Adrenal Cortical Carcinoma
Epidemiology and Treatment with Mitotane and a Review of the Literature
Marc D. Wooten, M.D., and David K. King, M.D., F.A.C.P.
Background. Adrenal cortical carcinoma is rare; the authors have treated only eight patients with the disease at Good Samaritan Regional Medical Center since 1974. No exhaustive collection of cases of this cancer has been done since 1952.
Methods. The authors retrospectively reviewed the medical records of their eight patients with adrenal corti- cal carcinoma. They also searched the English literature from 1952 to 1992 for reports of patients with the disease. They treated each report as a series if two or more previ- ously unreported patients were reported. They paid spe- cial attention to patients for whom stage of disease was noted at diagnosis, treatment with mitotane (o,p’-DDD) was used, and the outcome was reported.
Results. Five were male and three were female pa- tients. Five had nonfunctional tumors. None were pediat- ric. The authors found 1891 cases in the English litera- ture. Adrenal cortical carcinomas are more common in women (58.6%) than in men (41.4%). The age distribution of tumors is bimodal, with peaks in the first and fifth decades. Tumors in children are more commonly func- tional (83.5% in female patients, 85.6% in male patients), although nonfunctional tumors are more common in older patients (84.7%). Most (68%) of these tumors are diagnosed late in disease when surgery is no longer cura- tive. Only 35% of patients treated with mitotane had a clinical response.
Conclusions. Adrenal cortical carcinomas are diag- nosed most often in children because of functionality and older men because of mass effect. Most tumors are discov- ered too late for curative resection. Treatment of meta- static disease with mitotane has limited success. Cancer 1993; 72:3145-55.
Key words: adrenal cortical carcinoma, epidemiology, treatment, mitotane, chemotherapy.
From the Department of Oncology, Good Samaritan Regional Medical Center, Phoenix, Arizona.
The authors thank Greg Maynard, M.D., for his assistance in preparing the illustrations.
Address for reprints: David K. King, M.D., F.A.C.P., 1300 North 12th Street, Suite 612, Phoenix, AZ 85006.
Accepted for publication June 30, 1993.
Adrenal cortical carcinomas are rare tumors, with an estimated annual incidence of 0.5-2/1 million popula- tion.1 Among causes of tumor deaths, their incidence has been calculated at between 0.02%2,3 and 0.2%.4 No exhaustive compilation of cases has been done since Rapaport et al.5 collected the data to 1952, and there have been some differences in the conclusions about epidemiology and treatment of this cancer by different authors. Series with more than 50 patients have sug- gested that there is a bimodal age distribution in the occurrence of these tumors. Some series have observed that functional tumors occur more frequently in women than in men and in children than in adults.3,6 Series have differed as to whether tumors are more commonly of the left or right side.3,6 Finally, the efficacy of mito- tane has varied from series to series.3,7,8 To resolve these differences, we compiled almost 1900 published re- ports to assess the most common groups of patients affected and to assess the efficacy of mitotane in pro- longing survival in patients with advanced disease.
Materials and Methods
A retrospective review of the medical records of eight patients treated at Good Samaritan Regional Medical Center for adrenal cortical carcinoma since 1974 was performed with special attention to demographic data, clinical histories, operative treatment, and subsequent clinical course (including treatment with chemotherapy).
In addition, the English literature from 1952 to 1992 was searched for reports of patients with adrenal cortical carcinoma, using the MEDLINE and MESH headings of “adrenal,” “cortical,” and “carcinoma.” Bibliographies of these reports were searched for other studies. Each report was considered a series if two or more previously unreported patients were included. A tumor was considered clinically functional if any endo- crine hyperfunction was observed (Cushing syndrome, virilization, feminization, hyperaldosteronism, or hypo- glycemia). Tumors described as benign or with no
| Patient no. | Sex | Age (yr) | Endocrinopathy | Side | Stage at diagnosis | Surgery | Mitotane | Other therapy | Other primary cancers | Survival (mo) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 16 | Cushing | Right | IV | Resection | Yes (POD) | None | None | 5 |
| 2 | M | 38 | Nonfunctional | Right | IV | Biopsy | Yes (POD) | None | None | 3 |
| 3 | M | 59 | Nonfunctional | Left | II | Autopsy | No | None | Lung | 0 |
| 4 | F | 47 | Nonfunctional | Left | II | Resection | Yes (PR) | Chemo | Sarcoma | 74 |
| 5 | M | 71 | Nonfunctional | Left | II | Resection | No | None | None | 10 |
| 6 | F | 73 | Nonfunctional | Right | II | Resection | No | Chemo | Breast, ovary | 69 (AWD) |
| 7 | M | 33 | Feminization | Left | I | Resection | No | None | None | 105 (NED) |
| 8 | M | 20 | Cushing | Right | II | Resection | Yes (POD) | Chemo | None | 23 |
| M = male; F = female; POD = progression of disease; PR = partial remission; Chemo = cytotoxic chemotherapy; AWD = alive with disease; NED = no evidence of disease. | ||||||||||
pathologic designation of malignancy were excluded from this review.
Results
Good Samaritan Patients
Eight patients with adrenal cortical carcinoma were identified through a retrospective review of records at Good Samaritan Regional Medical Center, Phoenix, Arizona (Table 1). Five of them had nonfunctional tu- mors identified on the basis of mass effect (four) or at autopsy (one). Six patients had Stage I or II disease, yet only two of them are still alive; both patients with ad- vanced disease have died. Mean survival for patients with Stage I or II disease whose tumors were discovered clinically was 61 months (standard deviation (SD), ± 37 months), with a range of 10-105 months. Patients with Stage IV disease had a mean survival of 4 months (SD, ± 1 month), with a range of 3-5 months. Four patients were treated with mitotane (the two who had Stage IV disease and two with Stage II disease who later had distant metastases). Only one of these four patients had objective regression of disease as evidenced by tumor shrinkage.
Three (37%) of the eight patients had other primary carcinomas, which were of the SBLA (sarcoma, breast and brain tumors, lung and laryngeal cancers, leuke- mia, and adrenal cortical carcinoma) distribution.
Distribution by Sex, Function, and Side
In the English literature, 87 studies (1891 patients) re- ported the sex distribution and functional status of tu- mors (Table 2).2-88 In most of these, the distribution of tumor locations also was specified.
There was a slight female (4:3) predominance of these tumors. Most (59.3%) tumors were functional and most (in series in which tumor location was reported) were located on the left (52.8%). A few tumors (2.4%) were bilateral.
The data shown in Tables 3-8 represent subsets of the data from Table 2 and allow additional breakdown of this information.
Distribution of Functional and Nonfunctional Tumors
Seventy-three studies (1480 patients) related functional and nonfunctional tumors to the sex of the patient (Ta- ble 3). In these series, a predominance of functional tumors was reported in female patients (by a 7:3 ratio) and a predominance of nonfunctional tumors was re- ported in male patients (by a 3:2 ratio).
Distribution by Age
Seventy-seven series (1330 patients) provided data by patient age and sex. In most reports, patient age at diag- nosis was broken down into two groups: (1) 30 years of age or younger and (2) older than 30 years (Table 4).
Of the male patients reported, most tumors were found in men older than 30 years (by a 5:2 ratio). Tu- mors in female patients were slightly more common in patients older than 30 years than in patients 30 years or younger.
Distribution by Sex, Age, and Functionality
Sixty-nine series (908 patients) provided data by patient age at diagnosis, sex, and functional status of tumor (Tables 5 and 6). These tables captured a greater num- ber of functional tumors (65.4% versus 59.3% docu-
| Total patients | Male | Female | Functional | Nonfunctional | Left | Right | Bilateral | |
|---|---|---|---|---|---|---|---|---|
| Total | 1891 | 783 | 1108 | 1083 | 743 | 766 | 650 | 36 |
| Percentage | 100.0 | 41.4 | 58.6 | 59.3 | 40.7 | 52.8 | 44.8 | 2.4 |
mented in Table 2), but the number of tumors in female patients and the number of patients younger than 30 years were only slightly greater.
These data confirm the much greater frequency with which nonfunctional tumors are seen in older pa- tients of both sexes (85.6% in male patients; 83.5% in female patients). Males patients older than 30 years more commonly have nonfunctional tumors than do female patients, by a 3:2 proportion.
Functional tumors are more common in the pediat- ric population than in adults in both sexes (54.9% in male patients; 58.0% in female patients). Female pa- tients younger than 30 years more commonly have functional tumors than do male patients, by a 7:3 ratio.
Distribution by Sex, Age, Functionality, and Side
One thousand four patients were reported in which two or more of the following were stated: the patient’s age at diagnosis, patient’s sex, whether or not the tumor was functional, and the side of the tumor. This collec- tion of patient data included more female patients (61.4%), functional tumors (69.1%), and younger pa- tients (46.0%) than the larger sets shown in Tables 2 through 6.
These data confirm the bimodal distribution of in- cidence of tumors, with peaks in the first and fifth de- cades (Fig. 1). This pattern is less pronounced in female patients (except for the large number of tumors diag- nosed in infancy) (Fig. 2), but is clearly seen in male patients (Fig. 3).
The median patient age at diagnosis of disease in this cohort was 33 years. Within the pediatric and ado- lescent population, the median patient age at presenta- tion was 4 years. In adults, the median age at disease diagnosis was 44 years. A lower median age was noted for female patients (30 years) than for male patients (39 years).
Aside from an early peak in infancy, functional tu- mors have a bimodal distribution (Fig. 4). Nonfunc- tional tumors are noted primarily in older patients, with a peak in the fifth and sixth decades (Fig. 5). The me- dian patient age for diagnosis of functional tumors (24 years) was much lower than that for nonfunctional tu- mors (47 years).
Summary of Epidemiologic Parameters
Major epidemiologic parameters and their relative fre- quencies are shown in Table 7, along with differences in these percentages (plus or minus the standard error). Each of these relative frequencies has been extracted from percentages given in Tables 2-6. Using these 95% confidence intervals, we conclude: (1) the tumor occurs in women more often than in men; (2) most patients are older than 30 years; (3) functional tumors are more common than nonfunctional tumors; and (4) tumors of the left side are only slightly more common than are ones of the right side.
In these univariate calculations, the widest differ- ences are as follows: (1) tumors were found more often in male patients older than 30 years (71.7%) than in male patients younger than 30 years (28.3%); (2) female patients had functional tumors (73.8%) more often than they had nonfunctional tumors (26.2%); (3) non- functional tumors were seen more often in patients older than 30 years (84.7%) than in those younger than 30 years (15.3%); (4) in both sexes nonfunctional tu- mors were more common in patients older than 30 years (men, 85.6%; women, 83.5%).
Staging
The staging system proposed by MacFarlane35 and mod- ified by Sullivan et al.15 is the system most commonly in
| Total patients | Male total | Female total | Male functional | Male nonfunctional | Female functional | Female nonfunctional | |
|---|---|---|---|---|---|---|---|
| Total | 1480 | 634 | 846 | 270 | 364 | 624 | 222 |
| Percentage | 100.0 | 42.8 | 57.2 | 42.6 | 57.4 | 73.8 | 26.2 |
| Total patients | Age < 30 yr | Age > 30 yr | Male total | Female total | Male, age < 30 yr | Male, age > 30 yr | Female, age > 30 yr | Female, age > 30 yr | |
|---|---|---|---|---|---|---|---|---|---|
| Total | 1330 | 502 | 828 | 579 | 751 | 164 | 415 | 338 | 413 |
| Percentage | 100.0 | 37.7 | 62.3 | 43.5 | 56.5 | 28.3 | 71.7 | 45.0 | 55.0 |
use today. Stage I and II tumors are confined to the adrenal gland and are potentially curable with com- plete resection. Stage III and IV tumors represent local and distant metastasis, respectively. Twenty-six series (608 patients) provided stage at diagnosis or (in some smaller series) allowed retrospective classification from case reports (Table 8).
Most tumors were at an advanced stage at the time of diagnosis. Tumors that are potentially surgically cur- able (Stages I and II) accounted for only 31.8% of tu- mors at the time of diagnosis. Conversely, almost 70% of tumors had spread beyond the adrenal gland (Stages III and IV) at the time of diagnosis, necessitating addi- tional treatment (including mitotane therapy).
Response to Mitotane
Sixty-four reports (551 patients) on the use of mitotane were found (Table 9).2-4,6-31,89-110 Although some inves- tigators have used this drug adjuvantly with surgery or radiation therapy, patients treated adjuvantly with mi- totane were not included in this table. Mitotane remains the first drug of choice for treating advanced (Stage III and IV) tumors.
Of the patients reported, only one-third (194 of 551) had at least a partial response to mitotane. Unfortu- nately, the definition of “clinical response” was varied and broad. Some investigators included only patients with demonstrable tumor shrinkage or disappearance by objective means (computed tomography, repeat sur- gery, or autopsy). Others expanded the definition to include clinical findings (remission of hormonally in- duced symptoms in patients with functional tumors or tumor shrinkage documented by physical examination alone).
Discussion
Patients of Good Samaritan Regional Medical Center
The eight patients treated at Good Samaritan Regional Medical Center were adolescents or adults. Because six of these patients were older than 30 years, it was not surprising that more nonfunctional, rather than func- tional, tumors were seen. Only one patient (with a non- functional tumor) of four treated with mitotane had a response to this medication (tumor shrinkage), which was consistent with the literature reviewed. The distri- bution of metastases at death was consistent with pre- vious reports in the literature.3,34
One of our patients is alive after having had a sur- gical cure of his Stage I tumor. Another is alive with the adrenal cortical carcinoma in complete remission (at 69 months after diagnosis and surgical resection of a Stage II tumor). She is being treated with cytotoxic chemother- apy for metastatic breast and ovarian adenocarcinomas.
The mean survival for our patients with Stage I and II (61 months) tumors at diagnosis was greater than that for those with Stage IV tumors (4 months). Our re- sponse rate to mitotane (25%) is similar to that found in the literature.
That 37% of our patients should have other pri- mary carcinomas was surprising. Other primary carci- nomas are seen in kindreds with the SBLA syndrome (or Li-Fraumeni syndrome), which is thought to be at- tributable to a genetic defect or predisposition to these tumors.111,112 However, all patients in our series had family histories that were negative for other malignan- cies. Other series have reported an incidence of second malignancies of 12-24%.3,32 We speculate that our re- sults may have been caused by the small number of patients in our sample or by the fact that ours were
| Total patients | Male, functional, age < 30 yr | Male, functional, age > 30 yr | Male, nonfunctional, age < 30 yr | Male, nonfunctional, age > 30 yr | |
|---|---|---|---|---|---|
| Totals | 369 | 100 | 82 | 27 | 160 |
| Percentages | 100.0 | 27.1 | 22.2 | 7.3 | 43.4 |
| Total patients | Female, functional, age < 30 yr | Female, functional, age > 30 yr | Female, nonfunctional, age < 30 yr | Female, nonfunctional, age > 30 yr | |
|---|---|---|---|---|---|
| Total | 539 | 239 | 173 | 21 | 106 |
| Percentage | 100.0 | 44.3 | 32.1 | 3.9 | 19.7 |
adult patients (mean age, 44.6 ± 21.8 years). The fre- quency of second primary malignancies in these pa- tients points to a need for close surveillance.
Epidemiology
This study confirms previously imputed relationships in the incidence of adrenal cortical carcinoma between sex, age, and functionality. Specifically, it confirms that there is a bimodal age distribution to these tumors (ac- centuated in male patients). It supports the greater likeli- hood of discovering functional tumors in female (70%) than in male (40%) patients. Tumors of the left side are only slightly more common than are tumors of the right side, and bilateral tumors are rare.
The greater likelihood of a tumor being functional in an infant or child promotes recognition of such tu- mors.113 Functional tumors were more common in fe- male patients younger than 30 years. Functional tumors often were diagnosed in infant girls and pubertal girls based on hormonal syndromes (including Cushing syn- drome) that have virilization as a part of their presenta- tion. In male patients, the distribution of functional tu- mors was roughly equivalent in younger and older pa-
tients, perhaps because of the inability to recognize virilization in postpubertal male patients and the rela- tive infrequency of feminization syndromes caused by adrenal cortical carcinoma.
Most nonfunctional tumors were discovered in older patients who reported an abdominal mass or pain or were incidentally noted on abdominal computed to- mography scans performed for other reasons.19,34 These older patients were more likely to be men, but no clear explanation exists regarding why older men were more frequently affected than were older women. We specu- late that men are more prone to be exposed to environ- mental toxins (alcohol, tobacco); female hormones also may have a protective effect.
Most tumors were found in later stages (III and IV), for which where chemotherapy was necessary. A signif- icant tumor burden with early local extension and he- matogenous spread was needed in many patients to produce identifiable hormonal syndromes (because of the inefficiency of tumor in producing active hor- mone).19,37 Alternatively, because of the well-protected, deep retroperitoneal location of the adrenal glands (rendering them inaccessible to physical examination) and the rarity of the tumor, a nonfunctional tumor had to be large to cause mass effect or pain.3,32
| Epidemiologic parameter | % of patients | Epidemiologic parameter | % of patients | Difference in % (+SE) |
|---|---|---|---|---|
| Female patients | 58.6 | Males | 41.4 | 17.2 (±1.7) |
| Functional | 59.3 | Nonfunctional | 40.7 | 18.6 (±1.8) |
| Age > 30 yr | 62.3 | Age ≤ 30 yr | 37.7 | 24.6 (±2.3) |
| Left-sided | 54.1 | Right-sided | 45.9 | 8.2 (±1.4) |
| Males, nonfunctional | 57.4 | Males, functional | 42.6 | 14.8 (±2.8) |
| Males, age > 30 yr | 71.7 | Males, age ≤ 30 yr | 28.3 | 43.4 (+4.0) |
| Females, functional | 73.8 | Females, nonfunctional | 26.2 | 47.6 (±3.4) |
| Females, age > 30 yr | 55.0 | Females, age ≤ 30 yr | 45.0 | 10.0 (±2.1) |
| Nonfunctional, age > 30 yr | 84.7 | Nonfunctional, age ≤ 30 yr | 15.3 | 69.4 (±5.1) |
| Females, nonfunctional, age > 30 yr | 83.5 | Females, nonfunctional, age ≤ 30 yr | 16.5 | 67.0 (±8.2) |
| Males, nonfunctional, age > 30 yr | 85.6 | Males, nonfunctional, age ≤ 30 yr | 14.4 | 71.2 (±6.5) |
| Functional, age ≤ 30 yr | 57.1 | Functional, age > 30 yr | 42.9 | 14.2 (±2.8) |
| Females, functional, age ≤ 30 yr | 58.0 | Females, functional, age > 30 yr | 42.0 | 16.0 (±3.5) |
| Males, functional, age ≤ 30 yr | 54.9 | Males, functional, age > 30 yr | 45.1 | 9.8 (±4.3) |
| SE: standard error. |
| Total patients | Stage I | Stage II | Stage III | Stage IV | |
|---|---|---|---|---|---|
| Total | 608 | 18 | 176 | 117 | 297 |
| Percentage | 100.0 | 2.8 | 29.0 | 19.3 | 48.9 |
Staging and Outcome
The staging system introduced by MacFarlane35 and modified by Sullivan et al.15 pointed to the overall sur- vival advantage in patients whose tumors were discov- ered early enough to be resected. Patients with Stage I or II disease were potentially curable at surgery and had prolonged survival.8,9,11,114 Richie and Gittes114 noted that most male patients are seen with Stage III or IV tumors, whereas female patients have a more even dis- tribution of disease stages. Richie and Gittes114 also ob- served that younger patients tend to have tumors of lower stage.
The only other variable associated with prolonged survival after diagnosis is a younger age at diagnosis.8 Untreated patients were first noted by MacFarlane to have a mean survival of 2.9 months.35 The overall mean survival in the eight patients treated by the authors was 36 months.
Five-year survival rates have been between 25% and 43% in patients who were treated by all modali- ties.1 Mean survival times of patients in the study by Henley varied between 2.1 years for those with Stage I disease to 1.0 years for those with Stage IV disease,21 whereas Cohn et al.9 noted a mean patient survival of 5.0 years for those with Stage II disease and 2.3 years for those with Stage IV disease.
Treatment
Surgical resection remains the treatment of choice for patients with limited disease. However, almost 70% of
0.3
150
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100
0.1
50
0
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40
60
80
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patients present with Stage III or IV disease, which highlights the need for additional therapies.
The currently recommended first line of chemother- apy for patients with unresectable tumors and those for whom surgery is otherwise contraindicated is mitotane. Bergenstal et al.115 and Lubitz et al.,7 (who reported a 61% patient response rate), first demonstrated that functional and nonfunctional tumors in vivo are re- sponsive to mitotane.
However, it is apparent from the pooled data that only about 35% of tumors responded to this drug. Be- cause of the small number of patients with responses, it is not possible to identify factors that predict success or failure of this therapy. Hoffman and Mattox116 noted that their patients with functional tumors who had mea- surable disease response also had a significant reduc- tion in tumor steroid production. Functional and non-
0.20-
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0.15-
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0.10-
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0.05-
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0
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60
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0.20
0.15
60
PERCENTAGE
NUMBER OF PATIENTS
50
0.10
40
30
0.05
20
10
0
30
60
90
AGE
200
0.3
150
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100
0.1
50
0
20
40
60
80
AGE
functional tumors have responded to mitotane. Like- wise, patients of all age groups have experienced dis- ease remission.
It is unclear if tumor response or shrinkage corre- lates with prolonged patient survival. The length of re- mission varies from a short duration to documented cure. The longest sustained remission using mitotane was reported by Markoe et al.31 at just more than 17 years. However, several studies failed to show a signifi- cant increase in duration of survival for patients with response to mitotane,6,8,90,116 despite isolated reports showing prolonged or complete remission with mito- tane. 4,32,94,98,99,105,108,117
One study has suggested that achieving serum mi- totane levels of greater than 10 µg/ml may be crucial to the agent’s efficacy. Van Slooten et al. showed an in- crease in survival or tumor regression in 57% (8 of 14) of patients who had serum levels greater than 14 ug/ ml,22 with a complete remission in one patient.117 Con- versely, no patient with a serum drug level of less than
0.15
40
PERCENTAGE
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0.10
30
20
0.05
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60
90
AGE
| Reference | Year | Total no. of patients | Partial/total responses | Duration (mo) |
|---|---|---|---|---|
| Gabrilove10 | 1965 | 2 | 1 | 18-54 |
| Montgomery89 | 1965 | 1 | 1 | 3 |
| Hutter90 | 1966 | 59 | 20 | 1-46 |
| Gabrilove11 | 1970 | 3 | 0 | 1-5 |
| Halmi91 | 1971 | 1 | 1 | 34 |
| Six92 | 1972 | 1 | 0 | 2 |
| Lubitz7 | 1973 | 75 | 46 | 1-36 |
| Harrison93 | 1973 | 5 | 3 | 4-44 |
| Lewinsky12 | 1974 | 2 | 1 | 2-5 |
| Downing94 | 1974 | 1 | 1 | 48 |
| Ostuni95 | 1975 | 1 | 1 | 114 |
| Bradley13 | 1975 | 5 | 4 | NA |
| Bulger14 | 1977 | 5 | 0 | NA |
| Korth-Schutz96 | 1977 | 1 | 1 | 2 |
| Greenberg2 | 1978 | 2 | 1 | 1-108 |
| McKiernan97 | 1978 | 1 | 1 | 72 |
| Sullivan15 | 1978 | 7 | 3 | NA |
| Smith16 | 1979 | 1 | 0 | 5.5 |
| Kelly17 | 1979 | 3 | 1 | 1-2 |
| Hogan98 | 1980 | 5 | 3 | NA |
| Tattersall18 | 1980 | 4 | 2 | 6-12 |
| Bertagna19 | 1981 | 11 | 2 | 12-30 |
| Jarabak99 | 1981 | 1 | 1 | 156 |
| Schteingart20 | 1982 | 9 | 4 | 1-120 |
| Henley21 | 1983 | 24 | 6 | 3-24 |
| Kay100 | 1983 | 4 | 1 | 6-144 |
| Van Slooten22 | 1984 | 34 | 8 | 4-126 |
| Lefevre23 | 1984 | 11 | 4 | 1-42 |
| Holcombe24 | 1984 | 2 | 0 | 5-7 |
| Raney25 | 1984 | 1 | 0 | 19 |
| Chan101 | 1984 | 6 | 4 | 4-18 |
| Dehner102 | 1984 | 1 | 1 | 44 |
| Karakousis4 | 1985 | 10 | 2 | 1-29 |
| Watanobe103 | 1985 | 1 | 0 | 9 |
| Lee26 | 1985 | 1 | 0 | 9 |
| Cohn9 | 1986 | 8 | 2 | NA |
| Linos27 | 1986 | 4 | 1 | NA |
| Eriksson28 | 1987 | 3 | 2 | 9-78 |
| Magee104 | 1987 | 3 | 2 | NA |
| Krzisnik105 | 1988 | 1 | 1 | 36 |
| Ventakesh3 | 1989 | 72 | 21 | NA |
| Bodie6 | 1989 | 13 | 3 | 96-204 |
| Borrelli29 | 1989 | 4 | 1 | 2.4-30 |
| Luton8 | 1990 | 37 | 8 | 6-25 |
| Bukowski106 | 1990 | 41 | 10 | 2-13 |
| Epelman107 | 1990 | 16 | 6 | 3-65 |
| Lim108 | 1990 | 1 | 1 | 82 |
| Decker30 | 1991 | 36 | 8 | 2.6-82 |
| Markoe31 | 1991 | 5 | 3 | 34-205 |
| Koh109 | 1991 | 1 | 0 | 6 |
| Tsukamoto110 | 1992 | 1 | 0 | 3 |
| Current study | 1992 | 4 | 1 | 5-18 |
| Total | 551 | 194 | ||
| (35.2%) | ||||
| NA: not available. |
10 µg/ml had a significant therapeutic effect.22 How- ever, no other study exists that has corroborated these findings. Unfortunately, clinical parameters (including function) have not been noted to predict a response to mitotane.8,20,116 Use of the drug is complicated by a panoply of adverse effects and toxicities that limit its administration.22,116
Combining mitotane with cytotoxic chemotherapy also has been associated with limited success. Ostuni and Roginsky95 documented a complete remission in a patient receiving a combination therapy of mitotane and 5-fluorouracil. Eriksson et al.28 reported two re- sponses in metastatic disease with mitotane and strep- tozocin that allowed surgical resection of residual tu- mor and disease-free survival. Bukowski et al.106 re- ported one complete response with mitotane and cisplatin.
Thus treatment with mitotane is insufficient ther- apy for most patients with this tumor, whether this agent is given alone or in combination with other forms of chemotherapy.
Bias
All relevant articles we could identify in the English literature were included in this analysis; there was no intended data extraction bias in this study. Articles about adrenal cortical carcinoma may be subject to publication bias because only large or unique series are likely to warrant publication.
In the smaller data bases (Tables 5 and 6), there was probable selection bias because smaller series (which provide detailed case data) were more likely to focus on a unique aspect of the tumor. Thus, more of these tu- mors were functional, and more female patients were included. Hutter and Kayhoe34 surmised that functional tumors are more often the subject of case reviews and that endocrine syndromes are more easily detected in women.
Conclusions
A review of the English literature supports the observa- tions that adrenal cortical carcinomas (1) are more com- mon in women than in men; (2) have a bimodal distri- bution, with peaks in the first and fifth decades; (3) are more commonly functional in children; (4) are more commonly nonfunctional in older adults; (5) when nonfunctional, are more common in older men than older women; (6) are about equally distributed in either adrenal gland; (7) usually are diagnosed late in disease (Stages III or IV); and (8) are responsive to mitotane in
only approximately one-third of patients who are not cured by surgery.
The overall prognosis for patients with nonresect- able tumor remains dismal. Ongoing protocols to test alternative chemotherapeutic regimens for patients whose tumors could not be resected and who do not have a response to mitotane are needed as part of re- search in the management of this rare tumor.
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