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Breast cancer radiotherapy
For almost 100 years radiotherapy has been an uncontested treatment modality for patients with breast cancer. In the past 20 years patient treatment has been substantially improved by technological advances. In this contribution, state-of-the-art irradiation techniques and regimens tailored to local tumour conditions and patient age used in the clinical setting are reviewed.
Radiotherapy plays a key role in the management of breast cancer. Studies have shown that survival after Halsted’s radical mastectomy is not superior to the survival of less radically operated patients undergoing irradiation after breast-conserving surgery (BCS).1 Postoperative radiotherapy provides control of microscopic residuals of both invasive and intraductal breast cancers and an acceptable cosmetic outcome, while improving relapse-free and overall survival.
Whole-breast irradiation after breast-conserving surgery
After lumpectomies, residual tumour cells have been found to be present at a distance of more than 2 cm from the lesion in up to 41% of patients (two-thirds with intraductal and one-third with invasive cancer).2 Consequently, whole-breast irradiation is an appropriate treatment modality to minimize local tumour recurrence. In the NSABP B-06 study, lumpectomy in patients with clear margins was followed by ipsilateral relapse in 39% of patients who received no irradiation, compared with 14% in the irradiated group, at a follow-up time of 20 years.1 Overall survival was also superior in the irradiated group. In a meta-analysis of 7300 patients, the 15-year breast cancer mortality risk was significantly lower in the irradiation group (30.5% vs. 35.9%; P = 0.02).3 In the NASBP B-21 study, tamoxifen alone was compared with postoperative radiotherapy alone and radiotherapy plus tamoxifen in 1009 patients (of whom 50% were over 60 years) who had undergone lumpectomy for invasive breast cancer less than 1 cm in size. The rate of recurrent local cancer was 16.5% on tamoxifen alone compared with 9.3% after postoperative radiotherapy and 2.8% after radiotherapy combined with tamoxifen. Overall survival was more or less the same in the three groups.4
Conventional-fractionation external beam radiotherapy
In this standard mode, two tangential fields are irradiated with 45–50 Gy in 1.8–2 Gy fractions for 4.5–5 weeks based on three- or four-dimensional computed tomography (CT) planning.
Shorter fractionation regimens
To reduce the overall treatment time, patients older than 50 years with small breasts who harbour a low-risk tumour without nodal involvement and do not need chemotherapy may be subjected to shorter regimens. A randomized trial5 comparing an accelerated regimen of 40 Gy delivered in 15 fractions with 50 Gy in 25 fractions found no differences in the rate of local relapse or late adverse effects. In a Canadian trial comparing conventional fractionation (50 Gy in 25 fractions) with 42.5 Gy in 16 fractions in patients with clear margins and negative nodes after BCS, there was no difference between groups in relapse-free or overall survival, toxicity or cosmetic outcome.6 An ASTRO task force found a shorter dose fractionation regimen of 42.5 Gy in 16 fractions an excellent alternative to standard fractionation, albeit reserved for patients aged 50 years or older and with stage T1–T2, N0 cancer not in need of chemotherapy or boost irradiation.7 Hypofractionation with 42.5 Gy in 16 fractions also has a place in patients with carcinoma in situ.8 Consequently, this treatment modality can be administered to patients aged 50 years or older with stage pT1–2, pN0 disease without lymphovascular space invasion and without positive margins and who do not need chemotherapy or boost irradiation.
Boost irradiation after breast-conserving surgery and whole-breast irradiation
Boost irradiation delivers a dose to the tumour bed higher than the whole breast dose. Although not needed in all cases, it is recommended after conventional-fractionation whole-breast irradiation with 40–50 Gy in patients aged ≤ 50 years with positive axillary nodes, lymphovascular space invasion and positive or close resection margins.9 The boost dose delivered to the tumour bed is 10–18 Gy and depends on the whole-breast dose, i.e. 60 Gy for clear margins, 64 Gy for close margins and 66 Gy for positive margins. It can be administered with electrons and photons through external fields. The cosmetic outcome depends on the boost dose and energy delivered.10
Interstitial brachytherapy following whole-breast irradiation is an alternative for delivering boost doses to the tumour bed, but necessitates anaesthesia. A comparison of external-beam, photon and brachytherapy boosts found no differences in relapse rate, rate of metastases, overall survival or cosmetic outcome.11 Intraoperative boost irradiation during BCS is another alternative delivering boost doses of electrons or photons prior to whole-breast irradiation.12,13
Preliminary evidence suggests that intraoperative electron boost irradiation with 12 Gy during BCS and subsequent hypofractionated external beam irradiation of the whole breast with 13 × 2.85 Gy is an option.14 The cosmetic outcome is, however, as yet undocumented.
Simultaneous integrated boost doses in intensity-modulated radiotherapy (SIB-IMRT) following BCS delivers 50.4 Gy in fractions of 1.8 Gy to the ipsilateral breast and 61.1 Gy in 28 fractions of 2.2 Gy to the tumour bed.15
Post-mastectomy radiotherapy is an integral and highly effective component in the multimodal management strategy of advanced breast cancer. In particular, chest wall irradiation following mastectomy should be considered in patients with advanced breast cancer and extensive nodal involvement, whenever BCS is ruled out despite neoadjuvant chemotherapy.16–18
Extensive tumours, particularly those with lymphovascular space invasion, multicentricity and close or positive margins, are another indication for post-mastectomy radiotherapy, even if the nodes are clear.19
Patients undergoing post-mastectomy breast reconstruction have been found to have a higher risk of late complications following primary breast reconstruction and subsequent radiotherapy, while those undergoing primary post-mastectomy irradiation followed by breast reconstruction show a higher rate of acute reactions.20 In our experience, primary breast reconstruction followed by radiotherapy is beneficial for patients for psychosocial reasons. To minimize fibrosis a total dose of 50–54 Gy in single fractions of 1.8 Gy is delivered with a multisegmented tangential breast field technique. The cosmetic outcome is well accepted by the patients. Grade 1 fibrosis was reported in no more than 20% of cases in one study.21
Lymph node irradiation following breast-conserving surgery or mastectomy
In patients who undergo adjuvant whole-breast irradiation after BCS or mastectomy, tangential field irradiation should be combined with irradiation of the axillary and supraclavicular lymph nodes, if more than three nodes are involved. There is evidence from a major retrospective analysis showing that the internal mammary nodes need not be irradiated, because tangential field irradiation also covers the ipsilateral internal mammary nodes. Isolated or additional irradiation of the internal mammary nodes did not provide any benefit even if the tumour was central or medial.22
Partial breast irradiation
Accelerated partial breast irradiation (APBI) is an alternative to whole-breast irradiation following BCS. As most local relapses originate from the tumour bed, the usefulness of whole-breast irradiation in patients with small lesions has been questioned. APBI delivers a higher single dose in a shorter total treatment time to a defined (limited) breast volume. Its benefits are still unclear, as the results of randomized trials are not yet available. Interstitial multicatheter brachytherapy, intraoperative radiotherapy (IORT) with electrons produced by linear accelerators or 50-kV X-rays (intrabeam), the balloon catheter technique (MammoSite) or 3D-conformal external beam irradiation are most commonly used for APBI.23 Patients with small invasive oestrogen receptor-positive tumours after wide local excision and lymphadenectomy are candidates.24,25 APBI should not be used in patients with lobular cancer, intraductal cancer, lymphovascular space invasion or simultaneous chemotherapy.26 Despite its advantages, among them the shorter treatment time, the benefits of APBI are still controversial.27,28 For patients developing locally recurrent lesions in the irradiated breast, APBI is an option for breast conservation.29
Intensity-modulated radiotherapy (IMRT) is another effective modality for APBI in selected breast cancer patients after BCS. A total dose of 38 Gy in fractions of 3.8 Gy twice daily for 5 days was found to produce excellent homogeneous conformity in the clinical target volume (CTV), was well tolerated and spared critical organs, i.e. the lungs and heart.30
High-precision irradiation techniques
High-precision irradiation techniques include IMRT, SIB-IMRT, the multisegmented tangential breast field technique and the volumetric modulated arc technique (Figure 1). These require image guidance for precise field definition. On-board image guidance with port films or cone-beam CT improves the accuracy and precision of dose distribution.31 As the breast moves in synchronicity with breathing, planning for high-precision chest irradiation should be respiratory-gated (4D planning). This can be achieved by either deep inspiration breath-hold and audiovisual guidance or system-inherent real-time position management respiratory gating.32–35 Dose delivery should always match the inspiratory conditions during CT planning.
FIGURE 1 Volumetric modulated arc technique with rapid arc for left-sided breast cancer after BCS, based on 4D CT imaging. Cardiac and pulmonary dose reduction. Yellow, whole breast dose; red, higher dose to the tumour bed (SIB); purple, heart; blue, left lung.
Respiratory-gated radiotherapy improves conformity and precise volume definition by ruling out respiratory movements, which may reduce the target volume. In addition, reduced organ movements minimize complications referable to organs at risk, i.e. the lungs and the heart.
For both small and advanced breast cancer, locoregional radiotherapy is an indispensable treatment modality as part of a multimodal management strategy. Our recommendations tailored to individual predictive factors are shown in Table 1.
TABLE 1 Radiotherapy recommendations tailored to individual predictive factors
Postmenopausal women with pT1–pT2 and/or situ breast cancer after breast-conserving surgery and with clear resection margins and negative nodes
Short fractionation regimens: 40 Gy in 15 fractions of 2.67 Gy delivered to the whole breast or 42.5 Gy in 16 fractions of 2.66 Gy delivered to the whole breast
Women with sensitive skin
Conventional fractionation with 50 Gy in 25 fractions of 2 Gy without boost
Highly selected patients without intraductal components
Accelerated partial breast irradiation
Premenopausal and postmenopausal women with early-stage I/II breast cancer post BCS, with or without nodal involvement and/or intraductal components and with or without chemotherapy
Standard fractionation regimen: 50 Gy in 25 fractions with a boost to the tumour bed
Additional supraclavicular and axillary fields for positive nodes: 50 Gy in 25 fractions
Premenopausal and postmenopausal women with advanced breast cancer in need of mastectomy
Standard fractionation regimen: 50 Gy in 25 fractions delivered to the chest wall
Patients undergoing post-mastectomy breast reconstruction
Standard fractionation regimen:54 Gy in 30 fractions of 1.8 Gy with IMRT or multisegmented tangential breast field irradiation
Conflicts of interest
The author reports no potential conflicts of interest.
- 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; 347:1233–41.
- Holland R, Veling SH, Mravunac M, et al. Histologic multifocality of Tis, T1–2, breast carcinomas. Implications for clinical trials of breast conserving surgery, Cancer 1985; 56:979.
- Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and differences in the extent of surgery for early breast cancer and local recurrence and 15 year survival: an overview of the randomised trials. Lancet 2005; 366:2087.
- Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 2002; 20:4141.
- The START Trialists Group. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet 2008; 371:1098–107.
- Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010; 362:513.
- Smith BD, Bentzen SM, Correa CR, et al. Fractionation for whole breast irradiation: an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys 2011; 81:59.
- Williamson D, Dinniwell R, Fung S, et al. Local control with conventional and hypofractionated adjuvant radiotherapy after breast-conserving surgery for ductal carcinoma in-situ. Radiother Oncol 2010; 95: 317–20.
- Bartelink H, Horiot J-C, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the Randomized Boost Versus No Boost EORTC 22881-10882 Trial. J Clin Oncol 2007; 25:3259–65.
- Murphy C, Anderson PR, Li T, et al. Impact of the radiation boost on outcomes after breast-conserving surgery and radiation. Int J Rad Oncol Biol Phys 2011; 81:69–6.
- Hill-Kayser ChE, Chacko D, Hwang W-T, et al. Long-term clinical and cosmetic outcomes after breast conservation treatment for women with early-stage breast carcinoma according to the type of breast boost. Int J Rad Oncol Biol Phys 2011; 79:1048–54.
- Kraus-Tiefenbacher U, Bauer L, Scheda A, et al. Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery. Int J Rad Oncol Biol Phys 2006; 66:377–81.
- Wenz F, Welzel G, Keller A, et al. Early initiation of external beam radiotherapy (EBRT) may increase the risk of long-term toxicity in patients undergoing intraoperative radiotherapy (IORT) as a boost for breast cancer. Breast 2008; 17:617–22.
- Ivaldi GB, Leonardi MC, Orecchia R, et al. Preliminary results of electron intraoperative therapy boost hypofractionated external beam radiotherapy after breast-conserving surgery in premenopausal women. Int J Rad Oncol Biol Phys 2008; 72:485–93.
- Majumdar D, Mohammed SS, Naseer MA, et al. Respiratory gated simultaneous integrated boost-intensity modulated radiotherapy (SIB-IMRT) after breast conservative surgery for carcinoma of the breast: the Salmaniya Medical Complex experience. Gulf J Oncol 2011; 1(10):53–9.
- Zauls AJ, Watkins JM, Wahlquist AE, et al. Outcomes in women treated with MammoSite Brachytherapy or whole breast irradiation stratified by ASTRO Accelerated Partial Breast Irradiation Consensus Statement Groups. Int J Rad Oncol Biol Phys 2012; 82:21–9.
- Jagsi R, Pierce L. Postmastectomy radiation therapy for patients with locally advanced breast cancer. Semin Radiat Oncol 2009; 19:236–43.
- Le Scodan R, Selz J, Stevens D, et al. Radiotherapy for stage II and stage III breast cancer patients with negative lymph nodes after preoperative chemotherapy and mastectomy. Int J Rad Oncol Biol Phys 2012; 82:e1–e7.
- Matsunuma R, Oguchi M, Fujikan T, et al. Influence of lymphatic invasion on locoregional recurrence following mastectomy: indication for postmastectomy radiotherapy for breast cancer patients with one to three positive nodes. Int J Rad Oncol Biol Phys [Epub ahead of print].
- Adesiyun TA, Lee BT, Yueh JH, et al. Impact of sequencing of postmastectomy radiotherapy and breast reconstruction on timing and rate of complications and patient satisfaction. Int J Rad Oncol Biol Phys 2011; 80:392–7.
- Gulybán A, Kovács P, Sebestyén Z, et al. Multisegmented tangential breast fields: a rational way to treat breast cancer. Strahlenther Onkol 2008; 184:262–9.
- Obedian E, Haffty BG. Internal mammary nodal irradiation in conservatively-managed breast cancer patients: is there a benefit? Int J Rad Oncol Biol Phys 1999; 44:997–1003.
- Sauer R, Sautter-Bihl ML, Budach W, et al. Accelerated partial breast irradiation: consensus statement of 3 German Oncology societies. Cancer 2007; 110:1187–94.
- Husain ZA, Mahmood U, Hanlon A, et al. Accelerated partial breast irradiation via brachytherapy: a patterns-of-care analysis with ASTRO consensus statement groupings. Brachytherapy 2011; 10:479–85.
- Hattangadi JA, Powell SN, Macdonald SM, et al. Accelerated partial breast irradiation with low-dose-rate interstitial implant brachytherapy after wide local excision: 12 year outcomes from a prospective trial. Int J Radiat Oncol Biol Phys [Epub ahead of print].
- Wazer DE, Kaufman S, Cuttino L, et al. Accelerated partial breast irradiation: an analysis of variables associated with late toxicity and long-term cosmetic outcome after high-dose-rate interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2006; 64:489–95.
- Bensaleh S, Bezak E, Borg M. Review of MammoSite brachytherapy: advantages, disadvantages and clinical outcomes. Acta Oncol 2009; 48:487–94.
- Sautter-Bihl ML, Sedlmayer F, Budach W, et al. Intraoperative radiotherapy as accelerated as accelerated partial breast irradiation for early breast cancer: beware of one-stop shops? Strahlenther Onkol 2010;186:651–7.
- Kauer-Dorner D, Pötter R, Resch A, et al. Partial breast irradiation for locally recurrent breast cancer within a second breast conserving treatment: alternative to mastectomy? Results from a prospective trial. Radiother Oncol 2012;102:96–101.
- Lewin AA, Derhagopian R, Saigal K, et al. Accelerated partial breast irradiation is safe and effective using intensity-modulated radiation therapy in selected early-stage breast cancer. Int J Radiat Oncol Biol Phys 2011 [Epub ahead of print].
- Hasan Y, Kim L, Wloch J, et al. Comparison of planned versus actual dose delivered for external beam accelerated partial breast irradiation using cone-beam CT and deformable registration. Int J Radiat Oncol Biol Phys 2011; 80:1473–6.
- Vikström J, Hielstuen MH, Mjaaland I, Dybvik KI. Cardiac and pulmonary dose reduction for tangentially irradiated breast cancer, utilizing deep inspiration breath-hold with audio-visual guidance, without compromising target coverage. Acta Oncol 2011; 50:42–50.
- Bedi C, Kron T, Willis D, et al. Comparison of radiotherapy treatment plans for left-sided breast cancer patients based on three- and four-dimensional computed tomography imaging. Clin Oncol (R Coll Radiol) 2011; 23:601–7.
- Hielstuen MH, Mjaaland I, Vikström J, Dybvik KI. Radiation during deep inspiration allows loco-regional treatment of left breast and axillary, supraclavicular and internal mammary lymph nodes without compromising target coverage or dose restrictions to organs at risk. Acta Oncol [Epub ahead of print].
- Nicolini G, Vanetti E, Clivio A, et al. Pre-clinical evaluation of respiratory-gated delivery of volumetric modulated arc therapy with RapidArc. Phys Med Biol 2010; 55:N347–57.
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