Correlation between EGFr expression and accelerated proliferation during radiotherapy of head and neck squamous cell carcinoma

Abstract

Purpose: To investigate the correlation between the expression of Epidermal Growth Factor receptor (EGFr) and the reduction of the effective doubling time (TD) during radiotherapy treatment and also to determine the dose per fraction to be taken into account when the overall treatment time (OTT) is reduced in accelerated radiotherapy of head and neck squamous cell carcinoma (HNSCC).

Methods: A survey of the published papers comparing 3-years of local regional control rate (LCR) for a total of 2162 patients treated with conventional and accelerated radiotherapy and with a pretreatment assessment of EGFr expression, was made. Different values of TD were obtained by a model incorporating the overall time corrected biologically effective dose (BED) and a 3-year clinical LCR for high and low EGFr groups of patients (HEGFr and LEGFr), respectively. By obtaining the TD from the above analysis and the sub-sites' potential doubling time (Tpot) from flow cytometry and immunohistochemical methods, we were able to estimate the average TD for each sub-site included in the analysis. Moreover, the dose that would be required to offset the modified proliferation occurring in one day (Dprolif), was estimated.

Results: The averages of TD were 77 (27-90)95% days in LEGFr and 8.8 (7.3-11.0)95% days in HEGFr, if an onset of accelerated proliferation TK at day 21 was assumed. The correspondent HEGFr sub-sites' TD were 5.9 (6.6), 5.9 (6.6), 4.6 (6.1), 14.3 (12.9) days, with respect to literature immunohistochemical (flow cytometry) data of Tpot for Oral-Cavity, Oro-pharynx, Hypo-pharynx, and Larynx respectively. The Dprolif for the HEGFr groups were 0.33 (0.29), 0.33 (0.29), 0.42 (0.31), 0.14 (0.15) Gy/day if α = 0.3 Gy-1 and α/β = 10 Gy were assumed.

Conclusions: A higher expression of the EGFr leads to enhanced proliferation. This study allowed to quantify the extent of the effect which EGFr expression has in terms of reduced TD and Dprolif for each head and neck sub-site.

Figure 1

Linear regressions for L_EGFrgroup (diamonds) and H_EGFrgroup (circles) with y = ln(lnLCR^S/lnLCR^F) and x = (T^S-T^F) (days). The higher angular coefficient of H_EGFr group line demonstrate a reduction of effective doubling time with respect to L_EGFr group (proportionality with the inverse of the effective doubling time). Sub-figures refer to a different onset of accelerated repopulation (a) T_k = 0, (b) T_k = 14, (c) T_k = 21, (d) T_k = 28 days. Error bars represent the 95% confidence intervals.

Figure 2

Curves of T_Dobtained by varying T_k, for H_EGFr(black) and L_EGFr(gray) groups based on the immunohistochemistry (continuous) and flow cytometry (dashed) methods to estimate the sub-sites ⁱT_pot. Differences are shown for Oral-Cavity (a), Oropharynx (b), Hypopharynx (c) and Larynx (d).

Figure 3

Curves of D_prolifobtained by varying T_k, for H_EGFr(continuous) and L_EGFr(dashed) groups based on the flow cytometry (left column) and immunohistochemistry (right column) methods to estimate the sub-sites ⁱT_pot. Sensitivity analysis is shown with respect to different values of α with α/β = 10 Gy: α = 0.25 Gy^-1 (upper curves); α = 0.3 Gy^-1 (mean curves); α = 0.35 Gy^-1 (bottom curves). Differences are shown for Oral-Cavity (a,b), Oropharynx (c,d), Hypopharynx (e,f) and Larynx (g,h).

Figure 4

Histogram of ratios between T_Dvalues in the L_EGFrand H_EGFr groups. The error bars represent the 95% confidence intervals while the overlay trend line represent the average of values. Abbreviations: E1 = Eriksen from AO, E2 = Eriksen RO, BE = Bentzen JCO, SU = Suwinski IJROBP, SM = Smid IJROBP, CH = Chung IJROBP.