tumors arising on true vocal cords result in hoarseness at an early stage , and the incidence of positive lymph nodes for t1 - 2 glottic cancer is low due to minimal lymphatic drainage . based on clinical presentations and a favorable prognosis ,
the aim of therapeutic management is not only tumor control but also preservation of laryngeal function .
radiotherapy ( rt ) and co2 laser excision are the first choice of treatments for early glottic cancer . although both modalities produce similar outcomes , rt is the preferred option for improved voice quality , especially in cases of bulky tumors , infiltrative growth pattern , and tumors with anterior commissural involvement .
the historical data reported 5-year overall survival rates of 80%-85% and local control rate of 79% .
in current retrospective studies , the 5-year local control rates were 85%-95% for t1 and 70%-80% for t2 with definitive rt , and cause - specific survival rates were usually higher than 90% [ 7 - 11 ] .
however , the total rt dose , fractionation scheme , and target volume have been dependent on the institution s policy .
the purpose of this study is to present our long - term results of definitive rt for early - stage squamous cell carcinoma of the glottis .
we analyzed the prognostic factors that had a significant impact on local tumor control and evaluated patterns of failure .
after receiving an approval from the institutional review board , we reviewed 438 patients with malignancy in the glottic larynx referred to our clinic between january 1981 and december 2010 .
two hundred twenty - two consecutive cases of t1n0 or t2n0 glottic cancer treated with definitive rt were identified . in our institution ,
patients with synchronous primary cancer and with medical history of prior surgery of the neck or chemotherapy were excluded .
the american joint committee on cancer ( ajcc ) staging system used in this study was t1 for a tumor confined to a single ( t1a ) vocal cord or both ( t1b ) vocal cords , and t2 for a tumor with supraglottic or subglottic extension , with or without impaired vocal cord mobility .
old cases of t2a and t2b before applying the sixth version of the ajcc s staging system were re - staged .
magnetic resonance imaging , and positron emission tomography - computed tomography were not routinely performed .
rt was delivered using two - dimensional ( 2d ) conventional rt until 2005 , and the three - dimensional ( 3d ) conformal technique was used since 2006 .
the beam energy consisted of co and 4-mv or 6-mv photons , and co was used until 1992 .
right / left or right anterior oblique / left anterior oblique beams were used in 2d conventional rt , and the field size ranged from 20 to 42 cm based on the anatomy and extent of the disease . in the 3d conformal technique ,
the clinical tumor volume ( ctv ) was defined as the whole larynx , and the planning target volume was an expansion of ctv by 0.5 cm .
the borders of the rt field were ( 1 ) superior : lower level of hyoid bone , ( 2 ) inferior : lower margin of cricoid cartilage , ( 3 ) anterior : beyond the skin surface , and ( 4 ) posterior : anterior border of the vertebral body of cervical spine .
paired wedge filters of 15 , 30 , or 45 were used to improve dose homogeneity .
the median total rt dose was 66 gy ( range , 60 to 76 gy ) .
t1 and t2 patients received a median of 65 gy ( range , 60 to 76 gy ) and 67 gy ( range , 60 to 70.75 gy ) , respectively .
the fraction size ranged from 1.75 to 2 gy until december 1998 , and 2.5 gy was administered since january 1999 .
fifty - nine patients ( 38.1% ) with t1 and 11 ( 16.4% ) with t2 disease were treated with 2.5 gy / fx .
the median overall treatment time was 48.0 days ( range , 27.9 to 77.1 days ) for t1 and 53.1 days ( range , 32.1 to 69.0 days ) for t2 disease .
all patients were treated once daily with five fractions per week . as patients were treated with different doses and fractionation schemes , the biologically effective dose ( bed ) for tumors was calculated by considering tumor proliferation based on a linear quadratic model .
the definition of bed is the total dose multiplied by relative effectiveness , which is the first part of the above equation .
the second part consists of time - dependent factors that involve the compensatory effect of tumor repopulation during the treatment .
3 ) / : the dose at which the linear and quadratic portions of the cell killing are equal in radiation biology .
4 )  : the cell killing per gy on a log - linear plot of the linear quadratic model .
the range of 0.3 - 0.35/gy has been accepted for most epithelial tumors , and 0.35/gy was used in the present study .
6 ) tk ( day ) : the kick - off time , denoting the time between the start of treatment and the initiation of accelerated proliferation during the treatment .
7 ) tp ( day ) : the potential doubling time , representing the average doubling time of cancer cells during the treatment .
after the completion of rt , a radiation oncologist and/or otolaryngologist conducted regular follow - up evaluations .
the pre- and post - rt change in voice quality were recorded as  aggravated , ditto , and improved in a self - reported fashion .
acute and late toxicities were assessed according to common terminology criteria for adverse events ver .
overall survival ( os ) was defined as the interval from the start date of rt to the date of death .
local recurrence - free survival ( lrfs ) was defined as the interval from the start date of rt to the date of the diagnosis of local tumor recurrence .
the survival differences according to clinicopathological factors were evaluated by a two - sided log - rank test .
the results of the analyses were declared statistically significant if the p - value was less than 0.05 .
statistical analyses were performed with spss ver . 20.0 software ( ibm corp . , armonk , ny ) .
after receiving an approval from the institutional review board , we reviewed 438 patients with malignancy in the glottic larynx referred to our clinic between january 1981 and december 2010 .
two hundred twenty - two consecutive cases of t1n0 or t2n0 glottic cancer treated with definitive rt were identified . in our institution ,
patients with synchronous primary cancer and with medical history of prior surgery of the neck or chemotherapy were excluded .
the american joint committee on cancer ( ajcc ) staging system used in this study was t1 for a tumor confined to a single ( t1a ) vocal cord or both ( t1b ) vocal cords , and t2 for a tumor with supraglottic or subglottic extension , with or without impaired vocal cord mobility .
old cases of t2a and t2b before applying the sixth version of the ajcc s staging system were re - staged .
magnetic resonance imaging , and positron emission tomography - computed tomography were not routinely performed .
rt was delivered using two - dimensional ( 2d ) conventional rt until 2005 , and the three - dimensional ( 3d ) conformal technique was used since 2006 .
the beam energy consisted of co and 4-mv or 6-mv photons , and co was used until 1992 .
right / left or right anterior oblique / left anterior oblique beams were used in 2d conventional rt , and the field size ranged from 20 to 42 cm based on the anatomy and extent of the disease . in the 3d conformal technique , the clinical tumor volume ( ctv ) was defined as the whole larynx , and the planning target volume was an expansion of ctv by 0.5 cm .
the borders of the rt field were ( 1 ) superior : lower level of hyoid bone , ( 2 ) inferior : lower margin of cricoid cartilage , ( 3 ) anterior : beyond the skin surface , and ( 4 ) posterior : anterior border of the vertebral body of cervical spine . paired wedge filters of 15 , 30 , or 45 were used to improve dose homogeneity .
the median total rt dose was 66 gy ( range , 60 to 76 gy ) .
t1 and t2 patients received a median of 65 gy ( range , 60 to 76 gy ) and 67 gy ( range , 60 to 70.75 gy ) , respectively .
the fraction size ranged from 1.75 to 2 gy until december 1998 , and 2.5 gy was administered since january 1999 .
fifty - nine patients ( 38.1% ) with t1 and 11 ( 16.4% ) with t2 disease were treated with 2.5 gy / fx .
the median overall treatment time was 48.0 days ( range , 27.9 to 77.1 days ) for t1 and 53.1 days ( range , 32.1 to 69.0 days ) for t2 disease .
all patients were treated once daily with five fractions per week . as patients were treated with different doses and fractionation schemes , the biologically effective dose ( bed ) for tumors was calculated by considering tumor proliferation based on a linear quadratic model .
the definition of bed is the total dose multiplied by relative effectiveness , which is the first part of the above equation .
the second part consists of time - dependent factors that involve the compensatory effect of tumor repopulation during the treatment .
3 ) / : the dose at which the linear and quadratic portions of the cell killing are equal in radiation biology .
4 )  : the cell killing per gy on a log - linear plot of the linear quadratic model .
the range of 0.3 - 0.35/gy has been accepted for most epithelial tumors , and 0.35/gy was used in the present study .
6 ) tk ( day ) : the kick - off time , denoting the time between the start of treatment and the initiation of accelerated proliferation during the treatment .
7 ) tp ( day ) : the potential doubling time , representing the average doubling time of cancer cells during the treatment .
after the completion of rt , a radiation oncologist and/or otolaryngologist conducted regular follow - up evaluations .
the pre- and post - rt change in voice quality were recorded as  aggravated , ditto , and improved in a self - reported fashion .
acute and late toxicities were assessed according to common terminology criteria for adverse events ver .
overall survival ( os ) was defined as the interval from the start date of rt to the date of death .
local recurrence - free survival ( lrfs ) was defined as the interval from the start date of rt to the date of the diagnosis of local tumor recurrence .
the survival differences according to clinicopathological factors were evaluated by a two - sided log - rank test .
the results of the analyses were declared statistically significant if the p - value was less than 0.05 .
statistical analyses were performed with spss ver . 20.0 software ( ibm corp . , armonk , ny ) .
the median age was 60 years ( range , 35 to 86 years ) , with male preponderance ( male : female=43.4:1 ) .
t1a and t1b diseases were observed in 122 ( 55% ) and 33 ( 15% ) patients , respectively , and 56 ( 25% ) patients had tumors with anterior commissural involvement . with the median bed15 of 74.67 gy15 ( range , 67.88 to 85.96 gy15 )
, a total bed15  74.67 gy15 was delivered to 107 patients ( 48% ) , and the fraction size was < 1.8 gy in 11 ( 5% ) , 1.8 gy in 115 ( 52% ) , 2 gy in 26 ( 12% ) , and 2.5 gy in 70 ( 31% ) patients .
the median overall treatment time was 50 days ( range , 28 to 77 days ) .
the photon energy of 4 mv or 6 mv was used in 129 ( 58% ) patients .
the median duration of follow - up was 85.2 months ( range , 11.0 to 313.1 months ) .
the 5-year rates of lrfs and ultimate lrfs with voice preservation were 87.8% and 90.3% , respectively ( fig . 1a and b ) . in the univariate analysis for lrfs , t - stage ( t1 vs. t2 , p < 0.001 ) , anterior commissural involvement ( no vs. yes , p < 0.001 ) , rt fraction size ( 2.5 gy vs. < 2.5 gy , p=0.042 ) , and overall treatment time ( < 50 days vs.  50 days , p=0.001 ) were statistically significant ( table 2 ) . in the multivariate analysis , t2 disease ( hazard ratio [ hr ] , 2.30 ; 95% confidence interval [ ci ] , 1.08 to 4.94 ) and anterior commissural involvement ( hr , 3.37 ; 95% ci , 1.62 to 7.02 ) were significantly poor prognostic factors .
the 5-year lrfs rates were 94.7% and 72.0% for t1 and t2 disease , respectively ( fig .
2a ) , and 91.9% and 75.7% for tumors without and with anterior commissural involvement , respectively ( fig .
the 5-year lrfs rates were 92.5% and 85.5% for an rt fraction size of 2.5 gy and < 2.5 gy , respectively ( fig .
3a ) , and 92.4% and 83.2% for overall treatment time of < 50 days and  50 days , respectively ( fig .
the treatment failure involved local recurrences in 34 patients , and the median time to relapse was 1.4 years ( range , 0.3 to 13.2 years ) .
three patients had regional recurrences , and the median time to recurrence was 4.0 years ( range , 2.5 to 4.3 years ) .
the initial treatment failure did not include distant metastasis in any of the patients . in patients with local relapse
four patients had recurred tumors in the area of the subglottis . in the 40 patients who underwent salvage treatment ,
salvage surgery ( total laryngectomy , partial laryngectomy , laryngofissure and cordectomy , laser microsurgery , or neck node dissection ) was performed in 37 .
four patients complained of aggravation of voice quality , and 16 reported an improved status or no change . at the time of analysis ,
death events due to aggravation of glottic cancer and other malignancies were observed in 16 and 15 patients , respectively .
forty - seven patients had died of old age or other medical comorbidities . among the patients who received salvage treatment , 16 had died . there were seven and three events of cause - specific death and death from other malignancies , respectively .
one hundred eighty - one ( 82% ) patients reported an improvement of voice quality after the completion of rt . two and nine
patients reported acute toxicities of grade 3 dysphagia and hoarseness , respectively , with symptoms subsiding within several months .
grade 3 or higher chronic toxicities were not reported , and no patient required permanent tracheostomy due to persistent laryngeal edema .
the median age was 60 years ( range , 35 to 86 years ) , with male preponderance ( male : female=43.4:1 ) .
t1a and t1b diseases were observed in 122 ( 55% ) and 33 ( 15% ) patients , respectively , and 56 ( 25% ) patients had tumors with anterior commissural involvement . with the median bed15 of 74.67 gy15 ( range , 67.88 to 85.96 gy15 )
, a total bed15  74.67 gy15 was delivered to 107 patients ( 48% ) , and the fraction size was < 1.8 gy in 11 ( 5% ) , 1.8 gy in 115 ( 52% ) , 2 gy in 26 ( 12% ) , and 2.5 gy in 70 ( 31% ) patients .
the median overall treatment time was 50 days ( range , 28 to 77 days ) .
the photon energy of 4 mv or 6 mv was used in 129 ( 58% ) patients .
the median duration of follow - up was 85.2 months ( range , 11.0 to 313.1 months ) .
the 5-year rates of lrfs and ultimate lrfs with voice preservation were 87.8% and 90.3% , respectively ( fig . 1a and b ) . in the univariate analysis for lrfs , t - stage ( t1 vs. t2 , p < 0.001 ) , anterior commissural involvement ( no vs. yes , p < 0.001 ) , rt fraction size ( 2.5 gy vs. < 2.5 gy , p=0.042 ) , and overall treatment time ( < 50 days vs.  50 days , p=0.001 ) were statistically significant ( table 2 ) . in the multivariate analysis , t2 disease ( hazard ratio [ hr ] , 2.30 ; 95% confidence interval [ ci ] , 1.08 to 4.94 ) and anterior commissural involvement ( hr , 3.37 ; 95% ci , 1.62 to 7.02 ) were significantly poor prognostic factors .
the 5-year lrfs rates were 94.7% and 72.0% for t1 and t2 disease , respectively ( fig .
2a ) , and 91.9% and 75.7% for tumors without and with anterior commissural involvement , respectively ( fig .
the 5-year lrfs rates were 92.5% and 85.5% for an rt fraction size of 2.5 gy and < 2.5 gy , respectively ( fig .
3a ) , and 92.4% and 83.2% for overall treatment time of < 50 days and  50 days , respectively ( fig .
at the time of analysis , tumor relapse was reported in 37 patients ( 17% ) .
the treatment failure involved local recurrences in 34 patients , and the median time to relapse was 1.4 years ( range , 0.3 to 13.2 years ) .
three patients had regional recurrences , and the median time to recurrence was 4.0 years ( range , 2.5 to 4.3 years ) .
the initial treatment failure did not include distant metastasis in any of the patients . in patients with local relapse , 28 had ipsilateral vocal cord recurrences .
in the 40 patients who underwent salvage treatment , salvage surgery ( total laryngectomy , partial laryngectomy , laryngofissure and cordectomy , laser microsurgery , or neck node dissection ) was performed in 37 .
four patients complained of aggravation of voice quality , and 16 reported an improved status or no change . at the time of analysis ,
death events due to aggravation of glottic cancer and other malignancies were observed in 16 and 15 patients , respectively .
forty - seven patients had died of old age or other medical comorbidities . among the patients who received salvage treatment , 16 had died . there were seven and three events of cause - specific death and death from other malignancies , respectively .
one hundred eighty - one ( 82% ) patients reported an improvement of voice quality after the completion of rt . two and nine
patients reported acute toxicities of grade 3 dysphagia and hoarseness , respectively , with symptoms subsiding within several months .
grade 3 or higher chronic toxicities were not reported , and no patient required permanent tracheostomy due to persistent laryngeal edema .
the primary aim of early glottic cancer treatment is to eradicate the tumor with preservation of the larynx .
the maintenance of voice quality and swallowing function after the treatment is also very important .
as there have been no randomized trials to compare conservative surgery with rt , the evaluation of treatment outcomes has been mainly based on retrospective studies .
the present study is also a retrospective analysis of definitive rt for t1 - 2n0 glottic cancer .
however , we analyzed the long - term results of large - scale data from a single institution .
as shown in table 4 , the 5-year rates of lrfs and os in the present study are comparable to the results of other series [ 7 - 11 ] . in the multivariate analysis ,
this result is consistent with that of other retrospective studies [ 14 - 17 ] .
tumors at the anterior commissure tend to spread into the thyroid cartilage , resulting in early progression with partial cartilaginous or extra - laryngeal invasion .
reported that the 5-year local control rates of tumors , with and without anterior commissural involvement , were 74% and 89% ( p=0.0027 ) , respectively .
demonstrated that underestimation of the extent of the tumor due to insufficient radiological imaging and underdosage at the air - tissue interface could result in a negative impact of anterior commissural involvement on tumor control .
although there is still some controversy , we suggest that anterior commissural involvement should be considered for routine staging systems . in previous studies , t2 stage
was independently associated with a lower cure rate . a retrospective study which analyzed tis - t2 tumors identified that t2 disease was the only independently significant factor .
burke et al .   demonstrated that t - stage was significant in local control ( p=0.0009 ) and underlined the treatment - related implications in t2 tumors with inferior tumor control .
although both rt and co2 laser excision are the standard management options , conservative surgery can not guarantee voice quality in t2 or bulky tumors . to enhance the cure rate of early glottic cancer , accurate staging and discussion on optimal therapeutic modality are needed .
decreasing the accelerated repopulation of cancer cells and shortening the overall treatment time are the main objectives . in a prospective randomized study , yamazaki et al .  
reported superior local control with 2.25 gy / fx compared with 2 gy / fx . more recently , moon et al .   designed a randomized trial and demonstrated that local progression - free survival of a group that received 2.25 gy / fx was not inferior to that of a conventional arm . in our institution ,
the dose per fraction for early glottic cancer was 1.8 to 2.0 gy / fx until december 1998 , and treatment with 2.5 gy / fx was started from january 1999 .
the absence of significant differences in the multivariate analysis according to fraction size ( 2.5 gy vs. < 2.5 gy ) and overall treatment time ( < 50 days vs.  50 days ) may be attributed to an insufficient follow - up duration of hypofractionation in comparison with the conventional treatment . therefore , a longer follow - up is needed to assess the treatment efficacy of the hypofractionation strategy .
this study calculated the tumor bed ( gy15 ) considering both total rt dose and time - related factors .
the local tumor control was not significantly different according to the value of bed  74.67 gy15 or < 74.67 gy15 , and altering the cutoff values also did not result in statistically significant differences .
although the level of tumor bed that is adequate to kill laryngeal tumor cells has not been definitively established , tong et al .   demonstrated that total bed15 less than 65 gy15was related to poorer tumor control .
considering that the lowest value of bed was 67.88 gy15 in the present study , we suggest that total bed15 was sufficiently high and a differential tumoricidal effect of definitive rt could not be verified . with regard to patterns of local failure
, most recurrent tumors occurred in the ipsilateral vocal cord , with no isolated contralateral recurrence observed .
therefore , we suggest that the prevention of ipsilateral vocal cord recurrence is important in early glottic cancer . as we treated the whole larynx in each case , the lack of contralateral failure could be due to the fact that the contralateral vocal cord was treated .
more recently , dosimetric studies have reported the feasibility of the ipsilateral vocal cord intensity - modulated rt ( imrt ) , mainly in t1 disease [ 21 - 23 ] .
although the sparing of the organs - at - risk ( contralateral vocal cord , arytenoids , swallowing muscles , carotid arteries , thyroid gland , and spinal cord ) is the main advantage of the technique , the problems of tumor motion , hot spots , and contouring errors have limited the use of imrt in early glottic cancer . in a comparative study regarding imrt and 2d rt planning ,
imrt using image - guided technique resulted in comparable target coverage with significant reduction of radiation dose in normal tissues .
the authors suggested the potential for better functional preservation with the equivalent tumor control in imrt .
as mentioned in the present study , the poorer treatment outcomes of t2 disease and tumors with anterior commissural involvement remain unresolved .
an earlier study demonstrated the importance of shorter overall treatment time and a larger fraction size to improve local control in t2 tumors . in a recent study on early glottic tumors with anterior commissural involvement , higher tumor bed and a larger fraction size
were significantly positively associated with better local control , and the authors suggested a negative impact of underdosage at the air - tissue interface on the tumor control in such patients . since the increase in tumor dose is limited due to the normal tissue toxicities , the highly conformal rt technique can be beneficial in such high - risk subgroups .
further analyses are necessary to investigate the feasibility of the new rt method in t2 disease or tumors with anterior commissural involvement .
researchers at the university of texas southwestern performed a phase i study of unilateral vocal cord rt for t1a glottic cancer ( choy h , personal communication ) .
the sequential dose - fractionation scheme was 50 gy/15 fx , 45 gy/10 fx , and 42.5 gy/5 fx , and the results have not been reported yet . in our institution ,
patients with t1 or t2 single vocal cord tumors , without anterior commissural involvement , have undergone boost irradiation with the 3d conformal technique since january 2011 .
the dose - fractionation scheme involves initial treatment of the larynx ( 50 gy/20 fx ) , followed by boost irradiation of the unilateral vocal cord site ( 20 gy/8 fx ) , with a total of 70 gy administered to the primary lesion . between january 2011 and december 2012 ,
a total of 20 patients underwent definitive rt with the boost technique . with short - term follow - up
, the local tumor control of the new method was not found to be inferior to the conventional method .
most inflammatory changes of the glottis were mild and asymptomatic , and no further aggravation of the gross findings was observed .
fifteen patients had residual inflammatory signs on the laryngoscopic examinations at 6 months to 1 year after the completion of rt , of whom eight patients showed the ipsilateral hyperemia and wall thickening with the contralateral vocal cord relatively clear and well - healed .
although the boost irradiation technique also treated the whole larynx , the dose reduction in the contralateral side with conformal rt technique showed favorable toxicity profiles .
further studies are required to evaluate the clinical benefit of the single vocal cord irradiation in early glottic cancer .
from the present long - term analyses of definitive rt in early glottic cancer , a high cure rate , tolerable toxicity , and favorable voice quality were obtained .
t2 stage and anterior commissural involvement were the most important prognostic factors related to worse local control , and further investigations of the optimal treatment strategies in the high - risk tumors are needed .
although a larger fraction size and shorter overall treatment time showed a potential relationship with better tumor control , longer follow - up is needed to confirm this finding .
the higher incidence of ipsilateral local failure points out the importance of reducing recurrences at the site of the primary tumor . in the local field
rt of t1 - 2n0 squamous cell carcinoma of the glottis , optimization of the rt method would be a remaining subject to improve the therapeutic index .
 purposethis study evaluates the long - term results of definitive radiotherapy ( rt ) for early glottic cancer . 
 clinical and treatment factors related to local control and patterns of failure are analyzed.materials and methodswe retrospectively reviewed 222 patients with t1 - 2n0 squamous cell carcinoma of the glottic larynx treated with definitive rt from 1981 to 2010 . 
 none of the patients received elective nodal rt or combined chemotherapy . 
 the median total rt dose was 66 gy . 
 the daily fraction size was < 2.5 gy in 69% and 2.5 gy in 31% of patients . 
 the rt field extended from the hyoid bone to the cricoid cartilage.resultsthe median age was 60 years , and 155 patients ( 70% ) had t1 disease . 
 the 5-year rates of local recurrence - free survival ( lrfs ) and ultimate lrfs with voice preservation were 87.8% and 90.3% , respectively . 
 t2 ( hazard ratio [ hr ] , 2.30 ; 95% confidence interval [ ci ] , 1.08 to 4.94 ) and anterior commissural involvement ( hr , 3.37 ; 95% ci , 1.62 to 7.02 ) were significant prognostic factors for lrfs . in 34 patients with local recurrence , tumors recurred in the ipsilateral vocal cord in 28 patients . 
 there were no contralateral vocal cord recurrences . 
 most acute complications included grade 1 - 2 dysphagia and/or hoarseness . 
 there was no grade 3 or greater chronic toxicity.conclusiondefinitive rt achieved a high cure rate , voice preservation , and tolerable toxicity in early glottic cancer . 
 t2 stage and anterior commissural involvement were prognostic factors for local control . 
 further optimization of the rt method is needed to reduce the risk of ipsilateral tumor recurrence . 
Introduction
Materials and Methods
1. Patients
2. Treatment and follow-up
3. Statistical analysis
Results
1. Clinical characteristics
2. Local control and related predictive factors
3. Patterns of failure
4. Salvage treatment and causes of death
5. Treatment toxicity
Discussion
Conclusion