Plasma Concentrations of o,p’DDD, o,p’DDA, and o,p’DDE as Predictors of Tumor Response to Mitotane in Adrenocortical Carcinoma: Results of a Retrospective ENS@T Multicenter Study
Ilse G. Hermsen, Martin Fassnacht, Massimo Terzolo, Saskia Houterman, Jan den Hartigh, Sophie Leboulleux, Fulvia Daffara, Alfredo Berruti, Rita Chadarevian, Martin Schlumberger, Bruno Allolio, Harm R. Haak, and Eric Baudin
Department of Internal Medicine (I.G.H., H.R.H.) and MMC Academy (S.H.), Máxima Medical Centre, 5600 PD Eindhoven/Veldhoven, The Netherlands; Department of Internal Medicine (M.F., B.A.), University of Würzburg, 97070 Würzburg, Germany; Department of Clinical and Biological Sciences (M.T., F.D., A.B.), University of Turin, 10126 Turin, Italy; Department of Clinical Pharmacy and Toxicology (J.d.H.), University Medical Centre Leiden, 2300 RC Leiden, The Netherlands; Department of Nuclear Medicine and Endocrine Oncology (S.L., M.S., E.B.), Institute Gustave-Roussy, University Paris-Sud 11, 94805 Villejuif, France; and HRA-Pharma Paris (R.C.), 75003 Paris, France
Context: In patients with adrenocortical carcinoma (ACC) mitotane activity has been suggested to depend on plasma levels 14mg/liter or greater and metabolite formation.
Objective: The study was performed to confirm the correlation of the currently used mitotane (o,p’DDD) threshold of 14 mg/liter with tumor response and to evaluate the additional value of 1,1-(o,p’-dichlorodiphenyl) acetic acid (o,p’DDA) and o,p’DDE (1,1-(o,p’-dichlorodiphenyl)-2,2 di- chloroethene) levels for predicting tumor response.
Subjects/Methods: Plasma samples collected within 3 months of best response from 91 patients on mitotane therapy for advanced ACC were analyzed retrospectively. O,p’DDD and metabolites were assessed and related to tumor response and survival. Receiver operating characteristic curves were used. Sensitivity and specificity were calculated for different cutoff levels of o,p’DDD and metabolites.
Results: Objective tumor response was observed in 19% of patients. Median o,p’DDD level was higher in responders (P = 0.03). More responders were found among patients achieving o,p’DDD levels 14 mg/liter or greater (P = 0.02). Univariate and multivariate analysis showed significantly longer survival for patients with o,p’DDD levels 14 mg/liter or greater (hazard ratio 0.52, P = 0.04, hazard ratio 0.46, P = 0.03). An o,p’DDD cutoff value of 14 mg/liter was associated with a sensitivity of 65% and specificity 69%. An o,p’DDD level 20 mg/liter or greater or 14 mg/liter or greater combined with o, p’DDA level 92 mg/liter or greater was associated with a specificity of 90 and 92%, respectively.
Conclusions: Our data confirm the value of o,p’DDD plasma monitoring as well as targeting the 14 mg/liter cutoff level in the therapeutic management of ACC patients. Furthermore, our results suggest additional benefit of higher levels of o,p’DDD and combined measurement of o,p’DDD and o,p’DDA. (J Clin Endocrinol Metab 96: 1844-1851, 2011)
Copyright @ 2011 by The Endocrine Society
First Published Online April 6, 2011
Abbreviations: ACC, Adrenocortical carcinoma; AUC, area under the curve; CR, complete response; HR, hazard ratio; o,p’DDA, 1,1-(o,p’-dichlorodiphenyl) acetic acid; o,p’DDD, mitotane; o,p’DDE, 1,1-(o,p’-dichlorodiphenyl)-2,2 dichloroethane; PD, pro- gressive disease; p,p’DDA, structural isomer of o,p’DDA; PR, partial response; ROC, receiver operating characteristic; SD, stable disease.
A drenocortical carcinoma (ACC) is a rare and aggres- sive tumor with limited therapeutic options. The only chance of cure is complete resection of the tumor (1-4). However, ACC is often diagnosed at a late stage, and approximately 30% of the patients already have me- tastasis at diagnosis (1, 5, 6). The prognosis for advanced disease is particularly poor with less than 15% of patients with metastatic ACC alive 5 yr after diagnosis (7, 8).
Mitotane (o,p’DDD), an isomer of the insecticide di- chlorodiphenyltrichloroethane, remains one of the most active treatments for advanced ACC. Mitochondrial de- generation and destruction of the adrenal cortex after ad- ministration of analog of dichlorodiphenyltrichloroeth- ane was described in dogs (9) and later also by Bergenstal et al. in 1960 (10). Eventually it was demonstrated that o,p’DDD is the active component within the analog of dichlorodiphenyltrichloroethane solution (11) and that metabolic conversion as well as covalent binding to un- known mitochondrial protein targets is required for ad- renolytic activity (12). In terms of an antitumor effect, the drug was first used for the treatment of inoperable, lo- coregional, and/or metastatic ACC; objective responses were demonstrated in 13-33% of patients (6, 13-15). More recently an impact of adjuvant mitotane on ACC survival was suggested (3, 16), and an international panel of experts recommend adjuvant mitotane in patients at high risk of recurrence (17). However, one has to acknowledge that not all centers agree on this concept (18, 19).
The influence of o,p’DDD plasma concentration on tumor response has been suggested in two studies: in case of plasma mitotane levels 14 mg/liter or greater, an ob- jective response rate of 55-66% has been reported (13, 15), whereas only occasional responses have been re- ported when plasma mitotane levels remain below this threshold (20). However, due to the limited number of studies, the impact on survival of attaining this threshold is still questioned. In addition, a significant increase in neuro- logical toxicity has been reported when plasma mitotane lev- els exceed 20 mg/liter (15, 21). Therefore, o,p’DDD plasma monitoring is currently recommended for targeting and maintaining plasma levels between 14 and 20 mg/liter.
Metabolic activation of o,p’DDD within the liver results in the formation of two metabolites, 1,1-(o,p’-dichlorodi- phenyl) acetic acid (o,p’DDA) and 1,1-(o,p’-dichlorodiphe- nyl)-2,2 dichloroethene (o,p’DDE), which derive from ß- or a-hydroxylation of o,p’DDD, respectively (21). Previous studies have suggested a role for o,p’DDA as the active me- tabolite because ß-hydroxylation of o,p’DDD results in an adrenolytic effect, whereas «-hydroxylation of o,p’DDD re- sults in deactivation. Thus, it could be hypothesized that, for ACC patients, measurement of o,p’DDA may help to refine the prediction of response to mitotane therapy.
The objective of this retrospective multicenter study was (1) to confirm the correlation of the currently used o,p’DDD threshold of 14 mg/l with tumor response and survival and (2) to evaluate the (additional) value of o,p’DDA and o,p’DDE levels for predicting tumor response.
Patients and Methods
Patients
We retrospectively reviewed data on ACC patients treated with o,p’DDD between 2001 and 2007 in two European centers (University of Turin, Turin, Italy; Institut Gustave Roussy, Ville- juif, France,) and between 2005 and 2007 in three additional European centers (University of Würzburg, Würzburg, Germa- ny; Máxima Medical Centre, Eindhoven, The Netherlands; and Leiden University Hospital, Leiden, The Netherlands). All pa- tients met the following inclusion criteria: 1) histologically con- firmed unresectable and/or metastatic adrenal carcinoma (ENS@T stage 3 and 4 disease) at o,p’DDD initiation (22); 2) first-line therapy with o,p’DDD and/or chemotherapy; 3) age older than 18 yr; 4) available o,p’DDD plasma monitoring and banking within 3 months before the observation of best response or progression; and 5) tumor morphological evaluation every 2-3 months from diagnosis until progression.
None of the patients enrolled in the two previous studies (13, 15) defining the 14 mg/liter plasma cutoff as a potential predictor of response to o,p’DDD therapy were included in this study.
One hundred fifty patients were considered for enrollment in the study representing 32-75% of the total number of ACC patients referred to each institution during the period under study. After careful review of all files, 40 patients were excluded because of lack of sample availability at the time of best response, previous adjuvant o,p’DDD therapy (n = 10), or incomplete clinical follow-up data (n = 9). Finally, a total of 91 patients was included in the study. For each patient, informed consent and additional data were obtained by trained medical personnel in- cluding: demographic characteristics (age, sex), ACC character- istics (ENS@T tumor stage, tumor related hormone secretion status of the tumor), o,p’DDD characteristics (maximum dose, plasma levels at time of best response or progression), morpho- logical evaluation (best morphological response), associated che- motherapy, and last vital status.
Morphological evaluation
Evaluation of tumor response was reviewed in each center based on related to tumor response criteria (23): partial response (PR) requires at least a 30% decrease in the sum of the longest diameter of all target lesions; progressive disease (PD) is defined as at least a 20% increase in the sum of the longest diameter of all target lesions, progression of nontarget lesions, or the ap- pearance of one or more new lesions; and stable disease (SD) is defined as neither sufficient shrinkage to qualify for partial re- sponse nor sufficient increase to qualify for progressive disease. Subsequently, patients were divided into three groups according to the observed response: group 1 responders (CR + PR); group 2 SD, and group 3 nonresponders (PD).
Measurement of o,p’DDD and its metabolites
Plasma o,p’DDD samples were prospectively stored and fro- zen at a temperature of -20 C at the time of plasma mitotane monitoring during follow-up. All available plasma samples from a given patient were collected. In case of availability of multiple samples, the sample closest to the date of best response or pro- gression was selected (median 4 wk, range 0-12 wk). The se- lected frozen plasma samples were shipped to PAREXEL (bio- analytical services division of PAREXEL, Bloemfontein, South Africa) for measurements. o,p’DDD, o,p’DDA, and o,p’DDE plasma levels were determined in the same run.
The analytical method for assessment of o,p’DDD and its metabolites in plasma depends on protein precipitation followed by HPLC with UV detection (24).
Due to the unavailability of a reference standard for o, p’DDA, structural isomer of o,p’DDA (p,p’DDA) was used as reference standard. The lower limit of quantification of this method is 0.389 mg/ml for both o,p’DDD and o,p’DDE and 3.79 mg/ml for o,p’DDA. Coefficient of variation is 20% at the lower limit of quantification and within 15% at higher concentrations (>0.5 ng/ml).
Statistical analysis
Clinical characteristics of the patients are presented as mean + SD or median with range as appropriate. Spearman rank correlation was used to assess correlations between o,p’DDD and its metabolites o,p’DDE and o,p’DDA, respectively. The relationship between (mean, median) plasma level of o,p’DDD, o,p’DDE, and o,p’DDA and tumor response was determined using ANOVA. Receiver operating characteristic (ROC) curves were used to define cutoff values as defined by the lowest number of both false-positive and false-negative results for each metab- olite. Results of the ROC curves are expressed in terms of sen- sitivity and specificity. Sensitivity was defined as the proportion of responders above a given threshold divided by the total num- ber of responders, and specificity was defined as the proportion nonresponders below a given threshold divided by the total num- ber of nonresponders. After defining cutoff values for o,p’DDD, o,p’DDA, and o,p’DDE plasma levels, x2 analysis was per- formed to assess the relationship with the best cutoff level of each compound, as defined by ROC analysis, and tumor response. The x2 analysis was also performed to assess tumor response in relation to the predefined o,p’DDD plasma level less than 14 mg/liter vs. 14 mg/liter or greater. Kaplan-Meier curves were calculated to determine the effect of o,p’DDD levels 14 mg/liter or greater on survival. Survival was calculated from time of first o,p’DDD dose. Survival of patients who reached o,p’DDD levels 14 mg/liter or greater at the time of best response was compared with patients who did not. Cox regression analysis was used to evaluate the effect of, sex, stage, tumor-related hormone secre- tion (functional vs. nonfunctional tumors), and concomitant chemotherapy on survival. A P < 0.05 was considered signifi- cant. All analyses were performed using SPSS version 13.0 (SPSS Inc., Chicago, IL).
Results
Patient characteristics
Table 1 summarizes the clinical characteristics of the 91 ACC patients included in this study. All patients received
| Age (yr) | |
| Mean | 51 |
| Range | 24-82 |
| Sex | |
| Male | 35% (n = 32) |
| Female | 65% (n = 59) |
| Stage | |
| Stage 3 | 7% (n = 7) |
| Stage 4 | 93% (n = 84) |
| Tumor function | |
| Cushing | 47.3% (n = 43) |
| Virilization | 12.1% (n = 11) |
| Feminization | 2.2% (n = 2) |
| Conn | 1% (n = 1) |
| Nonfunctioning | 36.3% (n = 33) |
| Unknown | 1% (n = 1) |
| Therapy | |
| Mitotane monotherapy | 29.7% (n = 27) |
| Sz + mitotane | 23.1% (n = 21) |
| EDP + mitotane | 31.9% (n = 29) |
| Other | 15.3% (n = 14) |
| o,p'DDD serum level (mg/liter) | |
| Median | 12.7 |
| Range | 1.68-33.6 |
| o,p'DDA serum level (mg/liter) | |
| Median | 58.7 |
| Range | 3.79-136.0 |
| o,p'DDE serum level (mg/liter) | |
| Median | 0.71 |
| Range | 0.39-6.55 |
| Response (RECIST) | |
| PD | 53.8% (n = 49) |
| SD | 27.5% (n = 25) |
| PR | 17.6% (n = 16) |
| CR | 1.1% (n = 1) |
| Last status (01.01.08) | |
| Death | 67.0% (n = 61) |
| LWD | 29.7% (n = 30) |
| NED | 3.3% (n = 3) |
Sz, Streptozotocin; EDP, etoposid doxorubicin cisplatin; RECIST, response evaluation criteria in solid tumors; LWD, living with disease; NED, no evidence of disease.
o,p’DDD for treatment of nonoperable, localized or metastatic disease. o,p’DDD was given as monotherapy (n = 27) or in combination with chemotherapy (n = 64). Nineteen percent of patients (n = 17) were classified as responders (PR and CR), including one patient with complete response, 28% (n = 25) as SD, and 54% (n = 49) as nonresponders (PD). Of the 17 patients with tu- mor response, three patients received mitotane mono- therapy, and 14 received mitotane in combination with chemotherapy.
Median o,p’DDD plasma level was 12.7 mg/liter (range 1.68-33.6). Median plasma levels of o,p’DDA and o, p’DDE were 58.7 mg/liter (range 3.79-136.0) and 0.71 mg/liter (range 0.39-6.55), respectively.
Correlation of o,p’DDD with o,p’DDD metabolite plasma levels
Plasma levels of o,p’DDD showed a significant corre- lation with o,p’DDE (r = 0.61, < 0.001) as well as o, p’DDA (r = 0.67, P < 0.001).
| Cutoff | Sensitivity (%) | Specificity (%) |
|---|---|---|
| ROC results o,p'DDD (mg/liter) | ||
| 10 | 89 | 39 |
| 12 | 78 | 52 |
| 14 | 65 | 69 |
| 16 | 53 | 76 |
| 18 | 32 | 80 |
| 20 | 26 | 90 |
| ROC results o,p'DDA (mg/liter) | ||
| 75 | 42 | 70 |
| 80 | 42 | 76 |
| 85 | 42 | 81 |
| 90 | 35 | 81 |
| 92 | 35 | 84 |
| 95 | 26 | 88 |
| ROC results o,p'DDE (mg/liter) | ||
| 1.0 | 39 | 67 |
| 1.3 | 35 | 80 |
| 1.5 | 35 | 82 |
| 1.8 | 22 | 86 |
O,p’DDD plasma level, correlation with tumor response, and survival
Median o,p’DDD levels were 16.3 mg/liter (range 1.68-31.9 mg/liter) for responders, 11,6 mg/liter (range 2.69-22.30 mg/liter) for patients with stable disease, and 11.0 mg/liter (range 2.27-30.6 mg/liter) for nonre- sponders (P = 0.03).The area under the curve (AUC) for o,p’DDD was 0.67. After ROC curve analysis, the cutoff levels for o,p’DDD were determined (Table 2). The cur- rently used cutoff level of 14 mg/liter resulted in a sensi- tivity of 65% (11 of 17 responders with o,p’DDD above 14 mg/liter) and a specificity of 69% (34 of 49 nonre- sponders with o,p’DDD below 14 mg/liter). Using the 14 mg/liter cutoff level, 15 of 49 nonresponders (33%) had o,p’DDD plasma levels 14 mg/liter or greater vs. 11 of 17 responders (65%) (x2, P = 0.02).
Positive and negative predictive values of the o,p’DDD 14 mg/liter cutoff value were 42 and 85%, respectively. All responders with o,p’DDD levels below 14 mg/liter (n = 6) received concomitant chemotherapy. Cutoff values of 16, 18, and 20 mg/liter were associated with a lower sensitivity of 53, 32, and 26%, respectively, but a higher specificity of 76, 80, and 90%, respectively.
Survival was significantly longer for patients achieving the 14 mg/liter threshold [hazard ratio (HR) 0.52, 0.28- 0.97, P = 0.04] (Fig. 1A). The observed survival benefit was even greater for the patients on o,p’DDD mono- therapy (n = 27) in both univariate (HR 0.26, P = 0.03) (Fig. 1B) and multivariate analysis (HR 0.26, P = 0.02). No significant influence of age [HR 1.01 (0.99-1.04)], sex [HR 1.64 (0.94-2.90)], stage [HR 1.00 (0.24-4.18)], or
A
1,0
0,8
Cum Survival
0,6
≥ 14 mg/l (n=36), median 24 months
0,4
0,2
< 14 mg/l (n=55), median 18 months
7
0,0
0
20
40
60
80
100
120
time (months)
B
1,0
0,8
= 14 mg/l (n=13), median 119 months
Cum Survival
0.6
0,4
0,2
< 14 mg/l (n=14), median 18 months
0,0
0
20
40
60
80
100
120
time (months)
tumor-related hormone secretion [HR 1.29 (0.73-2.30)] on overall survival was observed.
O,p’DDA and o,p’DDE plasma levels and tumor response
Median o,p’DDA levels were 70.2 mg/liter (range 8.47-136.0 mg/liter) for responders, 44.8 mg/liter (range 0.39-128.0 mg/liter) for nonresponders, and 58.0 mg/li- ter (range 0.39-130.0 mg/liter) for patients with stable disease (P = 0.2).
The AUC for o,p’DDA was 0.67. After obtaining the ROC curves, cutoff levels were identified, demonstrating
an overall low sensitivity together with a high specificity (Table 2). For instance, an o,p’DDA cutoff level of 92 mg/liter resulted in a sensitivity of 35% (six of 17 respond- ers with o,p’DDA ≥ 92 mg/liter) and a specificity of 84% (41 of 49 nonresponders with o,p’DDA below 92 mg/ liter). Using the cutoff value of 92 mg/liter for o,p’DDA, six of 16 patients (38%) were responders above this level vs. 15% (11 of 75) below that level (P = 0.02). Positive and negative predictive values of o,p’DDA with a cutoff value of 92 mg/liter were 43 and 79%, respectively. Note that, in the subgroup of ACC patients on o,p’DDD monotherapy (n = 17), a significantly higher median o,p’DDA level was found for responding patients (n = 3); median levels were 111.0 mg/liter (range 74.2-136.0 mg/liter) in responders, 78,0 mg/liter (range 37.5-139.0 mg/liter) for patients with stable disease, and 62.5 mg/liter (range 1.90-93.0 mg/ liter) for nonresponding patients (P = 0.03).
Median o,p’DDE levels were 0.92 mg/liter (range 0.39- 4.13 mg/liter) for responders, 0.65 mg/liter (range 0.39-2.93 mg/liter) for patients with SD, and 0.50 mg/liter (range 0.39-6.55 mg/liter) for nonresponders (P = 0.2). The AUC for o,p’DDE was 0.61, indicating an overall low sensitivity together with a high specificity. For instance a cutoff value of 1.3 mg/liter resulted in a sensitivity of 35% (six of 17) and a specificity of 80% (39 of 49). When a cutoff level of 1.5 mg/liter was used, the sensitivity and specificity were 35 and 82%, respectively. No signifi- cant relationship was demonstrated with tumor re- sponse (P = 0.16).
Combined analysis of o,p’DDD and o,p’DDA
Of 36 patients with o,p’DDD levels 14 mg/liter or greater and 16 patients with o,p’DDA levels 92 mg/liter or greater, the levels of both compounds were above these levels in 11 cases. Of these 11 patients, 45% (five of 11) had a response. The combination of o,p’DDD levels 14 mg/liter or greater and o,p’DDA levels 92 mg/liter or greater resulted in a sensitivity of 29%, specificity of 92%, a positive predictive value of 55%, and a negative predictive value of 68%.
One of five patients with o,p’DDA levels 92 mg/liter or greater but o,p’DDD below 14 mg/liter experienced a re- sponse. This patient received o,p’DDD in combination with chemotherapy. Five of 51 patients (10%) with both o,p’DDD levels less than 14 mg/liter and o,p’DDA levels less than 92 mg/liter had a response.
Discussion
The present study demonstrates the importance of o, p’DDD plasma monitoring as well as the importance of
reaching the therapeutic o,p’DDD threshold of (at least) 14 mg/liter. An o,p’DDD level above 14 mg/liter was as- sociated significantly with tumor response and survival. In contrast, we observed a relationship only between o, p’DDA and tumor response in a subgroup of patients on mitotane monotherapy.
Fifty years after its first use, o,p’DDD is still considered the most active drug for ACC. Nonetheless, a number of limitations exist including poor bioavailability, signif- icant side effects, and a narrow range of optimal effi- cacy, making progress in the use of this drug highly important. In this setting, improved prediction of tumor response to o,p’DDD constitutes an attractive field of research. Therefore, our study was aimed at progress in the field of o,p’DDD pharmacokinetics and its atten- dant impact on patient outcome.
Findings of previous studies on the relevance of o, p’DDD plasma level 14 mg/liter or greater are confirmed in the present study because significantly higher median levels were found in responding patients compared with nonresponding patients and patients with stable disease (P = 0.03). Importantly, it confirms the currently used 14 mg/liter threshold for o,p’DDD as a good compromise for patients with unresectable ACC associated with a sensi- tivity of 65% and a specificity of 69%. Whether this threshold is also applicable for ACC patients in the adju- vant setting remains to be demonstrated; however, be- cause the same objectives applied in both conditions, we suggest to use the same strategy (17). Furthermore, the observation of response among patients with plasma levels below 14 mg/liter was also confirmed. However, all re- sponders with plasma levels of o,p’DDD below 14 mg/liter received concomitant cytotoxic chemotherapy. Thus, the response found for these patients might be the result of chemotherapy or the combination of drugs rather than o,p’DDD alone. Indeed, o,p’DDD has been shown to an- tagonize multidrug resistance-1 in vitro (25, 26), which is involved in resistance to doxorubicin and etoposide agents. However, the clinical relevance of this observation for ACC patients remains to be confirmed. Regarding the specificity of o,p’DDD associated with a 14 mg/liter cutoff plasma level, it was intermediate at 69% but increased up to 80% when the 18 mg/liter cutoff value was chosen, suggesting that for some patients reaching plasma levels of o,p’DDD above 18 mg/liter may become a new ther- apeutic target, if tolerated without major toxicity. Al- though not considered as an anticipated objective in the population of patients under study, o,p’DDD levels above 18 or 20 mg/liter were observed in 20 or 11% of cases, respectively.
Although some authors have already investigated the efficacy of mitotane plasma levels (13, 27), the impact of
these levels on survival is still uncertain. Improved survival of patients with o,p’DDD plasma levels within the ther- apeutic range has been suggested (13, 28, 29) but not al- ways confirmed (25, 30-32). Furthermore, survival was not always determined from the time of first o,p’DDD dose, which is the most appropriate for calculating o, p’DDD-associated survival. From the time of first o, p’DDD dose, we found a significantly improved survival for patients with mitotane plasma levels 14 mg/liter or greater compared with patients with plasma levels below 14 mg/liter. This finding emphasizes the importance of targeting plasma levels 14 mg/liter or greater, even for patients with progressive disease. In addition, a recent study suggested the importance of maintaining mitotane plasma levels 14 mg/liter or greater (29). We did not find a significant influence of age and tumor-related hormone secretion on overall survival, in contrast to one previous study (33). However, populations under study as well as the modality of o,p’DDD analysis were different, making direct comparison impossible.
Further progress in the scope of predictors of response to o,p’DDD is still needed; therefore, the second focus of our study was the evaluation of the predictive roles of the o,p’DDD metabolites, o,p’DDA and o,p’DDE. The pres- ent study for the first time evaluated the metabolites as potential predictors of antitumor activity compared with o,p’DDD.
Indeed, in preclinical studies, o,p’DDD has been demonstrated to be activated by the liver via transfor- mation to o,p’DDA (21, 34). Tumor response was found to be correlated to o,p’DDA but only in a sub- group of patients on mitotane monotherapy (n = 27). Furthermore, an o,p’DDA cutoff value of 92 mg/liter was found to be correlated with response to therapy and was associated with a 84% specificity rate in this sub- group of patients. However, only three responders were found in this subgroup of patients, which precludes de- finitive conclusions.
Regarding the entire population under study, the AUC of the ROC curves of o,p’DDA and o,p’DDD were in the same range due to a lower sensitivity but higher specificity of o,p’DDA compared with o,p’DDD. Taken together, these results suggest that a combination of both metabolite measurements may be a logical next step to be investigated in future prospective studies. Indeed, the combination of o,p’DDA 92 mg/liter or greater and o,p’DDD 14 mg/liter or greater yields a 92% specificity and 55% positive predictive value. These data are consistent with the positive but not per- fect correlation between plasma values of o,p’DDA and o,p’DDD, found in our study, suggesting that for some patients both compounds can provide complementary
information to some extent. Note that a similar range of specificity and positive predictive results were obtained than by setting the cutoff value of o,p’DDD at 18 mg/liter. Indeed combining o,p’DDD and o,p’DDA measurements may help to refine the predictions of o,p’DDD antitumor activity and avoid the risk of an increased toxicity rate. Patients with o,p’DDA 92 mg/liter or greater and o,p- ‘DDD 14 mg/liter or greater may not require an increase in mitotane dose. In contrast to o,p’DDA, our study does not confirm a correlation of o,p’DDE with tumor response as previously hypothesized in one study (35). As stated earlier, reaching the therapeutic threshold of 14 mg/liter is very important. However, only 40% of the ACC patients in this study reached an o,p’DDD level 14 mg/liter or greater. Low bioavailability of o,p’DDD treatment is a well-known drawback of this drug. Both the low absorption rate of o,p’DDD and its lipophilic nature partly explain this characteristic (36).
We acknowledge that our article has important lim- itations. Its retrospective nature, the still relatively low number of patients, and the use of o,p’DDD in combi- nation with other chemotherapy regimens in most cases constitute major limitations. In addition, we analyzed selected unresectable ACC patients, mainly based on the availability of stored plasma o,p’DDD samples, in which an unrecognized bias cannot be excluded. How- ever, to date these limitations cannot be overcome due to the scarcity of the disease and the delayed action of o,p’DDD. In addition, p,p’DDA but not o,p’DDA was measured in the plasma. Whether the o,p’DDA peak at HPLC is similar to the p,p’DDA peak remains to be proven.
In conclusion, our data confirm the value of o,p’DDD plasma monitoring as well as targeting the 14 mg/liter cutoff level of o,p’DDD in the therapeutic management of ACC patients. Furthermore, our results suggest some ad- ditional benefit of a targeting of higher plasma level of o,p’DDD and combined measurement of o,p’DDD and o,p’DDA, which has to be confirmed in a prospective study that is currently running as a substudy of the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment trial.
Acknowledgments
Address all correspondence and requests for reprints to: Ilse Hermsen, Department of Internal Medicine, Máxima Medical Centre, P.O. Box 90052, 5600 PD Eindhoven, The Netherlands. E-mail: i.hermsen@mmc.nl.
Disclosure Summary: I.G.H., S.H., J.d.H., S.L., F.D., A.B., M.S., B.A., and H.R.H. have nothing to declare. M.F. received
a grant for a pharmakinetic trial of mitotane sponsored by HRA-Pharma. M.T. received fees for participating on the ad- visory board for HRA-Pharma. R.C. is employed by HRA- Pharma. E.B. received lecture fees from HRA-Pharma. Mea- surements of o,p’DDD and metabolites were sponsored by HRA-Pharma.
References
1. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P 1996 The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119:161-170
2. Schulick RD, Brennan MF 1999 Long-term survival after complete resection and repeat resection in patients with adrenocortical car- cinoma. Ann Surg Oncol 6:719-726
3. Grubbs EG, Callender GG, Xing Y, Perrier ND, Evans DB, Phan AT, Lee JE 2010 Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol 17:263-270
4. Icard P, Chapuis Y, Andreassian B, Bernard A, Proye C 1992 Ad- renocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112:972-979; discussion 979-980
5. Wooten MD, King DK 1993 Adrenal cortical carcinoma. Epidemi- ology and treatment with mitotane and a review of the literature. Cancer 72:3145-3155
6. Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, Cougard P, Henry JF, Proye C 2001 Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons Study Group. World J Surg 25:891-897
7. Assié G, Antoni G, Tissier F, Caillou B, Abiven G, Gicquel C, Leboulleux S, Travagli JP, Dromain C, Bertagna X, Bertherat J, Schlumberger M, Baudin E 2007 Prognostic parameters of met- astatic adrenocortical carcinoma. J Clin Endocrinol Metab 92: 148-154
8. Allolio B, Hahner S, Weismann D, Fassnacht M 2004 Management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 60:273-287
9. Nelson AA, Woodard G 1948 Adrenal cortical atrophy and liver damage produced in dogs by feeding 2,2-bis-(parachloro-phenyl)- 1,1-dichloroethane. Fed Proc 7:277
10. Bergenstal DM, Hertz R, Lipsett MB, Moy RH 1960 Chemotherapy of adrenocortical cancer with o,p’-DDD. Ann Intern Med 53:672
11. Cueto C, Brown JH, Richardson Jr AP 1958 Biological studies on an adrenocorticolytic agent and the isolation of the active components. Endocrinology 62:334-339
12. Martz F, Straw JA 1980 Metabolism and covalent binding of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o, p,‘-DDD). Correlation between adrenocorticolytic activity and metabolic activation by adrenocortical mitochondria. Drug Metab Dispos 8:127-130
13. Haak HR, Hermans J, van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, Krans HM 1994 Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 pa- tients. Br J Cancer 69:947-951
14. Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Craw- ford ED 2000 Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study. Cancer 88:1159-1165
15. Baudin E, Pellegriti G, Bonnay M, Penfornis A, Laplanche A, Vassal G, Schlumberger M 2001 Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p’DDD) levels on the
treatment of patients with adrenocortical carcinoma. Cancer 92: 1385-1392
16. Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Re- imondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A 2007 Adjuvant mito- tane treatment for adrenocortical carcinoma. N Engl J Med 356: 2372-2380
17. Berruti A, Fassnacht M, Baudin E, Hammer G, Haak H, Leboulleux S, Skogseid B, Allolio B, Terzolo M 2010 Adjuvant therapy in pa- tients with adrenocortical carcinoma: a position of an international panel. J Clin Oncol 28:e401-e402; author reply e403
18. Huang H, Fojo T 2008 Adjuvant mitotane for adrenocortical can- cer-a recurring controversy. J Clin Endocrinol Metab 93:3730- 3732
19. Bodie B, Novick AC, Pontes JE, Straffon RA, Montie JE, Babiak T, Sheeler L, Schumacher P 1989 The Cleveland Clinic experience with adrenal cortical carcinoma. J Urol 141:257-260
20. Seki M, Nomura K, Hirohara D, Kanazawa M, Sawada T, Takasaki K, Demura H 1999 Changes in neoplastic cell features and sensi- tivity to mitotane during mitotane-induced remission in a patient with recurrent, metastatic adrenocortical carcinoma. Endocr Relat Cancer 6:529-533
21. van Slooten H, Moolenaar AJ, van Seters AP, Smeenk D 1984 The treatment of adrenocortical carcinoma with o,p’-DDD: prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol 20:47-53
22. Cai W, Counsell RE, Djanegara T, Schteingart DE, Sinsheimer JE, Wotring LL 1995 Metabolic activation and binding of mitotane in adrenal cortex homogenates. J Pharm Sci 84:134-138
23. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Chris- tian MC, Gwyther SG 2000 New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205-216
24. Hermsen IG, den Hartigh HJ, Haak HR 2010 Mitotane serum level analysis; good agreement between two different assays. Clin Endo- crinol (Oxf) 73:271-272
25. Abraham J, Bakke S, Rutt A, Meadows B, Merino M, Alexander R, Schrump D, Bartlett D, Choyke P, Robey R, Hung E, Steinberg SM, Bates S, Fojo T 2002 A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and eto- poside with daily mitotane as a P-glycoprotein antagonist. Cancer 94:2333-2343
26. Bates SE, Shieh CY, Mickley LA, Dichek HL, Gazdar A, Loriaux DL, Fojo AT 1991 Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycopro- tein) which is also expressed by adrenocortical carcinomas. J Clin Endocrinol Metab 73:18-29
27. Baudin E, Docao C, Gicquel C, Vassal G, Bachelot A, Penfornis A, Schlumberger M 2002 Use of a topoisomerase I inhibitor (irinote- can, CPT-11) in metastatic adrenocortical carcinoma. Ann Oncol 13:1806-1809
28. Wängberg B, Khorram-Manesh A, Jansson S, Nilsson B, Nilsson O, Jakobsson CE, Lindstedt S, Odén,A, Ahlman H 2010 The long-term survival in adrenocortical carcinoma with active surgical manage- ment and use of monitored mitotane. Endocr Relat Cancer 17:265- 272
29. Malandrino P, Al Ghuzlan A, Castaing M, Young J, Caillou B, Travagli JP, Elias D, de Baere T, Dromain C, Paci A, Chanson P, Schlumberger M, Leboulleux S, Baudin E 2010 Prognostic markers of survival after combined mitotane- and platinum-based chemo- therapy in metastatic adrenocortical carcinoma. Endocr Relat Can- cer 17:797-807
30. Venkatesh S, Hickey RC, Sellin RV, Fernandez JF, Samaan NA 1989 Adrenal cortical carcinoma. Cancer 64:765-769
31. Hutter Jr AM, Kayhoe DE 1966 Adrenal cortical carcinoma. Results of treatment with o,p’DDD in 138 patients. Am J Med 41:581-592
32. Lubitz JA, Freeman L, Okun R 1973 Mitotane use in inoperable adrenal cortical carcinoma. JAMA 223:1109-1112
33. Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X, Bertherat J 2006 Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 91:2650-2655
34. Cai W, Benitez R, Counsell RE, Djanegara T, Schteingart DE, Sin- sheimer JE, Wotring LL 1995 Bovine adrenal cortex transforma- tions of mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-di- chloroethane; o,p’- DDD] and its p,p’- and m,p’-isomers. Biochem Pharmacol 49:1483-1489
35. Kasperlik-Zaluska AA, Cichocki A 2005 Clinical role of determi- nation of plasma mitotane and its metabolites levels in patients with adrenal cancer: results of a long-term follow-up. J Exp Ther Oncol 5:125-132
36. Watson AD, Rijnberk A, Moolenaar AJ 1987 Systemic availability of o,p’-DDD in normal dogs, fasted and fed, and in dogs with hy- peradrenocorticism. Res Vet Sci 43:160-165
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