Mitotane Associated with Etoposide, Doxorubicin, and Cisplatin in the Treatment of Advanced Adrenocortical Carcinoma
Alfredo Berruti, M.D. Massimo Terzolo, M.D. Anna Pia, M.D. Alberto Angeli, Ph.D. Luigi Dogliotti, Ph.D. for the Italian Group for the Study of Adrenal Cancer
Dipartimento di Scienze Cliniche e Biologiche, Uni- versità di Torino, Clinica Medica e Oncologia Med- ica, Azienda Ospedaliera San Luigi, Orbassano, Italy.
Presented in part at the 33rd Annual Meeting of the American Society of Clinical Oncology, Denver, Colorado, May 17-20, 1997.
Supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy.
The following investigators in Italy participated and are coauthors of this study: Franco Mantero, Ph.D., Clinica di Endocrinologia, Università di Ancona, Azienda Ospedaliera Regionale di Torrette, An- cona; Mario Boscaro, Ph.D., Istituto di Semeiotica Medica, Divisione Universitaria di Endocrinologia, Azienda Ospedaliera, Padova; Otello Daniele, M.D., Divisione di Oncologia Medica, Azienda Osped- aliera, Padova; Paola Loli, M.D., Divisione di En- docrinologia, Ospedale Niguarda Cà Granda, Mi- lano; Andrea De Matteis, M.D., Oncologia Endocrinologica Istituto Tumori di Napoli, Fondazi- one Pascale; Claudio Verusio, M.D., Ambulatorio di Radiochemioterapia, Istituto San Raffaele del Monte Tabor, Milano; Daniela Bisbocci, M.D., Di- visione di Medicina Interna, Università di Torino, Ospedale San Vito, Torino; Claudio Marcocci, M.D., Istituto di Endocrinologia, Metodologia Clinica e Medicina del Lavoro, Università di Pisa, Tirrenia (Pisa); Bruno Ambrosi, Ph.D., Istituto di Scienze Endocrine, Università di Milano, Ospedale Mag- giore, Milano; Silvia Della Casa, M.D., Istituto di Endocrinologia, Università Cattolica, Policlinico A.Gemelli, Roma; Franco Desiderio, M.D., Divisione di Oncologia, Ospedale di Rimini; Antonio Frassol- dati, M.D., Cattedra di Oncologia, Università di Modena; Gregorio Moro, M.D., Divisione di Radiot- erapia, Ospedale degli Infermi, Biella; Michele Zini,
BACKGROUND. The use of either mitotane or chemotherapy in the treatment of advanced adrenocortical carcinoma (ACC) has led to scanty and controversial results. The recent finding that mitotane is able to reverse in vitro multidrug resistance has provided a rational basis for combining this agent with cytotoxic drugs. The association of mitotane with etoposide, doxorubicin, and cisplatin (EDP) in the treatment of patients with advanced, inoperable ACC was tested in an Italian multicenter Phase II trial.
METHODS. Twenty-eight patients (18 women and 10 men; median age, 47 years; range, 27-65 years) with measurable disease were enrolled in the study and evaluated for toxicity and response. There were 18 patients with clinical and/or biochemical evidence of steroid hypersecretion. An EDP schedule (etoposide 100 mg/m2 on Days 5-7, doxorubicin 20 mg/m2 on Days 1 and 8, and cisplatin 40 mg/m2 on Days 1 and 9) was administered intravenously every 4 weeks; concom- itantly, patients were given up to 4 g/day of oral mitotane or the maximum tolerated dose, without any interruption between chemotherapy cycles.
RESULTS. According to World Health Organization criteria, complete response was achieved in 2 patients and partial response in 13, for an overall response rate of 53.5% (95% CI, 35-72%). Stable disease was observed in 8 patients and progressive disease in 5. Responses occurred in patients with both functioning and nonfunc- tioning tumors, and more often in those bearing lymph node and lung metastases. Time to progression in responding patients was 24.4 months. Generally, the EDP regimen was well tolerated. Only 4 patients received reduced doses, whereas 3 discontinued early chemotherapy due to toxicity. The addition of mitotane in- creased neurologic and gastrointestinal side effects. Due to these additional tox- icities, only 9 patients regularly took the drug at the planned dose (4 g/day); 11 received the maximum tolerated dose of 3 g/day, 6 received 2 g/day, and 1 received 1 g/day. Mitotane was also responsible for raised serum levels of cholesterol and triglycerides. A complete hormone response (normalization of altered biochemical parameters) was observed in 9 of 16 evaluable patients with functioning tumors. CONCLUSIONS. EDP plus mitotane combination chemotherapy appears to be active and manageable treatment for patients with advanced ACC. Cancer 1998;83: 2194-200. @ 1998 American Cancer Society.
KEYWORDS: adrenocortical carcinoma, mitotane, etoposide, doxorubicin, cisplatin.
M.D., Servizio di Endocrinologia, Arcispedale Santa Maria Nuova, Reggio Emilia; Armando Santoro, M.D., Oncologia Medica, Istituto Clinico Humani- tas, Rozzano, Milano.
Address for reprints: Luigi Dogliotti, Ph.D., Onco-
logia Medica, Azienda Ospedaliera San Luigi, Re- gione Gonzole 10, 10043 Orbassano, Italy.
Received July 10, 1997; revisions received De- cember 29, 1997, and April 13, 1998; accepted April 13, 1998.
A drenocortical carcinoma (ACC) is a rare tumor that affects between 0.5 and 2 people per million.1 Surgical resection is the treatment of choice, but it remains a crucial problem that many patients present with locally advanced or metastatic disease, and ap- proximately 20-30% of those radically resected will relapse.1
Since 1960, oral administration of mitotane, a drug with adrenolytic properties, has been considered the treatment of choice for patients with advanced disease that is not amenable to surgery.2 Apart from some isolated reports of lasting responses,2 the effi- cacy of mitotane in bringing about objective tumor regression has been questioned in large retrospective studies.3-6
Experience with nonspecific chemotherapy is lim- ited.2 Some activity has been reported for single agents, such as doxorubicin7 and cisplatin,8,9 evalu- ated in small, nonhomogeneous series of patients. Studies of combination chemotherapy have described remissions achieved with various schemes using cis- platin,10-13 most of them including etoposide. How- ever, because so few patients were recruited in the studies, the response rate varied markedly.
Some failures of nonspecific chemotherapy may now be explained by the recent finding that the mul- tidrug resistance 1 gene (MDR-1) is highly expressed in ACC cells.14 Further research has shown that mito- tane is able to reverse in vitro the multidrug resistance mediated by MDR-1 expression,15 thus providing a rational basis for its use in combination with cytotoxic drugs. In the only prospective Phase II trial of ad-
vanced ACC conducted so far, the combination of cisplatin and mitotane resulted in 11 objective remis- sions in 37 eligible patients.16 It is known that MDR-1 is not involved in cisplatin resistance,17 so a possible potentiating effect of mitotane in this study could be ascribed to an additive effect.
To evaluate the activity and toxicity of mitotane in association with combination chemotherapy, we de- signed a prospective Phase II trial in which mitotane was administered concomitantly with an etoposide, doxorubicin, and cisplatin (EDP) scheme to patients with advanced ACC whose disease was not amenable to surgical resection.
PATIENTS AND METHODS Study Design
The study began in 1993 at a single institution, and from July 1994 onward it became an Italian multi- center Phase II trial. Up to June 1997, 28 patients were recruited from 16 centers. The inclusion criteria were as follows: a histologic diagnosis of adrenocortical car- cinoma; locally advanced or metastatic disease not
amenable to radical surgical resection; measurable disease; adequate bone marrow reserve (white blood cells ≥3500/mm3 or neutrophils ≥1500/mm3 and platelets ≥150,000/mm3); adequate renal and hepatic function (creatinine clearance >60 mL/min, bilirubin and the ratio of aspartate aminotransferase to alanine aminotransferase ≤1.5 times the upper limit of nor- mality); Eastern Cooperative Oncology Group (ECOG) performance status18 <3; life expectancy >3 months; age ≤65 years; clinical and radiologic evidence of dis- ease progression; and absence of previous chemother- apy treatment, except mitotane in an adjuvant setting. Previous radiotherapy was allowed only for sites other than those considered for response evaluation.
Exclusion criteria were as follows: active infection; severe heart disease; brain metastases; previous or concomitant malignancies, except squamous cell car- cinoma of the skin or carcinoma in situ of the uterine cervix; osteoblastic bone metastases; and ascites and/or pleural effusions as the only indicators of ad- vanced disease.
The EDP scheme consisted of intravenous admin- istration of etoposide at doses of 100 mg/m2 on Days 5, 6, and 7; doxorubicin 20 mg/m2 on Days 1 and 8; and cisplatin 40 mg/m2 on Days 2 and 9. Cycles were repeated every 4 weeks. Chemotherapy was accompa- nied by appropriate antiemetic therapy according to the routine of individual clinicians. Colony stimulat- ing factors were allowed. Dose reduction (25%) was planned in case of severe neutropenia (World Health Organization [WHO] Grade 4) or thrombocytopenia (Grade ≥3). Chemotherapy was delayed for a maxi- mum of 2 weeks in the presence of leukopenia (white blood cell count <1000/mm3), thrombocytopenia (platelet count <100,000/mm3), or Grade >2 extrahe- matologic toxicity on the day of treatment.
Mitotane was administered orally at a starting dose of 1 g/day, with further progressive dose incre- ments up to 4 g/day (or the maximum tolerated dose) given in divided doses. If tolerated, mitotane was con- tinuously administered concomitantly with chemo- therapy and during the rest period between successive cycles, and afterwards until a diagnosis of progression or the onset of severe toxicity. All patients received concomitant administration of hydrocortisone or dexamethasone to prevent adrenal insufficiency. Three patients received a mineral corticoid supple- ment (9a-fluorocortisol).
EDP administration was planned for a maximum of 6 cycles. Early discontinuation was to be permitted whenever there was disease progression or unaccept- able toxicity.
Patient Evaluation
Prechemotherapy staging procedures consisted of medical history and physical examination; perfor- mance status, determined by ECOG18 criteria; weight; complete blood cell counts and differential, routine chemistry, which included renal clearances, serum cholesterol, and serum triglycerides; electrocardiogra phy; chest radiography or computed tomography (CT) chest scanning, if necessary; and abdominal CT scan- ning. Bone scanning was performed if symptoms were compatible with bone involvement. Physical examina- tion and hematologic profile were made before each course of chemotherapy; white blood cell, differential, and platelet counts were recommended between the 12th and the 15th day from the start of EDP adminis- tration (nadir).
Endocrine screening included measurement of plasma adrenocorticotropic hormone (ACTH), se- rum and urinary cortisol, serum dehydroepiandros- terone sulfate (DHEA-S), androstenedione (44), 17- hydroxyprogesterone (17-OHP), and testosterone. Screening was recommended at the time the treat- ment started and at 3 and 6 months. Hormone tests with commercially available reagents were per- formed by different laboratories. Radioimmunoas- say (RIA) techniques were used for steroid measure- ments; ACTH was measured by immunoradiometric assay (IRMA).
Treatment Evaluation
According to WHO criteria,19 a complete response (CR) was defined as the disappearance of all clinical evidence of tumor on physical examination or on ra- diography and the complete recalcification of all os- teolytic metastases for a minimum of 4 weeks. Partial response (PR) required at least a 50% decrease in all measurable tumor size and ≥50% recalcification of osteolytic appearances for at least 4 weeks without the appearance of new lesions. Progressive disease (PD) was defined as a ≥25% increase in the size of any measurable lesion or the appearance of new lesions. The evaluation of response to treatment was planned for the third and sixth cycles. Responses were to be confirmed by evaluation after at least 4 weeks of treat- ment. Complete hormone response was defined as the normalization of all biochemical parameters above the normal range. Partial hormone response was de- fined as a greater than 50% reduction in altered bio- chemical parameters compared with baseline; other results were defined as no response. Toxicities were graded using WHO criteria.19 Time to progression (TTP) was defined as the time from the beginning of treatment until disease progression or the last date of follow-up.
RESULTS Patient Characteristics
Table 1 lists the pretreatment characteristics of the 28 patients enrolled. The median age was 47 years (range, 27-66), and women outnumbered men (64% vs. 36%). At study entry, 7 patients (25%) had locally advanced disease and 21 (75%) had metastatic disease. Nineteen patients (68%) had previously undergone radical sur- gery for primary disease: 12 had undergone 1 surgical resection and 7 had undergone multiple resections for local recurrence or metastatic disease. The disease free interval for patients who underwent radical resec- tion was 13.5 months (range, 1-120 months). Five patients with locally advanced disease did not receive radical excision of the primary malignancy and were shown to have measurable disease on postoperative CT scanning, four were judged to be unresectable at diagnosis, and six had previously received adjuvant mitotane therapy.
The functional status of 27 patients was assessed immediately before chemotherapy started. Cushin- goid features were clinically evident in eight, three of whom had coexisting hyperandrogenism or viriliza- tion; hyperandrogenism alone was found in five. Bio- chemical evidence of hormone activity was observed in 18 of 27 patients (no endocrine data were available for 1 patient). Hypersecretion of androgen or precur- sor steroids was more prevalent than that of cortisol.
Treatment Received and Toxicity
A total of 140 EDP courses were administered. The median was 6 (range, 1-8). Of the 16 patients who completed the treatment plan (6 cycles), 12 received full doses of cisplatin, etoposide, and doxorubicin; 2 received reduced doses of cisplatin due to renal tox- icity, and 2 received reduced doses of all 3 drugs due to leukopenia and thrombocytopenia. Progressive dis- ease was responsible for early discontinuation for 5 patients. The one patient who achieved CR after the third cycle received only one consolidation course. The four patients who achieved disease stabilization (minor response) after the fourth cycle were then re- ferred for surgery. Three patients discontinued the treatment due to toxicity, which consisted of myocar- dial infarction in one patient and prolonged leukope- nia in two. The EDP regimen was delayed 1 week for 12 patients, for a total of 15 courses, and 2 weeks for 10 patients, for a total of 13 courses. Leukopenia and/or infections were the principal reasons for these delays. The planned dose of mitotane (4 g daily) was regularly received by 9 patients (32%), 2 of whom took 5 and 6 g/day, respectively. The maximum tolerated dose was 3 g/day for 11 patients (39%), 2 g/day for 6 (21%), and
| Characteristics | No. (%) of patients |
|---|---|
| Males | 10/28 (36%) |
| Females | 18/28 (64%) |
| Performance status (ECOG) | |
| 0-1 | 22/28 (79%) |
| 2-4 | 6/28 (21%) |
| Age (yrs) | |
| Median (range) | 47 (27-66) |
| Stage at diagnosis | |
| I | 1/28 (3%) |
| II | 11/28 (40%) |
| III | 12/28 (43%) |
| IV | 4/28 (14%) |
| Stage at study entry | |
| II | 2/28 (7%) |
| III | 6/28 (21%) |
| IV | 20/28 (72%) |
| Disease sites | |
| Adrenal | 15/28 (54%) |
| Lung | 12/28 (43%) |
| Liver | 9/28 (32%) |
| Lymph nodes | 7/28 (25%) |
| Abdomen | 3/28 (11%) |
| Bone | 2/28 (7%) |
| Previous treatment | |
| Radical surgery | 19/28 (68%) |
| Nonradical surgery | 5/28 (18%) |
| Mitotane | 6/28 (21%) |
| Symptoms/signs | |
| Hirsutism/acne | 10/28 (36%) |
| Hypertension | 10/28 (36%) |
| Muscle weakness | 8/28 (29%) |
| Obesity | 8/28 (29%) |
| Hypocalcemia | 7/28 (25%) |
| Moon facies | 7/28 (25%) |
| Menstrual disorders | 7/13ª (54%) |
| Buffalo hump | 5/28 (18%) |
| Diabetes mellitus | 4/28 (14%) |
| Striae rubrae | 3/28 (11%) |
| Palpable abdominal mass | 7/28 (25%) |
| Abdominal pain | 8/28 (29%) |
| Hormonal hypersecretion | |
| Serum | |
| 17-OHP | 10/21 (48%) |
| Androstenedione | 9/23 (39%) |
| Testosterone | 9/25 (36%) |
| Progesterone | 4/11 (36%) |
| DHEAS | 7/23 (30%) |
| Cortisol | 7/24 (29%) |
| Urine | |
| Cortisol | 8/19 (42%) |
ECOG: Eastern Cooperative Oncology Group; DHEAS: dehydroepiandrosterone sulfate; 17-OHP: 17- hydroxyprogesterone.
a Only female patients in premenopause were included.
1 g/day for 1 (4%). One patient received no mitotane at all, because he had experienced severe peripheral neurotoxicity while taking the drug in an adjuvant
| WHO Grade | 0 | 1 | 2 | 3 | 4 |
|---|---|---|---|---|---|
| Gastrointestinal | |||||
| Nausea/vomiting | 5 (18%) | 8 (28%) | 12 (43%) | 3 (11%) | – |
| Mucositis | 21 (75%) | 4 (14%) | 3 (11%) | – | – |
| Diarrhea | 18 (64%) | 4 (14%) | 6 (21%) | – | – |
| Hepatic | 24 (86%) | 2 (7%) | 2 (7%) | – | – |
| Hematologic | |||||
| WBC | 16 (57%) | 5 (18%) | 5 (18%) | 2 (7%) | – |
| Neutrophil | 14 (50%) | 1 (3%) | 6 (21%) | 6 (21%) | 1 (3%) |
| Platelets | 25 (89%) | – | 3 (11%) | – | – |
| Hemoglobin | 7 (25%) | 7 (25%) | 11 (39%) | 1 (3%) | 2 (7%) |
| Nadir | |||||
| WBC | 8 (28%) | 3 (11%) | 11 (39%) | 5 (18%) | 1 (3%) |
| Neutrophil | 8 (28%) | 2 (7%) | 4 (14%) | 8 (28%) | 6 (21%) |
| Platelets | 16 (57%) | 2 (7%) | 6 (21%) | 3 (11%) | 1 (3%) |
| Other toxicities | |||||
| Renal | 24 (86%) | 3 (11%) | 1 (3%) | – | – |
| Neurologic | 15 (54%) | 7 (25%) | 4 (14%) | 2 (7%) | |
| Asthenia | 7 (25%) | 8 (28%) | 13 (46%) | – | – |
| Myalgia | 19 (68%) | 8 (28%) | 1 (3%) | – | – |
| Cardiac | 26 (93%) | 1 (3%) | 1 (3%) |
WHO: World Health Organization; WBC: white blood cells.
a For each patient, the greatest toxicity was recorded.
setting. The main reasons for reducing mitotane doses were neurologic or gastrointestinal toxicities. One pa- tient discontinued mitotane due to gastric intolerance after the third EDP cycle.
The worst grades recorded for each patient for common toxicities are listed in Table 2. At every recy- cle, Grade ≥3 toxicity for white blood cells and hemo- globin were recorded in 2 and 3 patients; no patients experienced a comparable degree of platelet toxicity. The corresponding Grade ≥3 toxicities at nadir were leukopenia in 6 patients (21%), neutropenia in 14 (49%), and thrombocytopenia in 4 (14%). The most common extrahematologic side effects were gastroin- testinal, neurologic, and asthenia, but they were less than Grade 3 in almost all cases (Table 2). Both pe- ripheral and central neurologic toxicities were ob- served (Table 3). It is noteworthy that in two patients the central neurologic toxicity mimicked brain metas- tasis, which was excluded on CT scanning. No treat- ment-related deaths were reported.
Serum cholesterol was evaluated before each ad- ministration of the EDP regimen in 20 patients; serum triglycerides were concomitantly assessed in 17. All but 1 patient showed increased cholesterol levels within the first 2 months, which persisted throughout the treatment schedule. The maximum elevation ranged from 17% to 118%. Four patients showed a gradual increase, whereas 15 had an initial increase followed by stabilization or a later decrease. Triglyc-
| Toxicity | No. (%) of patients |
|---|---|
| Central neurologic | |
| Lethargy | 3 (11%) |
| Dizziness | 2 (7%) |
| Headache | 2 (7%) |
| Mental impairment | 2 (7%) |
| Peripheral neurologic | |
| Paresthesia | 6 (22%) |
| Motility | |
| impairment | 1 (4%) |
erides also increased in 15 of 17 patients during treat- ment, rising to exceedingly high levels (above 1000 mg/dL) in 1 patient. The monthly profiles of choles- terol and triglycerides did not seem to be related to the mitotane dose.
Response
The best responses recorded for each patient are out- lined in Table 4. Of the 28 evaluable patients, 2 (7.1%) had CR and 13 (46.4%) had PR, for an overall response rate of 53.5% (95% CI, 35-72%). Eight patients experi- enced stable disease (SD) (28.5%) and 5 experienced progression (17.8%). Five patients (1 PR, 4 SD) became disease free after radical resection. Responses oc- curred more often when disease was located in the lungs and lymph nodes. No difference in response rate was found when patients with and without hormone- producing ACC were compared. No correlation was found between administration of full doses and treat- ment response to the EDP regimen.
Disease responses instead seemed to be more fre- quent among the 9 patients who took mitotane at the planned dose (4 g/day) than among the 19 patients who did not tolerate these doses (66.6% response rate vs. 47.4%). Of the four SD patients, two were previously subjected to laparotomy and were judged not to be ap- propriate candidates for radical surgery. After a minor response was obtained (a 25-50% reduction in tumor mass), radical surgery bacome possible. A third patient had multiple bilateral lung metastases; she underwent surgical resection of left lung lesions and underwent reoperation on the right side after four chemotherapy cycles. The fourth patient had initially been judged in- operable on the basis of CT scan imaging, but a radical resection appeared to be feasible after chemotherapy.
Among the 5 patients who underwent surgery af- ter receiving EDP plus mitotane, disease progression occurred in 3 of them after 5, 15, and 19 months, respectively, whereas 2 patients still remained disease free at the last follow-up evaluation 5+ and 21+ months after surgery, respectively.
| Response | No. (%) of patients |
|---|---|
| CR | 2/28 (7.1%) |
| PRª | 13/28 (46.4%) |
| SDª | 8/28 (28.6%) |
| PD | 5/28 (17.9%) |
| CR + PR | 15/28 (53.5%) (95% *CI: 33-75%) |
| Disease free after chemotherapy ± surgery | 7/28 (25.0%) |
| Site of Disease | CR | PR | SD | P |
|---|---|---|---|---|
| Adrenal | 1/15 | 4/15 | 7/15 | 3/15 |
| Lung | 1/12 | 7/12 | 2/12 | 2/11 |
| Liver | 1/9 | 3/9 | 2/9 | 3/9 |
| Lymph nodes | 1/7 | 5/7 | 1/7 | – |
| Abdomen | – | 2/3 | 1/3 | – |
| Bone | – | 1/2 | 1/2 | – |
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; P: progression; CI: confidence interval.
a One patient with PR to chemotherapy and four patients with SD underwent radical surgery.
The median time to progression for responding patients was 24.4 months. All responding patients showed normalization or a consistent reduction in steroid hypersecretion. A complete hormone response was observed in 9 of 16 evaluable patients with func- tioning tumors.
During the follow-up, markedly increased ACTH concentrations were seen in 12 of the 19 evaluable patients. Among the 7 with stable ACTH levels, 2 dis- played active Cushing’s syndrome. Clinical signs of acute adrenocortical insufficiency were observed in 3 patients after approximately 3 months of therapy.
DISCUSSION
The primary aim of this Phase II study was to assess the activity and toxicity of mitotane when adminis- tered in association with a combination regimen con- taining etoposide, doxorubicin, and cisplatin. The EDP scheme contained the chemotherapeutic drugs most often given to patients with ACC.2 The advantage to the concomitant administration of mitotane is the potentiating effect that this agent may exert on che- motherapy cytotoxicity.15
The combination of EDP and mitotane appeared active in more than 50% of the patients, with re- sponses lasting approximately 2 years. Surgical resec- tion of residual tumor mass, performed when feasible, improved the CR rate. No difference in treatment ac- tivity was observed between patients who received full EDP doses and those who did not. However, a trend could be observed in the correlation between the ad- ministered dose and the response of disease to mito-
tane. As described elsewhere,13,16 both functioning and nonfunctioning tumors respond to this regimen.
Although accompanied by major side effects and some toxicity-related deaths,20 the EDP scheme has demonstrated its antitumor activity and has been widely used against gastric carcinoma. The current study confirms, in a multicenter setting, our previous findings,21-22 and suggests that this combination is feasible for ACC patients with manageable toxicity. The enhanced manageability could be explained in two ways. Firstly, the limited toxicity recorded in this series could in part be ascribed to the administration of doses of etoposide lower than those in the original EDP scheme (100 mg/m2 instead of 120 mg/m2), and in part to the better performance status of patients with advanced ACC over those with advanced gastric carcinoma. Secondly, steroid hormone hypersecretion may also have contributed to reducing the chemother- apeutic toxicity. This reduction could be due to the stimulatory effect of androgens on hematopoiesis and to the well-known action of corticosteroids in limiting the nausea and vomiting related to chemotherapy.23
The concomitant administration of mitotane in a dose regimen comparable to that used in this study previously accounted for increased cisplatin toxicity, no- tably gastrointestinal and neurologic toxicity, and con- sequently led to mitotane withdrawal from about 47% of patients.16 The results of our current series confirm that the combination of EDP and mitotane had additive neu- rologic toxicity. By contrast, gastrointestinal toxicity was lower, possibly due to the systematic use of 5HT3 antag- onist drugs. Only one patient needed to discontinue mitotane prematurely, whereas most patients received a reduced dose instead of the one planned (4 g/day). Be- cause mitotane is able to cross the blood-brain barrier,24 the observed neurotoxicity is also related to an accumu- lation of the drug in the central nervous tissue. As pre- viously reported,25 the central neurotoxicity recorded for two patients mimicked a symptomatology compatible with brain metastasis, which was later excluded on CT scanning.
The addition of mitotane to the EDP regimen has provoked additive biochemical side effects, such as lipid disorders. The development of hypercholesterol- emia has been mentioned briefly in some reports3,26 and described in a few cases.27,28 The hypercholester- olemia attributed to increased cholesterol synthesis was due to the drug’s known ability to block cyto- chrome P450-mediated reactions, thus impairing the formation of oxysterols responsible for down-regulat- ing hepatic cholesterol synthesis.28 The occurrence of hypertriglyceridemia as a consequence of taking mi- totane has rarely been described. One study27 re- ported hypertriglyceridemia in 1 of 3 patients mani-
festing with hypercholesterolemia after mitotane administration. Conversely, other authors were un- able to find any variation in triglyceride serum levels after mitotane therapy.28 In our series, 14 of 16 pa- tients had raised triglyceride levels during therapy. Triglyceride elevation was moderate in almost all pa- tients without any apparent correlation with mitotane dosing, except in one patient with exceedingly high values (>1000 mg/dL). Moreover, it should be noted that lipid disorders were usually transient, showing an early rise followed by stabilization or reduction.
It has been found that mitotane, because of its lipophilic nature, accumulates in the chylomicron, low density lipoprotein (LDL), and very low density lipoprotein (VLDL).29 Mitotane-induced LDL forma- tion probably promotes its uptake in the adrenals; hypertriglyceridemia, by contrast, may counteract the entry of mitotane into the brain or adrenals, and thus work as a resistance mechanism.29 The lipid disorders induced by mitotane administration may in turn pro- voke altered drug pharmacokinetics. In light of this, the concomitant administration of triglyceride-lower- ing drugs, such as gemfibrosil, would be advisable for improving mitotane activity.
The results of the endocrine evaluation confirmed that most adrenal tumors produce androgen or precur- sor steroids in the cortisol synthesis pathway.3º Elevated hormone levels of testosterone (36%), androstenedione (39%), and 17-OHP (48%) were more frequently found. Any physical signs of hyperandrogenism in a patient with an adrenal mass, with or without cushingoid habit, should lead to suspicion of an ACC. Overall, biochemical evidence of steroid hypersecretion was found in 62% of cases. However, in four patients the examined hormone variables were below or near the lowest limit of normal- ity. Previous mitotane therapy or very recent surgery could well account for these findings. The possibility of interference from previous treatment should be remem- bered in any discussion about endocrine findings in patients with advanced ACC.
A favorable hormone response to treatment was observed in most patients with functioning tumors (58.3% CR, 16.6% PR); normalization of steroid secre- tion was also attained in 3 patients who did not expe- rience a significant reduction in tumor mass.
Markedly increased serum ACTH levels occurred in some patients, despite supplemental glucocorticoid therapy. Plausible explanations for why they did so could be the reported ability of corticosteroid binding globulin to rise up to six times the normal levels in chronic mitotane treatment31 and/or the mitotane- induced enhancement of steroid metabolism by mi- crosomial liver enzymes.32
Our findings suggest the need for steroid coverage
at doses higher than those previously thought. The additional support benefited some patients, even when individual schedules could not be assessed on the basis of serum ACTH.
In conclusion, combination chemotherapy con- sisting of EDP and mitotane appeared active and man- ageable. With respect to EDP alone, some additional side effects due to mitotane concomitant medication, such as neurotoxicity and hyperlipidemia, were ob- served. This combination regimen should be further explored with a larger series of patients.
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