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Title: Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer

Abstract

Purpose: To investigate hypoxia measured by pimonidazole binding, glucose transporter 1 (GLUT1) and carbonic anhydrase IX (CA-IX) expression, proliferation, and vascularity in liver metastases of colorectal cancer and to compare GLUT1 and CA-IX expression in corresponding primary tumors. Methods and Materials: Twenty-five patients with liver metastases of colorectal cancer, planned for metastasectomy, were included. The hypoxia marker pimonidazole and proliferation marker iododeoxyuridine were administered before surgery. After immunofluorescent staining of the frozen metastases, pimonidazole binding, vascularity, and proliferation were analyzed quantitatively. Thirteen paraffin-embedded primary tumors were stained immunohistochemically for GLUT1 and CA-IX expression, which was analyzed semiquantitatively in primary tumors and corresponding liver metastases. Results: In liver metastases, pimonidazole binding showed a pattern consistent with diffusion-limited hypoxia. The mean pimonidazole-positive fraction was 0.146; the mean distance from vessels to pimonidazole-positive areas was 80 {mu}m. When expressed, often co-localization was observed between pimonidazole binding and GLUT1 or CA-IX expression, but microregional areas of mismatch were also observed. No correlation between the level of pimonidazole binding and GLUT1 or CA-IX expression was observed. In some patients, a large fraction (up to 30%) of proliferating cells was present in pimonidazole-stained areas. Expression of CA-IX in primary tumors and metastases showed a significant correlation,more » which was absent for GLUT1 expression. Conclusions: Compared with other tumor types, liver metastases of colorectal cancer contain large amounts of hypoxic cells. The lack of correlation with pimonidazole binding brings into question the value of GLUT1 and CA-IX as endogenous markers of hypoxia.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [3];  [3];  [4];  [5];  [2]
  1. Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen (Netherlands). E-mail: h.vanlaarhoven@onco.umcn.nl
  2. Department of Radiation Oncology, Radboud University Nijmegen Medical Center, Nijmegen (Netherlands)
  3. Department of Surgery, Radboud University Nijmegen Medical Center, Nijmegen (Netherlands)
  4. Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen (Netherlands)
  5. Department of Radiology, Radboud University Nijmegen Medical Center, Nijmegen (Netherlands)
Publication Date:
OSTI Identifier:
20793307
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 64; Journal Issue: 2; Other Information: DOI: 10.1016/j.ijrobp.2005.07.982; PII: S0360-3016(05)02374-6; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANOXIA; CARBONIC ANHYDRASE; CARCINOMAS; GLUCOSE; IODODEOXYURIDINE; LIVER; METASTASES; PARAFFIN; PATIENTS; SURGERY

Citation Formats

Laarhoven, Hanneke W.M. van, Kaanders, Johannes, Lok, Jasper, Peeters, Wenny J.M., Rijken, Paul F.J.W., Wiering, Bastiaan, Ruers, Theo J.M., Punt, Cornelis J.A., Heerschap, Arend, and Kogel, Albert J. van der. Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer. United States: N. p., 2006. Web. doi:10.1016/J.IJROBP.2005.0.
Laarhoven, Hanneke W.M. van, Kaanders, Johannes, Lok, Jasper, Peeters, Wenny J.M., Rijken, Paul F.J.W., Wiering, Bastiaan, Ruers, Theo J.M., Punt, Cornelis J.A., Heerschap, Arend, & Kogel, Albert J. van der. Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer. United States. doi:10.1016/J.IJROBP.2005.0.
Laarhoven, Hanneke W.M. van, Kaanders, Johannes, Lok, Jasper, Peeters, Wenny J.M., Rijken, Paul F.J.W., Wiering, Bastiaan, Ruers, Theo J.M., Punt, Cornelis J.A., Heerschap, Arend, and Kogel, Albert J. van der. Wed . "Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer". United States. doi:10.1016/J.IJROBP.2005.0.
@article{osti_20793307,
title = {Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer},
author = {Laarhoven, Hanneke W.M. van and Kaanders, Johannes and Lok, Jasper and Peeters, Wenny J.M. and Rijken, Paul F.J.W. and Wiering, Bastiaan and Ruers, Theo J.M. and Punt, Cornelis J.A. and Heerschap, Arend and Kogel, Albert J. van der},
abstractNote = {Purpose: To investigate hypoxia measured by pimonidazole binding, glucose transporter 1 (GLUT1) and carbonic anhydrase IX (CA-IX) expression, proliferation, and vascularity in liver metastases of colorectal cancer and to compare GLUT1 and CA-IX expression in corresponding primary tumors. Methods and Materials: Twenty-five patients with liver metastases of colorectal cancer, planned for metastasectomy, were included. The hypoxia marker pimonidazole and proliferation marker iododeoxyuridine were administered before surgery. After immunofluorescent staining of the frozen metastases, pimonidazole binding, vascularity, and proliferation were analyzed quantitatively. Thirteen paraffin-embedded primary tumors were stained immunohistochemically for GLUT1 and CA-IX expression, which was analyzed semiquantitatively in primary tumors and corresponding liver metastases. Results: In liver metastases, pimonidazole binding showed a pattern consistent with diffusion-limited hypoxia. The mean pimonidazole-positive fraction was 0.146; the mean distance from vessels to pimonidazole-positive areas was 80 {mu}m. When expressed, often co-localization was observed between pimonidazole binding and GLUT1 or CA-IX expression, but microregional areas of mismatch were also observed. No correlation between the level of pimonidazole binding and GLUT1 or CA-IX expression was observed. In some patients, a large fraction (up to 30%) of proliferating cells was present in pimonidazole-stained areas. Expression of CA-IX in primary tumors and metastases showed a significant correlation, which was absent for GLUT1 expression. Conclusions: Compared with other tumor types, liver metastases of colorectal cancer contain large amounts of hypoxic cells. The lack of correlation with pimonidazole binding brings into question the value of GLUT1 and CA-IX as endogenous markers of hypoxia.},
doi = {10.1016/J.IJROBP.2005.0},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 2,
volume = 64,
place = {United States},
year = {Wed Feb 01 00:00:00 EST 2006},
month = {Wed Feb 01 00:00:00 EST 2006}
}
  • Purpose. We retrospectively evaluated the safety and efficacy of preoperative initial hepatic arterial infusion chemotherapy (HAIC) through a port-catheter system in patients with liver dysfunction due to synchronous and unresectable liver metastases. The aim of HAIC was to improve patients' clinical condition for later surgical removal of primary colorectal cancer. Methods. Port-catheter systems were placed radiologically in 21 patients (mean age 58.6 {+-} 8.1 years) with liver dysfunction due to synchronous liver metastases from colorectal cancer. Initial HAIC of 1,000 mg/m{sup 2} 5-fluorouracil was administered weekly as a 5 hr continuous infusion through this system. Surgical removal of the primarymore » lesion was planned after HAIC improved the liver function. Results. Port-catheter system placement was successful in all patients without severe complications. Patients were followed up for a median of 309 days (range 51-998 days). After starting HAIC, no severe adverse events that caused drug loss and treatment postponement or suspension were observed in any of the patients. HAIC was performed a mean of 4.5 {+-} 3.0 times and the liver function improved in all patients. Curative (n = 18) or palliative (n = 1) surgical removal of the primary lesion was performed. The remaining 2 patients died because extrahepatic metastases developed and their performance status worsened; thus, surgery could not be performed. The median survival times of all patients and the operated patients were 309 and 386 days, respectively. Conclusion. Initial HAIC administration is a safe and efficacious method for improving liver function prior to operative resection of primary colorectal cancer in patients with liver dysfunction due to synchronous and unresectable liver metastases.« less
  • The purpose of this study was to assess retrospectively the sequential treatment of hepatic arterial infusion (HAI) chemotherapy followed by systemic therapy using oxaliplatin plus 5-flourouracil (5-FU) and leucovorin, namely, FOLFOX, for patients with liver metastases from colorectal cancer. We reviewed 20 patients with unresectable liver metastases from colorectal cancer. Patients were initially treated with HAI chemotherapy until disease progression (5-fluorouracil, 1000 mg/m{sup 2} intra-arterial infusion, weekly) and then with FOLFOX thereafter (FOLFOX4, n = 13; modified FOLFOX6, n = 7). Adverse events, tumor response, and time to progression for each therapy were evaluated retrospectively, and overall survival was estimated.more » Toxicity of HAI chemotherapy was generally mild. Of 20 patients, adverse events leading to treatment discontinuation occurred in only 1 patient (5%) during initial therapy using HAI chemotherapy, while 9 patients (45%) exhibited adverse events during subsequent FOLFOX therapy. For HAI chemotherapy and FOLFOX, objective response rates were 85.0% and 35.0%, respectively, and median time to progression was 11.6 and 5.1 months, respectively. Median overall survival was 30.1 months. In conclusion, the sequence of HAI chemotherapy followed by FOLFOX is a promising treatment strategy for the long-term use of active chemotherapeutic agents, leading to a superior tumor response and fewer toxic effects in patients with unresectable liver metastases from colorectal cancer.« less
  • Clinical PET with generator-produced radiopharmaceutical is a viable option for PET centres without an on-site cyclotron. In view of the practical constraints imposed by the short half-lives of the Zn-62 (9.3 hr) parent and the Cu-62 (9.7 min) daughter, the objectives of this study were: (1) the preparation of in-house clinical Zn-62/ Cu-62 generators produced form targets irradiated at a remote cyclotron, (2) the optimisation of acquisition parameters for Cu-62 imaging with MUP-PET camera and (3) to evaluate the use of Cu-62-pyruvaldehyde bis(N4-methylthiosemicarbazone) (Cu-62-PTSM) in assessing blood flow changes induced by angiotensin II (AII) infusion in patients with colorectal livermore » metastases (CLM). Zn-62 was produced by bombardment of natural Cu targets at a remote cyclotron and the activity processed, in house, using anion-exchange chromatography techniques as previously reported. High activity (2.5-4.5 GBq) generators were prepared from which clinical grade Cu-62-PTSM doses were produced over a 3 day period. Eight patients undergoing regional fluorodeoxyuridine (FUdR) chemotherapy received regional administration of Cu-62-PTSM on three occasions before during and after a 40 min. AII infusion. Distribution of the radiotracer was measured using the MUP-PET camera. In seven of these patients an increase in the ratio of tumour to normal liver blood flow was demonstrated during AII infusion. This effect was prolonged and was sustained throughout the infusion period. This is the first clinical PET study to demonstrate an increase in relative tumour blood flow in patients with CLM during prolonged infusion of a vasoactive agent. Using generator-produced and medium half-life radiotracers, clinical PET is a workable alternative to short-lived racers from an on-site cyclotron.« less
  • The aim of this study was to evaluate the feasibility, safety, and efficacy of combined treatment with hepatic interstitial brachytherapy (HIB) and hepatic arterial infusion (HAI) of chemotherapy after interventional implantation of port catheter systems. Thirty-three patients with unresectable 'liver-only' metastases of colorectal cancer were treated with both HIB and HAI during the course of their disease. All 33 patients had recurrent disease and 27 had received previous chemotherapy. Of these, 15 received HAI first and were then consolidated with HIB, 9 started with HIB and were continued with HAI, and 9 received first HIB and subsequently HAI after hepaticmore » disease progression. Patients were evaluated for treatment characteristics, side effects, and efficacy. Comparisons between treatment groups were also performed. The median tumor diameter of metastases treated with brachytherapy was 4.6 cm (range: 1-12 cm). The median minimal irradiation dose inside the tumor margin was 18 Gy administered to a mean of two metastases in 69 interventions. Minor (n = 4) and major (n = 3) complications occurred in 10% of interventions. WHO grade III adverse events of the regional chemotherapy were observed in seven patients; grade IV, in one patient. At a median follow-up of 28 months (range: 7-74 months), the median time to disease progression after first treatment was 10.5 months (range: 1-35 months). Of 138 metastases treated by brachytherapy, 16 local recurrences were seen (mean, 12.3 months; range, 3-45 months). No signs of hepatic failure were observed in any of our patients. In conclusion, combinations of two minimally invasive therapeutic methods are feasible, with acceptable complication rates, and provide promising results in colorectal cancer patients with unresectable hepatic metastases.« less
  • The purpose of this study was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) is useful for early detection of the response of hepatic colorectal metastases to hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU). The subjects were 12 patients with hepatic colorectal metastases. The indwelling catheter for HAIC was placed in the hepatic artery, and 1000 mg/m{sup 2} 5-FU was given repeatedly once a week. DWI was performed before and 9 days after HAIC. The minimum and mean apparent diffusion coefficient (ADC) values (minADC and meanADC) were measured. The relative change in ADC values (%ADC) and the relative changemore » in tumor size on follow-up CT after 3 months (reduction ratio) were determined. Liver metastases were divided into two groups, responder and nonresponder. The correlation between %ADC and reduction ratio was determined, and %ADC was compared between the two groups. Eleven patients successfully completed HAIC over the 3-month period; 48 metastatic lesions were evaluated. Positive correlations were observed for relative change between %minADC and reduction ratio (r = 0.709) and between %meanADC and reduction ratio (r = 0.536). Both %minADC and %meanADC were significantly greater in the responder group than in the nonresponder group. With the threshold determined as < 3.5%, the receiver-operating curve analysis showed higher sensitivity and specificity values for %minADC (100% and 92.6%, respectively) than for %meanADC (66.7% and 74.1%, respectively). In conclusion, the relative change in minimum ADC values on DWI may be useful for early detection of the response of liver metastases to HAIC with 5-FU.« less