Adrenocortical Carcinoma
Murray F. Brennan, MD, MCh
Incidence
The exact incidence of adrenocortical car- cinoma is not known. Calculations from the National Cancer Institute’s Surveil- lance, Epidemiology and End Results (SEER) database would suggest an inci- dence of 75 to 115 new cases each year in the United States (0.5 per million per year);’ others have suggested as many as two per million per year.2 Adenomas of the adrenal gland are very common, with as many as two percent of all autopsies showing ade- nomatous change in the adrenal gland.’ Adrenocortical tumors, therefore, range from the very common, small, nonfunc- tional, incidentally identified adenoma, to the very uncommon, often large, sympto- matic, invasive adrenocortical carcinoma.
Age and Sex Distribution
Recent studies from our group suggest that the sex distribution is equal,3 although most
Dr. Brennan is Alfred P. Sloan Professor of Surgery and Chairman of the Department of Surgery at Memorial Sloan-Kettering Cancer Center, and Professor of Surgery at Cornell Uni- versity Medical College. in New York, New York.
The author gratefully acknowledges the con- structive criticism of the text by Dr. Daiva Ba- jorunas, and of the radiographs, by Dr. Barbara Demas. The manuscript could not have been prepared without the ongoing assistance of Ms. Gwen Besson.
authors have noted that more women have the functional type of tumor. The average age at presentation is 40 to 50 years, but there is a broad spectrum of all age groups+ (Fig. 1). In children, it has been suggested that there are two age peaks: an early one, at one to two years, followed by a decline until age seven, after which there is a more even distribution through ages nine to 16.5
Pathogenesis
The etiology of adrenocortical carcinoma is unknown. Whether the tumor arises de novo or develops in the setting of a hyper- plastic nodule is unclear. Arguments in fa- vor of a precursor lesion include the fact that some patients have abnormal adrenal steroid production that preceded the devel- opment of adrenal carcinoma by dec- ades.6.7
Classification and Staging
For practical purposes, adrenocortical tu- mors are classified as either functional or nonfunctional. The classic symptoms de- velop as a result of excess amounts of an- drogen or estrogen, corticosteroids, or min- eralocorticoids. Androgen, estrogen, and corticosteroid excess are far more common than aldosterone excess in adrenocortical carcinoma.
To some degree, however, the distinc- tion between functional and nonfunctional is academic. While the distinction is impor-
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tant in situations of clear hormonal excess, it is also true that some degree of hormone excess underlies all adrenocortical carci- nomas. Because adrenocortical carcinomas are less efficient in steroidogenesis, they are less likely to show obvious clinical syn- dromes of excess. It is important, there- fore, to make a specific search for precursor steroids that may be clinically inapparent, such as 4-5-pregnenolone and dehydro- isoandrosterone (DHEA); otherwise, the tumor will be inappropriately classified as nonfunctional.
Hypercortisolemia (which occurs in 50 percent of cases), virilization (20 percent), or combinations of the two (10 to 15 per- cent) are to be expected in adrenocortical carcinoma, with 10 to 15 percent of tumors being nonfunctional.8 In our recent study, 70 percent of adrenocortical carcinomas showed obvious function, with approxi- mately 20 percent excess androgen or es-
trogen, 20 percent excess cortisol produc- tion, and 20 percent mixed.3 Elevated hydroxysteroid or corticosteroid levels oc- curred in another 15 percent, without defin- able clinical syndromes of hormone ex- cess. Excess aldosterone as a predominant feature was seen in two percent, with the remaining 25 percent nonfunctional. In an earlier study, 16 percent were nonfunc- tional at presentation.4 The designation of functional versus nonfunctional is clearly an arbitrary term that usually depends on the vigor with which the classifier looks for excess hormone production.
Staging of the disease has been simpli- fied (Table 1), and is essentially equivalent to disease confined to or outside the adrenal gland. The vast majority of patients present with stages 3 or 4 disease. In our study, 72 percent were stage 4 at presentation,3 while in a Mayo Clinic study,9 66 percent were stages 3 or 4.
Presentation and Diagnosis
Adrenocortical carcinoma presents either as a functional tumor or as an intra-ab- dominal mass with associated symptoms related to local pressure, necrosis, or hem- orrhage. The functional lesions can be broadly divided into three groups-those with corticosteroid excess, those with min- eralocorticosteroid excess, and those with function derived from excess production of sex hormones. The presentation is different for each.
Corticosteroid excess is by far the more
Adenomas of the adrenal gland are very common, with as many as two percent of all autopsies showing adenomatous change in the adrenal gland.
common presentation and is much more readily recognized. Characteristic signs in- clude truncal obesity and redistribution of fat with buffalo hump, rounded facies, stria, and hypertension. These patients often have glucose intolerance, thinning of the skin, osteoporosis, and sometimes renal calculi. When the hormonal excess is high, psychi- atric problems are common.
The easily recognized signs of excess sex hormone production include excessive masculinization, or virilization, in women, and feminization in men. Combinations of hormonal excess can occur, however, mak- ing these patterns less apparent. Patients with a nonfunctional lesion usually present with a large mass, associated fever, and occasional anemia. The symptoms of those with a nonfunctional mass are mainly due to size, pressure, and invasion of contig- uous structures.
Adrenocortical carcinomas that pro- duce aldosterone almost exclusively are even rarer, and the majority also produce other adrenocortical hormones. 10-12 An esti- mated one to two percent of all patients
with primary aldosterone-producing tu- mors will develop carcinomas. Diagnostic suspicion of carcinoma can be raised if there is a loss of the circadian rhythm of aldosterone secretion, which is typical of most patients with adenomas, in the setting of a suppressed plasma renin concentration and stable plasma potassium levels. 10
Unfortunately, many carcinomas, especially those that are nonfunctional, present as large advanced masses. In our recent series,3 the average size at presenta- tion was 16 cm (range of six to 40 cm) and 1,190 gm (range of 320 to 2600 gm). The tumors are usually already outside the adre- nal gland. Seventy percent of our cases had extra-adrenal spread, mostly to the lungs (45 percent), liver (42 percent), or lymph nodes (24 percent) (Table 2).
For suspected corticosteroid excess in functional tumors, the signs and symptoms have been well documented, as they have been for androgen or estrogen excess (Ta- ble 3).1.8 Laboratory confirmation of the adrenocortical excess is made first, and the cause is confirmed, followed by localiza- tion tests. The most reliable screening test is urinary free cortisol.13 A value greater than 100 mg in 24 hours is abnormal. We have also employed the simple overnight suppression test to confirm the diagnosis- one mg of dexamethasone given at 11 PM, and a cortisol sample obtained the next morning at 8 AM. A normal response is suppression of serum cortisol to less than five mg/dl, with a value of greater than 10 mg/dl highly suspicious for cortisol excess. False negatives occur in less than two per- cent of those who are obese or taking other drugs,8 and false positives may occur in 10 percent.
The use of excretion of 170H steroids or 17-ketosteroids, although time-honored, has little if any extra value in screening for Cushing’s syndrome. Low-dose dexa- methasone suppression tests further con- firm the diagnosis (Fig. 2). Measurements of plasma adrenocorticotropic hormone (ACTH) are now readily available (normal is 20 to 100 pg/ml) and can rapidly direct the diagnosis of the cause of hypercortiso- lemia (Fig. 3). Since ACTH is unstable in plasma at room temperature and adsorbs to
| Stage | Criteria |
|---|---|
| 1 | Tumor <5 cm Negative Nodes No Local Invasion No Metastases |
| 2 | Tumor >5 cm Negative Nodes No Local Invasion No Metastases |
| 3 | Positive Nodes or Local Invasion |
| 4 | Positive Nodes and Local Invasion or Distant Metastases |
| *Adapted from Brennan." |
| Organ | Percent (N = 33) |
|---|---|
| Lung | 45 |
| Liver | 42 |
| Lymph Nodes | 24 |
| Bone | 15 |
| Pancreas | 12 |
| Spleen | 6 |
| Diaphragm | 12 |
| Miscellaneous (Brain, Peritoneum, Skin, Palate) | 12 |
| *Adapted from Cohn et al.3 | |
TABLE 3 CLINICAL MANIFESTATIONS OF ANDROGEN-ESTROGEN EXCESS*
| Virilization | |
|---|---|
| In Women | In Prepubertal Boys |
| Male Pattern Baldness | Precocious Puberty |
| Hirsutism | |
| Deepening Voice | |
| Breast Atrophy | |
| Clitoral Hypertrophy | |
| Decreased Libido | |
| Oligomenorrhea | |
| Feminization | |
|---|---|
| In Men | In Prepubertal Girls |
| Gynecomastia | Precocious Puberty |
| Breast Tenderness | |
| Testicular Atrophy | |
| Decreased Libido | |
| "Reprinted from Brennan1 | |
glass, careful collection and prompt sepa- ration and freezing of the samples are es- sential. Selective venous sampling can de- tect the source of ACTH with accuracy, and elevated inferior petrosal sinus values can confirm a pituitary source. 14
Localization and Staging
Once an adrenal tumor is suspected, com- puterized tomography (CT) is the investi- gative tool of choice. CT has largely superceded intravenous pyelography, ul- trasonography, and radionuclide scanning. CT provides localization, identifies meta- static disease, and often gives information about the lesion’s resectability and likeli-
hood of being a carcinoma. CT will not, however, clearly show whether liver inva- sion has occurred. In our experience, while liver approximation and adherence is com- mon and frequently interpreted as invasion by CT scan, invasion occurs only rarely (Fig. 4). Percutaneous needle biopsy under CT guidance can be performed, but should be reserved for patients in whom the suspi- cion of metastases to the adrenal is high and in whom no surgical intervention is contemplated.
Aortography can confirm the known adrenal blood supply from renal inferior phrenic, aortic, and occasionally capsular or gonadal, blood vessels. In our opinion, the only significant value of aortography is
to help differentiate a renal from an adrenal tumor. Magnetic resonance imaging (MRI) shows considerable ability in differentiat- ing adrenal masses (Figs. 5 and 6).
Factors Predictive of Cancer
Central necrosis on the CT scan and large size are among the factors predictive of carcinoma. The most important factor is the presence of vena cava involvement in right-sided lesions. This can often be deter- mined by CT (Fig. 7) or cavagram (Figs. 8 and 9). The advent of quality CT and MRI scans has largely eliminated the need for vena cavography; if there is any doubt, however, this study should still be per- formed to allow preoperative and post- operative surgical preparation.
Histopathologic evaluation can be dif- ficult. In one recent immunohistochemical analysis, 20 of 20 adrenocortical tumors were found to be reactive to vimentin, but not to a battery of other antibodies includ- ing carcinoembryonic antigen, cytokeratin S100 protein, epithelial membrane anti- gen, blood group isoantigens, and antilec- tin. 15
A review by Hough et al16 examined 41 patients, 14 of whom subsequently devel- oped metastases. In these patients, the fac- tors that would have predicted metastases in the primary tumor were weight loss, presence of fibrous bands, diffuse growth, necrosis, capsular invasion, mitotic index, nuclear pleomorphism, and size of the pri- mary. The smallest tumor that metasta- sized, however, was 39 gm, compared with 96 gm as reported by other authors. 17
In a similar study of 60 patients by van Slooten et al,18 18 patients who survived without metastases for 10 years were com- pared with 42 patients who showed metas- tases within 10 years. Examining necrosis, structure, nuclear atypia and hyperchro- masis, nucleolar morphology, mitotic ac- tivity, and capsular invasion, these authors then created a weighted value for each dis- criminant. Mitotic activity and regressive activity (necrosis, hemorrhage, fibrosis, or calcification) had the greatest discrimina- tory value, and the smallest tumor to metas- tasize was 160 gm.
Differentiation of Incidental Adrenal Masses
The normal adrenal gland can now be read- ily demonstrated in most patients by CT or MRI. Numerous adrenal lesions of 0.5 to 2.0 cm that were previously apparently un- detectable can now be detected. In a recent study of 1,930 consecutive CT scans, 19 63 of 1,459 patients (4.3 percent) had detect- able adrenal masses, 19 of which (1.3 per- cent of all patients examined) were seren- dipitous. Thirty percent of the patients with expected adrenal masses had serendip- itous masses. In 11 patients followed by CT for 11 to 36 months (average of 21.4 months), the size of the lesions ranged from 1.5 to 5.0 cm, with an average of 2.8 cm. The lesions were unchanged in nine pa- tients, shrank in one, and increased in size in one. This prevalence is similar to that seen in autopsy series, with microscopic lesions found in up to 50 percent of pa- tients. In large autopsy series, microscopic lesions have been found with incidences of 1.4, 1.45,20 1.97, and 2.86 percent.21
In any proposal for the management of apparently benign incidental lesions, the possibility of metastatic disease must first be considered and excluded. Patients should be clinically evaluated for potential adrenal function. The presence of a functional le- sion is a clear indication for surgical re- moval. When the density of the lesion can be evaluated by CT, lipomatous masses can be confirmed, and no further treatment is required. Lesions smaller than 2.5 cm can be followed without concern. The use of CT scans repeated initially at intervals of three months and then at one year should monitor the progression of any lesion.
An increase in size is an indication for operative intervention. We believe that all lesions greater than 5.0 cm should be re- moved, and for those in the range of 2.5 to 5.0 cm, individual selection is necessary. Major factors in this decision include the presence of associated disease and the age of the patient, with the older patient being more likely to be watched conservatively. Clinical factors that make one suspect that an adrenal mass is a carcinoma are outlined in Table 4.
Diagnosis Suspected
Evening Serum Cortisol >15 µg/dl Urine Free Cortisol >100 µg/24 hrs
Morning Serum Cortisol >10 µg/dl After One mg Dexamethasone at 11 PM
Urine 17-OH Corticosteroids Not Suppressed (<3 mg/24 hrs)
Urine Free Cortisol Not Suppressed (<25 µg/24 hrs) By Dexamethasone, 0.5 mg Every Six Hours for 48 Hours
Treatment
Surgery remains the primary. definitive. and only potentially curative treatment for adrenocortical carcinoma.
Surgical Approaches to Adrenocortical Carcinoma
Although the prognosis for patients with adrenocortical carcinoma is poor, the most effective treatment and the one currently preferred is complete resection. The ap- proach to the patient undergoing adrenal ablative surgery must permit exposure for adequate evaluation and resection. Pre- operative management of the patient re- quires careful attention to corticosteroid coverage and replacement, because bio- chemically active tumors may have sup- pressed the contralateral gland. The regi- men used is similar to that for patients
undergoing surgery who are receiving long- term exogenous steroids.
One hundred mg of water-soluble so- dium succinate hydrocortisone is given in- tramuscularly at the time of premedication. Absorption is rapid, and the effects are apparent within an hour. Excretion of this dose is complete in less than 12 hours, and blood levels are effectively diminished in six hours. When anesthesia is begun, an additional 100 mg is added to a continuous infusion of 5% dextrose or dextrose in sa- line. When the operation has been com- pleted, a further dose of 100 mg is given in the recovery room as a constant infusion over eight hours. Depending on the degree of adrenal ablation and the smoothness of the patient’s postoperative recovery, the dose is tapered by 50 to 100 mg/day, con- verting to an oral dose of 25 to 50 mg of cortisone acetate daily in the patient requir- ing long-term steroid maintenance.
Diagnosis Confirmed
Peripheral Plasma ACTH
Increased
Low
Selective Venous Catheterization
Adrenal Origin
Ectopic Source
Pituitary Origin
Confirm
Confirm
Confirm
· Lung Tomography
· Adrenal CT
· Production Site Tests
· Sella Tomography
· Adrenal CT
· Arteriography
The synthetic adrenocorticoid fludro- cortisone acetate, which has a potent min- eralocorticoid action, is given to patients who have had total adrenal ablation and require long-term steroid replacement. An initial dosage of 0.1 mg three times a week is adjusted according to serum electrolytes and weight gain, up to 0.1 mg/day. Greater doses of fludrocortisone are given in con- junction with low doses (10 to 25 mg) of corticosteroid.
Because it is difficult to predict whether the noninvolved adrenal gland will be atrophic as a consequence of ACTH suppression by excess tumor and because adrenal hypofunction was the major cause of postoperative mortality in earlier ser-
ies,22 preoperative glucocorticoid adminis- tration is strongly recommended.1 In pa- tients with Cushingoid stigmata, it can take up to 22 months before the benign adrenal gland resumes adequate steroid produc- tion, even following curative resections and in the absence of adjuvant chemotherapy.23 Common experience, however, suggests that the time for adequate functional response by the contralateral remaining adrenal gland is much shorter.
For small and medium-size tumors (less than 10 cm) known to be malignant, we recommend an anterior surgical approach using a bilateral subcostal incision, which permits assessment of the common sites of metastatic spread-the liver, omentum,
am
św 16 SS
peritoneum, and periaortic nodes. 24-28 Since early detection is not always possi- ble, invasion to adjacent vital structures is not unusual. In all but the smallest lesions confined to the adrenal itself, an en bloc excision of the kidney and regional nodes is indicated. Limited hepatic resection for metastases, as well as excision of omental and peritoneal implants, is justified be- cause patients with endocrinopathy will ob- tain relief in proportion to the amount of functional tumor resected. 24.28-30
For larger tumors, a thoracoabdominal approach may be necessary for safe re- moval. For simultaneous resection of pul- monary metastases, either a thoracoab- dominal or a transabdominal approach combined with median sternotomy may be used. In rare cases, even more extensive resections are warranted. 31
Patients undergoing curative excision of an adrenocortical carcinoma should be carefully followed for many years. If the tumor did not produce steroids initially. conventional procedures, such as physical examination and chest tomograms per- formed at regular intervals, are essential. Patients with high steroid excretion, how- ever, should be seen every one to two months, since a rise in this index of tumor activity will often indicate recurrence be- fore there is palpable or radiologic evi- dence of disease.
This need for continued long-term fol- low-up should be emphasized to the pa- tient. One patient, after undergoing an apparently curative resection, suffered a local recurrence 10 years later.3 Another investigator32 reported a recurrence 12 years after surgery. Careful follow-up also leads to early detection of second primary tu- mors. In our recent series, one additional primary cancer was detected, but another center reported a prevalence of 24 percent in 42 patients, with three cases of breast cancer. 33
In institutions that have had sufficient experience with those patients, reoperation on patients with surgically resectable ab- dominal recurrences or distant metastases can be accomplished without mortality and with negligible morbidity.3.34-36 Patients may survive longer than 12 months with un-
treated metastases;1 the average survival for our patients undergoing reoperation for recurrent metastatic disease has been 3.5 years. Surgery can be an effective method for prolonging the disease-free survival of patients with adrenocortical carcinoma.
Treatment with o,p’DDD
Isolated cases of responses of unresectable adrenocortical carcinoma to the chemo- therapeutic agent o,p’DDD (1, I dichloro- 2-[o-chlorophenyl]-2-[p-chlorophenyl]- ethane) (also known as mitotane) have been reported, and it is usually the first drug employed.37-39 A number of studies have suggested a biochemical response and oc- casional tumor regression (Table 5), but survival has been short and often variable.
In a case report by Boven et al, a patient with metastasized adrenal cortical carci- noma achieved a complete response, which was confirmed by laparotomy and sus- tained for two years after discontinuation of treatment.37 These authors also collected data on seven patients in whom complete response had been claimed, but none of which had been confirmed by reoperation. although one patient was free of disease at autopsy nine years later.37.44 Another case of a significant decrease in size of a large inoperable lesion after treatment with o.p’DDD has also been reported.3% This is a very rare occurrence, however. In a re- cent report of 60 cases, no sustained com- plete responses were achieved.6
The larger study emphasized that a bio- chemical response is obtainable in 70 per- cent of patients with initially elevated ste- roid levels. A minimum of four weeks is needed for response, since only 37 percent of these patients responded within 21 days. while 87 percent of those who eventually responded had evidence of tumor regres- sion in 30 days. The average dose of o.p’DDD required for response was 8.5 gm per day. Biochemical response, measured by decreased steroid levels, was attained more easily than objective antitumor re- sponse: Objective tumor regression was seen in 20 of 59 patients with measurable dis- ease (34 percent). The median duration of therapy until antitumor response occurred
TABLE 4 FACTORS RAISING THE SUSPICION THAT AN ADRENAL TUMOR IS AN ADRENOCORTICAL CARCINOMA*
Adrenal Cushing’s Syndrome Palpable Mass No Suppression with High-Dose Dexamethasone Patient Younger than 20 years Increased Urinary 17-Ketosteroids
Virilization or Feminization Syndromes
Adult with Palpable Abdominal Mass and CT-Positive for Adrenal Tumor Increased Urinary 17-Ketosteroids or 17-OH-Corticosteroids Weight Loss or Fever
*Reprinted from Brennan. 1
was six weeks, and the mean duration of response was 10.2 months.
In a report of an additional 115 patients with adrenal carcinoma treated with o,p’DDD from 1965 to 1969, Lubitz et al2 found a measurable disease response of 61 percent, compared with the previously re- ported figure of 34 percent, and a steroid excretion response of 89 percent, com- pared with the 72 percent noted by Hutter and Kayhoe. 39
There are few clinical options for the physician dealing with a patient with func- tioning unresectable adrenal cortical carci- noma. The one approach that may produce both antitumor effect and palliation of symptoms of hypercorticism employs ther- apy with o.p’DDD, escalating to a daily dose of eight to 10 gm. Successful treat- ment of a functioning tumor with o,p’DDD will result in signs of adrenal insufficiency, probably related mainly to the suppressed
hypothalamic-adrenal axis secondary to the long-standing massive steroid secretion by the tumor, and also to adrenal damage by the drug. Corticosterone replacement is therefore essential once therapy with o,p’DDD has begun, and the corticoste- rone should not be tapered until the patient has been off o,p’DDD for at least one month.
Toxic Reactions
When the dosage of o,p’DDD reaches the therapeutic range of eight to 10 gm per day, the majority of patients suffer some form of toxicity-usually gastrointestinal symp- toms of anorexia, nausea, vomiting, or diarrhea. Neuromuscular toxicity has been recorded in 40 to 60 percent of patients, usually in the form of lethargy and somno- lence, but occasionally resulting in severe suicidal depression. This latter event, while uncommon, is very real, and debilitating to
| Author(s) | Total Number of Patients | Responses | Dose (g/day) | Duration of Response (months) | Tumor Re- gression | Survival (months) | Comments | |
|---|---|---|---|---|---|---|---|---|
| Number | (Percent) | |||||||
| Boven et al3 | 7 | 7/7 | Complete Responses | |||||
| Bradley40 | 5 | 5 | (100)* | - | - | |||
| Hajjar et al 25 | 10 | 4 | ( 40)* | 2-10 | 1-4 | 1/10 | ||
| Hoffman and Mattox41 | 19 | 4 | ( 21)* | 3-10 | 3-24 | 4/14 | 1-86 | All Inoperable |
| Hogan et al42 | 4 | 3 | ( 75) | 5-6 | - | 2/3 | ||
| Hutter and Kayhoe39 | 62 59 | 45 20 | ( 73)* 34) | 2-10 | 7 (median) | 20/59 | ||
| Karakousis et al43 | 6 | 2 | ( 33) | 2-15 | - | 2/6 | ||
| Lubitz et al2 | 61 75 | 52 46 | ( 85)* ( 61) | 0.5-20 | 6 (median) | 46/75 | 6.5 | Responders |
| 100 | 54 | ( 54) ** | 3 | Nonresponders | ||||
| MacFarlane27 | 20 | 2.9 | Untreated, Inoperable | |||||
| Sullivan et al32 | 7 | 3 | ( 43) | - | - | 3/7 | ||
| *Decrease in steroid production. ** Subjective clinical response. | ||||||||
TABLE 6 LENGTH OF SURVIVAL (IN MONTHS) OF PATIENTS WITH ADRENAL CARCINOMA TREATED BY THREE DIFFERENT METHODS*
| Number of Patients | Mean | Range | Median | |
|---|---|---|---|---|
| Surgery ± Radiation Therapy | 6 | 10.3 ± 8.7 | ( 1- 24) | 8.5 |
| Surgery + o.p'DDD | 17 | 46.6 ± 42.7 | ( 1-120) | 24 |
| Surgery + Adjuvant o,p'DDD | 4 | 74 ± 33 | (36-108) |
Adapted from Schteingart et al.34
| TABLE 7 SURVIVAL IN ADRENOCORTICAL CARCINOMA | ||||
|---|---|---|---|---|
| Author(s) | Year | Number of Patients | Five-Year Survival (Percent) | Comments |
| Henley et al.9 | 1983 | 31 | 32 | Curative Resection |
| King and Lock29 | 1979 | 21 | 43 | |
| Cohn et al3 | 1986 | 47 | 25 | Median of 1.7 years (Range of 2 months to 15 years) |
| Javadpour et al4 | 1980 | 58 | 30 | Median of 16 percent with disease |
both patient and physician.
Fifteen percent of patients experience dizziness or vertigo or dermatologic reac- tions; leukopenia and liver function abnor- malities occur only rarely.
The Adjuvant Use of o.p’DDD
Schteingart et al have suggested that pa- tients with adrenocortical carcinoma can be helped by the use of adjuvant o,p’DDD.34 Their rationale for this is a retrospective review in which patients receiving adjuvant o.p’DDD had longer survival than those receiving o.p’DDD for disease progression only (Table 6). Unfortunately, the data are too limited for proper evaluation.
Other Cytotoxic Chemotherapy
A review of 27 trials of various chemo- therapeutic agents in 12 patients has been reported by Haq et al.45 The majority of patients (nine) had previously been given o.p’DDD. The responses to all agents used were of extremely short duration. Minimal tumor activity was seen with Adriamycin and cyclophosphamide.
Tattersall et al reported four patients responding to cisplatin.46 Our attempts to reproduce that response, however, have failed.47 Of 12 patients treated with at least two doses of cisplatin, only one minor re- sponse and one transient biochemical re- sponse were noted. The majority of pa- tients have since died. Tattersall et al noted regression of liver, lung, or intra-abdomi- nal disease within one month, with a me- dian survival of 12 months (range of seven to 14 months) from the diagnosis of metas- tasis.46 We have seen patients survive for longer than 12 months with metastatic dis- ease, apparently independent of therapy. Others with similar experience have not found a single agent to produce a signifi- cant response in 35 patients treated to the maximum tolerable dose of any of eight drugs.6
Sodium suramin, a new agent with a long half-life (40 to 50 days), has recently been investigated.48 It has shown response in isolated patients. In studies at a dose of 1.4 g/m2 per week, the drug was found to
reach toxic levels in eight to 12 weeks. 49
Alternative Treatments
In an attempt to control functional liver metastases, we have used embolization with only limited benefit. Surface antigens have been recently identified, although their po- tential for antibody development and sub- sequent localization and treatment is only now being explored.
Radiation therapy has shown little benefit, except for occasional palliation of bone pain, as in cases of spinal cord compression. There is, however, a solitary case report suggesting that an inoperable tumor was rendered operable for cure by radiation therapy.5
Antihormonal Therapy
Many attempts have been made to counter- act the effects of excess hormone produc- tion in patients with nonresectable func- tional disease that has not been responsive to antineoplastic therapy.
Excess Corticosteroid Production
Excess adrenal corticosteroid production caused by either adrenal or pituitary over- activity can be inhibited by the antifungal imidazole-derivative ketoconazole. The major inhibition appears to be the blockage of 11-B-hydroxylase, but other steps in the biosynthetic pathway of corticosteroid pro- duction are also inhibited.5º Ketoconazole has been used primarily in patients with pituitary Cushing’s disease or adrenal ad- enomata, and less so in patients with adrenocortical carcinoma and steroidal ex- cess. Maximum doses have been 800 mg a day for up to 13 months, given as 200 mg tablets initially twice a day and then in- creasing to 800 mg a day. All patients showed decreased excretion of urinary cor- tisol and 17-ketosteroid and decreases in the plasma concentration of dehydroepian- drosterone sulfate (DHEAS). A single case of regression of metastatic disease has also been reported.51
Aminoglutethimide inhibits cholesterol side-chain cleavage, and can be used to
100
90
80
70
Percent Alive
60
50
40
30
20
10
0
0
5
10
15
20
Years After Initial Operation
100
90
· = Stage 2 (14 Patients)
80
· = Stage 4 (33 Patients)
70
Percent Alive
60
50
40
30
20
10
0
0
5
10
15
Years After Initial Operation
inhibit cortisol synthesis. Patients with adrenocortical carcinoma show a decrease in plasma cortisol of about 50 percent dur- ing administration of this agent, 52 and 17OH corticosteroid excretion is reduced dispro- portionately. The drug is given in doses of 250 to 500 mg four times a day. Prolonged use will create adrenal insufficiency.
Metyrapone, which blocks cortisol for- mation, also increases mineralocorticoid production; prolonged use can result in hy- pertension and hypokalemia. Doses range from one to three gm daily.53
Aldosterone Excess
Aldosterone excess is conventionally treated with 100 to 400 mg a day of spironolac- tone, a competitive antagonist for the min- eralocorticoid receptor, or with 10 to 40 mg a day of aldactazide, a potassium-sparing diuretic. Both agents usually produce nor- mal serum potassium concentrations. In patients with adrenocortical carcinoma, however, these measures are often insuffi- cient to control the hormonal consequences of the tumor.
A new agent under investigation called
RU-486 has an affinity for glucocorticoid and progesterone receptors and is antago- nistic in action, allowing blockage of pe- ripheral cortisone action.34 Its usefulness in functional adrenocortical carcinoma has yet to be determined.
Survival Statistics
Because survival in adrenocortical carci- noma is extremely variable, interpretation and comparisons are difficult. Two of our patients have survived 15 and 17 years, respectively.3.4 Median survival, however, is much closer to six to 10 months (Table 7). It should be emphasized that five-year survival is not five-year cure: in our early series, 16 percent of patients were alive at five years with disease.4
In our series of 47 patients, stage 2 patients had a median survival of 3.3 years, and a mean of five years. Stage 4 patients had a median survival of one year, with a mean of 2.3 years. These data are consid- ered to be significant (Figs. 10 and 11),3 and the stage at the time of diagnosis ap- pears to be the most important factor in survival. @
References
1. Brennan MF: The adrenal gland, in De Vita VT Jr. Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. 2nd edi- tion. Philadelphia, JB Lippincott, 1985, pp 1192-1206.
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