The goal of this interactive R01 (I-R01) is to improve the long-term survival of patients with colorectal carcinoma metastatic to the liver. This will be accomplished by close collaboration between the clinical trials (Kemeny - I-R01), studies of drug resistance and genetics of colorectal cancer (Bertino - I-R01) and the diagnostic uses of monoclonal antibodies (Cohen - I-R01). Based on our previous work with hepatic arterial infusion (HAI) of FUDR and leucovorin which produced a median survival of greater than 29 months and a 4-year survival of 24%, we have the following aims: 1) to increase response rate and number of complete responses with HAI; 2) to test an adjuvant protocol after liver resection using HAI and systemic therapy; 3) to develop a salvage protocol for patients whose tumor does not respond to first line regional therapy; and 4) to determine if NMR spectroscopy will be able to predict response and/or toxicity.
Under aim 1) we have initiated a new Phase II trial of FUDR, leucovorin and dexamethasone to increase response and decrease toxicity. Mitomycin C, which has been shown to have an additive effect with FUDR infusion (Bertino - I-R01), will be added to our best protocol.
Under aim 2) we have initiated a new adjuvant study after liver resection to see if the addition of HAI to systemic therapy will improve the results over systemic therapy alone. Monoclonal antibodies for detection of occult disease will be used prior to surgery in an attempt to improve patient selection (Cohen - I-R01). both occult bone marrow metastases and occult intra-abdominal disease will be assessed and related to clinical outcome. Tumor tissue from these patients will be analyzed for drug resistance and cytogenetics and these will be correlated with patient survival and recurrence (Bertino - I-R01).
Under aim 3) two agents that show promise for HAI use: teroxirone, an alkylating agent, and fluorouridine (FUR), an old drug (toxic when used systemically, but may be selective when given by HAI) will be tested. FUR has a high hepatic extraction; we will test teroxirone extraction. both drugs are effective against colon cancer cell lines (Bertino - I-R01).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA061524-03
Application #
2102263
Study Section
Special Emphasis Panel (SRC (57))
Project Start
1993-08-01
Project End
1997-05-31
Budget Start
1995-06-01
Budget End
1996-05-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Fischer, Catha; Melstrom, Laleh G; Arnaoutakis, Dean et al. (2013) Chemotherapy after portal vein embolization to protect against tumor growth during liver hypertrophy before hepatectomy. JAMA Surg 148:1103-8
Covey, Anne M; Brown, Karen T; Jarnagin, William R et al. (2008) Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg 247:451-5
Parks, Rowan; Gonen, Mithat; Kemeny, Nancy et al. (2007) Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: analysis of data from two continents. J Am Coll Surg 204:753-61;discussion 761-3
Schwartz, L; Brody, L; Brown, K et al. (2006) Prospective, blinded comparison of helical CT and CT arterial portography in the assessment of hepatic metastasis from colorectal carcinoma. World J Surg 30:1892-9; discussion 1900-1
Jarnagin, W R; Zager, J S; Hezel, M et al. (2006) Treatment of cholangiocarcinoma with oncolytic herpes simplex virus combined with external beam radiation therapy. Cancer Gene Ther 13:326-34
Akhurst, Timothy; Kates, Tara J; Mazumdar, Madhu et al. (2005) Recent chemotherapy reduces the sensitivity of [18F]fluorodeoxyglucose positron emission tomography in the detection of colorectal metastases. J Clin Oncol 23:8713-6
Wong, Richard J; Chan, Mei-Ki; Yu, Zhenkun et al. (2004) Angiogenesis inhibition by an oncolytic herpes virus expressing interleukin 12. Clin Cancer Res 10:4509-16
Stanziale, Stephen F; Stiles, Brendon M; Bhargava, Amit et al. (2004) Oncolytic herpes simplex virus-1 mutant expressing green fluorescent protein can detect and treat peritoneal cancer. Hum Gene Ther 15:609-18
Yu, Zhenkun; Eisenberg, David P; Singh, Bhuvanesh et al. (2004) Treatment of aggressive thyroid cancer with an oncolytic herpes virus. Int J Cancer 112:525-32
Wong, Richard J; Chan, Mei-Ki; Yu, Zhenkun et al. (2004) Effective intravenous therapy of murine pulmonary metastases with an oncolytic herpes virus expressing interleukin 12. Clin Cancer Res 10:251-9

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