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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 192-200

Exploring the role of systemic therapy in adult adrenocortical carcinoma: A single-center experience

1 Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
3 Department of Urology, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
4 Department of Radiation Oncology, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
5 Department of Radiodiagnosis, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India

Date of Submission03-Apr-2020
Date of Decision18-Apr-2020
Date of Acceptance06-May-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai - 400 012, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_113_20

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Background: Adrenocortical carcinoma (ACC) is a rare malignancy with poor outcomes.
Objectives: To analyze the clinicopathologic features, treatment patterns and outcomes of patients with ACC who received systemic therapy at our center.
Patients and Methods: This was a retrospective study conducted in a tertiary cancer center in India. Patients aged 15 years and older who were diagnosed with ACC between January 2011 and December 2018 and received systemic therapy were included in this study. For tumor staging, the European Network for the Study of Adrenal Tumors (ENSAT) system was used. The outcomes were reported as progression-free survival (PFS) and overall survival (OS). All statistical calculations were performed using the SPSS statistical software for Windows version 20.0.
Results: Out of the 106 patients with ACC, 54 who received systemic therapy were included in this study. The median age of the cohort was 43 years (range, 15–72); 32 (59.3%) were men. Five (9.2%) patients had ENSAT Stage II, 31 (57.4%) had Stage III, and 18 (33.3%) had Stage IV (metastatic) disease at baseline. The chemotherapy drugs used in the palliative setting included etoposide (E), doxorubicin (D), and cisplatin (P), with or without mitotane. The median OS was 140 months (95% confidence interval [CI], 38.2–241.8) for ENSAT Stage II patients; 43 months for Stage III patients (95% CI, 27.2–58.7); and 22 months (95% CI, 9.4–34.6) for Stage IV patients, P = 0.012. The median PFS for patients treated with etoposide and platin (EP) and etoposide, doxorubicin, and platin (EDP) regimens was similar at 7 months (95% CI, 0–14.9) and 6 months (95% CI: 0–14.6) (P = 0.633), respectively. The corresponding median OS was 20.9 months (95% CI, 11.7–30.2) and 13.0 months (95% CI, 2.1–23.8) (P = 0.454), respectively. The patients who received palliative intent mitotane had a median PFS of 13 months (95% CI, 0–26.3) and those who did not had a median PFS of 6 months (95% CI, 1.2–10.7) (P = 0.492). The corresponding median OS was 22.6 months (95% CI, 17.8–27.5) and 15.5 months (95% CI, 5.8–25.2) (P = 0.351), respectively. Grade 3 or higher toxicities were observed in 25% of the patients receiving EP chemotherapy and 76.9% receiving EDP chemotherapy (P = 0.013).
Conclusions: The use of mitotane is limited in the real-world setting in view of the financial constraints. The results with palliative chemotherapy in patients with ACC continue to remain poor. Patients with ACC treated with EDP and EP protocols had similar survival, but the three-drug protocol was associated with higher toxicities.

Keywords: Adrenocortical carcinoma, adult, EDP chemotherapy, endocrine tumor, mitotane, real-world data

How to cite this article:
Kapoor A, Noronha V, Toshniwal A, Menon S, Joshi A, Patil VM, Menon N, Prakash G, Murthy V, Krishnatry R, Bakshi G, Pal M, Popat P, Sable N, Prabhash K. Exploring the role of systemic therapy in adult adrenocortical carcinoma: A single-center experience. Cancer Res Stat Treat 2020;3:192-200

How to cite this URL:
Kapoor A, Noronha V, Toshniwal A, Menon S, Joshi A, Patil VM, Menon N, Prakash G, Murthy V, Krishnatry R, Bakshi G, Pal M, Popat P, Sable N, Prabhash K. Exploring the role of systemic therapy in adult adrenocortical carcinoma: A single-center experience. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Sep 18];3:192-200. Available from: http://www.crstonline.com/text.asp?2020/3/2/192/287199

  Introduction Top

Adrenocortical carcinoma (ACC) is a rare malignancy with poor outcomes. Its annual incidence in the Western world is estimated to be 0.5–2 per million people, whereas for children younger than 15 years, it is estimated to be around 0.3 per million.[1],[2] The distribution of ACC has been shown to follow a regional pattern; the incidence in Southern Brazil is reported to be 3.4–4.2 per million children annually.[3] Comparative genomic hybridization from patients with nonfamilial ACC revealed multiple genetic aberrations, including a consistent gain of the chromosomal region 9q34.[3] There is a bimodal age distribution, with the first peak occurring before the age of 5 years and the second in the age group of 40–50 years.[4] Women are usually more commonly affected than men, with a ratio of 1.5–2.5.[5] Although most cases of ACC are sporadic, some occur as a component of hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Beckwith–Wiedemann syndrome, and multiple endocrine neoplasia type 1 (MEN1).[6]

Systemic therapy plays an important role in the management of this disease, as most cases are diagnosed at an advanced stage.[2] Besides, patients diagnosed with early-stage ACC are also candidates for adjuvant systemic therapy, if there are features of aggressive disease.[4] Many cytotoxic drugs have been studied in patients with advanced ACC, either alone or in combination with mitotane. The progress in the therapy of advanced ACC has been limited by the rarity of the disease and the relatively small number of patients in each study. As a result, large series reporting clinicopathological features and disease outcomes are sparse. We, therefore, evaluated the clinicopathological features, therapy, and outcomes of patients with ACC treated at our center.

  Patients and Methods Top

Study population

This was a retrospective study conducted in the Department of Medical Oncology of the Tata Memorial Center, a tertiary cancer center in Mumbai, India. All patients aged ≥15 years and diagnosed with ACC between January 2011 and December 2018 who received systemic therapy were included in this study. We excluded patients who did not receive any form of systemic therapy, including patients with metastatic disease who were not offered therapy due to various reasons such as poor performance status (PS), refusal to take therapy due to financial constraints, patients in whom the histopathology review was not confirmatory of ACC, and patients for whom the details of treatment were not available. The study was conducted according to various ethical guidelines such as the Declaration of Helsinki, International Council for Harmonization-Good Clinical Practice, and the Indian Council of Medical Research guidelines.

The electronic medical records were used to access the demographic details, comorbidities, family history, hormonal profile, surgical procedures, histopathology details, palliative/adjuvant chemotherapy, use of mitotane, follow-up details, and recurrences. The patients who had not returned to the hospital for follow-up were contacted by telephone to determine their status and survival. The functional status of the tumor was assessed from the symptoms recorded and the results of the endocrinology work-up.

The diagnosis of ACC was based on the Weiss scoring system, and a score of >3 was considered malignant.[7] For tumor staging, the European Network for the Study of Adrenal Tumors (ENSAT) system was used. The following baseline hormonal evaluations were performed in the patients as per the ENSAT recommendations and institution's practice: fasting blood glucose, serum potassium, cortisol, corticotropin (ACTH), 24-h urinary free cortisol, fasting serum cortisol at 8 AM, adrenal androgens (dehydroepiandrosterone sulfate and testosterone), and serum estradiol in men and postmenopausal women. A low-grade tumor was defined as <20 mitoses/50 high-power fields, whereas a high-grade tumor was defined by a higher number of mitoses. The patients were classified as high risk if they had ENSAT Stage III disease and/or had a high-grade tumor.

The management of patients was decided in a multidisciplinary genitourinary disease management group. High-risk patients were offered adjuvant mitotane for 2 years. The starting dose of mitotane, in both the adjuvant and palliative settings, was 1.5 g/day. As the plasma mitotane level testing was not available at our hospital, the dose of mitotane was titrated as per tolerance (gastrointestinal, hematologic, and hepatic toxicities). Glucocorticoid and mineralocorticoid supplementation were prescribed as per the clinical assessment and serum electrolyte levels in consultation with an endocrinologist. Adjuvant radiotherapy was offered to patients with microscopic margin positivity (R1 resection) or unknown margins (Rx resection).

Clinical outcomes

In patients with metastatic disease on palliative therapy, response assessment was performed using radiological assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Response assessment was done every 2–3 months on palliative systemic therapy or at the development of any symptoms/signs of clinical progression, whichever was earlier. Adverse events during treatment were documented and graded using the Common Terminology Criteria for Adverse Events, version 4.02. Progression-free survival (PFS) was defined as the interval from the date of starting systemic therapy to the date of progression or death due to any cause if it occurred before disease progression, or the last follow-up date, whichever was earlier. The patients who were lost to follow-up were censored on the date of their last follow-up. The overall survival (OS) was calculated from the date of histopathological diagnosis to the date of death. Patients who were still alive at the end of the study were censored on the date of the last contact. PFS and OS were also calculated separately for palliative treatment in which the starting date was taken as the date of starting palliative systemic therapy.

Statistical analysis

All statistical calculations were performed using the SPSS statistical software for Windows version 20.0 (IBM Corp., Armonk, New York, USA). Categorical and continuous variables were summarized using descriptive statistics. Time-to-event analysis was done using the Kaplan–Meier estimator, and hazard ratio (HR) was calculated using the Cox proportional model.[8],[9],[10] The log-rank test and Cox regression analysis were performed to compare the outcomes according to the various factors. All P values were two-sided with confidence interval (CI) at the 95% level, and P < 0.05 was considered statistically significant.

  Results Top

Baseline characteristics

A total of 106 patients diagnosed with ACC were screened for this study, and 54 patients were enrolled [Figure 1]. Functional hormone synthesis was identified biochemically in 20 of the 43 tested patients (46.5%). There were clinical manifestations of Cushing's syndrome in 9 (16.7%) and primary aldosteronism in 14.8% of the patients. The baseline characteristics of the patients are depicted in [Table 1]. The radiology details of baseline staging were available in 36 (66.7%) patients, with a median tumor size of 125 mm (range, 15–160 mm).
Figure 1: Patient flow diagram of the study showing the details of included and excluded patients. ACC: Adrenocortical carcinoma; PS: Performance status

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Table 1: Baseline characteristics of the patients diagnosed with adrenocortical carcinoma and who received systemic therapy

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Family history and genetic predisposition syndromes

A family history of malignancy was present in 5 (9.3%) patients; 3 patients had first degree relatives with head-and-neck cancers, one patient had a family history of lung cancer, whereas one patient had a family history of a pancreatic neuroendocrine tumor. Two patients had genetic syndromes; one had Lynch syndrome, and the other patient was suspected to have the MEN1 syndrome. The patient diagnosed with Lynch syndrome did not have a family history but had a personal diagnosis of synchronous transverse colon cancer and ACC at the age of 51 years and a second primary in the right colon 4 years later. This patient was detected to harbor a deleterious germline mutation in the MSH2 gene. The second patient also did not have a significant family history and was diagnosed with ACC and pancreatic neuroendocrine tumor Grade 1 at the age of 49 years. He was also diagnosed to have parathyroid adenoma due to the incidental findings of decreased serum calcium and increased serum phosphate and serum parathyroid hormone. He was planned for further evaluation and genetic testing but succumbed to metastatic ACC.

Treatment received

Radical therapy

Curative surgery was performed in 37 (68.5%) patients, out of which 26 (70.3%) patients required adrenalectomy alone, and 11 (29.7%) required nephrectomy/colectomy/splenectomy. Two patients underwent metastasectomy (hepatic metastasectomy and splenectomy) in the same sitting as the primary surgery.

Out of the 37 patients who underwent surgery, histopathological details were available for 22 (59.4%) patients who underwent surgery [Table 2]. The remaining 15 patients had undergone surgery outside, and evaluation of the tissue blocks could only confirm the diagnosis but not the complete histopathological details. Mitotic activity was detected in 13 (59.1%) patients; it ranged from 0 to 75/50 high-power fields. Margin status was known in 14 (63.6%) patients; 2 (9.1%) had positive margins. Adjuvant mitotane was offered to 20 (54%) patients; 19 patients had Stage III–IV disease, and one patient had Stage II high-grade disease. However, in view of financial constraints, adjuvant mitotane was taken by only 2 (10%) patients. Adjuvant radiotherapy was administered to 10 (27%) patients, out of which, 8 had unknown margins, whereas 2 patients had R1 margins. Three (30%) patients received three-dimensional conformal radiotherapy (3D CRT), and seven (70%) received intensity-modulated radiotherapy. The median radiotherapy dose was 45 Gy (range, 38–55) delivered in a median of 25 fractions (range, 19–25).
Table 2: Histopathological details of 22 patients with adrenocortical carcinoma for whom data were available

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Palliative therapy

Palliative intent chemotherapy was administered to 52 patients, of which 35 patients (67.3%) received it after progression post curative intent therapy. The most common regimens used were etoposide and platinum (EP) in 27 patients (51.9%), followed by etoposide, doxorubicin, and cisplatin (EDP) in 22 patients (42.3%). The median number of chemotherapy cycles given was 5 (range, 2–9).

Mitotane was used in a total of 15 patients (27.8%), with the principal limiting factor for its use being financial constraints. Mitotane was used in combination with chemotherapy in 10 (66.7%) patients, with EDP in 70% of the patients, followed by EP in 20% of the patients. In 5 (33.3%) patients, mitotane was used as a single agent. The median dose of mitotane used was 2 g (range, 1.5–4). Palliative radiotherapy was delivered to 8 (14.8%) patients. Second-line palliative chemotherapy could be given to 10 (27.8%) patients; 2 (20%) patients received gemcitabine and capecitabine, another 2 (20%) received mitotane alone, and 1 (10%) each received pembrolizumab, sunitinib, and temozolomide.


Toxicity data were available for 29 patients (55.7%). Grade 3 or higher toxicities developed in 4 out of the 16 patients (55.2%) who received EP and 10 (76.9%) out of the 13 patients who received EDP (P = 0.013). Grade 3/4 neutropenia occurred in 12 (41.4%), thrombocytopenia in 7 (24.1%), anemia in 10 (34.5%), and febrile neutropenia in 5 (17.2%) patients; dose modification was required in 5 (17.2%) patients. The most common adverse effects of mitotane were nausea and vomiting in 7 (46.6%), followed by hepatic transaminase elevation in 4 (26.7%) and dyslipidemia in 3 patients (20%).

Response to therapy

The data for response to first line-palliative chemotherapy were available for 24 (66.7%) patients; 10 (41.7%) achieved partial response, 4 (16.7%) stable disease, 9 (37.5%) progressive disease, and 1 patient (4.1%) had a complete response.


The median OS of the entire patient cohort was 40 months (95% CI, 26.3–53.7). The median PFS of the 37 patients who could receive curative intent therapy was 13 months (95% CI, 3.4–22.5). The median PFS for the patients treated with palliative systemic therapy was 6 months (95% CI, 3.5–8.4), and the median OS was 19 months (95% CI, 12.9–25.0).

On comparing the palliative intent chemotherapy regimens used, it was observed that the median PFS for EDP was 7 months (95% CI, 0–14.9) and that for EP was 6 months (95% CI, 0–14.6) (P = 0.633). The corresponding median OS was 20.9 months (95% CI, 11.7–30.2) and 13.0 months (95% CI, 2.1–23.8) (P = 0.454), respectively. The patients who received palliative intent mitotane had a median PFS of 13 months (95% CI, 0–26.3), whereas those who did not had a median PFS of 6 months (95% CI, 1.2–10.7) (P = 0.492). The corresponding median OS was 22.6 months (95% CI, 17.8–27.5) and 15.5 months (95% CI, 5.8–25.2) (P = 0.351), respectively.

Factors affecting survival

When considering patients based on the stage of the disease, the median OS for patients with ENSAT Stage II disease was 140 months (95% CI, 38.2–241.8), Stage III disease was 43 months (95% CI, 27.2–58.7), and Stage IV disease was 22 months (95% CI, 9.4–34.6) (P = 0.012) [Figure 2]. The corresponding percentage of patients surviving at 3 years was 75% (standard error [SE]: 21.7) for Stage II, 57.2% (SE 10.4) for Stage III, and 36.3% (SE 15.7) for Stage IV. The median OS of patients with early-stage disease (Stage II) was significantly higher (median OS, 140 months; 95% CI, 38.2-241.8) than that of patients with advanced disease (Stage III and IV) (median OS, 38 months; 95% CI, 24.1–51.9) (P = 0.005).
Figure 2: Kaplan–Meier survival curve of patients with adrenocortical carcinoma as per the European Network for the Study of Adrenal Tumors stage (median overall survival was 140 months for Stage II patients, 43 months for Stage III, and 22 months for Stage IV patients, P = 0.012)

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The survival outcomes were analyzed as per the various factors by the Kaplan–Meir and Cox regression univariate analysis [Table 3]. The factors that were determined to be significant (impacting survival negatively) were smoking, higher ENSAT stage, no possibility of curative surgery, and the use of adjuvant radiotherapy. On multivariate analysis, the only factor that maintained statistical significance was no possibility of curative surgery [Table 4].
Table 3: Univariate analysis of survival outcomes based on various factors by log-rank test

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Table 4: Univariate and multivariate analyses by Cox regression method of various factors

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  Discussion Top

Our study reports the largest real-world data from India on the clinicopathological features and outcomes of patients with ACC who received systemic therapy. In the palliative setting, 52% of the patients received the two-drug regimen of EP and 42% received the three-drug combination of EDP. Only 28% of the patients received mitotane. Grade 3 or higher toxicities occurred in 77% of the patients treated with EDP and 25% in those treated with EP (P = 0.013). Overall, the median PFS for the patients treated with palliative treatment was 6 months (95% CI, 3.5–8.4), and the median OS was 19 months (95% CI, 12.9–25.0). When comparing survival outcomes for the EDP and EP regimens, there was no significant difference in either the median PFS (7 months versus 6 months, respectively; P = 0.633) or the median OS (20.9 months versus 13 months, respectively; P = 0.454).

The Western literature reports a higher incidence of ACC in women, but in our study, men constituted the majority of the patients, with a male-to-female ratio of 1.5.[5] Another Indian study reported a similar male preponderance.[11] This could stem from the racial differences and different genetic backgrounds of the Indian population. Functioning tumor was identified in 46.5% of the patients, which is similar to the earlier reports.[12]

An increase in the incidence of functioning tumors has been reported in the last decade which is probably related to the availability of extensive hormonal panels in the laboratories of India.[13] In our study, we found one patient to be harboring Lynch syndrome, whereas another patient was suspected of having MEN1 syndrome. This is probably an underestimation, as routine genetic testing was not performed in our patients. The Western literature suggests that direct germline testing for MSH2, MSH6, PMS2, MLH1, EPCAM, MEN1, APC, and TP53 should be offered to all patients with ACC.[14] MEN1 syndrome is known to be a cancer predisposition syndrome for ACC, and 1%–2% of the adults with ACC have MEN1 syndrome.[6],[15] Around 3% of the patients with ACC have Lynch syndrome.[16] The timely diagnosis of this syndrome is important, as the identification of the index patient can lead to the testing of at-risk family members for the germline mutation, who can further undergo screening for colorectal and endometrial cancers if tested positive. Another important syndrome associated with ACC is LFS. ACC is the most common presenting malignancy for LFS. Up to 80% of the pediatric ACCs are associated with TP53 mutations; however, it should be noted that only 10% of the children with LFS will manifest ACC, and the frequency of TP53 germline mutation sharply falls with age to <10% in adult ACC.[17]

In our study, 68.5% of the patients could undergo curative intent therapy at baseline, which included surgery, followed by adjuvant therapy in 11 (29.7%) patients. Although there is no definite evidence of benefit from adjuvant therapy, some studies have reported its benefit in prolonging the PFS. Fassnacht et al. reported a decreased rate of local recurrence after adjuvant radiotherapy.[18] In a meta-analysis, adjuvant radiotherapy was reported to improve the local recurrence-free survival (RFS).[18] In our study, the use of adjuvant radiotherapy was associated with a significantly poorer survival in the univariate analysis. This can be explained by the fact that more advanced patients were planned for adjuvant radiotherapy which included positive margins and where details of surgical margins were not clearly available. Similarly, there are conflicting data on the use of adjuvant mitotane. Terzolo et al. reported that adjuvant mitotane significantly improved the RFS.[19] However, according to another study, adjuvant mitotane was not associated with an improvement in the OS or disease-free survival.[20] The European Society of Medical Oncology guidelines recommend the use of adjuvant mitotane in high-risk ACC (Stage III/IV or Ki67 expression in >10% of neoplastic cells).[21] At our center, we followed the above protocol; however, most of the patients could not receive adjuvant mitotane in view of financial constraints. The results of the Efficacy of Adjuvant Mitotane Treatment (ADIUVO) trial which is testing the efficacy of adjuvant mitotane with the primary end point of RFS in ACC are expected by December 2020.[22]

In our study, the median PFS and OS for EDP and EP regimens, and also mitotane versus no mitotane were comparable. After the New England Journal of Medicine publication in 2012, EDP plus mitotane became the standard. Mitotane increases the cytotoxic activity of other chemotherapeutic drugs on the human adrenal carcinoma cells in vitro, possibly by acting as an antagonist of the multidrug resistance protein, which is found in high concentrations in ACC, and functions as a drug efflux pump providing a rationale for combination therapy.[23] The FIRM-ACT study reported that patients treated with EDP in combination with mitotane had a significantly higher response rate than those treated with streptozocin and mitotane (23.2% vs. 9.2%, P < 0.001); they also had a significantly higher median PFS (5.0 months versus 2.1 months, respectively; HR, 0.55; 95% CI, 0.43–0.69; P < 0.001).[24] Although there was no significant difference in median OS (14.8 months and 12.0 months, respectively; P = 0.07), this regimen was accepted as the first-line therapy in view of better response rates and PFS with similar rates of severe adverse effects. The median PFS and OS with first-line therapy were slightly better in our study, with both the EDP and EP regimens. The rate of any serious adverse effects was 58.1% with EDP and mitotane in this study; however, in our study, this was 48% for patients receiving palliative chemotherapy with or without mitotane in the first line. The toxicities were slightly less in our study, as the two-drug regimen (EP) was also used in the first line. In our study, the median survival of early-stage patients was significantly higher (median OS, 140 months) than that of the advanced stage (Stage III and IV) patients (median OS, 38 months, P = 0.005). This is actually better than the OS reported in the series of 113 patients treated at Memorial Sloan Kettering Cancer Center, where patients with early-stage disease (n = 57) had a median survival of 101 months (5-year survival, 60%), whereas those with late-stage disease (n = 56) had a median survival of 15 months (5-year survival, 10%).[25] The better survival in our series might be attributed to the improvement in systemic therapy and supportive care, as the MSKCC study was published two decades back.

Our study has limitations of the retrospective design and small number of patients in the subgroups, though it is still one of the largest real-world data on ACC from India. Toxicity data were available in a limited number of patients, which is an inherent drawback of a retrospective study. Furthermore, complete information was missing for some patients from the database, which further reduced the value of the subgroup analysis. As measurement of the plasma levels of mitotane was not available, the titration of the dose of mitotane was done solely on the basis of tolerance of the patient. Moreover, mitotane could be administered only to 27.8% of the patients included in this study.

  Conclusions Top

The results with palliative chemotherapy in patients with ACC continue to remain poor. Although the three-drug EDP regimen resulted in significantly higher toxicities than the two-drug EP regimen, there was no difference in survival. The use of mitotane was limited due to the financial constraints.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]


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