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

Abstract

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.

Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy

“…It indicates accelerated repopulation of cells surviving the induction chemotherapy course. Our findings are in line with those of others who observed a rapid regrowth after irradiation of pulmonary metastases (Battermann et al, 1981), and after surgery in head-and-neck cancer (Trotti et al, 1998;Ang et al, 2001;Awwad et al, 2002). In their review, Davis and Tannock Accelerated regrowth of NSCL tumours after chemotherapy SY El Sharouni et al (2000) reported on repopulation of tumour cells between cycles of chemotherapy as a neglected factor.…”

p53, p16 and cyclin D1: Molecular determinants of radiotherapy treatment response in oral carcinoma

“…This is a matter of intense exploration in recent head and neck cancer clinical trials. 14,15 In our present study, 2 types of fractionation regimens were selected to explore the predictive potential of biological markers studied. The relative response of cells to fractionated regimens depends on the ␣/␤ values of the irradiated tissues.…”

Oral Sequelae of Head and Neck Radiotherapy

“…Both approaches have been shown to result in a modest gain in curing head and neck cancer when tested in randomized trials (Garden, 2001). Also, combinations of hyperfractionated and accelerated schedules have been shown to be especially successful for rapidly dividing tumors (Awwad et al 2002). The disadvantage of these new treatment techniques is the higher rates of acute toxicity, especially mucositis.…”

“…Such interruptions must be prevented, because they may result in prolongation of treatment time and thus a reduction in therapeutic effect (Fowler, 1986). As mentioned before, hyperfractionation, accelerated fractionation, and radiochemotherapy, although especially successful for the treatment of rapidly dividing tumors, result in higher rates of acute toxicity, especially mucositis (Bensadoun et al, 2001;Awwad et al, 2002).…”