乌鸦传媒

SAN FRANCISCO -- More than 90% of patients with neuroendocrine tumors had objective responses or stable disease when treated with an off-the-shelf chemotherapy doublet, results of a small study showed.

The combination of capecitabine (Xeloda) and temozolomide (Temodar) led to a median progression-free survival of almost 2 years among 28 patients, including more than 40 months in the subgroup of patients with pituitary tumors.

Overall survival continues to mature but the median has reached almost 2.5 years, , reported here at the Gastrointestinal Cancers Symposium (GiCS).

"[The combination] is associated with significant response rates and ongoing progression-free survival greater than 22.2 months," Fine said during a GiCS press briefing. "Overall survival data continue to mature. Significant responses were observed in carcinoid and pituitary tumors, both of which are traditionally chemoresistant. We have observed minimal toxicity."

Neuroendocrine tumors are a heterogeneous group of tumors, the most common of which being carcinoid tumors, followed by pancreatic neuroendocrine tumors (which the late Steve Jobs had), other neuroendocrine tumors, and pituitary tumors.

Small-cell neuroendocrine tumors tend to be chemoresponsive to chemotherapy, whereas well-differentiated tumors often demonstrate chemoresistance, reflected in an overall response rate of <10%, including <3% of carcinoid tumors.

Traditionally, octreotide (Sandostatin LAR) has been the standard of care for well-differentiated neuroendocrine tumors. More recently, the mTOR inhibitor everolimus (Afinitor) and the tyrosine kinase inhibitor sunitinib (Sutent) have demonstrated activity, associated with response rates <10% but stable disease rates as high as 60%.

Slow cytokinetic growth appears to be the principal mechanism of resistance in well-differentiated neuroendocrine tumors, said Fine. Therapies with activity in such tumors include external-beam radiation therapy, hormones, lipophilic alkylators, and continuous-infusion antimetabolites.

Prior exposure to the antimetabolite 5-fluorouracil has been shown to deplete thymidine, leading to increased cell-killing activity of temozolomide. The observation led to a phase II trial of Temozolomide and the oral fluoropyrimidine capecitabine -- a combination known as CAPTEM -- in patients with well-differentiated neuroendocrine tumors.

Fine reported interim data from an ongoing trial of the two-drug combination. Eligibility criteria for the trial include evidence of reduced growth kinetics (Ki-67≤20%), progressive disease in response to Sandostatin LAR, and radiographic evidence of tumor enlargement prior to enrollment. The trial had no limitations on prior therapy, with the exception of 5-FU and temozolomide.

The 28 patients included in the analysis comprised 12 patients with carcinoid tumors (10 typical, two atypical), 11 with pancreatic neuroendocrine tumors, three with pituitary tumors, and two with medullary thyroid tumors. Overall, 11% of the patients achieved complete responses, 32% had partial responses, and 54% had stable disease during treatment with the capecitabine-temozolomide combination. Two patients with pancreatic neuroendocrine tumors had progressive disease as best response (3%).

In the carcinoid subgroup, 41% of patients achieved objective response, including one complete response, and 58% had stable disease. Median PFS exceeded 23.9 months, and overall survival exceeded 31.5 months.

In the subgroup of patients with pancreatic neuroendocrine tumors, 36% achieved partial responses and 55% had stable disease. Median PFS was about 20 months and overall survival more than 24 months.

Two of the three patients with pituitary tumors had complete responses, and the third patient had a partial response. PFS and overall survival have surpassed 41.6 months.

"Pituitary tumors were extraordinarily sensitive to CAPTEM," said Fine. "End-stage patients who were intubated and on ventilators with pituitary masses had a 100% response rate," said Fine.

The two patients with medullary thyroid tumors had stable disease, PFS of 22.8 months, and overall survival of 27.7 months.

Fine characterized toxicity associated with CAPTEM as "extraordinarily light." The most frequent grade 3/4 adverse events were lymphopenia (35%), hyperglycemia (6%, probably unrelated to therapy), thrombocytopenia (3%), and diarrhea (3%). No deaths or opportunistic infections have occurred, and no patient required hospitalization.

The trial, though small and ongoing, has yielded interesting results thus far, said press briefing moderator Smitha Krishnamurthi, MD.

"The CAPTEM regimen led to responses in neuroendocrine tumors that are typically resistant to chemotherapy, including five of 12 patients with carcinoid tumors," said Krishnamurthi, of University Hospitals Case Medical Center in Cleveland. "This regimen is being investigated versus temozolomide in a cooperative group trial of patients with pancreatic neuroendocrine tumors."

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