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Hypofractionated radiotherapy may improve glottic cancer survival
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Hypofractionated radiotherapy improved survival in patients with early-stage glottic cancer compared with conventionally fractionated radiotherapy, according to a study published in Journal of the National Cancer Institute.
“The study was prompted by controversy about whether using a hypofractionated radiation approach was superior to standard radiation approaches for early-stage glottic cancer,” Zain A. Husain, MD, assistant professor of therapeutic radiology and director of head and neck radiotherapy at Smilow Cancer Hospital, told HemOnc Today. “The National Comprehensive Cancer Network guidelines currently say both standard-fraction and hypofractionated options are accepted; however, previous randomized data did suggest a control benefit to hypofractionated radiation.”
Previous studies showed an OS benefit with hypofractionation in patients with advanced-stage oropharyngeal and laryngeal cancers.
Conventionally fractionated radiotherapy includes receipt of 2 Gy per fraction to a total dose of 66 Gy to 70 Gy, whereas hypofractionated radiotherapy involves 2.25 Gy per fraction to a total dose of 63 Gy to 65.25 Gy.
Researchers divided patients diagnosed with stage I or stage II glottic cancer and treated with radiotherapy between 2004 and 2013 into those who had conventionally fractionated radiotherapy (n = 6,182; median age, 66 years; 86.4% men; 76.9% non-Hispanic white) and those who had hypofractionated radiotherapy (n = 4,030; median age, 65 years; 86.3% men; 77.1% non-Hispanic white).
A greater proportion of patients who received hypofractionated radiotherapy had stage T1 disease than those who received conventionally fractionated radiotherapy (82.2% vs. 76.6%; P < .001).
Aims of the study included to define OS and the use of hypofractionated radiotherapy over time.
Researchers conducted median follow-up at 5 years.
Hypofractionated radiotherapy improved 5-year OS compared with conventional radiotherapy on unadjusted (77.1% vs. 73.5%; P < .001) and multivariable analyses (HR = 0.89; 95% CI, 0.81-0.98).
Improvement in 5-year OS persisted with hypofractionated radiotherapy when researchers analyzed patients with clinical stage TI disease (78.2% vs. 76%; P = .05) and T2 disease (70.8% vs. 64.5%; P = .02). On multivariable analysis, the association in stage I disease lost significance (HR = 0.93; 95% CI, 0.84-1.03), whereas the association remained significant in stage II disease (HR = 0.79; 95% CI, 0.65-0.96).
The use of hypofractionated radiotherapy increased during the study period, from 22.1% in 2004 to 58% in 2013.
“Radiation using doses of 2.25 Gy per day was associated with an OS benefit for patients with early-stage glottic cancer,” Husain said. “Fortunately, the patterns-of-care portion of the study showed that hypofractionated radiation was being increasingly utilized nationally. In 2004 the rate was low at about only 25%, but by 2013 — the last year we assessed — the rate was about 50%, which demonstrates a rapid uptake of the technique.”
Factors associated with receipt of hypofractionated radiotherapy included clinical T1 disease, recent year of diagnosis, and treatment at academic and high-volume centers (P < .001 for all).
Although the optimal radiotherapy regimen for early-stage glottic cancer remains controversial, researchers noted the data from their study, combined with those from previous clinical trials, provide support for hypofractionated radiotherapy.
“Based on the results of the study, we would strongly suggest that hypofractionated radiation therapy be the preferred approach for patients with early-stage glottic cancer,” Husain said. – by Chuck Gormley
For more information:
Zain A. Husain, MD, can be reached at Department of Therapeutic Radiology, Smilow Cancer Hospital, 35 Park St., Suite LL 515, New Haven, CT 06511; email: zain.husain@yale.edu.
Disclosure: Husain reports research funding from Merck. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
Back to TopPrimary radiotherapy is a standard treatment option for early-stage glottic cancer. There are variations in patterns of practice in terms of radiation fractionation regimens. The importance of time-dose fractionation considerations has long been recognized in radiotherapy for head and neck cancer. In locally advanced disease, randomized trials have demonstrated that altered-fractionated radiotherapy is associated with improvement in locoregional control compared with conventional fractionation delivering 2 Gy per day in patients treated with radiotherapy alone. Large meta-analyses have shown that this advantage translates into improved OS.
The benefit of altered fractionation in earlier stage disease is less firmly established. Accelerated radiotherapy using a hypofractionated regimen — 2.25 Gy per day, which shortens the treatment by a week compared with conventional fractionation — is a common regimen used for early glottic cancer with excellent long-term outcomes reported in large single institution experiences. Several prospective randomized trials have compared accelerated radiotherapy using a hypofractionated regimen or hyperfractionation (1.2 Gy twice daily) with conventional fractionation in early glottic cancer. These studies demonstrate similar findings — about an 8% to 15% increase in local control with accelerated radiotherapy — although they do not consistently reach statistical significance. Cancer-specific survival is modestly higher in the accelerated radiotherapy arms of these studies, but without reaching statistical significance. It is possible that a survival advantage exists, but these studies are underpowered to confirm it.
Bledsoe and colleagues offer a nice analysis exploring survival outcomes as they relate to patients treated with hypofractionated or conventional fractionation radiotherapy for early glottic cancer (cT1-T2N0) based on data from the National Cancer Data Base for patients treated from 2004 to 2013. Overall, about 40% of patients underwent a hypofractionated regimen and 60% underwent conventional fractionation. Patterns of practice shifted to 58% treated with hypofractionation by the last year of the study period.
By analyzing a large cohort of more than 10,000 patients, this study has strength in numbers. Researchers found that hypofractionation modestly improved OS over conventional fractionation (5-year OS, 77% vs. 73.5%), which reached statistical significance on univariate and multivariate analysis.
Subset analysis by T stage found that the advantage of hypofractionation lessened for T1 disease (5-year OS, 78.2% vs. 76%) and no longer reached statistical significance on multivariate analysis. T2 disease demonstrated a more pronounced advantage (5-year OS, 70.8% vs. 64.5%), while still maintaining statistical significance. These findings make intuitive sense — with greater disease burden, the advantage of altered fractionation becomes more significant — and are in line with the wealth of data in locally advanced disease supporting this concept.
Limitations in this analysis are tied to the obvious limits of any retrospective analysis to account for all possible confounders. In addition, data regarding actual local disease control outcomes were not available, nor were data regarding the use of eventual salvage therapies including surgical salvage, which would impact on survival outcomes. Importantly, available retrospective and randomized studies as noted above suggest that hypofractionation in this patient population is well tolerated and associated with similar acute and late toxicity as conventional fractionation. In addition, there is advantage in terms of patient convenience and cost effectiveness of a shorter treatment course. These data add to the available literature supporting the routine use of hypofractionation in patients with early glottic carcinoma.
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Bourhis J, et al. Lancet. 2006;doi:10.1016/S0140-6736(06)69121-6.
Fu KK, et al. Int J Radiat Oncol Biol Phys. 2000;48:7-16.
Mendenhall WM, et al. J Clin Oncol. 2001;doi:10.1200/JCO.2001.19.20.4029.
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Yamazaki H, et al. Int J Radiat Oncol Biol Phys. 2006;doi:10.1016/j.ijrobp.2005.06.014.
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