Ultrasound-guided microwave ablation for secondary hyperparathyroidism: a systematic review and meta-analysis

Abstract Objectives Microwave ablation (MWA) is used for the treatment of severe secondary hyperparathyroidism (SHPT), but its efficacy and safety still remained unclear. This study aimed to investigate the efficacy and safety of ultrasound (US)-guided MWA in patients with SHPT. Methods The PubMed, Cochrane library, Embase, China national knowledge infrastructure (CNKI) and Wanfang databases were searched to identify published studies that evaluated the efficacy and safety of US-guided MWA in patients with SHPT. The primary outcomes were parathyroid hormone (PTH), serum calcium and phosphorus levels. Results A total of 26 studies with 932 patients were identified. The PTH levels showed significant reduction at 1 month [weighted mean difference (WMD) = 945.33, 95% CI: 797.15∼1093.52] and 6 months (WMD = 1,151.91, 95% CI: 990.93∼1312.89) after MWA of SHPT patients. The serum calcium (WMD = 0.39, 95% CI: 0.30 ∼ 0.48) and phosphorus levels (WMD = 0.64, 95% CI: 0.43 ∼ 0.85) showed significant reduction at 6 months after MWA of SHPT patients. The most common complications observed were hypocalcemia (35.2%) and transient hoarseness (9.2%). No other major complications or death occurred in our study patients. Conclusion These findings suggest MWA as a safe and effective minimally invasive technique for the management of SHPT. PTH, calcium, and phosphorus levels were significantly reduced at 1 and 6 months after MWA.


Introduction
Secondary hyperparathyroidism (SHPT) is a frequently encountered problem in patients with end-stage renal disease (ESRD) [1,2], and about one-third of the patients undergoing long-term dialysis are affected [3,4]. The patients with uncontrolled SHPT have increased risk of fractures and mortality [5,6]. Although disease development can be controlled clinically by using intravenous vitamin D analogs [7], orally active vitamin D sterols [8] and cinacalcet [9], parathyroidectomy in patients with severe SHPT is still considered necessary [10]. Surgical parathyroidectomy exposes patients to anesthesia risks and permanent parathyroid function reduction [11]. A minimally invasive alternative treatment with potential advantages of reduced risk, faster recovery, fewer side effects and lower costs when compared to traditional surgical treatment is warranted.
Recently, image-guided thermal ablation has been used for the treatment of hyperparathyroidism (HPT) [12,13]. As a method of ablation, ultrasound-guided percutaneous microwave ablation (MWA) has achieved good clinical results [14,15]. This technique has the advantages of least damage and effectively reduction of the levels of intact parathyroid hormone (iPTH), gradually becoming clinically acceptable. However, the results of existing studies on microwave ablation for SHPT are not completely consistent. Therefore, a systematic review and meta-analysis of published literature to evaluate the efficacy and safety of US-guided microwave ablation for SHPT was conducted. Although a previous metaanalysis has been constructed by Cao et al, the number of literatures included in the current study is more than triple that of it.

Materials and methods
The present meta-analysis study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [16].

Literature searches
The PubMed, EMBASE, Cochrane Library, China national knowledge infrastructure (CNKI) and Wanfang database were comprehensively searched from inception to March 2021 without any language restriction. The keywords used to search included "secondary hyperparathyroidism" plus "SHPT" and "microwave ablation" plus "MWA." The reference lists of the relevant studies identified were manually scanned using these search terms.

Study selection
Relevant studies were included based on the following criteria: (1) observational cohorts including prospective and retrospective studies comparing pre-ablative and post-ablative clinical results; (2) patients with SHPT who underwent USguided microwave ablation for therapy; (3) outcomes such as serum iPTH levels, serum calcium, serum phosphorus and complications; and (4) studies including a follow-up duration of at least 30 days. Studies were excluded if they met the following criteria: (1) studies published as case reports, conference abstracts, letters to editor, or reviews; (2) studies including patients with primary hyperparathyroidism; and (3) experimental studies of animal models or cell lines.

Data extraction and quality assessment
Data extraction was done using a standardized data collection form, which included author, year of publication, country, study design, number of patients, MWA power, number of lesion, age, gender, study duration, follow-up period and outcomes. The Newcastle-Ottawa Scale (NOS) [17] was used to evaluate the quality of included studies, in which studies with scores ! 6 represents high quality. Data extraction and quality assessment was independently done by two authors, and any disagreements between them were resolved by discussion.

Data synthesis and statistical analysis
Pooled estimates of proportions with corresponding 95% confidence intervals were calculated on the base of the Freeman Tukey double arcsine transformation [18,19]. Weighted mean difference (WMD) with 95% CIs were calculated as the difference between pre and post-treatment using random-effects model [20,21], in which I 2 >50% or p < 0.1 represents notable heterogeneity. To detect robustness of the results, sensitivity analysis was conducted by sequential elimination of each study from the pool [21,22]. Potential publication bias was assessed using visual inspection of funnel plots, Begg's and Egger's tests [23,24].

Literature search and study characteristics
A total of 122 studies were screened, and 41 full-texts of these were assessed for eligibility. Finally, 26 studies [14, were included in the current systematic review. A flowchart depicting the study selection process was presented in Figure 1. The eligible articles were published between 2015 and 2021, and included a total sample size of 932. Among these studies, seven were prospective studies and 19 were retrospective studies. The mean age of participants ranged from 38.67 to 69.1. Both male and female patients were included in the studies. The main characteristics of the included studies are presented in Table 1. The quality of included studies was shown in Table 2. The quality assessment scores ranged from 7 to 8, with an average score of 7.5 points, which represent satisfactory quality of the studies.

Sensitivity analysis
Sensitivity analyses were performed to examine the influence of exclusion of each study on the combined results, and assess the robustness of all results. Each study was excluded at a time, and the pooled results of the remaining studies showed no significant differences (Supplementary Figure 1).

Publication bias
The funnel plots for meta-analysis of US-guided microwave ablation for SHPT are shown in Supplementary Figure 2

Discussion
Despite potential complications associated with parathyroidectomy, such as transient or permanent hypocalcemia and laryngeal nerve injury, SHPT patients still obtained many benefits from this surgery. These include improvements in serum phosphorus and calcium levels, bone density, survival and relief from symptoms. Therefore, the Kidney Disease Improving Global Outcomes (KDIGO) currently recommends parathyroidectomy for patients with severe SHPT who are ineffective to drug treatment [50]. However, parathyroidectomy is not suitable for all patients with severe SHPT due to various reasons, such as preoperative hypocalcemia, the elderly with multiple comorbidities. Therefore, treatment strategies remain challenging in these patients and for clinicians. Several recent preliminary studies have confirmed that the destruction of parathyroid tissue in SHPT patients by ultrasound-guided MWA is considered as a safe and effective approach [14,28,30]. In this study, the efficacy and safety of US-guided MWA of SHPT patients were evaluated by systematic review and meta-analysis. Eighteen studies consisting of 932 patients were included. Our meta-analysis results revealed that PTH, serum calcium and phosphorus levels were significantly reduced at week 1, 1 month, 6 months and end of the follow-up period after MWA of SHPT patients. Different from the results of previous meta-analysis study [51], the current meta-analysis study has fully gathered the data from a wide range of results and provided more indepth insights on important clinical results. Also, due to the inclusion of additional studies and larger amounts of pooling, the results are different from that of the previous metaanalysis. A previous meta-analysis conducted by Cao et al. [51] has been limited due to inclusion of only eight studies that compared pre-ablative and post-ablative clinical results. The present study included 18 additional eligible studies. In addition, the results of this meta-analysis are not exactly the same as those of Cao et al. on the primary outcomes assessed. Cao et al. found no significant differences in terms of calcium levels at 6 months after MWA of SHPT patients, which were inconsistent with that of the previous meta-analysis. However, the present results indicated that calcium levels were significantly reduced at 6 months after MWA in patients with SHPT. The difference in these results might again be due to the larger sample size of this study as compared to the previous studies.
However, there are some limitations in this study that should be acknowledged. Firstly, the heterogeneity included in this study was significant and observed throughout the analysis. Despite the heterogeneity observed in the study, the results of sensitivity analysis were considered reliable and robust. Secondly, most of the samples included in this trial were small. Thirdly, although published bias and sensitivity analyses confirmed the credibility of our analysis, this meta-analysis still showed heterogeneity due to several factors such as patient characteristics, sample size and treatment procedures that were not included in our analysis. Finally, most of the articles included were retrospective studies, and not randomized controlled trials. This limitation leaves a large gap in the existing evidence, and so further analysis of randomized controlled trials should be conducted. These factors should be clarified in the future research.
In summary, this meta-analysis indicated that MWA significantly reduced PTH, serum calcium and phosphorus levels in SHPT patients without increasing overall complications. Therefore, MWA is considered as a minimally invasive technique that is safe and effective for the management of SHPT. In addition, large-scale studies, such as randomized controlled trials, should be designed in the future to obtain more results.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The study was supported by the Science and Technology Bureau of Changshu City, Jiangsu Province in 2019[CS201911].