Tumour proliferation assessed by combined histological and flow cytometric analysis: implications for therapy in squamous cell carcinoma in the head and neck

Based on the assumption that an accelerated proliferation process prevails in tumour cell residues after surgery, the possibility that treatment acceleration would offer a therapeutic advantage in postoperative radiotherapy of locally advanced head and neck cancer was investigated. The value of T pot in predicting the treatment outcome and in selecting patients for accelerated fractionation was tested. Seventy patients with (T2/N1 -N2) or (T3-4/any N) squamous cell carcinoma of the oral cavity, larynx and hypopharynx who underwent radical surgery, were randomized to either (a) accelerated hyperfractionation: 46.2 Gy per 12 days, 1.4 Gy per fraction, three fractions per day with 6 h interfraction interval, treating 6 days per week or (b) Conventional fractionation: 60 Gy per 6 weeks, 2 Gy per fraction, treating 5 days per week. The 3-year locoregional control rate was significantly better in the accelerated hyperfractionation (88+4%) than in the CF (57+9%) group, P=0.01 (and this was confirmed by multivariate analysis), but the difference in survival (60+10% vs 46+9%) was not significant (P=0.29). The favourable influence of a short treatment time was further substantiated by demonstrating the importance of the gap between surgery and radiotherapy and the overall treatment time between surgery and end of radiotherapy. Early mucositis progressed more rapidly and was more severe in the accelerated hyperfractionation group; reflecting a faster rate of dose accumulation. Xerostomia was experienced by all patients with a tendency to be more severe after accelerated hyperfractionation. Fibrosis and oedema also tended to be more frequent after accelerated hyperfractionation and probably represent consequential reactions. T pot showed a correlation with disease-free survival in a univariate analysis but did not prove to be an independent factor. Moreover, the use of the minimum and corrected P-values did not identify a significant cut-off. Compared to conventional fractionation, accelerated hyperfractionation did not seem to offer a survival advantage in fast tumours though a better local control rate was noted. This limits the use of T pot as a guide for selecting patients for accelerated hyperfractionation. For slowly growing tumours, tumour control and survival probabilities were not significantly different in the conventional fractionation and accelerated hyperfractionation groups. A rapid tumour growth was associated with a higher risk of distant metastases (P=0.01). In conclusion, tumour cell repopulation seems to be an important determinant of postoperative radiotherapy of locally advanced head and neck cancer despite lack of a definite association between T pot and treatment outcome. In fast growing tumours accelerated hyperfractionation provided an improved local control but without a survival advantage. To gain a full benefit from treatment acceleration, the surgery-radiotherapy gap and the overall treatment time should not exceed 6 and 10 weeks respectively.

Section: Discussionmentioning

confidence: 99%

Section: Cell Proliferation Kinetics Studiesmentioning

confidence: 99%

mentioning

confidence: 99%

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

Awwad¹,

Lotayef²,

Shouman³

et al. 2002

“…LI can be evaluated either by FCM of cell suspensions or by morphometry in immunohistochemically (IHC) stained tissue sections. T can thus be calculated with LI derived either from histology or from FCM (Bennett et al, 1992). The findings by Dische and Saunders (1989), Rew et al (1991) and Wilson (1991) suggest that cell proliferation evaluated with this technique might be of independent prognostic value.…”

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confidence: 99%

Systematic heterogeneity and prognostic significance of cell proliferation in colorectal cancer

Palmqvist

Öberg²,

Bergström³

et al. 1998

Summary The prognosis of colorectal cancer has not significantly changed during the last 30 years. While evaluation of tumour cell proliferation may provide prognostic information, results obtained so far have been contradictory. Heterogeneity in tumour cell proliferation may explain these contradictions. With in vivo injection of iododeoxyuridine (IdUrd), estimation of labelling index (LI), S-phase transit time (Ts) and potential doubling time (Tpot) may be performed from a single sample. A total of 109 colorectal cancers were studied after in vivo injection of IdUrd before surgical removal. From each cancer, four to eight samples were processed for both flow cytometrical (FCM) and immunohistochemical (IHC) visualization of IdUrd incorporation. Ll/IHC was morphometrically quantified at both the luminal border and the invasive margin of these tumours. LI was significantly higher at the luminal border compared with the invasive margin, although they were correlated with each other. Using combined IHC and FCM methods, rapidly growing colorectal cancers (high Li and/or low Tpot) showed an increased survival (significant for LI at the invasive margin and for 7pt at both the invasive margin and the luminal border) in the entire unselected material and for radically removed Dukes' B tumours. FCM data alone did not discriminate for survival, with the exception of T5 in diploid and radically removed Dukes' B tumours.

“…1995). An extension of the technique has allowed identification of the cells preparing for division in histological material and has shown that in most squamous cancers there are areas where there is a potential for the number to double in less than 2 days (Bennett et al, 1992). High cell loss factors owing to maturation and degeneration largely account for the difference between the volume doubling times and potential cell doubling times of these tumours (Denekamp, 1982).…”

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confidence: 99%

Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report. CHART Steering Committee

Saunders

Dische²,

Barrett³

et al. 1996

Self Cite

153

Summary While radiotherapy is proceeding. tumour cells may proliferate. The use of small individual doses reduces late morbidity. Continuous hy-perfractionated accelerated radiation therapy (CHART). which reduces overall treatment from 6-7 weeks to 12 days and gives 36 small fractions. has now been tested in multicentre randomised controlled clinical trials. The trial in non-small-cell lung cancer included 563 patients and showed improvement in survival: 30% of the CHART patients were alive at 2 years compared with 20% in the control group (P=0.006). In the 918 head and neck cases. there was only a small. non-significant improvement in the disease-free interval. In this interim anlavsis there was a trend for those with more advanced disease (T3 and T4) to show advantage: this will be subject to further analysis when the data are more mature. The earlv mucosal reactions appeared sooner and were more troublesome with CHART. however they quickly settled: so far no difference in long-term morbidity has emerged. These results support the hypothesis that tumour cell repopulation can occur during a conventional course of radiotherapy and be a cause of treatment failure.