Copyright RAD Magazine

Radiotherapy following excision of earlybreast cancer

RAD Magazine, 35, 412, 25-26September 2009

Dr Christy GoldsmithAcademic Unit of Radiotherapy

The Royal Marsden Hospital, Sutton

Professor John YarnoldAcademic Unit of Radiotherapy

The Royal Marsden Hospital, Sutton

RAD Magazine, 35, 412, 25-26

By Dr Christy Goldsmith and Professor John Yarnold

Academic Unit of Radiotherapy, The RoyalMarsden Hospital, Downs Road, Sutton, SM2 5PT

email: Christy.Goldsmith@icr.ac.uk

IntroductionBreast cancer is the most common cancer in theUK.1 Most women diagnosed with breast cancerhave early stage disease and will be treated with breast conserving surgery followed by wholebreast irradiation to maximise local tumour control.

This review briefly outlines the rationale forour current management strategy in early breastcancer, the clinical indications for radiotherapyfollowing excision of early breast cancer, technicaladvances in breast radiotherapy, dose-fractionation issues and future directions. Evidence for current management of women with early breast cancer In the 1980s, the standard surgical procedure for earlybreast cancer was the modified radical mastectomy, whichinvolved removal of the breast and axillary nodal dissectionwith preservation of the major pectoral muscle. The inci-dence of local recurrence following this procedure was low innode negative patients, but the operation had a negativeimpact on body image.2,3

Efforts to improve the functional and cosmetic outcome ofbreast cancer surgery led to breast-conserving surgery,involving the removal of the tumour with a rim of normaltissue followed by adjuvant radiotherapy. Landmark studiescompared breast conservation surgery followed by radio-therapy, with mastectomy alone, and reported equivalentsurvival.4,5

The Early Breast Cancer Trialists Collaborative Groupsystematic overview (2005) confirmed the benefits of radio-therapy following breast conservation surgery, with a three-fold reduction in local relapse risk at 10 years whichtranslated into a reduction in breast cancer mortality ofbetween 5% and 8%, depending on node status.6 For every100 women randomised to radiotherapy, there were 20 fewerlocal relapses and five fewer breast cancer deaths comparedwith 100 randomised to no radiotherapy (figure 1). Thus,avoiding four local recurrences prevents one breast cancerdeath, a benefit maintained at 15 years of follow-up. This 4:1ratio is an average effect and is based largely on trials withno systemic chemotherapy. Sub-groups of patients with verypoor prognostic factors, for example >10 nodes positive, arelikely to derive much less benefit in terms of breast cancermortality compared with subgroups with good prognosticfactors in whom local control is of paramount importancein preventing first metastasis, and where the ratio mightbe ≤2:1 (prevention of ≤2 local recurrence saves one life).7

Clinical indications for radiotherapy following local excision of breast cancer Recently updated NICE guidelines state that “patients withearly invasive breast cancer who have had breast-conservingsurgery with clear margins should have breast radiother-apy.” Adjuvant systemic therapies, including endocrine ther-apy, chemotherapy and biological therapy, eg trastuzumab,combines favourably with radiotherapy to further reducelocal relapse risk following breast conservation therapy.8

Radiotherapy following localexcision of early breast cancer

NICE guidance states also that “an external beam boost tothe site of local excision should be offered to patients withearly invasive breast cancer and a high risk of local recur-rence following breast-conserving surgery with clear mar-gins and whole breast radiotherapy.” This guidance is basedlargely on the EORTC boost trial in which younger age wasthe strongest prognostic factor for local recurrence at 10 years.9

Rates of local tumour relapse following breast conserva-tion therapy appear to be falling to <5% at five years. Thisimprovement is probably due to a combination of factors,including improved surgical management of the primarytumour, more effective adjuvant systemic therapy, moreolder patients with low risk disease and technical advancesin breast radiotherapy.10 While it is standard practice to giveradiotherapy to all patients following breast conservationtherapy, a research priority is to identify subgroups ofwomen who can safely avoid radiotherapy. Technical advances in breast radiotherapy Our surgical colleagues have pioneered techniques to min-imise the morbidity of breast cancer surgery, including sen-tinel node and reconstructive techniques where appropriate,without negatively impacting on local control or survival.Multi-disciplinary team working has encouraged closer col-laboration between radiologists, pathologists, surgeons andoncologists. For example, it is now standard practice inmany centres for titanium clips to be placed at the time ofsurgery, marking the wall of the excision cavity. The clipshelp oncologists to localise the tumour bed on radiotherapyplanning CT scans, which is of help in identifying the boostsite as well as being crucial in clinical trials of partial breastradiotherapy (figure 2).

Improvements in radiotherapy technique have been madeat each step in the radiotherapy pathway, including immo-bilisation (customised breast boards), treatment planningand verification (electronic portal imaging). Traditionally,conventional (2D) simulation has been used to plan breastradiotherapy. Many UK radiotherapy departments now rou-tinely perform 3D planning using large-bore CT scanners,which has several advantages over 2D techniques. The timeexpenditure for both patients and clinical staff is reduced,due to fast capture of CT images and rapid reconstruction ofimages as well as automatic skin outlining. Other technicaladvantages include verification of beam coverage of target,as well as critical organ (eg heart and lungs) avoidance inthree dimensions.11

3D planning allows the spatial distribution of hot spots(volumes receiving a dose >105% of prescribed dose) to beevaluated. This information can be used to modify the treat-ment plan, by the use of physical compensators, or step-and-shoot MLC fields (Intensity Modulated Radiotherapy), inorder to optimise dosimetry. Importantly, there is good evi-dence that the improvement of dosimetry that is now possi-ble with IMRT, translates into improved clinical outcomefor patients. A trial conducted at the Royal MarsdenHospital randomised patients requiring whole breast radio-therapy to standard 2D radiotherapy using wedge compen-sators (control arm) or 3D IMRT (test arm). The control armpatients were 1.7 times more likely to have a change inbreast appearance (judged by clinical photographs) than thetest arm patients12 (figure 3). However, IMRT does increasethe dose to other organs not normally considered in con-ventionally planned breast radiotherapy, eg contralaterallung and breast, thyroid, humeral head and oesophagus.The significance of this “low dose bath” effect iscurrentlyunknown, but the issue of possible late oncogenesis needs tobe studied carefully.13

FIGURE 2Surface rendered view of surgical cavity clips. Notethe clips of Patient B are positioned away from thesurgical scar.

FIGURE 3Examples of sagittaldose distribution for (a)standard wedged planand (b) IMRT plan. Dataare from the in-houseprogramme for onepatient. Colour scale:dark blue = 90%, midblue = 95%, light blue =98%, mid green = 100%,light green = 102%, yel-low = 105%, orange =110%, red = 112%.

Reprinted from The European Journal of Radiotherapy and Oncology,82(3), Ellen Donovan et al, Randomised trial of standard 2D radiotherapy(RT) versus intensity modulated radiotherapy (IMRT) in patients prescribedbreast radiotherapy, 82(3), 254-264. Copyright 2007, with permission from Elsevier.

(a) (b)

FIGURE 1Survival curves showing the importance of breast radiotherapy after breast conserving surgery in reducinglocal recurrence rate and mortality. Reprinted from The Lancet, 366, Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Effects of radiotherapy and of differences in the extent of surgeryfor early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials, 2087-2106. Copyright 2005, with permission fromElsevier.

60

50

40

30

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00 5 10 15

Time (years)

22.9

6.710.0

29.2BCS

BCS + RT

Isol

ated

loca

l rec

urre

nce

(%)

Five-year gain 16.1% (SE 1.0)

6097 women with BCS and node-negative disease60

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40

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Time (years)

8.9

8.0

20.3

17.4

31.2%BCS26.1%BCS + RT

Bre

ast ca

nce

r m

orta

lity

(%)

15-year gain 5.1% (SE 1.9)Logrank 2p=0.006

60

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00 5 10 15

Time (years)

11.0

41.1

46.5

13.1

BCS

BCS + RTIsol

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loca

l rec

urr

ence

(%)

Five-year gain 30.1% (SE 2.8)

1214 women with BCS and node-positive disease

60

50

40

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00 5 10 15

Time (years)

20.9

36.5

45.2

24.3

55.0%BCS

47.9%BCS + RT

Bre

ast ca

nce

r m

orta

lity

(%)

15-year gain 7.1% (SE 3.6)Logrank 2p=0.01

Dose-fractionation issues For many years, the international standard regimen foradjuvant breast radiotherapy has been 25 daily fractions of2 Gy to a total dose of 50 Gy over five weeks. Alternativehypofractionated schedules have also been widely used inthe UK and Canada on an empirical basis. The START Btrial,14 a multicentre study that recruited over 2200 women,aimed to compare these commonly used regimes, and con-cluded that, following surgery for early breast cancer, aradiotherapy schedule delivering 40 Gy in 15 fractions overthree weeks offers rates of loco-regional control and late nor-mal tissue effects comparable with 50 Gy in 25 fractions.The recently updated NICE guidance endorses the use of40 Gy in 15 fractions following breast conservation surgeryfor early breast cancer. This hypofractionated regime shouldresult in considerable saving of resources, both human andfinancial, as well as being more convenient and acceptable topatients. Future directions There has been a recent trend to stratify patients post-surgery by their prognostic risk factors and to tailor theirradiotherapy accordingly. Low-risk patientsPartial breast irradiation is being evaluated for low-riskindividuals, based on the observation that the majority oflocal relapses occur in the vicinity of the primary tumouror at least within the index quadrant of the breast. In addi-tion, it is not clear that whole breast radiotherapy reducesthe risk of ipsilateral breast tumour recurrence outside theindex quadrant, a high proportion of which are probablynew primary tumours.4,15,16 These two observations takentogether raise the possibility that only partial breast irradi-ation is important in achieving local control following breastconservation surgery in low-risk cancer patients. Againstthis background, IMPORT-Low is a multi-centre randomisedtrial testing partial versus whole breast radiotherapy deliv-ered with IMRT following complete local tumour excision oflow-risk early stage breast cancer17 (figure 4).

Accelerated Partial Breast Irradiation (APBI) is alsobeing evaluated in low-risk patients following breast con-servation surgery. The MammoSite system employs a dual-lumen spherical balloon catheter which is placed in thesurgical cavity and filled with water. A high-dose-rate (HDR)

Iridium-192 source placed in the central lumen delivers theradiotherapy in 10 fractions over five days.18 The concept ofAPBI is also being evaluated in trials of intra-operativeradiotherapy using either low energy x-rays (TARGIT)19 orelectrons (ELIOT).20

High-risk patients The IMPORT-High study is currently open to recruitmentfor women at a higher than average risk of local recurrence.This randomised trial tests dose-escalated intensity modu-lated radiotherapy in eligible women after breast conserva-tion surgery andappropriate systemic therapy.17

Summary Most women diagnosed with breast cancer have early stagedisease and will be treated with breast conservation surgeryfollowed by whole breast irradiation. A majority will have anexcellent prognosis, and the challenge in this group ofpatients is to reduce treatment morbidity, without nega-tively impacting on local control or survival rates. In con-trast, some women undergoing breast conservation surgeryhave poor prognostic factors and a higher than average riskof recurrence. The challenge in these women is to delivermore intense radiotherapy to improve local control and sur-vival while maintaining acceptable late normal tissue toxic-ity. It is hoped that recent technological advances inradiotherapy techniques and well co-ordinated clinical tri-als will help to meet these challenges.

References 1, Office for National Statistics. Series MB1 no.36, 2008. 2008. 2, Rosen, P R et al. A long-term follow-up study of survival in stage I

(T1N0M0) and stage II (T1N1M0) breast carcinoma. J Clin Oncol, 1989.7(3):p355-66.

3, Irwig, L and Bennetts, A. Quality of life after breast conservation ormastectomy: A systematic review. Aust N Z J Surg, 1997. 67(11):p.750-4.

4, Fisher, B et al. Twenty-year follow-up of a randomised trial comparingtotal mastectomy, lumpectomy and lumpectomy plus irradiation for the treat-ment of invasive breast cancer. N Engl J Med, 2002. 347(16):p.1233-41.

5, Veronesi, U et al. Comparing radical mastectomy with quadrantectomy,axillary dissection and radiotherapy in patients with small cancers of thebreast. N Engl J Med, 1981. 305(1):p.6-11.

6, Clarke, M et al. Effects of radiotherapy and of differences in the extentof surgery for early breast cancer on local recurrence and 15-year survival:An overview of the randomised trials. Lancet, 2005. 366(9503):p.2087-106.

7, Kyndi, M et al. Estrogen receptor, progesterone receptor, HER-2 andresponse to postmastectomy radiotherapy in high-risk breast cancer: TheDanish Breast Cancer Cooperative Group. J Clin Oncol, 2008. 26(9):p.1419-26.

8, Schnitt, S J and Harris J R. Evolution of breast-conserving therapyfor localised breast cancer. J Clin Oncol, 2008. 26(9):p.1395-6.

9, Poortmans, P M et al. The addition of a boost dose on the primarytumour bed after lumpectomy in breast conserving treatment for breast cancer.A summary of the results of EORTC 22881-10882 “boost versus no boost”trial. Cancer Radiother, 2008. 12(6-7):p.565-70.

10, Mannino, M and Yarno J R., Local relapse rates are falling afterbreast conserving surgery and systemic therapy for early breast cancer: Canradiotherapy ever be safely withheld? Radiother Oncol, 2009. 90(1):p.14-22.

11, Conway, J and Robinson M H. CT virtual simulation. Br J Radiol,1997. 70 Spec No: p.S106-18.

12, Donovan, E et al. Randomised trial of standard 2D radiotherapy (RT)versus intensity modulated radiotherapy (IMRT) in patients prescribed breastradiotherapy. Radiother Oncol, 2007. 82(3):p.254-64.

13, O’Donnell, H et al. Early experience of tomotherapy-based intensity-modulated radiotherapy for breast cancer treatment. Clin Oncol (R CollRadiol), 2009. 21(4):p.294-301.

14, Bentzen, S M et al. The UK Standardisation of Breast Radiotherapy(START) Trial B of radiotherapy hypofractionation for treatment of earlybreast cancer: A randomised trial. Lancet, 2008. 371(9618):p.1098-107.

15, Veronesi, U et al. Radiotherapy after breast-preserving surgery inwomen with localised cancer of the breast. N Engl J Med, 1993.328(22):p.1587-91.

16, Fowble, B et al. Breast recurrence following conservative surgery andradiation: Patterns of failure, prognosis and pathologic findings from mas-tectomy specimens with implications for treatment. Int J Radiat Oncol BiolPhys, 1990. 19(4):p.833-42.

17, Coles, C and Yarnold J. The IMPORT trials are launched (September2006). Clin Oncol (R Coll Radiol), 2006. 18(8):p.587-90.

18, Benitez, P R et al. Five-year results: The initial clinical trial ofMammoSite balloon brachytherapy for partial breast irradiation in early-stagebreast cancer. Am J Surg, 2007. 194(4):p.456-62.

19, Kraus-Tiefenbacher, U et al. Long-term toxicity of an intraoperativeradiotherapy boost using low energy x-rays during breast-conserving surgery.Int J Radiat Oncol Biol Phys, 2006. 66(2):p.377-81.

20, Intra, M et al. Surgical technique of intraoperative radiation therapywith electrons (ELIOT) in breast cancer; a lesson learned by over 1000 proce-dures. Surgery, 2006. 140(3):p.467-71.

FIGURE 4Planning CT scan showing GTV (blue contour)marked by surgical clips, CTV (red contour) and PTV(lavender colourwash) of a patient receiving partialbreast irradiation in the IMPORT Low trial.