Minimally invasive video-assisted versus conventional open thyroidectomy: a systematic review of available data

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1 DOI.07/s z ORIGINAL ARTICLE Minimally invasive video-assisted versus conventional open thyroidectomy: a systematic review of available data Jiao Liu Turun Song Mingqing Xu Received: 4 May 0 / Accepted: 7 July 0 Ó Springer 0 Abstract Purpose Minimally invasive video-assisted thyroidectomy (MIVAT) is now emerging as a novel and less invasive procedure for thyroid diseases. This study conducted a systematic review of the available data to evaluate the safety and efficacy of this new technique over conventional procedure. Methods A systematic literature search was performed on Medline, Embase, and The Cochrane Library. Randomized controlled trials comparing the MIVAT with open thyroidectomy were selected and meta-analyzed. Results Nine RCTs involving 70 patients were included and all were restricted to patients with a thyroid nodule no larger than 4 cm and surgery did not involve lymph node dissection. Both procedures were of similar efficacy in nodule resection. Open surgery had a.6 times higher rate of postoperative complications than the novel technique, with no significant difference (P = 0.08), especially in transient recurrent nerve palsy (OR = 0.9, P = 0.87). Although longer operative time was required for MIVAT (MD = 5.0 min, P \ ), patients experienced less postoperative pain, especially in the early postoperative period (MD =-.5, P = 0.000). There was also a shorter incision length (MD =-.6 cm, P \ ), Dr. Liu and Dr. Song contributed equally to this article. J. Liu M. Xu (&) Department of Liver and Vascular Surgery, West China Hospital, Sichuan University, Guoxue Xiang #7, Chengdu 604, Sichuan, People s Republic of China ljlovey@6.com T. Song Urology Department, West China Hospital, Sichuan University, Chengdu, People s Republic of China better cosmetic results and greater patient satisfaction in the novel technique group (WD =.59; P \ ). Conclusions MIVAT is a feasible, practical, and safe alternative with better cosmetic benefits, and it can be performed with an ease of manipulation that is similar to that of conventional neck surgery. Keywords Conventional thyroidectomy Minimally invasive video-assisted thyroidectomy Systematic review Abbreviation MIVAT Minimally invasive video-assisted thyroidectomy Introduction Huscher et al. [ 5] first reported performing endoscopic surgery in thyroid lobectomy for thyroid nodules. A novel procedure has been proposed in many medical centers and several techniques have been introduced including minimally invasive video-assisted thyroidectomy (MIVAT) [6 8] and minimal incision thyroidectomy [9, ]. MIVAT was intended to combine the benefits of an open procedure and endoscopic surgery. The potential advantages of MIVAT are better recognition of the anatomic entities during dissection, improved hemostasis, less postoperative pain, reduction of complications, and higher cosmetic satisfaction. However, endoscopic resection requires adequate training in performing open operations, and many other factors, especially the nodule size and thyroid volume thus lead to its limited its application. Although a study done by Ruggieri [] suggested that small nodules are one of the best indications for MIVAT, this procedure has not yet gained wide acceptance in comparison to conventional thyroidectomy.

2 The aim of this study was to test the hypothesis that MIVAT affords safety and efficacy comparable to the open conventional surgery in dealing with patients with small thyroid nodules. Although two reviews concerning this subject are available and their conclusions are not of certainty, more evidence has emerged since their work [, ], thus a new systematic review of the available data seems needed to exam the superiority and limitations of this novel technique. Materials and methods Search strategy Studies were identified through searching English databases up to March 0, including the Cochrane library, Embase, Medline, OVID, and the most commonly used Chinese databases, including CNKI, VIP, and CBM. Search terms were used separately and in combination to identify relevant studies. In addition, the references of listed studies were examined. The keywords used were randomized controlled trial ; controlled clinical trial ; thyroidectomy ; minimally invasive surgery ; mini incision and endoscopic surgery ; video-assisted thyroidectomy ; minimally invasive thyroidectomy ; MIVAT and conventional thyroidectomy (CT). Chinese words with the same meaning were used for the Chinese database. Study selection Identified studies were assessed for eligibility for inclusion in the review by scrutinizing the titles, abstracts and keywords of every record retrieved. Studies were restricted to those published in English and Chinese. Clinical studies concerning comparisons of any aspects between the MIVAT and CT were also included. Data abstraction Statistical analysis A formal meta-analysis (according to the guidelines of the QUOROM statement) was made for all RCTs [4, 5]. The results were reported as odds ratio (OR) with corresponding 95% CI for dichotomous data. The weighted mean difference and 95% CI was calculated if continuous data were available. A Revman software package version 5.0 was applied to do all the analyses. A P value \0.05 was considered statistically significant. One expert specialized in statistics from China Evidence-Based Medical Center was consulted during the whole procedure. Quality assessment of trials Eligible studies were assessed for quality based on the following criteria: randomization, allocation concealment, blindness, attrition, selective outcome report, and baseline comparable and incomplete outcome data. The studies were subdivided into three categories: (a) all quality components adequate low risk of bias; (b) one or more of the quality components unclear moderate risk of bias; (c) one or more of the quality components inadequate high risk of bias. Results Literature search results A search of the Cochrane library identified seven articles; fourteen in Embase and twenty-one in Medline. The reasons for the exclusion are described in Fig.. Another four articles were identified through the screening of the references of the included studies. Therefore, nine studies were included. Embase: 4 Medline: Cochrane: 7 The data were abstracted from each study on the possible condition, including the authors, year of publication, number of patients, age, gender ration, inclusion and exclusion criteria, total thyroidectomy or thyroid lobectomy, operative time, blood loss, visual analog scale (VAS) for postoperative pain at 6, 4, and 48 h, numerical score for cosmetic result, size of the nodule, incision length, length of hospital stay and complications. The corresponding authors of RCTs were contacted to obtain supplementary information, if necessary. Studies were selected for inclusion and exclusion independently by two reviewers (Liu and Song) and consensus was reached by discussions when they did not agree in the initial assignment. Duplicate: Not related: 9 Reference screening: 4 Included: 9 Fig. Screening of search results Not in English: Not RCTs: Comment:4

3 Study characteristics All randomized control trials (RCTs) comparing MIVAT with CT for thyroid nodular disease were identified [6 4]. The main characteristics of included studies are presented in Table and 70 patients were included. Although all studies claimed to be RCTs, not all matched the best standard required criteria for a RCT. Six studies had no descriptions of randomization, seven studies had no descriptions of allocation concealment and seven studies had no descriptions of blindness. One of the nine studies was level A, the rest were level B (Table ). The MIVAT in one study was total thyroidectomy, two studies were thyroid lobectomy thyroidectomy, another two studies were not reported and the rest with both procedures (Table ). The most common indication for the application of these procedures was follicular adenoma. Seven studies clearly excluded the thyroiditis, and five studies excluded malignancy (Table ). The follow-up period varied from days to. months. Demographic characteristics The demographic characteristics of all included populations are summarized in Table. No significant difference was found in age and gender ration between patients undergoing MIVAT and CT in most studies. The majority were female. Alesina et al. [] reported patients in the MIVAT group were significantly younger than the CT group (45 ± 5 vs. 54 ± years; P \ 0.000). Outcome measures Transient recurrent laryngeal nerve palsy and cosmetic results were considered the primary outcome measures, respectively, and the rest were secondary outcome measures. Primary outcome measures All studies reported intact nodule resection without any residue or recurrence requiring secondary surgical intervention. One study [7] reported that 4 of (.9%) patients having MIVAT underwent a conversion to conventional surgery because the recurrent nerve could not be identified. There was no mortality in either group. The recurrent laryngeal nerve frequently lies on the thyroid at the site of the ligament of Berry; just before the nerve enters the cricothyroid muscle [5], the recurrent laryngeal nerve is vulnerable to injury in the area. Transient recurrent laryngeal nerve palsy was observed in six studies, with a comparable nerve palsy rate. Alesina et al. [] even reported two cases with transient recurrent laryngeal nerve palsy in the CT group, but no case in the MIVAT group. No significant differences were observed between the two groups (OR = 0.9, 95% CI [0.40,.8], P = 0.87; Fig. ). Patients were asked to grade the cosmetic appearance of their wound by a numeric scale, which ranged from 0 to [6]. Five of the nine studies reported that patients in the MIVAT group were more satisfied with the cosmetic results (WD =.59, 95% CI [.5,.65], P \ ; Fig. ). In another study, the numeric scale of cosmetic result was higher for MIVAT than CT (9. vs. 8.9), but the difference was not statistically significant [0]. Secondary outcome The postoperative pain scores were measured using a -point VAS postoperatively. The patients were asked to assess the severity of pain by the means of a VAS, which usually consists of a -cm line with the words no pain on the left hand side and the worst pain imaginable on the other side [7]. A higher numeric pain score represented more severe pain. At 6 h after operation, it showed that the patients underwent MIVAT experienced much less pain than those underwent CT (MD =-.5, 95% CI [-7.8, -5.], P = 0.000; Fig. 4). Alesina et al. [] reported that the postoperative VAS were 6 ± for MIVAT and 6 ± 9 for CT 8 h after the operation (P = 0.8), respectively. Comparisons between two procedures concerning VAS score of 4 and 48 h, respectively, showed no statistically significant differences in favor of the MIVAT (MD =-4.9, 95% CI [-5.06, 5.], P = 0.5 and MD =-.5, 95% CI [-6.04,.96], P = 0.6, respectively; Figs. 5, 6). Similarly, Alesina et al. [] reported that the postoperative VAS was ± for MIVAT and ± for CT at 6 h after the operation (P = 0.4). The neck acts has an important role in the cosmetic appearance, thus the length of incision is also one of the surgeon s concerns. The mean incision length for the CT group were significantly longer than that for the MIVAT group (MD =-.6, 95% CI [-.85, -.86], P \ ; Fig. 7), this is consistent with Dionigi s report [4] that the postoperative incision length was slightly shorter in MIVAT than that of CT group (.9 vs. 5. cm; P \ 0.05). The operative time was measured to the nearest minute from initiation of the incision to subcuticular closure. The operation time (MD = 5.0, 95% CI [8.77,.44], P \ ; Fig. 8) was significantly shorter in favor of CT. The postoperative hospital stay was not significantly different in both groups (MD =-0.47, 95% CI = [-.7, 0.76], P = 0.45; Fig. 9), and Dionigi [4] found the MIVAT patients had a shorter postoperative hospital stay

4 Table Characteristics of included studies Author No. of patients Inclusion criteria Exclusion criteria Follow up Conclusion MIVAT CT MIVAT CT Miccoli 5 4 Nodules \5 mm, volume \0 ml Nodules [5 mm, volume [0 ml 8.8 months 9. months MIVAT offers advantages in postoperative pain and cosmetic results, CT offers an advantage in operative time Bellantone Nodule \ cm Previous neck irradiation/. months.8 months MIVAT is a valid alternative to CT cervical operation Chao TC 5 59 Single nodule \5 cm, Suggested malignancy months months MIVAT is a valid alternative to CT volume \0 ml Lombardi Nodule B0 mm Previous neck irradiation/ cervical operation Hegazy 5 Solitary nodules \4 cm, volume \0 ml Gal 5 5 Nodule \5 mm, volume \0 ml Alesina Nodule \5 mm, volume \0 ml EI-labban Unilateral nodular B.0 cm Dionigi Nodules \0 mm; volume \0 ml Thyroiditis/previous neck surgery/irradiation/suspicion of malignancy Thyroiditis/previous neck surgery/irradiation/enlarged cervical lymph node months months MIVAT provide benefit in terms of cosmetic results and postoperative pain NR NR MIVAT offers advantages of less postoperative pain and better cosmesis, CT offers an advantage of less operating time days days MIVAT offers advantages in cosmetic results and reduced postoperative distress. CT involves less operative time Thyroid cancer days days NR Thyroid carcinoma, active thyroiditis, previous neck surgery/neck irradiation Thyroiditis, previous neck surgery/irradiation; suspected malignancy or metastasis months months MIVAT is a valid alternative to CT 9 ± months 9 ± months Wound morbidity was significantly reduced after MIVAT relative to CT MIVAT minimally invasive video-assisted thyroidectomy, CT conventional thyroidectomy, NR not reported, MNG multinodular goiter

5 Table Quality of the included studies Author Year Randomization Allocation concealment Blindness Attrition Selective outcome report Base line comparable Incomplete result Quality level Miccoli 00 Not clear Not clear Not clear No No Yes No B Bellantone 00 Yes Not clear Not clear No No Yes No B Chao TC 004 Yes Not clear Not clear No No Yes No B Lombardi 005 Not clear Not clear Not clear No No Yes No B Hegazy 007 Not clear Not clear Not clear No No Yes No B Gal 008 Yes Not clear Not clear No No Yes No B Alesina 0 Not clear Not clear Not clear No No Yes No B EI-labban 0 Yes Yes Yes No No Yes No A Dionigi 0 Not clear Not clear Not clear No No Yes No B Table Demographic characteristics of the included population Author Age (year) Gender ration (M:F) Size of nodule (cm) Total/thyroid lobectomy MIVAT CT MIVAT CT MIVAT CT MIVAT CT Miccoli ± ±.8 / / NR NR 6/9 4/ Bellantone 5.8 ±.6 5. ±.8 4/7 7/4 NR NR 0/ 0/ Chao TC 9.5 ± ± 4.6 /40 7/5.6 ± ± 0.9 0/5 0/59 Lombardi 45.9 ± ±.8 0/ /8. ± 0.7. ± 0.54 /0 /0 Hegazy 9.8 ±.7 7 ±.4 4/9 5/0.5 ± 0.7. ± 0.7 4/9 5/0 Gal 9.9 ±.5 4. ±.8 / / NR NR /4 /4 Alesina 45 ± 5 54 ± 7/58 9/55 NR NR /7 49/45 EI-labban 40 ± 7 4 ± 9 /7 /8.7 ± ± 0. NR NR Dionigi 9.8(9 77) 4(5 68) 4/4 6/40.(0.7.0).0(0.4.0) NR NR MIVAT minimally invasive video-assisted thyroidectomy, CT conventional thyroidectomy, NR not reported MIVAT Conventional surgery Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI Alesina % 0.5 [0.0, 5.8] Chao TC % 0.66 [0.5,.9] Dionigi %.00 [0.9, 5.8] El-labban 0.0%.06 [0.8,.68] Hegazy %.06 [0.06, 7.7] Miccoli %.00 [0.7,.6] Total events Heterogeneity: Tau² = 0.00; Chi² =.7, df = 5 (P = 0.88); I² = 0% Test for overall effect: Z = 0.6 (P = 0.87) Fig. Transient recurrent laryngeal nerve palsy 0.0% 0.9 [0.40,.8] than the CT patients (. vs..6 days; P \ 0.05). Longer operative time and shorter length of hospital stay in the MIVAT group, together with additional cost for novel instruments, makes the total cost hard to determine. However, none of the included studies discussed this subject. The overall complication rate for MIVAT was lower than CT (OR = 0.6, 95% CI [0.7,.06], P = 0.08; Fig. ). Complications other than recurrent laryngeal nerve palsy are considered as minor including transient hypoparathyroidism and blood loss. There were no significant differences in transient hypoparathyroidism in two

6 Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Bellantone %.40 [.,.70] El-labban % 4.0 [.95, 4.45] Gal %.00 [.,.90] Lombardi % 0.90 [0.,.69] Miccoli %.0 [0.,.0] % Heterogeneity: Tau² =.5; Chi² =.06, df = 4 (P < ); I² = 96% Test for overall effect: Z = 4.79 (P < ).59 [.5,.65] Fig. Postoperative cosmetic results Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Hegazy 007 Lombardi 005 Miccoli % 8.8% 8.0% -.80 [-9.76, -.84] -.00 [-7.,.] [-8., -5.8] 68 Heterogeneity: Tau² =.96; Chi² =.9, df = (P = 0.); I² = 9% Test for overall effect: Z =.58 (P = 0.000) Fig. 4 Postoperative pain at 6 h measured by VAS % -.5 [-7.8, -5.] Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Alesina % [-8.98, 0.98] Bellantone % [-45.00, -4.00] El-labban % [-.0, -5.99] Hegazy % -.70 [-0.95, -.45] Lombardi % [-.07,.07] Miccoli % [-8., -4.87] 0.0% Heterogeneity: Tau² = 60.0; Chi² = 58.77, df = 5 (P < ); I² = 0% Test for overall effect: Z =.45 (P = 0.5) -4.9 [-5.06, 5.] Fig. 5 Postoperative pain at 4 h measured by VAS Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Alesina %.00 [-.6, 4.6] Bellantone % [-46.79, -45.] El-labban % -.00 [-., 0.] Hegazy % -7.0 [-6.98,.58] Lombardi % [-.0, -.70] Miccoli % [-8.40, 0.80] 0.0% -.54 [-6.04,.96] Heterogeneity: Tau² = 97.76; Chi² =., df = 5 (P < ); I² = 0% Test for overall effect: Z = 0.9 (P = 0.6) Fig. 6 Postoperative pain at 48 h measured by VAS

7 Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Alesina 0 El-labban 0 Hegazy %.0%.% -.90 [-.0, -.60] -.50 [-.86, -.4] -.70 [-.09, -.] Heterogeneity: Tau² = 0.6; Chi² =.84, df = (P = 0.00); I² = 8% Test for overall effect: Z = 9.6 (P < ) Fig. 7 Postoperative incision length 0.0% -.6 [-.85, -.86] Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Alesina 0 Bellantone 00 Chao TC 004 El-labban 0 Gal 008 Lombardi 005 Miccoli % 9.6% 5.7% 6.0%.8% 9.0%.% -.00 [-9.8, 5.8] 9.00 [7.4, 0.76] 5.0 [8.00,.40] 6.00 [9.4,.86] 5.0 [.66, 6.74].50 [-.80, 7.80] 0.80 [9.66,.] % Heterogeneity: Tau² = 50.86; Chi² =.6, df = 6 (P < ); I² = 8% Test for overall effect: Z = 4.7 (P < ) 5.00 [8.77,.4] Fig. 8 Operative time Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI Bellantone 00 El-labban % 49.7% -. [-.8, -.0] 0.6 [-0.04, 0.6] % Heterogeneity: Tau² = 0.79; Chi² = 8.0, df = (P < ); I² = 99% Test for overall effect: Z = 0. (P = 0.45) [-.7, 0.76] Fig. 9 Length of hospital stay MIVAT Conventional surgery Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Alesina 0 Chao TC 004 Dionigi 0 El-labban 0 Hegazy 007 Lombardi 005 Miccoli % 6.6% 40.5%.% 5.0% 4.4% 5.% 0.8 [0.4, 5.] 0.7 [0.07,.0] 0.46 [0.9,.].49 [0.4, 5.9].06 [0.4, 8.0].00 [0., 8.95] 0.96 [0., 7.40] % 0.6 [0.7,.06] Total events 8 4 Heterogeneity: Chi² = 4.58, df = 6 (P = 0.60); I² = 0% Test for overall effect: Z =. (P = 0.08) Fig. The total complication rate

8 MIVAT Conventional surgery Odds Ratio Odds Ratio Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI Alesina 0 El-labban 0 Hegazy 007 Miccoli % 40.6% 5.7% 5.6%.55 [0., 8.65].00 [0., 7.49].8 [0., 8.] 0. [0.0, 7.9] 7 9 Total events 5 4 Heterogeneity: Tau² = 0.00; Chi² =.4, df = (P = 0.70); I² = 0% Test for overall effect: Z = 0.4 (P = 0.69) Fig. Transient hypoparathyroidism 0.0%.0 [0.6, 4.70] groups (OR =.0, 95% CI [0.6, 4.70], P = 0.69; Fig. ). Blood loss was similar (P = 0.80) in the two groups. Discussion There is a difference in the incidence of thyroid nodules found through clinical examination and ultrasound examination: the former is 4 7%, the latter is up to 5% [8]. Autopsy studies have revealed this incidence increases as high as 50% with age [9]. Kocher s, developed the technique of thyroidectomy into a safe operation, and a new attempt came to improve the outcome of this procedure began 90 years later [0]. Several studies showed that MIVAT has some advantages over conventional thyroidectomy in terms of the cosmetic results and postoperative pain. However, the MIVAT may require special instruments that result in higher costs, and therefore patients should be consulted regarding this factor. This is the most comprehensive systematic review comparing MIVAT to the open conventional surgery in patients with small thyroid nodules. Nine studies were identified, all claiming to be RCTs; one of the nine studies was of level A quality, the rests were level B. The results showed that the MIVAT was of similar efficacy with the conventional open surgery. Though overall postoperative complications between the two procedures were comparable, the MIVAT harbored a lower incidence (OR = 0.6), indicating a superiority in safety of clinical significance. No difference was detected in transient recurrent nerve palsy. Mechanical factors (stretching and pinching), postoperative edema, inflammation and the use of diathermy, always lead to transient recurrent laryngeal nerve palsy []. Endoscopic magnification allows for the clear visualization of the nerves and vessels, and the relationship between the recurrent laryngeal nerve and the cricothyroid membrane can be easily distinguished. Sewing the ligament of Berry under the endoscopic magnification can be done without injuring the nerves. MIVAT had a much better cosmetic result and smaller incision length, which was also one of its most obvious advantages; most of the patients could accept a.5-cm scar rather than a scar that measures not less than 5 cm for a thyroidectomy. Moreover, cosmetic evaluation is done by patients after the operation for short term and the improvement in the patients satisfaction with this minimally invasive approach tends to increase with time []. A less painful postoperative course was also documented for MIVAT, especially in the early period. The smaller skin incision, the absence of neck hyperextension, avoidance of transecting the strap muscles, and avoidance of traction over the trachea all contribute to this finding. A longer operative time was required in MIVAT because the minimally invasive approach to the thyroid may increase the complexity of the operation. In addition, the learning curve also plays an important role. The operative time of MIVAT could decrease significantly to the level of conventional surgery as the surgeon gains experience in performing this technique. Patients that underwent open surgery were at higher risk of postoperative complications, and the overall rate was.6 times that of MIVAT. Though no statistical difference was detected in postoperative hypoparathyroidism between the two groups, the rate of hypoparathyroidism was still. times higher in patients that underwent MIVAT than that of open surgery, which may be explained by the better exposure in the conventional process leading to better protection of bilateral parathyroid glands. Despite the superiority of MIVAT over open surgery in many technically aspects, another important factor needing considered was cost. This novel procedure may require higher cost both to the patients and insurance company, but none of the included studies discussed this subject and no conclusion can be drawn. This analysis demonstrated that endoscopic thyroidectomy is a feasible, practical, and safe procedure with better cosmetic benefits, which can be performed with ease of manipulation, similar to conventional neck surgery. It is believed that endoscopic thyroidectomy would become

9 widely used as a surgical procedure for treating small thyroid nodules. However, the result should be interpreted with caution because: () most studies included were of moderate quality; () the follow-up in all studies were of relative periods, long-term postoperative results were not observed; () all included studies were performed in a single medical center and the study populations were small, a selective bias was possible; (4) most studies were done in Western countries and included populations of Caucasians, and Asian people were not well analyzed. Ethnic differences should be considered; (5) the total cost for the novel procedure was not addressed in all studies, the cost must be taken into consideration when expanding this technique, especially in developing countries. Conflict of interest None of the authors obtained any financial support of any organizations or any companies regarding this research. References. Huscher CS, Recher A, Napolitano G, Chiodini S. 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