SURGICAL
. and Other Interventional Techniques
AVDOSCOPY
Does laparoscopic adrenalectomy jeopardize oncologic outcomes for patients with adrenocortical carcinoma?
Amanda B. Cooper . Mouhammed Amir Habra . Elizabeth G. Grubbs . Brian K. Bednarski . Anita K. Ying . Nancy D. Perrier . Jeffrey E. Lee .
Thomas A. Aloia
Received: 19 April 2013 / Accepted: 13 May 2013 @ Springer Science+Business Media New York 2013
Abstract
Background For patients with known or suspected adre- nocortical carcinoma (ACC), considerable controversy exists over the use of laparoscopic adrenalectomy. The purpose of this study was to assess recurrence and survival patterns in patients with a pathologic diagnosis of ACC treated with laparoscopic versus open adrenalectomy.
Methods All patients referred to our center with a diag- nosis of ACC from April 1, 1993 to May 1, 2012 were reviewed. Three groups of patients were compared: patients referred after laparoscopic resection elsewhere, patients referred after open resection elsewhere, and patients treated primarily at our center (all resected by the open approach). Clinical factors and overall, recurrence- free, and peritoneal recurrence-free survivals were com- pared between groups.
Results During the study period, 46 patients presented after laparoscopic resection at an outside institution, 210 patients after open resection at an outside institution, and 46 patients were treated at our institution with open resection. Despite a smaller tumor size, patients treated
Presented at the SAGES 2013, Annual Meeting, April 17-20, 2013, Baltimore, MD.
A. B. Cooper · E. G. Grubbs · B. K. Bednarski .
N. D. Perrier . J. E. Lee . T. A. Aloia
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler, Houston, TX 77030, USA
e-mail: taaloia@mdanderson.org
M. A. Habra · A. K. Ying
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
laparoscopically developed peritoneal carcinomatosis more frequently compared to those treated with an open approach (p = 0.006 for number with peritoneal recur- rence). When controlling for tumor stage, open-approach patients experienced superior recurrence-free and overall survival.
Conclusion Despite typically being performed in patients with smaller tumors, laparoscopic adrenalectomy for ACC is associated with higher rates of recurrence, particularly peritoneal recurrence. For patients with known or sus- pected ACC, the oncologic benefits of open resection outweigh the short-term benefits of minimally invasive surgery.
Keywords Surgical approach · Peritoneal carcinomatosis . Recurrence patterns · Survival
Adrenocortical carcinoma (ACC) is a rare malignancy that frequently presents as a large retroperitoneal tumor. Given that patients with ACC have few effective treatment options, those with localized disease at presentation are best served by surgical resection. The goals of surgical therapy are to reduce recurrence and improve survival via complete circumferential dissection of the tumor with en bloc resection of regionally involved structures to include nephrectomy and lymphadenectomy as indicated by pre- operative and intraoperative findings [1-3]. Likewise, in patients with locally recurrent ACC, only complete resec- tion of all sites of disease is associated with improved survival [4].
It is well recognized that an open approach to the fre- quently challenging adrenal tumor dissection can provide superior exposure to these often friable masses, likely resulting in less risk of tumor rupture and improved margin
control. More recently, however, experience with mini- mally invasive surgical (MIS) approaches to adrenalec- tomy for non-ACC pathology has grown. Comparison of short-term outcomes after various approaches to adrenal- ectomy for non-ACC pathology has demonstrated several favorable features of the MIS approach, including lower morbidity and shorter intensive care unit and overall hospital length of stay [5, 6]. Although transfusion and complication rates have been reported to be higher in the open-approach group, it is unclear if the magnitude of intra-abdominal surgery required was adequately matched to allow isolation of the surgical approach as the critical dependent variable for these outcomes [6]. Regardless, the growing body of experience and published literature on short-term outcomes following MIS adrenalectomy for non-ACC pathology has led some surgeons to suggest that this is an acceptable method for resection of patients with ACC [7, 8].
In a previous publication we reported recognition of a unique pattern of multifocal peritoneal carcinomatosis in a small number of patients with ACC who had undergone resection using MIS approaches [9]. Since that publication, the general utilization of MIS techniques to resect patients with ACC has expanded [10-13], and we have seen increasing numbers of patients with ACC referred to our center after MIS adrenalectomy. The purpose of this pro- ject was to assess the long-term oncologic outcomes of this larger patient cohort with recurrent ACC referred to our center after open and MIS adrenalectomy. Facilitated by an extensive review of imaging, particular attention was focused on patterns of recurrence and their subsequent management. Finally, to provide context to this analysis, we assessed the short- and long-term outcomes of patients who presented at initial diagnosis to our center and were treated uniformly with an open surgical approach.
Materials and methods
Patients
This study was approved by the Institutional Review Board at the University of Texas MD Anderson Cancer Center. All patients referred to our center with a diagnosis of ACC from April 1, 1993 to May 1, 2012 were reviewed. All patients who underwent curative intent surgery (either at an outside hospital or at our institution) were included, except for those patients with metastatic disease at the time of diagnosis. Patients who underwent R2 resections were excluded from analyses of local recurrence and recurrence- free survival, but were included in the analyses of overall and peritoneal recurrence-free survival. Outcomes for three groups of patients were compared: those referred after
laparoscopic resection elsewhere, those referred after open resection elsewhere, and those treated primarily at our center (all resected by an open approach). Patients who underwent an initial laparoscopic dissection but were converted to an open operation were counted in the lapa- roscopic group.
Data collection
Data on patient characteristics, radiographic and pathologic tumor size, operative treatment, patterns and dates of dis- ease recurrence, and survival times were extracted from medical records. For the purposes of this study, disease recurrence was diagnosed on the basis of CT or MRI imaging. Recurrences were defined as local if they occur- red in the retroperitoneum in the same quadrant as the primary tumor or in the contralateral adrenal gland, as peritoneal if they occurred intraperitoneally with the exception of liver metastases, and as distant if they occurred outside of the adrenal bed or peritoneum.
Survival analyses
Both overall and recurrence-free survivals were calculated from the date of operation. Patients for whom date of death was known to be greater than 3 months from the time of last clinical encounter and who were free of recurrence at the time of last clinical encounter were counted in overall survival according to the date of death, but were censored for recurrence-free survival at the time of their last clinical encounter. Patients who were still alive at the time of last clinical encounter were censored at that time.
Statistical analysis
Statistical analysis was performed using SPSS software (version 21.0, IBM SPSS, Chicago, IL). Categorical vari- ables were compared with x2 tests and continuous variables were compared using one-way analysis of variance. Kaplan- Meier curves were constructed for overall, recurrence-free, and peritoneal recurrence-free survival for each group. Actuarial survival was compared between groups using the log-rank test. A Cox regression model was used to compare overall and recurrence-free survival between the laparo- scopic and combined open groups while adjusting for tumor characteristics. p values < 0.05 were considered significant.
Results
During the study period, 332 patients with a diagnosis of ACC were evaluated at our institution. Five patients were
excluded because curative intent surgery was not per- formed (i.e., exploratory laparotomy/laparoscopy with or without excisional biopsy was performed). Two patients were excluded due to a change in diagnosis from ACC to a sarcomatoid-type tumor after review of pathology. In addition, 23 patients were excluded because of the presence of metastatic disease at the time of initial diagnosis. Four patients underwent an initial laparoscopic dissection but were ultimately converted to an open operation and were counted in the laparoscopic group. The final study popu- lation included 46 patients who presented after laparo- scopic resection at an outside institution, 210 patients who presented after open resection at an outside institution, and 46 patients who were treated at our institution with open resection (index institution group). Median follow-up for all patients was 34.4 months. Median follow-up by treat- ment group was 29.2, 34.9, and 38.2 months for the lapa- roscopic, open resection at an outside institution, and open resection at the index institution groups, respectively.
Patient and tumor characteristics between groups are summarized in Table 1. Patients who underwent their ini- tial resection at the index hospital were significantly older than those who underwent an open operation or a laparo- scopic resection at an outside hospital (53.4 vs. 45 and 45.8 years, respectively). Tumors resected via a laparo- scopic approach were significantly smaller than those resected via an open approach (median tumor size: 8 vs. 12 cm at outside hospital and 12.3 cm at index hospital, p < 0.0001). Although the overall distribution of tumor stage (T stage) among groups was not statistically signifi- cant, none of the patients in the laparoscopic group had T4 tumors, while 16 and 22 % of the open at outside
institution and open at index institution patients had T4 tumors, respectively. Additionally, 20 % of the laparo- scopically resected tumors were T1 tumors versus 1 and 4 % of the open at outside hospital and open at index hospital tumors. A similar percentage of patients in both the laparoscopic and the open at outside institution patients were referred to the index center following tumor recur- rence. In addition, significantly fewer patients in the open at outside institution group were treated with adjuvant mitotane therapy (16.7 %) than in the laparoscopic (34.8 %) or open at the index institution (37 %) groups (p = 0.001). A higher percentage of patients who under- went laparoscopic adrenalectomy had a margin-positive (R1 or R2) resection (28.3 %) than those who underwent either open resection at an outside institution (17.6 %) or open resection at the index institution (8.7 %, p = 0.01, Table 2).
Recurrence and survival after resection
Unadjusted overall survival of patients in the three groups was not significantly different (Table 3). However, when a Cox regression model was used to compare overall survival adjusting for pathologic T stage, overall survival for patients who underwent open resection was longer than for patients treated with laparoscopic resection (p < 0.0001, Fig. 1). Unadjusted recurrence-free survival was longer for patients who underwent an open operation at the index institution (median = 19.6 months) than for those who underwent a laparoscopic operation (10.9 months) or an open operation at an outside institution (9.5 months) (p = 0.005, Table 3). However, similar to overall survival,
| Laparoscopic | Open outside hospital | Open index hospital | p value | |
|---|---|---|---|---|
| No. patients | 46 | 210 | 46 | |
| Patient characteristics | ||||
| Gender (m/f) | 18/28 | 68/142 | 20/26 | 0.30 |
| Age [median (range)] (years) | 45.8 (18.4-74.0) | 45 (1.9-78.9) | 53.4 (20.0-86.6) | 0.001 |
| Referred after recurrence [n (%)] | 27 (58.7) | 138 (65.7) | NA | 0.39 |
| Tumor characteristics | ||||
| Laterality (R/L/bilat) | 19/27/0 | 92/117/1 | 23/23/0 | 0.88 |
| Size [median (range)] (cm) | 8.0 (1.0-15.0) | 12.0 (4.0-26.0) | 12.3 (4.0-30.0) | <0.0001 |
| T stage [n (%)] | 0.10 | |||
| T1 | 9 (19.6) | 3 (1.4) | 2 (4.3) | |
| T2 | 20 (43.5) | 104 (49.5) | 24 (52.2) | |
| T3 | 16 (34.8) | 61 (29) | 10 (21.7) | |
| T4 | 0 (0) | 33 (15.7) | 10 (21.7) | |
| Adjuvant mitotane therapyª | 16 (34.8) | 35 (16.7) | 17 (37.0) | 0.001 |
a Neoadjuvant mitotane was not included
| Laparoscopic | Open outside hospital | Open index hospital | p value | |
|---|---|---|---|---|
| R0 | 25 (54.3 %) | 93 (44.3 %) | 41 (89.1 %) | 0.01 (R0 vs. R1/2) |
| R1 | 12 (26.1 %) | 30 (14.3 %) | 4 (8.7 %) | |
| R2 | 1 (2.2 %) | 7 (3.3 %) | 0 (0 %) | |
| Unknown | 8 (17.4 %) | 80 (38.1 %) | 1 (2.2 %) |
| Laparoscopic | Open outside hospital | Open index hospital | p value | |
|---|---|---|---|---|
| Peritoneal recurrences [n (%)] | 25 (54.3) | 58 (27.6) | 9 (19.6) | 0.006 |
| Median peritoneal RFS (months) | 31.1 | Not met | Not met | <0.0001 |
| Any recurrence [n (%)] | 35 (76.1) | 178 (87.3) | 27 (58.7) | 0.001 |
| Median RFS (months) | 10.9 | 9.5 | 19.6 | 0.005 |
| Deaths [n (%)] | 22 (47.8) | 152 (72.4) | 20 (43.5) | <0.0001 |
| Median overall survival (months) (95 % CI) | 53.5 (28.3-78.8) | 46.0 (39.2-52.8) | 109.8 (20.5-199.1) | 0.070 |
RFS recurrence-free survival
Overall Survival Controlling for T Stage
1.0
p<0.0001
Cumulative Survival
0.8
0.6
0.4
Surgery Type
Laparoscopic Open
0.2
0.0
0
12
24
36
48
60
72
Survival Time (months)
when pathologic T stage was adjusted for using a Cox regression model, recurrence-free survival was longer for the patients who underwent open resection relative to those who underwent laparoscopic resection (p < 0.0001, Fig. 2). Even without adjustment for T stage, peritoneal recurrence-free survival was lower for patients who underwent laparoscopic resection compared to those who underwent open resection at either an outside institution or at the index institution (p < 0.0001, Fig. 3). Of all the patients with a peritoneal recurrence, only 15.2 % were able to undergo subsequent surgical resection after disease recurrence, whereas 35.9 % of all patients with any type of recurrence were able to undergo subsequent resection (p = 0.0004).
Discussion
ACC is an aggressive malignancy with a high recurrence rate. It frequently occurs in relatively young patients and presents at advanced stages [1, 3]. For patients with local- ized disease at presentation, oncologic outcome and the success of surgical therapy are dependent on the complete- ness of resection of the primary tumor, surrounding retro- peritoneal tissues, and regional lymph nodes. Given the fragility of these tumors, it is imperative for surgeons to utilize an approach that provides adequate exposure and access to surrounding tissue planes and structures [14].
The results of this analysis indicate that surgical approach can have a significant impact on long-term
Recurrence Free Survival Controlling for T Stage
1.0
Cumulative Survival
0.8
p<0.0001
0.6
0.4
Surgery Type
Laparoscopic Open
0.2
0.0
0
12
24
36
48
60
72
Recurrence Free Survival (months)
Peritoneal Recurrence Free Survival
1.0
p<0.0001
Cumulative Survival
0.8
Surgery Type
open outside hospital laparoscopic open index hospital
0.6
0.4
0.2
0.0
0
12
24
36
48
60
72
Peritoneal Recurrence Free Survival (months)
outcomes for patients with ACC. Despite significantly smaller tumors and a corollary trend toward lower T stage lesions, patients with ACC resected using a laparoscopic approach were far more likely to develop multifocal peri- toneal carcinomatosis than those resected via an open approach. When controlling for T stage, recurrence-free survival and overall survival were superior in the open surgery cohort. Furthermore, those patients who recurred with the multifocal peritoneal carcinomatosis pattern associated with laparoscopic primary tumor resection were less likely to be candidates for salvage recurrence surgery than patients with other types of recurrence. This is an important point because patients with ACC recurrence who are amenable to complete surgical resection have been
shown to have significantly higher survival rates than those whose recurrence cannot be resected [4]. Combined, these data add support to several smaller studies that emphasized the importance of surgical approach in ACC patient out- come [12, 15, 16].
This study has several limitations, including its retro- spective nature, baseline differences between the three groups of patients, and potential referral bias. Given the rarity of ACC and the significant controversy surrounding the topic, a prospective randomized trial comparing lapa- roscopic and open adrenalectomy is unlikely to be accomplished. The low incidence of ACC also limits the number of cases that can be treated and prospectively followed at any one single institution. While there were
significant differences in the baseline characteristics of the patients and tumors in the groups in this study, these dif- ferences (smaller tumor size, younger patients, a trend toward lower-stage tumors, and frequent use of adjuvant mitotane), if anything, should bias the results for tumor recurrence and survival in favor of laparoscopic adrenal- ectomy. Any study that includes patients referred to a tertiary center has the potential for bias in favor of patients with higher-stage, more aggressive, and recurrent disease. While this potential certainly exists in our population, we feel that the similar percentage of patients who were referred after recurrence in both the laparoscopic and the open resection at outside hospital groups makes these two groups appropriate for comparison, particularly with regard to peritoneal recurrences.
The utilization of minimally invasive techniques for adrenalectomy has been an important and evolving advancement in the field of adrenal surgery. Patients with non-ACC histologies have certainly benefited from the reduced physiological insult and recovery time afforded by these approaches. However, the success of non-ACC minimally invasive adrenal surgery has led some to con- clude that it has a role in ACC resection [7, 8, 10, 11, 13, 17, 18]. We are deeply concerned by the application of short-term outcomes data for laparoscopic versus open adrenalectomy to the ACC patient population. These studies often provide incomplete pathologic data regarding margins and adequacy of resection. Furthermore, they tend not to contain detailed data regarding recurrence patterns, recurrence rates, and overall postoperative survival. Our analysis was designed to provide an oncological context to the choice of surgical approach. This information clearly favors the choice of open surgery for patients with known or suspected ACC. This recommendation is supported by The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Guidelines for the Minimally Invasive Treatment of Adrenal Pathology, which states that “for ACC, the best determinant of patient outcomes is an appropriate oncologic resection that includes en bloc resection of any contiguous involved structures and regional lymphadenectomy.” In addition to recommending the open approach, the statement subsequently comments that, “if a laparoscopic approach is chosen [due to diag- nostic ambiguity], conversion to open surgery is strongly recommended … ” [19].
Given the impact of approach on outcome, preoperative and/or intraoperative recognition of the diagnosis and stage of ACC become critical. All patients with adrenal masses require an adequate preoperative imaging and biochemical evaluation [20]. Previously, deficits in the sensitivity and specificity of diagnostic imaging resigned surgeons to using only tumor size as a crude diagnostic tool, with tumors greater than 4-6 cm without adrenaline production
often recommended for surgical resection on the basis of the potential for a diagnosis of ACC [3, 21-23]. Currently, however, significant advances in tumor characterization with CT, MRI, and even PET have dramatically increased the accuracy of preoperative imaging [24, 25]. In this modern imaging era, patients with adrenal masses should infrequently be brought to the operating room as diagnostic dilemmas [20]. The decision on surgical approach, should, therefore, rarely be in doubt.
In summary, the data and outcomes reported in this study strongly support the oncologic benefits of the open approach to resection of ACC. With recent advances in diagnostic imaging and biochemical evaluation, the diagnosis of adrenal tumor type should be made in the preoperative set- ting in the vast majority of cases. Recognition that, unique to ACC as an adrenal tumor pathology, the postadrenalectomy natural history of ACC is dramatically impacted by surgical approach should lead surgeons to perform open adrenalec- tomy for all patients suspected of having ACC or to refer them to a tertiary center that performs open resection with minimal morbidity and mortality.
Acknowledgments This research was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (CA016672).
Disclosures Amanda B. Cooper MD, Mouhammed Amir Habra MD, Elizabeth G. Grubbs MD, Brian K. Bednarski MD, Anita K. Ying MD, Nancy D. Perrier MD, Jeffrey E. Lee MD, and Thomas A. Aloia MD have no conflicts of interest to disclose relevant to this study.
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