ORIGINAL ARTICLE - ENDOCRINE TUMORS
Surgical Resection of Synchronously Metastatic Adrenocortical Cancer
Benzon M. Dy, MD1, Veljko Strajina, MD1, Ashley K. Cayo, MD2, Melanie L. Richards, MD1, David R. Farley, MD1, Clive S. Grant, MD1, William S. Harmsen, MD3, Doug B. Evans, MD4, Elizabeth G. Grubbs, MD2, Keith C. Bible, MD5, William F. Young, MD6, Nancy D. Perrier, MD2, Florencia G. Que, MD1, David M. Nagorney, MD1, Jeffrey E. Lee, MD2, and Geoffrey B. Thompson, MD1
1Department of Surgery, Mayo Clinic, Rochester, MN; 2Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX; 3Department of Statistics, Mayo Clinic, Rochester, MN; 4Department of Surgery, Medical College of Wisconsin, Milwaukee, WI; 5Department of Oncology, Mayo Clinic, Rochester, MN; ‘Department of Endocrinology, Mayo Clinic, Rochester, MN
ABSTRACT
Introduction. Metastatic adrenocortical carcinoma (ACC) is rapidly fatal, with few options for treatment. Patients with metachronous recurrence may benefit from surgical resection. The survival benefit in patients with hematoge- nous metastasis at initial presentation is unknown.
Methods. A review of all patients undergoing surgery (European Network for the Study of Adrenal Tumors) stage IV ACC between January 2000 and December 2012 from two referral centers was performed. Kaplan-Meier esti- mates were analyzed for disease-free and overall survival (OS).
Results. We identified 27 patients undergoing surgery for stage IV ACC. Metastases were present in the lung (19), liver (11), and brain (1). A complete resection (R0) was achieved in 11 patients. The median OS was improved in patients undergoing R0 versus R2 resection (860 vs. 390 days; p = 0.02). The 1- and 2-year OS was also improved in patients undergoing R0 versus R2 resection (69.9 %, 46.9 % vs. 53.0 %, 22.1 %; p = 0.02). Patients undergoing neoadjuvant therapy (eight patients) had a trend towards improved survival at 1, 2, and 5 years versus no neoadjuvant therapy (18 patients) [83.3 %, 62.5 %, 41.7 % vs. 56.8 %, 26.6 %, 8.9 %; p = 0.1]. Adjuvant therapy was associated with improved recurrence-free survival at 6 months and 1 year (67 %, 33 % vs. 40 %,
20 %; p = 0.04) but not improved OS (p = 0.63). Sex (p= 0.13), age (p=0.95), and location of metastasis (lung, p = 0.51; liver, p = 0.67) did not correlate with OS after operative intervention. Symptoms of hormonal excess improved in 86 % of patients.
Conclusion. Operative intervention, especially when an R0 resection can be achieved, following systemic therapy may improve outcomes, including OS, in select patients with stage IV ACC. Response to neoadjuvant chemother- apy may be of use in defining which patients may benefit from surgical intervention. Adjuvant therapy was associ- ated with decreased recurrence but did not improve OS.
Adrenocortical cancer is a rare and aggressive malig- nancy with an incidence of 1/1,000,000 individuals annually.1,2 About one-third of patients have distant metastases at initial presentation,3 and few options for definitive treatment. In patients with locoregional disease, surgery has been the mainstay of treatment, with overall 5-year survival ranging from 16 to 37 % in large series.4
In patients with hematogenous metastases, surgery has often been considered only in the palliative setting, such as for bleeding or hormonally active tumors. More than 50 % of patients may present with functional tumors, such as cortisol, aldosterone, or mixed hormonal-secreting tumors.” Hormonal excess, especially hypercortisolism, may be the cause of mortality in patients with a more indolent course associated with their adrenocortical carcinoma (ACC). However, the mainstay of care in patients with metastatic disease present at the time of initial presentation has been chemotherapy with multimodality treatment. The recently published results from the FIRM-ACT study showed
@ Society of Surgical Oncology 2014
First Received: 12 April 2014; Published Online: 5 August 2014
G. B. Thompson, MD e-mail: thompson.geoffrey@mayo.edu
efficacy in patients with stage IV ACC treated with mito- tane, etoposide, doxorubicin and cisplatin, and is considered by many to be the treatment of choice. This regimen is poorly tolerated due to its overall toxicity, and many patients are unable to undergo the entire course of prescribed therapy. Used as sole therapy, survival in these patients, despite this aggressive regimen, remains dismal, with response rates of only 23 % and median survival of 14 months.6
Surgery has been thought not to confer any survival advantage in patients with synchronous metastatic adre- nocortical cancer. Once disease has progressed beyond direct extension from the adrenal bed, no previous reports have clearly displayed a survival advantage to operative intervention. Given the poor survival statistics, even with aggressive therapy, the risks and recovery required from a multivisceral operation in attempts to eradicate disease has not been viewed favorably, with few institutions offering
aggressive intervention in these patients. The overall morbidity and rapidity of recurrence has been a deterrent to offering operative intervention to patients with extensive disease. There are no well-powered reports that have examined multimodality chemotherapy agents as neoad- juvant therapy combined with operative intervention.
When examining the current available literature, we find multiple difficulties are encountered when approaching previous data on these patients. Data are scarce, and these patients are often included in case series with ACC patients with either different stages or patients with metachronous metastases. The existence of two staging systems makes the analysis difficult as it may be unclear whether patients with stage IV disease have distant metastases which are favored in European systems or locally advanced disease with direct extension or nodal metastasis such as found in the American Joint Committee on Cancer (AJCC) staging system. The 2004 Union for International Cancer Control (UICC) staging classification for ACC was found to have significant limitations, and revised classification with superior prognostic accuracy that was previously proposed (European Network for the Study of Adrenal Tumors [ENSAT]) was used in this study.7 Describing this distinct group of patients in more detail is warranted to determine if there is a role for surgery and identify factors predictive of long-term survival.
METHODS
Records of patients who underwent surgery for ACC from January 2000 to December 2012 at the Mayo Clinic, Rochester, MN, and the University of Texas MD Anderson Cancer Center, Houston, TX, were reviewed retrospec- tively. Patients were included in this study if they showed
DFOV 96.1 cm
6.00
0.00
+
·
signs of hematogenous metastases at the time of presen- tation. Hematogenous metastases were defined as disease present in sites separate from the peri-adrenal area; patients with isolated direct extension, such as invasion of the renal capsule or hepatic parenchyma, those with only vena caval tumor thrombus, or those with only regional nodal metas- tasis were not included in this study unless they also showed signs of concurrent distant metastatic disease.
Patients were examined for recurrence-free survival (RFS), overall survival (OS), and use of neoadjuvant therapy or adjuvant therapy. Disease-free interval (DFI) was defined as the time from resection of ACC to detection of the first recurrence on imaging. OS was defined as the time from first resection to last follow-up or time of death.
Each patient underwent a comprehensive preoperative evaluation by a multidisciplinary team involving endocri- nologists, medical oncologists, and surgeons. Staging was evaluated according to the current ENSAT staging system. Follow-up was performed at regular intervals of 3-6 months postoperatively, with computed tomography scans as the main modality for documentation of recur- rence; positron emission tomography imaging with 18F- fluorodeoxyglucose was performed at the discretion of providers (Fig. 1). Institutional Review Board Approval was obtained for this study at both study sites.
Statistical analysis was performed with SAS software, version 9.2 (SAS Inc., Cary, NC, USA). Survival curves were performed using the Kaplan-Meier method. Pearson’s v2 or Fisher’s exact tests were used for comparison of nominal data for baseline characteristics. Ordinal data were compared with the Spearman rank-order correlation coefficient.
RESULTS
We identified 27 patients who presented with metastatic ACC and subsequently underwent surgery, 7 patients from the MD Anderson Cancer Center and 20 patients from the
| Feature | Median (range) |
|---|---|
| Age at time of surgery (years) | 50 (23-71) |
| Sex (male/female) | 4/23 |
| N | |
| Hormonal status on presentation | |
| Functional | 14 |
| Non-functional | 13 |
| Systemic therapy total | 23 |
| Neoadjuvant | 8 |
| Neoadjuvant mitotane only | 9 |
| Adjuvant | 8 |
| Adjuvant mitotane only | 6 |
SR
Mayo Clinic, Rochester (Table 1). Distant metastases at the time of diagnosis were present in the lung (15), liver (7), both the lung and the liver (4), and brain (1) (Fig. 2; Table 2). Two patients underwent cardiac bypass to remove associated tumor thrombus from direct extension of the tumor within the vena cava but did not experience complications associated with placement on bypass and tumor thrombus extraction. One patient died within 30 days postoperatively, with no patients requiring return to the operating room within the immediate postoperative period for surgical complications.
A complete resection (R0) was achieved in 11/27 patients. Of these patients, eight received neoadjuvant therapy prior to intervention. The median OS was improved in patients undergoing R0 versus R2 resection (860 vs. 390 days; p = 0.02) The 1- and 2-year OS was also improved in patients undergoing R0 versus R2
| Metastases | N |
|---|---|
| Single site | 23 |
| Lung | 15 |
| Liver | 7 |
| Brain | 1 |
| Multiple sites-lung and liver | 4 |
| Total metastasectomies | 15 |
| Liver resections | 10 |
| Lung resections | 5 |
| Liver and lung resections | 0 |
| Other metastasectomies | 0 |
| Disease status after resection | |
| NED | 9 |
| Not NED | 18 |
NED no evidence of disease
Survival by Resection Status
100
80
R0
Percent
60
40
20
R2
0
0
6
12
18
24
Number at Risk R0 12
Months
10
7
7
5
R2 15
7
6
3
1
resection (69.9 %, 46.9 % vs. 53.0 %, 22.1 %; p = 0.02) (Fig. 3).
Neoadjuvant therapy was administered to eight patients in the form of mitotane, etoposide, doxorubicin and cisplatin, and one patient receiving only mitotane preoperatively. Regression or stability of disease was confirmed radio- graphically in all but one patient who underwent neoadjuvant therapy. This patient showed slow progression of disease despite therapy, but radiographically showed that an R0 resection would be attainable with multivisceral resection including a partial hepatectomy. Those who underwent pre- operative therapy had a trend towards improved survival at 1, 2, and 5 years versus no neoadjuvant therapy (18 patients) (83.3 %, 62.5 %, 41.7 % vs. 56.8%, 26.6%, 8.9 %, p = 0.1) (Fig. 4).
Survival by Neoadjuvant Chemo
100
80
Neoadjuvant Chemo
Percent
60
40
No Neoadjuvant Chemo
20
0
0
6
12
18
24
Number at Risk
Months
Non-Neo19
10
8
6
3
Neoadj 8
7
5
4
3
Disease Free Survival by Adjuvant Therapy
100
80
No Adjuvant Therapy
Percent
60
40
20
Adjuvant Therapy
0
0
6
12
18
24
Number at Risk Non-Adj 7
Months
5
4
4
3
Adj
5
2
1
1
1
There were 14 patients who underwent postoperative adjuvant therapy with either systemic mitotane therapy alone or in combination with systemic cytotoxic chemo- therapy. One patient was noted to receive adjuvant radiation therapy in combination with chemotherapy. However, the small sample size of patients treated with radiation, as well as confounding factors such as combi- nation with chemotherapy, prevent analysis of its benefit. Systemic chemotherapy postoperatively in most cases involved the same regimen that was utilized in the neo- adjuvant setting. Adjuvant therapy was associated with improved RFS at 6 months and 1 year (67 %, 33 % vs. 40 %, 20 %; p = 0.04) (Fig. 5) compared with patients undergoing neoadjuvant therapy but not improved OS (p = 0.63).
Sex (p = 0.13), age (less than 50 years vs. greater than 50 years) [p = 0.95], and location of metastasis (lung, p = 0.51, liver p = 0.67) were not correlated with OS after operative intervention. In 86 % (12/14) of patients
undergoing surgery, symptoms of hormonal excess and pain improved, which was due to hypercortisolism in all cases.
DISCUSSION
Adrenocortical cancer is often diagnosed with distant metastatic disease.5,7 The only well-studied therapy has been systemic therapy, either in the form of mitotane therapy alone or combined with systemic cytotoxic ther- apy. However, this has produced few long-term survivors and is, overall, poorly tolerated secondary to significant toxicity and side effects. Data suggest that there may be a small survival advantage with mitotane therapy, which may need to reach therapeutic levels of 14-20 ug/dL to be effective.8 There has also been limited evidence supporting the use of radiation therapy in the palliative setting for the management of ACC, although a palliative response has been reported in up to 73 % of patients. However, patients with stage IV disease survived a median of only 5.6 months.9
The concept of using neoadjuvant therapy in stage IV patients emerged from several scenarios from different institutions. In patients with symptoms of excess cortisol levels, the surgical approach at Mayo Clinic has often been aggressive in managing these patients as their mortality can often be associated with their cortisol excess rather than tumor burden. Other patients with stage IV disease have been treated without intent for surgical resection. However, with favorable responses to therapy and either regression or lack of progression, especially in young patients, surgery has been considered and anecdotally appeared to delay progression of further disease. The MD Anderson Cancer Center has previously published the correlation between a favorable response to chemotherapy and improved post- operative outcomes in patients with resectable ACC.10 This combined experience, along with the improvements in therapy seen in the FIRM-ACT trial, led to examination of this unique patient population.
Complete surgical resection has consistently been found to be the most significant predictor for survival in patients with ACC and appears to be improved compared with patients treated with definitive chemotherapy based on comparison of median survival in previous studies. Grubbs et al.11 have emphasized the importance of complete resection relative to the modest benefit likely achieved with mitotane therapy in the adjuvant setting. While widely accepted for colorectal cancer liver metastases, surgery has also been shown to offer benefit in long-term survival for selected patients with non-colorectal liver metastases,1 although it is unclear if these data can be applied to met- astatic ACC. In our data we did find a significant
improvement in OS in patients achieving an R0 resection and, aside from palliation, is a main consideration before offering patients operative intervention for metastatic ACC. As an adjunct, adjuvant therapy has been used postoperatively but does not seem to have a clear survival benefit. We did find that it improved patients’ disease-free survival and once therapy ceased, there was no difference in mortality. It appears that surgery, especially with an R0 resection, may turn back the clock and aid in improving survival, while chemotherapy may only temporarily delay progression.
Icard et al. examined 253 patients with adrenocortical cancer over an 18-year period and identified 54 patients (21.3 %) with distant metastatic disease at the time of surgery whom underwent either operative biopsy or palli- ative resection. The 5-year survival rate was 0 % in this group of patients (p < 0.0001), with no survivors extend- ing beyond 9 months and few undergoing curative resection of their metastatic disease.5
Recently, several centers have published data regarding metastasectomy for stage IV disease, suggesting that this may result in improved OS compared with historical con- trols as median survival ranged from 22.8 to 50.2 months despite distant metastatic disease. However, these studies included both patients with synchronous and metachronous disease, and patients with stage IV at the time of presenta- tion represented between 13 and 44 %.13-15 This is an important issue as patients with metachronous disease may need to be observed separately, potentially representing less aggressive tumor biology. Indeed, longer DFI after primary adrenalectomy was associated with longer survival.14 Interestingly, the presence of synchronous versus metach- ronous metastases was not found to affect survival, although this may be attributed to small numbers of patients. 14,15 Therefore, we specifically addressed surgical management of patients with distant metastases at initial presentation as this distinct group may represent a particular challenge in surgical decision making. To our knowledge, this is the largest series of such patients showing that patients with stage IV disease also benefit from an aggressive surgical approach, with our study showing a 70 % 1-year and 47 % 2-year survival rate in patients achieving no evidence of disease status (NED) with resection.
Resection to NED should be the goal as it may offer survival advantage; however, the majority of patients pre- sented with symptoms resulting from either hormonal excess or compression and invasion into surrounding structures. While the impact on survival achieved by deb- ulking, with or without additional systemic treatment, remains unclear, the vast majority of patients (86 %) did experience symptomatic improvement. This is another potentially important role for surgery, even if complete resection is not thought to be feasible since the stigmata of
hypercortisolism and overall hormonal excess can be debilitating, if not the cause of mortality, in ACC patients.
A major challenge in patients with metastatic disease is determining who will benefit from surgical therapy. The University of Texas MD Anderson Cancer Center has approached these patients with a preference towards treatment with neoadjuvant therapy prior to offering operative intervention, an approach that has also been selectively utilized at Mayo Clinic. This has several potential benefits. It allows one to pretreat tumors possibly facilitating a complete resection with a lower rate of positive margins. In cases of recurrence or positive margins at time of surgery, it may be useful to know the tumor’s sensitivity to systemic agents for postoperative therapy.
Patients who regress or do not show progression of disease during administration of chemotherapy may have a more favorable tumor biology that may benefit from sur- gical intervention. Recent data from Bednarski et al. in patients with borderline resectable adrenocortical cancer has shown an improvement in OS with the use of neoad- juvant therapy, mainly in the form prescribed by the FIRM- ACT trial in a multimodality and multidisciplinary fashion. Regression of disease while on neoadjuvant therapy may facilitate an R0 resection, especially in cases of multivis- ceral resection, which is an important factor in improving OS.16
An inherent limitation of this study is its retrospective design. Patients are highly selected when offered operative intervention for stage IV disease at time of presentation, with combinations of radiographic appearance, response to neoadjuvant therapy, age, and overall health status evalu- ated by a multidisciplinary team. The response to neoadjuvant therapy has played a role in deciding who is a candidate for surgery. Although we did not reach statistical significance when comparing patients undergoing neoad- juvant therapy with those who did not, further studies and possibly multicenter trials would give us greater insight in understanding the role of neoadjuvant therapy combined with surgery.
CONCLUSION
Surgery may be appropriate for selected patients pre- senting with distantly metastatic ACC. In this study of two large referral centers, initial experience with surgery has been promising. The use of neoadjuvant therapy provides encouraging results as it appears to aid in achieving a complete resection of disease and shows a trend towards improved survival. These data support the importance of achieving an R0 resection when approaching patients with metastatic disease in order to prolong OS as this was found to be significant in extending OS, even in patients with hematogenous metastases of ACC. Palliation may be
achieved in patients with disseminated disease and hor- monal excess. Further studies and collaboration among multiple institutions are needed to further understand the role of surgery in patients with metastatic ACC.
DISCLOSURE Benzon M. Dy has nothing to disclose.
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