Impact of Adjuvant Mitotane on the Clinical Course of Patients with Adrenocortical Cancer
Rena Vassilopoulou-Sellin, M.D.,* Vincent F. Guinee, M.D., t Mary J. Klein, B.S.N.,* Sarah H. Taylor, M.P.H., t Kenneth R. Hess, Ph.D., t Pamela N. Schultz, R.N.,* and Naguib A. Samaan, M.D., Ph.D .*
Background. Adrenocortical carcinoma is a rare and aggressive disease with a poor prognosis. Adjuvant mitotane administration has been suggested as a strategy that might improve the outcome of patients with local- ized disease.
Methods. The authors analyzed the clinical out- come of patients with localized or regional adrenocorti- cal cancer. The study included 19 patients who were reg- istered at M. D. Anderson Cancer Center during a 3-year period and who had localized or regional disease at the time of surgery. Of these, eight patients received mito- tane postoperatively and continued the drug until their last contact or recurrence (Group A, adjuvant); five pa- tients began taking mitotane after surgery but discontin- ued it after 2-12 months for reasons unrelated to the dis- ease (Group P, postoperative); and six patients did not receive mitotane (Group N, no mitotane). All patients have been followed for at least 12 months.
Results. The treatment groups differed signifi- cantly in their time to recurrence; the disease-free inter- val was shortest in Group A (P = 0.0055, by log-rank test). There was no statistical difference in survival among the groups, but the profile remained unfavorable for Group A. The 2-year survival rate was 100% for Groups N and P but only 43% for Group A. Of the potentially confound- ing factors, gender, age, steroid hypersecretion, and tu- mor size, none had any influence on recurrence or sur- vival rates.
Conclusions. These findings do not support the conclusion that adjuvant mitotane is beneficial in pa- tients with localized or regional adrenocortical cancer. Neither the disease-free interval nor survival was im- proved by the drug. The authors suggest that alternative
therapeutic strategies be explored for the management of these patients. Cancer 1993; 71:3119-23.
Key words: adrenal cancer, mitotane, adjuvant, prog- nosis.
Adrenocortical carcinoma is a rare and extremely ag- gressive disease. The poor prognosis and short survival of patients with this malignancy have been attributed, at least in part, to the delayed diagnosis. The lack of specific symptoms and the rarity of the condition have commonly delayed recognition of the disease until widespread metastases have already developed.1-5 Sur- gical excision has been and remains the mainstay of therapy. Radiation therapy and chemotherapy are gen- erally ineffective. Some,6-12 but not all,13-15 studies have shown that mitotane is helpful in reducing the measur- able disease burden in some patients.
With the proliferation of computed tomography, small adrenal masses are now found incidentally long before any clinical syndrome develops.16,17 Thus, more adrenocortical cancers may be detected and resected while the disease is localized or regional. In this setting, mitotane may be more effective in controlling very low- volume residual disease. Its adjuvant use has been sug- gested by several investigators,5,8,15 although this mo- dality has not clearly been shown to prolong either the disease-free interval or survival.
We report on the clinical course of patients with localized or regional adrenocortical cancer who re- ceived adjuvant mitotane after surgery. Our findings do not support the conclusion that postoperative mitotane is beneficial.
Patients and Methods
Patients
Between January 1988 and March 1991, 38 patients reg- istered at The University of Texas M. D. Anderson
From the *Section of Endocrinology, Department of Medical Specialties, and the tDepartment of Patient Studies, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
The authors thank Mrs. T. Spear for her expert preparation of the manuscript.
Address for reprints: Rena Vassilopoulou-Sellin, M.D., Section of Endocrinology, Box 15, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
Accepted for publication December 11, 1992.
Cancer Center with the diagnosis of adrenocortical car- cinoma. The patient population was identified through a search of the data base maintained by the Department of Patient Studies. The tumors were staged according to the Surveillance, Epidemiology, and End Results classi- fication,18 as in our previous review.5 Among these pa- tients, 19 had limited or regional disease at the time of initial diagnosis; the current report focuses on a review of the disease-free interval and survival in these 19 pa- tients. These patients either had surgery at M. D. An- derson, or the operative reports were carefully re- viewed. In all cases, surgical pathologic specimens were reviewed, and the diagnosis of malignancy was con- firmed at our institution after careful consideration of the histologic features of each tumor.
Postoperative Management
Based on recent suggestions that adjuvant mitotane may be beneficial in patients with low-volume residual tumor, all patients with localized or regional disease have been advised to begin taking mitotane after initial surgery during the past 4 years. We divided the study population into three groups according to their use of mitotane. Eight patients (42%) began receiving mito- tane postoperatively and continued until last contact or
documented recurrence; these patients make up the “adjuvant” Group A. Five patients (26%) began taking mitotane postoperatively but discontinued the drug after 2-12 months because of unacceptable side effects; these patients constitute the “postoperative” Group P. The third group included six patients (32%) who either chose not to take mitotane or who had their initial sur- gery before their referral to M. D. Anderson; they con- stitute the “no mitotane” Group N.
All patients in Groups A and P were advised to increase their dose of mitotane gradually to the highest level tolerated; the dose varied greatly both among pa- tients and for individual patients over time. In general, most patients received 4-6 g of mitotane daily for the initial weeks and then gradually reduced their intake to 1-2 g daily. The dose was usually modified because of adverse gastrointestinal symptoms; we did not recom- mend dose reduction for secondary hyperlipidemia19 or decreased libido.11 In one patient, mitotane was discon- tinued because it precipitated symptomatic porphyria.
Follow-up evaluation included physical examina- tion, steroid measurements (especially in patients with functioning tumors), radiographs of the chest, and computed tomography of the abdomen. These studies were usually obtained every 3 months during the first year and every 6 months thereafter.
| Group | Patient no. | Age (yr) | Race | Sex | Tumor characteristics | Clinical course | ||
|---|---|---|---|---|---|---|---|---|
| Function* | Size (cm) | DFI (mo) | Survival (mo) | |||||
| A | 1 | 47 | W | M | Nonfunctioning | 20 | 25+ | 25 (-) |
| A | 2 | 28 | L | F | Cushing syndrome | 6 | 11 | 19 (+)} |
| A | 3 | 43 | W | M | Nonfunctioning | 14 | 8 | 11 |
| A | 4 | 22 | W | F | Cushing syndrome | 11 | 5 | 14 |
| A | 5 | 66 | W | M | Nonfunctioning | 10 | 10 | 12 |
| A | 6 | 69 | W | M | Nonfunctioning | 10 | 5 | 8 (+)} |
| A | 7 | 28 | W | M | Nonfunctioning | 7 | 12 | 49 (+)} |
| A | 8 | 39 | W | F | Cushing syndrome | 7 | 9 | 14 |
| P | 1 | 49 | W | F (8m) | Cushing syndrome | 6 | 14+ | 14 (-)} |
| P | 2 | 47 | W | F (2m) | Nonfunctioning | 16 | 15 | 64 (-)} |
| P | 3 | 45 | W | F (4m) | Cushing syndrome | 4 | 14 | 32 (-)# |
| P | 4 | 56 | W | M (9m) | Nonfunctioning | 8 | 13+ | 13 (-); |
| P | 5 | 51 | W | F (12m) | Nonfunctioning | 19 | 36 | 42 (+)} |
| N | 1 | 43 | W | F | Cushing syndrome | 5 | 12 | 34 |
| N | 2 | 30 | B | F | Cushing syndrome | 6 | 27+ | 27 (-)} |
| N | 3 | 42 | L | F | Nonfunctioning | 9 | 18t | 18 (-)} |
| N | 4 | 37 | W | F | Nonfunctioning | 2 | 33+ | 33 (-)} |
| N | 5 | 73 | W | F | Virilizing syndrome | NA | 12 | 44 |
| N | 6 | 30 | W | F | Cushing syndrome | 11 | 46 | 109 (+)} |
DFI: disease-free interval; (+): alive with metastatic/recurrent disease; (-): alive without evidence of disease.
* Steroid hypersecretion.
t No recurrence at the time of last contact.
# Patient was still alive at last contact.
Data Analysis
The cumulative disease-free interval and survival prob- abilities were estimated by the Kaplan-Meier method, and the distributions of time to recurrence or death were compared using the Cox-Mantel log-rank test (BMDP Statistical Software, Los Angeles, CA). Because of the small number of patients, we compared confi- dence intervals for the Kaplan-Meier estimates using an exact binomial method with an effective sample size equal to the number of patients remaining at risk di- vided by the estimated probability. In addition to treat- ment, four other factors were analyzed: patient age, gender, functional status (evidence of steroid hyperse- cretion), and tumor size (greatest dimension in centime- ters). P values less than 0.05 were considered statisti- cally significant. Because the treatment groups were not randomized, it was thought that differences in these factors might exist and confound the relationship be- tween treatment and survival or recurrence. Men and women were not evenly distributed among the treat- ment groups; therefore, the disease-free interval and survival were also analyzed by the treatment group for women only.
Results
Patient Population
The clinical and actuarial features of the individual pa- tients are outlined in Table 1. There were no differences in the pathologic assessments of tumor necrosis, vascu- lar-capsular or lymphatic invasion, and mitotic index among the groups. The patients’ ages ranged from 22- 73 years (median, 43 years; Table 2). Tumor size ranged from 2-20 cm (median, 8.5 cm; the tumor size was not available in one patient). The distributions of patient age and tumor size were not significantly different among the three treatment groups (P = 0.23 for age and P = 0.30 for size, by the Kruskal-Wallis test). Six pa- tients were men (32%), and 13 (68%) were women. Men and women were not evenly distributed among the treatment groups (P = 0.036, by Pearson chi-square test). The proportion of male patients was 62% in Group A, 20% in Group P, and 0% in Group N. Nine
| Group | Median age (range) (yr) | Function* | Sex (M/F) | Sizet |
|---|---|---|---|---|
| A | 45 (22-69) | 3/8 | 4/4 | 10.6 ± 4.6 |
| P | 49 (45-56) | 2/5 | 1/4 | 10.6 ± 6.5 |
| N | 37 (30-73) | 4/6 | 0/6 | 6.6 ± 3.5 |
* Steroid hypersecretion.
t Greatest dimension (cm), mean ± standard deviation.
100%
100%
Adjuvant (N=8)
100%
(5)
Postop (N=5)
None (N=6)
80%
( ) Number of patients at risk
80%
Disease Freedom
67%
67% (3)
67% (1)
(5)
60%
60%
40%
38% (1)
40%
20%
20%
12% (2)
12% (1)
0%
0% (1)
0%
0
6
12
18
24
30
36
42
48
Months
patients (47%) had Cushing syndrome; 10 patients (53%) did not. The proportion of patients with Cushing syndrome varied by treatment group (Group A, 38%; Group P, 40%; Group N, 67%), but these differences were not statistically significant (P = 0.52, by chi-square test).
Features That Influenced Recurrence
The treatment groups varied considerably in their time to recurrence (Fig. 1 and Table 3; P = 0.0055, by log- rank test). The disease-free interval was shortest for the group receiving adjuvant mitotane; only one patient re- mains without evidence of disease 25 months after the diagnosis. None of the potentially confounding factors (age, gender, function, and tumor size) were signifi- cantly associated with recurrence (log-rank test results for age, P = 0.98; gender, P = 0.30; function, P = 0.76; tumor size, P = 0.87). When male patients were ex- cluded from the analysis, the disease-free interval again varied according to treatment (P = 0.0003, by log-rank test). The least favorable trend remained with the group receiving adjuvant mitotane; all except one patient have had recurrent disease within 5-12 months after the diagnosis.
Features That Influenced Survival
The three treatment groups have markedly different survival curves (Fig. 2 and Table 4). However, with only six deaths, the statistical power for detecting differences in the time to death is low. Thus, it is not surprising that the apparent differences are not statistically significant at the 0.05 level (P = 0.10, by log-rank test). In Group N, four of six patients are still alive 18-109 months after the diagnosis; there have been no deaths in Group P. Of the potentially confounding factors (age, gender, func-
| Time (mo) | Group A (%) | Group P (%) | Group N (%) |
|---|---|---|---|
| 6 | [6]t 75, 35-97 | [5] 100,48-100 | [6] 100, 54-100 |
| 12 | [2] 12, 1-36 | [5] 100, 48-100 | [5] 67, 27-94 |
| 18 | - | [2] 37, 5-82 | [4] 67, 22-96 |
| 24 | - | [2] 37, 5-82 | [4] 67, 22-96 |
* Kaplan-Meier probability estimates, 95% confidence intervals.
t Number of patients remaining at risk.
tion, and tumor size), none was statistically associated with survival (P = 0.55, P = 0.23, P = 0.52, and P = 0.56, respectively). When male patients were ex- cluded from the analysis, the difference in survival among the treatment groups was significant (P = 0.019, by log-rank test). The group receiving mitotane contin- ued to have the least favorable trend.
Discussion
Based on this study, we cannot confirm that adjuvant mitotane provides an outcome benefit to patients with localized or regional adrenocortical carcinoma. Neither disease-free interval nor survival was prolonged by the administration of this drug.
Several earlier studies analyzed the antineoplastic effect of mitotane in patients with advanced, inopera- ble disease; in general, the drug has provided objective tumor regression in 10-50% of cases,6-15 and ameliora- tion of biochemical parameters (steroid hypersecretion) has been seen in the majority of patients with function- ing tumors.2,3,7,9 Because these responses have usually been short lived, it has been difficult to demonstrate a survival advantage. Nevertheless, mitotane has contin- ued to be considered a very important drug to treat
100%
100% (5)
100% (2) 100% (1)
100%
80%
80%
71% (6)
67% (2)
Adjuvant (N=8)
----. Postop (N=5)
Survival
60%
… None (N=6)
( ) Number of patients at risk
60%
40%
43% (2)
33% (1)
40%
20%
20%
0%
0%
0
12
24
36
48
60
72
84
96
108
120
Months
adrenocortical cancer because of its specificity and rela- tively favorable therapeutic profile.
Because of the high recurrence rates and poor sur- vival of patients with this disease (even when the tumor appears localized at the time of diagnosis), different strategies have been sought to prolong the disease-free survival. Currently, surgery is considered the treatment of choice for patients with localized and regional dis- ease. Because mitotane offers good specificity and a rea- sonable antineoplastic profile, it has been suggested that this compound may be beneficial as adjuvant ther- apy. One group observed the longest survival in pa- tients who received mitotane as adjuvant therapy be- fore clinical evidence of metastases was noted and in patients who were treated with mitotane and under- went further therapy for recurrent tumors (four patients in each group).8 By contrast, others could not demon- strate any survival advantage in 21 patients with local- ized and regional disease who received postoperative mitotane.14
More recently, in retrospective reviews analyzing the outcome of patients with adrenocortical cancer, two studies (n = 110 patients5 and n = 10515) addressed the role of mitotane in patients who took the drug before measurable disease was evident (6 and 23 patients, re- spectively). Both groups commented that statistically significant outcome benefit could not be demonstrated in their patients. However, the outcome trends and the- oretic considerations about the potential utility of the drug prompted both groups to recommend further study of the efficacy of mitotane in patients with surgi- cally resected, localized adrenocortical cancer.
It has been suggested that 5 g or more of the drug per day may be required to achieve therapeutic mito- tane levels. However, such doses are accompanied by unacceptable side effects for most patients who receive the mitotane for prolonged periods. Thus, even if theo- retically beneficial, this strategy is not feasible in most cases.
Mitotane is being recommended to patients with localized and regional disease who have no evidence of residual disease after initial surgery. Nineteen such pa- tients were treated since 1988 at M. D. Anderson. Be- cause our groups were not randomized, we also ana-
| Time (mo) | Group A | Group P | Group N |
|---|---|---|---|
| 12 | [6]t 71, 32-95 | [5] 100, 48-100 | [6] 100, 54-100 |
| 18 | [4] 43, 13-77 | [4] 100, 40-100 | [5] 100, 48-100 |
| 24 | [3] 43, 10-82 | [4] 100, 40-100 | [5] 100, 48-100 |
| 36 | [2] 43, 6-88 | [3] 100, 29-100 | [2] 67, 9-99 |
* Kaplan-Meier probability estimates, 95% confidence intervals.
t Number of patients remaining at risk.
lyzed the clinical outcome according to gender, age, tu- mor function, and tumor size. In addition, we considered separately the five patients who received mitotane for only a short time to safeguard against po- tential selection bias in the postoperative decision to prescribe the drug in patients who may not all appear equally at risk clinically.
The limited power of the statistical analysis when the sample size is small has been a common problem in the evaluation of many rare diseases, including adreno- cortical cancer. Although our sample size was small, the analysis of our data clearly suggested that adjuvant mi- totane offers neither disease-free interval nor survival advantage in patients with localized or regional disease. There were no statistical differences among the groups in any of the potentially confounding factors (tumor size or function and patient age or sex). As suggested by previous studies, neither the tumor size nor biochemical function had prognostic value. Because it was noted that female patients may have a better prognosis,6 we analyzed the outcome in women separately; again, we could not demonstrate any benefit from adjuvant mito- tane.
The proliferation of radiologic imaging techniques is allowing the diagnosis of smaller, localized adrenocor- tical malignancies that may be more amenable to cura- tive therapy. We are discouraged that mitotane does not appear to provide any benefit when used as adjuvant therapy in such cases. Based on our findings, we are, at this time, actively exploring alternative therapeutic strategies for our patients.
Note Added in Proof
Case Ai had documented disease recurrence at 32 months. Thus, all patients in Group A had recurrence.
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