Quality of life analysis after stereotactic radiofrequency ablation of liver tumors

The purpose of this study was to evaluate the health-related quality of life (HRQoL) after stereotactic radiofrequency ablation (SRFA) of liver tumors and identify variables associated with decreased HRQoL and to compare it to other treatments in case of concurrency. From 2011 to 2017 577 patients underwent SRFA for liver tumors in 892 ablation sessions. 303 (52.5%) patients completed a HRQoL questionnaire once after the ablation. HRQoL was assessed by the Short Form (SF)-12 health survey with mental and physical component scales and by a general questionnaire to assess disease and treatment-specific items as well as to compare tolerability of SRFA to transarterial chemoembolization (TACE), hepatic resection (HR) and chemotherapy (CTX). The median SF-12 PCS was 46.6 and MCS was 53.2. Patients experiencing pain or complications and patients refusing repeat SRFA showed significantly lower PCS (43.2 vs 48.6, p = 0.0003; 32.8 vs 46.9, p = 0.005 and 40.6 vs 46.9, p = 0.009). 355 (97.8%) patients indicated willingness to undergo repeat SRFA with little to no fear in 292 (80.7%) patients. Among patients with multiple therapies, SRFA was rated by 40 (90.9%) as preferred re-treatment, HR by 1 (2.3%) and CTX by 3 (6.8%). In conclusion, we have shown that SRFA has good HRQoL-outcomes and reported low morbidity rates. Consequently the vast majority of study patients would accept a repeated SRFA if necessary (97.8%), without fear (80.7%). SRFA was preferred among patients who experienced concurrent treatments, such as HR or CTX.

Scientific RepoRtS | (2020) 10:12809 | https://doi.org/10.1038/s41598-020-69331-1 www.nature.com/scientificreports/ morbidity rates up to 59.9% [2][3][4][5] and with a corresponding initial decline in HRQoL after surgery 6 . Radiofrequency ablation (RF) affords more rapid post-procedure recovery and thus good post-procedure HRQoL by virtue of its minimally invasive nature, and has been increasingly accepted as an alternative in the management of primary or metastatic liver tumors 7,8 . Supporting this, Huang et al. 2014 9 reported better post-treatment HRQoL after RFA compared to that after HR in patients with solitary small HCC. Impairment in HRQoL has been reported in patients with hepatocellular carcinomas (HCC) 10, 11 , however long-term preservation 12 after TACE in patients with unresectable HCC and only marginally affection after HR in patients with primary and secondary liver tumors, respectively, have been reported 13 . SRFA includes three-dimensional pre-ablation planning for optimal alignment of multiple RF probes to create larger coagulation volumes, permitting more complex ablations. It's unknown, to our knowledge, if this increased complexity compared to conventional single probe RF ablation might affect the post-procedure HRQoL. The present study was designed to assess the post-procedure HRQoL after SRFA in patients with primary or secondary liver tumors and to compare it to other concurrent treatments, such as TACE, CTX or HR. Our hypothesis states that, despite the complexity of the stereotactic RF procedure, HRQoL after SRFA is better compared to that after HR or CTX and comparable to that after TACE.

Materials and methods
Study population. The local institutional review board approved this study. All patients provided informed consent for both SRFA and QoL assessment. Since 2011, all patients undergoing SRFA for the treatment of primary or secondary liver tumors were asked to complete a HRQoL questionnaire once after the RF procedure (within first few weeks). Until 2017, of a total of 577 treated patients, 303 (52.5%) patients returned 363 questionnaires (311 via mail and 52 via telephone, 50 patients > 1 questionnaires in case of > 1 SRFA sessions). The SF-12 part was correctly completed in 337 of 363 cases (93%). The detailed patient characteristics are presented in Table 1.
SRfA procedure. The method of SRFA has previously been reported in detail [14][15][16] . In brief, the key steps are as follows: (I) Preparation: treatment is performed under general anesthesia with muscle paralysis and immobilization facilitated by a single (Bluebag, Medical Intelligence Schwabmünchen, Germany) or double vacuum fixation technique (BodyFix, Medical Intelligence, Germany); 10-15 broadly to the skin attached registration markers (Beekley Spots, Beekley Corporation, USA) are used for image-to-patient registration. www.nature.com/scientificreports/ (II) Planning: contrast-enhanced (CE) CT (SOMATOM Sensation Open, Siemens AG, Germany) with 3 mm slice thickness in the arterial and portal-venous phase; the obtained CT-data is transmitted to an optical based navigation system (Stealth Station Treon plus, Medtronic Inc., USA); needle trajectories are planned using multiplanar and reconstructed 3D images.
(III) Execution-needle placement: to minimize respiratory motion, temporary disconnections of the endotracheal tube are executed during the planning CT, each stereotactic needle placement and the final CT; after registration, an accuracy check and sterile draping, the ATLAS aiming device (Medical Intelligence Inc., Germany) is used for navigated trajectory alignment; 15G, 17.2 cm coaxial needles (Bard Inc., USA) are placed with the aiming device (without real-time imaging); the coaxial needles serve as guides for the radiofrequency electrodes; to verify proper needle placement, an unenhanced CT is fused with the planning CT by the navigation system; a 16G biopsy sample is obtained via one of the coaxial needles in patients with lack of histological confirmation.
(III) Execution-RF ablation: three 17G radiofrequency electrodes (Cool-tip, Medtronic, USA, 25 cm length with 3 cm exposure) are simultaneously placed through the coaxial needles for serial ablation using the unipolar Cool-tip radiofrequency generator with switching control (Cool-tip, Medtronic, USA); the standardized ablation time for three electrodes is 16 min; however, in case of significant increase of impedance (the so-called roll-off effect) the ablation process is finished; track ablation is done during every repositioning and final removal to avoid bleeding and tumor seeding; (IV) Final control: post-ablation completion contrast-enhanced CT in the arterial and portal venous phase, fused with the planning CT for verification of ablation zone coverage and for assessment of complications; comparative treatments. In CTX, therapeutics were used in standard dosage, frequency and duration according to international guidelines. All liver resections were performed under laparotomy. TACE was carried out in standard technique with administration of an emulsion of Lipiodol (Guerbet, Roissy, France) with epi-or doxorubicine. None of the patient was treated by stereotactic body radiotherapy for liver tumors.
instruments for HRQoL assessment. The HRQoL was primarily investigated using a specifically developed questionnaire consisting of general items, disease and current therapy related items, symptoms after treatment related items and if available, other items with direct comparison of previous and or additional treatments, such as CTX, TACE or HR (see Table 5 for details).
For comparison and reproducibility an internationally validated questionnaire, SF 12 consisting of twelve questions that measure eight health domains to assess physical and mental health, was used. Physical and mental component summary (PCS and MCS) are computed using the scores of twelve questions and range from 0-100, Statistical analysis. SPSS (SPSS Inc., Chicago, USA; version 24.0) was used for statistical analysis. Continuous variables were presented as the median with range. Categorical variables were reported both as numbers and as percentages. The Wilcoxon signed rank test was used for 1-sample testing. The distributions of categorical and numerical variables between independent groups were compared using Fisher's exact test, Mann-Whitney U test (two independent variables) and Kruskal-Wallis test (more than two independent variables), respectively. A p value < 0.05 was considered as statistically significant.  (Tables 2, 3, 4; Fig. 2) . The median PCS was 46.6 (range 39.1-53.3) and MCS 53.2 (range 47.1-57.9). The PCS of patients younger than 40 years in the study group was lower compared to the control population (Fig. 3).

Discussion
We have shown that SRFA has good HRQoL outcomes in a large series of patients and is perceived as less burdensome compared to HR or CTX to those patients who experienced both treatments. HR is still considered as the preferred treatment for primary and secondary liver tumors despite significant physical and psychological burdens. Recently minimally invasive curative treatments have gained more importance due to lower morbidity www.nature.com/scientificreports/ rates paired with comparable oncological outcomes [17][18][19][20][21][22][23] . SRFA has shown to be as effective as HR in the treatment of colorectal and breast cancer liver metastases, HCC and ICC 15,[24][25][26] . HRQoL has become increasingly important as an outcome measure and has not yet been investigated for SRFA treatments. The present study evaluated HRQoL after SRFA in patients with primary and secondary liver tumors using two different instruments. In this study, patients older than 40 years showed comparable overall PCS after the RF procedure compared to that of the general German control population. This is in contrast to HRQoL reports after HR, where HRQoL regularly shows an initial decline with considerable improvement after 6 months with the highest scores after 24 months 6 . According to Toro et al. and Dasgupta et al. 27,28 this pattern may be indicative of the regenerative capacity of the liver. Liver disease, age, tumor type, number and size did not significantly influence PCS or MCS in the present study. In agreement with the study of Poon et al. and Wang et al. 2007 29,30 , pain after the procedure had a significantly negative impact on the PCS (43.2 vs 48.6, p = 0.0003). Patients refusing repeated SRFA had significantly lower PCS and MCS (32.8 vs 46.9, p = 0.009; 42.6 vs. 53.3, p = 0.011, respectively). In accordance, patients experiencing complications after SRFA showed significant lower PCS with 40.6 vs 46.9 (p = 0.005), whereas MCS was not significantly different with 49.6 vs 53.3 (p = 0.317), respectively.
In patients with small HCC, Huang et al. 2014 9 reported better HRQoL after percutaneous RFA than after HR 30,31 , however with marked improvement 3-6 months after therapy in HR patients. The worsened HRQoL is explained by direct consequences of surgery, especially in the early postoperative period. In agreement, He et al. 2018 32 reported improved or stable HRQoL after RF ablation in HCC patients. In the present study, SRFA was preferred to CTX or HR by patients that experienced both treatments indicated by significantly lower (p = 0.000, Fig. 5A) median rated scores of physical stress. Given the increased complexity of SRFA compared www.nature.com/scientificreports/ to conventional RFA, these results may be surprising, but they underline that the complexity of SRFA does not hinder rapid post-procedural recovery. In line with our hypothesis, TACE showed comparable results in HRQoL. However, since conventional US-and CT-guided "freehand" RFA was completely replaced by SRFA at our intuition in 2002, we could not show any direct comparisons to conventional RFA. The most common reported symptoms such as pain or weakness (54% and 53%) were only temporary (up to a few weeks) and their rated impairment was low (median 2, Fig. 5B). This compares favorably with the reports after HR, where pain, dyspnoea and fatigue remained even at 36-48 months 28 . Toro et al. 2012 27 reported that patients who were treated by TACE showed a significant long term reduction of physical well-being, social/family well-being, emotional well-being, functional well-being and additional concerns. The potential explanation is that patients who undergo TACE commonly have already developed advanced liver or cancer disease, respectively. SRFA in its current from was introduced in 2003. A few technical improvements and modifications in the procedure were introduced thereafter. However, during the study period from 2011-2017 sRFA technology and procedure did not change anymore.
The complication rate reported by the patients was higher than that of the institutional medical reports (31, 8.6% vs. 16, 4.4%). Patients might have overrated complications as major complications or patients experiencing complications might be more likely to reply to the questionnaire than asymptomatic patients (selection bias). The presence of complications was associated with a significant decline in PCS (40.6 vs 46.9, p = 0.004).
The median reported in-patient-stay was significantly lower (3 days vs. 14 days, p = 0.000) after SRFA compared with that after HR, however not significantly different compared to that after TACE (3 days vs. 2.5 days, p = 1.000). www.nature.com/scientificreports/

Limitations
The limitations of the study are related to its single-arm design with heterogeneous patient collectives-some patients underwent only SRFA, while others received SRFA together with different additional therapies. Compared to other studies, HRQoL in the present study was obtained only once after therapy and thus no longterm HRQoL predictions could be made. The return rate of the questionnaire was 52.5%, with a relative major complication rate of 4.4% in the study group vs. 7.4% in the non-responder group. Hence, a possible bias could be that some patients who have suffered complications did not return a questionnaire. In addition, the cultural diversity of the study population could also represent a possible bias in the subjective assessment of quality of life.

conclusion
We have shown that SRFA has good HRQoL-outcome. The vast majority of patients in our survey would accept a repeated SRFA if necessary (97.8%), without fear (80.7%) and is preferred among patients who experienced concurrent treatments, such as HR or CTX.