Targeted drugs may help in rare adrenal cancer

Targeted drugs may help in rare adrenal cancer

9/12/2013

Adrenocortical carcinoma, a rare and dangerous endocrine malignancy with no effective drug treatments, may respond to targeted therapies, early studies suggest.

Preliminary trials of such treatments in patients with adrenocortical carcinoma (ACC) have been small and largely disappointing, but recent advances in the understanding of the molecular pathogenesis of the disease may lead to more effective targeted drugs, Yunze Xu of Ruijin Hospital, Shanghai, China, and colleagues wrote in the journal Clinical Endocrinology.

The researchers reviewed clinical trials testing novel therapies for ACC, which accounts for less than 5% of adrenal tumors found incidentally (incidentalomas).

ACC can develop at any age, but it is most commonly diagnosed in children under 5 years of age and in adults between the ages of 40 and 50. About 60% of patients with ACC present with symptoms of adrenal steroid excess, and rapidly progressing Cushing syndrome is the most frequent presentation.

"Complete surgical resection is virtually the sole hope of cure in ACC, but recurrence occurs in 60% to 80% of patients after so-called complete resection," the researchers wrote. "Those patients with apparently localized tumors at diagnosis frequently develop metastatic disease within 6 to 24 months of surgical resection."

About 30% to 40% of patients show evidence of metastatic disease when they are first diagnosed, and are not candidates for surgery.

Most adrenocortical carcinomas are sporadic, but some also occur as a component of hereditary tumor syndromes, including the Li-Fraumeni syndrome (LFS), Beckwith-Wiedemann syndrome, multiple endocrine neoplasia 1, Carney complex, and Lynch syndrome.

Advances in the understanding of the molecular pathogenesis of ACC have been made based on studies of gene expression profiling and of these genetic syndromes and have led to small clinical trials testing no fewer than seven different targeted therapies.

Drugs and drug combinations that have been the subjects of clinical trials include:

• Bevacizumab plus capecitabine: The rationale for the combination therapy was inhibition of VEGF signaling and promotion of cytotoxic response, but no responses were seen among the 10 study participants with advanced disease.
• OSI-906: In a phase III study of the small-molecule tyrosine kinase IGF-1R inhibitor, five of 16 patients with advanced ACC showed partial tumor responses or stable disease.
• Erlotinib plus gemcitabine: The combination was used to inhibit EGFR signaling and elicit cytotoxic response. Ten patients with advanced disease were treated, but only one experienced a minor response, leading the researchers to conclude that the treatment has "limited to no activity" in advanced ACC.
• Figitumumab: Eight of 14 patients with refractory ACC treated with the anti-IGF-1R monoclonal antibody had stable disease, leading the researchers to conclude that the drug warrants further consideration in the treatment of ACC.
• Gefitinib: The EGFR signal-inhibiting drug showed no activity in (no responses) in the phase II trial including 19 patients with unresectable ACC.
• Thalidomide: The anti-angiogenic compound that inhibits the activity of bFGF-2 elicited a partial response when used to treat a single patient.
• Imatinib: No responses were seen in four ACC patients with either c-KIT or PDGF-positive tumors.

The trial of the monoclonal antibody figitumumab would appear to be the most promising, but no relevant clinical activity was demonstrated. This led Xu and colleagues to conclude that the findings are "somewhat less encouraging" than they may seem.

The phase I study of the small-molecule tyrosine kinase IGF1R inhibitor OSI-906, which is made by Astellas Pharma, demonstrated one partial response and four patients with stable disease.

Xu and colleagues noted that an international phase III trial of OSI-906 has completed its accrual goal of 135 patients.

"The results of this trial are eagerly awaited," they wrote. "Early preclinical data suggested the activity of IGF-1R-targeted drugs in ACC, but the initial enthusiasm quickly encountered several challenges and disappointment."

Despite the setbacks, the researchers concluded that recent advances "offer the hope that targeted therapies can be developed and successfully implemented."

"It is acknowledged that improving the clinical care of patients with ACC will require a combination of basic science, translational research, and clinical trials," they wrote.

 

Source: MedPage Today: http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/43321