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Treatment and management of adrenal cancer in a specialized Australian endocrine surgical unit: approaches, outcomes and lessons learnt
Grace T. Y. Kwok OD,* Jing-Ting Zhao,* Anthony R. Glover DD,*+# Julian C. Y. Ip,*# Mark Sywak, t# Roderick Clifton-Bligh,*t§ Stephen Clarke, *[ Bruce Robinson*t§ and Stan B. Sidhu*++
*Cancer Genetics Laboratory, Kolling Institute, Northern Sydney Local Health District, Sydney, New South Wales, Australia tFaculty of Medicine and Health, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia
University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Sydney, New South Wales, Australia
§ Department of Endocrinology, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales, Australia and 1Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia
Key words
adrenal cancer, endocrine malignancy, long-term outcomes, multidisciplinary meeting, specialist endocrine surgery unit.
Correspondence
Professor Stan B. Sidhu, University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, 202/69 Christie Street, St Leonards, Sydney, NSW 2065, Australia. Email: stansidhu@nebsc.com.au
G. T. Y. Kwok BMBS; J. T. Zhao PhD; A. R. Glover FRACS, PhD; J. C. Y. Ip FRACS,
PhD; M. Sywak FRACS; R. Clifton-Bligh FRACP, PhD; S. Clarke PhD, FRACP; B. Robinson FRACP; S. B. Sidhu FRACS, PhD.
Accepted for publication 11 November 2018.
doi: 10.1111/ans.15032
Abstract
Background: Adrenocortical carcinoma is a rare and heterogeneous malignancy with poor outcomes. Recent research has suggested that outcomes may be improved by centralization of care in specialist centres. We review our evolving 21-year experience in managing adre- nocortical carcinoma with a view towards outcomes and lessons learnt.
Methods: A retrospective study of patients treated in our specialist endocrine surgical unit over 21 years was undertaken.
Results: Thirty-five patients were treated from diagnosis, 29 forming a primary study cohort. Additionally, seven patients were referred to us for quaternary care, forming a secondary study cohort. The European Network for the Study of Adrenal Tumours (ENSAT) stage and immu- nohistochemical marker Ki-67 index were strong prognostic indicators for survival.
Conclusions: Early stage, complete resection and Ki-67 <10% are the best prognosticators for survival. Aggressive surgical resection at index operation and of recurrent oligometa- static disease along with multimodal adjuvant treatment has led to long-term survivors of patients with Stage 4 disease in our aggregate cohort.
Introduction
Adrenocortical carcinoma (ACC) is a rare, heterogeneous endocrine malignancy with an incidence of two per million population.1 It is an orphan cancer for which outcomes and survival rates have not improved in the past decades. Many of the guidelines for diagnosis and management arise from European1,2 and American centres,3 that have the advantage of analysing large aggregated numbers of patients. The European Society of Endocrinology4 recently pub- lished consensus guidelines advocating for en bloc resection of sus- pected ACC with locoregional lymphadenectomy in localized disease. In patients with limited intra-abdominal metastases, total surgical resection in one operation where possible is recommended. However, there is a limited role for surgery in widespread intra- abdominal disease.
Various endocrine surgical units around the world have pub- lished their case series results. All report that earlier stage and cura- tive resection offer better prognoses.5-9 Current studies report on better outcomes according to pathological measures such as mitotic rate10 and Ki-67,11 response to mitotane treatment12 and reception of adjuvant treatment.13 There has been scant publication in Aus- tralasia regarding outcomes of ACC management. Ip et al.14 presented the first Australian ACC series examining clinical outcomes and prognostic factors at a state level using a cancer reg- istry, suggesting that management of ACC in a specialized tertiary surgical/oncological unit may confer improved outcomes. However, individual unit outcomes are yet to be reported. The University of Sydney Endocrine Surgery Unit at Royal North Shore Hospital has sought to establish multidisciplinary expertise and experience in treating this rare cancer to provide a resource and specialist care for
patients in Australia. Here, we describe our experience of ACC with a focus on approach, outcomes and lessons learnt.
Methods
The University of Sydney Endocrine Surgical Unit maintains a com- prehensive database of all cancers managed. Patients give written consent for tissue collected and clinical data used in research. A retro- spective review was conducted for all patients managed for ACC. Thirty-five patients whose primary management (work up, surgical and adjuvant management) was undertaken by our unit were identi- fied for review - accrued from 1 January 1997 to 31 December 2017. Six patients lost to follow-up were excluded. The final primary cohort comprised 29 patients. Seven patients formed a secondary cohort, referred to our unit for quaternary care, initially managed (neoadju- vant, surgical) at other Australian centres. Together, they formed an aggregate cohort of 36 patients for analysis.
For our primary cohort of 29 patients, information on age, gender, tumour size, clinical presentation, stage, histological assessment, treat- ment (type of surgery and neoadjuvant/adjuvant treatments including radiotherapy, chemotherapy and adrenolytic mitotane) and outcomes was collected. Tumour staging followed the European Network for the Study of Adrenal Tumours (ENSAT) staging system.15 Overall survival time was determined from date of operation to date of death or censor period of end 2017. Time to local recurrence was calculated from time of operation. Resection margins were determined from operation and histopathology reports. Medians and ranges were used for continuous data, while rates were used for categorical data. Survival curves were generated via the Kaplan-Meier method (GraphPad Prism, version 7.0b, San Diego, CA, USA) and compared by log-rank testing. Fisher’s exact test was used to determine the independence of categorical data. P-values of <0.05 were considered statistically significant.
Results
Patient clinical characteristics: primary cohort
The median age of the primary cohort was 49 years (range 25-77 years), with 14 males and 15 females treated. Weiss criteria16 were used for ACC diagnosis and five Stage 2 ACC patients had a histological subset of adrenocortical tumours - oncocytic tumours. Median follow-up time was 60 months (range 1-157 months). Of the 29 patients, 16 (55%) remain alive. The median survival of the pri- mary cohort is 130 months (range 8-157 months). Overall absolute 5- and 10-year survival rates were 52% (16/29) and 24% (7/29), respectively. There was recurrence in 13 patients (45%). Recurrence- free survival (RFS) was a median of 108 months (range 0-157).
Patients who presented with ACC had varied presentations with functional and non-functional tumours and underwent different sur- gical approaches and medical modalities. These and patient clinical characteristics are summarized in Table S1.
ENSAT stage confers survival advantage: primary cohort
In our primary cohort, ENSAT stage conferred survival advantage (P = 0.009; Fig. 1a). All Stage 1 and Stage 2 oncocytoma patients
remain alive at censor date. Median survival for Stage 2 (non-oncocy- toma) was 130 months, Stage 3 was 57 months and Stage 4 was 16 months.
Management of advanced disease: Stage 4 and recurrent disease in the aggregate cohort
In the primary cohort of 29 patients, recurrence in 13 (45%) patients saw four reoperated on. For the seven patients in the secondary cohort, median survival was 33 months (range 2-55 months) with most (86%) receiving etoposide, doxorubicin and cisplatin (EDP) chemotherapy and mitotane. These patients had a range of treatments including re-operation and trial of experimental therapies with sur- vival ranging from less than 12 months to greater than 4 years (Table S2). One salient aspect was that two patients had a primary surgical intervention with less than optimal oncological clearance - one had inadequate resection of aortocaval lymph node disease and another incomplete resection of hormonally functional adrenal tumour at laparoscopic surgery. In this group, even when surgical treatment was optimized at second surgery, disease was aggressive.
In the aggregate cohort, six cases of advanced ACC and recur- rence were managed aggressively with surgery: two patients had synchronous resection of hepatic metastases and four with oligome- tastatic recurrence, achieving alleviation of symptoms associated with excess cortisol. Non-surgical modes of therapy included radio- therapy, chemotherapy, mitotane, TACE and experimental nanocell (EnGeneIC Delivery Vehicles (EDVs), Sydney, New South Wales, Australia) treatment.17 There was significant usage (P = 0.03) of two and more modes of adjuvant therapy (chemotherapy, radiother- apy and mitotane) between the patients with recurrence (72%) and those without recurrence (39%). Two patients (11%) with recur- rence received chemotherapy, radiotherapy, mitotane and nanocell (EDV) therapy (four modes), reflecting our aggressive approach to managing recurrence (Table S3).
In the aggregate cohort, seven (19%) patients were assessed for nanocell therapy in an attempt to facilitate tissue-specific drug deliv- ery via bacterially derived EDV nanocells.18-20 Three were treated; one with microRNA-7 therapy,21 another with sequential treatment of nanocell-delivered siRNA (small interfering RNA) targeting MDR1 (Multidrug Resistance Protein 1)22 followed by nanocell- packaged doxorubicin23 and the third with a nemorubicin metabo- lite, PNU-159682, delivered by EDV nanocells (unpublished data). These three patients achieved survivals to 55, 18 and 9 months from index operation, one remaining alive (patient with the 9-month sur- vival at censor date). Finally, one patient received immune check- point inhibitor BGB-A317 in combination with a PARP (poly ADP ribose polymerase) inhibitor BGB-290 as part of a clinical trial.24
Impact and utility of multidisciplinary meetings on the management of ACC
Formal Endocrine Oncology Multidisciplinary Team (MDT) meet- ings were established in 2013. Secondary cohort patients referred to the unit within 12 months of index operation at other centres (6/7) were included for analysis. In this period, a greater proportion of advanced ACC was managed (70% Stage 3/4 disease in MDT period
(a)
(b)
Percentage survival (%)
100
Stage 1
MDT period
Stage 2 - oncocytoma
Percent survival (%)
100
Pre-MDT period
Stage 2
50
Stage 3
50
Stage 4
p=0.009
n=35
p=0.7
0
0
0
50
100
150
200
0
50
100
150
200
Months alive post surgery
Months survival
Percentage survival (%)
(d)
100
Percent survival (%)
100
Ki-67≥10% (High)
Ki-67≥10% (High)
Ki-67<10% (Low)
50
Ki-67<10% (Low)
50
n=24
p=0.005
p=0.02
0
0
0
50
100
150
200
0
50
100
150
200
Months alive post surgery
Recurrence free survival (months)
versus 60% in pre-MDT period; Table 1). The impact of the MDT has seen patients treated with increasingly multiple modes of therapy (40% versus 16% trimodal therapy, MDT versus pre-MDT) versus the pre-MDT period. However, there was no survival advantage for patients treated in the MDT period versus pre-MDT (Fig. 1b).
The Ki-67 index is a prognostic index in the aggregate cohort
In the aggregate cohort of 36 patients, Ki-67 indices were available for 24 patients. Significant survival differences were identified for overall survival - median survival for tumours with high Ki-67 (≥10)25 was 29 months (hazard ratio 10.4, 95% CI 3-36 months, P = 0.003; Fig. 1c) versus 103 months with low Ki-67 (<10). All but one low Ki-67 (<10) patients remain alive. Survival advantage for low Ki-67 was identified additionally for RFS with a median RFS for high Ki-67 of 8 months (P = 0.02, hazard ratio 7.1, 95% CI 2.0- 24.7 months; Fig. 1d) versus 84 months for low Ki-67.
Stage 4 disease, actively managed, can lead to long survival
In the aggregate cohort, active management of metastatic and recur- rent disease saw four Stage 4 patients (31%) achieving relatively long survival over 48 months. This management has been charac- terized by aggressive surgical resection of primary and oligometa- static disease (three patients received neoadjuvant therapy, two
with disease response), and oligometastatic recurrence with increased use of multimodal adjuvant therapy.
Discussion
Here, we present the clinical characteristics, treatment approaches and outcomes of adrenal cancer from our specialized Australian endocrine cancer unit.
Our 5- and 10-year survival rates of 52% and 24% are comparable to other series where 5-year survivals ranged from 35%5,8,26 to 63%27 and 10-year survival rates ranged between 7%28 and 38%.29 Factors associ- ated with clear RFS and overall survival in our cohort are ENSAT stage and Ki-67 level. One interesting subset includes five patients with
| MDT era (2013-2017) | Pre-MDT (1997-2012) | |
|---|---|---|
| Number of cases | 10 | 25 |
| Mean cases per year | 2 | 1.6 |
| Female | 60 (%) | 56 (%) |
| Functional | 40 (%) | 40 (%) |
| Stage 3/4 | 70 (%) | 60 (%) |
| Multimodal therapy | ||
| 0, 1 or 2 modes | 6 (60%) | 21 (84%) |
| 3 modes | 4 (40%) | 4 (16%) |
| Surgery | ||
| R0 resection | 6 (60%) | 19 (76%) |
| MDT, multidisciplinary team. | ||
oncocytic tumours. Oncocytic tumours, where at least 50% of the tumours comprise oncocytic cells, have been described as having more indolent courses compared to conventional ACC, with improved survival.30-32 This was confirmed in our cohort where Stage 2 oncocytic ACCs had equivalent survival to high Ki-67 non-oncocytic Stage 1 ACC.
Formal implementation of the MDT in 2013 coincided with a larger proportion of advanced disease being managed. In this MDT period versus prior period, patients were increasingly managed with multimodal therapies, including radiotherapy, chemotherapy and mitotane. Five of the seven referrals for nanocell therapy occurred in the MDT period. However, there was no survival advantage for MDT era patients, which may be explained by more aggressive dis- ease in the MDT period (40% versus 24% R1 resection). Although experimental treatment has yet to demonstrate improved survival, it remains a valuable option for patients who have exhausted conven- tional adjuvant treatments.
In contrast, cell proliferation marker Ki-67 conferred survival advan- tage for overall survival and RFS. In our aggregate cohort, high Ki-67 (≥10) had median overall survival of 29 months, one-third of low Ki- 67 patients. Low Ki-67 patients had a tenfold recurrence-free interval of 84 months compared with high Ki-67. Ki-67 has established impor- tance in adrenal tumour assessment,33,34 surpassing the role of mitotic rate.35 Studies have also linked Ki-67 as a powerful predictor for recur- rence11,36 and prognosis25 in ACC. Ki-67 clearly has great utility for counselling patients regarding prognosis and further treatment.
Beuschlein et al.11 established the value of Ki-67 in Stage 1-3 patients with R0 resection. In our cohort, the prognostic value of Ki- 67 was seen in Stage 4 patients and R1 resection as well. We note that two Stage 4 patients with multiple metastases with low Ki-67 levels responded well to adjuvant therapies. One is a long-term current sur- vivor and another had metastases to bone, liver, brain and thyroid sur- viving over 4 years from index operation. Although high Ki-67 indicates increased cell proliferation, its molecular role in tumour response to adjuvant therapy warrants further investigation. Given the apparent importance and utility of Ki-67 in predicting for recurrence and prognosis, we recommend routine Ki-67 reporting.
Our approach to advanced disease was aggressive: complete en bloc surgical resection where feasible which is supported by the international literature.2,4,37 There is evidence that complete re- section of primary adrenal disease confers survival benefits even in the presence of metastatic disease.38,39 In our secondary cohort, two patients were referred with incompletely resected disease at index operation, both undertaken laparoscopically. There is considerable literature cautioning against laparoscopic adrenalectomy for known malignancy;40,41 however, in both these cases the surgeon did not suspect malignancy. We recommend conversion to open operation in the presence of a hormonally functional adrenal mass over 6 cm with intraoperative evidence of local invasion, difficult dis- section planes or marked tumour vascularity.
Furthermore, we have observed a tendency to palliate patients with oligometastatic recurrence. In appropriate patients, surgical re- section has benefit and this is supported in the international literature.7,42-44 A major benefit of this approach is to palliate the symptoms of cortisol excess for functional tumours difficult to con- trol with medical management due to disease burden.
In our aggregate cohort, survival beyond 48 months post original resection in Stage 4 patients was achieved in four patients. They survived to 52, 54, 55 and 108 months, with two currently alive. These patients are characterized by having aggressive resection of their primaries, oligometastases and recurrences, followed by well- tolerated adjuvant therapy.
In conclusion, we report on our experience in managing ACC in our specialized endocrine surgical unit over 21 years, managing a large number of advanced and metastatic cases of ACC, as a quater- nary referral centre for ACC. We find it possible to achieve long sur- vival in Stage 4 ACC, these patients having in common response to neoadjuvant, adjuvant therapy and complete surgical resection. Ki- 67, a powerful prognostic indicator in ACC, is valuable in the Aus- tralasian setting for overall survival and RFS including R1 re- section and Stage 4 patients. We recommend Ki-67 be routinely performed in all ACC cases and considered when counselling patients for further treatment. Establishment of a formal endocrine MDT in 2013 has coincided with a greater proportion of advanced and com- plex disease, use of multimodal therapy and referral for experimental therapy where conventional treatment options are exhausted.
Acknowledgements
Grace Kwok is a recipient of the RACS Foundation for Surgery Catherine Marie Enright Kelly Scholarship for 2016.
Conflicts of interest
None declared.
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Supporting information
Additional Supporting Information may be found in the online ver- sion of this article at the publisher’s web-site:
Table S1. Clinical features and treatment modalities of the primary cohort of patients by their ENSAT (European Network for the Study of Adrenal Tumours) stage.
Table S2. Clinical courses of secondary cohort patients.
Table S3. Usage of adjuvant therapy in the aggregate cohort (n = 36) with recurrent and non-recurrent disease.