ORIGINAL RESEARCH
Laparoscopic versus Open Adrenalectomy for Stage I/II Adrenocortical Carcinoma: Meta-Analysis of Outcomes
George Sgourakis, MD, PhD, FACS,1 Sophocles Lanitis, MD, PhD,1 Andriana Kouloura, MD,1 Paraskevi Zaphiriadou, MD,1 Kyriakos Karkoulias, MD,1 Dimitrios Raptis, MD,1 Athina Anagnostara, MD,2 Constantine Caraliotas, MD, PhDÌ
1 2nd Surgical Department and Surgical Oncology Unit of “Korgialenio - Benakio”, Red Cross Hospital, Athens, Greece 2 Radiology Department of “Korgialenio - Benakio”, Red Cross Hospital, Athens, Greece
ABSTRACT
Aim: The aim of the present meta-analysis was to investigate the safety and oncologic efficacy of laparoscopic adrenalectomy for stage I and II adrenocortical carcinoma. The issue of level I evidence is entirely unreturned. Methods: Electronic databases were used to search for articles from 1992 to 2014 in the English language literature. The primary end point of the study was to evaluate the safety of the laparoscopic procedure in terms of compli- cations and the oncologic effectiveness of the procedure comparing the R0 resection, disease free survival and overall survival of patients treated with open adrenalectomy versus laparoscopic adrenalectomy. Results: Differ- ences in postoperative complications and R0 resections did not reach statistical significance between treatment arms. There were not statistical significant differences between treatment arms considering the two-year, three- year, four-year overall survival while five-year overall survival was in favor of open adrenalectomy group. There were not statistical significant differences between treatment arms considering the two-year, three-year, four-year, and five-year disease free survival. Conclusions: It seems that postoperative complications, R0-resection, overall, and disease free survival of stage I/II adrenocortical carcinoma are comparable and independent to the proce- dure though the five-year survival was in favor of the open group. Further research is likely to have an important impact on our confidence in the estimates of effect and may change the estimates.
Keywords: laparoscopic adrenalectomy; open adrenalectomy; meta-analysis; adrenocortical cancer; stage I and II adrenocortical cancer
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INTRODUCTION
In referral centers, laparoscopic adrenalectomy is now progressively used for bulky adrenal tumors and adrenal secondaries [1]. However, the role of laparo- scopic adrenalectomy remains debatable for the treat- ment of adrenocortical carcinoma, an infrequent but extremely aggressive malignancy [2]. Promising on- cological results after laparoscopic adrenalectomy for adrenocortical carcinoma has been proposed by var- ious studies, reporting only a small series of pa- tients with short-term follow-up [3, 4]. In opposition, many authors have mistrusted the role of laparoscopic adrenalectomy for accomplishing a tumor R0 resec-
tion, which is the requirement for long-term therapy of adrenocortical carcinoma [5].
In the present study, we have tried to address this particularly challenging problem considering only stages I and II of adrenocortical carcinoma according to the following two key issues: (a) complete surgical re- moval is the optimal treatment for patients with stage I and II adrenocortical carcinomas. The long-term sur- vival of patients with functioning and nonfunctioning tumors is equivalent. The removal of regional lymph nodes that are not clinically engorged is not suggested [6] and (b) a statistically significant difference was ob- served between 2008 ENSAT stage II and stage III pa- tients (p < . 001) [7].
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2 G. Sgourakis et al.
Preferably, a large prospective randomized trial, en- rolling more than 100 patients per arm, should be ac- complish to unequivocally endorse the similar onco- logical results of laparoscopic adrenalectomy and open adrenalectomy for adrenocortical carcinoma. Because of the scarcity of the cases, however, this type of study seems questionable and level I evidence is missing [8].
The aim of the present meta-analysis was to investigate the safety and oncologic efficacy of laparo- scopic adrenalectomy for stage I and II adrenocortical carcinoma.
METHODS
Literature Search
All comparative studies concerning overall and disease free survival on stage I and II adrenal cancer were iden- tified [8-11]. In order to identify appropriate studies, the electronic databases Medline, Embase, Pubmed, and the Cochrane Library were used to search for arti- cles from 1992 to 2014 in the English language literature that included the following terms and/or combina- tions in their titles, abstracts or keyword lists: Random- ized controlled trials, comparative studies, adrenal can- cer, laparoscopic adrenalectomy, open adrenalectomy, stage I adrenal carcinoma, stage II adrenal carcinoma. Where it was applicable the above mentioned terms were used in “[MESH]” (Pubmed and the Cochrane Library) otherwise the terms were combined with “AND/OR” and asterisks. Additionally, the abstracts from international conferences were searched using on- line search engines corresponding to the particular con- ference.
After the initial screen additional criteria were im- posed. These were as follows: (a) studies including pa- tients of mixed staging were excluded (b) the analy- sis to be by intention to treat, (c) studies of pediatric patients or both pediatric and adult patients were ex- cluded, and (d) access was exclusively transabdominal for both interventions. The scheme for this repetitive search is shown in the PRISMA flow diagram (Table 1).
Data Extraction
Two authors (G.S., C.K) independently selected stud- ies for inclusion and exclusion and reached consen- sus when they did not agree in the initial assignment. The following variables were recorded: authors, jour- nal and year of publication, trial duration, participant demographics, and data concerning complications, fol- low up and survival.
Interventions and Outcome Definition
Laparoscopic adrenalectomy was carried out by clas- sical approach described by Gagner et al. [12] with
the patient in flank position, using subcostal approach with 3 trocars for left adrenalectomy and 1 more trocar for liver retraction when facing a right adrenalectomy. Open adrenalectomy was carried out by classical mid- line abdominal approach.
Study end Points
The primary end point of the study was to evaluate the safety of the laparoscopic procedure in terms of com- plications and the oncologic effectiveness of the pro- cedure comparing the RO resection, disease free sur- vival and overall survival of patients treated with open adrenalectomy versus laparoscopic adrenalectomy.
Data Analysis
A formal meta-analysis (according to the guidelines of the PRISMA statement [13]) was made for all com- parative studies concerning laparoscopic versus open adrenalectomy for stage I and II tumors.
Yearly cumulating proportion surviving in those studies not given was extracted from the provided Kaplan-Meier curves in each of the included stud- ies after converting graphs to numbers with the Engauge Digitizer software (http://sourceforge.net/ projects/digitizer/postdownload?source=dlp last ac- cessed 31/03/2014).
In order to quantify the level of agreement between reviewers the Maxwell test statistic and the generalized McNemar statistic were calculated. Pooled estimates of outcomes were calculated using the randomized- effects model due to small sample size of the stud- ies and potential heterogeneity. For dichotomous data, results for each trial were expressed as an odds ratio (OR), with 95% confidence intervals (CIs). For each to- tal or subtotal the test for heterogeneity and the test for overall effect were given.
In order to explore sources of heterogeneity, sensi- tivity analysis was performed.
Study Quality Assessment
The Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses was used: Each study was judged on three broad perspectives: the selection of the study groups; the comparability of the groups; and the ascertainment of either the outcome of interest. (http://www.ohri.ca/programs/ clinical_epidemiology/oxford.asp last accessed 31/03/2014)
Results were significant if p < . 5. The RevMan software Version 5.2 was used for statistical analysis [14]
Identification
Records identified through database searching (n = 96)
Additional records identified through other sources (n = 0)
Records after reviews removed (n = 87)
Screening
Records screened (n =87)
Records excluded (Not for malignancy/single arm studies) (n = 80)
Full-text articles assessed for eligibility (n = 7)
Full-text articles excluded, (different outcomes) (n = 3)
Eligibility
Included
Studies included in quantitative synthesis (meta-analysis) (n = 4)
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RESULTS
Four out of 299 screened trials were finally included [8-11] with a total of 253 participants. The main criteria for trial exclusion included reviews, different primary outcomes, and noncomparative studies.
The follow-up varied among studies and is illus- trated in Table 2.
Maxwell test statistic was not significant (p = . 84) indicating that the raters mainly concurred. The gen- eralized McNemar statistic (p = . 57) indicated that the agreement was spread evenly.
The baseline characteristics of the patients in the in- cluded trials are summarized in Table 2.
Each of the included studies was allocated seven stars of The Newcastle-Ottawa Quality Assessment Scale Cohort Studies (Table 3).
Of the four studies, three [8, 10, 11] addressed the outcome of perioperative complications. There were neither heterogeneity (I 2 = 0%; p = .65) nor statisti- cal significant difference between treatment arms: OR [95% CI] = 2.84 [0.79, 10.31]; Test for overall effect: Z = 1.59; p = . 11)
Of the four studies, three [8-10] addressed the out- come of R0 resection. There was not statistical signifi- cant difference between treatment arms: OR [95% CI] = 0.60 [0.12, 3.09]; Test for overall effect: Z = 0.61; p = .54), while heterogeneity could not be assessed.
Of the four studies, three [8, 9, 11] addressed out- comes of two-year, three-year, and four-year overall survival and disease free survival. Three studies [8-10] provided data for five-year overall survival and all four studies [8-11] provided data for five-year disease free survival.
| Donatini [8] | Lombardi [10] | Fossa [9] | Porpiglia [11] | |||||
|---|---|---|---|---|---|---|---|---|
| Open | Lap | Open | Lap | Open | Lap | Open | Lap | |
| Year | 2014 | 2012 | 2013 | 2010 | ||||
| Patients | 21 | 13 | 126 | 30 | 15 | 17 | 25 | 18 |
| Age (mean) | 44 | 46 | 46.6 | 52 | 52 | 45 | 41.3 | 47 |
| Sex F/M | 15/6 | 11/2 | 81/45 | 19/11 | 10/5 | 13/4 | 16/9 | 10/8 |
| Tumor size (mm) | 68 | 55 | 90 | 77 | 130 | 80 | 105 | 90 |
| Localization R/L/BL* | – | – | 64/62/0 | 23/7/0 | 7/7/1 | 10/7/0 | – | – |
| Hospital stay (days) | 9 | 7 | 9.3 | 5.3 | 13 | 6 | – | - |
| Operative time (min) | – | – | 129 | 135 | 230 | 150 | – | – |
| Blood loss (ml) | – | - | – | – | 1700 | <400 | – | – |
| Conversion to open | – | 0 | – | 1 | – | 2 | – | – |
| R0 resection | 21 | 13 | 126 | 30 | 12 | 12 | – | – |
| Complications | 3 | 1 | 7 | 1 | 11 | 8 | 7 | 1 |
| Recurrence | 5 | 4 | 48 | 8 | – | 2 | 16 | 9 |
| Recurrence location L/D/LD ** | – | – | 14/27/7 | 4/3/1 | 1/9/5 | 1/8/3 | 6/10/0 | 6/4/0 |
| Adjuvant treatment | 15 | 8 | 41 | 9 | 2 | 0 | 15 | 12 |
| Follow up- median (months) | 57 | 80 | 40 | 50 | 60 | 60 | 38 | 38 |
| Disease free survival-median (months) | 47 | 46 | 48 | 72 | 8.1 | 15.2 | 18 | 23 |
| Overall survival-median (months) | 17 | 11 | 60 | 108 | 36.5 | 103.6 | – | – |
*R/L/BL: Right/Left/Bilateral.
** L/D/LD: Local/Distal/Local-Distal.
There were not statistical significant differences be- tween treatment arms considering the two-year, three- year, four-year overall survival while five-year overall survival was in favor of open adrenalectomy group (Ta- ble 4, Figure 1).
There were not statistical significant differences be- tween treatment arms considering the two-year, three- year, four-year and five-year disease free survival (Table 5, Figure 2).
There was no heterogeneity among studies in excep- tion of one comparison. The study of Fossa et al. [9] con- tributed in heterogeneity of the studies in the analysis of four-year disease free survival Heterogeneity: Tau2 = 3.57; Chi2 = 6.47, df = 2 (p = . 04); 12 = 69% when in- cluded and Heterogeneity: Tau2 = 1.38; Chi2 = 1.95, df = 1 (p =. 16); 12 = 49% when excluded.
Funnel plots showed no significant publication bias.
DISCUSSION
The results of the present meta-analysis showed that: (a) Differences in postoperative complications did not reach statistical significance between treatment arms, (b) Differences in R0 resections did not reach statisti- cal significance between treatment arms, (c) There were not statistical significant differences between treatment arms considering the two-year, three-year, four-year overall survival while five-year overall survival was in favor of open adrenalectomy group, and (d) There were not statistical significant differences between treatment arms considering the two-year, three-year, four-year, and five-year disease free survival.
| Donatini | Lombardi | Fossa | Porpiglia | |
|---|---|---|---|---|
| Selection | ||||
| Representativeness of the exposed cohort | ∗ | ∗ | ||
| Selection of the nonexposed cohort | – | – | – | – |
| Ascertainment of exposure | ∗ | ∗ | ||
| Demonstration that outcome of interest was not present at start of study | ∗ | ∗ | ||
| Comparability | ||||
| Comparability of cohorts on the basis of the design or analysis | ∗ | ∗ | ||
| Outcome | ||||
| Assessment of outcome | ∗ | ∗ | ||
| Was follow-up long enough for outcomes to occur | ∗ | ∗ | ||
| Adequacy of follow up of cohorts | ∗ | ∗ |
TABLE 4 Overall survival
Outcome
| overall survival | Studies | Participants | Statistical method | Effect estimate | Heterogeneity | Test for effect/ p-value |
|---|---|---|---|---|---|---|
| 2-year | 3 | 97 | Odds ratio (M-H, Random, 95% CI) | 2.47 [0.61, 10.06] | p =. 49 12 = 0% | Z = 1.26/p = . 21 |
| 3-year | 3 | 97 | Odds ratio (M-H, Random, 95% CI) | 1.48 [0.43, 5.03] | p = . 46 | Z = 0.62/ p = . 53 |
| 12 = 0% | ||||||
| 4-year | 3 | 97 | Odds ratio (M-H, Random, 95% CI) | 1.49 [0.55, 4.00] | p = . 70 | Z = 0.79 / p = . 43 |
| 12 = 0% | ||||||
| 5-year | 3 | 210 | Odds ratio (M-H, Random, 95% CI) | 2.17 [1.04, 4.50] | p = . 43 | Z = 2.07 / p = . 04 |
| 12 = 0% | (Favors open) |
Overall Completeness and Applicability of Evidence
The available literature on laparoscopic adrenalectomy has numerous drawbacks. Few small non randomized trials were obtainable, and most studies were retro-
spective in nature with increased risk for publication bias and other confounding factors. Three out of the four included studies have a small sample size making their results uncertain. Most of the studies do not report details on the surgeon’s expertise, and have been conducted in a single institution causing the
| Study or Subgroup | Lap Adrenalectomy | Open Adrenalectomy | Weight | Odds Ratio M-H. Random, 95% CI | Odds Ratio M-H. Random, 95% CI | ||
|---|---|---|---|---|---|---|---|
| Events | Total | Events | Total | ||||
| Donatini 2014 | 13 | 13 | 18 | 21 | 21.3% | 5.11 [0.24, 107.33] | |
| Fossa 2013 | 8 | 13 | 4 | 7 | 56.6% | 1.20 [0.19, 7.77] | |
| Porpiglia 2010 | 18 | 18 | 21 | 25 | 22.1% | 7.74 [0.39, 153.56] | |
| Total (95% CI) | 44 | 53 | 100.0% | 2.47 [0.61, 10.06] | |||
| Total events | 39 | 43 | |||||
| Heterogeneity: Tau == 0.00; Chi == 1.41, df = 2 (P = 0.49); 1 == 0% Test for overall effect: Z = 1.26 (P = 0.21) | 0.001 | 0.1 1 10 1000 | |||||
| Favours [Lap] Favours [Open] | |||||||
| A | Lap Adrenalectomy | Open Adrenalectomy | Weight | Odds Ratio M-H. Random, 95% CI | Odds Ratio M-H. Random, 95% CI | ||
|---|---|---|---|---|---|---|---|
| Study or Subgroup | Events | Total | Events | Total | |||
| Donatini 2014 | 11 | 13 | 18 | 21 | 40.0% | 0.92 [0.13, 6.38] | |
| Fossa 2013 | 8 | 13 | 4 | 7 | 43.1% | 1.20 [0.19, 7.77] | |
| Porpiglia 2010 | 18 | 18 | 21 | 25 | 16.9% | 7.74 [0.39, 153.56] | |
| Total (95% CI) | 44 | 53 | 100.0% | 1.48 [0.43, 5.03] | |||
| Total events | 37 | 43 | |||||
| Heterogeneity: Tau == 0.00; Chi == 1.54, df = 2 (P = 0.46); 1 == 0% Test for overall effect: Z = 0.62 (P = 0.53) | 0.001 0.1 1 10 1000 | ||||||
| Favours [Lap] Favours [Open] | |||||||
| B | Lap Adrenalectomy | Open Adrenalectomy | Weight | Odds Ratio M-H, Random, 95% CI | Odds Ratio M-H. Random, 95% CI | ||
|---|---|---|---|---|---|---|---|
| Study or Subgroup | Events | Total | Events | Total | |||
| Donatini 2014 | 11 | 13 | 18 | 21 | 25.9% | 0.92 [0.13, 6.38] | |
| Fossa 2013 | 7 | 13 | 2 | 7 | 25.2% | 2.92 [0.41, 20.90] | |
| Porpiglia 2010 | 14 | 18 | 18 | 25 | 48.9% | 1.36 [0.33, 5.59] | |
| Total (95% CI) | 44 | 53 | 100.0% | 1.49 [0.55, 4.00] | |||
| Total events | 32 | 38 | |||||
| Heterogeneity: Tau == 0.00; Chi == 0.70, df = 2 (P = 0.70); 1 == 0% Test for overall effect: Z = 0.79 (P = 0.43) | 0.001 | 0.1 1 10 1000 | |||||
| Favours [Lap] Favours [Open] | |||||||
| C | Lap Adrenalectomy | Open Adrenalectomy | Weight | Odds Ratio M-H. Random, 95% CI | Odds Ratio M-H. Random, 95% CI | ||
|---|---|---|---|---|---|---|---|
| Study or Subgroup | Events | Total | Events | Total | |||
| Donatini 2014 | 11 | 13 | 18 | 21 | 14.2% | 0.92 [0.13, 6.38] | |
| Fossa 2013 | 7 | 13 | 1 | 7 | 9.4% | 7.00 [0.65, 75.73] | |
| Lombardi 2012 | 20 | 30 | 60 | 126 | 76.4% | 2.20 [0.95, 5.07] | |
| Total (95% CI) | 56 | 154 | 100.0% | 2.17 [1.04, 4.50] | |||
| Total events | 38 | 79 | |||||
| Heterogeneity: Tau == 0.00; Chi == 1.69, df = 2 (P = 0.43); 1 == 0% Test for overall effect: Z = 2.07 (P = 0.04) | 0.002 | 0.1 1 10 500 Favours [Lap] Favours [Open] | |||||
| D | |||||||
FIGURE 1 Estimates and forest plots for two-year (A), three-year (B), four-year (C), and five-year (D) overall survival.
TABLE 5 Disease free survival
Outcome
| disease free survival | Studies | Participants | Statistical method | Effect estimate | Heterogeneity | Test for effect/ p-value |
|---|---|---|---|---|---|---|
| 2-year | 3 | 97 | Odds ratio (M-H, Random, 95% CI) | 1.87 [0.68, 5.20] | p =. 39 | Z = 1.21/ p = . 23 |
| I 2 = 0% | ||||||
| 3-year | 3 | 97 | Odds ratio (M-H, Random, 95% CI) | 0.53 [0.19, 1.48] | p =. 39 | Z = 1.21/ p = . 23 |
| 12 = 0% | ||||||
| 4-year | 3 | 97 | Odds ratio (M-H, Random, 95% CI) | 0.68 [0.05, 9.05] | p =. 04 12 = 69% | Z = 0.29 / p = . 77 |
| 5-year | 4 | 253 | Odds ratio (M-H, Random, 95% CI) | 0.53 [0.21, 1.30] | p =. 28 I 2 = 21% | Z = 1.39 / p = . 16 |
generalization of their findings difficult. Lastly, the proper pathologic tumor staging is unequivocally uncertain preoperatively and this issue has to be kept in mind when interpreting the results of the present study.
Current evidence suggests that adrenocortical car- cinoma should be clearly suspected in nonfunction- ing tumors > 4 cm with irregular margins or that are internally heterogenous. On unenhanced CTs, the Hounsfield unit (HU) number is typically higher in
| Study or Subgroup | Lap Adrenalectomy | Open Adrenalectomy | Weight | Odds Ratio M-H, Random, 95% CI | Odds Ratio M-H, Random, 95% CI | |||
|---|---|---|---|---|---|---|---|---|
| Events | Total | Events | Total | |||||
| Donatini 2014 | 12 | 13 | 18 | 21 | 18.4% | 2.00 [0.19, 21.57] | ||
| Fossa 2013 | 6 | 13 | 0 | 7 | 11.2% | 13.00 [0.62, 274.31] | ||
| Porpiglia 2010 | 10 | 18 | 12 | 25 | 70.4% | 1.35 [0.40, 4.57] | ||
| Total (95% CI) | 44 | 53 | 100.0% | 1.87 [0.68, 5.20] | ||||
| Total events | 28 | 30 | ||||||
| Heterogeneity: Tau == 0.00; Chi == 1.89, df = 2 (P = 0.39); 1 == 0% Test for overall effect: Z = 1.21 (P = 0.23) | 0.001 0.1 1 10 1000 | |||||||
| Favours [Lap] Favours [Open] | ||||||||
| A | Lap Adrenalectomy | Open Adrenalectomy | Weight | Odds Ratio M-H, Random, 95% CI | Odds Ratio M-H, Random, 95% CI | |||
|---|---|---|---|---|---|---|---|---|
| Study or Subgroup | Events | Total | Events | Total | ||||
| Donatini 2014 | 18 | 21 | 12 | 13 | 18.4% | 0.50 [0.05, 5.39] | ||
| Fossa 2013 | 0 | 7 | 6 | 13 | 11.2% | 0.08 [0.00, 1.62] | ||
| Porpiglia 2010 | 12 | 25 | 10 | 18 | 70.4% | 0.74 [0.22, 2.49] | ||
| Total (95% CI) | 53 | 44 | 100.0% | 0.53 [0.19, 1.48] | ||||
| Total events Heterogeneity: Tau == | 0.00; Chi == 1.89, 30 | df = 2 (P | = 0.39); 1 == 0% 28 | |||||
Test for overall effect: Z = 1.21 (P = 0.23)
0.001
0.1
1
10
1000
Favours [Lap]
Favours [Open]
| B | Lap Adrenalectomy | Open Adrenalectomy | Weight | Odds Ratio M-H, Random, 95% CI | Odds Ratio M-H, Random, 95% CI | |||
|---|---|---|---|---|---|---|---|---|
| Study or Subgroup | Events | Total | Events | Total | ||||
| Donatini 2014 | 9 | 13 | 17 | 21 | 41.0% | 0.53 [0.11, 2.63] | ||
| Fossa 2013 | 6 | 13 | 0 | 7 | 29.0% | 13.00 [0.62, 274.31] | ||
| Porpiglia 2010 | 0 | 18 | 8 | 25 | 30.0% | 0.06 [0.00, 1.04] | ||
| Total (95% CI) | 44 | 53 | 100.0% | 0.68 [0.05, 9.05] | ||||
| Total events | 15 | 25 | ||||||
| Heterogeneity: Tau == 3.57; Chi == 6.47, df = 2 (P = 0.04); 12= | 69% | 0.001 0.1 1 | 10 1000 | |||||
| Test for overall effect: Z = 0.29 (P = 0.77) | Favours [Lap] | Favours [Open] | ||||||
| C | Lap Adrenalectomy | Open Adrenalectomy | Weight | Odds Ratio M-H, Random, 95% CI | Odds Ratio M-H, Random, 95% CI | |||
|---|---|---|---|---|---|---|---|---|
| Study or Subgroup | Events | Total | Events | Total | ||||
| Donatini 2014 | 15 | 21 | 9 | 13 | 28.0% | 1.11 [0.25, 5.04] | ||
| Fossa 2013 | 0 | 7 | 6 | 13 | 8.2% | 0.08 [0.00, 1.62] | ||
| Lombardi 2012 | 0 | 25 | 0 | 18 | Not estimable | |||
| Porpiglia 2010 | 49 | 126 | 17 | 30 | 63.8% | 0.49 [0.22, 1.09] | ||
| Total (95% CI) | 179 | 74 | 100.0% | 0.53 [0.21, 1.30] | ||||
| Total events | 64 | 32 | ||||||
| Heterogeneity: Tau == 0.16; Chi == 2.54, df = 2 (P = 0.28); 1 == Test for overall effect: Z = 1.39 (P = 0.16) | 21% | 0.001 0.1 1 | 10 1000 | |||||
| Favours [Lap] | Favours [Open] | |||||||
D
FIGURE 2 Estimates and forest plots for two-year (A), three-year (B), four-year (C), and five-year (D) disease free survival.
For personal use only.
carcinomas than in adenomas, and a threshold value of 10 HU has been proposed as a means of distin- guishing benign from malignant adrenal tumors [15]. If the HU attenuation value is greater than 10 on unen- hanced CT, then enhanced CT and washout at 15 min is recommended. If the enhancement washout value is greater than 60% at 15 min, the tumor is likely be- nign [16]. MRIs more clearly document local invasion and involvement of the inferior vena cava than CT scans. Whether CT or MRI scans are performed, they should be performed using an adrenal protocol to de- termine size, heterogeneity, lipid content (MRI), con- trast washout (CT) and margin characteristics [17].
Contrast-enhanced sonography can be also used to differentiate adenomas and nonadenomatous lesions with sensitivity comparable with that of CT and MRI and may be a cost-effective method for preselection of patients with adrenal masses. The sensitivity and speci- ficity of contrast-enhanced sonography in the diagno- sis of malignant adrenal mass were 100% and 82% [18].
Quality of the Evidence
Our meta-analysis is free of worrisome variations (het- erogeneity) in the directions and degrees of results be- tween individual cohort studies.
According to the Oxford Centre for Evidence-based Medicine “Levels of Evidence 1” document the Level of Evidence attributed to the present study is 2a and the Grade of Recommendation is B.
Biases in the Review Process
Despite the visual presentation of the funnel plots the risk of bias is high. We hypothesize a great deal of selec- tion, performance and detection biases, while attrition and selective reporting biases are of low risk.
Agreements and Disagreements with other Studies
The Recommendations of the Society of American Gas- trointestinal and Endoscopic Surgeons [19] concerning large adrenal tumors without pre- or intraoperative evidence of primary adrenal cortical carcinoma state that: (a) These tumors can be approached laparoscop- ically by a surgeon skilled in advanced laparoscopy and adrenal surgery (+, weak) and (b) If there is any evidence for carcinoma found intraoperatively, con- version to an open approach is warranted (should be strongly considered) (+, strong).
Remarkably, these guidelines do not specifically ap- ply to stage I/II adrenocortical carcinoma.
Contrasted to our results, some reports have sug- gested that the laparoscopic approach should be
avoided in cases where ACC is suspected due to an in- creased risk of positive surgical margins [20]. Recently, a review of the German ACC registry recommended tumor size of 10 cm as the upper-most limit of feasibil- ity for laparoscopic adrenalectomy based on the sim- ilar oncologic outcomes of laparoscopic versus open adrenalectomy [3].
Minimally invasive adrenalectomy is related to a learning curve that may be difficult to surmount given the scarcity of these cases in general practice [19].
The issues of recurrence and adjuvant treatment (though using adjuvant treatment in stage II adreno- cortical carcinoma is debatable) could not be addressed by the present meta-analysis. The Italian Registry for Adrenal Cortical Carcinoma in an analysis of a multiin- stitutional series of 129 patients provides data concern- ing surgical treatment of recurrence. Authors state that surgery for recurrence should be attempted systemat- ically while the role of adjuvant therapies (obtained contrasting results) should be evaluated in prospective multicenter trials [21].
The results of a 253-patient series from the French Association of Endocrine Surgeons study group sug- gested that Mitotane benefited only patients not oper- ated on for cure. Curative resection, precursor secre- tion, recent diagnosis, and local stage were favorably associated with survival [22].
Although adjuvant mitotane has shown some progression-free or disease-free survival advantage, there has been no overall survival advantage demon- strated thus far for stages I and II adrenocortical carci- noma [23].
CONCLUSIONS
Based on the limitations of the present meta-analysis, firm recommendations are difficult. It seems that postoperative complications, R0-resection, overall and disease free survival of stage I/II adrenocortical carcinoma are comparable and independent to the procedure though the five-year survival was in favor of the open group. Further research is likely to have an important impact on our confidence in the estimates of effect and may change the estimates.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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[2] Fassnacht M, Johanssen S, Quinkler M, et al. Lim- ited prognostic value of the 2004 International Union
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