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EUROPEAN UROLOGY FOCUS Smoking and Urological Health
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Clinical Trial Update
Systemic Therapy in Locally Advanced or Metastatic Adrenal Cancers: A Critical Appraisal and Clinical Trial Update
Laura Ferrari, Mélanie Claps, Salvatore Grisanti, Alfredo Berruti *
Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Spedali Civili Hospital, Brescia, Italy
The management of patients with adrenocortical carcinoma (ACC) is difficult. Surgery is the mainstay of treatment. Mitotane and cytotoxic chemotherapy are currently the only systemic treatments available for locally advanced or metastatic ACC not amenable to surgery. Owing to the rarity of the disease, there was uncertainty for many years regarding the efficacy of mitotane and chemotherapy. Only recently an international task force demonstrated that long- term maintenance of mitotane levels >14 mg/dl is predic- tive of survival in patients with metastatic ACC [1] and that mitotane may be effective in the adjuvant setting according to a case-control study [2], supported by demonstration of the prognostic role of drug serum levels in this setting [3]. The most relevant finding was demonstration of the efficacy of chemotherapy in a multicenter, multinational, prospective randomized phase 3 trial (FIRM-ACT) trial [4]. In this trial, etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M) [5] was superior to streptozotocin plus mitotane (SZ-M) [6] in terms of response rate and progression-free survival (PFS). EDP-M also yielded better overall survival, without reaching statistical significance because of the crossover design whereby patients who progress on first-line treatment could receive the alterna- tive regimen.
All these data represent an important step forward in the management of this rare and challenging disease, but several issues remain unaddressed. (1) The combination of chemotherapy and mitotane is only supported by preclinical data showing a synergism between these two treatments [7] and by indirect comparison of results from case series or phase 2 trials [8]. (2) It has not been demonstrated that the efficacy of EDP-M is superior to that
of single-agent cisplatin plus mitotane, for which activity was confirmed in a multicenter phase 2 trial [9]. (3) ACC is a heterogeneous disease: although most patients with metastatic ACC die of disease progression within 1-2 yr, a subset of patients with more indolent disease may survive for longer. The best treatment approach should be tailored for each patient on the basis of tumor aggressiveness. EDP- M is the treatment mainstay for patients with aggressive disease (high tumor load, elevated proliferative activity in the primary tumor or metastases [Ki-67 protein >10%], short time from diagnosis to the onset of metastatic disease, Cushing syndrome), but mitotane monotherapy may be a reasonable systemic option for those with more indolent disease. Currently available prognostic factors [10,11] cannot discriminate between these two patient populations. More importantly, in the FIRM-ACT trial [4] the response rate was 23% for the EDP-M regimen compared to 9% for SZ-M, and the 5-yr survival was ~18% for patients initially treated with EDP-M compared to ~7% for SZ-M. Overall these results are modest, but they suggest that there is a small patient subset for whom EDP-M could confer a long-term benefit. In fact, we observed a complete pathologic response after surgical resection of postchemotherapy (EDP-M) residual disease in one patient who has possibly been cured [12]. Identifi- cation of a molecular signature that predicts EDP-M efficacy is of paramount importance so that this toxic regimen is only administered to patients who are predicted to obtain a long-term benefit.
As for other tumors, targeted therapy is the future for ACC management. Molecular characterization of ACC identified the insulin growth factor-1 receptor (IGF1R)
E-mail address: alfredo.berruti@gmail.com (A. Berruti).
| Study and year | Drug | Target | Setting | Phase | Patients (n) | Results |
|---|---|---|---|---|---|---|
| 2007 [15] | Gefitinib | EGFR | Pretreated advanced ACC | 2 | 19 | No disease response |
| 2008 [16 | Erlotinib + gemcitabine | EGFR | Pretreated advanced ACC | 2 | 10 | 1 minor response |
| 2010 [17] | Bevacizumab + capecitabine | Angiogenesis | Advanced ACC | 2 | 10 | No disease response |
| 2012 [18] | Sunitinib | Angiogenesis | Pretreated advanced ACC | 2 | 36 | SD >4 mo in 5 patients |
| 2012 [19] | Sorafenib and weekly paclitaxel | Angiogenesis | Pretreated advanced ACC | 2 | 10 | PD in all patients |
| 2014 [20] | Axitinib | Angiogenesis | Pretreated advanced ACC | 2 | 13 | No disease response |
| 2010 [21] | Figitumumab | IGF1R | Pretreated advanced ACC | 1/2 | 14 | SD ≥3 mo in 6 patients |
| 2011 [22] | Cixutumumab + temsirolimus | IGF1R + mTOR | Advanced tumors | 1/2 | 10 ACC | SD ≥8 mo in 4 patients |
| 2013 [14] | Cixutumumab + temsirolimus | IGF1R + mTOR | Pretreated advanced ACC | 2 | 26 | SD >6 mo in 11 patients |
| 2015 [13] | Linsitinib (vs placebo) | IGF1R | Pretreated advanced ACC | 3 | 139 | No difference in PFS or OS |
| EGFR = epidermal growth factor receptor; ACC = adrenocortical carcinoma; SD = stable disease; PD = progressive disease; IGF1R = insulin growth factor-1 receptor; PFS = progression free survival; OS = overall survival. | ||||||
signaling cascade and Wnt signaling through ß-catenin as major drivers and specific targets for antineoplastic therapies. In addition, since ACC comprises highly vascu- larized tumors and the epidermal growth factor receptor (EGFR) is frequently expressed, there is also a rationale for the use of antiangiogenic drugs and drugs targeting the EGFR. Several phase 2 trials have tested the activity of EGFR inhibitors and angiogenesis inhibitors either alone or in combination with cytotoxic drugs. The results were disappointing: none of the drugs or combinations exhibited activities that warrant further development (Table 1). With respect to IGFR inhibitors, a phase 3 trial comparing linsitinib to placebo observed no advantages of this small molecule in terms of progression-free and overall survival [13]. With regard to angiogenesis inhibitors, sunitinib, which targets the vascular endothelial growth factor receptor among other targets, had modest antitumor effects in a phase 2 trial [18]. The only potentially interesting data for disease stabilization were obtained for the combination of cixutumumab (monoclonal antibody targeting the IGFR) and temsirolimus (mTOR inhibitor); however, these prom- ising data need to be confirmed in a randomized prospective trial [14]. In summary, mitotane and EDP-M are the only therapies with demonstrated efficacy in advanced ACC. Prognostic and predictive factors are needed to identify patients who could obtain the best benefit from these treatments. Despite the strong rationale for their use, molecular targeted therapies have yet to exhibit efficacy in ACC.
Conflicts of interest: The authors have nothing to disclose.
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