Current
best practices and rationalistic perspectives in causation-based
prevention, early detection and multidisciplinary treatment
of breast and gastric cancer
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Volume 2 - Number 1 - Jan/May 2003 |
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EDITORIAL |
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Breast-conserving Treatment for Breast Cancer: Rational, Current Reality & Limitations Dimitrios H. Roukos, MD, Niki J Agnantis, MD, and Angelos M kappas, MD. From the Departments of Surgery (AMK, DHR), and Pathology (NJA), Ioannina University Medical School,
ABSTRACT Recently published 20-years follow-up scientific data confirm that there is no difference in survival after breast conservation therapy or total mastectomy in women with stage I or II breast cancer. However, breast conservation treatment is associated with an increased risk of both positive margins and local recurrence. Current estimates suggest that 10 to 20% of women after breast-conserving treatment is at high-risk of local failures. This is a characteristic example of limitations and lack of generalizability of randomized controlled trials, although they provide the best available evidence for treatment decision-making. |
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Most of the 20th century the Halsted radical mastectomy and during the last decades the modified total mastectomy, were the standardized operation for cancer of the breast in all stages, early or late. However, with advances in the understanding of breast cancer spread mechanisms a new concept towards a less radical surgery[1] has been developed with breast-conserving treatment increasingly to replacing mastectomy. |
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The rational of a less extensive surgical approach has been based on both histological data indicated that small solid tumors can be completely removed by limited surgery and clinical results suggested that this approach might result in a lower side-effects profile than extensive surgery without increasing risk of cancer death. This creative thoughtful concept represents an important advance towards a lower morbidity and better quality of life of patients with breast cancer1 and other solid tumors including gastric cancer.[2,3] |
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However, long-term survival data from randomized controlled trials (RCTs), that provide the best scientific evidence for a decision-making, are essential before the incorporation of a new treatment into routine clinical practice. A trend towards a less extensive surgery has already been started for the most common solid tumors such the prostate cancer, gynecologic cancer or gastrointestinal tract cancer and the effect of such limited surgery or minimally invasive approach on patient’s outcomes is now evaluating in ongoing RCTs. |
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For breast cancer however, there are now accumulating evidence-based data that allow us to drawn conclusions about the effectiveness of breast conservation therapy. Survival data from RCTs after a follow-up of 5 or 10 years[4-10] have showed that there is no significant difference in overall survival or breast-cancer specific survival after breast-conserving surgery and mastectomy. The lack of long-term follow-up data was an argument against breast-conserving surgery because of the long natural history of breast cancer. |
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Now, the recently published 20-years results by Fisher et al.[11] and Veronesi et al.[12] confirm that mastectomy is not superior to breast conservation treatment with respect to long-term survival. In an accompanying editorial Dr. Morrow points out that it is time to declare the case against breast-conserving therapy closed, to expand the eligibility criteria and to increase the currently low rate of breast-conserving surgery that is performed in approximately 42% of women with stage I or II breast cancer.[13] Indeed, as breast conservation therapy is a woman’s friendly and preferable procedure leading to a better quality of life than total mastectomy, a wider clinical use of breast conservation treatment is expected in the next years. |
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The key question from the increasing replacement of mastectomy by breast conservation procedures such lumpectomy, quadrantectomy or local/wide excision is whether this trend is parallel associated with an increased risk of close or positive margins and local recurrence in ipsilateral breast. Indeed, the analysis of scientific data available [14: details in positive margins in this issue of GBC] let no doubt that breast-conserving surgery is associated with higher rates of close or positive margins than mastectomy. The magnitude of this risk varies from 10% in the National Surgical Adjuvant Breast and Bowel Project (NSABP, B-06) trial[5,11] to 48% in the European Organization for Research and Treatment of Cancer (EORTC) trial.[9] The risk of local recurrence among women with close or positive margins is high and ranges between 9% and 20% with the surgical re-excision to remain a standard procedure.[14] Clear surgical margins continuous to be the principal goal of breast-conserving treatment despite the availability of current adjuvant treatment. |
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Local recurrence represents currently the major disadvantage of breast-conserving treatment. It occurs in 8.8% to 20% after breast-conserving surgery despite the use of adjuvant irradiation therapy in reports with long-term follow-up.[5,8-11] Postoperative adjuvant whole breast irradiation after breast-conserving surgery has been established effective in reducing local recurrence[2,5-9] and improving survival,[15] but it is unable to fully eliminate the risk of local failure. Particularly late recurrence is challenging occurring at a rate of approximately 1% per year after the tenth year of treatment.[16]Additional boost to the primary tumor bed, chemotherapy, and tamoxifen contribute to the reduction of local failure but in some patients they rather delay time to recurrence than fully eliminate late recurrence.[16,17] The underlying mechanisms of this late tumor formation are unclear but either it is a true recurrence or a new primary tumor[9] must take into account for primary treatment decision-making. |
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Efforts have been focused on the identification of risk factors and use of more effective treatment for risk-reduction local recurrence. Of multiple clinical, pathologic and treatment-related risk factors reported, young age, close or positive margins, extensive intraductal component (EIC) and the non-use of adjuvant systemic chemotherapy in node-negative patients or tamoxifen[9,16,17] are consistently associated with increased risk of local failure in most series.[12,14-17] Although with careful patient selection and appropriate multidisciplinary treatment local failures can be reduced, in some women with stage I or II breast cancer but at risk of local failure -if they undergo in breast-conservation treatment, total mastectomy may be indicated after patient consultation about the risk and benefits of each one of these treatment options. It should be noted however, that even after mastectomy some local failures can be occurred in the chest wall reflecting biologically aggressive disease. Promises for the identification of these patients provide current reports with new biologic markers such as particularly Gene-expression profiling[18,19] and Cyclin E levels[20,21] that may lead to a new tailored treatment and improved outcome. |
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Randomized controlled trials (RCTs) are the “gold standard” for treatment decision-making. They represent the best evidence-based available method necessary to assess the possible clinical risks of a new treatment before its incorporation into routine clinical practice. |
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However, RCTs are limited by the lack of generalizability to the individual patients.[22] Another pitfall for some patients enrolled in RCTs is an increased risk of morbidity and mortality. A characteristic example of limitations and pitfalls of RCTs is the critical analysis of the results of breast-conserving therapy available for breast cancer. Thousands of women have been enrolled in these trials that compared breast-conserving surgery with or without adjuvant irradiation, chemotherapy or tamoxifen and total mastectomy. Several hundreds of these women were affected by an inappropriate patient selection and treatment. The rate of positive margins after breast conserving surgery reached an unacceptable rate of 48% in the EORTC trial.[9] In the NSABP B-06 trial the incidence of local recurrence after lumpectomy among women without postoperative adjuvant irradiation was high (39%)[11] resulting in reduced survival as demonstrates a recent meta-analysis.[15] |
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The lack of generalizability of RCTS to individual patients is reflected by the fact that although for most women with stage I or II breast cancer breast conservation treatment is the treatment of choice, some others may benefit from total mastectomy rather than breast conservation. Current research efforts are focused on the pretreatment identification of these women. |
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References |
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1. Fisher B. Breast-cancer management: alternatives to radical mastectomy. N Engl J Med 1979;301:326-328. 2. Elisaf M., Roukos DH, Briasoulis E, Michos KM, Agnantis NJ, Kappas AM. Comparing recent advances in gastric and breast cancer. Gastric Breast Cancer 2002; 1(3): 59-64. 3. Roukos DH. Tumor stage-based tailored therapeutic strategy for gastric cancer: rational approach or new trend? Gastric Breast Cancer 2003; 2(1): 1-4. 4. Veronesi U, Saccozzi R, Del Vecchio M, et al. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N Engl J Med 1981;305:6-11. 5. Fisher B, Anderson S, Redmond CK, et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333:1456–1461. 6. Sarrazin D, Le MG, Arriagada R, et al. Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989;14:177-184. 7. Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. In: Consensus development conference on the treatment of early-stage breast cancer. Journal of the National Cancer Institute monographs. No. 11. Bethesda, Md.: National Cancer Institute, 1992:19-25. (NIH publication no. 90-3187.) 8. Arriagada R, Le MG, Rochard F, et al. Conservative treatment versus mastectomy in early breast cancer: Patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group. J Clin Oncol 1996;14:1558–1564. 9. van Dongen JA, Voogd AC, Fentiman IS, et al. Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 2000;92:1143-1150. 10. Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995;332:907-911. 11. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-1241. 12. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227-1232. 13. Morrow M, White J, Moughan J, et al. Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol 2001;19:2254-2262. 14. Roukos DH, Agnantis NJ, Batsis H, Paraskevaidis E, Kappas AM. Breast-conserving surgery and risk of positive margins in breast cancer. Gastric Breast Cancer 2003; 2(1): 15-19 Available online at http://www.gastriccancer.net 15. Early Breast Cancer Trialists' Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355:1757-1770. 16. Neuschatz AC, DiPetrillo T, Safaii H, et al. Long-term follow-up of a prospective policy of margin-directed radiation dose escalation in breast-conserving therapy. Cancer 2003;97:30-39. 17. Freedman GM, Hanlon AL, Fowble BL, Anderson PR, Nikolaou N. Recursive partitioning identifies patients at high and low risk for ipsilateral tumor recurrence after breast-conserving surgery and radiation. J Clin Oncol 2002; 20: 4015-21. 18. Van de Vijver MJ, He YD, van 't Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347:1999-2009. 19. Roukos DH, Pavlidis N, Agnantis NJ. Gene-expression profile: the future in the outcome prediction and treatment of breast cancer. Gastric Breast Cancer 2003; 2(1): 5-8. 20. Keyomarsi K, Tucker SL, Buchholz TA, et al. Cyclin E and Survival in Patients with Breast Cancer. N Engl J Med 2002 Nov;347:1566-75. 21. Agnantis NJ, Roukos DH, Paraskevaidis E, Elisaf M:Gastric Breast Cancer 2003; 2(1): 9-11. 22. Black N. Evidence-based surgery: A passing Fad? World J Surg 1999; 23: 789-93 |
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