Patients with advanced adrenocortical carcinoma lived no longer when standard therapy was combined with three-agent chemotherapy, but had a significantly higher response rate and progression-free survival (PFS), results of a large multicenter study showed.
Overall survival improved by almost 3 months with etoposide-doxorubicin-cisplatin (EDP) chemotherapy plus mitotane when compared with mitotane plus streptozocin, but the difference did not achieve statistical significance. Mitotane, a steroid-sparing synthetic analog of the insecticide DDT, is the only drug currently approved for adrenocortical carcinoma therapy.
Median PFS increased from 2.1 to 5 months among patients randomized to EDP, and the response rate more than doubled.
The three-drug combination did not significantly increase toxicity compared with monotherapy, as reported online in the New England Journal of Medicine.
“Although a significant improvement in overall survival was not achieved with EDP plus mitotane as first-line therapy, this regimen had high anti-tumor efficacy as both first- and second-line therapy than did streptozocin plus mitotane,” Martin Fassnacht, MD, of University Hospital of Wurzburg in Germany, and co-authors concluded.
Adrenocortical carcinoma has an estimated incidence of 0.7 to two cases per one million population worldwide, but has a poor prognosis, including a 5-year survival <15% among patients with metastatic disease.
Tumor – adrenal
Adrenocortical carcinoma is a cancer of the adrenal glands.
Causes, incidence, and risk factors
Adrenocortical carcinoma is most common in children younger than 5 and adults in their 30s and 40s.
Adrenocortical carcinoma may be linked to a cancer syndrome that is passed down through families (inherited). Both men and women can develop this tumor.
Adrenocortical carcinoma can produce the hormones cortisol, aldosterone, estrogen, or testosterone, as well as other hormones. In women the tumor often releases these hormones, which can lead to male characteristics.
The cause is unknown. About 2 people per million develop this type of tumor.
During an international consensus conference in 2003, participants laid the groundwork for a clinical trial to compare the two most successful regimens discussed at the conference. EDP had led to objective responses in more than half of patients in a small clinical trial (Cancer 1998; 83: 2194-2200), and 36% of patients in another small trial had responded to streptozocin (Ann Oncol 2000; 11: 1281-1287).
From June 2004 through October 2009, investigators at 40 centers in 12 countries enrolled 304 patients with newly diagnosed inoperable adrenocortical carcinoma. Patients were randomized to open-label treatment with EDP or streptozocin (Zanosar), each paired with mitotane.
ZANOSAR (streptozocin) is indicated in the treatment of metastatic islet cell carcinoma of the pancreas. Responses have been obtained with both functional and nonfunctional carcinomas. Because of its inherent renal toxicity, therapy with this drug should be limited to patients with symptomatic or progressive metastatic disease.
ZANOSAR INTERACTIONS
ZANOSAR (streptozocin) may demonstrate additive toxicity when used in combination with other cytotoxic drugs. Streptozocin has been reported to prolong the elimination half-life of doxorubicin and may lead to severe bone marrow suppression; a reduction of the doxorubicin dosage should be considered in patients receiving ZANOSAR concurrently. The concurrent use of streptozocin and phenytoin has been reported in one case to result in reduced streptozocin cytotoxicity.
Treatment continued until disease progression or development of intolerable toxicity, at which point patients switched to the opposite therapy, as prespecified in the study design. As a result, the primary trial had an embedded investigation of second-line therapy.
The primary endpoint was overall survival, and secondary endpoints were PFS, objective response, and quality of life. Additionally, investigators sought to determine whether the mitotane blood level influenced survival.
The trial concluded with a trend toward improved survival in the EDP arm (HR 0.79, 95% CI 0.61 to 1.02, P=0.07). PFS was significantly greater in the EDP arm (P<0.001), as was the response rate (23.2% versus 9.2% for streptozocin–mitotane group, P<0.001).
The authors reported that 185 patients crossed over to second-line therapy, which was associated with a median PFS of 5.6 months with EDP versus 2.2 months with streptozocin.
Patients who did not crossover to second-line therapy had almost a four-fold higher median overall survival with EDP (17.1 months) than with streptozocin (4.7 months). The 12-month results showed that 26.1% of patients who received first-line EDP were alive without progression compared with 7.2% of the first-line streptozocin group.
In both groups, mitotane was started 1 week before randomized therapy. Patients who had a baseline mitotane blood level ≥14 mg/L (N=54) had a trend toward improved survival versus patients who had lower levels (HR 0.76, P=0.13).
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Quality of life scores did not differ between the groups, although only about half the patients completed questionnaires as requested.
The authors offered several possible explanations for the lack of survival benefit with EDP including poorer-than-expected patient prognosis, lower-than-expected treatment effect, and a dampening effect of second-line therapy on first-line results.
Different types of treatments are available for patients with adrenocortical carcinoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Three types of standard treatment are used:
Surgery
Surgery to remove the adrenal gland (adrenalectomy) is often used to treat adrenocortical carcinoma. Sometimes the nearby lymph nodes are also removed.
Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.
Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.
Mitotane may be used to treat adrenocortical carcinoma. Mitotane stops the adrenal cortex from making hormones and relieves symptoms caused by the hormones.
New types of treatment are being tested in clinical trials.
They also pointed out that the study population could be considered representative of the overall population of patients with advanced adrenocortical carcinoma so the findings should be generalizable.
Fassnacht disclosed relationships with HRA Pharma, OSI Pharma, Pfizer, and Ipsen. Co-authors disclosed relationships with HRA Pharma, Novartis, Bayer, Italfarmaco, Ipsen, Pierre Fabre, Janssen Cilag, AstraZeneca, Roche, Eisai, OxiGene, Mol Cel Endocrinology, Sanofi, Exelixis, Genzyme, and Merck.
Primary source: New England Journal of Medicine
Source reference: Fassnacht M, et al “Combination chemotherapy in advanced adrenocortical carcinoma” N Engl J Med 2012;
DOI:10.1056/NEJMoa1200966.
