Oral Oncology 49 (2013) 634–642

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Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

Quality-of-life (QOL) outcomes in patients with head and neck squamous cell
carcinoma (HNSCC) treated with intensity-modulated radiation therapy (IMRT)
compared to three-dimensional conformal radiotherapy (3D-CRT): Evidence from
a prospective randomized study
Shrinivas Rathod, Tejpal Gupta ⇑, Sarbani Ghosh-Laskar, Vedang Murthy, Ashwini Budrukkar,
JaiPrakash Agarwal
Department of Radiation Oncology, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Hospital (TMH), Tata Memorial Centre, Kharghar,
Navi Mumbai, Mumbai, India

a r t i c l e i n f o s u m m a r y

Article history: Purpose: To prospectively evaluate and compare health-related quality-of-life (QOL) outcomes in
Received 26 January 2013 patients with head–neck squamous cell carcinoma randomized to either intensity-modulated radiation
Received in revised form 28 February 2013 therapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) and assess serial longitudinal
Accepted 28 February 2013
change in QOL over time.
Available online 4 April 2013
Methods: QOL outcomes were assessed using the European Organization for Research and Treatment of
Cancer (EORTC) QOL questionnaire (QLQ-C30) and Head-Neck module (HN-35) at baseline (pre-
Keywords:
treatment) and subsequently periodically on follow-up. Mean scores of individual domains/scales of
Conformal radiotherapy
Head–neck cancer
3D-CRT and IMRT were compared using ‘t’ test at each time point; while longitudinal change in mean
IMRT scores of both groups over time was evaluated by repeated measurement analysis of variance.
Quality-of-life Results: Fifty eight of the 60 randomized patients who filled the QOL questionnaire at least at one time
Survival point were included in the analysis. Several general (emotional functioning, role functioning, social
contact) as well as head and neck cancer-specific (dry mouth, opening mouth, sticky saliva, pain, senses)
QOL domains were better preserved with IMRT compared to 3D-CRT at different time points. Importantly,
none of the QOL domains were worse with IMRT at any time point. There was substantial deterioration in
QOL scores immediate post-treatment (3-months) in both arms. However, QOL scores gradually but
definitely improved over time for most domains. Global QOL, emotional/role functioning, nausea/vomit-
ing, pain, swallowing, speech, social contact/eating, insomnia showed rapid recovery (<6 months) while
physical/cognitive functioning, dry mouth, sticky saliva, fatigue, senses showed delayed recovery
(>6 months). There were no significant differences in loco-regional or survival between the two arms.
Conclusions: There is substantial deterioration in QOL after curative-intent head–neck irradiation that
gradually improves over time. IMRT results in clinically meaningful and statistically better QOL scores
for some domains compared to 3D-CRT at several time points with comparable disease outcomes that
could support its widespread adoption in routine clinical practice.
Ó 2013 Elsevier Ltd. All rights reserved.

Introduction including symptoms, performance, and toxicity. Traditionally,

The World Health Organization defines ‘quality-of-life’ (QOL) as
an individual’s perception of their position in life, in the context of
culture and value system in their life and in relation to their goals,
expectations, standards and concerns.1 Health-related QOL is the
subset that measures physical and psychological functioning
⇑ Corresponding author. Address: Radiation Oncology, ACTREC, Tata Memorial
Centre, Kharghar, Navi Mumbai 410 210, India. Tel.: +91 22 27405057;
fax: +91 22 27405061.
E-mail address: tejpalgupta@rediffmail.com (T. Gupta).
oncologic outcomes have focussed largely on the quantity (length
or duration) rather than quality (function and/or cosmesis) of
survival, which may be equally if not more relevant and important
to an individual.
Cancers arising in the head and neck sites are in close proximity
to several critical structures such as the spinal cord, brainstem,
parotid glands, optic apparatus (eyes, optic nerves, chiasma),
lacrimal glands, cochlea, and mandible that makes its treatment
difficult and challenging. Radical radiotherapy with concurrent
platinum-based chemotherapy remains the contemporary
standard of care2,3 in the non-surgical management of patients

1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.oraloncology.2013.02.013
 S. Rathod et al. / Oral Oncology 49 (2013) 634–642
with loco-regionally advanced head and neck squamous cell
carcinoma (HNSCC). Common acute toxicities of head–neck
(chemo)radiotherapy include mucositis, dysphagia, dysgeusia,
and dermatitis4 that can severely and adversely impact upon
QOL. The most common and debilitating late toxicity is xerostomia
– gross reduction in salivary output – leading to persistent dryness
of mouth, oral discomfort, difficulty in speech and swallowing,
impairment of taste, and deterioration of oro-dental hygiene.5,6
Some other late effects include subcutaneous fibrosis, hoarseness,
and mucosal atrophy resulting in chronic dysphagia and increased
risk of aspiration. Thus, both the disease (head–neck cancer) and
its treatment (chemo-radiotherapy) can significantly affect dis-
ease-specific health-related QOL domains such as speech, salivary,
and swallowing functions as well as more general QOL domains
such physical, mental, and social health.7–9
Over the years, major technological innovations have resulted
in substantial improvements in radiotherapy planning, delivery
and verification. The increasing use of computed tomography
(CT) imaging for target volume delineation coupled with availabil-
ity of computer-controlled treatment planning and delivery sys-
tems have progressively led to conformation of radiation dose to
the target tissues while sparing surrounding normal tissues i.e.
three-dimensional conformal radiotherapy (3D-CRT). The advent
of intensity-modulated radiation therapy (IMRT) defined as an ad-
vanced form of high-precision radiotherapy that uses non-uniform
radiation beam intensities that have been determined using vari-
ous computer-based optimization has ushered in a new paradigm
that has completely revolutionized contemporary radiotherapy
practice.10 The promise of generating highly conformal and con-
cave dose distributions around complex target volumes with steep
dose-gradients makes IMRT ideally suited for head–neck cancers.
To test the hypothesis that IMRT reduces toxicity (particularly
xerostomia) compared to 3D-CRT in curative-intent head and neck
irradiation, a randomized controlled trial was designed and
conducted. A secondary hypothesis of the trial was that this reduc-
tion in toxicity would lead to improved QOL outcomes in patients
treated with IMRT. This anticipated reduction in toxicity in
conjunction with comparable loco-regional control has prompted
widespread adoption of newer technology in head–neck
radiotherapy practice.10
Aims
The primary aim of this report was to prospectively evaluate
and compare health-related QOL outcomes in patients with HNSCC
treated with IMRT versus 3D-CRT in the context of a randomized
controlled trial. A secondary objective was to assess serial longitu-
dinal change in QOL over time for the entire study cohort.
Materials and methods
Study population
Sixty previously untreated patients with histopathologically
proven squamous carcinoma of the oropharynx, larynx, or hypo-
pharynx with American Joint Committee on Cancer (AJCC) stages
T1–T3, N0-2b, and M0 (excepting T1 glottic larynx) were accrued
on an institutional review board approved study in a single depart-
ment and randomly assigned to 3D-CRT or IMRT with or without
weekly concurrent platinum-based systemic chemotherapy. Acute
salivary gland toxicity was the primary endpoint while patterns of
failure, QOL, loco-regional control, disease-free survival, overall
survival, and late toxicity were secondary endpoints. All patients
provided written informed consent. The study is registered with
the Clinical Trials Registry-India (CTRI/2008/091/000045). Target
635
volume delineation, treatment planning, and delivery have been
reported in detail previously.11
QOL assessments
QOL assessment was done initially at baseline (pre-radiother-
apy) and then serially longitudinally on follow-up at 3, 6, 12, 18,
and 24 months post-treatment as pre-specified in the protocol.
QOL data were collected using the self-administered European
Organization for Research and Treatment of Cancer (EORTC) QOL
questionnaire (QLQ-C30) (version 3.0) and the EORTC head and
neck cancer module (HN-35),12,13 that has been validated previ-
ously14 and used in several earlier studies. Translated vernacular
language versions were used wherever applicable. This instrument
comprises of global QOL, functional, and symptom scales. All scores
were linearly transformed such that all scales ranged from 0 to 100
according to the EORTC scoring manual recommendations; missing
data were processed according to the EORTC manual guidelines.15
Higher functional or global QOL scale represents a good level of
functioning whereas a high score for a symptom scale represents
the presence of a symptom or problems.
Statistical analyses
Any patient who filled the QOL questionnaire at least at one
time-point was included in the present analysis. Although random
allocation to either 3D-CRT or IMRT should have ensured no signif-
icant differences between the two groups, baseline characteristics
of the two groups were compared using the chi-square test. As per
EORTC QLQ scoring manual guidelines mean scores of the QOL
scales were calculated.15 An independent sample ‘t’ test was used
to compare the mean scores between the two groups at each time
point. Changes in symptoms and QOL items were evaluated with
repeated measurement analysis of variance (ANOVA). All tests
were two-tailed, and differences were considered statistically sig-
nificant at the 0.05 level. For better interpretation of results, clini-
cal significance of the comparison of scales between the two arms
were also analyzed.16 For the EORTC questionnaires, changes in
time of 10 points or more are considered clinically relevant.17 Re-
sults were considered significant only if they were both statisti-
cally significant (p 6 0.05) as well as clinically meaningful (P10
point difference in mean scores). Since attrition is always a concern
in longitudinal QOL data, linear mixed model was used for imput-
ing missing values and enhancing power in a post-hoc exploratory
analysis. The linear mixed model includes the main effect of the
treatment group (difference in overall means between 3D-CRT
and IMRT) and an interaction effect of the treatment group with
time (difference in slope between 3D-CRT and IMRT). The linear
mixed model was fitted for each QOL scale score, adjusted for cor-
responding baseline assessment scores, time effect, age, gender,
disease site, and stage. The interaction between treatment (3D-
CRT versus IMRT) and time was initially examined for the similar-
ity of treatment effects at 3, 6, 12, 18, and 24 months, with a signif-
icance level for every interaction set at of 0.05. If non-significant,
the mixed model was refitted without the interaction of time,
and treatment effects were tested as an overall effect over the
post-treatment assessments. SPSS version 16.0 and Microsoft Excel
2007 was used for data processing and analyses.
Results
Between December 2005 and April 2008, 60 previously un-
treated patients with non-metastatic HNSCC were included in the
trial and randomized to either 3D-CRT or IMRT. Patient
demographics and baseline characteristics of the study cohort have
636 S. Rathod et al. / Oral Oncology 49 (2013) 634–642

Table 1 IMRT). Both groups were well balanced in terms of age and gender
Baseline patient and disease characteristics of the index study cohort (N = 60). distribution, primary site, TNM staging (and AJCC stage grouping).
Characteristics 3D-CRT (N = 28) IMRT (N = 32) p- The doses of radiotherapy were radiobiologically equivalent and
Value usage of chemotherapy (drugs, doses, cycles) was also similar be-
Median age (range) 55 (33– 51 (31– 0.10 tween the two arms. Baseline scores for global QOL, functional,
65 years) 65 years) and symptom scales were well balanced between the two arms
Gender distribution ensuring comparability. Although QOL questionnaires were mand-
Males 25 (89%) 29 (91%) 0.86
Females 03 (11%) 03 (09%)
atorily administered to all patients at baseline (pre-treatment) and
T-status at pre-specified intervals on follow-up, completion and return
T1–T2 12 (43%) 14 (44%) 0.94 rates were variable and could not be ensured at all time-points.
T3 16 (57%) 18 (56%) Reasons included patient refusal; not completing and/or not
N-status
returning questionnaires; not following-up as per protocol; and
N0–N1 19 (68%) 21 (66%) 0.86
N2a–b 09 (32%) 11 (34%) disease recurrence or death precluding such assessments. Fifty
Overall stage grouping eight of 60 (96.7%) randomized patients filled at least one QOL
I–II 05 (18%) 07 (22%) 0.91 questionnaire, while 22 (36.7%) filled the questionnaires at all
III 14 (50%) 16 (50%) the six time-points as per protocol.
IV 09 (32%) 09 (28%)
Primary site
Oropharynx 15 (53%) 17 (53%) 0.99
Hypopharynx 08 (29%) 09 (28%)
QOL outcomes comparison between 3D-CRT and IMRT
Larynx 05 (18%) 06 (19%)
Mean (SEM) Global QOL score 73 (5.1) 65 (4.3) 0.27 Mean scores of QOL domains at different time points in 3D-CRT
Mean (SEM) Dry Mouth score 30 (6.4) 20 (5.1) 0.19 versus IMRT arms is shown in Table 2. Global QOL was not signif-
Mean (SEM) Sticky Saliva 33 (8.3) 24 (5.7) 0.34
icantly affected by radiotherapy technique. Treatment with IMRT
score
had a positive effect on some general as well as several head and
3D-CRT = three-dimensional conformal radiation therapy; IMRT = intensity modu- neck cancer-specific QOL domains. General QOL domains such as
lated radiation therapy; QOL = quality-of-life; SEM = standard error of mean.
emotional functioning (12-months, p = 0.008), role functioning
(12-months, p = 0.008) and social contact (24-months, p = 0.03)
been described previously.11 There was no significant difference in were better with IMRT. Among the symptom scales, dry mouth
the baseline patient and disease characteristics (Table 1) between (6, 12 and 18-months) and opening mouth (6 and 24-months)
the two groups excepting for the treatment technique (3D-CRT or were significantly better (p < 0.05) at more than one time point

Table 2
Mean scores of quality-of-life (QOL) domains in patients treated with 3D-CRT versus IMRT at different time points.

Patients (3D-CRT:IMRT)a Baseline 3-month 6-month 12-month 18-month 24-month

21:29 patients 23:26 patients 22:26 patients 20:21 patients 17:17 patients 18:18 patients
EORTC QLQ-C30 domains
Global QOL 73:65 66:66 74:75 78:79 74:77 74:79
Physical functioning 84:87 85:81 83:86 82:89 88:88 88:85
Emotional functioning 84:90 83:87 86:94 86:98 (p = 0.008) 93:95 92:97
Cognitive functioning 86:88 84:83 83:92 86:87 88:83 88:86
Social functioning 83:84 85:79 83:90 82:89 88:86 85:95 (p = 0.03)
Role functioning 84:90 83:87 86:94 86:98 (p = 0.008) 93:95 92:97
Fatigue 25:18 31:35 28:26 24:17 20:22 22:19
Nausea/ Vomiting 7:6 11:10 6:4 7:2 2:7 2:5
Pain 23:18 28:22 20:15 15:17 13:10 12:9
Dyspnoea 11:6 4:9 11:8 7:5 6:6 7:6
Insomnia 13:10 17:10 12:8 13:3 14:4 (p = 0.05) 9:2
Appetite loss 21:21 35:31 26:28 22:13 18:14 22:11
Constipation 8:14 22:14 12:13 12:9 8:20 9:9
Diarrhoea 8:6 9:4 12:1 8:0 4:2 7:4
Financial difficulty 48:46 39:37 35:35 35:24 29:23 28:24
EORTC HN-35 domains
Pain 27:23 27:24 34:25 27:18 19:9 (p = 0.04) 15:15
Swallowing 24:22 34:20 (p = 0.05) 24:20 19:10 19:14 25:14
Senses (taste/smell) 15:9 31:21 29:13 (p = 0.04) 19:12 16:11 18:13
Speech 20:22 28:22 16:11 17:11 13:21 14:12
Social eating 23:23 29:20 21:21 17:10 18:16 12:10
Social contact 13:11 16:12 6:8 5:3 10:8 11:1 (p = 0.01)
Sexuality 11:21 20:26 15:24 17:19 12:24 6:22 (p = 0.02)
Teeth 25:20 38:32 36:23 28:24 29:31 28:24
Opening mouth 14:16 20:12 30:13 (p = 0.04) 12:14 16:12 22:7 (p = 0.04)
Dry mouth 30:20 49:40 56:37 (p = 0.03) 48:33 (p = 0.05) 47:30 (p = 0.03) 31:30
Sticky saliva 33:24 45:38 45:28 (p = 0.04) 33:22 37:27 35:24
Coughing 21:33 33:20 26:19 17:11 18:23 13:15
Feeling ill 27:24 30:26 30:15 (p = 0.03) 18:11 20:18 19:20
Pain killer 33:40 35:61 50:69 65:86 53:70 61:72
Nutritional supplement 57:76 65:85 73:73 65:72 82:88 61:83
Feeding tube 67:86 70:81 73:81 70:76 65:82 78:78
Weight Loss 48:48 43:35 54:38 55:48 59:65 33:50
Weight gain 71:79 70:65 50:65 70:57 65:53 72:55
a
Denotes number of patients at each time point in 3D-CRT:IMRT arms. Mean scores between 3D-CRT and IMRT have been compared at every time point using the
independent sample ‘t’ test.
 S. Rathod et al. / Oral Oncology 49 (2013) 634–642
Figure 1 Comparison of absolute change in mean scores for several QOL domains and symptom subscales between 3D-CRT and IMRT at different time points. Statistically
significant p-values are presented at appropriate time points.
with IMRT compared to 3D-CRT. Sticky saliva, pain, swallowing,
senses, sexuality, feeling ill and insomnia were generally better
with IMRT compared to 3D-CRT, and statistically significant at
least at one time point. Importantly, none of the QOL domains were
worse with IMRT in comparison with 3D-CRT at any time point.
Fig. 1 compares the absolute change in mean scores of QOL do-
mains at different time points between 3D-CRT and IMRT.
Time trends
QOL data from 58 patients (who completed at least one ques-
tionnaire) was used to study the time trends. Fig. 2 shows the pat-
tern of recovery (rapid versus slow) of QOL domains over time.
Absolute change in QOL scores is plotted over time; negative score
shows deterioration in QOL parameters whereas positive scores
indicate recovery. Global QOL, emotional functioning, role func-
tioning, nausea/vomiting, pain, swallowing, speech, social con-
tact/eating, insomnia recovered rapidly (within 6 months)
whereas physical functioning, cognitive functioning, dry mouth,
sticky saliva, fatigue, senses recovered gradually and slowly (be-
yond 6 months). Among the slow recovering QOL domains physical
functioning, cognitive functioning, sticky saliva, and fatigue recov-
ered within 12 months, while the slowest recovery pattern were
seen with dry mouth and senses (18-24 months).
QOL patterns
Overall QOL patterns were analyzed for the 22 patients com-
pleting QOL questionnaires at all six time intervals. There were sta-
tistically significant changes in several scales over these periods
637
(Table 3). Most QOL domains showed a trend for maximal deterio-
ration after RT followed by gradual recovery over time excepting
the use of pain killers which showed persistent worsening.
Amongst the symptom scales, pain, swallowing, senses (taste/
smell), social eating, dry mouth and sticky saliva showed signifi-
cant change over time (Table 3). Amongst the functional scales,
only role functioning showed any significant change over time.
Global quality of life score was expectedly worst at 3-months
though not statistically significant; however this recovered rapidly
by 6-months and then remained stable over time.
Linear mixed model analysis
There was significant interaction between treatment arm (3D-
CRT versus IMRT) and assessment intervals for 3 QOL subscales
viz. physical functioning, head–neck pain and head–neck coughing,
which were significantly better with IMRT (Table 4, Fig. 3). After
refitting the linear mixed model (without interaction of time),
swallowing and mouth opening scales had significantly better
scores with IMRT compared to 3D-CRT (Table 4, Fig. 3).
Disease outcomes
Of the entire study cohort of 60 patients, 12 patients had index
cancer-related failures (11 loco-regional failures and 1 isolated dis-
tant metastasis). Two of the loco-regional failures (one each in 3D-
CRT and IMRT arms) were successfully salvaged and are long-term
survivors. Three of 28 patients had loco-regional failure in the 3D-
CRT arm compared to 6 of 32 patients in the IMRT arm. Overall, 18
patients had died by the time of this analysis (8 of 28 patients in
638 S. Rathod et al. / Oral Oncology 49 (2013) 634–642
Figure 2 Patterns of recovery of different QOL domains in patients with head–neck cancers treated with high-precision conformal techniques (3D-CRT or IMRT).
3D-CRT and 10 of 32 patients in IMRT arm). Ten patients suc-
cumbed to their index cancer, 3 patients to a second new primary,
while 5 patients died of other causes (4 due to suspected cardio-
pulmonary events and 1 of unknown cause). At a median follow-
up of 40 months (inter-quartile range 26-50 months), the 3-year
estimates of loco-regional control with 95% confidence intervals
(95%CI) were 88.2% (75.4–100%) and 80.5% (66.1–94.9%) for the
3D-CRT and IMRT arms respectively (p = 0.45). Similar estimates
for 3-year overall survival were 70.6% (95%CI: 53–88.2%) and 68%
(95%CI: 51.2–84.8%) for 3D-CRT and IMRT respectively (p = 0.81)
suggesting no statistically significant differences in disease out-
comes between the two arms.
Discussion
Xerostomia, a common and debilitating adverse effect of com-
prehensive head–neck irradiation5,6 manifests typically as dryness
of the mouth that can cause significant oral discomfort, alteration
of taste, dental caries and difficulty in speech and swallowing with
resultant significant impairment in oral-health specific QOL do-
mains as well as general QOL domains.7–9 Preservation and maxi-
mization of QOL is thus an important end-point for long-term
outcomes in patients with head and neck cancer. Following con-
ventional radiotherapy, most QOL domains show significant dete-
rioration followed by gradual and partial recovery over time.
Given the reduction in OAR doses that can be achieved with IMRT,
it is expected that patients should experience lesser functional
deterioration with more rapid and complete recovery. Despite
the widespread adoption of IMRT for the treatment of head–neck
cancers and the resultant reduction in long-term toxicity including
xerostomia, there is surprisingly little prospective data on its im-
pact on patients’ QOL.
The largest study18 till date evaluated post-radiotherapy QOL in
640 head–neck cancer survivors using a cross-sectional survey de-
sign to assess the impact of technological advances over time.
Three hundred seventy one patients had been treated with two-
dimensional radiotherapy (2D-RT) in the earlier era, while confor-
mal techniques such as 3D-CRT (n = 127) or IMRT (n = 142) had
been employed in the modern era. Significant differences
(p < 0.05) in QOL outcomes by different techniques were observed
in 2 of the 15 scales in QLQ-C30 and 10 of the 13 scales in HN-35.
Compared with 2D-RT, IMRT had significantly better outcomes in
the scales of global QOL, physical functioning, swallowing, senses
(taste/smell), speech, social eating, social contact, teeth, opening
mouth, dry mouth, sticky saliva, and feeling ill. Only three scales
(teeth, dry mouth, and sticky saliva) with better results were ob-
served in 3D-CRT compared with 2D-RT. IMRT had better scores
in most scales compared to 3D-CRT, although it did not reach sta-
tistical significance.
In a large prospective study,19 Fang and colleagues analyzed
change in QOL and survival outcomes in patients with nasopharyn-
geal cancer treated with 3D-CRT (n = 93) or IMRT (n = 110).
Although the study was not randomized, the authors reported
comparable baseline patient and disease characteristics in the
two cohorts, thereby reducing the chances of a selection bias. A
general trend of maximal deterioration in most QOL domains
was observed during treatment followed by gradual recovery on
follow-up. No significant differences were noted in most subscales
at each time point between 3D-CRT and IMRT. However, at
 S. Rathod et al. / Oral Oncology 49 (2013) 634–642 639

Table 3
Mean scores of quality-of-life (QOL) domains for patients treated with 3D-CRT or IMRT completing questionnaires at baseline and all specified follow-up time points (N = 22)a.

Baseline 3-mth 6-mth 12-mth 18-mth 24-mth p-Value Significant time interval(s)
EORTC QLQ-C30 domains
Global QOL 78 72 79 79 75 76 NS
Physical functioning 88 82 82 84 88 85 NS
Emotional functioning 79 78 81 83 83 82 NS
Cognitive functioning 90 85 83 87 87 85 NS
Social functioning 83 87 83 83 87 86 NS
Role functioning 87 83 89 87 96 94 0.03 3-mth versus 18-mth
Fatigue 20 29 25 21 17 19 NS
Nausea/vomiting 5 8 6 4 3 3 NS
Pain 20 23 16 17 10 11 NS
Dyspnoea 9 3 5 6 6 4 NS
Insomnia 9 11 6 4 8 6 NS
Appetite loss 15 30 24 14 17 17 NS
Constipation 9 17 18 18 14 11 NS
Diarrhoea 5 11 11 8 3 4 NS
Financial difficulty 39 32 36 33 29 29 NS
EORTC HN-35 domains
Pain 25 33 21 16 14 11 0.004 3-mth versus 18-mth and 3-mth versus 24-mth
Swallowing 27 33 27 15 17 21 0.01 3-mth versus 12-mth and 3-mth versus 18-mth
Senses 11 32 22 21 15 16 0.01 Baseline versus 3-mth
Speech 20 25 14 15 15 13 NS
Social eating 22 28 22 15 17 9 0.02 3-mth vs 24-mth
Social contact 9 16 7 6 9 7 NS
Sexuality 22 27 24 24 18 17 NS
Teeth 24 40 27 32 38 29 NS
Opening mouth 15 14 18 11 17 12 NS
Dry mouth 21 45 52 41 42 26 <0.001 Baseline versus 3, 6, 12, 18-mth and 6-mth versus 24-mth
Sticky saliva 30 52 38 30 32 23 0.02 3-mth versus 12-mth and 3-mth versus 24-mth
Coughing 30 30 17 15 17 14 0.06
Feeling ill 26 29 26 15 15 18 NS
Pain killer 27 45 59 64 50 64 0.06
Nutritional supplement 68 73 68 68 86 73 NS
Feeding tube 68 73 68 68 68 73 NS
Weight Loss 36 36 36 45 50 27 NS
Weight gain 68 68 59 54 64 73 NS

mth = month; NS = non-significant.

a
Change in mean QOL scores over time evaluated by repeated measures analysis of variance (ANOVA).

67% treated with 3D-CRT (odds ratio = 0.34; 95%CI: 0.18–0.62;

Table 4
Exploratory linear mixed model analysis showing quality-of-life (QOL) measures that p < 0.001). Patient-rated mean xerostomia scores were signifi-
showed significant interaction between treatment arms (3D-CRT versus IMRT) and cantly worse with 3D-CRT compared to IMRT at all time points fol-
time. lowing treatment. The mean scores for dry mouth and sticky saliva
QOL measure Assigned to 3D-CRT Assigned to p- subscales on HN-35 were significantly better in patients treated
IMRT Value with IMRT. In addition, better scores were also noted for opening
Mean Standard Mean SD mouth, pain, swallowing, problems with teeth, and social eating
(least Deviation (least in IMRT patients. These differences also translated into signifi-
square (SD) square cantly better outcomes in general domains of QOL such as global
mean) mean) QOL, role functioning, cognitive functioning, social functioning, fa-
Physical functioning* 84.3 1.6 87.1 1.9 0.020 tigue, insomnia, and appetite loss in patients treated with IMRT
Head Neck (HN)-Pain* 18.7 3.1 16.4 2.6 0.010 compared to 3D-CRT.
HN-coughing* 20.8 4.2 18.3 3.6 0.050
Three randomized controlled trials have compared IMRT to con-
HN-swallowing$ 24.5 3.1 15.6 2.7 0.040
HN-mouth opening$ 22.6 3.6 10.5 3.1 0.020 ventional radiotherapy in HNSCC. Although, all three consistently
*
showed significant salivary sparing with IMRT, this did not neces-
p-Value is for interaction of arm and assessment time interval.
$ sarily translate into significantly better QOL outcomes. The first
p-Value is for treatment arm as an overall effect over all the assessment
intervals. such study21 by Pow et al. assessed QOL longitudinally using
Short-Form Health Survey (SF-36) as well as EORTC QLQ-C30 and
HN-35 in patients with early-stage nasopharyngeal cancers
3-months post-treatment, patients treated with IMRT had both (n = 52) randomized to either conventional 2D-RT or IMRT. Major-
statistically and clinically significant improvement in global QOL, ity of subscale scores were worse in both arms at 2, 6, and
fatigue, taste/smell, dry mouth, and feeling ill compared to 3D- 12 months after treatment than at baseline confirming the
CRT, leading the authors to conclude that the potential advantage deterioration in health-related QOL with radiotherapy. However,
of IMRT could lie in the recovery phase from acute toxicity. patients in the IMRT arm had significantly better scores for
Another large prospective non-randomized cohort study20 com- role-physical (p = 0.011) and bodily pain (p = 0.044) subscales of
pared patients treated with 3D-CRT (n = 150) or IMRT (n = 91) and SF-36 at 12 months post-treatment. There were significant
followed-up on a standardized program assessing toxicity and differences between the two groups in the role-functional scale
QOL. At 6-months post-treatment, 41% of patients treated with of the EORTC QLQ-C30 favouring IMRT (p = 0.035). A comparison
IMRT reported moderate to severe xerostomia compared with of scores at 2 and 12 months post-treatment revealed an increase
640 S. Rathod et al. / Oral Oncology 49 (2013) 634–642
Figure 3 Exploratory linear mixed model analysis demonstrating significant interaction of treatment arms (3D-CRT versus IMRT) with time.
in global health status, physical, role and social function scores and
a reduction in fatigue and appetite loss in both groups, indicating
significant improvement in QOL at 12 months than at 2 months.
Patients treated with IMRT had significantly lesser problems
(p < 0.05) with speech and swallowing on H&N35 module
3 months. Patients in the IMRT arm also had better scores for sticky
saliva and coughing (p < 0.05) but only a trend (p = 0.07) towards
lesser dry mouth symptoms compared to 2D-RT. Surprisingly there
was no significant difference in global QOL between 2D-RT and
IMRT, which the authors hypothesized may have been a result of
changes in patient expectations over the course of treatment and
recovery.
The second randomized trial22 also compared 2D-RT with IMRT
in patients with early stage nasopharyngeal cancers (n = 60) using
observer-rated severe xerostomia at 1-year post-treatment as pri-
mary endpoint. One-year after treatment, patients in IMRT arm
had lower incidence of observer-rated severe xerostomia than pa-
tients in 2D-RT arm (39.3% versus 82.1%; p < 0.001) in parallel with
a higher fractional stimulated parotid flow rate (0.90 versus 0.05;
p < 0.0001), and stimulated whole salivary flow rate (0.41 versus
0.20; p < 0.001). Although formal QOL assessment was not part of
the study protocol, patients filled a 6-item xerostomia question-
naire at baseline and periodically on follow-up. Despite signifi-
cantly better salivary flow-rates as well as lesser incidence of
observer-rated severe xerostomia, no significant differences were
noted on the xerostomia questionnaire between the two arms at
most time points. However, on test for trend of scores of each pa-
tient over time, significant improvement was noted in IMRT be-
tween 6 weeks and 1-year which was not seen with 2D-RT.
The largest, most recent, and only multi-centric randomized
trial23 compared conventional 2D-RT with parotid sparing IMRT
in 94 patients with pharyngeal cancers using delayed grade 2 or
worse xerostomia as the primary endpoint. QOL assessment was
done using the EORTC QLQ-C30, HN-35, and a modified xerostomia
questionnaire at baseline and periodically on follow-up. As ex-
pected, the incidence of Pgrade 2 xerostomia was significantly les-
ser (p < 0.05) at all time points with IMRT compared to 2D-RT. The
HN-35 subscale scores for dry mouth, senses, and sticky saliva
deteriorated significantly from baseline in both arms. Smaller
change in mean scores were noted for IMRT compared to 2D-RT
from baseline to 12-months and 24-months for the dry mouth sub-
scale, suggesting better recovery with IMRT. There were no statis-
tically significant differences between 2D-RT and IMRT with
respect to global health status. Mean change in global health status
from baseline to 12 months was 1.1 and 3.0 for 2D-RT and IMRT
respectively (p = 0.78). Changes at 24-months were 2.8 and 8.3
respectively (p = 0.14) corresponding to a between group differ-
ence in change scores of 11.1, favouring IMRT. Although this differ-
ence was not statistically significant, a difference in QOL score of
10 is considered clinically meaningful. In both the treatment arms,
all eight xerostomia questionnaire items were significantly worse
at 12 and 24 months than at baseline. However, the changes were
smaller in the IMRT arm compared to 2D-RT leading the authors to
conclude that IMRT results in consistently better global QOL and
lesser dry mouth which is clinically meaningful though not statis-
tically significant.
Despite overwhelming evidence that IMRT can reduce late func-
tional deficits in patients with head and neck cancer treated with
radiotherapy, a review of the indexed medical literature shows
conflicting results with regard to QOL outcomes.24,25 While the evi-
dence is reasonably robust for significant improvement in QOL do-
mains pertaining to salivary function and xerostomia, there is very
little evidence of significant benefit if any for most of the other
head–neck specific domains and more general QOL domains
including global QOL. First and foremost there could be a lack of di-
rect relationship between functional deficits and global QOL. Other
possible reasons could significantly heterogeneous patient popula-
tion (time since radiotherapy, mean parotid dose, tumor sub-sites,
definitive versus post-operative adjuvant radiotherapy, use of che-
motherapy); subjective nature of QOL assessment; use of different
QOL instruments; and lack of adjustment for pre-treatment scores.
This study adds to the growing literature on QOL outcomes after
curative-intent head–neck irradiation, although certain similarities
and differences exist compared to previously published data. It is
the first randomized controlled trial comparing IMRT with 3D-
CRT, as the three previous randomized trials compared IMRT with
2D-RT. Two of them21,22 were done exclusively in patients with
nasopharyngeal cancers, where IMRT is likely to be even more ben-
 S. Rathod et al. / Oral Oncology 49 (2013) 634–642
eficial, while this study and Nutting’s study23 excluded them com-
pletely. Consistent with earlier reports, this study reinforces the
benefits of parotid-sparing IMRT in head–neck cancers by reducing
xerostomia thereby improving xerostomia-related QOL (dryness
and sticky saliva). IMRT also had a positive impact on several
general and head–neck cancer specific QOL domains such as
emotional/role functioning, social functioning, swallowing,
opening mouth, feeling ill, senses (taste/smell), pain, insomnia,
social contact and sexuality as compared to 3D-CRT. Nutting et al.23
had reported significantly worse acute fatigue with IMRT
compared to conventional radiotherapy (74% versus 41%,
p = 0.015), possibly because of low-dose incidental posterior
cranial irradiation inherent to the use of posterior beams in IMRT.
Difference in acute fatigue between 3D-CRT and IMRT was not seen
in this study probably because the multi-field arrangements of
3D-CRT technique always included posterior beams with similar
potential of low-dose incidental focal cranial irradiation as IMRT.
Caveats and limitations
Although, this is the first study comparing QOL outcomes in 3D-
CRT versus IMRT in the context of a randomized controlled trial,
the data need to be interpreted cautiously in view of it being sec-
ondary analysis from a prospective study. The index study was
powered to demonstrate a significant reduction in physician-rated
grade 2 or worse xerostomia (from 85% in 3D-CRT to 50% in IMRT
arm) and not on the difference or change in QOL scores (where the
difference between the two arms was likely to be much lesser).
Although patients were mandated to fill QOL questionnaires at dif-
ferent time-points on follow-up, completion and return rates were
variable, with just over one third of patients completing the ques-
tionnaires at all time points limiting statistical robustness. More
importantly, QOL was not assessed at conclusion of (chemo)radio-
therapy when it is most likely to be at its nadir. The earliest post-
treatment assessment was at 3-months by which most of the acute
toxicity would have largely subsided. In addition, earlier studies
have also used a separate validated xerostomia-specific question-
naire in addition to the EORTC questionnaires as a QOL tool which
was lacking in this study. Several clinico-demographic variables
such as co-morbidities, level of education, socio-economic,
employment and marital status that may have had a significant
impact on QOL were not accounted for either at baseline or on fol-
low-up.
Conclusions
There is significant deterioration in QOL after curative-intent
head–neck irradiation, that gradually but definitely improves over
time. The magnitude of impairment for most QOL domains is lesser
and recovery more rapid and complete with IMRT. The use of IMRT
results in clinically meaningful and statistically better QOL scores
(for some domains and symptom subscales at several time points)
compared to 3D-CRT with comparable disease outcomes that could
support its widespread adoption in routine clinical practice.
Conflict of interest statement
None declared.
Funding
The index study (randomized controlled trial) was financially
supported and funded partially through a research grant from Sie-
mens Oncology Care Systems, USA.
641
Acknowledgements
Late Dr. Ketayun Dinshaw, formerly Professor, Radiation Oncol-
ogy and Director, Tata Memorial Centre, Mumbai, who was a key
member in the design and conduct of the index randomized con-
trolled trial.
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