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Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study
Pien Debetsa, Koen M.A. Dreijerink b,k, Anton Engelsman ”, Max Dahele , Harm R. Haak e, f, g, Rebecca V. Steenaard e,f,j, Ellen Kapiteijnh, Eleonora Corssmit1, C. Willemien Menke-van der Houven van Oordta, k,
ª Amsterdam UMC location VU Medical Center, department of Medical Oncology, Amsterdam, the Netherlands
b Amsterdam UMC location VU Medical Center, department of Endocrinology and Metabolism, Amsterdam, the Netherlands
” Amsterdam UMC location VU Medical Center, department of Surgery, Amsterdam, the Netherlands
d Amsterdam UMC location VU Medical Center, Department of Radiation Oncology and Cancer Center Amsterdam, Amsterdam, the Netherlands
e Maxima Medical Center, department of Internal Medicine, Eindhoven, the Netherlands Maastricht University, CAPHRI School for Public Health and Primary Care, Ageing and Long-Term Care, Maastricht, the Netherlands
8 Department of Internal Medicine, Division of General Internal Medicine, Maastricht University Medical Centre+, Maastricht, the Netherlands
h Leiden University Medical Center, Department of Medical Oncology, Leiden, the Netherlands
Leiden University Medical Center, Center of Endocrine Tumours, Division of Endocrinology, Department of Internal Medicine, Leiden, the Netherlands
Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, the Netherlands
k Cancer Center Amsterdam, the Netherlands
ARTICLE INFO
Keywords:
Metastatic adrenocortical carcinoma Chemotherapy
Palliative adrenalectomy
Mitotane
Survival analysis
ABSTRACT
Introduction: Historically, stage IV adrenocortical carcinoma (mACC) has a poor prognosis with a median overall survival (OS) of only 5 months. Based on the FIRM-ACT trial published in 2012, guidelines now advise first line systemic treatment with etoposide, cisplatin, doxorubicin and mitotane (EDP-M). The effect of EDP-M on patient survival in clinical practice in the Netherlands is unknown.
Methods: The data of all patients with mACC (2005-2020) were obtained from the Netherlands comprehensive cancer organization (IKNL). The effect of EDP-M on patient survival was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis including clinical, therapy and tumor characteristics.
Results: In total 167 patients with mACC were included. For patients diagnosed from 2014 onwards, EDP-M (in 22 patients (22%)) lead to a numerically but not statistically significant improved OS compared to those not receiving EDP-M (11.8 vs 5.6 months, p = 0.525). For systemic treatments, patients treated with mitotane only had the best 5-year OS (11.4%, p = 0.006) regardless of year of diagnosis. In multivariate Cox regression analysis EPD-M was not associated with OS; palliative adrenalectomy (HR: 0.26, p = <. 001) and local treatment of metastases (HR: 0.35, p = 0.001) were associated with a better OS and a primary tumor Ki-67 index > 20% (HR: 2.67, p = 0.003) with a worse OS from 2014 onwards. Patients diagnosed before 2014 had a significantly poorer OS compared to from 2014 onwards (5-yr: 4.5 vs 8.4%, OS: 6.8 vs 8.3 months, p = 0.032).
Conclusion: OS for mACC in the Netherlands has improved in the last decade. Receiving EDP-M did not signif- icantly improve OS for patients with mACC. The use of multimodality treatment including palliative adrenal- ectomy, mitotane and local treatment of (oligo-)metastases in appropriately selected patients has improved the OS for mACC patients since 2014.
1. Introduction
Each year around one in a million people are diagnosed with adre- nocortical carcinoma (ACC) in the Netherlands [1]. ACC can be
subdivided into two types of tumors: (1) functional tumors (50-60%) that show adrenocortical hormone excess, causing symptoms such as muscle weakness, weight gain, hypertension and diabetes mellitus [2,3]; (2) non-functional tumors which only show symptoms due to significant
* Correspondence to: Amsterdam UMC location VU Medical Center, Department of Medical Oncology, De Boelelaan 1117, Amsterdam 1081HV, the Netherlands. E-mail address: c.menke@amsterdamumc.nl (C.W. Menke-van der Houven van Oordt).
https://doi.org/10.1016/j.ejca.2023.113424
0959-8049/ 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
tumor growth. Functional tumors are linked to an increased mortality rate [3]. The detection of non-functional ACC is often an incidental finding on imaging. Due to the lack of symptoms, approximately 33% of patients with ACC are stage IV upon diagnosis. Since current effective treatment options are limited, the 5-year survival rate of metastatic ACC (mACC) is less than 15%. Treatment options for mACC include surgical resection of the primary tumor or oligometastatic disease in selected patients, radiotherapy for selected primary and (oligo-)metastatic le- sions and mitotane therapy alone or combined with chemotherapy [4]. Aggressive surgical resection can be unfavorable in case of fast recur- rence of disease in combination with the risks of surgery [5].
In 2012, the FIRM-ACT phase III randomized trial reported on the first-line treatment strategy of etoposide, doxorubicin and cisplatin combined with mitotane (EDP-M) for mACC compared to streptozocin with mitotane, finding a progression free survival (PFS) of 5 months vs 2.1 months (HR: 0.55, CI95: 0.43 - 0.69) and an overall survival (OS) of 14.8 months vs 12 months (HR: 0.79, CI95: 0.61 - 1.02), respectively [6]. On the basis of a higher response rate and PFS, current practice guidelines recommend EDP-M in patients with mACC [4,7]. However, despite this study, there is still much controversy on the benefits of chemotherapy, especially for patients with mACC and a limited perfor- mance status. Real world evidence on the efficacy of EDP-M has not been reported yet. Therefore, this study focused on evaluating whether EDP-M has led to an improved overall survival for patients with mACC in the Netherlands.
2. Materials and methods
2.1. Data collection
The data of all patients with ACC (n = 167) in the Netherlands comprehensive cancer organization (IKNL) between 2005 and 2020 were collected. The patient inclusion criteria were initial diagnosis of, or progression to mACC and age at diagnosis of 18 years and older.
2.2. Variables and outcome parameters
Variables included in the study were sex, age at diagnosis, age at metastasis, stage at diagnosis, chemotherapy (cisplatin, doxorubicin, etoposide, other), adrenalectomy (primary or palliative), mitotane therapy, radiotherapy of primary tumor (area), local treatment (surgical or radiotherapy of metastases), hormone production (e.g. non- functioning, cortisol, androgens), surgical margin, Ki-67 index and Weiss score. The cancer registry does include ECOG performance status data. For the variables: hormone production, Ki-67 score and Weiss score no data were available prior to 2014 in the Netherlands Cancer Registry. The stage of disease was determined by the TNM-classification according to the year of diagnosis: 7th and 8th editions of the TNM and ENSAT classification [4,7]. For all of these the criterium for diagnosis of stage IV ACC (M1) is presence of distant metastases. Some patient data prior to 2010 included an extent of disease (EoD) classification which was con- verted to their corresponding TNM stage. In this study, the term adre- nalectomy in stage I-III disease refers to an oncological primary adrenalectomy, whereas in stage IV it is a palliative resection of the affected adrenal gland (palliative adrenalectomy). Adrenalectomy sur- gical margins were classified as either R0: negative surgical margin or R+ : positive surgical margin. The Ki-67 scores of patients were grouped into ≤ 10%, < 20% and > 20% since a Ki-67 index > 10% is an indicator for mitotane treatment and/or chemotherapy and clinical outcome has been shown to differ between similar ACC cohorts according to Ki-67 status [4, 8]. Patient data was split into two groups, pre and post introduction of EDP-M by the year of diagnosis 2014; 2014 being the year that the first patient was treated with EDP-M therapy. Overall survival (OS) was used as the survival outcome parameter. Additionally, patient data was split into favorable and unfavorable profile groups, with a favorable profile being a Ki-67 score ≤ 10%, a Weiss score < 4 or a primary diagnosis 9
months or more before the diagnosis of metastasis 4, 9, 10,. We were unable to split patients into groups based on the GRAS criteria since data on tumor grade and symptoms were not available [12].
2.3. Statistical analysis
The data comparison between the groups (pre and post 2014) was evaluated using a t-test, chi-square or Fisher’s exact test depending on whether the variable being considered was binary, categorical or continuous. The Kaplan-Meier method was used to analyze the effect of EDP-M on OS and the log rank test was used for statistical comparison. Based on the data presented by Fassnacht et al, [6] OS of the FIRM-ACT trial was extracted using Plot Digitizer software (version 2.6.9) and converted into a Kaplan-Meier curve for comparison with our clinical data set. A Cox regression analysis was used to assess which variables could be linked to OS. The hazard ratio (HR) with 95% confidence in- terval (CI) was assessed for the various variables. The time interval between diagnosis of metastatic disease and date of death was used as time parameter in the analysis. The variables adrenalectomy and local treatment of metastases were assessed only for those patients with an initial diagnosis of stage IV ACC in univariate analysis. Therefore, the multivariate Cox regression was also performed on this subgroup of patients. Variables that proved significant (p < 0.05) were included in the multivariate cox regression. The variables stage at diagnosis and age at metastasis were excluded from the multivariate Cox regression.
3. Results
A group of 167 patients with mACC diagnosed between 2005 and 2020 was identified from the Netherlands comprehensive cancer orga- nization (IKNL) database. Within the group, 98 patients were female (59%) and the mean age at diagnosis was 56.8 years. The majority of patients had an initial diagnosis of stage IV ACC (75%), the remaining 25% progressed to stage IV during follow up after an initial diagnosis of localized disease. In total 15 patients received only chemotherapy (9%), 45 patients received mitotane monotherapy (27%) and 30 patients received a combination of chemotherapy and mitotane (18%). Only treatment during stage IV disease was considered. EDP-M treatment was first administered to a patient in 2014. In total, 22 of the 99 patients diagnosed from 2014 onwards received EDP-M (22%). Table 1 shows the demographic and clinical characteristics of all patients and corre- sponding subgroups.
When comparing the subgroups (pre and post 2014), the number of patients diagnosed at an earlier disease stage showed a significant in- crease from 2014 onwards (p = <. 001). The number of patients receiving chemotherapy remained relatively stable (p = 0.410). As ex- pected, the use of EDP-M increased significantly compared to other types of chemotherapy from 2014 onwards (p < 0.001). Additionally, a sig- nificant increase in the administration of mitotane (p = <. 001), primary adrenalectomies (p = 0.019) and negative surgical margins (p = 0.036) was observed for mACC patients from 2014 onwards.
3.1. Effect of systemic therapies on OS
As shown in Figure 1A, OS significantly improved for patients with mACC diagnosed from 2014 onwards compared to pre-2014 (p = 0.032). The median OS improved from 6.8 months prior to 2014-8.3 months post 2014, with a 5-year survival rate of 4.7% vs 19.7%. Patients diagnosed from 2014 onwards receiving EDP-M as part of their therapy showed a numerically improved OS (11.8 vs 5.6 months) compared to those that did not, however this was not statistically significant (p = 0.525) (Figure 1B). Compared to the FIRM-ACT trial, there was no sig- nificant difference in OS for patients with mACC treated in daily clinical practice with EDP-M in the Netherlands [6] (11.8 months vs 14.8 months, p = 0.184) (Figure 1C). There is no information available regarding only the EPD part of treatment, as mitotane is always part of
| Total (N) | Pre-2014 | Post 2014 | P-value | |
|---|---|---|---|---|
| Sex | ||||
| Male | 69 | 32 | 37 | |
| Female | 98 | 36 | 62 | 0.212 |
| Age diagnosis | 167 | 68 | 99 | |
| Mean | 55.6 | 57.6 | 0.373 | |
| Age metastasis | 167 | 68 | 99 | |
| Mean | 55.6 | 57.8 | 0.315 | |
| Stage diagnosis | ||||
| Stage I | 1 | 0 | 1 | |
| Stage II | 16 | 1 | 15 | |
| Stage III | 24 | 3 | 21 | |
| Stage IV | 126 | 64 | 62 | < 0.001 |
| Vital status | ||||
| Alive | 26 | 4 | 22 | |
| Deceased | 140 | 64 | 76 | 0.004 |
| Chemotherapy | ||||
| No | 122 | 52 | 70 | |
| Yes | 45 | 16 | 29 | 0.410 |
| Mitotane | ||||
| No | 108 | 62 | 46 | |
| Yes | 59 | 6 | 53 | < 0.001 |
| EDP-M | ||||
| No | 145 | 68 | 77 | |
| Yes | 22 | 0 | 22 | < 0.001 |
| Primary Adrenalectomyª | ||||
| No | 2 | 1 | 1 | |
| Yes | 38 | 2 | 36 | 0.019 |
| Palliative Adrenalectomy | ||||
| No | 67 | 39 | 28 | |
| Yes | 60 | 26 | 34 | 0.094 |
| b Local treatment of metastases | ||||
| No | 111 | 43 | 68 | |
| Yes | 56 | 25 | 31 | 0.463 |
| Radiotherapy | ||||
| No | 159 | 66 | 93 | |
| Yes | 8 | 2 | 6 | 0.475 |
| Hormone production | ||||
| No | 23 | x | 23 | |
| Yes | 72 | x | 72 | x |
| Surgical Margins | ||||
| R0 | 39 | 6 | 33 | |
| R+ | 45 | 16 | 29 | 0.036 |
| Ki-67 | ||||
| ≤ 10% | 21 | x | 21 | x |
| < 20% | 10 | x | 10 | |
| > 20% | 32 | x | 32 |
ª Initial diagnosis of stage I - III with progression into metastatic disease
b Surgery and Radiotherapy of metastases
the therapy schedule. The total duration of EDP-M treatment varied widely between patients, with a median of 229 days (SD: 348.7) and mean of 355 days (SE: 74.3). A small number of patients was treated with other types of chemotherapy; inclusion of these patients did not change OS after 2014 compared to treatment with any chemotherapy before 2014 (p = 0.754) (Figure 1D). Before 2014, a wide variety of chemotherapy was administered with platinum-based therapy being the most common. Patients with synchronous metastases (n = 126) had a worse OS from time of diagnosis of stage IV disease compared to those with metachronous metastases (n = 41) (5 vs 18 months, p < . 001) (Appendix A1). Treatment with chemotherapy in this synchronous group did not significantly improve OS (p = 0.351) (Appendix A2).
Patients diagnosed from 2014 onwards treated with mitotane alone had the highest 5-year survival rate (32.2%) compared to chemotherapy and mitotane combination therapy (7.1%) and no systemic therapy (13.4%). However, the median OS was similar for systemic treatment with mitotane alone vs chemotherapy and mitotane in combination (11.2 vs 11.8 months, p = 0.096) (Figure 2A). When comparing patients initially diagnosed with stage IV ACC (between 2005 and 2020), treat- ment with mitotane only again showed the highest 5-year survival
(26.5%) compared to chemotherapy and mitotane combination therapy (0%) and no systemic therapy (3.4%) (p = 0.004). However, the median OS of patients treated with chemotherapy only and chemotherapy in combination with mitotane was numerically higher compared to mito- tane only (Figure 2B). Similar results are shown when these systemic treatment options are compared for all patients (Figure 2C). Within the study there was no significant difference in frequency of treatment with chemotherapy (p = 0.618) or frequency of mitotane therapy (p = 0.478) between patients initially diagnosed with stage I-III pro- gressing to stage IV and stage IV at diagnosis.
3.2. Effect of local therapies on OS
From 2014 onwards, an increase in number of adrenalectomies performed was noted which can be linked to the increased number of patients with an initial stage I-III at diagnosis. Most likely, increased awareness, dissemination of treatment algorithms as well as incidental findings on imaging for other reasons has led to this stage shift at diagnosis [11]. In general, patients diagnosed with stage I-III disease underwent adrenalectomy more frequently than patients initially diag- nosed with stage IV mACC (p <. 001). However, patients initially diagnosed with stage IV ACC had a better OS when treated with a palliative adrenalectomy (11.2 months vs 3.2 months, p = <. 001) (Figure 3A). Furthermore, the OS of patients initially diagnosed with stage IV ACC who underwent local treatment of metastatic sites was significantly better than that of patients who did not receive local treatment (12.7 vs 3.9 months, p = <. 001) (Figure 3B). A similar pattern of increased survival was seen when data for all patients (initial diag- nosis stage I - IV) was assessed (p = <. 001) (Appendix B).
3.3. Prognostic factors and multivariate analyses
To investigate a correlation between survival and prognostic factors, patients diagnosed from 2014 onwards were divided into favorable (n = 33): primary diagnosis of 9 months or more before diagnosis of metastases, a Ki-67 score ≤10% or a Weiss score <4 [4,9,10]) and un- favorable (n = 66) groups. Patients with a favorable profile had showed a better OS than patients with an unfavorable profile (5.1 vs 19.3 months, p < 0.001) (Appendix C). Chemotherapy was administered in similar frequency in both groups and did not improve OS in either of the two groups (unfavorable: p = 0.781, favorable: p = 0.433).
Lower stage at diagnosis (HR stage II: 0.37, stage III: 0.69, p = 0.009), treatment with palliative adrenalectomy (HR: 0.26, p = <. 001) and local treatment of metastases (radiotherapy or surgery) (HR: 0.35, p = 0.001) were linked to an improved OS from 2014 on- wards. A higher Ki-67 score (HR: 2.67, p = 0.003) was linked to worse survival. In the multivariate Cox regression only including patients diagnosed from 2014 onwards, the variables palliative adrenalectomy (HR: 0.23, p = <. 001) and local treatment of metastases (HR: 0.43, p = 0.021) remained associated with survival. Neither chemotherapy (HR: 0.95, p = 0.821) nor EDP-M (HR: 0.75, p = 0.246) showed an as- sociation with patient survival from 2014 onwards. Additionally, in the Cox regression including the whole dataset (2005 - 2020) neither chemotherapy (HR: 0.85, p = 0.396) nor EDP-M (HR: 0.75, p = 0.246) showed an association with patient survival (Appendix D). Mitotane was linked to survival in both univariate (HR: 0.64, p = 0.013) and multi- variate Cox regression (HR: 0.48, p = 0.030) when the whole dataset was included (Appendix D). However, in the Cox regression only including patients diagnosed from 2014 onwards mitotane was no longer significantly linked to survival (p = 0.182) (Table 2).
4. Discussion
This retrospective analysis of real-world data examined the overall survival for patients with stage IV ACC in the Netherlands and the effect of treatment with EDP-M. The analysis showed an improvement in the
A
10
Initial diagnosis stage IV
B
1.0
Year of diagnosis > 2014
EDP-M
NO
NO
Yes
0.8
Yes
0.8
Overall Survival
Median OS (mo)
Overall Survival
Median OS (mo)
0.6
<2014: 6.8
0.6
No: 5.6
>2014: 8.3
Yes: 11.8
0.4
0.4
0.2
P = 0.032
0.2
P = 0.525
0.0
0.0
0 12 24 36 48 60 72 84 96 108 120 132 144 156
·
12
24
36
48
60
72
84
96
Time (months)
Time (months)
C
1.0
EDP-M Current data FIRMACT trial
D
1.0
Patients treated with chemotherapy
Year of diagnosis
<2014
0.8
0.8
>2014
Overall Survival
Median OS (mo)
Current data: 11.8 FIRMACT: 14.8
Overall Survival
Median OS (mo)
0.6
0.6
<2014: 9.4
>2014: 11.8
0.4
0.4
0.2
P = 0.184
0.2
P = 0.754
0.0
0.0
0 12 24 36 48 60 72 84 96 108 120 132 144 156
·
12 24 36 48 60 72 84 95 108 120 132 144 156
Time (Months)
Time (months)
OS of patients diagnosed with mACC in the Netherlands in the last decade compared with the prior decade (p = 0.032). Earlier research by Kerkhofs et al showed a median OS of 5 months (95% CI: 2-7) for pa- tients with mACC diagnosed before 2010 1. More recent data report a median OS of 10-15 months for patients with mACC, depending on sub stage IVa-c [4]. In our study, patients diagnosed from 2014 onwards had a median overall survival of 8 months (95% CI: 3-13). Since 22% of patients diagnosed from 2014 onwards were still alive at the data cut off point, the true median OS could be higher. Thus, these real-world data support an improvement in survival of patients with mACC in the Netherlands.
Clinical guidelines for mACC advise treatment with etoposide, cisplatin, doxorubicin and mitotane since the FIRM-ACT trial showed a higher rate of tumor response (ORR) and progression free survival (PFS) for EDP-M compared to a streptozocin mitotane treatment, although no positive impact on the OS was demonstrated [4,6]. The real-world EDP-M data in the Netherlands since 2014 does not statistically differ from the data of the FIRM-ACT trial (OS: 14.8 vs 11.8 months, p = 0.184). Consistent with both the FIRM-ACT trial and a recent study by Uchihara et al, we were unable to show a significant positive effect of EDP-M on OS of patients with mACC [6,13].
When comparing patients treated with chemotherapy pre and post 2014 no improvement is shown (p = 0.754), and in the multivariate analysis neither chemotherapy nor EDP-M was a significant variable, suggesting neither is significantly linked to patient survival (chemo- therapy: HR= 0.95, p = 0.821, EDP-M: HR= 0.75, p = 0.246).
Multivariate analysis on post-2014 data confirmed a link between stage at diagnosis, Ki-67, the performance of palliative adrenalectomy and local treatment of metastases to patient survival. These prognostic factors have been linked to ACC previously [14-16].
Interestingly, the survival of patients treated solely with mitotane
proved to be significantly higher than that of patients treated with chemotherapy or a chemotherapy plus mitotane combination (p = 0.006). The median OS for chemotherapy plus mitotane was slightly better compared to mitotane only, but the 5-year survival of patients treated solely with mitotane was 28.3% vs. 5.6% for patients treated with both chemotherapy and mitotane. In the guidelines, mito- tane monotherapy is recommended for patients with a low tumor burden and/or more favorable prognostic parameters [4]. These retro- spective data support that the mitotane monotherapy is indeed being prescribed to this patient population. As anticipated, the patients with a more favorable disease profile showed better survival compared to pa- tients with an unfavorable disease profile. However, the systemic use of mitotane also remains a controversial topic as no prospective data on its effectiveness are available [17,18]. Retrospective studies report mito- tane response rates of 13-35% [4]. In this study, we see an increase in the use of mitotane from 2014 onwards. However, mitotane is no longer linked to survival for patients diagnosed from 2014 onwards in uni- variate analysis (p = 0.182), this is most likely a limitation in statistical power for the group of patients diagnosed from 2014 onwards. The guidelines further recommend treating patients with chemotherapy when they progress on mitotane or have unfavorable characteristics [4]. In our patient population, no association between poor prognostic fac- tors and preferential chemotherapy administration could be identified. Patients treated with chemotherapy did not show a better OS in either of the two profiled groups. This suggests that no type of systemic treatment is linked to the increase in survival that was found from 2014 onwards. Limitations in this aspect of the study are the number of patients, the lack of data on tumor burden, symptoms or number of organs involved. In addition, to our knowledge, there have been no randomized, placebo-controlled clinical trials for EDP-M, comparing the systemic treatment with supportive care.
A.
1.0
Patients diagnosed > 2014
Systemic Therapy
B.
1.0
Patients with initial diagnosis stage IV
Systemic Therapy
None
None
0.8
Mitotane
Chemotherapy
0.8
Mitotane
Chemotherapy
Overall Survival
Mitotane +
Chemotherapy
Overall Survival
Mitotane +
Chemotherapy
0.6
Median OS (mo)
0.6
Median OS (mo)
None: 3.2
None: 3
0.4
Mitotane: 11.2
Mitotane +
0.4
p = 0.096
p = 0.004
Mitotane: 6
Chemotherapy: 8.9
Chemotherapy: 11.8
Mitotane +
0.2
0.2
Chemotherapy: 7.8
0.0
0.0
0
12
24
36
48
60
72
84
96
108
120
32
144
156
0
12
24
36
48
60
72
84
96
108
120
132
144
156
Time (months)
Time (months)
C.
1.0
Systemic Therapy
None
0.8
Mitotane
Chemotherapy
Overall Survival
Mitotane +
0.6
Chemotherapy
Median OS (mo)
None: 3.8
0.4
Mitotane: 11.2
p = 0.006
Chemotherapy: 8.9
Mitotane +
0.2
Chemotherapy: 15.2
0.0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
Time (months)
A.
1.0
Adrenalectomy
B.
1.0
Local Treatment
☐ No
Yes
FINO
0.8
Median OS (mo)
0.8
Yes
Overall Survival
No: 3.2
Median OS (mo)
No: 3.9
0.6
Yes: 11.2
Overall Survival
0.6
Yes: 12.7
0.4
0.4
p =<. 001
p =<. 001
0.2
0.2
0.0
0.0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
0
12
24
36
48
60
72
84
96
108
120
132
144
156
Time (months)
Time (months)
Regarding the effect of local therapies, a positive association be- tween a surgical approach for the primary tumor in synchronous met- astatic disease and patient survival has been suggested by multiple studies over the years [5,19-21]. The guidelines advise considering palliative adrenalectomy only in case of severe hormone excess and/or when all lesions can be resected. Patients with widespread mACC upon initial diagnosis are often not considered candidates for a surgical approach [4,7]. Our data confirms a significant survival benefit for palliative adrenalectomy, not limited to patients with excess of hormone production. There is no information in the patient registry on the completeness of local therapy for metastatic disease when palliative adrenalectomy was performed. However, in many institutes’ tumor
burden (e.g. large vs small primary tumor and/or limited number of metastases vs. more extensive disease) is considered when deciding for/against palliative adrenalectomy. The results of the current study support palliative adrenalectomy on an individual patient basis taking co-morbidities, tumor burden and aggressiveness of the disease into account. All patients and their individual treatment plan should be discussed on a multidisciplinary tumor board [22].
This retrospective study has some limitations. Data prior to 2014 was more often unavailable and therefore absent in the data set. Specifically, data of patients with an initial diagnosis of stage I-III that progressed into stage IV disease was more often absent prior to 2014. Additionally, data on patients Ki-67, hormone production and Weiss scores were often
| Variables > 2014 | Median OS (months) | Univariate HR (95% CI) | P-value | Multivariateª HR (95% CI) | P-value |
|---|---|---|---|---|---|
| Overall | 8 | ||||
| Sex | |||||
| Male | 15 | reference | x | x | |
| Female | 5 | 1.61 (1.00-2.58) | 0.051 | x | x |
| Age at diagnosis | 1.02 (1.00-1.03) | 0.086 | x | x ☒ | |
| Age at stage IV | 1.01 (1.00-1.03) | 0.111 | x | x ☒ | |
| Stage at diagnosis | |||||
| Stage IV | 5 | reference | 0.056 | x ☒ | x ☒ |
| Stage III | 14 | 0.69 (0.39-1.22) | 0.200 | x ☒ | x ☒ |
| Stage II | 39 | 0.37 (0.17-0.78) | 0.009 | x | x |
| Chemotherapy | |||||
| No | 5 | reference | x ☒ | x ☒ | |
| Yes | 12 | 0.95 (0.58-1.54) | 0.821 | x ☒ | x |
| Mitotane | |||||
| No | 5 | reference | x ☒ | x | |
| Yes | 11 | 0.74 (0.47-1.16) | 0.182 | x | x |
| EDP-M | |||||
| No | 6 | reference | x | x | |
| Yes | 12 | 0.75 (0.45-1.23) | 0.246 | x | x |
| Palliative Adrenalectomyª | |||||
| No | 2 | reference | reference | ||
| Yes | 15 | 0.26 (0.15-0.47) | <. 001 | 0.23 (0.11-0.46) | < . 001 |
| Radiotherapy | |||||
| No | 8 | reference | x | x | |
| Yes | 16 | 0.69 (0.25-1.89) | 0.470 | x | x |
| Local treatment of metastasesª | |||||
| No | 7 | reference | reference | ||
| Yes | 16 | 0.35 (0.18-0.67) | 0.001 | 0.43 (0.21-0.88) | 0.021 |
| Hormone production | |||||
| No | 12 | reference | x | x | |
| Yes | 7 | 1.21 (0.70-2.09) | 0.489 | x | x |
| Surgical Marginsª | |||||
| R0 | 6.8 | reference | x | x | |
| R+ | 13.3 | 1.34 (0.55 - 3.27) | 0.517 | x | x |
| Ki-67 | |||||
| ≤ 10% | 24 | reference | 0.002 | reference | 0.232 |
| < 20% | 18 | 0.54 (0.18 - 1.64) | 0.280 | 0.27 (0.03 - 2.27) | 0.229 |
| > 20% | 5.6 | 2.67 (1.40-5.08) | 0.003 | 1.13 (0.48 - 2.64) | 0.781 |
Inclusion criteria for the multivariate cox regression is p < 0.050.
a Only patients with initial diagnosis stage IV included
not registered. From 2014 onwards, records were more detailed and consistent. No information could be gathered regarding the PFS and ORR due to patient data sensitivity. Furthermore, only a limited number of patients with mACC (27%) were treated with chemotherapy in the Netherlands. In comparison, a similar small-scale study in an expert Japanese center reported treatment with chemotherapy in 48.8% of all mACC patients (n = 43) [13]. When limited benefits are observed from a treatment in terms of effectiveness and gain of quality of life, costs should be taken into account. A cost evaluation was outside the scope of this study.
Based on the findings in this study and others, considering the strain chemotherapy can have on a patients’ quality of life and the limited overall benefits, one might question the overall patient benefit of treatment with EDP-M, especially in patients with a limited performance status [2]. Although treatment options for mACC remain very limited, better criteria for prediction of response to chemotherapy are needed to identify those patients that can benefit most from it rather than risking treating too many patients with toxic chemotherapy. On the other hand, the limited overall benefit of EDP-M shows once more the urgency for innovation in the field of mACC. The results of ongoing studies to identify novel effective treatment strategies for mACC are eagerly awaited, such as with chemotherapy (cabazitaxel), tyrosine kinase in- hibitors (cabozantinib) and immune therapy alone or in combination with therapeutic vaccines [23-25].
5. Conclusion
This retrospective analysis shows that after the FIRM-ACT trial, the introduction of etoposide, doxorubicin, cisplatin and mitotane (EDP-M) into the Netherlands for patients with mACC was not associated with a significant improvement in OS. Still, patient outcome has improved in the last decade, most likely due to more personalized, multimodality treatment in appropriately selected patients. The last decade showed an increase in both the number of adrenalectomies performed and systemic use of mitotane. Furthermore, local treatment of (oligo-)metastases has been shown to benefit overall survival for selected patients both before and from 2014 onwards. All patients with mACC should be discussed in multidisciplinary tumor boards and there is an urgent need for novel treatment options for patients with mACC.
Funding
None.
CRediT authorship contribution statement
Pien Debets: Methodology, Formal analysis, Writing - original draft. C. Willemien Menke-van der Houven van Oordt: Conceptualization, Methodology, Writing - review & editing. Koen Dreijerink: Writing -
review & editing. Anton Engelsman: Writing - review & editing. Max Dahele: Writing - review & editing. Harm Haak: Writing - review & editing. Rebecca Steenaard: Data collection, Writing - review & edit- ing. Ellen Kapiteijn: Writing - review & editing. Eleonora Corssmit: Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial or personal relationships that could be of influence on the work reported in this paper.
Data Availability
The analyzed data supporting the findings in this paper is available on request from the Netherlands comprehensive cancer organization (IKNL). Information regarding the data analysis is available upon request from the corresponding author.
Acknowledgements
The authors would like to thank the Netherlands comprehensive cancer organization (IKNL) for the collection of the data presented in this paper. Additionally, the authors would like to thank S.L. van der Pas of the VUMC Amsterdam department of Epidemiology and Data Science for her advice concerning the statistics methods used in this paper. M. Dahele: Research grants and honorarium from Varian Medical Systems, outside the scope of this work.
Appendix A. Supporting information
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.ejca.2023.113424.
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