Current Status of Radiation in the Treatment of Breast Cancer

The article by Dr. William Smallon the role of radiation therapyin the treatment of breast cancer is a comprehensive review of the currentstandards of care and highlights the controversies surrounding recent trends.Breast cancer treatment has come full circle in the last 20 years, with emphasisnow being placed on technical advances and treatment techniques as new datasubstantiate the impact of radiation therapy on survival following local surgeryand mastectomy.

Ductal Carcinoma In Situ

The effort to define a subpopulation of patients in whom lesstreatment can be given while maintaining or improving local control and survivalrates is noble. Whether moving from mastectomy to breast-conservation therapy orfrom breast-conservation therapy to excision alone, Dr. Small diplomaticallypoints out the need for caution and the role of good randomized trials. Althoughbreast-conservation therapy has become the accepted standard of care forpatients with ductal carcinoma in situ (DCIS), mastectomy remains the procedurethat offers the lowest rate of recurrence. National Surgical Adjuvant Breast andBowel Project (NSABP) B-06 data on 22 patients who underwent a mastectomy withnegative margins showed that 41% had residual DCIS in the same breast quadrantupon pathologic review.[1] As Dr. Small reported, there are currently nopublished randomized trials that have compared mastectomy andbreast-conservation therapy in patients with DCIS.

The Eastern Cooperative Oncology Group (ECOG) is currentlyconducting a randomized trial of local excision without breast irradiation in asubgroup of patients with DCIS and favorable factors.[2] Dr. Small’s articleclearly cautions against making generalizations from nonrandomized trials suchas that of Silverstein et al who tried to classify DCIS patients according totheir need for mastectomy, local excision alone, or local excision andradiation.[3] The reproducibility of such data is a major concern.

Sivlerstein’s results (and findings from other nonrandomizedtrials), however, do provide an excellent foundation on which to base futurerandomized studies. Until the ECOG data have matured, management of DCIS shouldconform to the results of the NSABP B-22 study, which, to date, has provided theclearest guidelines. Routine radiation to the breast following a lumpectomyremains the current standard of care for all patients with this disease.

Invasive Breast Cancer

Full axillary dissection for invasive breast cancer is slowlybeing replaced by sentinel lymph node biopsy, although no randomized trial hasestablished that the two procedures are equivalent. The NSABP B-32 and AmericanCollege of Surgeons Oncology Group (ACOSOG) trials are currently addressing thisissue and hopefully will determine the efficacy of the axillary dissectionprocedure itself.[2] Now that immunohistochemical staining can identify singlemetastatic cells in lymph nodes, we are faced with new challenges in definingthe role of chemotherapy as well as the addition of nodal irradiation. Theabove-mentioned trials will be investigating patient outcomes related toimmunohistochemical studies.

The traditional lumpectomy cavity radiation boost has also beenchallenged for patients with stage I/II breast cancer. Nevertheless, recentlypresented data from the European Organization for Research and Treatment ofCancer (EORTC) "boost vs no boost" trial[4] showed that boostradiation decreased the risk of local failure and had the greatest impact inyounger women. The study also found that local failure increased the risk ofsystemic metastasis by 8.3%. The best method for delivering the boost has yet tobe determined, but generally, direct electron fields are used.

Postmastectomy Radiation

While the role of radiation in DCIS and early-stage invasivebreast cancer has been challenged, the role of postmastectomy chest wallradiation has been expanded over the last 2 years. During the era from the 1960sthrough the late 1970s when the Haagensen surgical criteria for breast cancerwere used, it became apparent that chest wall recurrence was a significantproblem for patients with class C or D disease and that the addition of chestwall and nodal irradiation was important for local control and survival.[5] Withthe advent of chemotherapy, the survival advantage associated with radiation waslost, thereby decreasing the use of radiation over the last 10 to 15 years.

As Dr. Small has pointed out, results from both the DanishBreast Cancer Cooperative Group Trial and the British Columbia study document asurvival advantage in premenopausal, node-positive women who underwentmastectomy, chemotherapy, and radiation of the chest wall and regional nodes. Infact, the Canadian study implies a survival benefit for chest wall radiationfollowing mastectomy in patients with one to three positive nodes, as comparedto those with four or more nodes (whose risk of systemic failure issignificantly higher). The Intergroup trial is investigating postmastectomyradiation in women with one to three positive nodes. The radiation fields inthis study include the internal mammary nodes. This highlights yet anotherquestion—whether radiation to the internal mammary nodes contributes tosurvival. These and other recent trials further support the paradigm that localcontrol remains paramount for overall survival and that chemotherapy, althoughimportant for control of systemic disease, has less of an impact on localcontrol.

Radiation Techniques

Techniques for delivering radiation have thus become a focalpoint, in light of the younger population and the increased survival of thesepatients. Dr. Small mentions his preference for the Marks’ technique intreating the internal mammary nodes.[6] This approach, which eliminates the needfor matching internal mammary fields, becomes even more significant when oneconsiders recent data from the Joint Center of Radiation Therapy.[7] These datarevealed that younger patients
(< 50 years) treated with breast irradiation had a 43% increase in unexpectedsecond, nonbreast malignancies.

Among seven patients who developed sarcomas, four developed thesarcoma within an area of match-line fibrosis. The authors postulate that thefibrosis was related to an older matching technique and conclude that perhapsnewer methods of delivering radiation to the breast and lymph node areas mayreduce the risk of secondary nonbreast malignancies.[7]

Conclusions

Clearly, the current investigational focus is on reproduciblydefining the subpopulations for whom a particular therapy offers optimal localand survival benefit while limiting the toxicities of treatment. The pendulumcontinues to swing as technical advances are made. If one could morespecifically define the region that needs to be treated, coupled with the adventof the technology that allows our treatments to be more focused (such as withintensity-modulated radiation therapy, deep inspiration breathhold, andbrachytherapy), then our goals may be achieved.[8-11]

While preliminary studies of intensity-modulated radiationtherapy using conventional field arrangements have demonstrated improved dosehomogeneity within the breast, the potential advantage of this technology liesin its ability to deliver doses differentially with combinations of photons andelectrons. With the apparent need to continue using tumor boosts,intensity-modulated radiation therapy can selectively treat the boost volumewhile simultaneously treating the whole breast volume. Also, defining thevolumes of interest to include the nodal sites in higher-risk patients, withinverse planning, may help to develop novel radiation field arrangements.However, the question remains: Is less really more?

References:

1. Fisher B, Anderson S, Redmond CK, et al: Reanalysis andresults after 12 years of follow-up in a randomized clinical trial comparingtotal mastectomy with lumpectomy with or without irradiation in the treatment ofbreast cancer. N Engl J Med 333:1456-1461, 1995.

2. Cheson B, Abrams J, Gravell A, for the NCI: Clinical trialsreferral resource. Oncology 15(2):176-185, 2001.

3. Silverstein MJ: Ductal carcinoma in situ of the breast. BrMed J 317:734-739, 1998.

4. Bartelink H, Collette L, Forquet A, et al: Impact of a boostof 16 Gy on the local control and cosmesis in patients with early breast cancer:The EORTC "boost versus no boost" trial. Int J Radiat Oncol Biol Phys48(suppl 1):1, 2000.

5. Fletcher G: Primary Management of Breast Cancer, in FletcherG (ed): Textbook of Radiotherapy, pp 336-358. Philadelphia, Lea & Febiger,1966.

6. Marks LB, Herbert ME, Bentel G, et al: To treat or not totreat the internal mammary nodes: A possible compromise. Int J Radiat Oncol BiolPhys 29:903-909, 1994.

7. Galper S, Gelman R, Recht A, et al: Second non-breastmalignancies after conservative surgery and radiation therapy for early-stagebreast cancer. Int J Radiat Oncol Biol Phys 48(suppl 1):68, 2000.

8. McCormick B, Hong L, Chui C, et al: Breast IMRT: Thepotential for treatment improvement with intensity modulation in left-sideddisease. Int J Radiat Oncol Biol Phys 48(suppl 1):2066, 2000.

9. Kuske RR, Bolton JS, Fuhrman G, et al: Wide volumebrachytherapy alone for select breast cancers: The ten-year experience of theOchsner Clinic. Int J Radiat Oncol Biol Phys 48(suppl 1):2063, 2000.

10. Lomas A, Cella L, Weber D, et al: Potential role of IMRT andprotons in the treatment of the breast and regional nodes. Int J Radiat OncolBiol Phys 48(suppl 1):2065, 2000.

11. Kestin L, Sharpe M, Frazier R, et al: Intensity modulationto improve dose uniformity with tangential breast radiotherapy. Int J RadiatOncol Biol Phys 48(suppl 1):2062, 2000.