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Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 290-292

Treating advanced adrenal cortical carcinoma: The long, winding, and endless road

Basavatarakam Indo American Cancer Hospital and Research Center, Hyderabad, Telangana, India

Date of Submission30-Apr-2020
Date of Decision02-May-2020
Date of Acceptance02-May-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Senthil Rajappa
Basavatarakam Indo American Cancer Hospital and Research Center, Banjara Hills, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_165_20

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How to cite this article:
Rajappa S. Treating advanced adrenal cortical carcinoma: The long, winding, and endless road. Cancer Res Stat Treat 2020;3:290-2

How to cite this URL:
Rajappa S. Treating advanced adrenal cortical carcinoma: The long, winding, and endless road. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Sep 18];3:290-2. Available from: http://www.crstonline.com/text.asp?2020/3/2/290/287215

Adrenal cortical carcinoma (ACC) is a rare aggressive tumor with a bimodal age distribution, with one peak before the age of 5 years and the other in the fourth and fifth decades of life.[1] Majority of the ACCs are sporadic. They can also be a part of Li-Fraumeni syndrome, Beckwith–Wiedemann syndrome, and multiple endocrine neoplasia, type 1 (MEN 1) syndrome. Molecular pathogenesis of sporadic ACC is poorly understood. The most commonly occurring mutation is in the TP53 gene.[2] ACCs present with symptoms of hormone excess in 60% of the cases, the most common being Cushing's syndrome followed by mixed Cushing's syndrome and virilization.

In the absence of local invasion and metastasis, the Weiss criteria are used to assess malignant behavior, with a score of ≥3 confirming the malignancy.[3] Approximately half of all the patients with ACC present at an advanced stage. Surgery with potentially curative intent is the treatment of choice for localized disease. Those with localized and locoregional disease have a 5-year disease-specific survival of 50%–82%, whereas those with Stage IV disease have a dismal survival of 14%.[4]

In this issue of CRST, Kapoor et al. have published a retrospective review of their 8-year experience with patients with ACC.[5] Although they started with 106 patients, this report is restricted to a cohort of 54 patients who received systemic therapy. Barring the two patients who received adjuvant mitotane, the rest were treated with systemic therapy for metastatic disease (52 patients). One-third (17 patients) of these presented with de novo Stage IV disease, while the rest were patients who recurred after potentially curative surgery. Twenty-seven percent of the patients received adjuvant radiotherapy for R1 or unknown resection margins. The median progression-free survival (PFS) for the group of 37 patients who underwent surgery was 13 months, reflecting the aggressive behavior of ACC.

Among the patients who received systemic therapy with palliative intent, majority received chemotherapy only. The regimens used were etoposide and platinum (EP) in 51.9% and etoposide, doxorubicin and platinum (EDP) in 42.3%. Fifteen patients received mitotane, 5 as a single agent and the rest with chemotherapy. The dose of mitotane was titrated based on the adverse events, the median dose being 2 g. In their series, the addition of doxorubicin increased the Grade 3–4 toxicities without any improvement in the PFS (median PFS was 6 months for EP and 7 months for EDP, P = 0.66). Although the addition of mitotane to chemotherapy increased the PFS to 13 months, this was not significant compared to the 6 months without mitotane (P = 0.4).

In more than a decade, very few studies of chemotherapy, with or without mitotane, have been published. Most of these are single-arm studies with a response rate (RR) of 7%–54%.[6] Although the addition of mitotane to chemotherapy is superior to chemotherapy alone, this has never been proven in a randomized controlled trial. The FIRM-ACT study randomized 304 patients with inoperable/metastatic ACC to EDP plus mitotane or single-agent streptozotocin.[7] The objective RR was 23 versus 9%, PFS was 5 versus 2.1 months, and overall survival (OS) was 14.8 versus 12 months for Etoposide, Doxorubicin, Platinum - Mitotane (EDP-M) and streptozotocin, respectively. The lack of OS benefit was attributed partly to the crossover effect. Based on these data, EDP-M is considered the preferred regimen for metastatic ACC. Results with other chemotherapy drugs, including taxanes, capecitabine, and irinotecan, as single agents and in combination with platinum have been disappointing.

Majority of the patients in this series received chemotherapy only. In resource-constrained settings, it is common to offer palliative chemotherapy without mitotane. It would have been interesting to compare the results with chemotherapy in a matched cohort of patients who did not receive chemotherapy in the initial set of 106 patients. Unfortunately, this analysis was not performed. Moreover, the role of the three-drug chemotherapy (EDP) compared to the two drugs (EP) is unclear. In the small subgroup analysis presented here, there was no difference in the PFS.

The median OS of the patients who received palliative systemic therapy was 17 months, with a third of patients receiving second-line therapy. The RR (41.7%), PFS (6 months), and OS (17 months) of their cohort were numerically higher than those reported in the EDP-M arm of the FIRM-ACT study. The authors attribute the improved OS to better supportive care and improvements in systemic therapy. However, in the past many years, there have hardly been any new drugs or treatment modalities for advanced ACC.

Mitotane (a congener of the pesticide diphenyl- dichloro-trichloroethane) is a drug with adrenocorticolytic effects.[8] It is used in the adjuvant setting as a single agent in patients with a high risk of recurrence after surgery and in the recurrent/metastatic setting as a single agent or in combination with chemotherapy. Although the role of adjuvant mitotane in improving the OS is controversial, the International Consensus Panel recommends adjuvant mitotane for a minimum of 2 years in all patients with potential residual disease (R1 or Rx resection) or high Ki-67 (>10%).[9] Mitotane has been used as a single agent and with chemotherapy in the palliative setting. The results of chemotherapy alone, when not combined with mitotane, are disappointing. Mitotane acts on the multidrug resistance efflux pump and increases the cytotoxicity of chemotherapy.[10]

There are many practical difficulties in using mitotane. Lack of access and affordability are the most important ones. Others include multiple drug interactions, unfavorable adverse event profile, and the need for drug-level monitoring to achieve therapeutic concentrations. These difficulties are reflected in the present series; the proportion of patients who actually took mitotane was only 10% of those who were recommended mitotane in the adjuvant setting and 27% in the metastatic setting.

Although the authors have done their best, there are some shortcomings in the data, and one has to interpret these results with caution. Response evaluation and toxicity data were available only for 24 (66.7%) and 29 (55.7%) patients, respectively. This could have skewed the RR and PFS results. Small numbers and retrospective single-institution series tend to be biased and almost always report better results than larger multicenter studies. The subgroups are too small to make any meaningful comparisons between treatment regimens. Furthermore, a significant number of patients had missing surgical pathology data (40.6%). It would have been useful if the authors had reported the demographic and basic pathology data for the entire cohort of 106 patients; it would have added great value to their findings. Having said that, it is not uncommon in the real world setting to have missing data, especially in low middle income countries. Hence, the authors must be commended for putting together this very useful data set that reflects results in the real-world setting with constrained resources.

Where do we go from here? It is unlikely that we will see any major improvements in the survival with more chemotherapy or modifications to the existing treatment backbone. Recent studies with immunotherapy have shown some promising results. In a Phase II study, pembrolizumab has shown a RR of 23%, with a PFS and OS of 2 and 23 months, respectively.[11] Therapies targeting molecular abnormalities in ACC, such as the insulin-like growth factor-1 receptor inhibitors, vascular endothelial growth factor, and epidermal growth factor receptor inhibitors, have been disappointing.[12],[13],[14] As ACC is a rare disease, getting large number of patients from a single center is impossible. Any fight against ACC has to be multicentric and multipronged. It is important to establish a regional registry comprising centers that manage patients with this rare disease. This could give us better information regarding demographics and outcomes, which will pave the way for more collaborative research and clinical trials. Until then, we will have to continue the difficult journey with our patients on the long, winding, and seemingly endless road.

  References Top

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Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, et al. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 2001;61:6762.  Back to cited text no. 2
Aubert S, Wacrenier A, Leroy X, Devos P, Carnaille B, Proye C, et al. Weiss system revisited: A clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol 2002;26:1612-9.  Back to cited text no. 3
Icard P, Goudet P, Charpenay C Andreassian B, Carnaille B, Chapuis Y, et al. Adrenocortical carcinomas: Surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001;25:891.  Back to cited text no. 4
Kapoor A, Noronha V, Toshniwal A, Menon S, Joshi A, Patil VM, et al. Exploring the role of systemic therapy in adrenocortical carcinoma - Single center experience. Cancer Res Stat Treat 2020;3:192-200.  Back to cited text no. 5
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Henley DJ, van Heerden JA, Grant CS, Carney JA, Carpenter PC. Adrenal cortical carcinoma-a continuing challenge. Surgery 1983;94:926-31.  Back to cited text no. 8
Berruti A, Fassnacht M, Baudin E, Hammer G, Haak H, Leboulleux S, et al. Adjuvant therapy in patients with adrenocortical carcinoma: A position of an international panel. J Clin Oncol 2010;28:e401-2.  Back to cited text no. 9
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