a report by

P r o f e s s o r C a i G r a u and D r Mo r t e n H o y e r

Department of Oncology, Aarhus University Hospital, Denmark

T h e R o l e o f R a d i o t h e r a p y i n C a n c e rMan a g emen t

Radiotherapy plays an increasingly dominant role in the comprehensive multidisciplinarymanagement of cancer today. About half of allcancer patients will receive radiotherapy either as apart of the initial treatment with curative intent oras palliative treatment. The need for radiotherapyhas been increasing over the last few years as aresult of the expanding indications in many of thefrequent cancer sites.

In Denmark (population 5.3 million) the number oftreatments will almost double within a 10-yearperiod, from 110,000 fractions in 1997 to anestimated 208,000 in 2007, according to the 2005Danish Cancer Control Plan update. Primary radicalradiotherapy is used for diseases with predominantlyloco-regional spread, such as cancers of the head andneck cancer, prostate, cervix, lung or bladder.Adjuvant radiotherapy is used in combination withsurgery or chemotherapy for a wide range of cancers,of which breast, lung and rectum, in that order, arethe most important. Curative radiotherapy is given inmany small fractions over five to eight weeks, andgenerally it is not possible to give this type ofirradiation again in the same area. Palliativeradiotherapy is indicated for bone metastases,superior vena cava syndrome, spinal cordcompression, tumour ulcerations or bleedings. Oneor more fractions are often sufficient to relieve thesymptoms, and in some cases this results in life-prolongation. The treatment can be repeated.Although half of all cancer patients are treated withradiation therapy, the cost of radiotherapy constitutesonly 5% of the total expenses in oncology accordingto one Swedish report.1

H i g h - p r e c i s i o n C o n f o rma lR a d i o t h e r a p y

A number of technological developments withinthe last decade have opened up a huge and rapidlyexpanding interest from clinicians, scientists and

industry specialists in making radiation therapymore conformal and precise. By reducing thetechnical and clinical uncertainties in tumourtargeting, it is possible to deliver the radiation dosemore precisely to a specified target. It has thereforebecome possible to increase the radiation dose tothe relevant target and/or decrease the volume ofirradiated normal tissue. This should result in animproved therapeutic ratio, meaning that morepatients will be cured with fewer side effects. Thebest examples of high-precision radiotherapy areintensity-modulated radiotherapy (IMRT) andstereotactic radiotherapy. Both techniques requirevery firm immobilisation of the patient,incorporation of radiological examination in thetreatment planning for precise definition of thetarget and highly precise and technical advancedradiation equipment.

I MR T

In IMRT, the dose intensity varies within each ofthe many conformal fields, allowing highlyindividualised dose gradients throughout thetreated volume. This can be utilised to spare criticalnormal tissue in the vicinity – or even surroundedby areas – of tumour or regional lymph nodes.Different doses can be assigned to macroscopic andmicroscopic tumour volumes, allowing a so-calledintegrated boost in a single dose plan (see Figure 1).In head and neck cancer, IMRT results in lesssevere xerostomia and dysphagia compared withconformal radiotherapy. Sparing of the eye, opticalpathways and spinal cord are other importantfeatures of head and neck IMRT. In prostatecancer, IMRT has allowed dose distributionbecause the technique can be used to reduce thedose to bladder and rectum.

S t e r e o t a c t i c R a d i o t h e r a p y o fI n t r a c r a n i a l L e s i o n s

In stereotactic radiotherapy, multiple smallconformal fields from different angles are directedagainst a precisely defined volume. This results in a

High-prec i s ion Rad io therapy

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1. Norlund A, SBU Survey Group, “Costs of radiotherapy”, Acta Oncol. (2003); 42 (5–6): pp. 411–415.

Professor Cai Grau

Dr Morten Hoyer

Cai Grau is Professor of RadiationOncology, and Radiation Therapy

Programme Leader at theDepartment of Oncology at AarhusUniversity Hospital, Denmark. He is

board-certified in oncology.Professor Grau is member of theboards of the Danish Society for

Clinical Oncology, the Danish Societyfor Head and Neck Oncology andthe Scandinavian Society for Head

and Neck Oncology. He received hismedical degree at Aarhus Universityfollowed by postgraduate speciality

training at Aarhus UniversityHospital and a fellowship atVancouver Cancer Centre inBritish Columbia, Canada.

Dr Morten Hoyer is AssociateProfessor and Consultant at the

Department of Oncology at AarhusUniversity Hospital. He has special

interest in stereotactic radiotherapyof tumours of the brain, lung and

liver and in radiotherapy of prostatecancer. He is member of the boardsof the Danish Prostate Cancer Group

and the Scandinavian ProstateCancer Group. His PhD at Aarhus

University in 1994 was based on athesis on studies of cancer cellkinetics and his postgraduate

speciality training was at AarhusUniversity Hospital and

Copenhagen University Hospital.

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DOI: 10.17925/EOH.2005.0.0.40

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high central dose with minimal doses to thesurrounding normal tissue. Stereotactic radiotherapyor radiosurgery (SRS) was primarily developed in thetreatment of benign brain tumours as a non-invasivealternative to neurosurgery. In intracranialstereotactic radiotherapy, the head of the patient isimmobilised with a frame attached to the skull of thepatient with screws. A computed tomography (CT)scan is performed with the frame in place as anexternal co-ordinate system. The CT images arefused with previous magnetic resonance imaging

(MRI) in the dose-planning system for better targetdefinition (see Figure 2). The treatment is given as asingle fraction and in some cases as fractionatedtreatment. Typical indications are inoperablemeningeomas, pituitary adenomas, acousticneurinomas, arterio-venous malformations or solitarybrain metastases.

S t e r e o t a c t i c B o d y R a d i o t h e r a p y

Stereotactic body radiotherapy (SBRT) fortumours outside the brain has been usedincreasingly over the last 10 years. In Aarhus, morethan 300 patients have been treated since 1999.2–4

By stereotactic radiotherapy, a small volume isirradiated with a single or few radiation fractions byhigh-precision, firm immobilisation of the patientin a body frame and by use of multiple fieldarrangements. In this way it is possible to apply ahigh dose to a small tumour volume and to sparethe surrounding normal tissue, potentially reducingthe incidence and severity of acute and late side effects.

In contrast to conventional radiotherapy,stereotactic radiotherapy uses an external co-ordinate system for target localisation. InSBRT, a very firm immobilisation can be obtainedby the stereotactic body frame, which also carries aradio-oblique fiducial system for targeting of theradiation beams to the tumour (see Figure 3).

In the management of lung cancer, SBRT can resultin more patients being treated with curative intent.Limited-stage non-small-cell lung cancer is generallytreated surgically. However, a large proportion ofpatients with lung cancer have a poor lung functiondue to tobacco smoking and they may be medicallyinoperable; such patients are candidates forradiotherapy (see Figure 4). Retrospective studiesshow that the five-year survival after conventionalprimary radiotherapy for non-small-cell lung canceris in the range of 15% to 20%. With SBRT, thepreliminary results from prospective phase 1–2studies show a local control rate of up to 83% inlimited stage disease. In the phase 2 study fromAarhus University Hospital, 48% of the patients werewithout evidence of disease after two years.Toxicity has generally been judged to be limited,mainly as deterioration of pulmonary function andperformance status.

Figure 1: Typical Dose Distribution for IMRT of a

Pharyngeal Cancer

2. Hoyer M, Sengelov L, Roed H, Ohlhuis L, Traberg A, Petersen J, Palshof T, Engelholm S A, von der Maase H, “Stereotacticradiotherapy of primary lung cancer. Results of a phase II trial”, Eur. J. Cancer Sup. 1 (5), September 2003, S323.

3. Hoyer M, Roed H, Sengelov L, Hansen, A T, Ohlhuis L, Petersen J, Nellemann H, Berthelsen A K, Eberholst F,Engelholm S A, von der Maase H, “Phase-II study on stereotactic radiotherapy of lo-cally advanced pancreatic carcinoma”,Radiother. Oncol. (2005); (in press).

4. Hoyer M, Sengelov L, Roed H, Traberg A, Petersen J, Engelholm S A, von der Maase H, “Stereotactic radiotherapy ofcolo-rectal metastases: Results of a phase II trial”, J. Radiosurg. June 2003.

Note the relative sparing of spinal cord and contralateral parotid gland.

Figure 2: Dose Distribution in Stereotactic

Radiotherapy of a Brain Tumour

The prescribed dose was 22.5Gy as a single dose.

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For liver tumours, SBRT is best established in thetreatment of patients with liver metastases fromcolorectal cancer, while studies are under wayregarding hepatocellular carcinoma, cholangio-carcinoma, carcinoid tumour and selected patientswith liver metastasis from other cancer types. Thebackground for local treatment of colorectal liver

metastases is based on experience from surgicalresection of liver metastases, where up to 25% to30% of patients survive five years after treatment.

SBRT so far has been offered as the ‘last resort’when surgery or radiofrequency ablation has notbeen possible. Aarhus University Hospital has usedSBRT for liver tumours since 1999 in aprospective phase 2 study. For colorectalmetastases, the preliminary results showed a two-year local tumour control rate of 82%, aprogression-free survival of 15% and a two-yearoverall survival rate of 28%. The toxicity has beenacceptable with grade 0–1 in 53% of the patientswithin six months after treatment. More detailedexperimental and clinical studies are still needed todescribe the outcome of SBRT of tumours of the liver.

F u t u r e A s p e c t s

Although the clinical data so far on high precisionradiotherapy are encouraging, experimental andclinical studies are needed to describe thevolume/time/dose/fractionation relationships oncontrol of the tumours and on damage of the normaltissue. Also, studies on the proper use of adjuvantchemotherapy and novel biological targeting inconjunction with IMRT or SBRT are warranted.

The technical challenges are still enormous.Incorporation of positron emission tomography(PET)-CT may allow a more precise definition ofthe target, including areas of tumour that cannot bevisualised by CT alone and to exclude areas ofnormal tissue from the irradiated volume. Image-guided radiotherapy with X-ray equipmentmounted on the accelerators or in the treatmentroom may be used to image the patient or tumourin the treatment position (see Figure 5). Theobtained film or cone-beam CT is compared withpre-treatment planning information, and it is thenpossible to correct online for set-up uncertaintieson a daily or weekly basis. The result is a potentialfor reduced technical margins, and thus lessirradiated volume. The respiratory motion oftumours in the liver and lung can be substantial,and is most often compensated by routine additionof an internal margin in the target outline.

Frameless SBRT based on implanted gold markersand/or cone-beam CT may prove to be anattractive alternative, and novel adaptive imagingand delivery techniques with respiratory gatingshould make it possible to reduce treatmentmargins. With image-guided adaptive radiotherapyit may be possible to dose-escalate against smallertumours, and/or to treat larger tumours than arecurrently being treated. ■

Figure 3: Immobilisation in Stereotactic Body

Radiotherapy Using the Stereotactic Body Frame

Figure 4: Dose Distribution in Stereotactic Body

Radiotherapy of a Limited Stage Non-small Cell

Lung Cancer

Figure 5: In image-guided radiotherapy, high-

resolution X-ray equipment mounted on the

accelerators can be used to image the patient or

tumour in the treatment position

The prescribed dose was 45 Gy in three fractions in one week.

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