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Letter to the Editor
Response to Letter RE: Impact of EDP-M on survival of patients with metastatic adrenocortical carcinoma: A population-based study
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Dear Editor,
We would like to thank Dr Laganà and colleagues for the insights into and valuable comments on our study. The purpose of the study was to assess whether the implementation of the EDP-M schedule influenced the overall survival (OS) of patients with metastatic adrenocortical carcinoma (mACC) in the Netherlands. As you acknowledged, our analysis showed an improved survival in the last decade [1]. Besides the implementation of the EDP-M chemotherapy scheme, health care in the Netherlands for rare tumors has become more centralized in centers of expertize, where more multimodality as well as personalized treatment approaches are pursued, and it seems likely that this change in patient management throughout the country has contributed to improved sur- vival. As pointed out by Dr Lagana et al., the European ESMO guidelines recommend first-line treatment with either EDP-M or mitotane alone in combination with local therapies, in case patients with advanced ACC are not amenable to complete resection [2]. In addition, guidelines suggest treatment individualization based on e.g. patient preference, number of lesion(s), speed of progression, other prognostic factors and local expertize. For selected patients with limited (oligo-metastatic) or slow growing (indolent) disease mitotane monotherapy is suggested and surgery and/or other local therapies should be adopted whenever fea- sible/appropriate [2,3]. If there is high-volume or rapidly progressive disease, then EDP-M is recommended by the guidelines (other combi- nations can be used when the patient is not fit for EDP). All options should be discussed between the individual patient and his/her treating physician in order to make a shared decision regarding the risks and benefits of systemic therapy. As our study included all patients with mACC in the Netherlands in the study period, the fact that only 22% were treated with EDP-M most likely reflects the fact that many (on average older, see Table 1 below) patients with extensive disease choose to not undergo burdensome chemotherapy with limited survival gain. However, it is also possible that other factors such as physicians’ own (less favorable) perceptions of the available therapy played a role. Another real-world study in an expertize center in Japan, also showed a lower than expected proportion of patients (40%) receiving EDP-M compared to the estimate of 70% estimation based on the percentage of high-volume disease [4].
As suggested by Lagana and colleagues, it could have been that within our study population, patients with a poorer prognosis were more likely to be treated with chemotherapy and that this contributed to the lack of impact on OS. However, we showed that chemotherapy was equally administered to patients with a favorable and unfavorable dis- ease profile (appendix C). In this letter, we provide additional data to show that the EDP-M receiving mACC population in this study did not differ demographically or clinically from patients treated without EDP- M (Table 1). The only statistical difference between the EDP-M and non-
EDP-M subgroups (diagnosed from 2014 onwards) was that patients receiving EDP-M were, on average, younger (mean age: 50.6 vs 59.7). The lower age and the fact that the EDP-M cohort had a numerically better survival than the non-EDP-M treated cohort also speak against the assumption that the patients treated with EDP-M would have had a lower performance status (PS). The authors suggest correcting for po- tential bias using propensity score matching. However, the only signif- icant difference is age, which would be a bias against poorer PS [5]. We consulted the academic department of data science for statistical support and since there are no other significant differences between the two groups, there is no strong argument for propensity score matching.
We agree that the risk of bias has to be taken into account for any retrospective study. Both this, and the low number of patients included in the EDP-M analyses were discussed and stated as study limitations. It is important to note that within our study we compared the survival of patients treated with chemotherapy before and after the implementation of EDP-M, which should reduce the selection bias for receiving chemo- therapy compared to other treatment strategies. This is supported by the finding of no significant difference between the proportion of patients who received versus who did not receive chemotherapy before and after 2014 (Table 1 in the article p = 0.410). We found that survival was not significantly different (p = 0.754) between patients receiving chemo- therapy before and after 2014 (Figure 1D in the article), indicating that the increase in OS after 2014 was not due to the new chemotherapy regimen. Of course, these data do not preclude EDP-M being beneficial for individual patients with mACC. Better ways are needed to identify which patients stand to gain most from it.
As Lagana et al., state in their letter, we agree that EDP-M has limited efficacy [6]. Within our study, EDP-M receiving patients had a better numerical (median) OS (11.8, 95% CI 1.9- 21.6) compared to those who did not (5.6, 95% CI 0.7 - 10.5). However, the 95% confidence intervals of the median OS overlap and the survival curves cross, leading to the observation that receiving EDP-M did not improve survival (p = 0.525, Figure 1B in the article). The authors’ retrospective study looking at the efficacy of EDP-M in locally advanced and mACC showed a better PFS and OS than our analysis and the FIRM-ACT trial. However, there are notable differences that prevent a straightforward comparison: our study only assessed survival from the moment of diagnosis of stage IV disease compared to both stage III and stage IV within their study. In addition, the patients that were referred to their expert center were relatively younger, with an average age of 47 years, and in their study 46% of patients became amenable for surgery after EDP-M, whereas in our study only in 23% of patients EDP-M was followed by local therapy. These, and potentially other factors might explain the difference be- tween the two retrospective studies. Unfortunately, we do not have in- formation on response rates to EDP-M, so this cannot be compared. It is
| EDP-M | p-value | ||
|---|---|---|---|
| Yes | No | ||
| Sex | |||
| Male | 12 (55%) | 50 | |
| Female | 10 (45%) | 27 | 0.374 |
| Age diagnosis | |||
| Mean | 50.6 | 59.7 | 0.016 |
| Stage diagnosis | |||
| Stage I | 0 (0%) | 1 (1%) | |
| Stage II | 4 (18%) | 11 (14%) | |
| Stage III | 7 (32%) | 14 (18%) | |
| Stage IV | 11 (50%) | 51 (66%) | 0.444 |
| Primary Adrenalectomy | |||
| No | 0 (0%) | 1 (4%) | |
| Yes | 11 (100%) | 25 (96%) | 0.510 |
| Palliative Adrenalectomy | |||
| No | 4 (36%) | 24 (47%) | |
| Yes | 7 (64%) | 27 (53%) | 0.518 |
| Local treatment of metastases | |||
| No | 17 (77%) | 51 (66%) | |
| Yes | 5 (23%) | 26 (34%) | 0.325 |
| Radiotherapy | |||
| No | 21 (95%) | 72 (94%) | |
| Yes | 1 (5%) | 5 (6%) | 0.736 |
| Hormone production | |||
| No | 6 (27%) | 17 (23%) | |
| Yes | 16 (73%) | 56 (77%) | 0.702 |
| Surgical margins | |||
| R0 | 9 (53%) | 24 (53%) | |
| R+ | 8 (47%) | 21 (47%) | 0.978 |
| Ki-67 | |||
| ≤ 10% | 6 (31.5%) | 15 (34%) | |
| < 20% | 3 (15.5%) | 7 (16%) | |
| < 30% | 10 (53%) | 22 (50%) | 0.137 |
remarkable that both studies found a positive association between sur- gery/local therapy and an improved OS.
We agree with Lagana et al., that for some patients with a low PS, this may be due to the disease burden and/or Cushing’s syndrome. More adequate inhibition of cortisol synthesis, by using metyrapone and in particular the recently approved 11ß-hydroxylase inhibitor osilodrostat, is likely to result in further improving PS in patients with mACC and Cushing syndrome before starting EDP-M [7]. We have read with in- terest their observations on megestrol to combat nausea and its potential anti-neoplastic effects against ACC and look forward to see the future studies [8]. However, other chemotherapy related side effects such as loss of hair, the risk of infection and hospital admissions for chemo- therapy administration can take its toll on a patient’s quality of life in the metastatic setting, further supporting shared decision making regarding the treatment choices.
In conclusion, within our nationwide study population treatment with EDP-M did not significantly improve OS in patients with mACC. However, this does not mean that it cannot be beneficial for an indi- vidual patient with mACC. While acknowledging the possibility of physician bias (both ‘for’ or ‘against’ chemotherapy), the results of this study and that of Lagana and colleagues, advocate for an open discussion between patients and their treating physician taking into account as objectively as possible, the limited survival benefits for the study pop- ulations as a whole, while acknowledging the difficulties in predicting outcome for individual patients (i.e. some may benefit considerably more than others), potential risks and side-effects of the EDP-M chemotherapy regimen, and potential effects on quality of life. We support referral of all mACC patients to expert centers for a personal- ized, multimodality treatment approach. Lastly, all available data including this study underscore the importance of future research into novel treatment strategies for this rare and difficult to treat disease.
Funding
none.
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. M. Dahele: Research grants and honorarium from Varian Medical Systems, outside the scope of this work.
References
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Pien Debetsª, Koen M.A. Dreijerinkb,k, Anton Engelsman”, Max Dahele”, Harm R. Haake,f,g, Rebecca V. Steenaarde,f.j, Ellen Kapiteijnh, Eleonora Corssmiti,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
f 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
* Correspondence to: Amsterdam UMC location VU Medical Center, Department of Medical Oncology, De Boelelaan 1117, 1081HV Amsterdam, the Netherlands.
E-mail address: c.menke@amsterdamumc.nl (W. Menke - van der Houven van Oordt).