Abstract. Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. It has been difficult to establish a strict treatment program for. ACC, and better ...
World J. Surg. 22, 605– 612, 1998
WORLD Journal of
SURGERY © 1998 by the Socie´te´ Internationale de Chirurgie
Adrenocortical Carcinoma: Surgery and Mitotane for Treatment and Steroid Profiles for Follow-up A. Khorram-Manesh, M.D.,1 H. Ahlman, M.D., Ph.D.,1 S. Jansson, M.D., Ph.D.,1 B. Wa¨ngberg, M.D., Ph.D.,1 O. Nilsson, M.D., Ph.D.,2 C.E. Jakobsson,3 B. Eliasson,3 S. Lindstedt, M.D., Ph.D.,3 L.E. Tisell, M.D., Ph.D.1 1
Department of Surgery, Sahlgrenska University Hospital, S-413 45 Go ¨teborg, Sweden Department of Pathology, Sahlgrenska University Hospital, S-413 45 Go ¨teborg, Sweden 3 Department of Clinical Chemistry, Sahlgrenska University Hospital, S-413 45 Go ¨teborg, Sweden 2
Abstract. Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. It has been difficult to establish a strict treatment program for ACC, and better treatment alternatives and diagnostic tools must be sought. Even though surgery is the treatment of choice, the role of surgery in advanced disease has been questioned. Eighteen consecutive patients were treated at our unit over a 22-year period (1975–1997). All patients underwent surgery and were followed by our protocol, which includes urinary steroid profiles, clinical examinations, analysis of steroid hormones, and radiologic investigations. Twelve patients received mitotane with drug concentration measurements to deliver an effective, nontoxic dose. The median duration of mitotane treatment was 12 months. Few side effects were observed. Four patients with low-stage tumors underwent second-look operations with no pathologic findings. Five patients were subjected to repeat operations, and the mean duration of the disease-free interval before repeat surgery for these patients was 59 months. There was a significant positive correlation between the disease-free interval and the observed survival after repeat surgery. Eleven patients with intentionally curative surgery had their urinary steroid profiles tested several times postoperatively. For five patients preoperative urine samples were also available. Steroid profiles indicated recurrent disease despite normal radiologic findings in two of these five patients. The follow-up ranged from 6 weeks to 24 years. The predicted 5-year survival was 58% according to the Kaplan-Meier method. We conclude that monitoring serum concentrations of mitotane makes long-term treatment possible with few side effects; steroid profile analysis can be used for early detection of tumor recurrence; and repeat surgery for recurrence is of value for patients with long disease-free intervals.
Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. The annual incidence is 0.5 to 2.0 per million inhabitants; that is, up to 16 new cases can be expected in Sweden each year [1]. Most of the ACC patients are referred to university hospitals, and different surgical strategies have been used; few multicenter trials have been performed. Reports of more than 50 patients from one institution are unusual. In previous retrospective studies the overall 5-year survival was less than 30% with some improvement (35– 46%) over the last decade [2–10]. The disease is often advanced at the time of diagnosis, and about half the patients have hormonal symptoms. The accuracy of diagnosis has been questioned [1] in some series This International Association of Endocrine Surgeons (IAES) article was presented at the 37th World Congress of Surgery International Surgical Week (ISW97), Acapulco, Mexico, August 24 –30, 1997. Correspondence to: A. Khorram-Manesh, M.D.
including that of small adrenocortical tumors referred to as “atypical adenomas.” Inclusion of potentially benign lesions has an impact on survival analysis. Histologic indexes of malignancy that can predict prognosis have been elaborated [3, 11, 12, 32]. ACCs are usually aneuploid but may also be diploid. Therefore DNA ploidy is not a reliable indicator of diagnosis or prognosis [13, 14]. Some reports stress the poor prognosis in patients with large tumors and hormonal activity [11, 15], but multivariate analysis has failed to confirm this [2, 5]. Others have noted a better prognosis in young patients and in those with certain patterns of steroid secretion (e.g., androgen or pregnenolone secretion) [5, 7]. The most severe prognostic factor is the presence of metastases. Surgery is the treatment of choice for resectable primary and secondary tumors and for recurrent disease [2, 4, 8]. The role of adjuvant chemotherapy has been more controversial. Mitotane [o,p9-DDD: 1,1-dichloro-2-(o-chlorophenyl)-2(p-chlorophenyl)ethane] has potent adrenolytic effects and may retard the growth of ACCs [16–18]. In a large retrospective multicenter study, mitotane improved the survival rate only in patients with metastases [7]. Determination of urinary steroid profiles has been proposed as a sensitive tool for diagnosing ACC and for detecting recurrent disease [1, 19 –23]. ACCs express several enzyme deficiencies in steroid biosynthesis, resulting in accumulation of intermediate metabolites, which can be detected by gas chromatography and mass spectrometry [15, 24, 25]. We report herein the results of an active treatment program in 18 consecutive patients with ACC (1975–1997). All patients were offered surgery. Recurrences were treated surgically if possible. From 1991 mitotane was recommended for all patients, and their urinary steroid profiles were monitored to facilitate early detection of recurrence. Materials and Methods Patients Eighteen consecutive patients with ACCs were operated on from January 1975 to December 1996 at the Department of Surgery, Sahlgrenska University Hospital, Go ¨teborg, Sweden. The fol-
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Table 1. Tumor stage, surgical treatment, and outcome of 13 ACC patients with limited primary operations. Case no. (year of 1st operation)
Tumor stage (diameter, cm)
Extent of 1st operation
3 9 12 16 18 1 6 11 17 14 5
III (.5) II (24) II (11) II (12) II (6) II (10) IV (15) II (11) IV (17) IV (5, 7) II (17)
Adrenalectomy Adrenalectomy Adrenalectomy Adrenalectomy Adrenalectomy Adrenalectomy Adrenalectomy 1 RLW Adrenalectomy Adrenalectomy Adrenalectomy, bilateral Adrenonephrectomy
8 (1986)
II (15)
Adrenonephrectomy
7 (1986)
IV (15)
Adrenonephrectomy
(1979) (1989) (1990) (1996) (1996) (1971) (1986) (1990) (1996) (1993) (1984)
2nd Look/site of recurrence
Extent repeat
2nd Look 2nd Look 2nd Look 2nd Look Local 1 liver 1 lung Local 1 thorax
Exploration 1 biopsy Exploration 1 biopsy Exploration 1 biopsy Exploration 1 biopsy LE 1 DPE 1 SPLE ATE 1 N 1 DPE 1 SPLE
Local 1 caval vein
LE 1 CWR
1st Local 2nd Local and liver 1st Spine 2nd Local and liver
Excision LE 1 DPE 1 LLE Laminectomy LE 1 LLE
Outcome (follow-up, months) NED (71) NED (81) NED (78) NED (14) AWD (9) NED (288) NED (136) DOD (42) DOD (3) DOD (14) NED (159) DOD (72) DOD (9)
LLE: liver lobectomy; LE: local excision; ATE: abdominothoracic excision; CWR: caval wedge resection; N: nephrectomy; DPE: distal pancreatectomy; SPLE: splenectomy; RLW: resection of liver wedge; NED: no evidence of disease; AWD: alive with disease; DOD: dead of disease.
low-up period ended with May 1997. Seventeen of the patients were primary cases, but one patient underwent a second operation during the period of study. The mean age at diagnosis was 53 6 3 years (range 36 –76 years). The female/male ratio was 0.8:1.0.
Table 2. Surgical treatment and outcome of five ACC patients with extensive primary operations. Case no. (year of 1st operation)
Tumor stage (diameter, cm)
Surgical Treatment
4 (1981) 15 (1996) 2 (1976)
II (20) II (9) IV (.5)
10 (1990) 13 (1991)
IV (10) IV (13)
All patients with ACC were surgically explored, and the adrenal tumor with surrounding soft tissue was excised en bloc. Thirteen patients had adrenalectomy alone or in combination with nephrectomy (Table 1). Five patients had more extensive operations (Table 2). When a recurrence was suspected because of clinical, radiologic, or biochemical changes, reexploration was done to excise the recurrence or to reduce the tumor burden. Reexploration for recurrent disease was performed in five patients after a mean disease-free interval of 59 months (range 7–168 months) (Table 1). Four patients with stage II tumors without signs of recurrence underwent second-look operations (Table 1). Medical Treatment After 1991 twelve of fourteen patients were treated with mitotane after surgery, irrespective of tumor stage. The two exceptions (nos. 8 and 9) were older than 70 years and were hesitant to undertake therapy with potential side effects. The individual dose of mitotane was titrated by measuring the serum concentrations of the drug. Blood samples were obtained prior to the morning dose of mitotane. All patients on mitotane had cortisone replacement and sometimes fludrocortisone. Five patients (nos. 7, 8, 10, 11, 17) with a high-stage tumor or recurrent disease received additional treatment with radiation therapy (n 5 1), cytotoxic drugs (streptozotocin, n 5 4; doxorubicin, n 5 1), or chemoembolization of the liver with doxorubicin (n 5 1) or interferon (n 5 1). Morphologic Examinations Tumor stage at the time of primary surgery was determined in all patients, using criteria according to MacFarlane and later investigators [2, 29, 33]: Stage I: tumor ,5 cm in diameter and confined to the adrenals.
Extent of operation A 1 N 1 DPE 1 SPLE A 1 N 1 SPLE A 1 N 1 DPE 1 SPLE 1 LLE A 1 LLE A 1 LLE 1 CWR
Outcome (follow-up: months) NED (176) NED (16) DOD (1.5) DOD (4) DOD (4)
A: adrenalectomy; N: nephrectomy; DPE: distal pancreatectomy; SPLE: splenectomy; LLE: liver lobectomy; CWR: caval wedge resection; NED: no evidence of disease; AWD: alive with disease; DOD: dead of disease.
Stage II: tumor .5 cm in diameter and confined to the adrenals. Stage III: tumor of any size with lymph node metastases or local invasive growth (i.e., tumor growth outside the adrenal but not involving adjacent organs). Stage IV: tumor of any size with lymph node metastases and local invasive growth, growth into adjacent organs, or distant metastases. Data for tumor staging were obtained by reexamining both the pathologic reports and specimens as well as reevaluating the radiologic findings and surgical reports. Only unequivocal positive findings of tumor spread were accepted, meaning that there is a possibility that some tumors may have been underscored as to stage. Biochemical Methods Steroid concentrations were measured by radioimmunoassay except pregnanetriol (gas chromatography) and 17-ketosteroids and 17-hydroxycorticosteroids (colorimetric assays using Zimmermann’s reaction). For the past 7 years complete urinary steroid profiles have been determined; the steroids were extracted by the method described by Schmidt et al. [21] and analyzed by gas chromatography and mass spectrometry (GC-MS) [1]. The con-
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centration of mitotane in serum was measured by capillary gas chromatography [26]. Clinical Examinations and Follow-up Protocol At diagnosis eight patients underwent both ultrasonography (US) and computed tomography (CT). Seven patients had only CT and two patients only US prior to surgery. Angiography was used in nine patients. During recent years angiography has been performed only in patients with large tumors in whom preoperative embolization was believed to minimize peroperative bleeding. Preoperative tumor embolization was done in two cases with suitable vascular anatomy. Patients with large right-sided tumors had a cavogram. The glomerular filtration rate of each kidney was determined separately by measuring the renal clearance of chromium-EDTA. Determination of urinary steroid profiles was introduced at our hospital in 1991, which led to fewer separate analyses of specific steroids in serum and urine [cortisol, aldosterone, dihydroepiandrosterone (DHEA)], unless hormonal symptoms were present. After surgery the patients were followed at 3-month intervals during the first postoperative year. At follow-up visits a clinical examination was done, and urine was collected for steroid profiles. CT was done at 6-month intervals. After the first year patients without evidence of disease were followed at 6-month intervals. In 1991 we started to recommend mitotane treatment postoperatively to all patients with ACC concomitant with determination of the serum mitotane concentration. We tried to keep the concentration within the range of 14 to 20 mg/ml as recommended by Van Slooten [27]. During the first 3 months of treatment the patient had serum mitotane measurements every 1 to 2 weeks. These determinations helped us to keep the mitotane concentration within the desired interval. Subsequent measurements were done every 3 to 6 months or on clinical suspicion of side effects. Statistics The predicted survival was calculated with the Kaplan-Meier method. Correlation was calculated as Pearson’s coefficient of correlation. All p values are two-tailed. Results The clinical manifestations of the disease in our patients were fatigue (56%), abdominal pain (50%), abdominal mass (33%), metastatic disease (28%), and hormonal syndromes (33%). Loss of libido was an early symptom in three men. Patient Survival One patient (no. 2) died of hepatic failure 6 weeks after major surgery. In the other patients both primary and the repeat operations were uneventful. The follow-up time ranged from 6 weeks to 24 years. The predicted 5-year survival according to the Kaplan-Meier method was 58% (Fig. 1). The median follow-up of the eight patients who died of ACC was 0.5 year (range 0.13– 6.0 years). The median observation time for the other 10 patients was 7.2 years (range 0.58 –24.50 years). The five patients with repeat surgery for recurrent disease survived for a mean of 55 months (range 2–120 months) after the
Fig. 1. Predicted 5-year survival according to the Kaplan-Meier method was 58%.
second operation. One of these patients is still alive without evidence of disease (no. 5), one died of other causes 10 years after repeat surgery (no. 1), one is alive with disease (no. 18), and two (nos. 8 and 11) died of ACC. The mean disease-free interval before repeat surgery for these five patients was 59 months. In this group of patients there was a significant positive correlation between the disease-free survival and the observed survival after repeat surgery (r 5 0.95, p 5 0.014). Mitotane Therapy The median dose of mitotane was 4 g (range 2.0 – 6.5 g), and the median serum mitotane concentration was 14.5 mg/ml (range 13–20 mg/ml). For this group of patients there was no correlation between the mitotane dose and the serum concentration of the drug. The median duration of mitotane treatment was 12 months (range 1–136 months). Possible adverse reactions appeared in five patients. Three patients (nos. 6, 8, 16) had nausea, one of whom had stage II disease with a negative second-look operation. She refused further medical treatment. One of the two other patients with nausea had also visual disturbances. The symptoms disappeared in all patients after dose reduction. Two patients (nos. 7 and 12) had a skin rash that vanished during continued treatment. The association between the skin rash and the treatment is uncertain. Figure 2 illustrates the serum mitotane concentrations in a patient treated with this drug (no. 17). On a daily dose of 6.5 g of mitotane, nausea appeared and the dose had to be reduced. In this case it took about 20 weeks before the mitotane concentration had stabilized with a dose that did not cause side effects. In most patients it took 12 to 15 weeks before an individual dose without side effects was titrated. Urinary Steroid Profiles Twelve patients (nos. 1, 5, 6, 8, 9, 11–14, 16 –18), who underwent intentionally curative surgery had their urinary steroid profiles determined several times postoperatively. For five of these patients (nos. 13, 14, 16, 17, 18), preoperative urine samples were also available for analysis. Each steroid hormone can be determined by GC-MS. Because there are no age- or sex-related normal values for this method, the steroid patterns of each
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Fig. 2. Serum mitotane concentrations in a patient (no. 17) treated with this drug. On a daily dose of 6.5 g mitotane, nausea appeared and the dose had to be reduced. In this case it took about 20 weeks before the mitotane concentration had stabilized with a dose that did not cause side effects. In most patients it took 12 to 15 weeks before an individual dose without side effects was titrated.
Fig. 3. Patient 9 (male) had no hormonal symptoms and underwent resection of a stage II tumor. When the first postoperative urinary steroid profile (A) was compared with one (B) 3 years later, an almost identical steroid pattern was found. The patient has now been followed for more than 6 years without evidence of recurrent disease. 11-HA: 11-hydroxyandrosterone; 11-HE: 11-hydroxyetiocholanolone; P3: pregnanetriol; THE: tetrahydrocortisone; aTHF: allo-tetrahydrocortisol; ES: external standard; IS: internal standard.
patients must be evaluated versus previous samples from the same patient. Patients with long observation periods without recurrent disease had steroid profiles identical with those in their first postoperative urine collections (Fig. 3, no. 9). However, one patient with virilism (no. 12) developed a selective increase in the secretion of pregnanediol, pregnanetriol, and androstenetriol, which led to reoperation with normal macroscopic findings. In subsequent samples these steroids were again reduced. Four years later this patient is without evidence of recurrent disease. In two of five patients with pre- and postoperative urine samples the steroid profiles indicated recurrent disease despite normal radiologic findings. One patient (no. 13) had normal radiologic findings after primary surgery. However, production of high amounts of 3-b-hydroxy-5-ene steroids persisted and rapidly increased. The patient died of disseminated disease 4 months later. The other patient (no. 18) had a rapid recurrence with a steroid pattern typical of the original tumor (Fig. 4). She was reoperated 6 months later when she had positive radiologic findings and disseminated disease. One patient (no. 17) with a pathologic preoperative steroid profile underwent surgical exci-
Fig. 4. Patient 18 (female) had severe Cushing syndrome and underwent resection of a stage II tumor. In the preoperative urinary steroid profile (A) there was a pattern with androgens, pregnanediol, and pregnanetriol and high levels of glucocorticoids and their metabolites (tetrahydrocortisone/cortisol, cortolone, and cortoles). One month postoperatively the androgens and pregnanediol and pregnanetriol had almost disappeared, and the glucocorticoid pattern was similar, but reduced, compared with the first sample (B). Two months later (C) a pattern closely resembling the original tumor pattern was found. The patient was reexplored 3 months later, when positive radiologic findings were present. She was then diagnosed as having disseminated disease (D). E: etiocholanolone; A: androsterone; P2 pregnanediol; P3: pregnanetriol.
sion of the primary tumor with residual liver metastases. The steroid profile after surgery showed diminished secretion of androgens (androsterone, etiocholanolone, DHEA, and 11-hydroxyandrosterone), but there was persistence of pregnanediol,
Khorram-Manesh et al.: Treatment and Follow-up of ACC
609 Table 3. Analysis of survival in surgically treated patients in the literature.
Fig. 5. Patient 17 (female) had severe Cushing syndrome including virilism. She underwent resection of the primary tumor due to stage IV disease. The preoperative urinary steroid profile revealed a pattern with androgens, pregnanediol, pregnanetriol, pregnenediol, pregnenetriol, and androstenetriol as well as glucocorticoids and their metabolites (A). After excision of the primary tumor, but with residual liver metastases present, the steroid profile changed: androgen disappearance, a different pattern of the pregnane and pregnene compounds, but a persistent glucocorticoid pattern (B). These findings suggest that the primary tumor was the main source of androgen production.
pregnanetriol, pregnenediol, pregnenetriol, and secretion of glucocorticoids and metabolites (tetrahydrocortisone/cortisol, cortolone and cortoles) (Fig. 5). These findings suggest the primary tumor as the source of androgen production. Discussion In this limited series we found that tumor stage at the time of the first operation was an important prognostic factor. Henley et al. [2] reported that the 5-year survival doubled (up to 32%) if patients with ACC underwent intentionally curative resection even though tumor tissue was present outside the adrenals (stage III and IV disease), which was the case in two-thirds of their patients. Cohn et al. [4] also reported enhanced survival rates with active surgical treatment. One-third of their 47 patients had stage II and IV tumors with mean survival times of 5.0 and 2.3 years, respectively, which agrees well with our survival rates: Stage II: eight patients alive (seven disease-free, one with residual disease) and two patients dead of disease; mean survival time 7.8 years Stage III: one patient dead of other causes, with no evidence of disease at a postoperative follow-up of 5.9 years. Stage IV: one patient with long survival (.10 years); mean survival for six patients dead of disease was 2.0 years. In a French multicenter study [7] the mean survival times for stage I, II, III, and IV tumors were 34, 40, 22, and 8 months, respectively. At the end of our study 8 of 18 patients had died of ACC.
Study
Year
Overall no. of patients
Overall survival (%)
Didolkar et al. [28] Nader et al. [34] Henley et al. [2] Venkatesh et al. [6] Gro ¨ndal et al. [1] Icard et al. [7] Pommier and Brennan [8] Current study
1981 1983 1983 1989 1990 1992 1992 1997
42 77 62 110 54 156 73 18
24 30 16 23 19 34 35 58
The deceased survived only for a mean of 0.5 years after surgery, whereas the others were observed for a mean of 7.2 years. The predicted 5-year survival of 58% in our series equals that in the best published results [2, 7, 8] (Table 3). It has been reported that ACC recurrence can appear as long as a decade after the initial operation [29]. In this study one patient (no. 1) had a recurrence 14 years after initial surgery. Five of our patients had repeat operations for recurrence. Before repeat surgery these patients had a mean survival of 59 months. The observed survival after repeat surgery averaged 55 months. The length of the observed survival was positively correlated to the disease-free interval after the initial operation. Our findings thus indicate that patients with long disease-free intervals after primary surgery benefit from repeat surgery. With stage II disease the prognosis in our series was good. Second-look laparotomy in four such patients without biochemical or radiologic evidence of recurrent disease could not identify any tumor tissue. One patient with stage II disease rapidly developed an aberrant urinary steroid profile following the primary operation, indicating recurrent disease. This biochemical signal did not lead to reexploration until radiologic signs were present 3 months later, when disseminated disease was found. The urinary steroid profile is a tool with the potential of early identification of recurrent disease, as also evidenced in one patient with stage IV disease subjected to intentionally curative surgery. The use of steroid profiles are still limited owing to a lack of age- and sex-distributed reference values and of identification of truly pathologic intermediate metabolites. Lipsett et al. [15] suggested that relative enzyme deficiencies in the steroid metabolic pathway were more common in patients with ACC than in those with benign adrenocortical disease. Gro ¨ndal et al. [1] used GC-MS in their investigation of urinary steroid profiles of 24 patients with ACC. Of these patients, 23 had elevated levels of tetrahydro-11-deoxycortisol, 3-b-hydroxy-5-enesteroids, or both compared with a small reference material. Most of the ACC patients had hormonal symptoms. Effective adjuvant medical therapy for ACC patients has long been sought. The literature on the adrenolytic drug mitotane as an antineoplastic agent is contradictory. In early studies high tumor regression rates were reported (61%), little influencing median survival [16]. High-dose regimens (6 –10 g) were also tested without convincing effects, but they led to side effects in the gastrointestinal tract and the central nervous system [30]. Because of severe side effects lower doses (2 g) were recommended to all patients with ACC [17]. A group in Leiden in 1984 introduced the determination of serum mitotane levels [27]. They found that
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seven of eight responders had serum levels exceeding 14 mg/ml and 19 of 20 nonresponders had levels less than 10 mg/ml, suggesting a critical therapeutic interval. Because the drug can be metabolized in several ways, it seems logical to monitor the individual drug concentration in each patient to reach the therapeutic interval using the lowest possible effective dose without side effects, as demonstrated in this study (median level 14.5 mg/ml, range 13–20 mg/ml). In the large French multicenter study, mitotane significantly improved survival in patients with metastases who received the drug subsequent to surgery. In the dosage used (3– 4 g daily, not more than 8 g/day), the drug had relatively high patient compliance [7]. Haak et al. [9] evaluated the efficacy of mitotane treatment of 96 patients treated between 1959 and 1992. In this series complete tumor resection was achieved in 49% and subtotal resection in 39%. Adjuvant mitotane treatment did not influence the results after total resection. In all, 62 patients were given mitotane at some time during their disease. High mitotane levels (.14 mg/ml) was shown to be an independent factor that influenced survival favorably. The recent finding that multidrug resistance mediated by MDR-1/P glycoprotein can be reversed by mitotane suggests the use of mitotane in combination with other chemotherapeutic agents for patients with advanced ACC. In multicenter trials of such patients of the South Western Oncology Group (SWOG) the combination of mitotane and cisplatin resulted in tumor regression in one-third of patients [31]. Conclusions We conclude from this study that active surgical treatment, with reoperation at signs of recurrence, is most important to obtain optimal survival and symptom palliation for ACC patients. Repeat surgery for recurrence is especially valuable in patients with a long disease-free interval. In this limited material we cannot evaluate the effects of adjuvant mitotane therapy, either as a potential prophylactic drug or as an antineoplastic agent. However, no objective tumor regression was observed in any of the patients. Because of the side effects of the drug, we advocate close monitoring of serum concentrations of mitotane in individual patients. The diagnostic value of urinary steroid profiles is promising, but to be able to evaluate this tool coordinated multicenter investigations and assembly of a solid reference material are required. Re´sume´ Le cancer de la corticosurre´nale (CCS) est rare, son pronostic est mauvais. Un attitude the´rapeutique stricte est difficile `a ´etablir; aussi a t’on cherche´ `a trouver des alternatives the´rapeutiques et de meilleurs outils diagnostiques. Bien que la chirurgie soit le traitement de choix, le ro ˆle de la chirurgie en cas de maladie avance´e reste proble´matique. Dix-huit patients conse´cutifs ont ´ete´ ope´re´s dans notre unite ´ pendant 22 ans (1975–1997). Tous les patients ont ´ete´ suivis par notre programme de surveillance comprenant des dosages ste´roı¨diens urinaires, des examens cliniques, une analyse des hormones ste´roı¨diennes et des examens radiologiques. Douze patients ont rec¸u du mitotane dont les concentrations ont ´ete´ contro ˆle´es afin d’assurer une dose efficace et non-toxique. La dure´e me´diane du traitement a ´ete´ de 12 mois avec tre`s peu d’effets secondaires. Quatre patients avec des tumeurs de bas grade ont eu des interventions «second-look» sans trouver de maladie ´evolutive. Cinq patients ont eu une deuxie`me
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intervention apre`s une dure´e moyenne sans maladie de 59 mois. La survie apre`s chirurgie secondaire ´etait corre ´le´e de fac¸on significative avec la dure´e de survie sans maladie avant la reprise. Onze patients avec chirurgie `a vise´e curative ont eu des examens urinaires plusieurs fois en postope´ratoire. Les re ´sultats des examens d’urines pre´ope´ratoires ´etaient disponibles pour 5 patients. Les re´sultats ´etaient en faveur d’une reprise ´evolutive malgre ´ des investigations radiologiques ne´gatives chez 2 de ces 5 patients. La dure´e du suivi allait de 6 semaines `a 24 ans. La survie `a 5 ans attendu a ´ete´ de 58% selon la me´thode de Kaplan-Meier. Nous concluons que 1) le monitoring des concentrations se´riques du mitotane rend possible un traitement au long cours avec peu d’effets secondaires; 2) l’analyse des me´tabolites ste ´roı¨diens peut ˆetre utile pour de´tecter la re´cidive tumorale `a un stade pre´coce, et 3) la chirurgie ite´rative pour re ´cidive est valable pour les patients ayant un long intervalle sans maladie.
Resumen El adenocarcinoma adrenocortical (CAC) es una enfermedad poco frecuente y de mal prono ´stico, para la cual ha sido muy difı´cil establecer un programa estricto de tratamiento; se hace necesario investigar nuevas alternativas terape´uticas, ası´ como nuevos me´todos diagno ´sticos. Aunque la cirugı´a constituye el tratamiento de escogencia, se ha cuestionado su papel en los casos de enfermedad avanzada. Dieciocho pacientes consecutivos fueron tratados en nuestro servicio en un periodo de 22 an ˜os (1975–1997). Todos los casos fueron sometidos a intervencio ´n quiru ´rgica y seguidos segu ´n nuestro programa, el cual incluyo ´ perfiles de esteroides urinarios, exa´menes clı´nicos, ana´lisis de hormonas esteroideas e investigaciones radiolo ´gicas. Doce pacientes recibieron mitotano con mediciones de la concentracio ´n plasma´tica de la droga con el fin de lograr dosis efectivas y no to ´xicas. La duracio ´n media del tratamiento con mitotano fue de 12 meses; se registraron muy pocos efectos secundarios. En cuatro pacientes con tumores en estados menores se practicaron reexploraciones de control (“second look”), con hallazgos patolo ´gicos negativos. Cinco fueron sometidos a operaciones repetidas, siendo 59 meses el intervalo medio del estado libre de enfermedad antes de la cirugı´a repetida. Se encontro ´ una correlacio ´n significativamente positiva entre el intervalo libre de enfermedad y la supervivencia luego de la cirugı´a repetitiva. En once casos que tuvieron cirugı´a intencionalmente curativa se practicaron perfiles de esteroides urinarios en varias oportunidades en el curso del seguimiento postoperatorio. En cinco casos tambie´n se dispuso de muestras urinarias preoperatorias. Los perfiles de esteroides revelaron enfermedad recurrente en dos de los 5, a pesar de hallazgos radiolo ´gicos normales. El periodo de seguimiento oscilo ´ entre 6 semanas y 24 an ˜os. La supervivencia predecible a 5 an ˜os, segu ´n el me´todo de Kaplan-Meier, fue de 58%. Nuestras conclusiones son las siguientes: 1) La monitorı´a de los niveles se´ricos de mitotamo permite realizar un tratamiento a largo lazo con escasos efectos secundarios; 2) El ana´lisis de los perfiles de esteroides puede ser utilizado para la deteccio ´n temprana de recurrencia tumoral; iii) La cirugı´a repetitiva es de valor en el manejo de recurrencias en los pacientes con periodos prolongados libres de enfermedad.
Khorram-Manesh et al.: Treatment and Follow-up of ACC
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Invited Commentary Murray F. Brennan, M.D. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
Adrenocortical carcinoma is an uncommon neoplasm and remains a significant challenge for physician, surgeon, and patient. Efficacious treatment has improved little over the last 20 years.
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Complete surgical resection remains the mainstay for both primary and recurrent disease; but cure, once metastasis is established, is virtually unheard of. Occasional long-term stabilization is seen in patients with metastatic disease, as with other neuroendocrine tumors. This manuscript from Go ¨teborg emphasizes many of these points. Eighteen patients were treated over a period of 22 years, emphasizing the rarity of the disease. All patients underwent operation, and 12 patients received mitotane for a median duration of 12 months. The paper addresses three issues: (1) the value
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of mitotane; (2) the value of surgical resection for recurrence; and (3) monitoring the urinary steroid profile for the detection of recurrence. The authors used angiography in nine patients and argue that it may be of value in preoperative embolization. Only two patients were embolized, and most centers would not utilize this approach, given the extensive vascular supply and the rare tumor that has a single arterial supply. Five of eighteen operated patients underwent reexploration for recurrence, two of whom had no evidence of disease (NED) at the time of follow-up. Four patients underwent elective second-look operations, but nothing was found, and they all remained NED. Twelve of fourteen patients received mitotane, the indications for which were unclear. Evaluation of the effect was confused by additional treatment in five. The authors have a surprisingly aggressive follow-up program, with urinary steroid profiles every 3 months and CT every 6 months. This is difficult to understand, as elective second-look operations did not find any recurrence and only two of five patients were NED after reoperation for recurrence. It is unclear whether this aggressive approach detected recurrence earlier than it might have been found based on clinical or even simple serum analysis of, for example, DHEAS, given the small number of patients and the poor outcome for any recurrence. The argument for vigorous steroid excretion evaluation is difficult to sustain. One patient had virilism and elevated urine levels, but nothing was found at operation. There was no subsequent recurrence. Two patients with early urinary steroid recur-
World J. Surg. Vol. 22, No. 6, June 1998
rence had no radiologic findings, but at operation they had disseminated disease and were not helped. Use of mitotane was monitored with serum levels, which required weekly measurements for the first 3 months to keep mitotane at a “desired interval.” This again appears to be expensive, and it is unclear what the justification is for 14 to 20 mg/ml as the desired concentration. The dose of mitotane utilized would be considered low by most authors. The range, 2.0 to 6.5 g, is not proportional to the serum concentration of the drug. This is consistent with the fact that only 5 of 12 patients had any symptomatic side effects. Three consisted of nausea. The low incidence of side effects is consistent with the low dose of the drug. In summary, the authors highlight the problems associated with adrenocortical carcinoma. The disease is rare, it is often advanced at the time of presentation, operation provides the only chance for survival, and with selected patients reoperation may prolong survival. Not surprisingly, overall survival in patients with recurrence is influenced by disease-free survival. I do not believe the authors have provided any proof that the extensive use of urinary steroid profiles necessarily identifies early disease or, if it does, influences outcome. In addition, the data suggest that extensive use and monitoring of serum levels of mitotane as a benefit to the patient is not supported. In fact, by the authors’ own claim, “adjuvant mitotane treatment did not influence the results after resection.” Unfortunately, we need new therapeutic strategies rather than minor manipulation of current approaches.
