Adrenocortical Cancer in the Real World: A Comprehensive Analysis of Clinical Features and Management from the Turkish Oncology Group (TOG)
Hatime Arzu Yasar,1 Burak Yasin Aktas,2 Gokhan Ucar,3 Sema Sezgin Goksu,4 Irem Bilgetekin,5 Burcu Cakar,6 Abdullah Sakin,7 Ozturk Ates,8 Tugba Basoglu,9 Cagatay Arslan,10 Atike Gokcen Demiray,11 Semra Paydas, 12 Irfan Cicin, 13 Mehmet Ali Nahit Sendur,14 Nuri Karadurmus,15 Hakan Kosku,1 Aytuğ Uner,5 Perran Fulden Yumuk,9,24 Gungor Utkan,1 Umut Kefeli,16 Ozgur Tanriverdi, 17 Havva Cinkir,18 Ozge Gumusay,19 Nazım Serdal Turhal,20 Serkan Menekse,21 Engin Kut,21 Ismail Beypinar,22 Teoman Sakalar,23 Hacer Demir,22 Emre Yekeduz,1 Saadettin Kilickap,2 Mustafa Erman,2 Yuksel Urun1
Abstract
Adrenocortical cancer is a rare and poor prognostic malignant tumor. The definitions of prognostic factors in localized and metastatic diseases are important. In this paper, we defined the clinical features, management, and prognostic factors related to survival in patients with metastatic and nonmetastatic ACC. Cox regres- sion analysis showed that age, Ki67 value, ECOG PS, and hormonal activity were significantly associated with survival in patients with nonmetastatic disease. Only patients who underwent surgery had significantly better OS compared with patients without surgery in univariate analyses of metastatic disease.
Introduction: Adrenocortical carcinoma (ACC) is a rare yet highly malignant tumor associated with significant morbidity and mortality. This study aims to delineate the clinical features, survival patterns, and treatment modalities of ACC,
1 Medical Oncology Department, Ankara University, Ankara, Turkey
2 Medical Oncology Department, Hacettepe University, Ankara, Turkey
3 Medical Oncology Department, Ankara Numune Training and Research Hospital, Ankara, Turkey
4 Medical Oncology Department, Akdeniz University, Antalya, Turkey
5 Medical Oncology Department, Gazi University, Ankara, Turkey
6 Medical Oncology Department, Ege University, Izmir, Turkey
7 Medical Oncology Department, Van Yuzuncu Yıl University, Van, Turkey
8 Medical Oncology Department, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey 9 Medical Oncology Department, Marmara University, Istanbul, Turkey
10 Medical Oncology Department, Bahcesehir University, MedicalPark Hospital, Izmir, Turkey
11 Medical Oncology Department, Pamukkale University, Denizli, Turkey
12 Medical Oncology Department, Adana Cukurova University, Adana, Turkey
13 Medical Oncology Department, Trakya University, Edirne, Turkey
14 Medical Oncology Department, Ankara Yıldırım Beyazıt University, Ankara, Turkey
15 Medical Oncology Department, Gulhane Training and Research Hospital, Ankara, Turkey
16 Medical Oncology Department, Kocaeli University, Kocaeli, Turkey
17 Medical Oncology Department, Mugla Sıtkı Kocman University, Mugla, Turkey
18 Medical Oncology Department, Gaziantep University, Gaziantep, Turkey 19 Medical Oncology Department, Gaziosmanpaşa University, Tokat, Turkey
20 Medical Oncology Department, Anadolu Medical Center, Istanbul, Turkey
21 Medical Oncology Department, Manisa City Hospital, Manisa, Turkey
22 Medical Oncology Department, Afyon Health Sciences University, Afyon, Turkey
23 Medical Oncology Department, Aksaray University, Aksaray, Turkey
24 Medical Oncology Department, Koç University, Istanbul; Turkey
Submitted: Aug 27, 2023; Revised: Mar 10, 2024; Accepted: Mar 11, 2024; Epub: 15 March 2024
Address for correspondence: Yuksel Urun, MD, Medical Oncology Department, Ankara University, Balkiraz Mahallesi, Tıp Fakültesi Caddesi No: 1/4, 06620, Ankara, Turkey E-mail contact: yuksel.urun@ankara.edu.tr
providing insights into the disease’s prognosis. Materials and Methods: A retrospective analysis of 157 ACC patients was performed to assess treatment methodologies, demographic patterns, pathological and clinical attributes, and laboratory results. The data were extracted from the hospital’s database. Survival analyses were conducted using the Kaplan-Meier method, with univariate and multivariate analyses being performed through the log-rank test and Cox regression analyses. Results: The median age was 45, and 89.4% had symptoms at the time of diagnosis. The median tumor size was 12 cm. A total of 117 (79.6%) patients underwent surgery. A positive surgical border was detected in 26 (24.1%) patients. Adjuvant therapy was administered to 44.4% of patients. The median overall survival for the entire cohort was 44.3 months. Median OS was found to be 87.3 months (95% confidence interval [CI] 74.4-100.2) in stage 2, 25.8 (95% CI 6.5-45.1) months in stage 3, and 13.3 (95% CI 7.0-19.6) months in stage 4 disease. Cox regression analysis identified age, Ki67 value, Eastern Cooperative Oncology Group performance status, and hormonal activity as significant factors associated with survival in patients with nonmetastatic disease. In metastatic disease, only patients who underwent surgery exhibited significantly improved overall survival in univariate analyses. Conclusion: ACC is an uncommon tumor with a generally poor prognosis. Understanding the defining prognostic factors in both localized and metastatic diseases is vital. This study underscores age, Ki67 value, Eastern Cooperative Oncology Group performance status, and hormonal activity as key prognostic determinants for localized disease, offering critical insights into the complexities of ACC management and potential avenues for targeted therapeutic interventions.
Clinical Genitourinary Cancer, Vol. 22, No. 3, 102077 @ 2024 Elsevier Inc. All rights reserved. Keywords: Adjuvant therapy, Adrenocortical carcinoma, Mitotane, Neutrophil-lymphocyte ratio, Prognostic factors
Introduction
Adrenocortical carcinoma (ACC) is a rare malignant tumor.1 ACC is more common in women and the first and fifth decades.2 Half of the patients are asymptomatic and 30% to 40% of ACCs are metastatic at the time of diagnosis. In symptomatic patients, symptoms related to the mechanical effect of tumor size or steroid hormone synthesis, are seen. ACCs have a low cure rate and a high recurrence rate.3 Recurrence occurs in 2/3 of patients presenting with local disease. The 5-year survival rate is 80% in stage 1 disease and 13% in stage 4 disease. Surgical treatment is the mainstay of treatment in localized disease.3 Open surgery and lymphadenec- tomy are recommended.4 Mitotane is used in adjuvant therapy or in combination with chemotherapy in metastatic disease.5 The efficacy of adjuvant therapy with mitotane is still controversial. Most studies failed to demonstrate the survival contribution of mitotane. The lack of effective treatment for metastatic disease is the most important problem. Chemotherapy and mitotane are still recommended in the first line in advanced ACC. Researches continue for novel therapeutic drugs due to poor survival outcomes. ACC can be seen sporadically as well as with genetic syndromes. Li-Fraumeni syndrome, Lynch syndrome, Beckwith-Wiedemann syndrome, Carney complex, and multiple endocrine neoplasia type I are related to ACC.6 Beyond these syndromes, dysregulated molec- ular pathways are attempted to be defined. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor recep- tor (VEGFR) are often overexpressed in ACC.6 Tyrosine kinase inhibitors have also been evaluated in terms of treatment because the results of treatment options are not sufficient in advanced ACC.7-9 Various targeted therapies and immunotherapies are currently underway.10 Prognostic factors related to overall survival (OS) in metastatic and nonmetastatic disease were defined in some studies. Age, gender, Ki67 value, hormonal activity, and stage were found to be prognostic factors in ACC.11-15 In addition, the neutrophil- lymphocyte ratio (NLR) was determined as a prognostic factor in
many different tumor types. It was shown that there is a relation between NLR and OS in lung, bladder, colon, pancreas, and renal cell cancer.16-20 Since ACC is a rare malignant tumor, it is impor- tant to underline the characteristics of the tumor. In this context, our purpose was to define the clinical features, management, and prognostic factors related to survival in patients with metastatic and nonmetastatic ACC.
Materials and Methods Patients and Data Collection
All patients with a histopathological diagnosis of ACC were included in the study. In this multicenter study, 157 patients with ACC were retrospectively analyzed. The treatment methods, demographics, pathological and clinical characteristics, and labora- tory results of these patients were scanned from hospital database. The baseline neutrophil (N) and lymphocyte counts were used to calculate the NLR. Eastern Cooperative Oncology Group perfor- mance status (ECOG PS) and date of death or last follow-up were recorded.
Statistical Analyses
In patients with nonmetastatic disease at the time of diagnosis, gender, presence of symptoms, T stage, N stage, Ki67 value, Weiss score, ECOG PS, hormonal activity, symptoms related to hormonal secretion, surgery, surgical borders, adjuvant therapy, and radiother- apy effects on survival were evaluated with log-rank test.
The univariate effects of gender, being symptomatic, lung metas- tasis, liver metastasis, number of metastatic sites, Ki67 group, Weiss score, ECOG PS group, hormonal activity, symptoms related to hormonal secretion, surgery, surgical borders, adjuvant therapy, and radiotherapy were evaluated with log-rank test in patients with metastatic disease.
Receiver operating characteristic (ROC) analysis was used to define the cutoff value of NLR. The NLR cutoff value was defined
as 2.76. The patients were grouped based on cutoff value as NLR ≤2.76 and NLR >2.76.
Survival analyses were calculated by the Kaplan-Meier method. The possible factors identified by the log-rank test were further evaluated by backward selection Cox-regression analysis to identify independent predictors of survival. Among the correlated factors with similar effects on survival, only those of clinical significance were included. Data that did not meet the proportional hazard assumption were not included.
P < . 05 was considered as statistically significant difference. IBM SPSS statistics version 20 (IBM Corp, Armonk, NY, USA) was used in the analyses of the data.
Results
Patient Characteristics
The median age was 45 (minimum [min]-maximum [max]: 13- 83), 58.4% of patients were between the ages of 41 to 70, 5.4% were under 20, and 2.7% were over 70 years old. Also, 53.5% (N = 84) of patients were women. The median tumor size was 12 cm (min- max: 2.4-25 cm). Lymph node positivity was detected in 25.7% (N = 27) of patients. At the time of diagnosis, 5.9% (N = 8); 28.7% (N = 39); 18.4% (N = 25); and 47.1% (N = 64) of patients were stage 1, 2, 3, and 4, respectively. In 88.5% of patients, ECOG PS was ≤1 (N =108).
The 10.6% of patients were incidentally diagnosed, 89.4% (N = 118) had symptoms at the time of diagnosis. A wide variety of symptoms were seen in patients. The most frequent symptoms were abdominal bloating and pain. Hormonal activity was seen in 39.1% (N = 52) of patients. 48.2% (N = 41) of patients had symptoms related to the hormonal activity. Hirsutism was seen in 18.9%, hypertension in 36%, and hyperpigmentation in 14.3% of the patients. The details are shown in Table 1.
Treatment Modalities
Total of 117 (79.6%) patients underwent surgery. A positive surgical border was detected in 26 (24.1%) patients. Adjuvant therapy was administered to 44.4% of patients. Mitotane was used in 79 (62.2%) patients in metastatic or adjuvant settings. Adverse events related to mitotane were seen in 43 (84.3%) patients. Fatigue and nausea were the most seen adverse events of mitotane. Mitotane doses varied from 1 to 9 g. Adjuvant radiotherapy was used in 30.6% (N = 15) of patients.
The median (min-max) follow-up was 20.9 months (1.25-155.86 months). Recurrence was observed in 79.1% (N = 34) of patients at follow-up. The recurrence was seen in 76.5% (N = 26) of R0 resected patients, 37.8% of patients had lung metastasis and 40% had liver metastasis. The other metastatic regions are shown in Table 1.
Chemotherapy was applied to 59.1% (N = 78) of patients when the disease relapsed or metastatic at diagnosis. The median chemotherapy cycle at the first line was 4 cycles. Treatment proto- cols are shown in Table 1. Second-line chemotherapy was applied to 31 patients. The number of patients receiving radiotherapy was 27 (27.3%).
| Median Age (y) | N (%) 46.3 (14.1-84.21) |
|---|---|
| Gender | |
| Male | 73 (46.5%) |
| Female | 84 (53.5%) |
| Symptom | |
| Yes | 118 (89.6%) |
| No | 14 (10.4%) |
| Hormonal active | |
| Yes | 51 (38.9%) |
| No | 80 (61.1%) |
| Stage | |
| Locally advanced | 72 (52.9%) |
| Metastatic | 64 (47.1%) |
| Metastatic region | N(%) |
| Lung | 56 (37.8 %) |
| Liver | 58 (40%) |
| Lymphadenopathy | 19 (27.5%) |
| Brain | 2 (2.9%) |
| Bone | 15 (21.7%) |
| Other | 7 (10%) |
| Chemotherapy regimes | |
| Mitotane | 7 (9%) |
| Platin, doxorubicin, etoposide +/- mitotane | 26 (33.4%) |
| Platin + etoposide +/- mitotane | 28 (35.9%) |
| Doxorubicin-based | 5 (6.4%) |
| Dacarbazine-based | 3 (3.9%) |
| Streptozocin | 2 (2.6%) |
| Platin + paclitaxel | 4 (5.1%) |
| Other | 3 (3.9%) |
Survival Analyses
The median OS was 44.3 months in all patients (Figure 1). Median OS was 85.9 months (95% confidence interval [CI] 70.1- 101.7) and 13.3 (95% CI 7.0-19.6) months in nonmetastatic and metastatic patients, respectively (P < . 001) (Figure 2). The median OS for stages 1, 2, 3, and 4 was statistically different from each other. In stage 1 disease, the median OS could not be reached. Median OS was found to be 87.3 months (95% CI 74.4-100.2) in stage 2, 25.8 (95% CI 6.5-45.1) in stage 3, and 13.3 (95% CI 7.0-19.6) months in stage 4 disease.
Univariate analyses of gender, being symptomatic, T stage, Weiss score, symptoms related to hormonal secretion, surgery, surgi- cal borders, adjuvant therapy, radiotherapy, and NLR revealed no significant association with OS in patients with nonmetastatic disease at the time of diagnosis.
The lymph node positive group was associated with decreased OS compared with the lymph node negative group (P = . 002) (median OS: 18.7 months [95% CI 0.029-37.4]) vs not reached (NR) in patients with nonmetastatic disease.
Survival Function
Survival Function
1,0
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0,8
Cum Survival
0,6
0,4
0,2
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Ki67 value >10 was associated with decreased OS compared with Ki67 value ≤10 (P <. 001) (48.4 [95% CI 30.5-66.4] months vs NR) in nonmetastatic disease (Figure 3).
Overall survival was 45.8 (95 % CI 26.2-65.4) and NR in patients with ECOG PS >1 and ECOG PS ≤1, respectively in nonmetastatic disease (P= . 026).
Hormonal activity was associated with significantly decreased OS compared to the nonactive group (median OS: 30.2 [95% CI 0- 97.2] months vs. 85.9 [95% CI 51.7-120.0] months; P < . 05) in nonmetastatic disease (Figure 4).
Univariate analysis and multivariate analysis results are shown in Tables 2 and 3.
Age, lymph node positivity, Ki67 value, ECOG PS, and hormonal activity were examined in a multivariate model. Age (hazard ratio [HR]: 8.742 [95% CI 1.574-48.553]), Ki67 value (HR: 10.647 [95% CI 2.384-47.559]), hormonal activity (HR: 10.099 [95% CI 1.364-74.771]), ECOG PS (HR: 10.521 [95% CI 21.375-80.490]) remained significantly independent prognostic factors in patients with non-metastatic disease (P < . 05).
Univariate analyses of gender, being symptomatic, lung metas- tasis, liver metastasis, number of metastatic sites, Ki67 group, Weiss score, ECOG PS, hormonal activity, symptoms related to hormonal secretion, surgical borders, adjuvant therapy, radiother- apy, chemotherapy, and NLR revealed no significant association with OS in patients with metastatic disease. Univariate analysis results are shown in Table 4 . Only patients who underwent radical
surgery (median OS 26.4 [95% CI 10-42.8] months) had signifi- cantly better OS compared with patients without surgery (median OS 8.4 [95% CI 3.1-13.7] months) in univariate analyses (P < . 05) in metastatic disease.
Discussion
In this comprehensive assessment, we meticulously analyzed the clinical and pathological attributes, prognostic determinants, and treatment approaches of 157 patients diagnosed with ACC. Given the rarity and orphanness of this malignant tumor, our sample size is notably substantial, lending robustness to our findings. Our data revealed that ACC predominantly presents in individuals aged between 40 and 70 years, with a scarcity of cases reported in those under 20 or over 70 years of age. Interestingly, mirroring patterns observed in the extant literature, our cohort also demonstrated a higher incidence of ACC in females.21
We found that most of the cases were symptomatic at the time of the diagnosis, as similar to the literature. It was declared that only 10% to 15% of cases were detected incidentally by imaging studies. 21,22
In the literature, age is a parameter associated with survival in many cancers.23,24 In our study, we found that age was an indepen- dent prognostic factor, similar to the literature.
In our study, Ki67 value was defined as an independent prognos- tic factor for OS in patients with nonmetastatic disease. In the litera- ture, Ki67 cut-off value varies (Ki67>4 vs. < 4, Ki67>10 vs. >10,
| Factor | n | Median Survival 5-y OS Rates | P-Value |
|---|---|---|---|
| Age | .001 | ||
| ≥65 | 6 | 20.8 ± 18.4 | |
| <65 | 59 | 65.1 ±7.4 | |
| Gender | .933 | ||
| Female | 36 | 65.7 ± 8.6% | |
| Male | 30 | 55.2 ± 11.9% | |
| Symptom | .563 | ||
| Yes | 52 | 64.5 ± 7.6% | |
| No | 8 | 24.3 ± 20.6% | |
| Lymph node | .002 | ||
| Negative | 47 | 72.2 ±8.4% | |
| Positive | 6 | 16.7 ± 15.2% | |
| Ki67 (%) | <. 001 | ||
| ≤10 | 27 | 85.4 ± 7.9% | |
| >10 | 24 | 25.6 ± 14.5% | |
| Weiss score | .378 | ||
| 3-6 | 21 | 61.4 ± 12.6% | |
| 7-9 | 7 | 68.6 ± 18.6% | |
| ECOG-PS | .026 | ||
| <1 | 33 | 76.4 ± 8.9% | |
| ≥1 | 26 | 38.1 ± 13.3 | |
| Hormonal activity | .029 | ||
| Yes | 18 | 64.1 ± 9.2% | |
| No | 45 | 48.6 ± 12.1% | |
| Hormone related symptom | .377 | ||
| Yes | 13 | 57 ± 15.1% | |
| No | 24 | 63.3 ± 12.7% | |
| Surgery | .115 | ||
| Yes | 61 | 62 ± 7.4% | |
| No | 4 | 50 ± 25% | |
| Surgical border | .101 | ||
| R0 | 51 | 68.1 ±8.0 | |
| R1-2 | 7 | 42.9 ± 18.7 | |
| Adjuvant therapy | .781 | ||
| Yes | 36 | 56.4 ± 10.6 | |
| No | 25 | 67.8 ± 10.1% | |
| RT | .162 | ||
| Yes | 15 | 33.6 ± 17.6% | |
| No | 30 | 71.3 ± 9.4% | |
| NLR | .159 | ||
| ≤2.76 | 28 | 68.1 ± 11.6% | |
| >2.76 | 21 | 45 ± 13.9 |
Abbreviations: ACC = adrenocortical carcinoma; ECOG PS = Eastern Cooperative Oncology Group performance status; NLR = neutrophil-lymphocyte ratio; OS = overall survival; RT = radiotherapy. P < . 05 was considered as statistically significant difference.
Figure 2 Overall survival (OS) according to the stage group.
Survival Functions
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| Risk Factors | Univariate Analysis | Multivariate Analysis (n = 40) | ||
|---|---|---|---|---|
| HR (95% CI) | P-Value | HR (95% CI) | P-Value | |
| Age at diagnosis ≥65(vs. < 65) | 0.215 (0.078-0.593) | .003 | 8.742 (1.574-48.553) | .013 |
| Male sex | 0.966 (0.428-2.179) | .933 | – | – |
| Presence of symptom | 1.380 (0.460-4.139) | .566 | – | – |
| T stage III-IV (vs. I-II) | 2.210 (0.833-5.862) | .111 | – | – |
| Presence of LN metastasis | 4.678 (1.566-13.976) | .006 | 6.555 (0.965-44.524) | 054 |
| Ki-67>10 (vs. ≤10) | 8.092 (2.185-29.97) | .002 | 16.815 (3.178-88.965) | .001 |
| Weiss score 7-9 (vs. 3-6) | 1.860 (0.457-7.565) | .386 | – | – |
| ECOG-PS ≥1 (vs. 0) | 2.791 (1.088-7.163) | .033 | 10.521 (1.375-80.490) | .023 |
| Presence of hormonal activity | 2.383 (1.063-5.342) | .035 | 10.099 (1.364-74.771) | .024 |
| Presence of hormon related symptom | 1.677 (0.525-5.353) | .382 | – | – |
| Presence of surgery | 0.320 (0.072-1.424) | .135 | – | – |
| R1-2 resection (vs. R0) | 2.337 (0.823-6.633) | .111 | – | – |
| Presence of adjuvant therapy | 1.133 (0.469-2.738) | .782 | – | – |
| Presence of radiotherapy | 1.987 (0.746-5.291) | .169 | – | – |
| NLR | 0.907 (0.798-1.031) | .136 | – | – |
Abbreviations: CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; HR = hazard ratio; LN = lymph node; NLR = neutrophil-lymphocyte ratio. P < . 05 was considered as statistically significant difference.
Survival Functions Stage_grup: Localized
1,0
ki67grup
ki67 ⇐ 10
ki67>10
ki67 ⇐ 10-censored
ki67>10-censored
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0,4-
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20,00
40,00
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80,00
100,00
120,00
140,00
OSmonths
or Ki67 >20 vs. < 20). The cut-off value for Ki67 was taken as 10 in this study. There is no clear evidence as to which cut-off value should be taken.13,25,26 Beuschlein et al.25 showed that Ki67 value was associated with recurrence and OS in nonmetastatic patients. Zhang et al.27 also announced that Ki67 value was an independent prognostic factor. Duregon et al.12 Helsinki Score (a formula includ- ing mitotic number, Ki67 value, and necrosis), and Weiss Score were prognostic markers for OS. Parianos et al.13 showed that OS associ- ated with stage at diagnosis, the Weiss score, and the Ki67 index. In our study, no correlation was found between Weiss score and survival. The data of necrosis can’t be evaluated due to retrospective data review.
The mainstay of the treatment is radical resection in nonmetastatic disease. In the literature, open adrenalectomy was preferred to laparoscopic adrenalectomy in patients with suspected ACC because of the high recurrence risk.28-30 In our data, we couldn’t reach the data of type of the surgery. Although some case series reported that laparoscopic adrenalectomy could be performed, the sample size of these studies was not large enough and their design was retrospective.31,32 European Society of Medical Oncol- ogy (ESMO) and European Reference Networks for All Rare Cancer (EURACAN) Clinical Practice Guidelines recommended open surgery with transperitoneal access in ACC management.
In the literature; age, stage, and radical resection were defined as predictive models for ACC-specific mortality.11 Toke et al.14 reported that high proliferative activity, positive surgical borders,
and hormonal activity were related to decreased survival. In our study, positive surgical margins were not found to be significant in terms of prognosis in multivariate analysis in nonmetastatic disease. In the literature, it was declared that even after complete surgery, recurrence was frequent.33 In our study, recurrence rate was 79.1%.
ESMO and EURACAN Clinical Practice Guidelines recommend routine lymph node resection involving periadrenal and hilar lymph nodes. There was no clear data about the number of lymph nodes that needed to be removed. Deschner et al.34 reported that lymph node positivity, regardless of the number of lymph nodes, was related to advanced-stage tumors and worse survival in patients with curatively resected, whereas Tseng et al.35 showed that the number of positive lymph nodes was associated with worse survival in nonmetastatic patients. Tseng et al. also reported that having >4 positive lymph nodes caused a 4-fold increase in the risk of death. In this study, lymph node positivity was related to survival in univariate analysis but there was no relationship between survival and lymph node positivity in multivariate analysis. In our study, we could not reach the data about number of positive lymph nodes.
Berruti et al.26 reported cortisol secreting tumors were associ- ated with reduced recurrence free survival in patients with resected tumor. Vantrabant et al.36 showed that cortisol-secreting ACC was associated with decreased survival in systematic review and meta- analysis. Similar to the literature, hormonal activity was defined as an independent prognostic factor for OS, in patients with nonmetastatic disease.
Survival Functions Stage_grup: Localized
1,0
hormonalaktivite
aktifdegil
hormonalaktif
aktifdegil-censored
hormonalaktif-censored
0,8
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0,6-
0,4-
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150,00
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In our study, we showed that surgery was associated with OS in patients with metastatic disease in univariate analyses. Sougi et al.37 and Bronswijk et al.38 reported that cyto-reductive surgery contributed to survival even in metastatic disease. The European Society of Endocrinology Clinical Practice Guidelines recommend surgery if complete resection of all lesions seems feasible.4 ESMO and EURACAN Clinical Practice Guidelines recommend surgery in selected patients with metastatic disease.
In our study, the number of metastatic sites was not corre- lated with OS in advanced ACC, unlike the literature. Assie et al. showed that correlation between the number of metastatic sites and survival.39
Libe et al.40 reported age, grade, resection status, and symptoms were found as prognostic factors in patients with advanced disease. In our study, there was no relation between survival and resection status, age, and symptoms in patients with metastatic disease.
There are some controversial points in management of ACC. Terzola et al.41 showed that recurrence-free survival and OS were longer in patients under the treatment of adjuvant mitotane. Grubbs et al.42 showed that adjuvant mitotane had improved disease-free survival but there was no difference in OS between the groups. Huang et al.43 argued that mitotane had a beneficial effect on recurrence-free survival but not on OS. In our study, adjuvant therapy was not associated with OS in patients with nonmetastatic disease. Considering all these controversial points and since mitotane is a toxic drug, it needs to be well clarified which patient group gains the most benefit from it.
In recent years, 2 phase 3 trials were designed to show the efficacy of mitotane in patients with ACC. One of them is the ADIUVO trial. This phase 3 trial was designed to show the effect of adjuvant mitotane on recurrence-free survival in patients with ACC at low intermediate risk of recurrence. Patients who were completely resected, had no evidence of residual disease, stage 1 to 3 disease, and Ki67 <10% were included in this trial (NCT00777244). The other one is the ADIUVO-2 trial. This phase 3 trial was designed to show the effect of adjuvant mitotane with or without cisplatin and etoposide on recurrence-free survival in patients with ACC at high risk of recurrence. Patients who were completely resected with microscopically positive margins or undetermined margins, had no evidence of metastatic disease, stage 1 to 3, and Ki67 >10% were included in this trial (NCT03583710). A clear view of the contribu- tion of mitotane treatment would probably be obtained after these trials have been completed.
Fassnacht et al.44 showed that response rates and progression- free survival were significantly better in the mitotane plus etopo- side, doxorubicin, and cisplatin combination than in the strepto- zocin plus mitotane combination for advanced ACC in the FIRM- ACT trial (P < . 001). FIRM-ACT trial did not show a significant difference in OS between the groups. In our study, as similar to the literature, the contribution of chemotherapy for OS in metastatic disease, was not shown.
The association between NLR ratio and OS were shown in various cancers such as lung, bladder, colon, pancreas, and renal cell cancer.16-20 Diem et al.16 showed that elevated NLR was associated
| Factor | n | 2-y OS Rates | P-Value |
|---|---|---|---|
| Age | .645 | ||
| ≥65 | 5 | 60 ± 21.9% | |
| <65 | 51 | 29.3 ± 6.8% | |
| Gender | .664 | ||
| Female | 31 | 30.9 ± 9.1% | |
| Male | 25 | 32.9 ± 9.8% | |
| Symptom | .345 | ||
| Yes | 45 | 33.7 ± 7.7% | |
| No | 3 | 0 | |
| Lung metastasis | .612 | ||
| Yes | 40 | 31.2 ± 7.7 | |
| No | 16 | 32.5 ± 13.1 | |
| Liver metastasis | .559 | ||
| Yes | 38 | 28.8 ± 7.8% | |
| No | 18 | 39.2 ± 12.4% | |
| Number of metastatic sites | .855 | ||
| >2 | 19 | 35.6 ± 11.9% | |
| ≤2 | 31 | 32 ± 8.7% | |
| Ki67 (%) | .281 | ||
| ≤10 | 5 | 60 ± 21.9% | |
| >10 | 23 | 6.6 ± 6.2% | |
| Weiss score | .722 | ||
| 3-6 | 14 | 28.6 ± 12.1% | |
| 7-9 | 5 | 40 ± 21.9% | |
| ECOG-PS | .973 | ||
| <1 | 14 | 36.9 ± 13.8% | |
| ≥1 | 28 | 25.9 ± 8.9% | |
| Hormonal activity | .665 | ||
| Yes | 28 | 27.0 ± 9.0% | |
| No | 19 | 29.2 ± 10.8% | |
| Hormone related symptom | .277 | ||
| Yes | 22 | 29.8 ± 10% | |
| No | 10 | 25 ± 14.8% | |
| Surgery | |||
| Yes | 31 | 52.6 ± 9.7% | |
| No | 24 | 9.1 ± 6.1% | .006 |
| Surgical border | .123 | ||
| R0 | 12 | 27.3± 13.4% | |
| R1-2 | 19 | 54.0 ± 12.3% | |
| Adjuvant therapy | .995 | ||
| Yes | 13 | 19.2 ± 11.7% | |
| No | 29 | 32.3 ± 9.4% | |
| RT | .433 | ||
| Yes | 11 | 46.2 ± 16.7% | |
| No | 32 | 29.5 ±8.2% |
(continued on next page)
| Factor | n | 2-y OS Rates | P-Value |
|---|---|---|---|
| Chemotherapy | .394 | ||
| Yes | 40 | 21.0 ±7.3% | |
| No | 10 | 40 ± 15.5% | |
| NLR | .859 | ||
| ≤2.76 | 6 | 26.7 ± 22.6% | |
| >22.76 | 32 | 30.8 ±8.6% |
Abbreviations: ACC = adrenocortical carcinoma; ECOG PS = Eastern Cooperative Oncology Group performance status; NLR = neutrophil-lymphocyte ratio; OS = overall survival; RT = radiotherapy.
P < . 05 was considered as statistically significant difference.
with shorter OS in patients with non-small cell lung cancer. Chen et al. reported that NLR was an independent factor for recurrence in nonmuscle invasive bladder cancer. Lin et al. announced that NLR was a prognostic factor in patients with metastatic colorec- tal cancer.45 Hizal et al. reported that elevated NLR was related to poor prognosis.19 de Jong et al.46 reported that elevated NLR was related to shorter OS in nonmetastatic patients and Mangone et al.47 showed that elevated NLR was associated with poor OS in metastatic ACC. In our study, we did not find any association between NLR and OS.
In the literature, it was shown that there was no contribution to the survival in advanced ACC patients treated with tyrosine kinase inhibitors.7-9 Cabozantinib is a multikinase inhibitor acting through the VEGFR, rearranged during transfection (RET), neurotrophic factor receptor (MET), and AXL pathways. In the literature, there were limited data on a limited number of patients treated with cabozantinib but it is not appropriate to draw conclusions with this data.48 Phase 2 clinical trial of cabozantinib is ongoing in advanced ACC (NCT03370718). In our study, none of the patients received tyrosine kinase inhibitors.
In our study, none of the patients received immunotherapy. The roles of nivolumab, pembrolizumab, avelumab, and ipili- mumab were investigated in the management of ACC, but results were generally not satisfactory as a response rate or progression-free survival. Phase 2 trials of camrelizumab plus apatinib (NCT04318730), and Dovitinib (NCT01514526) in advanced ACC are also under investigation. Clinical trials investi- gating the effect of immunotherapy in the treatment of ACC are ongoing. 49-52
The present study, while providing valuable insights, is not without its limitations. Foremost, the retrospective design inherently constrains the comprehensiveness of the available data, hindering the complete extraction of all relevant details. Particularly, the risk classification for localized disease remained elusive due to the insuffi- ciency of the required data. Furthermore, the assessment of mitotane levels and the associated side effect profile in patients undergoing mitotane therapy was impeded by both the study’s retrospective nature and the prevailing laboratory conditions. These constraints necessitate caution in interpreting the findings and underscore the need for prospective studies to substantiate and extend our under- standing of ACC’s complex clinical landscape.
Conclusion
Adrenocortical carcinoma is a rare and complex malignancy, presenting both diagnostic and therapeutic challenges. In our study of a considerable cohort, we identified key clinical features, includ- ing age, Ki67 value, and hormonal activity, as prognostic factors and emphasized the role of surgery. However, the limitations inherent in our retrospective design, particularly regarding risk classification and mitotane levels, necessitate caution. These findings highlight the urgent need for well-structured, prospective trials to deepen our understanding and refine our approach to ACC, ultimately enhanc- ing survival outcomes for those affected by ACC.
Clinical Practice Points
· Prognostic factors have been defined differently in various studies. Additionally, in the literature, there are some controversial points about adjuvant treatment.
· We defined the clinical features, management, and prognos- tic factors related to survival in patients with metastatic and nonmetastatic ACC. We showed that age, Ki67 value, and hormonal activity were significantly associated with survival in patients with nonmetastatic disease.
· Only patients who underwent surgery had significantly better OS compared with patients without surgery in metastatic disease.
· We defined the factors affecting the prognosis of this rare cancer in the locally advanced and early stages, which is controversial in the literature.
Institutional Review Board Statement
The study protocol was approved by the ethics committee of Ankara University Medical Faculty (Approval code: 10-801-19, 27 May 2019).
Disclosure
The authors declare no conflict of interest.
CRediT authorship contribution statement
Hatime Arzu Yasar: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Writing - origi- nal draft, Writing - review & editing. Burak Yasin Aktas: Resources, Investigation. Gokhan Ucar: Resources, Investigation. Sema Sezgin Goksu: Resources, Investigation. Irem Bilgetekin: Resources, Investigation. Burcu Cakar: Resources, Investigation. Abdullah Sakin: Resources, Investigation. Ozturk Ates: Resources, Investigation. Tugba Basoglu: Resources, Investigation. Cagatay Arslan: Investigation, Resources. Atike Gokcen Demiray: Investi- gation, Resources. Semra Paydas: Investigation, Resources. Irfan Cicin: Investigation, Resources. Mehmet Ali Nahit Sendur: Inves- tigation, Resources. Nuri Karadurmus: Investigation, Resources. Hakan Kosku: Investigation, Resources. Aytuğ Uner: Investiga- tion, Resources. Perran Fulden Yumuk: Investigation, Resources. Gungor Utkan: Investigation, Resources. Umut Kefeli: Inves- tigation, Resources. Ozgur Tanriverdi: Investigation, Resources.
Havva Cinkir: Investigation, Resources. Ozge Gumusay: Investi- gation, Resources. Nazım Serdal Turhal: Investigation, Resources. Serkan Menekse: Investigation, Resources. Engin Kut: Inves- tigation, Resources. Ismail Beypinar: Investigation, Resources. Teoman Sakalar: Investigation, Resources. Hacer Demir: Investi- gation, Resources. Emre Yekeduz: Formal analysis, Investigation, Resources, Methodology. Saadettin Kilickap: Conceptualization. Mustafa Erman: Conceptualization. Yuksel Urun: Conceptualiza- tion, Methodology, Writing - review & editing.
Acknowledgments
This research received no external funding.
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