Initial results of a study comparing two of the most successful combination chemotherapy treatments for advanced adrenal cancer suggest the possibility of a new treatment standard. Patients treated with etoposide, doxorubicin, and cisplatin (EDP) with mitotane had slightly better outcomes than patients treated with streptozocin with mitotane, according to the research, conducted at 40 cancer specialty centers across 12 countries (NEJM 2012;366:2189–2197).
“Adrenal cancer is a serious disease with short life expectancy. But, the combination of the four drugs seems to be somewhat better than the combination of the two drugs,” one of the researchers, David E. Schteingart, MD, Professor Emeritus of Internal Medicine at University of Michigan, said in an interview. “This was statistically significant because the study was adequately powered.”
The study found that EDP plus mitotane as a first-line therapy versus streptozocin plus mitotane resulted in higher rates of objective tumor response (23.2% vs. 9.2%) and increased progression-free survival (5.3 vs. 2.1 months), and saw more patients without disease progression at 12 months (26.1% vs. 7.2%).
Mitotane, the only drug currently approved for treatment of adrenocortical carcinoma (used both for advanced disease and adjuvant therapy) is not effective on all adrenocortical carcinomas, so additional tumor-killing drugs (like streptozocin or the EDP combo) are often added to treatment protocols, he explained. Current treatment strategies have previously been based on retrospective studies and small Phase II trials.
This study was the largest prospective trial of adrenal cancer patients comparing the two therapies, he said. “The problem is that because adrenal cancer is very rare, it was difficult to get enough power to the study to be able to do statistical analysis for comparing the two protocols. For the first time there is prospective randomized data, which is the gold standard of any clinical trial.”
An international adrenal cancer consortium met in 2003 at the University of Michigan to investigate treatment regimens and developed the trial, which recruited 304 patients from 12 countries at 40 specialized centers for adrenocortical carcinoma treatment. None of the trial's patients had been given other cytotoxic drugs and none were surgery candidates. All were randomly assigned to receive EDP-plus-mitotane or streptozocin-plus-mitotane as a first-line therapy.
Self-reported quality-of-life scores were consistent between the two groups. And, because at one year, 26.1 percent of the EDP-mitotane group were alive without disease progression, versus 7.2 percent of the streptozocin-mitotane group, the researchers concluded that EDP plus mitotane reduced the risk of death by 21 percent, compared with the streptozocin-plus-mitotane protocol.
Though previous research suggests that streptozocin may have fewer side effects than the EDP combination, Schteingart says that extending life expectancy is one of the most important factors in choosing one protocol over the other: “Adding the three others [EDP] to the protocol is more powerful than the streptozocin. The combination of the four drugs seems to be somewhat better than the combination of the two drugs, and switching people from one protocol to the other did not improve their life expectancy.”
But, he emphasized, more research is needed, because even the objective tumor responses seen with the EDP-plus-mitotane protocol were often not long-lasting, and life expectancy is still short with either treatment.
The next step in researching adrenal cancer treatments, he said, is investigating targeted therapies and better understanding which gene mutations are involved in adrenocortical carcinomas. Ongoing research suggests the insulin-like growth factor is overexpressed in adrenal cancer, particularly in malignant tumors, although initial trials of drugs targeting this mutation show only short-term effects.