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ORIGINAL ARTICLE
Increased local failure risk with prolonged radiation treatment time in head and neck
cancer treated with concurrent chemotherapy
Donald M. Cannon, MD,1* Heather M. Geye, MS,1,2 Gregory K. Hartig, MD,2 Anne M. Traynor, MD,3 Tien Hoang, MD,3
Timothy M. McCulloch, MD,2 Peggy A. Wiederholt, RN,1 Richard J. Chappell, PhD,4 Paul M. Harari, MD1
1
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 2Department of Surgery – Otolaryngology, Head and Neck
Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 3Department of Medicine – Medical Oncology, University of Wisconsin School of
Medicine and Public Health, Madison, Wisconsin, 4Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison,
Wisconsin.
Accepted 10 June 2013
Published online 27 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23419
ABSTRACT: Background. Prolonged radiation treatment time (RTT) in
head and neck squamous cell carcinoma (HNSCC) is associated with
inferior tumor control in patients treated with radiation therapy (RT)
alone. However, the significance of prolonged RTT with concurrent
chemotherapy is less clear.
Methods. We reviewed outcomes for 171 patients with primary HNSCC
treated with curative intent RT and concurrent drug therapy from 2001
to 2009. The effects of RTT and other variables on local control and survival were analyzed.
Results. Patients with RTT >7 weeks had a significantly increased
risk of local failure (hazard ratio [HR], 2.6; p 5 .018) and death (HR, 1.9
INTRODUCTION
Radiation therapy (RT) with concurrent chemotherapy has
been embraced as a standard of care for the treatment for
locally advanced head and neck squamous cell carcinoma
(HNSCC) in appropriately selected patients. Compared to
radiation alone, this approach has been associated with an
approximately 6.5% improvement in overall survival,1 but
at the expense of increased toxicity. Side effects in the
form of mucositis, neutropenia, fatigue, and dehydration
may occasionally require treatment breaks and therefore
prolong treatment time.
Although treatment breaks (planned or unplanned) may
allow for some tempering of treatment toxicity, evidence
from multiple retrospective studies has shown that prolonged treatment time is associated with inferior outcome
in patients with HNSCC treated with RT alone.2–7 This
has been attributed largely to accelerated repopulation of
tumor clonogens.3 For patients with HNSCC treated with
RT alone, prospective randomized clinical trials have
*Corresponding author: D. M. Cannon, Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave
K4/B100, Madison, WI 53792. E-mail: [email protected]
This work was presented in part at the American Society for Radiation Oncology (ASTRO) 53rd Annual Meeting in Miami, Florida, October 2011.
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p 5 .035). These results retained significance even after adjustment for
tumor stage (age was not significant).
Conclusion. For patients treated with concurrent chemoradiotherapy
(chemoRT), prolonged RTT may compromise tumor control as has been
established in the setting of RT alone. Symptoms of patients with HNSCC
undergoing definitive chemoRT should be managed aggressively to limit
C 2013 Wiley Periodicals, Inc. Head Neck 36:
treatment interruptions. V
1120–1125, 2014
KEY WORDS: head and neck cancer, chemoradiotherapy, accelerated repopulation, treatment time, prognostic factors
shown benefit to treatment acceleration in an effort to
counter the effects of repopulation.8–10
In contradistinction to the setting of patients treated
with RT alone, recent randomized controlled trials demonstrate no benefit to treatment acceleration in patients
undergoing concurrent chemoradiotherapy (chemoRT)
for locally advanced HNSCC.11,12 This result, however,
does not necessarily exclude a detriment in outcome
with prolonged treatment times for patients treated with
chemoRT. Sher et al13 recently reported a post hoc analysis of data from the TAX-324 study evaluating induction chemotherapy followed by radiation with concurrent
carboplatin in locally advanced HNSCC and found that
prolonged radiation treatment time (RTT) was associated
with a significantly inferior overall survival and locoregional control rate, independent of other prognostic
factors.
Beginning in the year 2000, the majority of medically
fit patients at our institution undergoing definitive RT for
locally advanced HNSCC were treated with concurrent
chemotherapy. We sought to evaluate the impact of RTT
on outcome in these patients as it has been our institutional practice to maintain treatment breaks to a strict
minimum. We postulate that in patients with HNSCC
receiving concurrent chemoRT, overall RTT remains an
important variable that may influence ultimate clinical
outcome.
IMPACT
MATERIALS AND METHODS
Patient selection
The University of Wisconsin Hospitals and Clinics
Institutional Review Board approved this retrospective
study. From 1990 to the present, a database of all consenting patients with head and neck cancer treated at the
University of Wisconsin has been maintained and updated
in a prospective fashion under institutional review board
approval and with written patient consent. As mentioned
above, concurrent chemotherapy has been recommended
routinely for suitable patients at our institution from
approximately 2000 forward. We limited our analysis to
patients with stage III or nonmetastatic stage IV HNSCC
treated with primary radiation and concurrent drug therapy (including cetuximab) between the years 2001 and
2009. The following disease subsites were included: oropharynx, nasopharynx, hypopharynx, and larynx. Specifically, patients with T1N0 or T2N0 tumors of the glottic
larynx were excluded, as were patients with oral cavity
tumors (the vast majority of whom were treated with primary surgery), unknown primary, those treated after radical surgery to the primary tumor, and patients with
recurrent disease. Patients receiving palliative doses of
radiation (ie, <60 Gy) were also excluded from the analysis. The p16 immunohistochemistry results were available
for a subset of patients and were included in the analysis.
Statistical analysis and definition of variables
The RTT was defined as the duration in days of the
entire course of radiotherapy. For comparison to prior
reports,14 we calculated an average weekly dose (AWD),
which was defined as D 3 7 4 RTT, where D is the total
dose delivered to the primary tumor. For each patient we
also defined DRTT as RTT minus the number of days
that would be expected for the patient to complete their
given fractionation schedule (assuming a Monday start).
Local control of the primary tumor was the primary endpoint of the study, with the time to event of interest
defined from initiation of RT. Death from any cause was
analyzed as a secondary endpoint. Patients were censored
at the time of their last follow-up at the cancer center.
Estimates of local control and overall survival were
obtained via the Kaplan–Meier method.
A Cox proportional hazards model was used to analyze
variables associated with local control and overall survival. RTT was analyzed as a continuous variable and as
a dichotomous variable with cut points at the median and
between the third and fourth quartile. This was done in
similar fashion to Sher et al13 because of a very narrow
distribution of RTT among patients with a difference
between the first quartile and median RTT of only 1 day.
Tests for imbalances among patient groups were performed using Fisher’s exact test for categorical variables
or the t test for continuous variables.
RESULTS
Patient characteristics
The characteristics of the 171 patients who met study
criteria are summarized in Table 1 along with the distribution of the types of fractionation schedules used. The
OF CONCURRENT RADIOCHEMOTHERAPY TREATMENT TIME IN
HNSCC
TABLE 1. Patient and tumor characteristics.
Characteristic
No.
(%)
Total no. of patients
Age, y
<60
60–70
>70
Sex
Male
Female
Disease site
Nasopharynx
Oropharynx
Hypopharynx
Larynx
Stage
III
IV
T classification
T1–2
T3–4
N classification
N0–1
N2–3
Chemotherapy, drug*
Cisplatin
Cetuximab
Other
p16 status
Positive
Negative
Not available
Chemotherapy sequencing
Concurrent
Neoadjuvant and concurrent
Fractionation scheme
Six fractions/wk
Concomitant boost
Once daily
171
(100%)
109
51
11
(64)
(30)
(6)
139
33
(81)
(19)
19
118
13
21
(11)
(69)
(8)
(12)
20
151
(12)
(88)
85
86
(50)
(50)
31
140
(18)
(82)
162
13
20
(94)
(8)
(12)
26
2
143
(15)
(1)
(84)
162
10
(94)
(6)
6
34
131
(4)
(20)
(77)
*Note that some patients received more than 1 type of drug with treatment, thus totals add to
greater than 100%.
median age was 57 years (range, 36–83 years). Median
follow-up was 43 months (range, 4–110 months) and
>75% of patients had follow-up more than 2 years. The
majority of patients were treated with concurrent weekly
cisplatin 30 mg/m2, and treated to doses of 65.6 to 74.4
Gy (median, 70 Gy) with the most common prescription
dose being 70 Gy in 33 fractions (49% of patients).15 A
significantly higher percentage of patients with N0 or N1
disease had advanced tumors (T3 or T4) compared with
patients with N1 or N2 disease (84% vs 43%; p < .005).
Patients who received drug therapy before radiation had
similar average RTT compared to those without any prior
drug therapy (47.4 vs 46.7 days; p 5 .48). Six of these
10 patients were treated with a single dose of bevacizumab before RT as part of an institutional clinical trial,
whereas the others received only 1 or 2 cycles of chemotherapy before RT.
The distribution of RTT among patients was relatively
narrow, with a median RTT of 46 days (range, 39–58
days). The upper quartile consisted of 36 patients (21%)
with an RTT >49 days, and only 3 patients (2%) had an
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RTT >56 days. For the 131 patients (77%) treated with
once-daily fractionation, the median RTT was 47 days
(range, 42–58 days) whereas for the 34 patients (20%)
treated with a concomitant boost fractionation schedule,
median RTT was 44 days (range, 40–58 days). The 6
patients (4%) treated with 6 fractions per week on Radiation Therapy Oncology Group 0522 had a median RTT of
39 days (range, 39–41 days). No planned breaks were
incorporated into any treatment schedules.
effect of induction chemotherapy (p 5 0.69) or total dose
(p 5 .88) but, interestingly, N2 or N3 nodal disease was
a predictor for local control, which was not unusual given
the less advanced T classification compared to N0 or N1
patients, as described above. There was a trend for
patients treated with an AWD >10 Gy/week to be at
decreased risk for local recurrence (p 5 .06). The parameter DRTT, intended to be a surrogate for treatment
breaks, was not significant, but given its retrospective
definition does contain some uncertainty in accurately
accounting for all deviations from a prescribed radiation
course.
Adjusting for T classification, patients with RTT >49
days still had significantly higher risk for local failure
(HR, 2.4; 95% CI, 1.07–5.2; p 5 .044) and the trend for
increased risk with RTT as a continuous variable persisted but with diminished significance (HR, 1.09; 95%
CI, 0.99–1.2; p 5 .07). When patients treated with induction drug therapy were excluded, the effect on worse local
control with RTT >49 days persisted (HR, 2.3; p 5
.044).
The p16 status was not included in the univariate analyses for local control and overall survival because only 2
of 28 patients with immunohistochemistry data were p16negative. However, an exploratory analysis showed that
in the subset of 26 patients who were classified as p16positive, RTT >49 days was still significant for local failure (HR, 1.24; 95% CI, 1.3–33; p 5 .022), although RTT
as a continuous variable was not significant (p 5 .13).
When adjusting for all primary tumor subsites in a multivariate proportional hazards model, RTT >49 days was
still significant for local failure at p 5 .031, although
when analyzed as a continuous variable it was no longer
significant (p 5 .067).
Impact on local control
Impact on overall survival
A total of 26 patients (15%) experienced local failure,
with a 5-year local control rate of 83% (95% confidence
interval [CI], 77% to 90%). The distribution of RTT
coded for local disease control is shown in Figure 1. Univariate analysis of factors potentially affecting local control showed that when RTT was analyzed as a continuous
variable, there was an increased risk of local failure for
each day of RTT (p 5 .049). As shown in Figure 2A,
patients in the upper quartile of RTT (>49 days) had a
higher local recurrence rate compared to those with RTT
49 days (p 5 .014 by log-rank test). With this grouping,
there was no difference between the percentage of
patients with advanced (T3 or T4) tumors (56% and 49%
for RTT and >49 days, respectively; p 5 .57), mean
age (p 5 .73), or those treated with induction chemotherapy (p 5 .69). For patients treated with RTT > median
RTT (46 days), the trend for worse local control persisted, although was not statistically significant (hazard
ratio [HR], 1.95; p 5 .097). Limiting the analysis to
patients treated over a course of 7 weeks or less, there
was no significant difference (p 5 .35) in risk for local
failure in those treated within 6 weeks (42 days) versus
those treated within 7 weeks (range, 43–49 days).
A summary of the univariate analysis of local control is
given in Table 3. As expected, more advanced tumor was
associated with local failure (p 5 .002). There was no
Overall survival at 5 years for the entire cohort was
74% (95% CI, 63% to 78%). The results of a univariate
analysis describing risks of death from any cause are
shown in Table 3. A significant increased risk was found
in patients with RTT >49 days (Figure 2B; p 5 .035 by
the log-rank test). For patients treated with RTT >
median RTT, a similar trend was seen, but this was not
statistically significant (p 5 .06). However, when RTT
was modeled as a continuous variable, no significant
association was seen (p 5 .49). Age, sex, and use of
induction chemotherapy were not significantly associated
with overall survival on univariate analysis, but advanced
T classification was (p < .005). Both RTT >49 days and
advanced T classification were independently associated
with worse overall survival on multivariate analysis (p 5
.049 and < .005, respectively).
FIGURE 1. Histogram of radiation treatment time (RTT) according to
whether or not patients experienced a local failure or maintained primary tumor control after radiochemotherapy. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
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DISCUSSION
The relationship between RTT and outcome in patients
with HNSCC treated with RT and concurrent chemotherapy remains to be fully defined. A recent retrospective
study suggested that an AWD >10.0 Gy (which combines
total dose and the inverse of treatment time) was associated with improved locoregional control in patients
treated with radiation alone but not in patients treated
IMPACT
OF CONCURRENT RADIOCHEMOTHERAPY TREATMENT TIME IN
HNSCC
FIGURE 2. (A) Local control according to radiation treatment time (RTT). Patients with RTT 49 days had a superior 3-year local control rate compared
to those with RTT >49 days (88% vs 71%; p 5 .014 by log-rank test). (B) Overall survival according to RTT. Survival at 3 years was superior in patients
with RTT 49 days (81% vs 58%; p 5 .032 by log-rank test).
TABLE 2. Fractionation schedule characteristics.
Fractionation scheme
Representative schedules
Median RTT, d (range)
Median AWD, Gy (range)
Six fx/wk (n 5 6)
Concomitant boost (n 5 34)
Once daily (n 5 131)
70 Gy/35 fx (6 wk)
72 Gy/42 fx (6 wk)*
70 Gy/33 fx (6.5 wk)
70 Gy/35 fx (7 wk)
39 (39–41)
44 (40–58)
47 (42–58)
12.6 (12–12.6)
11.4 (8.5–12.6)
10.4 (8.2–11.7)
Abbreviations: RTT, radiation treatment time; AWD, average weekly dose; fx, fractions.
*Using BID dosing for last 12 treatment days as per Radiation Therapy Oncology Group 9003 (1.8 Gy to large field followed by 1.5 Gy to boost field >6 hours afterward).
TABLE 3. Univariate analysis of local control and overall survival.
Local control
Variables
HR (95% CI)
RTT, continuous (per d)
RTT upper quartile (>7 wk)
RTT > median
DRTT, continuous (per d)
AWD >10 Gy per wk
Dose to primary (per Gy)
T3 or T4 tumor
N2 or N3 nodal disease
Age at diagnosis > median (57 y)
Sex (male vs female)
Tumor subsite
Oropharynx
Nasopharynx
Larynx
Hypopharynx
Altered fractionation* (vs once daily)
Induction systemic therapy
1.1 (1–1.2)
2.6 (1.2–5.8)
1.95 (0.9–4.3)
1.04 (0.97–1.1)
0.48 (0.2–1.03)
1.02 (0.7–1.4)
4.9 (1.8–12.9)
0.44 (0.2–1.0)
1.6 (0.7–3.5)
1.4 (0.5–4.0)
1
2.6 (0.9–7.5)
1.4 (0.4–5.0)
4.0 (1.5–10.8)
0.9 (0.4–2.3)
1.3 (0.3–5.5)
Overall survival
p value
HR (95% CI)
p value
.049
.018
.097
.29
.06
.88
.002
.057
.23
.55
1.02 (0.96–1.1)
1.9 (1.1–3.3)
1.7 (0.98–2.9)
1.02 (0.97–1.1)
0.6 (0.3–1.02)
1.2 (0.95–1.5)
3.4 (1.8–5.8)
0.58 (0.3–1.1)
1.54 (0.9–2.6)
0.9 (0.56–2.1)
.47
.035
.058
.50
.06
.13
.0001
.073
.11
.81
NA
.068
.59
.006
.89
.69
1
1.8 (0.8–3.9)
2.0 (0.98–4.2)
3.1 (1.5–6.5)
1.4 (0.8–2.4)
0.39 (0.05–2.8)
NA
.13
.057
.003
.25
.35
Abbreviations: HR, hazard ratio; CI, confidence interval; RTT, radiation treatment time; DRTT, RTT minus the number of days that would be expected for the patient to complete their given fractionation schedule; AWD, average weekly dose; NA, not applicable.
*Altered fractionation includes concomitant boost technique or giving 6 fractions per week.
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with concurrent chemoRT.14 Two older studies using
split-course RT and concurrent chemotherapy found no
significant detriment in outcomes despite longer treatment
times.16,17 The report from the University of Chicago16
contained a multivariate analysis including duration of
radiation and total radiation dose, with only total dose
significant for local failure. However, the conclusion that
radiation treatment duration was not significant for local
control is confounded by the fact that 20 of 21 of the
local failures were in patients with recurrent disease who
were often treated to lower doses and with shorter treatment times. In this subset of patients, no predictor for
local control could be found because of the exceptionally
high risk for recurrence regardless of treatment duration
or dose. It is appreciated, however, that excellent local
control was found in the group with no prior therapy
despite having treatment durations ranging from approximately 60 to 160 days.
In contrast, the results of the present study provide support for the hypothesis that even in patients treated with
concurrent chemotherapy, prolonged RTT is associated
with inferior local control and possibly overall survival as
well. In our cohort of patients, significant and independent predictors for local failure were advanced T classification and RTT >7 weeks. When RTT was analyzed as a
continuous variable rather than using a cut-point of 7
weeks, it remained associated with a significant risk for
local failure (p 5 .049).
These results are congruent with those in the recent
study by Sher et al13 in which data from the TAX 324
trial was analyzed retrospectively for an effect of treatment duration on outcomes. This was a phase III trial
comparing docetaxel, cisplatin, and fluorouracil to cisplatin and fluorouracil as induction chemotherapy followed
by radiotherapy with concurrent carboplatin in patients
with newly diagnosed locally advanced HNSCC. Multivariable analysis showed that a prolonged radiotherapy
course (modeled both as a continuous variable and with a
cut-point at the upper quartile, or 8 weeks) was independently associated with an increased risk for locoregional
failure and death. However, overall treatment time
(defined as total duration of treatment including induction
and chemoRT) was not.
Results from retrospective analyses should be interpreted with an understanding of the possibility of hidden
biases and confounding variables. For the present study, it
is possible that prolonged RTT could be associated with
patient medical comorbidity because of less physiological
reserve to tolerate the rigors of treatment. We were not
able to rigorously adjust for underlying medical comorbidity with the available data, but, as a surrogate, we
observed that age did not vary significantly in patients in
the upper quartile of RTT compared to the remainder of
the cohort (p 5 .7) and was not a predictor for either
overall survival or local control.
We also cannot exclude that patients with shorter RTT
had tumors with a more favorable biology. Patients with
human papillomavirus (HPV)-positive HNSCC treated
with definitive chemoRT have been shown to have superior locoregional control and overall survival.11 As risk
factors and demographics in patients with HPV-positive
tumors are known to differ from patients with
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HPV-negative tumors,18,19 one can hypothesize that
patients with HPV-negative tumors may have been more
likely to have longer RTT because of medical comorbidity or less social support. We commenced routine HPV
testing for all oropharyngeal patients in 2009 and thus did
not have HPV data for this entire 2001 to 2009 cohort.
However, 28 patients within our cohort had p16 status
made available as part of a current research protocol.
Despite small numbers, when our analysis was limited to
the 26 confirmed p16-positive patients, the detrimental
effect of prolonged RTT on local control persisted. This
is consistent with the results of the Danish Head and
Neck Cancer Group 6 and 7 study in which the effect of
treatment time was independent of HPV status.20
Our data could also be viewed as resulting from the possibility that patients with larger tumors or more extensive
nodal disease would have larger volumes of sensitive tissue
receiving high-dose radiation and thus a given patient
would be more susceptible to toxicity requiring treatment
breaks. However, we did not find any significant difference
in the distribution of T classification in patients with longer
RTT. Interestingly, advanced nodal disease was inversely
correlated with risk for local failure. However, this was
likely because of a greater proportion of T3 and T4 tumors
in patients with N0 and N1 disease (p < .005). Also, when
adjusting for T classification, an effect on local control
with RTT >49 days was still seen.
Finally, some of our results were based on a cutoff at
the upper quartile of RTT and could be interpreted as statistical artifacts of a post hoc analysis. This cutoff, however, was not arbitrary13 and analysis of RTT as a
continuous variable also indicated an effect.
Although our data are consistent with the results of
randomized studies indicating that RT acceleration in the
setting of concurrent chemotherapy is of no significant
clinical benefit,11,12 the detriment seen with RTT >7
weeks can be used to inform selection of a fractionation
schedule. Similar to others,15 our current institutional
practice has been to prescribe a dose of 70 Gy in 33 fractions (2.12 Gy per fraction; 6.5 weeks) for the treatment
of gross disease in HNSCC. This provides a measure of
acceleration relative to a full 7-week course and allows
for a cushion of a few days in the event of a missed
treatment.
CONCLUSION
Despite select trials suggesting lack of benefit to accelerated fractionation in patients with HNSCC treated with
concurrent chemoradiation, our results from 171 patients
treated with definitive chemoradiation suggests that prolonged radiation treatment time may still be associated
with an adverse impact on local control and overall survival. For patients with HNSCC treated with curative intent
chemoradiation, attention to treatment time and strict limitation of treatment interruption seems to be warranted.
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