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The Breast 19 (2010) 172e175

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The Breast

journal homepage: www.elsevier .com/brst

Original article

What are the minimal standards of radiotherapy planning and dosimetryfor “hypofractionated” radiotherapy in breast cancer?

N. MacLeod a, A. McIntyre b, P.A. Canney a,*

aDivision of Clinical Oncology, The Beatson West Of Scotland Cancer Centre, Great Western Road, Glasgow G12 0YN, United KingdombRadiography Department, The Beatson West Of Scotland Cancer Centre, Great Western Road, Glasgow G12 0YN, United Kingdom

Keywords:Breast cancerRadiotherapyDosimetry

* Corresponding author.E-mail addresses: nicholas.macleod@ggc.scot.nh

mcintyre@ggc.scot.nhs.uk (A.McIntyre), peter.canney@

0960-9776/$ e see front matter � 2010 Elsevier Ltd.doi:10.1016/j.breast.2010.03.007

a b s t r a c t

Hypofractionated radiotherapy regimens have become increasingly popular in breast cancer, particularlyin the UK and Canada. However, there are some potential problems inherent to providing such regimens,such as the concern of increased toxicity. In this article we discuss the planning and dosimetry andrequirements for hypofractionated radiotherapy in breast cancer and make recommendations both forthe planning process and for treatment monitoring.

� 2010 Elsevier Ltd. All rights reserved.

Introduction

Radiotherapy has played a pivotal role in the management ofearly stage breast cancer for a number of years. Several trials haveshown that breast conservative surgery followed by radiotherapy isan effective method of reducing the risk of local recurrence andimproving the long-term outcome of women with breast cancer.1,2

The international “Gold Standard” radiotherapy fractionationremains 50 Gy in 1.8e2.0 Gy per fraction, plus or minus a boost ofup to 16 Gy in 8 fractions.3 However, recent data suggest thathypofractionated regimes may provide a viable alternative to thisstandard approach. These results potentially offer treatment withsimilar clinical outcomes but with reduced number of visits to theradiotherapy department: there are clear potential benefits interms of cost savings for both radiotherapy departments andpatients. However, if these hypofractionated regimes are to becomethe new standard of care, important considerations need to begiven to patient selection, radiotherapy planning, dosimetry andtreatment delivery if they are to be employed safely and repro-ducibly. This article will consider aspects of planning, dosimetryand radiotherapy delivery.

Background

There have been many reports of hypofractionation regimensbut prospective randomised trials from Canada and the UK havebrought hypofractionation into focus.4,5

s.uk (N. MacLeod), anne.ggc.scot.nhs.uk (P.A. Canney).

All rights reserved.

Theoretically fewer larger fractions will result in less toleranceof variations in biological dose; that is for a similar dose variation(inhomogeneity) the clinical effect would be greater for a hypo-fractionation regimen than for a regimen of 50 Gy in 25 fractions.6

High dose regions within a Planned Treatment Volume, whenexamined in terms of biological equivalent dose, can provide thepotential for “double trouble” effects that manifest as normal tissuedamage, with high dose effects being further exacerbated by use ofhypofractionation. However this effect is modest for the ranges ofdose per fractions between 2 Gy and 6e7 Gy. For a 20% increase inphysical dose across a planned volume, no more than 5% additionalBiological Equivalent Dose (BED) would accrue due to hypo-fractionation alone compared to standard fractionation. Neverthe-less if the BED is close to tolerance for the tissues irradiated thissmall increment could contribute to toxicity.

Limits on heart exposure using conventional planning andfractionation have been well defined.7 However these are derivedfrom data obtained in an era when cardiotoxic systemic therapywas not used,8 and the now routine use of such therapy, with evenmodest BED increments from hypofractionated radiotherapy, is ofmore concern, particularly as late cardiac toxicity may take manyyears to declare itself.

Lind et al. showed that 50% of patients had pulmonary compli-cations with internal mammary node and supraclavicular fieldtreatment along with tangential breast field.9 A Central LungDistance (CLD) of greater than 2.5 cm was shown to be directlyrelated to the probability of lung complications. Rothwell et al.showed that radiation pneumonitis and irradiated lung volume isa sigmoid curve.10 The incidence and severity of pneumonitis wasshown to increase exponentially with irradiated lung volume.When 60 cm2 lung area was irradiated to 28 Gy the incidence of

N. MacLeod et al. / The Breast 19 (2010) 172e175 173

radiological pneumonitis was 50%. With good treatment tech-niques, when CLD is reduced to 1e2 cm, the clinical pneumonitis isusually less that 1% so hypofractionation should not be an issue inrespect of lung toxicity.

Until relatively recently, in most centres in the UK, breast dosedistribution was determined by planning a 2-dimensional contourtaken along the central plane of the breast.11 Variations in thebreast contour either side of this central plane were not taken intoaccount resulting in large, and generally unknown dose inhomo-geneities. 3-dimensional planning is now universally accepted asbeing superior to 2-D planning in terms of improved dose homo-geneity.12 There are now 2 reports of randomised trials of correct-ing dose homogeneities in breast cancer radiotherapy using IMRTtechniques showing patient benefit in terms of late radiationseffects13 and also early reactions14 from these techniques. Thesetrials used standard fractionations and although the use of hypo-fractionation has increased the need for accurate planning anddosimetry for breast treatments, accurate planning should now bethe routine regardless of the fractionation schedule.

The EORTC boost trial showed that higher total dose increasestumour control.3 This suggests that, for tumour control, theschedule of 50 Gy in 25 fractions is within a critical point of thedose-response curve and under dosing should therefore also beavoided. These data are suggestive that the biological effect ofunder dosing may be magnified when hypofractionation regimensare employed.

Planning

The essence of breast radiotherapy planning is to produce a planthat complies with ICRU 50 and ICRU 62 and which is reproduc-ible.15,16 This ideally requires access to a large-bore planning CTscanner, a virtual planning system and a dosimetry system. Thissystem should be able to provide full 3-D data and allow IMRT, bothlower, 4e6 Mev, and higher, 10þ Mev treatment machines, multi-leaf collimation for additional shielding, if needed, and electronicportal imaging.

Fig. 1. (a) Virtual simulator image of tangential fields placement. Note clips helping toidentify tumour bed. (b) Virtual simulator image of beams eye view.

Simulation

Avoidance of critical structures, heart and lung, by accurate fieldplacement is the best way to reduce doses to these organs: equallythis is required to cover the target volume satisfactorily. Evensophisticated dosimetry cannot compensate for poor field place-ments. Field placement should be performed using a large-boreplanning CT simulator. The patient should be scanned in thetreatment position with one or both arms above the head usinga purpose built breast board. It is of great benefit to the radio-therapy planning process if the surgeons clip the tumour bed asotherwise this can be difficult to define, particularly in thosepatients who have had chemotherapy and so may be severalmonths post surgery at the time of radiotherapy planning.17 Thisshould reduce the risk of geographical errors resulting in underdosing which, as noted above, may have a larger impact for hypo-fractionation regimens.

Dose volume histograms of heart and lung can be obtained, butinterpretation is difficult in routine practice Maximum (CLD) of<2 cm on the lateral field and Maximum Heart Depth (MHD) of1.0 cm as measured during field placement on a virtual simulatorare acceptable alternatives.9,7 Differences in biological effect,particularly late effects in heart and lung, resulting from increasedfraction size are not known and normal tissues should be shieldedas much as possible if this does not compromise target volumecoverage.

The Clinical Tumour Volume covers the soft tissue of the wholebreast down to the deep fascia, but not including underlyingmuscle and ribcage, nor overlying skin and excision scar.18 ThePlanned Treatment Volume covers the entire breast with a 1.5 cmmargin to palpable breast tissue. Medial and lateral margins shouldnot normally extend beyond the anterior midline or the mid axilla.However, it is desirable to reduce these margins in selectedpatients, if the tumour bed does not encroach, in order to reducethe volume of heart and/or lung in the high dose zone. Adjustmentto the collimator angle and gantry angle will usually be neededdepending on the anterior chest wall and the sternal angle. Usingvirtual simulation it is usually easy to choose a posterior fieldborder and angle to exclude heart and lung such that no or minimalfurther shielding is necessary (Figs.1 and 2b). Central slice planningalone, whether by means of CT data or manual contour, is whollyinadequate for assessing heart doses as the heart encroaches onlywithin the lower potion of the tangential fields.19 In addition themajority of hot spots occur in the superior or inferior parts of thebreast (Fig. 2).

Fig. 2. (a) Dose colour wash showing hotspot on a superior slice. (b) Field in field MLccompensation. (c) Dose colour wash showing improved dosimetry due to field in fielddose compensation.

N. MacLeod et al. / The Breast 19 (2010) 172e175174

Dosimetry

Dose may be prescribed to the ICRU reference point, or toa minimum dose to cover the target volume of 95%. The treatmentplan should achieve the dose homogeneity constraints set by

international standards ICRU 50 and 62.15,16 Based on the VirtualSimulator field placement, a full plan is generated with the aim tocover PTV with 95e107% isodose with Multi-Leaf-Collimator (MLC)shielding for any critical structure (cardiac or large lung volume). Inapproximately 70% of patients a simple wedge 2 field plan willresult in significant dose inhomogeneities and so will require dosecorrection fields.21e23 Pignol et al. in a randomised trial showedthat IMRT significantly improved dose distribution within thebreast.14 This translated into clinically significant improvement inacute reactions, with the use of IMRT planning and breast size beingassociated with a reduction in moist desquamation. In a separateprospective trial Donovan et al. showed that a similar improvementin dose distribution by use of IMRT resulted in reduced late softtissue reactions.13

In practice field in field dose compensation “IMRT” may beachieved by taking the beams eye view of the dose distribution forthe whole target volume then adding one or two extra fields withthe same orientation but with the high dose areas shielded outwithMLCs (Fig. 2). The contribution of the additional field(s) to the totaldose is around 10%.21 This simple forward planning IMRT willproduce the required dose distribution for most patients and moresophisticated planning methods do not significantly improve dosedistributions.24,25 For patients where the field separation is large,say >21 cm, a higher energy may need to be used such as 10 Mev.21

With breast radiotherapy planning reducing critical organ doses ismore an issue of careful field placement rather than sophisticateddosimetry planning.

Brachial plexus dose considerations

It is not possible to avoid including the brachial plexus in thehigh dose volume when treating the supraclavicular area. Thetolerance of the brachial plexus is dependent on both the dose perfraction and the total dose, with the risk of radiation-inducedbrachial plexopathy less than 1% with doses per fraction between2.2 and 2.5 Gy when the total dose is up to 40 Gy.20 However, whenthe biological effective dose is greater than 55 Gy, the risk ofradiation-induced brachial plexopathy increases rapidly. In thestart trials A and B only 196 and 82 patients respectively had nodalirradiation within the hypofractionation arms5 and no nodal irra-diation was used in the Whelan trial.4 Several centres do routinelygive nodal irradiationwhen using a 40 Gy in 15 fraction schedule,21

without any reports of brachial plexopathies, but in view of the lackof data from the randomised trials, nodal irradiation is not rec-ommended for hypofractionated treatment.

Tumour bed

Tumour control rates are related to dose3 and this remains truefor hypofractionation regimens. It is preferable to plan a boost fromthe same CT images obtained to treat the whole breast. Therequired shifts can be made from the reference tattoos and patientswill therefore be treated in the same position as for the wholebreast. This allows the orientation of the electron boost to beadjusted to avoid exiting through the heart for left sided tumours.Patients with deep seated tumours which cannot be adequatelycovered by an electron field, and some patients in whom thetumour bed directly overlies the heart, can be treatedwith a photonboost where fields are placed using mini tangents with similargantry and collimator parameters for the whole breast radio-therapy but smaller fields in the sup-inf and ant-post directions.Local experience suggests that this reduces under dosing of thedose area at the deep margin.

N. MacLeod et al. / The Breast 19 (2010) 172e175 175

On-treatment monitoring

From the virtually simulated digitally reconstructed radiographs(DRRs) standardmeasurements should be taken for comparisonwithparameters later noted during electronic portal imaging review.These should include CLD (central lung distance), but departmentsmay choose other measurements such as inferior flash and anteriorflash. Simulator check-films of the fields generated by virtual simu-lation are not required. Lateral images alone are sufficient as imagesof both fields add little or nothing to on-treatment monitoring.Patients should have a baseline Electronic Portal Image prior tofraction 1, on day 1 andweekly images thereafter. All imagesmust bereviewed in real time by comparison with the CT generated DRR.

A daily variation of �5 mm is allowable before adjustments aremade.

Discussion

Breast radiotherapy technique has come to receive considerableattention over the last few years due to the recognition that it hasthe potential to offer as much as systemic therapies to survival frombreast cancer. The same analyses that showed significant benefits incause-specific survival also highlighted severe late toxicity, partic-ularly cardiac, which abrogated much of the overall survival gains.1

The significant late toxicities due to irradiation of organs at risk,predominantly heart and lungs, can be dealt with by accurateplanning of field placements using simulator CT scanner anda virtual planning system. MLC leafs may be needed to provideextra shielding particularly for heart. In contrast the toxicities dueto dose inhomogeneities within the breast tend to be in relation tosoft tissues and skin and these may be ameliorated by accuratedosimetry of breast treatments in linewith ICRU recommendations.There are only 3 prospective randomised trials published assessingthe benefit of IMRT for breast radiotherapy.13,14,21 However there isa consistent theme from all of these that IMRT produces a signifi-cant reduction in dose inhomogeneities, and two of these trialshave demonstrated that this improvement converts into a clinicallysignificant benefit in terms of soft tissue reactions.13,14 It is nolonger acceptable to treat with less than full 3-D planning withmultislice CT and dosimetry criteria based on whole breast isodosecorrections. This is true for all situations but the advent of hypo-fractionation schedules has amplified this need. In very generalterms the larger the fraction size the more critical it is to be accu-rate with field placements, dosimetry and treatment delivery.Currently it would appear that the minimum standards of radio-therapy planning and dosimetry are also the optimum in terms ofimproving dose distributions24 and also in terms of relatively littleeffect on radiotherapy planning resources.21

None of the randomised trials have been large enough nor hadlong enough follow-up to assess late cardiac toxicity. There remainsis a concern that higher doses per fraction may potentially causegreater toxicity to dose sensitive organs such as heart. The imple-mentation of accurate radiotherapy planning and field placementof breast treatments using virtual simulation and data from mul-tislice CT planning scans should help overcome such concerns.

Conflicts of interest statement

None declared.

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