EGFR-TK inhibition before radiotherapy reduces tumour volume but does not improve local control: differential response of cancer stem cells and nontumourigenic cells?

Radiother Oncol. 2007 Jun;83(3):316-25. doi: 10.1016/j.radonc.2007.04.014. Epub 2007 May 24.

Abstract

Background and purpose: Waiting times before radiotherapy may reduce tumour control probability due to proliferation of tumour cells. The aim of the experiment was to test whether the growth inhibiting effect of epidermal growth factor receptor (EGFR)-inhibitors after surgery or tumour transplantation results in a lower tumour mass at time of irradiation and can thereby improve local tumour control.

Materials and methods: The EGFR-tyrosine kinase inhibitor BIBX1382BS was applied over 14days starting from microscopically non-in-sano-resection of FaDu tumours or from tumour transplantation, followed by irradiation (5f/5d). Endpoint was local tumour control. In addition, vital tumour areas, pimonidazole hypoxic fraction, BrdU labelling index, and colony forming ability in vitro were tested in control tumours and after BIBX1382BS treatment (starting from transplantation).

Results: The tumour volume at start of irradiation was significantly lower in the BIBX1382BS treated tumours as compared to the control groups by factors of 11 (post-surgery setting) and 2.7 (transplantation setting). However, the reduced volume did not translate into improved local control after irradiation. The TCD(50) values after surgery were 25.4Gy [95% CI 18; 33Gy] in the control group and 30.5Gy [24; 37] in the BIBX1382BS group (p=0.25). Treatment after transplantation resulted in TCD(50) values of 41.1Gy [35; 47] in the control group and 41.1Gy [33; 49] in the BIBX1382BS group (p=1). While the proportion of S-phase cells decreased after BIBX1382BS treatment, no differences were observed between the pimonidazole hypoxic fractions and in vitro colony forming ability.

Conclusions: EGFR-TK inhibition with BIBX1382BS over 14days between macroscopically complete tumour resection or tumour transplantation and start of radiotherapy significantly reduced tumour volume but did not improve local tumour control. One possible explanation is that the EGFR-TK inhibitor has a higher activity in nontumourigenic cancer cells compared to cancer stem cells. This hypothesis, along with the observation that tumours of similar size were significantly more radiosensitive after surgery than without surgery, warrants further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / physiopathology
  • Carcinoma, Squamous Cell / radiotherapy*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • ErbB Receptors / antagonists & inhibitors*
  • Female
  • Hypopharyngeal Neoplasms / pathology
  • Hypopharyngeal Neoplasms / physiopathology
  • Hypopharyngeal Neoplasms / radiotherapy*
  • Male
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / radiation effects*
  • Organic Chemicals / pharmacology*
  • Tumor Burden / drug effects*
  • Tumor Burden / radiation effects
  • Tumor Stem Cell Assay

Substances

  • Antineoplastic Agents
  • BIBX 1382BS
  • Organic Chemicals
  • ErbB Receptors