ORIGINAL ARTICLE - ENDOCRINE TUMORS
Improving Outcomes in Adrenocortical Cancer: An Australian Perspective
Julian C.Y. Ip, MBBS, BMedSc1,2,3, Tony C.Y. Pang, MS, FRACS2,4, Anthony R. Glover, FRACS, MBBS1,2,3, Patsy Soon, PhD, FRACS5, Stephen Clarke, MBBS, PhD, MD, FRACP, FAChPM2, Arthur Richardson, MBBS, FRACS4, Peter Campbell, FRACS, MBBS5, Bruce G. Robinson, FRACP, MD1,2, and Stan B. Sidhu, PhD, FRACS1,2,4
1Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and The University of Sydney, Sydney, NSW, Australia; 2Northern Clinical School, The University of Sydney, Sydney, NSW, Australia; 3Endocrine and Oncology Surgical Unit, Royal North Shore Hospital and the University of Sydney, Sydney, NSW, Australia; 4Department of Surgery, Westmead Hospital, University of Sydney, Sydney, NSW, Australia; 5South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia
ABSTRACT
Background. Adrenocortical carcinoma (ACC) is a rare malignancy that carries a poor prognosis. There has yet to be a large Australian series that documents the character- istics of ACC and there are a paucity of data on management and the long-term outcomes. We sought to provide a unique insight into the management of ACC in Australia as well as to identify factors associated with prognosis and survival.
Methods. A multivariate analysis of a cohort of patients identified with ACC between 1998 and 2013 was under- taken. Recurrence-free survival (RFS) and overall survival (OS) were assessed as the main outcome measures and correlated with multiple clinical variables in order to identify prognostic markers.
Results. Of the 104 patients identified, a total of 98 patients with complete clinical and outcome data were included in the study. Median OS was 56 months, with the 5-year survival being 48 % (95 % confidence interval 36- 59). On multivariate analysis, age ≥50 years, metastases at presentation, and evidence of extra-adrenal invasion were found to be statistically associated with reduced OS. RFS was analyzed in patients without metastases. On multi- variate analysis, extra-adrenal invasion and no preoperative endocrine investigations were found to be statistically
significant poor prognostic factors, with a non-significant trend for higher individual surgeon volume to be associated with improved resection margins and RFS.
Conclusions. We present clinical outcomes and prognostic factors for patients with ACC in a landmark Australian series. We suggest that management in a specialized ter- tiary endocrine and/or surgical oncology unit is more likely to lead to improved outcomes.
Adrenocortical carcinoma (ACC) is a rare heteroge- neous malignancy, with an incidence of 0.5-2.0 per million population.1 Significant morbidity and resultant mortality arises as a result of locally aggressive disease, frequent metastases, as well as abnormal hormone production. The disease typically has a bimodal age presentation, occurring in the pediatric years as well as in the 40-50 years age bracket.2 Its pathogenesis has been poorly understood and has been linked to various inherited cancer syndromes, although the majority are sporadic.3 As such, there has been a significant amount of research examining the genomic, epigenomic, and transcriptome alterations in benign and malignant adrenal tumors.4
Despite the significant advances in understanding of the disease, ACC carries a dismal prognosis, with reported 5-year overall survival (OS) rates varying between 35 and 60 %.5-9 Our understanding of the clinical outcomes for patients with ACC have largely arisen from various case series in European and Northern American tertiary referral centres.6
To the best of our knowledge, there has yet to be an Australian series summarizing the clinical care and
@ Society of Surgical Oncology 2014
S. B. Sidhu, PhD, FRACS e-mail: stansidhu@nebsc.com.au
outcomes of patients with ACC. We sought to provide a unique Australian perspective that summarizes the impor- tant clinical aspects of ACC, from initial diagnosis and workup to management and outcomes. We also sought to determine factors associated with prognosis and survival.
METHODS
This multicenter study was undertaken with approval by the Northern Sydney Human Research Ethics Committee, with appropriate site-specific approval obtained. The lead investigating center was the University of Sydney Endo- crine Surgery Unit, Royal North Shore Hospital, with collection of data from teaching and district hospitals, both public and private across New South Wales (NSW). A cohort of 104 patients diagnosed with ACC that had been notified postoperatively to the NSW Cancer Registry from 1998 to 2013 was identified. Relevant clinical and outcome data were obtained from various sources, including hospital records and treating clinicians, and independently recorded by four investigators (JI, TP, AG, PS) to ensure accuracy in the data collection. All data were then entered into one database using Microsoft Excel 2011 (Microsoft Corpora- tion, Redmond, WA, USA) and then verified and agreed upon by at least two investigators.
Endocrine workup of each patient was assessed by exam- ining the medical records for results of biochemical investigations related to hormonal overproduction. Resection margins were determined from operative and histopathology reports and recorded in a standard fashion (R0, complete resection; R1, microscopic evidence of residual tumor with positive margins; R2, macroscopic evidence of residual tumor). The European Network for the Study of Adrenal Tumours (ENSAT) staging system was utilized as it was considered superior to TNM staging.11,12 The evaluation of medical management included an assessment of the use of adjuvant radiotherapy, chemotherapy, and mitotane therapy.
Clinical outcome data were determined from the date of death, as recorded by the NSW Cancer Registry. Survival times were determined from the date of surgery. OS was defined by censoring at the date of death from any cause or the date of last follow-up. Recurrence-free survival (RFS) was only determined in patients with no evidence of metastases at presentation. Time to recurrence in this case was determined by the date of death or date of recurrence of any type (local regional or distant). Patients were otherwise censored at date of last follow-up.
Statistical Analyses
Descriptive statistics were presented as mean ± stan- dard deviation, median (interquartile range [IQR]), or as
counts (%), depending on distribution. The relationship between surgeon volume and R status was evaluated using Fisher’s exact test.
Survival analysis of the cohort was described using the Kaplan-Meier method. Inferential univariate and multi- variate analyses for survival were made using the Cox proportional hazard model. Covariates with p < 0.2 on univariate analysis were included in the initial multivariate model. The purposeful selection of covariates method was used to select variables for the final model (stepwise removal with clinically relevant covariates retained as necessary). The final model was then assessed for validity of the proportional hazards assumption using Schoenfeld residuals and goodness-of-fit using Cox-Snell residuals.
P values <0.05 were considered statistically significant. All analyses were performed on Stata SE version 11.2 for Windows (StataCorp LP, College Station, TX, USA).
RESULTS
Clinical Presentation and Patient Characteristics
In the 15-year period studied, a total of 104 patients underwent surgery to treat ACC in NSW. Of these patients, six had large amounts of missing clinical and follow-up data and were therefore excluded, leaving a total of 98 patients in the study. Patients’ clinical characteristics are summarized in Table 1.
Of note, most patients were female (n = 55 [56 %]) and the mean age was 48 ± 16 years. Metastases on imaging were noted in 19 patients (20 %), with 30 patients (32 %) having evidence of local invasion on preoperative imaging. The most common form of presentation was that of an incidental finding (n = 42 [43 %]), followed by hormonal symptoms (n = 33 [34 %]). Of the hormonally-active tumors, cortisol hyperse- cretion was the most common (n = 23 [23 %]). There were 5 patients (5 %) with ENSAT stage I disease, 36 patients (37 %) with stage II disease, 25 patients (26 %) with stage III disease, and 32 patients (33 %) with stage IV disease.
Treatment
Of the 98 patients included in the study, 94 (96 %) underwent operative management for their ACC. Of note, 9 (9.6 %) of these patients had no preoperative endocrine biochemical workup.
The operative approach for the majority of patients was via an open anterior laparotomy (n = 73 [74 %]). Intra- operative evidence of adjacent organ invasion was present in 38 patients (40 %), and intraoperative metastases were present in 28 patients (30 %). R0 resection was achieved in 48 patients (51 %), 36 patients (39 %) had an R1 resection,
| TABLE 1 Summary of patient characteristics | |
| Demographic characteristics | |
| Male sex | 43 (44) |
| Age [years; mean ± SD] | 48 ± 16 |
| Imaging characteristics | |
| Side (left) | 52 (55) |
| Imaging size [cm; mean ± SD] | 11 ± 5.2 |
| Metastatic disease on imaging | 19 (20) |
| Local invasion on imaging | 30 (32) |
| Presentation (each patient may present with | |
| multiple findings) | |
| Incidental | 42 (43) |
| Hormonal symptoms | 33 (34) |
| Mass | 21 (21) |
| Mets | 7 (7.1) |
| Hemorrhage | 5 (5.1) |
| Paraneoplastic | 2 (2) |
| Hormone secretion | |
| Cortisol | 23 (23) |
| Sex hormones | 9 (9.2) |
| Aldosterone | 5 (5.1) |
| Multiple | 4 (4.1) |
| Catecholaminesª | 1 (1.0) |
| Pathology | |
| Maximum tumour dimension [cm; mean ± SD] 11 ± 5.9 | |
| Weight [g; median (IQR)] | 312 (126-1,035) |
| Evidence of histological invasion | 37 (39) |
| Weiss scoreb [median (IQR)] | 4.5 (3.5-7.5) |
| ENSAT staging | |
| I | 5 (5) |
| II | 36 (37) |
| III | 25 (26) |
| IV | 32 (33) |
| Operation characteristics | |
| Approach | |
| Laparoscopic anterior | 17 (17) |
| Conversion | 3 (3.1) |
| Open anterior | 73 (74) |
| Open posterior | 1 (1.0) |
| No operation | 4 (4.1) |
| Metastatic disease at operation | 28 (30) |
| Invasive disease at operation | 38 (40) |
| Margin status | |
| R0 | 48 (52) |
| R1 | 36 (39) |
| R2 | 8 (9) |
| Medical therapy | |
| Radiotherapy | 67 (72) |
| Chemotherapy | 65 (66) |
| Mitotane | 45 (46) |
| TABLE 1 continued | |
| Survival | |
| Median follow-up [months] | 28 |
| Median overall survival [months (95 % CI)] | 56 (34-105) |
| 5-year overall survival [% (95 % CI)] | 48 (36-59) |
| Median recurrence-free survival [months; median (IQR)] | 60 (20-NR) |
| 5-year recurrence-free survival [% (95 % CI)] | 48 (32-62) |
Data are expressed as N (%) unless otherwise specified
ENSAT European Network for the Study of Adrenal Tumours, R0 no evidence of tumour, complete resection, R1 microscopic evidence of residual tumour with positive margins, R2 macroscopic evidence of residual tumour, NR not reached, SD standard deviation, IQR inter- quartile range, CI confidence interval
a Catecholamines only marginally elevated, final pathology showed adrenocortical carcinoma
b Only available for 40 patients
| Cases performed | Resection status [n (%)] | |
|---|---|---|
| R0 | R1/2 | |
| <5 | 18 (41) | 26 (59) |
| ≥5 | 30 (63) | 18 (38) |
and 8 patients (8.7 %) underwent an R2 resection. Two patients had missing data on resection status. Of the 20 patients who underwent laparoscopic resection and lapa- roscopic converted to open surgery, 3 (15 %) patients had tumor rupture/capsular breach.
There were 47 treating surgeons in this cohort; 41 (87 %) had operated on less than five of the cases during the study period, four surgeons (8.5 %) had done 5-10 of the cases, and only two surgeons (4.3 %) had done more than 10 resections. There was a trend for surgeons with a higher caseload to achieve a higher R0 resection rate (p = 0.06) [Table 2].
Radiotherapy was the most common medical treatment employed postoperatively, with 67 patients (72 %) receiving treatment as either adjuvant or palliative therapy. There were more than 15 different types of chemotherapy regimens utilized in 65 patients (66 %); however, only 18 of these patients (28 %) had data available for their che- motherapy regimens. Mitotane was utilized for 45 patients (46 %) of the total cohort.
Recurrence-Free and Overall Survival
The median follow-up for patients who underwent operative management (n = 94) was 28 months (Table 1).
A
100
Overall Survival (%)
75
50
25
0
0
24
48
72
96
120
144
168
Months
ENSAT 1
ENSAT 2
ENSAT 3
ENSAT 4
B
100
Disease-free Survival (%)
75
50
25
0
0
24
48
72
96
120
144
168
192
216
240
264
288
302
336
Months
95% Cl
Survivor function
Median OS in these patients was 56 months, with the 5- year survival being 48 % (95 % confidence interval [CI] 36-59). OS times in relation to ENSAT stage are shown in Fig. 1a.
On univariate analysis, age ≥50 years, size ≥10 cm, metastases at presentation, evidence of invasion on imag- ing, incomplete resection (R1/2 vs. R0 resection), evidence of histological invasion, and the lack of biochemical endocrine investigations preoperatively were all associated with reduced OS. Surgeon volume was not found to be a statistically significant factor. On multivariate analysis, only age ≥50 years, metastases on presentation, and evi- dence of extra-adrenal invasion were found to be statistically associated with poorer outcome. There was a trend for the lack of biochemical endocrine investigations preoperatively to be associated with poorer OS (Table 3).
RFS was analyzed in patients without metastases (Fig. 1b). There were a total of 66 patients with no
metastases. The 5-year RFS was 48 % (95 % CI 32-62), with a median RFS of 60 months (Table 1). Univariate analysis showed that male sex, evidence of invasion on imaging, R1/R2 resection, evidence of histological inva- sion, lack of endocrine biochemical investigations, and surgeon volume <5 cases were associated with poorer RFS (Table 4). On multivariate analysis, only evidence of extra- adrenal invasion and no endocrine investigations were found to be statistically significant poor prognostic factors. Importantly, there was a non-significant trend (p = 0.089) for higher surgeon volume to be associated with improved RFS (Table 4).
DISCUSSION
ACC remains a rare disease that has been the focus of intense study over the past few decades, yet still carries a poor prognosis. Australia has a widely-dispersed popula- tion with geographically scattered tertiary referral centres. When factoring in the rarity of ACC, the paucity of accumulated data on patients with ACC and their clinical outcomes is significant. We have collected data on a large cohort of ACC treated in an Australian healthcare envi- ronment utilizing data notified to a centralized state-wide cancer registry (NSW Cancer Registry) and report for the first time, outcomes in this cancer treated by a large number of different practitioners.
Older series have shown that even when patients present with early-stage disease, prognosis remains grim.13 More modern series have seen a small improvement in 5-year OS,5-9 possibly due to the increased use of mitotane and a better understanding of chemotherapeutic regimens.
The clinical features of patients in our cohort are com- parable to previous series.6-10 The 5-year OS rate of these other studies has ranged from 35 % to 45 %. Our 5-year OS rate of 48 % is also similar to what has been reported by these larger studies. The majority of patients in our cohort presented with stage II disease (37 %). This is consistent with the findings of Fassnacht and colleagues in 2009 when they reported the ENSAT classification system as providing a superior means of predicting prognosis over the 2004 Union for International Cancer Control (UICC) TNM staging system. 11,12
R0 resection remains the only potentially curative treatment of choice for ACC.5,7,9,10,14 Our results confirm previous reports, where an R1 or R2 resection is associated with significantly poorer outcomes, both for RFS and OS.1,9 There has been considerable debate regarding the role of laparoscopic surgery for ACC, with various retro- spective studies demonstrating comparable outcomes to patients with open adrenalectomy, whereas others have stated that the current standard of care for known cases of
| Covariate | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95 % CI) | p value | HR (95 % CI) | p value | |
| Age ≥50 years | 1.8 (1.0-3.3) | 0.040 | 3.5 (1.8-6.8) | <0.001 |
| Male sex | 1.6 (0.90-2.9) | 0.11 | ||
| Right side | 1.1 (0.59-1.9) | 0.81 | ||
| Size on imaging ≥10 cm | 2.1 (1.1-4.0) | 0.019 | ||
| Incidental presentation | 0.75 (0.41-1.4) | 0.36 | ||
| Hormonal symptoms | 1.3 (0.75-2.4) | 0.33 | ||
| Metastases on presentation | 3.7 (2.1-6.6) | <0.001 | 2.3 (1.2-4.5) | 0.014 |
| Invasion on imaging | 4.6 (2.4-8.8) | <0.001 | Not tested℃ | |
| Functional tumour | 1.2 (0.69-2.2) | 0.48 | ||
| Tumour weight ≥300 g | 1.2 (0.6-2.4) | 0.59 | ||
| R1/2 vs. R0 resection | 4.8 (2.3-9.7) | <0.001 | ||
| Histological invasion | 15 (5.0-43) | <0.001 | Not tested℃ | |
| Laparoscopic approachª | 0.52 (0.22-1.2) | 0.14 | ||
| Any invasionb | 12 (5.0-28) | <0.001 | 13.5 (5.0-36) | <0.001 |
| No endocrine investigations | 2.3 (1.0-5.2) | 0.046 | 2.1 (0.8-5.5) | 0.14 |
| Surgeon volume ≥5 | 0.94 (0.52-1.7) | 0.85 | ||
| Adjuvant chemotherapy | 1.7 (0.94-3.0) | 0.078 | Not testedd | |
| Mitotane | 1.7 (0.91-3.2) | 0.097 | Not testedd | |
| Radiotherapy | 1.2 (0.64-2.3) | 0.55 | Not testedd | |
Bold values are statistically significant (p < 0.05)
HR hazard ratio, CI confidence interval
a Laparoscopic approach included those who required conversion
b Evidence of extra-adrenal invasion either on imaging or on histopathological examination
” These two covariates were not tested in the multivariate model because the combined variable ‘any invasion’ was tested
d Adjuvant therapies were not tested as these treatments relate to poor prognosis and therefore cannot logically be tested as predictors of poor prognosis
ACC is still via an open approach, performed by a surgeon experienced in adrenal surgery.1,15-17 In our cohort, a total of 17 patients underwent complete laparoscopic resection, 3 of which were converted to an open operation. Of these 20 patients, 3 (15 %) had documented tumor capsule breach during laparoscopy. In several of the patients undergoing laparoscopic resection, the preoperative diag- nosis was that of a benign adrenal tumor. Whilst a preoperative diagnosis of ACC cannot always be made, we believe that if there is any suspicion of ACC, either pre- operatively or intraoperatively, an open approach or conversion to an open approach, with maximal exposure, is the ideal modality to achieve an R0 resection.
Although surgery remains the only potentially curative treatment, many patients, even with stage I/II disease, develop local and distant recurrence, presumably due to occult local and metastatic disease.2,18 Recurrence varies between 21 and 91 % in various series, most likely due to reporting variability and patient selection.5,14,19 If a tumor is considered unresectable, or in situations of local or
distant recurrence, there is some evidence to support deb- ulking as there may be survival benefits.5,9,20 However, some only advocate for debulking of hormonally-active tumors, where surgery may be of benefit in controlling the effects of hormone hypersecretion not otherwise controlled medically, and that may be hindering other therapies.2,14
Given that complete surgical resection is paramount in predicting outcomes, there are arguments to support that surgery for ACC should be undertaken in specialist centres.14,20 Outcomes in adrenal surgery are strongly linked with surgical volume for both benign and malig- nant disease, where Lombardi and colleagues showed that patients receiving operative care in high-volume centres (0.8 ± 0.3 cases per year) had a much better prognosis than those in low-volume centres (0.2 ± 0.2 cases per year).21 Consistent with this is our finding that patients operated by higher-volume surgeons had a higher R0 rate. There was a trend for these patients to have an improved RFS if they did not present with metastases (p = 0.089).
| Covariate | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95 % CI) | p value | HR (95 % CI) | p value | |
| Age ≥50 years | 1.8 (0.83-3.7) | 0.14 | ||
| Male sex | 2.4 (1.1-5.0) | 0.025 | ||
| Right side | 0.84 (0.37-1.9) | 0.68 | ||
| Size on imaging ≥10 cm | 1.2 (0.57-2.5) | 0.64 | ||
| Incidental presentation | 1.2 (0.55-2.5) | 0.68 | ||
| Hormonal symptoms | 1.3 (0.63-2.8) | 0.45 | ||
| Invasion on imaging | 3.5 (1.3-9.7) | 0.016 | Not testede | |
| Functional tumour | 1.0 (0.47-2.1) | 0.99 | ||
| Tumour weight ≥300 g | 1.1 (0.46-2.4) | 0.89 | ||
| R1/2 vs. R0 resection | 4.5 (2.1-9.6) | <0.001 | 2.4 (0.9-6.1) | 0.08 |
| Histological invasion | 11 (3.8-31) | <0.001 | Not tested | |
| Laparoscopic approachª | 0.87 (0.38-2.0) | 0.75 | ||
| Any invasionb | 7.4 (3.2-17) | <0.001 | 3.2 (1.2-9.0) | 0.024 |
| No endocrine investigations | 6.6 (2.2-20) | 0.001 | 4.4 (1.3-15) | 0.018 |
| Surgeon volume ≥5 | 0.40 (0.18-0.86) | 0.019 | 0.49 (0.21-1.1) | 0.089 |
| Adjuvant chemotherapy | 2.3 (1.1-4.8) | 0.027 | Not testedd | |
| Mitotane | 1.6 (0.7-3.4) | 0.26 | Not testedd | |
| Radiotherapy | 1.2 (0.52-2.7) | 0.68 | Not testedd | |
Bold values are statistically significant (p < 0.05)
HR hazard ratio, CI confidence interval
a Laparoscopic approach included those who required conversion
b Evidence of extra-adrenal invasion either on imaging or on histopathological examination
” These two covariates were not tested in the multivariate model because the combined variable ‘any invasion’ was tested
d Adjuvant therapies were not tested as these treatments relate to poor prognosis and therefore cannot logically be tested as predictors of poor prognosis
For these patients, access to a specialist center may confer a survival advantage, presumably through a more thorough preoperative assessment in an experienced mul- tidisciplinary setting with experienced endocrinologists, endocrine surgeons, and oncologists and pathologists experienced in adrenal pathology. It allows the patient to be linked to research programs so that more complete data can be obtained on all patients. Appropriate selection of adjuvant therapy would be available to patients as well as being exposed to systematic follow-up with hormone pro- file surveillance, together with monitoring of mitotane levels and other adjuvant treatments to ensure maximum efficacy with the lowest toxicity.
The benefit of a specialist referral center can be inferred from the data from our cohort. However, statistically sig- nificant evidence is lacking from our retrospective review. Whilst all patients had some form of imaging undertaken prior to surgery, either for initial diagnosis or confirmatory purposes, 9.3 % (n = 9) received no endocrine biochemi- cal investigations preoperatively. To ensure that test results were not missed during data collection as opposed to ‘not
performed’, a thorough search of each patient’s records (hospital and outpatient) and multiple treating surgeons’ and physicians’ records and correspondence was under- taken. These patients did significantly worse on both univariate and multivariate analysis for RFS. There was also a non-significant trend for poorer OS. The biochemical profile helps to determine the type of adrenocortical tumor, investigates for autonomous cortisol production, which may accelerate postoperative adrenal failure if missed, and allows for more focussed postoperative monitoring.1 Although hormone production is seen in both benign and malignant disease, it is the screening for hormone precur- sors and urinary metabolites that may reveal subtle changes that may be seen in ACC and not benign adrenal tumors.22 Not performing a biochemical workup may also reflect that the surgeon is unaware that they are dealing with a mass of adrenal origin. For example, there were several cases in our cohort where the preoperative diagnosis was presumed to be that of a renal or hepatic malignancy. As such, a thor- ough endocrine workup was not considered and the diagnosis of ACC was not clear until either during surgery
or on final histopathology. We recommend the minimum biochemical and imaging workup as suggested by the ENSAT group.14
Adjuvant therapy with mitotane has been shown to be efficacious, although the drug has significant side effects.19, 23,24 There are no clear guidelines or appropriate indica- tions for patients who have an R0 resection and stage I/II disease, and the optimal dosing regimen, target levels, and duration of therapy are the subject of debate. Most guide- lines recommend minimum treatment duration of 2 years if tolerated,” which is also the duration of testing recom- mended in the Efficacy of Adjuvant Mitotane Treatment (ADIUVO) trial.25 Almost half of our cohort (46 %) received adjuvant mitotane therapy, although where data were available there was a wide variety of dosing regimens and treatment duration, a reflection of both the lack of clear guidelines on therapy, dose monitoring, and response, as well as the limitations due to the drug’s side effect profile.
As with any retrospective review, there are shortcom- ings due to patient selection and referral bias. A large proportion of patients in our cohort were sourced from reports to the NSW Cancer Registry, which relies on notifications by pathologists or clinicians. Occasional omissions and misclassifications as well as reporting and recording errors are always inherent in such a system. As such, our cohort is not an exhaustive list of all patients with ACC and only represents a snapshot of patients over the last 15 years.
CONCLUSIONS
To the best of our knowledge, there has yet to be an Australian study reporting the outcomes of ACC with full clinical annotation prior to this series. Factors associated with worse OS include advanced age, evidence of local invasion, and evidence of metastatic spread on imaging. Of note, patients who are inadequately investigated according to approved international guidelines prior to surgery have significantly poorer RFS. There was also a trend, but no statistical evidence, that higher surgeon volume was associated with improved resection margins and RFS.
The data for our cohort is in concordance with larger single and multicenter studies and demonstrates that treatment in Australia for ACC is commensurate with the world stage. However, we suggest that appropriate endo- crine assessment and surgical treatment in specialized endocrine and/or surgical oncology units is optimal for managing a rare cancer.
ACKNOWLEDGMENT Julian Ip is an RACS Foundation for Surgery Richard Jepson Research Scholar. Stan Sidhu is a University of Sydney Medical School Foundation Fellow. The authors wish to
acknowledge the clinicians who have kindly provided access to their patients’ medical records, which has made this study possible.
DISCLOSURES Julian C.Y. Ip, Tony C.Y. Pang, Anthony R. Glover, Patsy Soon, Stephen Clarke, Arthur Richardson, Peter Campbell, Bruce G. Robinson, and Stan B. Sidhu have no conflicts of interests to declare.
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