Combination Chemotherapy in Advanced Adrenocortical Carcinoma

Fassnacht, Martin; Terzolo, Massimo; Allolio, Bruno; Baudin, Éric; Haak, Harm R.; Berruti, Alfredo; Welin, Staffan; Schade‐Brittinger, Carmen; Lacroix, André; Jarząb, Barbara; Sørbye, Halfdan; Torpy, David J.; Stepan, Vinzenz; Schteingart, D.E.; Arlt, Wiebke; Kroiß, Matthias; Leboulleux, Sophie; Sperone, Paola; Sundín, Anders; Hermsen, I G C; Hahner, Stefanie; Willenberg, Holger S.; Tabarin, Antoine; Quinkler, Marcus; Fouchardière, Christelle De La; Schlumberger, Martin; Mantero, Franco; Weismann, Dirk; Beuschlein, Felix; Gelderblom, Hans; Wilmink, Hanneke; Sender, Monica; Edgerly, Maureen; Kenn, W.; Fojo, Tito; Müller, Hans‐Helge; Skogseid, Britt

doi:10.1056/nejmoa1200966

Cited by 724 publications

(563 citation statements)

References 35 publications

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“…Additional findings of our study that may have an impact on practice are that mitotane concentrations can be used as a factor predicting the response to treatment, and that the dosing schedule used at the initiation of mitotane treatment is less important than striving for reaching and maintaining target mitotane levels during adjuvant therapy. This piece of evidence may help in structuring an articulated systemic treatment of ACC that remains challenging as the rarity of the disease hampered the development of effective therapeutic options beyond surgery (33).…”

Section: Discussionmentioning

confidence: 99%

Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection

Terzolo

Baudin

Ardito

et al. 2013

European Journal of Endocrinology

122

109

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Context: Mitotane plasma concentrations R14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting. Objective: To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations R14 mg/l vs patients who did not. Design and setting: Retrospective analysis at six referral European centers. Patients: Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14-20 mg/l. Main outcome measures: RFS (primary) and overall survival (secondary). Results: Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22-0.79; PZ0.007), while the risk of death was not significantly altered (HR: 0.59, PZ0.20). Grades 3-4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity. Conclusions: Mitotane concentrations R14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.

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Section: Discussionmentioning

confidence: 99%

Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection

Terzolo

Baudin

Ardito

et al. 2013

European Journal of Endocrinology

122

109

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“…The starting point for this preclinical study was our recent observation of active internalization of liposomes by Control ( NCIh295 and SW-13 cells (Hantel et al 2012), which indicated that liposomally encapsulated drugs could represent an interesting treatment option specifically advantageous for treating tumors of adrenocortical origin. As two components of the clinically utilized EDP-M scheme (Fassnacht et al 2012), doxorubicin and cisplatin, are available as sterically stabilized liposomal formulations, we replaced these free agents with their liposomal variants. Although successful liposomal encapsulation has also been described for etoposide (Sengupta et al 2000, Sistla et al 2009 is not yet available as a commercial preparation.…”

Section: Discussionmentioning

confidence: 99%

“…Leukopenia is one of the dose-limiting side effects of the classical Berruti (EDP-M) protocol (Berruti et al 2005) and further commonly observed serious adverse effects associated with doxorubicin or cisplatin include cardiotoxicity and nephrotoxicity (Fassnacht et al 2012). Liposomal encapsulation of cisplatin (Boulikas 2004, Devarajan et al 2004) and doxorubicin (Harrington et al 2002, Huwyler et al 2008 has been shown to quench these drug-specific side effects.…”

Section: Discussionmentioning

confidence: 99%

“…However, these therapeutic agents in general result in only partial responses and complete remissions are rarely observed. Only recently, a prospective randomized interventional trial for late-stage ACC patients has been finalized to compare the most frequently administered therapeutic treatment schemes in a cross-over design: streptozotocin plus mitotane (Sz-M) vs etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M) (Fassnacht et al 2012). Within this study design, EDP-M resulted in higher response rates and longer progression-free survival in comparison with Sz-M.…”

Section: Introductionmentioning

confidence: 99%

“…Within this study design, EDP-M resulted in higher response rates and longer progression-free survival in comparison with Sz-M. Nevertheless, overall therapeutic efficacy was still dissatisfactory and treatment regimens were associated with severe and dose-limiting adverse effects (Fassnacht et al 2012). In recent years, different nanotechnological modifications have been used to improve classical chemotherapies by increasing therapeutic efficacy and diminishing side effects.…”

Section: Introductionmentioning

confidence: 99%

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Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model

Hantel¹,

Jung²,

Mussack³

et al. 2014

Endocrine-Related Cancer

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Owing to high relapse rates and early metastatic spread, prognosis in adrenocortical carcinoma (ACC) patients remains poor, highlighting the importance of developing new treatment alternatives for them. Recently, polychemotherapy regimens including etoposide, doxorubicin, and cisplatin together with mitotane (EDP-M) have been defined as the standard treatment for late-stage disease patients. Nevertheless, the administration of conventional cytostatic drugs is associated with severe and dose-limiting side effects. In an attempt to optimize existing clinical treatment regimens, in this study, we investigated the therapeutic efficacy of EDP-M in comparison with that of a paclitaxel-modified scheme (paclitaxel, doxorubicin, cisplatin plus mitotane (PDP-M)) in preclinical in vitro and in vivo models. In addition, based on an extraordinary uptake phenomenon of liposomes in ACC cells, we further evaluated liposomal variants of these protocols (etoposide, liposomal doxorubicin, liposomal cisplatin plus mitotane (LEDP-M) and nab-paclitaxel, liposomal doxorubicin, liposomal cisplatin plus mitotane (LPDP-M)). In vitro, PDP-M was more potent in the induction of apoptosis and inhibition of cell viability as well as cell proliferation than EDP-M. Following the administration of a single therapeutic cycle, we further demonstrated that LEDP-M and LPDP-M exerted significant antitumoral effects in vivo, which were not as evident upon EDP-M and PDP-M treatments. These results were confirmed in a long-term experiment, in which the highest and sustained antitumoral effects were observed for LEDP-M. In summary, liposomal cytostatic substances could represent a promising option that deserves testing in appropriate clinical protocols for the treatment of ACC patients.

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An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate

2019

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IMPORTANCE Approximately one-third of cancer drugs are approved based on response rate (RR)-the percentage of patients whose tumors shrink beyond an arbitrary thresholdtypically assessed in a single-arm study. OBJECTIVE To characterize RR end points used by the US Food and Drug Administration (FDA) for cancer drug approval. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of FDA-approved drug indications in oncology from 2006 to 2018. EXPOSURES Data related to cancer type, line of therapy (first-line, second-line, or third-or-later-line treatment for advanced/metastatic disease), type of FDA approval pathway, trial design, sample size, and level of innovation were extracted. MAIN OUTCOMES AND MEASURES The primary outcome was the RR used as the basis for FDA approval. The secondary outcome was rate of complete response. RESULTS Eighty-five indications for 59 cancer drugs were identified, 32 (38%) received regular approval, and 53 (62%) were granted accelerated approval. Twenty-nine (55%) accelerated approvals were later converted to regular approval. Of these, 6 (21%) approvals showed overall survival benefit, 16 (55%) later established progression-free survival benefit, and 7 (24%) continued to use RR but gained regular approval. The median RR among the 85 indications was 41% (interquartile range [IQR], 27%-58%). Among them, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%. The median complete RR for 81 participants was 6% (IQR, 2%-22%). The median sample size among studies leading to approval was 117 (IQR, 76-182; range, 18-1052 participants). Drugs with accelerated approval pending confirmatory data had lower RR compared with drugs that have completed most postmarketing efficacy requirements (median, 28%; IQR, 15%-50% vs median, 42%; IQR, 31%-58%; P = .02). CONCLUSIONS AND RELEVANCE Many cancer drugs approved on the basis of response rate offer numerically low or modest response rates. Most premarket studies accrue more than 100 patients. Some of these drugs could potentially be tested in premarket randomized clinical trials measuring directly end points that demonstrate clinical benefit.

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Combination Chemotherapy in Advanced Adrenocortical Carcinoma

Cited by 724 publications

References 35 publications

Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection

Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection

Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model

An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate

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