title: Targeted chemoradiation in metastatic colorectal cancer: a phase I trial of 131I-huA33 with concurrent capecitabine.
abstract: huA33 is a humanized antibody that targets the A33 antigen, which is highly expressed in intestinal epithelium and more than 95% of human colon cancers but not other normal tissues. Previous studies have shown huA33 can target and be retained in a metastatic tumor for 6 wk but eliminated from normal colonocytes within days. This phase I study used radiolabeled huA33 in combination with capecitabine to target chemoradiation to metastatic colorectal cancer. The primary objective was safety and tolerability of the combination of capecitabine and (131)I-huA33. Pharmacokinetics, biodistribution, immunogenicity, and tumor response were also assessed.
  
  
  METHODS
  Eligibility included measurable metastatic colorectal cancer, adequate hematologic and biochemical function, and informed consent. An outpatient scout (131)I-huA33 dose was followed by a single-therapy infusion 1 wk later, when capecitabine was commenced. Dose escalation occurred over 5 dose levels. Patients were evaluated weekly, with tumor response assessment at the end of the 12-wk trial. Tumor targeting was assessed using a γ camera and SPECT imaging.
  
  
  RESULTS
  Nineteen eligible patients were enrolled. The most frequently observed toxicity included myelosuppression, gastrointestinal symptoms, and asymptomatic hyperbilirubinemia. Biodistribution analysis demonstrated excellent tumor targeting of the known tumor sites, expected transient bowel uptake, but no other normal tissue uptake. (131)I-huA33 demonstrated a mean terminal half-life and serum clearance suited to radioimmunotherapy (T1/2β, 100.24 ± 20.92 h, and clearance, 36.72 ± 8.01 mL/h). The mean total tumor dose was 13.8 ± 7.6 Gy (range, 5.1-26.9 Gy). One patient had a partial response, and 10 patients had stable disease.
  
  
  CONCLUSIONS
  (131)I-huA33 achieves specific targeting of radiotherapy to colorectal cancer metastases and can be safely combined with chemotherapy, providing an opportunity to deliver chemoradiation specifically to metastatic disease in colorectal cancer patients.
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Australia.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Herbertson
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.forename: Fook-Thean
authors.initials: FT
authors.lastname: Lee
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gill
authors.forename: Bridget
authors.initials: B
authors.lastname: Chappell
authors.forename: Tina
authors.initials: T
authors.lastname: Cavicchiolo
authors.forename: Tim
authors.initials: T
authors.lastname: Saunder
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: O'Keefe
authors.forename: Aurora
authors.initials: A
authors.lastname: Poon
authors.forename: Sze Ting
authors.initials: ST
authors.lastname: Lee
authors.forename: Roger
authors.initials: R
authors.lastname: Murphy
authors.forename: Wendie
authors.initials: W
authors.lastname: Hopkins
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Scott
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000069287:Capecitabine; D059248:Chemoradiotherapy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000532:radiotherapy* / Q000628:therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018579:Patient Selection; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000964:Antimetabolites, Antineoplastic; D019275:Radiopharmaceuticals; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil
keywords: chemotherapy; colorectal cancer; radioimmunotherapy