version 4.02). After the repeated treatment, all patients were submitted to follow-up with laboratory, imaging, and clinical examinations.

Results:

The mean cumulative activity administered considering both treatments was 2.7 ± 0.5 GBq. After the second treatment, 3 patients presented complete metabolic response (33.3%) and 6 had partial response (66.6%). The following adverse events were registered: transient increased levels of liver enzymes (grade 1 = 4; grade 2 = 2), hyperbilirubinemia (grade 1 = 2), ascites (grade 2 = 1), and duodenal ulcer (grade 2 = 1). Two patients developed a significant shrinking of the targeted hepatic lobe, as for radiation lobectomy. No case of RE-induced liver disease was registered. Median overall survival was 16.5 ± 1.4 months after the first RE.

Conclusions:

The authors' results suggest that repeated administration of ⁹⁰Y-microspheres may be considered in patients affected by ICC relapsed after the first ⁹⁰Y-RE.

Introduction

Intrahepatic cholangiocarcinoma (ICC) is a rare and severe malignancy.¹ Surgery, the only curative approach, is often not practicable due to the extension of the tumor mass at diagnosis. Systemic chemotherapy with gemcitabine plus cisplatin is used as a first-line approach in patients with unresectable disease.² Locoregional treatments (such as transarterial chemoembolization [TACE], radiofrequency ablation, etc.) are other therapeutic options for ICC.^3,4 In particular, TACE has been applied for treating ICC with a satisfying rate of disease control.⁵

Radioembolization (RE) is an emerging therapy for ICC^6,7; it is based on the selective transarterial delivery of ⁹⁰Y-microspheres to the tumors. It has been reported that RE may significantly improve the outcome of ICC patients, indicating that this therapeutic approach might be particularly effective in those subjects, in which the administration of ⁹⁰Y-micropsheres is not preceded by other treatments.⁸

However, ICC is an aggressive malignancy and relapse can occur after locoregional treatments. In particular, in a cohort of 62 patients with ICC submitted to repeated TACE, it has been reported that 20 subjects (i.e., 32.2%) relapsed after the first cycle with median time to progression of 8 months and were therefore submitted to a second cycle of TACE.⁹ Whether or not it is safe to repeat locoregional therapy with ⁹⁰Y-RE in patients affected by ICC and relapsed after the first administration of ⁹⁰Y-microspheres is a still debated and few explored issue. In this regard, Zarva et al. reported tolerable toxicity for repeated cycles of ⁹⁰Y-RE in a cohort of 21 patients affected by primary or secondary hepatic tumors.¹⁰ It has to be pointed out that, among the subjects included in the cited article, only 1 was affected by cholangiocellular carcinoma.

The aim of this study was to evaluate the safety and efficacy of repeated ⁹⁰Y-RE in ICC patients with disease progression after the first RE.

Materials and Methods

Patients

The authors retrospectively evaluated the clinical data of 9 patients affected by unresectable and chemotherapy-refractory ICC and relapsed after a first treatment with ⁹⁰Y-resin microspheres. The enrolment criteria were as follows: histologic proof of ICC; liver-only or liver-predominant disease; age ≥18 years; ability and willingness to provide written informed consent; life expectancy >3 months; Eastern Cooperative Oncology Group (ECOG) performance status ≤2; bilirubin <2.0 mg/dL, albumin >2.0 g/dL, international normalized ratio <1.5; creatinine <2.0 mg/dL; platelets ≥100,000/μL, Hb ≥9.0 g/dL, and white blood cell ≥1500/μL. Patients with predominant extrahepatic disease, active central nervous system metastases, or diffuse peritoneal metastases were excluded.

Study design

All patients provided written informed consent before procedure and associated risk. Preprocedural evaluation included baseline imaging studies, clinical, and laboratory examinations.

Angiography with selective visceral catheterization was performed to evaluate the vascular and tumor anatomy and blood-flow dynamics, enabling a determination of the optimal placement of the catheter for selective treatment. ^99mTc-macroaggregated albumin (^99mTc-MAA) scan was performed to test gastrointestinal flow and to estimate the percent of injected activity shunted to the lungs. After 7- 10 d, the patients returned to the department for the treatment session performed by selective catheterization of the main hepatic artery by transfemoral approach, embolization of gastroduodenal, and gastric artery. After selective catheterization of the right/left hepatic artery, the patient, without sedation, was administered with by a slow, manually controlled injection lasting about 30 min, under intermittent fluoroscopic guidance, alternating the ⁹⁰Y-microspheres suspended in 5% glucose solution with contrast medium for assessing persevered anterograde arterial flow. In all cases, resin spheres (SIR-Spheres; Sirtex Medical, Sydney, Australia) were administered.

The prescribed ⁹⁰Y activity was calculated as the patient-specific activity according to the manufacturer's vial applying the body surface area (BSA) formula.¹¹ Before the repeated administration of ⁹⁰Y-microspheres after progression, angiography and ^99mTc-MAA scintigraphy were repeated to exclude extrahepatic accumulations caused by collaterals or shunts to the lung that have increased in the meantime. The prescribed activity was not reduced due to the repeated procedure, but only in case of significant (i.e., 10%–20%) hepatopulmonary shunt.

⁹⁰Y positron emission tomography imaging

All subjects underwent positron emission tomography (PET) scan to evaluate the pattern of spheres distribution.¹²

¹⁸F-fluorodeoxyglucose PET imaging

All patients were submitted to PET-computed tomography (CT) scan 60 min after the intravenous administration of 3.7 MBq/kg of ¹⁸F-fluorodeoxyglucose (FDG). FDG PET was performed at baseline for patients' restaging (i.e., 1 week before the procedure) and for the assessment of the response at 1 month and then every 3 months after ⁹⁰Y-RE. The PET-CT device was a Discovery ST (GE, Milwaukee, WI) with bismuth germanate crystal units arranged to form 24 rings combined with a 16-slice Light Speed Plus CT scanner. The average full width at half maximum (FWHM) axial resolution of PET is 5.2 mm and system sensitivity 9.3 cps/KBq for three-dimensional (3D) acquisition mode. Scanning was performed from the neck to the proximal tight in 3D modality, with an acquisition time of 3 min per table position. Images were reconstructed by using an ordered subset expectation maximization iterative algorithm (OSEM-SV, VUEPoint HD, GE, 2 iterations, 15 subsets). The CT was performed immediately before PET in the identical axial field of view using a standardized protocol consisting of automatic tube current modulation with auto mA-tube rotation time of 0.5 s/rotation and slice thickness of 3,75 mm. The CT data were resized from 512 × 512 to a 256 × 256 matrix to match the PET data.

The data were transmitted to a nuclear medicine database, fused, and displayed using a dedicated software (Advantage, GE).

Assessment of response to treatment

Patients were restaged at 1 month after the procedure with FDG PET-CT and contrast enhanced CT, then repeated every 3 months. The follow-up PET-CT was compared to the pretreatment scan, and metabolic response was defined as a reduction of standardized uptake value according to the PET response criteria in solid tumors (PERCIST).¹³ In 2 patients showing a significant volumetric reduction of the hepatic lobe targeted with repetitive ⁹⁰Y-administrations, the change in the hepatic lobar volume (HLV) after the two RE procedures was calculated on the coregistered nonenhanced CT image.

Safety

Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.02, on the basis of laboratory tests, CT or PET imaging, and clinical examinations. Before the procedure, all patients underwent physical examination; CT and FDG PET imaging; and laboratory tests, including total bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatase, γ-glutamyl transpeptidase. After treatment, all patients resumed a routine schedule of laboratory tests which were performed at 2 and 4 weeks after the procedure and repeated at 3-monthly interval. Clinical toxicities, including pain, fever, fatigue, and gastrointestinal adverse events, were assessed at the regular follow-up visits.

Survival

The overall survival (OS) was calculated by the Kaplan–Meier method (MedCalc 11.3.8.0; MedCalc Software, Mariakerke, Belgium), measured from the date of the first procedure to the death of the patients.

Results

Table 1 summarizes the clinical features and the survival after repeated therapy with ⁹⁰Y-microspheres. The authors enrolled 9 patients (5 male, 4 female, mean age: 65.4 ± 8.0). Among the subjects included in the study, 6 had received a first ⁹⁰Y-RE to the right hepatic lobe, 2 to the left hepatic lobe, and the remaining 1 subject had received a separate sequential lobar ⁹⁰Y-administration with a 6-week interval between the two procedures. Two patients presented extrahepatic disease with localizations in the abdominal nodes; in such cases, hepatic tumor involvement was considered the most relevant prognostic factor for survival. The mean interval of time between the first RE and relapse was 7.3 ± 1.5 months.

Table 1.

Patients' Clinical Features and Their Survival After Repeated Therapy with ⁹⁰Y-Microspheres

Patients	Age (years)/sex	Therapy before the first ⁹⁰Y-RE	Extrahepatic	Tumor load (%)	90Y-RE first cycle	Metabolic response	Time form the first ⁹⁰Y-RE to relapse (months)	Second ⁹⁰Y-RE	Retreated lobe	Metabolic response	Liver enzymes	Bilirubin	GI tox	Overall survival (months)
1	68/M	CIS+GEM	None	10	LHL, 1.7 GBq	CR	9	1.8 GBq	LHL	CR^a	None	None	None	22
1	68/M	CIS+GEM	None	10	LHL, 1.7 GBq	CR	9	1.8 GBq	LHL	ΔHLV = 68%	None	None	None	22
2	55/F	CIS+GEM	None	18	RHL+LHL, 1.3 + 1.1 GBq	PR	6	1.6 GBq	LHL	CR	G2	None	Ascites G2	16
3	64/F	CIS+GEM	Abdominal nodes	10	RHL, 1.4 GBq	PR	9	1.0 GBq	RHL	PR	G1	G1	Vominting, Nausea G2	14
4	80/F	Surgery	None	13	RHL, 1.0 GBq	PR	9	1.3 GBq	RHL	CR^a	None	None	None	25
4	80/F	CIS+GEM	None	13	RHL, 1.0 GBq	PR	9	1.3 GBq	RHL	ΔHLV = 71%	None	None	None	25
5	70/M	CIS+GEM	None	18	LHL, 1.1 GBq	PR	6	1.3 GBq	LHL	PR	G1	None	Duodenal ulcer G2	13
6	60/F	CIS+GEM	Abdominal nodes	12	RHL, 1.2 GBq	PR	6	1.4 GBq	RHL	PR	G1	None	Vomiting, nausea G2	14
7	62/M	Surgery	None	13	RHL, 1.4 GBq	PR	9	1.5 GBq	RHL	PR	G2	G1	None	15
8	73/M	CIS+GEM	None	15	RHL, 1.3 GBq	SD	6	1.4 GBq	RHL	PR	G1	None	None	13
9	57/M	RFA	None	12	RHL, 1.2 GBq	PR	6	1.5 GBq	RHL	PR	None	None	Vomiting, nausea G2	17

Patients showing significant hypotrophy of the repeated treated lobe with compensatory hypertrophy of the contralateral one.

Y-RE, ⁹⁰Y-radioembolization; BIL, bilirubin levels; CIS + GEM, cisplatin plus gemcitabine; CR, complete response, PR, partial response; F, female; G1, grade 1; G2, grade 2; GI tox, gastrointestinal toxicity; LHL, left hepatic lobe; M, male; RFA, radiofrequency ablation; RHL, right hepatic lobe; ΔHLV, decrease in hepatic lobar volume.

Six patients received repeated treatment with ⁹⁰Y-microspheres to the right hepatic lobe and 3 to the left. The mean cumulative activity administered considering both treatments was 2.7 ± 0.5 GBq. Median OS was 16.5 ± 1.4 months (95% CI 13.8–19.3) calculated from the first ⁹⁰Y-RE (Fig. 1).

FIG. 1.

Overall survival of patients calculated form the first ⁹⁰Y-RE as represented by Kaplan–Meier curve. RE, radioembolization.

⁹⁰Y PET imaging

No extrahepatic sites of ⁹⁰Y microspheres uptake were registered.

Assessment of response to treatment

According to PERCIST, after the second treatment, 3 patients presented complete metabolic response (33.3%) and the remaining 6 had partial response (66.6%). Two of the 3 subjects with complete response after the second treatment also presented a significant hypotrophy of the targeted lobe, with a decrease in the HLV value of, respectively, 67% and 71%, and compensatory hypertrophy of the contralateral one (Fig. 2).

FIG. 2.

Eighty years old female patient affected by ICC and relapsed 9 months after the first ⁹⁰Y-RE. (A) Upper row: FDG PET (right side) and the corresponding nonenhanced CT (left side) axial slices acquired before the second administration of ⁹⁰Y-microspheres demonstrated two areas of focal FDG uptake in the right lobe. (B) Lower row: FDG PET acquired 1 month after the repeated ⁹⁰Y-RE demonstrated complete metabolic response (right side) while the corresponding nonenhanced CT slices (left side) depicted a significant volumetric reduction (71%) of the right hepatic lobe with compensatory hypertrophy of the contralateral one as for radiation lobectomy. CT, computed tomography; FDG, ¹⁸F-fluorodeoxyglucose; ICC, intrahepatic cholangiocarcinoma; PET, positron emission tomography.

Toxicity

Figure 3 represents the adverse effects registered after the repeated administration of ⁹⁰Y-microspheres. Immediate complications such as vomiting and nausea (grade 2) were registered in 3 patients in the 6 h following RE. Routine medications were administered for obtaining a complete remission of these symptoms. The lung-shunt fraction was calculated to be less than 10% in all patients both at first and second procedure and no pulmonary toxicity was registered during follow-up. The following adverse events were registered: transient increased levels of liver enzymes (grade 1 = 4; grade 2 = 2) and hyperbilirubinemia (grade 1 = 2). One subject showed moderate ascites (grade 2 = 1) as depicted in Figure 4. One patient developed duodenal ulcer (grade 2). Among patients receiving the repeated administration of ⁹⁰Y-microspheres, none presented a significant worsening of the liver function as assessed according to the Child-Pugh class. No case of radioembolization-induced liver disease (REILD) was registered.

FIG. 3.

Histogram representation of the adverse reactions after repeated administration of ⁹⁰Y-microspheres.

FIG. 4.

Fifty-five years old female patient affected by ICC relapsed 6 months after the first sequential lobar ⁹⁰Y-RE. (A) Upper row: FDG PET (right side) and the corresponding nonenhanced CT (left side) axial slices performed before the second administration of ⁹⁰Y-microspheres demonstrated two areas of intense FDG uptake in the hepatic parenchyma. (B) Lower row: FDG PET acquired 1 month after the repeated ⁹⁰Y-RE showed complete metabolic response (right side) while the corresponding nonenhanced CT depicted a moderate amount of ascites which completely resolved after diuretic therapy (left side).

Discussion

Despite many advances in diagnosis and therapy, the management of ICC still remains a challenge for physicians. Furthermore, the incidence of ICC is increasing worldwide and now represents the second most primary liver tumor in the United States.¹⁴ When surgery is unfeasible, locoregional therapies should be considered for contrasting disease progression and reducing tumor-related symptoms. In such cases, both TACE and ⁹⁰Y-RE have been demonstrated effective for treating patients affected by unresectable ICC.¹⁵ However, while several published articles suggest that TACE can be safely used as a repetitive procedure,¹⁶ the scientific data focusing on the repeatability of ⁹⁰Y-RE are really limited.¹⁰

Lam et al. evaluated 247 patients with hepatic tumors submitted to ⁹⁰Y-RE between 2004 and 2011, 8 of whom underwent repeated treatments of a targeted part of the liver with resin microspheres.¹⁷ Among subjects submitted to repeated ⁹⁰Y-administrations, the authors registered 2 cases of death after the second treatment due to REILD. Repeated RE resulted to be the only independent risk factor for REILD in multivariate analysis. REILD is the most severe complication after ⁹⁰Y-RE: it was described for the first time by Sangro et al. in 2008 as a distinct clinical picture appearing 4 to 8 weeks after treatment, characterized by veno-occlusive features at the histologic examination and a poor prognosis.¹⁸ As concerns toxicity after ⁹⁰Y-RE, Seidensticker et al. evaluated 34 patients with noncirrhotic liver and hepatic malignancies submitted to locoregional therapy with ⁹⁰Y-microspheres as either whole liver or sequential lobar treatment. Three months after whole liver RE, the authors registered 14 liver-related grade 3/4 events. Of note, 3 patients treated with whole liver RE suffered from REILD.¹⁹

The safety of repeated administration of ⁹⁰Y-microspheres has been more recently assessed by Zarva et al. in a cohort of 21 patients with hepatic tumors.¹⁰ It has to be pointed out that the majority of the enrolled subjects were affected by metastases from breast or colorectal cancer, 8 had hepatocellular carcinoma, and only 1 presented ICC. In contrast to the results reported by Lam et al., the authors did not register any case of REILD after the second session of ⁹⁰Y-RE. Most frequent adverse events were ascites, elevation of bilirubin or liver enzymes, and decrease of serum albumin levels.

Mosconi et al. evaluated the safety and the efficacy of RE in 23 patients affected by ICC.⁸ Among these subjects, 3 patients (13%) repeated the locoregional treatment with ⁹⁰Y-microspheres without any relevant toxicity. In the authors' study, the most common late adverse effect was represented by transient and self-limiting increasing of hepatic enzyme value. It has to be pointed out that, both in their cohort and in that of the previously cited article,^8,10 there was no grade 4 or 5 toxicity. Of their patients, one developed a duodenal ulcer despite no extrahepatic deposition of the microspheres detected at the ⁹⁰Y-PET-CT. Thus, they hypothesized that the ulcer might have been due to transient ischemic injury occurred in the periprocedural phase.

The potential repeatability of ⁹⁰Y-RE is of particular interest in the case of ICC, as this neoplasia has a significant rate of recurrence with limited therapeutic options. To the authors' knowledge, their report is the first specifically focused on the safety and efficacy of repeated administrations of ⁹⁰Y-microspheres in ICC relapsed after the first session of RE. Two of their patients presented a significant hypotrophy of the hepatic lobe submitted to repetitive ⁹⁰Y-RE with compensatory hypertrophy of the controlateral lobe. This clinical feature, also called radiation lobectomy, has been previously described by Gaba et al. who evaluated the hepatic volumetric changes in 315 patients treated with ⁹⁰Y-microspheres.²⁰ In their cohort, 20 of the treated patients (i.e., 6.4%) presented a dramatic reduction in HLV with high response rate and prolonged survival. Among their patients, they registered 2 cases of radiation lobectomy. Both subjects received repeated unilobar administrations of ⁹⁰Y-microspheres and, in agreement with the results reported by Gaba et al., showed complete response after the 2 consecutive procedures and were characterized by longer OS. It might be reasonable to hypothesize that the repeated administration of ⁹⁰Y-microspheres may have triggered the phenomenon of radiation lobectomy in the targeted hepatic lobe.

TACE and ⁹⁰Y-RE both represent transarterial locoregional procedures. In which sequence (i.e., TACE before ⁹⁰Y-RE or vice versa) these two treatments should be placed in the therapeutic algorithm of ICC is a still unclear and debated argument, also due to the rarity of the neoplasia and the lack of randomized controlled clinical trials.²¹ As concerns, the impact of TACE on survival, Kiefer et al. performed lobar or segmental chemoembolization with cisplatinum, doxorubicin, mitomycin-C, ethiodol, and polyvinyl alcohol particles in a cohort of 62 patients for an overall number of 122 procedures with a median survival from time of first chemoembolization of 15 months.⁹ It is worth noting that, although there is a significant variability in the survival reported after TACE, a recent meta-analysis performed by Ray et al. reported a cumulative OS of 13.4 months from the first TACE treatment.²² In their cohort of patients, they registered an OS of 16.5 ± 1.4 months, slightly higher than the median OS of 15.2 months reported in a recently published review collecting the data on the use of ⁹⁰Y-microspheres for the treatment of ICC.⁷ However, it has to be stressed that none of the aforementioned reports was specifically focused on ICC patients relapsed after a first administration of ⁹⁰Y-microspheres, most probably affected by more aggressive and therapy-resistant lesions. In this regard, the survival data in the authors' cohort are substantially in line with those reported by Zarva in patients with advanced primary and secondary liver tumors and progressive disease after first selective internal radiotherapy.¹⁰

This study presents several limitations. The main limitation concerns patients' dosimetry: in the authors' cohort of ICC patients submitted to repeated administrations of ⁹⁰Y-microspheres, BSA method was used for activity calculation. Although currently applied in clinical practice, BSA method represents a semiempirical approach and does not provide a previsional calculation of the effective dose delivered to tumor and nontumoral liver tissue.²³ On the contrary, the so-called partition model based on the count ratios from the ^99mTc-MAA pretreatment scan, describes the distribution of the microspheres into three compartments (lung, tumor, and nontumoral liver parenchyma) thus allowing predictive dosimetry to be performed for the each of the aforementioned compartments before ⁹⁰Y-RE.⁶ This issue is of great importance, as it has been fixed at 52 Gy the tolerance dose of the whole liver leading to a 50% complication probability (i.e., toxicity> grade 2).²⁴ Therefore, their preliminary results need to be confirmed implementing a previsional dosimetric approach. Furthermore, the small sample size of the patient population did not allow a statistically robust examination of the safety and efficacy of repeated ⁹⁰Y-RE in ICC. Finally, it is worth mentioning that there are two commercially available medical devices for the locoregional treatment of liver tumors through RE.^25,26 The authors limited their analysis to the resin spheres, but it would be worthwhile to evaluate also the effects of repetitive administrations of glass spheres, which differ in the size of the single spheres, base material, and specific activity.

Conclusions

This study suggests that repeated administration of ⁹⁰Y-microspheres in patients affected by ICC and relapsed after the first ⁹⁰Y-RE may have a favorable impact on survival with a tolerable profile of toxicity. These preliminary results need to be confirmed implementing a personalized and previsional dosimetric approach. Furthermore, studies with larger series are needed to better define the potential benefits of repetitive ⁹⁰Y-RE in ICC also taking into consideration the different commercially available ⁹⁰Y-labeled microspheres.

Footnotes

Authors' Contributions

L.F.: Treatment and follow-up of patients, assessment of response and toxicity, and writing of the article. G.G.D.C.: Enrollment and follow-up of patients and assessment of toxicity. R.T.: Enrollment and follow-up of patients and assessment of toxicity. G.P.: Interventional procedure and assessment of response. R.C.: Interventional procedure and assessment of response. O.S.: Review of the clinical data and editing of the article. O.B.: ⁹⁰Y-PET Imaging and assessment of the response.

Disclosure Statement

There are no existing financial conflicts.

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Repeated Treatment with 90 Y-Microspheres in Intrahepatic Cholangiocarcinoma Relapsed After the First Radioembolization

Abstract

Background:

Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Patients

Study design

90Y positron emission tomography imaging

18 F-fluorodeoxyglucose PET imaging

Assessment of response to treatment

Safety

Survival

Results

90Y PET imaging

Assessment of response to treatment

Toxicity

Discussion

Conclusions

Footnotes

Authors' Contributions

Disclosure Statement

References

⁹⁰Y positron emission tomography imaging

¹⁸F-fluorodeoxyglucose PET imaging

⁹⁰Y PET imaging