Impact of Monitoring Plasma 1,1- Dichlorodiphenildichloroethane (o,p’DDD) Levels on the Treatment of Patients with Adrenocortical Carcinoma
E. Baudin, M.D.1
G. Pellegriti, M.D.1
M. Bonnay, M.D.2
A. Penfornis, M.D.3
A. Laplanche, M.D.A
G. Vassal, M.D.5
M. Schlumberger, M.D.1
1 Service de Médecine Nucléaire, Institut Gustave- Roussy, Villejuif, France.
2 Département de Biologie Clinique, Institut Gustave-Roussy, Villejuif, France.
3 Service d’Endocrinologie, Centre Hospitalier et Universitaire de Besançon, Besançon, France.
4 Département de Statistique, Institut Gustave- Roussy, Villejuif, France.
5 Département de Pédiatrie et Laboratoire de Phar- macotoxicologie et Pharmacogénétique, Institut Gustave-Roussy, Villejuif, France.
The authors are indebted to the nurses of the Nuclear Medicine Department and to L. Saint Ange for editing.
Address for reprints: E. Baudin, M.D., Institut Gustave-Roussy, 39 rue Camille Desmou- lins,94805 Villejuif Cedex, France; Fax: 33 (1) 42 11 52 23; E-mail: baudin@igr.fr
Received March 22, 2001; revision received June 18, 2001; accepted June 19, 2001.
BACKGROUND. It has been suggested recently that 1,1-dichlorodiphenildichloro- ethane (o,p’DDD) elicits a dose effect relation in the treatment of patients with adrenocortical carcinoma (ACC). The authors performed a single-center, prospec- tive study with two major objectives: 1) to confirm the interest of plasma o,p’DDD level measurement as a prognostic factor of response to o,p’DDD therapy; and 2) to look for parameters associated with a therapeutic plasma o,p’DDD level, espe- cially the daily o,p’DDD dose.
METHODS. Since 1995, patients with ACC who were referred to the Gustave-Roussy Institute have been enrolled prospectively in the study. Therapy with o,p’DDD was given as first-line therapy in 13 patients with metastatic disease or as adjuvant therapy in 11 patients. Oral o,p’DDD was given in three separate doses up to at least 6-12 g per day together with substitutive adrenal therapy. Plasma o,p’DDD levels were measured using high-performance liquid chromatography every 2 months. The o,p’DDD therapy was monitored to achieve plasma o,p’DDD levels within 14-20 mg/L. World Health Organization criteria were used to evaluate tumor response and toxicity.
RESULTS. Twenty-four patients with ACC were studied, and a plasma o,p’DDD level > 14 mg/L was achieved in 14 patients (58%). An objective tumor response was observed in four patients with metastatic lesions (31%): One was response was complete, and three were objective hormonal responses. These tumor responses were observed among the six patients who achieved therapeutic plasma o,p’DDD levels. In contrast, no response was observed among the seven patients with plasma o,p’DDD levels that remained consistently low. Eight of 11 patients who received o,p’DDD as adjuvant therapy had disease recurrence, although the plasma o,p’DDD level was > 14 mg/L in 6 patients. Grade 3 or 4 neurologic toxicity was observed in three patients (12%), all with an o,p’DDD level > 20 mg/L. The daily o,p’DDD dose was the only parameter associated with the highest plasma o,p’DDD trough levels: It explained 35% of the variability in the plasma o,p’DDD level. A median interval of 3.7 months was found necessary to achieve the highest o,p’DDD trough levels.
CONCLUSIONS. The results confirm the prognostic impact of the plasma o,p’DDD level in patients with metastatic ACC and its interest in avoiding toxicity. Cancer 2001;92:1385-92. @ 2001 American Cancer Society.
KEYWORDS: adrenocortical carcinoma, 1,1-dichlorodiphenildichloroethane, plasma levels.
A drenocortical carcinoma (ACC) is a rare tumor with a 5-year survival rate attaining 20-35%.1-8 In patients with metastatic ACC, objective tumor responses have been reported with 1,1-dichlo- rodiphenildichloroethane (o,p’DDD) and/or cisplatin-based chemo-
therapy, although complete responses were few and far between, and the impact on survival was debat- able.8-11
The usefulness of o,p’DDD therapy as an adreno- lytic agent in patients with metastatic ACC was re- ported first in the 1960s, with response rates ranging from 14% to 38% but with significant toxicity.12-14 o,p’DDD also was considered capable of antagonizing hormonal secretion in up to 75% of ACC patients2 and of partially reversing the multidrug resistance pheno- type.15 Subsequently, o,p’DDD was proposed as adju- vant therapy for patients with ACC, although its im- pact on disease free and overall survival rates remains debatable.16-22
In a previous study, the plasma o,p’DDD level was shown to have an impact on patient prognosis, with a 55% objective response rate in patients with plasma levels > 14 mg/L and no response in patients with plasma levels < 14 mg/L.19 In addition, plasma o,p’DDD measurement was considered potentially useful for monitoring toxicity, because side effects were observed only in patients with plasma levels > 20 mg/L.23 Furthermore, the monitoring of plasma o,p- ‘DDD levels provides a means of comparing o,p’DDD therapy using various vehicles and various daily doses. To our knowledge, the impact of plasma o,p’DDD level monitoring on the therapeutic management of patients with ACC still has not been confirmed.
We carried out a single-center, prospective study in patients with ACC who were referred to the Gustave-Roussy Institute with two major objectives: 1) to confirm the prognostic impact of plasma o,p’DDD levels on tumor response and toxicity and 2) to look for parameters associated with plasma o,p’DDD lev- els, especially the daily o,p’DDD dose.
MATERIALS AND METHODS Patients
Since 1995, all patients with ACC for whom o,p’DDD therapy was initiated at the Gustave-Roussy Institute were enrolled in this study. All pathologic diagnoses were reviewed by a single pathologist (B. Caillou, In- stitut Gustave-Roussy, Villejuif, France). Functional tumors were defined on the basis of an increase in glucocorticoids assessed by measuring plasma and urinary excretion of cortisol; and/or androgen was assessed by measuring plasma testosterone, andro- stenedione, and dehydroepiandrosterone sulfate; and/or estrogen was assessed by measuring estradiol-17ß lev- els. Plasma 17-hydroxyprogesterone and 11-desoxy- cortisol levels also were measured in all patients as well as aldosterone and 11-desoxycorticosterone lev- els to assess mineralocorticoid function. Patients were assigned to Group 1 if they presented metastatic ACC
and to Group 2 if they were in complete remission after surgery.
Doses of o,p’DDD were given in capsules con- taining 0.5 g of micronized drug mixed with cellu- lose acetylphtalate (Mitotane; Pharmacie Centrale de l’Assistance Publique-Hôpitaux de Paris, Paris, France). This o,p’DDD vehicle, with enteric-coated, gastric-resistant granules, initially was prepared to enhance digestive tolerance. It was given either as first-line therapy to patients in Group 1 or as adju- vant therapy to patients in Group 2. The o,p’DDD was administered orally three times per day with the objective of reaching at least a 6-12 g daily dose within 3 weeks and maintaining the highest dose attained over at least 3 months or until the plasma o,p’DDD level was ≥ 14 mg/L. Such high daily doses of o,p’DDD usually are given with this vehicle.2 Therapy with o,p’DDD was monitored according to the evolution of the tumor load, side effects, and plasma o,p’DDD level. We tried to maintain the plasma o,p’DDD level between 14 mg/L and 20 mg/L in all patients. Substitutive adrenal therapy, i.e., hydrocortisone (30-60 mg per day) and fludro- cortisone acetate (25-50 µg per day), was given to all patients and was associated with a normal salt diet. No other therapy was given during the study.
Plasma o,p’DDD Measurements
The plasma o,p’DDD level was measured at least every 2 months during the first 6 months of treatment and then depending on each patient. Trough plasma sam- ples were collected 12 hours after the preceding dose after overnight fasting.
Heparinized plasma samples were deproteinized with cold ethanol. After centrifugation, the superna- tant (20 µL) was injected into a high-performance liquid chromatography system. Chromatography was performed on a Nucleosil C18 column (250 mm × 4.6 mm; 5um particle size). The mobile phase, a meth- anol:water 90:10 mixture, was delivered at a speed of 1.2 mL/mn. Ultraviolet detection was set at 240 nm, and the analysis was performed at 15 minutes. Stan- dard and quality-control samples were used for each run by spiking normal human plasma with proper dilutions of two different stock solutions. The analytic range for o,p’DDD measurement was validated be- tween 0 mg/L and 50 mg/L.
Response and Toxicity Criteria
Complete clinical, biologic, and morphologic evalua- tions, including an abdominal ultrasound and com- puterized tomography (CT) scan, a chest CT scan, and bone scintigraphy, were performed every 2 months or at the discontinuation of o,p’DDD therapy. According
to World Health Organization (WHO) criteria, a com- plete response was defined as the disappearance of all clinical, biologic, and morphologic evidence of tumor for at least 1 month. A partial response was defined as a 50% decrease in the sum of the products of the greatest perpendicular dimensions of all measurable tumors for at least 1 month without the appearance of new lesions. An objective biologic response was de- fined as a 50% decrease in the hormone level. Progres- sive disease was defined as a 25% increase in the sum of the products of the greatest perpendicular dimen- sions of all measurable tumors or the appearance of new lesions. A complete response was evaluated from the date it was first documented to the date progres- sive disease was first noted. A partial response was evaluated from the first day of therapy to the date of progressive disease. Toxicities were graded according to WHO criteria. For patients who received adjuvant therapy, the interval between adrenal surgery and dis- ease recurrence or the last date of follow-up was taken into account.
Statistics
Correlations were sought between plasma o,p’DDD levels, the time elapsed between the diagnosis of ACC and the initiation of o,p’DDD therapy, and tumor response or tumor recurrence rates. Correlations were then sought between plasma o,p’DDD levels and pa- tient age, gender, body mass index (weight/[size]2), and tumor secretory activity. Correlations also were sought between the total cumulative o,p’DDD dose and the highest plasma o,p’DDD trough level within the first 6 months of therapy.
The Fisher exact test was used to compare pro- portions, whereas the distribution of quantitative data was compared using nonparametric tests: the Wil- coxon test or the Kruskal-Wallis test when there were more than two groups. A linear regression analysis was performed to compare the o,p’DDD dose and its plasma level. This study was performed in accordance with local ethical rules.
RESULTS Patients
Twenty-four patients with ACC (8 males and 16 fe- males; median age, 50 years; range, 20-76 years) who were referred to our institution were assigned to one of two groups. The main clinical characteristics of the two groups of patients are detailed in Tables 1 and 2. Briefly, Group 1 was comprised of 13 patients with distant metastases, 9 patients with secretory ACC, and 12 patients who previously underwent adrenal surgery (Table 1). Group 2 was comprised of 11 patients who had no evidence of persistent disease after undergoing
resection of a large ACC associated with the removal of hepatic metastases in 2 patients, 4 patients had secre- tory activity, and 2 patients had undergone further surgery for regional recurrence (Table 2). The median time since diagnosis before the initiation of o,p’DDD therapy was 3 months (range, 0-18 months) and 4 months (range, 1-63 months) for in Groups 1 and 2, respectively. The median follow-up after diagnosis was 21 months (range, 7-67 months) and 24 months (range, 7-63 months) for Groups 1 and 2, respectively.
Response to o,p’DDD Therapy and Toxicity: Correlation with Plasma o,p’DDD Levels
All patients were evaluable for response. In Group 1, 4 of 13 patients (31%; 95% confidence interval, 18-44%) achieved an objective response, which was complete for 1 patient. The durations of response, respectively, were 10 months, 11 months, and 33 months for the three patients who achieved a partial response and 48 months in the patient who achieved a complete re- sponse. A hormonal response was observed only in the three patients who had an objective tumor re- sponse and a secretory ACC. These four responses were observed among the six patients (66%) with plasma o,p’DDD levels > 14 mg/L, whereas no re- sponse was observed among the seven patients with plasma o,p’DDD levels that remained < 14 mg/L (P = 0.02). It is noteworthy that, for the four patients who responded to o,p’DDD therapy, the o,p’DDD level was < 14 mg/L at the time of disease progression. In Group 2, eight patients (72%) developed a recurrence. Seven of these patients had their disease recurrence within 1 year after the initiation of o,p’DDD therapy, and six patients had plasma o,p’DDD levels > 14 mg/L at the time of the recurrence. Among the three pa- tients who did not have a disease recurrence, two had a plasma o,p’DDD level > 14 mg/L. The recurrence rate in this group was not different statistically be- tween patients who reached the 14 mg/L plasma o,p- ‘DDD level and those who did not. The time between the diagnosis of ACC and the initiation of o,p’DDD therapy was not found to influence the objective re- sponse or recurrence rates.
Treatment toxicities are detailed in Tables 1 and 2. Nausea was observed in 11 patients, even when plasma o,p’DDD levels were low; o,p’DDD was dis- continued in only two patients with low plasma o,p’DDD levels (Patients 9 and 16) because of diges- tive intolerance. Poor compliance was suspected in only these two patients. Grade 3 or 4 neurologic tox- icity was observed in three of six patients with o,p- ‘DDD levels > 20 mg/L. No major side effects were observed in the 18 other patients with o,p’DDD levels
| Age (yrs) | Gender | Hormone production | Surgery | Time since diagnosis (months) | Mitotane maximum dose (g/day) within the first 6 months | Duration of o,p'DDD therapy (months) | Highest plasma 0,p'DDD (ng/ml) 6 first months | Tumor response | Side effects | Survival since diagnosis (months) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1-56 | Male | — | Yes | 1.3 | 12.0-9.0 | 66.0 | 26.7 (6 months) | CR | Anorexia G2, cutaneous rash G1, gynecomastia G1 | AWD (67.3) |
| 2-34 | Male | Androgens, estrogens | Yes | 0.2 | 12.0 | 7.3 | 17.1 (5 months) | PD | None | Dead (21.0) |
| 3-50 | Female | Cortisol | Yes | 18.2 | 9.0 | 7.0 | 10.2 (3 months) | PD | None | AWD (28.3) |
| 4-42 | Female | — | Yes | 15.5 | 9.0-7.5 | 6.5 | 15.4 (4 months) | PD | None | AWD (40.5) |
| 5-51 | Female | Cortisol, androgens | No | 2.5 | 9.0-6.0 | 13.0 | 33.1 (6 months) | PR | Neurologic G3 (confusion) | Dead (19.1) |
| 6-34 | Female | Cortisol, androgens | Yes | 0.2 | 9.0 | 4.0 | 12.9 (4 months) | PD | None | Dead (12.3) |
| 7-67 | Female | — | Yes | 2.0 | 9.0 | 4.0 | 13.7 (3 months) | PD | Nausea G1 | Dead (17.2) |
| 8-25 | Female | Androgens | Yes | 10.2 | 9.0 | 1.5 | 13.8 (2 months) | PD | Nausea G1, neurologic G1 (dizziness) | AWD (27.6) |
| 9-20 | Female | Cortisol, androgens | Yes | 0.9 | 9.0 | 1.2 | 10.8 (1 month) | PD | Nausea G4, cutaneous rash G1 | Dead (19.4) |
| 10-69 | Male | Cortisol, androgens, estrogens | Yes | 5.8 | 9.0 | 1.0 | 5.0 (1 month) | PD | Nausea G2, anorexia G2, liver G2 | Dead (7.7) |
| 11-42 | Male | Cortisol | Yes | 3.5 | 9.0-7.5 | 11.0 | 16.7 (6 months) | PR | None | AWD (47.6) |
| 12-53 | Female | Androgens | Yes | 0 | 9.0-7.5 | 4.0 | 17.3 (6 months) | PR | Nausea G1 | AWD (45.5) |
| 13-43 | Male | — | Yes | 8.0 | 9.0-7.5 | 4.5 | 5.1 (3 months) | PD | Nausea G1 | Dead (19.0) |
o,p’DDD: 1,1-dichlorodiphenildichloroethane; CR: complete response; G1: Grade 1; G2: Grade 2; AWD: alive with disease; PD: progressive disease; PR: partial response.
| Age (yrs) | Gender | Hormone production | Tumor size (cm)/weight (g) | Time since diagnosis (months) | Mitotane maximum dose (g/day) within the first 6 months | Duration of o,p'DDD therapy (months) | Highest plasma o,p'DDD (ng/ml) (months) | Recurrence (months) | Side effects | Survival since diagnosis (months) |
|---|---|---|---|---|---|---|---|---|---|---|
| 14-36 | Female | — | 18 (1950) | 2.3 | 12.0-9.0 | 7.0 | 30.1 (6) | Yes (7) | Nausea G1, neurologic G3 (dizziness, loss of | Dead (24.4) |
| 15-62 | Male | — | 14 | 1.0 | 12.0-9.0 | 7.0 | 20.2 (7) | Yes (7) | vision, somnolence) Nausea G1, pruritus G1, gynecomastia G1, | DF (63.5)ª |
| neurologic G1 (somnolence) | ||||||||||
| 16-64 | Female | Androgens | 15 (900) | 0.1 | 12.0 | 1.5 | 10.6 (2) | Yes (4.5) | Nausea G4, liver G1 | Dead (16) |
| 17-36 | Female | Cortisol | 18 (1045) | 0.9 | 12.0-10.0 | 3.0 | 5 (3) | Yes (3) | None | AWD (7.5) |
| 18-68 | Male | — | 7 (hepatic metastases) | 2.3 | 10.5 | 7.0 | 19.4 (4) | Yes (4) | None | Dead (39.5) |
| 19-54 | Female | — | 13 (690) | 3.0 | 10.5-9.0 | 15.0 | 28.3 (5) | No | Sweating G1, neurologic G2 (dizziness, blurred vision, somnolence, paresthesias) | DF (21.2) |
| 20-76 | Female | — | 13 (623) | 0.5 | 9.0 | 6.0 | 13.8 (3) | No | None | DF (7) |
| 21-64 | Male | Cortisol, | 14 (400) | 1.1 | 9.0 | 4.0 | 17.1 (4) | Yes (4) | Neurologic G1 | Dead (21) |
| androgens | (paresthesias) | |||||||||
| 22-33 | Female | — | 11 (370) | 2.1 | 9.0-6.0 | 32.0 | 25.4 (3) | No | Neurologic G4 (dizziness, diplopia, somnolence, seizure), nausea G1 | DF (38.6) |
| 23-57 | Female | Cortisol | 15 (hepatic metastases) | 0.5 | 7.5-6.0 | 11.0 | 18.8 (2) | Yes (11) | Neurologic G1 | AWD (32.1) |
| (somnolence) | ||||||||||
| 24-31 | Female | — | 9 (160) | 60.0 | 9.0-6.0 | 22.0 | 17.4 (11) | Yes (22) | Neurologic G1 (dizziness), nausea G1 | AWD (89.2) |
o,p’DDD: 1,1-dichlorodiphenildichloroethane; G1-G4: Grades 1-4; DF: disease free; AWD: alive with disease.
ª This patient was disease free after chemotherapy.
Plasma o,p’DDD Levels in the Management of ACC/Baudin et al.
Highest trough level (mg/L)
35
n=24
r2=0.346
28
p=0.0025
21
14
7
0
0
500
1000
1500
2000
2500
Cumulative Dose (g)
that remained < 20 mg/L. All adverse effects were reversible once the daily o,p’DDD dose was lowered.
Parameters Associated with Therapeutic Plasma o,p’DDD Levels and Plasma o,p’DDD Kinetics
The highest daily doses of o,p’DDD, which are de- tailed in Tables 1 and 2, were attained within 3 weeks in all patients. The maximum daily o,p’DDD dose during the first 6 months or until disease progression or side effects were evident was 9-12 g in 8 patients, 9 g in 8 patients; and 6-9 g in the other 8 patients. A plasma o,p’DDD level ≥ 14 mg/L was achieved in 14 of 24 patients (58%). No correlation was found be- tween plasma o,p’DDD level and age, gender, or body mass index. A significant correlation (Fig. 1) was ob- served between the highest plasma o,p’DDD trough level and the cumulative daily dose of o,p’DDD at the same time (correlation coefficient [r2] = 0.346; P = 0.0025). This result means that the daily o,p’DDD dose accounted for 35% of the variability in the plasma o,p’DDD level between patients.
The median time from the initiation of o,p’DDD therapy to achieving the highest plasma o,p’DDD level was 113 days (mean ± standard deviation [SD]: 119 days ± 47 days; range, 23-204 days) after a median cumulative dose of 1103 g (1156 g ± 502 g; range, 207-2196 g). Three patients reached a plasma o,p’DDD level > 14 mg/L within 2 months, seven patients reached this level during the third or fourth month, three patients reached this level during the fifth or sixth month, and 1 patient reached this level at 11 months. The mean time needed to achieve the
therapeutic o,p’DDD dose as well as the slow decrease in the o,p’DDD levels after lowering the o,p’DDD dose or after its discontinuation are illustrated in Figure 2. Finally, o,p’DDD was undetectable 11 months after its discontinuation.
DISCUSSION
The current study emphasizes the impact of plasma o,p’DDD level monitoring on the therapeutic manage- ment of patients with metastatic ACC: Only patients with plasma o,p’DDD levels > 14 mg/L achieved ob- jective tumor responses. Furthermore, Grade 3-4 neu- rologic toxicity was observed only in patients with plasma o,p’DDD levels > 20 mg/L. In contrast, it was found that gastrointestinal toxicity was not correlated with plasma o,p’DDD levels. To our knowledge, this is the first study that has evaluated prospectively the impact of plasma o,p’DDD level monitoring on tumor response and that corroborates previously reported data.19,23 In addition, plasma o,p’DDD level monitor- ing may help improve patient compliance to o,p’DDD therapy by indicating the minimal effective o,p’DDD dose.
The efficacy of o,p’DDD therapy in patients with ACC is rather low: A tumor response was observed in only 31% of patients, and all patients experienced disease recurrence after a few months, in agreement with findings from previous studies.8 Whether these tumors became resistant to o,p’DDD or whether the o,p’DDD level was inaccurate at the time of disease progression remains an open question. It is notewor- thy that all four patients who initially responded to o,p’DDD had a plasma o,p’DDD level < 14 mg/L at the time of tumor progression, suggesting that sec- ondary resistance may not be the rule in all patients. The low efficacy of o,p’DDD is highlighted further by the 72% recurrence rate among patients on adjuvant o,p’DDD therapy despite achieving a plasma o,p’DDD level within the therapeutic range in 72% of patients. Alternative therapeutic regimens should be developed both for the management of patients with metastatic ACC and for patients on adjuvant therapy. Neverthe- less, in this context, plasma o,p’DDD measurement still permits the selection of patients who may re- spond to therapy, because a tumor response was ob- served in 66% of patients with plasma o,p’DDD levels > 14 mg/L, whereas no patient with plasma o,p’DDD levels below this value achieved a tumor response.
The results of this study also underscore two other important issues: First, despite the high daily o,p’DDD dose (6-12 g), only 58% of our patients achieved ther- apeutic o,p’DDD levels. This is in agreement with the study by Haak et al.,19 who found that 48% of patients had a plasma o,p’DDD level < 14 mg/L during main-
30- mg/L
25
20
15
10
g / day
5
0
3
6
9
12
15
18
21
24
27
30
33
35
38
41
44
months
tenance therapy with mitotane administered in tablet form after initial therapy with mitotane (4-8 g per day) given in chocolate, milk powder, or oil-emulsion preparations. In contrast, in a recent study, all eight patients who were treated prospectively with low doses of o,p’DDD (2-3 g daily) in tablet form reached the therapeutic o,p’DDD level.24 Moreover, those au- thors found a highly significant correlation between the total cumulative o,p’DDD dose and plasma o,p- ‘DDD levels. We also found that the cumulative o,p- ‘DDD dose was the only parameter associated with the plasma o,p’DDD trough level. However, the daily o,p’DDD dose explained only 35% of the variability between patients in the plasma o,p’DDD level, sug- gesting that other parameters should be sought to explain the plasma o,p’DDD dose. It is noteworthy that both the daily o,p’DDD dose and the o,p’DDD vehicles were different in the two above-mentioned studies and in the current study. Considering these results together, we hypothesize that a high or low daily o,p’DDD dose may not be the only explanation for discrepancies, but the various vehicles used in these studies also may be contributing factors. The impact of the o,p’DDD vehicle is highlighted further by the study by Moolenaar et al.,25 who reported that the mean plasma o,p’DDD level after a 2-g dose was higher administered in tablet form compared with the enteric-coated, gastric-resistant granules in the cap- sules used in our study. Those authors also demon- strated that milk or emulsion may improve o,p’DDD resorption. Even if poor patient compliance cannot be ruled out in our study, we believe that this is unlikely for the majority of our patients.
Second, a mean of 3.7 months was necessary to reach the highest o,p’DDD levels when all patients or only patients who reached the 14 mg/L cut-off value
were considered. Likewise, the therapeutic threshold was reached 3-5 months after the initiation of o,p’DDD therapy in tablet form in the study by Ter- zolo et al.24 Again, this result suggests that the main difference between the various o,p’DDD vehicles may be various resorption rates. From a clinical point of view, this result suggests that patients with ACC that exhibits a highly aggressive course may require first- line therapy using other and/or associated chemo- therapeutic drugs. The time to reach therapeutic plasma o,p’DDD levels as well as the slow plasma o,p’DDD level decrease after discontinuation of the drug is compatible with its accumulation in lipid stores, as suggested previously.26,27
The results of this prospective study confirm the impact of o,p’DDD plasma level measurement on the medical management of patients with ACC who are treated with o,p’DDD. We confirm the therapeutic impact of plasma o,p’DDD levels > 14 mg/L. The daily o,p’DDD dose explained 35% of the highest plasma o,p’DDD trough levels. Finally, physicians should be aware of the mean time needed to achieve therapeutic o,p’DDD levels. Alternative therapeutic modalities should be developed for the therapeutic management of patients with ACC.
REFERENCES
1. Nader S, Hickey RC, Sellin RV, Samaan NA. Adrenal cortical carcinoma: a study of 77 cases. Cancer 1983;52:707-11.
2. Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, et al. Clinical features of adrenocortical carci- noma, prognostic factors, and the effect of mitotane ther- apy. N Engl J Med 1990;322:1995-201.
3. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery 1992;112:963-71.
4. Icard P, Louvel A, Chapuis Y. Survival rates and prognostic factors in adrenocortical carcinoma. World J Surg 1992;16: 753-8.
5. Latronico AC, Chrousos GP. Adrenocortical tumors. J Clin Endocrinol Metab 1997;82:1317-24.
6. Gicquel C, Baudin E, Lebouc Y, Schlumberger M. Adreno- cortical carcinoma. Ann Oncol 1997;8:423-7.
7. Barzon L, Fallo F, Sonino N, Daniele O, Boscaro M. Adre- nocortical carcinoma: experience in 45 patients. Oncology 1997;54:490-6.
8. Wooten MD, King DK. Adrenal cortical carcinoma. Epide- miology and treatment with mitotane and a review of the literature. Cancer 1993;72:3145-55.
9. Bukowski RM, Wolfe M, Levine HS, Crawford DE, Stephens RL, Gaynor E, et al. Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. J Clin Oncol 1993;11:161-5.
10. Bonacci R, Gigliotti A, Baudin E, Wion-Barbot N, Emy P, Bonnay M, et al. Cytotoxic therapy with etoposide and cis- platin in advanced adrenal cortical carcinoma. Br J Cancer 1998;78:546-9.
11. Carpenter PC. Mitotane failure in adrenocortical cancer: where next [editorial]? Cancer 1993;71:2900-1.
12. Bergenstal DM, Hertz R, Lipsett MB, Moy RH. Chemother- apy of adrenocortical cancer with o,p’DDD. Ann Intern Med 1960;53:672-82.
13. Lipsett MB, Hertz R, Ross GT. Clinical and pathophysiologic aspects of adrenocortical carcinoma. Am J Med 1963;35: 374-83.
14. Hutter AM Jr., Kayhoe DE. Adrenal cortical carcinoma: re- sults of treatment with o,p’DDD in 138 patients. Am J Med 1966;41:581-92.
15. Bates SE, Shieh CY, Mickley LA, Dichek HL, Gazdar A, Lori- aux L, et al. Mitotane enhances cytotoxicity of chemother- apy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed in adreno- cortical carcinomas. J Clin Endocrinol Metab 1991;73:18-29.
16. Schtiengart DE, Motazedi A, Noonan RA, Thompson NW. Treatment of adrenal carcinomas. Arch Surg 1982;117: 1142-6.
17. Venkatesh S, Hickey R, Sellin R, Fernandez JF, Samaan NA. Adrenal cortical carcinoma. Cancer 1989;64:765-9.
18. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, Taylor SH, Hess KR, Schultz PN, et al. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 1994;73:1533-4.
19. Haak HR, Hermans J, Van de Velde CJH, Lentjes EGWM, Goslings BM, Fleuren GJ, et al. Optimal treatment of adre- nocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994;69:947-51.
20. Kasperik-Zaluska AA, Migdalaska BM, Zgiczynski S, Ma- kowska A. Adrenocortical carcinoma-a clinical study and treatment results of 52 patients. Cancer 1995;75:2587-91.
21. Dickstein G, Shechner C, Arad E, Best LA, Nativ O. Is there a role for low doses of mitotane (o,p’DDD) as adjuvant ther- apy in adrenocortical carcinoma ? J Clin Endocrinol Metab 1998;83:3100-3.
22. Dickstein G. Is there a role for low doses of mitotane (o,p- ‘DDD) as adjuvant therapy in adrenocortical carcinoma [au- thors’ response]? J Clin Endocrinol Metab 1999;84:1488-9.
23. Van Slooten H, Moolenaar AJ, Van Seters AP, Smeenk D. The treatment of adrenocortical carcinoma with o,p’DDD: prog- nostic implications of serum level monitoring. Eur J Clin Oncol 1984;20:47-53.
24. Terzolo M, Pia A, Berruti A, Osella G, Ali A, Carbone V, et al. Low-dose monitored mitotane treatment achieves the ther- apeutic range with manageable side effects in patients with adrenocortical cancer. J Clin Endocrinol Metab 2000;85: 2234-8.
25. Moolenaar AJ, Van Slooten H, van Seters AP, Smeenk D. Plasma levels of o,p’DDD following administration in vari- ous vehicles after a single dose and during long-term treat- ment. Cancer Chemother Pharmacol 1981;7:51-4.
26. Touitou Y, Moolenaar AJ, Bogdan A, Auzépi A, Luton JP. o,p’DDD (mitotane) treatment for Cushing’s syndrome: ad- renal drug concentration and inhibition in vitro of steroid synthesis. Eur J Clin Pharmacol 1985;29:483-7.
27. Cueto C, Brown JHU. Biological studies on an adrenocorti- colytic agent and the isolation of the active components. Endocrinology 1958;62:334-9.