Mitotane Monotherapy in Patients With Advanced Adrenocortical Carcinoma
Felix Megerle,1 Wiebke Herrmann,1 Wiebke Schloetelburg,2 Cristina L. Ronchi,1,3 Alina Pulzer,1 Marcus Quinkler,4 Felix Beuschlein,5,6 Stefanie Hahner,1 Matthias Kroiss,7 and Martin Fassnacht,1,7 for the German ACC Study Group
1Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg, University of Würzburg, 97080 Würzburg, Germany; 2Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, University of Würzburg, 97080 Würzburg, Germany; 3Institute of Metabolism and System Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; 4Endocrinology in Charlottenburg, 10627 Berlin, Germany; 5Department of Internal Medicine IV, Klinikum der Universität München, 80336 Munich, Germany; 6Department of Endocrinology, Diabetology and Clinical Nutrition, Universitätsspital Zürich, 8091 Zurich, Switzerland; and 7Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg, Germany
Context: Although mitotane is the only approved drug for the treatment of adrenocortical car- cinoma (ACC), data on monotherapy in advanced disease are still scarce.
Objective: To assess the efficacy of mitotane in advanced ACC in a contemporary setting and to identify predictive factors.
Design and Setting: Multicenter cohort study of three German referral centers.
Patients: One hundred twenty-seven patients with advanced ACC treated with mitotane monotherapy.
Outcome Measures: Response Evaluation Criteria in Solid Tumors evaluation, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method, and predictive factors by Cox regression.
Results: Twenty-six patients (20.5%) experienced objective response, including three with complete remission. Overall, median PFS was 4.1 months (range 1.0 to 73) and median OS 18.5 months (range 1.3 to 220). Multivariate analysis indicated two main predictive factors: low tumor burden (<10 tumoral lesions), hazard ratio (HR) for progression of 0.51 (P = 0.002) and for death of 0.59 (P= 0.017); and initiation of mitotane at delayed advanced recurrence, HR 0.35(P < 0.001) and 0.34 (P < 0.001), respectively. Accordingly, 67% of patients with low tumor burden and mitotane initiation ≥360 days after primary diagnosis experienced a clinical benefit (stable disease >180 days). Patients who achieved mitotane levels > 14 mg/L had significantly longer OS (HR 0.42; P = 0.003).
Conclusions: At 20.5% the objective response rate was slightly lower than previously reported. However, >20% of patients experienced long-term disease control at >1 year. In general, patients with late diagnosis of advanced disease and low tumor burden might especially benefit from mitotane monotherapy, whereas patients with early advanced disease and high tumor burden are probably better candidates for combined therapy of mitotane and cytotoxic drugs. (J Clin Endocrinol Metab 103: 1686-1695, 2018)
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright @ 2018 Endocrine Society
Received 29 November 2017. Accepted 9 February 2018.
First Published Online 14 February 2018
Abbreviations: ACC, adrenocortical carcinoma; CI, confidence interval; CR, complete response; HR, hazard ratio; OS, overall survival; PD, progressive disease; PFS, progression- free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
A drenocortical carcinoma (ACC) is a rare and ag- gressive disease with dismal prognosis and limited therapeutic options in advanced tumor stages (1, 2). Mitotane is the only drug approved for treatment of ACC and has been in clinical use both in an adjuvant and palliative setting for many years (3-5). However, data on the benefit of mitotane treatment are limited.
Although the approval of mitotane in most countries is restricted to ACC not amenable to complete re- section, data on mitotane monotherapy in advanced ACC are scarce (2). In fact, only 11 series with >10 patients have reported a total number of 395 patients treated with mitotane monotherapy in advanced dis- ease. Of these studies [three prospective (6-8), eight retrospective (3, 9-15)] the largest series included just 67 patients in a retrospective evaluation. The overall response rate reported is only ~25%. Therefore, re- sponse prediction factors would help clinicians choose the right treatment for each patient. Furthermore, the relevance of these studies for contemporary medicine is likely to be limited because most studies were per- formed in or even before the 1990s. Accordingly, in the majority of studies tumor response assessment was heterogeneous, and criteria are mostly not comparable with Response Evaluation Criteria in Solid Tumors (RECIST), which are now the standard of care and major endpoint in cancer trials. Of note, according to the labeling of mitotane in several countries (e.g., in the European Union) the effects of mitotane in non- functioning tumors has not been established. How- ever, data supporting or disproving this statement are lacking. Although interest in mitotane as a sole first- line therapy in advanced ACC has increased recently, the lack of convincing data on monotherapy has un- settled clinicians. One reason for this “revival” of mitotane monotherapy comes indirectly from the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment. The results of this trial suggested that the most effective therapy, the combination of etoposide, doxorubicin, cisplatin, and mitotane, is as effective as second-line therapy as it is as first-line therapy (16). Therefore, it seems justified to test other drugs (e.g., mitotane) first.
Despite efforts by several groups, the mechanisms of action of mitotane have not been clarified. Although we recently demonstrated that mitotane induces endo- plasmic reticulum stress specifically in adrenocortical carcinoma cell lines and identified inhibition of sterol O-acyltransferase 1 as a key molecular event (17), other mechanisms are likely to be relevant and may overlap, given the high mitotane concentrations needed for effi- cacy. In addition, pharmacokinetic properties including
basic aspects such as intestinal resorption and metabolic transformation have been only partially elucidated.
Several small studies have suggested the importance of drug monitoring in the use of mitotane. First, in 1984 van Slooten et al. (14) measured mitotane blood levels in 34 patients and found a relationship to the response rate. This concept was then confirmed in a larger retrospective series (n = 58) (11) and a small prospective study (n = 13) (8). Since that time most authors have recommended aiming at plasma mitotane levels between 14 and 20 mg/L to increase the response rate and limit toxicity (1, 2).
In the current large cohort study we analyzed 127 patients with advanced ACC treated at three German centers with the aim of providing efficacy data on mitotane monotherapy based on contemporary imaging methods and identifying predictive factors for treatment response to mitotane.
Subjects and Methods
Study population
Patients and clinical and histological parameters [sex; age at diagnosis; tumor size; evidence of hormone excess; tumor stage according to the European Network for the Study of Adrenal Tumors classification (18); date of documented unresectability; Weiss score; Ki67 index; presence, site, size, and number of tumor lesions; mitotane plasma concentration; and follow-up information) were retrieved from the German ACC Registry and the European Network for the Study of Adrenal Tumors Registry (www.ensat.org/registry). Both registries have been approved by the ethics committee of the University of Würzburg (approval numbers 86/03 and 88/11). The study is part of the German Adrenocortical Carcinoma Study group. Written in- formed consent was obtained from all patients. We included patients from three German centers (Würzburg, Berlin, and Munich) who fulfilled the following eligibility criteria: age ≥18 years, histologically confirmed ACC, advanced (i.e., not completely resectable) disease at initial diagnosis or during the course of the disease, mitotane monotherapy for ≥30 days, and cross-sectional imaging (abdominal and thoracic computed to- mography scans, magnetic resonance imaging, or fluorodeoxy- glucose positron emission tomography/computed tomography) before the start of mitotane therapy (≤30 days) and regularly during mitotane treatment (at least every 4 months in the first year; median 93 days). To ensure the use of contemporary imaging methods and sufficient follow-up, inclusion was restricted to patients with a start of mitotane treatment between 01 January 1997 and 31 December 2016. Exclusion criteria were incomplete information on primary diagnosis or follow-up, concomitant therapies such as radiotherapy or cytotoxic che- motherapy, and previous therapy with mitotane.
Mitotane dosage and drug monitoring
Mitotane was given as tablets (Lysodren, Bristol Myers Squibb, Princeton, NJ, before 2004, then HRA Pharma, Paris, France). Before 2005, the drug was administered at dosages usually ≤3.5 g/d (19). After 2005, in most cases a high-dose starting schedule (20, 21) was used, with a median maximal dosage
| Parameter or Subgroup | |
| Entire cohort | 127 |
| Age at start of mitotane | |
| Median, y | 58.6 |
| Range, y | 19.8-85.8 |
| ≤58 y, n (%) | 63 (49.6%) |
| >58 y, n (%) | 64 (50.4%) |
| Sex, n (%) | |
| Female | 77 (60.6%) |
| Male | 50 (39.4%) |
| Body mass index, kg/m2 (n = 99) | |
| Median | 25.1 |
| Range | 17.2-42.9 |
| Endocrine activity of the primary tumor, n (%) | |
| Cortisol (+ others) | 49 (38.6%) |
| Pure sex hormones and precursors | 9 (7.1%) |
| Pure aldosterone | 2 (1.6%) |
| No hypersecretion | 20 (15.7%) |
| Not determined | 47 (37%) |
| Predefined subgroup: endocrine activity, n (%) (n = 80) | |
| Hypersecretion of cortisol | 49 (61.2%) |
| No hypersecretion of cortisol | 31 (38.8%) |
| Ki67 index, % (n = 90) | |
| Median | 10 |
| Range | 1-70 |
| Ki67 index subgroups (n = 90) | |
| ≤10% | 46 (51.1%) |
| 10.1%-20% | 22 (24.4%) |
| >20% | 22 (24.4%) |
| Number of tumoral lesions at mitotane initiation | |
| ≤2 | 28 (22.0%) |
| 3 or 4 | 23 (18.1%) |
| 5-9 | 21 (16.5%) |
| ≥10 | 55 (43.3%) |
| Sum of diameter of all tumoral lesions at start of mitotane, n (%) (n = 124) | |
| ≤3 cm | 19 (15.3%) |
| 3.1 to <10 cm | 46 (37.1%) |
| ≥10 cm | 59 (47.6%) |
| Affected organs, n | |
| Lung only | 30 |
| Liver only | 10 |
| Local recurrence only | 8 |
| Others | 14 |
| Tumoral lesions at multiple locations | 65 |
| Timing of mitotane initiation, n (%) | |
| At initial diagnosis (with advanced disease) | 49 (38.6%) |
| At early advanced recurrence (<360 d since initial diagnosis) | 22 (17.3%) |
| At delayed advanced recurrence (360-999 | 33 (26%) |
| d since initial diagnosis) | |
| At delayed advanced recurrence (≥1000 d since initial diagnosis) | 23 (18.1%) |
| Peak mitotane blood level during mitotane monotherapy, mg/L (n = 96) | |
| Median | 19.6 |
| Range | 2.5-66.4 |
| Peak mitotane blood level, n (%) (n = 96) | |
| <10 mg/L | 13 (13.5%) |
| 10-13.9 mg/L | 14 (14.6%) |
| 14-20 mg/L | 33 (34.3%) |
| >20 mg/L | 36 (37.5%) |
| (Continued) | |
| Parameter or Subgroup | |
| Peak mitotane blood level after 3 mo of therapy, mg/L (n = 74) | |
| Median | 13.05 |
| Range | 2.46-66.40 |
| Peak mitotane blood level after 3 mo of therapy, n (%) (n = 74) <10 mg/L | 24 (32.4%) |
| 10-13.9 mg/L | 13 (17.6%) |
| 14-20 mg/L | 22 (29.7%) |
| >20 mg/L | 15 (20.2%) |
Mitotane blood levels in a total of 489 blood samples were measured (median 4 blood samples per patient, range 1 to 12).
of 7.5 g/d. Starting in 2005, mitotane plasma levels were measured centrally by the Lysosafe service (www.lysosafe.com). Before this service was available mitotane was analyzed in three different German laboratories that offered blood concentration assess- ment of mitotane. However, only 19 of our 127 patients started mitotane before 2005.
Response assessment
Treatment response was recorded according to routine ra- diologic assessment and qualified as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD), in analogy to the RECIST 1.1 (22). In uncertain cases (n = 12), we applied RECIST 1.1 via a blinded review of all images by a radiologist (W.S.).
Statistical analysis
Progression-free survival (PFS) was defined as the interval between the start of mitotane therapy and first documentation of PD during follow-up or censored at last follow-up. Overall survival (OS) was calculated as the time between the start of mitotane therapy and death, with censoring at last follow-up otherwise. PFS and OS were evaluated by the Kaplan-Meier method. We defined meaningful clinical benefit as disease control of >180 days, because in a recent placebo-controlled trial none of the patients without active treatment experienced disease stabilization for >150 days (23). The following po- tential prognostic and predictive factors were defined before the analysis: age (dichotomized at the median), sex, endocrine ac- tivity, Ki67 index of the primary tumor, tumor burden, pattern of affected organs at the start of mitotane therapy, peak mitotane blood concentration during monotherapy or within the first 3 months of treatment, and timing of mitotane initi- ation. In this context patients were classified according to whether mitotane treatment was initiated for advanced disease at the time of initial diagnosis or at recurrence during follow-up. In the latter case (treatment of recurrent advanced disease) we differentiated patients according to the time between primary diagnosis and start of mitotane (<360 days, 360 to 999 days, or ≥1000 days). All factors were investigated by univariate analysis via Cox regression. In case of P < 0.1 in univariate analysis, multivariate analyses were performed. Tumor burden was assessed in the multivariate analysis only as the sum of tumoral lesions. The association between variables and PFS or OS was expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). Statistical significance was set at P < 0.05. To
calculate possible differences in response rate dependent on mitotane blood levels, we used the Fisher exact test. Results are presented as median and range unless stated otherwise. For statistical calculations, SPSS 24.0 (IBM Corp., Armonk, NY) was used.
Results
At the time of analysis (March 2017) 127 patients (77 female, 50 male) were included. Forty-nine patients (38.6%) had advanced ACC at initial diagnosis and started mitotane therapy within 3 weeks after establishment of the di- agnosis. Seventy-eight patients (61.4%) started mitotane after experiencing re- currence with unresectable disease during follow-up. Median age was 58.6 years, with a range of 19.8 to 85.8 years. Other baseline characteristics are given in Table 1.
Best objective response, PFS, and OS
Best response was CR in three pa- tients (2.4%), PR in 23 (18.1%), and SD in 32 patients (25.2%). Of the patients with SD, disease was controlled in 23 of them for ≥180 days. A total of 69 pa- tients (54.3%) had PD at the time of first tumor evaluation. PFS was 4.1 months (range 1 to 73 months), and OS was 18.5 months (1.3 to 220 months) after initiation of mitotane (Fig. 1). Overall, 50 patients (40.9%) experienced clinical benefit (disease control >180 days), in- cluding 28 (22.0%) with a long-term benefit of >12 months.
Predictive factors of PFS and OS
To identify possible predictive factors, univariate and multivariate analyses (adjusted by age, sex, tumor bur- den, and timing of mitotane initiation) were performed. Results are given in Table 2 and Fig. 2. In short, uni- variate analyses showed better prognosis regarding PFS and OS for patients with Ki67 index <10%, mitotane initiation at delayed advanced recurrence (≥360 days after initial diagnosis), and low tumor burden, repre- sented by <10 tumoral lesions. Multivariate analyses indicated a better outcome only for low tumor burden (PFS HR 0.51, P = 0.002; 95% CI, 0.33 to 0.79; OS HR 0.59, P = 0.0017, 95% CI, 0.39 to 0.91) and timing of mitotane initiation at delayed advanced recurrence (PFS HR 0.35, P < 0.001; 95% CI, 0.23 to 0.55; OS HR 0.34,
A
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P < 0.001; 95% CI, 0.22 to 0.52). For detailed analysis including subgroups, see Table 2.
Influence of mitotane drug levels on efficacy
Patients who reached mitotane blood levels ≥14 mg/L had superior PFS and OS as compared with patients in whom this blood concentration was not achieved (Table 3). Because the association with response might be confounded by the long time interval needed to reach an effective plasma concentration, we performed a subgroup analysis in which only mitotane levels in the first 3 months were considered. Here, the effect was statisti- cally not significant. Remarkably, the 15 patients who reached a level >20 mg/L within these first 3 months had a median PFS of 277 days (Table 3). The objective response rate in patients with mitotane levels ≥14 mg/L was also significantly higher compared with <14 mg/L
| Prognostic Factors for PFS | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| n | Median PFS, d | Range | Univariate Analysis | Multivariate Analysis | |||||
| HR | 95% CI | P | HR | 95% CI | P | ||||
| Sex | 127 | ||||||||
| Female | 77 | 109 | 28-1518 | 1 | 1 | ||||
| Male | 50 | 181 | 34-2196 | 0.69 | 0.46-1.03 | 0.07 | 0.85 | 0.56-1.29 | 0.45 |
| Age at start of mitotane, y | 127 | ||||||||
| ≤58 | 63 | 117 | 28-1518 | 1.09 | 0.74-1.61 | 0.65 | |||
| >58 | 64 | 165 | 32-2196 | 1 | |||||
| Endocrine activity | 80 | ||||||||
| Cortisol-producing | 49 | 102 | 28-1518 | 1 | |||||
| Not cortisol-producing | 31 | 122 | 33-964 | 1.07 | 0.66-1.72 | 0.79 | |||
| Ki67 index | 90 | ||||||||
| ≤10% | 46 | 197 | 46-948 | 0.63 | 0.36-1.1 | 0.10 | 0.80 | 0.43-1.5 | 0.50 |
| 10.1%-20% | 22 | 90 | 28-2196 | 1.06 | 0.54-2.06 | 0.86 | 1.07 | 0.52-2.2 | 0.85 |
| >20% | 22 | 92 | 33-644 | 1 | 1 | ||||
| Number of tumoral lesions | 127 | ||||||||
| ≤2 | 28 | 171 | 35-1079 | 0.57 | 0.35-0.94 | 0.027 | 0.53 | 0.31-0.92 | 0.023 |
| 3 or 4 | 23 | 139 | 35-746 | 0.52 | 0.29-0.92 | 0.026 | 0.48 | 0.26-0.91 | 0.025 |
| 5-9 | 21 | 185 | 52-2196 | 0.56 | 0.32-0.98 | 0.042 | 0.50 | 0.28-0.91 | 0.023 |
| ≥10 | 55 | 83 | 28-1518 | 1 | 1 | ||||
| Timing of mitotane initiation | 127 | ||||||||
| At initial diagnosis | 49 | 92 | 28-644 | 1 | 1 | ||||
| At early advanced recurrence | 22 | 99 | 52-1079 | 0.56 | 0.32-0.98 | 0.041 | 0.65 | 0.35-1.2 | 0.17 |
| (<360 d since initial diagnosis) | |||||||||
| At delayed advanced recurrence | 33 | 232 | 32-1518 | 0.40 | 0.24-0.66 | <0.001 | 0.33 | 0.19-0.56 | <0.001 |
| (360-999 d since initial diagnosis) | |||||||||
| At delayed advanced recurrence | 23 | 269 | 49-2196 | 0.26 | 0.14-0.48 | <0.001 | 0.27 | 0.14-0.50 | <0.001 |
| (≥1000 d since initial diagnosis) | |||||||||
| Prognostic Factors for OS | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| n | Median OS, d | Range | Univariate Analysis | Multivariate Analysis | |||||
| HR | 95% CI | P | HR | 95% CI | P | ||||
| Sex | 127 | ||||||||
| Female | 77 | 553 | 39-6611 | 1 | |||||
| Male | 50 | 556 | 70-3848 | 0.78 | 0.52-1.18 | 0.24 | |||
| Age at start of mitotane, y | 127 | ||||||||
| ≤58 | 63 | 621 | 39-6611 | 0.88 | 0.60-1.31 | 0.55 | |||
| >58 | 64 | 511 | 40-4033 | 1 | |||||
| Endocrine activity | 80 | ||||||||
| Cortisol-producing | 49 | 555 | 39-3603 | 1 | |||||
| Not cortisol-producing | 31 | 531 | 40-6611 | 0.94 | 0.56-1.57 | 0.82 | |||
| Ki67 index | 90 | ||||||||
| ≤10% | 46 | 754 | 72-4033 | 0.36 | 0.20-0.67 | 0.001 | 0.52 | 0.25-1.08 | 0.08 |
| 10.1%-20% | 22 | 512 | 70-2572 | 0.75 | 0.40-1.42 | 0.38 | 0.77 | 0.37-1.57 | 0.47 |
| >20% | 22 | 374 | 39-2432 | 1 | 1 | ||||
| Number of tumoral lesions | 127 | ||||||||
| ≤2 | 28 | 790 | 81-4033 | 0.63 | 0.38-1.06 | 0.08 | 0.55 | 0.32-0.96 | 0.035 |
| 3 or 4 | 23 | 711 | 64-3820 | 0.65 | 0.38-1.13 | 0.13 | 0.55 | 0.31-0.99 | 0.047 |
| 5-9 | 21 | 553 | 251-2660 | 0.78 | 0.44-1.38 | 0.39 | 0.70 | 0.39-1.29 | 0.26 |
| ≥10 | 55 | 433 | 39-6611 | 1 | 1 | ||||
| Timing of mitotane initiation | 127 | ||||||||
| At initial diagnosis | 49 | 389 | 39-3848 | 1 | 1 | ||||
| At early advanced recurrence | 22 | 415 | 64-3820 | 0.69 | 0.40-1.2 | 0.18 | 0.78 | 0.44-1.38 | 0.39 |
| (<360 d since initial diagnosis) | |||||||||
| At delayed advanced recurrence | 33 | 874 | 59-6611 | 0.38 | 0.23-0.63 | <0.001 | 0.33 | 0.2-0.57 | <0.001 |
| (360-999 d since initial diagnosis) | |||||||||
| At delayed advanced recurrence | 23 | 863 | 72-4033 | 0.31 | 0.17-0.56 | <0.001 | 0.27 | 0.14-0.51 | <0.001 |
| (≥1000 d since initial diagnosis) | |||||||||
Only possible prognostic factors that showed at least a trend (P ≤0.10) in univariate analysis were further investigated by multivariate analysis (adjusted by age, sex, tumor burden, and timing of mitotane initiation). Subgroups with <127 patients in total were analyzed separately (adjusted by age, sex, tumor burden, and timing of mitotane initiation).
A
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- “Mitotane initiation at delayed advanced recurrence 360-1000 d
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.5 - 9 tumoral lesions
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≤ 2 tumoral lesions
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(31.9% vs 11.1%; P = 0.041). However, there were two patients with partial and one patient with CR whose peak levels were never >13 mg/L, including one patient with PR and a maximum documented level <10 mg/L.
Response rates in different subgroups
In the next step we checked response rates to mitotane monotherapy in subgroups defined by potential predictive factors suggested by the current study or previous studies (9, 24-26). We found objective response rates (PR, CR) were highest (30%) in patients with both low tumor burden and mitotane initiation at delayed advanced recurrence (≥360 days after initial diagnosis) (Table 4). In contrast no objective response was seen in patients with both high
tumor burden and mitotane initiation at initial diagnosis or early recurrence (<360 days after primary diagnosis). Furthermore, in this subgroup only 6.3% experienced a clinical benefit (>180 days), whereas such a benefit was present in more than 67% of patients in the complementary group (Table 4). Additionally, in 54% patients with low Ki67 index (≤10%) long-term disease control was achieved in comparison with only 24% with Ki67 >20%.
Discussion
Although mitotane is the only approved drug for the treatment of patients with ACC, reliable data on mitotane monotherapy are surprisingly scarce. Here, we present the
| Influence of Mitotane Blood Level on PFS | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| n | Median PFS, d | Range | Univariate Analysis | Multivariate Analysis | |||||
| HR | 95% CI | P | HR | 95% CI | P | ||||
| Peak mitotane blood level, mg/L | 96 | ||||||||
| <10 | 13 | 77 | 34-667 | 1 | 1 | ||||
| 10-13.9 | 14 | 146 | 32-509 | 0.73 | 0.32-1.66 | 0.46 | 0.71 | 0.29-1.74 | 0.45 |
| 14-20 | 33 | 208 | 39-2196 | 0.40 | 0.19-0.83 | <0.05 | 0.55 | 0.24-1.27 | 0.16 |
| >20 | 36 | 181 | 28-1518 | 0.42 | 0.20-0.85 | <0.05 | 0.49 | 0.22-1.2 | 0.09 |
| Peak mitotane blood level within | 74 | ||||||||
| 3 mo, mg/L | |||||||||
| <10 | 24 | 125 | 32-1079 | 1 | |||||
| 10-13.9 | 13 | 179 | 38-644 | 0.82 | 0.37-1.81 | 0.62 | |||
| 14-20 | 22 | 144 | 39-2196 | 0.85 | 0.45-1.64 | 0.64 | |||
| >20 | 15 | 277 | 52-1518 | 0.64 | 0.31-1.34 | 0.23 | |||
| Influence of Mitotane Blood Level on OS | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| n | Median OS, d | Range | Univariate Analysis | Multivariate Analysis | |||||
| HR | 95% CI | P | HR | 95% CI | P | ||||
| Peak mitotane blood level, mg/L | 96 | ||||||||
| <10 | 13 | 262 | 70-1599 | 1 | 1 | ||||
| 10-13.9 | 14 | 502 | 46-2577 | 0.60 | 0.28-1.30 | 0.2 | 0.35 | 0.15-0.83 | 0.017 |
| 14-20 | 33 | 814 | 106-3820 | 0.29 | 0.14-0.58 | 0.001 | 0.26 | 0.12-0.59 | 0.001 |
| >20 | 36 | 770 | 84-6611 | 0.25 | 0.12-0.51 | <0.001 | 0.18 | 0.08-0.42 | <0.001 |
| Peak mitotane blood level within | 74 | ||||||||
| 3 mo, mg/L | |||||||||
| <10 | 24 | 685 | 70-2660 | 1 | |||||
| 10-13.9 | 13 | 535 | 46-1803 | 1.52 | 0.67-3.44 | 0.31 | |||
| 14-20 | 22 | 857 | 90-2422 | 0.83 | 0.41-1.67 | 0.60 | |||
| >20 | 15 | 679 | 84-6611 | 0.62 | 0.28-1.38 | 0.24 | |||
Only possible prognostic factors that showed at least a trend (P ≤0.10) in univariate analysis were further investigated by multivariate analysis (adjusted by age, sex, tumor burden, and timing of mitotane initiation).
largest study analyzing the effects of mitotane mono- therapy in 127 patients with advanced disease. We dem- onstrate that mitotane leads to an objective response rate of 21% (including three patients with CR). Furthermore, an additional 25% of patients experienced SD, translating to a median PFS of 4.1 months and OS of 18.5 months.
Although a median PFS of 4 months is not impressive, it compares favorably with those of other drugs investigated for ACC [23, 27-30; for review see (2)]. However, without a doubt these trials are not readily comparable (e.g., because of different imaging intervals). Nevertheless, this study clearly shows that mitotane can induce objective response in a percentage of patients and can control ad- vanced disease in a subgroup for a long time.
A key result of our study is the observation that pa- tients who started mitotane after late recurrence did much better than those who had advanced disease at the time of initial diagnosis. Patients with late recurrence have a better prognosis because these tumors are usually less aggressive (31). However, this fact does not necessarily explain the higher objective response rate in this cohort (Table 4). High tumor burden, described in terms of
maximal tumor diameter or number of tumoral lesions or organs, is associated with poor prognosis in literature (2, 32). Here, we confirm that tumor load is an important prognostic factor. Of note, our data seem to suggest that low tumor burden is also a predictive factor for response to mitotane treatment, because 71% of patients with <10 tumoral lesions experienced disease control for >6 months, whereas this was the case in only 18% of patients with higher tumor load.
Patients with a Ki67 index ≤10% had a longer OS than patients with a Ki67 index ≥20%. These results are in line with previous studies that described Ki67 as an important prognostic marker in ACC, which appears to have less discriminative value in advanced disease (33). Tumors with low Ki67 seem to respond slightly better than tumors with high proliferative activity. However, Ki67 staining of the primary tumor is most probably not the ideal way to judge the clinical behavior of a tumor that recurred in almost half of the patients >1 year after the initial surgery.
Mitotane therapy and mitotane blood levels have been shown to be correlated with objective response rate and
| CR | PR | CR + PR | SD | Benefit >180 d | PD | |
|---|---|---|---|---|---|---|
| Timing of mitotane initiation | ||||||
| At initial diagnosis or at early recurrence | 0 | 7 (9.9%) | 7 (9.9%) | 17 (24%) | 16 (22.5%) | 47 (66.2%) |
| (<360 d since initial diagnosis) | ||||||
| At delayed advanced recurrence | 3 (5.3%) | 16 (28.6%) | 19 (33%) | 15 (26.7%) | 34 (60.7%) | 22 (39.3%) |
| (≥360 d since initial diagnosis) | ||||||
| Number of tumoral lesions | ||||||
| <10 | 2 (2.7%) | 6 (8.3%) | 8 (15.7%) | 22 (30.5%) | 36 (70.6%) | 21 (41.2%) |
| ≥10 | 1 (1.8%) | 17 (30.9%) | 18 (23.7%) | 10 (18.1%) | 14 (18.4%) | 48 (63.2%) |
| Ki67 (n = 90) | ||||||
| ≤10% | 1 (2.2%) | 11 (23.9%) | 12 (26%) | 15 (32.6%) | 25 (54.3%) | 19 (41.3%) |
| 10.1%-20% | 0 | 4 (18.1%) | 4 (18.1%) | 4 (18.1%) | 2 (8.7%) | 15 (65.2%) |
| >20% | 0 | 3 (13.6%) | 3 (13.6%) | 3 (13.6%) | 5 (23.8%) | 15 (71.4%) |
| Endocrine activity (cortisol, n = 80) | ||||||
| Yes | 1 (2%) | 8 (16.3%) | 9 (18.4%) | 6 (12.2%) | 16 (32.6%) | 16 (51.6%) |
| No | 0 | 10 (32.2%) | 10 (32.2%) | 10 (32.2%) | 13 (41.9%) | 29 (59.0%) |
| Cohort who fulfilled the following criteria | ||||||
| At initial diagnosis or at early recurrence | 0 | 0 | 0 | 3 (9.3%) | 2 (6.3%) | 29 (90.6%) |
| (<360 d since initial diagnosis) + ≥10 tumoral lesions (n = 32) | ||||||
| At delayed advanced recurrence (≥360 d since initial diagnosis) + <10 tumoral lesions (n = 33) | 2 (6%) | 8 (24.2%) | 10 (30.3%) | 11 (33.3%) | 22 (66.7%) | 12 (36.4%) |
Benefit is defined as SD, PR, or CR for >180 days.
PFS or OS in patients with advanced or recurrent ACC (8, 9, 11, 34). In our study a trend toward longer PFS with higher peak mitotane blood levels during therapy could be seen in multivariate analysis. Regarding OS, results show a significant correlation between higher mitotane levels and longer survival. However, the so-called im- mortal time bias may partially explain this finding, meaning that higher mitotane levels correlate with treatment duration, and this certainly comes with longer survival. If we used only the mitotane measurements in the first 3 months of therapy, there was no significant correlation with PFS or OS. However, the number of patients in this subanalysis might have been too small to allow strong conclusions. Furthermore, the initial dosage of mitotane might influence the time interval to reach relevant plasma levels, although an earlier analysis sug- gested no significant difference between two starting regimens in the first 12 weeks (21). Therefore, additional studies on mitotane blood levels in the first weeks after initiation are warranted to investigate its value as pre- dictive marker for outcome. Interestingly, we have seen objective response in three patients who never reached the “therapeutic concentration” of 14 mg/L. Thus, a level ≥14 mg/L seems desirable, but lower levels do not preclude clinical benefit.
Several studies have shown worse prognosis for cortisol-producing tumors (26, 35, 36). In our cohort we could not show any difference in PFS and OS between patients with and without cortisol-producing ACC. This limitation might reflect the small number of patients
(n = 80) for whom we had sufficient information about the endocrine function of their ACC. Furthermore, only 34 patients had overt Cushing syndrome, and only 5 had to be treated with steroidogenesis inhibitors, suggesting that only a minority of the cohort had severe hyper- cortisolism not controlled by mitotane. However, our study provides important additional information for the official labeling of mitotane in several countries (e.g., in the European Union), where it is mentioned that the effects of mitotane in nonfunctioning tumors have not been established. Our study clearly suggests that mitotane is effective independent of the endocrine activity of the tumor. Therefore, as is already clinical practice in most expert centers, we recommend administering mitotane in both functioning and nonfunctioning tumors.
Our study has obvious limitations. Its retrospective design and the lack of a control group hinder a proper separation of the effects of mitotane from other known and unknown prognostic factors in ACC. However, a placebo-controlled trial might be unethical because it is well known that almost all ACCs progress rapidly if left untreated, as prospectively demonstrated in the placebo- controlled phase III trial with linsitinib (23). Furthermore, patients in our cohort probably are not representative of the entire group of patients with advanced ACC because patients with aggressive tumors might be selected for the immediate start of adjunctive cytotoxic chemotherapy. Another weakness is the small number of cases, which precluded detailed subgroup analyses. On the other hand, 127 patients can be considered a large number in
comparison with earlier reports. A cohort of >500 probably would be needed to allow better statistical power, and such a cohort size is unlikely to be achievable. Thus, these results probably are the most reliable for the time being. The long study period and the modification of mitotane management in 2005 might have influenced the results. However, the fact that only 19 patients were recruited before 2005 suggests that the overall influence of this modification is limited. Finally, we did not report adverse events. However, it is well established that reli- able data on adverse events require prospective data collection, and to avoid underreporting we preferred not to elaborate on this issue.
Conclusions
This study on mitotane monotherapy demonstrated that this drug is able to achieve clinical benefit for patients with advanced ACC. Although the objective response rate was slightly lower than reported previously, the fact that a fifth of the cohort had clear tumor shrinkage proves the efficacy of the drug. This finding is further sub- stantiated by the 20% of patients who experienced long- term disease control for >1 year. Our study suggests that patients with less aggressive tumors (e.g., low-grade tu- mors with low tumor burden and a long interval between initial diagnosis and the need to start systemic therapy) might be especially good candidates for mitotane mon- otherapy. In contrast, patients with advanced disease at primary diagnosis and high tumor loads probably benefit more from early administration of cytotoxic drugs.
Acknowledgments
This study was made possible by the ACC database of the Eu- ropean Network for the Study of Adrenal Tumors. We are thankful for continuous help in data documentation from Michaela Haaf and Martina Zink. Furthermore, we are grateful for the statistical advice from Olaf Dekkers (Leiden, The Netherlands).
Financial Support: This study was supported by the Ger- man Research Foundation (Deutsche Forschungsgemeinschaft) via an individual grant to M.F. and M.K. (FA 466/4-1, FA 466/4-2, KR 4371/1-1, KR 4371/1-2) and within CRC/Transregio 205/1, “The Adrenal: Central Relay in Health and Disease,” to M.K., F.B., S.H., and M.F. Furthermore, this study was supported by an unrestricted grant by Millendo Therapeutics, Inc. (Ann Arbor, MI) to S.H.
Clinical Trial Information: ClinicalTrials.gov no. NCT00453674 (registered January 2003).
Author Contributions: F.M. contributed to the data col- lection, performed the statistical analyses, and wrote the first draft of the manuscript. W.H. contributed to the data collection and performed the statistical analyses. W.S. reevaluated the radiological images. C.L.R., A.P., M.Q., F.B., S.H., and M.K.
contributed to the data collection and data interpretation. M.F. conceived the design of the study, contributed to the data collection and interpretation, and supervised the entire study. All authors edited the manuscript and approved the final version and its submission.
Correspondence and Reprint Requests: Martin Fassnacht, MD, University Hospital of Würzburg, Department of Inter- nal Medicine I, Division of Endocrinology and Diabetes, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany. E-mail: fassnacht_m@ukw.de.
Disclosure Summary: The authors have nothing to disclose.
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