Surgery for recurrent adrenocortical carcinoma: A multicenter retrospective study
Guénolé Simon, MD,a François Pattou, MD, PhD,b Eric Mirallié, MD,a
Jean Christophe Lifante, MD, PhD,” Claire Nominé, MD,d Vincent Arnault, MD,e Loïc de Calan, MD,e Cécile Caillard, MD,a Bruno Carnaille, MD,b Laurent Brunaud, MD, PhD,d Nathalie Laplace, MD,” Robert Caiazzo, MD, PhD,b and Claire Blanchard, MD,a Nantes, Lille, Lyon, Nancy, and Tours, France
Background. Adrenocortical carcinoma is a rare neoplasm with a high rate of recurrence. We studied the impact of surgery on the survival in recurrent adrenocortical carcinoma patients.
Methods. We performed a retrospective review of patients with recurrent adrenocortical carcinoma, managed in 5 French University Hospitals between 1980 and 2014. We compared surgery and medical management for ACC recurrence.
Results. Fifty-nine patients were included, 46 of whom had an initial R0 resection. Twenty-nine patients underwent reoperation for recurrence, while 30 had nonoperative treatments. Operated patients had a greater median overall survival after recurrence than nonoperated patients (91 vs 15 months;
P <. 001). Patients operated on for local or distant recurrence had similar overall survival (110 vs 91 months; P = . 81). In nonoperated patients, types of medical managements did not impact survival. Surgery for recurrence (P = . 037) and a disease-free interval between initial resection and recurrence >12 months (P = . 059) were both prognostic factors for improved survival, whereas age, stage, and tumor size (P ≥.2 each) were not. A Ki67 <25% tended to be associated with better overall survival (P = . 051).
Conclusion. Both surgery for recurrence and disease-free interval between the initial resection of an adrenocortical carcinoma and recurrence > 12 months are associated with better overall survival. (Surgery 2016 ;:. )
From the Clinique de Chirurgie Digestive et Endocrinienne (CCDE),” Institut des Maladies de l’Appareil Digestif (IMAD), Centre Hospitalier Universitaire (CHU) Nantes-Hôtel Dieu, Nantes, France; the Chirurgie Générale et Endocrinienne, CHU Lille, Lille, France; the Service de Chirurgie Endocrinienne et Générale,“ CHU Lyon, Lyon, France; the Service de Chirurgie Digestive, Hepatobiliaire, Pancréatique, Endocrinienne et Cancérologique,ª CHU Nancy, Nancy, France; and the Service de Chirurgie Digestive Endocrinienne et Bariatrique, et Transplantation hépatique,e CHU Tours, Tours, France
ADRENOCORTICAL CARCINOMA (ACC) is a rare neoplasm with a poor prognosis. Estimated annual incidence is 1-2 per million inhabitants.1,2 Women are affected more often; indeed, a recent analysis of the literature showed a median female to male ratio of 1.6 (range 0.9-2.6).3 Most tumors are diag- nosed at an advanced stage with invasion of adja- cent organs or metastatic disease. Patients may either be asymptomatic or have symptoms due to
The authors declare no conflicts of interest.
Accepted for publication August 16, 2016.
Reprint requests: Claire Blanchard, MD, Clinique de Chirurgie Digestive et Endocrinienne, CHU Tours, Tours, France. E-mail: claire.blanchard@chu-nantes.fr.
http://dx.doi.org/10.1016/j.surg.2016.08.058
hormonal release by the neoplasm due to a mass effect.
Complete resection is the only curative treat- ment for ACC.4 Patients with European Network for the Study of Adrenal Tumors (ENSAT) stages I-II (intra-adrenal tumors) with a complete resec- tion have a 5-year survival of 40%.5 Despite com- plete initial resection, recurrences occur in up to 74% of patients.6 There are 2 types of recurrences: local recurrences and distant metastases. Local re- currences are more frequent and are often symp- tomatic because of the mass effect of the tumor and/or hormonal secretion. Patients with metasta- tic ACC have an overall 5-year survival of <20%.7 Recurrences are a turning point in ACC, because they are often disseminated, and the treatment is mainly medical. Some selected patients, however, may benefit from reoperation in an attempt to resect completely the recurrence.8
For unresectable tumors, therapeutic options are limited. Mitotane is the first drug used for nonoperable patients and used often as adjuvant therapy in selected patients with controversial outcomes.3,9 Different systemic chemotherapies have been tried, but the effects are often tempo- rary. In a randomized study, patients treated with a combination of etoposide, doxorubicin, and cisplatin had an overall survival of 14.8 months.10 Some studies showed a benefit of postoperative external radiotherapy on the site of the adrenalec- tomy in advanced tumors; however a retrospective cohort showed discordant results.11
Patients with ACC have not benefited from the global improvement in oncologic treatments compared to other tumors. 2 Currently, the man- agement of ACC recurrence is not standardized and remains limited to a few chemotherapy op- tions but with poor efficacy. If possible, complete resection of the recurrence seems to be the only option to increase survival.13,14 Currently, a few studies have shown a benefit on survival in patients undergoing reoperation for recurrent ACC but with a median survival after recurrence of >60 months.13,14
The first objective of this study was to define the role of operative intervention in the management of local or distant ACC recurrences. The second objective was to find predictive factors for improved survival with operative resection. There- fore, we evaluated outcomes of patients with recurrent ACC after initial resection in 5 French University Hospitals.
METHODS
We performed a retrospective study of patients with recurrence after initial resection for an ACC between 1980 and 2014 in five French University Hospitals: Lille, Lyon, Nancy, Nantes, and Tours. Data on initial diagnosis, operative intervention, histopathologic findings, and treatment proced- ures were collected retrospectively. All patients were followed in regular interval with clinical, biologic, and radiologic examinations according to local recommendations.
Patients with histologically confirmed ACC who had a local or distant recurrent disease after initial complete resection (R0 or R1) were eligible for evaluation. We excluded patients with an R2 resection at the initial operation. Stage classifica- tion was based on the ENSAT classification.15 Tu- mors located in the adrenal bed were considered as local recurrences, whereas other locations were considered as distant metastases. Nonoperative treatments were mitotane, cytotoxic chemotherapy
| Site | n (%) |
|---|---|
| Isolated recurrences | 42 (71) |
| Adrenalectomy site | 24 (41) |
| Liver | 8 (14) |
| Lung | 8 (14) |
| Brain | 1 |
| Bones | 1 |
| Multiple recurrences | 17 (29) |
| Adrenalectomy site + metastases | 10 (17) |
| Adrenalectomy site + liver | 1 |
| Adrenalectomy site + lung | 3 (5) |
| Adrenalectomy site + liver + lung | 2 |
| Adrenalectomy site + liver + bones | 1 |
| Adrenalectomy | 3 (5) |
| site + liver + lung + bones | |
| Multiple metastases | 7 (12) |
| Liver + lung | 5 (9) |
| Liver + lung + bones | 2 |
combination of etoposide and platinum in first- line, radiotherapy, and others (cryoablation and radiofrequency ablation).
Disease-free interval (DFI) was calculated as the time between the initial resection and the date of the diagnosis of recurrent disease. Overall survival (OS) after recurrence was defined as the time between the date of the recurrence and the death or last follow-up. Survival curves were made using the Kaplan-Meier method, and the log-rank test was used to compare continuous, nonparametric variables between subgroups. Univariate and multi- variate analyses were conducted to find relevant prognostic variables using a Cox proportional hazards model. The association between each variable and the OS was expressed as a 95% confidence interval (CI) for the hazard ratio (HR). Statistical calculations were performed with SPSS statistics software (version 23.0; IBM Corp, Armonk, NY).
RESULTS
Sixty-one patients, followed for recurrence after initial operative resection, were identified in 5 French University Hospitals. Two patients were excluded because of an initial R2 resection. Of the 59 patients, 46 (78%) had an R0 resection, and 13 (22%) had an R1 resection. Patients were classified by ENSAT stage as follow: 5 (9%) patients were stage I, 23 (39%) were stage II, 22 (37%) were stage III, 3 (5%) were stage IV, 6 (10%) had an unknown stage.
| Reoperated, 29 patients | Medically managed, 30 patients | P value | |
|---|---|---|---|
| Age (y) at first operation (median, range) | 53 (19-81) | 54 (31-74) | .103 |
| Sex | .176 | ||
| Men | 6 (21%) | 11 (37%) | |
| Women | 23 (79%) | 19 (63%) | |
| Clinical presentation | |||
| Hormone secretion | 10 (34%) | 13 (43%) | .486 |
| Tumor symptoms | 11 (38%) | 12 (40%) | .871 |
| No symptom | 8 (28%) | 7 (23%) | .708 |
| Tumor side | .083 | ||
| Right | 9 (31%) | 16 (53%) | |
| Left | 20 (69%) | 14 (47%) | |
| Techniques of resection of primary ACC | |||
| Laparotomy | 19 (66%) | 28 (93%) | .008 |
| Laparoscopy | 10 (35%) | 2 (7%) | |
| Extended surgery* | 7 (24%) | 22 (73%) | .0002 |
| Tumor characteristics (median, range) | |||
| Size (mm) | 90 (40-190) | 110 (55-200) | .139 |
| Weiss score | 6 (3-8) | 7 (4-9) | .23 |
| Ki67% | 20 (7-70) | 20 (5-50) | .86 |
| ENSAT stage of original neoplasm | |||
| I | 5 (17%) | 0 | .017 |
| II | 12 (41%) | 11 (37%) | .691 |
| III | 9 (31%) | 13 (43%) | .318 |
| IV | 0 | 3 (10%) | .08 |
| Site of recurrence | |||
| Adrenalectomy | 24 (83%) | 0 | <. 00001 |
| Liver | 3 (10%) | 18 (60%) | .00004 |
| Lung | 1 (3%) | 21 (70%) | <. 00001 |
| Bone | 0 | 6 (20%) | .008 |
| Brain | 1 (3%) | 0 | .322 |
| DFI > 12 mo | 18 (62%) | 11 (37%) | .051 |
*Resection of adjacent invaded organs.
Recurrences occurred after a median delay of 12 months (1-134) from the date of the initial resection. Twenty-four (41%) patients had local recurrences, and 35 (59%) had distant metastases. The different sites of recurrence are listed in Table I. Seventeen patients (29%) had ≥2 sites of recur- rence. Forty-six (78%) patients received mitotane af- ter the initial resection (some stage II and most stages III and IV). After recurrence, almost all patients had mitotane during follow-up (55 patients, 93%). Cyto- toxic chemotherapies were administered after the failure or mitotane to control the disease.
Among the 59 patients, 29 (49%) underwent operative exploration for recurrence, whereas 30 (51%) had medical management only. Demo- graphic data of both groups are listed in Table II. Groups were similar for sex, age, tumor side, and histopathologic characteristics (size, Ki67%, and Weiss score). Groups were also similar in terms of initial ENSAT stage: 9 (31%) patients were stage
III or IV in the operated group vs 16 (53%) pa- tients in the nonoperated group (P= . 10). Patients operated on for recurrence had more often a local recurrence than nonoperated patients: 24 (83%) vs 10 (33%; P < . 001). Non-operated patients all had distant recurrences, and among them, 17 had ≥2 sites of recurrence; in this group, 10 had a local recurrence (adrenalectomy bed) associated with liver and/or lung metastases. Only one of the operated patients received cytotoxic chemotherapy prior to resection of recurrence.
The sites of recurrence in patients who under- went operative management were the adrenal bed (n = 24, 83%), liver (n = 3, 10%), lung (n = 1) and brain (n = 1). Among the 29 operated patients, 22 had a locoregional resection (76%): 7 had resec- tion of only the tumor bed, and 15 had resection of adjacent organs (8 splenectomies, 7 resections of abdominal nodules, 6 nephrectomies, 3 distal pancreatectomies, 3 segmental colectomies, and
Survival according to management of recurrent ACC
1,0
Log rank p=0.001
No surgery Surgery
0,8-
Kaplan-Meier
0,6-
Surgical management
0,4-
No surgery
0,2-
0,0
0
50
100
150
200
Time (Months)
2 minor hepatectomies). Isolated metastasecto- mies were performed in 5 patients (17%): 3 in the liver (2 right hepatectomies and 1 tumorec- tomy), and 1 each in the lungs brain. Two patients had operative exploration only because of a diffuse disease (7%). The 4 patients who had an R1 resec- tion (14%) had local recurrences.
Thirty-day mortality was 3%: one patient died because of hemorrhagic shock at day 1, and a second died because of a gastric necrosis at day 43. Global serious morbidity after surgery was 7%: 1 patient had a pancreatic fistula with a spontaneous resolution and another developed an intra- abdominal abscess.
Among the 59 patients, median OS after diagnosis of recurrence was 91 months (95% CI = 6-176 months) in the 29 operated patients versus 15 months (95% CI = 6-24 months) in the 30 nonoperated patients (P <. 001) (Fig). In non- operated patients, there was no difference between those who had systemic chemotherapy, radio- therapy, or mitotane therapy regarding their OS: 18 months (95% CI = 0-36 months), 9 months (95% CI = 3-15 months), and 18 months (95% CI = 8-28 months), respectively.
In the operated group, patients who had distant metastases had similar median OS as patients who had local recurrences (110 months vs 91 months; P= . 81). Patients who had resection of the adrenal bed only had similar median OS as patients who had adjacent organ resections (47 months vs 89 months; P = . 75). After excluding the 2 deaths and the 2 nonresective, operative explorations, 25 patients remained. Among them, 5 (17%) had
| Hazard ratio | 95% CI | P value | |
|---|---|---|---|
| Age, y | 0.99 | 0.97-1.02 | .537 |
| Sex | |||
| Female | 1 | ||
| Male | 1.22 | 0.60-2.49 | .577 |
| Tumor size, cm | |||
| <10 | 1 | ||
| ≥10 | 1.85 | 0.92-3.71 | .085 |
| ENSAT stage | |||
| I | 1 | ||
| II | 4.92 | 0.65-37.50 | .124 |
| III | 5.55 | 0.73-41.99 | .097 |
| IV | 15 | 1.52-148.42 | .021 |
| R0 status | 2.25 | 0.93-5.44 | .072 |
| Weiss score | |||
| ≤6 | 1 | ||
| >6 | 0.88 | 0.44-1.78 | .729 |
| Ki67% | |||
| <25 | 1 | ||
| ≥25 | 3.37 | 0.99-11.39 | .051 |
| Site of recurrence >1 | 3.45 | 1.64-7.28 | .001 |
| Local recurrence | 0.44 | 0.21-0.91 | .028 |
| only | |||
| DFI | |||
| >12 mo | 1 | ||
| ≤12 mo | 2 | 1.02-3.95 | .045 |
| Site of recurrence | |||
| Adrenalectomy site | 0.82 | 0.42-1.63 | .578 |
| Liver | 1.67 | 0.83-3.36 | .152 |
| Lung | 2.82 | 1.4-5.7 | .004 |
| Bone | 5.67 | 2.22-14.52 | .0003 |
| Brain | 1.18 | 0.16-8.68 | .872 |
| Reoperation for | 0.29 | 0.14-0.60 | .001 |
| recurrence |
no second recurrence and were alive after a me- dian follow-up of 69 months (7-148).
Twenty patients (69%) developed a second recurrence after a median delay of 9 months (2-65) (12 distant and 8 local recurrences), only 8 (28%) of whom were reoperated (5 local re- sections, 2 lung resections, and 1 liver resection). Median OS after the first diagnosis of recurrent disease of the 12 patients who did not undergo a second reoperation for recurrence was 29 months (14-110) vs 141 months (47-151) for the 8 reoper- ated patients (P= . 002). Two patients underwent 5 reoperations for recurrences (local resections then distal resections) with an OS after the first diag- nosis of recurrent disease of 141 and 151 months, respectively.
In the operated group, patients with initial ENSAT stages I-II (n = 17) tended to have a longer
| Hazard ratio | 95% CI | P value | |
|---|---|---|---|
| Age | |||
| <50 | 1 | ||
| ≥50 | 0.29 | 0.05-1.89 | .197 |
| Sex | |||
| Female | 1 | ||
| Male | 33.78 | 1.77-645.65 | .019 |
| Tumor size, cm | |||
| <10 | 1 | ||
| ≥10 | 1.52 | 0.18-12.76 | .699 |
| ENSAT stage | |||
| Stages I & II | 1 | ||
| Stages III & IV | 4.39 | 0.31-62.35 | .275 |
| Ki67% | |||
| <25 | 1 | ||
| ≥25 | 2.2 | 0.28-17.05 | .45 |
| Site of recurrence >1 | 16.61 | 0.47-582.28 | .122 |
| DFI | |||
| >12 mo | 1 | ||
| ≤12 mo | 10.53 | 0.91-121.29 | .059 |
| Reoperation for | 0.12 | 0.02-0.88 | .037 |
| recurrence | |||
median OS than those with stages III-IV (n = 9): 141 months vs 29 months (P= . 066). Furthermore, in this group, a Ki67 <25% tended to be predictive of a better OS: 91 months vs 29 months (P= . 055).
In univariate analysis, factors that increased the OS after recurrence were local disease (HR = 0.44, P = . 028), a DFI >12 months between the initial resection and the diagnosis of recurrence (HR = 0.5, P = . 045), and reoperation for recur- rence (HR = 0.29, P = . 001) (Table III). Lung and bone metastases were both associated with decreased OS. Factors related to the original tu- mor size, grade, ENSAT stage, and the first opera- tive approach (laparoscopy or open laparotomy) were not predictive for OS, but a Ki67 index <25% increased the OS (P = . 051).
In multivariate analysis, reoperation for recur- rence was independently associated with an improved OS among patients with recurrent ACC (HR = 0.12, P= . 037) (Table IV). Patient sex was a predictor of survival, because women had an improved OS (HR = 0.03, P = . 019). Multivariate analysis suggested that a DFI <12 months was asso- ciated with decreased OS (HR = 10.5; P = . 059).
DISCUSSION
This multicenter study showed that resection when possible was a justified option for treatment
of recurrences after initial resection of ACC. We compared 2 groups of patients with recurrent disease: the first included patients operated for local or isolated distant recurrence, and the sec- ond included patients managed without reopera- tion. In our study, the overall survival after recurrence was significantly improved in the oper- ated group.
The two groups did not differ in terms of age, sex, initial characteristics of the neoplasm, and ENSAT stage, but the nonoperated patients with recurrent ACC tended to have more advanced disease at the time of their initial resection, because they had undergone more extensive initial resections and they tended to recur with distant metastases. It is interesting to note that more patients with a left-sided primary tumor underwent reoperation; this observation may be explained by the fact that resection of invaded left organs (kidney, spleen, pancreas) is easier than resection of right organs (liver, inferior vena cava).
Reoperation for ACC recurrence is a relatively safe option, because mortality and morbidity in the operated group remained acceptable. In our study, we distinguished local resection and resection for distant metastatic disease, but there appeared to be no difference between these 2 groups in terms of OS, suggesting that metastasectomy for distant recur- rence of ACC appears to be an option for isolated, completely resectable metastases. Furthermore, 28% of the operated patients had ≥2 reoperations with good OS (141 months), again suggesting that an aggressive policy of repeated resections for recurrent ACC is possible in selected patients.
In patients with recurrent ACC, it is first necessary to evaluate the resectability of the recurrent disease. In our study, each expert center evaluated the resectability of the recurrences. The DFI between the initial resection and the first recurrence appeared to be an important prog- nostic factor for OS. Indeed, we found that a DFI of >12 months was independently associated with an improved survival. These results are consistent with several studies.13-16 Erdogan et al13 in the German ACC registry (154 patients with recurrent ACC), estimated that a DFI of >12 months and an R0 resection of the recurrence were correlated with a survival of >60 months in a multivariate analysis. In our study, among the patients who did undergo resection for recurrence, 18 who had a DFI of >12 months had an OS of 110 months (95% CI = 26-194 months), whereas the 11 who had a DFI <12 months had an OS of 29 months (95% CI = 17-41). The difference was statistically significant (P = . 51).
The role of the Ki67 index also appeared to be important in the decision to reoperate. Indeed, despite a non-statistically significant difference in our study, a Ki67 >25% seemed to correlate with a decreased survival. Ki67 had already demonstrated its importance as a predictive factor of recurrence in completely resected patients. A recent study showed that patients with a Ki67 <10% had an OS after initial resection of 181 months vs 42 months for Ki67 ≥20%.17 In our opinion, a Ki67 >25% should not definitely contraindicate reoperation, but in these patients, a comprehensive evaluation of resectability (computed tomography and positron emission tomography-fluoro-D-glucose) should be performed to make as certain as possible that all the disease can be resected.
In this present study, age, tumor size, Weiss score, and ENSAT stage had no obvious impact on the prognosis of ACC recurrences. The small number of patients in our study may explain why ENSAT stage was not correlated to the OS. In addition, patients with stage III may be under- staged, because lymph nodes were not resected systematically and reported thoroughly in patho- logic examination. The study of Reibetanz et al18 showed the prognostic value of lymphadenectomy. In our operated group, we found a trend toward a better OS in stages I-II patients than stages III-IV patients. In a recent study from the ENSAT network, Libé et al19 found that a modified ENSAT classification for advanced ACC (stages III and IV) based on the number of recurrent sites appeared to be a relevant survival prognostic factor for ACC. In our study, the type of the first operative approach (open laparotomy versus laparoscopy) was not correlated with OS, but a recent meta- analysis recommended open laparotomy as the standard surgical management of ACC.20
The major limitation of the present study is its retrospective, nonrandomized design covering a long period with a small number of patients. Diagnosis, radiologic evaluation, and treatment management regarding ACC have changed consid- erably over the period of the study, but the rarity of the disease complicates the feasibility of larger, prospective investigations.
The discussion about reoperation for recurrent ACC must not ignore the importance of the quality of the initial resection of the primary ACC. Indeed, despite that in our study, the initial R1 status was not correlated with a decrease in survival, we know that tumor rupture or dissemination and R1 or R2 resections are associated with high recurrence rates and poor OS.21,22 A recent study confirmed that a positive margin of resection is associated with
worse, long-term survival (patients with an R0 resec- tion had an OS of 96 months vs 25 months for pa- tients with an R1 resection).23 Resection of ACCs should be performed in an expert center by expe- rienced surgeons able to undertake en-bloc resec- tion of the tumor and an associated regional lymphadenectomy.18,24 We and others believe that open laparotomy should be preferred.20
In conclusion, this study confirms the role of re- resection in management of selected patients with recurrence of ACC. It appears to be a reliable option to reach a long-term survival. This thera- peutic strategy should be offered to patients who have a resectable recurrence tumor and who recur after a DFI between the initial resection and the first recurrence of >12 months.
The authors wish to thank Marine Mirallié and Manon Simon for English revision.
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DISCUSSION
Dr Bradford K. Mitchell (Lansing, MI): Nothing to disclose. The group of nonoperated patients in your study, were they offered resection?
Dr Claire Blanchard: Thanks you for your question.
Dr Bradford K. Mitchell (Lansing, MI): The question is, as I see it, you are comparing a group who did not get offered resection in the retrospec- tive analysis. One would assume they were not offered resection because of unfavorable clinical features. Therefore, your estimate of the benefit in improved survival is a function of selection bias. So although you may improve the survival by operating on patients who have apparently sur- gically resectable disease based on your imaging, your comparison group, the patients who were not operated on-and I did not see the data to sug- gest that those patients who were not operated upon were not simply a subset of the patients who had much more advanced disease.
Dr Claire Blanchard: Yes, in this retrospective study, we compared 2 groups: 29 patients under- went surgery for recurrence and 30 had nonopera- tive treatments. Patients with histologically confirmed ACC, who had a local or distant recur- rent disease after initial complete radical surgery (R0 or R1), were eligible for evaluation. Groups were also similar in terms of initial ENSAT stage: 9 (31%) patients were stages III or IV in the oper- ated group vs 16 (53.3%) patients in the nonoper- ated group. Patients operated on for recurrence had more often a local recurrence than nonoper- ated patients: 24 (82.8%) vs 10 (33.3%). Nonoper- ated patients all had distant recurrences and among them 10 had a local recurrence associated with metastases. In this group, 16 had 2 or more sites of recurrence.
Dr Richard A. Prinz (Evanston, IL): Thank you very much for sharing this very large experience with us. It seems as I saw your data that you were more willing to do a reoperation on patients who had had an initial laparoscopic procedure rather than an open procedure. So if that is correct, is there a difference in the sites of recurrence with laparoscopy, or is the difference I am alluding to due to the original extent of disease or the fact that the surgeon may be more unwilling to go back if there has been a prior open operation?
Dr Claire Blanchard: Yes, in the surgery group, we had more laparoscopy. But the first surgical approach (laparoscopy or open laparotomy) was not predictive for OS. A recent meta-analysis pub- lished in surgery recommended open laparotomy as the standard surgical management of ACC.
Dr Janice Pasieka (Calgary, AB): I think what you showed us is that proper patient selection leads to a better survival, and whenever we are un- dertaking reoperative surgery, it is important for us to appropriately select the patients. So maybe you could tell us what is the workup that these patients
go through when they develop a recurrence. Do they get complete biochemical workup? And does that influence selection? Do they all get a PET scan? So shed some light on the workup and how you selected that group.
Dr Claire Blanchard: Yes, this patient with a re- operation, we selected this with CT scan and PET scan and with a DFI between the initial resection and the first recurrence of more than 12 months. We did not have biochemical workup. One patient had 5 surgeries for recurrence in this group. We looked at recurrence, and nodule size of carci- noma at the moment of surgery. The role of the Ki67 index also appeared to be important in the
decision to reoperate. But a Ki67 level ≥25% only in ACC may not contraindicate surgery for recurrence. Actually, I think the better option for these patients is the surgery.
Dr Elizabeth G. Grubbs (Houston, TX): Did all patients receive the same adjuvant therapy after their original surgery? If not, how did you handle that as a confounder?
Dr Claire Blanchard: No, it is a limitation of this study. All the patients did not have the same the medical treatment. Forty-six (78.0%) patients received mitotane after the initial resection (some stage II and most of the stages III and IV).