Treatment of Adrenocortical Carcinoma with o,p’-DDD
David L. Hoffman, M.D., and Vernon R. Mattox, Ph.D.
In 1959 and 1960, Bergenstal and associates achieved encouraging results in 18 cases of metastatic adrenocortical carcinoma by treat- ment with o,p’-DDD (1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)- ethane; mitotane). Subsequently the National Cancer Institute supplied pure samples of this compound to all investigators with suitable patients, who would reciprocate with complete case reports and appropriate periodic studies of the drug’s efficacy and safety. Hutter and Kayhoe performed the difficult task of accumulating, correlating, and summariz- ing the resultant data and prepared the initial report of the experience of 105 investigators with 138 patients treated between 1960 and 1965. Then Okun, in 1970, summarized results of studies of an additional 115 patients treated by 95 investigators between June 1965 and January 1969. The FDA approval of o,p’-DDD in July 1970 has made it appropri- ate for us to review our own experience with it from 1959 through 1971. The drug is now marketed by Calbiochem under the name Lysodren in 0.5 gm tablets as prepared originally for the National Cancer Institute.
DDD is an analogue of DDT (Fig. 1) and was produced commercially as an insecticide in the early 1940’s. Toxicologic studies by Nelson and Woodard showed that administration of technical DDD to dogs produced adrenocortical necrosis and atrophy. Subsequently Cueto and Brown showed that technical DDD was a mixture of two isomers (p,p’-DDD and o,p’-DDD) that the o,p’ isomer was responsible for the hemorrhagic nec- rosis in the dog adrenal cortex but otherwise was generally less toxic.
As yet the cytotoxic action responsible for the destruction of canine or human adrenocortical cells is unexplained. Extensive studies of ani- mals and of treated patients have led to partial elucidation of the me- chanics of the interference with steroidogenesis by o,p’-DDD. As stated in the recent review by Hart, o,p’-DDD hinders the ACTH-mediated in- tramitochondrial conversion of cholesterol to pregnenolone and the in- tramitochondrial 118-hydroxylation of 11-deoxycortisol. It appears that o,p’-DDD reduces the production, availability, or utilization of reduced triphosphopyridine nucleotide within the adrenal cells. This suppression
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of normal adrenal corticosteroid production nearly always results in adre- nal insufficiency in the treated patient and requires administration of cor- tisol or a similar steroid and frequently of 9a-fluorohydrocortisone as well.
Additional significant abnormalities occur in extra-adrenal steroid metabolism and degradation (reviewed by Fukushima). There is a de- crease in the usual metabolites of steroids, the glucuronides of tetrahy- drocortisone, tetrahydrocortisol, cortol, cortolone, etc. A great increase of 66-hydroxycortisol is due presumably to the induction of 63-hydroxylase, which causes 63-hydroxycortisol to be formed more rapidly than the tetrahydrometabolites. Owing to its low solubility in commonly used organic solvents, 66-hydroxycortisol is incompletely recovered by the usual techniques* for measuring urinary excretion of 17-hydroxycor- ticosteroids; and consequently the values obtained give a misleading suggestion of decreased production of these compounds. Determination of cortisol secretion rates has been advocated by Liddle for better evalua- tion of adrenocortical function when o,p’-DDD is administered. Fuku- shima believed that special measures may be necessary also for accurate measurement of cortisol secretion rates under the influence of o,p’-DDD.
The effects of o,p’-DDD on the metabolism of aldosterone, estrogen, and specific androgens have not been widely studied in the laboratory; but clinical trials have adequately demonstrated suppression of the urinary excretion of aldosterone and estrogen as well as reversal of their anatomic and physiologic effects.
MATERIALS AND METHODS
Nineteen patients having adrenocortical carcinoma were treated with o,p’-DDD at the Mayo Clinic between November 1959 and January 1971. (Every case was incorporated, in whole or part, in the previously published collaborative studies.10, 16 The seven cases previously reported by Molnar et al. from this institution are included in this report, although they are numbered differently and presented with a somewhat different emphasis.)
The cancers in all 19 cases were inoperable but surgically proved,
*When aqueous solutions which contained 12 and 40 mg of 68-hydroxycortisol per liter were assayed by use of sodium bismuthate as oxidant,4 the recovery of product as 17-ketogenic steroid was 7 and 13 per cent respectively.
and their mitotic activity ranged from grade 1 to 3. More lesions were re- current or metastatic than primary. None of the patients had received ra- diation therapy within 3 months of the recorded treatment with o,p’-DDD; and only 1 patient (case 19) received concurrent chemother- apy, which was 5-fluorouracil in the usual dosage.
Early in the course of our experience with o,p’-DDD, control observa- tions and initial treatment and study were carried out in a hospital; but later studies were made in the out-patient clinic, and mailed-in urine specimens often were utilized.
After obtaining control steroid data, and usually data on ACTH stimu- lation and dexamethasone suppression as well, we began administration of o,p’-DDD (supplied by the Cancer Chemotherapy National Service Center, Bethesda, Maryland). The initial dosage usually was 3 to 4 gm given in four increments daily. In 3 to 6 days dosage was increased to 6 or 8 gm daily, and within another week to 10 gm per day unless toxicity prevented. After a favorable tumor or steroid response, the dosage usually was lowered to the maximum tolerated without uncomfortable side-effects. This amount varied from 2 to 10 gm, depending on the course of the steroid values and the gastrointestinal and neurologic symptoms.
For protection from adrenal insufficiency, all patients received daily either dexamethasone (0.75 to 1.0 mg in divided doses) or, more rarely, cortisone (30 to 40 mg). When appropriate, 9a-fluorohydrocortisone was given in amounts of 0.1 mg or less per day. Chlordiazepoxide (Librium), prochlorperazine (Compazine), diazepam (Valium), amytriptyline (Ela- vil), methylphenidate (Ritalin), and commonly used antihistaminics, skin creams, antacids, and anticholinergics were given for support as needed to combat the toxic manifestations of o,p’-DDD. Free diet was allowed, and activity as tolerated.
After 4 to 6 weeks of treatment the clinical response and possible roentgenographic and biochemical changes were assessed. If the disease had clearly progressed, o,p’-DDD treatment was terminated. If there was uncertainty, it was continued for another 4 to 6 weeks and the situation then was reevaluated. As long as tumor or clinical regression was main- tained, treatment was continued with only brief occasional interruptions because of toxicity.
Urinary 17-ketosteroid excretion was measured by a modification3 of the method of Callow and associates. Urinary formaldehydogenic cortico- steroids were measured initially3 by a method similar to that of Corcoran and Page; but in 1961 this was supplanted by a 17-ketogenic steroid procedure.4 The (3a,17,21-trihydroxy-5-pregnane-11,20-dione; tetrahy- drocortisone, Tetrahydro-E) and THS (3a,17,21-trihydroxy-53-preg- nan-20-one; Tetrahydro-S) were measured by previously described proce- dures.12 The methods of Albert were utilized to measure the urinary concentrations of estrogen2 and of pituitary gonadotropin hormone.1 Al- though the data will not be presented herein, except as needed, aldo- sterone determinations were made in many cases by the method of Mattox and Lewbart. Serial cholesterol determinations were made in 15 cases by the method of Zak and associates.
Although it is well recognized that a functioning adrenal cancer may
produce a variety of active corticosteroid and sex hormones, the patients were divided into clinical classifications depending on the presenting en- docrine pattern. Thus classified, there were two men and one woman with Cushing’s syndrome; three women with mixed virilization and Cushing’s findings and two with virilization, and three men with femini- zation. One man had the clinical features of hyperaldosteronism. The remaining seven patients presented no predominant endocrine clinical pattern, but only two of them-both women (cases 5 and 8)-proved to have truly nonfunctioning adrenal tumors. Six of the seven had palpable abdominal tumors. At the time of treatment with o,p’-DDD, the women were 23 to 59 years old and the men 34 to 63.
“Measurable disease” was defined as a distinct tumor or tumors, pal- pable under the skin or in the abdomen or apparent by chest roentgeno- gram. “Tumor regression” was defined as a diminution in the pulmonary nodules as measured on the roentgenograms, or as a directly measurable diminution of the tumor. Reduction in the size of a large abdominal mass was not easy to establish; and in this study, regression of such tumors was not accepted unless all observers agreed that it was definite. Perhaps because of this strictness, there are no instances of regression of masses that lay in the abdomen, liver, or retroperitoneal space. Clinical improve- ment in the liver function or reduction of steroid excretion was not ac- cepted as proof of regression of the tumor.
Baseline steroid values were obtained within the 4 weeks preceding the start of o,p’-DDD treatment (usually within a few days), at a time when they were not affected by either ACTH stimulation or dex- amethasone suppression. Many of the values recorded were means of several measurements. Although precise chemical determinations were made, the data are presented here as multiples of the normal range for the patient’s age and sex. This permits comparisons not only between pa- tients of differing age and sex but between those whose 17-hydroxycor- ticosteroid excretion had been measured in different ways, such as the formaldehydogenic and the 17-ketogenic steroid methods. When appro- priate, values for corticosteroid metabolites (THE, THS), aldosterone, es- trogens, and pituitary gonadotropins were obtained; these will be men- tioned in the text or listed in Table 1.
Post-treatment values were obtained at intervals of days to weeks after the start of o,p’-DDD therapy, usually 4 weeks in the early course of a case. Later, the intervals were from 4 to 8 weeks, and in some instances of unusually good response they were extended to 3 months.
Following the convention applied by Hutter and Kayhoe and Okun in their extensive reviews, we have recorded the steroid response to o,p’-DDD treatment as good, for reduction of pretreatment values by more than 50 per cent; fair, for reduction by 30 to 50 per cent; and no response, for reduction by less than 30 per cent. In a few cases, the precise values for estrogen or aldosterone are recorded for more vivid demonstration of the elevation and degree of suppression. In our labora- tory, normal values for daily urinary excretion of aldosterone are 2 to 16 ug, and those of estrogen 10 to 15 rat units (RU) for middle-aged males and 0 to 100 for females in the menstruating age group.
RESULTS
The results of treatment are summarized in Table 1. Cases are listed in chronologic order of treatment with o,p’-DDD. The duration of disease prior to o,p’-DDD treatment, determined with reasonable certainty from the history, ranged from 7 months to 12 years. The long duration of illness prior to serious complication or widespread metastasis is consist- ent with the frequently slow course of this rare malignancy.
Measurable disease (as earlier defined) was present in only 14 pa- tients, and in only 4 of these (cases 1, 9, 14, 15) was tumor regression demonstrated-in each by shrinkage or disappearance of pulmonary lesions.
As might be expected in a series of patients with widely varying degrees of sickness, the duration of life after initiation of the o,p’-DDD treatment also varied widely -from 5 weeks to 86 months.
In case 1 there was a good response in respect to suppression of 17-ketosteroid and 17-ketogenic steroid excretion for the full 8 month period of tumor regression and the full duration of the course of o,p’-DDD, which was terminated because of evidence of increasing tumor growth.
In case 9 the remission was more brief, persisting for only 3 months before the nodules increased in size and number. But in this case also, there was a good response in respect to suppression of the excretion of 17-ketosteroids, 17-ketogenic steroids, and estrogen, which persisted longer than the period of tumor regression; but all of these hormones es- caped from suppression 1 month later, despite dosage of 4 to 6 gm of o,p’-DDD daily.
In case 14 there was excellent reduction of the previously elevated adrenal steroids and the estrogen levels for 24 months as well as com- plete disappearance of numerous pulmonary nodules. (More detail will be given in a review below.)
In case 15 there was complete clearing of pulmonary nodules, good suppression of ketosteroid and ketogenic steroid excretion, and slow but good suppression of estrogen excretion over a 9 month period. (In this case, and in case 14 as well, the suppression of estrogen excretion lagged 2 to 3 months behind equivalent suppression of adrenal steroids.) Ad- ministration of o,p’-DDD was discontinued because of increasing size of the pulmonary nodules and of the abdominal tumor.
Thus, among the 14 patients with measurable lesions, all 4 of those with tumor regression (which extended over 3 to 24 months) also had good suppression of both ketogenic steroids and ketosteroids. Among the 10 with measurable lesions that did not regress, 7 had good or fair suppression of ketosteroids and 4 (all of which were among the 7) had good suppression of ketogenic steroids. As noted earlier, none of the large abdominal or retroperitoneal masses responded significantly, despite the favorable steroid suppression noted in cases 8, 16, and 18. The tumors in case 8 and in case 5, which were nonfunctioning, continued to grow; and there was no steroid response in case 5. But in both cases, only a brief trial of o,p’-DDD was carried out before further tumor growth became ap-
| CASE NO. | SEX, AGE | ENDOCRINE STATUS | DISEASE* | PRETREATMENT STEROID DATA t | POST-TREATMENT STEROID DATAŤ | SUPPRESSION, DURATION OF | o,pʼ-DDD | SURVIVAL, FROM START OF o,p'-DDD | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Duration | urable Meas- | KS | KGS | Est.# | KS | KGS | Est. + | Steroids | Tumor | How long | Why stopped | ||||
| 1 | F. 23 | Viril. | 18 mo | + | N§ | N§ | GR | GR | GR | 8 mo | 8 mo | 8 mo | Tumor growth | 24 mo | |
| 2 | F, 43 | Viril. | 6 yr | + | N§ | N§ | 0 | 3 mo | New tumor | 84 mo | |||||
| (47) | 10 yr | + | 1 | 1 | GR | GR | 5 mo | 0 | 5 mo | Tumor growth | 36 mo | ||||
| 3 | F, 40 | Mixed | 2 yr | 0 | N | 2 | FR | NR | 0 | 0 | 3 mo | No response | 7 mo | ||
| 4 | F, 35 | Mixed | 2 yr | 0 | 4 | 2 | GR | GR | 8 mo | 0 | 8 mo | Died | 8 mo | ||
| 5 | F, 57 | None | 2 yr | + | N | N | NR | NR | 0 | 0 | 10 wk | New tumor | 16 mo | ||
| 6 | M, 43 | None | 7 mo | + | 3 | 1 | FR | NR | 5 wk | 0 | 5 wk | Died | 5 wk | ||
| 7 | M, 34 | Femin. | 3 yr | + | N§ | N§ | 100 | GR | NR | 40 | 2 mo | 0 | 6 mo | Tumor growth | 12 mo |
| 8 | F, 50 | None | 3 yr | + | N | N | GR | GR | 7 wk | 0 | 7 wk | Tumor growth | 14 mo | ||
| 9 | M, 59 | Femin. | 1 yr | + | 2 | 1 | 59 | GR | GR | 36 | 4 mo | 3 mo | 5 mo | Tumor growth | 6 mo |
| 10 | F, 53 | Cush. | 8 yr | 0 | 3 | 1 | GR | GR | 66 mo | 0 | 6 mo | Remission | 86 mo | ||
| (59) | Cush. | 14 yr | 0 | 4 | 3 | 140 | GR | GR | 15 | 18 mo | 0 | 18 mo | 18 mo (living) | ||
| 11 | M, 52 | Aldo. | 0 | N | 1 | FR | FR | 14 mo | 0 | 14 mo | Liver tumor | 21 mo | |||
| 55A | 54 | ||||||||||||||
| 12 | F, 25 | None | 9 mo | + | 2 | 1 | FR | NR | 7 wk | 0 | 7 wk | Tumor growth | 6 mo | ||
| 13 | M, 63 | Cush. | 2 yr | 0 | N | 2 | NR | NR | 0 | 0 | 3 mo | Liver disease | 5 mo | ||
| 14 | F,40 | Mixed | 2 yr | + | 2 | 3 | 478 | GR | GR | 45 | 19 mo | 24 mo | 19 mo | Liver disease | 24 mo |
| 15 | M, 48 | Femin. | 1 yr | + | 1 | 3 | 1253 | GR | GR | 160 | 9 mo | 9 mo | 10 mo | Tumor growth | 11 mo |
| 5A | 5ª | ||||||||||||||
| 16 | M, 55 | None | 6 mo | + | 2 | 1 | GR | GR | 2 mo | 0 | 2 mo | Tumor growth | 3 mo | ||
| 17 | F,57 | Cush. | 20 mo | + | 1 | 2 | NR | NR | 0 | 0 | 8 wk | Died | 8 wk | ||
| 18 | F, 47 | None | 4 yr | + | 3 | 3 | GR | GR | 5 wk | 0 | 5 wk | Died | 5 wk | ||
| 19 | M, 47 | None | 3 yr | + | 3 | 2 | NR | NR | 0 | 0 | 8 wk | Tumor growth | 10 mo | ||
*Duration: prior to start of o,p’-DDD therapy. For measurable, see text.
tFor ketosteroids and ketogenic steroids: N = normal range; 1 = 1 to 2 x N; 2 = 2 to 3 x N, etc .; NR =< 30% reduction; FR=30-50% reduction; GR ⇒50% reduction.
24 hr.
§Surgical treatment had already reduced previously elevated values.
^ Aldosterone, pg/24 hr.
DAVID L. HOFFMAN AND VERNON R. MATTOX
parent. In case 10 (without measurable disease) and case 11 (in which such disease developed during treatment) the patients enjoyed a return to active and effective life, free from the effects of the respective steroid hormone excess, even though it was impossible to prove a favorable tumor response.
In some cases-mostly those with fair to good steroid re- sponse -treatment was continued at the maximal tolerated dosage for many months in the hope that some tumor regression would be obtained later. The usual causes for termination of treatment were further growth of tumor, appearance of new metastases, continued toxic effects without therapeutic benefit, and death. Four patients died during treatment-one from mediastinal emphysema and collapse, one from cerebral hemor- rhage, and the other two from carcinomatosis.
A secondary response to increased dosage of o,p’-DDD occurred in three cases, where rising steroid values declined again when the mainte- nance dosage was increased; but there was no instance in which an ex- panding tumor which had responded previously to o,p’-DDD shrank with increase in dosage.
Serial cholesterol values were available in 15 cases. Among the four patients whose tumors responded, the serum cholesterol concentration rose significantly in three and fell in one. Among the 11 patients whose tumors did not regress, it rose in 8, fell in 1, and was unchanged in 2. Seemingly the usual cholesterol response to o,p’-DDD is a rise without prognostic usefulness.
Pituitary gonadotropic hormone was found in greatly increased amounts in case 9, despite very high levels of estrogen. The values for both of these substances fell with o,p’-DDD treatment, suggesting that the tumor was producing gonadotropin itself or in some way stimulating its production. THS and THE determinations were useful occasionally in following the excretion of other adrenal steroids produced by the car- cinoma. Plasma testosterone values were elevated in one patient with a mixed pattern of Cushing’s syndrome and virilization.
Case 14
A 40-year-old married woman was referred in January 1966, because her physician suspected an adrenal tumor. Since delivery of her last child in Sep- tember 1964, she had developed epigastric burning, menometrorrhagia, weight gain, hirsutism, acne and floridity of complexion, edema, and hypertension.
Her blood pressure was 200 mm Hg systolic, 120 diastolic. There was a mass in the region of the right kidney. The findings were suggestive but not diagnostic of Cushing’s disease. Elevated values were reported for both ketosteroid and ke- togenic steroid excretion and for plasma concentration of cortisol. Dexamethasone did not suppress the steroid values, and metyrapone (Metopirone) stimulation produced no increase in excretion of ketogenic steroids. The estrogen value was elevated at 238 RU.
A 335 gm hemorrhagic adrenocortical adenocarcinoma, grade 2, was removed. After that, the steroid excretion declined to normal and the estrogen level fell to 38 RU. There was a complete clinical remission until the autumn of 1966, when men- strual irregularity recurred and several small metastatic nodules were found by chest roentgenography. The ketogenic steroid excretion rose to 26 mg/24 hr, and the estrogen level to 138. Use of o,p’-DDD was considered at this time; but since the patient was able to function well, we deferred treatment until January 1967, when the ketosteroid measured 32 mg/24 hr and the ketogenic steroids 40, and
the estrogen value had jumped to 478 RU. Pregnanetriol was elevated at 5.3 mg/24 hr and THS was 30 mg/24 hr. Initially 4 gm of o,p’-DDD was given daily in divided doses. The maximal dosage achieved was 7 gm/day, which could not be exceeded without fatigue, exhaustion, sleepiness, and nausea. Within 2 weeks the keto- steroid value had dropped to 17, but that for ketogenic steroids was not changed. After a month of treatment, ketosteroids were half the control value; but the ke- togenic steroids were still not well suppressed and the estrogens were even higher at 534 RU.
Since the lung nodules had not clearly changed, administration of o,p’-DDD was continued for another month. This brought a definite decrease in the size of the pulmonary nodules, and by the end of a third month the nodules completely disappeared. With a dose of 3 gm of o,p’-DDD per day, ketosteroid levels of 0 to 1.2 mg/24 hr were reached and ketogenics of 1.5 to 7 mg. Estrogen values, however, fell very slowly and reached their lowest point, 18 RU, only after 10 months of treatment. Despite the usual replacement of endogenous hormones with dex- amethasone and 9a-fluorohydrocortisone, the patient developed increased pigmen- tation characteristic of adrenal insufficiency. This persisted even though cortisone was substituted, in divided doses totaling 40 mg/day. The administered cortisone yielded no appreciable increase in the urinary excretion of ketogenic steroids or ke- tosteroids.
A full clinical remission was obtained, so the patient was able to take full care of her nine children, do her own housework and shopping, and return to normal ac- tivities. Her body contours and facial appearance returned to their previous normal state. However, in June 1968 the daily excretion of ketogenic steroids rose to 19 mg and that of estrogens to 111 RU. Doubling of the o,p’-DDD dosage did not prevent a further increase in excretion of the ketogenic steroids and of THS. When the dosage was raised to 8 to 10 gm/day, there was a further suppression of the ke- tosteroid and ketogenic steroid excretion, but the estrogen excretion continued to rise.
In September 1968, hospitalization was necessary because of increasing evi- dence of liver disease with BSP retention and two episodes of right-sided jack- sonian seizures. Examination disclosed no evidence of cerebral or hepatic metas- tasis, and liver biopsy was negative. Despite the known infrequency of liver disease resulting from administration of o,p’-DDD, we were suspicious and with- held it. She felt so much better while not taking the drug that we deferred to her wish not to resume. Without o,p’-DDD but with continuation of maintenance with cortisone and 9a-fluorohydrocortisone, her skin lightened and her spirits im- proved. Her strength, appetite, and stamina returned to normal, and she was able to resume full household management. The chest lesions remained imperceptible by roentgenography, and over the next 4 months she continued to feel well. Excre- tion of ketogenic steroids rose to 90 mg/day and excretion of ketosteroids to 44; and estrogen excretion increased slowly. In February 1969, when still feeling well, she had a cerebral hemorrhage and died within a few hours.
Autopsy disclosed two large metastases in the liver and a small nest of residual tumor at the site of the original tumor. No brain metastasis was found, but his- topathologic sections of the lungs contained residual small areas of metastatic car- cinoma not detectable by x-ray.
An interesting feature of this case is the development of typical ad- disonian pigmentation during treatment with o,p’-DDD, despite amounts of dexamethasone or cortisone ordinarily sufficient to prevent it. A simi- lar change was noted in 2 other cases among the 19, suggesting that the extra-adrenal degradation of exogenous steroid is altered in such a way that the circulating cortisol-like material is insufficient to suppress ACTH release. Presumably the alteration is attributable to increased 66-hydroxylation by the liver, but there may well be other changes in the degradation of circulating steroids as the result of induction or suppres- sion of microsomal enzymes in other organs as well.
This case also illustrates the suppression of metastatic disease in one region while the tumor is growing actively in another.
The reluctance to continue taking o,p’-DDD, despite its evident beneficial effects, was typical of many of our patients, who felt relief when they no longer were forced to take the medicine even though they knew they were relinquishing a weapon against the disease that was des- troying them.
The delay before the suppression of estrogen production by o,p’-DDD remains unexplained. A similar delay in the response of estrogen excre- tion was seen in case 15 (feminizing tumor of the adrenal), in which there was excellent and early suppression of 17-ketosteroid and 17-ke- togenic steroid excretion but the estrogen response was very slow and in- complete.
Case 10
A 53-year-old woman first registered in 1962 because of symptoms and find- ings characteristic of Cushing’s syndrome. In 1956, right adrenalectomy and nephrectomy, performed elsewhere for Cushing’s syndrome, had included remov- al of a large adenocarcinoma, grade 2, of the adrenal cortex. An excellent remis- sion had been obtained, which lasted 4 years; but then hypertension had devel- oped, and a year before admission the characteristic findings of Cushing’s syndrome had gradually returned.
On admission here, nephrotomograms disclosed a recurrent right retroperi- toneal tumor; and removal of this 390 gm lesion was followed by a second labora- tory and clinical remission.
In 1964, a rise in 17-ketosteroid excretion and return of Cushing’s syndrome led to removal of a recurrent metastatic adenocarcinoma from the retroperitoneal space and abdomen. Partial remission was obtained, but the patient returned 5 months later with elevated excretion of ketogenic steroids and ketosteroids, which 8 mg of dexamethasone did not suppress. Administration of o,p’-DDD was insti- tuted with a dosage of 6 gm/day. From the pretreatment rate of 65 mg/24 hr, keto- steroid excretion dropped to 20 in 2 weeks and to 2.5 by the end of 6 weeks. Similarly, ketogenic steroid excretion fell from 17 mg to 3.6 and to 2.5. The weakness, anxiety, depression, and anorexia that accompanied use of o,p’-DDD caused its omission for a month. Thereafter it was resumed in a dosage of 3 gm/day for a 6 month period and then discontinued for 6 years.
The patient returned to work and normal activities. Reexamination in Sep- tember 1967 disclosed no evidence of hyperfunctioning adrenal tumor or metasta- tic disease. She continued taking 9a-fluorohydrocortisone and dexamethasone and diuretics as necessary until April 1970, when 17-ketosteroid excretion had risen to 43 and 17-ketogenic steroid excretion to 33.
In the succeeding months, florid Cushing’s syndrome developed again; but despite extensive radiologic studies, we were not able to demonstrate the source of hormone production. Treatment with o,p’-DDD was reinstituted in June 1970; and in 1 month the ketosteroid excretion fell from the pretreatment level of 74 to 15 and the ketogenic excretion fell from 42 to 18. Plasma cortisol was suppressed to a third of the previous concentration and the excretion of pregnanetriol and THS was reduced. At the same time, the cholesterol concentration rose from 267 to 399 mg/100 ml. By the end of 6 weeks there was striking clinical improvement, but the patient’s emotional state had worsened. Profound depression, anorexia, nausea, vomiting, lethargy, and exhaustion interfered with her ability to carry on her nor- mal activities. At this time the ketosteroid excretion was further suppressed to 2.4 mg/day and the ketogenic steroid excretion to 6.9. The cholesterol concentration had risen to 444. The 3-gm dose of o,p’-DDD had to be reduced to 1 gm daily, but excellent suppression continued. With control of the Cushing’s disease, there was a transient increase of the serum calcium. Potassium chloride supplements and
diazepam (Valium) were given, as well as dexamethasone, 9a-fluorohydrocor- tisone, and o,p’-DDD.
In June 1971, the patient was taking 1.5 gm of o,p’-DDD daily and there still was no perceptible tumor. Her skin became normal. Her strength and stamina improved greatly, but she continued to feel rundown and complained of head- aches. In August the excretion of ketogenic steroids rose to 23. The dex- amethasone dosage was raised to 3 gm/day, which strengthened the suppression of these steroids; but hospitalization elsewhere became necessary because of ex- treme fatigue, anxiety, depression, anorexia, and psychologic disorganization. Again reduction of o,p’-DDD dosage improved her psychologic state and ami- triptyline (Elavil) improved her spirits.
In December, while the o,p’-DDD dosage was 2 gm/day, the daily excretion of ketosteroids was 1.3 and that of ketogenic steroids 4.7. Any increase in the dosage of o,p’-DDD resulted in psychiatric symptoms and diarrhea. Despite the absence of measurable or even identifiable malignant adrenal disease, the o,p’-DDD has produced a beneficial effect over a long period, either by suppressing tumor production of cortisol and ketosteroids or by destruction of the tumor itself. Unfor- tunately, the steroid response to o,p’-DDD has been obtained at a cost of much toxic reaction, which up to the present seriously limits the patient’s effectiveness and enjoyment of life.
Case 11
A 52-year-old man was seen in 1964 for routine medical evaluation 7 years after removal of a “high-grade necrotic 900 gm carcinoma” from the left adrenal. There had been no evidence of recurrence or illness until 1962, when he developed mild angina pectoris and persistent hypertension (210/105 mm Hg). No abnormal mass could be demonstrated by physical examination or roentgenographic studies.
Laboratory studies showed persistent elevation of aldosterone excretion and persistent hypokalemia. Exploration of the abdomen in October 1964 disclosed multiple hepatic metastases. Needle biopsy confirmed the presence of metastatic carcinoma, grade 3, of adrenal origin. Ketosteroid excretion was normal but ke- togenic steroid excretion was mildly elevated (16 to 21 mg/24 hr). Aldosterone val- ues ranged between 40 and 58 µg/24 hr.
Treatment was begun with o,p’-DDD in a dosage of 4 gm/day, increasing to 6 gm. This resulted in nausea, drowsiness, diarrhea, and peripheral neuropathy af- fecting mostly the lower extremities. Despite these reactions, the dosage was pushed to 8 gm/day; and in 1 month the aldosterone excretion had fallen to 5 µg, ketosteroid excretion was 7 mg, and ketogenic excretion 9 to 13. With mainte- nance dosage at 6 gm/day, good suppression of adrenal steroids and aldosterone continued. Although the blood pressure stayed at normal levels without any antihypertensive treatment, potassium supplementation was necessary. Continu- ing administration of 2 to 4 gm of o,p’-DDD each day maintained good control of excretion of aldosterone as well as of ketosteroids and ketogenic steroids until December 1965, when fever, anemia, increasing hepatic mass, and gynecomastia developed. Because of the increasing size of the liver mass, the administration of o,p’-DDD was abandoned after 14 months of treatment. The patient died 7 months later of progressive hepatic failure and ascites after the failure of other forms of antitumor therapy.
His course indicates that a favorable response may be obtained in patients whose predominant clinical abnormalities are results of hyperaldosteronism sec- ondary to adrenal cancer, even though the cancer itself is not measurably dimin- ished.
COMMENT
Untoward Effects
The noxious effects of o,p’-DDD should not be taken lightly. All of our patients found it unpleasant to take-some early, some only after weeks
of treatment. In just three cases were the toxic effects so minimal that the patients were able to maintain almost normal activities at work and leisure; but two of these three received the drug only for 5 and 8 weeks before death ended the treatment. The majority suffered general lassi- tude, gloom, and apathy which ranged from mild dulling of interest to profound psychotic depression. Anorexia, nausea, vomiting, diarrhea, and nocturnal diarrhea were the commonest gastrointestinal symptoms. Fatigue, somnolence, and lethargy were the commonest neurologic com- plaints; cranial and peripheral neuropathies were much less prevalent.
Vertigo and dizziness occurred in about half of the patients some- where in the course of treatment. Irritability was striking in one patient. Another had extrapyramidal, involuntary slow movements of the lower limbs and later a pattern of signs resembling that of subacute combined degeneration of the spinal cord. Three patients had toxic retinopathy that included papilledema, small retinal hemorrhages, and edema which could not be attributed to other drugs or illness; and a subcapsular cata- ract developed in another. Three patients had a maculopapular rash of brief duration.
There was no instance of massive tumor necrosis with o,p’-DDD. One patient who developed fever and increased tenderness in the tumor dur- ing the o,p’-DDD treatment, undoubtedly had necrosis; but his may have been part of the natural history of the tumor. No untoward reactions to other drugs administered in the course of o,p’-DDD treatment were ob- served, although it is possible that we may not have recognized them among the multiple symptoms produced by the o,p’-DDD and the varied manifestations of the progressive malignant disease.
When the o,p’-DDD treatment was withdrawn, the patients very frequently expressed a feeling of relief, as if the clouds had lifted, allow- ing a return to normal participation and enjoyment of life unless their disease was so terminal or severe as to prevent it. Despite their natural disappointment at failure of the drug trial, they began to eat well, to become more active, and to participate more in family activities than they could during medication.
It became our policy not to prescribe o,p’-DDD just because there was evidence of metastatic or recurrent carcinoma. We preferred to have evi- dence of advancing, increasing, or disabling disease before initiating such an unpleasant experience. In many cases the wishes of colleagues or patients or their families favored early employment of the drug. From our experience, it is not certain that early use is justified, even though the patients with large tumors did less well than those with smaller ones.
Other Reports
The initial report of Hutter and Kayhoe showed that 61 per cent of pa- tients with elevated 17-hydroxycorticosteroid excretion achieved good or fair responses, three quarters of them reaching normal rates. In cases where rates declined to 70 per cent of the control values, the great major- ity did so within 30 days. Elevated excretion rates for 17-ketosteroids responded to o,p’-DDD more slowly, a third of them requiring more than 3 weeks; but 86 per cent responded within 30 days. (This was the basis for selection of 4 weeks as the trial period.) The more important finding was
that an objective tumor response was obtained in 34 per cent of the 59 cases of measurable lesions. This response was first noted from 2 to 28 weeks after initiation of the o,p’-DDD treatment, averaging 9 weeks in the 15 cases wherein the beginning of the response could be determined definitely. Data were not sufficient for correlating the level of response with the dosage, and the usual dosage varied widely (0.5 to 20 gm). In only one case was a second tumor regression noted in response to in- creased dosage after tumor growth had resumed despite continuation of the previous lower dosage. It became apparent also that to obtain a mea- surable disease response did not require pushing the dosage to the point of toxicity, nor suppressing the excretion of both 17-hydroxycorticoids and ketosteroids. Among the 10 patients whose steroid excretion was nor- mal prior to treatment, 2 had measurable disease response, whereas among the 34 whose initial ketogenic or ketosteroid value was high, 12 had such a response.
No patient had a measurable disease response without a good steroid response, but only 42 per cent of the steroid responders had a tumor response. The mean duration of steroid response was 5 months and the mean duration of measurable disease response was 10 months. There was no significant difference in length of survival, however, between those with a tumor response and those without, nor between male and female. Both steroid response and tumor response were important in producing a clinical response. No correlation was demonstrated between the chance of benefit and age, sex, or location of tumor or of metastasis.
The subsequent 5 year experience reported by Okun showed even more grounds for enthusiasm. Again, nearly all patients who had a mea- surable disease response also had a steroid response (34 of 36). Among 75 cases wherein such evaluation was possible, 46 had a measurable disease response with mean duration of 10 months, median of 6 months, and range of 1 to 36 months. An equally favorable result was a definite “clinical response” in 54 of 100 cases. The incidence of toxic effects was essentially the same in both series. Hematologic and hepatic disease were so rare that the authors of both reports believed that if either entity was found, it would be best to think of causes other than o,p’-DDD toxicity.
Okun suggested that the difference between his results and those of the earlier collaborative study might have been due to the more common knowledge of the availability and effect of o,p’-DDD treatment and the advantage of consequently earlier treatment. He believed that earlier treatment was desirable and that the use of o,p’-DDD should be consid- ered postoperatively if there was uncertainty about possible tumor seed- ing. Continuous treatment seemed advisable, since retreatment after es- cape from suppression was considerably less effective.
Conclusion
The wide variation in the duration of the disease and size of the tumor at the time of diagnosis and treatment, the inherent variation in the growth rate of adrenal cancers, and the influence of excess adrenal steroids in producing illness all contribute to the difficulty in arriving at worthwhile survival statistics. Thus far, there is no convincing evidence
that o,p’-DDD has materially prolonged the lives of the patients suffering from adrenal cancer. Yet one cannot help being strongly influenced by the subsidence of large nodules and the complete reversal of changes of Cushing’s syndrome, virilization, feminization, and hyperaldosteronism. Observations of this type lead one to feel that in individual cases o,p’-DDD has been of great benefit and has probably prolonged effective life. There still remains no way of predicting who will respond in this gratifying fashion except that, in the course of treatment, those with a steroid response have a much greater chance for tumor response. The toxicity of the medicament is a serious handicap, and there is also a need to protect the patient from adrenal insufficiency. Since this situation may develop rapidly, it seems to us best to raise the glucocorticoid umbrella early in the course of treatment.
SUMMARY
Nineteen patients with adrenocortical carcinoma were treated with o,p’-DDD at the Mayo Clinic between 1959 and 1971. The drug was ad- ministered in maintenance doses of 1 to 10 gm daily for periods of 5 weeks to 19 months. Two patients were treated twice: one 4 years after her initial course of o,p’-DDD, the other 6 years after. Tumor regression was obtained in only four cases, and suppression of the control keto- steroid and ketogenic steroid excretion was greater than 50 per cent in each of them. The length of the tumor regression ranged from 3 to 24 months. Two patients without proven tumor response had remission of the clinical features. One reversed her severe Cushing’s manifestations after 6 months of treatment and enjoyed a complete remission for 51/2 years without treatment, and then a second remission for 11/2 years with continuous treatment. The second patient was freed of manifestations of hyperaldosteronism for 14 months, although his tumor continued to grow.
In our hands, o,p’-DDD has not been so effective as the reports cited would lead one to expect. Toxicity has been a major deterrent to its use, for despite reduction of the maintenance dose after the first objectives of treatment had been achieved, the majority of our patients continued to be distressed by central nervous system or gastrointestinal symptoms. As yet there is no way to know beforehand which patient will respond, but trial of o,p’-DDD is justified in cases where surgery cannot be used to eradicate adrenocortical carcinoma and in cases where there is hope of restoring some measure of health by interfering with the excessive production of adrenocortical hormones.
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