Breast Cancer: New Radiation Treatment Options

Six published randomized trials[1-6] and one meta-analysis[7] of published and unpublishedtrials have demonstrated thatbreast-conserving therapy (breast-conservingsurgery plus breast irradiation)is equivalent to mastectomy interms of survival. As a result, breastconservingtherapy is the option preferredby many women for thetreatment of early-stage breast cancer.[8] Breast irradiation followingbreast-conserving surgery is an integralpart of breast-conserving therapy.There are seven other publishedrandomized trials demonstrating thatbreast irradiation substantially reducesthe rate of local recurrence andprevents the need for subsequent mastectomy.[9-15] A recent meta-analysisalso supports the conclusion that breastcancer patients who receive breast irradiationhave improved survival.[16]Despite this demonstrated effectiveness,up to 30% of patients treatedwith breast-conserving surgery maynot receive radiation therapy.[17,18]The reasons for this are multifactorial,but they are primarily related tothe inconvenience, side effects, andcost of treatment.[19,20] While breastirradiation is generally well tolerated,it is an inconvenient treatment thatrequires daily visits for up to 6 or 7weeks. Common early toxicities includefatigue, breast pain, edema, skinerythema, and irritation, all of whichcan have a significant impact on qualityof life.[21] The difficulties encounteredin delivering and receivingradiation treatment are believed to accountfor the poor utilization of breastconservingtherapy in some regionsof North America.Modified Radiation Strategies
In an effort to improve convenienceand quality of life for patients whoreceive breast irradiation, investigatorshave evaluated shorter or acceleratedradiation therapy schedules.A Canadian trial compared acceleratedwhole-breast irradiation given in3 weeks to a more conventional courseof whole-breast irradiation given in5 weeks.[22] With a median followupof approximately 6 years, the ratesof local recurrence and adverse cosmeticoutcome as a measure of latemorbidity were equivalent between thetwo approaches. A similar randomizedtrial in the United Kingdom evaluatingless frequent radiation treatments demonstratedsimilar findings.[23]As a result, accelerated wholebreastirradiation is now an option forwomen, to improve convenience anddecrease costs associated with breastirradiation following breast-conservingsurgery. While there remains someconcern about potentially increasedlong-term morbidity associated withaccelerated therapy, the results obtainedso far suggest that this outcomeis unlikely to be substantiallyworse than that seen with conventionaltreatment. Accelerated wholebreastirradiation is now widely usedin Canada and the United Kingdom.The article by Arthur et al in thisjournal provides a thorough summaryof the next generation of acceleratedradiation therapy approaches followingbreast-conserving surgery. Radiationmorbidity is directly related tothe volume of tissue irradiated.[24]By delivering only partial-breast irradiation,larger doses of radiation canbe delivered in an even shorter periodof time (1 to 5 days) with the expectationthat there will be limited morbidity.A number of approaches havebeen developed, including interstitialbrachytherapy, the MammoSite device,three-dimensional conformaltherapy, and intraoperative treatment.Some of these approaches, especiallyinterstitial brachytherapy, have undergoneextensive phase II testing andare now being evaluated in phase IIIrandomized trials.Importance of Clinical Trials
As indicated by the authors, it islikely that with careful selection ofpatients and the use of appropriatequality assurance measures, a numberof these approaches may prove tobe equally effective to current wholebreastirradiation. However, it is importantthat these approaches becarefully evaluated. Previous advancesin breast-conserving treatment havebeen based on carefully performedphase II and extensive phase III testing.As a result, our current approachto breast-conserving therapy as comparedto more radical surgery, hasbeen shown to result in equivalentoutcomes for women for up to 20years following treatment.[9,25]It is of some interest that the onlyrandomized trial of partial-breastirradiation performed more than10 years ago demonstrated decreasedlocal control and worse cosmetic outcomeas compared to whole-breastirradiation.[26] This has been attributedto suboptimal selection of patientsand inadequate techniquesfor tumor localization. In the nextdecade, it will be important to buildon our previous successes throughcarefully performed research studies.Advances in Technology
Other recent advances in radiationtherapy for breast cancer have beenthe application of technology to adequatelylocalize the tumor cavity, identifycritical structures, and provide amore homogeneous dose. These advanceshave included the use of computedtomography (CT) planning andintensity-modulated radiation therapy(IMRT). IMRT utilizes modern technologyto deliver a number of radiationfields and to vary the intensity of thesefields. As Arthur and colleagues pointout in their review, numerous studieshave now demonstrated that IMRT resultsin improved homogeneity of thedose to the breast and decreased exposureto the heart and lungs.This application may be of particularrelevance for locoregional radiationwhere the target extends beyondthe breast and chest wall to includethe regional nodes at risk, whichwould normally increase the risk ofadditional radiation to the lungs andheart. IMRT compared to conventionaltechniques may be associated withincreased low-dose radiation exposureto tissues beyond the breast-eg, thyroidand contralateral breast-so,again, it is imperative that such approachesbe formally evaluated in prospectivephase III trials.Conclusions
The newer approaches to radiationtherapy for breast cancer are excitingand hold much promise. As we moveforward, we must not forget that advancesin the local treatment of breastcancer have come through rigorousevaluation resulting in high levels oflocal control that can be consistentlyachieved in many different institutions.New treatment approaches are attractivefrom the perspectives of appliedtechnology, reduction in morbidity,improvement in patient convenience,and decreased costs. However, theseapproaches need to meet the highstandards of established radiation therapytechniques through equally rigorousevaluation, to ensure that thesepotential advantages do not come atthe expense of local control or unacceptableside effects.

Disclosures:

The authors have nosignificant financial interest or other relationshipwith the manufacturers of any productsor providers of any service mentioned in thisarticle.

References:

1.

Arriagada R, Le MG, Rochard F, et al:Conservative treatment versus mastectomy inearly breast cancer: Patterns of failure with 15years of follow-up data. Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol14:1458-1464, 1996.

2.

Blichert-Toft M, Rose C, Andersen JA, etal: Danish randomized trial comparing breastconservation therapy with mastectomy: Sixyears of life-table analysis. Danish Breast CancerCooperative Group. J Natl Cancer InstMonogr 11:19-25, 1992.

3.

Fisher B, Redmond C, Poisson R, et al:Eight-year results of a randomized clinical trialcomparing total mastectomy and lumpectomywith or without irradiaton in the treatment ofbreast cancer. N Engl J Med 320:822-828,1989.

4.

Van Dongen JA, Voogd AC, Fentiman IS,et al: Long-term results of a randomized trialcomparing breast-conserving therapy withmastectomy: European Organization for Researchand Treatment of Cancer 10801 trial. JNatl Cancer Inst 92:1143-1150, 2000.

5.

Veronesi U, Banfi A, Salvadori B, et al:Breast conservation is the treatment of choicein small breast cancer: Long-term results of arandomized trial. Eur J Cancer 26:668-670,1990

6.

Jacobson JA, Danforth DN, Cowan KH,et al: Ten-year results of a comparison of conservationwith mastectomy in the treatment offstage I and II breast cancer. N Engl J Med332:907-911, 1995.

7.

Early Breast Cancer Trialists’ CollaborativeGroup: Favourable and unfavourable effectson long-term survival of radiotherapy forearly breast cancer: an overview of the randomizedtrials. Lancet 355:1757-1769, 2000.

8.

Whelan T, Levine M, Willan A, et al: Effectof a decision aid on knowledge and treatmentdecision making for breast cancer surgery:A Randomized Trial. JAMA 292:435-441,2004.

9.

Fisher B, Anderson S, Bryant J, et al:Twenty-year follow-up of a randomized trialcomparing total mastectomy, lumpectomy, andlumpectomy plus irradiation for the treatmentof invasive breast cancer. N Engl J Med347:1233-1241, 2002.

10.

Liljegren G, Holmberg L, Bergh J, et al:10-year results after sector resection with orwithout postoperative radiotherapy for stage 1breast cancer: a randomized trial. J Clin Oncol17:2326-2333, 1999.

11.

Clark RM, Whelan T, Levine M, et al:Randomized clinical trial of breast irradiationfollowing lumpectomy and axillary dissectionfor node-negative breast cancer: An update. JNatl Cancer Inst 88:1659-1664, 1996.

12.

Veronesi U, Luini A, Del Vecchio M, etal: Radiotherapy after breast-preserving surgeryin women with localized cancer of the breast.N Engl J Med 328:1587-1591, 1993.

13.

Forrest AP, Stewart HJ, Everington D, etal: Randomised controlled trial of conservationtherapy for breast cancer: 6-year analysis of theScottish trial. Lancet 348:708-713, 1996.

14.

Holli K, Saaristo R, Isola J, et al:Lumpectomy with or without postoperative radiotherapyfor breast cancer with favourableprognostic features: Results of a randomizedstudy. Br J Cancer 84:164-691, 2001.

15.

Malström P, Holmberg L, Anderson H,et al, for the Swedish Breast Cancer Group:Breast conservation surgery, with and withoutradiotherapy, in women with lymph node-negativebreast cancer: A randomized clinical trialin a population with access to public mammographyscreening. Eur J Cancer 39:1690-1697,2003.

16.

Vinh-Hung V, Verschraegen C: Breastconserving surgery with or without radiotherapy:Pooled-analysis for risks of ipsilateralbreast tumor recurrence and mortality. J NatlCancer Inst 96:115-121, 2004.

17.

Nattinger AB, Hoffmann RG, KneuselRT, et al: Relation between appropriateness ofprimary therapy for early-stage breast carcinomaand increased use of breast-conservingsurgery. Lancet 30:356: 1148-1153, 2000.

18.

Morrow M, White J, Moughan J, et al:Factors predicting the use of breast-conservingtherapy in stage I and II breast carcinoma.J Clin Oncol 19:2254-2262, 2001.

19.

McGinnis LS, Menck HR, Eyre HJ, etal: National Cancer Data Base Survey of breastcancer management for patients from low incomezip codes. Cancer 88:933-945, 2000.

20.

Atas WF, Adams-Cameron M, Hunt WC,et al: Travel distance to radiation therapy andreceipt of radiotherapy following breast-conservingsurgery. J Natl Cancer Inst 92:269-271,2000.

21.

Whelan TJ, Levine M, Julian J, et al:The effects of radiation therapy on quality oflife of women with breast carcinoma: Resultsof a randomised trial. Ontario Clinical OncologyGroup. Cancer 88:2260-2266, 2000.

22.

Whelan T, Mackenzie R, Julian J, et al:Randomized trial of breast irradiation schedulesafter lumpectomy with lymph node-negativebreast cancer. J Natl Cancer Inst 94:1143-1150, 2002.

23.

Yarnold J, Owen R, Ashton A, et al:Fractionation sensitivity of change in breastappearance after radiotherapy for early breastcancer: Results of a phase III randomized trial(abstract 154). Breast Cancer Res Treat69:230, 2001.

24.

Lymon JT: Compication probability asassessed from dose-volume histograms. RadiatRes Suppl 8(suppl 1):3-9, 1985.

25.

Veronesi U, Cascinelli N, Mariani L, etal: Twenty-year follow-up of a randomizedstudy comparing breast conserving surgerywith radical mastectomy for early breast cancer.N Engl J Med 347:1227-1232, 2002.

26.

Ribeiro GG, Magee B, Swindell R, etal: The Christie Hospital Breast ConservationTrial: An update at 8 years form inception. ClinOncology 5:278-283, 1993.