In vivo cell kinetics in head and neck squamous cell carcinomas predicts local control and helps guide radiotherapy regimen.

Corvò, Renzo; Giaretti, Walter; Sanguineti, Giuseppe; Geido, Elio; Orecchia, Roberto; Guenzi, M.; Margarino, G; Bacigalupo, Almalina; Garaventa, G; Barbieri, Marco

doi:10.1200/jco.1995.13.8.1843

Cited by 77 publications

(33 citation statements)

References 22 publications

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“…Values for effective repopulation doubling times (Teff) during the latter part of radiotherapy in head and neck tumors, calculated from retrospective clinical data, are of the order of 4±5 days [20,21,53]. These are in good agreement with Tpot values measured in other series [2,6,11,14,31,34,44,48,49,54], leading to the hypothesis that Tpot may indeed be a predictor of Teff [19], and was the stimulus for carrying out several of the studies contributing to the present analysis. The combined results of 11 studies presented here, however, do not support this hypothesis.…”

Section: Discussionsupporting

confidence: 70%

“…An added advantage is that these methods could be applied after in vivo labeling of the patient with the analogue, avoiding potential in vitro artifacts. Several studies have employed such methods to assess the predictive value of pre-treatment cell kinetic parameters after radiotherapy [2,3,5,6,11,14,31,34,43,47,54]. Results have been variable, some showing positive association with outcome [3,5,14,47,54], and some not [11,18,31,34,43].…”

Section: Introductionmentioning

confidence: 99%

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

Begg

Haustermans

Hart

et al. 1999

Radiotherapy and Oncology

133

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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

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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

Begg

Haustermans

Hart

et al. 1999

Radiotherapy and Oncology

133

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“…Proliferation can be studied by incorporation of the thymidine analogues bromo-and iododeoxyuridine, which can be identified using a monoclonal antibody with either flow cytometry analysis or immunohistochemical end points Wilson et al, 1985). Measurements of potential doubling time (Tpot) are currently being undertaken in a series of trials comparing conventional with accelerated fractionation, and some show good evidence that pretreatment cell kinetics can predict treatment outcome (Wilson et al, 1988;Begg et al, 1992; Corvo et al, 1995). The degree of hypoxia within a solid tumour is important as hypoxic cells will be up to three times more resistant to radiotherapy than their better oxygenated counterparts (Gray et al, 1953).…”

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confidence: 99%

Cell cycle distribution of hypoxia and progression of hypoxic tumour cells in vivo

Webster

Hodgkiss²,

Wilson³

1998

Br J Cancer

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Summary Hypoxia was assessed in three murine tumour models in vivo by measuring the incorporation of 7-(4'-(2-nitroimidazole-1-yl)-butyl)-theophylline (NITP), an immunologically identifiable hypoxia marker that binds bioreductively to cells under low-oxygen conditions. Proliferating cells were labelled in the same tumours by administering the thymidine analogue bromodeoxyuridine (BrdUrd). The relative hypoxia in each cell cycle phase of cells isolated from tumours was assessed by addition of propidium iodide with analysis by flow cytometry. There was no relationship between tumour volume and hypoxia in either the anaplastic sarcoma SaF or the poorly differentiated carcinoma CaNT and only a slight negative correlation in moderately well-differentiated carcinoma Rh. The G1/Go phase contained the greatest number of aneuploid hypoxic cells (aneuploid hypoxia ranging from less than 1% up to 40%, 38% and 71% in SaF, CaNT and Rh respectively), although there were significant amounts of hypoxia present in S-and G/M phases for all three tumours examined. However, the highest proportion of hypoxia occurred in the G/M phase, in which up to 60% of the cells were hypoxic. Simultaneous measurement of hypoxia, proliferation and DNA content using a novel triple-staining flow cytometry method showed that hypoxic cells could actively participate in the cell cycle. In addition, the cell cycle distribution of NITP and BrdUrd labelling showed that hypoxic cells could progress through the cell cycle, although their rate of progression was slower than that of better oxygenated cells.

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“…Studies have demonstrated elevated levels of cell proliferation in a high proportion of SCCHN tumors, and proliferation rates have been related to patient survival, and used in patient treatment strategies. [5][6][7] Thus, genes that encode regulators of cell proliferation may prove useful in establishing patient prognosis or as targets in therapy regimens.…”

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confidence: 99%

Cyclin D1 Polymorphism and Expression in Patients with Squamous Cell Carcinoma of the Head and Neck

Holley

Parkes

Matthias

et al. 2001

The American Journal of Pathology

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We have previously reported that the cyclin D1 (CCND1) GG 870 genotype was associated with poorly differentiated tumors and reduced disease-free interval in patients with squamous cell carcinoma of the head and neck (SCCHN). We have now examined the association of this and a second CCND1 polymorphism with gene expression and outcome in SCCHN patients. Analysis of a CCND1 G/C 1722 polymorphism revealed that CCND1 CC 1722 genotype was associated with poorly differentiated tumors [P ‫؍‬ 0.005; odds ratio (OR), 5.7; 95% CI, 1.7 to 19.2), and reduced disease-free interval (P ‫؍‬ 0.003; Hazard Ratio (HR), 7.3; 95% CI, 1.1 to 27.2.) independently from the influence of CCND1 GG 870 genotype. Patients whose tumors were negative for cyclin D1 were associated with reduced disease-free interval (P ‫؍‬ 0.028; HR, 4.1; 95% CI, 1.4 to 14.2). Although G/C 1722 genotypes were not associated with expression, we found a significant trend between reduced expression of cyclin D1 in patients with the CCND1 GG 870 genotype (P ‫؍‬ 0.04). Splicing of CCND1 mRNA in head and neck tissues was modulated by CCND1 A/G 870 alleles, thus CCND1 transcript a was spliced equally from CCND1 A 870 and G 870 alleles, whereas CCND1 transcript b was spliced mainly from the CCND1 A 870 allele. Our analysis has also identified differences in cyclin D1 genotype and protein expression and the pathogenesis of SCCHN in males and females. Thus, CCND1 CC 1722 genotype was more common in female patients (P ‫؍‬ 0.019; OR, 3.3; 95% CI, 1.3 to 10) and cyclin D1 expression was more frequent (chi-square 1 , 3.96; P ‫؍‬ 0.046) and at higher levels (P ‫؍‬ 0.004) in tumors from female patients. In summary, our data show that the two CCND1 polymorphic sites are independently associated with tumor biology and clinical outcome. CCND1 A/G 870 alleles affect gene expression in head and neck tissues. We also provide preliminary evidence that the molecular genetics of SCCHN development may be influenced by patient gender. (Am J Pathol 2001, 159:1917-1924)

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In vivo cell kinetics in head and neck squamous cell carcinomas predicts local control and helps guide radiotherapy regimen.

Abstract: Pretreatment tumor Tpot appears to be an important independent prognostic factor for local control of HN-SCC treated by primary radiotherapy.

Cited by 77 publications

References 22 publications

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

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

Cell cycle distribution of hypoxia and progression of hypoxic tumour cells in vivo

Cyclin D1 Polymorphism and Expression in Patients with Squamous Cell Carcinoma of the Head and Neck

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