• Objective response rate
  

• Overall response rate
  
• Functional response
  
• Toxicity
  
• Progression-free survival
  
• Overall survival
  
• Molecular markers predictive of response to chemotherapy
  
• Quality of life
  

OBJECTIVES:

Primary

• To determine the objective response rate in patients with neuroendocrine tumors treated with capecitabine and streptozocin with or without cisplatin.

Secondary

• To determine the overall response rate, including both objective and biochemical responses, to these regimens.
• To determine the functional response to these regimens.
• To determine the toxicity of these regimens.
• To identify the optimal drug doses in each regimen to be recommended for a subsequent phase III trial.
• To determine the progression-free and overall survival of patients receiving these regimens.
• To determine the quality of life of these patients.
• To determine molecular markers predictive of response to chemotherapy.

OUTLINE: This is a multicenter study. Patients are stratified according to site of origin (known vs unknown primary site), prior antitumor treatment, tumor function (functional vs nonfunctional), and study center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive streptozocin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-21.
• Arm II: Patients receive cisplatin IV over 2 hours on day 1 and streptozocin and capecitabine as in arm I.

In both treatment arms, treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients complete the EORTC QLQC30 questionnaire and EORTC QLQ-GI.NET21 module for quality-of-life assessment at baseline, every 9 weeks during treatment, and at 12 weeks post-treatment.

Tumor tissue is obtained at baseline and assessed for Ki67 and mitotic index. Novel tissue-specific transcription factors (e.g., CDX2) are also assessed. Blood samples are collected at baseline and 9 weeks and examined by DNA, RNA, and proteomic analysis.

After completion of study therapy, patients are followed every 12 weeks.

DISEASE CHARACTERISTICS:

• Histologically confirmed unresectable, advanced, and/or metastatic disease meeting one of the following types:

  • Gastroentero-neuroendocrine tumor of the foregut
  • Pancreatic neuroendocrine tumor
  • Neuroendocrine tumor of unknown primary
• Measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (the longest diameter) ≥ 20 mm by conventional CT scanning or ≥ 10 mm by spiral CT scan or MRI
• No bronchial neuroendocrine tumors (NETs) or other NETs where the primary site is situated in organs above the diaphragm (e.g., laryngeal and pharyngeal NETs)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• Hemoglobin ≥ 10 g/dL
• Platelet count ≥ 100,000/mm³
• WBC ≥ 3,000/mm³
• ANC ≥ 1,500/mm³
• Bilirubin ≤ 2 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 5 times ULN
• AST and ALT ≤ 5 times ULN
• GFR ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study therapy
• No other serious or uncontrolled illness that would preclude study participation
• No medical or psychiatric condition that would influence the ability to provide consent

PRIOR CONCURRENT THERAPY:

• At least 3 weeks since prior interferon therapy
• No prior systemic chemotherapy or chemotherapy administered as part of a chemo-embolization regimen, or for this condition
• No receptor-targeted radiolabeled therapy within the past 6 months
• No investigational agent within the past 4 weeks
• Prior and concurrent somatostatin analogues allowed provided symptoms are no longer controlled by this treatment or there is documented measurable disease progression on serial CT scans performed up to 6 months apart

• No palliative radiotherapy involving lesions used to measure disease

  • Palliative radiotherapy to regions not involved in measurement of disease allowed
• No other concurrent chemotherapy for this condition