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Expert Insights: Breast Cancer

Trends in Proton and Carbon Ion Therapy to Assist Clinical Choices and Research Pursuits

Lisa McGee, MD


Proton Therapy Remains an Attractive Modality for Partial Breast Irradiation

Lisa McGee, MD

Mayo Clinic Phoenix

Partial breast irradiation (PBI) is a reasonable treatment option for older women with early-stage, favorable-risk breast cancer (BCa).  The potential benefits of PBI versus whole-breast radiotherapy (WBRT) include shorter treatment courses as well as better radiation dose sparing of non-targeted adjacent tissues (1-4).  Randomized trials have demonstrated excellent efficacy with low toxicity rates utilizing various radiotherapy techniques (5-13); however, there is no consensus on which technique is optimal.

Utilizing an external-beam technique for PBI is appealing as it eliminates catheter need, thereby potentially reducing seroma and infection risk.  Intensity-modulated radiotherapy (IMRT) is effective with acceptable toxicity and cosmesis (12-16).  Conversely, 3-dimensional conformal radiotherapy (3DCRT) data suggest late toxicity and cosmesis may be undesirable if treating large target volumes or if nontargeted breast is not adequately spared (17-21).  Proton therapy (PT) may be a more attractive external-beam treatment option for PBI.

Dosimetric analyses evaluating PT for PBI have demonstrated improved dosing distribution compared to 3DCRT, IMRT, and brachytherapy.  These dosimetric comparisons have consistently demonstrated excellent conformality of dose to the target with better sparing of adjacent tissues such as nontargeted breast, skin, lung, and heart for PT plans (22-25).  Reported data of BCa patients treated with PBI PT show excellent BCa control rates along with favorable cosmesis, minimal side effects, and encouraging patient-reported outcomes (26-31).

ASTRO consensus guidelines do not make a specific recommendation for or against the use of external beam-based PBI (3).  The American Brachytherapy Society consensus statement recognizes that the data supporting the use of IMRT for PBT are strong, and acknowledges the conflicting data regarding cosmesis and fibrosis associated with 3DCRT, stating there is moderate evidence to support its use.  However, the ABS guidelines state that the evidence for using PT for PBI is weak due to the limited amount of prospective data and variety of fractionation schedules (2).

These remarks suggest there is an opportunity to publish additional data supporting the use of PT for PBI.  In addition to its dosimetric and clinical benefits, and the large potential population of appropriate patients, the cost of PT delivery for PBI is competitive compared to external-beam and brachytherapy techniques (33-34).   Furthermore, new dosing regimens which reduce treatment time and possibly toxicity are presently under investigation (35-36).  This may be the optimal time to solidify the utility of PBI PT in BCa treatment. .

1.    Shah C, Vicini F.  Accelerated partial breast irradiation-redefining the treatment target for women with early stage breast cancer. Breast J. 2019;25(3):408-417.

2. Shah C, Vicini F, Shaitelman SF, Hepel J, Keisch M, Arthur D, Khan AJ, Kuske R, Patel R, Wazer DE.  The American brachytherapy Society consensus statement for accelerated partial-breast irradiation.  Brachytherapy.  2018;17(1):154-70.

3. Correa C, Haris EE, Leonardi MC, Smith BD, Taghian AG, Thompson AM, White J, Harris JR.  Accelerated partial breast irradiation: executive summary for the update of an ASTRO evidence-based consensus statement.  Pract Radiat Oncol.  2017;7(2):73-79.

4. Smith BD, Arthur DW, Buchholz TA, Haffty BG, Hahn CA, Hardenbergh PH, Julian TB, Marks LB, Todor DA, Vicini FA, Whelan TJ, White J, Wo JY, Harris JR.  Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO).  Int J Radiat Oncol Bio Phys.  2009;74(4)987-1001.

5. Polgar C, Van Limbergen E, Potter R, Kovacs G, Polo A, Lyczek J, Hildebrandt G, Niehoff P, Guinot JL, Guedea F, Johansson B, Ott OJ, Major T, Stmad V, GEC-ESTRO breast cancer working group.  Patient selection for accelerated partial-breast irradiation (APBI) after breast conserving surgery:  Recommendations of the Groupe European de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence.  Radiother Oncol.  2010;94(3):264-73.

6. Polgar C, Fodor J, Major T, Sulyok Z, Kasler M.  Breast-conserving therapy with partial or whole breast irradiation:  10 year results of the Budapest randomized trial.  Radiother Oncol 2013;108(2):197-202.

7. Strnad V, Ott OJ, Hildebrandt G, Kauer-Dorner D, Knauerhase H, Major T, Lyczek J, Guinot JL, Dunst J, Gutierrez Miguelez C, Slampa P, Allgäuer M, Lössl K, Polat B, Kovács G, Fischedick AR, Wendt TG, Fietkau R, Hindemith M, Resch A, Kulik A, Arribas L, Niehoff P, Guedea F, Schlamann A, Pötter R, Gall C, Malzer M, Uter W, Polgár C; Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO.  5-year results of accelerated partial breast irradiation using sole interstitial multi catheter brachytherapy versus whole-breast irradiation with boost after breast conserving surgery for low-risk invasive and in-situ carcinoma of the female breast:  A randomized, phase 3, non-inferiority trial.  Lancet.  2016;387(10015):229-38.

8. Polgar C, Ott OJ, Hildebrandt G Kauer-Dorner D, Knauerhase H, Major T, Lyczek J, Guinot JL, Dunst J, Miguelez CG, Slampa P, Allgäuer M, Lössl K, Polat B, Kovács G, Fischedick AR, Fietkau R, Resch A, Kulik A, Arribas L, Niehoff P, Guedea F, Schlamann A, Pötter R, Gall C, Uter W, Strnad V; Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO).  Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast:  5 year results of the randomized, controlled, phase 3 trial.  Lancet Oncol.  2017;18(2):259-68.

9. Olivotto I, Whelan TJ, Parpia S, Kim DH, Berrang T, Truong PT, Kong I, Cochrane B, Nichol A, Roy I, Germain I, Akra M, Reed M, Fyles A, Trotter T, Perera F, Beckham W, Levine MN, Julian JA.  Interim cosmetic and toxicity results from RAPID:  A randomized trial of accelerated partial breast irradiation using 3D conformal external beam radiation therapy.  J Clin Oncol.  2013;31(32):4038-45.

10. Julian TB, Constantino JP, Vicini FA, et al.  Early toxicity results with 3D conformal external beam (CEBT) from the NSABP B-39/RTOG0413 accelerated partial breast irradiation (APBI) trial.  J Clin Oncol.  2011;29:S1011.

11. Rodriguez N, Sanz X, Dengra J, Foro P, Membrive I, Reig A, Quera J, Fernández-Velilla E, Pera Ó, Lio J, Lozano J, Algara M.  Five-year outcomes, cosmesis, and toxicity with 3 dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation.  Int J Radiat Oncol Bio Phys.  2013;87(5):1051-57.

12. Livi L, Meattini I, Marrazzo L, Simontacchi G, Pallotta S, Saieva C, Paiar F, Scotti V, De Luca Cardillo C, Bastiani P, Orzalesi L, Casella D, Sanchez L, Nori J, Fambrini M, Bianchi S.  Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation:  5-year survival analysis of a phase 3 randomized controlled trial.  Eur J Cancer.  2015;51(4):451-63.

13. Coles C, Griffin CL, Kirby AM , Titley J, Agrawal RK, Alhasso A, Bhattacharya IS, Brunt AM, Ciurlionis L, Chan C, Donovan EM, Emson MA, Harnett AN, Haviland JS, Hopwood P, Jefford ML, Kaggwa R, Sawyer EJ, Syndikus I, Tsang YM, Wheatley DA, Wilcox M, Yarnold JR, Bliss JM; IMPORT Trialists.  Partial breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomized, controlled, phase 3 non-inferiority trial.  Lancet.  2017;390(10099):1048-60.

14. Lei RY, Leonard CE, Howell KT, Henkenberns PL, Johnson TK, Hobart TL, Fryman SP, Kercher JM, Widner JL, Kaske T, Carter DL.  Four-year clinical update from a prospective trial of accelerated partial breast intensity-modulated radiotherapy (APBIMRT).  Breast Cancer Res Treat.  2013;140(1):119-33.

15. Reeder R, Carter DL, Howell K, Henkenberns P, Tallhamer M, Johnson T, Kercher J, Widner J, Kaske T, Paul D, Sedlacek S, Leonard CE.  Predictors of clinical outcomes after accelerated partial breast intensity-modulated radiotherapy.  Int J Radiat Oncol Bio Phys.  2009;74(1):92-7.

16. Lewin AA, Derhagopian R, Saigal K, Panoff JE, Abitbol A, Wieczorek DJ, Mishra V, Reis I, Ferrell A, Moreno L, Takita C.  Accelerated partial breast irradiation is safe and effective using intensity-modulated radiation therapy in selected early-stage breast cancer.  Int J Radiat Oncol Bio Phys.  2012;82(5):2104-10.

17. Hepel JT, Tokita M, MacAusland SG, Evans SB, Hiatt JR, Price LL, DiPetrillo T, Wazer DE.  Toxicity of 3-dimensional conformal radiotherapy for accelerated partial breast irradiation.  Int J Radiat Oncol Bio Phys.  2009;75(5):1290-96.

18. Jagsi R, Ben-David, MA, Moran JM, Marsh RB, Griffith KA, Hayman JA, Pierce LJ.  Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation.  Int J Radiat Oncol Bio Phys.  2010;76(1):71-78.

19. Liss A, Ben-David A, Jagsi R, Hayman JA, Griffith KA, Moran JM, Marsh RB, Pierce LJ.  Decline of cosmetic outcome following accelerated partial breast irradiation using intensity modulated radiation therapy; results of the single-institution prospective clinical trial.  IJROBP.  2014;89(1):96-102.

20. Olivotto I, Whelan TJ, Parpia S, Kim DH, Berrang T, Truong PT, Kong I, Cochrane B, Nichol A, Roy I, Germain I, Akra M, Reed M, Fyles A, Trotter T, Perera F, Beckham W, Levine MN, Julian JA .  Interim cosmetic and toxicity results from RAPID:  A randomized trial of accelerated partial breast irradiation using 3D conformal external beam radiation therapy.  J Clin Oncol.  2013;31(32):4038-45.

21. Julian TB, Constantino JP, Vicini FA, et al.  Early toxicity results with 3D conformal external beam (CEBT) from the NSABP B-39/RTOG 0413 accelerated partial breast irradiation (APBI) trial.  J Clin Oncol.  2013;29:S1011.

22. Kozak KR, Katz A, Adams J . Crowley EM, Nyamwanda JA, Feng JK, Doppke KP, Delaney TF, Taghian AG  Dosimetric comparison of proton and photon three-dimensional conformal, external beam accelerated partial breast irradiation techniques.  Int J Radiat Oncol Bio Phys.  2006;65(5):1572-78.

23. Bush DA, Slater JD, Garberoglio C, Yuh G, Hocko JM, Slater JM. A technique of partial breast irradiation utilizing proton beam radiotherapy: comparison with conformal x-ray therapy.  Cancer J.  2007;13(2):114-18.

24. Moon SH, Shin KH, Kim TH, Yoon M, Park S, Lee DH, Kim JW, Kim DW, Park SY, Cho KH.  Dosimetric comparison of four different external beam partial breast irradiation techniques: three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, helical tomotherapy and proton beam therapy.  Radiother Oncol. 2009;90(1):66-73.

25. Taghian AG, Kozak KR, Katz A, Adams J, Lu HM, Powell SN, DeLaney TF.  Accelerated partial breast irradiation using proton beams: initial dosimetric experience.  Int J Radiat Oncol Bio Phys.  2006;65(5): 1404-10.

26. Bush DA, Do S, Lum S, Garberoglio C, Mirshahidi H, Patyal, B, Grove R, Slater JD.  Partial breast  radiation therapy with proton beam:  5-year results with cosmetic outcomes.  Int J Radiat Oncol Bio Phys.  2014;90(3):501-05.

27. Bush DA, Slater JD, Garberoglio C, Do S, Lum S, Slater JM.  Partial breast irradiation delivered with proton beam:  results of a phase II trial.  Clin Breast Ca.  2011;11(4):241-45.

28. Chang JH, Lee NK, Kim JY, Kim YJ, Moon SH, Kim TH, Kim JY, Kim DY, Cho KH, Shin KH.  Phase II trial of proton beam accelerated partial breast irradiation in breast cancer.  Radiother Oncol.  2013;108(2):209-14.

29. Galland-Girodet S, Pashtan I, MacDonald SM, Ancukieqicz M, Hirsch AE, Kachnic LA, Specht M, Gadd M, Smith BL, Powell SN, Recht A, Taghian AG.  Long-term cosmetic outcomes and toxicities of proton beam therapy compared with photon-based 3-dimensional  conformal accelerated partial-breast irradiation: a phase I trial.  Int J Radiat Oncol Bio Phys.  2014;90(3);493-500.

30. Ovalle V, Strom EA, Shaitelman S, Hoffman K, Amos R, Perkins G, Tereffe W, Smith BD, Stauder M, Woodward W.  Proton partial breast irradiation:  detailed description of acute clinico-radiologic effects.  Cancers.  2018;10(4).

31. Teichman SL, Do S, Lum S, Teichman TS, Preston W, Cochran SE, Garberoglio CA, Grove R, Davis CA, Slater JD, Bush DA.  Improved long-term patient-reported health and well-being outcomes of early-stage breast cancer treated with partial breast proton therapy.  Cancer Med.  2018;7(12)6064-76.

32. Ovalle V, Strom EA, Godby J, Shaitelman SF, Stauder MC, Amos RA, Kuerer HM, Woodward WA, Hoffman KE.  Proton partial-breast irradiation for early stage cancer: is it really so costly?  Int J Radiat Oncol Bio Phys.  2016;95(1):49-51. 

33. Balagamwala EH, Manyam BV, Leyrer CM, Karthik N, Smile T, Tendulkar RD, Cherian S, Radford D, Al-Hilli Z, Vicini F, Shah C.  Most patients are eligible for an alternative to conventional whole breast irradiation for early stage breast cancer:  A National Cancer Database analysis.  Breast J.  2018;24(5):806-10.

34. Khan AJ, Chen PY, Yashar C, Poppe MM, Li L, Abou Uehia Z, Vicini FA, Moore D, Dale R, Arthur D, Shah C, Haffty BG, Kuske R.  Three-fraction accelerated partial breast irradiation (APBI) delivered with brachytherapy applicators is feasible and safe:  first results from the TRIUMPH-T trial. Int J Radiat Oncol Bio Phys.  2019;104(1):67-74.

35. Jethwa KR, Park SS, Gonuguntla K, Wick SM, Vallow LA, Deufel CL, Whitaker TJ, Furutani KM, Ruddy KJ, Corbin KS, Hieken TJ, Mutter RW.  Three-fraction intracavitary accelerated partial breast brachytherapy:  Early provider and patient reported outcomes of a novel regimen.  Int J Radiat Oncol Bio Phys.  2019;104(1):75-82.

36. Wilkinson JB, Chen PY, Wallace MF, Shah CS, Benitez PR, Martinez AA, Vicini FA.  Six-year results from a phase I/II trial for hypofractionated accelerated partial breast irradiation using a 2-day dose schedule.  Am J Clin Oncol.  2018;41(10):986-91.


Quality of Life and Patient-Reported Outcomes Data in Breast Cancer Patients Treated with Proton Therapy

Proton therapy (PT) for breast cancer treatment reduces the radiation dose to non-targeted organs compared to photons, which can reduce long-term toxicity risk. Late adverse effects, such as cardiotoxicity, take decades to develop following radiotherapy. Without long-term follow-up of breast cancer (BCa) patients treated with PT demonstrating toxicity reduction compared to photons, the medical community and insurance companies have been reluctant to recognize the value of PT for BCa treatment. Dosimetric comparisons can predict long-term toxicity reduction and several published series have reported acceptable acute toxicity outcomes. Another way to assess PT’s value could be through patient-reported outcomes (PROs) and quality of life (QOL) [1].

To date, three articles have described PROs for early-stage BCa in patients receiving accelerated partial breast irradiation (APBI) with PT [2-4]. Patient-reported cosmesis from a phase I PT APBI trial were favorable for patients receiving PT (n=19) or mixed photons/electrons (n=79) [2]. With 7 years of follow-up, patient-reported cosmesis using the Harvard 4-point scale reported good or excellent cosmetic outcomes in 92% of patients receiving PBT versus 96% for patients receiving mixed photons/electrons (P=0.95). Overall patient satisfaction for the entire cohort was 93%. Cosmesis PROs from a phase II PT APBI trial demonstrated 90% of patients (N=100) reported good to excellent cosmetic outcomes and were maintained throughout 5-year follow-up [3]. Investigators at Loma Linda recently reported QOL PROs in a cross sectional study of stage 0-II BCa patients treated with lumpectomy followed by whole breast radiation versus PT APBI. With a median follow-up of 6.5 years, patients’ QOL PROs significantly favored PT APBI in the following domains: cosmetic breast cancer treatment outcome scale, breast pain, breast texture, clothing fit, fatigue, impact of daily fatigue on personal relations, and self-consciousness [4].

While the cosmesis and QOL PROs are favorable for BCa patients treated with PT APBI, data are lacking for locally advanced BCa (LABC) patients requiring comprehensive lymph node coverage treated with PT. Current data on PT for LABC treatment are limited to dosimetric comparisons of PT versus photons showing reduction of heart and lung dose as well as initial series reporting physician-assessed acute toxicity. Assessment of QOL PROs could further improve the perceived value of PT as treatment for LABC until late cardiotoxicity data matures.

1. Verma V, Simone C, Mishra M. Quality of life and patient-reported outcomes following proton radiation therapy: a systematic review. JNCI. 2018;110(4):341-53.

2. Galland-Girode S, Pashtan I, MacDonald SM, Ancukiewicz M, Hirsch AE, Kachnic LA, Specht M, Gadd M, Smith BL, Powell SN, Recht A, Taghian AG. Long-term cosmetic outcomes and toxicities of proton beam therapy compared with photon-based 3-dimensional conformal accelerated partial-breast irradiation: a phase I trial. Int J Radiat Oncol Biol Phys. 2014;90(3):493-500.

3. Bush DA, Do S, Lum S, Garberoglio C, Mirshahidi H, Patyal B, Grove R, Slater JD. Partial breast radiation therapy with proton beam: results with cosmetic outcomes. Int J Radiat Oncol Biol Phys. 2014;90(3):501-05.

4. Teichman SL, Do S, Lum S, Teichman TS, Preston W, Cochran SE, Garberoglio CA, Grove R, Davis CA, Slater JD, Bush DA. Improved long-term patient-reported health and well-being outcomes of early-stage breast cancer treated with partial breast proton therapy. Cancer Med. 2018;1-13.

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