ORIGINAL ARTICLE
High daily fraction dose external radiotherapy for T1 glottic carcinoma: Treatment results
and prognostic factors
Melis Gultekin, MD,1 Enis Ozyar, MD,1 Mustafa Cengiz, MD,1 Gokhan Ozyigit, MD,1* Mutlu Hayran, MD,2 Sefik Hosal, MD,3 Fadil Akyol, MD1
1
Department of Radiation Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey, 2Department of Preventive Oncology, Faculty of Medicine, Hacettepe University,
Ankara, Turkey, 3Department of Ear, Nose, and Throat Surgery, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Accepted 20 May 2011
Published online 2 November 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.21860
ABSTRACT: Background. The purpose of this study was to investigate
the prognostic factors and treatment results of T1N0M0 glottic laryngeal
carcinoma irradiated with 2.3 Gray (Gy) per fraction.
Methods. A total of 183 patients with glottic carcinoma treated between
June 1998 and January 2007 were retrospectively evaluated. Of the 183
patients, 163 patients (89%) had T1a and 20 patients (11%) had T1b
disease. All patients received 2.3 Gy per fraction to a median total dose
of 64.4 Gy.
Results. The median follow-up was 63 months. The 5-year overall
survival (OS), local control, and cancer-specific survival rates were 89%,
81%, and 90%, respectively. Multivariate analysis showed overall
Glottic carcinoma is one of the most common head and
neck malignancies, and the goals of treatment are definite
cure and laryngeal voice preservation. Treatment for early
laryngeal cancer consists of radiotherapy (RT), surgery,
endoscopic surgery with cold steel, or laser resection.1,2
Voice quality is an important predictive factor of treatment decision. Providing the advantage of preserving
voice quality in most patients, RT is an excellent alternative for patients with early-stage glottic carcinoma.3,4
Highly successful local control rates with RT ranging
from 80% to 95% for T1 disease have been reported,
and with surgical salvage, the ultimate control rate is
98%.5 Several institutes reported 90% local control
rates using 2.1 to 2.25 Gray (Gy)/fraction with a shorter
overall treatment time.6,7 The only available prospective
randomized trial comparing conventional fractionation
with 2.25 Gy daily fraction showed that standard fractionation had a negative impact on treatment outcomes.8 In
our department, 2.3 Gy per fraction has been applied
since 1998, to reduce overall treatment time and to
improve local control in T1 glottic laryngeal carcinomas.
In this background, we undertook a retrospective study
on 183 patients with T1 glottic carcinoma treated with a
homogeneous RT fractionation scheme (2.3 Gy per frac-
*Corresponding author: G. Ozyigit, Department of Radiation Oncology, Faculty of
Medicine, Hacettepe University, Ankara, Turkey.
E-mail: [email protected]
treatment time and age to be significant prognostic factors for local
control and OS. We observed no grade IV or grade V acute toxicity.
Trachea–esophageal fistula as late toxicity was observed in only 1
patient.
Conclusions. High daily fraction scheme seems to be a feasible schedule
C 2011 Wiley Periodicals, Inc. Head Neck
for early glottic carcinomas. V
34: 1009–1014, 2012
KEY WORDS: larynx, early glottic carcinoma, radiotherapy,
prognostic factors
tion once a day) to determine whether any prognostic
factor could predict the outcome.
MATERIALS AND METHODS
The medical charts of patients with T1N0M0 glottic laryngeal carcinoma treated with definitive RT between
June 1998 and January 2007 at the Hacettepe University,
Department of Radiation Oncology, were retrospectively
evaluated. All patients were treated with curative intent
and a continuous course of external beam RT. All patients
were treated in the supine position with cobalt 60 using
bilateral parallel opposed wedged fields. A thermoplastic
immobilization mask was used during treatment. Bolus
was not used. Radiation dose was specified to the isocenter. In that treatment period CT planning was not used in
our department. Therefore, a dosimetric calculation was
taken from a contour plan from a single slice at the
isocenter.
Patients with nonsquamous cell carcinoma and <2
years of follow-up were excluded from analysis. Followup information was obtained from the department charts,
any hospital notes, referring doctors, general directorate
of population and citizenship affairs, and, as a last resort,
from patients and/or next of kin.
All statistical analysis was conducted using SPSS version 13.0 (SPSS Inc., Chicago, IL). Local control and survival analysis were carried out using the Kaplan–Meier
method and compared using the log-rank test. All timerelated events (failure or death) were calculated from the
diagnosis to last follow-up or death. Local control was
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defined as complete and continuous disappearance of tumor at the primary site. Cancer-specific survival (CSS)
and local control were assessed in addition to overall survival (OS). The Cox proportional hazards test was used
for multivariate analysis. Age (<60 vs 60 years), sex
(female vs male), subglottic extension (present vs absent),
anterior commissure involvement (present vs absent), T
classification (T1a vs T1b), smoking status (yes vs no vs
unspecified), overall treatment time (38 vs >38 days),
and radiation field size (36 vs >36 cm2) were included
as covariates. All analysis used the conventional p < .05
level of significance.
RESULTS
The median age was 59 years (range, 35–86 years).
There were 3 female patients and 180 male patients (2%
and 98%, respectively). The most common presenting
symptom was hoarseness (93%). The most common tumor location was right vocal cord (45%). Of the 183
patients, 163 patients (89%) had T1a and 20 patients
(11%) had T1b disease in accord with American Joint
Committee on Cancer (AJCC) classification (6th Edition,
2002).9 Histological grade for 44% of patients was not
otherwise specified. The anterior commissure was
involved in 31 patients (17%). The patient and tumor
characteristics are summarized in Table 1.
Patients were diagnosed with biopsy (79%), stripping
(16%), or cordectomy (3%). All patients were treated
with parallel opposed wedged fields. The median total
dose was 64.4 Gy (range, 59.8–66.7 Gy). All patients
received 2.3 Gy per fraction. All received continuouscourse irradiation, 5 days/week. The median overall treatment duration was 37 days (range, 31–70 days). We did
not use elective nodal irradiation. Field size was determined considering vocal cord movements and swallowing
during conventional simulation. Treatment details are
listed in Table 1.
The median follow-up was 63 months (range, 2–140
months). All living patients had at least 24 months of follow-up after RT. The data of 17 patients were received as
death from the general directorate of population and citizenship affairs; therefore, the last control information was
indicated as death due to local recurrence in these
patients. No patients developed distant metastases. Local
recurrence was detected in 41 patients (22%). Twentyone patients (12%) underwent salvage surgery (14 with
total laryngectomy, 7 with conservative surgery). Fourteen of the patients who underwent salvage surgery were
rescued (67%), and in 5 of 21 patients (23%), surgical
salvage was possible with function preservation. One
patient (1%) was reirradiated, and 6 patients (3%)
received palliative cisplatin-based chemotherapy. Twentytwo patients (12%) died due to local recurrence. One
patient (1%) was alive with metastatic second primary
carcinoma, and 4 patients (2%) died due to comorbid
medical diseases. We did not observe any nodal recurrence. At the time of reporting, 152 patients (83%) were
in complete remission, with no evidence of disease,
whereas 4 patients were alive with local recurrence. Eight
patients (4.2%) developed second primary malignancies.
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TABLE 1. Patient and disease characteristics and treatment details.
Factor
Patient characteristics
Age, y
<60
60
Sex
Male
Female
Presenting symptom
Hoarseness
Unspecified
Smoking status
Yes
No
Unspecified
Alcohol intake
Yes
No
Unspecified
Disease characteristics
Classification
T1a
T1b
AC involvement
Yes
No
Pathology
Well-differentiated SCC
Moderately differentiated SCC
Poorly differentiated SCC
NOS
Treatment details
Overall treatment time, day
38
>38
Field size, cm2
36
>36
No. of patients (%)
94 (51)
89 (49)
180 (98)
3 (2)
170 (93)
13 (7)
149 (81)
6 (3)
28 (16)
57 (31)
65 (36)
61 (33)
163 (89)
20 (11)
31 (17)
152 (83)
61 (33)
35 (19)
7 (4)
80 (44)
122 (67)
61 (33)
106 (58)
77 (42)
Abbreviations: AC, anterior commissure; SCC, squamous cell carcinoma; NOS, not otherwise
specified.
Local control
The actuarial 5-year local control rate was 81%. The
median interval for the development of local recurrence
was 20 months after RT. Univariate analyses revealed
that age, overall treatment time, and radiation field size
had a significant impact on local control (Table 2) (see
Figure 1 and Figure 2). Multivariate analysis showed
overall treatment time and age to be significant prognostic factors of local control (Table 3).
Survival
The actuarial 5-year OS rate was 89% and the CSS
rate was 90%, respectively. In univariate analysis, age (p
¼ .05), overall treatment time (p < .001), and radiation
field size (p ¼ .04) were the significant variables for CSS
(Table 2). Age (p ¼ .008) and overall treatment time (p
¼ .001) were significant factors for OS (Table 2) (see
Figure 1 and Figure 2). Involvement of the anterior commissure, radiation field size >36 cm2, and overall treatment time >38 days were found to be significant
TREATMENT
RESULTS OF EARLY-STAGE GLOTTIC CARCINOMAS
TABLE 2. Univariate analysis of prognostic factors for 5-year overall
survival, cancer-specific survival, and local control.
Variable
Sex
Female
Male
Age, y
<60
60
Smoking status
Yes
No
Unspecified
Classification
T1a
T1b
Subglottic
extension
Yes
No
AC involvement
Yes
No
Overall treatment
time, day
38
>38
Radiation field
size, cm2
36
>36
5-y cancer5-y overall
specific
survival p
survival
p
(%)
value (%)
value
.55
100
89
.58
100
90
.008
93
85
.05
.53
.63
.07
.13
.75
.53
.16
.001
75
82
<.001
95
81
.19
92
88
.98
.16
81
92
94
81
.29
83
64
75
90
78
92
.39
81
100
87
92
70
75
90
.05
86
77
89
100
93
92
67
.42
100
81
93
86
88
100
93
5-y local
control p
(%)
value
93
88
Acute grade III skin complications (moist desquamation) were observed in 6 patients (3%). Acute grade III
mucosal complications (diffuse coating and edema of
the vocal cords) were noted in 13 patients (7%). Seventeen patients (9%) required steroid administration for reversible laryngeal edema during RT. One of the physicians was concerned about probable laryngeal edema
and gave prophylactic steroid treatment. All patients
who developed severe complications had no treatment
break. We did not observe any grade IV or grade V
acute toxicities during RT. No patient required tracheostomy or laryngectomy as management of an RT complication. No patient required a permanent feeding tube.
As a late toxicity, trachea–esophageal fistula was
detected in 1 patient. It is difficult to attribute this toxicity only related to RT because this patient underwent
salvage total laryngectomy, occurring after a postradiotherapy time of 10 months.
DISCUSSION
.65
79
82
.03
85
74
.04
Complications of radiotherapy
.05
85
77
Abbreviation: AC, anterior commissure.
predictors of CSS in multivariate analysis (Table 3). Multivariate analysis also revealed that overall treatment time
>38 days and age 60 years were significant prognostic
factors for OS (Table 3).
This study reports on treatment results and prognostic
factors for local control, OS, and CSS in patients treated
for T1 glottic carcinoma with RT. We observed a 5-year
OS rate of 89% and a 5-year local control rate of 81%,
and we found that overall treatment time and age were
significant predictors both for OS and local control. Similarly, the 5-year local control rates reported in series of
patients with T1 disease treated with radiation ranges
from 85% to 94%, and an ultimate disease control rate
reaching 98% with salvage surgery.10,11
Numerous retrospective studies have evaluated the
influence of dose per fraction for T1 disease and demonstrated that larger dose per fraction yields better local
control rates.11–19 Burke et al12 reported control rates in
100 patients with T1 and T2 disease treated with 2 Gy
per fraction that was only 44% compared with 92% for
patients treated with a fraction size >2.1 Gy. Similar
FIGURE 1. Kaplan–Meier curves of local control (A) and overall survival (B) according to age.
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FIGURE 2. Kaplan–Meier curves of local control (A) and overall survival (B) according to overall treatment time.
studies also indicated that higher local control rates were
obtained with a larger dose per fraction (2.1–2.5 Gy).13,14
Spector et al15 reported the outcomes of 194 patients with
T1 glottic carcinoma treated with low-dose (ie, a mean
dose of 58 Gy over 6–7 weeks) or high-dose RT (ie, a
mean dose of 66.5 Gy at 2–2.25 Gy per fraction). In that
trial, high-dose RT had a better local control rate than
that of low-dose RT (89% vs 78%). According to a retrospective analysis reported by Rudoltz et al,16 patients
treated with <2 Gy/fraction had a local control rate of
62%; however, it significantly increased to 87% for those
treated with 2 Gy/fraction. Mendenhall et al18 reported
a 100% local control rate in patients with T1 glottic cancer treated with similar total doses of 61–67 Gy in
TABLE 3. Multivariate analysis of prognostic factors for 5-year overall
survival, cancer-specific survival, and local control.
Event
RR (95% CI)
5-year Overall survival
Overall treatment time, day (Ref. 38)
>38
Age, year (Ref. <60)
60
5-year Cancer-specific survival
AC involvement (Ref. No)
Yes
Radiation field size, cm2 (Ref. 36)
>36
Overall treatment time, day (Ref. 38)
>38
Age, year (Ref. >60)
60
5-year Local control
Overall treatment time, day (Ref. 38)
>38
Age, year (Ref. >60)
60
4.1 (1.8–9.7)
.001
4.0 (1.6–10.0)
.003
3.0 (1.1–8.1)
.031
2.7 (1.1–6.9)
.032
6.6 (2.5–17.6) <.001
2.4 (0.95–6.0)
.065
2.2 (1.2–4.2)
.017
2.2 (1.1–4.4)
.021
Abbreviations: RR, relative risk; CI, confidence interval; AC, anterior commissure.
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p value
JULY 2012
2.25 Gy fractions. On the contrary, the patients treated
with 2–2.2 Gy fractions had a local control rate of 80%
in that series. The use of RT with 2.25 Gy per fraction to
63 Gy in a continuous course involving fields limited to
glottis has been recommended by the University of Florida.20 Being the only prospective randomized study in the
literature, Yamazaki et al8 reported the comparison of RT
fraction dose and total treatment time for 189 patients
with T1N0 glottic cancers. In this study, daily fraction
doses of 2 and 2.25 Gy have been compared. They concluded that a daily fraction dose of 2 Gy and an increase
in overall treatment time had a negative impact in treatment outcomes. Fraction dose and overall treatment time
correlated so closely that it was difficult to determine
which the dominant factor was. Because of the very close
correlation between overall treatment time and fraction
size, they excluded the covariant overall treatment time
from the multivariate analysis. Their results were simultaneously affected by the overall treatment time and could
thus not reflect the importance of fraction size only. In
the current study, all patients were treated with 2.3 Gy/
fraction. This scheme shortened the overall treatment
time, which may have some potential radiobiologic
advantages over those of conventional fractionated RT.
Our local control and survival rates with this scheme
were comparable to those of previous series that used
high daily fraction doses (>2 Gy per fraction). Local control rates could be low compared with other series
because the last control information was indicated as
death due to local recurrence for 17 patients, reported as
death by the general directorate of population and citizenship affairs. We actually could not get local control data
and we could just learn that they were dead. Consequently, our local control rates might be around 90%.
Local control after irradiation is adversely influenced
by several parameters, including anterior commissure
involvement, increasing T classification, prolonged
overall treatment time, male sex, age, low pretreatment
hemoglobin level, large fields (>36 cm2), and poor
TREATMENT
RESULTS OF EARLY-STAGE GLOTTIC CARCINOMAS
histologic differentiation.13,21,22 Beam energy, daily
fraction size, and total dose were also found to be correlated with treatment outcomes.12,15 Several authors
suggested that overall treatment time is the most important prognostic factor.8,16,23 Rudoltz et al16 demonstrated a decrease in local control rate with increasing
overall treatment time (<43 days: 100%; >55 days:
50%). One of the other important prognostic parameters
is anterior commissure involvement. Fein et al6 and
Warde et al21 found involvement of this site to have
no impact on local control, whereas Le et al7 found it
to be statistically important. It is interesting, however,
that the only prospective randomized trial to date does
not find a significant influence of anterior commissure
involvement on local control.8 In the current report, we
found that age, anterior commissure involvement, overall treatment time, and radiation field size were important prognostic factors. Overall treatment time was not
prolonged in the older patients. Likewise, increased
toxicity was not observed in the same group. However,
in our results, older age adversely affected local control
and OS on multivariate analysis. A larger field might
have fewer geographic misses and could treat more
elective nodal areas; however, a larger field size was
associated with worse CSS on multivariate analysis.
The result could not be explained by any reason. However, Small et al22 also found that larger fields were
associated with poor outcomes. Since we used uniform
daily fraction dose and beam energy, we did not evaluate those factors.
Excellent local control and survival obtained with
high daily fraction doses generally did not cause unacceptable toxicity.8,13 Mendenhall et al13 showed that
shorter treatment time/larger fraction doses resulted in
higher rates of local control and larynx preservation
without a significant increase in acute morbidity.
Besides, voice preservation can be achieved without
any detrimental effect on voice quality. We previously
evaluated the voice quality in 27 patients receiving a
2.3 Gy daily fraction dose with objective voice analysis
methods, and we found that this fraction regimen did
not affect the voice quality.4 On the other hand, severe
complications were observed in trials using 3 Gy
fraction.24,25 In 15 years of follow up, van der Voet et
al23 reported grade 3–4 complications as >10% with
3 Gy fraction. Cellai et al3 conducted a retrospective
study, and they showed that larger field size, higher
total dose, and fraction dose significantly increased the
incidence of late effects. Minor and major complications were detected in 5% of patients treated with field
size <36 cm2 because those complication rates were
16% with field size >49 cm2. In our study, high acute
complication rates may be explained with the use of
larger field size (42% of the patients’ field size >36
cm2). However, we did not observe any serious acute
adverse event, and our late toxicity rate was 0.5%.
One of the main problems in patients with head and
neck cancer is the development of second primary cancer.
The incidence of the second primary cancer ranges
between 10% and 30%. The most common tumors are
lung and esophageal carcinomas.26 In our study, the second primary cancer rate was 4.2%. The most detected
cancer type is lung cancer. Because of having the possibility of the second primary cancer risk, the patients with
laryngeal carcinoma should be followed closely and the
exposition to carcinogenic agents, particularly smoking
and alcohol, must be prevented.
Our study has many limitations due to its retrospective
nature. Moreover, many patients did not attend regular
follow-up. Despite those limitations, the results of all retrospective studies along with 1 prospective study showed
that 2.1 Gy per day fraction is more effective, and can
be safely applied to patients with T1 glottic cancer.
CONCLUSION
Although it is retrospective in nature and therefore has
all the drawbacks of this type of analysis, a daily 2.3 Gy/
fraction scheme seems to be an acceptable treatment
schedule for early glottic carcinomas.
REFERENCES
1. Shah JP, Karnell LH, Hoffman HT, et al. Patterns of care for cancer of the
larynx in the United States. Arch Otolaryngol Head Neck Surg 1997;123:
475–483.
2. Ferlito A, Bradley PJ, Rinaldo A. What is the treatment of choice for T1
squamous cell carcinoma of the larynx? J Laryngol Otol 2004;118:
747–749.
3. Cellai E, Frata P, Magrini SM, et al. Radical radiotherapy for early glottic
cancer: results in a series of 1087 patients from two Italian radiation oncology centers. The case of T1N0 disease. Int J Radiat Oncol Biol Phys 2005;
63:1378–1386.
4. Selek U, Akyol F, Özyar E, et al. Daily high dose per fraction radiotherapy
in early glottic laryngeal tumors with concurrent analysis of voice quality
and vocal function. UHOD (Int J Hematol Oncol) 2003;13:190–199.
5. Fletcher GH, Goepfert H. Larynx and hypopharynx. In: Fletcher G, editor.
Textbook of radiotherapy. Philadelphia: Lea & Febiger; 1980.
pp 330–363.
6. Fein DA, Lee WR, Hanlon AL, Ridge JA, Curran WJ, Coia LR. Do overall
treatment time, field size, and treatment energy influence local control of
T1–T2 squamous cell carcinomas of the glottic larynx? Int J Radiat Oncol
Biol Phys 1996;34:823–831.
7. Le QT, Fu KK, Kroll S, et al. Influence of fraction size, total dose, and
overall time on local control of T1–T2 glottic carcinoma. Int J Radiat
Oncol Biol Phys 1997;39:115–126.
8. Yamazaki H, Nishiyama K, Tanaka E, Koizumi M, Chatani M. Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time. Int J
Radiat Oncol Biol Phys 2006;64:77–82.
9. American Joint Committee on Cancer. Manual for staging of cancer. 6th
ed. New York: Springer-Verlag; 2002.
10. Chatani M, Matayoshi Y, Masaki N. Radiation therapy for larynx carcinoma: long term results of stage I glottic carcinoma. Strahlenther Onkol
1993;169:102–106.
11. Wang CC. Carcinoma of the larynx. In: Wang C, editor. Radiation therapy
for head and neck neoplasms, 3rd ed. New York: Wiley–Liss; 1997.
pp 221–256.
12. Burke LS, Greven KM, McGuirt WT, Case D, Hoen HM, Raben M. Definitive radiotherapy for early glottic carcinoma: prognostic factors and implications for treatment. Int J Radiat Oncol Biol Phys 1997;38:37–42.
13. Mendenhall WM, Amdur RJ, Morris CG, Hinerman RW. T1–T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. J
Clin Oncol 2001;19:4029–4036.
14. Hellquist H, Lundgren J, Olofsson J. Hyperplasia, keratosis, dysplasia and
carcinoma in situ of the vocal cords: a follow-up study. Clin Otolaryngol
1982;7:11–27.
15. Spector JG, Sessions DG, Chao KS, et al. Stage I (T1 N0 M0) squamous
cell carcinoma of the laryngeal glottis: therapeutic results and voice preservation. Head Neck 1999;21:707–717.
16. Rudoltz MS, Benammar A, Mohiuddin M. Prognostic factors for local
control and survival in T1 squamous cell carcinoma of the glottis. Int J
Radiat Oncol Biol Phys 1993;26:767–772.
17. Kok G. Influence of the size of the fraction dose on normal and tumor tissue in cobalt-60 radiation treatment of carcinoma of the larynx and inoperable carcinoma of the breast. Radiol Clin Biol 1971;40:100–115.
18. Mendenhall WM, Parsons JT, Million RR, Fletcher GH. T1–2 squamous cell
carcinoma at the glottic larynx treated with radiation therapy: relationship of
HEAD & NECK—DOI 10.1002/HED
JULY 2012
1013
GULTEKIN ET AL.
dose fraction factors to local control and complications. Int J Radiat Oncol
Biol Phys 1988;15:1267–1273.
19. Yu E, Shenouda G, Beaudet MP, Black MJ. Impact of radiation therapy
fraction size on local control of early glottic carcinoma. Int J Radiat Oncol
Biol Phys 1997;37:587–591.
20. Mendenhall WM, Werning JW, Hinerman RW, Amdur RJ, Villaret DB.
Management of T1–T2 glottic carcinomas. Cancer 2004;100:
1786–1792.
21. Warde P, O’Sullivan B, Bristow RG, et al. T1–T2 glottic cancer managed by external beam radiotherapy: the influence of pretreatment hemoglobin on local control. Int J Radiat Oncol Biol Phys 1998;41:
347–353.
1014
HEAD & NECK—DOI 10.1002/HED
JULY 2012
22. Small W Jr, Mittal BB, Brand WN, et al. Results of radiation therapy in
early glottis carcinoma: multivariate analysis of prognostic and radiation
therapy variables. Radiology 1992;183:789–794.
23. van der Voet JC, Keus RB, Hart AA, Hilgers FJ, Bartelink H. The impact
of treatment time and smoking on local control and complications in T1
glottic cancer. Int J Radiat Oncol Biol Phys 1998;42:247–255.
24. Harwood AR, Tierie A. Radiotherapy of early glottic cancer—II. Int J
Radiat Oncol Biol Phys 1979;5:473–476.
25. Randall ME, Springer DJ, Raben M. T1–2 carcinoma of the glottis: relative hypofraction. Radiology 1991;179:569–571.
26. Schwartz LH, Ozsahin M, Zhang GN, et al. Synchronous and metachronous head and neck carcinomas. Cancer 1994;74:1933–1938.