The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis

Abstract

Purpose: The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy.Materials and methods: Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from¯ow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own¯ow cytometry analysis.Results: From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of signi®cance. For the cell kinetic parameters, univariate analysis showed that only LI was signi®cantly associated with local control (P 0:02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not signi®cant (P 0:06). Tpot showed no trend (P 0:8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P 0:4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P 0:02). In the multivariate analysis of local control, LI lost its signi®cance (P 0:16). Conclusions: The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using¯ow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer. q

Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation

“…In case of radical radiotherapy of HNC, the influence of pretreatment tumour proliferation parameters on the treatment outcome is a controversial issue (Awwad et al, 1992;Lochin et al, 1992;Bourhis et al, 1993;Eschwege et al, 1997;Zackrisson et al, 1997;Høyer et al, 1998). A multicenter analysis of 476 patients in which 11 centres participating failed to demonstrate an association (Begg et al, 1999). Such negative results do not support the notion that T pot can predict repopulation taking place during radical radiotherapy.…”

“…Patients less than 65 years of age with (T2/N1 -2) or (T3-4/any N) squamous cell carcinoma of the oral cavity, larynx and hypopharynx who underwent radical surgery were admitted to the study provided that: (a) there was no evidence of gross residual disease or distant metastases; (b) performance status score 42 according to the WHO scale, 1980;(c) liver, kidney and other vital functions were within normal. The patient written consent was also required.…”

A New Look at Proliferation

“…Indeed, combining BrdUrd detection with DNA staining using ow cytometry (12) led to the development of delayed biopsy techniques (13) that launched a new era where dynamic cell proliferation measurements could be applied routinely in the study of human tumours (14). However, the promise of Tpot as a predictor of outcome in radiotherapy has, like other markers of proliferation ( 3 HTdR, S-phase fraction, PCNA and Ki-67), failed to provide conclusive data (15) or make an impact in clinical practice.…”

Treatment planning optimisation based on imaging tumour proliferation and cell density

“…As could be seen from the comparison of Figures 2 and 5, relatively quiescent tumours with few foci of high proliferation like that presented in Figure 1 could have poorer response to uniform irradiation than tumours with almost uniform, though moderate proliferation like the case presented in Figure 4. An interesting question is whether this could be the explanation for the clinical studies that failed to show that global pre-treatment proliferation parameters could predict the treatment outcome [36]. This is an interesting aspect that highlights once again the need for accurate information regarding the distribution of proliferation rates in tumours.…”