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Quality of life in patients with liver tumors treated with holmium-166 radioembolization

  • Caren van RoekelEmail author
  • Maarten L. J. Smits
  • Jip F. Prince
  • Rutger C. G. Bruijnen
  • Maurice A. A. J. van den Bosch
  • Marnix G. E. H. Lam
Open Access
Research Paper
  • 147 Downloads

Abstract

Holmium-166 radioembolization is a palliative treatment option for patients with unresectable hepatic malignancies. Its influence on quality of life has not been evaluated yet. Since quality of life is very important in the final stages of disease, the aim of this study was to evaluate the effect of holmium-166 radioembolization on quality of life. Patients with hepatic malignancies were treated with holmium-166 radioembolization in the HEPAR I and II studies. The European Organization for Research and Treatment of Cancer QLQ-C30 and LMC21 questionnaires were used to evaluate quality of life at baseline, 1 week, 6 weeks and at 6, 9 and 12 months after treatment. The course of the global health status and symptom and functioning scales were analyzed using a linear mixed model. Quality of life was studied in a total of 53 patients with a compliance of 94%. Role functioning was the most affected functioning scale. Fatigue and pain were the most affected symptom scales. Changes in almost all categories were most notable at 1 week after treatment. A higher WHO performance score at baseline decreased global health status, physical functioning, role functioning and social functioning and it increased symptoms of fatigue, dyspnea and diarrhea. Quality of life in salvage patients with liver metastases treated with holmium-166 radioembolization was not significantly affected over time, although a striking decline was seen during the first week post-treatment. A WHO performance score > 0 at baseline significantly influenced quality of life.

Keywords

Radioembolization Holmium-166 Quality of life Hepatic metastases 

Abbreviations

90Y

Yttrium-90

99mTc-MAA

Technetium 99mTc macro-aggregated albumin

166Ho

Holmium-166

AP

Appetite loss

CF

Cognitive functioning

CO

Constipation

DI

Diarrhoea

DY

Dyspnoea

EF

Emotional functioning

EORTC

European Organization for Research and Treatment of Cancer

FA

Fatigue

FI

Financial difficulties

GHS

Global health status

HCC

Hepatocellular carcinoma

LMCDM

Dry mouth

LMCEp

Emotional problems

LMCFati

Fatigue

LMCFeelings

Talking about feelings

LMCFr

Contact with friends

LMCJ

Jaundice

LMCPA

Pain

LMCPN

Peripheral neuropathy

LMCSM

Sore mouth/tongue

LMCSx

Sex life

LMCTA

Taste

LMCWL

Weight loss

LMNutri

Eating

MRI

Magnetic resonance imaging

NV

Nausea and vomiting

PA

Pain

PF

Physical functioning

QoL

Quality of life

RE

Radioembolization

RECIST 1.1

Response Evaluation Criteria In Solid Tumours

RF

Role functioning

SF

Social functioning

SL

Insomnia

SPECT

Single photon emission computed tomography

WHO

World health organization

Background

Radioembolizaton (RE) is an intra-arterial therapeutic option for patients with unresectable hepatic malignancies. Tumors within the liver receive their blood supply almost entirely from the hepatic artery whereas the normal liver is supplied mainly from the portal vein. Therefore, infusion of radiolabeled microspheres into the arterial system results in delivery of effective doses of radiation to the tumor without causing intolerable toxicity to the normal liver [1].

Holmium-166-poly(L-lactic acid) (166Ho)-microspheres (QuiremSpheres®, Quirem Medical B.V., The Netherlands) have been developed as an alternative to yttrium-90 (90Y) microspheres. The main advantage of 166Ho-microspheres is the ability to be visualized in vivo by SPECT and MRI, which enables quantitative biodistribution imaging [2]. 166Ho-microspheres have a mean diameter of 30 µm (range 15–60 µm). Overall, RE is safe and well tolerated, with primarily short-term toxicity. Mild clinical side effects of RE consist mainly of abdominal pain, nausea, vomiting, fatigue and fever and usually occur within 4–6 weeks after treatment (post-embolic syndrome) [3, 4]. Palliative chemotherapy in the same setting, however, is known to be associated with substantial side effects [5]. With the advances in cancer treatment and increased survival, quality of life (QoL) has become increasingly important [6]. Tumor-specific therapy can potentially prolong life, but, due to its possible toxicity, may considerably reduce QoL [7]. The majority of patients (82–95%) value the impact on QoL of the treatment at least as much as the survival benefit [8, 9]. Factors known to influence QoL in cancer patients are, among others, age, gender, cancer type, performance status, and high symptom burden [10, 11, 12, 13]. In patients with hepatic malignancies, specifically, extrahepatic recurrence is of significant influence on QoL [14]. To form an impression of the influence of RE on QoL, we performed a systematic review of the literature (See Figure S1 for the search strategies). The effect of Y90-RE on QoL was investigated in 14 studies [15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28]. In most studies, QoL did not change significantly after Y90-RE (Table 1) [15, 17, 19, 20, 21, 23, 25, 27]. In a minority, QoL either improved [16, 26] or worsened after 90Y-RE [18, 24]. The purpose of the current study was to evaluate the effect of 166Ho-RE on QoL. Based on the literature, our hypothesis was that QoL would not be significantly affected by 166Ho-RE, similar to what is known for 90Y-RE. Furthermore, the hypothesis was that QoL may be impaired by the known short-term side-effects of 90Y-RE, i.e. the post-embolization syndrome.
Table 1

Overview of literature

Solely Y-RE

First author, year

Treatment arm

Control arm

n (Y-RE/other)

Primary tumor(s)

RE approach

Questionnaires

Scale range

Timing

Outcome

 

Cosimelli et al. [15]

Y-RE

14a

Colorectal

Whole liver, re–RE in 3 patients

QLQ-C30, QLQ-LMC21, QLQ-CR38

0–100

Baseline, 6 weeks

QoL was not adversely affected

 

Kalinowski et al. [16]

Y-RE

9

Neuroendocrine tumour

7 patients whole liver, 2 patients bilobar with re–RE

QLQ-C30, QLQ-LMC21

0–100

Baseline, 3-monthly (up to 44 months)

After 6 months, QoL significantly improved

Salem et al. [17]

Y-RE

TACEb

29/27

HCCc

20 patients lobar, 9 patients segmental

Fact-Hep

0–180

Baseline, 2 weeks, 4 weeks

No significant difference between arms

Steel et al. [18]

Y-RE

TACE

14/14

HCC

Whole liver

Fact-Hep

0–180

Baseline, 3 months, 6 months, 1 year

At 3 months, significantly higher QoL scores for Y-RE group than control group. No significant difference at 6 months

Kolligs et al. [19]

Y-RE

TACE

8/10d

HCC

5 patients lobar, 1 patient segmental, 7 patients whole liver

Fact-Hep

0–180

Baseline, 6 weeks, 12 weeks

No significant difference between groups

Cramer et al. [23]

Y-RE

30

Neuroendocrine tumour

Lobar

Short Form-36 Health Survey Form

0–100

Baseline, 1,3,6,12,24 months

QoL was sustained for up to 24 months following treatment

Vilgrain et al. [28]

Y-RE

Sorafenib

184/206

HCC

205 lobar treatments, 81 segmental/sector treatments

QLQ-C30, EORTC-HCC18

0–100

Baseline, 1 month, 3-monthly (up to 12 months)

Global health status was significantly better in the Y-RE group than in the sorafenib group

Kirchner et al. [25]

Y-RE

TACE

21/46

HCC

NR

QLQ-C30, EORTC-HCC18

0–100

Baseline, 2 weeks

QoL was not significantly affected and there was no significant difference between groups

Gill et al. [26]

Y-RE

TACE, sorafenib

 

HCC

NR

Online survey

NR

NR

QoL improved after RE and TACE compared to sorafenib

Xing et al. [27]

Y-RE

30

HCC

Lobar

Short Form-36 Health Survey Form

0–100

Baseline, 1, 3, 6 months

No significant changes in QoL

Y-RE + chemo

Gray et al. [20]

Y-RE & 5-FU

5-FUe

36/34

Colorectal

Whole liver

Self Assessment Scale

 

Baseline, 3-monthly (up to 18 months)

No significant difference, in both arms QoL tended to improve

Van Hazel et al. [21]

Y-RE & 5-FU/LV

5-FU/LVf

11/10

Colorectal

Whole liver

FLIC questionnaire, Spitzer index

 

Baseline, 3-monthly (up to 36 months)

No significant difference between arms

Chow et al. [22]

Y-RE & sorafenib

29

HCC

20 patients whole liver, 9 patients lobar

EQ-5D Index

 

Baseline, every month until progression, 6-month intervals after progression

EQ-5D index in BCLCg stage B decreased over time, while it increased in BCLC Stage C

Wasan et al. [24]

Y-RE & FOLFOX

FOLFOX

554/549

Colorectal

NAh

EQ-5D-3L Index

0–1

Baseline, 2-3,6,12,24 months

EQ-5D-3L index decreased over time in both groups, no clinically meaningful differences

aOf 50 included patients, 14 were evaluated for QoL

bTransarterial chemoembolization

cHepatocellular carcinoma

d10 patients with missing baseline data were excluded from QoL analysis

e5-Fluorouracil

fLeucovorin

gBarcelona Clinic Liver Cancer

hNot available

Materials and methods

Patients and study design

QoL was evaluated in patients included in the HEPAR I and HEPAR II studies (clinicaltrials.gov identifier NCT01031784 and NCT01612325). The inclusion criteria for treatment were exactly the same and the patient population in both studies was comparable (Table S1). In these studies, patients with unresectable, chemorefractory liver metastases of any primary origin and cholangiocarcinoma were included. Patients were eligible if they were diagnosed with liver-dominant disease, had a life expectancy of > 3 months, had measurable disease on CT, had adequate liver, renal and bone marrow function, and had a WHO performance score of ≤ 2. The institutional review board approved these studies and all patients provided written informed consent. The aim of the HEPAR I study was to assess the safety and the maximum tolerated radiation dose of 166Ho-RE. The maximum tolerated dose was found to be 60 Gy and its safety and efficacy was established in the HEPAR II study. A more detailed description of the study designs and the main study results have been published elsewhere [29, 30, 31].

Treatment

Patients received a work-up angiography approximately 1 week before treatment in which extra-hepatic vessels were coil-embolized, if necessary. A scout dose of 99mTc-MAA (150 MBq, Technescan LyoMAA®; Mallinckrodt Medical B.V., Petten, The Netherlands) was administered to assess the extrahepatic and intra-hepatic distribution. After a 1–2 week interval, patients were scheduled for a second and third angiography. The second angiography was planned in the morning, during which patients received a scout dose of 166Ho-microspheres, directly followed by SPECT and MRI. The treatment dose of 166Ho-microspheres was administered that same afternoon and was followed by SPECT and MR image acquisition 3–5 days later [30, 31].

Quality of life assessment

QoL in patients was assessed using the validated European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0 and QLQ-LMC21 questionnaires [32] [33]. The EORTC QLQ-C30 contains 30 questions and the EORTC QLQ-LMC21 contains 21 items. They are composed of both multi-item scales and single-item measures: from the questionnaires, a Global Health Status/Quality of Life (GHS), 5 functioning scales and 22 symptom scores were derived. All but two items are scored on 4-point Likert scales (1: not at all, 2: a little, 3: quite a bit, 4: very much). The two other items are scored on a 7-point linear analogue scale. The raw subscale scores are transformed to a 0–100 scale, where a high score in a functioning scale represents unimpaired functioning and a high score in a symptom scale represents a high level of symptomatology. The functioning scales are: physical functioning (PF), role functioning (RF), emotional functioning (EF), cognitive functioning (CF) and social functioning (SF). The symptom scales are: fatigue (FA), nausea and vomiting (NV), pain (PA), dyspnea (DY), insomnia (SL), appetite loss (AP), constipation (CO), diarrhea (DI), financial difficulties (FI)(QLQ-C30); and eating (LMNutri), fatigue (LMCFati), pain (LMCPA), emotional problems (LMCEp), weight loss (LMCWL), taste (LMCTA), dry mouth (LMCDM), sore mouth/tongue (LMCSM), peripheral neuropathy (LMCPN), jaundice (LMCJ), contact with friends (LMCFr), talking about feelings (LMCFeelings), and sex life (LMCSx) (QLQ-LMC21).

Patients received the questionnaires at baseline, 6 weeks and 3 months after treatment. Follow-up in the HEPAR II study was longer, so those patients also received the questionnaires at 6, 9 and 12 months after treatment. The last included 26 patients of the HEPAR II study received an extra questionnaire 1 week after treatment to better reflect patients’ transient symptoms shortly after treatment [30, 31].

Response assessment

Response assessment was based on contrast-enhanced CT at 3 months posttreatment, according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 [34].

Scoring and statistical analysis

Scoring of the questionnaires was performed according to the scoring manual provided by the EORTC (EORTC scoring manual). Missing values were imputed using multiple imputation. Internal consistency of the multi-item scales was determined using Cronbach’s alpha.

Kolmogrov-Smirnov and Shapiro–Wilk tests were carried out for all categories at the different time points and showed that the data were not normally distributed (p ≤ 0.001).

Descriptive analyses were performed to summarize patient demographics and treatment characteristics. A linear mixed-effects regression model was fitted to evaluate the development of QoL, taking into account all available data [35]. The influence of the following variables on QoL was tested, as these were believed to be of possible influence on QoL: gender (male versus female), previous treatments (systemic, locoregional, both or none), extrahepatic disease at baseline (yes/no), performance status at baseline (WHO score 0, 1 or 2), primary tumor type (colorectal carcinoma versus other), time and response category (complete response, partial response, stable disease or progressive disease). Random effects were tested based on Akaike’s information criterion and fixed effects were tested using a backward stepwise approach.

A relatively conservative P value ≤ 0.001 (instead of ≤ 0.05) was considered statistically significant in order to reduce type I errors [36]. Statistical analyses were performed using R (version 3.5.1).

Results

QoL was studied in a total of 53 patients treated with 166Ho-RE between November 2009 and March 2015; 15 patients in the HEPAR I study and 38 patients in the HEPAR II study (Flowchart for study inclusions: Figure S2). Patient characteristics are listed in Table 2.
Table 2

Baseline characteristics of treated patients in the HEPAR I and II studies

Characteristic

Value

N

 

53

Age (years)

 Median (range)

66 (38–87)

Gender

 Male (%)

31 (58%)

Primary tumour—no.

 Colorectal

29

 Ocular melanoma

8

 Cholangiocarcinoma

6

 Breast carcinoma

5

 Neuroendocrine tumour

2

 Pancreatic cancer

1

 Gastric cancer

1

 Thymoma

1

Administered activity (MBq)

 Median (range)

6210 (1615–13187)

Aimed whole liver dose (Gray)—no.

 20

6

 40

3

 60

41

 80

3

Previous therapies

 Systemic treatment

43

 Locoregional treatment

10

Treatment procedure

 Whole liver

48

 Lobar

5

WHO performance status

 0

45

 1

7

 2

1

Extrahepatic metastases

 Bone

4

 Lung

9

 Lymph node

8

 None

33

Baseline characteristics of patients treated with 166Ho-RE in the HEPAR I and II studies

Due to the dose-escalating nature of the HEPAR I study, 9 patients received an aimed whole liver dose < 60 Gy (i.e. 20 Gy [n = 6], 40 Gy [n = 3]). The other 44 patients received an aimed whole liver dose of ≥ 60 Gy. One patient was excluded from response analysis because this patient did not receive contrast at 3-month follow-up CT-scan. Based on 3-month follow-up CT (using the RECIST 1.1 evaluation), 8 patients had partial response and 14 patients had stable disease. The remaining 28 patients had progressive disease.

Compliance

Fifty of 53 patients (94%) filled out the baseline questionnaire and at least 1 follow-up questionnaire. Since patients were withdrawn from the HEPAR II study after diagnosis of progressive disease, there was quite some variability in follow-up time. Three patients failed to fill out the questionnaire at baseline and 3 months after treatment and were therefore excluded from analysis. Three patients failed to fill out a follow-up questionnaire (1 patient at 6 weeks and 2 patients at 6 months after treatment) and these questionnaires were pairwise excluded from analysis. Four patients left a question blank.

Development of QoL

Median and interquartile ranges of all categories at the different time points are listed in table S3 and graphically displayed in Figs. 1 and 2 and supplemental figure S3a-d. Cronbach’s alpha was determined for the multi-item scales at baseline and at 3 months follow-up and varied from 0.52 to 0.95 (Table S2).
Fig. 1

Median global health score over time with interquartile range (shaded area). A high score represents a good health score

Fig. 2

Median role functioning scores over time with interquartile ranges (shaded areas). BL baseline, 1w 1 week, 6w 6 weeks, 3 m 3 months, 6 m 6 months, 9 m 9 months, 12 m 12 months. A high score represents good functioning

From the figures it can be depicted that changes in almost all categories were most notable at 1 week after treatment. Role functioning was the most affected functioning scale. Fatigue and pain were the most affected symptom scales. Although there were very few patients that filled in the questionnaires beyond 3 months follow-up, all categories seemed to stabilize over time. At every time point, there was a lot of variation between patients in all categories except FI, LMCSM, LMCJ and LMCFeelings.

The development of QoL was best explained by a linear mixed-effects regression model using a random intercept per patient, to allow for different starting points at baseline.

For GHS, as a general measure of quality of life, an increase of on average 0.55 points per time point was found. However, this was not significant (p = 0.48) and there was quite some variation between patients, as can be seen in Fig. 1. Still, there was a steep decline in functioning scores and rise of symptoms from baseline to 1 week. Patients with a higher WHO performance score had on average 20 points lower GHS (p = 0.0002, 95% CI [− 32.3;− 8.8]). No other variables were of significant influence on the development of GHS. Figure 3 shows the development of GHS per patient for patients with WHO performance scores of 0 versus scores 1 or 2. Although there is a lot of variation between patients, patients with a lower WHO performance score have on average a higher QoL.
Fig. 3

Global health status in patients with different WHO performance scores. The black lines depict the development of GHS per patient. The blue lines with shaded area represent the geometric mean with standard deviation. BL baseline, 1w 1 week, 6w 6 weeks, 3 m 3 months, 6 m 6 months, 9 m 9 months, 12 m 12 months. (Color figure online)

In functioning scales, PF, RF and SF were significantly influenced by WHO performance status, where a higher WHO performance status at baseline decreased functioning (p < 0.001 in all categories).

In symptom scales, a higher WHO performance status increased mean symptom scores of FA, DY, DI, and LMCFati (p < 0.001 in all categories). There were no other variables that had a significant influence on the various symptom scores. Both within and between patients, there was a lot of variation in scores.

Discussion

The purpose of the current study was to evaluate the effect of 166Ho-RE on QoL. The hypotheses were that there would be no significant change in QoL over time and that the post-embolization syndrome would have an impact on QoL. This study showed that the first hypothesis was correct: QoL was not significantly affected over time, although there was a lot of variation between and within patients. Regarding the second hypothesis; a decline in QoL and a rise of symptoms was seen at 1 week post-treatment, which is most likely due to the post-embolization syndrome, however, this was not statistically significantly different from the scores at baseline. In the linear mixed model analysis, it was shown that a higher WHO performance score significantly influenced PF, RF, SF, FA, DY, DI and LMCFati. This is not surprising, as patients with a higher WHO performance score are known to be in a debilitating physical condition, which likely influences their QoL.

There were no other variables that had a significant influence on QoL.

The GHS score was used as a general measure of QoL and is based on 2 questions. The other 49 questions (i.e. functioning and symptom scores) provide further insights why GHS changed. In this study, role functioning and social functioning were the most affected functioning scales. Role functioning is based on the patient’s ability to perform hobbies or other daily activities. Social functioning is measured to establish if one’s family life and social activities are influenced. Factors other than the treatment itself may influence these scores. Social functioning may for instance be affected by the instructions for radiation safety: all RE patients are instructed to keep a safe distance from family and relatives for the first days after treatment. In addition, participation in a clinical study with intensive monitoring and follow-up visits poses a significant time, psychological and physical burden, which may be reflected in decreased role- and social functioning. For the symptom scores, there was a rise in fatigue, pain, appetite loss, eating and contact with friends. The latter is coherent with social functioning. The prominent rise in pain and fatigue symptom scores is in accordance with the well-known side effects of RE: clinical side effects usually occur within the first 4 to 6 weeks after treatment and may consist of abdominal pain, nausea, vomiting, fatigue and slight fever [3].

In a subset of 26 patients, QoL assessment was added at 1 week post-treatment because it was thought this would better reflect the short-term adverse effects of the treatment. The steep decline in functioning scores and the rise of symptoms from baseline to 1 week is striking. This may be explained by the so-called post-embolization syndrome, which is known to occur after embolization therapies [3, 4, 37]. Future interventional oncology studies are encouraged to evaluate QoL shortly after treatment (i.e. < 2 weeks).

Due to a large number of differences between the available studies on QoL in patients treated with 90Y-RE and the HEPAR studies, such as the use of different questionnaires, different timing of the QoL evaluations and concomitant treatment with chemotherapy (Table 1), it is impossible to make a fair comparison. Only three studies studied QoL in patients treated with RE as a monotherapy, whereas the others studied RE in combination or in comparison with other therapies. Moreover, in the HEPAR studies, all patients received a whole-liver approach in a single session. This is a more aggressive treatment approach of RE and may have influenced QoL.

A higher number of 166Ho- and 90Y-resin microspheres (somewhere between 30–50 million) are typically injected for treatment in comparison with glass microspheres (typically several million). 166Ho- and 90Y-resin microspheres will therefore have a larger embolic effect and likely also more post-embolic symptoms such as pain, fever and loss of appetite. The study of Cosimelli et al. is most comparable to the HEPAR I and II studies. Cosimelli et al. reported that QoL was not adversely affected in their cohort of patients with metastatic colorectal carcinoma. However, QoL was not tested shortly after treatment, which is an important difference [15].

The changes in QoL after RE were also investigated in a first-line setting. In the SIRFLOX, FOXFIRE and FOXFIRE-Global studies, the possible role for RE as a first-line treatment was investigated. QoL was assessed in the patient group receiving systemic therapy alone and in the patient group receiving RE as an addition to systemic therapy. QoL was slightly worse in the combination group at 2-3 months follow-up, but this was not deemed clinically meaningful [24].

There are several limitations to this study. First, the total number of patients was limited. Second, there was a large loss to follow-up since patients were excluded from the HEPAR II study after diagnosis of progressive disease. This may also have led to a biased representation of the QoL of our study population and it may explain why response category did not significantly influence QoL in the analyses. Third, the QLQ-LMC21 questionnaire, created for patients with colorectal liver metastases, was used to complement the more general QLQ-C30 questionnaire, although colorectal cancer was not the only tumor type in this study. One of the strengths of this study is its prospective nature and the high compliance rate regarding the QoL questionnaires. QoL was frequently assessed and especially the 1-week post treatment questionnaire offered valuable insight in the short-term effects on QoL and patients’ transient symptoms. Another strength of this study is the use of a longitudinal approach for the data analysis. By using a mixed model with a random intercept per patient, the variation between patients and data clustering were taken into account.

More knowledge on the influence of 166Ho-RE on QoL is important for several reasons. Above all, this information is needed to better inform patients on treatment-related adverse effects and may help them to make a well-informed choice between all the available palliative treatment options. In selected populations, such as older patients or patients with multiple comorbidities, QoL is largely maintained. This can be a reason to prefer RE over other treatment modalities [28]. Furthermore, since RE is becoming more important in the first- and second-line settings, the impact of this therapy on QoL is also becoming more significant.

Conclusion

In conclusion, QoL in salvage patients with liver metastases treated with 166Ho-RE was not significantly affected over time, apart from a decline during the first week after treatment. Changes in QoL were most notable during the first week post-treatment, probably due to the post-embolization syndrome. A WHO performance score > 0 at baseline significantly influenced QoL. Knowledge of the influence on quality of life of 166Ho-RE is important for patients to make a deliberate choice between palliative treatment options.

Notes

Acknowledgements

The authors would like to thank G.C. Krijger, R. de Roos, F. van het Schip, J.F.W. Nijsen, T.B. Bosma, A.E.M. Hamersma, and B.A. Zonnenberg for their notable efforts in this study.

Author contributions

MS and ML developed the idea for the study. CR performed the data analyses and contributed to writing of the manuscript. MS collected clinical data of HEPAR I study, helped performing data analyses, helped draft the manuscript. JP collected clinical data of HEPAR II study, contributed in the redaction of the manuscript. RB contributed in the redaction of the manuscript. MB was the principal investigator of HEPAR II study and contributed in the redaction of the manuscript. ML helped draft the manuscript. All authors read and approved the final version of the manuscript.

Funding

The department of Radiology and Nuclear Medicine of the University Medical Center Utrecht has received royalties and research support from Quirem Medical. The HEPAR I and II studies were sponsored by a grant from the Dutch Cancer Society (Grant No. UU2009-4346) and the Technology Foundation STW (Grant No. 6069).

Compliance with ethical standards

Conflict of interest

M.G.E.H. Lam is a consultant for BTG and Terumo. M.L.J. Smits has served as a speaker for Sirtex and Terumo.

Ethical approval

Ethics approval and consent to participate. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or compatible ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10585_2019_10006_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 19 kb)
10585_2019_10006_MOESM2_ESM.xlsx (65 kb)
Supplementary material 2 (XLSX 65 kb)
10585_2019_10006_MOESM3_ESM.tif (38.6 mb)
Search strategy for literature review of quality of life studies in patients treated with RE (TIFF 39490 kb)
10585_2019_10006_MOESM4_ESM.tif (55 kb)
Flowchart of included patients in the HEPAR I and II studies (TIFF 54 kb)
10585_2019_10006_MOESM5_ESM.tiff (197.8 mb)
a–d Median symptom scores over time with interquartile ranges (shaded areas). BL = baseline, 1w = 1 week, 6w = 6 weeks, 3m = 3 months, 6m = 6 months, 9m = 9 months, 12m = 12 months. A high score represents a high level of symptomatology (TIFF 202500 kb)
10585_2019_10006_MOESM6_ESM.tiff (197.8 mb)
Supplementary material 6 (TIFF 202500 kb)
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Supplementary material 7 (TIFF 202500 kb)
10585_2019_10006_MOESM8_ESM.tiff (197.8 mb)
Supplementary material 8 (TIFF 202500 kb)

References

  1. 1.
    Townsend AR, Chong LC, Karapetis C, Price TJ (2016) Selective internal radiation therapy for liver metastases from colorectal cancer. Cancer Treat Rev 50:148–154.  https://doi.org/10.1016/j.ctrv.2016.09.007 CrossRefPubMedGoogle Scholar
  2. 2.
    Smits ML, Elschot M, van den Bosch MA, van de Maat GH, van het Schip AD, Zonnenberg BA, Seevinck PR, Verkooijen HM, Bakker CJ, de Jong HW, Lam MG, Nijsen JF (2013) In vivo dosimetry based on SPECT and MR imaging of 166Ho-microspheres for treatment of liver malignancies. J Nucl Med 54(12):2093–2100.  https://doi.org/10.2967/jnumed.113.119768 CrossRefPubMedGoogle Scholar
  3. 3.
    Braat AJ, Smits ML, Braat MN, van den Hoven AF, Prince JF, de Jong HW, van den Bosch MA, Lam MG (2015) (9)(0)Y hepatic radioembolization: an update on current practice and recent developments. J Nucl Med 56(7):1079–1087.  https://doi.org/10.2967/jnumed.115.157446 CrossRefPubMedGoogle Scholar
  4. 4.
    Riaz A, Awais R, Salem R (2014) Side effects of yttrium-90 radioembolization. Front Oncol 4:198.  https://doi.org/10.3389/fonc.2014.00198 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tominaga T, Nonaka T, Sumida Y, Hidaka S, Sawai T, Nagayasu T (2016) The C-reactive protein to albumin ratio as a predictor of severe side effects of adjuvant chemotherapy in stage III colorectal cancer patients. PLoS ONE 11(12):e0167967.  https://doi.org/10.1371/journal.pone.0167967 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Finlayson CS, Chen YT, Fu MR (2015) The impact of patients’ awareness of disease status on treatment preferences and quality of life among patients with metastatic cancer: a systematic review from 1997–2014. J Palliat Med 18(2):176–186.  https://doi.org/10.1089/jpm.2014.0222 CrossRefPubMedGoogle Scholar
  7. 7.
    Laryionava K, Sklenarova H, Heussner P, Haun MW, Stiggelbout AM, Hartmann M, Winkler EC (2014) Cancer patients’ preferences for quantity or quality of life: german translation and validation of the quality and quantity questionnaire. Oncol Res Treat 37(9):472–478.  https://doi.org/10.1159/000366250 CrossRefPubMedGoogle Scholar
  8. 8.
    Meropol NJ, Egleston BL, Buzaglo JS, Benson AB 3rd, Cegala DJ, Diefenbach MA, Fleisher L, Miller SM, Sulmasy DP, Weinfurt KP (2008) Cancer patient preferences for quality and length of life. Cancer 113(12):3459–3466.  https://doi.org/10.1002/cncr.23968 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Meropol NJ, Weinfurt KP, Burnett CB, Balshem A, Benson AB 3rd, Castel L, Corbett S, Diefenbach M, Gaskin D, Li Y, Manne S, Marshall J, Rowland JH, Slater E, Sulmasy DP, Van Echo D, Washington S, Schulman KA (2003) Perceptions of patients and physicians regarding phase I cancer clinical trials: implications for physician-patient communication. J Clin Oncol 21(13):2589–2596.  https://doi.org/10.1200/JCO.2003.10.072 CrossRefPubMedGoogle Scholar
  10. 10.
    Thong MSY, Doege D, Koch-Gallenkamp L, Bertram H, Eberle A, Holleczek B, Waldeyer-Sauerland M, Waldmann A, Zeissig SR, Brenner H, Arndt V (2019) Age at diagnosis and sex are associated with long-term deficits in disease-specific health-related quality of life of survivors of colon and rectal cancer: a population-based Study. Dis Colon Rectum.  https://doi.org/10.1097/DCR.0000000000001489 CrossRefPubMedGoogle Scholar
  11. 11.
    Heydarnejad MS, Hassanpour Dehkordi A, Solati Dehkordi K (2011) Factors affecting quality of life in cancer patients undergoing chemotherapy. Afr Health Sci 11(2):266–270PubMedPubMedCentralGoogle Scholar
  12. 12.
    Cheng KK, Yeung RM (2013) Symptom distress in older adults during cancer therapy: impact on performance status and quality of life. J Geriatr Oncol 4(1):71–77.  https://doi.org/10.1016/j.jgo.2012.08.006 CrossRefPubMedGoogle Scholar
  13. 13.
    Prigerson HG, Bao Y, Shah MA, Paulk ME, LeBlanc TW, Schneider BJ, Garrido MM, Reid MC, Berlin DA, Adelson KB, Neugut AI, Maciejewski PK (2015) Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol 1(6):778–784.  https://doi.org/10.1001/jamaoncol.2015.2378 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Tohme S, Sanin GD, Patel V, Bress K, Ahmed N, Krane A, Tsung A, Steel JL (2019) Health-related quality of life as a prognostic factor in patients after resection of hepatic malignancies. J Surg Res 245:257–264.  https://doi.org/10.1016/j.jss.2019.07.061 CrossRefPubMedGoogle Scholar
  15. 15.
    Cosimelli M, Golfieri R, Cagol PP, Carpanese L, Sciuto R, Maini CL, Mancini R, Sperduti I, Pizzi G, Diodoro MG, Perrone M, Giampalma E, Angelelli B, Fiore F, Lastoria S, Bacchetti S, Gasperini D, Geatti O, Izzo F (2010) Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer 103(3):324–331.  https://doi.org/10.1038/sj.bjc.6605770 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kalinowski M, Dressler M, Konig A, El-Sheik M, Rinke A, Hoffken H, Gress TM, Arnold R, Klose KJ, Wagner HJ (2009) Selective internal radiotherapy with Yttrium-90 microspheres for hepatic metastatic neuroendocrine tumors: a prospective single center study. Digestion 79(3):137–142.  https://doi.org/10.1159/000209849 CrossRefPubMedGoogle Scholar
  17. 17.
    Salem R, Gilbertsen M, Butt Z, Memon K, Vouche M, Hickey R, Baker T, Abecassis MM, Atassi R, Riaz A, Cella D, Burns JL, Ganger D, Benson AB 3rd, Mulcahy MF, Kulik L, Lewandowski R (2013) Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization. Clin Gastroenterol Hepatol 11(10):1358–1365.  https://doi.org/10.1016/j.cgh.2013.04.028 CrossRefPubMedGoogle Scholar
  18. 18.
    Steel J, Baum A, Carr B (2004) Quality of life in patients diagnosed with primary hepatocellular carcinoma: hepatic arterial infusion of Cisplatin versus 90-Yttrium microspheres (Therasphere). Psycho-oncology 13(2):73–79.  https://doi.org/10.1002/pon.725 CrossRefPubMedGoogle Scholar
  19. 19.
    Kolligs FT, Bilbao JI, Jakobs T, Inarrairaegui M, Nagel JM, Rodriguez M, Haug A, D’Avola D, op den Winkel M, Martinez-Cuesta A, Trumm C, Benito A, Tatsch K, Zech CJ, Hoffmann RT, Sangro B, Haug A (2015) Pilot randomized trial of selective internal radiation therapy versus chemoembolization in unresectable hepatocellular carcinoma. Liver Int 35(6):1715–1721.  https://doi.org/10.1111/liv.12750 CrossRefPubMedGoogle Scholar
  20. 20.
    Gray B, Van Hazel G, Hope M, Burton M, Moroz P, Anderson J, Gebski V (2001) Randomised trial of SIR-Spheres plus chemotherapy versus chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol 12(12):1711–1720CrossRefGoogle Scholar
  21. 21.
    Van Hazel G, Blackwell A, Anderson J, Price D, Moroz P, Bower G, Cardaci G, Gray B (2004) Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol 88(2):78–85.  https://doi.org/10.1002/jso.20141 CrossRefPubMedGoogle Scholar
  22. 22.
    Chow PK, Poon DY, Khin MW, Singh H, Han HS, Goh AS, Choo SP, Lai HK, Lo RH, Tay KH, Lim TG, Gandhi M, Tan SB, Soo KC (2014) Multicenter phase II study of sequential radioembolization-sorafenib therapy for inoperable hepatocellular carcinoma. PLoS ONE 9(3):e90909.  https://doi.org/10.1371/journal.pone.0090909.g001 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cramer B, Xing M, Kim HS (2016) Prospective longitudinal quality of life assessment in patients with neuroendocrine tumor liver metastases treated with 90Y radioembolization. Clin Nucl Med 41(12):e493–e497.  https://doi.org/10.1097/RLU.0000000000001383 CrossRefPubMedGoogle Scholar
  24. 24.
    Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, Peeters M, Findlay MP, Weaver A, Mills J, Wilson C, Adams R, Francis A, Moschandreas J, Virdee PS, Dutton P, Love S, Gebski V, Gray A, Van Hazel G, Sharma RA (2017) First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol 18(9):1159–1171CrossRefGoogle Scholar
  25. 25.
    Kirchner T, Marquardt S, Werncke T, Kirstein MM, Brunkhorst T, Wacker F, Vogel A, Rodt T (2018) Comparison of health-related quality of life after transarterial chemoembolization and transarterial radioembolization in patients with unresectable hepatocellular carcinoma. Abdom Radiol.  https://doi.org/10.1007/s00261-018-1802-y CrossRefGoogle Scholar
  26. 26.
    Gill J, Baiceanu A, Clark PJ, Langford A, Latiff J, Yang PM, Yoshida EM, Kanavos P (2018) Insights into the hepatocellular carcinoma patient journey: results of the first global quality of life survey. Future Oncol 14(17):1701–1710CrossRefGoogle Scholar
  27. 27.
    Xing M, Kokabi N, Camacho JC, Kim HS (2018) Prospective longitudinal quality of life and survival outcomes in patients with advanced infiltrative hepatocellular carcinoma and portal vein thrombosis treated with Yttrium-90 radioembolization. BMC Cancer 18(1):75.  https://doi.org/10.1186/s12885-017-3921-1 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux G-P, Sibert A, Bouattour M, Lebtahi R, Allaham W, Barraud H (2019) Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenb in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial. Lancet Oncol 18(12):1624–1636.  https://doi.org/10.1016/S1470-2045(17)30683-6 CrossRefGoogle Scholar
  29. 29.
    Smits ML, Nijsen JF, van den Bosch MA, Lam MG, Vente MA, Huijbregts JE, van het Schip AD, Elschot M, Bult W, de Jong HW, Meulenhoff PC, Zonnenberg BA (2010) Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial. J Exp Clin Cancer Res 29:70.  https://doi.org/10.1186/1756-9966-29-70 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Smits MLJ, Nijsen JFW, van den Bosch MAAJ, Lam MGEH, Vente MAD, Mali WPTM, van het Schip AD, Zonnenberg BA (2012) Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study. Lancet Oncol 13(10):1025–1034.  https://doi.org/10.1016/s1470-2045(12)70334-0 CrossRefPubMedGoogle Scholar
  31. 31.
    Prince JF, van den Bosch M, Nijsen JFW, Smits MLJ, van den Hoven AF, Nikolakopoulos S, Wessels FJ, Bruijnen RCG, Braat M, Zonnenberg BA, Lam M (2017) Efficacy of radioembolization with holmium-166 microspheres in salvage patients with liver metastases: a phase 2 study. J Nucl Med.  https://doi.org/10.2967/jnumed.117.197194 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Blazeby JM, Fayers P, Conroy T, Sezer O, Ramage J, Rees M (2009) Validation of the European organization for research and treatment of cancer QLQ-LMC21 questionnaire for assessment of patient-reported outcomes during treatment of colorectal liver metastases. Br J Surg 96(3):291–298.  https://doi.org/10.1002/bjs.6471 CrossRefPubMedGoogle Scholar
  33. 33.
    Fayers P, Bottomley A (2002) Quality of life research within the EORTC - the EORTC QLQ-C30. Eur J Cancer 38:S125–S133CrossRefGoogle Scholar
  34. 34.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247.  https://doi.org/10.1016/j.ejca.2008.10.026 CrossRefGoogle Scholar
  35. 35.
    Dragset IG (2009) Analysis of longitudinal data with missing values. Norwegian University of Science and TechnologyGoogle Scholar
  36. 36.
    Colquhoun D (2014) An investigation of the false discovery rate and the misinterpretation of p-values. R Soc Open Sci 1(3):140216.  https://doi.org/10.1098/rsos.140216 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mahnken AH (2016) Current status of transarterial radioembolization. World J Radiol 8(5):449–459.  https://doi.org/10.4329/wjr.v8.i5.449 CrossRefPubMedPubMedCentralGoogle Scholar

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Department of Radiology and Nuclear MedicineUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands

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