FAVORABLE RESPONSE OF METASTATIC ADRENOCORTICAL CARCINOMA TO ETOPOSIDE, ADRIAMYCIN AND CISPLATIN (EAP) CHEMOTHERAPY. REPORT OF TWO CASES
Alfredo Berruti,’ Massimo Terzolo,’ Piero Paccotti,’ Franco Veglio,’ Anna Pia,’ Luigi Dogliotti ’ and Alberto Angell ’ (’ Dipartimento di Scienze Cliniche e Biologiche, and 2 Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino)
The usefulness of non-specific chemotherapy for advanced adrenocortical carcinoma (ACC) is controversial. We report on 2 young female patients (25 and 19 yr) who presented with a clinical picture of Cushing’s syndrome due to histologically confirmed ACC. The first patient underwent radical surgery, but after a disease-free interval of 6 months a local recurrence was apparent. She was reoperated and treated with 6 courses of cisplatin and etoposide chemotherapy. Mitotane (8 g daily) was begun, but 2 months later debulking surgery was again performed. A second-line chemotherapy with the etoposide,
adriamycin, cisplatin (EAP) scheme attained a partial remission lasting 7 months, then metastatic spread to the brain led to death of the patient. The survival time was 30 months. The second patient underwent radical surgery and adjuvant mito- tane (4 g daily), but multiple lung and mediastinal metastases were diagnosed after an interval of 29 months. Chemotherapy with the EAP regimen (6 courses) without interrupting mitotane attained a partial remission lasting 21+ months. We suggest that the EAP scheme is active In advanced ACC and that Its association with mitotane is feasible.
Adrenocortical carcinoma (ACC) is a rare and highly malignant tumor (2, 3, 14). In early stages the only po- tentially curative treatment is surgery, whereas the manage- ment of patients with locally recurrent tumor or with metastatic disease is controversial since success is poor in most cases. Mitotane or o,p’-DDD(1,1-dichloro-2-(o-chloro- phenyl)-2-(p-chlorophenyl)ethane) is widely employed al- though the effect on survival time remains unclear (12). Experience with non-specific chemotherapy is limited. The use of cisplatin either as a single agent (3, 5, 14, 16) or in multiple-drug combinations (9, 11, 15, 18) has determined temporary improvement in a certain number of cases. Here we report on 2 patients bearing ACC in progression under mitotane therapy and treated with the combination regimen of etoposide, adriamycin and cisplatin (EAP).
Case reports
Patient 1. A 25-year-old female was seen in October 1988 because of Cushing’s syndrome due to a 7-cm-wide adrenal mass. She complained of a 6-month history of symptoms. Surgery was apparently radical; histology con- firmed the presence of ACC. Disease was classified as stage II according to Brennan (3). After surgery, clinical signs of Cushing’s syndrome disappeared with normalization of endocrine tests (Table 1). The disease-free interval was 6 months, before imaging of a functioning recurrent mass of 5 cm that infiltrated the diaphragm and the abdominal wall. In June 1989, the patient underwent surgical debulking with an estimated residual disease of about 30%. Hence, chemotherapy was started 3 weeks after surgery, with 6
courses of cisplatin (100 mg/m2 on day 1) and etoposide (120 mg/m2 on days 1, 2, 3) every 21 days. The treatment was well tolerated with moderate hematologic and gastro- intestinal toxicity (WHO grade II). Restaging after chemo- therapy documented a complete remission and normal steroid secretion (Table 1). Mitotane (8 g daily, the maximal tolerated dose) was begun together with replacement gluco- corticoid therapy. Two months later, a local recurrence (5 cm in diameter) was demonstrated and a third surgical resection was performed. Due to C hepatitis, any chemo- therapeutic approach was not allowed over the sub- sequent 3 months. Mitotane was discontinued to avoid further hepatic damage. Meanwhile, the tumor mass grew to 9 cm and a liver metastases became apparent. A marked elevation of circulating adrenal steroids was found and performance status worsened (ECOG 2).
In June, 1990 we decided to try a second-line combina- tion chemotherapy using the EAP scheme as follows: etoposide (120 mg/m2 on days 4, 5, 6), adriamycin (20 mg/m2 on days 1, 7), cisplatin (40 mg/m2 on days 2, 8). After 2 cycles, the patient attained a partial remission (reduction > 50% of the liver metastatic lesions) and a minimal response (reduction between 25-50%) of the local recurrence. Serum adrenal steroid levels fell markedly (Table 1). The EAP regimen was well tolerated with moderate gastrointestinal and hematologic toxicity (WHO grade II). The duration of the response was about 7 months; thereafter the clinical picture worsened progres- sively with reappearance of some stigmata of Cushing’s syndrome associated with cachexia, headache and impaired mentation. Massive metastatic spread to the brain rapidly
To whom correspondence should be addressed: Prof. Luigi Dogliotti, Clinica Medica, Oncologia Medica, Ospedale S. Luigi Gon- zaga, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.
| October 1988, diagnosis | February 1989, after surgery | May 1989, 1st relapse | November 1989, after 6 cycles of CDDP+VP16 | June 1990, 2nd relapse before EAP | December 1990, after 6 cycles | March 1991, 3rd relapse | |
|---|---|---|---|---|---|---|---|
| F (µg/dl) | 25.3 | 7.4 | 10.3 | 13.9 | 11.8 | 11.4 | 32.0 |
| S (ng/ml) | 18.0 | 5.7 | - | 5.9 | 15.9 | 9.3 | 14.8 |
| DHEAS (ng/dl) | 859.0 | 111.0 | 1224.0 | 63.0 | 414.0 | 872.0 | 1427.0 |
| Delta 4-A (ng/dl) | 436.0 | 84.0 | 450.0 | 127.0 | 258.0 | 448.0 | 1861.0 |
| 17 OHP (ng/ml) | 6.2 | 2.5 | 5.7 | 1.2 | 4.7 | 3.9 | 7.1 |
| T (ng/nl) | 2.5 | 0.5 | 1.8 | 0.6 | 1.4 | 2.1 | 2.7 |
| F-Dex (u.g/dl) | 25.8 | <0.25 | 10.8 | <0.25 | - | - | 29.3 |
F = cortisol, normal values (n.v.): 5-15.
S = 11-deoxycortisol, n.v .: 6-16.
DHEAS = dehydroepiandrosterone sulphate, n.v .: 70-390.
Delta4-A = androstenedione, n.v .: 90-270.
17-OHP = 17-hydroxyprogesterone, n.v .: 0.3-3.
T = testosterone, n.v .: < 1.
These hormonal data are the mean of six measurements over 24h. F-Dex = morning cortisol after overnight dexamethasone (8 mg). CDDP = Cisplatin.
VP16 = Etoposide.
EAP = Etoposide, Adriamycin, Cisplatin.
led to death of the patient. The survival time from the diagnosis was 30 months.
Patient 2. A 19-year-old woman was admitted in May 1988 because of Cushing’s syndrome with a 5-month history of symptoms. A functioning ACC 10 cm in diameter was radically resected, and there were no apparent metastases. Serum steroid levels fell to within normal ranges (Table 2), and adjuvant therapy with mitotane (4 g daily, the maximum tolerated dose) was begun. After a disease-free interval of 29 months, multiple lung metastases and mediastinal node involvement were detected (Fig. 1). Serum steroid levels were high (Table 2), and the performance status was ECOG 1. The patient received 6 cycles of EAP, without inter- rupting mitotane (2 g daily). Remission was documented at the completion of the second cycle and became evident during the following 2 cycles; residual disease was 20% (Fig. 2) and steroid hypersecretion stopped. Toxicity was moderate, with WHO grade I nausea and vomiting,
| May 1988, diagnosis | November 1990, relapse | May 1991, after 6 cycles of EAP1 | |
|---|---|---|---|
| F (µg/dl) | 17.9 | 19.0 | 17.0 |
| S (ng/ml) | 16.8 | 14.9 | - |
| DHEAS (ng/dl) | 516.0 | 200.0 | 55.0 |
| Delta 4-A (ng/dl) | 784.0 | 638.0 | 200.0 |
| 17 OHP (ng/ml) | 2.7 | 6.7 | 3.0 |
| T (ng/ml) | 1.5 | 0.8 | 0.3 |
| F-Dex (u.g/dl) | 15.8 | 12.2 | - |
For legend, see Table 1.
1On mitotane (2 g/die) and cortisone replacement (37.5 mg/die)
grade II leukopenia, and grade II anemia. Treatment was discontinued after 6 cycles while maintaining mitotane (4 g daily). In July 1992 the disease was stable with a partial response lasting 21+ months, and the performance status was excellent (ECOG 0). The survival time from the diagnosis was 53 months.
Discussion
ACC is considered an intrinsically drug-resistant cancer, although two reports have suggested activity of intensive cisplatin-based combinations (15, 18). The combination of etoposide, adriamycin and cisplatin was chosen on the basis of the reported activity in the treatment of advanced gastric adenocarcinoma, which is often refractory to chemo- therapy (13). We employed this regimen in one case as a first-line treatment and in the other case as a second- line approach after a successful previous therapy with a cisplatin-containing regimen. Our experience, although lim- ited, demonstrates that EAP has therapeutic activity in controlling both tumor growth and steroid hypersecretion. In fact, EAP attained a positive response in patient 1 (heavily pretreated and with a very aggressive disease) as well as in patient 2, who still has stable disease at imaging and biochemical monitoring 53 months after the diagnosis.
In our patients the elevation of androgen and precursor glucocorticoid molecules was the most sensitive index of tumor progression, preceding that of serum cortisol, in agreement with other observations of ACC causing a full- blown Cushing’s syndrome at diagnosis. This has been explained as a consequence of the block of enzymatic steps of the cortisol synthesis by the exceedingly high concentra- tion of steroids accumulated in the tumor (10) or, alter- natively, as an inherent abnormality associated with the neoplastic process itself (6).
Mitotane is extensively used in the therapy of ACC, since it is able to obtain a biochemical response in most pa-
C
tients with initially elevated steroid levels (12). Mitotane can also induce objective responses, yet survival in patients with metastatic disease is poor and improvement by treat- ment with mitotane is not generally accepted. As illustrated by our cases, progression can occur during adjuvant mitotane therapy, but cisplatin combination chemotherapy can favorably alter the course of the disease.
The multidrug resistance gene (MDR-1), which encodes the multidrug efflux P-glycoprotein, was found highly ex- pressed in ACC (8), and this could provide an explanation for the reported failure of chemotherapy (5). Mitotane was recently found to reverse in vitro the multidrug resistance mediated by MDR-1 expression, thus providing a rational basis for its use in combination with chemotherapeutic agents (1). In a phase II study performed on 41 patients, the association of cisplatin with mitotane (4 g daily) was reported to be feasible, yet at the cost of additive gastro- intestinal and neurologic toxicity (4). We continued mi- totane, although at a lower dose, during EAP cycles in patient 2, who had a very long duration of response. She did not complain of any important additional toxicity. Negligible nausea and vomiting was attained with the systematic use of tropisetron, a 5-HT3 receptor antagonist antiemetic drug (7).
In conclusion, our report deserves attention due to the rarity of the disease and the lack of standard treatments. In our hands, the EAP scheme proved to be active in the treatment of advanced ACC. The association of mitotane is
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feasible and has an interesting rationale: it is promising as a combined therapeutic approach.
Efficacia di etoposide, adriamicina e cisplatino (EAP) nel trat- tamento del carcinoma surrenalico avanzato. Esperienza su 2 casi
L’impiego della chemioterapia nel trattamento del carcinoma surrenalico avanzato è controverso. Gli autori riferiscono di 2 giovani donne, di anni 25 e 19, affette da sindrome di Cush- ing per la presenza di carcinoma funzionante. La prima pazien- te venne sottoposta a chirurgia radicale; una recidiva locale fu evidenziata dopo 6 mesi circa di Intervallo libero. Dopo nuovo intervento chirurgico e 6 cicli di chemioterapia con cisplatino e VP16 fu giudicata in remissione completa. Venne Iniziata te- rapia con mitotane (8 g/die), ma due mesi dopo l’ulteriore ripresa locale di malattia impose il terzo intervento chirurgico. Fu decisa chemioterapia di Il linea con lo schema EAP (etopo- side, adriamicina e cisplatino). Si ottenne remissione parziale della durata di 7 mesi; il successivo spray metastatico encefa- lico portò la paziente all’exitus. La sopravvivenza globale fu di 30 mesi. La seconda paziente venne sottoposta a chirurgia ra- dicale, seguita da terapia adiuvante con mitotane (4 g/die). Dopo 29 mesi vennero evidenziate multiple metastasi polmona- ri e mediastiniche. Fu decisa chemioterapia con lo schema EAP (6 cicli) senza interrompere l’assunzione di mitotane, otte- nendo remissione parziale della durata di 21 mesi. In conclu- sione, lo schema EAP si è dimostrato attivo nel trattamento del carcinoma surrenalico avanzato. L’associazione con mitotane è attuabile, essendo risultata priva di effetti collaterali aggiuntivi.
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