Large-Scale Analysis Confirms Superiority of Hyperfractionation in HNSCC

Hyperfractionated radiotherapy demonstrated a superior improvement in overall survival rates compared to standard and accelerated radiotherapy when administered without concomitant chemotherapy in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), according to results from a meta-analysis of over 11,000 patients presented at the 2013 European Cancer Congress.

The meta-analysis was conducted by the MARCH collaborative group, which previously published a 15-trial 6,515-patient meta-analysis on altered fractionation radiotherapy (AFRT) regimen in HNSCC. This study showed an OS benefit associated with AFRT when compared to standard fractionation radiotherapy (SFRT) in the absence of concomitant chemotherapy. Other trials have been completed since, demonstrating superiority specifically for hyperfractionated regimens.

“The hyperfractionated regime is the most effective in terms of overall survival. Indeed, in this group of trials the risk of death is reduced by 18% by the use of hyperfractionated radiotherapy, with 41% of patients alive at five years compared to 33% in the SFRT group,” commented the lead author, Pierre Blanchard, MD, from Institut Gustave Roussy, Villejuif, France, in a statement.  

In HNSCC a hyperfractionated schedule generally delivers radiotherapy twice daily at 1.15 to 1.25 Gy for 7 weeks, which results in a total dose of approximately 80 Gy. For SFRT the total dose size is 70 Gy, which is administered in larger once daily fractions of 1.8 to 2.0 Gy for 7 weeks.

The meta-analysis examined patients that received the 80 Gy hyperfractionated schedule, a standard 70 Gy approach, and an accelerated schedule with or without total dose reductions. On this schedule, the overall treatment time was reduced (5 weeks) but the total dose sizes remained the same or lower as the standard treatment (70 Gy). The smaller dose size with hyperfractionation allows for normal tissue to repair radiation-induced damage, resulting in comparable long-term side effects.

“While the acute side-effects of AFRT are increased compared to those experienced by patients on SFRT, the late side-effects are comparable and, overall, side-effects are more than compensated for by the significant increase in survival in the AFRT group,” Blanchard said in a release.

In the analysis, after a median follow-up of 7.6 years, an 8% reduction in risk of death was observed in the AFRT group (hyperfractionated and accelerated) compared with SFRT. AFRT demonstrated an event-free survival rate of approximately 9% (HR = 0.91, 0.87-0.94, P < .0001). Furthermore, hyperfractionation demonstrated an 18% reduction in risk of death compared to an accelerated schedule (HR = 0.82, 0.74-0.92, P = .04).

“This large-scale analysis of patients with head and neck cancer shows that hyperfractionation increases survival, and local control is also improved by the use of this technique,” Cornelis Jan Hadde van de Velde, MD, PhD, President, European Cancer Organization, said in a statement. “This is an important step forward in the treatment of this devastating disease.”

The retrospective study included data from 40 trials, representing 12,003 patients. At the time of the presentation, data from 31 trials and 11,085 patients (92% of potential population) were collected, with less than 1% missing data in major covariates.

Currently, concomitant chemoradiation is the standard of care for patients with locally advanced HNSCC. At the meeting, Blanchard noted that hyperfractionation should be considered in patients who need intensified treatment and concomitant chemoradiation is not feasible due to pre-existing conditions such as cardiac or renal disease.

“These data are a major advance for understanding the role in AFRT in head and neck squamous cell carcinoma,” Blanchard said in a statement. “By carrying out a large-scale analysis such as this one, we believe that we have provided enough evidence to indicate that doctors should recommend AFRT as a validated treatment option for head and neck cancer patients."

Blanchard P, Lacas B, Bourhis J, et al. Meta-analysis of radiotherapy in head and neck carcinomas: An update. Presented at: European Cancer Congress 2013 (ECCO-ESMO-ESTRO); September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 26.