Long-Term Progression-Free Survival With Sunitinib in Advanced Recurrent Adrenocortical Carcinoma
To the Editor:
Adrenocortical carcinoma (ACC) is a rare disease with limited treatment options. The annual worldwide incidence of adrenocortical carcinoma is 0.5-2 indi- viduals per million population.1 Although the incidence follows a bimodal age dis- tribution with peaks in the first 5 years and fourth decade of life, the median age at diagnosis is 55 years. Although aggres- siveness of the disease varies with the stage, the general prognosis is poor because of the fact that most patients are diagnosed at a later stage. Median survival for advanced adrenocortical carcinoma is 11 months.2 ACC can present with hor- monal overproduction syndromes, such as Cushing syndrome, hyperandrogenism, or primary hyperaldosteronism.3 Prognosis is generally slightly worse with secretory tu- mors. High mitotic rate, age, and the R0 resection are other prognostically signifi- cant factors.
Patients with localized adrenocorti- cal carcinoma have the potential for cure through complete surgical resection. However, even after an R0 resection, recurrence may occur in a significant pro- portion of patients.4 In such cases, if recur- rence is operable, the potential benefits of surgery remain debatable because there is no strong data available to guide decision making. However, if recurrence occurs beyond 6 months, the general clinical rec- ommendation is a surgical approach given the lack of effective systemic treatment options.5
Systemic treatment choices for advanced adrenocortical carcinoma are very limited. Mitotane can be used in both
advanced and adjuvant settings. Based on FIRM-ACT randomized clinical trial, platinum-based chemotherapy combina- tion with mitotane is generally a first-line treatment choice for advanced adrenocorti- cal carcinoma. However, beyond progres- sion with the first-line treatment, there is no strong evidence to guide the selection of second-line systemic treatment.2
The phase 2 trial of metronomic 5FU/capecitabine and gemcitabine proto- col showed a 7% objective response rate and 9.8 months of overall survival. In addition, preclinical studies suggest that temozolomide may be effective in the treatment of adrenocortical carcinoma.6
Adrenocortical carcinoma is a tumor with a very low mutation burden, and despite ongoing targeted therapy studies, there is no specific option for advanced adrenocortical carcinoma that significantly extends progression-free survival or over- all survival.7
Sunitinib is a multityrosine kinase inhibitor targeting VEGFR1-2, c-KIT, Fms-like tyrosine kinase 3, and PDGFR. In the phase 2 study of 35 advanced adrenocortical carcinoma pa- tients treated with the sunitinib, the median progression-free survival was 2.8 months, and the median overall sur- vival (OS) was 5.4 months.6
In this study, we present a patient with advanced recurrent adrenocortical carcinoma, treated with sunitinib in the second-line systemic therapy, achieving a progression-free survival of >1 year. Because it is rare to report this long PFS with advanced ACC, this case report could serve as evidence for further trials and potentially supporting exploration of sunitinib as a treatment option for advanced recurrent adrenocortical carcinoma.
A 33-year-old patient with no known comorbidities presented to our clinic with complaints of back pain and weight loss. After diagnostic evaluation, abdominal imaging revealed a 188 x 145 mm mass in the left surrenal region. A biopsy of the mass confirmed the diagnosis of adrenocortical carcinoma. Subsequently, the mass was totally excised in December 2021. Unfortunately, the patient did not attend any follow-up after this date and pre- sented again in March 2023 with com- plaints of abdominal pain and loss of appetite. Multiple metastatic lesions
were detected in the liver. A biopsy of the liver lesions confirmed metastasis of adrenocortical carcinoma. First-line sys- temic therapy with a combination of cis- platin, etoposide, and mitotane was initiated in May 2023. After 4 cycles of this treatment, an increase in both the number and size of liver lesions was observed. Owing to the early pro- gression, we initiated search for a poten- tial targeted therapy. Pathologic and genetic analyses of the biopsy sample showed MSI stable, CerbB2, PD-L1, c-KIT negative. The patient was dis- cussed with a multidisciplinary commit- tee and progressed lesions were found to be suitable for local ablative treatment. With the addition of local ablative treat- ment, we continued the same first-line systemic therapy, and the first control PET-CT (after 3 months) revealed pro- gressive disease with newly developed liver lesions. In January 2024, we initi- ated sunitinib as a second-line systemic treatment at the standard dose (50 mg/d, 4 weeks on, 2 weeks off). After 3 months of treatment, PET-CT showed partial regression in the liver lesions that was maintained for a 12-month period. The patient did not experience any severe side effects related to sunitinib.
This case report highlights the challenges in managing advanced recurrent ACC, particularly in the second-line setting where treatment options are limited. The patient’s response to sunitinib, with >1 year of progression-free survival, is notable given the poor outcomes typically associated with ACC. Although suniti- nib has shown limited effectiveness in phase 2 studies, this case suggests that further exploration of sunitinib in this setting is warranted.
Owing to the lack of effective systemic treatments for advanced ACC, there is an urgent need for novel and more effective therapeutic options. This case provides valuable insight into the potential role of sunitinib in the treatment of recurrent ACC, warranting further inves- tigation in future clinical trials.
Ali Turker, MD1 Mahmut Buyuksimsek, MD1 İrem Kolsuz Turker, MD2 Mehmet Turker, MD1 İrfan Alisan, MD3
1Department of Medical Oncology, Adana City Education and Research Hospital, Adana, Turkey
2Department of Endocrinology, Cukurova University Faculty of Medicine, Adana, Turkey
3Department of Internal Medicine, Adana City Education and Research Hospital, Adana, Turkey
References
1. Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev. 2014; 35:282-326.
2. Pak C, Yoon S, Lee JL, et al. Current status and future direction in the treatment of advanced adrenocortical carcinoma. Curr Oncol Rep. 2024;26:307-317.
3. Fassnacht M, Dekkers OM, Else T, et al. European society of endocrinology clinical practice guidelines on the management of adre- nocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2018;179: G1-G46.
4. Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol. 1999;6:719-726.
5. Datrice NM, Langan RC, Ripley RT, et al. Operative management for recurrent and meta- static adrenocortical carcinoma. J Surg Oncol. 2012;105:709-713.
6. Konda B, Kirschner LS. Novel targeted thera- pies in adrenocortical carcinoma. Curr Opin Endocrinol Diabetes Obes. 2016;23:233-241.
7. Hescheler DA, Hartmann MJM, Riemann B, et al. Targeted therapy for adrenocortical carcinoma: a genomic-based search for available and emerg- ing options. Cancers (Basel). 2022;14:2721.
Comment on “Efficacy and Safety Profile of Finerenone in the Management of Diabetic Nephropathy in Its Early Stages”
To the Editor:
We read with great interest the article, entitled “Efficacy and Safety Profile of Finerenone in the Management of Diabetic Nephropathy in Its Early Stages,” recently published in the American Journal of Therapeutics.1 Finerenone, a highly
The author has no conflicts of interest to declare. Copyright @ 2025 Wolters Kluwer Health, Inc. All rights reserved.
selective nonsteroidal inhibitor of the mineralocorticoid receptor with a 50% inhibitory concentration of 18 nM, has been shown to enhance diastolic func- tion in patients with type 2 diabetes mel- litus.2 Additionally, finerenone has been reported to aid in the prevention of left ventricular dysfunction and decrease ventricular hypertrophy.2 In this ran- domized, prospective, controlled, clini- cal study, it was suggested that a combination treatment, including finer- enone, irbesartan, and canagliflozin, decreased urine protein levels in patients with diabetic nephropathy compared with that in a control group, which received irbesartan, canagliflozin, and a placebo.1 Consequently, we would like to comment on the statistical inaccura- cies that were overlooked in this study. First, comparisons of several variables (fasting blood sugar, glycosylated hemo- globin, systolic blood pressure, serum potassium, blood creatinine, etc.) between the 2 groups (control vs. obser- vation) at multiple time points (before treatment and at 4, 8, 12, and 24 weeks after treatment) were performed by means of a t test.1 However, to adjust for type I errors due to multiple compar- isons (5 time points), a 2-way repeated- measures analysis of variance followed by Bonferroni multiple comparison test or a linear mixed-effects model would have been more appropriate.3-5 Second, the reported P value derived from the t value (0.512) for the comparison of fast- ing blood glucose levels before treat- ment and 24 weeks after treatment in the control group was stated as 0.756 (Table 2).1 However, based on the given t value (0.512) and degrees of freedom (55), the correct P value is 0.617. This indicates an inaccuracy in the reported statistical calculations. Third, an appro- priate sample size should have been cal- culated before initiating the randomized controlled study.6 The study included 56 patients in each group, but crucial details such as type I errors, statistical power (1 -type II error), and effect size used for sample size calculation were not described.1,3,6,7 An inadequate sample size may lead to false-negative results, whereas an excessively large sample size may yield statistically significant differences that lack clinical rele- vance.3,6,7 Fourth, the z-value and t value were used interchangeably in
Table 2.1 The z-value is typically used when the population variance is known or when the data can be assumed to fol- low a normal distribution. However, this was not mentioned in the article, making it difficult for readers to understand the results and thereby causing confusion. Because the population variance is usu- ally unknown, it would be more appro- priate to use the t value. Additionally, the reported P value from the Z-value (2.51) for the comparison of 24-hour urine protein quantification (g) between the control and observation groups before treatment was stated as 0.092 (Table 2).1 However, the correct P value for a Z-value of 2.51 in a 2-tailed test is 0.0121, suggesting another statistical in- accuracy. Finally, the “F0632 test” described in the study for the compari- son of counting data appears to be a typographical error.1
In conclusion, although this study provides valuable insights into the effi- cacy and safety of finerenone for the management of diabetic nephropathy, certain statistical analyses require clari- fication and correction. Addressing these statistical concerns would enhance the credibility and reliability of the study’s findings.
Sung-Hyo Seo, PhD1 Ju-Tae Sohn, MD2,3
1Department of Biomedical Research Institute, Gyeongsang National University Hospital, Jinju-si, Republic of Korea 2Department of Anesthesiology and Pain Medicine, Gyeongsang National University College of Medicine, Gyeongsang National University Hospital, Jinju-si, Gyeongsangnam-do, Republic of Korea 3Institute of Medical Science, Gyeongsang National University, Jinju-si, Republic of Korea
REFERENCES
1. Zhang FP, Jiang X. Efficacy and safety profile of finerenone in the management of diabetic nephropathy in its early stages. Am J Ther. 2024. doi:10.1097/MJT.0000000000001800.
2. Kolkhof P, Jaisser F, Kim SY, et al. Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardi- orenal diseases: comparison at bench and bed- side. Handb Exp Pharmacol. 2017;243:271- 305.
3. AbdulRaheem Y. Statistics in medical research: common mistakes. J Taibah Univ Med Sci. 2023;18:1197-1199.