RAPID PUBLICATION
Rapidly progressing high o,p’DDD doses shorten the time required to reach the therapeutic threshold with an acceptable tolerance: preliminary results
Antongiulio Faggiano*, Sophie Leboulleux*, Jacques Youngt, Martin Schlumberger* and Eric Baudin*
*Department of Nuclear Medicine and Endocrinological Oncology, Gustave-Roussy Institute, Villejuif, +Endocrinology Unit, Centre Hospitalier Universitaire de Bicêtre, Assistance Publique-Hôpitaux de Paris, and Faculté de Médecine Paris-Sud, Paris, France
Summary
Introduction It has been reported that the therapeutic threshold of mitotane, plasma level above 14 µg/ml, is achieved within 3-5 months after o,p’DDD treatment initiation in patients with adren- ocortical carcinoma (ACC).
Objective and design We evaluated pharmacokinetic and toler- ance of a high-dose schedule of pure o,p’DDD treatment given in 500-mg tablets of mitotane (Lysodren, Bristol-Myers Squibb, HRA Pharma, Paris, France) in four patients with ACC and two patients with Cushing’s syndrome-related endocrine tumours. It was administered at a starting dosage of 3 g/day, which was rapidly increased to 6-9 g/day within 2 weeks according to digestive tolerance and then adjusted according to tolerance and plasma o,p’DDD monitoring. Patients were followed up until they reached the therapeutic threshold of mitotane, and toxicity was recorded. A relationship between o,p’DDD dose and plasma level was sought.
Results The highest starting dosage given ranged between 6 and 9 g a day, during the first two weeks. The daily maintenance dose ranged 4.5-9 g during the next 2 weeks and 3-9 g by the second month of treatment. The therapeutic threshold was reached in all four patients who received o,p’DDD treatment for at least 1 month. Among these four patients, the toxic threshold (plasma mitotane level > 20 µg/ml) was even reached at 6 weeks of therapy in three patients. Grade 1, 2 or 3 toxicity was observed in 3, 2 and 1 patients, respectively. Toxicity resolved after reduction or discontinuation of o,p’DDD therapy. A significant linear correlation was found between plasma mitotane dose and plasma level.
Conclusions These results suggest that a high-dose o,p’DDD ther- apeutic schedule is feasible with an acceptable toxicity and may shorten the time required to reach the therapeutic schedule from 3-5 months to 4 weeks. These patients require a close follow-up, combining clinical and plasma o,p’DDD level monitoring every second week. A confirmatory study is ongoing.
(Received 17 May 2005; returned for revision 12 June 2005; finally revised 8 July 2005; accepted 27 July 2005)
Introduction
More than 40 years after its first use, o,p’DDD, 1,1-dichloro-2-(o- chlorophenyl)-2-(p-chlorophenyl) ethane remains one of the most attractive agents both for controlling tumour growth and inhibiting steroid hypersecretion in patients with adrenocortical carcinoma (ACC)1,2 and in those with Cushing’s syndrome-related endocrine tumour as well.3 A 30% objective response rate has been observed in patients with ACC, but cure is rarely achieved and its impact on survival is questioned.46 Recently, two studies have suggested that patients in whom plasma mitotane levels reach 14 µg/ml may expect a 55-66% objective response rate.7,8 These new data reinforce the use of o,p’DDD in patients with ACC but also highlight two major features of o,p’DDD therapy: first, a 14 ug/ml plasma level was obtained after 3-5 months, which delays the effective therapeutic activity of o,p’DDD therapy, and second, discrepancies in bioavailability between o,p’DDD formulations were suspected. Using a cumulative dose of 1303 g of micronized o,p’DDD mixed with cellulose acetyl- phtalate (mitotane 500-mg gelatine capsules, Assistance Public- Hôpitaux de Paris), we reported a 58% success rate8 and in contrast, another study reported 100% success in obtaining 14 µg/ml plasma levels with a cumulative dose of 383 g pure o,p’DDD not mixed with vehicle (mitotane 500-mg tablets, Lysodren, Bristol-Myers Squibb).7
Therefore, we studied whether high-dose therapy with pure o,p’DDD may help to shorten the time needed to reach the thera- peutic threshold in consecutive patients with ACC or Cushing’s syndrome-related endocrine tumour. Associated short-term toxicity, between time since onset of therapy and first therapeutic mitotane levels, was recorded. A relationship between o,p’DDD dose and plasma level was sought.
Patients and methods
Six consecutive patients (three men and three women; median age, 48 years; range, 34-71 years) entered the study. Population study
included four ACC and two Cushing’s syndrome-related endocrine tumours, one secondary to a medullary thyroid carcinoma (MTC) and the other to a lung carcinoid. Three of the four patients with ACC had Weiss scores above 3 and were treated in an adjuvant setting, and the fourth patient was treated at a metastatic stage of the disease. o,p’DDD (mitotane 500-mg tablets) was administered orally three times per day during a meal containing fat, at a starting dosage of 3 g a day, which was rapidly increased (1-5 g per day) to 6-9 g a day within 2 weeks according to digestive tolerance. The highest tolerated dose was used as maintenance dose over 6 weeks. All patients except two with Cushing’s syndrome (one ACC-related and one lung carcinoid-related Cushing’s syndrome) received adrenal replacement therapy, i.e. hydrocortisone (30-60 mg/day) and fludrocortisone acetate (25-50 µg/day) when o,p’DDD therapy was started (three patients with ACC) or 2 weeks after the beginning of o,p’DDD therapy (a patient with MTC-related Cushing’s syndrome). Other drugs given included: insulin or hypoglycaemic agents in four patients, levothyroxine in one, antihypertensive drugs in two, anxyolythics in two, and heparinic therapy in two patients.
Fasting morning plasma o,p’DDD levels (at least 12 h after the previous dose) were measured by high-pressure liquid chromato- graphy, as previously described® every second week. Toxicity criteria were scored according to the NCI-CTC classification. A linear regression analysis was performed between the cumulative dose of o,p’DDD, expressed as grams per day of treatment and the plasma mitotane levels at each time-point evaluated (significance was set at 5%).
Results
The maximum daily dosage administered within the first 2 weeks ranged between 6 and 9 g/day (see Table 1). The maintenance dosage given during weeks 3 and 4 ranged between 4-5 and 9 g a day, and
during weeks 5 and 6, ranged between 3 and 9 g a day. Only patient 2 had a decreased mitotane dosage between weeks 3-4 and 5-6. The therapeutic threshold, corresponding to a plasma mitotane level above 14 ug/ml, was reached within 2 weeks in one patient and within 4 weeks in three other patients (see Table). The two remaining patients did not succeed in reaching the 14 ug/ml plasma mitotane level: patient 1, with a metastatic ACC, died after 18 days of pulmo- nary embolism and patient 4, with a lung carcinoid-related Cush- ing’s syndrome, underwent a surgical bilateral adrenalectomy after 23 days. Among the four patients who reached the 14 ug/ml plasma mitotane level, a toxic threshold (plasma mitotane level > 20 µg/ml) was reached at 6 weeks of therapy in three of them. Among the three patients with Cushing’s syndrome, serum/urinary cortisol levels were decreased to the lower limits of the normality range in the patient with MTC, and mildly decreased but not normalized in the remaining two patients.
Toxicities were scored according to NCI-CTC criteria: nausea grade 1 was observed in two patients (nos. 2 and 3) or grade 3 in one (no. 1) who had also diarrhoea grade 2. Both grades 2 and 3 digestive toxicities (no. 1) resolved after reduction of o,p’DDD dos- age from 9 to 6 g a day and the improvement of digestive complaints was observed since the first day of dose reduction. As a whole, diges- tive side effects occurred early after the beginning of o,p’DDD treat- ment and were independent from the achievement of the plasma mitotane toxic threshold. On the contrary, neurologic toxicity was observed in two patients (nos. 2 and 5) after the first month of o,p’DDD treatment. Patient 5 experienced a grade 1 neurologic toxicity (vertigo) in association with a plasma mitotane level ranging 14-20 µg/ml and patient 2 experienced a grade 2 neurological tox- icity (vertigo, ataxia, sleepiness and confusion) in association with a plasma mitotane level > 20 µg/ml, which persisted after reduction of the o,p’DDD dosage from 7.5 to 3 g a day and rapidly resolved after o,p’DDD discontinuation for 1 week (see Table 1). None of the two other patients experiencing a higher than 20 µg/ml mitotane
| Week | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | Patient 6 |
|---|---|---|---|---|---|---|
| Age (years) | 38 | 34 | 51 | 68 | 45 | 6 |
| Sex | M | F | M | F | F | M |
| Body weight | 72.5 | 57 | 65-5 | 79 | 62 | 73 |
| Clinical diagnosis | ACC | ACC | MTC + CS | LC + CS | ACC | ACC + CS |
| Maximum o,p'DDD dose | 9 | 7.5 | 9 | 6 | 6 | 6 |
| Maintenance o,p'DDD dose | 6 | 3* | 9 | 6 | 6 | 4.5 |
| Highest plasma mitotane levels | ||||||
| During weeks I-II | 5.3 | 6.3 | 17.3 | 8.9 | 11.1 | 12.9 |
| During weeks III-IV | 5.0 | 15.1 | 17.3 | 3.0 | 16-7 | 14.9 |
| During weeks V-VI | – | 23-2 | 35.0 | – | 17-6 | 26-3 |
| Toxicities (WHO criteria) | ||||||
| Nausea | Grade III | Grade I | Grade I | |||
| Diarrhoea | Grade II | |||||
| Neurologic | Grade II | Grade I | ||||
| Treatment duration | 18 day | 6 weeks | 6 weeks | 23 days | 6 weeks | 6 weeks |
*The o,p’DDD dosage was decreased from 7.5 to 3 g/day at the 5th week of treatment, whereas the maintenance dosage was 7.5 g/day during the first month; ACC, adrenocortical carcinoma; MTC, medullary thyroid cancer; CS, Cushing’s syndrome; LC, lung carcinoid; M, male; F, female.
450
350
Total o,p’DDD dose
250
150
50
50
40
30
20
10
0
0
5
10
15
20
25
30
35
40
Plasma mitotane levels
levels complained of neurological toxicity. Nevertheless, mitotane dose was halved in one patient and 1.5 g reduced in another patient, allowing to achieve a 14-20 µg/ml mitotane plasma level within 1 and 2 weeks, respectively.
A significant linear correlation (r = 0.75; P < 0-0001), was found between plasma mitotane level and cumulative mitotane dose (Fig. 1).
Discussion and conclusions
This preliminary study suggests that treatment with high, escalating dosage of pure o,p’DDD enables to shorten the time required to reach mitotane therapeutic threshold in patients with ACC or Cush- ing’s syndrome. Moreover, the patient’s tolerance was considered acceptable. Indeed, even if four of six patients experienced side effects commonly seen with o,p’DDD therapy and leading to an o,p’DDD reduction or discontinuation in patients 5 and 1, respec- tively, we consider that the high-dosage schedule of pure o,p’DDD triggered an earlier occurrence of side effect instead of an increased severity.
In one of six, and four of four patients who received o,p’DDD treatment, a therapeutic plasma mitotane levels were reached within 2 and 4 weeks, respectively. In fact, all patients treated at least 4 weeks reached an above 14 µg/ml o,p’DDD plasma level. Strikingly, an above 20 µg/ml plasma mitotane levels were even reached in three of four patients within 6 weeks of therapy. Therefore, a close clinical follow-up is warranted together with every second week of plasma o,p’DDD measurement in these patients. Of note, those results were obtained in patients treated with at least 6 g a day initial o,p’DDD dosage and at least 4.5 g a day maintenance dosage during the first month. These results compare favourably with our previous study in which comparable initiation o,p’DDD therapy was employed with another o,p’DDD formulation.8 Indeed, only 58% patients achieved a higher than 14 g/ml plasma mitotane over a 3-1-month mean time. Furthermore, 2 months were necessary before the first patients reach the therapeutic mitotane levels. We hypothesize that various vehicles, the altered cellulose acetylphtalate galenic formulation used in our initial study, initially dedicated to improve digestive
tolerance, account for a reduced bioavailability of this formulation as previously suggested.º A European multicentre mitotane trial addressing the pharmacokinetics of o,p’DDD in patients with ACC receiving either high or low mitotane dose is in progress, which we hope will definitely confirm the present data in a larger group of patients.
A severe neurological toxicity yielding to an o,p’DDD therapy dis- continuation was observed in only one of six patients. Interestingly, only one of three patients, for whom a higher than 20 µg/ml mito- tane level was reached, experienced a significant neurological toxicity during short- but also long-term follow-up. As previously stated, these results confirm the absence of a strict relationship between plasma mitotane levels and occurrence of secondary effects.4,8 Interestingly, severe digestive toxicity rapidly resolved after dose reduction, suggesting a direct toxic effect on the digestive mucosa. Although a prospective randomized study is warranted to definitely establish which o,p’DDD formulation may offer the best efficacy over toxicity ratio, the scarcity of these diseases combined with the critical need for new active agents suggest that such study is not considered a leading priority by most teams involved in this field.
In line with previous results,” we confirm a significant relationship between mitotane cumulative dose and mitotane plasma levels. Although obtained in a smaller group of patients, we observed a smaller variability between plasma level and cumulative mitotane dose than in our previous study in which micronized o,p’DDD mixed with cellulose acetylphtalate was used. These results may sug- gest that mitotane formulation partly accounts for the variability between patients in the plasma o,p’DDD dose. Of note, the lowest cumulative mitotane dosage requested to reach the therapeutic threshold was 18 g per day.
In conclusion, our preliminary results suggest that a pure o,p’DDD high-dose therapeutic schedule, which includes an at least 6 g a day initial o,p’DDD dosage achieved within 2 weeks and a main- tenance o,p’DDD dosage of at least 4.5 g a day for the following 2 weeks allows the achievement of a higher than 14 ug/ml mitotane level in 100%-treated patients within 4 weeks together with an acceptable toxicity. A closed clinical follow-up together with the every second week plasma o,p’DDD measurements constitute the basis of the early monitoring of these patients. A confirmatory study is ongoing.
References
1 Gicquel, C., Baudin, E., Lebouc, Y. & Schlumberger, M. (1997) Adren- ocortical carcinoma. Annals of Oncology, 8, 423-427.
2 Allolio, B., Hahner, S., Weismann, D. & Fassnacht, M. (2004) Management of adrenocortical carcinoma. Clinical Endocrinology, 60, 273-287.
3 Arnaldi, G., Angeli, A., Atkinson, A.B., Bertagna, X., Cavagnini, F., Chrousos, G.P., Fava, G.A., Findling, J.W., Gaillard, R.C., Grossman, A.B., Kola, B., Lacroix, A., Mancini, T., Mantero, F., Newell-Price, J., Nieman, L.K., Sonino, N., Vance, M.L., Giustina, A. & Boscaro, M. (2003) Diagnosis and complications of Cushing’s syndrome: a con- sensus statement. Journal of Clinical Endocrinology and Metabolism, 88, 5593-5602.
4 van Slooten, H., Moolenaar, A.J., van Seters, A.P. & Smeenk, D. (1984) The treatment of adrenocortical carcinoma with o,p’-DDD: prognostic
implications of serum level monitoring. European Journal of Cancer Clinical Oncology, 20, 47-53.
5 Wooten, M.D. & King, D.K. (1993) Adrenal cortical carcinoma. Epi- demiology and treatment with mitotane and a review of the literature. Cancer, 72, 3145-3155.
6 Haak, H.R., Hermans, J., van de Velde, C.J., Lentjes, E.G., Goslings, B.M., Fleuren, G.J. & Krans, H.M. (1994) Optimal treatment of adren- ocortical carcinoma with mitotane: results in a consecutive series of 96 patients. British Journal of Cancer, 69, 947-951.
7 Terzolo, M., Pia, A., Berruti, A., Osella, G., Ali, A., Carbone, V., Testa, E., Dogliotti, L. & Angeli, A. (2000) Low-dose monitored mitotane treat-
ment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer. Journal of Clinical Endocrinology and Metabolism, 85, 2234-2238.
8 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.
9 Moolenaar, A.J., Van Slooten, H., van Seters, A.P. & Smeenk, D. (1981) Plasma levels of o,p’-DDD following administration in various vehicles after a single dose and during long-term treatment. Cancer Chemo- therapy and Pharmacology, 7, 51-54.