Impact of Adjuvant Mitotane on the Clinical Course of Patients with Adrenocortical Cancer

Impact of Adjuvant Mitotane on the Clinical Course of Patients with Adrenocortical Cancer Rena Vassilopoulou-Sellin, M.D.,* Vincent F. Guinee, M.D.,t May 1. 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.* 3119 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 localized disease. Methods. The authors analyzed the clinical outcome of patients with localized or regional adrenocortical cancer. The study included 19 patients who were registered 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 mitotane postoperatively and continued the drug until their last contact or recurrence (Group A, adjuvant); five patients began taking mitotane after surgery but discontinued it after 2-12 months for reasons unrelated to the disease (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 significantly in their time to recurrence; the disease-free interval 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 confounding factors, gender, age, steroid hypersecretion, and tumor size, none had any influence on recurrence or survival rates. Conclusions. These findings do not support the conclusion that adjuvant mitotane is beneficial in patients with localized or regional adrenocortical cancer. Neither the disease-free interval nor survival was improved by the drug. The authors suggest that alternative 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. therapeutic strategies be explored for the management of these patients. Cancer 1993; 71:3119-23. Key words: adrenal cancer, mitotane, adiuvant, prognosis. Adrenocortical carcinoma is a rare and extremely aggressive 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 Surgical excision has been and remains the mainstay of therapy. Radiation therapy and chemotherapy are generally ineffective. Some,6-2 but not all, -15 studies have shown that mitotane is helpful in reducing the measurable disease burden in some patients. With the proliferation of computed tomography, small adrenal masses are now found incidentally long before any clinical syndrome develop^.'^,'^ 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 lowvolume residual disease. Its adjuvant use has been suggested by several investigator^,^,^,'^ although this modality 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 received 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 patientsregistered at The University of Texas M. D. Anderson

3120 CANCER May 15, 1993, Volume 71, No. 10 Cancer Center with the diagnosis of adrenocortical carcinoma. 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 classification, as in our previous re vie^.^ Among these patients, 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 patients. These patients either had surgery at M. D. Anderson, or the operative reports were carefully reviewed. In all cases, surgical pathologic specimens were reviewed, and the diagnosis of malignancy was confirmed 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 begn 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 mitotane 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 surgery before their referral to M. D. Anderson; they constitute 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 vaned greatly both among patients 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 recommend dose reduction for secondary hyperlipidemia or decreased libido. In one patient, mitotane was discontinued because it precipitated symptomatic porphyria. Follow-up evaluation included physical examination, 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. Table 1. Characteristics of Patient Population Tumor characteristics Clinical course Size DFI Survival Group Patient no. Age (yr) Race Sex Function km) (mo) (mo) A 1 47 w M Nonfunctioning A 2 28 L F Cushing syndrome A 3 43 W M Nonfunctioning A 4 22 w F Cushing syndrome A 5 66 W M Nonfunctioning A 6 69 W M Nonfunctioning A 7 28 W M Nonfunctioning A 8 39 W F Cushing syndrome P 1 49 w F (8m) Cushing syndrome P 2 47 w F ( 24 Nonfunctioning P 3 45 w F ( 44 Cushing syndrome P 4 56 M (9m) Nonfunctioning P 5 51 w F (12m) Nonfunctioning N 1 43 w F Cushing syndrome N 2 30 B F Cushing syndrome N 3 42 L F Nonfunctioning N 4 37 W F Nonfunctioning N 5 73 w F Virilizing syndrome N 6 30 w F Cushing syndrome 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. 20 25 t 25 (-1 6 11 19 (+)$ 14 8 11 11 5 14 10 10 12 10 5 8 (+)$ 7 12 49 (+)$ 7 9 14 6 14t 14 (-)$ 16 15 64 (-)$ 4 14 32 (-I$ 8 13t 13 (-I$ 19 36 42 (+I$ 5 12 34 6 27t 27 (-)$ 9 1st 18 (-)$ 2 33t 33 (-)$ NA 12 44 11 46 109 (+)$

Adjuvant Mitotane for Adrenal Cancer/Vassilopouiou-Sellin et al. 3121 Data Analysis -.l -7 100% Adjuvant (N.8) looo% i I (5) ----. Postop IN=5) : I... None (N.6) The cumulative disease-free interval and survival prob- : I I ) Number 01 petlents at risk :I 80%. I 80% abilities were estimated by the Kaplan-Meier method, 67% i *; 67% 13) 67% (1) (5) and the distributions of time to recurrence or death &...I...... 4... were compared using the Cox-Mantel log-rank test U. 6o01a t 1!! 160% (BMDP Statistical Software, Los Angeles, CA). Because of the small number of patients, we compared confidence 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- 12% 12) 12% (1) I ;o% (1) vided by the estimated probability. In addition to treat-.. : ment, four other factors were analyzed: patient age, 0 6 12 18 24 30 36 42 48 Months gender, functional status (evidence of steroid hyperse- Figure 1. Effect of mitotane on disease freedom. x-axis: available cretion), and tumor size (greatest dimension in centimefollow-up in months; y-axis: percentage of patients who remain ters). P values less than 0.05 were considered statisti- disease-free (Kaplan-Meier estimates by treatment group); log-rank cally significant. Because the treatment groups were not test for differences: P = 0.0055 randomized, it was thought that differences in these factors might exist and confound the relationship between treatment and survival or recurrence. Men and women were not evenly distributed among the treatment groups; therefore, the disease-free interval and survival were also analyzed by the treatment group for women only. 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 werenot statistically significant (P = 0.52, by chi-square test). looa'r-- - I Results Patient Population The clinical and actuarial features of the individual patients are outlined in Table l. There were no differences in the pathologic assessments of tumor necrosis, vascular-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 patients 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 Table 2. Characteristics of the Three Groups Median age Group (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 f 3.5 * Steroid hypersecretion. t Greatest dimension (cm), mean? standard deviation. Features That Influenced Recurrence The treatment groups varied considerably in their time to recurrence (Fig. 1 and Table 3; P = 0.0055, by logrank test). The disease-free interval was shortest for the group receiving adjuvant mitotane; only one patient remains without evidence of disease 25 months after the diagnosis. None of the potentially confounding factors (age, gender, function, and tumor size) were significantly 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 excluded 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-

3122 CANCER May 15, 1993, Volume 71, No. 10 Table 3. Freedom From Recurrence According to Treatment* Time (mo) Group A (YO) Group P (Yo) 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 excluded from the analysis, the difference in survival among the treatment groups was significant (P = 0.019, by log-rank test). The group receiving mitotane continued 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, inoperable disease; in general, the drug has provided objective tumor regression in 10-50% of ~ases,~-l~ and amelioration of biochemical parameters (steroid hypersecretion) has been seen in the majority of patients with functioning t~mors.*,~,'*~ Because these responses have usually been short lived, it has been difficult to demonstrate a survival advantage. Nevertheless, mitotane has continued to be considered a very important drug to treat loo% F7;" -------*------ 100% 80% 80% I t 20% 2ovo '... ----. Poslop (N.5)...-. None IN=W I I Number 01 pallenls at rlsk?lyi i67k (21 - Adluvanl (N=O a. '3% 12): 33K (1) s... 1 60% -I 40% I 1 oval ' '." '.. ' I 0% 0 12 24 36 48 60 72 84 96 108 120 Months Figure 2. Effect of mitotane on survival. x-axis: available follow-up in months; y-axis: percentage of patients who remain alive (Kaplan-Meier estimates by treatment group); log-rank test for differences: P = 0.10. adrenocortical cancer because of its specificity and relatively favorable therapeutic profile. Because of the high recurrence rates and poor survival 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 disease. Because mitotane offers good specificity and a reasonable antineoplastic profile, it has been suggested that this compound may be beneficial as adjuvant therapy. One group observed the longest survival in patients who received mitotane as adjuvant therapy before clinical evidence of metastases was noted and in patients who were treated with mitotane and underwent further therapy for recurrent tumors (four patients in each group).* By contrast, others could not demonstrate any survival advantage in 21 patients with localized and regional disease who received postoperative rnit~tane.'~ 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, respectively). Both groups commented that statistically significant outcome benefit could not be demonstrated in their patients. However, the outcome trends and theoretic considerations about the potential utility of the drug prompted both groups to recommend further study of the efficacy of mitotane in patients with surgically resected, localized adrenocortical cancer. It has been suggested that 5 g or more of the drug per day may be required to achieve therapeutic mitotane levels. However, such doses are accompanied by unacceptable side effects for most patients who receive the mitotane for prolonged periods. Thus, even if theoretically 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 patients were treated since 1988 at M. D. Anderson. Because our groups were not randomized, we also ana-

Adjuvant Mitotane for Adrenal CancerlVassilopoulou-Sellin et al. 3123 Table 4. Survival According to Treatment* ~~ 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, tumor function, and tumor size. In addition, we considered separately the five patients who received mitotane for only a short time to safeguard against potential 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 adrenocortical cancer. Although our sample size was small, the analysis of our data clearly suggested that adjuvant mitotane 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 mitotane. The proliferation of radiologic imaging techniques is allowing the diagnosis of smaller, localized adrenocortical malignancies that may be more amenable to curative 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. References 1. Lewinsky BS, Grigor KM, Symington T, Neville AM. The clinical and pathologic features of non-hormonal adrenocortical tumors. Cancer 1974; 33:778-90. 2. Plager JE. Carcinoma of the adrenal cortex: clinical description, diagnosis and treatment. lilt Adv Surg Oncol 1984; 7:329-53. 3. Brennan MF. Adrenocortical carcinoma. CA Cancer J Clin 1987; 37:348-65. 4. Barzilay JI, Pazianos AG. Adrenocortical carcinoma. Urol Clin North Am 1989; 16:457-68. 5. Venkatesh S, Hickey RC, Vassilopoulou-Sellin R, Fernandez JF, Samaan NA. Adrenal cortical carcinoma. Cancer 1989; 64:765-9. 6. Hutter AM, Kayhoe DE. Adrenal cortical carcinoma: results of treatment with o,p DDD in 138 patients. Am ] Med 1966; 41:581-92. 7. Hoffman DL, Mattox VR. Treatment of adrenocortical carcinoma with o,p -DDD. Med Clin North Am 1972; 56:999-1012. 8. Schteingart DE, Motazedi A, Noonan RA, Thompson NW. Treatment of adrenal carcinomas. Arch Surg 1982; 117:1142-6. 9. Gutierrez ML, Crooke ST. Mitotane (o,p -DDD). Cancer Treat Rev 1980; 7:49-55. 10. Hogan F, Citrin DL, Johnson BM, Nakamura S, Davis TE, Borden EC. o,p -DDD (mitotane) therapy of adrenal cortical carcinoma: observations on drug dosage, toxicity, and steroid replacement. Cancer 1978; 42:2177-81. 11. Van Slooten H, Moolenaar AJ, Van Seters AP, Smeenk D, et al. The treatment of adrenocortical carcinoma with o,p -DDD: prognostic implications of serum level monitoring. Eur J Cancer 1984; 20:47-53. 12. Nader S, Hickey RC, Vassilopoulou-Sellin R, Samaan NA. Adrenal cortical carcinoma: a study of 77 cases. Cancer 1983; 52:707-11. 13. King DR, Lack EE. Adrenal cortical carcinoma: a clinical and pathologic study of 49 cases. Cancer 1979; 44:239-44. 14. Bodie B, Novick AC, Pontes JE, Straffon RA, Montie JE, Babiak T, et al. The Cleveland Clinic experience with adrenal cortical carcinoma. ] Urol 1989; 141:257-60. 15. Luton JP, Cerdas 5, Billaud L, Thomas G, Guilhaume, Bertagna X Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl Med 1990; 322:1195-201. 16. Abecassis M, McLoughlin MJL, Langer B, Kudlow JE. Serendipitous adrenal masses: prevalence, significance, and management. Am J Surg 1985; 149:783-8. 17. Penn I, Moulton 1, Bracken 8. Diagnosis and management of adrenal masses: 1987 Du Pont lecture. Can ]Surg 1988; 31:105-9. 18. National Institutes of Health. Summary staging guide for cancer surveillance, epidemiology and end result reporting program: April 1977. Bethesda, MD: The Institutes, 1977:12-4. 19. Vassilopoulou-Sellin, Samaan NA. Mitotane administration: an unusual cause of hypercholesterolemia. Horm Metab Res 1991; 23.619-20.