Intensity-Modulated Radiotherapy, Not

3 Dimensional Conformal, Is the Preferred

Technique for Treating Locally Advanced
Disease With High-Dose Radiotherapy: The
Argument Against
Allan Price, PhD, MB BCh, FRCP(Ed), FRCR
Intensity-modulated radiotherapy (IMRT) allows the delivery of high-dose radiotherapy to
target volumes, while sparing adjacent normal tissues. This has been mooted as a method
of treating larger and otherwise untreatable lung cancers or of escalating radiotherapy
doses. The possibility of achieving these aims has been conrmed in many planning
studies, but there is little supporting clinical data. No randomized trial has compared
conformal and IMRT, few studies have reported the late outcomes of IMRT, and there is no
evidence for improved control of lung cancer with increased radiation dose. Currently
IMRT should be regarded as a promising but unproven experimental therapy in locally
advanced nonsmall cell lung cancer. Searches of PubMed were performed looking for the
terms lung cancer and radiotherapy and lung cancer and intensity-modulated radiotherapy. The former was carried out for the period 2007, when the author last reviewed
this topic, until 2014 and the latter from the rst reference to this topic to the present. The
rst search produced 8000 and the second 929 hits. A standard hierarchy of evidence
exists for interventions in medicine, ranging from systematic reviews of randomized trials
to case-control studies and mechanism-based reasoning. The best evidence so far
available for IMRT in stage III lung cancer is level 3 or 4 (low level evidence), and no
currently accruing phase II or phase III trials are listed on the National Cancer Institute
clinical trials website, although 1 study at the MD Anderson is open but not currently
recruiting patients. This evidence will be reviewed. It would not be regarded as remotely
adequate for the licensing of a new pharmacologic agent, and it does not seem
unreasonable that the same standards of evidence for efcacy and safety should apply
to the 2 branches of nonsurgical oncology.
Semin Radiat Oncol 25:117-121 C 2015 Elsevier Inc. All rights reserved.

Planning and In Silico Studies

he hypothesis that intensity-modulated radiotherapy

(IMRT) would improve outcomes for patients with stage

NHS Lothian and University of Edinburgh, Edinburgh Cancer Centre, Western

General Hospital, Edinburgh, UK.
The author declares no conicts of interest.
Address reprint requests to Allan Price, NHS Lothian and University of
Edinburgh, Edinburgh Cancer Centre, Western General Hospital, Crewe
Road, Edinburgh EH4 2XU, UK. E-mail: allan.price@nhslothian.scot.nhs.
uk

http://dx.doi.org/10.1016/j.semradonc.2014.11.004
1053-4296/& 2015 Elsevier Inc. All rights reserved.

III disease comes initially from planning rather than clinical

studies.1-4
Grills et al5 in an early study of 18 patients, 10 with stage III
disease, reported a 7%-8% increase in mean target dose but with
greater heterogeneity, and 15% reduction in V20 and mean lung
dose with IMRT compared with 3-dimensional (3D) conformal
radiotherapy (CRT) in node-positive tumors. These normal
tissue differences were not seen in node-negative tumors, and
target dose was not analyzed according to node status.
Murshed et al6 replanned 41 cancers treated with 3D CRT
using IMRT and observed a 7%-10% reduction in lung V10 and
V20 but an increase in V5 in more than half the patients.
117

118
Christian et al7 constructed intensity-modulated plans for
10 patients and compared these with 3D conformal plans,
using the planning target volume 90: lung V20 ratio as an end
point. All 5, 7, and 9 eld intensity-modulated plans were
superior to the 3D conformal plans, whereas the 9 eld plans
were also superior to the 5 and 7 eld plans.
More recently, volumetric-modulated arc therapy (VMAT)
has been proposed as an even more effective way of achieving
these ends. Scorsetti et al8 found that planning objectives were
achieved in all 24 patients treated with Rapid Arc, although the
contralateral mean lung dose was 13.7 3.9 Gy. Chan et al9
reported that VMAT produced a 2% reduction in V20 and
0.5-Gy reduction in mean lung dose compared to 3D conformal
therapy, a statistically signicant but rather small difference in
these metrics, which might not be expected to be associated with
changes in clinical outcome. Bertelsen et al10 reported similarly
small differences in favor of VMAT over IMRT. This was further
reinforced by a study of 13 patients by Guckenberger et al,11
which found a 5.6% reduction in mean lung dose with IMRT
compared with 3D CRT. Warren et al12 investigated the
feasibility of using IMRT to escalate the dose to central tumors,
but could not exceed 70.2 Gy, comparable to the dose achieved
in INDAR (individualized isotoxic accelerated radiotherapy).13
One of the concerns about intensity-modulated radiotherapy has been the effect of the increased lung volume receiving
doses up to 10 Gy, a feature of the lung bath produced by the
multiple elds or arcs used in IMRT and VMAT. A high
mortality rate with IMRT in mesothelioma has been related to
these dose levels.14 A modeling study15 of 18 patients treated
with helical tomotherapy compared this plan with 3D CRT
and xed-eld IMRT. The possibility was raised that although
radiation pneumonitis might be less common in patients
receiving IMRT without chemotherapy, the sensitizing effect
of chemotherapy in the low-dose areas might make the risk of
radiation pneumonitis higher when IMRT was combined with
chemotherapy. A study by Stathakis et al16 suggested a 30%
increased risk of second malignancy owing to these increased
low-dose volumes.
These planning studies suggest that modest increases in
prescribed dose and reductions in lung toxicity might be
possible with IMRT. They have not shown that larger cancers
might be treated more effectively with IMRT than with 3D
CRT. Whether early and late lung toxicity is more affected by
the increased volume receiving a low radiation dose or the
reduced mean dose will only be made clear by prospective
comparative studies.

Clinical Studies
The clinical evidence for the use of IMRT derives from
retrospective studies published from various centers in the
US, Holland, China, and Korea. No formal prospective phase II
or phase III studies with a predened primary end point have
been reported.
Yom et al17 reported the incidence of radiation pneumonitis
in 68 patients with advanced lung cancer treated with
concurrent chemotherapy and IMRT between 2002 and

A. Price
2005, compared with 222 similar patients receiving concurrent chemotherapy and 3D CRT, although the decision to
use IMRT was based on the inadequacy of 3D conformal plans.
The radiotherapy doses were similar, whereas the treatment
volumes were slightly larger with IMRT. Grade 3 or greater
pneumonitis was observed in 8% of those receiving IMRT and
32% of those receiving 3D CRT. Liao et al18 reported a second,
overlapping, series of 91 patients with advanced lung cancer
treated at the MD Anderson with concurrent chemotherapy
and IMRT between 1999 and 2006, compared with 318
similar patients receiving concurrent chemotherapy and 3D
CRT. Median survival rate was 16.8 16.3 months with
IMRT and 10.2 6.4 months with 3D CRT (hazard ratio
0.64 [0.41-0.98], P 0.039). Although the difference appeared mainly in local control, this result might have been inuenced by the substantially greater use of positron emission
tomography/computed tomography in staging the IMRT
group. A third series19 from this center covering the period
2005-2006 comprised 165 patients of whom 125 had stage III
and 22 stage IV disease, and not all of whom had received
chemotherapy in addition to radiotherapy. The series included
some with undened stage IV disease, making survival
comparisons with other reports unhelpful, but 2-year overall
survival rate was 46%. The pneumonitis rate was 14%. A fourth
series20 from the MD Anderson reported by Lopez Guerra
compared changes in transfer factor between patients receiving
photons, 3D conformal, and IMRT. No differences were seen.
Sura et al21 reported 55 patients treated with IMRT at
Memorial Sloan Kettering between 2001 and 2005. The 2-year
survival rate was 58%, and 11% developed radiation pneumonitis. No comparison was made with other radiotherapy
techniques.
In a series22 of 188 patients from the Netherlands Cancer
Institute, the 2-year survival rate was 52%, but 35% patients
experienced grade 3 toxicity or higher, of which 22% was
either esophageal (15%) or pulmonary (7%). In a second
Dutch single-center retrospective review, Govaert et al23
reported a 2-year survival rate of 56% without any grade
3 toxicity or treatment-related deaths. Their planning used a
standard radiation beam geometry not encompassing the
healthy contralateral lung.
Two reports have raised concerns about the volume of lung
receiving low doses of radiotherapy. Song et al24 reported a 2year survival rate of 56% in 37 patients treated with helical
tomotherapy. However, there were 4 fatal radiation-induced
lung injuries. When the volume of contralateral lung receiving
5 Gy was 460%, pneumonitis occurred in 35%, but in no
patients where this was less than 60%. Shi et al25 thought the
key parameter was a V10 o 50%, with 29% pneumonitis when
this gure was exceeded and 6% when it was not.
A phase II study26 of 30 participants who were treated with
intensity-modulated radiotherapy and weekly cetuximab
reported a 2-year survival rate of 35% and 3% grade III
pneumonitis; survival and toxicity both less than would be
expected from standard chemoradiotherapy techniques.
Scorsetti et al27 reported 75 patients with stage III nonsmall
cell lung cancer receiving 54-72 Gy with VMAT. The 5-year
actuarial local control was 67%, but median survival was only

IMRT: The case against

19 months and 5-year survival rate 15%. Whether this
represents a slightly disappointing outcome no better than
expected from conventional treatment and overtreatment of
patients with very advanced local disease or a substantial
improvement in a population with a very poor outcome is
impossible to know without comparative data. Wiersma et al28
have reported that their experience of outcomes in patients
with larger tumors with planning target volume 4700 cm3
was substantially worse than for smaller tumors. One-quarter
of their patients were dead within 6 months, and median
survival was half that observed in patients with tumors smaller
than 700 cm3, but 18% were alive at 3 years.
Only the MD Anderson data provide any support for the
idea that IMRT gives better outcomes than 3D conformal
treatment, and those data are far from conclusive, at best
offering level 3 evidence. The 2 Dutch studies reported
outcomes at the upper end of the range of published outcomes
for stage III nonsmall-cell lung cancer, but offered no
comparative data. Currently, this cannot be regarded as
sufcient to justify the routine use or widespread introduction
of IMRT or VMAT.

Other Evidence
In the absence of clinical trial evidence, it has become
fashionable to collate data from large retrospective databases.
This often has the advantage of very large numbers, but the
disadvantage of not controlling for biases in patient selection.
A review of the National Cancer Database29 from 20032005 identied 13,292 patients with stage III disease of whom
1330 received 3D CRT and 237 IMRT. Overall 2-year survival
rate was 28%. The 5-year survival rate was 14% with either
IMRT or 3D CRT, but 11% with 2D radiotherapy (P o
0.0001).
A further review of the Surveillance, Epidemiology, and End
Results database30 from 2002-2009 analyzed a cohort of 6894
patients. The use of IMRT increased from 2%-25% of radical
radiotherapy in parallel with a decrease in 2D CRT from 32%3%. In univariate analysis, IMRT seemed superior to other
techniques, but when confounders were controlled, there was
no difference in overall survival, cause-specic survival or
toxicity between IMRT and 3D CRT. Shirvani et al31 used the
Surveillance, Epidemiology, and End Results database to
identify patients receiving IMRT and 3D CRT and Medicare
claims to identify toxicities. No differences in the incidence of
pneumonitis or esophagitis were observed.
A systematic review from the Ontario group32 found only
the 2 retrospective comparative series from the MD Anderson
described earlier, which they considered insufcient evidence
on which to make recommendations. They did think IMRT
could be used where doses to organs at risk prevented radical
doses being administered when other techniques were used.
Again this evidence does not suggest that IMRT offers a huge
advantage over 3D CRT and its use might be limited initially to
the group described earlier, where evidence of the safety of the
technique might be sought and evidence that these large and

119
difcult tumors are not at too high a risk of systemic relapse to
render IMRT pointless.

How Do We Resolve This

Situation?
One would expect the introduction of a new treatment to
follow a dened program. A small number of centers would be
involved in the development of the technique to establish the
process and its safety. For a new drug, this would require a
phase I trial. In radiotherapy, one would expect a small singlecenter series reporting no increase in early death and no
obvious increase in expected or the occurrence of unexpected toxicities. The next step would be a formal phase II
trial, with acceptable and unacceptable primary end points and
toxicities.
Recent reports of CRT given concomitantly with chemotherapy have included the INDAR program13 from Maastricht
where 137 patients with stage III nonsmall-cell lung carcinoma
received individualized radiotherapy, with a 2-year survival rate
of 52% but grade 3 or higher toxicity of 36%, predominantly
esophagitis; and SOCCAR (sequential or concurrent chemotherapy and radiotherapy) from the United Kingdom that
reported a 2-year survival rate of 54%.33 Thus, a phase II
design for IMRT might be constructed with a primary end point
of acceptable 2-year survival rate of 55% and unacceptable 40%.
This would require between 70 and 95 participants and could
be used to justify a subsequent phase III trial powered to show
survival benet. The 2 Dutch studies showed about this level of
2-year survival rate and contained 3 times as many patients. The
number of centers able to do this would mean that the numbers
would be achieved very quickly. Ideally, a phase III trial would
look for approximately a 10% survival benet over 3D CRT at
2 years. Other factors that might argue for the routine use of
IMRT might also come out of such a trial. Thus, toxicity might
be reduced from the 36% in INDAR to less than 30%. It might
be that more large tumors could be treated in the experimental
but not conventional arm or that planning might be easier.
Treatment time would be more with multield xed-beam
IMRT, but not much different with VMAT. Moreover, such a
trial might help standardize international practice and facilitate
future trials in all areas of respiratory radiotherapy.

Conclusions
Radiation oncology does not have a strong record of producing
good evidence for technical advances, and in respiratory
oncology of responding to what evidence we do have.34 This
is made more difcult by the subtle differences in technologies
between centers, the drive to continue those technical developments rather than spend time collecting evidence of benet,
and by the lack of the sort of large-scale funding that
pharmaceutical companies provide for trials of new drugs.
Despite this, we have reached a stage where it is clear that
targeted therapies will only be applicable to a small proportion
of patients and are, unlike radiotherapy, not curative therapies;

120
that the efcacy of combining radiotherapy and chemotherapy
is proven,35 but again applicable to only the minority of
patients36; that dose escalation is ineffective37; and that altered
fractionation is effective.34 Although there remain questions
that need to be answered about integrating weekly or daily
chemotherapies with radiotherapy,38 it would appear that
testing the value of IMRT, and establishing the limits of what
can be achieved with it, is an obvious next step in extending the
number of patients eligible for curative therapies. Unfortunately, there seems to be no prospect of this happening and we
will simply again assume that newer must be better and ignore
the possibility that the effects of lung baths or risks of low-dose
carcinogenesis might be harming our patients.

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