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Minimally Invasive Versus Open Adrenalectomy in Patients with Adrenocortical Carcinoma: A Meta-analysis
Xu Hu, MD1, Wei-Xiao Yang, MM1, Yan-Xiang Shao, MD1, Wei-Chao Dou, MD1, San-Chao Xiong, MM1, and Xiang Li, MD2
1West China School of Medicine/West China Hospital, Sichuan University, Chengdu, People’s Republic of China;
2Department of Urology, West China Hospital, West China Medical School, Sichuan University, Chengdu, People’s Republic of China
ABSTRACT
Background. Open surgery remains the preferred surgical treatment of adrenocortical carcinoma (ACC), while the role of minimally invasive adrenalectomy surgery (MIS) in ACC is still controversial. The present study was conducted to compare MIS with open adrenalectomy (OA) in ACC. Methods. The Embase, PubMed, and Cochrane Library databases were comprehensively searched. The weighted mean difference (WMD), relative risk (RR), and hazard ratio (HR) were pooled.
Results. A total of 15 studies incorporating 2207 patients were included in the present study. MIS approaches were likely to have a comparable operation time (WMD - 17.77; p = 0.150) and postoperative complications (RR 0.74; p = 0.091) compared with OA, and were significantly associated with less blood loss (WMD - 1761.96; p = 0.016) and shorter length of stay (WMD - 2.96; p < 0.001). MIS approaches were also more likely to have an earlier recurrence (WMD - 8.42; p = 0.048) and more positive surgical margin (RR 1.56; p = 0.018) and peri- toneal recurrence (RR 2.63; p < 0.001), while the overall recurrence (RR 1.07; p = 0.559) and local recurrence (RR 1.33; p = 0.160) were comparable between the two groups. Furthermore, surgical approaches did not differ in
overall survival (HR 0.97; p = 0.801), cancer-specific survival (HR 1.04; p = 0.869), and recurrence/disease-free survival (HR 0.96; p = 0.791).
Conclusions. In the present study, MIS approaches were likely to have a better recovery. Although MIS approaches were associated with earlier recurrence and more positive surgical margin and peritoneal recurrence, no significant differences in survival outcomes were found. OA should still be considered as the standard treatment, but MIS approaches could be offered for selected ACC cases, and performed by surgeons with appropriate laparoscopic expertise, ensuring an improved survival for patients.
Adrenocortical carcinoma (ACC) is a rare but aggres- sive malignancy, with an incidence of two patients per million per year, accounting for 0.2% of cancer-caused deaths.1 The prognosis of ACC is poor, with a high rate of recurrence. Reportedly, the 5-year survival rate of patients with stage I-II disease is approximately 60%,2 while for stages III and IV disease, the 5-year survival rates are 40% and 28%, respectively. In light of evidence showing that chemotherapy and radiation are not effective in most ACC cases, operative resection with a complete oncology resection remains the most important component in cura- tive intent therapy.3,4
Open adrenalectomy (OA) has traditionally been rec- ommended because of the large size of ACCs and a tendency for local invasion, allowing for a large, complete oncology resection.5,6 Laparoscopic adrenalectomy (LA) was first described in 1992 and has since been adopted as the preferred treatment for benign adrenal masses.7 LA has been shown to have less perioperative complications and better postoperative recovery compared with OA.8
Xu Hu, Wei-Xiao Yang and Yan-Xiang Shao have contributed equally to this article.
@ Society of Surgical Oncology 2020
First Received: 26 December 2019
X. Li, MD e-mail: hx_uro@sina.com
Recently, the robotic approach has also been introduced for adrenal surgery.9 The increasing experience in minimally invasive adrenalectomy surgery (MIS) and the excellent oncologic outcomes of MIS have led to increased enthu- siasm for MIS for large and potentially malignant adrenal tumors.2,10-14 However, some studies found that MIS approaches are more likely to have a higher rate of recur- rence and positive surgical margin (PSM); 15,16 therefore, we conducted the present study to compare MIS with OA in patients with ACC in terms of safety and efficacy.
METHODS
Literature Search Strategy
The present study was conducted following the Pre- ferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement.17 We comprehensively searched the Embase, PubMed, and Cochrane Library databases from the earliest date available through November 2019, using the following keywords or Medical Subject Heading (MeSH) terms: adrenocortical carcinoma (ACC) and adrenalectomy (open, laparoscopic, robot). References from the retrieved studies were also manually screened in case of missing data. The citation search was independently conducted by two investigators.
Study Selection Criteria
The studies were independently reviewed by two authors and any discrepancies were resolved by discussion and consensus. Studies were included based on the fol- lowing criteria: (1) population-based study; (2) only involved patients with ACC; (3) compared MIS approaches (laparoscopic or robot) with OA; (4) reported relevant clinical outcomes; and (5) included sufficient data for analyses. We excluded studies with the following criteria: (1) non-English language; (2) patients with other adrenal diseases; (3) did not compare MIS with OA; (4) insufficient data for analyses; and (5) were review or conference abstracts. For duplicated records, we extracted the data from the latest report.
Data Extraction and Study Quality Assessment
We extracted the following relevant information from each eligible study: surname of the first author, published year, enrollment data and location, disease, treatment, number, age and follow-up duration of patients, outcomes data for analysis. For observational studies, we used the Newcastle-Ottawa Quality Assessment Scale (NOS) to assess quality. The NOS tool consists of three key domains,
including selection, comparability, and exposure/outcome. The studies with a score of no less than 7 were regarded as high quality.
Statistical Analysis
For continuous variables, such as operation time and hospital study, we used the weighted mean difference (WMD) and 95% confidence interval (CI), while dichoto- mous variables, such as postoperative complications and incidence of recurrence, were characterized by relative risk (RR) and 95% CI. For oncologic outcomes, including overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and disease-free survival (DFS), hazard ratio (HR) and 95% CI were applied.18 We identified heterogeneity among studies by calculating the Q and 12 statistics. If p < 0.10 or 12 > 50%, we used the random-effects model, otherwise the fixed-effects model was used.19 Furthermore, we performed sensitivity analysis to identify the stability of the results. To evaluate publi- cation bias among the included studies, we conducted the Egger’s test and Begg’s test. If publication bias existed, we used the trim and fill method to estimate the number of missing studies.2º All statistical analyses were carried out using STATA version 12 (StataCorp LLC, College Station, TX, USA). A two-sided p value < 0.05 was considered statistically significant.
RESULTS
Search Results
The initial search yielded 514 records. After removing 96 duplicate records, the remaining 418 records were browsed based on titles and abstracts, resulting in further screening of 55 full-text records. The present study even- tually included 15 studies incorporating 2207 patients.2,4, 5,12-16, 21-27 A study selection flowchart is presented in Fig. 1.
Clinical Characteristics of the Included Studies
Of the 15 included studies, all were retrospective stud- ies. A total of 2207 patients from China, the USA, Norway, France, Italy, and Germany were included in the present study, of whom 695 patients were treated with MIS approaches and 1512 patients were treated with OA. Of the included studies, staging was performed based on the American Joint Committee on Cancer (AJCC) or European Network for the Study of Adrenal Tumors (ENSAT) pathologic stage.2,5 Four studies involved stage I-II ACC, five studies involved patients with stage I-III disease, and
Identification
Identified studies through database search (N=514)
Excluded duplicate articles (n=96)
Screening
418 articles remained after duplicates removed
Excluded based on titles and abstracts (n=363)
55 articles were accepted for further review
Eligibility
Involve other adrenal diseases (n=18) Did not compare between two groups (n=9) No available data for analysis (n=6) Other exclusion(n=7)
Included
15 articles were enrolled in the final analysis
the remaining studies included patients with stage I-IV disease. The MIS group had a higher proportion of local- ized stage (I-II) tumor (RR 1.27, 95% CI 1.17-1.38; p = 0.067). Three studies compared MIS approaches with OA, while the remaining studies compared LA with OA. The median age of the included patients ranged from 41 to 61 years. Furthermore, there were no significant differ- ences in patients’ age between the two groups (WMD 1.75, 95% CI - 0.39 to 3.88; p = 0.108), and patients treated with OA were likely to have a larger tumor (WMD 4.12, 95% CI 2.85-5.39; p < 0.001). The proportion of males was similar between OA and MIS (RR 0.91, 95% CI 0.81-1.03; p = 0.147). Seven studies reported the function
of ACC; functional tumors were comparable between the two groups (RR 0.89, 95% CI 0.59-1.35; p = 0.589).2,12-14,21-23 Ten studies reported the adjuvant therapy mitotane was the most used therapy, and the pro- portion of adjuvant therapy was similar (RR 0.97, 95% CI 0.78-1.22; p = 0.820). Regarding the study quality, all included studies were considered high quality. Detailed study information is summarized in Table 1.
Perioperative Outcomes
Regarding operation time, six studies reported relevant information. No statistical differences in operation time
| Study, year published | Enrollment date, location | Study type | Diseases | Treatment | No. of patients | Age, years (mean ± SD, unless otherwise stated) | Adjuvant therapy | Follow-up, months | Nos |
|---|---|---|---|---|---|---|---|---|---|
| Zheng et al., | April 2003-July 2015, | Retrospective | Stage I-III | LA | 20 | 45.2 ± 10.9 | 0 | Maximum 3 years | 7 |
| 201821 | China | ACC | OA | 22 | 48.5 ± 14.1 | 0 | |||
| Wu et al., 201814 | January 2009-September | Retrospective | Stage I-II | LA | 21 | 44.9 ± 16.2 | 2 | Mean 34 ± SD 25 | 7 |
| 2017, China | ACC | OA | 23 | 45.6 ± 14.5 | 4 | ||||
| Calcatera et al., | 2010-2014, USA | Retrospective | Stage I-IV | MIS | 200 | 55 ± 14 | NR | NR | 7 |
| 20185 | ACC | OA | 388 | 53 ± 15 | |||||
| Maurice et al., 201716 | 2010-2013, USA | Retrospective | Stage I-IV ACC | MIS | 161 | Median 61 (IQR 50-69) | NR | Median 23.6 (IQR 14.6-33.8) | 8 |
| OA | 320 | Median 56 (IQR 43-67) | Median 25.0 (IQR 16.7-36.4) | ||||||
| Lee et al., 201722 | 1994-2014, USA | Retrospective | Stage I-IV | MIS | 47 | Median 53 (range 23-85) | 9 | 5 years | 7 |
| ACC | OA | 154 | Median 51 (range 11-87) | 28 | |||||
| Donatini et al., 201412 | 1985-2011, France | Retrospective | Stage I-II ACC | LA | 13 | 46 ± 14 | Mitotane 8 | Median 80 (range 1-130) | 8 |
| OA | 21 | 44 ± 19 | 15 | Median 57 (range 0-132) | |||||
| Mir et al., 20134 | 1993-2011, USA | Retrospective | Stage I-IV ACC | LA | 18 | Median 53 (range 45-61) | Mitotane 9 | Median 18 (range 15-21) | 8 |
| OA | 26 | Median 48 (range 42-54) | 9 | Median 31 (range 28-35) | |||||
| Fossa et al., | January 1998-December | Retrospective | Stage I-III | LA | 17 | Median 45 (range 29-75) | Mitotane 0 | Median 29.1 (range | 8 |
| 201323 | 2011, Norway | ACC | OA | 15 | Median 52 (range 38-71) | 2 | 11-104) | ||
| Cooper et al., | 1 April 1993-1 May 2012, | Retrospective | Stage I-IV | LA | 46 | Median 45.8 (range 18.4-74.0) | Mitotane 16 | Median 34.4 | 8 |
| 201324 | USA | ACC | OA | 46 | Median 53.4 (range 20.0-86.6) | 17 | |||
| Miller et al., 201215 | 2005-2011, USA | Retrospective | Stage I-III ACC | LA | 46 | Median 50 (range 20-80) | NR | Median 19 (range 1.11-145.9) | 8 |
| OA | 110 | Median 47 (range 18-75) | Median 29.5 (range 0.9-188.5) | ||||||
| Lombardi et al., | December 2003-July 2010, | Retrospective | Stage I-II | LA | 30 | 52.0 ± 17.0 | 9 | Mean 46.6 ± SD 15.1 | 8 |
| 20122 | Italy | ACC | OA | 126 | 46.6 ± 15.1 | 41 | Mean 40 ± SD 34 | ||
| Porpiglia et al., 201013 | January 2002-June 2008, Italy | Retrospective | Stage I-II ACC | LA | 18 | Median 47 (range 28-69) | Mitotane 12 | Median 30 (range 12-54) | 8 |
| OA | 25 | Median 41.3 (range 24-68) | 15 | Median 38 (range 11-72) | |||||
| Miller et al., | July 2003-August 2008, | Retrospective | Stage I-III | LA | 17 | Median 48.2 (range 20-68) | NR | Mean 36.5 ± SD 43.6 | 7 |
| 201025 | USA | ACC | OA | 71 | Median 45.9 (range 18-81) | ||||
| Retrospective | LA | 6 | Median 54 (range 23-79) | NR | 7 |
MIS Versus Open Adrenalectomy in ACC
| Nos months | 8 (range (range | (range | NOS Newcastle- | between MIS approaches and OA were observed (WMD - 17.77, 95% CI - 41.94 to 6.40; p = 0.150, I2 = 85.2%) (Fig. 2a). Regarding estimated blood loss (EBL, mL), MIS approaches were significantly associated with less blood loss compared with OA (WMD - 1761.96, 95% CI |
| Follow-up, | Median 64 Median 35 1-372) 22-109) 27 8 | Median 32 6-131) 11 1 | standard deviation, | - 3198.55 to - 325.37; p = 0.016, I2 = 98.9%) (Fig. 2b). Furthermore, there was a significantly shorter length of hospital stay (LOS) in MIS approaches when compared with OA (WMD - 2.96, 95% CI - 3.65 to - 2.28; p < 0.001, 1 = 58.3%) (Fig. 2c). Seven studies revealed |
| Adjuvant therapy | versus Mitotane | versus Irradiation | range, SD | postoperative complications; the incidence of postopera- tive complications of MIS approaches and OA were 19.4% (31/160) and 21.8% (81/372), respectively, which did not |
| ± SD, unless | 23-78) | 20-87) | IQR interquartile | reach a significant difference (RR 0.74, 95% CI 0.53-1.05; p = 0.091, I2 = 0.0%) (Fig. 2d). Furthermore, four studies graded complications based on the Clavien-Dindo classi- fication.28 There were no significant differences in major complications (grades 3-5) between the two groups (RR |
| 0.44, 95% CI 0.19-1.02; p = 0.055, 12 = 0.0%). | ||||
| (mean stated) | (range | (range | surgery, | |
| Oncologic Outcomes | ||||
| years | 50.7 | 52.3 | ||
| Age, otherwise | Mean | Mean | invasive | With regard to the overall recurrence rates, there were |
| of patients | minimally | no significant differences between MIS approaches and OA (RR 1.07, 95% CI 0.85-1.36; p = 0.559, 12 = 72.3%) (Fig. 3a). Similarly, there were no significant differences | ||
| No. | 58 35 | 117 | MIS | in local recurrence rates between the two groups (RR 1.33, 95% CI 0.89-1.99; p = 0.160, 12 = 0.0%) (Fig. 3b), while |
| Treatment Diseases | OA LA ACC ACC Stage I-III Stage I-IV | OA | laparoscopic adrenalectomy, | MIS approaches were significantly associated with more peritoneal recurrence (RR 2.63, 95% CI 1.66-4.15; p < 0.001, 12 = 0.0%) (Fig. 3c). Regarding the time to recurrence/progression, MIS approaches were associated with shorter time to recurrence/progression (WMD - 8.42, 95% CI - 16.77 to - 0.07; p = 0.048, I2 = 94.6%) (Fig. 3d). In terms of PSM, 10 studies reported the inci- dence of PSM; patients treated with MIS approaches had a |
| Study type | Retrospective | adrenalectomy, LA reported | significantly higher incidence of PSM compared with patients treated with OA (23.6% [94/399] vs. 16.5% [153/ 927]; RR 1.56, 95% CI 1.08-2.24; p = 0.018, 12 = 47.0%) (Fig. 4a). For OS, no significant differences between the two groups were observed (HR 0.97, 95% CI 0.79-1.20; | |
| location | Germany 2003-April | open NR not | p = 0.801, I2 = 0.0%) (Fig. 4b). Similarly, CSS was comparable between the two groups (HR 1.04, 95% CI | |
| date, | France | OA Scale, | 0.66-1.63; p = 0.869, 1 = 0.0%) (Fig. 4c). Furthermore, | |
| MIS approaches had a comparable RFS/DFS compared | ||||
| 2009, | with OA (HR 0.96, 95% CI 0.74-1.26; p = 0.791, I2 = 26.4%) (Fig. 4d). | |||
| Enrollment | 1996-2009, November | carcinoma, Assessment | ||
| et al., | adrenocortical Quality | Sensitivity Analysis and Publication Bias | ||
| year | et al., | Sensitivity analysis was carried out by excluding each | ||
| Study, published | Leboulleux 201027 201026 Brix | ACC Ottawa | study in sequence to evaluate the stability of the final results. Sensitivity analysis was performed for LOS, |
A
B
Study
%
Study
%
ID
WMD (95% CI)
Weight
ID
WMD (95% CI)
Weight
Zheng 2018
-44.75 (-52.92, -36.58)
22.52
Wu 2018
8.00 (-19.35, 35.35)
17.84
Zheng 2018
-621.25 (-738.38, -504.12)
26.38
Lee 2017
-12.50 (-65.38, 40.38)
10.97
Lee 2017
-3781.25 (-4185.58, -3376.92)
25.88
Mir 2013
24.73 (-15.94, 65.40)
13.97
Mir 2013
78.25 (-192.44, 348.94)
26.18
Fossa 2013
-62.75 (-105.52, -19.98)
13.41
Fossa 2013
-2967.50 (-4293.91, -1641.09)
21.57
Lombardi 2012
-13.10 (-27.80, 1.60)
21.29
Overall (I-squared = 98.9%, p = 0.000)
:
-1761.96 (-3198.55, -325.37)
100.00
Overall (I-squared = 85.2%, p = 0.000)
-17.77 (-41.94, 6.40)
100.00
NOTE: Weights are from random effects analysis
NOTE: Weights are from random effects analysis
-106
0
106
-4294
0
4294
C
D
Study
%
Study
%
ID
WMD (95% CI)
Weight
ID
RR (95% CI)
Weight
Zheng 2018
-2.63 (-3.24, -2.01)
23.68
Zheng 2018
0.77 (0.36, 1.63)
18.39
Wu 2018
-23 (-4.15, -0.46)
9.39
Wu 2018
0.55 (0.05, 5.61)
3.69
Maurice 2017
-2.78 (-3.25, -2.31)
25.69
-6.75 (-9.13, -4.37)
Lee 2017
0.95 (0.55, 1.62)
37.83
Lee 2017
6.47
Donatini 2014
-2.00 (-5.74. 1.74)
3.02
Donatini 2014
0.54 (0.06, 4.65)
4.43
Mir 2013
-2.00 (-2.95, -1.05)
18.78
Mir 2013
0.29 (0.04, 2.27)
7.90
Fossa 2013
-4.75 (-8.83, -0.67)
2.58
Fossa 2013
0.64 (0.36, 1.16)
22.57
Lombardi 2012
-4.00 (-5.71, -2.29)
10.38
Lombardi 2012
0.60 (0.08, 4.69)
5.20
Overall (I-squared = 58.3%, p = 0.019)
-2.96 (-3.65, -2.28)
100.00
Overall (I-squared = 0.0%, p = 0.917)
0.74 (0.53, 1.05)
100.00
NOTE: Weights are from random effects analysis
-9.13
0
9.13
.0368
1
27.2
overall recurrence rates, PSM, and RFS/DFS, and no big differences were observed (Fig. 5). Due to the small number of included studies, publication bias was only evaluated for PSM and overall recurrence rates. There was no evidence of publication bias based on the Begg’s test (PSM: p = 0.466; overall recurrence: p = 0.640) and Egger’s test (PSM: p = 0.355; overall recurrence: p = 0.292).
Subgroup Analysis
Subgroup analyses were conducted for overall recur- rence rates and RFS/DFS based on region, number of patients, and stages. Regarding the overall recurrence rates, no significant differences were found between MIS approaches and OA in each subgroup, which is consistent with previous results. Similarly, in most subgroups, MIS approaches were not associated with worse RFS/DFS compared with OA. In the American region and stage I-IV subgroups, MIS approaches were more likely to have a worse RFS/DFS [HR 2.11 (p = 0.028) and 2.11 (p = 0.028), respectively]. Detailed data are presented in Table 2.
DISCUSSION
ACC is a rare but aggressive malignancy with a high rate of recurrence. Given that ACC had few effective treatments, complete resection with negative margins and an intact adrenal capsule is necessary for curative intent.3,4 Considering the fragility of ACC, it is imperative for sur- geons to choose an appropriate approach that provides adequate exposure and access to the surrounding tissues and structures. 29
In the present study, we found that MIS had a shorter operation time and less postoperative complications, but did not reach a significant difference. Furthermore, MIS was significantly associated with shorter LOS and less EBL compared with OA, suggesting a better postoperative recovery; however, MIS approaches were more likely to have PSM. We found that the incidences of overall and local recurrence were comparable between the two groups, while MIS approaches had a higher incidence of peritoneal recurrence and a shorter time to recurrence/progression. In terms of oncologic outcomes, we did not detect a signifi- cant discrepancy in OS, CSS, and RFS/DFS between MIS approaches and OA. Furthermore, we performed sensitivity analysis for LOS, overall recurrence rates, PSM, and RFS/
DFS, and did not observe any big differences, suggesting the robustness of our results. Additionally, no evidence of publication bias was revealed.
Historically, open surgery was the gold standard for clinically suspected ACC. The advantages of minimally invasive adrenal surgery are clear, including less blood loss, shorter recovery time, and reduced pain after surgery.” 7 In the present study, we found that MIS approaches had favorable perioperative outcomes, including less EBL, shorter LOS, and comparable operation time and postop- erative complications. Some studies also did not find a significant difference in operation time between groups, consistent with our findings.4,14 Furthermore, some studies found that MIS approaches are more likely to have a shorter operation time,21,23 but most studies were retro- spective with small sample sizes, and selection bias may exist. Furthermore, we could not assess the learning curve impact, which means that the different experiences of different surgeons and assistants could have an effect on the operation time. There was significantly less EBL in the MIS approaches. In the open cases, EBL was probably
more extensive, requiring the removal of adjacent organs, which in turn may result in more blood loss. However, only a few studies with few patients reported EBL, and larger series are needed to yield more evidence. LOS was clearly in favor of MIS approaches, which are well known, and two large cohorts also observed that MIS approaches had a shorter LOS.16,22,30 LOS after surgery is a function of recovery of both extirpative and reconstructive parts of the operation. Small incision, absence of traction of the abdominal wall, and reduced pain may be a benefit for recovery and hence reduce the LOS. Nonetheless, we did not detect a difference in postoperative complications between the two groups. The low incidence of postopera- tive complications may lead to an insignificant difference. Other potential explanations for this finding may be asso- ciated with the inherent risk for complete resection or the absence of anastomoses that leads to surgical complica- tions in relation to other tumors.22 More large series are necessary to verify the results.
A
B
Study
%
Study
ID
RR (95% CI)
%
Weight
ID
RR (95% CI)
Weight
Zheng 2018
0.93 (0.55, 1.58)
8.28
Wu 2018
1.00 (0.57, 1.77)
7.79
Zheng 2018
1.76 (0.69, 4.50)
15.71
Donatini 2014
1.29 (0.42, 3.95) 3.35
Mir 2013
1.20 (0.67, 2.16)
7.54
Wu 2018
1.39 (0.65, 2.98)
23.58
Fossa 2013
0.72 (0.52, 0.99)
11.29
Donatini 2014
0.81 (0.08, 8.05)
5.04
Cooper 2013
1.30 (0.97, 1.74)
11.69
Fossa 2013
€
0.88 (0.06, 12.91)
3.50
Miller 2012
2.12 (1.64, 2.75)
12.14
Lombardi 2012
0.70 (0.37, 1.32)
6.98
Lombardi 2012
1.20 (0.43, 3.39)
17.76
Porpiglia 2010
0.78 (0.45, 1.35)
8.02
Porpiglia 2010
1.39 (0.53, 3.61)
16.57
Miller 2010
1.00 (0.68, 1.48)
10.21
Miller 2010
1.19 (0.45, 3.17)
17.84
Brix 2010
1.11 (0.90, 1.38)
12.71
Overall (I-squared = 0.0%, p = 0.994)
H
1.33 (0.89, 1.99)
100.00
Overall (I-squared = 72.3%, p = 0.000)
1.07 (0.85, 1.36)
100.00
NOTE: Weights are from random effect analysis
.253
1
3.95
.0603
1
16.6
C
D
Study
%
Study
%
ID
RR (95% CI)
Weight
ID
WMD (95% CI)
Weight
Wu 2018
5.48 (0.70, 43.14)
5.43
Zheng 2018
-27.30 (-42.66, -11.94)
11.90
Fossa 2013
4.44 (0.23, 85.83)
3.01
Wu 2018
3.00 (-10.59, 16.59)
13.04
Cooper 2013
2.78 (1.46, 5.28)
51.19
Donatini 2014
-1.00 (-25.89, 23.89)
7.19
Miller 2010
1.57 (0.46, 5.29)
17.58
Mir 2013
-4.13 (-6.66, -1.59)
19.57
Leboulleux 2010
3.33 (1.54, 7.23)
12.31
Miller 2012
-17.80 (-18.95, -16.65)
19.85
Brix 2010
0.84 (0.10, 7.24)
10.48
Lombardi 2012
2.00 (-10.71, 14.71)
13.63
Porpiglia 2010
(Excluded)
0.00
Miller 2010
-9.60 (-20.57, 1.37)
14.82
Overall (I-squared = 0.0%, p = 0.734)
!
2.63 (1.66, 4.15)
100.00
Overall (I-squared = 94.6%, p = 0.000)
-8.42 (-16.77, -0.07)
100.00
NOTE: Weights are from random effect analysis
.0117
1
85.8
-42.7
0
42.7
A
B
Study
%
Study
%
ID
RR (95% CI)
Weight
ID
HR (95% CI)
Weight
Maurice 2017
1.99 (1.26, 3.12)
18.83
Wu 2018
0.82 (0.37, 1.83)
6.72
Lee 2017
0.98 (0.56, 1.73)
16.15
Calcatera 2018
0.99 (0.68, 1.43)
31.06
Mir 2013
1.01 (0.47, 2.15)
12.42
26.10
Fossa 2013
1.47 (0.42, 5.14)
Maurice 2017
1.20 (0.80, 1.80)
6.47
3.25 (1.14, 9.23)
Lee 2017
0.47 (0.13, 1.66)
2.65
Cooper 2013
8.40
Miller 2012
1.86 (1.01, 3.42)
Mir 2013
2.00 (0.83, 5.00)
15.28
5.32
Miller 2010
3.13 (1.58, 6.20)
13.76
Fossa 2013
0.58 (0.24, 1.39) 5.56
Brix 2010
0.51 (0.12, 2.17)
5.20
Lombardi 2012
0.92 (0.52, 1.62)
13.29
Leboulleux 2010
0.46 (0.07, 2.85)
3.51
Porpiglia 2010
0.48 (0.12, 1.93)
2.22
Donatini 2014
(Excluded)
0.00
Brix 2010
0.79 (0.36, 1.71)
7.07
Overall (I-squared = 47.0%, p = 0.057)
1.56 (1.08, 2.24)
100.00
Overall (I-squared = 0.0%, p = 0.472)
0.97 (0.79, 1.20)
100.00
NOTE: Weights are from random effects analysis
.745
1
13.4
.12
1
8.33
C
D
Study
Study
%
%
ID
HR (95% CI)
Weight
ID
HR (95% CI)
Weight
Zheng 2018
1.33 (0.46, 3.85)
6.18
Wu 2018
0.91 (0.43, 1.91)
12.54
Wu 2018
0.82 (0.31, 2.18)
21.19
Lee 2017
1.72 (0.64, 4.63)
7.12
Donatini 2014
1.49 (0.29, 7.74)
7.47
Donatini 2014
1.03 (0.27, 3.97)
3.86
Mir 2013
2.50 (0.83, 5.00) 8.65
Mir 2013
1.40 (0.68, 2.91)
38.14
Fossa 2013
0.48 (0.23, 1.02)
12.57
Brix 2010
0.79 (0.36, 1.71)
Lombardi 2012
0.78 (0.44, 1.37)
33.20
21.61
Porpiglia 2010
0.57 (0.18, 1.80)
5.26
Overall (I-squared = 0.0%, p = 0.675)
1.04 (0.66, 1.63)
100.00
Brix 2010
1.07 (0.61, 1.87)
22.22
Overall (I-squared = 26.4%, p = 0.210)
0.96 (0.74, 1.26)
100.00
.129
1
7.74
.18
1
5.56
Regarding pathological outcome, we revealed that MIS approaches were associated with a higher incidence of PSM. Cooper et al. also found LA had a higher percentage of margin-positive resection than OA (28.3% vs. 8.7%; p = 0.01),24 while Autorino et al. did not detect a differ- ence in the rate of negative surgical margins (61.9% for LA, 57.6% for OA; p = 0.98).31 Maurice et al. included 527 participants and conducted a multivariable analysis, adjusting for covariates. Their findings indicated that MIS was associated with a twofold risk of PSM (odds ratio [OR] 2.0, 95% CI 1.1-3.6; p = 0.03).16 Furthermore, they found T3 stage accounted for the only significant difference in PSM rates between approaches, with MIS associated with a 22% higher rate of PSM for T3 disease than OA. It may be explained that both approaches could have a satisfactory complete resection in the localized stage (pT1-pT2), which is consistent with a previous report,12 whereas in the pT4 stage, both approaches may not resect the tumor com- pletely due to invasion of the adjacent organs. The higher incidence of PSM in the T3 stage of MIS may be due to several factors, such as incorrect preoperative diagnosis or
pathological upstaging;16 therefore, the different stages of the included studies may result in heterogeneity and may affect the final results. Further large-scale studies are required.
Although there was a higher incidence of PSM in the MIS approaches, we did not detect a significant difference in overall and local recurrence rates between the two groups. However, we found that MIS approaches were significantly associated with more peritoneal recurrence and earlier recurrence/progression compared with OA. Wu et al. included localized ACC (stage I-II) and found the incidence of overall recurrence, local recurrence, peritoneal recurrence, and time to recurrence were comparable between the two groups.14 Porpiglia et al. also revealed that no differences in terms of the pattern of recurrences were recorded in 43 patients with stage I-II ACC.13 Further- more, the median RFS was comparable between OA and LA (18 months vs. 23 months; p = 0.8), which is different from our results. Miller et al. observed a significantly shorter time to recurrence in the LA groups (p < 0.005), while overall, local, and peritoneal recurrence were similar
A
Meta-analysis estimates, given named study is omitted
B
Meta-analysis estimates, given named study is omitted
L ower CI Limit
oEstimate
Upper CI Limit
Lower CI Limit
o Estimate
Upper CI Limit
Zheng 2018
Zheng 2018
Wu 2018
Wu 2018
Donatini 2014
Maurice 2017
Mir 2013
Lee 2017
Fossa 2013
Cooper 2013
Donatini 2014
Miller 2012
Mir 2013
Lombardi 2012
Porpiglia 2010
Fossa 2013
Miller 2010
Lombardi 2012
Brix 2010
-4.20
-3.65
-2.96
-2.28-2.12
0.80 0.85
1.07
1.36
1.43
C
D
Meta-analysis estimates, given named study is omitted
Meta-analysis estimates, given named study is omitted
L ower CI Limit
Estimate
Upper CI Limit
L ower CI Limit
o Estimate
Upper CI Limit
Zheng 2018
Maurice 2017
Wu 2018
Lee 2017
Donatini 2014
Lee 2017
Mir 2013
Donatini 2014
Fossa 2013
Mir 2013
Cooper 2013
Fossa 2013
Miller 2012
Lombardi 2012
Miller 2010
Brix 2010
Porpiglia 2010
Leboulleux 2010
Brix 2010
0.94
1.08
1.56
2.24
2.51
0.67
0.74
0.96
1.26
1.41
(p = 0.22).25 Leboulleux et al. found that type of surgery was associated with the occurrence of peritoneal recurrence through the log-rank test (p = 0.016).26 Furthermore, Zheng et al. observed that the OA group showed a longer mean DFS of 44.8 months than that of the LA group (17.5 months), with a significant statistical difference (p = 0.023).21 We also performed subgroup analysis, when stratified by region, number of patients, and stage; overall recurrence rates were comparable between MIS and OA. The controversial results regarding recurrence rates and time to recurrence could be partially explained by the small number of patients in each study, different duration of follow-up, and others. Moreover, these studies might be confounded by additional factors such as surgical experi- ence and volume of the center. Therefore, studies with a multicentric, large sample size and long follow-up duration are required to validate our findings.
We also evaluated the effect of surgical approaches on time-to-event outcomes, including OS, CSS, and RFS/DFS, using the estimated HR.18 We found that oncologic out- comes in terms of OS, CSS, and RFS/DFS were comparable between MIS approaches and OA. In the
subgroup analysis of RFS/DFS, we found there were also no significant differences between MIS approaches and OA in most subgroups. Time-to-event outcomes take both event and time into consideration and reflect when that event occurred. Moreover, the HR provided significantly larger treatment effect estimates than the ratio of restricted survival times;32 therefore, these results might be more convincing in relation to the evaluation of oncologic out- comes. Furthermore, a systematic review performed by Langenhuijsen et al. revealed there was no difference in OS (HR 1.12; p = 0.65) and DFS (HR 0.83; p = 0.41).33 Fur- thermore, a multi-institutional study incorporating 201 patients suggested that surgical approach is not the prog- nostic factor for OS and DFS after adjusting for significant factors.22 These researchers found that EBL (p = 0.038) and T stage (p = 0.045) were independent prognostic fac- tors. Additionally, Mir et al. observed that OA was associated with a 60% RR reduction in recurrence (HR 0.4; p = 0.099), and a 50% RR reduction in mortality (HR 0.5; p = 0.122) was associated with a decreased risk of recur- rence, although the differences were not significant.4 In our subgroup analysis, we pooled two studies with stage I-IV
TABLE 2 Subgroup analysis
| Outcome | Variable | No. of studies | Model | RR/HR (95% CI) | p value | I 2 (%) |
|---|---|---|---|---|---|---|
| Overall recurrence | Total | 11 | Random | 1.07 (0.85-1.36) | 0.559 | 72.3 |
| Region | ||||||
| America | 4 | Random | 1.38 (0.96-1.99) | 0.079 | 76 | |
| Europe | 5 | Random | 0.88 (0.68-1.14) | 0.336 | 41.2 | |
| Asia | 2 | Random | 0.96 (0.66-1.42) | 0.853 | 0 | |
| Patients | ||||||
| ≥ 50 | 5 | Random | 1.23 (0.88-1.70) | 0.223 | 81.0 | |
| < 50 | 6 | Random | 0.86 (0.70-1.05) | 0.147 | 0 | |
| Stage | ||||||
| I-II | 4 | Random | 0.86 (0.62-1.18) | 0.349 | 0 | |
| I-III | 5 | Random | 1.11 (0.75-1.65) | 0.602 | 87.2 | |
| I-IV | 2 | Random | 1.28 (0.98-1.66) | 0.066 | 0 | |
| RFS/DFS | Total | 9 | Fixed | 0.96 (0.74-1.26) | 0.791 | 26.4 |
| Region | ||||||
| America | 2 | Fixed | 2.11 (1.09-4.11) | 0.028 | 0 | |
| Europe | 5 | Fixed | 0.78 (0.57-1.09) | 0.144 | 0 | |
| Asia | 2 | Fixed | 1.03 (0.56-1.90) | 0.921 | 0 | |
| Patients | ||||||
| ≥ 50 | 3 | Fixed | 1.00 (0.69-1.45) | 1 | 0 | |
| < 50 | 6 | Fixed | 0.93 (0.64-1.36) | 0.706 | 43.5 | |
| Stage | ||||||
| I-II | 4 | Fixed | 0.80 (0.54-1.20) | 0.289 | 0 | |
| I-III | 3 | Fixed | 0.86 (0.57-1.31) | 0.489 | 44.2 | |
| I-IV | 2 | Fixed | 2.11 (1.09-4.11) | 0.028 | 0 |
RFS recurrence-free survival, DFS disease-free survival, RR relative risk, HR hazard ratio, CI confidence interval
disease in America and found that MIS approaches might have an inferior RFS/DFS. Additionally, Mir et al. sug- gested that patients with suspicious ACC should be considered for OA, while a retrospective analysis of 152 patients with stage I-III ACC with a tumor size ≤ 10 cm showed that LA and OA did not differ in death (p = 0.92) and RFS (p = 0.69), using multivariate analysis.27 These researchers thought that LA undertaken by an experienced expert is not inferior to OA in regard to oncologic out- comes for localized ACC sized ≤ 10 cm. Similarly, Fossa et al. included 32 patients who were identified with ACC stage I-III and found LA seems to have similar long-term oncological outcomes compared with OA in patients with resectable ACC stage I-III.23 In our stage I-III subgroup, we also detected similar oncological outcomes in terms of RFS/DFS between MIS approaches and OA. Porpiglia et al. performed a retrospective analysis of 43 patients with stage I-II ACC and observed a comparable RFS (p = 0.34) based on multivariate analysis.13 Lombardi et al. also revealed that the operative approach does not affect the oncologic outcome of patients with localized ACC.2
Furthermore, a long-term follow-up study also suggested that LA did not compromise the long-term oncological outcome of stage I-II ACC patients with a tumor size ≤ 10 cm.12 An analysis of adrenalectomies indicated that adrenal volume and laparoscopic expertise are of key importance for optimum outcomes for adrenal tumor, which may be of even greater relevance in radical LA for ACC.34 Based on the above-mentioned findings, as well our findings, we found that MIS approaches might have a comparable oncologic outcome compared with OA for patients with localized (stage I-II) or resectable ACC (I-III) if the principle of surgical oncology was respected. However, most studies were retrospective and involved a small number of patients, hence bias may exist. As a result, surgeons should carefully evaluate the condition of the patients and choose the surgical approach conducted in an oncologically appropriate manner to minimize the risk of recurrence and improve survival. Furthermore, more well- conducted studies with a large sample size are required to verify our findings.
Our study is not devoid of limitations. First, we only included 15 studies incorporating 2207 patients, which is a small number and may limit the power of the final results. Next, all studies were retrospective with inherent bias, which may affect our results and partially explain the heterogeneity among studies. As a result, we performed sensitivity and subgroup analyses to further evaluate the stability of the results. Additionally, several factors may have an impact on the results, such as adjuvant therapies, surgical volume, duration of follow-up, and others. Some studies performed multivariate analysis to minimize the effect of other factors; we also performed subgroup anal- ysis based on the available information. Enrolled patients ranged widely, from 1985 to 2017, and equipment and surgical techniques have changed a lot, which may affect patient outcomes. Finally, the reports regarding robotic surgery in ACC are few5,16,21 and more relevant studies are required.
CONCLUSIONS
In the present study, MIS approaches were more likely to have a better recovery. Furthermore, although MIS approaches were associated with a higher incidence of PSM and peritoneal recurrence, as well as earlier recur- rence, we did not detect a significant difference in OS, CSS, and RFS/DFS. OA should still be considered the standard treatment, but MIS approaches could be offered for selected ACC cases and be performed by surgeons with appropriate laparoscopic expertise, ensuring improved survival for patients.
FUNDING This study did not receive any financial support.
DISCLOSURE Xu Hu, Wei-Xiao Yang, Yan-Xiang Shao, Wei- Chao Dou, San-Chao Xiong and Xiang Li declare they have no conflicts of interest.
REFERENCES
1. Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282-326.
2. Lombardi CP, Raffaelli M, De Crea C, et al. Open versus endoscopic adrenalectomy in the treatment of localized (stage I/II) adrenocortical carcinoma: results of a multiinstitutional Italian survey. Surgery. 2012;152(6):1158-64.
3. Tran TB, Liou D, Menon VG, Nissen NN. Surgical management of advanced adrenocortical carcinoma: a 21-year population- based analysis. Am Surg. 2013;79(10):1115-8.
4. Mir MC, Klink JC, Guillotreau J, et al. Comparative outcomes of laparoscopic and open adrenalectomy for adrenocortical carci- noma: single, high-volume center experience. Ann Surg Oncol. 2013;20(5):1456-61.
5. Calcatera NA, Hsiung-Wang C, Suss NR, Winchester DJ, Moo- Young TA, Prinz RA. Minimally invasive adrenalectomy for
adrenocortical carcinoma: five-year trends and predictors of conversion. World J Surg. 2018;42(2):473-81.
6. Grubbs EG, Callender GG, Xing Y, et al. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol. 2010;17(1):263-70.
7. Gagner M, Lacroix A, Prinz RA, et al. Early experience with laparoscopic approach for adrenalectomy. Surgery. 1993;114(6):1120-4; discussion 1124-5.
8. Elfenbein DM, Scarborough JE, Speicher PJ, Scheri RP. Com- parison of laparoscopic versus open adrenalectomy: results from American College of Surgeons-National Surgery Quality Improvement Project. J Surg Res. 2013;184(1):216-20.
9. Brandao LF, Autorino R, Laydner H, et al. Robotic versus laparoscopic adrenalectomy: a systematic review and meta- analysis. Eur Urol. 2014;65(6):1154-61.
10. Lombardi CP, Raffaelli M, De Crea C, Bellantone R. Role of laparoscopy in the management of adrenal malignancies. J Surg Oncol. 2006;94(2):128-31.
11. Miccoli P, Raffaelli M, Berti P, Materazzi G, Massi M, Bernini G. Adrenal surgery before and after the introduction of laparo- scopic adrenalectomy. Br J Surg. 2002;89(6):779-82.
12. Donatini G, Caiazzo R, Do Cao C, et al. Long-term survival after adrenalectomy for stage I/II adrenocortical carcinoma (ACC): a retrospective comparative cohort study of laparoscopic versus open approach. Ann Surg Oncol. 2014;21(1):284-91.
13. Porpiglia F, Fiori C, Daffara F, et al. Retrospective evaluation of the outcome of open versus laparoscopic adrenalectomy for stage I and II adrenocortical cancer. Eur Urol. 2010;57(5):873-8.
14. Wu K, Liu Z, Liang J, et al. Laparoscopic versus open adrenalectomy for localized (stage 1/2) adrenocortical carcinoma: experience at a single, high-volume center. Surgery. 2018;164(6):1325-9.
15. Miller BS, Gauger PG, Hammer GD, Doherty GM. Resection of adrenocortical carcinoma is less complete and local recurrence occurs sooner and more often after laparoscopic adrenalectomy than after open adrenalectomy. Surgery. 2012;152(6):1150-7.
16. Maurice MJ, Bream MJ, Kim SP, Abouassaly R. Surgical quality of minimally invasive adrenalectomy for adrenocortical carci- noma: a contemporary analysis using the National Cancer Database. BJU Int. 2017;119(3):436-43.
17. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.
18. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Prac- tical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.
19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60.
20. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta- analysis. Biometrics. 2000;56(2):455-63.
21. Zheng GY, Li HZ, Deng JH, Zhang XB, Wu XC. Open adrenalectomy versus laparoscopic adrenalectomy for adreno- cortical carcinoma: a retrospective comparative study on short- term oncologic prognosis. OncoTargets Ther. 2018;11:1625-32.
22. Lee CW, Salem AI, Schneider DF, et al. Minimally invasive resection of adrenocortical carcinoma: a multi-institutional study of 201 patients. J Gastrointest Surg. 2017;21(2):352-62.
23. Fossa A, Rosok BI, Kazaryan AM, et al. Laparoscopic versus open surgery in stage I-III adrenocortical carcinoma-a retro- spective comparison of 32 patients. Acta Oncol. 2013;52(8):1771-7.
24. Cooper AB, Habra MA, Grubbs EG, et al. Does laparoscopic adrenalectomy jeopardize oncologic outcomes for patients with adrenocortical carcinoma? Surg Endosc. 2013;27(11):4026-32.
25. Miller BS, Ammori JB, Gauger PG, Broome JT, Hammer GD, Doherty GM. Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma. World J Surg. 2010;34(6):1380-5.
26. Leboulleux S, Deandreis D, Al Ghuzlan A, et al. Adrenocortical carcinoma: Is the surgical approach a risk factor of peritoneal carcinomatosis? Eur J Endocrinol. 2010;162(6):1147-53.
27. Brix D, Allolio B, Fenske W, et al. Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and onco- logic outcome in 152 patients. Eur Urol. 2010;58(4):609-15.
28. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250(2):187-96.
29. Porpiglia F, Miller BS, Manfredi M, Fiori C, Doherty GM. A debate on laparoscopic versus open adrenalectomy for adreno- cortical carcinoma. Horm Cancer. 2011;2(6):372-7.
30. Jacobs JK, Goldstein RE, Geer RJ. Laparoscopic adrenalectomy. A new standard of care. Ann Surg. 1997;225(5):495-501 (dis- cussion 501-492).
31. Autorino R, Bove P, De Sio M, et al. Open versus laparoscopic adrenalectomy for adrenocortical carcinoma: a meta-analysis of
surgical and oncological outcomes. Ann Surg Oncol. 2016;23(4):1195-202.
32. Trinquart L, Jacot J, Conner SC, Porcher R. Comparison of treatment effects measured by the hazard ratio and by the ratio of restricted mean survival times in oncology randomized controlled trials. J Clin Oncol. 2016;34(15):1813-9.
33. Langenhuijsen J, Birtle A, Klatte T, Porpiglia F, Timsit MO. Surgical management of adrenocortical carcinoma: impact of laparoscopic approach, lymphadenectomy, and surgical volume on outcomes-a systematic review and meta-analysis of the current literature. Eur Urol Focus. 2016;1(3):241-50.
34. Park HS, Roman SA, Sosa JA. Outcomes from 3144 adrenalec- tomies in the United States: which matters more, surgeon volume or specialty? Arch Surg. 2009;144(11):1060-7.
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