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the two reports together emphasize the point that patients should
be closely followed by dedicated head and neck caregivers for the
duration of their lifetime to screen for new onset severe late
dysphagia.
Our study differs from RTOG 91-11 not only in its retrospective
nature but also in the radiotherapy fractionation and the intensity
of chemotherapy. Most patients in the current study received com-
bination cisplatin and 5-FU concurrent and conventional radio-
therapy and 37% received BID fractionation. Regardless, oncologic
outcomes in the current study appear similar or improved to those
described in RTOG 91-11 in terms of 5-year overall survival (58%
91–11 vs. 70% current study), locoregional control (54.8% 91–11
vs. 80% current study) and distant control (85.3% 91–11 vs. 84%
current study). A low rate of competing events combined with a
more intense chemotherapy regimen may have increased the inci-
dence of severe late dysphagia in the current study compared to
the current era of treatment with IMRT and single-agent
chemotherapy although power to detect this on univariate analysis
is limited.
This study highlights the challenge of measurement of late tox-
icity following radiotherapy in the management of head and neck
cancer. The insights RTOG 91-11 provided into the incidence, tim-
ing and nature of late toxic events were limited by the method of
recording a maximum grade late toxicity leading to the speculation
that the increased late mortality in the concurrent chemoradio-
therapy group reflected an increase in unmeasured or unrecorded
severe late dysphagia. Our study provides a more detailed analysis
accounting for competing risks of recurrence or death and suggests
that this explanation is incorrect. The analysis method we used is
therefore a strength of the current report in comparison to the
methods used by most studies investigating physician-reported
severe toxicity.
The univariate regression demonstrating an association
between twice-daily (BID) fractionation and severe late dysphagia
(
Table 4
) is likely related to practice patterns at our institution
rather than an independent contribution of fractionation. Twice-
daily radiotherapy with dose-escalation to 74.4 Gy was a regimen
used during the earliest years of this study for patients with locore-
gionally advanced disease in attempt to improve oncologic out-
comes
[5]
. Nearly all of these patients received combination
cisplatin and 5-FU along with conventional radiotherapy. There-
fore, the result on univariate analysis may be a surrogate for older
treatment regimens rather than a true independent contribution of
fractionation on severe late dysphagia. This is generally supported
by the long-term results of RTOG 90-03 which did not demonstrate
a clear difference in severe late toxicity within the hyperfraction-
ated arm compared to standard fractionation
[12]
.
The limitations of this study include its retrospective nature, a
modest sample-size, patients with an unknown cause of death
and the heterogeneity in radiotherapy and chemotherapy regimens
used. While the study-size is modest, in comparison the concurrent
chemotherapy arm of RTOG 91-11 analyzed 174 patients and expe-
rienced more attrition due to locoregional recurrence or death. The
follow-up in the current study, although less than RTOG 91-11,
appears sufficient to capture the majority of severe late dysphagia
events according to the cumulative incidence curves presented
(
Fig. 2
) but may be insufficient to capture very late dysphagia orig-
inating beyond 5 years and further study is required. Additionally,
six patients in our report died but the cause of death could not be
determined. This is a common challenge with elucidating a cause
of death and a similar rate was observed on RTOG 91-11 despite
the prospective nature of the trial. Although it is impossible to
say for sure, there is no reason to suggest that these patients suc-
cumbed to severe late dysphagia at a higher rate than the rest of
the cohort. In addition, the heterogeneity in chemotherapy and
radiotherapy techniques was inherent to changes in practice pat-
terns over the years. Although including older techniques limits
the application to modern patients, the low incidence of deaths
related to severe late dysphagia remains relevant in the modern
era and enforces that good candidates for larynx-preservation
should continue to be offered chemoradiotherapy. With modern
IMRT techniques and chemotherapy regimens, the incidence of
SLD is likely to continue to decrease.
Conclusion
In conclusion, after a detailed time-to-event analysis accounting
for the competing risks of recurrence or death in patients other-
wise eligible for larynx-preservation strategies, we did not identify
a contribution of severe late dysphagia to late mortality. Larynx
preservation should continue to be offered to patients who meet
criteria for RTOG 91-11. Because severe late dysphagia can occur
beyond five years, patients should be followed closely by a dedi-
cated head and neck caregiver to monitor for recurrence, second
primary or toxicity for the remainder of their lifetime. Future clin-
ical trials should carefully track the incidence of late toxicity to
allow for clarity in elucidating the timing and incidence of
radiotherapy-induced dysphagia.
Conflicts of interest/Financial disclosures
None declared.
Table 4
Univariate Fine-Gray competing risk regression for factors associated with severe late dysphagia.
HR
95% CI
p
Age
1.03
0.984–1.09
0.18
Smoking history
Current/After RT vs Never/Former
0.814
0.233–2.84
0.75
Pack-years smoking
0.995
0.985–1.00
0.32
Disease subsite
Supraglottic vs Glottic or NOS
1.35
0.526–3.46
0.53
T stage
T3–4 vs T2
1.82
0.417–7.93
0.43
N stage
N2a-3 vs N0-1
1.35
0.598–3.03
0.47
Grouped stage
Stage IV vs Stage III
1.71
0.745–3.92
0.21
Year treated
0.99
0.929–1.05
0.76
Neck dissection
Yes vs No
1.32
0.525–3.30
0.56
Chemo type
Multiagent vs Single agent
5.78
0.805–41.5
0.08
RT type
IMRT vs 3D
0.353
0.084–1.47
0.15
RT dose
0.937
0.743–1.18
0.58
Altered fractionation
BID vs QD
2.51
1.10–5.72
0.028
Feeding tube type
NG vs None
2.00
0.623–6.45
0.24
PEG vs None
1.94
0.606–6.21
0.26
NG vs PEG
1.03
0.407–2.62
0.94
M.C. Ward et al. / Oral Oncology 57 (2016) 21–26
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