O BIOL T
WORLD Journal of SURGERY $ 2001 by the Sociéte Internationale de Chirurgie
Cytotoxic Treatment of Adrenocortical Carcinoma
Håkan Ahlman, M.D., Ph.D.,1,4 Amir Khorram-Manesh, M.D.,1,4 Svante Jansson, M.D., Ph.D.,1,4 Bo Wängberg, M.D., Ph.D.,1,4 Ola Nilsson, M.D., Ph.D.,2,4 Carl-Erik Jacobsson, M.D., Ph.D.,3 Sven Lindstedt, M.D., Ph.D.3
1Department of Surgery, Sahlgrenska University Hospital, Göteborg University, S-413 45 Göteborg, Sweden
2Department of Pathology, Sahlgrenska University Hospital, Göteborg University, S-413 45 Göteborg, Sweden
3Department of Clinical Chemistry, Sahlgrenska University Hospital, Göteborg University, S-413 45 Göteborg, Sweden
+Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital. Göteborg University, S-413 45 Göteborg, Sweden
Published Online: June 27, 2001
Abstract. Adrenocortical carcinoma (ACC) is a rare, aggressive tumor that is often detected in an advanced stage. Medical treatment with the adrenotoxic drug mitotane has been used for decades, but critical pro- spective trials on its role in residual disease or as an adjuvant agent after surgical resection are still lacking. The concept of a critical threshold plasma level of the drug must be confirmed in controlled studies. Because individual responsiveness cannot be predicted, the use mitotane is still advised for nonresectable disease. In case of cortisol or other steroid overproduction, several drugs (e.g., ketoconazole or aminoglutethimide) may be used. Chemotherapy with single agents (e.g., doxorubicin or cisplatin) have been disappointing, with low response rates (< 30%) and a short response duration. Part of this refractoriness may be explained by the fact that ACC tumors express the multidrug-resistance gene MDR-1. Chemotherapy with multiple agents has been tested in smaller series and has resulted in significant side effects. The best results were achieved by the combination of etoposide, doxorubicin, and cisplatin associated with mitotane, achieving a response rate of 54%, including individual complete responses. To be able to make progress in treating advanced ACC disease, adjuvant multicenter trials must be encouraged. When mitotane-based therapies are used, monitored drug levels are mandatory.
Adrenocortical carcinoma (ACC) is a rare tumor with a dismal prognosis. It is slightly more common in women than in men. With an annual incidence of 0.5 to 2.0 per million population, 16 new cases are diagnosed in Sweden each year [1, 2]. The age distribu- tion is bimodal, with peaks during the first and fifth decades. Retrospective studies of combined surgical and medical therapy indicate an overall 5-year survival of 35% to 58% at best [2]. The therapeutic results are largely dependent on tumor stage as de- fined by MacFarlane and later investigators [3-5] (Table 1). The most severe prognostic factor is the presence of metastases. More than half of ACCs are hormonally active, which eventually may lead to early diagnosis. In children ACCs are commonly func- tional. In elderly patients ACC tumors are usually detected at an advanced stage because of the mass effect or incidentally by radiologic investigations [6, 7]. Some reports have emphasized the
poor prognosis in patients with large tumors and endocrine symp- toms [8, 9], but multivariate analyses have failed to confirm such a correlation [5, 10]. A better prognosis has been claimed for young individuals and patients with predominantly androgen and pregnenolone secretion [10, 11]. In reviews that included small series of patients there is a probable selection bias due to empha- sis of unique tumor aspects leading to overrepresentation of functional tumors (e.g., female patients with more easily detected endocrine symptoms) [7].
Surgery is the treatment of choice for patients with resectable primary and secondary tumors and for recurrent disease [4, 5, 9, 12, 13]. Because most ACCs in adults are diagnosed in advanced stages, however, effective medical treatment have been sought. Mitotane (o,p’-DDD) has potent adrenolytic (anticortisol) effects and may retard the growth of individual ACCs [14-16]. In a large retrospective multicenter study mitotane seemed to improve the survival rate but only in patients with metastases [11]. Several cytotoxic agents have been used as monotherapy or combination therapy to treat advanced disease. The objective response rates have been low, so the search for better medical treatment proto- cols for ACC-is a continuing challenge [17-20]. Radiotherapy has been used to palliate pain due to bone metastases and occasion- ally as an adjunct to chemotherapy, but its therapeutic value has not been fully explored [12, 21-23].
Mitotane
Based on the initial observation in dogs of an adrenolytic effect of the insecticide DDD (selective destruction of zonae reticularis and fasciculata with reduced secretion of 17-hydroxycorticoste- roids and inhibited response to ACTH), Bergenstal et al. [24] in 1960 introduced treatment with o,p’-DDD [1,1-dichloro-2-(o- chlorophenyl)-2(p-chlorophenyl) ethane; mitotane] in 18 ACC patients and reported significant tumor regression and reduced corticosteroid secretion in 7. Mitotane blocks cortisol synthesis by inhibiting 118-hydroxylation and cholesterol chain cleavage [25]
Correspondence to: H. Ahlman, M.D., e-mail: hakan.ahlman@surgery. gu.se
| Stage | Criteria |
|---|---|
| I | Tumor < 5 cm in diameter and confined to the adrenal |
| II | Tumor > 5 cm in diameter and confined to the adrenal |
| III | Tumor of any size with lymph node metastases or local invasive growth (i.e., tumor growth outside the adrenal but not involving adjacent organs) |
| IV | Tumor of any size with lymph node metastases and local invasive growth, growth into adjacent organs, or distant metastases |
CHOLESTEROL
desmolase
PREGNENOLONE
hydroxylase
> 17 OH-PREGNENOLONE
DEHYDROEPI- ANDROSTERONE
3 8 - OH dehydrogenase; A” A” isomerase
4
1.7 a
PROGESTERONE
> 17 OH-PROGESTERONE
4 & ANDROSTENE 3,17 - DIONE
21 - hydroxylase
ANDROGENS
11 - DEOXYCORTICOSTERONE 11 - DEOXYCORTISOL
11 B - hydroxylase
ESTRADIOL
CORTICOSTERONE
CORTISOL
18 - hydroxylase 18 OH - dehydrogenase
☒ GLUCOCORTICOIDS
ALDOSTERONE
☒ MINERALOCORTICOIDS
(Fig. 1). Even though the doses of the drug were high (8-10 g) with abundant side effects in the central nervouse system, liver, kidney, and bone marrow, these findings encouraged the National Cancer Institute to conduct a large trial in 138 patients.
Hutter and Kayhoe [26] reported this study in 1966 and noted reduced steroid-and non-steroid-induced symptoms (pain, weak- ness, anorexia) in about half of the patients. Of 59 patients with measurable disease, 20 (34%) showed objective tumor regression at a daily mitotane dose of 8 to 10 g with a median duration of 7
months. However, decreased steroid levels were not correlated with tumor regression and thus cannot be used as an indicator of the antiproliferative response. The most common side effects were nausea and vomiting, but diarrhea, skin rash, depression, and neurologic disorders (somnolence, vertigo, ataxia) occurred as well; all were reversible with cessation of treatment. A matched control group without mitotane was not included so prolonged survival due to treatment was not proven. Nevertheless, the au- thors concluded that mitotane was indicated in patients with inoperable ACC, with or without hormonally induced symptoms.
During the early 1970s Lubitz et al. [14] investigated 115 pa- tients with inoperable ACC using increasing doses of mitotane until side effects occurred. Most patients were treated with 5 to 10 g daily, but the maintenance doses varied greatly (0.5-20.0 g). Among the patients with steroid hypersecretion, 85% showed a biochemical response. Of 75 patients with measurable disease, 46 (61%) showed tumor regression. The survival in this series of mitotane-treated patients was twice as high as reported in histor- ical controls. The survival advantage was interpreted to be due to the treatment. In comparison with the study of Hutter and Kayhoe [26], the more favorable response rates were biased by a shorter time interval between diagnosis and treatment. During the same time period Hoffmann et al. [16] reported a small series of 19 patients given mitotane in variable doses (1-10 g) for periods of 5 weeks to 19 months with much less convincing antiproliferative effects and substantial toxicity. Because individual patients had long periods of remission, these reports concluded that a trial with mitotane is justified in inoperable cases and in cases with severe steroid hypersecretion. Several groups have later reported in- creased serum cholesterol levels after high-dose mitotane owing to induction of the rate-limiting enzyme 3-hydroxy-3-methylgiu- taryl coenzyme A (HMG CoA) reductase [25].
The enthusiasm for mitotane peaked during the mid-1980s, when Boven et al. [27] reported a patient with a histology-proven complete response and referred to seven similar cases from the literature. Subsequent large trials were less encouraging, with transient partial responses in 19% to 34% of the patients and no complete responses [10, 12, 28, 29]. Several studies failed to show a significant increase in survival even in patients with an objective response to mitotane [7].
The concept of mitotane as adjuvant therapy was introduced during the 1980s. Low maintenance doses were used to avoid side effects and enable long-term treatment in patients without metas- tases. Schteingart et al. [15] studied ACC patients after resection of the primary tumor, local radiation therapy, or both. No che- motherapy was given to one group of patients (n = 6), and mitotane was given to the other group (n = 17). A high dose was used (6-10 g) in the presence of metastatic disease; but in patients without metastases or prior to debulking a recurrent tumor a low maintenance dose (1-2 g) was used. In this limited study with two groups of patients, comparable in terms of tumor stage and steroid production, survivals were four times longer in the mito- tane-treated group. The therapeutic response seemed to depend on when in the course of disease the mitotane treatment was instituted. As expected, the longest survival was seen in tumor- free patients with adjuvant mitotane therapy, and in patients on mitotane prior to resection of a recurrent tumor. Additional support for this concept was offered by Venkatesh et al. [29], who reported that six of seven patients on adjuvant mitotane were alive 1 to 4 years after surgery. Recurrent or metastatic disease devel-
oped in all seven patients studied by Pommier and Brennan [13], with no demonstrable increase in the disease-free interval. Vassi- lopoulou-Sellin et al. [30] reported that the 2-year survival after surgery was rather negatively influenced by adjuvant mitotane therapy. In a recent Italian series 26 patients with localized or regional disease were divided into two comparable groups given mitotane treatment (4-8 g daily) or not after tumor resection. Cumulative disease-free interval and survival rates were not sig- nificantly different for the two groups [31, 32].
The toxicity of mitotane has been a major obstacle in the treatment of ACC patients [16, 33]. Van Slooten et al. [33] evaluated toxic and nontoxic levels of the drug by monitoring its serum concentration and tried to relate serum levels to therapeu- tic effects. In their retrospective study of 34 high-risk patients (high-stage tumors or peroperative tumor spillage), increased survival was seen in 14 patients with mitotane levels exceeding 14 ng/ml compared with patients not treated after the discovery of metastases. No therapeutic effects were seen in patients with mitotane levels lower than 10 ug/ml. Levels exceeding 20 µg/ml were associated with neuromuscular toxicity. This study pointed out the possibility of individually adjusted mitotane therapy with few side effects and a potential threshold level for effective ther- apy.
In a French multicenter study of 156 patients mitotane treat- ment improved survival only in patients with metastases who received the drug subsequent to surgery [11]. In the average dosage used (3-4 g daily) the drug had relatively high patient compliance.
In a large retrospective study from a single institution Haak et al. [34] evaluated the efficacy of mitotane treatment in 96 patients. Total tumor resection was accomplished in 47 patients and sub- total resection in 37. Mitotane treatment was classified as high dose or low dose relative to the 14 ug/ml threshold. Adjuvant mitotane treatment did not influence survival after complete re- section. In all, 62 patients were given mitotane at some time during their illness, but only 30 patients reached the threshold value. Mitotane treatment reaching this level was demonstrated to be an independent factor influencing survival positively.
Over a 23-year period we have treated 22 consecutive patients with ACC (12 stage II, 2 stage III, and 8 stage IV tumors) with a favorable 5-year survival of 65%. Our treatment program has included an active surgical attitude, monitoring urinary steroid profiles as potential markers of recurrent disease, and for the last 8 years monitoring serum mitotane levels [2]. During the latter period all 16 patients were offered mitotane therapy; 2 refused, but 14 received monitored therapy with a median dose of 4 g, reaching a drug concentration just above the threshold. Because the drug can be metabolized in several ways, it seems logical to monitor its concentration in each patient to reach a potential threshold with the lowest effective dose to avoid side effects. Five patients experienced mild side effects; one patient preferred to stop her medication. No objective tumor regression was observed. Kaplan-Meier analyses indicate a 5-year survival for stage II tumors of 100% without mitotane (n = 6) and 50% with mitotane (n = 6); for stage IV tumors the corresponding figures were 0% (n = 4) and 50% (n = 4), respectively. All patients with stage IV tumors not treated with mitotane died within 1 year. Both stage III patients were treated with mitotane and are presently without signs of recurrent disease; one has been observed for 3 years and the other for 14 years.
In yet another retrospective study Kasperlik-Zaluska et al. [6] reviewed their experience with long-term mitotane therapy. Pa- tients with severe hypercortisolism were treated before surgery by mitotane in combination with another inhibitor of steroidogene- sis, aminoglutethimide. The authors also addressed the problem of defining an effective maintenance dose of mitotane without monitoring serum levels of the drug and the unsolved problem of how long treatment should be continued in patients with resected disease and no recurrence. Two groups of patients (n = 13 each) were given mitotane adjuvantly; one group started immediately after surgery, and in the other, treatment was delayed for 3 to 15 months; the survival advantage was in the former group.
After almost 40 years of use the critical prospective multicenter studies on mitotane as an antiproliferative agent for residual ACC or as an adjuvant agent after complete resection are still lacking. The concept of a critical threshold level of the drug also must be confirmed in controlled studies. With the introduction of World Health Organization (WHO) response criteria in 1979, the effi- cacy of mitotane in providing objective tumor regression in accor- dance with these guidelines has been questioned [10]. Because of the inability to predict individual responsiveness, most authors still advise mitotane only in nonresectable cases and long-term therapy in the case of a clinical response. In nonresponders other chemotherapy protocols, possibly combined with mitotane, must be explored (see below).
Inhibitors of Steroid Biosynthesis
Metyrapone was introduced as a tool to diagnose disorders of pituitary adrenalism but was later established as a therapeutic agent blocking the final step (11ß-hydroxylation) in cortisol syn- thesis [25] (Fig. 1). The drug can be used for management of patients with all types of Cushing syndrome; it has a rapid onset of action [35]. Because of its mode of action, androgen synthesis can be enhanced, and hirsutism and virilism may occur. Metyrapone is an effective second-line drug for controlling cortisol secretion with reversible effects; it is not a cytotoxic agent.
Ketoconazole is an antimycotic imidazole, inhibiting both go- nadal and adrenal steroid synthesis. The drug acts on the cyto- chrome P-450 enzymes with inhibition of 118-hydroxylase and 18-hydroxylase (Fig. 1). It has a slower onset than metyrapone but has the clear advantage of reducing circulating androgens. In contrast to mitotane, it is a potent inhibitor of cholesterol synthe- sis, but hepatotoxicity is a serious side effect [25]. The drug has been reported to be a particularly effective treatment for hyper- cortisolism caused by ACC and may have antiproliferative effects as well [36-38].
Aminoglutethimide blocks the conversion of cholesterol to preg- nenolone in all tissues and therefore reduces the synthesis of cortisol, aldosterone, and estrogens. The aromatase inhibition leads to potent antiestrogen effects, and it is used in the treatment of breast cancer [25]. The drug can be limited by its side effects (hypothyroidism, skin rash, fever).
Glucocorticoid Receptor Antagonist
RU 486 (mifepristone) is a potent glucocorticoid receptor antago- nist [39] that can be effective in the treatment of Cushing syn- drome [40]. One obvious limitation when monitoring the clinical
response is that cortisol levels are not lowered and hypoadrenal- ism is not easily identified.
Chemotherapy
The natural history of metastatic ACC is somewhat similar to that of other endocrine malignancies, with long survivals in occasional patients. Cytotoxic treatment with its side effects has therefore been reserved for patients with severe symptoms, progressive disease, or disease with poor prognostic factors. Several cytotoxic agents have historically been tried, with objective response rates in 10% to 40% [41]. ACCs usually have strong expression of the multidrug-resistance gene MDR-1, resulting in production of P- glycoprotein, which facilitates the efflux of cytotoxic agents. In cell line studies, mitotane partially reversed MDR-1/P-glycoprotein multidrug resistance by reducing drug efflux, which theoretically favors combined treatment with mitotane and a cytotoxic agent [42, 43]. Candidate agents with antiproliferative effects on ACCs are doxorubicin, cyclophosphamide, 5-fluorouracil, etoposide (VP 16), cisplatin, and suramin [41, 44]. It should be noted that MDR-1 is not involved in cisplatin resistance [45].
Single-agent Chemotherapy
Suramin is an antitrypanosomal agent that accumulates in the primate adrenal cortex. In vitro the drug induces cytotoxic effects and down-regulates steroid production [46-48]. In pilot studies one patient was subject to the most dreaded side effect, acute demyelinating neuropathy, and another died of thrombocytopeni hemorrhage. The response rate was low when tested in 21 patients (14%); therefore this treatment has been abandoned [48].
Gossypol is a spermatotoxin from cottonseed oil that inhibits growth of human ACC in nude mice [49]. It has mild side effects and can be given orally on an outpatient basis. (It is used as a contraceptive by men in China.) In a series of ACC patients with metastatic disease that was progressive on mitotane, 18 patients were evaluated after a minimum of 6 weeks of gossypol treatment. Only three showed more durable partial responses [50]. Its cyto- toxic effect is probably mediated via uncoupling of oxidative phos- phorylation and destruction of mitochondria [51].
Doxorubicin (40 mg/m2 every 4 weeks) was first tested in 1980 in a small series of ACC patients with a low response rate (12.5%) [52]. With the ECOG protocol, somewhat better response rates (19%) were seen with increased dosage (60 mg/m2 every 3 weeks). Of 16 patients, 2 had durable responses of 51 and 78 months, respectively [17]. The ECOG study with a prospective nonran- domized design included 52 patients with advanced ACC. Alto- gether, 16 patients with poorly differentiated tumors without ste- roid production received monotherapy with doxorubicin, and 36 patients with well differentiated tumors or poorly differentiated tumors with steroid production first received mitotane (6 g daily) for 3 months; 22% of these patients responded to mitotane, but the patients with progressive disease on mitotane were crossed over to doxorubicin. No objective response was noted in the latter group of patients. Doxorubicin thus seemed to be ineffective as second-line chemotherapy for patients with well differentiated, or functional, ACCs for which mitotane was ineffective. Severe tox- icity occurred in one-third of the mitotane-treated patients and in one-fourth of the doxorubicin-treated ones.
During the mid-1980s cisplatin was reported to induce individ-
| Study/protocol | Duration of treatment | No. of patients | Response rate |
|---|---|---|---|
| Van Slooten [56] | |||
| Cisplatin 50 mg/m2 | 3 Weeks | 11 | 2 PR (18%) |
| Doxorubicin 40 mg/m2 Cyclophosphamide 600 mg/m2 | |||
| Schlumberger [57] | 1 CR+ 2 PR (23%) | ||
| Cisplatin 120 mg/m2 Doxorubicin 60 mg/m2 5-FU 1500 mg/m2 | 4 Weeks | 13 | |
| Johnson [58] | |||
| Cisplatin 120 mg/m2 | 3 Weeks | 2 | 2 PR |
| Etoposide 100 mg/m2 | |||
| Hesketh [54] | |||
| Cisplatin 40 mg/m2 | 4 Weeks | 4 | 1 CR+ 2 PR |
| Etoposide 100 mg/m2 Bleomycin 30 mg | |||
| Burgess [59] | |||
| Cisplatin | 13 | 6 PR | |
| Etoposide | |||
| Zidon [60] | |||
| Cisplatin 50 mg/m2 | 3 Weeks | 1 | 1 CR |
| Etoposide 300 mg/m2 | |||
| Bonacci [61] | |||
| Cisplatin 100 mg/m2 Etoposide 100 mg/m2× 3 days | 4 Weeks | 18 | 3 CR+ 3 PR (33%) |
| Mitotane 3-9 g/day | |||
| Berutti [20] | |||
| Cisplatin 40 mg/m2 on days 5-7 | 4 Weeks | 28 | 2 CR + 13 PR (54%) |
| Etoposide 100 mg/m2 on days 5-7 | |||
| Doxorubicin 20 mg/m2 on days 1+ 8 Mitotane 1-4 g/day |
PR: partial response; CR: complete response; 5-FU: 5-fluorouracil.
ual transient complete responses [53, 54]. In the SWOG protocol, cisplatin (75-100 mg/m2 every 3 weeks) was combined with mito- tane (4 g daily), resulting in a 30% response rate with an average duration of 8 months in patients with residual metastatic disease [18]. Low doses of the drug were given to 29 good risk patients and high doses to 8 poor risk patients. The most common side effects were gastrointestinal, renal, and neurologic problems; the toxicity of the treatment was monitored and found to be moderate to severe. In other clinical studies the addition of mitotane to cisplatin did not enhance the response rate [53, 55], in accordance with the concept that MDR-1 is not involved in cisplatin resis- tance.
With our present knowledge single-agent chemotherapy does not seem to be a rational choice for treatment of residual ACC.
Multiple-agent Chemotherapy
The first studies using several cytotoxic agents that included more than 10 patients were based on cisplatin and doxorubicin with addition of cyclophosphamide or 5-fluorouracil [56, 57]. The re- sponse rate was about 20% and included one complete response over 42 months and four partial responses; it was thus comparable to that seen with cisplatin alone (Table 2). The combination of cisplatin and etoposide was first tried in small studies; in one study
bleomycin was added [54, 58-60]. Among seven patients there were two complete responses lasting more than 1 year and four partial responses (Table 2).
Bonacci et al. [61] gave a combination of cisplatin and etopo- side to 18 patients with advanced ACC and maintained mitotane therapy in 14 patients, with an overall response rate of 33% (Table 2). Tumor responses were observed in three of six patients with progressive disease on mitotane therapy; all had been given an effective dosage of mitotane as indicated by serum levels exceed- ing 14 ug/ml. This observation indicates no cross resistance be- tween the two treatments. Nausea occurred in all patients, my- elosuppression in almost half of the patients, and neurologic effects in one patient. Nephrotoxicity was not observed. Because of the relatively short duration of the responses, these authors strongly suggested therapeutic trials with other drug combina- tions. In cell line studies the antimicrotuble agent taxol had antiproliferative effects involving both cytotoxicity and activation of apoptosis [19].
In a phase II multicenter trial by the Italian group for the Study of Adrenal Cancer [20], the combination of etoposide, doxorubi- cin, and cisplatin (EDP) was tested in association with mitotane with no interruption between the chemotherapy cycles (Table 2). The overall response rate among the 28 patients with advanced ACC and measurable disease was high, with 15 responses (2 complete and 13 partial ones), stable disease in 8 patients, and progressive disease in 5 patients. The time to progression in responding patients was 2 years. Responses were seen in patients with both functioning and nonfunctioning tumors. The EDP treat- ment was reasonably well tolerated, and only a few patients received reduced doses or discontinued their chemotherapy; in those who discontinued it, it was mainly due to hematologic side effects. The most common side effects were gastrointestinal or neurologic. The addition of mitotane increased side effects, which led to reduction of the planned mitotane dose (4 g daily) in most patients. All patients received hydrocortisone to prevent adrenal insufficiency, which was eventually combined with a mineralocor- ticoid supplement. Mitotane caused increased cholesterol and triglyceride levels, the latter finding previously only occasionally reported. Mitotane is a lipophilic substance that accumulates in chylomicrons and low density (LDL) and very low density (VLDL) lipoproteins, which promotes its uptake in the adrenals and brain; on the other hand, hypertriglyceridemia may counter- act such an effect [62]. To maintain full mitotane activity, the use of triglyceride-lowering drugs might be useful. Among five pa- tients subjected to surgical tumor reduction after response to EDP and mitotane, the disease progressed in three after 5 to 19 months; two patients remained disease-free at latest follow-up (at 5 and 21 months after surgery, respectively).
The EDP protocol has been widely used for gastric carcinoma patients. It can be accompanied by significant side effects and toxicity-related death [63]. It was manageable in ACC patients, however, which may be due to the somewhat lower dosage of etoposide and the better performance status of the ACC patients. Endogenous factors such as steroid secretion may play a role (e.g., androgen stimulation of the bone marrow and the antiemetic effects of cortisol). In this phase II trial EDP combined with mitotane appeared to be an active, tolerable treatment for ad- vanced ACC and should be further explored.
In recent cell line studies lonidamine (an energolytic derivative of indazole carboxylic acid) was investigated regarding its modu-
latory effects on the cytotoxic activity of doxorubicin, epidoxoru- bicin, etoposide, and cisplatin. Potentiated effects were seen for epidoxorubicin and cisplatin in the presence of lonidamine [64]. If such combination therapy were proved clinically effective, it would offer an interesting alternative to mitotane-based combinations.
The slow progress in the medical treatment of ACC may be due to several factors. Because ACCs are rare, aggressive tumors associated with short survival, the disease has not allowed ade- quate drug trials, especially not when combined with delayed diagnosis and resistance to chemotherapy [65]. The relatively low survival rate for patients with stage I or II tumors should stimulate active follow-up using newer biochemical tests (steroid profiles) and imaging tools [spiral computed tomography, position emis- sion tomography (AEs)]. Of special interest is the new PET imaging agent 11C-etomidate, developed for imaging the adrenal cortex [66]. Earlier diagnosis of recurrent disease would facilitate repeat surgery. Studies of specific gene expression in sporadic ACC (11p 15) and in the rare families with an inherited suscep- tibility to ACC and the Li-Fraumeni and Beckwith-Wiedenmann syndromes, may offer diagnostic possibilities in the future [67]. To make progress in the treatment of patients with residual nonre- sectable ACC, adjuvant multicenter trials should be encouraged. When mitotane-based therapies are used, monitored drug levels are mandatory.
Résumé
Le cancer de la corticosurrénale (CCS) est une tumeur rare mais agressive, détectée souvent à un stade avancé. Le traitement médical par le mitotane, une drogue adrénotoxique, est utilisée depuis plusieurs décennies, mais, on manque d’essais prospectifs critiques sur son rôle dans la maladie résiduelle ou comme agent adjuvant après résection chirurgicale. Le concept d’un niveau plasmatique dont le seuil critique doit être confirmé par des études contrôlées. Puisqu’on ne peut prédire la réponse individuelle, le mitotane est toujours conseillé dans les maladies nonréséquables. En cas d’hyperproduction de cortisol, ou d’autres stéroïdes, d’autres drogues, comme par exemple, le cétoconazole ou l’aminogluthétimide peuvent être utilisées. La monochimiothérapie, avec par exemple la doxorubicine et le cisplatine, est décevante avec un taux de réponse bas (<30%) et une durée de réponse courte. Une partie de cette non-réonse peut être expliquée par le fait que les CCS expriment un gène de résistance multidrogues, le MDR-1. La plurichimiothérapie a été testée dans de plus petites séries avec des effets secondaires importants. Les meilleurs résultats ont été avec la combinaison d’étoposide, de doxorubicine et de cisplatine associés au mitotane: le taux de réponse a été de 54%, avec quelques réponses individuelles complètes. Pour faire des progrès dans le CCS avancé, il faut encourager des essais multicentriques de traitement adjuvant. En cas de thérapie utilisant le mitotane, il faut obligatoirement monitorer le taux des drogues.
Resumen
El carcinoma adrenocortical (CAC) es un tumor agresivo poco frecuente que comúnmente se detecta cuando ya está en etapas avanzadas de su desarrollo. Desde hace décadas se practica tratamiento médico con una droga adrenotóxica, el mitotane, pero no se dispone de ensayos clínicos prospectivos que soporten
su valor en enfermedad residual o como adyuvante de la resección quirúrgica. También se hace necesario confirmar el concepto de niveles críticos de la droga mediante estudios controlados. Puesto que no es posible predecir la respuesta individual, todavía se aconseja el uso del mitotane en casos de enfermedad no resecable. Cuando hay superproducción de cortisol o de otros esteroides, se pueden utilizar algunas drogas como el Ketoconazol o la aminoglutetimida. La quimioterapia con agentes únicos, por ejemplo doxorubicina y el cisplatino, ha sido decepcionante, por las bajas tasas (<30%) y la corta duración de la respuesta. Parte de tal situación refractaria puede explicarse por el hecho de que los CAC expresan el gen MDR-1 de resistencia multidroga. La quimioterapia con agentes múltiples ha sido ensayada en series más pequeñas, con efectos secundarios significativos. Los mejores resultados se logran con la combinación de etopósido, doxorubicina y cisplatino asociada con mitotane, alcanzando una tasa de respuesta del 54%, incluyendo respuestas completas. Para lograr progreso en el manejo del CAC avanzado se debe estimular la realización de ensayos multi-institucionales. La monitoría de los niveles de droga son obligatorios cuando se usan terapias con base en mitotane.
Acknowledgments
The authors are grateful for valuable revision of the manuscript by Professor Luigi Dogliotti, Medical Oncology, and Professor Al- berto Angeli, Internal Medicine, University of Turin, Italy. This work was supported by the Swedish MRC (5220), the Swedish Cancer Society (3911), the Göteborg Medical Society, and the Assar Gabrielsson Cancer Foundation.
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