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Two targeted therapies, sorafenib and the novel agent everolimus, have modest activity in patients with metastatic neuroendocrine cancers, according to a pair of phase II trial presentations.
Sorafenib (Nexavar) monotherapy produced an objective response rate (including minor responses) of 19% in a dual-cohort study of patients with islet cell carcinoma or carcinoid tumors, Dr. Timothy J. Hobday reported. At 6 months, 65% of patients were progression free, he added.
An angiogenesis inhibitor, sorafenib is approved for the treatment of advanced kidney cancer.
Sorafenib's targets include the enzyme RAF kinase and the vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGR)-beta signaling cascade.
"Many groups have shown overexpression of VEGF and PDGR and their receptors in neuroendocrine tumors, and Dr. [James C.] Yao's group at M.D. Anderson [Cancer Center] has shown that overexpression of VEGF is associated with inferior progression-free survival," said Dr. Hobday of the Mayo Clinic in Rochester, Minn.
He added that expression of the tumor proliferation antigen Ki-67 above 2% is associated with inferior outcome. "Thus, an agent that targets both angiogenesis and proliferation would be promising."
The carcinoid tumor cohort included 51 patients, and the islet cell carcinoma cohort numbered 42. The median ages were 60 years and 56 years, respectively.
Overall survival data were not mature, but 7% of the carcinoid tumor patients and 11% of those with islet cell carcinoma had confirmed partial responses.
In addition, Dr. Hobday said about half of carcinoid tumor patients had biochemical responses indicative of hormonal patterns that affect quality of life.
These gains came at a cost of significant toxicity, however.
"Despite dose reductions and drug holidays, two-thirds of the 93 patients went off trial because of adverse events or refusal of further therapy, and only one-third went off due to disease progression," Dr. Hobday said.
Grade 2 or higher adverse events included fatigue (39%), diarrhea (30%), hand-foot syndrome (28%), skin rash (22%), hypertension (22%), nausea (16%), and anorexia (15%).
In a discussion of the trial, Dr. Lee M. Ellis, said anti-VEGF therapy should become the foundation of combination therapies.
"Single-agent anti-VEGF therapy has activity in neuroendocrine tumors, and this is consistent across trials and centers," said Dr. Ellis of the University of Texas M.D. Anderson Cancer Center in Houston.
"However, the mTOR inhibitor people would say mTOR should be the foundation, but in any case we're moving forward with targeted therapies," he added. "As we do so, we need to be aware of toxicities."
Everolimus (RAD001/Certican), an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, also was the subject of a single-arm, dual-cohort trial.
Sponsored by Novartis, developer of everolimus, the study compared a daily dose of 5 mg (30 patients) to 10 mg (30 patients) in 60 patients with well-differentiated neuroendocrine tumors, both islet cell and carcinoid.
Equal numbers of men and women were enrolled between February 2005 and July 2006, and response was evaluated every 12 weeks, reported Dr. James C. Yao of the University of Texas M.D. Anderson Cancer Center in Houston. The two most common disease sites were the pancreas (29) and the small bowel (16).
All participants also received 30 mg once a month of depot octreotide (Sandostatin LAR).
The overall response rate was 20% (12) with the islet cell patients comprising two-thirds of the responders, according to Dr. Yao. At 24 weeks, 86% of the patients were progression free. Median progression-free survival was 59 weeks overall: 64 weeks in the carcinoid group and 50 weeks in the islet cell group. Disease was stabilized in 72% of the patients.
By everolimus dosage, the response rates were 13% for the 5-mg cohort and 27% in the 10-mg group. Progression-free survival was 50 weeks and 62 weeks, respectively.
Because of an incomplete balance between the islet cell and carcinoid groups, Dr. Yao said it cannot be determined whether the response difference was due to the drug dose or to the type of tumor being treated. A total of 11 patients remain in the study.
The most common adverse event was mild aphthous ulceration, with no statistically significant difference between the 5-mg and 10-mg dose. Grade 3-4 toxicities included thrombocytopenia (3), neutropenia (3), hypophosphatemia (5), hyperglycemia (4), hypoglycemia (2), hypokalemia (2), fatigue (6), diarrhea (6), aphthous ulcer (5), rash (3), and 1 each of anemia, hypertriglyceridemia, and bilirubin.
Although the combination was well tolerated and showed clear activity in this trial, it's too early to recommend that everolimus be added to depot octreotide in the treatment of low-grade neuroendocrine tumors, according to the discussant, Dr. Gary K. Schwartz.
"We need to await the outcomes of clinical trials comparing Sandostatin alone to Sandostatin plus RAD001. With one trial ongoing, we should see some data in another year or 2," said Dr. Schwartz of the Memorial Sloan-Kettering Cancer Center in New York City.
Hobday T.J. et al. MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. Abstract 4504.
Yao J.C. et al. Phase II study of RAD001 (everolimus) and depot octreotide (Sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNET). Abstract 4503.
Commentary |
What is the best therapy for a patient with metastatic neuroendocrine cancer? This is a question for which you will get many different expert opinions, usually based upon local experience and single-arm cohort experiences. Unlike many other solid tumors, recommendations about disease management reflect consensus views of experts who treat the disease, as opposed to randomized clinical trials. The uncommon incidence of neuroendocrine cancer, lack of clarity and consistency around the pathological reporting, and the heterogeneity of disease biology all further confound attempts to better define appropriate standards. In advanced disease there is clearly a role for debulking in selected patients either surgically or via embolization. Nonetheless, the unfortunate fact is that even with relatively indolent tumors, patients eventually succumb to advanced uncontrollable disease. The activity of streptozotocin-based systemic chemotherapy, particularly in pancreatic islet cell cancers, was described over a decade ago in trials done by Dr. Charles G. Moertel and others at the Mayo Clinic. Many patients do not respond or are not able to tolerate such therapy, however, and until recently little progress in systemic therapy was seen. As is demonstrated by these two studies, that situation is changing. The antivascular agents and the mammalian target of rapamycin (mTOR) inhibitors showed some level of activity in both these current abstracts and in other recent studies of agents against these targets. This has energized the field and encouraged several promising developments that will lead to better therapy for neuroendocrine cancer in the future. Several phase III trials of new targeted therapies are now underway; the National Cancer Institute has created a disease-specific task force for neuroendocrine cancer under the leadership of Dr. Lillian Siu from Princess Margaret Hospital in Toronto that brings together all the North American experts in the field; and the cooperative groups are about to open their first phase III study in neuroendocrine cancer evaluating the relative benefits of interferon and bevacizumab. It will be chaired by Dr. James Yao at the University of Texas M.D. Anderson Cancer Center in Houston. We will soon have better and more clearly defined answers for the question of "What is the best therapy for a patient with metastatic neuroendocrine cancer?" as a result of these initiatives. — Malcolm J. Moore, M.D.
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