Current Trends and Challenges in Real-World Breast Cancer Adjuvant Radiotherapy: A Practical Review. New trends in adjuvant radiotherapy in BC

Grazia Lazzari (1), Angela Pia Solazzo (2), Ilaria Benevento (3), Antonietta Montagna (4), Luciana Rago (5), Giovanni Castaldo (6), Giovanni Silvano (7)
(1) Radiation Oncology Unit, San Giuseppe Moscati Hospital, Taranto, Italy, Italy,
(2) Radiation Oncology Unit, IRCCS-CROB, Rionero in Vulture (PZ), Italy , Italy,
(3) Radiation Oncology Unit, IRCCS-CROB, Rionero in Vulture (PZ), Italy, Italy,
(4) Radiation Oncology Unit -IRCCS CROB Rionero in Vulture, Italy,
(5) Radiation Oncology Unit -IRCCS CROB Rionero in Vulture, Italy, Italy,
(6) Radiation Oncology Unit -IRCCS CROB Rionero in Vulture, Italy,
(7) Emicenter Casoria -Napoli, Italy

Abstract

Background: The treatment of breast cancer (BC) remains a constant and rapidly evolving issue for multidisciplinary breast cancer teams. Considering the emerging understanding and advances in the biological course of this disease, new trends in radiotherapy fractionation, systemic therapies, and oncoplastic surgical techniques are revolutionizing adjuvant treatment approaches to BC. Novel challenges are questioning the integration of adjuvant radiotherapy (ART) into the real-world clinical setting.


Methods: PubMed literature search was conducted in order to extract data supporting the role of new trends in breast cancer adjuvant approach according to rising issues in the multidisciplinary team discussion such as sequencing with chemotherapy (CT) plus whole breast hypofractionated radiotherapy (HF-WBRT); the role of ART after neoadjuvant CT (NACT) followed by breast conservative surgery (BCS) in early BC achieving pathological complete remission (pCR); and the integration of ART in immediate autologous breast oncoplastic reconstruction after mastectomy (a-IBR). Furthermore, there are still several concerns about toxicity with adjuvant trastuzumab emtansine (T-DM1) or breast re-irradiation after BCS relapse in long-term survivors refusing mastectomy.


Results:  Among 40 hits, only 12 studies answered to these issues. Many of them were retrospective studies. Less than 500 patients met the criteria for these issues and several conclusions were found exhaustive.


Conclusion:  Few issues seem to have literature solutions, while there are still open questions in regard to these new trends. Novel strategies through prospective or randomized studies and new consensus guidelines are required.

Full text article

Generated from XML file

References

Overgaard M, Nielsen HM, Tramm T, Højris I, Grantzau TL, Alsner J, et al. Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial. Radiotherapy & Oncology 2022; 170 : 4-13. doi: 10.1016/j.radonc.2022.03.008

Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994;12:447–453. doi: 10.1200/JCO.1994.12.3.447.

Espenel S, Chargari C, Blanchard P, Bockel S, Morel D, Rivera S, et al. Practice changing data and emerging concepts from recent radiation therapy randomised clinical trials. Eur J Cancer 2022; 171:242-58. doi: 10.1016/j.ejca.2022.04.038

START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK standardisation of breast radiotherapy (START) trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008; 9:331–341. doi:10.1016/S1470-2045(08)70077-9.

START Trialists' Group, Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008 Mar 29;371(9618):1098-107. doi: 10.1016/S0140-6736(08)60348-7.

Murray Brunt A, Haviland JS, Wheatley DA, Sydenham MA, Alhasso A, Bloomfield DJ, et al. Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. Lancet. 2020 ;395(10237):1613-1626. doi: 10.1016/S0140-6736(20)30932-6.

Asselain B, Barlow W, Bartlett J, Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;19(1):27–39. doi: 10.1016/S1470-2045(17)30777- 5

von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019 Feb 14;380(7):617-628. doi: 10.1056/NEJMoa1814017.

Panchal H, Matros E. Current Trends in Post-Mastectomy Breast Reconstruction. Plast Reconstr Surg. 2017; 140(5): 7S–13S. doi:10.1097/PRS.0000000000003941

Brewster AM, Hortobagyi GN, Broglio KR, Kau SW, Santa-Maria CA, Arun B, et al. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008; 100(16):1179-183. doi: 10.1093/jnci/djn233

Freedman GM, Fowble BL. Local recurrence after mastectomy or breast-conserving surgery and radiation. Oncology (Williston Park). 2000; 14(11):1561-1581; discussion 1581-1562, 1582-1564.

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. doi:10.3322/caac.21262

Al-Hilli Z, Thomsen KM, Habermann EB, Jakub JW, Boughey JC. Reoperation for complications after lumpectomy and mastectomy for breast cancer from the 2012 National Surgical Quality Improvement Program (ACS-NSQIP). Ann Surg Oncol. 2015; 22(Suppl 3):S459–S69. doi: 10.1245/s10434-015-4741-7

Aerts L, Christiaens MR, Enzlin P, Neven P, Amant F. Sexual functioning in women after mastectomy versus breast conserving therapy for early-stage breast cancer: a prospective controlled study. Breast. 2014; 23(5):629–36. doi: 10.1016/j.breast.2014.06.012

Moran MS, Truong PT. Hypofractionated radiation treatment of breast cancer: The time is now. Breast J. 2020;00:1–8. doi: 10.1111/tbj.13724

Gupta A, Ohiri N, Haffty BG. Hypofractionated radiation treatment in the management of breast cancer. Expert Rev Anticancer Ther. 2018; 18(8): 793–803. doi:10.1080/14737140.2018.1489245

Pondè NF, Zarvadas D, Piccart M. Progress in adjuvant systemic therapy for breast cancer- Nat Rev Clin Oncol. 2019 Jan; 16(1):27-44. doi: 10.1038/s41571-018-0089-9

Syed YY. Oncotype DX Breast Recurrence Score ®: A Review of its Use in Early-Stage Breast Cancer. Mol Diagn Ther. 2020 Oct;24(5):621-632. doi: 10.1007/s40291-020-00482-7

Almstedt K, Mendoza S, Otto M, Battista MJ, Steetskamp J, Heimes AS, et al. EndoPredict® in early hormone receptor-positive, HER2-negative breast cancer. Breast Cancer Res Treat. 2020 Jul;182(1):137-146. doi: 10.1007/s10549-020-05688-1

Recht A, Come SE, Henderson IC, Gelman RS, Silver B, Hayes DF, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early stage breast cancer. N Engl J Med .1996; 334:1356- 61, doi: 10.1056/NEJM199605233342102

Bellon JR, Come SE, Gelman RS, Henderson IC, Shulman LN, Silver BJ, et al. Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial. J Clin Oncol. 2005 Mar 20;23(9):1934-40. doi: 10.1200/JCO.2005.04.032

Belletti B, Vaidya JS, D'Andrea S, Entschladen F, Roncadin M, Lovat F, et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin Cancer Res. 2008 Mar 1;14(5):1325-32. doi: 10.1158/1078-0432.CCR-07-4453.

Formenti SC, Demaria S. Local control by radiotherapy: is that all there is? Breast Cancer Research 2008, 10:215-22. doi:10.1186/bcr2160.

Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E. Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 1989; 49: 1996–2001

Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384: 164–72. doi: 10.1016/S0140-6736(13)62422-8

von Minckwitz G, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Eiermann W, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol 2013; 31: 3623–30. doi: 10.1200/JCO.2012.45.0940.

Cortazar P, Geyer CE jr. Pathological complete response in neaoadjuvant treatment of breast cancer. Ann Surg Oncol. 2015 May;22(5):1441-6. doi: 10.1245/s10434-015-4404-8

Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer. 2012; 48(18): 3342–54. doi: 10.1016/j.ejca.2012.05.023

Denkert C, Liedtke C, Tutt A, von Minckwitz G. Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet. 2017 Jun 17;389(10087):2430–42. doi: 10.1016/S0140-6736(16)32454-0.

McGuire SE, Gonzalez-Angulo AM, Huang EH, Tucker SL, Kau SW, Yu TK, et al. Postmastectomy radiation improves the outcome of patients with locally advanced breast cancer who achieve a pathologic complete response to neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys. 2007 Jul 15;68(4):1004-9. doi: 10.1016/j.ijrobp.2007.01.023.

Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, et al. NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC). Journal of Clinical Oncology 2019. doi: 10.1200/JCO.2019.37.15_suppl.TPS600.

Boughey J, Haffty B, Buchholz T, Symmans WF, Hunt K, Armer J, et al. Alliance A011202: A Randomized Phase III Trial Comparing Axillary Lymph Node Dissection to Axillary Radiation in Breast Cancer Patients (cT1-3 N1) Who Have Positive Sentinel Lymph Node Disease After Receiving Neoadjuvant Chemotherapy. Available from: https://www.allianceforclinicaltrialsinoncology.org/main/cmsfile?cmsPath=/Public/Annual%20Meeting/files/A011202-Boughey-May2019.pdf

Mandish S, Gaskins JT, Yusuf MB, Amer YM, Eldredge-Hindy H. The effect of omission of adjuvant radiotherapy after neoadjuvant chemotherapy and breast conserving surgery with a pathologic complete response. Acta Oncol 2020; 59(10): 1210-17. doi: 10.1080/0284186X.2020.1797161

von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019; 380: 617-28. doi: 10.1056/NEJMoa1814017

Mamounas EP, Untch M, Mano MS, Huang CS, Geyer CE Jr, von Minckwitz G, et al. Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE. Annals of Oncology,2021.32(8): 1005-14. doi: 10.1016/j.annonc.2021.04.011

Zolcsák Z, Loirat D Fourquet A , Kirova YM. Adjuvant Trastuzumab Emtansine (T-DM1) and Concurrent Radiotherapy for Residual Invasive HER2-positive Breast Cancer: Single-center Preliminary Results. Am J Clin Oncol. 2020 Dec 1;43(12):895-901. doi:10.1097/COC.0000000000000769

Poppe MM, Agarwal JP. Breast Reconstruction With Postmastectomy Radiation: Choices and Tradeoffs. J Clin Oncol. 2017;35(22):2467-2470. doi: 10.1200/JCO.2017.72.7388

Spear SL, Ducic I, Low M, Cuoco F. The effect of radiation on pedicled TRAM flap breast reconstruction: Outcomes and implications. Plast Reconstr Surg .2005; 115:84-95

Christante D, Pommier SJ, Diggs BS, Samuelson BT, Truong A, Marquez C, et al. Using complications associated with postmastectomy radiation and immediate breast reconstruction to improve surgical decision making. Arch Surg. 2010; 145:873-78. doi: 10.1001/archsurg.2010.170

Jagsi R, Momoh AO, Qi J, Hamill JB, Billig J, Kim HM, et al. Impact of Radiotherapy on Complications and Patient-Reported Outcomes After Breast Reconstruction. J Natl Cancer Inst. 2018 Feb 1;110(2):157-165. doi: 10.1093/jnci/djx148

Kaidar-Person O, Vrou Offersen B, Hol S, Arenas M, Aristei C, Bourgier C, et al. ESTRO ACROP consensus guideline for target volume delineation in the setting of postmastectomy radiation therapy after implant-based immediate reconstruction for early stage breast cancer. Radiot Oncol .2019; 137 159–166. doi: 10.1016/j.radonc.2019.04.010

Smolanka II, Bagmut IY, Sheremet MI, Lyashenko AO, Movchan OV, Smolanka II Jr, et al. Delayed breast reconstruction with tram-flap and various modifications after radical mastectomy. J of Med and Life. 2021 ; 14 (6) : 847-52. doi: 10.25122/jml-2021-0354

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011; 378: 1707-16. doi: 10.1016/S0140-6736(11)61629-2

Marta GN, Hijal T, de Andrade Carvalho H. Reirradiation for locally recurrent breast cancer. Breast .2017; 33:159–65. doi: 10.1016/j.breast.2017.03.008

Walstra C JEF, Schipper RJ, Poodt IGM, van Riet YE, Voogd AC, van der Sangen MGC, et al. Repeat breast-conserving therapy for ipsilateral breast cancer recurrence: A systematic review. Eur J Surg Oncol. 2019;45(8):1317-27. doi.org/10.1016/j.ejso.2019.02.008

Walstra C JEF, Schipper RJ, van Riet YE, van der Toorn PPG, Smidt ML, vd Sangen MJS. Repeat breast conserving treatment of ipsilateral breast cancer recurrence: a nationwide survey amongst breast surgeons and radiation oncologists in the Netherlands. Breast Cancer Research and Treatment. 2021; 187:499–514. doi: 10.1007/s10549-021-06154-2

Resch A, Fellner C, Mock U, Handl-Zeller L, Biber E, Seitz W, et al. Locally recurrent breast cancer: pulse dose rate brachytherapy for repeat irradiation following lumpectomy – a second chance to preserve the breast. Radiology. 2002; 225: 713-18. doi: 10.1148/radiol.2253011913

Vavassori A, Riva G, Cavallo I, Spoto R, Dicuonzo S, Fodor C, et al. High-dose-rate Brachytherapy as Adjuvant Local rEirradiation for Salvage Treatment of Recurrent breast cancer (BALESTRA): a retrospective monoinstitutional study. J Contemp Brachytherapy 2020; 12, 3: 207–215. doi: 10.5114/jcb.2020.96860

Montagne L, Hannoun A, Hannoun-Levi JM. Second conservative treatment for second ipsilateral breast tumor event: A systematic review of the different re-irradiation techniques. Breast. 2020 49:274-280. doi: 10.1016/j.breast.2020.01.003.

Blandino G, Guenzi M, Belgioia L, Bonzano E, Configliacco E, Tornari E, et al. Adjuvant intraoperative radiotherapy for selected breast cancers in previously irradiated women: evidence for excellent feasibility and favorable outcomes. Rep Pract Oncol Radiother 2017;22: 277- 83. doi 10.1016/j.rpor.2017.02.009

Thangarajah F, Heilmann J, Malter W, Kunze S, Marnitz S, Mallmann P, et al. Breast conserving surgery in combination with intraoperative radiotherapy after previous external beam therapy: an option to avoid mastectomy. Breast Canc Res Treat 2018;168: 739-44. doi: 10.1007/s10549-017-4657-y

Janssen S, Rades D, Meyer A, Fahlbusch FB, Wildfang I, Meier A. Local recurrence of breast cancer: conventionally fractionated partial external beam re-irradiation with curative intention. Strahlenther Onkol. 2018; 194: 806–14. doi: 10.1007/s00066-018-1315-1 S

Arthur DW, Winter KA, Kuerer HM, Haffty BG, Cuttino LW, Todor DA, et al. NRG Oncology-Radiation Therapy Oncology Group Study 1014: 1-year toxicity report from a phase 2 study of repeat breast-preserving surgery and 3-dimensional conformal partial-breast reirradiation for in-breast recurrence. Int J Radiat Oncol Biol Phys. 2017;98(5): 1028-1035. doi: 10.1016/j.ijrobp.2017.03.016

Arthur DW, Winter KA, Kuerer HM, Haffty B, Cuttino L, Todor DA, et al. Effectiveness of Breast-Conserving Surgery and 3-Dimensional Conformal Partial Breast Reirradiation for Recurrence of Breast Cancer in the Ipsilateral Breast The NRG Oncology/RTOG 1014 Phase 2 Clinical Trial. JAMA Oncol. 2020 Jan 1;6(1):75-82. doi: 10.1001/jamaoncol.2019.4320.

Thorpe CS, Niska JR, Girardo ME, Kosiorek HE, McGee LA, Hartsell WF. Proton beam therapy reirradiation for breast cancer: Multi‐institutional prospective PCG registry analysis. Breast J. 2019;00:1–11. doi: 10.1111/tbj.13423

Merino T, Tran WT, Czarnota GJ. Re-irradiation for locally recurrent refractory breast cancer. Oncotarget 2015; 6(33): 35051-62. doi: 10.18632/oncotarget.6036

Fattahi S, Ahmed SK, Park SS, Petersen IA, Shumway DA, Stish BJ,et al. Reirradiation for Locoregional Recurrent Breast Cancer. Adv Radiat Oncol. 2021;6:100640. doi: 10.1016/j.adro.2020.100640.

Authors

Grazia Lazzari
lazzarigrazia@gmail.com (Primary Contact)
Angela Pia Solazzo
Ilaria Benevento
Antonietta Montagna
Luciana Rago
Giovanni Castaldo
Giovanni Silvano
Author Biographies

Angela Pia Solazzo, Radiation Oncology Unit, IRCCS-CROB, Rionero in Vulture (PZ), Italy

MD Radiation Oncologist 

Ilaria Benevento, Radiation Oncology Unit, IRCCS-CROB, Rionero in Vulture (PZ), Italy

MD Radiation Oncologist

Antonietta Montagna, Radiation Oncology Unit -IRCCS CROB Rionero in Vulture

MD Radiation Oncologist

Luciana Rago, Radiation Oncology Unit -IRCCS CROB Rionero in Vulture, Italy

MD Radiation Oncologist

Giovanni Castaldo, Radiation Oncology Unit -IRCCS CROB Rionero in Vulture

MD Radiation Oncologist

Giovanni Silvano, Emicenter Casoria -Napoli

MD Radiation Oncologist -Radiotherapy Unit 

1.
Lazzari G, Solazzo AP, Benevento I, Montagna A, Rago L, Castaldo G, Silvano G. Current Trends and Challenges in Real-World Breast Cancer Adjuvant Radiotherapy: A Practical Review. : New trends in adjuvant radiotherapy in BC. Arch Breast Cancer [Internet]. 2022 Dec. 27 [cited 2024 Apr. 25];10(1):6-14. Available from: https://www.archbreastcancer.com/index.php/abc/article/view/643

Article Details