Adjunctive treatment of adrenocortical carcinoma Massimo Terzoloª and Alfredo Berrutib
ªDepartment of Clinical and Biological Sciences, Internal Medicine and Department of Clinical and Biological Sciences, Medical Oncology, University of Turin, Turin, Italy
Correspondence to Professor M. Terzolo, MD, Medicina Interna I, A.S.O. San Luigi, Regione Gonzole, 10, 10043 Orbassano, Italy Tel: +39 011 9026292; fax: +39 011 9038655; e-mail: terzolo@usa.net
Current Opinion in Endocrinology, Diabetes & Obesity 2008, 15:221-226
Purpose of review
Description of the adjunctive treatment strategies in patients with adrenocortical carcinoma after complete surgical resection.
Recent findings
A retrospective analysis showing that adjuvant mitotane may prolong recurrence-free survival in a large cohort of patients with radically resected adrenocortical carcinoma has recently been published. Debate continues as to whether mitotane may, however, be beneficial as an adjuvant treatment.
Summary
Radical surgical resection of adrenocortical carcinoma offers the best chance for prolonged recurrence-free survival; however, a significant number of patients without objective and biochemical evidence of residual tumor after surgery are destined to relapse. Mitotane, an analogue of the insecticide dichlorodiphenyltrichloroethane, has been used for treatment of advanced adrenocortical carcinoma since the 1960s, but its use as an adjunctive postoperative measure has remained controversial. Adjunctive treatments different from mitotane have been employed infrequently; a recent retrospective study showed benefit of local radiotherapy. The recent demonstration that mitotane treatment following macroscopically complete removal of adrenocortical carcinoma was associated with beneficial effects on outcome in a well designed, multicenter, international study should renew interest in adjuvant mitotane therapy.
Keywords
adjunctive treatment, adrenocortical cancer, mitotane, radiotherapy
Curr Opin Endocrinol Diabetes Obes 15:221-226. @ 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1752-296X
Introduction
Adrenocortical carcinoma (ACC) is a rare tumor charac- terized by a dismal prognosis as the 5-year survival rate after diagnosis is less than 40% [1,2,3 ** ]. The most import- ant predictor of outcome is the possibility to attain a complete resection and, as a matter of fact, prognosis is extremely poor when surgical removal of ACC is not feasible with radical intent [1,2,3 ** ,4-9]. Most patients have resectable disease at presentation; however, fully half of the patients who have undergone complete removal of the tumor are destined to relapse, often with distant metastases [4-8]. The reasons why a significant number of patients with ACC (even stage I-II) are destined to relapse are presently unknown. Several poten- tial predictive factors of recurrence in radically resected ACC have been identified [10,11 ** ], but the issue of defining prognostic factors is complicated by the great variability of clinical presentation and heterogeneity of biological behavior of ACC.
Early studies with adjunctive mitotane
The high recurrence rate of ACC has prompted many investigators to consider the use of adjuvant therapy fol-
1752-296X @ 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
lowing radical resection of the tumor. Mitotane, [1,1- dichlorodiphenildichloroethane (o,p’-DDD)], an analogue of the insecticide dichlorodiphenyltrichloroethane (DDT), has been widely employed in this setting [1,2,3 ** ], but the relevant studies produced conflicting results. Several reasons may likely explain the inconsis- tency of the literature.
First, most studies [5,12-15] had limited statistical powers to conduct a reliable evaluation of the treatment efficacy. In fact, only four groups reported the outcome of adjuvant mitotane treatment in series of more than 20 patients. In the series of Luton et al. [14], however, the results of mitotane treatment in patients with advanced disease have been analyzed together with those of the 23 patients treated adjuvantly, thus precluding a specific evaluation of the outcome of ad- junctive mitotane.
Second, many studies [5,8,13-17] did not include a concomitant control group of untreated patients with comparable baseline characteristics, whereas in some series a number of patients underwent multiple adjuvant treatments in various sequences [7,14]. In addition, the
222 Adrenal cortex
definition of recurrence-free survival has not been uniform, and the duration of response has been some- times unclear.
Finally, all studies but one [16] were retrospective and employed different formulations of mitotane at doses ranging from 3 to 20 g daily, which were given for differ- ent time periods.
Characteristics and outcome of the main studies with adjunctive mitotane are summarized in the Table 1.
Other adjunctive strategies
In the study of Khan et al. [22], the combination of streptozotocin and mitotane was given to 17 of 28 radi- cally operated ACC patients. The patients who received adjunctive therapy had significantly longer disease-free survivals than the 11 patients who did not receive any therapy after operation.
In a retrospective analysis of the German ACC registry, it has been shown that the 14 patients who received tumor bed radiotherapy in an adjuvant setting had significantly reduced rates of local recurrence than their matched con- trols. Regretfully, disease-free and overall survival were
not significantly different between the two groups [23°]. These preliminary data may suggest a role for adjuvant radiotherapy in patients at high risk of local recurrence and seems to contradict the view that ACC is radioresistant.
Recent developments
Given the recognized toxicity of mitotane, which appears to have a narrow therapeutic index [3 ** ,16,19], and the lack of clear evidence for a beneficial effect in some studies [5,7,12,16,18-20], mitotane use as an adjunctive treatment has declined in recent years, and no recom- mendation regarding adjuvant treatment was made at a 2003 consensus conference on ACC held in Ann Arbor, Michigan, USA [24].
Very recently, however, the results of a retrospective analysis involving a large cohort of patients with ACC, who were followed for up to 10 years at different institu- tions in Italy and Germany, have been published [25 ** ]. Adjuvant therapy was given to 47 Italian patients after radical surgery, and recurrence-free survival in these patients (the primary outcome of the study) was compared with that of two independent groups of 55 Italian and 75 German patients whose surgery was not followed by mitotane treatment. Recurrence-free survival was
| References | Patients | Mitotane dose (g/day) | Outcome |
|---|---|---|---|
| Schteingart [8] | 4 | 6 | Mean survival of 74 ±33 months in patients who received adjuvant MIT. No control group. |
| Venkatesh et al. [9] | 7 | NA | After 1-4 years from surgery, 6/7 patients treated with adjuvant MIT are still alive. No control group. |
| Bodie et al. [12] | 21 | NA | No difference in survival between patients with or without (n= 25) adjuvant MIT. No information on DFS is given. |
| Pommier and Brennan [7] | 7 | NA | Mean DFS was 2.4 years for 10 patients treated adjuvantly (MIT in 7 and radiotherapy in 3 patients) and 2.5 years for 43 untreated patients (NS). |
| Vassilopoulou-Sellin et al. [18] | 8 | 4-6 | Median DFS was 10 months for the patients treated with adjuvant MIT vs. 23 months for 6 untreated patients (P <0.01). MIT was discontinued early in 5 patients for toxicity. |
| Haak et al. [19] | 11 | 4-8 | Median survival of the patients treated with adjuvant MIT was 51 vs. 61 months for untreated patients (n= 15) (NS). Six patients had MIT levels >14 mg/l. |
| Barzon et al. [20] | 7 | 4-8 | Median DFS of 8 months in the patients treated with adjuvant MIT vs. 13 months for untreated patients (n= 11) (NS). Nevertheless, 5/7 patients in MIT group are disease-free at the last follow-up (range 5-54 months), in contrast to 3/11 in the control group. |
| Dickstein et al. [17] | 4 | 1.5-2 | DFS ranged 18-68 months. No control group. |
| Kasperlik-Zaluska et al. [15]ª | 55 | 4-5 | At the last follow-up, 18/32 (56%) patients treated immediately after surgery are alive vs. 6/27 (22%) patients treated with delay. Only 1/8 (12%) untreated patients is surviving. Adjuvant MIT was given irrespective of staging and completeness of surgery. |
| Icard et al. [5]b | 83 | 3-8 | Adjuvant MIT did not have an independent effect on survival. It is not reported whether the patients in MIT group had comparable prognostic factors with the untreated patients. No information on DFS is given. |
| Baudin et al. [16] | 11 | 6-12 | Recurrence developed in 8 patients within 1 year; 6 of them had MIT levels >14 mg/l. No control group. |
DFS, disease-free survival; MIT, mitotane.
ª The study includes the patients reported previously by Kasperlik-Zaluska et al. [13].
b The study includes the patients reported previously by Icard et al. [21].
significantly prolonged in the mitotane group, as compared with the two groups of untreated patients (median recur- rence-free survival, 42 versus 10 months in the Italian control group and 25 months in the German control group). The patients who were left untreated after radical resec- tion of ACC had a significantly higher risk of recurrence than those receiving mitotane (Fig. 1). Although our study was retrospective, the mitotane group and the Italian control group were highly comparable for the clinical characteristics known to affect outcome, whereas the control group from Germany had better prognostic factors making mitotane effects even more impressive. Indeed, multivariate analysis confirmed that mitotane treatment gave a significant advantage for recurrence-free survival. Similarly, overall survival appeared to be superior in patients receiving adjuvant mitotane [25 ** ].
An important finding of our study is that favorable outcomes were achieved with low doses of mitotane (1-5 g/day), thus explaining why treatment was associated with acceptable adverse event rates [25 ** ]. Conversely,
severe and disabling toxicity was observed in the studies in which high, rapidly increasing, daily doses of mitotane were employed [7,18].
In contrast to our experience, Bertherat et al. [26] did not observe a significant advantage with adjuvant mitotane after complete removal of ACC. In a cohort of 166 patients who underwent complete tumor removal, they found that mitotane use was not associated with any improvement in disease-free survival; however, they found a tendency for the benefit of adjuvant mitotane in the patients with cortisol-secreting tumors. As mitotane was administered to only half of the patients in this cohort, it is very likely that the treated patients were selected for unfavorable prognostic factors, and selection bias might have contrib- uted to the lack of efficacy of adjuvant mitotane. In our study [25 ** ], conversely, mitotane was recommended on the basis of the treatment policy of the center, inde- pendent of the characteristics of either the tumors or the patients. The predefined treatment assignment and the inclusion of well matched control groups are major
Cumulative proportion 1.0 of disease-free survival
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
20
40
60
80
100
120
140
Number at risk
Months
Adjuvant mitotane
47
30
20
8
5
4
2
2
…
German controls
75
37
15
10
5
4
2
1
Italian controls
55
19
13
6
5
1
0
0
Hazard ratio of recurrence for Italian controls, 2.91; 95% confidence interval, 1.77-4.78; P < 0.001. Hazard ratio of recurrence for German controls, 1.97; 95% confidence interval, 1.21-3.20; P= 0.005. o, completed and +, censored. Adapted from [25 ** ].
advantages of our study as compared with other studies, that had less clear treatment assignments and often used historical controls or no controls at all [27 ** ].
Bertherat et al. [26] raised also the question whether the efficacy of mitotane may change as a function of the secretory activity of ACC. It is biologically plausible that hypercortisolism may contribute to an unfavorable outcome in patients with advanced ACC, and in a previous report by the same group, it was observed a beneficial effect of mitotane in patients with Cushing’s syndrome [11 ** ]. When mitotane is used in disease-free patients, however, its antisecretory activity may be less important to determine outcome.
The availability of mitotane monitoring gives the oppor- tunity to address the issue of an eventual dose-effect relationship [28]. The pharmacokinetics of mitotane, which is characterized by a long half-life, may explain why therapeutic concentrations of the drug can be reached with sustained low-dose treatment [29]. In our study, 16 of the 22 patients in whom serum mitotane concentrations were monitored received a daily mitotane dose that was 3 g or less. The small number of patients for whom mitotane levels were available does not permit us to conclude whether there are differences in efficacy between lower and higher doses [30]. In previous studies [16,19], no association between elevated mitotane concen- trations and outcome was observed in an adjuvant setting, whereas mitotane levels greater than 14 mg/l were associ- ated with higher rates of objective response when treating advanced ACC.
We can, however, confirm the relationship between elevated concentrations of mitotane and occurrence of toxicity; thus, the monitoring of circulating mitotane levels may at least be useful to limit side effects attaining better tolerance. We can also confirm that low doses of mitotane are able to consistently provide maintenance mitotane concentrations higher than 14 mg/l [29].
Adjuvant therapy or follow-up?
Whenever ACC is completely removed, and there is no evidence of residual disease, physicians should solve a clinical dilemma: instituting adjuvant therapy or simply follow patients without initiating treatment?
Schteingart [27 ** ] concluded that our study provides a compelling rationale for the use of low-dose mitotane as adjuvant therapy in patients presenting with stages I-III ACC whose surgical resection has been macroscopically complete, but the controversy concerning mitotane as adjuvant therapy may continue [26,31]. It is arguable that discrepant outcomes existing among published studies may not only be the result of unintended bias
or differences in study design and methodology but also reflect a highly variable response to the drug among apparently similar tumors [27 ** ]. An important issue is that mitotane requires metabolic transformation for therapeutic action [32]; thus, ACC may maintain the ability to metabolize the drug to respond. Moreover, variations in tumor biology (molecular alterations) may be a key in determining response to treatment and, in the future, the molecular approach will help selecting patients that could benefit from specific therapies [33 ** ].
According to Lee [31], observation without the use of adjuvant mitotane remains a preferable approach for many patients, given that mitotane therapy is complex owing to its toxicity, the need to monitor levels, and the need for corticosteroid replacement. This consideration is important but, in our opinion, is insufficient to recom- mend against adjunctive mitotane proven that such patients are managed in referral centers with specific expertise. Conversely, mitotane monitoring is more readily available at least in Europe, where it is provided as a free service by the company distributing mitotane (info@lysodren-europe.com), giving the possibility to guide dose adjustments and prevent severe toxicity. Thus, one of the main limits of adjunctive mitotane therapy, which is the possibility to cause harm to patients who are disease-free, is becoming a less import- ant issue to be considered when choosing to treat or not.
Practical guidelines to adjunctive mitotane therapy
In our practice, we advice patients to start adjunctive mitotane treatment as soon as possible after surgery, at the very last within 3 months. We do not institute mitotane therapy before surgery, as advocated by Dickstein et al. [34]. We prefer a low-dose regimen, because it is better tolerated with less impact on the quality of life of the patients. In some centers, however, mitotane is currently administered at high, rapidly esca- lating doses (up to 6-9g daily) [35°]. This regimen may shorten the time required to reach the therapeutic levels of mitotane, but requires closer follow-up, combining clinical and mitotane level monitoring, and may be more frequently associated with side effects. Low-dose mitotane schedule are listed below (recommendations based on personal experience):
(1) Start with 1 g daily with progressive weekly incre- ments up to 6 g daily, or the maximum tolerated dose.
(2) Give mitotane in divided doses with meals or snacks.
(3) In the event of slight gastrointestinal manifestations, continue mitotane and use symptomatic therapy.
(4) In the event of moderate side effects, return to lower mitotane dose and use symptomatic therapy.
(5) In the event of severe side effects, discontinue mito- tane temporarily and institute specific treatment. After interruption, restart with a lower dose.
(6) Clinical assessment, biochemical and hormonal evaluation, and mitotane level monitoring every 3 months or when significant side effects occur.
(7) Adjust mitotane dose according to circulating levels and tolerability.
(8) In the event of severe side effects, discontinue mito- tane temporarily and institute specific treatment. After interruption, restart with a lower dose.
(9) Aim at serum mitotane concentrations of 14-20 mg/l. When this range is achieved, maintenance dose may be lower.
Management of adjunctive mitotane therapy remains a demanding task that needs experience and a refined clinical judgment to offer the best care to such patients, who may require a number of concomitant medications and a careful tailoring of the schedule of mitotane admin- istration. Supportive therapies to adjuvant mitotane are listed below (recommendations based on Ref. [3 ** ] and personal experience):
(1) Start glucocorticoids concomitantly with mitotane.
(2) High-dose glucocorticoid replacement is required in the long-term (50 mg hydrocortisone or 75 mg corti- sone acetate daily may be needed).
(3) Glucocorticoid replacement is monitored best with careful clinical assessment and measurement of electrolytes, since assessment of steroid hormones and adrenocorticotropic hormone (ACTH) is con- founded by the mitotane-induced increase in corti- sol-binding globulin (CBG) and current steroid supplementation.
(4) Look for clinical and biochemical signs of mineralo- corticoid deficiency in the long-term; give fludrocor- tisone if needed.
(5) Look for clinical and biochemical signs of hypogo- nadism in the long term. The biochemical picture is characterized by low free testosterone and normal total testosterone due to increase in sex-hormone binding globulin (SHBG).
(6) Monitor thyroid function.
(7) Replace thyroxine and/or sex steroids in selected cases.
The optimal duration of therapy remains to be defined. The time to first recurrence after complete tumor resec- tion is highly variable from some months to more than 10 years, but most recurrences occur within 2 years of primary surgery [1,2,3 ** ,7,10]. In our own series, about 70% of relapses took place in the first 2 years of follow-up, whereas the frequency of late (>5 year) relapses was less than 1% [25 ** ]. It is our current practice to accommodate patient preferences between a range of possibilities
(2, 5 or even more years of therapy) in a shared decision-making depending on tumor and patient charac- teristics.
Given the adrenolytic activity of mitotane, all patients treated with the drug should receive concomitant admin- istration of glucocorticoids to prevent adrenal insufficiency. Mineralocorticoid supplementation is not mandatory in all patients. High-dose glucocorticoid replacement is typically required due to an increased metabolic clearance rate of glucocorticoids induced by mitotane [3 ** ,36,37]. Inadequately treated adrenal insufficiency enhances mito- tane-induced side effects and reduces tolerance [15].
Mitotane has complex effects on thyroid and gonadal function that are still not completely understood and whose clinical significance remains uncertain at present. It has been clearly demonstrated that mitotane has a weak estrogen-like action [38°] that may contribute to sexual dysfunction in men. In practice, thyroxin and sex steroid replacement, or both, may become necessary in selected patients on the basis of clinical and laboratory findings [3 ** ,37].
The most common unwanted effects are gastrointestinal manifestations that occur early in the course of treatment and are partially independent from mitotane levels [35°]. These effects can be managed with temporary dose reduction and supportive therapy. Elevated y-glutamyl- transferase levels are very frequently observed whereas clinically significant liver toxicity is uncommon, being characterized by marked increase in transaminases and bilirubin, or both. Neurologic toxicity, usually of central origin, is more closely associated with elevated circulating mitotane concentrations, and may require temporary drug withdrawal in the event of severe manifestations. Nevertheless, well informed and motivated patients are able to cope with side effects without discontinuing permanently mitotane proven that expert care and careful counseling are provided [3 ** ,37].
Conclusion
ACC is a rare disease with a high risk of relapse after radical surgery. In our centers, institution of adjuvant mitotane therapy following complete removal of ACC has become the standard of care, because a large, multicentric study showed that postoperative mitotane treatment may prolong recurrence-free survival. The retrospective nature of the study, however, warrants caution in the interpretation of the results. A better understanding of factors determining prognosis and response to treatment will help stratifying patients according to their risk of relapse, with the aim to identify subgroups of patient for whom the benefits of adjunctive therapies (mitotane and local radiotherapy, or both) are maximal.
It is crucial to establish prospective studies to confirm that adjuvant mitotane treatment may become the stan- dard of care after complete resection of ACC. Such projects should be implemented on an international basis to be successful, taking advantage from the existence of a number of collaborative networks that have been estab- lished in recent years [European Network for the Study of Adrenal Tumors (ENS@T) and Collaborative Group for Adrenocortical Carcinoma Therapy (COACT)].
Acknowledgements
The present work was partially supported by the Italian Ministry of University and Scientific Research and by the University of Turin.
Dr Terzolo reports being an investigator in a clinical trial sponsored by HRA Pharma. There is no conflict of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
· of special interest
·· of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 284).
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