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Endocrine
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Treatment Outcomes in Patients with Recurrent Adrenocortical Carcinoma
Tamara Dojcinovic, Karin Zibar Tomsic, Ivana Dora Vodanovic, Tina Dusek, Ivana Kraljevic, Anja Barac Nekic, Tanja Skoric Polovina, Nikola Knezevic, Ana Marija Alduk, Zrna Antunac Golubic & Darko Kastelan
To cite this article: Tamara Dojcinovic, Karin Zibar Tomsic, Ivana Dora Vodanovic, Tina Dusek, Ivana Kraljevic, Anja Barac Nekic, Tanja Skoric Polovina, Nikola Knezevic, Ana Marija Alduk, Zrna Antunac Golubic & Darko Kastelan (2025) Treatment Outcomes in Patients with Recurrent Adrenocortical Carcinoma, Endocrine Research, 50:1, 43-49, DOI: 10.1080/07435800.2024.2397561
To link to this article: https://doi.org/10.1080/07435800.2024.2397561
Published online: 02 Sep 2024.
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Treatment Outcomes in Patients with Recurrent Adrenocortical Carcinoma
Tamara Dojcinovic (Da,b, Karin Zibar Tomsic (DC, Ivana Dora Vodanovic (DC, Tina Dusek (Dcd, Ivana Kraljevic iDc,d, Anja Barac Nekic DDc, Tanja Skoric Polovina De, Nikola Knezevic @Dd,e, Ana Marija Alduk @Ddf, Zrna Antunac Golubic (Dg, and Darko Kastelan (Dcd
aDepartment of Endocrinology of the Internal medicine clinic, University Clinical Centre of the Republic of Srpska, Banja Luka, Bosnia and Herzegovina; bSchool of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina; “Department of Endocrinology, University Hospital Center Zagreb, Zagreb, Croatia; dSchool of Medicine, University of Zagreb, Zagreb, Croatia; eDepartment of Urology, University Hospital Centre Zagreb, Zagreb, Croatia; ‘Department of Radiology, University Hospital Centre Zagreb, Zagreb, Croatia; 9Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia
ABSTRACT
Background: While numerous studies have explored treatment outcomes for the overall ACC patient cohort, data on the subpopulation of patients with recurrent disease are limited. Therefore, the aim of this study was to assess treatment outcomes in patients with recurrent ACC. Methods: In this retrospective study, we included 18 patients median age 49 years (42-62); 67% female) diagnosed with recurrent ENSAT stage I-III ACC who underwent either R0 (n = 16) or Rx (n = 2) surgical resection of the tumor.
Results: The median time from the initial surgery to ACC recurrence was 29 months (IQR 18-50). Seven patients (39%) manifested local recurrence, while 11 patients (61%) developed distant metastases. The median follow-up duration after tumor recurrence was 32 months (IQR 25-53). Regarding the treatment of ACC recurrence, 10 patients underwent a second surgery either as an alone procedure (n =4), or in combination with mitotane (n =4), mitotane and chemotherapy (n = 1), or mitotane combined with radiotherapy (n = 1). The remaining patients received treatment involving chemotherapy+mitotane (n =4) and locoregional therapy ±chemotherapy (n = 3). One patient chose not to proceed with further management and follow-up. The median PFS was 17 (95% CI 8-26) months while the median OS was not reached. In the multivariate model, increased mortality was associated with advanced age (p = 0.04) and a shorter interval to ACC recurrence (p=0.03).
Conclusion: A significant proportion of patients with ACC recurrence experience disease progres- sion or second recurrence, despite all treatment efforts. Nevertheless, by integrating diverse treatment modalities, many patients have the potential to attain long-term survival.
ARTICLE HISTORY
Received May 2, 2024 Revised July 17, 2024 Accepted August 22, 2024
KEYWORDS
Adrenocortical carcinoma; chemotherapy; locoregional therapy; mitotane; recurrence
Introduction
Adrenocortical carcinoma (ACC) represents a rare malignancy with an unfavorable prognosis, where com- plete surgical resection stands as the only potential cure. In addition to surgery, adjuvant mitotane is recom- mended for at least two years in a subset of patients at high risk of disease recurrence.1-4 Despite this proactive approach, the recurrence rate of ACC remains remark- ably high, affecting up to 80% of patients.5-7
While numerous studies have explored treatment outcomes for the overall ACC patient cohort, data on the subpopulation of patients with recurrent disease are limited. Existing studies indicate that surgical interven- tion for recurrent disease might be associated with pro- longed survival, especially among patients experiencing recurrence beyond 12 months post-initial surgery. 5,7-10
Additionally, Calabrese et al. stressed also the important role of systemic chemotherapy and various locoregional treatment options, such as radiofrequency and radio- therapy, in managing patients with recurrent ACC.7 Nevertheless, it is important to recognize the limitations inherent in these studies, characterized by their retro- spective nature, relatively small sample size, and the application of diverse treatment modalities. Therefore, to expand upon existing knowledge, our present study analyzed the treatment outcomes in our cohort of patients with recurrent ACC.
Methods
In this retrospective study, we included 18 patients med- ian age 49 years (42-62); 67% female) diagnosed with
recurrent ENSAT stage I-III ACC who underwent either R0 (n = 16) or Rx (n = 2) surgical resection of the tumor between 2005 and 2022. Patients below the age of 18 and those diagnosed with disease recurrence within 3 months post-surgery were excluded from the study. Demographic details, results of hormonal work-ups, pathology reports, and treatment details were systematically retrieved from the electronic medical records of the patients. The study received approval from the Ethics Committee at the University Hospital Centre Zagreb.
Adrenocortical carcinoma (ACC) was diagnosed using the Weiss scoring system, with the Lin-Weiss- Bisceglia scoring system applied for patients presenting oncocytic adrenocortical tumors. The resection status (R0, Rx, R1, R2), mitotic activity, and Ki-67 expression were assessed in all cases. Tumor staging was carried out based on the ENSAT classification system. All tumor specimens were analyzed by a single pathologist.
The follow-up after surgery involved clinical, hormo- nal, and imaging evaluations every 3 months in the first postoperative year, followed by assessments every 3-6 months thereafter. However, three patients, who initi- ally underwent surgery in a non-expert center, deviated from that protocol by having their follow-up visits scheduled at longer time intervals. The primary out- comes of the study were progression-free survival (PFS) and overall survival (OS) after tumor recurrence. PFS was defined as the duration of the initial recurrence to subsequent disease progression or the last imaging follow-up, while OS was defined as the time from ACC recurrence to death or the last follow-up visit.
Statistical Analysis
Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) ver. 17.0 for Windows. Variables were described as median (IQR, interquartile range) and as numbers (percentages). Survival was ana- lyzed with the Kaplan-Meier method. For multivariate analysis, the Cox regression model was applied. A confidence interval of 95% was used. The statistical significance level was set at p value <0.05.
Results
Patient Characteristics
In our cohort of 55 patients who underwent R0/Rx tumor resection, 18 individuals (33%) exhibited recurrent dis- ease and were consequently included in this study. The median time from the initial surgery to ACC recurrence was 29 months (IQR 18-50), with three patients experi- encing recurrence within 12 months post-surgery.
| Sex - N (%) | |
| Male | 6 (33%) |
| Female | 12 (67%) |
| Age at diagnosis - year | |
| Median [IR] | 49 (42 - 62) |
| ENSAT stage - N (%) | |
| Stage I | 1 (5%) |
| Stage II | 10 (56%) |
| Stage III | 7 (39%) |
| Hormone secretion - N (%) | |
| Nonsecreting tumors | 8 (44%) |
| Cortisol ± other steroids | 10 (56%) |
| Weiss score | |
| Median [IR] | 6(6-8) |
| Ki67 index | |
| Median [IR] | 14%(8-21) |
| Reccurence patterns - N | |
| Local | 7 (39%) |
| Distant metastases | 11 (61%) |
| Multiple organs | 4 |
| Single organ | 7 |
| Adjuvant therapy - N | |
| Mitotane | 8 (44%) |
| Mitotane+chemotherapy | 2 (11%) |
| None | 8 (44%) |
Following the initial surgery, adjuvant treatment was administered to 10 out of 18 patients, all of whom exhibited the Ki-67 index above 10%. Among them, eight patients received mitotane, while the remaining two underwent three cycles of chemotherapy (EP) in addition to mitotane. The median duration of the adju- vant mitotane treatment was 23 months (IQR 12-30). Among the eight patients who did not receive adjuvant mitotane, five had a Ki-67 index ≤10%, in one mitotane was discontinued after 2 months of treatment due to liver toxicity, whereas in two patients, the initial surgery was conducted in a non-expert center, and they were referred to our center upon the disease recurrence. Detailed demographic and clinical characteristics of the patients are presented in Table 1.
Regarding recurrence patterns, seven patients (39%) manifested local recurrence, while 11 patients (61%) developed distant metastases. Among those with distant metastases, seven exhibited lesions in a single organ, whereas four presented metastatic lesions in multiple organs (three in two organs, one in three organs). The organs most frequently affected by metastases were the lungs (8 patients), followed by the abdomen (3 patients), liver (2 patients), pelvis (2 patients), and bones (1 patient). The median follow-up duration after tumor recurrence was 32 months (IQR 25-53).
Treatment Modalities and Patient Outcomes
Surgery + Mitotane + Chemotherapy
Following the recurrence of ACC, surgical treatment, with or without adjuvant mitotane or chemotherapy,
was administered to nine patients: five with local recurrence and four with distant metastases (two in the lungs, one in the abdomen, and one in the pelvis). Surgical intervention led to complete remission in eight patients and palliative response in one. Mitotane was continued in two patients, initiated de novo in three patients, and was not employed in the management of recurrent disease in four patients. Additionally, one patient underwent EDP chemother- apy alongside mitotane. Among the patients in this subgroup, seven exhibited further disease progression after a median PFS of 14 months (IQR 11-17). Three patients died 7, 27 and 29 months after the initial ACC recurrence.
Surgery + radiotherapy + mitotane
After experiencing local recurrence of ACC, one patient underwent curative surgery followed by radiotherapy of the tumor bed. Mitotane was administered in an adju- vant setting after the initial surgery and continued upon recurrence. The patient faced further disease progres- sion after 24 months and died from an unrelated cause 81 months after the ACC recurrence.
Chemotherapy + Mitotane
EP/EDP chemotherapy + mitotane was administered to four patients, all of whom had distant metastases in multiple organs (2 in the lungs and abdomen, 1 in the lungs and liver, and 1 in the lungs, liver, and bones). One patient exhibited stable disease after 12 months of follow-up, while three patients experienced further dis- ease progression after 5, 24, and 29 months, with one patient dying due to the disease 29 months after recurrence.
Locoregional Therapy (Excluding Surgery) + Chemotherapy
This subgroup comprised of three patients, all pre- senting with distant metastases confined to a single region/organ (one in the lungs and two in the pel- vis). Two patients underwent microwave ablation (MWA), while one received embolization of the metastatic lesions. In conjunction with locoregional treatment, two patients underwent EDP chemother- apy. All patients experienced disease progression after 3, 17, and 18 months, respectively. None of the patients within this subgroup died.
No Intervention Administered
Following the ACC recurrence, one patient opted not to proceed with further management and follow-up. The patient died from the disease 28 months after recurrence.
Overall Survival and Progression Free Survival
In our cohort of 17 patients treated for recurrent ACC, 14 manifested disease progression, one maintained stable disease, while two achieved complete remission at their last follow-up assessments. Six patients (33%) died, including one who opted for no treatment of recurrent disease. The median PFS was 17 (95% CI 8-26) months while the median OS was not reached. Furthermore, the one, three and five-year OS rates were 94%, 68%, and 68%, respectively (Figure 1).
In the multivariate model incorporating age, gender, ENSAT stage, duration from ACC diagnosis to first recurrence, adjuvant mitotane treatment, glucocorticoid hypersecretion, recurrence pattern, and site of recur- rence, no single factor exhibited significant association with disease progression. In contrast, increased mortal- ity was associated with advanced age (p =0.04) and a shorter interval to ACC recurrence (p = 0.03; Tables 2 and 3).
Discussion
While a considerable body of literature exists detailing outcomes in patients with ACC, reports specifically addressing outcomes of patients with recurrent disease remain scarce.5,7-10 Furthermore, the majority of these studies have concentrated on the outcomes associated with surgical management, without analyzing the out- comes resulting from various treatment modalities across the entire cohort of patients. In the present study, we disclosed management details and outcomes of patients with recurrent ACC, incorporating a range of therapeutic approaches tailored to the pattern and site of recurrence, time to recurrence, clinical characteris- tics, and individual preferences.
Surgical intervention is considered the preferred treat- ment for localized ACC.1 However, even after a complete surgical resection of ACC, which offers the best potential for cure, a substantial proportion of patients experience disease recurrence. In addressing the treatment of these patients, existing guidelines, lacking definitive evidence from randomized studies, advocate for surgical interven- tion, or alternatively, other local therapies when feasible and when the disease-free interval exceeds 12 months. Conversely, if the interval between the initial surgery and ACC recurrence is less than 6 months, the recom- mended regimen involves a combination of EDP with mitotane. However, a study involving 154 patients from the German ACC Registry, revealed that, following sur- gical treatment for recurrent disease, 94% of patients experienced a second recurrence or progressive disease.9 Similar findings were also observed in other studies.6,7,11 Within our cohort, 10 patients with ACC recurrence
Survival Function Censored
1.0
Overall survival after recurrence
0.8
0.6
0.4
0.2
0.0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
168
180
92
204
Time (months)
underwent surgical intervention either alone or in com- bination with mitotane, chemotherapy, or radiotherapy. Among the nine patients for whom surgery was curative, 78% experienced a second disease recurrence after a median RFS of 14 months.
In a recent study by Calabrese et al.,7 the importance of aggressive treatment for ACC recurrence was empha- sized. Their approach involved surgery or other locor- egional therapies, whenever possible, in combination with mitotane. This led to a second median RFS of 15 months and a median survival time from disease recur- rence of 23 months. We adopted this management strat- egy for our patients; 77% received locoregional treatment - 10 underwent surgery, two received MWA, and one underwent embolization. In contrast, four patients, all with distant metastases in multiple organs, received chemotherapy combined with mito- tane. Notably, the median PFS in our study was 17 months (95% CI 8-26) whereas median overall survival was not reached as only six patients had died after a median follow-up of 32 months (IQR 25-53).
Various factors have been identified to correlate with adverse outcomes in patients with ACC, including age, stage of disease, resection status, Ki-67 index, inflam- matory response to the tumor and the presence of glucocorticoid excess.12-17 However, factors that play a prognostic role in patients with recurrent ACC are less well-known. It has been reported that a time to the first recurrence of less than 12 months, a substantial tumor burden, the presence of distant metastases, and incomplete tumor resection7,9 had a negative impact on PFS and OS. Additionally, Calabrese et al. reported that Ki-67 expression, adjuvant mitotane treatment, and the pattern of recurrence were independent factors influen- cing OS.7 Within our patient cohort, no singular factor demonstrated a significant association with subsequent disease progression following the initial recurrence. Nevertheless, advanced age and a shorter time interval to the initial ACC recurrence emerged as predictive factors of poor survival.
All subjects included in this study were managed in a high-volume referral center with extensive expertise in
| Sex | Age at diagnosis | Tumor size (mm) | R status Ro/Rx | Adjuvant treatment | Time to recurrence (months) | Recurrence pattern | Number of organs | Treatment of recurrence | Further progression (months) | Death (months) | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1. | M | 42 | 150 | R0 | Mitotane | 22 | Local | 1 | Surgery, mitotane, radiotherapy | 24 | 81 |
| 2. | F | 18 | 87 | R0 | Mitotane | 42 | Local | 1 | Surgery, mitotane, chemotherapy | 15 | / |
| 3. | F | 60 | 110 | R0 | Mitotane | 29 | Local | 1 | Surgery | 13 | 29 |
| 4. | F | 38 | 45 | R0 | / | 45 | Distant metastasis | 1 | Surgery | 8 | / |
| 5. | M | 63 | 100 | R0 | / | 21 | Distant metastasis | 1 | Surgery, mitotane | 14 | 27 |
| 6. | F | 40 | 156 | R0 | Mitotane | 64 | Local | 1 | Surgery, mitotane | Complete | / |
| remission | |||||||||||
| 7. | M | 48 | 120 | R0 | Mitotane | 33 | Local | 1 | Surgery | Complete remission | / |
| 8. | F | 43 | 160 | Rx | Mitotane+ Chemotherapy | 19 | Local | 1 | Surgery, mitotane | 5 | 7 |
| (PE) | |||||||||||
| 9. | M | 32 | 110 | R0 | / | 97 | Local | 1 | Surgery | 7 | / |
| 10. | F | 45 | 140 | R0 | / | 29 | Distant metastasis | 1 | Surgery, mitotane | 60 | / |
| 11. | F | 62 | 140 | R0 | / | 80 | Distant metastasis | 1 | Locoregional therapy (PVA) | 10 | / |
| 12. | F | 42 | 75 | R0 | Mitotane | 85 | Distant metastasis | 1 | Locoregional therapy (PVA, MWA) mitotane, chemotherapy, | 17 | / |
| 13. | M | 50 | 250 | R0 | / | 40 | Distant metastasis | 1 | Locoregional therapy (3xPVA, 1×MWA), chemotherapy | 22 | / |
| 14. | F | 59 | 180 | R0 | / | 19 | Distant metastasis | 2 | Mitotane, chemotherapy | 29 | / |
| 15. | F | 51 | 90 | R0 | / | 8 | Distant metastasis | 2 | Mitotane, chemotherapy | 24 | 29 |
| 16. | F | 66 | 130 | R0 | Mitotane | 7 | Distant metastasis | 2 | Mitotane, chemotherapy | Stable disease | / |
| 17. | F | 63 | 106 | Rx | Mitotane+ Chemotherapy (PE) | 13 | Distant metastasis | 3 | Mitotane, chemotherapy | 5 | / |
| 18. | M | 71 | 55 | R0 | / | 8 | Distant metastasis | 1 | Mitotane | 8 | 28 |
PE - etoposide, cisplatin, EDP - etoposide, doxorubicin, cisplatin, PVA - polyvinyl alcohol ablation, MWA - microwave ablation.
| Variable | PFS OR (95% CI), P | OS OR (95% CI), P |
|---|---|---|
| Age | 1.00 (0.95-1.05), 0.91 | 1.11 (1.01-1.22), 0.04 |
| Gender | 0.75 (0.23-2.44), 0.63 | 1.61 (0.32-8.07), 0.57 |
| ENSAT stage | 3.85 (0.37-39.96),0.26 | 3.28 (0.67-16.08),0.14 |
| Time to recurrence | 1.01 (0.99-1.03), 0.45 | 0.92 (0.84-0.99), 0.03 |
| Adjuvant mitotane treatment | 1.04 (0.33-3.31), 0.95 | 2.07 (0.36-11.97),0.42 |
| Glucocorticoid hypersecretion | 0.62 (0.18-2.12), 0.45 | 0.49 (0.08-2.96), 0.44 |
| Site of recurrence: | ||
| Liver metastases | 2.00 (0.42-9.19), 0.39 | 2.69 (0.30-24.22),0.38 |
| Pulmonary metastases | 0.90 (0.29-2.75), 0.85 | 0.77 (0.14-4.27), 0.77 |
| Abdominal metastases | 0.89 (0.19-4.11), 0.88 | 2.04 (0.22-18.67),0.53 |
| Recurrence pattern: | ||
| Local metastasis | 1.10 (0.35-3.47), 0.87 | 1.16 (0.23-5.78), 0.86 |
| Distant metastasis | 0.91 (0.29-2.87), 0.87 | 0.86 (0.17-4.30), 0.86 |
treating ACC patients, representing a major strength of the study. Our prior research emphasized the favorable outcomes associated with managing these patients in expert centers.18 Consequently, the current patient cohort demonstrates a median time of 29 months elapsed from the initial surgery to recurrence,
surpassing the recurrence free survival duration reported in comparable studies.7-10 Furthermore, our patients exhibited extended median PFS and OS follow- ing disease recurrence, underscoring the positive impact of our treatment approach. However, the study is also subject to certain limitations, primarily due to its
retrospective design and small sample size, which con- sequently hampers the ability to analyze the influence of various clinical factors on patient outcomes. Nevertheless, given the rarity of the disease and the scale of the Croatian population, we can assert that the included patient cohort is representative and devoid of any selection bias.
In summary, a significant proportion of patients with ACC recurrence experience further disease progression or second recurrence, despite all treatment efforts. Nevertheless, by integrating diverse treatment modal- ities, many patients have the potential to attain long- term survival, underscoring the pivotal role of expert centers in their management.
Disclosure Statement
No potential conflict of interest was reported by the author(s).
Funding
The author(s) reported that there is no funding associated with the work featured in this article.
ORCID
Tamara Dojcinovic (D http://orcid.org/0009-0007-1183-8940 Karin Zibar Tomsic (D http://orcid.org/0000-0002-1694-6891 Ivana Dora Vodanovic (D http://orcid.org/0000-0002-5380- 4411
Tina Dusek (D http://orcid.org/0000-0002-1266-3501
Ivana Kraljevic (D http://orcid.org/0000-0002-4379-2250
Anja Barac Nekic (D http://orcid.org/0000-0003-2672-8529 Tanja Skoric Polovina (D http://orcid.org/0000-0003-3785- 6657
Nikola Knezevic (D http://orcid.org/0000-0001-9198-310X Ana Marija Alduk (D http://orcid.org/0000-0002-5438-4439 Zrna Antunac Golubic (D http://orcid.org/0000-0003-3914- 7600
Darko Kastelan (D http://orcid.org/0000-0003-3034-5598
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