Biomed Imaging Interv J 2007; 3(1):e3
© 2007 Biomedical Imaging and
Improving radiation therapy for non-small cell lung cancer: molecular imaging and a team-based approach
SJ Everitt1, BAppSci, Med Rad (RT),
M Mac Manus2, FRCR FFRRCSI FRANZCR
1 Radiation Therapy Services, Peter MacCallum
Cancer Centre, Melbourne, Australia
2 Department of Radiation Oncology, Peter MacCallum Cancer Centre,
The successful integration of molecular imaging and
radiation therapy has been shown to significantly impact the management of
patients with non-small cell lung cancer (NSCLC). The collaboration of
multidisciplinary team members, including radiation oncologists, radiation
therapists, nuclear medicine physicians and physicists, has enabled PET/CT to
be utilised for routine use throughout the radiotherapy treatment trajectory. Applications
include disease diagnosis and staging, target volume definition for radiation
therapy and monitoring tumour response to treatment. Not only has the adoption
of this technology demonstrated benefits for our current patients, it is also
opening doors for significant research in the future. � 2007 Biomedical Imaging
and Intervention Journal. All rights reserved.
Keywords: Positron emission tomography, radiation therapy,
3DCRT, non small cell lung cancer
The safe and accurate delivery of radiation therapy (RT) to
patients with cancer has always demanded a team approach. For much of the
history of RT, treatments could be planned and delivered by a small team that
included a physician and a radiation therapist together with the engineering
and medical physics staff required to ensure that treatment machines gave the
output that was prescribed. In recent years, as treatments have become
enormously more complex and somewhat more effective, the membership of the RT
team has increased. The planning and delivery of RT frequently requires
contributions from radiation oncologists, radiation therapists (also known as
therapy radiographers in many countries), medical physicists and dosimetrists,
together with nuclear medicine and diagnostic imaging specialists. In the past,
many of these specialist disciplines have tended to operate in autonomous
environments. However, with the burgeoning complexity of RT planning and
delivery, these disciplines are increasingly integrating to combine their
expertise for the benefit of patients treated with RT.
One of the most striking recent examples of change is the
increasingly close involvement of nuclear medicine in patient selection and RT
treatment planning. Positron emission tomography (PET), primarily using 2-[18F]
fluoro-2-deoxy-D-glucose (FDG) as the radiopharmaceutical, has increasingly
been employed in the diagnosis and staging of non-small cell lung cancer
(NSCLC) and other common cancers. In NSCLC, many studies have been published
showing that PET has a significant impact on the selection of patients for
curative therapy, most commonly surgery, by identifying candidates without
gross systemic metastatic disease and without intrathoracic disease too
extensive for an attempt at cure. PET scanning was first employed at the Peter
MacCallum Cancer Centre (Peter Mac) as a staging tool for patients with NSCLC a
decade ago. At that time, we commenced the first large study of the use of PET
staging for NSCLC patients who were candidates not for surgery but for radical
RT. In this prospective study PET staging was conducted for 153 patients
considered eligible for radical RT based on the results of conventional staging
investigations. Results of this study published by Mac Manus et al
revealed that 46/153 (30%) patients were deemed ineligible for radical RT
following PET because of detection of distant metastatic disease or
intrathoracic disease too extensive for radical radiation . Mah et al
reported similar findings, stating that where PET data were incorporated into
the disease staging process the treatment intent was changed from radical to
palliative for 7 out of 30 patients (23%) . Hicks et al supported the
work of other researchers, reporting that in such cases where PET indicated a
poor prognosis, patients were spared from the lengthy duration and unwarranted
morbidity of futile aggressive treatment . In addition to ensuring that only
those patients who are most likely to benefit from curative therapy were
treated intensively, the significant costs and resources associated with such
radical treatment were also avoided in these cases. These results have led to
the routine incorporation of molecular imaging into the RT planning process at
In recent years there have been many attempts to improve
outcomes for patients with unresectable but still potentially curable NSCLC
through altered dose and fractionation regimens and by prescribing radiation in
combination with a wide range of chemotherapeutic agents. The most successful
of these efforts have been the use of continuous hyper-fractionated
radiotherapy (CHART)  and platinum based chemotherapy combined with RT ,
both of which give superior survival to conventional RT alone. The importance
of tumour imaging for RT target delineation and dosimetry is becoming
increasingly recognised and is an area of intense interest at present. Even the
most effectively fractionated or highly chemo-sensitised RT will have a low
chance for success if the tumour is not effectively contained within the high
dose RT volume. Until the late 1990�s, target volumes for RT planning were
based solely on diagnostic CT scan data, a practice that continues in many
centres today. Protocols for tumour delineation routinely documented that the
gross tumour volume (GTV) included the primary disease and ipsilateral hilar
and mediastinal lymph nodes, which were electively irradiated irrespective of
their radiologic appearance. Since tumour volume delineation was based on CT
alone, all lymph nodes thought to be involved (>1cm short axis diameter)
were also encompassed in the volume. In centres where elective nodal irradiation
is not routine, a 1.5�2.0cm margin is typically applied to the GTV, and an
additional margin is often applied to allow for motion of the tumour with the
respiratory cycle, the sum of these, thereby generating the planning target
volume (PTV). The PTV is the volume that must be treated as uniformly as
possible to the prescribed radiation dose and critical tissues outside this
volume should be treated to as low a dose of radiation as possible.
With the advent of PET imaging, the process of defining RT target
volumes is changing. Many studies have reported the potential advantages of
PET-assisted target volume definition in NSCLC [1,2,6-15]. These studies
suggest that the benefits of PET in staging this disease, particularly through
more reliable identification of tumour bearing lymph nodes, also translate into
superior target definition. The superior accuracy of PET over CT in staging
mediastinal lymph nodes has been demonstrated by a large number of prospective
studies [16-21]. In a comprehensive meta-analysis Toloza et al reviewed
18 studies that used PET and 20 that used CT for staging mediastinal disease
. They demonstrated that the accuracy of CT scanning for mediastinal
staging had not improved over the past decade, despite improvements in CT scan
resolution . Of the 3438 patients examined, the pooled sensitivity of CT
scanning was 0.57 (95% CI, 0.49 to 0.66), and the pooled specificity was 0.82
(95% CI, 0.77 to 0.86). Another meta-analysis of 42 CT studies performed
between 1980 and 1988 reported sensitivities of 79% and specificities of 78%
. The superiority of PET is highlighted in the meta-analysis by Toloza et
al, where sensitivity and specificity for mediastinal staging were reported
as 84% (95% CI, 0.78 to 0.89), and 89% (95% CI, 0.83 to 0.93), respectively.
Other authors not included in the analysis by Toloza et al have also
reported similar results [17,18, 23]. Overall, these authors have demonstrated
increased evidence and confidence in the ability of PET to detect tumour in
normal sized lymph nodes and also to exclude tumour in abnormally enlarged
nodes. As a result of these findings, the radiotherapeutic management of
patients with mediastinal involvement can reasonably be altered by taking PET
information into account .
Another significant advantage of PET in target volume
delineation is its ability to differentiate tumour from atelectatic lung with
greater accuracy than other imaging modalities [6,7,9,12]. This is particularly
difficult to achieve using the morphologic information given by CT .
Without PET information, target volumes may incorporate unnecessarily large
volumes of disease free collapsed or consolidated lung. Conversely, 3DCRT
target volumes based on PET/CT information focus radiation on metabolically
active disease, thereby sparing adjacent normal lung tissue from unnecessary
dose and reducing the potential for radiation pneumonitis.
At our institution we began to incorporate PET information
into the process of tumour volume definition for patients planned to receive RT
for NSCLC in 1996. Radiation oncologists incorporated PET data into the RT
treatment planning process simply by visually estimating the location and
extent of PET positive structures on PET hard copies in relation to anatomical
landmarks on planning CT scans. The impact of this method was assessed for 102
eligible patients at our centre . Overall, 41/102 (40%) patients required
changes to their RT plan to ensure appropriate treatment of tumour detected by
PET. In 22/102 (22%) cases PET led to a significant increase in the target
volume because of inclusion of structures previously considered not involved by
tumour. In 16/102 (16%) cases the target volume was significantly reduced,
where PET demonstrated areas of lung collapse or consolidation and/or enlarged
lymph nodes with low 18F-FDG uptake that were excluded from the treatment
volume. In addition to this, primary tumours seen on PET were not identified on
CT in 3/102 (3%) patients.
This was an ad-hoc, low technology method that did not fully
utilise the three-dimensional information from PET. At the time we had no means
of incorporating PET information directly into the treatment planning software.
As previously published, one of our physicists overcame this barrier by writing
software that allowed importation and co-registration of separately acquired
PET and CT images . This technique was investigated for 10 consecutive
patients with NSCLC. The method was robust and practical and we saw similar
changes in PET/CT plans compared to CT-alone plans to those that were observed
in our earlier studies performed without co-registration.
Other studies have demonstrated similar findings to our own
[2,6,8,9,12-14]. Bradley et al reported that 14/24 patients (58%)
planned for definitive RT had significant alterations in the GTV and PTV,
attributable to the detection by PET of additional nodal (n=10) or primary
disease (n=1) or to the demarcation of gross tumour within atelectatic lung
(n=3) . Erdi et al reported that the PTV was increased in 7/11 (64%)
patients studied, to incorporate additional regional nodal disease detected
with PET . In a retrospective study, Nestle et al reported that the
incorporation of overall PET findings altered the shape of the radiation
portals in 12/34 (35%) patients . Similarly, Kiffer et al reported
the use of PET images for planning would have altered the RT portals in 7/15
patients (47%) . In all studies, the inclusion of PET has had a significant
impact on target volume definition in a substantial proportion of patients
(approximately 30�60%), and in those cases PET has influenced the design of the
PTV and consequently the design of RT dosimetry to ensure optimal coverage of
the tumour. Each of these changes could be expected to lead to more accurate delineation
of target volumes for 3DCRT. In turn, improvements in tumour coverage may have
facilitated improved patient outcomes through minimised risks of excluding
gross tumour and avoidance of unnecessarily irradiating surrounding normal
tissues, although this would be exceedingly difficult to prove.
In 2001, the Centre for Molecular Imaging at Peter Mac
acquired an integrated PET-CT scanner, providing true fused images for RT
planning. Our previous co-registration method became obsolete at a stroke. Because
PET and CT data are acquired at a single session potential inaccuracies
associated with separate acquisitions were eliminated, including patient
position reproducibility, different breathing patterns and errors associated
with fiducial marker co-registration and image registration. Both CT and PET
data are readily visualised simultaneously on the RT planning computer for
target volume delineation. This system is now routinely used for all patients
treated with radical RT for NSCLC and oesophageal cancer at our centre. PET
information is also commonly used to assist with RT target definition in cervix
and head and neck cancers, paediatric cancers and lymphomas.
Successfully integrating this technology into routine
practice has relied upon continuous and effective communication between
disciplines in molecular imaging and RT, including physicians, radiation
therapists, nuclear medicine technologists and medical physicists. The nuclear
medicine physician plays a key role in assisting the radiation oncologist to
accurately contour gross tumour. Radiation oncologists generally have little
training in PET and without expert support may not use PET information
effectively. As a team we acknowledged the potential pitfalls and sources of
error involved in this process and invested considerable effort to ensure
reproducibility of scanning conditions and consistency of PET/CT image display
on RT planning computers. Because radiation oncologists undertake target volume
delineation in close consultation with their diagnostic imaging colleagues, a
true multi-disciplinary assessment occurs. We therefore believe that the
highest quality information available to us is used for target volume
A key goal of research in radiation oncology is to maximise
the therapeutic ratio. The addition of PET to CT for defining target volumes
for RT has the potential to help achieve this goal by targeting the tumour
accurately and sparing normal structures previously thought to contain tumour.
We are currently conducting a prospective study that will recruit 50 patients
who go on to receive radical RT for NSCLC after PET staging. A similar study is
commencing in the USA under the auspices of the Radiation Therapy Oncology
Group (RTOG). Each of these studies will compare dosimetry based on tumours
defined with PET/CT compared to volumes derived using CT alone. In time, we
hope that valuable information relating to tumour control, normal tissue
toxicity and patient survival will validate the impact of PET on overall
Apart from initial target volume definition, there remains
great potential to further improve outcomes for patients with NSCLC.
Preliminary research has explored the value of integrating PET data into
during-treatment and post-treatment tumour assessment. A recent Peter Mac study
by MacManus et al investigated patterns of metabolic tumour response and
disease progression for 88 patients after PET information was used together
with CT to stage and plan radical RT . 73/88 (83%) patients received concurrent
platinum-based radical chemo/RT and 15/88 (17%) received radical RT alone. A
restaging PET scan, performed to investigate patterns of metabolic tumour
response, was conducted at a median time of 70 days after treatment. The scan
results demonstrated that the tumour was stable in 72/88 (81%) patients,
including 40/88 (45%) who had attained a complete metabolic response. However,
by the final follow-up at four years 70/88 (80%) patients demonstrated
progressive disease with disease relapsing locally in 62/88 (71%), either alone
or in combination with distant metastasis. Only 17/88 (19%) patients survived
for four years. Of all the patients who attained a complete metabolic response
half eventually had local failure. The very high rate of local progression
after radical RT confirms yet again that a prescribed radiation dose 60Gy is
inadequate to control more than a low percentage of lung cancers, even when
combined with concurrent chemotherapy. Nevertheless, the high rate of isolated
loco-regional recurrence suggests that intensification of local therapy could
potentially improve outcomes in future clinical trials.
In conclusion, we believe that the combination of advanced
imaging with advanced RT planning is an excellent example of how teamwork and a
true multidisciplinary approach can help us harness new technology for the
future benefit of our patients. New avenues for research are opening up that
suggest that the future potential of this approach is immense.
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|Received 29 November 2006; received in revised form 28 January 2007, accepted 6 February 2007
Correspondence: Radiation Therapy Services, Peter MacCallum Cancer Centre, St Andrew�s Place, East Melbourne, Victoria, 3002, Australia. Tel.: 613 9656 1111; Fax: 613 9656 1424; E-mail: email@example.com (Sarah Everitt).
Please cite as: Everitt SJ, MacManus M,
Improving radiation therapy for non-small cell lung cancer: molecular imaging and a team-based approach, Biomed Imaging Interv J 2007; 3(1):e3
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