The Role of Surgery in the Management of Recurrent Adrenocortical Carcinoma
Ilknur Erdogan,* Timo Deutschbein,* Christian Jurowich, Matthias Kroiss, Christina Ronchi, Marcus Quinkler, Jens Waldmann, Holger S. Willenberg, Felix Beuschlein, Christian Fottner, Silke Klose, Anke Heidemeier, David Brix, Wiebke Fenske, Stefanie Hahner, Joachim Reibetanz, Bruno Allolio, and Martin Fassnacht, on behalf of the German Adrenocortical Carcinoma Study Group
Department of Internal Medicine I (I.E., T.D., M.K., C.R., W.F., S.H., B.A., M.F.), Endocrine and Diabetes Unit and Departments of General, Visceral, Vascular, and Pediatric Surgery (C.J., J.R.), Radiology (A.H.), and Urology and Pediatric Urology (D.B.), University Hospital Würzburg, D-97080 Würzburg, Germany; Department of Endocrinology, Diabetes, and Nutrition (M.Q.), Charité University Medicine, D-10117 Berlin, Germany; Department of General Surgery (J.W.), University Hospital Marburg, D-35032 Marburg, Germany; Department of Endocrinology, Diabetes, and Rheumatology (H.S.W.), Medical Faculty, Heinrich-Heine University Düsseldorf, D-40225 Düsseldorf, Germany; Endocrine Research Unit (F.B., M.F.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-81675 Munich, Germany; Department of Endocrinology and Metabolism (C.F.), University Hospital Mainz, D-55129 Mainz, Germany; and Department of Endocrinology and Metabolism (S.K.), University Hospital Magdeburg, D-39120 Magdeburg, Germany
Context: Surgery is the standard of care for localized adrenocortical carcinomas, but its role for recurrent disease is not well defined.
Objective: Our objective was to evaluate clinical outcome after surgery for recurrence.
Design: We conducted a retrospective analysis in 154 patients with first recurrence after initial radical resection from the German Adrenocortical Carcinoma Registry.
Main Outcome Measures: We evaluated progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method and identified prognostic factors by Cox regression analysis.
Result: A total of 101 patients underwent repeated surgery (radical resection, n = 78), and 99 received (additional) nonsurgical therapy. After a median of 6 (1-221) months, 144 patients (94%) experienced progression. Multivariate analysis adjusted for age, sex, tumor burden, time to first recurrence (TTFR), surgery for recurrence (including resection status), and additional therapy indicated that only two factors were significantly associated with shorter PFS [hazard ratio for progression: for TTFR ≤ 12 months, 1.8 (95% confidence interval = 1.3-2.6) vs. TTFR > 12 months; for macroscopically incomplete resection, 3.4 (1.5-7.9), and for no surgery, 3.4 (1.6-7.0) vs. microscopically complete (RO)-resection and OS [hazard ratio for death: for TTFR > 12 months, 3.1 (2.0-4.7) vs. TTFR ≤ 12 months; for macroscop- ically incomplete resection, 2.7 (1.1-6.9), and no surgery, 4.2 (1.8-9.6) vs. RO-resection]. Patients who had both TTFR over 12 months and RO-resection of recurrent tumors (n = 22) had the best prognosis (median PFS, 24 months; median OS, >60 months).
Conclusions: The best predictors of prolonged survival after first recurrence are TTFR over 12 months and R0-resection. Our data suggest that patients with longer TTFR and tumors amenable to radical resection should be operated, whereas individualized treatment decisions are needed for patients with short TTFR or with not completely resectable tumors. (J Clin Endocrinol Metab 98: 181-191, 2013)
First Published Online November 12, 2012
* I.E. and T.D. contributed equally to this work. Abbreviations: CI, Confidence interval; CT, computed tomography; ENSAT, European Net- work for the Study of Adrenal Tumors.
A drenocortical carcinoma is a rare malignancy with an estimated annual incidence of fewer than two cases per million people (1-3). When initially diagnosed, ap- proximately half of the patients suffer from signs and symptoms of adrenal steroid hormone excess and a sub- stantial number of patients already have distant metasta- ses. However, even in the presence of localized tumors, the prognosis of adrenocortical carcinomas is usually dismal. Recurrence rates of up to 85% have been reported (4, 5), although recent data suggest a relevant selection bias in most retrospective series (6). Five-year survival may vary between about 90% (in stage I and II patients) and less than 15% (in stage IV patients) (6-11). In the last few years, significant progress has been made in the clinical management of patients with adrenocortical carcinoma (12-15), but data on the treatment of recurrent disease are still scarce. Because complete removal of the tumor is the only potentially curative option, initial surgery is the treat- ment of choice in localized tumors (12, 16). In case of inoperable or metastatic disease, however, therapeutic op- tions are severely limited. Both the adrenolytic agent mi- totane (17-22) and cytotoxic chemotherapies or targeted therapies (15, 23-27) are usually only temporarily effec- tive, and its use is often associated with significant adverse effects. In addition, there is no consensus on whether or not patients with advanced disease benefit from incom- plete tumor resection (12). At the time of recurrence, re- peated surgery (with the aim of complete tumor removal) may be regarded as a potential treatment option, but only few studies on this topic have been published so far (4, 7, 8, 28, 29). Although surgical resection was generally re- garded as beneficial, several evaluations suffered from methodological flaws, and multivariate analyses for the detection of prognostic and predictive parameters for pro- longed survival were not performed in most of these series. Moreover, the study cohorts were rather small, with only 234 patients in total. Consequently, we examined the Ger- man Adrenocortical Carcinoma Registry to evaluate the outcome of different treatment modalities and to search for predictors of prolonged survival in patients having their first recurrence after initial radical resection.
Patients and Methods
Data sources
To facilitate the assessment of patients suffering from adre- nocortical carcinoma, the German Adrenocortical Carcinoma Registry was established in 2003 (30). At the beginning, most data were retrospectively obtained from chart review, but over time, more and more patients were prospectively included. Pa- tients had to provide written informed consent before enroll- ment. Data on initial symptoms, diagnostic procedures, surgical interventions, histopathological findings, and treatment modal-
ities were collected by trained medical personnel using standard- ized evaluation forms as previously described (11, 21). All pa- tients were followed up on a regular basis (usually every 3 months). The registry protocol has been approved by the local ethics committee (approval number 86/03).
Patients
Patients with histologically confirmed adrenocortical carci- noma who had experienced recurrent disease after initial radical resection were eligible for the current evaluation. Exclusion cri- teria were as follows: age less than 18 yr and incomplete infor- mation on primary diagnosis and/or follow-up.
Each patient was assessed before the initial surgery, and fol- low-up included staging approximately every 3 months. Patients were evaluated with complete history, physical examination, and biochemical profile. The standard procedure used for im- aging-based evaluation was computed tomography (CT); how- ever, some patients underwent magnetic resonance imaging or positron emission tomography with [18F]fluorodeoxyglucose. Stage designation was based on the recently published European Network for the Study of Adrenal Tumors (ENSAT) criteria (11). Patients were assigned progressive disease in case of grow- ing tumor mass (i.e. an increase of the sum of tumoral lesions of ≥20%) or appearance of a new lesion larger than 5 mm, adopt- ing the Response Evaluation Criteria In Solid Tumors (RECIST) guideline version 1.1 for interpretation of imaging results (31).
To acknowledge the heterogeneity of the cohort, patients were retrospectively classified according to the potential resect- ability of the tumor. The first group comprised subjects with localized and/or limited metastatic disease who were regarded as potentially amenable to radical resection, the second group consisted of patients in whom complete tumor removal was considered as not feasible due to advanced disease (i.e. not amenable to radical resection). For this selection, patients’ medical history (including histopathological findings) and im- aging data were reviewed, and ambiguous cases were analyzed in a blinded fashion by an interdisciplinary team of a radiol- ogist, a surgeon (trained in thoracic and abdominal surgery), and an internist/endocrinologist.
Definition of subgroups and statistical analysis
Tumors that were located in the original tumor bed were regarded as local recurrence, whereas all other tumor lesions were considered to be metastases. The resection status was de- fined as follows: R0, microscopically complete resection; R1, microscopically incomplete resection; R2, macroscopically in- complete resection; and RX, unknown resection status. A partial tumor resection not aiming at completeness already before sur- gery (e.g. presence of metastases that were not surgically tar- geted) was judged as debulking surgery. The sites of recurrence were grouped as local, abdominal/retroperitoneal, bone, liver, lung, and other origins. The number of affected sites and mea- surable lesions were then individually summarized. Patients whose imaging reports included phrases like multiple lesions, diffuse metastasis, or peritoneal carcinosis were grouped to- gether with patients with a minimum of 10 tumor lesions, not aiming to exactly count the number of lesions. The nonsurgical treatment modalities were mitotane, cytotoxic chemotherapy, radiotherapy, and combinations of these modalities.
Time to first recurrence was defined as the time lag between the initial radical resection and first documentation of recurrent
| Entire cohort | Patients categorized as potentially amenable to radical resection | Patients categorized as not amenable to radical resection | |
|---|---|---|---|
| Number of patients | 154 | 86 | 68 |
| Sex (n) | |||
| Male | 60 (39%) | 35 (41%) | 25 (37%) |
| Female | 94 (61%) | 51 (59%) | 43 (63%) |
| Age at first recurrence (yr) | |||
| 18-30 | 8 | 7 | 1 |
| 31-40 | 25 | 17 | 8 |
| 41-50 | 39 | 22 | 17 |
| 51-60 | 32 | 15 | 17 |
| 61-70 | 34 | 15 | 19 |
| <70 | 16 | 10 | 6 |
| Median | 53 | 47 | 57 |
| Range | 18-85 | 18-80 | 29-85 |
| Time to first recurrence (months) | |||
| ≤6 | 46 | 16 | 30 |
| >6 to ≤12 | 32 | 23 | 9 |
| >12 to ≤24 | 38 | 22 | 16 |
| >24 | 38 | 25 | 13 |
| Median | 11 | 15 | 8 |
| Range | 1-224 | 1-224 | 1-189 |
| Localization of recurrence (n) | |||
| Local recurrence | 85 | 53 | 32 |
| Abdominal/retroperitoneal lesions | 25 | 5 | 20 |
| Bone | 6 | 2 | 4 |
| Liver | 54 | 28 | 26 |
| Lung | 59 | 18 | 41 |
| Other origins | 2 | 0 | 2 |
| Number of tumor lesions (n) | |||
| ≤2 | 59 | 56 | 3 |
| 3-4 | 21 | 18 | 3 |
| 5-9 | 18 | 12 | 6 |
| ≥10 | 56 | 0 | 56 |
| Median | 4 | 2 | ?ª |
| Range | 1 -? ª | 1-7 | 2 -? ª |
| Sum of tumor diameters (cm) | |||
| ≤3.0 | 21 | 21 | 0 |
| >3.1 to <10.0 | 48 | 45 | 3 |
| ≥10.0 | 85 | 20 | 65 |
| Number of affected sitesb (n) | |||
| 1 | 81 | 68 | 13 |
| 2 | 51 | 18 | 33 |
| 3 | 20 | 0 | 20 |
| 4 | 2 | 0 | 2 |
| Median | 1 | 1 | 2 |
| Range | 1-4 | 1-2 | 1-4 |
| Resection status (n) | |||
| No surgery | 53 | 8 | 45 |
| R0 | 33 | 33 | 0 |
| R1 | 13 | 13 | 0 |
| RX | 22 | 22 | 0 |
| R2 | 10 | 10 | 0 |
| Debulking | 23 | 0 | 23 |
| Additional therapy (n) | |||
| Mitotane only | 59 (38%) | 25 (29%) | 34 (50%) |
| Cytotoxic chemotherapy only | 10 (6%) | 2 (2%) | 8 (12%) |
| Radiotherapy only | 4 (3%) | 3 (4%) | 1 (1%) |
| Combinations | 26 (17%) | 5 (6%) | 21 (31%) |
| No | 55 (36%) | 51 (59%) | 4 (6%) |
Patients with recurrent adrenocortical carcinoma were retrospectively categorized as potentially amenable to radical resection due to localized and/ or limited metastatic disease or not amenable to radical resection due to advanced disease. R0, Microscopically complete resection; RX, unknown resection status; R1, microscopically incomplete resection; R2, macroscopically incomplete resection.
a These values were judged as uncountable (see Patients and Methods for further details).
b Local recurrence was regarded as a separately affected site.
disease. Various time spans [including a 12-month interval that had previously been suggested by Jensen et al. (28) and Datrice et al. (29)] were arbitrarily chosen to evaluate the impact of time to first recurrence on patients’ outcome. Progression-free sur- vival was defined as the interval between first recurrence and either documentation of subsequent progressive disease or dis- ease-specific death (i.e. death related to adrenocortical carci- noma). Overall survival was calculated as the time between first documentation of recurrent disease and death or last follow-up. Survival curves were constructed using the Kaplan-Meier method, and the log-rank test was used to compare continuous nonparametric variables between subgroups. Relevant prognos- tic variables were identified by univariate and multivariate anal- yses, using the Cox proportional hazards model. All factors that showed at least a trend on progression-free or overall survival in the univariate analysis (P < 0.1), together with sex and age, were further investigated by multivariate analysis. However, because several of the assessed parameters were associated with tumor burden (e.g. localization of recurrence, sum of tumor diameters,
number of tumor lesions, and number of affected sites), we de- cided to include only one of these parameters (the one with the strongest level of significance) into subsequent multivariate anal- yses. The association between each variable and the overall sur- vival was expressed as 95% confidence interval (CI) for the haz- ards ratio. Statistical significance was taken as P < 0.05, and results are presented as the median and range unless otherwise stated. SPSS version 19.0 (SPSS Inc., Chicago, IL) was used for statistical calculations.
Results
Patient characteristics
At the time of the analysis (February 2011), 350 pa- tients with an initial radical resection were identified from the German Adrenocortical Carcinoma Registry; 218
350 patients with an initial radical resection
132 patients excluded due to lack of recurrence at the time of the analysis (February 2011)
218 patients with recurrent disease
64 patients excluded due to age < 18 years (n= 10) or incomplete patient records (n = 54)
154 patients included into the current analysis
86 patients retrospectively regarded as “potentially amenable to radical resection” due to localized disease
68 patients retrospectively regarded as “not amenable to radical resection” due to advanced disease
78 patients with surgical resection at first recurrence
8 patients no surgical resection at first recurrence
23 patients with surgical debulking at first recurrence
45 patients no surgical debulking at first recurrence
Follow up
(62%) of these patients were found to have recurrent dis- ease during subsequent follow-up visits of whom 64 pa- tients were excluded because they were younger than 18 yr of age (n = 10) or had incomplete patient records (n = 54). Consequently, 154 patients were finally enrolled (perti- nent data are given in Table 1). Most of these patients suffered from localized disease at the time of presentation (ENSAT stage I, 12 patients; ENSAT stage II, 74 patients; ENSAT stage III, 61 patients; ENSAT stage IV, five pa- tients; tumor stage unknown, two patients). The median follow-up time after first recurrence in patients who were still alive (n = 41) was 69 months (range 30-297 months). A flowchart of patient selection is shown in Fig. 1.
Time to and pattern of first recurrence
Patients were found to have their first recurrence after a median interval of 11 months (range 1-224 months) to the date of the initial surgery (pertinent data are given in Table 1). Forty-two patients (27%) had only local recur- rence, 57 patients (37%) suffered from metastatic disease, and 55 patients (36%) had both local recurrence and dis- tant metastases. Lung and liver were the predominant sites of metastasis, and a median of one affected site and four measureable lesions per patient was observed.
Treatment of first recurrence
As shown in Table 1, 86 patients with localized and/or limited metastatic disease were retrospectively regarded as potentially amenable to radical resection. Of these, 78 patients were actually operated for recurrent disease (R0 resection, 33 patients; RX resection, 22 patients; R1 resection, 13 patients; R2 resection, 10 patients). Of the 68 patients with advanced disease who were retrospec- tively regarded as not amenable to radical resection, 23 ac- tually had a debulking procedure. Consequently, a total of 101 patients underwent repeated surgery. Ninety-nine pa- tients (including all of the 53 patients who did not undergo
a second operation) received (additional) nonsurgical ther- apy: mitotane monotherapy (n = 59), cytotoxic chemother- apy without additional mitotane (n = 10), radiotherapy only (n = 4), or combinations of these modalities (n = 26).
Progression-free and overall survival after first recurrence
One hundred forty-four patients (94%) experienced second recurrence or progressive disease; the median pro- gression-free survival was 6 months (range 1-221 months) (Fig. 2A). Median survival after first recurrence was 32 months (range 1-297 months), and disease-specific death was reported for 112 patients (73%) (Fig. 2B). In addition, one patient with an acute exacerbation of an underlying chronic obstructive pulmonary disease died from severe respiratory failure.
Predictive factors of progression-free and overall survival after first recurrence
Univariate and multivariate analyses were performed to identify relevant prognostic factors of progression-free and overall survival after first recurrence, using the data of all 154 patients (pertinent data are given in Tables 2 and 3). In summary, univariate analysis suggested that time to first recurrence of 12 months or less, presence of distant metastases, larger tumor burden, incomplete tumor resec- tion, and administration of additional therapy were asso- ciated with poor prognosis. However, multivariate anal- ysis indicated that only the time to first recurrence and the resection status were significantly correlated with both progression-free and overall survival after first recurrence (Fig. 3). In comparison with patients with a R0 resection, the risk for recurrence was about 2-fold increased for RX- or R1-resected patients and about 4-fold increased for patients with macroscopically incomplete surgery. Inter- estingly, patients who underwent either incomplete (i.e. R2-resection or tumor debulking) or no surgery had a
A
Progression
B
1,0
Censored
1,0
Survival
Censored
Progression-free survival probability after first recurrence
0,8-
Overall survival probability after first recurrence
0,8
0,6-
0,6-
0,4-
0,4
0,2-
0,2-
0,0-
0,0
0
12
24
36
48
60
0
12
24
36
48
60
Time (months)
Time (months)
| n | Median progression- free survival (months) | 95% CI | Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | ||||
| Sex | |||||||||
| Male | 60 | 6 | 3-9 | 1 | 1 | ||||
| Female | 94 | 6 | 4-8 | 1.24 | 0.88-1.75 | 0.210 | 1.22 | 0.83-1.78 | 0.311 |
| Age at first recurrence (yr) | |||||||||
| ≤50 | 70 | 7 | 4-10 | 1 | 1 | ||||
| >50 | 84 | 5 | 3-7 | 1.18 | 0.85-1.64 | 0.324 | 1.26 | 0.88-1.81 | 0.211 |
| Time to first recurrence (months) | |||||||||
| >12 | 76 | 10 | 7-13 | 1 | 1 | ||||
| ≤12 | 78 | 4 | 3-5 | 1.88 | 1.34-2.64 | 0.000 | 1.80 | 1.26-2.58 | 0.001 |
| Localization of recurrence | |||||||||
| Local recurrence | 42 | 10 | 6-14 | 1 | |||||
| Distant metastasis | 57 | 4 | 3-5 | 1.51 | 0.99-2.31 | 0.055 | |||
| Both | 55 | 6 | 4-8 | 1.66 | 1.09-2.55 | 0.019 | |||
| Number of tumor lesions | |||||||||
| ≤3 | 73 | 10 | 6-14 | 1 | |||||
| 4-9 | 25 | 9 | 6-12 | 1.49 | 0.91-2.42 | 0.112 | |||
| ≥10 | 56 | 3 | 2-4 | 2.52 | 1.72-3.70 | 0.000 | |||
| Sum of tumor diameters (cm) | |||||||||
| ≤3 | 21 | 10 | 6-15 | 1 | |||||
| >3 -< 10 | 48 | 9 | 3-15 | 1.03 | 0.60-1.78 | 0.905 | |||
| ≥10 | 85 | 4 | 3-5 | 1.93 | 1.17-3.20 | 0.010 | |||
| Number of affected sites | |||||||||
| 1 | 81 | 9 | 6-12 | 1 | 1 | ||||
| 2 | 51 | 6 | 3-9 | 1.62 | 1.12-2.34 | 0.010 | 1.10 | 0.69-1.75 | 0.682 |
| 3-4 | 22 | 3 | 2-4 | 2.25 | 1.37-3.69 | 0.001 | 1.18 | 0.64-2.17 | 0.606 |
| Resection status | |||||||||
| R0 | 33 | 19 | 5-33 | 1 | 1 | ||||
| RX | 22 | 6 | 0-12 | 1.74 | 0.98-3.10 | 0.059 | 1.95 | 1.06-3.58 | 0.031 |
| R1 | 13 | 9 | 6-12 | 1.67 | 0.84-3.31 | 0.142 | 2.08 | 1.00-4.33 | 0.051 |
| R2 | 10 | 6 | 3-9 | 2.95 | 1.39-6.26 | 0.005 | 3.42 | 1.48-7.93 | 0.004 |
| Debulking | 23 | 5 | 3-7 | 3.33 | 1.85-5.99 | 0.000 | 4.59 | 2.04-10.3 | 0.000 |
| No surgery | 53 | 4 | 3-5 | 3.04 | 1.87-4.96 | 0.000 | 3.40 | 1.64-7.03 | 0.001 |
| Additional therapy | |||||||||
| No | 55 | 9 | 6-12 | 1 | 1 | ||||
| Yes | 99 | 5 | 4-6 | 1.61 | 1.13-2.28 | 0.008 | 0.62 | 0.37-1.06 | 0.079 |
Only factors that showed at least a trend on progression-free survival in the univariate analysis (P < 0.1), together with sex and age, were further investigated by multivariate analysis. Local recurrence was regarded as a separately affected site. HR, Hazard ratio; R0, microscopically complete resection; RX, unknown resection status; R1, microscopically incomplete resection; R2, macroscopically incomplete resection.
similar progression-free survival (Fig. 3B), whereas overall survival was worst in patients who were not operated at all (Fig. 3D).
The 22 patients who qualified for both criteria (i.e. having a time to first recurrence of >12 months as well as an R0 resection of the recurrent tumor) were found to have the best prognosis, with a median progression-free sur- vival after recurrence of 24 months (range 3-221 months) and a median survival after recurrence of more than 60 months (range 18-221 months) (Fig. 4).
Influence of time to first recurrence on progression-free and overall survival after first recurrence
Apart from the arbitrarily chosen interval of 12 months, we also analyzed the influence of other time spans
between initial diagnosis and documentation of first re- currence. A recurrence that occurred already within the first 6 months after initial radical resection (n = 46) in- dicated a particularly poor prognosis, with a median pro- gression-free survival of 3 months (range 1-52 months), and a median overall survival of 13 months (range 2-81 months). In contrast, patients who developed their recur- rence after more than 24 months (n = 41) demonstrated a median progression-free survival of 17 months (range 2-221 months) and a median overall survival of 115 months (range 5-297 months). The following hazard ra- tios were calculated: for progression, 2.3 (95% CI = 1.6- 3.4) for time to first recurrence of 6 months or less vs. more than 6 months and 2.2 (95% CI = 1.5-3.3) for time to first recurrence of 24 months or less vs. more than 24 months;
| n | Median overall survival (months) | 95% CI | Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | ||||
| Sex | |||||||||
| Male | 60 | 31 | 22-39 | 1 | 1 | ||||
| Female | 94 | 33 | 21-44 | 1.08 | 0.74-1.58 | 0.693 | 0.89 | 0.58-1.36 | 0.580 |
| Age at first recurrence (yr) | |||||||||
| <50 | 70 | 38 | 10-65 | 1 | 1 | ||||
| ≥50 | 84 | 28 | 19-37 | 1.44 | 0.98-2.09 | 0.061 | 1.26 | 0.83-1.93 | 0.280 |
| Time to first recurrence (months) | |||||||||
| >12 | 76 | 69 | 53-85 | 1 | 1 | ||||
| ≤12 | 78 | 17 | 13-21 | 3.18 | 2.15-4.71 | 0.000 | 3.08 | 2.02-4.70 | 0.000 |
| Localization of recurrence | |||||||||
| Local recurrence | 42 | 64 | 24-104 | 1 | |||||
| Distant metastasis | 57 | 31 | 15-47 | 1.28 | 0.79-2.06 | 0.319 | |||
| Both | 55 | 23 | 11-36 | 1.58 | 1.00-2.52 | 0.052 | |||
| Number of tumor lesions | |||||||||
| ≤3 | 73 | 69 | 52-87 | 1 | |||||
| 4-9 | 25 | 58 | 24-91 | 1.29 | 0.74-2.25 | 0.376 | |||
| ≥10 | 56 | 13 | 7-19 | 3.58 | 2.36-5.43 | 0.000 | |||
| Sum of tumor diameters (cm) | |||||||||
| ≤3 | 21 | 69 | 48-90 | 1 | |||||
| >3 -< 10 | 48 | 64 | 27-101 | 1.50 | 0.76-2.96 | 0.247 | |||
| ≥10 | 85 | 17 | 14-20 | 2.84 | 1.50-5.39 | 0.001 | |||
| Number of affected sites | |||||||||
| 1 | 81 | 64 | 33-94 | 1 | 1 | ||||
| 2 | 51 | 30 | 9-52 | 1.46 | 0.97-2.21 | 0.071 | 0.88 | 0.51-1.50 | 0.628 |
| 3-4 | 22 | 8 | 3-13 | 4.20 | 2.47-7.14 | 0.000 | 1.90 | 0.99-3.66 | 0.055 |
| Resection status | |||||||||
| R0 | 33 | 88 | 67-108 | 1 | 1 | ||||
| RX | 22 | 64 | 19-109 | 1.61 | 0.81-3.23 | 0.178 | 1.82 | 0.89-3.72 | 0.100 |
| R1 | 13 | 35 | 0-86 | 1.34 | 0.57-3.14 | 0.500 | 1.52 | 0.62-3.69 | 0.360 |
| R2 | 10 | 30 | 3-58 | 2.83 | 1.25-6.43 | 0.013 | 2.70 | 1.06-6.90 | 0.038 |
| Debulking | 23 | 22 | 11-32 | 2.71 | 1.38-5.34 | 0.004 | 3.38 | 1.38-8.28 | 0.008 |
| No surgery | 53 | 11 | 6-15 | 4.81 | 2.70-8.56 | 0.000 | 4.16 | 1.81-9.58 | 0.001 |
| Additional therapy | |||||||||
| No | 55 | 72 | 57-88 | 1 | 1 | ||||
| Yes | 99 | 22 | 13-31 | 2.13 | 1.42-3.19 | 0.000 | 0.94 | 0.52-1.69 | 0.828 |
Only factors that showed at least a trend on overall survival in the univariate analysis (P < 0.1), together with sex and age, were further investigated by multivariate analysis. Local recurrence was regarded as a separately affected site. HR, Hazard ratio; R0, microscopically complete resection; RX, unknown resection status; R1, microscopically incomplete resection; R2, macroscopically incomplete resection.
for overall survival, 3.2 (95% CI = 2.1-4.8) for time to first recurrence of 6 months or less vs. more than 6 months and 3.8 (95% CI = 2.3-6.3) for time to first recurrence of 24 months or less vs. more than 24 months.
Subanalysis of patients retrospectively regarded as potentially amenable to radical resection
Because radical resection was found to be a major pre- dictor of progression-free and overall survival after first recurrence, a separate analysis was performed for the 86 patients retrospectively regarded as potentially amenable to radical resection. Again, multivariate analysis identified prolonged time to first recurrence [hazard ratio for pro- gression for time to first recurrence ≤12 months was 2.4 (95% CI = 1.4-4.0) in comparison with time to first re- currence >12 months; hazard ratio for death for time to first recurrence ≤12 months was 3.3 (1.8-6.0) in com-
parison with time to first recurrence >12 months] as the only significant predictor of improved clinical outcome.
Discussion
Complete resection of an adrenocortical carcinoma is the only potentially curative treatment option (12, 16). How- ever, data on the effectiveness of surgery in the manage- ment of recurrent disease are still scarce. Our study clearly suggests two major predictors for clinical outcome after first recurrence, namely time to first recurrence and re- sectability of tumor lesions. Other analyzed factors such as age, sex, and tumor burden had no, or at least no relevant, impact on the prognosis of these patients. Because the five published studies on this topic presented the outcome of fewer than 240 patients (and only one group performed a
A
B
1,0-
Time to first recurrence
>12 months (n = 76)
1,0
Resection status
≤12 months (n = 78)
RO (n = 33)
Progression-free survival probability after first recurrence
Progression-free survival probability after first recurrence
RX+R1 (n = 35)
- R2 (n = 10)
0,8-
0,8-
debulking (n = 23)
. . ”. no augery (n = 53)
0,6-
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0,4
0,4-
0,2-
0,2
0,0
0,0
0
12
24
36
48
60
0
12
24
36
48
60
Time (months)
Time (months)
C
1,0
Time to first recurrence
D
>12 months (n = 76)
1,0-
Resection status
≤12 months (n = 78)
RO (n = 33)
RX+R1 (n = 35)
R2 (n = 10)
debulking (n = 23)
Overall survival probability after first recurrence
0,8
Overall survival probability after first recurrence
0,8
. . ”. no surgery (n = 53)
0,6
0,6-
0,4
0,4
0,2
0,2-
0,0
0,0
0
12
24
36
48
60
0
12
24
36
48
60
Time (months)
Time (months)
multivariate analysis) (4, 7, 8, 28, 29), our current analysis (with a cohort of 154 patients) provides a major step for- ward to allow for distinct treatment recommendations in case of recurrent adrenocortical carcinoma.
Time to first recurrence as a key prognostic factor was first suggested and subsequently validated in two National Institutes of Health studies (28, 29). Although the missing multivariate analyses were important drawbacks of these publications, it was clearly illustrated that a time span of more than 12 months between initial diagnosis and first documentation of recurrent disease was associated with prolonged survival. This is in line with our observation that the shorter the time to first recurrence the poorer the prognosis.
In contrast to the disease-free interval that has to date been taken into account only by the National Institutes of Health group, the necessity to aim for completely resected recurrent tumors has already been repeatedly advocated
(4, 7, 8). Surgical approaches were generally regarded as superior to treatment regimes consisting only of drug ther- apy; however, these studies did not adjust for other con- founding factors like tumor burden. In one study, patients were stratified according to the completeness of their sec- ond intervention. The authors found that the survival time in patients with complete resection was up to 5-fold longer than in subjects in whom the second resection was incom- plete (median overall survival, 74 vs. 16 months) (8). We observed a less pronounced difference (median overall sur- vival, 88 months for R0-resected patients vs. 34 months for incompletely resected patients, i.e. a less than 3-fold variance). This finding can possibly be explained by im- proved therapeutic options over the last decade (even for patients facing a highly palliative situation).
Another interesting observation is that macroscopi- cally incomplete surgery did not have a substantial influ- ence on progression-free survival but at least some impact
A
B
1,0-
Time to first recurrence and resection status
1,0-
>12 months + RO (n = 22)
all other patients (n = 65)
Progession-free survival probability after first recurrence
≤12 months + R1 / R2 / RX (n = 67)
0,8-
Overall survival probability after first recurrence
0,8-
0,6-
0,6-
0,4-
0,4-
0,2-
0,2-
Time to first recurrence and resection status
>12 months + RO (n = 22)
0,0
0,0
all other patients (n = 65)
≤12 months + R1 / R2 / RX (n = 67)
0
12
24
36
4S
60
0
12
24
36
48
60
Time (months)
Time (months)
on overall survival when compared with no surgery (Fig. 3, B and D). One might speculate that disease progression in general is not a matter of absolute tumor mass, whereas overall survival may be affected by reduction of tumor burden and better control of hormone excess. Unfortu- nately, a proper endocrine workup was not performed in a relevant number of these patients, thereby preventing a sound conclusion on this topic. However, because we can- not exclude that tumor debulking may have at least a par- tial impact on prolonging life, individualized treatment decisions are required for patients suffering from not com- pletely resectable tumors.
Apart from the disease-free interval and the resection status, several other potentially relevant prognostic fac- tors for improved outcome have been evaluated, such as age, sex, initial tumor stage, hormonal functionality, lo- calization of the primary tumor, and chemotherapeutic intervention (4, 7, 8, 29). The initial tumor stage, surgical approaches in general, and the resection status were fre- quently described as beneficial, whereas age, sex, chemo- therapeutic intervention, and hormonal functionality were found to have no significant impact on patients’ out- come. However, these observations were usually made on the basis of univariate analyses, which are highly suscep- tible to relevant biases (particularly for relatively small study cohorts). In this context, Schulick and Brennan (8) were the first to present data derived from multivariate analysis. Both the initial tumor stage and the initial resec- tion status were identified as significant predictors of dis- ease-specific survival, whereas hormonal functionality, age, sex, and site of tumor appearance had no significant impact. Additional research and larger study cohorts are needed to clarify whether at least some of these contro-
versies can be attributed to the limited statistical power of relatively small series. For instance, different formulas have been used to calculate survival (time between initial diagnosis and death vs. time between first recurrence and death as in our study). Although the latter definition ap- pears to be more appropriate in the context of surgery for recurrence, this controversy highlights the need to agree on generally accepted outcome criteria.
Of note, all of the above-mentioned studies reported a similar pattern of recurrence (4, 7, 8, 28, 29). The majority of patients suffered from metastatic disease, whereas iso- lated local recurrence was present only in about 30% of patients. Lung and liver were by far the most predominant sites of metastasis, followed by bone lesions and diffuse abdominal metastases. Because these findings are strik- ingly similar to our observations, we strongly recommend abdominal CT or magnetic resonance imaging as well as adequate thoracic imaging by CT during follow-up. How- ever, the total number of patients with brain metastasis in these series was almost negligible, leading us to the pro- posal that cranial imaging is required only in the presence of signs or symptoms suggestive of cranial involvement.
One might speculate that patients with advanced dis- ease who are not considered for a second surgery harbor other prognostic factors than patients who are preopera- tively regarded as amenable to radical resection. To ac- knowledge this potentially relevant issue, our patients were retrospectively classified according to the potential resectability of their recurrent tumor. Because both mul- tivariate analyses (the first of the entire study cohort of 154 patients, the second of the subcohort of 86 patients who were retrospectively regarded as potentially amenable to radical resection) indicated that time to first recurrence is
a strong predictor for clinical outcome, this factor appears to be very robust for both progression-free and overall survival. Furthermore, we hypothesized that the unknown resection status (RX) that was described in 22 patients may have had an influence on the identification of prog- nostic factors for recurrence or survival. Consequently, all analyses were also performed without these subjects, but results were strikingly similar to those of the entire cohort (data not shown).
An obvious limitation of our current evaluation is its retrospective design. For instance, detailed data on surgi- cal morbidity were frequently not available, although these aspects are of particular interest for both patients and physicians before deciding on whether or not to intervene surgically. Moreover, a complete endocrine workup was lacking in many of our patients, thereby ham- pering a proper analysis on the impact of hormonal hy- persecretion in this situation. Therefore, we are also not able to comment on the effects of tumor debulking on clinical symptoms, which certainly could have an impact on quality of life and outcome in these patients. Finally, even though our current study is the largest series pub- lished so far, it is still rather small in comparison with other tumor entities. As to be expected, however, the rarity of the disease complicates the aim of larger (ideally prospec- tive) investigations. In this context, the currently estab- lished ENSAT database (www.ensat.org) may greatly fa- cilitate future (prospective) approaches.
In conclusion, more than 90% of patients with recur- rent disease after initial radical resection will experience recurrent and/or progressive disease. The best predictors of prolonged survival after first recurrence of adrenocor- tical carcinoma are a time to first recurrence of more than 12 months and the feasibility of R0 resection during sec- ond surgery. Thus, we recommend that surgery for first recurrence should not be performed without considering these circumstances. Although our data suggest that sur- gery is indicated if both criteria are fulfilled, individualized treatment decisions are needed for patients who have ei- ther recurrent tumors within 6 months after initial surgery or advanced disease not amenable to radical resection.
Acknowledgments
This study was part of the German Adrenal Network Improving Treatment and Medical Education (GANIMED). We are grate- ful to all the colleagues who supplied patient data for the German Adrenocortical Carcinoma Registry. The following hospitals provided patient data for at least two of our 154 currently eval- uated patients (sorted by number of cases in descending order): University Hospital Würzburg, Charité University Medicine Ber- lin, University Hospital Marburg, University Hospital Düssel-
dorf, University Hospital Magdeburg, Ludwig Maximilians Uni- versity Munich, University Hospital Mainz, University Hospital Leipzig, University Hospital Regensburg, Leopoldina Hospital Schweinfurt, Free University of Berlin, University Hospital Lü- beck, University Hospital Tübingen, University Hospital Hom- burg, University Hospital Cologne, University Hospital Bonn, University Hospital Halle, University Hospital Heidelberg, Uni- versity Hospital Jena, and University Hospital Münster. We ap- preciate the support for establishing (Uwe Maeder) and main- taining (Michaela Haaf) the database of the German Adrenocortical Carcinoma Registry.
Address all correspondence and requests for reprints to: Martin Fassnacht, M.D., Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, University of Würzburg, Oberdürrbacher Strasse 6, D-97080 Würzburg, Ger- many. E-mail: fassnacht_m@medizin.uni-wuerzburg.de.
This research was supported by grants from the German Min- istry of Education and Research (Grant 01KG0501 to B.A. and M.F.) and the Deutsche Krebshilfe (Grant 107111 to M.F.).
Disclosure Summary: The authors have nothing to disclose.
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