MDR1 gene expression in solid tumours

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; concomitantly, 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 nonfunctioning 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 increased neurologic and gastrointestinal side effects. Due to these additional toxicities, 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;83:2194-2200. © 1998 American Cancer Society.

Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma

Childhood adrenocortical tumors (ACT) are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of Sao Paulo and Parana. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations) and selected genetic syndromes (Beckwith-Wiedemann syndrome) have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syndromes (virilizing and/or Cushing). Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S), which are abnormal in approximately 90% of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifications with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the management of childhood ACT has not been established although occasional tumors are responsive to mitotane or cisplatin-containing regimens. Because of the heterogeneity and rarity of the disease, prognostic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagnosis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.

/pdf/adrenocortical-tumors-in-children-3qumx6amef.pdf

Adrenocortical tumors in children.

Objective: To identify the pathologic features of prognostic significance in patients with resectable adrenocortical carcinomas. Design: Retrospective review. Setting: Tertiary referral center. Patients: Review of the Memorial Sloan-Kettering Cancer Center prospective adrenocortical carcinoma database from 1986 through 1996 identified 46 patients who underwent curative adrenalectomy for primary disease. All cases were reviewed by a single pathologist and each primary tumor was characterized by 16 separate pathologic parameters. Main Outcome Measure: Overall survival rates in the patient population. Results: The 5-year overall survival rate for the entire cohort was 36% (median survival rate, 28 months). Of the pathologic factors analyzed, tumor size, number of mitotic figures, and the presence of intratumoral hemorrhage were independent prognostic factors. Patients presenting with primary tumors larger than 12 cm (n=30) had a worse outcome compared with those with smaller tumors (n=16) (5-year survival rate: 53% vs 22%, P<.05). Mitotic count (≥6 per 10 high-power fields) was a negative prognostic feature (n=15) with a 5-year survival rate of 13% vs 51% for 0 to 6 mitotic figures per 10 high-power fields (n=31, P<.05). Intratumoral hemorrhage (n=23) was also a negative prognostic factor compared with no evidence of intratumoral hemorrhage (n=23) (5-year survival rate, 53% vs 22%, P<.05). Overall survival rates were also calculated based on the number of pathologic risk factors. Patients with no risk factors had an 83% 5-year survival rate, which decreased to 42% with 1 factor, 33% with 2 factors, and 0% with all 3 risk factors. Conclusions: Tumor size, hemorrhage, and mitotic count correlate with survival rates for patients undergoing curative resection. Based on these pathologic factors, adrenocortical carcinomas may be divided into low- and high-risk groups.

Pathologic Features of Prognostic Significance for Adrenocortical Carcinoma After Curative Resection

BACKGROUND

Adrenocortical carcinoma (ACC) is rare, nearly always fatal, and to the authors' knowledge has few nonsurgical treatment options. Based on in vitro studies demonstrating the efficacy of mitotane as a P-glycoprotein (Pgp) antagonist, and expression of high levels of Pgp in ACC, the authors conducted a study of infusional doxorubicin, vincristine, and etoposide with oral mitotane ± surgical resection in patients with metastatic ACC.



METHODS

Thirty-six patients with metastatic ACC received daily oral mitotane (mean, 4.6 g/day) and 96-hour infusional doxorubicin (10 mg/m2/day), etoposide (75 mg/m2/day), and vincristine (0.4 mg/m2/day). Four responding patients (11%) underwent surgery.



RESULTS

Thirty-five patients were evaluable; all had metastatic disease. Eleven patients had not undergone resection of the primary tumor. Approximately 53% of patients had functional tumors. A total of 190 cycles were administered to 36 patients. Responses were observed in 8 patients (22%): 1 complete, 4 partial, and 3 minor responses. The mean duration of response was 12.4 months. Using a landmark method, the median survival of patients who did not respond to chemotherapy was 11.6 months from a point 4 months after the initiation of therapy, whereas that of 8 patients who demonstrated a response to chemotherapy was 34.3 months from that same landmark. High levels of Pgp expression were documented in nine of nine tumors. Mitotane levels > 10 μg/mL, previously shown to antagonize Pgp in vitro, were achieved in 25 of 36 patients (69%). However, rhodamine efflux from CD56-positive cells was not impaired, suggesting poor in vivo Pgp inhibition. The predominant Grade 3/4 toxicity (according to the Common Toxicity Criteria of the National Cancer Institute) was neutropenia in 66% of cycles; however, fever occurred in only 3% of cycles. Daily mitotane was associated with Grade 1/2 nausea, diarrhea, fatigue, and neuropsychiatric changes in 31 of 36 patients (86%).



CONCLUSIONS

Using a combination regimen of daily mitotane with infusional doxorubicin, vincristine, and etoposide in patients with metastatic ACC, responses were observed in 22% of patients. The superiority of this combination over single-agent mitotane is uncertain. The side effects of mitotane made treatment difficult. More effective Pgp antagonists are needed. Cancer 2002;94:2333–43. © 2002 American Cancer Society.



DOI 10.1002/cncr.10487

A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist.

P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma.

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P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma.