ENDOCRINE SOCIETY
OXFORD
Progression of Vertebral Fractures in Patients with Adrenocortical Carcinoma Undergoing Mitotane Therapy
Deborah Cosentini,1 Salvatore Grisanti,1.[D Julien Hadoux,2 Rossella Libe,3 Michele Frigerio,4 Marta Laganà,1 Frederic Deschamps,5 Manuel Zamparini,1 Livia Lamartina,2 Rebecca Pedersini,1 Clara Valsecchi,4 Roberto Maroldi,4 Abir Al Ghuzlan,2 Massimo Terzolo,6,[D Roberto Gasparotti,7 Eric Baudin,2,[D and Alfredo Berruti1.[D
‘Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia. ASST Spedali Civili, Brescia, Italy
2Department of Nuclear Medicine and Endocrine Oncology, and Interventional Medicine, Institute Gustave Roussy, Villejuif, France 3Department of Endocrinology, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
4Radiology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia. ASST Spedali Civili, Brescia, Italy
5Department of Interventional Radiology, Institute Gustave Roussy, Villejuif, France
6Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Orbassano, Italy; and 7Neuroradiology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia. ASST Spedali Civili Hospital, Brescia, Italy
Correspondence: Alfredo Berruti, MD, Oncologia Medica, ASST Spedali Civili, Piazzale Spedali Civili 1, 25123 Brescia, Italy. Email: alfredo.berruti@gmail.com.
Abstract
Context: Patients with adrenocortical carcinoma (ACC) are frequently on mitotane therapy for a long time period. The drug exerts adrenolytic activity requiring glucocorticoid supplementation, which can be potentially detrimental for bone.
Objective: To explore whether mitotane with/without chemotherapy is associated with an increased proportion of morphometric vertebral frac- tures (VFs) in ACC patients. Secondary objectives were proportion of patients with VF progression, or worsening of the spinal deformity index (SDI) during mitotane therapy; and to explore predictive factors of VF progression and a prognostic role of VF progression.
Methods: Multicenter, retrospective cohort study of patients with ACC who received mitotane alone or in association to chemotherapy, re- cruited from January 2010 to January 2020 in 2 reference centers in Italy and France.
Results: A significant increase in the frequency of VFs before and after mitotane therapy was seen both in Italian (28.3% vs 47.8%, P = . 04) and French (17.8% vs 35.6%, P = . 04) series. VF progression was observed in 39.1%, and 28.9% of patients, respectively. Baseline VFs and increased patient body mass index, but not the dose of cortisol supplementation, showed an independent association with VF progression at multivariate analysis. Among the 72 advanced ACC patients, progression of VFs was associated with a poorer survival.
Conclusion: The administration of mitotane with/without chemotherapy in ACC patients impairs bone health independently from cortisol sup- plementation. Appropriate preventive measures to decrease the fracture risk should be implemented in these patients.
Key Words: adrenal tumor, bone health, mitotane, steroid supplementation, vertebral fractures
Abbreviations: ACC, adrenocortical carcinoma; AI, aromatase inhibitor; BC, breast cancer; BMI, body mass index; CT, computed tomography; EDP, etoposide, doxorubicin, and cisplatin; M, mitotane; SDI, spinal deformity index; VF, vertebral fracture.
Adrenocortical carcinoma (ACC) is a rare and aggressive ma- lignant disease with an incidence of 0.7 to 2 new cases per million population per year (1). The majority of ACCs are functioning at presentation. and Cushing syndrome is the most frequent clinical manifestation (2).
Radical surgery represents the mainstay of treatment of lo- calized tumors (1) and it is the only treatment strategy that can offer the chance of a cure to patients. Despite radical re- section, however, most patients are destined to relapse, often within the first 2 years. Based on the results of a retrospective cross-sectional study (3, 4), whose results have been confirmed by other retrospective studies (1), adjuvant mitotane therapy for at least 2 years is currently prescribed and recommended
by available guidelines (1, 5). Single-agent mitotane or com- bination of mitotane plus chemotherapy are the treatment strategies adopted in patients with locally advanced or meta- static disease not suitable for surgery (6). Etoposide, doxo- rubicin, and cisplatin administered in association of mitotane (EDP-M) is the standard chemotherapeutic regimen (7, 8). The efficacy of this regimen is limited, although a subgroup of patients can obtain long-term survival (9). Nonprogressing patients after 6 cycles of EDP usually continue mitotane therapy until progression.
Mitotane exerts adrenolytic activity requiring gluco- corticoid supplementation, which is tapered on the basis of clinical assessment (10). Cortisone acetate or hydrocortisone
are the recommended drugs for steroid replacement (1, 5). Due to increased steroid clearance and increased cortisol- binding globulin levels induced by mitotane, a higher replace- ment dose is usually required than that prescribed for the management of Addison disease (1). Glucocorticoid replace- ment in patients taking mitotane is empirically carried out and may lead to either mild hypo- or hypercortisolism (11). Glucocorticoid administration, even at low doses, is associ- ated with rapid bone loss and fragility (12). Glucocorticoids negatively affect bone health via a complex mechanism that includes both a decrease in bone formation and an increase in bone resorption. Glucocorticoid-induced inhibition of bone formation involves multiple pathways, including a reduc- tion in osteoblast proliferation via suppression of the growth factors BMP2 and TGFb1, upregulation of Wnt antagonists (Dkk-1, Wif-1, and Sost), and downregulation of the Wnt re- ceptor complex (frizzled 4, 7, Dsh1, and Axin1). This results in strong suppression of osteoblast differentiation, matur- ation, and activity (13). Skeletal fragility is a frequent com- plication of Cushing syndrome, and fragility fractures may be the first clinical manifestation of the disease. However, im- provement of bone mineral density was reported after reso- lution of hypercortisolism (14).
Therefore, a detrimental effect of steroid replacement on bone deserves attention in ACC patients on mitotane therapy. This issue is relevant since many patients are receiving mitotane after surgery in an adjuvant setting and a number of patients with advanced disease are on mitotane therapy for a long time period. To the best of our knowledge, the effect of mitotane (and associated steroid replacement) on fracture risk has never been explored. Vertebral fractures (VFs) are the classical hallmark of glucocorticoid-induced osteoporosis and bone fragility (15, 16), and are associated with impaired quality of life and an increased risk of future fractures (17). The majority of VFs are mild and asymptomatic, and are diag- nosed through a radiological examination. Vertebral morph- ometry is a quantitative method to identify VFs. It is based on the measurement of dorsal and lumbar vertebrae on lat- eral radiographic images (morphometric X-ray radiography) or on dual X-ray absorptiometry scans (morphometric X-ray absorptiometry) (18). With the purpose to evaluate the fre- quency of VFs in ACC patients during mitotane therapy, we conducted a retrospective case-control study in 2 reference institutions for the management of ACC patients in Italy and France. The primary aim was to assess the frequency of VFs before and after mitotane treatment; secondary aims were as- sessment of the proportion of patients with progression of VF or worsening of the spinal deformity index (SDI) during mitotane therapy, identification of risk factors for progression of VF, and the impact of VFs on patient prognosis.
Patients and Methods
Study Design and Objectives
This was a retrospective, multicentric, case-control study. Data of patients from the Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili in Brescia (Italy) and Institute Gustave Roussy in Villejuif (France) meeting the eligibility criteria and recruited from January 2010 to January 2020, were col- lected. Italian patients were the primary cohort and French patients the validation cohort. To be included in the study, the patients met the following eligibility criteria: age >18 years;
histological diagnosis of ACC; mitotane treatment alone or in association with chemotherapy for at least 6 months; avail- ability of computed tomography (CT) scans with sagittal view performed at baseline and during treatment. Exclusion cri- teria were the following: other malignancies except basal cell carcinoma or in situ cervical cancer diagnosed within 5 years before the diagnosis of ACC, concomitant diseases known to affect bone, previous or concomitant bisphosphonate therapy or other bone active drugs except vitamin D supplements, and bone metastases. All patients received steroid supplementa- tion, which consisted of cortisone acetate in Italian patients and hydrocortisone in the French patients. The equivalence between the 2 steroids is hydrocortisone 20 mg = cortisone acetate 25 mg. The primary objective was to evaluate the prevalence of morphometric VFs during at least 6 months of treatment with mitotane with/without chemotherapy in the overall series, and in the primary and validation cohorts. Secondary endpoints were the following: evaluation of pro- portion of patients with VF progression and worsening of the SDI during mitotane therapy, identification of bone fra- gility factors at baseline (ie, hormone hypersecretion, age, sex, body mass index (BMI), menopausal status, defined as age ≥60 years or no menses for 1 year in the absence of prior chemotherapy or tamoxifen use, or ovariectomy), and dosage of cortisol replacement therapy as independent risk factors of VF progression; prognostic role of VFs on overall survival in the subgroup of patients with metastatic disease.
In addition to ACC patients on mitotane, 2 different con- trol groups were also included: (1) ACC patients not treated with mitotane and (2) breast cancer (BC) patients treated with aromatase inhibitors (AIs) in an adjuvant setting for at least 2 years. Patients with BC had normal renal function, and none of them were receiving previous or current treatment with anti-osteoporotic drugs (except for calcium and vitamin D) or glucocorticoids. Previous chemotherapy was permitted, but tamoxifen use was not. In group 1 volumetric spine CT scans obtained at ACC diagnosis and during the follow up period were evaluated for VFs (at least every 6 months); in group 2 CT scans were prospectively evaluated at baseline conditions, before the beginning of AI treatment, and at sub- sequent follow-up assessments.
All the ACC patients enrolled in the present study are re- gistered in the ENS@T ACC registry approved by the local ethics committees of both Brescia and Villejuif. Patients with BC were included in a clinical study conducted at Medical Oncology and Breast Unit of ASST-Spedali Civili in Brescia (19, 20). All patients included had given their written in- formed consent.
Data Collection and Assessment of Vertebral Fractures
Demography data, comorbidities, clinical and pathological tumor characteristics, and treatment information were col- lected. Volumetric spine CT scans obtained before the be- ginning of mitotane treatment were evaluated and compared with those obtained after at least 6 months of treatment. The sagittal reformatting view with a bone window was used for the analysis performed by the same experienced radiologists, following a standardized semi-quantitative morphometric ap- proach applied to the dorsal and lumbar vertebrae.
Vertebrae T4 to L4 were assessed for the presence of VFs according to the validated Genant’s semi-quantitative method
(21). The Genant grades were defined as percentage reduc- tion of the anterior, middle, and/or posterior height: grade 1 (mild fracture) 20% to 25%; grade 2 (moderate fracture) 25% to 40%; grade 3 (severe fracture) >40%. Wedge, bicon- cave, and concave fractures were also separately identified. Prevalent VFs were analyzed at baseline. VFs of any grade present at follow-up, but not at baseline, were considered new VFs. Progression of VFs was defined as the development of new/incident VFs (in patients with no VFs or in patients with previous VFs in other vertebrae) and/or the documented minimum 1-point increase in the Genant scoring in pre- existing VFs during the period of follow-up.
An SDI, which has been demonstrated to be a good pre- dictor of incident vertebral fractures, was calculated by sum- ming in each patient the grade of each vertebra from T4 to L4 (22).
Radiographs were individually assessed simultaneously by a team of 3 experienced observers (M.F., R.G., and C.V.) who were blinded to any patient characteristics. In case of a dis- crepancy in assessment, a consensus opinion was obtained.
Statistical Analysis
Descriptive statistics were used to analyze patient clinical characteristics. Differences between categorical variables were assessed by the chi-square or Fisher test when indicated. Continuous variables were compared through parametric (T-test) and nonparametric (Wilcoxon test, Mann-Whitney U-test) tests when indicated. Logistic regression model was employed to assess the ORs and 95% CIs in the univariate and the multivariate analysis, with the lowest risk group as the reference group. Only factors that obtained P < . 10 in univariate analysis entered the multivariate model. Overall survival (OS) curves have been calculated with Kaplan-Meier method and compared with the log-rank test. Statistical sig- nificance was set at P < . 05. SPSS v23.0 software was used for statistical analyses (SPSS Inc., Chicago, IL).
Results
Patient Characteristics
A total of 91 ACC consecutive patients, meeting the eligi- bility criteria and treated with mitotane entered the study: 46 were enrolled at the Medical Oncology Unit at ASST-Spedali Civili in Brescia (Italy) and 45 at the Endocrine Oncology and Nuclear Medicine Department, Gustave Roussy Cancer Institute in Villejuif (France). Patient and tumor characteris- tics are summarized in Table 1. Median age at the beginning of mitotane therapy was 51 years (range 18-72) in the Italian group, and 44 (range 17-78) in the French group. Median BMI was 24.3 (range 16.4-31.2) and 23.8 (range 18.9-36.9) in the 2 groups, respectively. Although not statistically significant, a higher percentage of Italian women had a postmenopausal status at diagnosis: 43.5%, vs 26.7% of the French counter- part (P = . 24). Tumor hypersecretion at diagnosis was pre- sent in 29 Italian patients (63.0%) and 36 French patients (80.0%) (P = . 10). In particular, cortisol hypersecretion was higher in the French cohort (68.9%) than in the Italian co- hort (47.8%, P = . 05). Nine (18%) patients in the Italian and 19 (38%) in the French cohort had cortisol hypersecretion at the time of starting systemic antineoplastic therapy (P = . 04).
At the time of the first evaluation, the proportions of pa- tients with limited (stage I-II), locally advanced (stage III) or
metastatic disease (stage IV) were 19.6%, 15.2%, and 65.2% in the Italian group and 24.4%, 40.0% and 35.6% in the French series (P = . 01). During the study period, 7 Italian and 19 French patients progressed from nonmetastatic to meta- static disease.
In the whole population, 31 patients (34.1%) were treated with single agent mitotane (27 as adjuvant therapy 4 as pal- liative therapy), 43 patients (47.2%) with mitotane in as- sociation with EDP or EP (EDP/EP-M). Seventeen patients (18.7%), initially treated with mitotane in an adjuvant setting also received the EDP or the EP regimen at disease progres- sion while continuing mitotane (these patients were counted in both groups). Comparing the 2 cohorts, a larger number of patients was treated with mitotane monotherapy in the French cohort, whereas in the Italian one a higher number received concomitant mitotane and chemotherapy (P = . 008 and P = . 0001, respectively).
Hydrocortisone dose was converted to the equivalent corti- sone acetate dose and the median supplementation dose was cortisone acetate 62.5 mg/day (range 12.5-150).
Patients were followed for a median of 30.6 months. At the last follow-up examination, 40 patients (43.9%) had died. The median OS of the overall series was 24.2 months (range 6.2-194.7).
Table 1 also describes the characteristics of patients not re- ceiving mitotane therapy (control group 1). Median age at diagnosis was 44 years (range 21-74), 71.4% of patients were females, and tumor hypersecretion was present in 61.4% of cases.
The control group of patients with BC consisted of 176 women (control group 2). Their median age was 64 years (range 30-74), all of them were postmenopausal (physio- logical or drug induced) and the median BMI was 25.0 (range 16.5-42.2). Regarding histological subtype, 150 patients (85.2%) had a hazard ratio (HR) positive/HER2 negative whereas 26 patients (14.8%) had a HER2 positive/HR posi- tive tumor. All of the considered patients (100%) underwent surgery for BC. Neoadjuvant or adjuvant chemotherapy were used in 6.3% and 36.4% of the patients, respectively. All of the patients received adjuvant hormone therapy: 155 patients (88.1%) received AI alone, whereas 21 patients (11.9%) were treated with AI plus luteinizing hormone releasing hormone. CT scans performed in each patient at baseline and every 6 months were prospectively evaluated.
Vertebral Fractures in ACC Patients at Baseline
At baseline conditions, 13 out of 46 patients (28.3%) in the Italian group, 8 out of 45 patients (17.8%) in the French group, who subsequently received mitotane therapy, and 3 out of 21 (14.3%) ACC patients not treated with mitotane had at least 1 prevalent VF. Among ACC patients treated with mitotane, 12 (26.1%) and 4 (8.9%) patients, respectively, had ≥1 mild VF, 4 (8.7%), and 2 (4.4%) had ≥1 moderate VF, and 1 (2.2%) and 3 (6.7%) had ≥1 severe VF. Five Italian patients and 1 French patient had multiple VFs with different grades. Considering all patients together, VFs were found in 24 pa- tients (21.4%) at baseline, 13 (11.6%) classified as mild, 7 (6.2%) moderate, and 4 (3.6%) severe. Seven (6.2%) patients had multiple VFs with different grades. As depicted in Table 2, baseline VFs significantly correlated with older age and sex, while no significant relationship was found with BMI, cor- tisol excess, and, among women, menopausal status.
| Patients treated with Mitotane | Patients NOT treated with mitotane | ||||
|---|---|---|---|---|---|
| Italian | French | P value | Total | ||
| N | 46 | 45 | 91 | 21 | |
| Age | |||||
| Median (range) | 51 (18-72) | 44 (17-78) | .14 | 48 (17-78) | 44 (21-74) |
| Sex, N (%) | |||||
| Male | 18 (39.1) | 18 (40.0) | 1.00 | 36 (39.6) | 6 (28.6) |
| Female | 28 (60.9) | 27 (60.0) | 55 (60.4) | 15 (71.4) | |
| BMI | |||||
| Median (range) | 24.3 (16.4-31.2) | 23.8 (18.9-36.9) | .59 | 24.0 (16.0-37.0) | 21 (100%) |
| Not available, N (%) | 0 (0.0) | 3 (6.6) | 3 (3.3) | ||
| Menopausal status | |||||
| N (%) | 20 (43.5) | 12 (26.7) | .24 | 32 (35.1) | 32 (35.1) |
| Not available, N (%) | 0 (0.0) | 3 (6.7) | 3 (3.3) | 3 (3.3) | |
| Tumor secretory status at diagnosis, N (%) Secreting tumors, Cortisol excess | 29 (63.0) | 36 (80.0) | .10 | 65 (71.4) | 11 (52.4) |
| (± other hormones) | 22 (47.8) | 31 (68.9) | .05 | 53 (58.2) | 11 (52.4) |
| Androgens only | 5 (10.9) | 5 (11.1) | 1.00 | 10 (11.1) | 0 (0.0) |
| Other | 1 (2.2) | 0 (0.0) | 1 (1.1) | 0 (0.0) | |
| Nonsecreting tumors | 17 (37.0) | 9 (20) | 26 (28.6) | 10 (47.6) | |
| Cortisol hypersecretion at the time of mitotane starting, N (%) | 9 (18.0) | 19 (38.0) | .04 | 28 (56.0) | |
| ENSAT stage, N (%) | |||||
| I-II | 9 (19.6) | 11 (24.4) | .62 | 20 (22.0) | 14 (66.7) |
| III | 7 (15.2) | 18 (40.0) | .01 | 25 (27.5) | 7 (33.3) |
| IV | 30 (65.2) | 16 (35.6) | .006 | 46 (50.5) | 0 (0.0) |
| Treatment administered, N (%) | |||||
| Only mitotane | 10 (21.7) | 21 (46.7) | .008 | 31 (34.1) | |
| Adjuvant mitotane and then chemotherapy plus mitotane | 7 (15.2) | 10 (22.2) | .10 | 17 (18.7) | |
| Concomitant chemotherapy plus mitotane | 29 (63.0) | 14 (31.1) | .0001 | 43 (47.2) | |
| Mitotane therapeutic range attainment, N (%) | 28 (60.9) | 29 (64.4) | .50 | 57 (62.6) | |
| Not available | 0 (0.0) | 3 (6.7) | 3 (3.3) | ||
| Cortisone acetate supplementationª, N (%) | 46 (100) | 45 (100) | 1.00 | 91 (100) | |
| Median mg/day | 50 (range 12.5-150) | 62.5 (range 25-100) | .037 | 62.5 (range 12.5-150) | |
Abbreviations: BMI, body mass index; NA not available.
“Italian patients were supplemented with cortisone acetate whereas French patients with hydrocortisone. Hydrocortisone dose was converted in the equivalent cortisone acetate dose.
Vertebral Fractures in the Follow-up
In the patient subset treated with mitotane with/without chemotherapy assessed after a median treatment time of 13.2 months (range 6.3-48.3) in the Italian patients and 24.4 months (range 7.0-41.0) in the French ones, a sig- nificant increase in the frequency of VFs was seen in both series (P = . 043 and P = . 047, respectively) (Table 3). In par- ticular, progression of VFs was observed in 18 Italian patients (39.1%), and in 13 French patients (28.9%).
Considering the 2 series together, 53 patients (58.2%) remained free from VF during the study period; baseline fractures remained stable in 7 (7.7%) patients, whereas a VF progression was seen in 31 (34.1%) patients (Table 3). Moreover, the total number (37) of VFs at baseline (22 G1, 9 G2, 6 G3) increased to 113 after treatment (38 G1, 42 G2, 33 G3). The distribution of VF severity and SDI before and after mitotane with/without chemotherapy is given in Fig. 1. In particular, the proportions of mod- erate and severe VFs were 5.5% and 4.4% at baseline and 11% and 15.4% after mitotane. A worsening in SDI was seen in 18 (39.1%) Italian patients and in 13 (28.9%) French ones. In the whole series, 34.1% of patients had a worsened SDI.
Conversely, in ACC patients not treated with mitotane there was only 1 new fracture in the follow-up, and the in- crease in the proportion of patients with vertebral fractures was not statistically significant (P = . 50) (Table 3). In the BC patient subset, the treatment with AIs led to a statistically sig- nificant rise in the proportion of patients with at least 1 VF (13.5% vs 20.2%, P = . 04). Moreover, 13 patients developed new VFs (7.4%) and 5 patients had worsened VFs (2.8%). Figure 1 gives the distribution of VF severity and SDI before and after AIs in patients with BC. The proportions of mod- erate and severe VFs were 5.6% and 0.6% at baseline and 8.4% and 1.7% after AI therapy and 11.9% of patients had a worsened SDI (Table 3).
| VFs | No | Yes | P value |
|---|---|---|---|
| Age at mitotane start, N/Tot (%) | .004 | ||
| <48 years | 51/112 (45.5) | 6/112 (5.4) | |
| ≥48 years | 37/112 (33.0) | 18/112 (16-1) | |
| Sex, N/Tot (%) | .05 | ||
| Male | 29/112 (25.9) | 13 (11.6) | |
| Female | 59/112 (52.7) | 11 (9.8) | |
| BMI,N/Tot (%) | .07 | ||
| <24 | 37/88 (42.0) | 7/88 (8.0) | |
| ≥24 | 30/88 (34.1) | 14/88 (15.9) | |
| Cortisol excessª, N/Tot (%) | .11 | ||
| Yes | 44/112 (39.3) | 16/112 (14.3) | |
| No | 44/112 (39.3) | 8/112(7.1) | |
| Menopausal status, N/Tot (%) | .62 | ||
| Yes | 33/66 (50.0) | 6/66 (9.1) | |
| No | 23/66 (34.8) | 4/66 (6.1) |
Abbreviation: VF, vertebral fractures.
“At the time of starting mitotane therapy.
Risk Factors of VF Progression in ACC Patients Receiving Mitotane Therapy
At univariate analysis, the following baseline characteristics: age ≥48 years, BMI ≥24, and the presence of a VF were associ- ated with an increased risk of vertebral fractures progression. Both the presence of baseline VFs and BMI maintained an in- dependent association at multivariate analysis (OR 4.2, 95% CI 1.3-12.9, P = . 01; and OR 2.6, 95% CI 1.0-7.1, P = . 05, respectively) (Table 4).
Relationship Between VF Progression and Patient Outcome
Among the 72 metastatic patients, 28 (38.9%) had VF pro- gression after treatment. VF progression was associated with a poorer survival (median 20.9 vs 41.5 months, HR 0.50, 95% CI 0.26-0.95, P = . 032) (Fig. 2).
Discussion
This multicentric, retrospective study was designed to obtain data on the impact on bone fragility of systemic treatment administered in patients with ACC. Patients with ACC under- going mitotane with/without chemotherapy from 2 reference centers for this rare disease were included in the study. We also evaluated a control group of patients with ACC not re- ceiving mitotane therapy and a series of patients with BC undergoing aromatase inhibitors, a treatment known to be associated with an increased frequency of fragility fractures.
This study demonstrates for the first time a progression of VFs in 34% of patients with ACC treated with mitotane during a median follow-up period of 30 months. A recent multicenter, multinational, retrospective study showed that bone metastases in ACC patients are associated with high risk of adverse skeletal related events (23). In this patient series without bone metastases, we showed that oncological treat- ment may also contribute to increased bone fragility and elevated fracture risk. The Italian and French patients were similar in terms of sex distribution and BMI at baseline con- ditions; however, Italian patients were older and had a greater proportion of menopausal women than the French counter- part. With regard to tumor characteristics, ACCs in the Italian population were more advanced and less frequently hormone secreting than in the French one. Consequently, a greater proportion of Italian patients received chemotherapy in as- sociation with mitotane. These differences notwithstanding, a significant progression of VFs was demonstrated in both series considered separately.
About 23% of patients of patients treated with mitotane had at least 1 VF at baseline. Although this proportion is similar to the VF frequency in the general population of healthy indi- viduals (men and women) ≥50 years age (24), it was superior to that in the control patients with ACC who did not receive mitotane. Most of the patients treated with mitotane had ad- vanced disease, and this condition, even in the absence of bone metastases, predisposes for higher bone turnover (25). The fre- quency of VFs consistently increased in patients treated with mitotane with/without chemotherapy (42%) but not in un- treated patients. Mitotane therapy was also associated with a consistent increase in VF severity: grade 2-3 VFs according to the Genant scale increased from 40.5% at baseline to 66.4% after treatment and this observation is noteworthy, since mod- erate-severe VFs are clinically relevant (26). It is known that
| ACC patients treated with Mitotane ± chemotherapy | ACC patients not treated with Breast cancer patients treated mitotane with AI | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Italian patients | French patients IT+FR patients | ||||||||||
| Baseline | After M ± CHT | Baseline | After M ± CHT | Baseline | After M ± CHT | Baseline | After | Baseline | After AI | ||
| VFs, N/Tot (%) | |||||||||||
| No VFs | 33/46 (71.7) | 24/46 (52.2) | 37/45 (82.2) | 29/45 (64.4) | 70/91 (76.9) | 53/91 (58.2) | 18/21 (85.7) | 17/21 (80.9) | 154/176 (87.5) | 141/176 (80.1) | |
| VFs | 13/46 (28.3) | 22/46 (47.8) | 8/45 (17.8%) | 16/45 (35.6) | 21/91 (23.1) | 38/91 (41.8) | 3/21 (14.3) | 4/21 (19.1) | 22/176 (12.5) | 35/176 (19.9) | |
| P.04ª | P.04ª | P | .005ª | P | .50ª | P | .04ª | ||||
| New VFs, N/Tot (%) | 17/46 (36.9) | 13/45 (28.9) | 30/91 (32.9) | 1/21 (4.7) | 13/176 (7.4) | ||||||
| Worsened VFs, N/Tot (%) | 4/46 (8.7) | 2/45 (4.4) | 6/91 (6.6) | 0/21 (0.0) | 5/176 (2.8) | ||||||
| Both new and worsened | 3/46 (6.5) | 2/45 (4.4) | 5/91 (5.5) | 0/21 (0.0) | 2/176 (1.1) | ||||||
| VFs, N/Tot (%) | |||||||||||
| Stable VFs, N/Tot (%) | 4/46 (8.7) | 3/45 (6.7) | 7/91 (7.7) | 3/21 (14.3) | 19/176 (10.8) | ||||||
| SDI,mean (±SD) | 0.89 (±3.16) | 2.20 (±4.63) | 0.38 (±0.91) | 2.67 (±5.29) | 0.64 (±2.34) | 2.43 (±4.94) | 0.19 (±0.51) | 0.29 (±0.64) | 0.25 (±0.74) | 0.39 (±0.95) | |
| P.03 | P.03 | P | .002 | P.33 | P.0001 | ||||||
| SDI ≥2, N/Tot (%) | |||||||||||
| No | 40/46 (87.0) | 31/46 (67.4) | 40/45 (88.9) | 31/45 (68.9) | 80/91 (87.9) | 62/91 (68.1) | 20/21 (95.2) | 19/21 (90.5) | 161/176 (91.5) | 156/176 (88.6) | |
| Yes | 6/46 (13.0) | 15/46 (32.6) | 5/45 (11.1) | 14/45 (31.1) | 11/91 (12.1) | 29/91 (31.9) | 1/21 (4.7) | 2/21 (9.5) | 15/176 (8.5) | 20/176 (11.4) | |
| P.02 | P.02 | P .001 | P.10 | P | .24 | ||||||
| Worsened SDI, N/Tot (%) | 18/46 (39.1) | 13/45 (28.9) | 31/91 (34.1) | 1/21 (4.7) | 21/176 (11.9) | ||||||
Abbreviations: Pt, patients; VFs, vertebral fractures; CHT, chemotherapy. @One-tailed chi-square.
A
ACC PATIENT
B BREAST CANCER PATIENT
No VFs
Mild
Moderate
Severe
No VFs
Mild
Moderate
Severe
76,9
86,5
79,8
58,2
13,2
15,4
15,4
5,5
4,4
11
7,3
5,6
10,1
0,6
8,4
1,7
VFS AT BASELINE (% PATIENTS)
VFS AFTER AI (% PATIENTS)
VFS AT BASELINE (% PATIENTS)
VFS AFTER AI (% PATIENTS)
C
SDI IN ACC PATIENT
D
SDI IN BREAST CANCER PATIENTS
SDI<2 2≤SDI<4
SDI≥4
SDI<2 2≤SDI<4
SDI≥4
88
91
89
68
15
17
10
8
0
N
1
~
SDI AT BASELINE (% PATIENTS)
SDI AFTER AI (% PATIENTS)
SDI AT BASELINE (% PATIENTS)
SDI AFTER AI (% PATIENTS)
AI administration in women with BC is associated with an increased risk of bone fragility and fractures, and bone loss preventive therapy with bisphosphonates or denosumab is cur- rently recommended by international guidelines in this setting (16, 27, 28). The absolute increase in VF after AI in patients with BC evaluated in this study (+6.7%) was lower than that observed in ACC patients treated with mitotane (+18.7%), and VF progression occurred in 2.8% vs 6.6% of patients, re- spectively. This observation is relevant and provides a measure of the considerable deterioration of bone health observed in patients on mitotane therapy.
We also performed some exploratory analyses to evaluate the impact of other well-known parameters associated with
bone fragility on the fracture risk of the patients included in the study. At baseline, only age and sex were associated with the presence of VFs. Other bone fragility parameters such as BMI, menopause, and cortisol hypersecretion at diag- nosis failed to show a significant relationship. Older age and the presence of at least 1 VF at baseline significantly correl- ated with an increased risk of VF progression after mitotane treatment in univariate analysis. The presence of fractures at baseline maintained the statistical significance in multivariate analysis while age just failed to enter the model. These data are consistent with what is observed in postmenopausal osteopor- osis where both age and history of previous fractures strongly predict fracture risk regardless of bone mineral density (29).
| VF progression | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| Yes | No | OR (95% CI) | P value | OR (95% CI) | P value | |
| Age, N/Tot (%) | ||||||
| <48 years | 9/31 (29.0) | 35/60 (58.3) | 1 | .010 | 1 | .07 |
| ≥48 years | 22/31 (71.0) | 25/60 (41.7) | 3.4 (1.4-8.7) | 2.5 (.9-7.0) | ||
| Sex, N/Tot (%) | ||||||
| Male | 12/31 (38.7) | 24/60 (40.0) | 1 | .90 | ||
| Female | 19/31 (61.3) | 36/60 (60.0) | 1.1 (0.4-2.6) | |||
| BMI, N/Tot (%) | ||||||
| <24 | 10/31 (32.2) | 23/57 (40.4) | 1 | .02 | 1 | .05 |
| ≥24 | 21/31 (67.8) | 34/57 (59.6) | 3.1 (1.2-7.8) | 2.6 (1.0-7.1) | ||
| Menopausal status (total number of patients 51), N/Tot (%) | ||||||
| Yes | 14/18 (77.8) | 18/33 (54.5) | 2.9 (0.8-10.8) | .11 | ||
| No | 4/18 (22.2) | 15/33 (45.5) | 1 | |||
| Mitotane in range, N/Tot (%) | ||||||
| Yes | 18/31 (58.1) | 39/57 (68.4) | 1 | .33 | ||
| No | 13/31 (41.9) | 18/57 (31.6) | 1.6 (0.6-3.9) | |||
| Steroid replacement dose, N/Tot (%) | ||||||
| ≤62.5 mg/day | 18/31 (58.1) | 39/60 (65.0) | 1 | .52 | ||
| >62.5 mg/day | 13/31 (41.9) | 21/60 (35.0) | 1.3 (0.6-3.3) | |||
| Chemotherapy, N/Tot (%) | ||||||
| Yes | 23/31 (74.2) | 37/60 (61.7) | 1.8 (0.7-4.7) | .23 | ||
| No | 8/31 (25.8) | 23/60 (38.3) | 1 | |||
| VFs at baseline, N/Tot (%) | ||||||
| Yes | 14/31 (45.2) | 7/60 (11.7) | 6.2 (2.2-18.0) | .001 | 4.2 (1.3-12.9) | .01 |
| No | 17/31 (54.8) | 53/60 (88.3) | 1 | 1 | ||
Overall Survival
Strata
VFs stability = = VFs progression
1.00-
Survival probability
0.75
0.50
0.25
0.00
0
12
24
36
48
60
Time (months)
Number at risk by time
VFs stability 44
37
27
17
7
4
VFs progression 28
19
7
4
2
1
However, in this series, high BMI appeared to be associated with an increased fracture risk after mitotane therapy and this is the opposite of what is observed in postmenopausal osteoporosis where low BMI is an independent risk factor (30, 31). The association between adiposity and bone fra- gility is complex (32). On one hand, obesity has a protective role in relation to the higher concentrations of estrogens due to higher aromatase activity, on the other hand it is as- sociated with detrimental effects on bone quality via several mechanisms, including alteration of bone-regulating hor- mones, increased oxidative stress and inflammation, and al- tered bone cell metabolism (32). In a recent cross-sectional study, elevated fat body mass was found to have a direct
relationship with fracture risk in women under AI therapy (19). A plausible mechanism is that AIs induce a profound inhibition of estrogen synthesis leading to a loss of estrogen protection against fragility-related fracture and allowing the deleterious effect of adiposity to prevail. Mitotane has been shown to inhibit the aromatase enzyme (33) and, similarly to what we observed in women with BC under AIs, this mech- anism may explain the correlation between high BMI and VF. Another possible alternative is that the deleterious effect of adipose tissue on bone quality in patients with high BMI may be synergistic with steroid supplementation associated with mitotane therapy. However, the dose of steroids did not show any correlation with VF and this suggests that steroid supple- mentation does not play a major role on the bone fragility of patients on mitotane therapy.
Finally, the present study also showed that, in patients with advanced ACC without overt bone metastases, the oc- currence of VFs was associated with poorer prognosis. This observation is in line with what observed both in the general population (34) and in cancer patients undergoing specific antineoplastic therapy (35).
The relatively high number of patients enrolled and the sig- nificant increase in the number and severity of VFs, which oc- curred after treatment both in the exploratory and validation series, are strengths of this study. The retrospective nature and the different observation period to which patients were sub- jected are the main limitations.
In conclusion, this study demonstrated for the first time that ACC patients who undergo mitotane therapy are at high
risk of developing fragility fractures. Previous fractures and high BMI are independent risk factors. These data should be taken into consideration in order to adopt appropriate pre- ventive measures, such as the prescription of bone resorption inhibitors.
Financial Support
This work was supported in part by Fondazione Beretta, Brescia, Italy.
Disclosure Summary
A.B. personal fees from Novartis, AAA, Janssen, Ipsen, Astellas, Amgen and research funds to the Institution from Astellas, Sanofi, Janssen, outside the submitted work. H.J. personal fees from Pfizer, AAA, outside the submitted work. L.L. personal fees from EISAI, Bayer, outside the sub- mitted work. M.T. grants from HRA RARE DISEASES, per- sonal fees from HRA RARE DISEASES, outside the submitted work. D.C. travel grant from Fondazione Beretta. The other authors have nothing to disclose.
Data Availability
Some data generated and analyzed during this study are in- cluded in this published article.
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