Biomed Imaging Interv J 2006; 2(1):e2
doi: 10.2349/biij.2.1.e2
© 2006 Biomedical Imaging and
Intervention Journal
 GUEST
EDITORIAL
Conformal radiotherapy and molecular
imaging: complementary technologies in cancer therapy MP
Mac Manus, MD, FRCR, FRANZCR
Department of Radiation Oncology, Peter MacCallum Cancer Institute, East Melbourne, Australia
This issue of the journal highlights some of the significant
advances that have taken place in radiotherapy in recent years.
The use of ionising radiation has a venerable history in cancer
treatment. The first recorded radiobiology ‘experiment’
occurred in 1898 when Henri Becquerel developed a skin reaction
to a vial of radium kept in his shirt pocket. Skin cancers were
successfully treated in Stockholm as early as 1899. Throughout
the 20th century, rapid technological advances led to the development
of orthovoltage x-ray therapy machines, and then in rapid succession,
the linear accelerator or ‘linac’ and telecobalt
apparatus. The development of computer technology for treatment
planning and delivery late in the 20th century and more recently
the availability of advanced linear accelerators with multileaf
collimators, capable of independent movement, has transformed
the capability of radiotherapy to accurately target localised
cancers. Radiotherapy has been transformed from a discipline
that was in danger of stagnation and was becoming marginalised
by the rapid advances in systemic therapy, to a dynamic high-technology
therapeutic modality at the centre of combined modality therapy
for a majority of the most common cancers. A significant factor
in this resurgence of radiotherapy is the recently enhanced
ability to precisely deliver therapy to the sites of gross disease
and to simultaneously reduce irradiation of healthy normal tissues.
This has the potential to minimise toxicity while maximising
the chance for disease control.
For patients with potentially curable locally or locoregionally
advanced disease, conformal three dimensional treatment planning
is now routine. The availability of complex dosimetric information
allows the routine use of dose volume histogram analysis to
determine the dose delivered to precise volumes of normal tissues.
This information is extremely valuable in optimising treatment
planning to give the safest possible dose distribution to normal
tissues while adequately and uniformly delivering dose to tumour
volumes. For the most complex planning situations, the routine
use of intensity modulated radiotherapy (IMRT) facilitates the
delivery of therapy to irregular three dimensional shapes, often
with concave regions; an especially remarkable achievement given
that photons travel in straight lines! IMRT has already shown
clinical utility in prostate cancer, allowing very high doses
to be delivered with acceptable toxicity and with emerging evidence
of superior disease control [1]. Another outstanding
clinical example is the use of parotid sparing IMRT to obtain
tumour control without unacceptable toxicity in head and neck
cancers [2], especially carcinomas of the
nasopharynx [3]. A chronically dry mouth has
historically been one of the most distressing toxicities of
head and neck radiotherapy [4]. These complex
techniques are time consuming, requiring laborious contouring
of tumour and normal tissues on planning CT scans and they demand
teamwork from radiation oncologists, physicists, dosimetrists
and radiation therapists. Further work is required to prove
that the additional complexity and expense is worthwhile in
a range of common clinical scenarios. In many clinical situations,
IMRT might actually represent an unduly costly treatment option.
As our capacity to accurately deliver ionising radiation in
cancer therapy has increased, it has become very clear that
an accurate assessment of the distribution of tumour in 3-dimensional
(and more recently, four dimensional) space is essential. The
basis for conformal radiotherapy planning has long been the
CT scan. Because of the information on electron density contained
in the CT dataset, there is no better medium for determining
dose distribution in three dimensions. However, at many disease
sites, the CT scan has serious limitations for delineating the
true tumour extent. One of the best characterised disease entities
where CT is deficient is non-small cell lung cancer (NSCLC).
Surgical series have shown that CT scanning is quite poor at
determining the true status of mediastinal lymph nodes, a crucially
important parameter when determining the target volumes of the
thorax to irradiate in a patient with unresectable NSCLC. Another
example is lymphoma where CT scanning is very poor at showing
disease in a non-enlarged spleen or at other extranodal sites
such as bowel or salivary gland and cannot detect disease in
non-enlarged lymph nodes. These deficiencies in CT imaging are
a major problem for planning radiotherapy, when imaging must
be relied upon to determine the gross tumour volumes. Another
crucial area where imaging can help is in patient selection
for aggressive therapy. CT scanning and other conventional imaging
often fails to detect gross distant metastasis and many patients
have historically received futile radical radiotherapy when
they had incurable disease at the outset.
It is fortuitous that one of the major recent advances in the
management of cancer has been the rapid progress in molecular
imaging with positron emission tomography (PET) and more recently
with integrated PET/CT scanners that simultaneously acquire
structural and metabolic information. PET scanning provides
complementary staging information to CT and can greatly increase
the accuracy of disease assessment in a range of common cancers.
The most successful PET radiopharmaceutical has been 18F-fluorodeoxyglucose
(FDG), a glucose analogue that is selectively taken up by and
trapped in tumour cells. FDG-PET has proven to be of particular
value in improving the quality of staging, not only in a wide
range of epithelial cancers, including lung, head and neck,
cervix, bowel and oesophageal cancers, but also in malignant
melanoma, soft tissue sarcomas and in lymphomas. A meta-analysis
has proven the superiority of PET over CT in the staging of
the mediastinum in NSCLC [5]. The increasing
use of PET and especially PET/CT for staging cancer and for
determining the spatial distribution of local and locoregional
disease has shown us that, in the past, our assessments of cancer
patients with conventional imaging have often been inadequate.
Even if patients selected for radical radiotherapy really do
have potentially curable locoregionally-confined disease, without
PET, many of them would have had radiotherapy plans that failed
to treat their disease adequately because of geographic miss.
Data from our prospective studies at the Peter MacCallum Cancer
Centre [6] and other series show that PET
can detect disease too advanced for aggressive therapy in about
one third of candidates for radical radiotherapy with NSCLC.
These patients would be unable to benefit from an intensive
and toxic local therapy and can be spared from futile radical
chemoradiation because of PET. Simply by using PET to exclude
patients with a poor prognosis, much higher survival can be
observed in a series of patients treated with radiotherapy,
primarily as a result of better patient selection [7].
Treatment planning studies, including those from our own centre
and from the University of Washington [8]
suggest that, without PET, a quarter or more of this patient
population would have a geographic miss of some gross tumour.
Therefore, without PET scanning, dose escalation using our new
radiotherapy capabilities would be futile in many cases of NSCLC.
Although lung cancer is the malignancy for which the utility
of PET in radiotherapy planning is best established, evidence
is accumulating to suggest that it may be useful in other cancers
such as oesophageal, and head and neck cancers [9].
It would be a mistake however, to emphasise the technical advances
in radiotherapy and imaging in isolation. Radiotherapy by itself,
no matter how technically advanced, can never be a curative
therapy in its own right for most patients with malignant disease.
Rapid improvements in our understanding of the biology of cancers
are bringing about a revolution in the development of ‘combined
modality therapy’ for patients with apparently locoregionally-confined
malignant disease. Numerous studies have shown that platinum-based
chemotherapy improves local disease control and often survival
in a wide range of tumours treated with radiotherapy, including
lung [10], head and neck , rectum and cervix.
The combination of accurately delivered radiotherapy with new
molecularly-targeted therapies has great therapeutic potential.
Tirapazemine is a cytotoxic agent specific for hypoxic cells
that shows great promise in combination with radiotherapy [11].
It is now possible to attack specific molecular targets in selected
cancers, such as gastrointestinal stromal tumours (GISTs) using
imatinib [12], a molecule that specifically
targets the surface tyrosine kinase receptor c-Kit (CD117),
now recognised as the hallmark immunohistochemical cell marker
of GIST. A monoclonal antibody directed at the epidermal growth
factor receptor (EGFR), cetuximab [13], has
been approved by the U.S. Food and Drugs Administration for
the treatment of patients with colorectal cancer who no longer
respond to standard chemotherapy treatment with irinotecan.
Inhibition of EGFR in combination with radiotherapy may have
therapeutic potential in a range of cancers characterised by
EGFR overexpression.
In conclusion, these are exciting times in radiotherapy. Advances
in radiotherapy technology, and anatomic and functional imaging
together with new insights into tumour biology and new pharmaceuticals
are leading to rapid developments in our approach to patients
with potentially curable cancers. For the foreseeable future,
radiotherapy will remain a critically useful tool in our struggle
to control malignant disease.
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Received 28 December 2005; accepted
31 December 2005
Correspondence: Department of Radiation
Oncology, Peter MacCallum Cancer Institute, St Andrew’s
Place, East Melbourne, Vic 3002, Australia. Tel.: +613-96561111;
Fax.: +613-96561424; E-mail: mmanus@petermac.unimelb.edu.au
(Michael Mac Manus).
Please cite as: MP Mac Manus, Conformal
radiotherapy and molecular imaging: complementary technologies
in cancer therapy, Biomed Imaging Interv J 2006;2(1):e2
<URL: http://www.biij.org/2006/1/e2/>
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