Annals Academy of Medicine [626892]

32
Annals Academy of Medicine
A 13-Year Single Institutional Experience with Definitive Radiotherapy in
Hypopharyngeal Cancer
Dear Editor,
Patients with hypopharyngeal carcinoma often present
with locally advanced disease. Treatment options are
usually multimodality and involve surgery, radiotherapy
(RT) and chemotherapy. Definitive RT with or without
chemotherapy present a functional organ preservation
strategy in selected patients or in patients with extensive
inoperable local disease. Whereas upfront surgery followed
by adjuvant RT may be more appropriate in patients with
disease which limits the adequate recovery of speech and
swallowing function with organ preservation strategy.
Patients with significant cartilage destruction or bilateral
vocal cord destruction may also have better function after
laryngectomy and rehabilitation following surgery.
The landmark V A trial investigated the feasibility of organ
preservation in laryngeal cancer patients using sequential
chemotherapy-RT as an alternative to upfront surgery.1 More
than half of the patients had their larynx preserved with
comparable survival to the surgical group. This encouraging
result opened new avenues for application of this strategy
in patients with locally advanced cancer of other head and
neck primary sites. Similar conclusion was also established
in the subsequent EORTC 24981 trial which included 152
hypopharyngeal cancer patients.2,3
Concomitant radio-chemotherapy (CRT) strategy arose
from the RTOG 91-11 trial and meta-analysis which
demonstrated improved loco-regional control (LRC)
and laryngeal preservation rates compared to induction
chemotherapy followed by radical RT.4-7 This approach is
now widely practised in many centres worldwide.
We adopted the concurrent CRT approach as the organ
preservation strategy in treating selected patients with
hypopharyngeal cancer. The aim of our study was to
retrospectively review the outcome following curative
intent RT with or without chemotherapy in hypopharyngeal
cancer patients treated in our centre and also to determine
the prognostic factors on LRC and survival in this group
of patients.
Materials and Methods
This is a retrospective analysis of all patients with
hypopharyngeal cancer treated with curative intent RT in
our Department of Radiation Oncology in National Cancer
Centre Singapore (NCCS) between January 2000 and December 2013. Pretreatment evaluation included history
taking, clinical examination, endoscopic examination of
the upper aero-digestive tract and computer tomography
of the neck and chest. The patients were discussed in a
multidisciplinary tumour board and treatment decisions
were made based on stage of disease, performance status
and the anticipated swallowing and speech outcome. There
were a total of 58 eligible patients during this period.
Radiotherapy
All patients were immobilised with customised
thermoplastic mask and treated with 6MV photon
encompassing the primary bearing area and regional
lymph nodes. Patients who received upfront radical RT
were treated with 66-70 Gy delivered in 33-35 fractions,
whereas patients who received adjuvant RT were treated
with 60-66 Gy in 30-33 fractions.
The gross tumour volume (GTV) was defined as any
visible gross disease based on radiological and clinical
findings. High risk clinical target volume (CTV) is an
expansion of 5-10 mm margin around the GTV , and with
editing off natural tumour barriers. This volume was treated
with 66-70 Gy. Intermediate risk CTV included the possible
local subclinical infiltration of the primary site as well as
first echelon nodal stations and was prescribed 60 Gy. Low
risk CTV included regional nodal stations which are not
first echelon nodes and were not adjacent to the levels of
involved nodes and was prescribed 50 Gy. In the adjuvant
setting, the tumour bed and involved nodal stations were
treated to 60 Gy with a further 6 Gy boost to areas of
extracapsular extension or close/positive margin.
Twenty-nine of 58 patients were treated using a
2-dimensional (2D) technique and the other 29 with intensity
modulated radiotherapy (IMRT). In the IMRT technique,
all dose levels were delivered within the same plan with
the higher doses effected through a simultaneous integrated
boost. In the 2D technique, the RT was delivered via 2
shaped lateral parallel opposed fields with a low anterior
neck match in 2 or 3 phases using shrinking field technique.
Follow-Up
Patients were reviewed at least once a week during
RT. Thereafter, patients were reviewed once a month
for the first year, 2-monthly for the second year, 3-to-4
Radiotherapy in Hypopharyngeal Cancer—Kiattisa Sommat et alLetter to the Editor

January 2017, V ol. 46 No. 133
monthly for the third year and 6-monthly after the third
year. Treatment response was assessed by clinical and
endoscopic examination, aided by computed tomography
(CT) or magnetic resonance imaging (MRI) at 3 months
post-RT, and repeated when warranted.
Statistical Analysis
Kaplan-Meier curves were generated for all the survival
analysis. The Cox proportional hazards regression was used
to analyse the prognostic factors for overall survival (OS),
progression-free survival (PFS) and LRC. A two-sided
P value <0.05 was considered statistically significant.
Duration of all types of survival analysis was computed
from the date of diagnosis of hypopharyngeal cancer.
Prognostic factors identified were age, gender, T stage (T1/2
vs T3/4), N stage (N0/1 vs N2/3), group stage (stage II/III
vs IV A/B), RT technique (IMRT vs 2D), surgery (yes vs
no), chemotherapy (yes vs no), smoking status (yes vs no),
and tumour subsite (pyriform fossa vs others). Statistical
analyses were performed using the STATA 12.0 software
(Stata Corp, College Station, 2012, TX, USA).
Results
Patient Characteristics
Out of 58 hypopharyngeal cancer patients who had
definitive RT treatment, 51 (87.9%) were male and the
median age of all hypopharyngeal cancer patients in this
study was 66.5 years; 70.7% of hypopharyngeal cancer
patients in this study had stage IV A disease (Table 1).
Fifteen patients underwent surgery followed by adjuvant
RT. Out of the 15 patients, 14 had neck dissection, 4
had total laryngectomy, 6 had laryngopharyngectomy, 2
had partial pharyngectomy and 3 had pharyngo-laryngo-
esophagectomy. The remaining 43 patients received upfront
radical RT.
Concurrent chemotherapy was administered to 33
patients and consisted of mainly cisplatin monotherapy.
The median RT dose delivered was 70 Gy in 35 fractions,
with a median overall treatment time of 47 days. Half of
the patients were treated with IMRT, and the other half
were treated with 2D RT. Other demographics and clinical
characteristics together with their treatment characteristics
are summarised in Table 1.
Response to Treatment
Fifty-one patients achieved complete response at 3 months
post-RT whereas 7 patients had persistent/residual disease
(3 in the primary site only, 3 in the primary and regional
nodes and 1 in the regional nodes only). Out of these 7
patients, 2 patients were inoperable or unfit for salvage
surgery and received palliative treatment. The remaining Table 1. Demographics and Clinical Characteristics of Hypopharyngeal
Cancer Patients in National Cancer Centre Singapore
Variable No. %
Total 58 100
Age at diagnosis
Median (range) 66.5 (44 – 87)
Age, years
≤70 38 65.5
>70 20 34.5
Gender
Male 51 87.9
Female 7 12.1
Subsite
Posterior wall 18 31.0
Pyriform fossa 32 55.2
Postcricoid space 8 13.8
Cancer stage
II 3 5.2
III 7 12.1
I VA 41 70.7
IVB 7 12.1
T stage
T1 2 3.5
T2 16 27.6
T3 9 15.5
T4 31 53.4
N stage
N0 15 25.9
N1 8 13.8
N2 32 55.1
N3 3 5.2
Chemotherapy
Yes 33 56.9
No 25 43.1
Surgery
Yes 15 25.9
No 43 74.1
RT technique
Conventional 29 50.0
IMRT 29 50.0
Smoking status*
Yes 43 74.1
No 9 15.5
Unknown 6 10.3
Number of pack-years (n = 43)
<10 39 90.7
>10 4 9.3
IMRT: Intensity modulated radiotherapy; RT: Radiotherapy
*Inclusive of current and ex-smoker.
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Annals Academy of Medicine
5 patients proceeded to salvage surgery. One of these 5
patients underwent a salvage neck dissection for isolated
nodal recurrence and has subsequently remained disease-
free from hypopharyngeal carcinoma, although he died at
20 months post-RT from a second primary lung cancer.
The rest of the patients died of disease recurrence despite
salvage surgery.
Patterns of Failure
Median follow-up was 15.9 months for all patients. In
those alive, the median follow-up was 21.7 months (range:
Fig. 1. Loco-regional control (LRC) of hypopharyngeal cancer following RT.
Table 2. Univariate Analysis of Patients with Hypopharyngeal Cancer
VariableOverall Survival (OS) Loco-Regional Control (LRC) Progression-Free Survival (PFS)
Hazard Ratio
(95% CI )P Value†Hazard Ratio
(95% CI )P Value†Hazard Ratio
(95% CI )P Value†
Age, years
Per year increase 0.99 (0.96 – 1.03) 0.629 0.99 (0.95 – 1.04) 0.775 1.00 (0.96 – 1.04) 0.915
Gender
Male 2.35 (0.71 – 7.83) 0.62 (0.21 – 1.82) 0.88 (0.31 – 2.53)
Female 1 0.163 1 0.387 1 0.818
Chemotherapy
Yes 0.82 (0.44 – 1.53) 0.75 (0.36 – 1.57) 0.87 (0.45 – 1.66)
No 1 0.530 1 0.443 1 0.669
Subsite
Pyriform fossa 1.09 (0.59 – 2.00) 0.75 (0.35 – 1.58) 0.87 (0.45 – 1.67)
Others 1 0.793 1 0.448 1 0.677
RT technique
IMRT 0.52 (0.20 – 1.35) 0.59 (0.18 – 1.97) 0.57 (0.20 – 1.63)
2D 1 0.18 1 0.391 1 0.297
Smoking status‡
Yes 0.86 (0.33 – 2.24) 0.59 (0.20 – 1.75) 0.61 (0.23 – 1.59)
No 1 0.764 1 0.343 1 0.313
T stage
T1– T2 0.46 (0.22 – 0.96) 0.40 (0.16 – 0.99) 0.28 (0.12 – 0.69)
T3 – T4 1 0.040*1 0.049*1 0.005*
N stage
N0 – N1 0.66 (0.35 – 1.28) 0.57 (0.25 – 1.27) 0.56 (0.28 – 1.13)
N2 – N3 1 0.220 1 0.166 1 0.104
Group stage
IV A – IVB 2.36 (0.92 – 6.05) 2.73 (0.81 – 9.14) 3.69 (1.12 – 12.10)
II – III 1 0.075 1 0.104 1 0.032*
Surgery
No 1.09 (0.53 – 2.23) 3.24 (0.97 – 10.79) 1.41 (0.64 – 3.09)
Yes 1 0.818 1 0.055 1 0.396
IMRT: Intensity modulated radiotherapy; RT: Radiotherapy; 2D: 2-dimensional
*P value <0.05 is statistically significant.
†P value is based on Cox-proportional hazard.
‡Patients with unknown smoking status were excluded from the analysis.
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January 2017, V ol. 46 No. 135
6.6 to 81.1 months). The median LRC was 26 months with
a 3-year LRC rate of 45% (95% CI, 29.6% to 59.2%) (Fig.
1). Local recurrence was observed in 12 patients, whereas 2
patients developed regional recurrence and 14 patients had
both local and regional recurrence. The overall incidence
of distant metastasis was 36.2% (n = 21). The lung was
the most frequent site of distant metastasis (76.2%). The
3-year distant recurrence-free survival rate was 58.2% (95%
CI, 41% to 72%). In univariate analysis, T stage was the
only significant predictor found for LRC ( P = 0.049) with
a hazard ratio (HR) of 0.40 (95% CI, 0.16 to 0.99) of T1/
T2 against T3/T4 as reference (Table 2).
Survival
Forty-three patients died over the study period and the
cause of death was cancer-related in most of the patients
(35/43). Of the others who died, 6 patients died from
pneumonia, 1 patient died from a second esophageal
primary, 1 patient died from a second lung primary. At the
time of analysis, 15 patients were alive and 14 of them were
disease-free at the last follow-up. The median OS was 21.0
months with a 3-year OS rate of 33.5% (95% CI, 20.8% to
46.7%) (Fig. 2). The median PFS was 12.8 months with a
3-year PFS rate of 34.9% (95% CI, 22% to 48.2%) (Fig.
3). Univariate analysis showed that T stage was the only
significant prognostic factor for OS. Group stage and T
stage were respectively significant univariate prognostic
factors for PFS. In a multivariate analysis, only T stage
was significant with T1/T2 showing a HR of 0.28 (95%
CI, 0.12 to 0.69, P = 0.005) vs T3/T4 (Table 2).
Discussion
Our study results demonstrated the poor outcome expected
in hypopharyngeal carcinoma with 3-year OS of 33.5%
and LRC of 45%. The majority of patients (83%) in our
cohort presented with very advanced stage (stages IV A & IVB). Although 88% of patients managed to achieve
complete response 3 months after completion of treatment,
loco-regional recurrence remained the major cause of
failure following curative intent RT. Most deaths occurred
in patients who succumbed to loco-regional rather than
systemic failure.
Our centre has increasingly employed IMRT in the last
decade for the definitive treatment of head and neck cancer.
The use of IMRT has allowed the delivery of high dose
conformal RT whilst achieving normal tissue tolerances. The
earlier group of patients in our study was treated with 2D RT
and the latter half received IMRT. On univariate analysis, the
use of IMRT was not found to be a statistically significant
prognostic factor affecting OS, PFS and LRC compared to
conventional RT. However, the small number of patients
and significant shorter follow-up period of IMRT patients
(median follow-up: 12.0 months in IMRT group vs 22.4
months in 2D group) may have accounted for this finding.
Few studies have reported the outcomes of IMRT due
to the relative rarity of hypopharyngeal cancer. Mok et al8
compared 3-dimensional (3D) RT and IMRT in 181 patients
with hypopharyngeal squamous cell carcinoma (SCC),
40% of which had T1/T2 stage. The IMRT group had a
higher 3-year LRC (75% vs 58%) compared with the 3D
RT group, but both groups had similar OS (50% vs 52%)
and distant relapse rate. Huang et al9 reported the results
of 47 hypopharyngeal patients treated with concomitant
IMRT-chemotherapy, although 30% of these patients were
treated in the adjuvant setting. After a relatively short median
follow-up of 18.8 months, the 5-year OS for all patients was
37% and the 5-year LRC in the concomitant CRT group
was 53%. Longer follow-up and bigger cohort of patients
are needed to validate these IMRT findings with regard to
control rates and toxicities.
These results provide a clear rationale for efforts aimed
at improving LRC and OS. Strategies that are being
explored include altered fractionation, use of conformal RT
Fig. 2. Overall survival (OS) of hypopharyngeal cancer patients following RT. Fig. 3. Progression-free survival (PFS) of hypopharyngeal cancer following RT.
Radiotherapy in Hypopharyngeal Cancer—Kiattisa Sommat et al

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Annals Academy of Medicine
such as IMRT, and intensification of concurrent systemic
chemotherapy. Several reports have shown improvement in
LRC and a small benefit of OS with altered fractionation,
often at the price of significant morbidities.10,11 Gujraj et al
reported the long-term outcome of a phase I/II accelerated RT
study of dose-escalated IMRT for locally advanced laryngo-
hypopharyngeal cancers.12,13 This study demonstrated that
dose-escalated IMRT at 67.2 Gy in 28# (2.4 Gy per fraction)
to PTV1 and 56 Gy in 28# (2 Gy per fraction) to PTV2
resulted in 5-year local control rate of 75% and 5-year OS
of 67.6% with acceptable late toxicity. This dose level is
currently being investigated in the context of a randomised
controlled trial (ART-DECO) in the United Kingdom.
Significant advances have been made over the last
2 decades with the development of more complex RT
delivery techniques such as IMRT, volumetric modulated
arc therapy (VMAT), and proton therapy. The increasing
incorporation of newer imaging modalities such as MRI
and positron emission tomography (PET) also allows for
more precise staging, tumour localisation and assessment
of treatment response. There is also ongoing interest and
research to investigate the role of imaging to improve target
delineation and possibly identify areas of radio-resistance
within the tumour for dose painting/escalation.14 Further
clinical research is needed to assess the utilisation of newer
highly conformal RT techniques combined with novel
systemic agents in head and neck cancers.
Conclusion
Patients with hypopharyngeal cancers often presented
with advanced stage with extensive nodal involvement and
were at high risk of developing distant metastasis. Tumour
load is the most important prognostic factor for outcome.
Intensification of treatment is warranted to enhance local
control and OS rates.
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Kiattisa Sommat , 1MRCP , FRCR , Sook Kwin Yong ,2MPH,
Kam Weng Fong , 1FRCR, Terence WK Tan, 1FRCR,
Joseph TS Wee, 1FRCR, Yoke Lim Soong , 1FRCR
1Division of Radiation Oncology, National Cancer Centre Singapore, Singapore
2Division of Clinical Trial and Epidemiological Sciences, National Cancer
Centre Singapore, Singapore
Address for Correspondence: Dr Kiattisa Sommat, Division of Radiation
Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore
169610.
Email: kiattisa.sommat@singhealth.com.sg
Radiotherapy in Hypopharyngeal Cancer—Kiattisa Sommat et al