Phase II Study of Capecitabine and Temozolomide for Progressive, Differentiated, Metastatic Neuroendocrine Cancers

Neuroendocrine tumor (NET) is a classification that has evolved over time to include a group of related tumors which all originate from neuroendocrine cells. This group includes carcinoid tumors, pancreatic endocrine tumors (PETs), catecholamine-secreting tumors (e.g. pheochromocytomas), medullary carcinoma of the thyroid and small cell lung cancer. Carcinoid tumors are mostly derived from serotonin-producing enterochromaffin cells, occuring most frequently in the gastrointestinal tract (67.5%) and the bronchopulmonary system (25.3%). Pancreatic endocrine tumors (PETs) arise from the several types of pancreatic islet cells, which manifest as insulinomas, somatostatinomas or glucagonomas. NETs are broadly classified as functional or nonfunctional, as determined by whether plasma hormone elevation and endocrine symptoms occur. NETs are classified into two groups: 1) rapidly growing anaplastic small cell cancers such as small cell lung cancer and small cell carcinomas of the GI tract and 2) slow growing, more differentiated NETs such as carcinoid and PET.

In total, an estimated 12,000 - 15,000 cases of NETs (not counting small cell carcinomas) are diagnosed in the United States annually. The incidence of carcinoid tumors alone is estimated to be 2 per 100,000 in the United States (5,400 cases/yr/U.S.). PETs are less common, with about 1,000 new cases per year in the United States. Carcinoids and PETs are potentially curable by surgical resection; the 5-year survival rates in patients with localized carcinoid is 78.2%. However, these tumors are frequently indolent in their growth and patients often present with unresectable or metastatic disease (80% of all cases). The hormonal symptoms that may accompany their disease, as exemplified by carcinoid syndrome, complicate the management of these patients. Hormonal therapy, namely octreotide, is used to relieve symptoms and has been reported to have a response rate of 1-5% by itself. Metastatic disease is associated with significantly worse prognosis; carcinoid patients with visceral metastases have a 5-year survival rate of 38.5%. Based on the efficacy of the combination of cisplatin and etoposide in treating small cell lung cancer, these agents have been explored in the treatment of pancreatic islet cell tumors and carcinoids. In general, etoposide-cisplatin regimens have poor response rates for the slow growing, differentiated NET group with an average response rate of 7-10%. Furthermore, these cisplatin-etoposide regimens have been associated with significant toxicities, including frequent severe neutropenia, ototoxicity, neurotoxicity and nephrotoxicity.

An Eastern Cooperative Oncology Group (ECOG) trial of patients with metastatic or unresectable progressive pancreatic islet cell tumors, including poorly and well-differentiated PETs, showed that a regimen of streptozocin and doxorubicin had a significantly superior objective response rate compared to a combination of streptozocin and fluorouracil (69 versus 45%, p=0.05). The study used a definition for objective response that included regression of the tumor mass, regression of malignant tumor causing hepatomegaly or a reduction in excessive hormone production. Streptozocin-doxorubicin was also significantly superior to streptozocin-fluorouracil in terms of median time to tumor progression and of median overall survival (2.2 versus 1.4 years, p=0.004). However, significant toxicity was associated with either streptozocin-based regimen with roughly 80% in either arm experiencing vomiting that lasted throughout the 5-day course of streptozocin per cycle. Additionally, Grade 3/4 leukopenia occurred in 25% of patients who received streptozocin-fluorouracil, with one treatment-related death secondary to leukopenia complicated by sepsis. Notably, streptozocin has significant renal toxicity causing significant proteinuria. Thus, the doubtful efficacy of streptozocin-based combinations and the significant associated toxicity has limited the role of cytotoxic chemotherapy in the treatment of differentiated NETs.

In the lab, the investigators have found that capecitabine (5-DFUR), an oral pro-drug for 5-fluorouracil (5-FU), and temozolomide were synergistic for induction of apoptosis in 2 human NET cell lines. The mechanism and pathways involved are under investigation, but it was found to be important for the synergism that temozolomide be exposed to the NET cell lines during the end of the capecitabine exposure. The team believes that the combination of temozolomide and capecitabine will prove to be an effective regimen. Our hypothesis is that the DNA damage induced by capecitabine by incorporation of 5-FdUTP into DNA and reducing thymidine pools by inhibition of thymidylate synthase via 5-FdUMP will synergistically potentiate the effect of temozolomide as an alkylator by reducing the repair activity of O6-alkylguanyl-alkyl-transferase (O6-AGAT). O6-AGAT is a DNA repair enzyme which removes temozolomide-alkylated groups from guanine. A 5-day regimen of temozolomide is vital to decreasing O6-AGAT levels by direct binding which leads to a suicide inactivation of O6-AGAT-mediated DNA repair. This saturates O6-AGAT after 23 days of temozolomide, thus allowing the last 23 days of dosing to induce alkylation of DNA and thereby induce apoptosis. The investigators found that cells with prior 5-FU exposure were more sensitive to the induction of apoptosis by temozolomide.

Another fundamental rationale and hypothesis which the investigators have developed into the synthesis of a novel regimen for NET is based upon cytokinetics and p53. NET are characteristically very slow growing, yet fatal, cancers with the great majority of them having wild type p53. Therefore, their drug resistance is probably not based upon mutational p53 causes because of the wild type p53 status but rather upon their slow cytokinetics. The best way to kill slow growing tumors with a long interval in G0 phase is with lipophilic alkylators (i.e. Temodar) and utilizing continuous exposure to antimetabolites such as Xeloda or continuous infusion 5-FU. Xeloda's half-life is 11 hrs so q 12 hr dosing is roughly equivalent to continuous infusion. The investigators believe that the hypothesis is correct and well grounded in pharmacologic and cell cycle principles.