Radiotherapy and Oncology 109 (2013) 8–12

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Radiotherapy and Oncology

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Hypofraction in lung cancer

Accelerated hypo-fractionated radiotherapy for non small cell lung

cancer: Results from 4 UK centres
Omar S. Din a, Susan V. Harden b, Emma Hudson c, Nazia Mohammed d, Laura S. Pemberton a,
Jason F. Lester c, Debashis Biswas b, Lavinia Magee b, Aisha Tufail d, Ross Carruthers d, Ghazia Sheikh d,
David Gilligan b, Matthew Q.F. Hatton a,⇑
a
Dept. of Clinical Oncology, Weston Park Hospital, Sheffield; b Dept. of Oncology, Addenbrookes Hospital, Cambridge; c Dept. of Clinical Oncology, Velindre Hospital, Cardiff; and d Dept.
of Clinical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK

a r t i c l e i n f o a b s t r a c t

Article history: Background and purpose: A variety of radiotherapy fractionations are used as potentially curative treat-
Received 4 January 2013 ments for non-small cell lung cancer. In the UK, 55 Gy in 20 fractions over 4 weeks (55/20) is the most
Received in revised form 22 July 2013 commonly used fractionation schedule, though it has not been validated in randomized phase III trials.
Accepted 27 July 2013
This audit pooled together existing data from 4 UK centres to produce the largest published series for this
Available online 3 October 2013
schedule.
Materials and methods: 4 UK centres contributed data (Cambridge, Cardiff, Glasgow and Sheffield). Case
Keywords:
notes and radiotherapy records of radically treated patients between 1999 and 2007 were retrospectively
Radiotherapy
Lung
reviewed. Basic patient demographics, tumour characteristics, radiotherapy and survival data were col-
Cancer lected and analysed.
Accelerated Results: 609 patients were identified of whom 98% received the prescribed dose of 55/20. The median age
Hypofractionated was 71.3 years, 62% were male. 90% had histologically confirmed NSCLC, 49% had stage I disease. 27% had
received chemotherapy (concurrent or sequential) with their radiotherapy. The median overall survival
from time of diagnosis was 24.0 months and 2 year overall survival was 50%.
Conclusion: These data show respectable results for patients treated with accelerated hypo-fractionated
radiotherapy for NSCLC with outcomes comparable to those reported for similar schedules and represent
the largest published series to date for 55/20 regime.
Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 109 (2013) 8–12

Lung cancer is the leading cause of cancer mortality throughout in 2 year survival (29% v 20%, p = 0.004) with no evidence of a dif-
the world and in 2008, was the cause of 1.4 million deaths [1]. ference in acute or long-term toxicity [4]. Within the UK, NICE (Na-
Non-Small Cell Lung Cancer (NSCLC) accounts for 80% of all cases tional Institute for Health and Clinical Excellence) recommends
of lung cancer. In the UK, only about 5% of patients survive 5 years that CHART or a radiobiological equivalent should be used in the
[2]. Potentially curative external beam radiotherapy is usually potentially curative treatment of NSCLC. Accelerated hypo-frac-
considered in patients presenting with localized NSCLC unsuitable tionated regimen of 55 Gy in 20 daily fractions over 4 weeks (55/
for surgery though there is a disappointingly low long-term sur- 20) is in keeping with this NICE guidance and is one of the most
vival of about 15% at 5 years. The international standard radical commonly prescribed in the UK. However, this regimen has not
radiotherapy schedule is 60–66 Gy delivered with once daily been validated through randomized phase III trials that compare
2 Gy fractions over 6–6.5 weeks evolving from the study by the it to other fractionation schedules. This regimen shortens the over-
Radiation Therapy Oncology Group (RTOG) [3]. all treatment time which is believed to be beneficial in terms of tu-
In the UK, several dose-fractionation radiotherapy schedules mour repopulation [5]. Studies in squamous cell carcinomas of the
are used in the radical treatment of NSCLC. Continuous Hyper- head and neck demonstrated that on average clonogen repopula-
fractionated Accelerated Radiation Therapy (CHART) to 54 Gy tion occurred after a lag period of approximately 4 weeks with a
using 1.5 Gy fractions 3 times per day for 12 consecutive days dose increment of 0.6 Gy per day required just to compensate for
(including weekends), when compared with conventional radio- this repopulation [5].
therapy, (60 Gy in 6 weeks) showed a 9% absolute improvement Recently, data from 5 UK centres have been pooled confirming
CHART in clinical practice is deliverable and effective [6]. The pur-
pose of this audit was to perform a similar analysis for the 55/20
⇑ Corresponding author. Address: Dept. of Clinical Oncology, Weston Park
fractionation and thereby produce the largest published series to
Hospital, Sheffield S10 2SJ, UK.
date for this schedule.
E-mail address: [email protected] (M.Q.F. Hatton).

0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.radonc.2013.07.014
 O.S. Din et al. / Radiotherapy and Oncology 109 (2013) 8–12 9

Materials and methods was used as an event or they were censored at last follow-up. Mul-
tivariate analysis was performed using Cox Regression.
Design and eligibility
Four centres were identified that had been using 55/20 as a Follow up
standard fractionation – Cambridge, Cardiff, Glasgow and Sheffield.
In these centres all patients for radical radiotherapy were consid- Patients were reviewed regularly following treatment with
ered initially unresectable or medical inoperable following discus- initial reviews in the 6 weeks after completion for toxicity assess-
sion in a multi-disiplinary meeting that had input from thoracic ment which was graded according to the Common Terminology
surgeons. One centre, the largest contributor to the series, only Criteria for Adverse Events (http://evs.nci.nih.gov/ftp1/CTCAE).
offered this schedule; the remaining three centres also offered Treatment response was assessed by CT imaging between 6 weeks
the CHART fractionation schedule. In these centres the selection and 3 months which were reported by local radiologists and not
between the two regimes was largely on the basis of patient independently verified. Subsequently patients were reviewed at 3
preference for in- versus out-patient treatment and the timing monthly intervals when examination, toxicity assessment and
and availability of the next CHART treatment. It should be noted chest plain film radiography were performed. Other investigations
that in the 1990s CHART routinely included prophylactic nodal were performed as clinically indicated with CT imaging (±bron-
irradiation which may have lead to a higher percentage of periph- choscopy) done on suspicion of recurrence.
eral lesions receiving the 55/20 fractionation in three of the con-
tributing centres when CHART slots were filled in the first few
Results
years of our cohort.
A database was designed to collect anonymized retrospective
Six hundred and fifteen patients were identified as having been
demographic, treatment and outcome data on all patients treated
intended to receive 55/20. The clinical records could not be traced
with 55/20 between 1999 and 2007 inclusive. Patients were rou-
for 6 patients leaving 609 suitable for analysis. Five hundred and
tinely staged with bronchoscopy and CT scan; FDG PET imaging be-
ninety-three received the actual dose of 55/20 over four weeks;
came a routine investigation in the UK in 2005. Staging used the
the remaining patients received doses between 49.5 and 54 Gy
6th edition of the TNM classification. Eligibility for treatment
given in 18–20 fractions. A summary of patient and tumour char-
was based on individual centre protocols. Broadly, all patients
acteristics are shown in Table 1.
had a histological or radiological diagnosis of non-metastatic
At the time of analysis, 406 of the 609 patients had died. The 1,
NSCLC, which was unresectable or the patients were deemed unfit
2, 3 and 5 year overall survival rates measured from diagnosis were
for or declined surgery. Patients were considered suitable if their
81%, 50%, 36% and 20%, respectively, as illustrated in Fig. 1. Stage IA
WHO performance status was 0–2 and there was a reasonable
disease conveyed the best prognosis with a 2 year survival of 72%
respiratory reserve; the minimum FEV1 accepted by any centre
(median survival of 38 months) which falls to 51% for stage IB dis-
was FEV1 > 0.8 litres.
ease. As expected the worst outcomes were seen in stage III pa-
tients with a 2 yr survival of 40% (median survival 20 months).
Radiotherapy treatment planning Adenocarcinomas had a better median survival (31 months) than
squamous cell carcinoma (20.4 months) (Fig. 2).
A single phase technique was generally used, without elective Both univariate and multivariate analyses were performed to
nodal irradiation. During the early part of this time period, there explore the different prognostic factors. Univariate analysis, as
was a change in planning technique from 2-D to 3-D conformal demonstrated in Table 2 revealed response, stage, gender and his-
radiotherapy planned using pencil beam algorithms. For 3-D plan- tology, to be significant prognostic factors but not performance
ning, gross tumour volume (GTV) included the primary tumour status or prior chemotherapy. None of the prognostic factors re-
and any involved lymph nodes defined by a short axis greater than mained significant on multivariate analysis.
10 mm on CT imaging. Clinical target volume (CTV) was achieved 378 patients from three of the centres had response, site of
by a 5 mm expansion of GTV in all directions. Planning target relapse data and toxicity data collected. These were categorized
volume (PTV) was derived by CTV expansion of 10 mm in the hor- as follows: complete response (24.3%), partial response (46.3%),
izontal plane and 15 mm cranio-caudally. Dose was prescribed to stable disease (13.8%), progressive disease (2.6%) and unknown
the ICRU 50 reference point with correction for lung inhomogene- (13.0%). In 37% of patients local recurrence was documented;
ity. Dose volume histograms were calculated on all those having CT patients treated for stage II disease accounted for the majority
based treatment plans with the recommendation that the PTV and recorded local recurrence rates for stage 1 disease was low
receives 100 ± 7% of the prescribed dose. Lung and spinal cord were at 10%. In 31% overall metastatic relapse was documented. The
identified as the organs at risk and the percentage volume of total commonest sites of metastases were the lung, bone, brain and li-
lung receiving greater than 20Gy (V20) was calculated and this va- ver. There were no grade III – V toxicities identified using the
lue was used to limit the risk of post radiation pneumonitis [7] and CTCAEv3 and the incidence of recorded grade I and II toxicities
the policy at the time of this study was to ensure a V20 (including was also low. For example grade I/II radiation pneumonitis was
the PTV) of less than 40%. documented clinically in 15.1% of patients and radiologically de-
tected pneumonitis diagnosed in 18%.
In this series 168 (28%) of 609 received combined treatment
Statistical analysis
with sequential chemo-radiotherapy. Of this group of patients,
Statistical analysis was performed using SPSS version 16.0 sta- 115 (69%) were male, with a median age of 66 years (range
tistical software. Survival analysis was undertaken using Kaplan 33–86 years) with a histological distribution very similar to that
Meier methodology and log rank test for significance. Overall sur- described for the whole trial population. The distribution according
vival (OS) was calculated from date of diagnosis (or date first seen to stages I, II and III was 8%, 8% and 83%, respectively. Eighty-three
in a few patients where date of diagnosis was unavailable) to date percent received platinum based doublet chemotherapy. Other
of death or censored at date of last follow-up, if alive. Progression- regimens used included MIC, MVP, and concurrent gemcitabine
free survival (PFS) was calculated from date of diagnosis to date of (patients on the GRIN study). The median number of cycles given
relapse (any site). In those patients without relapse, date of death was 4 (range 1–5). The overall survival of the chemotherapy group
10 Hypo-fractionated radiotherapy for NSCLC

Table 1
Summary of patient and tumour characteristics.

Demographic Number of patients Percentage of patients

(n = 609) (%)
Age Median 71.3 Range 33–89
Centre
Cambridge 231 37.9
Cardiff 167 27.4
Glasgow 72 11.8
Sheffield 139 22.8
Gender
Male 378 62.1
Female 231 37.9
Performance status
0 56 9.2
1 206 33.8
2 65 10.7
3 9 1.5
Unknown 273 44.8
Histology
Number at risk
NSCLC 173 28.4
SCC 242 39.7
609 487 262 128 57 29 7 2 0
Adeno 98 16.1
Large cell 27 4.4
No diagnostic 62 10.2 Fig. 1. Overall survival for all patients treated with 55/20.
histology
Other 7 1.1
Stage
IA 111 18.2
IB 187 30.7 Adenocarcinoma

II 90 14.8
Squamous Cell
IIIA 100 16.4
IIIB 117 19.2 No histology
IV/unknown 4 0.3
Prior chemotherapy NSCLC

No 441 72.4
Large cell
Yes 168 27.6
Total dose (Gy)
650 4 0.7
52–52.5 10 1.7
54 2 0.3
55 593 97.4

Adenocarcinoma 99 84 52 28 14 7 3 0 0
was not statistically significantly different to those who did not re- Squamous Cell 242 187 90 43 21 9 1 0 0
ceive chemotherapy (21 months vs 26 months, p = 0.332). For No histology 62 52 30 16 6 5 2 2 0
those with stage III disease only, there was a trend to improved NSCLC 173 135 77 36 12 7 1 0 0
Large Cell 27 22 8 3 2 0 0 0 0
survival in the chemotherapy group (21 months vs 19 months,
p = 0.068). Fig. 2. Overall survival by histology.

Discussion [4,11,12]. Any reported oesophagitis was mild (RTOG 6 2) and

there have been no reported cases of myelitis or spinal cord dam-
Within the UK the 55/20 hypo-fractionated radiotherapy sche- age. With the low levels of toxicity recorded in the case notes we
dule has served as the basis for two randomized control trials do not feel that further analysis to link toxicity to stage, prior che-
[8,9] despite the presence of very little published evidence regard- motherapy and other predisposing factors that might affect the
ing outcome and toxicity. This series reports the experience of 4 severity of side effects would be justified with the small numbers
large UK centres and represents the largest published series of of patients reporting toxicities preventing any conclusions being
treatment with 55/20. The outcome data we report are in keeping drawn.
with the published literature, Pemberton et al. [10] and Lester et al. The cohort of patients included in this report were treated be-
[11] reported a 2YS of 45% and two other small studies using fore Stereotactic Ablative Body Radiotherapy (SABR) was devel-
52.5 Gy in 15 daily fractions in early stage and 52.5 Gy in 20 frac- oped as a treatment option in the UK and contains a high
tions in majority T2–3N0 patients demonstrated 56% 2YS and 36% number of patient with stage I disease who would now be consid-
3YS, respectively [12,13]. ered for SABR treatment. Over the past 5 years the published evi-
We believe that series should allay some of the toxicity con- dence for SABR has increased [14–16]. These studies are
cerns that have been associated with non-conventional fraction- important and the local control rates following SABR impressive
ation. Clearly the strength of our assessment is limited by the at around 90% at 5 years. Van Baardwijk et al. have performed a
study being retrospective but no grade III or greater toxicities were systematic review that extends the SABR information by including
documented and the pneumonitis (RTOG P grade 2) rates were data from high dose ‘conventional’ radiotherapy series where
less than 20% which corresponds to other reports in the literature treatment course lasted around 4 weeks [17]. These accelerated
 O.S. Din et al. / Radiotherapy and Oncology 109 (2013) 8–12 11

Table 2 schedules can be reproduced in daily practice with 99% of patients

Univariate analysis for overall survival. completing treatment and less than 1% suffering grade 4/5 toxicity.
Median survival 2 year overall P value The feasibility of adding induction chemotherapy has also been
(months) survival (%) (univariate) demonstrated by the INCH trial [23] which suggests this approach
All 24 50 would be associated with less toxicity than concurrent schedules.
Histology <0.001 Two other phase III trials that also used accelerated hyper-fraction-
NSCLC 27.5 53 ated schedules but that omitted the week-end treatment HART
SCC 20.4 43 [24] and CHARTWEL [25] are included in meta-analysis. When
Adeno 31 59 reported individually neither showed any significant improve-
Large 17.8 30
No diagnostic 28.1 58
ments when compared to conventionally fractionated treatments
histology (64–66 Gy in 32–33 fractions) but the meta-analysis overall
Prior chemotherapy
showed a HR of 0.88 in favour of the accelerated hyperfractionated
Yes 21.4 44 schedules equating to a 2.5% improvement in 5 year survival. Our
No 25.6 52 0.332 study supports data from the EORTC 08972–22973 trial [26] which
Stage <0.001 delivered an accelerated hypo-fractionated concurrent chemo-
IA 37.6 72 radiotherapy schedule over 5 weeks; and we can confirm that
IB 24.1 51 hypo-fractionated radiotherapy is also well tolerated as a single
II 20.7 42
modality treatment or when given following induction
III 20.5 42
Response (n = 378) chemotherapy.
CR 31.7 66 <0.001 Two UK phase III trials have been based on the 55/20 fraction-
PR 22.8 44 ation unfortunately neither was able to reach their recruitment
SD 19 44 targets and have been reported as phase II studies. The GRIN study
PD 10 10
Unknown 11 21
[8] compared radio-sensitizing concurrent weekly gemcitabine
100 mg/m2 with 55/20 over 4 weeks to radiotherapy alone. The
Gender
Female 28.2 56 0.007
trial recruited 111 patients but did not demonstrate any significant
Male 22.3 47 improvement in outcome. There was a trend towards improved
outcome in the concurrent arm with an overall 3 year survival of
45 vs 37% p = 0.53. The overall toxicity was classified as mild
though two deaths from accelerated interstitial lung disease were
‘conventional’ treatments also report good local control in stage I reported the chemotherapy arm. The second study was the SOC-
disease with a local relapse figure of 13%. However, it should be CAR [9] comparison of concurrent or sequential cisplatin / vinorel-
noted that the published evidence does not yet include any ran- bine chemotherapy with the 55/20 fractionation. The trial closed
domized trial data comparing SABR with ‘conventionally’ fraction- after recruitment of 130 patients without showing a significant dif-
ated radiotherapy and that the 2 year survival figures reported in ference between the two groups (overall 3 year survival 47 vs 32%
these SABR publications are within the 51–72% that we document p = 0.25) though results favoured the concurrent arm. Both of these
for stage 1A and 1B disease. This suggests that the currently open trials reported encouraging survival outcomes but both indicate
studies that compare SABR with conventionally fractionated re- careful patient selection is essential when chemotherapy is added
main important in helping define the role for an accelerated dose to the 55/20 schedule.
escalated approach to lung cancer radiotherapy. In the UK there is a depth of experience in the use of accelerated
The vast majority of the remaining 50% of patients included in fractionations though unfortunately, recent phase III trials of accel-
our series has locally advanced disease and in NSCLC neo-adjuvant, erated radiotherapy for NSCLC [8,9,23] have finished early without
concomitant and adjuvant chemotherapy have well documented recruiting the number of patients required to define the additional
survival benefits and combined treatment is commonly benefit of chemotherapy. However, we feel strongly that it is
recommended for this group of patients. The NSCLC Collaborative important to continue to develop the evidence base for accelerated
Group Meta-analysis [18] established the benefits and toxicities fractionations regimens and a co-ordinated series of phase I/II/III
for conventionally fractionated radiotherapy with the addition of dose escalation studies looks to build on the UK experience with
neo-adjuvant cisplatin-based chemotherapy giving a 2-year sur- accelerated schedules and there are plans to take the SOCCAR con-
vival benefit of 4% with selected trials showing an improvement current chemo-radiotherapy schedule into a randomized phase III
of around 10% for this sequential approach. This translates into study against a conventionally fractionated regime.
an increase in median survival of 3–4 months (from 10 months The toxicity data from this study and the similar retrospective
to 13–14 months). Meta-analysis of the 14 trials that have com- review of CHART outcome [6] along with reports of dose escalation
pared concurrent treatment with radiotherapy alone confirms the studies using 5 and 6 week schedules [27,28] suggest there is room
improvement in two year survival with a hazard ratio of 0.89 for dose escalation within these shorter accelerated radiotherapy
(95% CI 0.81–0.98) in favour of concurrent treatment [19]. The treatments. In many stage III NSCLC patients, the oesophagus is ex-
comparison of sequential with concurrent treatment produces a pected to be within the radiotherapy field and data relating dose
similar hazard ratio in favour of the concurrent treatment (0.84, and fractionation to oesophagitis incidence and severity are un-
95% CI 0.74–0.95) [20]. Concomitant chemo-radiotherapy has clear. We know that shorter schedules and schedules with higher
pushed median survival to around 16 months by improving local doses per fraction are more prone to oesophagitis, hence, there is
control and reducing the risks of metastatic disease [20]. It needs a co-ordinated series of phase I/II trials testing dose escalation
to be remembered that the potential toxicity from the concurrent for CHART, 4-week and 6-week schedules currently open in the
approach can be significant with population based studies showing UK. The aim will be to establish a single dose escalated, accelerated
performance status, age and co-morbidities exclude a high number sequential chemo-radiotherapy that could then be compared with
of patients from the concurrent form of treatment [21]. a conventionally fractionated regime in a phase III trial.
There is meta-analysis evidence for improved local control and This report represents the largest published series to date for
survival using accelerated or hyperfractionated radiotherapy 55 Gy given in 20 fractions over 4 weeks used to radically treat
schedules [22]. Din et al. [6] showed that these results from these NSCLC. The outcomes reported are comparable to those previously
12 Hypo-fractionated radiotherapy for NSCLC

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Conflict of Interest Statement [17] Baardwijk A, Tome WA, Elmpt W, et al. Is high dose stereotactic body
radiotherapy (SBRT) for stage I Non Small Cell lung Cancer (NSCLC) overkill? A
systematic review. Radiother Oncol 2012;105:145–9.
There are no conflicts of interest.
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cell lung cancer: a meta-analysis using updated data on individual patients
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